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FOR PG MEDICAL ENTRANCE EXAMS

HARRISON’S 19th Rased
u yy
NOTE BOOK
DAMS Faculty's Perspective
FEATURES
ONE LINERS
IMPORTANT TABLES
HIGH YIELDING TOPICS
CHIEF EDITOR & AUTHOR
DR. RAHUL RAJEEV
J.R. (GENERAL MEDICINE)
CONTRIBUTING AUTHORS
DR. ARVIND K. CHOUDHARY
MD MEDICINE
DR. ACHIN MEHRA
DNB MEDICINE
DR. SUMER SETHI
MD RADIOLOGY
Publishing
FOR PG MEDICAL ENTRANCE EXAMS
i
PREFACE
On behalf of DAMS, i am proud to introduce before you my humble endeavour “DAMS

HARRISON NOTE BOOK-FOR PG ENTRANCE” . Ever since its first edition in 1949,
Harrison’s Principles of Internal Medicine has been a companion and reference book for every
medical student as well as practitioner. As far as the scenario of PG Medical Entrance exams
is concerned, a lot of questions are often handpicked from Harrison. But often there is a time
shortage to cover important topics from Harrison before the exam. As the title of the book
suggests, it is my “NOTE BOOK” of USEFUL ONELINERS, MOST COMMONS, IM¬
PORTANT TABLES and CHARTS based on Harrison’s I9th edition thatIhave prepared
after meticulous reading of the book. However,this book is by no means a substitute for text
book and is solely intended for the purpose of PG Entrance exams. As somebody who has
cleared the PG entrance exams recently, I am quite aware of the recent pattern of questions
for AIPGMEE, AIIMS & DNB.Ihave also included page numbers of “HIGH YIELDING
TOPICS” from Harrison’s 19th edition for those students interested in further reading.Ihave
tried my level best to make this book simple but high yielding for all PG aspirants. Hope that
this book will be an indispensable weapon for you to crack the entrance exams.
Dr Rahul Rajeev
Junior Resident in General Medicine
Chief Editor
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iii
Preface
Acknowledgement v
Chapter 1 MISCELLANEOUS 1
Chapter 2 HEMATOLOGY 24
Chapter 3 GENETICS 28
Chapter 4 ONCOLOGY 30
Chapter 3 HEMATOPOIETIC DISORDERS 39
Chapter 6 INFECTIOUS DISEASES 58
Chapter 7 CARDIOVASCULAR SYSTEM 92
Chapter 8 RESPIRATORY SYSTEM 112
Chapter 9 DISORDERS OF KIDNEY AND URINARY TRACT 119
Chapter 10 ALIMENTARY TRACT 127
Chapter 11 LIVER AND BILIARY TRACT DISEASE 130
Chapter 12 DISEASES OF IMMUNITY 139
Chapter 13 ENDOCRINOLOGY & METABOLISM 156
Chapter 14 NEUROLOGY 196
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TABLE WELLS CLINICAL PREDICTION RULE FOR PULMONARY EMBOLISM

Clinical Feature Points
Clinical signs of deep vein thrombosis 3
Alternative diagnosis is less likely than pulmonary embolism 3
Heart rate >100 beats/min 1.5
Immobilization > 3 days or surgery in previous 4 weeks 1.5
History of deep vein thrombosis or pulmonary embolism 1.5
Hemoptysis 1
Malignancy (with treatment within 6 months) or palliative 1
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HARRISON’S 19TH BASED NOTE BOOK M
Interpretation
Score >6.0 High
Score 2.0-6.0 Intermediate
Score <2.0 Low
In December, 2013 The American College of Obstetricians and Gynecologists issued a re¬
port summarizing the findings and recommendations of their Task Force on Hypertension in
Pregnancy. With respect to preeclampsia several pertinent revisions to the diagnostic criteria
were made including: proteinuria is no longer an absolute requirement for making the diagno¬
sis; the terms mild and severe preeclampsia have been replaced, and the disease is now termed
preeclampsia either with or without severe features; removal of fetal growth restriction as a
defining criterion for severe preeclampsia.
USEFUL ONE LINERS
• Most commonvalvular disease causing death during pregnancy is mitral stenosis.

• Most common cause of hyperthyroidism during pregnancy is Grave’s disease.
• Hyperthyroidism is most difficult to control in the first trimester of pregnancy and easiest
to control in the third trimester.
• Bell’s palsy is three times more likely to occur in the third trimester of pregnancy than in
the general population.
• Most common peripheral nerve and movement disorder in pregnancy is restless leg syn¬
drome.
• Crohn’s disease may be associated with exacerbations in the second and third trimesters
of pregnancy.
• Ulcerative colitis is associated with diseas exacerbations in the first trimester and during
the early postpartum period.
• Intrahepatic cholestasis of pregnancy is generally a third-trimester event.
• Most common congenital viral infection is cytomegalovirus.
HORMONES THAT DECREASE, REMAIN STABLE, AND INCREASE WITH

TABLE
AGING
Decrease No Change Increase
Growth hormone Prolactin Cholecystokinin
Luteinizing hormone (men) Thyrotropin Luteinizing hormone (wom-
Insulin growth factor 1 Thyroid hormones en)
Testosterone Epinephrine Follicle-stimulating hormone
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HARRISON’S I9TH BASED NOTE BOOK
Estradiol Glucagon-like peptide 1 Cortisol

Dehydroepiandrosterone Gastric inhibitory polypep- Prolactin
Pregnenolone tide Norepinephrine
25 -Hydroxyvitamin D Insulin
Aldosterone Parathormone
Vasoactive intestinal peptide
Melatonin
PAINFUL CONDITIONS THAT RESPOND TO TRICYCLIC ANTIDEPRES¬

TABLE
SANTS
Postherpetic neuralgia*
Diabetic neuropathy*
Tension headache*
Migraine headache*
Rheumatoid arthritis*-*
Chronic low back pain*
Cancer
Central poststroke pain
"Controlled trials demonstrate analgesia. Controlled studies indicate benefit but not analgesia
USEFUL ONE LINERS
• The rash of measles typically spares palms and soles.

• Forcheimer spots (palatal petechiae) are seen in german measles, infectious mononucleosus
and scarlet fever.
• Most common causative organism of hand-foot -and-mouth disease is Coxsackievirus
A16.
• Slapped cheek appearance of rash is seen in erythema infectiosum(fifth disease) caused by
parvovirus B19.
• ‘Pastia lines’ are accentuated petechiae in body folds seen in scarlet fever.
• “Hot-tub folliculitis” is caused by pseudomonas.
TABLE FEATURES OF PERIPHERAL AND CENTRAL VERTIGO
• Nystagmus from an acute peripheral lesion is unidirectional, with fast phases beating
away from the ear with the lesion. Nystagmus that changes direction with gaze is due to
a central lesion.

HARRISON’S 19TH BASED NOTE BOOK S3!
• Transient mixed vertical-torsional nystagmus occurs in BPPV, but pure vertical or pure
torsional nystagmus is a central sign
• Nystagmus from a peripheral lesion may be inhibited by visual fixation, whereas central
nystagmus is not suppressed
• Absence of a head impulse sign in a patient with acute prolonged vertigo should suggest
a central cause
• Unilateral hearing loss suggests peripheral vertigo. Findings such as diplopia, dysarthria,
and limb ataxia suggest a central disorder _
TABLE SIGNS THAT DISTINGUISH THE ORIGIN OF WEAKNESS
Sign Upper Motor Lower Mo- Myopa- Psychogenic
Neuron tor Neuron thic
Atrophy None Severe Mild None
Fasciculations None Common None None
Tone Spastic Decreased Normal/ Variable/paratonia
decreased
Distribution of Pyramidal/re¬ Distal/seg- Proximal Variable/inconsistent with
weakness gional mental daily activities
Muscle stretch Hyperactive Hypoactive/ Normal/ Normal
reflexes absent hypoactive
Babinski sign Present Absent Absent Absent
TABLE CAUSES OF EPISODIC GENERALIZED WEAKNESS

Electrolyte disturbances, e.g., hypokalemia, hyperkalemia, hypercalcemia, hyperna¬
tremia, hyponatremia, hypophosphatemia, hypermagnesemia
2. Muscle disorders
a. Channelopathies (periodic paralyses)
b. Metabolic defects of muscle (impaired carbohydrate or fatty acid utilization;
abnormal mitochondrial function
3. Neuromuscular junction disorders
a. Myasthenia gravis
b. Lambert Eaton myasthenic syndrome
4. Central nervous system disorders
a. Transient ischemic attacks of the brainstem
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HARRISON’S 19TH BASED NOTE BOOK
b. Transient global cerebral ischemia

c. Multiple sclerosis
5. Lack of voluntary effort
a. Anxiety
b. Pain or discomfort
c. Somatization disorder
USEFUL ONE LINERS
• Hyperesthesia means pain or increased sensitivity in response to touch.

• Allodynia describes the situation in which a nonpainful stimulus, once perceived, is expe¬
rienced as painful, even excruciating.
• Hyperalgesia denotes severe pain in response to a mildly noxious stimulus.
• Hyperpathia, is a broad term, encompasses all the phenomena described by hyperesthesia,
. allodynia and hyperalgesia.
FEATURES OF CEREBELLAR ATAXIA, SENSORY ATAXIA, AND

TABLE
FRONTAL GAIT DISORDERS
Cerebellar
Feature Sensory Ataxia Frontal Gait
Ataxia
Base of sup- Wide-based Narrow base, looks Wide-based
port down
Velocity Variable Slow Very slow
Stride Irregular, lurching Regular with path Short, shuffling
deviation
Romberg test +/- Unsteady, falls +/-
Heel —> shin Abnormal +/- Normal
Initiation Normal Normal Hesitant
Turns Unsteady +/- Hesitant, multistep
Postural ++++ +++ +
instability Poor postural synergies
rising from a chair

HARRISON’S 19TH BASED NOTE BOOK m
TABLE CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS
First Symp¬ Neuropsy¬

Disease Mental Status Neurology Imaging
tom chiatry
AD Memory loss Episodic mem¬ Irritability, Initially Entorhinal
ory loss anxiety, de¬ normal contex and
pression hippocampal
atrophy
FTD Apathy; poor Frontal/execu- Apathy, May have Frontal,
judgment/in- tive and/or lan- disinhibition, vertical gaze insular, and/
sight, speech/ guage; spares overeating, palsy, axial or temporal
language; drawing compulsivity rigidity, dys- atrophy;
hyperorality tonia, alien usually spares
hand, or posterior
MND parietal lobe
DLB Visual hal- Drawing and Visual hal¬ Parkinsonism Posterior
lucinations, frontal/exec- lucinations, parietal atro¬
REM sleep utive; spares depression, phy; hippo¬
behavior dis- memory; deliri- sleep disorder, campi larger
order, delirium-prone delusions than in AD
um, Capgras
syndrome,
parkinsonism
CJD Demen¬ Variable, fron- Apathy, delu- Usually mo¬ Cortical rib¬
tia, mood, tal/executive, sions, anxiety tor slowing, boning and
anxiety, cognitive slow¬ spasticity; basal ganglia
movement ing; can spare can be nor¬ or thalamus
disorders memory mal hyperintensi¬
ty on diffu-
sion/FLAIR
MRI
Vascular Often but Frontal/execu- Apathy, delu- Usually mo¬ Cortical and/
not always tive, cognitive sions, anxiety tor slowing, or subcortical
sudden; vari- slowing; can spasticity; infarctions,
able; apathy, spare memory can be nor¬ confluent
falls, focal mal white matter
weakness disease

M HARRISON’S 19TH BASED NOTE BOOK
Abbreviations: AD-Alzheimer’s disease; CBD-Cortical basal degeneration; CJD-Creutzfeldt-

Jakob disease; DLB-Dementia with Lewy bodies; FLAIR-Fluid-attenuated Inversion recov-
ery; FTD-Frontotemporal dementia; MND-Motor Neuron Disease; MRI-Magnetic Reso¬
nance Imaging; PSP- Progressive supranuclear palsy; REM-Rapid Eye Movement
CLINICAL FEATURES OF APHASIAS AND RELATED CONDITIONS

TABLE
COMMONLY SEEN IN CEREBROVASCULAR ACCIDENTS
Comprehension Repetition of Spo- Naming Fluency
ken Language
Wernick’s Impaired Impaired Impaired Preserved of
increased
Broca’s Preserved (except Impaired Impaired Decreased
grammar)
Global Impaired Impaired Impaired Decreased
Conduction Preserved Impaired Impaired Preserved
Nonfluent (anteri- Preserved Preserved Impaired Impaired
or) transcortical
Fluent (posterior) Impaired Preserved Impaired Preserved
transcortical
Isolation Impaired Echolalia Impaired No purpose¬
ful speech
Anomic Preserved Preserved Impaired Preserved
except for
word-finding
pauses
Pure word deaf¬ Impaired only for Impaired Preserved Preserved
ness spoken language
Pure alexia Impaired only for Preserved Preserved Preserved
reading
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• Anomic aphasia is the single most common language disturbance seen in head trauma,
metabolic encephalopathy, and Alzheimer’s disease.
• Apraxia designates a complex motor deficit that cannot be attributed to pyramidal, ex-
trapyramidal, cerebellar, or sensory dysfunction and that does not arise from the patient’s
failure to understand the nature of the task.

HARRISON’S 19TH BASED NOTE BOOK n
• Aphemia is a severe form of acute speech apraxia that presents with severely impaired flu¬
ency (often mutism).
• In approximately 90% of right-handers and 60% of left-handers, aphasia occurs only alter
lesions of the left hemisphere.
> Gerstmann’s syndrome - combination of acalculia (impairment of simple arith¬
metic), dysgraphia (impaired writing), finger anomia (an inability to name in¬
dividual fingers such as the index and thumb), and right-left confusion (an in¬
ability to tell whether a hand, foot, or arm of the patient or examiner is on the
right or left side of the body). When Gerstmanns syndrome arises acutely and in
isolation, it is com monly associated with damage to the inferior parietallobule
(especially the angular gyrus) in the left hemisphere.
> Bilateral involvement of the network for spatial attention, especially its pa¬
rietal components, leads to a state of severe spatial disorientation known as
Balints syndrome. It involves ;
i deficits in the orderly visuomotor scanning of the environment (oculomotor
apraxia).
ii accurate manual reaching toward visual targets (optic ataxia), and
iiithe ability to integrate visual information in the center of gaze with more pe¬
ripheral information (simultanagnosia).
USEFUL ONE LINERS
• Narcolepsy is a disorder of REM sleep.

• Narcolepsy is caused by loss of the hypothalamic neurons that produce the orexin neuro¬
peptides (also known as hypocretins).
• Narcolepsy has the strongest known HLA association. HLA DQB1*06:02 is found in
about 90% of people with narcolepsy.
Keep in mind Anisocoria that increases in dim light indicates a sympathetic paresis of the iris dila¬
tor muscle. Anisocoria that increases in bright light suggests a parasympathetic palsy.
USEFUL ONE LINERS
• In Nothnagel’s syndrome, injury to the superior cerebellar peduncle causes ipsilateral oc¬
ulomotor palsy and contralateral cerebellar ataxia.
• In Benedikt’s syndrome, injury to the red nucleus results in ipsilateral oculomotor palsy
and contralateral tremor, chorea, and athetosis.
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• Claude’s syndrome incorporates features of both of these syndromes, by injury to both the
red nucleus and the superior cerebellar pedunde.
• In Weber’s syndrome, injury to the cerebral pedunde causes ipsilateral oculomotor palsy
with contralateral hemiparesis.
• Foville’s syndrome — occurs after dorsal pontine injury, includes lateral gaze palsy, ipsilat¬
eral facial palsy, and contralateral hemiparesis incurred by damage to descending cortico¬
spinal fibers.
• Millard-Gubler syndrome- resultsfrom ventral pontine injury is similar to Foville s syn¬
drome, except for the eye findings. There is lateral rectus weakness only, instead of gaze
palsy, because the abducens fascicle is injured rather than the nucleus.
• Most common cause of bilateral internuclear ophthalmoplegia is multiple sclerosis.
• One-and-a-half syndromeis due to a combined lesion of the medial longitudinal fasciculus
and the abducens nucleus on the same side. The patient’s only horizontal eye movement is
abduction of the eye on the other side.
USEFUL ONE LINERS
• Most common primary tumor of eye is melanoma.

• Most common virus implicated in conjunctivitis is adenovirus.
• Orbital pseudotumor idiopathic, inflammatory orbital syndrome that is distin¬
is an
guished from Graves’ ophthalmopathy by the prominent complaint of pain. Imaging often
shows swollen eye muscles (orbital myositis) with enlarged tendons. By contrast, in Graves’
ophthalmopathy, the tendons of the eye muscles usually are spared.
• Total palsy of the oculomotor nerve causes ptosis, a dilated pupil, and leaves the eye “down
and out” because of the unopposed action of the lateral rectus and superior oblique.
Parinaud’s Syndrome
• This is a distinct supranuclear vertical gaze disorder caused by damage to the posterior
commissure.
• Also known as dorsal midbrain syndrome.
• It is a classic sign of hydrocephalus from aqueductal stenosis. Pineal region or midbrain
tumors, cysticercosis,and stroke also cause Parinaud’s syndrome.
• Features include loss of upgaze (and sometimes downgaze), convergence-retraction nystag-
mus on attempted upgaze, downward ocular deviation (“setting sun” sign), lid retraction
(Collier’s sign), skew deviation, pseudoabducens palsy, and light -near dissociation of
the
pupils.
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Opsoclonus
• It is a rare, dramatic disorder of eye movements consists of burst's of consecutive saccades
(saccadomania).
• When the saccades are confined to the horizontal plane, the term ocularflutteris preferred.
• It can result from viral encephalitis, trauma, or a paraneoplastic effect of neuroblastoma,
breast carcinoma, and other malignancies.
• It has also been reported as a benign, transient phenomenon in otherwise healthy patients.
Keep in mind Downbeat nystagmus results from lesions near the craniocervical junction (Chiari
malformation, basilar invagination). It also has been reported in brainstem or cerebellar stroke,
lithium or anticonvulsant intoxication, alcoholism, and multiple sclerosis. Up beat nystagmus is
associated with damage to the pontine tegmentum from stroke, demyelination, or tumor. _
• Syndromes associated with hearing loss are ;
> Alports syndrome
> Branchiootorenal (BOR) syndrome
> Jervell and Lange Neilson syndrome
> Norries disease
> Pendred s syndrome
> Treacher Collins syndrome
> Ushers syndrome
> Waardenburg s syndrome
SAAG
f
> 1.1 g/dl < 1.1 g/dl
£ 1
Ascitic protein < 2.5 g/dl Ascitic protein > 2.5 g/dl
Cirrhosis
I Heart
I
failure/constrictive
>r
Biliary leak
Late Budd-Chiari syndrome
pericarditis
Nephrotic syndrome
Early Budd-Chiari syndrome
Massive liver metastases Pancreatitis
IVC obstruction
Peritoneal carcinomatosis
Sinusoidal obstruction
Tuberculosis
syndrome

Algorithm for the diagnosis of ascites according to the serum-ascites albumin gradient
(SAAG). IVC, inferior vena cava.
TABLE LABORATORY FINDINGS IN ACUTE RENAL FAILURE

Oliguric Acute Renal
Index Prerenal Azotemia Failure
BUN/PrCr ratio >20:1 10-15:1
Urine sodium UNa, meq/L <20 >40
Urine osmolality, mosmol/L H20 >500 <350
Fractional excretion of sodium* <1% >2%
Urine/plasma creatinine UCr/PCr >40 <20
Urinalysis (casts) None or hyaline/granular Muddy brown
"F
r =
UN x& xl
N
PN X Cr
Abbreviations: BUN, blood urea nitrogen; PCr, plasma creatinine concentration; PNa, plasma
sodium concentration; UCr> urine creatinine concentration; UNa, urine sodium concentration;
USEFUL ONE LINERS
• Oliguria refers to 24 hour urinary output < 400 ml.

• Anuria refers to 24 hour urinary output <100 ml.
• Hematuria is defined as two to five RBCs per high-power field (HPF).
• Persistent or significant hematuria means >3 RBCs/ HPF on three urinalyses, a single
urinalysis with >100 RBCs, or gross hematuria.
• Polyuria refers to 24 hour urine output >3 litres.
• FLUID AND ELECTROLYTE DISTURBANCES (Pg:295-312)

• HYPERCALCEMIA AND HYPOCALCEMIA (Pg:313-15)
• ACIDOSIS AND ALKALOSIS (Pg:315-24)

HARRISON’S 19TH BASED NOTE BOOK i£
Assessment of volume status
I
Hypovolemia Euvolemia (no edema) Hypervolemia
•Total body water 4 •Total body water t •Total body water TT
•Total body sodium 44 •Total body sodium <—> •Total body sodium t
I I
UN3 > 20 UNa<20 UNa>20 UNa>20 UNa<20
Renal losses Extrarenal losses Glucocorticoid deficiency Acute or chronic Nephrotic syndrome
Diuretic excess Vomiting Hypothyroidism renal failure Cirrhosis
Mineral corticoid deficiency Diarrhea Stress Cardiac failure
Salt-losing deficiency Third spacing of fluids Drugs
Bicarbonaturia with Burns Syndrome of inappropriate
renal tubal acidosis and Pancreatitis antidiuretic hormone
metabolic alkalosis Trauma secretion
Ketonuria
Osmotic diuresia
Cerebral salt wasting
syndrome
DIAGNOSTIC APPROACH TO HYPONATREMIA

• Two important physical signs in hypocalcemia are ;
> i Chvostek’s sign — Twitching of the circumoral muscles in response to gentle
tapping of the facial nerve just anterior to the ear.
> ii Trousseaus sign - Carpal spasm may be induced by inflation of a blood pres¬
sure cuff to 20mmHg above the patients systolic pressure for 3 min.
TABLE CAUSES OF HIGH-ANION GAP METABOLIC ACIDOSIS

Lactic acidosis Toxins
Ketoacidosis Ethylene glycol
Diabetic Methanol
Alcoholic Salicylates
Starvation Propylene glycol
Pyroglutamic acid (5-oxoproline)
Renal failure (acute and chronic)
TABLE CAUSES OF NON-ANION GAP ACIDOSIS

I. Gastrointestinal bicarbonate loss
A. Diarrhea

B. External pancreatic or small-bowel drainage

C. Ureterosigmoidostomy, jejunal loop, ileal loop
D. Drugs
1. Calcium chloride (acidifying agent)
2. Magnesium sulfate (diarrhea)
3. Cholestyramine (bile acid diarrhea)
II. Renal acidosis
A. Hypokalemia
1. Proximal RTA (type 2)
Drug induced: acetazolamide, topiramate
2. Distal (classic) RTA (type 1)
Drug induced: amphotericin B, ifosfamide
B. Hyperkalemia
1. Generalized distal nephron dysfunction (type 4 RTA)
a. Mineralocorticoid deficiency
b. Mineralocorticoid resistance (PHA I, autosomal dominant)
c. Voltage defect (PHA I, autosomal recessive, and PHA II)
d. Tubulointerstitial disease
C. Normokalemia
1. Chronic progressive kidney disease
III. Drug-induced hyperkalemia (with renal insufficiency)
A. Potassium-sparing diuretics (amiloride, triamterene, spironolactone, epler-
enone)
B. Trimethoprim
C. Pentamidine
D. ACE-Is and ARBs
E. Nonsteroidal anti-inflammatory drugs
F. Calcineurin inhibitors
IV. Other
A. Acid loads (ammonium chloride, hyperalimentation)
B. Loss of potential bicarbonate: ketosis with ketone excretion
C. Expansion acidosis (rapid saline administration)
D. Hippurate
E. Cation exchange resins

Abbreviations: ACE-I- Angiotensin converting enzyme inhibitor; ARB- Angiotensin recep-
tor blocker; PHA-Pseudohypoaldosteronism; RTA- Renal tubular acidosis
TABLE DRUGS ASSOCIATED WITH ERECTILE DYSFUNCTION

Classification Drugs
Diuretics Thiazides
Spironolactone
Antihypertensives Calcium channel blockers
Methyldopa
Clonidine
Reserpine
Beta blockers
Guanethidine
Cardiac/antihyperlipidemics Digoxin
Gemfibrozil
Clofibrate
Antidepressants Selective serotonin reuptake inhibitors
Tricyclic antidepressants
Lithium
Monoamine oxidase inhibitors
Tranquilizers Butyrophenones
Phenothiazines
H2 antagonists Ranitidine
Cimetidine
Hormones Progesterone
Estrogens
Corticosteroids
GnRH agonists
5MReductase inhibitors
Cyproterone acetate
Cytotoxic agents Cyclophosphamide
Methotrexate
Roferon-A
Anticholinergics Disopyramide
Anticonvulsants

Recreational Ethanol
Cocaine
Marijuana
TABLE DESCRIPTION OF PRIMARY SKIN LESIONS

Macule: A flat, colored lesion, <2 cm in diameter, not raised above the surface of the sur¬
rounding skin. A “freckle,” or ephelid, is a prototypical pigmented macule.
Patch: A large (>2-cm) flat lesion with a color different from the surrounding skin. This
differs from a macule only in size.
Papule: A small, solid lesion, <0.5 cm in diameter, raised above the surface of the sur¬
rounding skin and thus palpable (e.g., a closed comedone, or white - head, in acne).
Nodule: A larger (0.5- to 5.0-cm), firm lesion raised above the surface of the surrounding
skin. This differs from a papule only in size (e.g., a large dermal nevomelanocytic nevus).
Tumor: A solid, raised growth >5 cm in diameter.
Plaque: A large (>l-cm), flat-topped, raised lesion; edges may either be distinct (e.g., in
psoriasis) or gradually blend with surrounding skin (e.g., in eczematous dermatitis).
Vesicle: A small, fluid-filled lesion, <0.5 cm in diameter, raised above the plane of sur¬
rounding skin. Fluid is often visible, and the lesions are translucent (e.g., vesicles in allergic
contact dermatitis caused by Toxicodendron [poison ivy]).
Pustule: A vesicle filled with leukocytes. Note: The presence of pustules does not neces¬
sarily signify the existence of an infection.
Bulla: A fluid filled, raised, often translucent lesion >0.5 cm in diameter.
Wheal: A raised, erythematous, edematous papule or plaque, usually representing short¬
lived vasodilation and vasopermeability.
Telangiectasia: A dilated, superficial blood vessel.
TABLE SELECTED DERMATOLOGIC CONDITIONS

Diagno- Common Usual Mor- Diagno- Distribution Usual Mor¬
sis Distribution phology sis phology
Acne vul- Face, upper Open and Sebor- Trunk, face Brown plaques
garis back, chest closed comedo- rheic with adherent,
nes, erythem- keratosis greasy scale,
atous papules, “stuck on”
pustules, cysts appearance
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E9
Rosacea Blush area of Erythema, Follicu- Any hair Follicular pus¬
cheeks, nose, telangiectases, litis bearing area tules Papules,
forehead, chin papules, pus- Impetigo Anywhere vesicles, pus¬
tules tules, often with
honey-colored
crusts
Seborrheic Scalp, eye- Erythema with Herpes Lips, geni- Grouped ves¬
dermatitis brows, perina- greasy yellow simplex talia icles progress¬
sal areas brown scale ing to crusted
erosions
Atopic. Antecubital Patches and Herpes Dermatomal, Vesicles limited
dermatitis and popliteal plaques of ery- zoster usually trunk to a dermatome
fossae; may be thema, scaling, but may be (often painful)
widespread and lichenifica- anywhere
tion; pruritus
Stasis der- Ankles, lower Patches of Varicella Face, trunk, Lesions arise
matitis legs over me- erythema and relative in crops and
dial malleoli scaling on sparing of quickly progress
background of extremities from erythema¬
hyperpigmenta¬ tous macules, to
tion associated papules, to vesi¬
with signs of cles, to pustules,
venous insuffi¬ to crusted sites
ciency
Dyshi¬ Palms, soles, Deep vesicles Pityriasis Trunk Symmetric

drotic sides of fingers rosea (Christmas erythematous
eczema and toes tree pattern); patches with
herald patch a collarette of
followed scale
by multi¬
ple smaller
lesions

Allergic Anywhere Localized Tinea Chest, back, Scaly hyper or

contact erythema, vesi- versicolor abdomen, hypopigmented
dermatitis cles, scale, and proximal macules
pruritus (eg., extremities
fingers, ear¬
lobes—nickel;
dorsal aspect
of foot—shoe;
exposed surfac¬
es—poison ivy)
Psoriasis Elbows, knees, Papules and Candidi- Groin, be- Erythematous
scalp, lower plaques covered asis neath breasts, macerated areas
back, finger with silvery vagina, oral with satellite
nails (may be scale; nails have cavity pustules; white,
generalized) pits friable patches
on mucous
membranes
Lichen Wrists, ankles, Violaceous flat Derma- Feet, groin, Varies with
planus mouth (may topped papules tophyto- beard, or site, (eg, tinea
be widespread) and plaques sis scalp corporis—scaly
annular plaque)
Keratosis Extensor sur- Keratotic fol- Scabies Groin, axil- Excoriated pap-
pilaris faces of arms licular papules lae, between ules, burrows,
and thighs, with surround¬ fingers and pruritus
buttocks ing erythema toes, beneath
breasts
Melasma Forehead, Tan to brown Insect Anywhere Erythematous
cheeks, tem¬ patches bites papules with
ples, upper lip central puncta
Vitiligo Periorificial, Chalk-white Cherry Trunk Red, blood-
trunk, exten- macules angioma Anywhere filled papules
sor surfaces of Keloid (site of previ- Firm tumor,
extremities, ous injury) pink, purple, or
flexor wrists, brown
axillae

Page | 17
HARRISON’S 19TH BASED NOTE BOOK I®
Derma- Anywhere Firm red to
toflbro- brown nodule
ma that shows
dimpling of
overlying skin
with lateral
compression
Actinic Sun-exposed Skin-colored Acro- Groin, axilla, Fleshy papules
keratosis areas or red-brown chordons neck
macule or pap- (skin
ule with dry, tags)
rough, adherent
scale
Basal cell Face Papule with Urticaria Anywhere Wheals, some¬
carcinoma pearly, telangi¬ times' with sur¬
ectatic border rounding flare;
on sun-dam- pruritus
aged skin
Squamous Face, especial¬ Indurated and Transient Trunk, espe- Erythematous
cell card- ly lower lip, possibly hyper acan- dally anterior papules .
noma ears keratotic lesions tholytic chest
often showing derma-
ulceration and/ tosis
or crusting
Xerosis Extensor Dry, erythem-
extremities, atous, scaling
especially legs patches; pru¬
ritus
• ATOPIC DERMATITIS (Pg:344)

• PSORIASIS (Pg:347-48)
• LICHEN PLANUS (Pg:349)
• PITYRIASIS ROSEA (Pg:349)
• URTICARIA (Pg:363)
• DERMATITIS HERPETIFORMIS (Pg:373)
Page) 18 Email: info@damsdelhi.com | Website: www.damsdelhi.com

Ml HARRISON’S 19TH BASED NOTE BOOK
• DERMATOMYOSITIS (Pg:374-75)
TABLE CLINICAL FEATURES OF ATOPIC DERMATITIS
1. Pruritus and scratching
2. Course marked by exacerbations and remissions
3. Lesions typical of eczematous dermatitis
4. Personal or family history of atopy (asthma, allergic rhinitis, food allergies, or eczema)
5. Clinical course lasting >6 weeks
6. Lichenification of skin _
TABLE PAPULOSQUAMOUS DISORDERS
Clinical Features Other Notable Histologic
Features Features
Psoria- Sharply demarcated, erythematous May be aggravated Acanthosis,
sis plaques with mica-like scale; pre domi¬ by certain drugs, in- vascular pro-
nantly on elbows, knees, and scalp; atyp- fection; severe forms liferation
ical forms may localize to intertriginous seen in asso- ciatioh
areas; eruptive forms may be associated with HIV
with infection
Lichen Purple polygonal papules marked by Certain drugs may Interface
planus severe pruritus; lacy white markings, induce: thiazides, an- dermatitis
especially associated with mucous mem- timalarial drugs*
brane lesions
Pityria- Rash often preceded by herald patch; oval Variable pruritus; Pathologic
sis rosea to round plaques with trailing scale; most self-limited, resolv- features of-
often affects trunk; eruption lines up in ing in 2-8 weeks; ten nonspe-
skinfolds giving a “fir tree-like” appear- may be imitated by cific
ance; generally spares palms and soles secondary syphilis
Derma- Polymorphous appearance depending KOH preparation Hyphae and
tophy- on dermatophyte, body site, and host re- may show branch- neutrophils
tosis sponse; sharply defined to ill-demarcated ing hyphae; culture in stratum
scaly plaques with or without inflamma- helpful corneum
tion; may be associated with hair loss
USEFUL ONE LINERS

• KOH preparation from scaling lesions in Tinea versicolor shows “sphagetti and meatballs”
appearance.
• Most common malignancy associated with erythroderma is Cutaneous T cell lymphoma.
• “Moth eaten” alopecia is a manifestation of secondary stage of syphilis.
• Periungual telangiectasias are pathognomonic signs of the three major autoimmune con-
nective tissue diseases: lupus erythematosus,systemic sclerosis, and dermatomyositis.
• There are four systemic diseases that should be considered in a patient with skin findings
suggestive of vitiligo-Vogt-Koyanagi Harada syndrome,systemic sclerosis,onchocerciasis,
and melanomaassociated leukoderma.
• Earliest cutaneous sign of tuberous sclerosis is ash leaf spot.
• Most common cardiac lesion in tuberous sclerosis is rhabdomyoma.
• Sudden appearance of multiple seborrheic keratoses is known as “sign of Lesser Trelat and
alerts the clinician to search for an internal malignancy.
• The metabolic causes of hyperpigmentation include porphyria cutanea tarda (PCT),
hemochromatosis,vitamin B12 deficiency,folic acid deficiency,pellagra,and malabsorp¬
tion,including Whipple’s disease.
• Most common autoimmune disorders associated with diffuse hyperpigmentation are sys¬
temic sclerosis and biliary cirrhosis.
• Drugs implicated in pseudoporphyria — Naproxen and other NSAIDs, Furosemide, Tetra¬
cycline and Voriconazole.
• Neurofibromas invaginate into the skin with pressure in a manner similar similar to a
hernia. This is called “button-hole” sign.
• The presence of multiple tricho lemmomas on the face and'cobblestoning of the oral mu¬
cosa points to the diagnosis of Cowden disease.
• Most common setting for eruptive xanthomas is uncontrolled diabetes mellitus.
• Most common malignancy associated with Sweet syndrome is Acute Myelogenous Leukemia.
• “Naked granulomas” are a histopathological finding in sarcoidosis.
• In a form of mastocytosis known as Urticaria Pigmentosa, stimuli such as rubbing of skin
causes mast cells to degranulate leading to the formation of localised urticaria. This is
known as Darier’s sign,
• Patients with congenital or acquired A V fistulas and venous hypertension can develop pur¬
ple papules on the lower extremities that can resemble Kaposi’s sarcoma clinically and his¬
tologically; this condition is referred to as pseudo-Kaposi’s sarcoma (acral angiodermatitis).
• In the Gardner-Diamond syndrome (autoerythrocyte sensitivity),female patients develop
large ecchymoses within areas of painful, warm erythema.
• Hypersensitivity to the anti-HIV medication abacavir is strongly associated with HLA
B*57:01

• Most common drug implicated in DIHS/DRESS is Allopurinol.

• Most common causative organism of impetigo is Staph aureus.
• In Discoid lupus erythematosus,when the scale is removed,its underside shows small ex-
crescences that correlate with the openings of hair follicles (so-called “carpet racking ), a
finding relativelyspecific for DLE.
• Gottron’s papules are pathognomonic of dermatomyositis.
Disease
iHV
Figure Gottron’s papules. Dermatomyositis often involves the hands as erythematous flat-
topped'papules over the knuckles. Periungual telangiectases are also evident.
TABLE IMMUNOLOGICALLY MEDIATED BLISTERING DISEASES
Clinical Manifes- Histology Immunopathol- Autoantigens*

tations ogy
Pemphigus Flaccid blisters, Acantholytic Cell surface de- Dsg3 (plus
vulgaris denuded skin, oro- blister formed in posits of lgG on Dsgl in pa-
mucosal lesions suprabasal layer keratinocytes tients with skin
of epidermis involvement)
Pemphigus Crusts an shallow Acantholytic Cell surface de- Dsgl
foliaceus erosions of scalp, blister formed in posits of lgG on
central face, upper superficial layer keratinocytes
chest, and back of epidermis
Parane- Painful stomatitis Acantholysis, Cell surface Plakin protein
oplastic with papulosqua- keratinocyte deposits of lgG family members
pemphigus mous or lichenoid necrosis, and and C3 on ke¬ and desmosom-
eruptions that may vacuolar inter¬ ratinocytes and al cadherins
progress to blisters face dermatitis (variably)similar
immunoreactants
in epidermal
BMZ
Bullous Large tense blisters Subepidermal Linear band of BPAG1, BPAG2

Pemphi¬ on flexor surfaces blister with lgG and/or C3 in
goid and trunk eosinophil-rich epidermal BMZ
infiltrate
Pemphi- Pruritic, urticarial Tear- Linear band of BPAG2 (plus
BPAG1 in some
goid gesta- plaques rimmed by drop-shaped, C3 in epidermal
patients)
tionis vesicles and bullae subepidermal BMZ
on the trunk and blisters in der-
extremities mal papillae;eo-
sinophil-rich
infiltrate
Dermatitis Extremely prutitic Subepidermal Granular deposits Epidermal trans¬
herpeti- small papules and blister with of IgA in dermal glutaminase
formis vesicles on elbows, neutrophils in papillae
knees, buttocks, dermal papillae
and posterior neck
Linear IgA Pruritic small Subepidermal Linear band of IgA in BPAG2
disease papules on extensor blister with epidermal BMZ
surfaces; occasion- neutrophil-rich
ally larger, arciform infiltrate
blisters
Epidermol- Blisters, erosions, Subepidermal Linear band of Type VII col-
ysis bullosa scars, and milia blister that may IgG and/or C3 in lagen
acquisita on sites exposed or may not epidermal BMZ
to trauma; wide¬ include a leuko-
spread, inflamma- cytic infiltrate
tory, tense blisters
may be seen intially
Mucous Erosive and/or Subepidermal Linear band of BPAG2, lami-
membrane blistering lesions of blister that may lgG, IgA, and/or nin-332, or
pemphi¬ mucous membranes or may not C3 in epidermal others
goid and possibly the include a leuko¬ BMZ
skin; scarring of cytic infiltrate
some sites
"Autoantigens bound by these patients’ autoantibodies are defined as follows; Dsgl, desinoglein 1;
Dsgl, desmogein 1; Dsg3, desmogein 3; BPAGl, bullous pemphigoid antigen 1; BPAG2, bullous pem¬
phigoid antigen 2.

Abbreviation: BMZ, basement membrane zone
Keep in mind The predominant neoplasms associated with paraneoplastic pemphigus(PNP)

are non-Hodgkins lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell tu¬
mors, Waldenstrom’s macroglobulinemia, and Castleman’s disease; the last-mentioned neo¬
plasm is particularly common among children with PNP.
• Drugs causing hypertrichosis ;
> Anti-inflammatory drugs
> Glucocorticoids
> Vasodilators (Diazoxide, Minoxidil)
> Diuretics (Acetazolamide)
> Anticonvulsants (Phenytoin)
> Immunosuppresive agents (Cyclosporine A)
> Psoralens
> Zidovudine

CHAPTER 2 HEMATOLOGY
A 3
a
USEFUL ONE LINERS
• The World Health Organization defines anemia as a hemoglobin level <13 g/dL in men
and <12 g/dL in women.
• Normal reticulocyte count is 1-2%.
• Prematurely released reticulocytes into the circulation are called “shift cells”.
• The normal serum iron ranges from 50-130 pmol/dL, whereas the normal TIBC is 300-
360 g/dL; the normal transferrin saturation ranges from 25 to 50%.
• The minimum number of stem cells necessary to support hematopoiesis is estimated to be
400-500 at any one time.

Physiological Classification of Anemia Based on Reticulocyte Production Index

| Anemia ]
I
CBC, reticulocyte count
I
Cjndex < 2jfÿ) (ÿJndex >
Red cell Hemolysis/

morphology hemorrhage
I
- Blood loss
Normocytic n Micro or - Intravascular
ormochromic macrocytic
hemolysis
I - Metabolic defect
I
— Hypoproliferative | —|Maturation disorder!
- Membrane
abnormality
- Marrow damage - Cytoplasmic defects
•Infiltration/fibrosis •Iron deficiency - Hemoglobinopathy
•Aplasia •Thalassemia
- Iron deficiency •Sideroblastic
Immune destruction
anemia - Fragmentation
L 1Stimulation hemolysis
- Nuclear defects
•Inflammation •Folate deficiency
•Metabolic defect •Vitamin B12 deficiency
•Renal disease
•Drug toxicity
•Refractory anemia
TABLE RED BLOOD CELL INDICES

Index Normal Value
Mean cell volume (MCV) = (hematocrit x 10) /(red cell count x 106) 90 ± 8 fL
Mean cell hemoglobin (MCH) = (hemoglobin x 10)/(red cell count x 106) 30 ± 3 pg
Mean cell hemoglobin concentration = (hemoglobin x 10)/hematocrit,
33 ± 2%
or MCH/MCV
TABLE PRIMARY HEMOSTATIC (PLATELET PLUG) DISORDERS

Defects of Platelet Adhesion
Von Willebrand disease

Bernard-Soulier syndrome (absence or dysfunction of platelet Gp Ib-IX-V)
Defects of Platelet Aggregation
Glanzmann’s thrombasthenia (absence or dysfunction of platelet glycoprotein [Gp] llb/llla)
Afibrinogenemia
Defects of Platelet Secretion
Decreased cyclooxygenase activity
Drug-induced (aspirin, nonsteroidal anti-inflammatory agents, thienopyridines)
Inherited
Granule storage pool defects
Inherited
Acquired
Nonspecific inherited secretory defects
Nonspecific drug effects
Uremia
Platelet coating (e.g., paraprotein, penicillin)
Defect of Platelet Coagulant Activity
Scott’s syndrome
TABLE DISEASES ASSOCIATED WITH MASSIVE SPLENOMEGALY3 j
Chronic myeloid leukemia Gaucher’s disease

Lymphomas Chronic lymphocytic leukemia
Hairy cell leukemia Sarcoidosis
Myelofibrosis with myeloid metaplasia Autoimmune hemolytic anemia
Polycythemia vera Diffuse splenic hemangiomatosis
"The spleen extends >8cm below the left costal margin and/or weighs >1000 g
Stages of neutrophil development shown schematically. Granulocyte colony-stimulating fac¬

tor (G-CSF) and granulocyte macrophage colony-stimulatingfactor (GM-CSF) are critical to
this process. Identifying cellular characteristics and specific cell-surface markers are listed for
each maturational stage.
The primary/azurophil granules contain hydrolases, elastase, myeloperoxidase cathepsin G, ca¬
tionic proteins, and bactericidal/ permeability-increasing protein, which is important for killing
gram-negative bacteria. Azurophil granules also contain defensins, a family of cysteine-rich poly¬
peptides with broad antimicrobial activity against bacteria, fungi, and certain enveloped viruses.
r
i
Cell Stage Surface Markers a Characteristics
Prominent
MYELOBLAST CD33, CD13, CD15 nucleoli
PROMYELOCYTE CD33, CD13, CD15 LARGE CELL

PRIMARY granules
appear
•*' Secondary
MYELOCYTE CD33, CD13, CD15, CD14, CD11b
granules appear
•* •
*
%
••
# Kidney bean¬
i METAMYELOCYTE CD33, CD13, CD15, CD14, CD11b shaped nucleus
©
CD33, CD13,
CD15, CD14, Condensed, band¬
BAND FORM
CD11b CD10, shaped nucleus
CD16
CD33, CD13,
v j NEUTROPHIL CD15, CD14,

CD11b, CD10,
CD16
Condensed,
multilobed
nucleus
aCD = Cluster Determinant;
The specific, or secondary,

• Nucleolus;
granules,
• Primary granule;
•
Secondary granule.
contain unique (specific) constituents such as lactofer-
rin,vitamin B 12-binding protein, membrane components of the reduced nicotinamide-ade¬
nine dinucleotide phosphate (NADPH) oxidase required for hydrogen peroxide production,
histaminase, and receptors for certain chemoattractants and adherence-promoting factors
(CR3) as well as receptors for the basement membrane component, laminin.
• CHEDIAK HIGASHI SYNDROME (Pg:4l9)

• CHRONIC GRANULOMATOUS DISEASE (Pg:4l9-21)
• JOB’S SYNDROME (Pg:423)
CHAPTER 3 GENETICS
/
Vi
GENETIC PROGEROID SYNDROMES

They are syndromes associated with premature aging. They include;
• Werner’s syndrome
• Hutchinson-Gilford progeria syndrome
• Cockayne syndrome

Male Female Unknown sex
Deceased male Multiple siblings Spontaneous abortion
M
Affected male Affected female Proband
I o
Hetrozygous male Hetrozygous female Female carrier of
X-linked trait
I I
1 2
Mating Consanguineous union
]
rr :
H
1
M
2 3
Monozygotic twins Dizygotic twins
Figure Standard pedigree symbols.

CHAPTER 4 ONCOLOGY
M
4.
I
X |3
to
TABLE TUMOR MARKERS

Tumor Markers Cancer Nonneoplastic Conditions
Hormones
Human chorionic gonado¬ Gestational trophoblas Pregnancy
tropin tic disease, gonadal
germ cell tumor
Calcitonin Medullary cancer of
the thyroid
Catecholamines Pheochromocytoma
Oncofetal Antigens

K Fetoprotein Hepatocellular carci¬ Cirrhosis, hepatitis

noma, gonadal germ
cell tumor
Carcinoembryonic antigen Adenocarcinomas of Pancreatitis, hepatitis, inflam¬
the colon, pancreas, matory bowel disease, smoking
lung, breast, ovary
Enzymes
Prostatic acid phos- phatase Prostate cancer Prostatitis, prostatic hypertrophy
Neuron specific enolase Small cell cancer of the
lung, neuroblastoma
Lactate dehydrogenase Lymphoma, Ewing’s Hepatitis, hemolytic anemia,
sarcoma many others
Tumor-Associated Proteins
Prostate specific antigen Prostate cancer Prostatitis, prostatic hypertrophy
Monoclonal immunoglobulin Myeloma Infection, MGUS
CA-125 Ovarian cancer, some Menstruation, peritonitis, preg¬

lymphomas nancy
CA19-9 Colon, pancreatic, Pancreatitis, ulcerative colitis
breast cancer
CD30 Hodgkin’s disease,
anaplastic large cell
lymphoma
CD25 Hairy cell leukemia,
adult T cell leukemia/
lymphoma
Abbreviatiotv MGUS, monoclonal gammopathy of uncertain significance
TABLE SUSPECTED CARCINOGENS

Carcinogens* Associated Cancer or Neoplasm
Alkylating agents Acute myeloid leukemia, bladder cancer
Androgens Prostate cancer
Aromatic amines (dyes) Bladder cancer
Arsenic Cancer of the lung, skin

HARRISON’S 19TH BASED NOTE BOOK 8
Asbestos Cancer of the lung, pleura, peritoneum
Benzene Acute myelocytic leukemia
Chromium Lung cancer
Diethylstibestrol (prenatal) Vaginal cancer (clear cell)
Epstein Barr virus Burkitt’s lymphoma, nasal T cel lymphoma
Estrogens Cancer of the endometrium, liver, breast
Ethyl alcohol Cancer of the breast, liver, esophagus, head and neck
Helicobacter pylori Gastric cancer, gastric MALT lymphoma
Hepatitis B or C virus Liver cancer
Human immunodeficiency Non Hodgkin’s lymphoma. Kaposi’s sarcoma, squamous
virus cell carcinomas (especially of the urogenital tract)
Human papilloma virus Cancers of the cervix, anus, oropharynx
Human T cell lymphotropic Adult T cell leukemia/lymphoma
virus type 1 (HTL V-l)
Immunosuppressive agents Non -Hodgkin’s lymphoma
(azathioprine, cylosporine,
glucocorticoids)
Ionizing radiation (therapeutic Breast, bladder, thyroid, soft tissue, bone, hematopoietic,
or diagnostic) and many more
Nitrogen mustard gas Cancer of the lung, head and neck, nasal sinuses
Nickel dust Cancer of the lung, nasal sinuses
Diesel exhaust Lung cancer (miners)
Phenacetin Cancer of the renal pelvis and bladder
Polycyclic hydrocarbons Cancer of the lung, skin (especially squamous cell carci¬
noma of scrotal skin)
Radon gas Lung cancer
Schistosomiasis Bladder cancer (squamous cell)
Sunlight (ultraviolet) Skin cancer (squamous cell and melanoma)
Tobacco (including smokeless) Cancer of the upper aerodigestive tract, bladder
Vinyl chloride Liver cancer (angiosarcoma)

"Agents that are thought to act as cancer initiators and/or promoters

jjjl HARRISON’S 19TH BASED NOTE BOOK
TABLE ANTIBODIES USED IN CANCER TREATMENT

Drug Target Indications and Features of Use
Tumor Regulatory Antibodies
Rituximab CD20 B cell neoplasms (also emerging role in autoimmune dis¬
ease); chimeric antibody
with frequent mouse-derived sequences; frequent infusion
reactions, particularly on initial doses; reactivation of
infections, particularly hepatitis; progressive multifocal
leukoencephalopathy; tumor lysis syndrome
Ofatumumab CD20 active in CLL; fully human antibody with distinct binding
site compared to rituximab; decreased intensity infusion
reactions;
Trastuzumab HFR2/neu Active in breast cancer and G1 cancers expressing HFR2/
neu; cardiotoxicity, particularly in setting of prior anthra-
cyclines, requires monitoring; infusion reactions
Pertuzumab HER2/neu Breast cancer; targets distinct binding site from trastu¬
zumab, inhibiting dimerization of HER2 family members;
infusion reactions; cardiac toxicity
Cetuximab EGFR Colorectal cancers with wild-type Ki-ras oncoprotein; head
and neck cancers with radiation; rash, diarrhea, infusion
reactions
Panitumumab EGFR Colorectal cancers with wild-type Ki-ras oncoprotein; fully
humanized; decreased infusion reactions; different IgG
subtype than cetuximab
Bevacizumab VEGF Metastatic colorectal cancer and non-small-cell lung can¬
cer (nonsquamous) with chemotherapy; renal cancer and
glioblastoma as single agents; prominent HBP, proteinuria,
G1 perforations, hemorrhage, thrombosis (venous and
arterial)
Immunoregulatory Antibodies
Alemtuzumab CD52 CLL, T cell lymphomas; activates complement after
binding to cell surface; infusion reactions, hypersensitivity,
tumor lysis, activation of infections, cytopenias

Ipilimumab CTLA4 Melanoma; inhibits the negative proliferative signal to T
cells acting through CTLA4, resulting in prominent T cell
activation; side effects include immune-mediated toxicity
to liver, skin, pituitary, gut, which if severe calls for ste¬
roids, which inhibit antineoplastic effect
Pembrolizumab PD-1 Melanoma unresectable or metastatic and if B-RAF V600
mutated, refractory to a B-RAF inhibitor; also can cause
immune related colitis, hepatitis, hypophysitis, nephritis,
and altered thyroid function; also consider steroids for
treatment of severe adverse events
Abbreviations: CLL-Chronic Lymphocytic Leukemia; EGFR-Epidermal growth factor re¬

ceptor; GI-Gastrointestinal; HBP-High blood pressure; VEGF- Vascular Endothelial Growth
Factor.
• Tumor-regulatory antibodies target tumor cells directly or indirectly to modulate intracel¬
lular functions or attract immune or stromal cells.
• Immunoregulatory antibodies target antigens expressed on the tumor cells or host im¬
mune cells to modulate primarily the host’s immune responsiveness to the tumor.
USEFUL ONE LINERS
• Most common type of melanoma is superficial spreading melanoma.

• Most common type of melanoma in blacks, asians and hippanics is acral lentiginous mel¬
anoma. ,
• Most common site for melanoma in men is back.
• Most common site for melanoma in women is back and lower leg.
• Type of melanoma associated with perineural invasion and greater tendency for local re¬
currence is desmoplastic melanoma.
HEREDITABLE (AUTOSOMAL DOMINANT) GASTROINTESTINAL

TABLE
POLYPOSIS SYNDROMES
Syndrome Distribution of Histologic Malignant Associated Lesions
Polyps Type Potential
Familial adeno- Large intestine Adenoma Common None
matous polyp-
osis

Gardner’s syn¬ Large and small Adenoma Common Osteomas, fibromas,

drome intestines lipomas, epidermoid
cysts, ampullary cancers,
congenital hypertro¬
phy of retinal pigment
epithelium
Turcot’s syn¬ Large intestine Adenoma Common Brain tumors
drome
MYH-associat- Large intestine Adenoma Common None
ed polyposis
Nonpolypo¬ Large intestine Adenoma Common Endometrial and ovarian

sis syndrome (often proxi- tumors (most frequently)
(Lynch’s syn¬ mal) gastric, genitourinary,
drome) pancreatic, biliary can¬
cers (less frequently)
Peutz-Jeghers Small and Hamartoma Rare Mucocutaneous pigmen¬
syndrome large intestines, tation; tumors of the
stomach ovary, breast, pancreas,
endometrium
Juvenile polyp¬ Large and small Hamartoma, Rare Various congenital ab¬
osis intestines, rarely pro¬ normalities
stomach gressing to
adenoma
FACTORS ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING

TABLE
HEPATOCELLULAR CARCINOMA
Common Unusual
Cirrhosis from any cause Primary biliary cirrhosis
Hepatitis B or C chronic infection Hemochromatosis
Ethanol chronic consumption Aj Antitrypsin deficiency
NASH/NAFL Glycogen storage diseases
Aflatoxin B, or other mycotoxins Citrullinemia
Porphyria cutanea tarda
Hereditary tyrosinemia
Wilson’s disease

IS..
Abbreviations: NAFL, nonalcoholic fatty liver; NASH, nonalcoholic steatohepatitis
HIGH YIELDING TOPIC
• FIBROLAMELLAR HCC (Pg:552)

• NEUROCUTANEOUS SYNDROMES (Pg:603-04)
Genetic syndromes associated with an increased incidence of neuroendocrine tumor-
sare :
• MEN typel
• Von Hippel Lindau disease
• Von Recklinghausen’s disease
• Tuberous sclerosis
USEFUL ONE LINERS
• Individuals who develop endocarditis or septicemia from Streptococcus bovis have a high
risk of occult colorectal tumors and possibly upper gastrointestinal cancers as well.
• Most common presenting symptom of gastrinoma is abdominal pain.
• Characteristic dermatitis associated with glucagonoma is migratory necrolytic erythema.
• Metastasis to the brain most commonly develop at gray matter-white matter junction.
CLASSIFICATION OF EPITHELIAL NEOPLASMS ARISING FROM THE

TABLE
KIDNEY
Carcinoma Type Growth Pattern Cell of Origin Cytogenetics

Clear cell Acinar or sarcomatoid Proximal tubule 3p- 5q+, l4q—
Papillary Papillary or sarcomatoid Proximal tubule +7, +17, -Y
Chromophobe Solid, tubular, or sarco¬ Distal tubules/corti- Whole arm losses
matoid cal collecting duct (1, 2, 6, 10, 13, 17,
and 21)
Oncocytic Tumor nests Cortical collecting Undetermined
duct
Collecting duct Papillary or sarcomatoid Medullary collect¬ Undetermined
ing duct

£3 HARRISON’S 19TH BASED NOTE BOOK
USEFUL ONE LINERS
• Most common histologic type of renal cell carcinoma is clear cell carcinoma.
• Apart from breast cancer, women with BRCA1 mutations have an increased risk of de¬
veloping ovarian cancers, and women with BRCA2 mutations have an increased risk of
pancreatic cancer.
TABLE PARANEOPLASTIC HEMATOLOGIC SYNDROMES
Cancers Typically Associated
Syndrome Proteins
with Syndrome
Renal cancers, hepatocarci- noma,
Erythrocytosis Erythropoietin
cerebellar hemangioblastomas
Lung cancer, gastrointestinal can¬
Granulocytosis G-CSF, GM-CSF, IL-6 cer, ovarian cancer, genitourinary
cancer, Hodgkin’s disease
Lung cancer, gastrointestinal can¬
Thrombocytosis IL-6 cer, breast cancer, ovarian cancer,
lymphoma
Eosinophilia IL-5 Lymphoma, leukemia, lung cancer
Lung cancer, pancreatic cancer,
gastrointestinal cancer, breast can¬
Thrombophlebitis Unknown
cer, genitourinary cancer, ovarian
cancer, prostate cancer, lymphoma
Abbreviations: G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte macro phage colo¬
ny-stimulating factor, IL, interleukin
ANTIBODIES TO INTRACELLULAR ANTIGENS, SYNDROMES, AND

TABLE
ASSOCIATED CANCERS
Antibody Associated Neurologic Syndrome(s) Tumors
Encephalomyelitis, subacute sensory
Anti-Hu (ANNA1) SCLC
neuronopathy
Anti-Yo (PCA1) Cerebellar degeneration Ovary, breast
Anti-Ri (ANNA2) Cerebellar degeneration, opsoclonus, Breast, gynecologic,
brainstem encephalitis SCLC

HARRISON’S 19TH BASED NOTE BOOK sn
Anti-Tr Cerebellar degeneration Hodgkin’s lymphoma
Encephalomyelitis, chorea, optic neuritis, SCLC, thymoma,
Anti-CRMP5 (CV2) other
uveitis, peripheral neuropathy
Limbic, hypothalamic, brainstem en¬ Testicular (Ma2),
Anti-Ma proteins
cephalitis other (Ma)
Anti-amphiphysin Stiff-person syndrome, encephalomyelitis Breast, SCLC
Cancer-associated retinopathy (CAR)
Recoverin, bipolar cell SCLC (CAR), mela¬
Melanoma-associated retinopathy
antibodies, others'* noma (MAR)
(MAR)
Stiff-person, cerebellar syndromes, lim¬ Infrequent tumor as¬
Anti-GAD
bic encephalitis sociation (thymoma)
"A variety of target antigens have been identified
Abbreviations: CRMP, collapsing response-mediator protein; SCLC, small-cell lung cancer.

i
CHAPTER 5
*
HEMATOPOIETIC DISORDERS
im OQ 1
M
% .
to 1
V
TABLE DIAGNOSIS OF MICROCYTIC ANEMIA
Tests Iron Defi- Inflammation Thalassemia Sideroblastic

ciency Anemia
Smear Micro/hypo Normal micro/ Micro/hypo Variable
hypo with tergeting
Serum iron (pg/dL) <30 <50 Normal to Normal to high
high
TIBC (pg/dL) >360 <300 Normal Normal
Percent saturation <10 10-20 30-80 30-80
Ferritin (pg/L) <15 30-200 30-300 50-300

Hemoglobin pattern Normal Normal Abnormal Normal
on electrophoresis with 2 thalas¬
semia; can be
normal with a
thalassemia
Abbreviation: TIBC, total iron-binding capacity
• SICKLE CELL SYNDROMES (Pg:634-35)

• THALASSEMIA SYNDROMES (Pg:637-38)
• MEGALOBLASTIC ANEMIAS (Pg:640-49)
• HEREDITARY SPHEROCYTOSIS (Pg:651-52)
• PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (Pg:660-62)
• APLASTIC ANEMIA (Pg:663-67)
• POLYCYTHEMIA VERA (Pg:672-74)
• ACUTE MYELOID LEUKEMIA (Pg:678-87)
• CHRONIC MYELOID LEUKEMIA (Pg:687-95)
USEFUL ONE LINERS
• Gene for intrinsic factor is located on chromsome llq.

• Prophylactic folic acid in pregnancy has been found in some but not all studies to reduce
the subsequent incidence of acute lymphoblastic leukemia (ALL) in childhood.
• Congenital cobalamin malabsorption is also known by the terms Imerslund s sydrome/
Imerslund-Grasbeck syndrome/Autosomal recessive megaloblastic anemia.
• Fish tapeworm (Diphyllobothrium latum) infestation predisposes to Vitamin B12 defi¬
ciency.
TABLE CLASSIFICATION OF HEMOLYTIC ANEMIAS3 :

Intracorpuscular Defects Extracorpuscular Factors
Hereditary Hemoglobinopathies Enzymop- Familial (atypical) hemolyticuremic syndrome
athies
Membrane-cytoskeletal defects
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££ HARRISON’S 19TH BASED NOTE BOOK
Acquired Paroxysmal nocturnal hemoglo- Mechanical destruction (microangiopath-

binuria (PNH) ic)
Toxic agents
Drugs
Infectious
Autoimmune
"Hereditary causes correlate with intracorpuscular defects, because these defects are due to in-
herited mutations; the one exception is PNH, because the defect is due to an acquired somatic
mutation. Similarly, acquired causes correlate with extracorpuscular factors, because mostly these
factors are exogenous; the one exception is familial hemolyticuremic syndrome (HUS; often re¬
ferred to as atypical HUS), because here an inherited abnormality allows complement activation
to be excessive, with bouts of production of membrane attack complex capable of destroying
normal red cells.
FEATURES COMMON TO MOST PATIENTS WITH A HEMOLYTIC

TABLE
DISORDER
General examination Jaundice, pallor
Other physical findings Spleen may be enlarged; bossing of skull in severe congenital cases
Hemoglobin level From normal to severely reduced
MCV, MCH Usually increased
Reticulocytes Increased
Bilirubin Increased (mostly unconjugated)
LDH Increased (up to 10 time normal with intravascular hemolysis)
Haptoglobin Reduced to absent (if hemolysis in part intravascular)
TABLE CLASSIFICATION OF ACQUIRED IMMUNE HEMOLYTIC ANEMIAS

Type of Antibody
Clinical Setting Cold, Mostly IgM, Optimal Warm, Mostly IgG, Opti¬
Temperature 4-30°C mal Temperature 37°C; or
mixed
Primary CAD AIHA (idiopathic)
Secondary to viral EBV HIV
infection CMV Viral vaccines
Other
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Secondary to/asso¬ CAD in: AIHA in:
ciated with other Waldenstrom’s disease SLE
disease Lymphoma CLL
Other malignancy
Chronic inflammatory
disorders (e.g., IBD)
After allogeneic HSCT
Secondary to Small minority (e.g., with lenalid- Majority: currently most com-
drugs: omide) mon culprit drugs are cefo-
Drug-induced tetan, ceftriaxone, piperacillin
immune
Hemolytic anemia
Drug-dependent: antibody destroys red cells only when drug pres¬
ent (e.g., rarely penicillin)
Drug-independent : antibody can destroy red cells even when drug
no longer present (e.g., methyldopa)
Abbreviations: AIHA-autoimmune hemolytic anemia; CAD-Cold agglutinin disease;

CLL-Chronic lymphocytic leukemia; CMV-cytomegalovirus; EBV-Epstein-Barr virus;
HIV-human immunodeficiency virus; HSCT- Hematopoietic stem cell transplantation;
IBD-Inflammatory bowel disease; SLE-Systemic lupus erythematosus.
TABLE DIFFERENTIAL DIAGNOSIS OF PANCYTOPENIA
Pancytopenia with Hypocellular Bone Marrow
Acquired aplastic anemia
Constitutional aplastic anemia (Fanconi anemia, dyskeratosis congenita)
Some myelodysplasia
Rare aleukemic leukemia
Some acute lymphoid leukemia
Some lymphomas of bone marrow
Pancytopenia with Cellular Bone Marrow
Primary bone marrow diseases Secondary to systemic diseases
Myelodysplasia Systemic lupus erythematosus
Paroxysmal nocturnal Hypersplenism
hemoglobinuria Bj2, folate deficiency
Myelofibrosis Overwhelming infection
Some aleukemic leukemia Alcohol
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Myclophthisis Brucellosis
Bone marrow lymphoma Sarcoidosis
Hairy cell leukemia Tuberculosis
Leishmaniasis
Hypocellular Bone Marrow ± Cytopenia
Q fever
Legionnaires’ disease
Anorexia nervosa, starvation
Mycobacterium
Fanconi Anemia
• Autosomal recessive disorder

• Manifests as congenital developmental anomalies, progressive pancytopenia,and an in¬
creased risk of malignancy.
• Chromosomes in Fanconi anemia are peculiarly susceptible to DNA cross-linking agents,
the basis for a diagnostic assay.
• Patients typically have short stature, cafe au lait spots and anomalies involving the thumb,
radius, and genitourinary tract.
Keep in min Dyskeratosis congenita is characterized by the triad of mucous membrane

leukoplasia, dystrophic nails,reticular hyperpigmentation, and with the development of
aplastic anemia in childhood._ _
TABLE CLASSIFICATION OF PURE RED CELL APLASIA
Self-limited
Transient erythroblastopenia of childhood
Transient aplastic crisis of hemolysis (acute B19 parvovirus infection)
Fetal red blood cell aplasia
Nonimmune hydrops fetalis (in utero B19 parvovirus infection)
Hereditary pure red cell aplasia
Congenital pure red cell aplasia (Diamond-Blackfan anemia)
Acquired pure red cell aplasia
Cancer
Thymoma
Lymphoid malignancies (and more rarely other hematologic diseases)
Paraneoplastic to solid tumors

Connective tissue disorders with immunologic abnormalities
Systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid arthritis
Multiple endocrine gland insufficiency
Viruses
Persistent B19 parvovirus, hepatitis, adult T cell leukemia virus, Epstein-Barr virus
Pregnancy
Drugs
Especially phenytoin, azathioprine, chloramphenicol, procainamide, isoniazid
Antibodies to erythropoietin
Idiopathic _ " __
TABLE DISORDERS CAUSING MYELOFIBROSIS
Malignant Nonmalignant
Acute leukemia (lymphocytic, myelogenous, megakaryocytic) HIV infection
Chronic myeloid leukemia Hyperparathyroidism
Hairy cell leukemia Renal osteodystrophy
Hodgkin’s disease Systemic lupus erythema¬
Primary myelofibrosis tosus
Lymphoma Tuberculosis
Multiple myeloma Vitamin D deficiency
Myelodysplasia Thorium dioxide exposure
Metastatic carcinoma Gray platelet syndrome
Polycythemia vera Gray platelet syndrome
Systemic mastocytosis
Systemic mastocytosis
TABLE CAUSES OF THROMBOCYTOSIS
Tissue inflammation: collagen vascular disease, Hemorrhage
inflammatory bowel disease
Malignancy Iron-deficiency anemia
Infection Surgery
Myeloproliferative disorders: polycythemia vera, Rebound: Correction of vitamin
primary myelofibrosis, essential thrombocytosis, B12 or folate deficiency, post- etha¬
chronic myelogenous leukemia nol abuse
Myelodysplastic disorders: 5q-syndrome, idiopathic Hemolysis
refractory sideroblastic anemia
Postsplenectomy or hyposplenism
_ Familial: Thrombopoietin
production, _ MPL mutations
over-

INFECTIOUS AGENTS ASSOCIATED WITH THE DEVELOPMENT OF

TABLE LYMPHOID MALIGNANCIES
Infectious Agent Lymphoid Malignancy
Epstein-Barr virus Burkitt’s lymphoma
Post-organ transplant lymphoma
Primary CNS diffuse large B-cell lymphoma
Hodgkin’s lymphoma
Extranodal NK/T-cell lymphoma, nasal type
HTLV-1 Adult T-cell leukemia/lymphoma
HIV Diffuse large B-cell lymphoma
Burkitt’s lymphoma
Hepatitis C virus Lymphoplasmacytic lymphoma
Helicobacter pylori Gastric MALT lymphoma
Human herpesvirus 8 Primary effusion lymphoma
Multicentric Castleman’s disease
Abbreviations: CNS, central nervous system; HIV, human immunodeficiency virus; HTLV, hu¬
man T-cell lymphotropic virus; MALT, mucosa-associated lymphoid tissue; NK, natural killer.
DISEASES OR EXPOSURES ASSOCIATED WITH INCREASED RISK OF

TABLE
DEVELOPMENT OF MALIGNANT LYMPHOMA
Inherited immunodeficiency disease Autoimmune disease
Klinefelter’s syndrome Sjogren’s syndrome
Chediak-Higashi syndrome Celiac sprue
Ataxia-telangiectasia syndrome Rheumatoid arthritis and systemic
Wiskott-Aldrich syndrome lupus erythematosus
Common variable immunodeficiency disease Chemical or drug exposures
Acquired immunodeficiency diseases Phenytoin
Iatrogenic immunosuppression Dioxin, phenoxy herbicides
HIV-1 infection Radiation
Acquired hypogammaglobulinemia Prior chemotherapy and radiation therapy
TABLE THE ANN ARBOR STAGING SYSTEM FOR HODGKIN’S LYMPHOMA

Stage Definition
Involvement of a single lymph node region or lymphoid structure (eg., spleen,
I
thymus, Waldeyer’s ring)

Involvement of two or more lymph node regions on the same side of the dia¬
II phragm (the mediastinum is a single site; hilar lymph nodes should be consid¬
ered “lateralized” and, when involved on both sides, constitute stageI disease)
Involvement of lymph node regions or lymphoid structures on both sides of the
III
diaphragm
Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac
HI,
nodes, or portal nodes
Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes
III.
plus structures in IIIj
Involvement of extranodal site(s) beyond that designated as “F” More than one
IV
extranodal deposit at any location Any involvement of liver or bone marrow
A No symptoms
Unexplained weight loss of >10% of the body weight during the 6 months be¬
fore staging investigation
B Unexplained, persistent, or recurrent fever with temperatures >38°C during the
previous month
Recurrent drenching night sweats during the previous month
Localized, solitary involvement of extra lymphatic tissue, excluding liver and
E
bone marrow
USEFUL ONE LINERS
• Most common type of Non-Hodgkin’s lymphoma is Diffuse large B cell lymphoma.

• Most common presentation of mantle cell lymphoma is palpable lymphadenopathy.
• Most common presentation for follicular lymphoma is with new, painless lymphadenopathy.
• Most common site of MALT lymphoma is stomach.
• Most common lymphoid leukemia is B cell CLL/small lymphocytic lymphoma.
• Patients with hairy cell leukemia are prone to unusual infections, including infection by
Mycobacterium avium intracellulare.
• In Adult T-cell lymphoma/leukemia, peripheral smear reveals characteristic, pleomorphic
abnormal CD4-positive cells with indented nuclei, which have been called “flower” cells.
• Most common initial manifestation of Hodgkin’s lymphoma is mediastinal lymphadenopathy.
• BURKETTS LYMPHOMA (Pg:706)

• HODGKIN’S LYMPHOMA (Pg:708-09)
USEFUL ONE LINERS
• Most important cytokine involved in myeloma cell proliferation is IL-6.

• Most commonvsymptom of myeloma is bone pain.
• Most common infections in myeloma patients are pneumonias and pyelonephritis.
• Most common cause of renal failure in myeloma patients is hypercalcemia.
• Earliest manifestation of renal tubular damage in multiple myeloma is Fanconi s syn¬
drome.
• Normocytic normochromic anemia occurs in 80% of myeloma patients.
• Most common serum M component in multiple myeloma is Ig G.
• Serum 22 microglobulin is the single most powerful predictor of survival in multiple my¬
eloma and can substitute for staging.
• International Staging System (ISS) for myeloma is based onserum 22-microglobulin and
albumin levels.
DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA, MYELOMA VARIANTS, AND

TABLE
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
Monoclonal Gammopathy of Undetermined Significance (MGUS)

M protein in serum <30g/L
Bone marrow clonal plasma cells <10%
No evidence of other B cell proliferative disorders
No myeloma- related organ or tissue impairment (no end organ damage, including bone
lesions)'2
Smoldering Multiple myeloma(Asymptomatic Myeloma)
M protein in serum >30g/L and/ or
Bone marrow clonal plasma cells >10%
No myeloma- related organ or tissue impairment (no end organ damage, including bone
lesions)" or symptoms
Symptomatic Multiple Myeloma
M protein in serum and / or urine
Bone marrow (clonal) plasma cells* or plasmacytoma
Myeloma -related organ organ or tissue impairment (end organ damage, including
Bone lesions)

- Non secretory Myeloma
No M protein in serum and/or urine with immunofixation
Bone marrow clonal plasmacytosis >10% or plasmacytoma
Myeloma-related organ or tissue impairment (end organ damage, including bone lesions)"
Solitary Plasmacytomsa of Bone
No M protein in serum and/or urineÿ
Single area of bone destruction due to clonal plasma cells
Bone marrow not consistent with multiple myeloma
Normal skeletal survey (and magnetic resonance imaging of spine and pelvis if done)
No related organ or tissue impairment (no end organ damage other than solitary bone
lesion)"
POEMS Syndrome
All of the following four criteria must be met
1. Polyneuropathy
2. monoclonal plasma cell proliferative disorder
3. Any one of the following: (a) organomegaly (splenomegaly, hepatomegaly, or lymph-
adenopathy); (b) extravascular volume overload (edema, pleural effusion, or ascites); (c)
endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic); (d) skin
changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocy¬
anosis, flushing, and white nails); (e) papilledema; (f) thrombocytosis/polycythemiaÿ
"Myeloma-relaed organ or tissue impairment (end organ damage); calcium levels increased serum cal¬
cium >0.25 mmol/L above the upper limit of hormal or >2.75 mmol/L; renal insufficiency: creatinine
> 173 mmol/L ; anemia: hemoglobin 2 g/dL below the lower limit of normal or hemoglobin >10g/dL;
bone lesions: lytic lesions or osteoporosi with compression fractures (magnetic resonance imaging or
computed tomography may clarigy); other: symptomatic hyperviscosity, amyloidosis, recurrent bacte¬
rial infections (>2 episodes in 12 months). *If flow cytometry is performed, most plasma cells (>90%)
will show a “neoplastic” phenotype. CA small M component may sometimes be present. “These features
should have no attributable other causes and have temporal relation with each other.
HIGH YIELDING TOPIC
• PLASMA CELL DISORDERS (Pg:710-19)

USEFUL ONE LINERS
• The term amyloid was coined by Rudolf Virchow.

• Most common type of amyloidosis is AL (primary amyloidosis)
• The regular 2-sheet structure of amyloid deposits exhibits a unique “apple green” birefrin-
gence by polarized light microscopy when stained with Congo red dye.
• Most common fornfof localised amyloidosis is A 2 .
• Although all kappa and lambda light chain subtypes have been identified in AL amyloid
fibrils, lambda/subtypes
predominate.
• Most frequently affected organon
amyloidosis is kidney.
• Second most common affected' organ in amyloidosis is heart.
• Most common cause of deathÿ in primary amyloidosis is due to cardiac involvement.
• Most common cause of death in secondary amyloidosis is due to renal involvement.
• Macroglossia, though a pathognomonic sign of AL amyloidosises seen in only 10% of patients.
kmr.
*
r
A 0
Figure Clinical signs of AL amyloidosis A. Macroglossia, B. Periobital ecchymoses, C.
Fingernail dystrophy.
TABLE CHARACTERISTICS OF SELECTED BLOOD COMPONENTS

Component Volume, Content Clinical Response
mL
PRBC 180-200 RBCs with variable leukocyte Increase hemoglobin 10 g/L
content and small amount of and hematocrit 3%
plasma
Platelets 50-70 5.5 x 10*0/RD unit Increase platelet count 5000-
10,000/pL
200-400 >3 x 10n/SDAP product CCI> 10 x 109/L within 1 h
and >7.5 x 109/L within 24 h
posttransfusion
\> F7P 200—250 Plasma proteins—coagulation Increases coagulation factors
factors, proteins C and S, about 2%
anti- thrombin
- Cfyoprecip-
itate
10-15 Cold-insoluble plasma pro¬ Topical fibrin glue, also 80 IU
t teins, fibrinogen, factor VIII, factor VIII
VWF

V
Abbreviations: CCI, corrected count increment; FFP, fresh-frozen plasma; PRBC, packed
red blood cells; RBC, red blood cell; RD, random donor; SDAP Je-donor apheresis plate¬
‘
lets; VWF, von Willebrand factor

Direct Coombs test/direct antiglobulln test
-------
Antigens on Human Antihumans antibodies Positive test result
the red blood anti-RBC (Coombs reagent)
cell surface antibodies „ .
8— #Blood sample from a

patient with immune
mediated haemolytic
The patient washed
RBCs are incubated with
antihuman antibodies
RBCs agglutinate antihuman
antibodies form links between
RBCs by binding to the human
anaemia: antibodies (Coombs reagent) antibodies on the RBCs.
are shown attached
to antigens on the
RBC surface
Indirect Coombs test/indirect antiglobulin test
Positive test
S
result
/•
V>A
Recipient’s
serum is
obtained ,
containing
Donor’s blood
to the tube with

serum.
it -w
Recipient s Ig’s that
sample is added tar9et the donor’s
reÿ blood cells form
antibody-antigen
Anti-human Ig’s
(Coombs
antibodies)
are added to the
Agglutination of red
blood cells occurs,
because human Ig’s are
attached to red blood cells,
\
antibodies complexes. solution

(ig’s).
Figure Direct and indirect Coombs test. The direct Coombs (antiglobulin) test detects the pres¬
ence of antibodies (or complement) on the surface of erythrocytes. The indirect Coombs (antiglob-
ulin) test detects antibodies in the serum that may bind to donor erythrocytes RBC, red blood cell.

USEFUL ONE LINERS

• Rh gene is located on chromosome 1.
• Genes determining A and B phenotypes are located on chromosome 9p.
• The Duffy blood group antigens also serve as receptors for plasmodium vivax.
• Most common cause of transfusion related fatalities is Transfusion Related Acute Lung
Injury(TRALI).
Keep in mind Acute Graft Versus Host Disease (GVHD) usually occurs within the first 3
months after transplant. Chronic GVHD occurs most commonly between 3 months and 2
years after allogeneic transplant.
TABLE PHARMACOKINETIC AND BIOPHYSICAL LIMITATIONS OF HEPARIN

Limitations Mechanism
Binds to endothelial cells and macro¬
Poor bioavailability at low doses
phages
Dose-dependent clearance Binds to macrophages
Binds to plasma proteins whose levels
Variable anticoagulant response
vary from patient to patient
Reduced activity in the vicinity of platelet-rich Neutralized by platelet factor 4 re¬
thrombi leased from activated platelets
Reduced capacity of heparin- anti¬
Limited activity against factor Xa incorporated in
thrombin complex to inhibit factor
the prothrombinase complex and thrombin bound
Xa bound to activated platelets and
to fibrin
thrombin bound to fibrin
\
TABLE FEATURES OF HEPARIN-INDUCED THROMBOCYTOPENIA
v Features Details
-N,V
Platelet count of < 100,000/pL or a decrease
Thrombocytopenia
in platelet count of > 30%
Platelet count falls 5-10 days after starting
\ Timing V
V heparin
Type of heparin More common with unfractionated heparin
than low-molecular-weight heparin
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HARRTSON’S 19TH BASED NOTE BOOK
More common ' . . Agical patients and

Type of patient patients yith cancer than general medical pa¬
tients, more common in women than in men
Venous thrombosis more common than arte¬
Thrombosis rial thrombosis
TABLE MANAGEMENT OF HEPARIN-INDUCED THROMBOCYTOPENIA
Stop all heparin.

Give an alternative anticoagulant, such as lepirudin, argatroban, bivalirudin, or
fondaparinux.
Do not give platelet transfusions.
Do not give warfarin until the platelet count returns to its baseline level. If warfarin was
administered, give vitamin K to restore the INR to normal.
Evaluate for thrombosis, particularly deep vein thrombosis.
Abbreviation: INR, international normalized ratio
TABLE ADVANTAGES OF LMWH OVER HEPARIN

Advantage Consequence
Can be given subcutane-
Better bioavailability and longer half- life after subcutaneous ously once a twice daily
injection for both prophylaxis and
treatment
Dose-independent clearance Simplified dosing
Coagulation monitoring
Predictable anticoagulant response is unnecessary in most
patients
Safer than heparin foTshort-
Lower risk of heparin-induced thrombocytopenia or long- term administra¬
tion ';VV
Lower risk of osteoporosis Safer than heparin for ex¬

tended administration
Abbreviation: LMWH, low molecular weight heparin
• Drug-induced thrombocytopenia due to heparin differs from that seen with other drugs
in two major ways.

counts rarely
(1) The thrombocytopenia is not usually severe, with nadir
<20000/pL.
(2) Heparin-induced thrombocytopenia (HIT) is not associated with bleeding
and, in fact,1markedly increases the risk of thrombosis.
• Heparin Induced Thrombocytopenia results from antibody formation to a complex of the
platelet-specific protein platelet factor 4 (PF4) and heparin.
HIT only if heparin Delayed-onset
in last -100 days
Risk of HIT HIT occurs rarely
0 5 14
Days of heparin (UFH or LMWH) exposure
Figure Time course of heparin-induced thrombocytopenia (HIT) development after heparin
exposure. The timing of development after heparin exposure is a critical factor in determining the
likelihood of HIT in a patient. HIT occurs early after heparin exposure in the presence of preexisting
heparin/platelet factor 4 (PF4) antibodies, which disappear from circulation by -100 days following
a prior exposure. Rarely, HIT may occur later after heparin exposure (termed delayed-onset HIT). In
this setting, heparin/PF4 antibody testing is usually markedly positive. HIT can occur after exposure
to either unfractionated (UFH) or low-molecular-weight heparin (LMWH).
TABLE COMPARISION OF LMWH AND FONDAPARINUX

Features LMWH Fondaparinux
Number of saccharide units 15-17 5
Catalysis of factor Xa inhibition Yes Yes
Catalysis of thrombin inhibition Yes No
Bioavailability after subcutaneous administration (%) 90 100
Plasma half-life (h) 4 17
Renal excretion Yes Yes
Induces release of tissue factor pathway inhibitor Yes No
Neutralized by protamine sulfate Partially No
TABLE
COMPARISON OF THE PHARMACOLOGIC PROPERTIES OF THE NEW
ORAL ANTICOAGULANTS
.
Characteristic Rivaroxaban Apixaban Edoxaban Dabigatran
Target Factor Xa Factor Xa Factor Xa Thrombin
Prodrug No No No Yes
Bioavailability 80% 60% 50% 6%
V
\ Email: info@damsdelhi.com | Website: www.damsdelhi.com
Page | 53
Dosing qd (bid) bid qd bid (qd)

Half-life 7-11 h 12 h 9—11 h 12-I7b
Renal 33% (66%) 25% 35% J0%
Monitoring No No No No
Interactions 3A4/P-gp 3A4/P-gp P-gp p~gP
Abbi'eviations:bid, twice a day, P-gp, P-glycoprotein, qd., once a day

Non-functional Functional
Prozymogens Zymogens
Y-glutamyl
carboxylase
o2 'Oz
Reduced Vitamin K Oxidized
vitamin K cycle vitamin K
Vitamin K
reductase
CYP1A1
CYP1A2 -«-] R-Warfarin l S-Warfarin |~» CYP2C9
CYP3A4
Warfarin
metabolism
[ Warfarin |
Figure Mechanism of action of warfarin. A racemic mixture of S- and R-enantiomers, S-warfarin

is most active. By blocking vitamin K epoxide reductase, warfarin inhibits the conversion of oxidized
vitamin K into its reduced form. This inhibits vitamin K-dependent y- carboxylation of factors II, VII, IX,
and X because reduced vitamin K serves as a cofactor of a y-glutamyl carboxylase that catalyzes the
y-carboxylation process, thereby converting prozymogens to zymogens capable of binding calcium
and interacting with anionic phospholipid surfaces. S-warfarin is metabolized by CYP2C9. Common
genetic polymorphisms in the Cl subunit of vitamin K reductase (VKORC1) also can affect the suscep¬
tibility of the enzyme to warfarin induced inhibition, thereby influencing warfarin dosage requirements."

m HARRISON’S 19TH BASED NOTE BOOK

• IMMUNE THROMBOCYTOPENIC PURPURA (Pg:728)
• VON WILLEBRAWDDISEASE (Pg:730-31)
• HEMOPHILIA (Pg:732-34)
COMMON CLINICAL CAUSES OF DISSEMINATED INTRAVASCULAR
TABLE
COAGULATION
Sepsis Immunologic Disorders
• Bacterial • Acute hemolytic transfusion reac¬
Staphylococci, streptococci, pneumococci, tion
meningococci, gram negative bacilli • Organ or tissue transplant rejec¬
• Viral tion
• Mycotic • Immunotherapy
• Parasitic • Graft versus host disease
• Rickettsial
Trauma and Tissue Injury Drugs
• Brain injury (gunshot) • Fibrinolytic agents
• Extensive burns • Aprotinin
• Fat embolism • Warfarin (especially in neonates
• Rhabdomyolysis with protein C deficiency)
• Prothrombin complex concen¬
trates
• Recreational drugs (amphet¬

amines)
Vascular Disorders Envenomation
• Giant hemangiomas (Kasabach Merritt syn- • Snake
drome)
• Insects
• Large vessel aneurysms (eg, aorta)
Obstetrical Complications Liver Disease
• Abruptio placentae • Fulminant hepatic failure
• Amniotic fluid embolism • Cirrhosis
j •_ Dead fetus syndrome • Tatty liver of pregnancy
• Septic abortion

HARRISON'S 19TH BASED NOTE BOOK
iS
Cancer Miscellaneous
• Adenocarcinoma (prostate, pancreas, etc) • Shock
• Hematologic malignancies (acute promyelocytic • Respiratory distress syndrome
leukemia) • Massive transfusion
TABLE FEATURES OF GPIIB/IIA ANTAGONISTS

Feature Abciximab Eptifibatide Tirofiban
Fab fragment of humanized Cyclical KGD con- Nonpeptidic
Description taining heptapeptide RGD mimetic
mouse monoclonal antibody
Specific for Gp Yes Yes
llb/llla
Plasma half life Short (min) Long (2.5 h) Long (2.0 h)
Platelet bound Short (s)
Long (days) Short (s)
half life
Renal clearance No Yes Yes
USEFUL ONE LINER
• Most common inherited bleeding disorder is Von Willebrand Disease.
Plasminogen activators
PAI-1
| Plasminogen [ÿ \ Plasmin|
a2-antiplasmin
l Fibrin } Fibrin degradation

products
Figure The fibrinolytic system and its regulation. Plasminogen activators convert plasmino¬
gen to plasmin. Plasmin then degrades fibrin into soluble fibrin degradation products. The system
is regulated at two levels. Type 1 plasminogen activator inhibitor (PAM) regulates the plasminogen
activators, whereas a2-antiplasmin serves as the major inhibitor of plasmin.
A
s'
I
Page | 56 Email: infb@damsdelhi.com | Website: www.damsdelhi.com
B HARRISON’S 19TH BASED NOTE BOOK
s If %f
/;i: Plasminogen
L.
f
4
.
s
m
w
m M
ML-
sx\
-
A
Figure Mechanism of action of streptokinase. Streptokinase binds to plasminogen and induc¬

es a conformational change in plasminogen that exposes its active site. The stretokinase/ plas¬
minogen) complex then serves as the activator of additional plasminogen.

_
rQQ& J'TOH 03? A8 HTO WOjmM±_ 131
CHAPTER 3 INFECTIOUS DISEASES
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TABLE CAUSES OF RELATIVE BRADYCARDIA

Infectious Causes
Intracellular organisms
Gram-negative bacteria Salmonella typhi
Francisella tularensis
Brucella spp.
Coxiella burnetii (Q fever)
Leptospira interrogans
Legionella pneumophila
Mycoplasmapneumoniae
Page,|,58 Eraail:; irtfo@damsdelhi.com |;Websitexw)yw,damsdelhi.com -j

Tick-bome organisms Rickettsia spp. s. »

Orientia tsutsugamushL(scrub typhus)
§ <I5 ?. ‘ja
BabesiasppL g ||
I I
S'
Corynebacterium diphihenae i
<fef||1 k Pldsmodium spp. (maldrid)
Viriises/viral infections Yellow fever: virus 6 2 si
§’ 3
| 1
o ®
N;Viral helnorrhagic %y|rsf- f IS

?• 5 I cViral myocarditis o ’S-
~~ iHr
Noninfectious Causes
_
: }t;t Drug fever
Beta blocker use
I
o
3
S
£
l
It Hi cS 5 r
Is
§ Central nervous system- lesions
Mklignanfrlymphoma'J
Fictitious fever
U
g
o
o*
2.2
S’
"Primarily early in the course ofinfection with Marburg or EBola virus = g

I i a ~I~ - I
s c
TABLE
PAUSES OF AN EXTREMELY ELEVATEDHERYYHROC'fTE I 0|2 i
4S)lfo1ENTA-RON fÿATE
(>100 <" |g J
mm/h| | 55 8
a rfl
Etiologic Category (% of Cases) Specific Causes §

a Q
Infectious diseases (35-4Q) 3 Subacute bacterial endocarditisÿ a.i g
11 § 8 Accesses
Osteomyelitis -~ f
g|f 3
? gi
2.< g3
Tuberculosis 5
i 4:
2». m
. Urinarytr&et infection
5? E
Inflammatory diseases (15—20)o Gianf'cell arteritis og § 5 a a 23
|8
r Rheumatoid arthritis g S CO
o
Systemic lupus erythematosus
Malignancies (15—20) Multiple myeloma g 03
g- % -g 5
! § 5T o
3 Leukemiaf
I
dz
Lymphomas
Carcinomas
Q -J- g
_ ; i5
Other (20-35) I P 1 <S
_|
2 j' I'
I1 f Jo ?I
f P/ug hypersensitivity
tissue injury/ttaUriia V
(drug fever) §
£ 0 3 SRenal diseases o'- Q •€. y
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*3
g
CO
TABLE TYPICAL CSF PROFILES MENINGITIS AND ENCEPHALITS3 O
o
Parasitic Menin¬ Tuberculous Encephalitis Z
Normal Bacterial Viral Men¬ Fungal Menin¬ Meningitis CO
Meningitis ingitis gitis6 gitis
H
X
50-500 03
25-500 40-600 150-2000 25-100 >
WBC count <5 >1000 CSi
01
(per pL) a
Differential 60-70% lym- T PMNs (> Predomi¬ Lymphocytes or t Eosinophils (> Predominant- Predominantly z
phocytes, 80%) nantly PMNs, depend¬ 50%)' ly lympho- lymphocytes' O
of WBC
<30% mono- lymphocy- ing on specific cytes' W
cytes/mac- tesa' organism 03
o
w
3
rophages o
Positive (in Negative Rarely positive Negative Occasionally Negative 75
Gram’s stain Negative
% >60% of positive'
a
o’ cases)
I® <40 Normal normal Normal <50 in 75% Normal
fr Glucose 40-85 to
3 (mg/dL) of cases
G-
CL
P
o Protein (mg/ 15-45 >100 20-80 150-300 50-200 100-200 50-100
3 dL)
a
Opening 50-180 >300 100-350 160-340 Normal 150-280 Normal to T
pressure
S' (mmH20)
f!
Common Streptococcus Enterovi- Candida, Cryp¬ Angiostrongylus Mycobacteri- Herpesviruses,
causes pneumoniae, ruses tococcus, and cantonensis, Gna- um tubercu¬ enteroviruses,
ft.
w Neisseria men¬ Aspergillus spp.
3W thostoma spini- losis influenza virus,
ingitidis gerum, Baylisascaris rabies virus
2.
i
P procyonis
n
3
TABLE EXAMPLES OF MICROBIAL LIGAND RECEPTOR INTERACTIONS

Microorganism Type of Microbial Ligand Host Receptor
Viral Pathogens
Influenza virus Hemagglutinin Sialic acid
Measles virus
Vaccine strain Hemagglutinin CD46/moesin
Wild type strains Hemagglutinin Signaling lymphocytic activation mole¬
cule (SLAM)
Human herpesvi- ? CD46
rus type 6
Herpes simplex Glycoprotein C Heparan sulfate
virus
HIV Surface glycoprotein CD4 and chemokine receptors (CCR5
and CXCR4)
Epstein-Barr virus Envelope protein CD21 (CR2)
Adenovirus Fiber protein Coxsackie-adeno virus receptor (CAR)
Coxsackievirus Viral coat proteins CAR and major histo compatibility class
I antigens
Bacterial Pathogens
Neisseria spp Pili Membrane cofactor protein (CD46)
Pseudomonas aeru- Pili and flagella Asialo-GMI
ginosa
Lipopolysaccharide Cystic fibrosis trans membrane conduc
tance regulator (CFTR)
Escherichia coli Pili Ceramides/mannose and digalactosyl

residues
Streptococcus Hyaluronic add capsule CD44
pyogenes
Yersinia spp Invasin/accessory invasin 2jSS Integrins
locus
Bordetetta pertussis Filamentous hemag gluti- CR3
nin

Legionellaipm-i - Adsorbed C3B03f : aMASUCHOiOHOIM 10 H.qrW-J /;,/
mophila
loicfsssfl tsoH bnsgiJ IsidoioiM to eqyT mainBQTooioilW
Mycobacterium Adsorbed C3bi CR3; DC-SIGN4
2nagoriteci JsiiV
tuberculosis ?,miv £\Ti-;miiai
bbr; Dikii ninhuiggfiflisH
Fungal Pathogens
;y.r> i 7 x.off-./r;M
Blastomyces derma- WI-1 Possibly matrix proteins and integrins
ni?.aofn\dt‘G_.> aun nicm bnix-sV
titidis
Extr&iatoteaaS *r-! UiW
Protozoal Pathogens f . -ivssaqioii nsmuH

Plasmodium vivax Merozoite form Duffy Fy antigen c:> 3qyi am
Plasmodium falci- Erythrocyte-binding pro- Glycophorin.A, , ;
parum tein 17S (FBA-175) i!7 i l
Jwfefefe KTJ_ A’-A«;.ylgiuc,,S;umnc VIH

lytica
aA novel dendritic cell-specificÿ Ityp&lectin ni3ioiq oqobvnd ziniv nfiS-nimzqS
A ’"b
CONTRAINDICATIONS AND PRECAUTIONS FOR1COMMONLY USED

TABLE
|A/AC,G1NES:INADULTS RAD xnbjoiq isoo bn: ?* mivoid31;axoD
Vaccine For- Contraindicatibnÿ ahd Precautions

mulation ansjDortlsÿ InnetOBS
All nisCdÿraindi'catibriÿnaM mq <\<y. vAwivvA.

Severe alkrgicÿactjionle.g, anaphylaÿisÿafÿrjaÿpreÿ|ous vaccineÿdoÿe or.,
to a vaccine component
Precaution
onbnoD illness wi Defer vaccination
uhtillllnessfysolverÿ'
Td lv?-o30Kk«ib iPrecautions rn sisD m
GBS within 6 w£ekk 'after a previous dose of TT - containing vaccine
History of arthus retype hypershnsitivityreactionkiaftfer a previousdosenA
of TD or DT containing vaccines (including MCV4). Defer vaccination,ÿ
unt
v\<Y>. Wuurn'f
Tdap Contraindication
History of encephalopathy (e,g. coma or. prolonged,seizures) not attrib-
L1
utable
, •/-‘br. ,,-iTijH 3r,njrÿi>jiput3Tni;U-l ,
to another identifiable cause within 7 days or administration or a
vaccine with pertussis components, such as DTaP or Ydap
Page4-‘62 Email:* yfo@damsdelhi!C6Wd' mi wwWidahftilelh’i/coA

*
Precautions
GBS within 6 weeks after a previous dose of TT - containing vaccine
Progressive or unstable neurologic disorder, uncontrolled seizures, or pro¬
gressive encephalopathy. Defer vaccination until a treatment regimen has
been established and the condition has stabilized
History of arthus type hypersensitivity reactions after a previous dose of
-
TT or DT containing vaccines (including MCV4) Defer vaccination
until at least 10 years have elapsed since the last dose
HPV , Contraindication
History of immediate hypersensitivity to yeast (for Gardasil)
Precaution
Pregnancy. If a woman is found to be pregnant after initiation of the
.vaccination series, the remainder of the 3 dose regimen should be delayed
until after completion of the pregnancy. If a vaccine dose has been admin¬
istered during pregnancy, no intervention needed Exposure to Gardasil
during pregnancy should be reported to Merck (800 986 8999); exposure
to Cervarix during pregnancy should be reported to GlaxoSmithKline
(888 452 9622).
MMR Contraindications
History of immediate hypersensitivity reaction to gelatina or neomycin
Pregnancy , o ..
Known severe immunodeficiency (e.g. hematologic and solid tumors; che¬
motherapy; congenital immunodeficiency; long term immunosuppressive
therapy; severe immunocompromise due tofdlV infection)
Precautions
Recent receipt (within 11 months) of antibody-containing blood product
History of thrombocytopenia or thrombocytopenic purpura
Varicella Contraindications
Pregnancy
Known severe immunodeficiency
History of immediate hypersensitivity reaction to gelatin4 or neomycin
Precaution
Recent receipt (within 11 months) of antibody-containing blood product
Influenza, Precautions
inactivated, History of severe allergic reaction (e.g;-anaphylaxis) to egg protein* (note:
injectable not a precaution for Flublok recombinant influenza vaccine, which is
approved for persons 18-49 years of age and is manufactured without the
use of eggs) If.- < V, fj. ;•,! ;•) ,,v , .
History of GBS within 6 weeks after, a. previous influenza vaccine dose

Email: info@damsdelhi.eom | Website: www.damsdelhi.com Page | 63
Influenza, live Contraindications
attenuated History of severe allergic reaction (e.g., anaphylaxis) to egg protein*
nasal spray Age >50 years
Pregnancy
Immunosuppression, including that caused by medications or by HIV
infection; known severe immunodeficiency (e.g, hematologic and solid
tumors; chemotherapy; congenital immunodeficiency; long-term immu¬
nosuppressive therapy; severe immunocompromise due to HIV infection)
Certain chronic medical conditions, such as diabetes mellitus; chronic
pulmonary disease (including asthma); chronic cardiovascular disease
(except hypertension); renal, hepatic, neurologic/neuromuscular, hemato¬
logic or metabolic disorders
Close contact with severely immunosuppressed persons who require a
protected environment, such as isolation in a bone marrow transplanta¬
tion unit
Close contact with persons with lesser degrees of immunosuppression
(eg., persons receiving chemotherapy or radiation therapy who are not
being cared for in a protective environment, persons with HIV infection)
is not a contraindication or a precaution. Health care personnel in neo¬
natal intensive care units or oncology clinics may receive live attenuated
influenza vaccine
Precautions
History of GBS within 6 weeks of a previous influenza vaccine dose
Receipt of specific antiviral agents (i.e, amantadine, rimantadine; zana-
mivir, or osdtamivir) with 48 h before vaccination
Pneumococcal None, other than those listed for all vaccines
polysaccharide
Pneumococcal None, other than those listed for all vaccines
conjugate
Hepatitis A Precaution
Pregnancy
Hepatitis B Contraindication
History of immediate hypersensitivity to yeast
Meningococcal Contraindication
conjugate History of severe allergic reaction to dry natural rubber (latex) (certain
vaccine formulations; see text)
Page | 64 Email: info@damsdelhi.com | Website: wwvv.damsdelhi.com
Meningococcal Contraindication
polysaccharide History of severe allergic reaction to dry natural rubber (latex)
Zoster Contraindications
Age <50 years
Pregnancy
Known severe immunodeficiency
History of immediate hypersensitivity reaction to gelatin" a neomycin
Precaution
__
Receipt of specific antiviral agents (i.e., acyclovir, famciclovir, or valacy-
clovir) within 24 h before vaccination
"Extreme caution must be exercised in administering MMR, varicela, or zoster vaccine to persons with a history of
anaphylactic reaction to gelatin or gelatin containing products. Before administration, skin testing for sensitivity to
gelatin can be considered. However, no specific protocols for this purpose have been published. Recommendations
fa safely administering influenza vaccine to persons with egg allergies are reported in the annual ACIP recommenda¬
tions for influenza vaccination (www.cdc.gov/vaccines/hcp/acip-recs/vacc-speciftc/flu.html).
Abbl'einations: DT, diphtheria toxoid; DTaP, diphtheria, tetanus, and pertussis; GBS, Guillain-Barre syndrome; HPV,
human papillomavirus; MCV4, quadrivalent meningococcal conjugate vaccine; MMR, measles, mumps, and rubelajTd,
tetanus and diphtheria toxoids; Tdap, tetanus and diphtheria toxoids and acellular pertussis; TT, tetanus toxoid
TABLE
CLINICAL CONDITIONS ASSOCIATED WITH AND LIKELY PATHOGENS
IN HEALTH CARE-ASSOCIATED PNEUMONIA
Pathogen
Condition MRSA Pseudomonas Acineto- MDR Enterobacte-
aeruginosa bacter spp. riaceae
Hospitalization for > 48 h V V V V
Hospitalization for > V V
2days in prior 3 months
Nursing home or extend- V V V
ed-care-facility residence
Antibiotic therapy in V
preceding 3 months
Chronic dialysis V
Home infusion therapy V
Home wound care V
Family member with V V
MDR infection

HARRISON’S 19TH BASED NOTE BOOK 351
Abbreviations: MDR, multidrug-resistant; MRSA. methicillin-resistant Staphylococcus aureus
MICROBIAL CAUSES OF COMMUNITY-ACQUIRED PNEUMONIA, BY SITE

TABLE
OF CARE
Hospitalized Patients
Outpatients Non-ICU ICU
Streptococcus pneumoniae S. pneumoniae S. pneumoniae
Mycoplasma pneumoniae M. pneumoniae Staphylococcus aureus
Haemophilus influenzae Chlamydia pneumo- Legionella spp.
niae
C. pneumoniae H. influenzae Gram-negative bacilli
Respiratory virusef Legionella spp. Respi- H. influenzae
ratory virusef _
"Influenza A and B viruses, human metapneumovirus, adenoviruses, respiratory syncytial viruses,
parainfluenza viruses.
Note: Pathogens are listed in descending order of frequency. ICU, intensive care unit.
EPIDEMIOLOGIC FACTORS SUGGESTING POSSIBLE CAUSES OF

TABLE
COMMUNITY-ACQUIRED PNEUMONIA
Factor Possible Pathogen(s)
Alcoholism Streptococcuspneumoniae, oral anaerobes,
Klebsiella pneumoniae, Acinetobacter spp.,
Mycobacterium tuberculosis
COPD and/or smoking Haemophilus influenzae, Pseudomonas aerugi¬
nosa, Legionella spp., S. pneumoniae, Moraxel-
la catarrhalis, Chlamydia pneumoniae
Structural lung disease (e.g., bronchiectasis) P. aeruginosa, Burkholderia cepacia, Staphylo¬
coccus aureus
Dementia, stroke, decreased level of con¬ Oral anaerobes, gram-negative enteric bac¬
sciousness teria
Lung abscess CA-MRSA, oral anaerobes, endemic fungi,
M. tuberculosis, atypical mycobacteria
Travel to Ohio or St. Lawrence river valleys Histoplasma capsulatum

Travel to southwestern United States Hantavirus, Coccidioides spp.

Travel to Southeast Asia Burkholderia pseudomallei, avian influenza
virus
Stay in hotel or on cruise ship in previous Legionella spp.
2 weeks
Local influenza activity Influenza virus, S. pneumoniae, S. aureus
Exposure to bats or birds H. capsulatum
Exposure to birds Chlamydiapsittaci
Exposure to rabbits Francisella tularensis
Exposure to sheep, goats, parturient cats Coxiella burnetii
Abbreviations: CA-MRSA, community-acquired methicillin-resistant Staphylococcus au¬
reus; COPD, chronic obstructive pulmonary disease.
TABLE RISK FACTORS FOR EARLY DETERIORATION IN CAP

Multilobar infiltrates Hypoalbuminemia
Severe hypoxemia (arterial saturation <90%) Neutropenia
Severe acidosis (pH <7.30) Thrombocytopenia
Mental confusion Hyponatremia
Severe tachypnea (>30 breaths/min) Hypoglycemia
HIGH YIELDING TOPIC
• PNEUMONIA SEVERITY INDEX & CURB-65(Pg:806-07)

TABLE MICROBIOLOGIC CAUSES OF VENTILATOR-ASSOCIATED PNEUMONIA
Non-MDR Pathogens MDR Pathogens
Streptococcus pneumoniae Pseudomonas aeruginosa
Other Streptococcus spp. MRSA
Haemophilus influenzae Acinetobacter spp.
MSSA Antibiotic-resistant
Antibiotic-sensitive Enterobacteriaceae
Enterobacteriaceae Enterobacter spp.
Escherichia coli ESBL-positive strains
Klebsiella pneumoniae Klebsiella spp.

Page | 67
Proteus spp. Legionella pneumophila
Enter obacter spp. Burkholderia cepacia
Serratia marcescens Aspergillus spp
Abbreviations: ESBL, extended-spectrum 2-lactamase; MDR, multidrug-resistant; MRSA,
methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive S. aureus.
HIGH YIELDING TOPIC
• INFECTIVE ENDOCARDITIS (Pg:8l6-27)
USEFUL ONE LINERS

Organisms Causing Major Clinical Forms of Endocarditis
• Most common cause of native valve endocarditis - Staph aureus

• Most common cause of prosthetic valve endocarditis < 1 year after valve surgery — Coag-
ulase negative Staph
• Most common cause of prosthetic valve endocarditis > 1 year after valve surgery - Strep
viridans
• Most common cause of right sided endocarditis in i.v drug users - Staph aureus
• Most common cause of left sided endocarditis in i.v drug users - Enterococci > Staph
aureus
• Most common cause of endocarditis in i.v drug users overall - Staph aureus
THE MODIFIED DUKE CRITERIA FOR THE CLINICAL DIAGNOSIS OF

TABLE
INFECTIVE ENDOCARDITIS3
Major Criteria
1. Positive blood culture
Typical microorganism for infective endocarditis from two separate blood cul¬
tures
Viridans streptococci, streptococcus gallolyticus, HACEK group organisms,
staphyiococcusaureus, or
Community acquired enterococci in the absence of a primary focus,
Or
Persistently positive blood culture, defined as recovery of a microorganism con¬
sistent with infective endocarditis from
Page | 68 Email: info@damsdeIhi.com | Website: www.damsdelhi.com

Blood cultures drawn > 12 h apart, or

All of 3 or a majority of >4 separate blood cultures, with first and last drawn at
least 1h apart
Or
Single positive blood culture for Caxiellaburnetti or phasel IgG antibody titer of
>1800
2. Evidence of endocardial involvement
Positive echocardial involvement
Positive echocardiogram"
Oscillating intracardiac mass on valve or supporting structures or in the path
of regurgitant jets or in implanted material, in the absence of an alternative
anatomic explanation, or
Abscess, or
New partial dehiscence of prosthetic valve,
Or
New valvularregurgitation( increase or change in preexisting murmur not suffi¬
cient).
Minor Criteria
1. Predisposition: Predisposing heart conditions0 or injection drug use
2. Fever >38.0°C ( >100.4°F)
3. Vascular phenomena: major arterial emboli, septic pulmonary infacts, mycotic aneurysm,
intracranial hemorrhage, conjunctival hemorrhages, Janeway lesions
4. Immunologic phenomena: glomerulonephritis Osier’s nodes, Both’s spots, rheu¬
matoid factor
5. Microbiologic evidence : positive blood culture but not meeting major criterion, as noted
previously11, or serologic evidence of active infection with an organism consistent with
infective endocarditis
"Definite endocarditis is defined by documentation of two major criteria, of one major criterion and
three minor criteria, or of five minor criteria. 'Transophageal echocardiography is required for optimal
assessment of possible prosthetic valve endocarditis or complicated endocarditis. “Valvular disease with
stenosis or regurgitation, presence of a prosthetic valve, congenital heart disease including corrected or
partially, corrected conditions (except isolated artial septal defect, repaired ventricular septal defect, or
closed patent ductus arteriosus) prior endocarditis, or hypertrophic cardiomyopathy. “'Excluding single
positive cultures for coagulase-negative staphylococci and diphtheroids, which are common culture
contaminants, or for organisms that do not cause endopcarditis frequently, such as gram- negative
bacii.

jjjl
TABLE BACTERIAL FOOD POISONING
Incubation Period, Organism Symptoms Common Food Sources
1-6 h
Staphylococcus aureus Nausea, vomiting, diar- Ham, poultry, potato or egg
rhea salad, mayonnaise, cream
pastries
Bacillus cereus Nausea, vomiting, diar¬ Fried rice
rhea
8-16 h
Clostridium perfringens Abdominal cramps, diar- Beef, poultry, legumes,
rhea (vomiting rare) gravies
B. cereus Abdominal cramps, diar- Meats, vegetables, dried
rhea (vomiting rare) beans, cereals
>16 h
Vibrio cholerae Watery diarrhea Shellfish, water
Enterotoxigenic Escherichia coli Watery diarrhea Salads, cheese, meats, water
Enterohemorrhagic E. coli Bloody diarrhea Ground beef, roast beef,
salami, raw milk, raw vege¬
tables, apple juice
Salmonella spp. Inflammatory diarrhea Beef, poultry, eggs, dairy
products
Campylobacter jejuni Inflammatory diarrhea Poultry, raw milk
Shigella spp. Dysentery Potato or egg salad, lettuce,
raw vegetables
Vibrio parahaemolyticus Dysentery Mollusks, crustaceans
HIGH YIELDING TOPIC
• PSEUDOMEMBRANOUS COLITIS (Pg:857-61)

TABLE DIAGNOSTIC FEATURES AND MANAGEMENT OF VAGINAL INFECTION

Feature Normal Vaginal Vulvovaginal Trichomonal Bacterial Vagi¬
Examination Candidiasis Vaginitis nosis
Etiology Uninfected; lac- Candida albicans Trichomonas vag- Associated with
tobacilli predom¬ inalis Gardnerella
inant vaginalis, various
anaerobic and/
or noncultured
bacteria, and
mycoplasmas
Typical None Vulvar itching Profuse discharge; Malodorous,
symptoms and/or irritation vulvar itching slightly increased
discharge
Discharge Variable; usually Scant Often profuse Moderate
Amount scant White White or yellow White or gray
Color* Clear or translu- Clumped; ad¬ Homogeneous Homogeneous,
Consisten- cent herent plaques low viscosity;
cy Non homoge¬ uniformly coats
neous, flocculent vaginal walls
Inflam¬ None Erythema of Erythema of None
mation of vaginal epithe¬ vaginal and vulvar
vulvar or lium, introitus; epithelium; colpi¬
vaginal vulvar derma¬ tis macularis
epithelium titis, fissures
common
pH of vagi- Usually < 45 Usually < 45 Usually > 25 Usually >45
nal fluid*
Amine None None May be present Present
(“fishy”)
odor with
10% KOH

M
Microscopyÿ Normal epithe- Leukocytes, Leukocytes; mo- Clue cells; few
lial cells; lacto- epithelial cells; tile trichomonads leukocytes; no
bacilli predom- mycelia or seen in 80 - 90% lactobacilli or
inant pseudomycelia of symptomatic only a few out-
in up to 80% patients, less often -numbered by
of C. albicans in the absence of profuse mixed
culture-positive symptoms microbiota,
persons with nearly always
typical symp¬ including G.
toms vaginalis plus
anaerobic species
on Gram’s stain
(Nugent’s score
>7)
Other Isolation of Can- Isolation of T. vag¬
laboratory dida spp inalis or positive
findings NAAT*
Usual treat- None Azole cream, Metronidazole Metronidazole,
ment tablet, or sup¬ or tinidazole. 2 g 500 mg PO bid
pository— e.g. orally (single dose) for 7 days
miconazole Metronidazole, Metronidazole
(100-mg vaginal 500 mg PO bid gel, 0.75%, one
suppository) or for 7 days applicator (5 g)
clotrimazole intravaginally
(100-mg vaginal once daily for 5
tablet) once dai¬ days
ly for 7 days Clindamycin,
Fluconazole, 150 2% cream, one
mg orally (single full applicator
dose) vaginally each
night for 7 days
Usual man- None None; topical Examination for None
agement treatment if sexually trans-
of sexual candidal derma- mitted infection;
partner titis of penis is treatment with
detected metronidazole, 2 g
PO (single dose)

IS HARRISON’S 19TH BASED NOTE BOOK
°Color of discharge is best determined by examination against the white background of a swab.
bA pH determination is not useful if blood is present or If the test is performed on endocervical
secretions. To detect fungal elements, vaginal fluid is digested with 10% KOH prior to microscop¬
ic examination, to examine for other feature, fluid is mixed (1:1) with physiologic saline Gram’s
stain is also excellent for detecting yeasts(less predictive of vulvovaginitis) and pseudomycelia or
mycelia (strongly predictive of vulvovaginitis) and for distinguishing normal flora from the mixed
flora seen in bacterial vaginosis, but it is less sensitive than the saline preparation for detection of
T. vaginalis. nucleic acid amplification test (where available).
TABLE CLINICAL FEATURES OF GENITAL ULCERS

Feature Syphilis Herpes Chancroid Lymphogranu- Donovanosis
loma Venereum
Incu- 9-90 days 2-7 days 1-14 days 3 days- 6 weeks 1-4 weeks (up to 6
bation months)
period
Early Papule Vesicle Pustule Papule, pustule, Papule
primary or vesicle
lesions
No. of Usually one Multiple Usually mul- Usually one; often Variable
lesions tiple, may not detected,
coalesce despite lymphade-
nopathy
Diame- 5—15 mm 1—2 mm Variable 2-10 mm Variable
ter
Edges Sharply Erythem- Undermined, Elevated, round, Elevated, irregular

demarcated, atous ragged, irreg- or oval
elevated, ular
round, or
oval
Depth Superficial Superfi- Excavated Superficial or Elevated
or deep cial deep
Base Smooth, Serous, Purulent, Variable, nonvas- Red and velvety,
nonpu- erythem- bleeds easily cular bleeds readily
rulent, atous,
relatively nonvas-
nonvascular cular

HARRISON’S 19TH BASED NOTE BOOK HI
Indura- Firm None Soft Occasionally firm Firm
tion
Pain Uncommon Fre- Usually very Variable Uncommon
quently tender
tender
Lymph- Firm, Firm, lender, may Tender, may sup- None; pseudobu-
adenop- nontender, tender, suppurate, purate, loculated, boes
athy bilateral often loculated, usually uni lateral
bilateral usually uni
with lateral
initial
_ episode
USEFUL ONE LINERS
• Most common cause of meningitis in adults > 20 years of age is Streptococcus pneumonia.
• Gram-negative bacilli cause meningitis in individuals with chronic and debilitating dis¬
easessuch as diabetes,cirrhosis,or alcoholism and in those with chronic urinary tract in¬
fections.
• 80% of patients with proven HSV encephalitis have MRI abnormalities involving the
temporal lobes.
TABLE
ANTIBIOTICS USED IN EMPIRICAL THERAPY OF BACTERIAL
MENINGITIS AND FOCAL CENTRAL NERVOUS SYSTEM INFECTIONS3
Indication Antibiotic
Preterm infants to infants <1 month Ampicillin + cefotaxime
Infants 1-3 months Ampicillin + cefotaxime or ceftriaxone
Immunocompetent children >3 months and Cefotaxime, ceftriaxone, or cefepime +
adults <55 vancomycin
Adults >55 and adults of any age with alcohol- Ampicillin + cefotaxime, ceftriaxone or
ism or other debilitating illnesses cefepime + vancomycin
Hospital acquired meningitis, posttraumatic Ampicillin + ceftazidime or meropenem
or postneurosurgery meningitis, neutropenic + vancomycin
patients, or patients with impaired cell-mediat-
ed immunity _

CEREBROSPINAL FLUID (CSF) ABNORMALITIES IN BACTERIAL

TABLE
MENINGITIS
Opening pressure >180mmH2O
White blood cells 10/ÿiL to 10,000/pL; neutrophils predominate
Red blood cells Absent in nontraumatic tap
Glucose <2.2 mmol/L (<40 mg/dL)
CSF/serum glucose <0.4
Protein >0.45 g/L (>45 mg/dL)
Gram’s stain Positive in >60%
Culture Positive in >80%
Latex agglutination May be positive in patients with meningitis due to Strep¬
tococcus pneumoniae, Neisseria meningitidis, Haemophilus
influenzae type b, Escherichia coli, group B streptococci
Limulus lysate Positive in cases of gram-negative meningitis
PCR Detects bacterial DNA
Abbreviation: PCR, polymerase chain reaction
ANTIMICROBIAL THERAPY OF CENTRAL NERVOUS SYSTEM

TABLE
BACTERIAL INFECTIONS BASED ON PATHOGEN3
Organism Antibiotic
Neisseria meningitides Penicillin G or ampicillin
Penicillin sensitive Ceftriaxone or cefotaxime
Penicillin resistant
Streptococcus pneumoniae Penicillin G
Penicillin sensitive Ceftriaxone or cefotaxime or cefepime
Penicillin-intermediate Ceftriaxone (or cefotaxime or cefepime) +
Penicillin resistant vancomycin
Gram-negative bacilli (except Pseudomonas Ceftriaxone or cefotaxime
spp.)
Pseudomonas aeruginosa Ceftazidime or cefepime or meropenem
Staphylococci spp Nafcillin
Methicillin-sensitive Vancomycin
Methicillin-resistant
Listeria monocytogenes Ampicillin + gentamicin

Page | 75
Haemophilus influenzae Ceftriaxone or cefotaxime or cefepime
Streptococcus agalactiae Penicillin G or ampicillin
Bacteroidesfragilis Metronidazole
Fusohacterium spp. Metronidazole
• The rationale for giving dexamethasone 20 min before antibiotic therapy in meningitis
is that dexamethasone inhibits the production of TNFAT by macrophages and microglia
only if it is administered before these cells are activated by endotoxin.lt helps indecreasing
meningeal inflammation and neurologic sequelae such as the incidence of sensorineural
hearing loss.
USEFUL ONE LINERS
• Most common parasitic disease of the CNS worldwide is neurocysticercosis.

• Most common manifestation of neurocysticercosis is new-onset partial seizures with or
without secondary generalization.
HIGH YIELDING TOPIC
• SUBACUTE SCLEROSING PANENCEPHALITIS (SSPE) (Pg:900)

COMMON SOURCES OF INFECTIONS AFTER HEMATOPOIETIC STEM
TABLE
CELL TRANSPLANTATION
Period after Transplantation
Infection Site Early (<1 Month) Middle (1-4 Late (>6 Months)
Months)
Disseminated Aerobic bacteria Candida, Aspergil- Encapsulated bacteria
(gram-negative, lus, EBV CStreptococcuspneumoniae,
gram-positive) Haemophilus influenzae,
Neisseria meningitidis)
Skin and mu¬ HSV HHV-6 VZV, HPV (warts)
cous membranes
Lungs Aerobic bacteria CMV, seasonal Pneumocystis, Nocardia, S.
(gram-negative, respiratory viruses, pneumoniae
gram-positive), Pneumocystis, Toxo-
Candida, Aspergillus, plasma
other molds, HSV

iH HARRISON’S 19TH BASED NOTE BOOK
CMV, adenovirus, EBV, CMV, B. enterica

Gastrointestinal Clostridium difficile
Bradyrhizobium (cord blood cells)
tract
enterica (cord blood
cells)
Kidney- BK virus, adeno¬
virus
Brain HHV-6, Toxoplas- Toxoplasma, JC virus (rare)
ma
Bone marrow CMV, HHV-6 CMV, HHV-6
Abbreviations: CMV, cytomegalovirus, EBV, Epstein-Barr virus; HHV-6, human herpes¬

virus type 6; HPV, human papillomavirus; HSV, herpes simplex virus; VZV, varicella-zoster
virus:
COMMON INFECTIONS AFTER SOLID ORGAN TRANSPLANTATION, BY

TABLE
SITE OF INFECTION
Period after Transplantation
Infect- Early(<1 Month) Middle (1-4 Months) Late (>6 Months)
ed Site
Donor Bacterial and fungal CMV infection EBV infection (may present in
organ infections of the graft, allograft organ)
anastomotic site, and
surgical wound
Systemic Bacteremia and CMV infection (fe- CMV infection, especially in
candidemia (often ver, bone marrow sup patients given early posttrans¬
resulting from central pression) plantation prophylaxis; EBV
venous catheter colo¬ proliferative syndromes (may
nization) occur in donor organs)
Lung Bacterial aspiration Pneumocystis infec- Pneumocystis infection; granulo¬
pneumonia with tion; CMV pneumo- matous lung diseases (nocardial
prevalent nosocomial nia (highest risk in and reactivated fungal and
organisms associated lung transplantation), mycobacterial diseases)
with intubation and Aspergillus infection
sedation (highest risk (highest risk in lung
in lung transplanta- transplantation)
tion)
Email: info@damsdeIhi.com | Website:

HARRISON’S 19TH BASED NOTE BOOK SB
Kidney Bacterial and fungal Kidney transplan¬ Kidney transplantation: bac¬
tsCandida) infections tation: BK virus terial infections (late urinary
(cystitis, pyelonephri- infection (associated tract infections, usually not
tis) associated with with nephropathy); associated with bacteremia);
urinary tract catheters JC virus infection BK virus infection (nephrop¬
(highest risk in kid¬ athy, graft failure, generalized
ney transplantation) vasculopathy)
Liver Cholangitis CMV hepatitis CMV hepatitis
and
biliary
tract
Heart Toxoplasma gondii T. gondii (highest risk in heart

infection (highest transplantation)
risk in heart trans¬
plantation); endo¬
carditis (,Aspergillus
and gram-negative
organisms more com¬
mon than in general
population)
Gastro- Peritonitis, especially Colitis secondary to Colitis secondary to C difficile
intesti- after liver transplan- Clostridium difficile infection (risk can persist)
nal tract tation infection (risk can
persist)
Central Listeria infection Listerial meningitis; crypto-
nervous meningitis); 77 gondii coccal meningitis; nocardial
system infection; CMV abscess; JC virus-associated
infection PML
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; PML, progressive multifo¬
cal leukoencephalopathy
• PNEUMOCOCCAL VACCINES (Pg:953)

• STAPHYLOCCAL TOXIC SHOCK SYNDROME ,STAPHYLOCOCCAL SCALD¬
ED SKIN SYNDROME (Pg:959)
• LANCEFIELD CLASSIFICATION OF STREPTOCOCCI (Pg:963-64)

• SCARLET FEVER (Pg:966)

• IMPETIGO (Pg:966-67)
• STREPTOCOCCAL TOXIC SHOCK SYNDROME (Pg:968-69)
• GROUP B STREPTOCOCCI (Pg:969-70)
• DIPHTHERIA-CLINICAL MANIFESTATIONS,TREATMENT & PREVENTION
(Pg:978-80)
• LISTERIOSIS -CLINICAL MANIFESTATIONS (Pg:983)
• TETANUS-TREATMENT AND PREVENTION (Pg:986-87)
• BOTULISM-TYPES AND CLINICAL FEATURES (Pg:987-89)
• GAS GANGRENE (Pg:992-94)
• MENINGOCOCCAL INFECTION-CLINICAL FEATURES,TREATMENT,PRE¬
VENTION (Pg:998-1003)
• GONOCOCCAL INFECTION-CLINICAL FEATURES,TREATMENT (Pg:1005-
09)
• HEMOPHILUS INFLUENZAE- CLINICAL MANIFESTATIONS,TREAT¬
MENT,PREVENTION (Pg:1011- 12)
• CHANCROID (Pg:1012-13)
• LEGIONELLOSIS-EPIDEMIOLOGY,CLINICAL FEATURES (Pg:1015-16)
• PERTUSSIS-CLINICAL MANIFESTATIONS,PREVENTION (Pg:1022-24)
• E.COLI INFECTIONS (Pg:1027-31)
• KLEBSIELLA-CLINICAL FEATURES (Pg:1032)
• HELICOBACTER PYLORI INFECTIONS-EPIDEMIOLOGY,CLINICAL MANI¬
FESTATIONS,DIAGNOSIS AND TREATMENT (Pg:1039-42)
• PSEUDOMONAS INFECTIONS-CLINICAL MANIFESTATIONS (Pg:1044-47)
• BURKHOLDERIA PSEUDOMALLEIINFECTION (Pg:1048)
• ENTERIC FEVER (Pg:1050-53)
• SHIGELLOSIS-PATHOGENESIS,CLINICAL MANIFESTATIONS,TREATMENT
(Pg:1056-58)
• CAMPYLOBACTER JEJUNI-EPIDEMIOLOGY,CLINICAL FEATURES (Pg:1059-
60)
• CHOLERA-EPIDEMIOLOGY,PATHOGENESIS.CLINICAL MANIFESTA-
TIONSTREATMENT (Pg:1061- 64)
• VIBRIO PARAHAEMOLYTICUS (Pg:1065)

. PLAGUE-CLINICAL
75)
MANIFESTATIONS,TREATMENT,PREVENTION (Pg:1072-
. CAT-SCRATCH DISEASE (Pg:1078-80)

• BACILLARY ANGIOMATOSIS (Pg:1082)
. NOCARDIOSIS-CLINICAL MANIFESTATION & TREATMENT (Pg:1084-88)
. ACTINOMYCOSIS-CLINICAL MANIFESTATIONS (Pg:1088-90) .
MANIFESTATIONS,DIAGNOSIS,TREAT-
• TUBERCULOSIS-CLINICAL
MENT,PREVENTION (Pg:l107-21)
• LEPROSY-EPIDEMIOLOGY,CLINICAL SPECTRUM,COMPLICATIONS,TREAT¬
MENT (Pg:1123 -28)
• NONTUBERCULOUS MYCOBACTERIAL INFECTION-CLINICAL MANIFES¬
TATIONS,TREATMENT (Pg:l129-32)
• SYPHILIS-NATURAL COURSE,CLINICAL MANIFESTATIONS,LAB EXAM¬
INATIONS,TREATMENT (Pg:l134-40)
• LEPTOSPIROSIS-EPIDEMIOLOGY,CLINICAL MANIFESTATIONS,DIAGNO¬
SIS,TREATMENT (Pg:l141-45)
• RELAPSING FEVER-ETIOLOGICAL AGENT,CLINICAL MANIFESTATIONS
(Pg:l146-47)
• LYME DISEASE-ETIOLOGICAL AGENT,CLINICAL MANIFESTATIONS
(Pg:1149-51)
• ROCKY MOUNTAIN SPOTTED FEVER-ETIOLOGICAL AGENT,CLINICAL
MANIFESTATIONS (Pg:1154-56)
• EPIDEMIC TYPHUS,ENDEMIC TYPHUS,SCRUB TYPHUS (Pg:l158-59)
• Q FEVER (Pg:1161-62)
• MYCOPLASMA PNEUMONIAE- CLINICAL MANIFESTATIONS (Pg:l163-64)
• CHLAMYDIAL INFECTIONS (Pg:1167-72)
• HERPES SIMPLEX VIRUS INFECTIONS (Pg:l175-81)
• CHICKENPOX & HERPES ZOSTER-CLINICAL MANIFESTATIONS,TREAT¬
MENT,PREVENTION (Pg:l183-86)
• EPSTEIN BARR VIRUS INFECTIONS (Pg:l186-90)
• CYTOMEGALOVIRUS INFECTIONS-CLINICAL MANIFESTATIONS &
TREATMENT (Pg:1191-94)
• PARVOVIRUS INFECTIONS-CLINICAL MANIFESTATIONS (Pg:1196)

• HUMAN PAPILLOMA VIRUS INFECTION-EPIDEMIOLOGY,CLINICAL MANI¬

FESTATIONS,TREATMENT,HPV VACCINES (Pg:l197-1201)
• CORONA VIRUS INFECTION-EPIDEMIOLOGY,CLINICAL MANIFESTA¬
TIONS (Pg:1204)
• ADENOVIRUS INFECTIONS-CLINICAL MANIFESTATIONS (Pg:1208)
• INFLUENZA-AGENT,EPIDEMIOLOGY,CLINICAL MANIFESTATIONS,
TREATMENT,PROPHYLAXIS (Pg:1209-14)
• HUMAN IMMUNODEFICIENCY VIRUS DISEASE-AIDS AND RELATED DIS¬
ORDERS (Pg:1215-85)
• POLIOVIRUS INFECTION (Pg:1290-91)
• OTHER ENTEROVIRUS INFECTIONS (Pg:1291-93)
• PREVENTION AND ERADICATION OF POLIOVIRUS (Pg:1294-95)
• MEASLES-EPIDEMIOLOGY,CLINICAL MANIFESTATIONS,COMPLICA-
TIONS,PREVENTION (Pg:1295-99)
• RABIES-PATHOGENESIS,CLINICAL FEATURES,PREVENTION (Pg:1300-04)
• HANTAVIRUS PULMONARY SYNDROME (Pg:1319-20)
• YELLOW FEVER (Pg:1322-23)
• EBOLA VIRUS INFECTIONS (Pg:1323-29)
• HISTOPLASMOSIS-PATHOGENESIS,CLINICAL FEATURES(Pg:1332-33)
• CRYPTOCOCCOSIS-CLINICAL MANIFESTATIONS,TREATMENT (Pg:1340-4l)
• CANDIDIASIS-CLINICAL MANIFESTATIONS,TREATMENT (Pg:1342-45)
• ASPERGILLOSIS-CLINICAL FEATURES,TREATMENT (Pg:1346-49)
• MUCORMYCOSIS-CLINICAL FEATURES,TREATMENT (Pg:1350-53)
• SPOROTRICHOSIS-EPIDEMIOLOGY,CLINICAL MANIFESTATIONS (Pg:1353-
54)
• PNEUMOCYSTIS INFECTIONS (Pg:1358-62)
• AMEBIASIS (Pg:1363-68)
• MALARIA (Pg:1368-84)
• LEISHMANIAISIS-ETIOLOGICAL AGENTS,CLINICAL FEATURES,TREAT¬
MENT (Pg:1387-94)
• CHAGA’S DISEASE-ETIOLOGICAL AGENT,CLINICAL COURSE (Pg:1394-95)
• SLEEPING SICKNESS-ETIOLOGICAL AGENT.CLINICAL COURSE (Pg:1396-97)

Page | 8 1
HARRISON’S 19TH BASED NOTE BOOK Kl
• TOXOPLASMOSIS-LIFE CYCLE,CLINICAL FEATURES,TREATMENT (Pg:1398-
1404)
• GIARDIASIS-LIFE CYCLE,CLINICAL FEATURES,TREATMENT (Pg:l405-06)
• CUTANEOUS LARVA MIGRANS (Pg:l412)
• ASCARIASIS-LIFECYCLE,CLINICAL FEATURES,TREATMENT (Pg:l4l3-14)
• HOOKWORM-LIFECYCLE,CLINICAL FEATURES,TREATMENT (Pg:l4l4-15)
• LYMPHATIC FILARIASIS-PATHOGENESIS,CLINICAL FEATURES, DIAGNO¬
SIS,TREATMENT (Pg:l4l7-19)
• TROPICAL PULMONARY EOSINOPHILIA (Pg:l420)
• ONCHOCERCIASIS (Pg:l420-21)
• LOIASIS (Pg:1421-22)
• SCHISTOSOMIASIS-CLINICAL FEATURES (Pg:l426-27)
• CYSTICERCOSIS (Pg:l430-32)
• ECHINOCOCCOSIS (Pg:l432-34)
USEFUL ONE LINERS
• Most common cause of septic arthritis in native joints in both adults and children is Staph.
aureus.
• Most common coagulase negative staph causing human infection is Staph epidermidis.
• Most abundant bacterial species in normal skin flora of humans is Staph epidermidis.
• Most common causative organism of impetigo is Streptococcus pyogenes.
• Erythrasma is a cutaneous infection caused by Corynebacterium minutissimum. Under
Wood s lamp,it shows coral red fluorescence.
• Drug of choice for listeriosis is Ampicillin.
• Granulomatosis infantiseptica is an overwhelming listerial fetal infection with miliary mi¬
croabscesses and granulomas, most often in the skin,liver and spleen.
• Most common clinical manifestation of gonorrhea in male patients is acute urethritis.
• Most common bacterial cause of exacerbation of COPD is non-typable H.influenzae.
• Most common species isolated from cases of HACEK endocarditis is Haemophilus para-
influenzae.
• Most common mode of transmission of Legionella is aspiration > aerosolization.
• Urinary antigen test is highly sensitive and specific for detection of legionella.
• Most common heart valve affected in Bartonella endocarditis is aortic valve.
• Most common form of nocardial disease in the respiratory tract is pneumonia.

brain.
• Most common extra-pulmonary site of dissemination of nocardia is
• Drug of choice for nocardiosis is sulfonamide.
• Most common site of postprimary disease in tuberculosis is apical and posterior segments
of upper lobe.
• Most common site of spinal TB in children-upper thoracic spine.
• Most common site of spinal TB in adults- lower thoracic and upper lumbar vertebrae.
• First bacterium to be etiologically associated with human disease was Mycobacterium lep-
rae.
• “Fish tank granuloma” is associated with Mycobacterium marinum.
• First antimicrobial agent used for the treatment of tuberculosis was Streptomycin.
• Least potent first line drug against Mycobacterium tuberculosis is Ethambutol.
• Pyrazinamide is more active against slowly replicating M.tuberculosis than against actively
replicating organisms.
• Most common causative organism of nongonococcal arthritis and postgonococcal arthri¬
tis is Chlamydia trchomatis.
• Most common clinical manifestations of first episode of HSV-1 infection is gingivostoma¬
titis and pharyngitis.
• Most common clinical manifestation of reactivation of PISV-1 infection is recurrent her¬
pes labialis.
• Most common cause of recurrent lymphocytic meningitis(Mollaret meningitis) is HSV.
• Neonatal HSV infection is more commonly caused by HSV-2 >HSV-1.
• Most common infectious complication of varicella is secondary bacterial superinfection
of the skin, which is usually caused by Streptococcus pyogenes or Staphylococcus aureus.
• Most common extracutaneous site of involvement of chickenpox in children is the CNS.
• Most common clinical manifestation of CMV infection in immunocompetent hosts be¬
yond the neonatal period is heterophile-antibody negative mononucleosis syndrome.
• Most common viral pathogen complicating organ transplantation is CMV.
• Most common hematologic abnomalty in HIV infected patients is anemia.
• Most common abnormal fundus finding in HIV infection are cotton wool spots.
Most common aspergillus species implicated in fungal ball (aspergilloma) is
A.fumigatus
Most common form of mucormycosis is rhino-orbito-cerebral mucormycosis.
Primary amebic meningoencephalitis is caused by Naegleria fowleri.

• Granulomatous amebic encephalitis is caused by Acanthamoeba species.
• Enlargement of the nodes of the posterior cervical triangle, or Winterbottom’s sign is a
classic finding in sleeping sickness.
• Cutaneous larva migrans is also known as “creeping eruption”.
• Most common cause of human eosinophilic meningitis is Angiostrongylus cantonensis.
• Angiostrongylus cantonensis is also known as “rat lungworm”.
• Largest intestinal nematode parasite of humans is Ascaris lumbricoides.
• Onchocerciasis is also known as “river blindness”.
• African eye worm is Loa Loa.
• Lung fluke is Paragonimus westermani.
• Beef tapeworm is Taenia saginata.
• Pork tapewworm is Taenia solium.
• Most common cestode infection is Hymenolepiasis nana.
• Hymenolepiasis nana is also known as “dwarf tapeworm”.
RADIOLOGY OF THE SPINE: DIFFERENTIATION OF BRUCELLOSIS
TABLE
FROM TUBERCULOSIS
Brucellosis Tuberculosis
Site Lumbar and others Dorsolumbar
Vertebrae Multiple or contiguous Contiguous
Diskitis Late Early

Body Intact until late Morphology lost early
Canal compression Rare Common
Epiphysitis Anterosuperior (Poms General: upper and lower disk re¬
sign) gions, central, subperiosteal
Osteophyte Anterolateral (parrot Unusual
beak)
Deformity Wedging uncommon Anterior wedge, gibbus
Recovery Sclerosis, whole-body Variable
Paravertebral abscess Small, well-localized Common and discrete loss, transverse
process
Psoas abscess Rare More likely

Keep in mind In Aspiration pneumonia,chest x-rays show consolidation in dependent pul¬

monary segments: in the basilar segments of the lower lobes if the patient has aspirated while
upright and in either the posterior segment of the upper lobe (usually on the right side) or
the superior segment of the lower lobe if the patient has aspirated while supine. _
TABLE COMPARISON OF THE TREPONEMES AND ASSOCIATED DISEASES
Feature Venereal Syphilis Yaws Endemic Syphilis Pinta

Organism 77 pallidum subsp. T;pallidum 77 pallidum subsp. 77 carateum
pallidum subsp. pertenue endemicum
Common Sexual, transpla- Skin to skin Mouth to mouth or Skin to skin
modes of cental via shared drink¬
transmission ing/eating utensils
Usual age of Sexual maturity or Early child- Early childhood Late childhood
acquisition in utero hood
Primary Cutaneous ulcer Papilloma, of- Mucosal papule, Nonulcerat¬
lesion (chancre) ten ulcerative rarely seen ing papule
with satellites,
pruritic
Common Genital, oral, anal Extremities Oral Extremities,
location face
Secondary Mucocutaneous le- Cutaneous Mucocutaneous Pintides,
lesions sions; con dylomata papulosqua- lesions (mucous pigmented,
lata mous lesions; patch, split papule, pruritic
condylomata condylomata lata);
lata, osteoperi- osteoperiostitis
ostitis
Infectious -25% Common Unknown Unknown
relapses
Late compli- Gummas, cardio- Destructive Destructive gum¬ Nondestruc¬
cations vascular and cen- gummas of mas of skin, bone, tive, dyschro-
tral nervous system skin, bone, cartilage mic, achromic
involvement" cartilage macules

Page | 85
3$
TABLE CMV DISEASE IN THE IMMUNOCOMPROMISED HOST
Population Risk Factors Principal Syndromes Treatment Prevention
Fetus Primary mater- Cytomegalic inclusion Ganciclovir Avoidance of
nal infection/ disease for symp¬ exposure; pos¬
early pregnancy tomatic sibly, maternal
neonates treatment with
CMV immuno¬
globulin during
pregnancy
Organ Seropositivity Febrile leukopenia; Ganciclovir Prophylaxis
transplant of donor and/or gastrointestinal disease; or valganci- or preemptive
recipient recipient; potent pneumonia clovir therapy with
immunosup¬ ganciclovir or
pressive regi¬ valganciclovir
men; treatment
of rejection
Fiematopoi- Graft vs.-host Pneumonia; gastroin- Ganciclovir Prophylaxis
etic stem cell disease; older testinal disease or valganci- or preemptive
transplant age of recipient; clovir or therapy with
recipient seropositive re¬ foscarnet, ganciclovir or
cipient; viremia + CMV valganciclovir
immuno¬
globulin
Person with < 100 CD4+ T Retinitis; gastrointesti- Ganciclovir, Oral valganci-
AIDS cells/p L; CMV nal disease; neurologic valganciclovir
seropositivity disease clovir,
foscarnet, or
cidofovir
CDC STAGE 3 (AIDS) DEFINING OPPORTUNISTIC ILLNESSES

TABLE
INFECTION
Bacterial infections, multiple or recurrent"
Candidiasis of bronchi, trachea, or lungs
Candidiasis of esophagus
Cervical cancer, invasive4
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 month’s duration)

Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month
Cytomegalovirus retinitis (with loss of vision) Encephalopathy attributed to HIV
Herpes simplex chronic ulcers (>1 month’s duration) or bronchitis, pneumo nitis, or esoph¬
agitis (onset at age >1 month)
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month’s duration)
Kaposi’s sarcoma
Lymphoma, Burkitt’s (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis of any site, pulmonary/ disseminated, or extrapulmonary
Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jirovecii (previously known as Pneumocystis carnii) pneumonia
Pneumonia, recurrentÿ
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain, onset at age >1 month
Wasting synarome attributed to HIV
"Only among children < 6 years/Only among adults,adolescents and children age >6 years.
TABLE
CHARACTERISTICS OF IMMUNE RECONSTITUTION INFLAMMATORY
SYNDROME (IRIS)
• Paradoxical worsening of an existing clinical condition or abrupt appearance of a new
clinical finding (unmasking) is seen following the initiation of antiretroviral therapy
• Occurs weeks to months following the initiation of antiretroviral therapy
• Is most common in patients starting therapy with a CD4+ T cell count <50/p L who
experience a precipitous drop in viral load
• Is frequently seen in the setting of tuberculosis; particularly when cART is starting soon
after initiation of anti-TB therapy
• Can be fatal
TABLE CAÿSESOF BONE MARROW SUPPRESSION IN PATIENTS WITH HIV

HIV infection Medications
Mycobacterial infections Zidovudine
Fungal infections Dapsone
B19 parvovirus infection Trimethoprim/sulfamethoxazole
Lymphoma Pyrimethamine
5 -Flucytosine
Ganciclovir
Interferon K
Trimetrexate
Foscarnet
TABLE NEUROLOGIC DISEASES IN PATIENTS WITH HIV INFECTION

Opportunistic infections HIV-1 infection
Toxoplasmosis Aseptic meningitis
Cryptococcosis HIV-associated neurocognitive disorders
Progressive multifocal leukoencephalop- (HAND), including HIV encephalopa-
athy thy/AIDS dementia complex
Cytomegalovirus Myelopathy
Syphilis Vacuolar myelopathy
Mycobacterium tuberculosis Pure sensory ataxia
HTLV-1 infection Paresthesia/dysesthesia
Amebiasis Peripheral neuropathy
Neoplasms Acute inflammatory
Primary CNS lymphoma demyelinating polyneuropathy (Guil-
Kaposi’s sarcoma lain-Barre syndrome)
Chronic inflammatory demyelinating
polyneuropathy (CIDP)
Mononeuritis multiplex
Distal symmetric polyneuropathy
Myopathy
COMMON TRANSIENT AND PERMANENT MANIFESTATIONS IN INFANTS

TABLE
WITH CONGENITAL RUBELLA SYNDROME
Transient Manifestations Permanent Manifestations
Hepatosplenomegaly Hearing impairment/deafness
Interstitial pneumonitis Congenital heart defects (patent ductus arterio¬
sus, pulmonary arterial stenosis)

Thrombocytopenia with purpura/ Eye defects (cataracts, cloudy cornea, microph-

petechiae (e.g., dermal erythropoiesis, thalmos, pigmentary retinopathy, congenital
a “blueberry muffin syndrome”) glaucoma)
Hemolytic anemia Microcephaly
Bony radiolucencies Central nervous system sequelae (mental and
Intrauterine growth retardation motor delay, autism)
Adenopathy
Meningoencephalitis
WELL-RECOGNIZED FACTORS AND CONDITIONS PREDISPOSING TO

TABLE
HEMATOGENOUSLY DISSEMINATED CANDIDIASIS
Antibacterial agents Abdominal and thoracic surgery
Indwelling intravenous catheters Cytotoxic chemotherapy
Hyperalimentation fluids Immunosuppressive agents for organ trans¬
Indwelling urinary catheters plantation
Parenteral glucocorticoids Respirators
Severe burns Neutropenia
HIV-associated low CD4+ T cell counts Low birth weight (neonates)
Diabetes
TABLE CHARACTERISTICS OF PLASMODIUMSPEC\ES INFECTING HUMANS

Finding for Indicated Speciesa
Characteristic P.falciparum P. vivax P. ovale P. malariae
Duration of intrahe- 55 8 9 15
patic phase (days)
Number of merozoites 30,000 10,000 15,000 15,000
released per infected
hepatocyte
Duration of erythro¬ 48 48 50 72
cytic cycle (hours)
Red cell preference Younger cells Reticulocytes Reticulocytes Older cells

(but can invade and cells up to
cells of all ages) 2 weeks old

Page | 89
Morphology Usually only Irregularly Infected Band or

ring forms*; shaped large erythrocytes, rectangular
banana-shaped rings and enlarged and forms of
gametocytes trophozoites; oval with trophozoites
enlarged eryth- tufted ends; common
rocytes; Schuff- Schiiffner’s
ner’s dots dots
Pigment color Black Yellow-brown Dark brown Brown-black
Ability to cause re¬ No Yes Yes No
lapses
The U.S. Centers for Disease Control and Prevention (CDC) classifies potential biologic
threats into three categories: A, B, and C
TABLE CDC CATEGORY A,B,AND CAGENTS
Category A
Anthrax {Bacillus anthracis)
Botulism [Clostridium botulinum toxin)
Plague ( Yersinia pestis)
Smallpox (Variola major)
Tularemia {Francisella tularensis)
Viral hemorrhagic fevers
Arenaviruses: Lassa, New World (Machupo, Junin, Guanarito, and Sabia)
Bunyaviridae: Crimean-Congo, Rift Valley
Filoviridae: Ebola, Marburg
Category B
Brucellosis {Brucella spp.)
Epsilon toxin of Clostridium perfringens
Food safety threats (e.g. Salmonella spp., Escherichia coli 0157:PI7, Shigella)
Glanders {Burkholderia mallei)
Melioidosis {Burkholderiapseudomallei)
Psittacosis {Chlamydophila psittaci)
Q. fever {Coxidla burnetii)
Ricin toxin from Ricinus communis (castor beans)
Staphylococcal enterotoxin B
Typhus fever {Rickettsia prowazekii)
Viral encephalitis (alphaviruses [e.g., Venezuelan, eastern, and western equine encephalitis])
Water safety threats (e.g., Vibrio cholerae, Cryptosporidium parvum)

Category C
rus, and pandemic influenza _ __

Emerging infectious diseases threats such as Nipah, hantavirus, SARS or MERS coronavi-
_
Abbreviations: MERS-Middle East Respiratory Syndrome; SARS-Severe Acute Respiratory
Syndrome.

CHAPTER 7
CARDIOVASCULAR SYSTEM
-
1
w
-
mt
i
o
©
USEFUL ONE LINERS
• Differential cyanosis refers to isolated cyanosis affecting the lower but not the upper ex¬
tremities in a patient with a large patent ductus arteriosus (PDA) and secondary pulmo¬
nary hypertension with rightto-left to shunting at the great vessel level.
• Palmar crease xanthomas are specific for type III hyperlipoproteinemia.
• Pseudoxanthoma elasticum, a disease associated with premature atherosclerosis, is mani¬
fested by a leathery,cobblestoned appearance of the skin in the axilla and neck creases and
by angioid streaks on fundoscopy.
• Bifid uvula has been described in patients with Loeys-Dietz syndrome.
• Straight back syndrome refers to the loss of the normal kyphosis of the thoracic spine and
has been described in patients with mitral valve prolapse (MVP) and its variants.

• Patients with the Holt-Oram syndrome have an unopposable, finngerized thumb.

• Kussmaul’s sign is defined by either a rise or a lack of fall of the JVP with inspiration
and is classically associated with constrictive pericarditis,although it has been reported in
patients with restrictive cardiomyopathy, massive pulmonary embolism, right ventricular
infarction,and advanced left ventricular systolic heart failure.
• The length and width ofthe blood pressure cuffbladder should be 80% and 40% of the
arm’s circumference, respectively.
• Orthostatic hypotension is defined by a fall in systolic pressure > 20 mmHg or in diastolic
pressure > 10 mmHg in response to assumption of the upright posture from a supine po¬
sition within 3 min.
HIGH YIELDING TOPIC
• JUGULAR VENOUS PRESSURE (Pg:1443-44)
A
I r\Diarotic notch
'
0
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CMcnKIc notch
W NW
C
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Is"-
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Figure Schematic diagrams of the configurational changes in carotid pulse and their dif¬
ferential diagnoses. Heart sounds are also illustrated. A. Normal. S4, fourth heart sound; S,, first
heart sound; A2 aortic component of second heart sound; P2 pulmonic component of second heart
sound. B. Aortic stenosis. Anacrotic pulse with slow upstroke to a reduced peak. C. Bisferiens pulse
with two peaks in systole. This pulse is rarely appreciated in patients with severe aortic regurgitation.
D. Bisferiens pulse in hypertrophic obstructive cardiomyopathy. There is a rapid upstroke to the first
peak (percussion wave) and a slower rise to the second peak (tidal wave). E. Dicrotic in patients
with sepsis or during intraaortic ballon counterpulsation with inflation just after the dicrotic notch.

USEFUL ONE LINERS
• The character of the pulse is best appreciated at the carotid level .
• A weak and delayed pulse (pulsus parvus et tardus) defines severe aortic stenosis (AS).
• Some patients with AS may also have a slow, notched, or interrupted upstroke (anacrotic
pulse) with a thrill or shudder.
• With chronic severe AR, the carotid upstroke has a sharp rise and rapid fall-off (Corrigan s
or water-hammer pulse).
• Some patients with advanced AR may have a bifid or bisferiens pulse in which two sys¬
tolic peaks can be appreciated. A bifid pulse is also described in patients with hypertrophic
obstructive cardiomyopathy (HOCM), with inscription of percussion and tidal waves. A
bifid pulse is easily appreciated in patients on intraaortic balloon counterpulsation (IAB-
P), in whom the second pulse is diastolic in timing.
• Pulsus paradoxus refers to a fall in systolic pressure >10 mmHg with inspiration that
is seen in patients with pericardial tamponade but also is described in those with mas-
sive pulmonary embolism, hemorrhagic shock, severe obstructive lung disease,and tension
pneumothorax.
• Pulsus alternans, is defined by beat-to-beat variability of pulse amplitude.lt is seen in
patients with severe left ventricular systolic dysfunction and is thought to be due to cyclic
changes in intracellular calcium and action potential duration.
EFFECTS OF PHYSIOLOGIC AND PHARMACOLOGIC INTERVENTIONS
TABLE
ON THE INTENSITY OF HEART MURMURS AND SOUNDS
Respiration Right-sided murmurs and sounds generally increase with inspiration, except
for the PES. Left-sided murmurs and sounds are usually louder during expiration.
Valsalva maneuver Most murmurs decrease in length and intensity. Two exceptions are
the systolic murmur of HOCM, which usually becomes much louder, and that of MVP,
which becomes longer and often louder. After release of the Valsalva maneuver, right-sided
murmurs tend to return to control intensity earlier than do left-sided murmurs.
After VPS or AF Murmurs originating at normal or stenotic semilunar valves increase in
the cardiac cycle after a VPB or in the cycle after a long cycle length in AF. By contrast,
systolic murmurs due to AV valve regurgitation do not change, diminish {papillary muscle
dysfunction), or become shorter (MVP).
Positional changes With standing, most murmurs diminish, with two exceptions being the
murmur of HOCM, which becomes louder, and that of MVP, which lengthens and often is
intensified. With squatting, most murmurs become louder, but those of HOCM and MVP
usually soften and may disappear. Passive leg raising usually produces the same results.

PS, MS)
Exercise Murmurs due to blood flow across normal or obstructed valves (e.g.,
become louder with both isotonic and submaximal isometric (hand grip) exercise. Mur-
murs of MR, VSD, and AR also increase with hand grip exercise. However, the murmur
of HOCM often decreases with nearly maximum hand grip exercise. Left-sided S4 and S3
sounds are often accentuated by exercise, particularly when due to ischemic heart disease.
EXPIRATION INSPIRATION
I
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Figure Heart sounds. A. Normal. first heart sound; S2, Second heart sound; A2, aortic compo¬
nent of the second heart sound; P2, pulmonic component of the second heart sound. B. Atrial septal
defect with fixed splitting of S2. C. Physiologic but wide splitting of S2 with right bundle branch block
(RBBB). PA. pulmonary artery. D. Reversed or paradoxical splitting of
block (LBBB). E. Narrow splitting of S2 with pulmonary hypertension.
S2 with left bundle branch
TABLE DIFFERENTIAL DIAGNOSIS OF ST-SEGMENT ELEVATIONS

Ischemia/myocardial infarction
Noninfarction, transmural ischemia (Prinzmetal’s angina, and probably Tako-tsubo
syndrome, which may also exactly simulate classical acute infarction)
Acute myocardial infarction
Postmyocardial infarction (ventricular aneurysm pattern)
Acute pericarditis

m
Normal variants (including benign “early repolarization patterns)
Left ventricular hypertrophy/left bundle branch block"
Other (rarer)
Acute pulmonary embolism"
Brugada patterns (right bundle branch block-like pattern with ST elevations in rig t
precordial leads)"
Class 1C antiarrhythmic drugs"
DC cardioversion
Hypercalcemia"
Hyperkalemia"
Hypothermia (J [Osborn] waves)
Nonischemic myocardial injury
Myocarditis
Tumor invading left ventricle
Trauma to ventricles
"Usually localized to Vj-V., or V3.
Abbreviations: AF, atrial fibrillation; AR, aortic regurgitation; HOCM, hypertrophic ob¬
structive cardiomyopathy; MR, mitral regurgitation; MS, mitral stenosis; MVR mitral valve
prolapse; PCS, pulmonicejection sound; Hi pulmonic regurgitation; PS pulmonic stenosis;
TR, tricuspid rcgurgitation;TS, tricuspid stenosis; VPB, ventricular premature beat; VSD,
ventricular septal defect.
HIGH YIELDING TOPIC
• ATRIAL FIBRILLATION (Pg:l485-89)

TABLE NEW YORK HEART ASSOCIATION CLASSIFICATION
Functional Capacity Objective Assessment
ClassI Patients with cardiac disease but without re¬
sulting limitation of physical activity. Ordi¬
nary physical activity does not cause undue
fatigue, palpitations, dyspnea, or anginal
pain.
Class II Patients with cardiac disease resulting in
slight limitation of physical activity. They
are comfortable at rest. Ordinary physical
activity results in fatigue, palpitation, dys¬
pnea, or anginal pain.

Class III Patients with cardiac disease resulting in

marked limitation of physical activity. They
are comfortable at rest. Less than ordinary
activity causes fatigue, palpitation, dyspnea,
or anginal pain.
Class IV Patients with cardiac disease resulting in
inability to carry on any physical activity
without discomfort. Symptoms of heart
failure or the anginal syndrome may be
present even at rest. If any physical activity
is undertaken, discomfort is increased. _
TABLE ETIOLOGY OF CHRONIC COR PULMONALE
Diseases of the Lung Parenchyma
Chronic obstructive pulmonary disease
Emphysema
Chronic bronchitis
Cystic fibrosis
Idiopathic interstitial pneumonitis
Idiopathic pulmonary fibrosis
Nonspecific interstitial pneumonitis
Sarcoidosis
Bronchiectasis
Pulmonary Langerhans cell histiocytosis
Lymphangioleiomyomatosis
Disorders of Chronic (Alveolar) Hypoxia
Alveolar hypoventilation syndromes
Obesity hypoventilation syndrome
Central hypoventilation syndrome
Neuromuscular respiratory failure
Chest wall disorders
Kyphoscoliosis
Living at high altitude
Diseases of the Pulmonary Vasculature
Pulmonary arterial hypertension (PAH)
Idiopathic PAH
Heritable PAH
Associated PAH
Venoocclusive disease
Chronic thromboembolic pulmonary hypertension
Pulmonary tumor thrombotic microangiopathy

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in the serum potassium concentration, the QRS complexes widen, the P waves decrease in amplitude and may disappear,
and finally a sine-wave pattern leads to asystole unless emergency therapy is given. (After AL Goldberger et al:Goldberger’s
Clinical Electrocardiography: A Simplified Approach, 8th ed. Philadelphia, Elsevier/Saunders, 2013.)
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Figure Classic triad of findings for pericardial effusion with cardiac tamponade: (1) Sinus tachycardia; (2) low QRS volt¬ CS
ages; and (3) electrical alternans (best seen in leads V3 and V4) in the case; arrow ). This triad is highly specific for pericardial H
effusion, usully with tamponade physiology, but of limited sensitivity. (Adapted from LA Nathanson et al; ECG Wave-Maven. http:// I
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HIGH YIELDING TOPIC
• CONGENITAL HEART DISEASES IN THE ADULT (Pg:1519-28)
USEFUL ONE LINERS

• Most common ASD is ostium secundum type.
• The three most common causes of aortic root-to-right-heart shunts are congenital aneu-
rysm of an aortic sinus of Valsalva with fistula coronary arteriovenous fistula, and anom-
alous origin of the left coronary artery from the pulmonary trunk.
• Most common associated cardiac defect in Williams-Beuren syndrome is supravalvular
aortic stenosis.
• Most common site of coarctation of aorta is distal to the origin of the left subclavian artery
the insertion of the ligamentum arteriosum.
near
• Most common associated cardiac anomaly in coarctation of aorta is bicuspid aortic valve.
HIGH YIELDING TOPIC

• AORTIC VALVE DISEASE (Pg:1528-38)
USEFUL ONE LINERS

• Most common congenital heart valve defect is bicuspid aortic valve.
• Occasionally the murmur of Aortic Stenosis is transmitted downward and to the apex,
where it may be confused with the systolic murmur of mitral regurgitation - Gallavardin
effect.
HIGH YIELDING TOPIC
• MITRAL VALVE DISEASE (Pg:1539-47)
USEFUL ONE LINERS

• Most common cause of mitral stenosis is rheumatic fever.
• In normal adults, the area of the mitral valve orifice is 4-6 cm2.
• When the mitral valve opening is reduced to <1.5 cm2, referred to as “severe” MS, an LA
i
-
pressure of 25 mmHg is required to maintain a normal cardiac output.
• Mitral valve prolapse is also variously termed the systolic dick-murmur syndrome, Bar¬
low’s syndrome, floppy-valve syndrome, and billowing mitral leaflet syndrome.

in HARRISON’S 19TH BASED NOTE BOOK
MMa
A
Wm
yMm
Figure Inoue balloon technique for percutaneous mitral balloon valvotomy. A. After trans-
septal puncture, the deflated balloon catheter is advanced across the interatrial septum, then
across the mitral valve and into the left ventricle. B-D. The balloon is inflated stepwise within the
mitral orifice.
HIGH YIELDING TOPIC

• TRICUSPID AND PULMONIC VALVE DISEASE (Pg:1547-50)
USEFUL ONE LINERS
• Dysplastic pulmonic valves can occur as a part of Noonan’s syndrome.
• Characteristic physical examination hallmark of Pulmonary regurgitation is Graham
Steell murmur.
• Tricuspid regurgitation is characterised by a blowing holosystolic murmur along the lower
left sternal margin which may be intensified during inspiration (Carvallo’s sign).

• CARDIOMYOPATHY & MYOCARDITIS (Pg:1553-70)
• TAKOTSUBO CARDIOMYOPATHY (Pg:1565)
pappKONI’S 19TH BASED NOTE BOOK
TABLE PRESENTATION WITH SYMPTOMATIC

CARDIOMYOPATHY
Restrictive Hypertrophic
Dilated
25-50% >60%
Ejection frac- Usually <30% when
tion (normal symptoms severe
>55%)
Left ventric- >60 mm <60 mm (may be de¬ Often decreased
ular diastolic creased)
dimension (nor¬
mal <55 mm)
Left ventricular Normal or decreased Normal or increased Markedly in¬
wall thickness creased
Atrial size Increased, may also be Increased; may be massive Increased; related
primarily affected to elevated filling
pressures
Valvular regur- Related to annu- Related to endocardial in- Related to

gitation lar dilation; mitral volvement; frequent mitral valve-septum
appears earlier during and tricuspid regurgita- interaction; mitral
decompensation; tion, rarely severe regurgitation
tricuspid regurgitation
with right ventricular
dysfunction
Common first Exertional intolerance Exertional intolerance, Exertional intol-
symptoms fluid retention early, may erance; may have
have dominant-right sided chest pain
symptoms
Congestive Left before right, ex- Right often dominates Left-sided con¬
symptoms* cept right prominent gestion at rest
in young adults may develop late
Arrhythmias Ventricular tach¬ Ventricular uncommon Ventricular tach-
yarrhythmia; con¬ except in sarcoidosis, yarrhythmias;
duction block in conduction block in atrial fibrillation
Chagas’disease, and sarcoidosis and amyloi-
some families. Atrial dosis. Atrial fibrillation.
fibrillation

"Left-sided symptoms of pulmonary congestion: dyspnea on exertion, orthopnea, paroxysmal noctur-
nal dyspnea. Right sided symptoms of systemic venous congestion: hepatic and abdominal distention,
discomfort on bending, peripheral edema
USEFUL ONE LINERS
• Most common toxin implicated in chronic dilated cardiomyopathy is alcohol.

• Most common infective cause of cardiomyopathy is Chagas disease.
• Peripartum cardiomyopathy (PPCM) develops during the last trimester or within the first
6 months after pregnancy.
HIGH YIELDING TOPIC
• PERICARDIAL DISEASE (Pg:1571-77)
FEATURES THAT DISTINGUISH CARDIAC TAMPONADE FROM

TABLE
CONSTRICTIVE PERICARDITIS AND SIMILAR CLINICAL DISORDERS
Characteristic Tam- Constric- Restrictive RVMI Effusive
ponade tive Peri- Cardiomyop- Constric¬
carditis athy tive Peri¬
carditis
Clinical
Pulsus paradoxus +++ + +++
Jugular veins
Prominent y descent ++ + +
Prominent x descent +++ ++ +++ + +++
Kussmaul’s sign +++ + +++ ++

Third heart sound + + +
Pericardial knock ++
Electrocardiogram
Low ECG voltage ++ ++ ++ ++
Electrical alternans ++
Echocardiogram

Page | 103
Thickened pericardium - +++ ++

Pericardial calcification - ++
Pericardial effusion +++ ++

RV size Usualry Usualy Usualy nor- En-
small normal mal larged
RA and RV +++
Exaggerated respira¬ +++ +++ +++
tory variation in (flow
velocity
CT/MRI
Thickened pericardium ++ +++
Cardiac catheterization
Equalization of diastol- ++ +++ +++
ic pressures
Abbrevations: +++, always present: +++, usualy present: +, rare: absent; DC distolic colapse;
ECG electrocardiopgraph: RA, right atrium, RV, right ventride; RVMI, right ventricular
myocardial infarction
USEFUL ONE LINERS
• Most common primary cardiac tumor in adult is myxoma.

• Most common primary malignant tumor of pericardium is mesothelioma.
• Tumors metastatic to the heart are much more common than primary tumors.
• Most common primary originating sites of cardiac metastases are carcinoma of the breast
and lung.
• Most common tumor of cardiac valves is papillary fibroelastoma.
• Most common cardiac tumors in infants and children are rhabdomyomas anf fibromas.
• Most common form of non-penetrating cardiac injury is myocardial contusion.
• Sudden emotional or physical trauma, even in the absence of direct cardiac trauma,may
precipitate a transient catecholamine-mediatedcardiomyopathy referred to as tako-tsubo
cardiomyopathy or the apical ballooning syndrome.

Keep in mind Blunt,nonpenetrating,often, innocent-appearing injuries to the chest may

trigger ventricular fibrillation even in absence of overt signs of injury. This syndrome,
referred to as commotio cordis,occurs most often in adolescents during sporting events
(eg:baseball,hockey,foot ball,and lacrosse) and probably results from an impact to the chest
wall overlying the heart during the susceptible phase of repolarization just before the peak
of the T wave. _
COMMON SYSTEMIC DISORDERS AND THEIR ASSOCIATED CARDIAC
TABLE
MANIFESTATIONS
Systemic Disorder Common Cardiac Manifestations
Diabetes mellitus CAD, atypical angina, CMP, systolic or diastolic CHF
Protein-calorie malnutrition Dilated CMP, CHF
Thiamine deficiency High-output failure, dilated CMP
Hyperhomocysteinemia Premature atherosclerosis
Obesity CMP, systolic a diastolic CHF
Hyperthyroidism Palpitations, SVT, atrial fibrillation, hypertension
Hypothyroidism Hypotension, bradycardia, dilated CMP, CHF, pericardial
effusion
Malignant carcinoid Tricuspid and pulmonary valve disease, right heart failure
Pheochromocytoma Hypertension, palpitations, CHF
Acromegaly Systolic or diastolic heart failure
RJieumatoid arthritis Pericarditis, pericardial effusions, coronary arteritis, myo¬
carditis, valvulitis
Seronegative arthropathies Aortitis, aortic and mitral insufficiency, conduction ab¬
normalities
Systemic lupus erythematosus Pericarditis, Libman-Sacks endocarditis, myocarditis,
arterial and venous thrombosis
HIV Myocarditis, dilated CMP, pericardial effusion
Amyloidosis CHF, restrictive CMP, valvular regurgitation, pericardial
effusion
Sarcoidosis CHF, dilated or restrictive CMR ventricular arrhythmias,
heart block

Page | 105
Hemochromatosis CHF, arrhythmias, heart block
Marfan syndrome Aortic aneurysm and dissection, aortic insufficiency,

mitral valve prolapse
Ehlers-Danlos syndrome Aortic and coronary aneurysms, mitral and tricuspid valve
prolapse
Systemic sclerosis Pericardial effusion, CHF (systolic and diastolic), myocar¬
Tachyarrhythmias _
ditis, coronary microvascular vasospasm,
_
Abbreviations: CAD, coronary artery disease; CHF, congestive heart failure; CMP, cardio¬
myopathy, SVT, supraventricular tachycardia
TABLE CLASSIFICATION OF MYOCARDIAL INFARCTION

Typel: Spontaneous Myocardial Infarction
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, Assur¬
ing, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary
arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte
necrosis. The patient may have underlying severe coronary artery disease (CAD) but on occasion
nonobstructive or no CAD
Type2: Myocardial Infarction Secondary to an Ischemic Imbalance
In Instances of myocardial injury with necrosis where a condition other than CAD contributes to
an imbalance between myocardial oxygen supply and/ or demand, eg. coronary endothelial dys¬
function, coronary artery spasm, coronary embolism, Tachybrady- arrthythmias, anemia respira¬
tory failure, coronary embolism , tachybrady- arrthyhmias, anemia, respiratory failure, hypoten¬
sion, and hypertension with or without left ventricular hypertrophy.
Type 3: Myocardial Infarction resulting in Death Whn biomarker values Are Unavailable
Cardiac Death with symptoms suggestive of myocardial ischemia and presumed new ischemic elec¬
trocardiogram (ECG) changes or new left bundle branch block (LBBB), but death occurring before
blood samples could be obtained or before cardiac biomarker could rise, or in rare cases, cardiac
biomarkers were not collected.
Type4a: Myocardial Infarction Related to Percutaneous Coronary Intervention (PCI)
Myocardial infarction associated with PCI is arbitrarily defined by elevation of cardiac
troponin (cTn) values (s99th percentile URL) or a rise of cTn values £ 20% if the baseline
values are elevated and are stable or falling . In addition, either (i) symptoms suggestive of
myocardial ischemia, or (ii) new ischemic ECG changes or new LBBB, or (iii) angiograph¬
ic loss of patency of a major coronary artery or a side branch or persistent slow or no flow
or ambolization, or 9iV) imaging demonstration of new loss of viable myocardium or new
regional wall motion abnormality is required

n HARRISON’S 19TH BASED NOTE BOOK
Type4b: Myocardial Infarction Related to stent Thrombosis

Myocardial infarction associated with stent thrombosis is detected by coronary angiogra¬
phy or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac
biomarker values with at least one value above the 99th percentile URL.
Type 5 Myocardial Infarction Related to Coronary Artery Bypass Grafting (CABG)
Myocardial infarction associated with CABG is arbitrarily defined by alevation of cardiac
biomarker values > 10* 99th percentile URL in patients with normal baseline cTn values
( 99 percentile URL). In addition, either (i) new pathologic Q waves or new LBBB, or (ii)
angiographic documented new graft or new native coronary artery' occlusion, or (iii) imag-
ing evidence of new loss of viable myocardium or new regional wall motion abnormality.
TABLE SYSTOLIC HYPERTENSION WITH WIDE PULSE PRESSURE

1. Decreased vascular compliance (arteriosclerosis)
2. Increased cardiac output
a. Aortic regurgitation
b. Thyrotoxicosis
c. Hyperkinetic heart syndrome
d. Fever
e. Arteriovenous fistula
f. Patent ductus arteriosus
USEFUL ONE LINERS

• Most common congenital cardiovascular cause of hypertension is Coarctation of aorta.
• The term resistant hypertension refers to patients with blood pressures persistently >
140/90 mmHg despite taking three or more antihypertensive agents,including a diuretic.
PREFERRED PARENTERAL DRUGS FOR SELECTED HYPERTENSIVE

TABLE
EMERGENCIES
Hypertensive encephalopathy Nitroprusside, nicardipine, labctalol
Malignant hypertension (when IV therapy is indi- Labetalol, nicardipine, nitroprusside
cated) enalaprilat
tr°kC Nicardipine, labetalol, nitroprusside
Myocardial infarction/unstable angina Nitroglycerin, nicardipine, labetalol,
csmolol
Email: mfo@damsdeIhi.com | Website:

www.damsdclhi.com Page | 107
M
Acute left ventricular failure Nitroglycerin, enalaprilat, loop
diuretics
Aortic dissection Nitroprusside, esmolol, labetalol
Adrenergic crisis Phentolamine, nitroprusside
Postoperative hypertension Nitroglycerin, nitroprusside, labeta¬

lol, nicardipine
Preeclampsia/eclampsia of pregnancy Hydralazine, labetalol, nicardipine
• MALIGNANT HYPERTENSION (Pg:l630)

• DEEP VEIN THROMBOSIS & PULMONARY EMBOLISM (Pg:l631-37)
USEFUL ONE LINERS
• Most common acquired cause of thrombophilia is Antiphospholipid antibody syndrome

and is associated with venous or arterial thrombosis.
• Most common gas exchange abnormalities in pulmonary embolism are arterial hypoxemia
and an increased alveolar-arterial Intension gradient.
• The sensitivity of the D-dimer is >80% for DVT (including isolated calfDVT) and >95%
for PE. The D-dimer is less sensitive for DVT than for PE because the DVT thrombus
size is smaller.
• Most specific ECG finding in pulmonary embolism is the S1Q3T3 sign: an S wave in lead
1, a Qwave in lead III,and an inverted T wave in lead III.
• The best-known indirect sign of pulmonary embolism on transthoracic echocardiography
is McConnell’s sign: hypokinesis of the RV free wall with normal or hyperkinetic motion
of the RV apex. _
Keep in mind -A normal or nearly normal chest x-ray often occurs in Pulmonary embolism. Well-es¬
tablished abnormalities include focal oligemia (Westermark’s sig ), a peripheral wedged-shaped den¬
sity above the diaphragm (Hamptons Hump), and an enlarged right descending pulmonary artery
(Palla’s sign).
• AORTIC ANEURYSM (Pg:1637-40)

• AORTIC DISSECTION (Pg:l640-4l)

Typo A
|i
A
.
T:
, ;
i
Figure Classification of aortic dissections. Stanford classification: Type A dissections (top)

involve the ascending aorta independent of site of tear and distal extension; type B dissections
(bottom) involve transverse and/or descending aorta without involvement of the ascending aorta.
DeBakey classification: Type I dissection involves ascending to descending aorta (top left); type II
dissection is limited to ascending or transverse aorta, without descending aorta (top center + top
right); type III dissection involves descending aorta only (bottom left).
USEFUL ONE LINERS
• Medial degeneration is the most common pathology associated with ascending aortic an¬
eurysms,whereas atherosclerosis is the condition most frequently associated with aneu-
rysms of the descending thoracic aorta.
• 90% of syphilitic aneurysms are located in the ascending aorta or aortic arch.
• Tuberculous aneurysms typically affect the thoracic aorta.
• A mycotic aneurysm is a rare condition that develops as a result of staphylococcal,strep¬
tococcal,Salmonella, or other bacterial or fungal infections of the aorta, usually at an
atherosclerotic plaque.

• TAKAYASU ARTERITIS (Pg:1642)

• FIBROMUSCULAR DYSPLASIA (Pg:l645)
• THROMBOANGIITIS OBLITERANS (Pg:1645-46)
USEFUL ONE LINERS
• Most common peripheral artery aneurysm is popliteal artery aneurysm.

• Takayasu’ s arteritis is also termed pulseless disease because of the frequent occlusion of the
large arteries originating from the aorta.
HIGH YIELDING TOPIC
• RAYNAUD’S PHENOMENON (Pg:l647-49)

TABLE CLASSIFICATION OF RAYNAUD’S PHENOMENON
Primary or idiopathic Raynaud’s phenomenon
Secondary Raynaud’s phenomenon
Collagen vascular diseases: scleroderma, systemic lupus erythematosus, rheumatoid arthri¬
tis, dermatomyositis, polymyositis, mixed connective tissue disease, Sjogren’s syndrome
Arterial occlusive diseases: atherosclerosis of the extremities, thromboangiitis obliterans,
acute arterial occlusion, thoracic outlet syndrome
Pulmonary hypertension
Neurologic disorders: intervertebral disk disease, syringomyelia, spinal cord tumors, stroke,
poliomyelitis, carpal tunnel syndrome, complex regional pain syndrome
Blood dyscrasias: cold agglutinins, cryoglobulinemia, cryofibrinogenemia, myeloprolifera¬
tive disorders, lymphoplasmacytic lymphoma
Trauma: vibration injury, hammer hand syndrome, electric shock, cold injury, typing,
piano playing
Drugs and toxins: ergot derivatives, methysergide, 2-adrenergic receptor blockers, bleomy¬
cin, vinblastine, cisplatin, gemcitabine, vinyl chloride
USEFUL ONE LINER

• May Thurner syndrome - Left iliac vein is occluded or stenosed by extrinsic compression
from the overlapping right common iliac artery.

HIGH YIELDING TOPIC
• PULMONARY HYPERTENSION (Pg:1655-60)

Five Categories of Pulmonary Hypertension (Who)
Group 1. Pulmonary arterial hypertension
Group 2. Pulmonary hypertension due to left heart disease
Group 3. Pulmonary hypertension due to chronic lung disease
Group 4. Pulmonary hypertension due to chronic thromboemboli
Group 5. Miscellaneous causes
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• Most common presenting symptom of pulmonary hypertension is dyspnea.

Page | 111
CHAPTER 8 RESPIRATORY SYSTEM
iff*
t
7,0,
•tT
o 4
o
USEFUL ONE LINER
• Most of the consistent findings in bronchial asthma have been associated with polymor¬
phisms of genes on chromosome 5q.
TABLE PULMONARY INFILTRATES WITH EOSINOPHILIA

Primary Pulmonary Eosinophilic Disorders
Acute eosinophilic pneumonia
Chronic eosinophilic pneumonia
Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome)
Hypereosinophilic syndrome
Pagej 112 Email: info@damsdelhi.com | Website: www.damsdelhi.com

S£ HARRISON’S 19TH BASED NOTE BOOK
Pulmonary Disorders of Known Cause Associated with Eosinophilia

Asthma and eosinophilic bronchitis
Allergic bronchopulmonary aspergillosis
Bronchocentric granulomatosis
Drug/toxin reaction
Infection (Table 310-4)
Parasitic/helminthic disease
Nonparasitic infection
Lung Diseases Associated with Eosinophilia
Cryptogenic organizing pneumonia
Hypersensitivity pneumonitis
Idiopathic pulmonary fibrosis
Pulmonary Langerhans cell granulomatosis
Malignant Neoplasms Associated with Eosinophilia
Leukemia
Lymphoma
Lung cancer
Adenocarcinoma of various organs
Squamous cell carcinoma of various organs
Systemic Disease Associated with Eosinophilia
Postradiation pneumonitis
Rheumatoid arthritis
Sarcoidosis
Sjogren’s syndrome
USEFUL ONE LINERS

• The excess frequency of lung cancer in asbestos workers is associated with a minimum
latency of 15-19 years between first exposure and development of the disease.
• Relatively shortterm asbestos exposures of <l-2years,occurring up to 40 years in the
past,have been associated with the development of mesotheliomas.
• The clinical and pathologic features of acute silicosis are similar to those of pulmonary
alveolar proteinosis.
• In Silicosis,the chest radiograph may show profuse miliary infiltration or consolidation,and
there is a characteristic HRCT pattern known as “crazy paving”.
• Calcification ofhilar nodes may occur in as many as 20% of cases of silicosis and produces
a characteristic “eggshell” pattern.

m
• Because silica is.cytotoxic to alveolar macrophages,patients with silicosis are at greater risk
of acquiring lung infections that involve these cells as a primary defense (Mycobacterium
tuberculosis, atypical mycobacteria and fungi).
• Caplan syndrome ,first described in coal miners but subsequently in patients with silicosis,
is the combination of pneumoconiotic nodules and seropositive rheumatoid arthritis.
• Byssinosis is characterized clinically as occasional (early-stage) and then regular (late-stage)
chest tightness toward the end of the first day of the workweek (“Monday chest tightness’ ).
• Bronchiectasis is more common among women than among men.
• The most common form of bronchiectasis is cyclindrical or tubular .
• Bronchiectasis seen in association with cystic fibrosis and post radiation fibrosis mostly
involves the upper lung fields.
• Bronchiectasis resulting from infection by nontuberculous mycobacteria (NTM), most
commonly the Mycobacterium avium-intracellulare complex (MAC), often preferentially
affects the midlung fields.
• Congenital bronchiectasis in association with immotile cilia syndrome involves predomi¬
nantly the midlung fields.
• Allergic Bronchopulmonary aspergillosis also is associated with central bronchiectasis.
• BRONCHIECTASIS (Pg:1694-96)
• CYSTIC FIBROSIS (Pg:l697-99)
TABLE GOLD CRITERIA FOR SEVERITY OF AIRFLOW OBSTRUCTION IN COPD

GOLD Stage Severity Spirometry
I Mild FEV/FVC <0.7 and FEV,, 2: 80%
predicted
II Moderate FEV/FVC <0.7 and FEV,, ;> 50% but
<80% predicted
III Severe FEV/FVC <0.7 and FEV,, *30% but
<50% predicted
IV Very severe FEV/FVC <0.7 and FEV,, <30% pre¬
dicted
Abbreviations: COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for
Lung Disease
DIAGNOSTIC VALUE OF BRONCHOALVEOLAR LAVAGE IN

TABLE INTERSTITIAL LUNG DISEASE
Condition Bronchoalveolar Lavage Finding

Sarcoidosis Lymphocytosis; CD4;CD8 ratio >3-5 most
specific of diagnosis
Hypersensitivity pneumonitis Marked lymphocytosis (>30%)
Organizing pneumonia Foamy macrophages; mixed pattern of increased
cells characteristic; decreased CD4:CD8 ratio
Eosinophilic lung disease Eosinophils >25%
Diffuse alveolar bleeding Hemosiderin laden macrophages, red blood
cells
Diffuse alveolar damage, drug toxicity Atypical hyperplastic type 1 pneumocytes
Opportunistic infections Pneumocystis carinii, fungi, cytomegalovirus
transformed cells
Lymphangitic carcinomatosis, alveolar Malignant cells
cell carcinoma, pulmonary lymphoma
Alveolar proteinosis Milky effluent, foamy macrophages and lipo¬
protein aceous intraalveolar material (periodic
acid-Schiff stain-positive)
Lipoid pneumonia Fat globules in macrophages
Pulmonary Langerhans cell histiocytosis Increased CD1+ Langerhans cells, electron
microscopy demonstrating Birbeck granule in
lavaged macrophage (expensive and difficult to
perform)
Asbestos related pulmonary disease’ Dust particles, ferruginous bodies
Berylliosis Positive lymphocyte transformation test to
beryllium
Silicosis Dust particles by polarized light microscopy
Lipoidosis Accumulation of specific lipopigment in alveo-
lar macrophages
USEFUL ONE LINERS

• Most common form of Idiopathic Interstitial Pneumonia is Idiopathic Pulmonary Fibro¬
sis.

Page | 115
• Acute Interstitial Pneumonia is also known as Hamman-Rich-Syndrome.
• Desquamative Interstitial Pneumonia is the form of ILD that is exclusively found in smok¬
ers.
• Pulmonary Alveolar Proteinosis is an autoimmune disease with a neutralizing antibody
of immunoglobulin G isotype against granulocyte-macrophage colonystimulating factor
(GM-CSF).
• Pulmonary Lymphangioleiomyomatosis is a rare condition that afflicts premenopausal
women and should be suspected in young women with emphysema, recurrent pneumo¬
thorax, or chylous pleural effusion.
• Hermansky-Pudlak syndrome is an autosomal recessive disorder in which granulomatous
colitis and ILD may occur.
• Lymphocytic Interstitial Pneumonitis is a rare form of ILD, that has been reported in
Sjogren syndrome and HIV infection.
• Light’s criteria for differentiating exudative and transudative pleural effusion. Exudative
pleural effusions meet at least one of the following criteria,whereas transudative pleural
effusions meet none.
1. Pleural fluid protein/serum protein >0.5
2. Pleural fluid LDH/serum LDH >0.6
3. Pleural fluid LDH more than two-thirds the normal upper limit for serum
USEFUL ONE LINERS
• A pleural fluid N-terminal pro-brain natriuretic peptide (NT-proBNP) >1500 pg/mL is

virtually diagnostic that the pleural effusion is secondary to congestive heart failure.
-
• The three tumors that cause 75% of all malignant pleural effusions are lung carci¬
noma,breast carcinoma and lymphoma.
• The most common cause of chylothorax is trauma (most frequently thoracic surgery)
• Drug-induced pleural disease
a. Nitrofurantoin
b. Dantrolene
c. Methysergide
d. Bromocriptine
e. Procarbazine •
f. Amiodarone
g. Dasatinib

HIGH YIELDING TOPIC

(Pg:1723-27)
• OBSTRUCTIVE SLEEP APNEA/HYPOPNEA SYNDROME
OBSTRUCTIVE SLEEP APNEA/HYPOPNEA SYNDROME (OSAHS):
TABLE QUANTIFICATION AND SEVERITY SCALE
of sleep
• Apnea-hypopnea index (AHI/ Number of apneas plus hypopneas per hour
• Respiratory disturbance index (RDl): Number of apneas plus hypopneas plus RERAs per
hour of sleep
• Mild OSAHS: AHI of 5-14 events/h
• Moderate OSAHS: AHI of 15-29 events/h
• SevereOSAHS: AHI of >30 events/h
TABLE CLINICAL DISORDERS COMMONLY ASSOCIATED WITH ARDS

Direct Lung Injury Indirect Lung Injury
Pneumonia Sepsis
Aspiration of gastric contents Severe trauma
Pulmonary contusion Multiple bone fractures
Near-drowning Flail chest
Toxic inhalation injury Head trauma
Burns
Multiple transfusions
Drug overdose
Pancreatitis
Postcardiopulmonary bypass
TABLE DIAGNOSTIC CRITERIA FOR ARDS

Severity: Oxygenation On- Chest Radio¬ Absence of Left Atrial
set graph Hypertension
Mild: 200 mmHg Acute Bilateral alveo- PCWP £ 18 mmHg or no
< Pao2/Flo2 < 300 mmHg lar or interstitial clinical evidence of in¬
Moderate: 100 mmHg infiltrates creased left atrial pressure
< Pao2/Flo2 < 200 mmHg
Severe: Pao2/Flo2 <, 100
mmHg
Abbreviations: ARDS, acute respiratory distress syndrome; F102, inspired 02 percentage;
Pao2, arterial partial pressure of 02, PCWP pulmonary capillary wedge pressure
USEFUL ONE LINERS

• Most common cause of superior vena cava syndrome is small cell carcinoma lung.
• Erosion of the pedicles (the “winking owl” sign) is the earliest radiologic finding of verte¬
bral metastatic tumor.
• Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyperkalemia, hyper¬
phosphatemia, and hypocalcemia and is caused by the destruction of a large number of
rapidly proliferating neoplastic cells.

CHAPTER 9
i
DISORDERS OF KIDNEY AND URINARY !
TRACT
l ..... -
;
J
:
•»;
F
V
L O
TABLE DRUGS THAT INHIBIT NEPHROGENESIS

Dexamethasone
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Gentamicin
Nonsteroidal anti-inflammatory drugs
USEFUL ONE LINERS
• Acute Kidney Injury secondary to acute interstitial nephritis can occur as a consequence
of exposure to many antibiotics,including penicillins,cephalosporins,quinolones,sulfon¬
amides, and rifampin.
• Normal sized kidneys are expected in AKI. Enlarged kidneys in a patient with AKI sug¬
gests the possibility of acute interstitial nephritis.

>
CTC
rt 2
CO
o
o
Z
C/5
Urinary sediment in AKI
s
>r x
03
Abnormal >
co
'r
Z
> r i r >r >r >r o
Normal or few RBC or
RBCs WBCs
Renal tubular
epithelial (RTE)
5
WBC or hyaline casts Granular casts Eosinophiluria Crystalluria
RBC casts WBC casts cells RTE casts C
m Pigmented casts C
3
5' Acute uric acid

Interstitial Allergic
o' Prerenal nephropathy
nephritis ATN interstitial
Postrenal GN ATN Calcium oxalate
a. GN Tubulointerstitial nephritis
Arterial thrombosis Vasculitis GN (ethylene glycol
3 Pyelonephritis nephritis Atheroembolic
M or emboloisim Malignant Vasculitis intoxication)
Allograft Acute cellular disease
Preglomerular hypertension Tubulo¬ Drugs or toxins
2=
=ÿ vasculitis Thrombotic
rejection alograft rejection
interstitial
Pyelonephritis
(acyclovir,
Malignant Myoglobinuria Cystitis
n HUS or TTP microangiopathy nephritis indinavir,
infiltration of the Hemoglobinuria Glomerulo¬
3 Scleroderma crisis sulfadiazine
kidney nephritis
amoxicillin)
o_
S- Figure Interpretation of urinary sediment findings in acute kidney injury (AKI). ATN, acute tubular necrosis; GN, glomerulone¬
phritis; HUS, hemolytic-uremic syndrome; RBCs, red blood cells; RTE, renal tubular epithelial; TTP, thrombotic thrombocytopenic
purpura; WBCs, white blood cells, (Adapted from L Yang, JV Bonventre: Diagnosis and clinical evaluation of acute kidney injury.
a. In Comprehensive Nephrology, 4th ed.)
fu
3
Q-
£L
¥ÿ
n
3
USEFUL ONE LINERS
• In Chronic Kidney Disease, kidneys are usually smaller unless the patient has diabetic
nephropathy, HIV -associated nephropathy,or infiltrative diseases.
• Peak GFR in a normal adult is achieved during third decade of life,following which there
is decline.
• Cardiac troponin levels are frequently elevated in CKD without evidence of acute ischemia.
> Calciphylaxis (calcific uremic arteriolopathy) is a devastating condition seen
almost exclusively in patients with advanced CKD. It is heralded by livedo re¬
ticularis and advances to patches of ischemic necrosis, especially on the legs,
thighs,abdomen,and breasts.Pathologically, there is evidence of vascular oc¬
clusion in association with extensive vascular and soft tissue calcification.
Calciphylaxis
i i
Figur Calciphylaxis. This Peritoneal dialysis patient was on chronic warfarin therapy for
atrial
fibrillation. She noticed a small painful nodule on the abdomen that was followed by progressive
skin necrosis and ulceration of the anterior abdominal wall. She was treated with hyperbaric oxygen
intravenous thiosulfate, and discontinuation of warfarin, with slow resolution of the ulceration
TABLE CAUSES OF ANEMIA IN CKD

Relative deficiency of erythropoietin
Diminished red blood cell survival

Page | 121
Bleeding diathesis
Iron deficiency
Hyperparathyroidism/bone marrow fibrosis
Chronic inflammation
Folate or vitamin B12 deficiency
Hemoglobinopathy
Comorbid conditions: hypo-/hyperthyroidism, pregnancy, HIV-associated disease, auto-
immune disease, immunosuppressive.drugs
A skin condition unique to CKD patients called nephrogenic fibrosing dermopathy con-
sists of progressive subcutaneous induration,especially on the arms and legs. The condition
is similar to scleromyxedema and is seen very rarely in patients with CKD who have been
exposed to the magnetic resonance contrast agent gadolinium. Current recommendations are
that patients with CKD stage 3 (GFR 30-59 mL/min) should minimize exposure to gadolin¬
ium, and those with CKD stages 4-5 (GFR <30 mL/min) should avoid the use of gadolinium
agents unless it is medically necessary.
THE MOST COMMON OPPORTUNISTIC INFECTIONS IN RENAL

3=3 TRANSPLANT RECIPIENTS
Peritransplant (<1 month) Late (>6 months)

Wound infections Aspergillus
Herpesvirus Nocardia
Oral candidiasis BK virus (polyoma)
Urinary tract infection Herpes zoster
Early (1-6 months) Hepatitis B
Pneumocystis jiroveci Hepatitis C
Cytomegalovirus
Legionella
Listeria
Hepatitis B
Hepatitis C
TABLE CLASSIFICATION FOR LUPUS NEPHRITIS
ClassI Minimal mesangial Normal histology with mesangial deposits

Class II Mesangial proliferation Mesangial hypercellularity with expansion of the
mesangial matrix

Class III Focal nephritis Focal endocapillary ± extracapillary proliferation

with focal subendo-thelial immune deposits and mild
mesangial expansion
Class IV Diffuse nephritis Diffuse endocapillary ± extracapillary proliferation
with diffuse subendo-thelial immune deposits and
mesangial alterations
Class V Membranous nephritis Thickened basement membranes with diffuse subep-
ithelial immune deposits; may occur with class III or
IV lesions and is sometimes called mixed membra¬
nous and proliferative nephritis
Class VI Sclerotic nephritis Global sclerosis of nearly all glomerular capillaries
USEFUL ONE LINERS
• Patients with lupus nephritis class V are predisposed to renal vein thrombosis and other
thrombotic complications.
• The renal biopsy in poststreptococcal glomerulonephritis demonstrates hypercellularity
of mesangial and endothelial cells, glomerular infiltrates of polymorphonuclear leuko¬
cytes,granular subendothelial immune deposits of IgG,IgM,C3,C4,and C5-9 and subepi-
thelial deposits (which appear as “humps”).
• Goodpasture’s syndrome appears in two age groups: in young men in their late twenties
and in men and women in their sixties and seventies.
• IgA nephropathy is one of the most common forms of glomerulonephritis worldwide.
• POST STREPTOCOCCAL GLOMERULONEPHRITIS (Pg:1837)

• LUPUS NEPHRITIS (Pg:1838)
• IgA NEPHROPATHY (Pg:1839)
TABLE MEMBRANOPROLIFERATIVE GLOMERUALONEPHRITIS
Type 1Disease (Most Common)
Idiopathic
Subacute bacterial endocarditis

Hepatitis C ± cryoglobulinemia
Mixed cryoglobulinemia
Hepatitis B
Cancer: Lung, breast, and ovary (germinal)
TypeIIDisease (Dense Deposit Disease)
Idiopathic
C3 nephritic factor-associated
Partial lipodystrophy
Type III Disease
Idiopathic
Complement receptor deficiency
USEFUL ONE LINERS

• Most common cause of nephrotic syndrome in elderly is membranous glomerulonephritis.
• Dot and fleck retinopathy is seen in Alport’s syndrome.
• The lesion in HIV associated nephropathy (HIVAN) is FSGS, characteristically revealing
a “collapsing glomerulopathy”.
• The renal lesions most commonly seen in hepatitis C, in order of decreasing frequency,are
cryoglobulinemicglomerulonephritis, MGN.and typeIMPGN.
• The schistosoma strain most commonly associated with clinical renal disease is Schisto¬
soma mansoni.
• Serum lipid profiles in humans are greatly affected by apolipoprotein E polymorphisms;
the E4 allele is accompanied by increases in serum cholesterol and is more closely associat¬
ed with atherogenic profiles in patients with renal failure. Mutations in E2 alleles,particu¬
larly in Japanese patients,produce a specific renal abnormality called lipoprotein glomeru¬
lopathy associated with glomerular lipoprotein thrombi and capillary dilation.
USEFUL ONE LINERS

• Autosomal dominant polycystic kidney disease is caused mutations in PKDl and PKD2
genes on chromosome I6p and 4q respectively.
• ADPKD is the most common adult-onset,single-gene form of kidney disease.
• Autosomal recessive polycystic kidney disease is caused by mutations in the gene PKHDl
gene located on chromosome6p.
• Most common renal lesion in tuberous sclerosis is angiomyolipoma.
n HARRISON’S 19TH BASED NOTE BOOK
• Most common inherited childhood form of kidney failure requiring kidney replacement
therapy is Nephronophthisis.
• Most common renal manifestation of Sjogren’s syndrome is tubulointerstitial nephritis
with a predominant lymphocytic infiltrate.
HIGH YIELDING TOPIC
• TUBEROUS SCLEROSIS (Pg:1854)
INDICATIONS FOR CORTICOSTEROIDS AND IMMUNOSUPPRESSIVES

TABLE
IN INTERSTITIAL NEPHRITIS
Absolute Indications _
• Sjogren’s syndrome
• Sarcoidosis
• SLE interstitial nephritis
• Adults with TINU
• Idiopathic and other granulomatous interstitial nephritis
Relative Indications
• Drug-induced or idiopathic AIN with:
> Rapid progression of renal failure
> Diffuse infiltrates on biopsy
> Impending need for dialysis
> Delayed recovery
• Children with TINU
• Postinfectious AIN with delayed recovery (?)
Abbreviations: AIN, acute interstitial nephritis; SLE, systemic lupus erythematosus; TINU,
tubulointerstitial nephritis with uveitis.
HIGH YIELDING TOPIC
• THROMBOTIC MICROANGIPATHY (Pg:729,1848, 1863-64,)

USEFUL ONE LINERS
• Inherited TTP is also known as Upshaw Schulman syndrome.
• Scleroderma renal crisis occurs in 12% of patients with diffuse systemic sclerosis but in
only 2% of those with limited systemic sclerosis.
m
• Renal vein thrombosis more commonly involves the left renal vein, and two-third of cases
are bilateral.
• Most common renal stones are calcium oxalate stones.
• The two most common and well-characterized rare monogenic disorders that lead to stone
formation are primary hyperoxaluria and cystinuria.
• Struvite stones,also known as infection stones or triplephosphate stones,form only when
the upper urinary tract is infected with urease-producing bacteria such as Proteus mirabi-
lis,Klebsiella pneumoniae, or Providencia species.
• Struvite stones may grow quickly and fill the renal pelvis producing staghorn calculi.
Page | 126
www.damsdelhi.com
CHAPTER 10 ALIMENTARY TRACT
r i
i
i
W
o
DIEULAFOY’S LESION
• It is a large-caliber arteriole that runs immediately beneath the gastrointestinal mucosa

and bleeds through a pinpoint mucosal erosion.
• It is also called persistent caliber artery.
• Seen most commonly on the lesser curvature of the proximal stomach.
• C/F- Impulsive arterial hemorrhage.
• Endoscopic therapy,such as thermal coagulation or band ligation,is typically effective for
control of bleeding and ablation of the underlying vessel once the lesion has been identi¬
fied.

Page | 127
USEFUL ONE LINERS
• The most sensitive test for diagnosis of Gastroesophageal reflux disease is 24-hour ambu¬
latory pH monitoring.
• A lower esophageal mucosal ring,also called a B ring, is a thin membranous narrowing
at the squamocolumnar mucosal junction. When the lumen diameter is less
than 13
mm, distal rings are usually associated with episodic solid food dysphagia and are called
Schatzki rings.
• Schatzki ring is one of the most common causes of intermittent food impaction,also
known as “steakhouse syndrome” because meat is a typical instigator.
• The most common congenital esophageal anomaly is esophageal atresia.
• Radiographically, a “corkscrew esophagus”, “rosary bead esophagus”, pseudodiverticula.or
curling can be indicative of Diffuse Esophageal Spasm, but these are also found with
spastic achalasia.
Figure Diffuse esophageal spasm. The characterstic “corkscrew esophagus results from
spastic contraction of the circular muscle in the esophageal wall: more precisely, this is actually a
helicalarray of muscle. These findings are also seen with spastic achalasia.
TABLE DIFFERENT CLINICAL, ENDOSCOPIC, AND RADIOGRAPHIC FEATURES
Ulcerative Colitis Crohn’s Disease

Clinical
Gross blood in stool Yes Occasionally
Mucus Yes Occasionally
Page) 128 Email: info@damsdclhi.com | Website: www.damsdelhi.com

Occasionally Frequently
Systemic symptoms
Pain
Rarely Yes
Abdominal mass
No Frequently
Significant perineal disease
No Yes
Fistulas
No Frequently
Small intestinal obstruction
Colonic obstruction Rarely Frequently
No Yes
Response to antibiotics
Recurrence after surgery No Yes
Endoscopic
Rectal sparing Rarely Frequently
Continuous disease Yes Occasionally
“Cobblestoning” No Yes
Granuloma on biopsy No Occasionally
Radiographic
Small bowel significantly abnormal No Yes
Abnormal terminal ileum No Yes
Segmental colitis No Yes
Asymmetric colitis No Yes
Stricture _
HIGH YIELDING TOPIC
• INFLAMMATORY BOWEL DISEASE (Pg:1947-65)

TAB LE DIAGNOSTIC CRITERIA FOR IRRITABLE BOWEL SYNDROME3
Recurrent abdominal pain or discomfort* at least 3 days per month in the last 3 months
associated with two or more of the following:
1. Improvement with defecation
2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool
"Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to
diagnosis. means an uncomfortable sensation not described as pain. In patho¬
physiology research and clinical trials, a pain/discomfort frequency of at least 2 days a week
during screening evaluation is required for subject eligibility.

CHAPTER 11
:
LIVER AND BILIARY TRACT DISEASE
’C
-TT —
w 1
o
io
I
TABLE CHILD-PUGH CLASSIFICATION OF CIRRHOSIS
Factor Units Points Toward Total Score

1 2 3
Serum bilirubin pmol/L <34 34-51 >51
mg/dL <2.0 2.0-3.0 >3.0
Serum albumin g/L >35 30-35 <30
g/dL >3.5 3.0-3.5 <3.0
Prothrombin time seconds prolonged <4 4-6 >6
INR- <1.7 1.7-2.3 >2.3
Ascites None Easily controlled Poorly controlled
Hepatic encephalopathy None Minimal Advanced
“International normalized ratio
Note: The Child-Pugh score is calculated by adding the scores for the five factors and can
range from 5 to 15. The resulting Child-Pugh class can be A (a score of
5-6), B (7-9), or C
10). Decompensation indicates cirrhosis, with a Child-Pugh score of (class B). This level
has been the accepted criterion for listing a patient for liver transplantation
PRINCIPAL DIFFERENTIAL CHARACTERISTICS OF GILBERT AND

TABLE
CRIGLER-NAJJAR SYNDROMES
Crigler Najjar Syndrome

Feature Type I Type II Gillbert Syndrome
Total serum biliru- 310-755 (usually 100-430 Typically <70 pmol/L (< 4 mg/dL)
bin, pmol/L (mg/ >345) (18-45 (usually in absence of fasting or hemolysis
dL) [usually >20]) <345) (6-25
[usually
*20])
Routine liver tests Normal Normal Normal
Response to phe- None Decreases Decreases bilirubin to normal
nobarbital Usual bilirubin No
Kernicterus Normal by>25% Usually normal; increased lipofus-
Hepatic histology Rare cin pigment in some
Normal
Bile characteristics Pale or colorless Pigmented Normal dark color
Color >90% unconju- Largest frac¬ Mainly diconjugates but monocon¬
Bilirubin frac- gated tion (mean: jugates increased (mean: 23%)
tions 57%) mono¬
conjugates
Bilirubin Typically absent; Markedly Reduced: typically 10-33% of
UDP-glucurono- traces in some reduced: normal
syltransferase patients 0-10% of Promoter mutation: recessive
activity Recessive normal Missense mutations: 7 of 8 domi¬
Inheritance (all Predom¬ nant; 1 reportedly recessive
autosomal) inantly
recessive
Email-, info@damsdelhi.com |
Website: www.damsdelhi.com
Page | 131
TABLE CLINICAL AND EPIDEMIOLOGIC FEATURES OF VIRAL HEPATITIS
Feature HAV HBV HCV HDV HEV
Incubation 15-45, mean 30-180, mean 15-160, mean 30-180. 14-60, mean
(days) 30 60-90 50 mean 60-90 40
Onset Acute Insidious or Insidious Insidious or Acute
acute acute
Age prefer¬ Children, Young adults Any age, but Any age Epidemic
ence young adults (sexual and more com¬ (similar to cases: young
percutane¬ mon in adults HBV) adults (20-
ous), babies, 40 years);
toddlers sporadic
cases; older
adults (>60)
Transmis¬
sion
Fecal-oral +++ +++
Percutane- Unusual +++ +++ +++
ous +++ ±a +
Perinatal ± ++ ±a ++
Sexual
I
Clinical
Severity Mild Occasionally Moderate Occasionaly Mild
Fulmi¬ 0.1% severe 0.1% severe 1-2%’
nant None 0.1-1% Common 5-20%b Nonel
Progres- None Occasional (85%) Commond’ None
sion to None (1-10%) (90% 15-3.2% Variable* None
chronicity Fxcellent of neonates) + ± Good
Carrier 0.1-30%c Moderate Acute, good
Cancer + (neonatal Chronic poor
Prognosis infection)
Worse with
age, debility
Prophylaxis Ig, inactivat- HBIG, None HBV vaccine Vaccine
ed vaccine recombinant (none for
vaccine HBV carri¬
ers)

Therapy None Interferon Pegyiated in- Pegyiated None*

Lamivudine terferon plus interferon ±
Adefovir ribavirin,
Pegyiated telaprevir,
interferon boceprevir
Entecavir
Telbrvudine
Tenofovir
"Primarily with HIV co infection and high level viremia in index case; risk -5% bUp to 5% in acute
HBVAHDV co infection; up to 20% in HDV superinfection of chronic HBV infection ‘cVaries con-
siderably throughout the world and in subpopulations within countries; see text din acute HBV/HDV
co infection, the frequency of chronicity is the same as that for HBV; in HDV superinfection, chronic-
ity is invariable. '10 20% ft pregnant womenExcept as observed in immunosuppressed liver allograft
recipents or other imunosuppressed hosts. ‘'Common in Mediterranean countries; rare in North Amer¬
ica and western Europe. hAnecdotal reports and retrospective studies suggest that pegyiated interferon
and/or ribavirin are effective in treating chronic hepatitis E observed in immunocompromised persons
COMMONLY ENCOUNTERED SEROLOGIC PATTERNS OF HEPATITIS B

TABLE
INFECTION
HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe Interpretation
Acute hepatitis B, high infec-
+ IgM +
tivity"
Chronic hepatitis B, high infec-
+ IgG +
tivity
1. Late acute or chronic hepati¬
tis B, low infectivity
+ IgG + 2. HBeAg negative (“precore
mutant”) hepatitis B (chronic
or, rarely, acute)
1. HBsAg of one subtype and
+ + + +/- +/- heterotypic anti-HBs (common)
2. Process of seroconversion
from HBsAg to anti-HBs (rare)
IgM +/- 1. Acute hepatitis B1
+/—
2. Anti-HBc “window”
IgG 1. Low level hepatitis B carrier
+/—
2. Hepatitis B in remote past

Page | 133
+ IgG +/— Recovery from hepatitis B
1. Immunization with HBsAg
(after vaccination)
+ 2. Hepatitis B in the remote
past (?)
3. False positive
SIMPLIFIED DIAGNOSTIC APPROACH IN PATIENTS PRESENTING WITH

TABLE
ACUTE HEPATITIS
Serologic Tests of Patient’s Serum

HBsAg IgM Anti-HAV IgM Anti-HBc Anti-HCV Diagnostic Interpretation
+ + Acute hepatitis B
+ Chronic hepatitis B
+ + Acute hepatitis A superim¬
posed on chronic hepatitis B
+ + + Acute hepatitis A and B
+ Acute hepatitis A
+ + Acute hepatitis A and B (HB¬
sAg below detection threshold)
+ Acute hepatitis B (HBsAg
below detection threshold)
+ Acute hepatitis C
TABLE CLINICAL AND LABORATRY FEATURES OF CHRONIC HEPATITIS

Type of Hepatitis Diagnostic Test(s) Autoantibodies Therapy
IFN-a, PEG IFN-a
Oral agents:
First line: entecavir,
Chronic hepatitis B HBsAg, IgG
anti-HBc,
Uncommon tenofovir
HBeAg, HBV DNA
Second line: lami-vu-
dine, adefovir, telbivu-
dine

im HARRISON’S 19TH BASED NOTE BOOK
PEG IFN-a plus

ribavirin
Chronic hepatitis C Anti-HCV, HCV RNA Anti-LKMl Telaprevir*
Boceprevirÿ
Anti-HDV, HDV
Chronic hepatitis D RNA, HBsAg, IgG Anti LKM3 IFN-a, PFG IFN-otc
anti HBc
ANAd
Autoimmune hep- (homogeneous), an- ANA,anti-LKMl Prednisone, azathio-
atitis ti-LKMI (±) anti SLAe prine
Hyperglobulinemia
Drug associated Uncommon Withdraw drug
Prednisone (?),
Cryptogenic All negative None
azathioprine(?)
"Antibodies to liver kidney microsomes type 1 (autoimmune hepatitis type 1 and some cases
of hepatitis C). as a triple drug combination with PEG IFN and ribavirin.
Between the writing and publication of this chapter, two additional drugs were approved
for hepatitis C, simeprevir and sofosbuvir (see www.hcvguidelines.org) ‘Early clinical trials
suggested benefit of IFN-a therapy; PEG IFN-a is as effective, if not more so, and has sup¬
planted standard IFN-a antibody (autoimmune hepatitis type 1). eAntibodies
to soluble liver antigen (autoimmune hepatitis type III)
Abbreviations: HBC, hepatitis B core; HBeAg. hepatitis B e antigen; HBsAg, hepatitis B
surface antigen; HBV, hepatitis B virus; HCV. hepatitis C virus; HDV. hepatitis D virus;
IFN-a, interferon a IgG, immunoglobulin G; LKM, liver-kidney microsome; PEG IFN-a
pegylated interferon a; SLA, soluble liver antigen
• AUTOIMMUNE HEPATITIS (Pg: 2049-52)

• NAFLD AND NASH (Pg:2054-57)

Page | 135
| Alcoholic Hepatitis I
Alcohol abstinence
Nutritional support
Discriminant function > 32

or MELD >21
(with absence of co-morbidity)
options
(ÿPreferredÿ) (ÿAlternativeÿ)
Prednisolone 32 mg Pentoxifylline 400 mg

p.o. daily for 4 weeks, p.o. TID for 4 weeks
then taper for 4 weeks
Figure Treatment algorithm for alcoholic hepatitis. As identified by a calculated discriminant
function >32 (see text) patients with severe alcoholic hepatitis, without the presence of gastrointes¬
tinal bleeding or infection, would be candidates for either glucocorticoids or pentoxifylline admin¬
istration.
A discriminant function calculated as; 4.6 x (the prolongation of the prothrombin time
above control [seconds]) + serum bilirubin (mg/dL) can identify patients with a poor prognosis
(discriminant function > 32). The drug of choice for alcoholic hepatitis with poor discrimi¬
nant function is steroids.
Keep in mind Zieves svndrome is a unique form of hemolytic anemia that occurs in patients with
severe alcoholic hepatitis. _
TABLE CAUSES OF CIRRHOSIS
Alcoholism Cardiac cirrhosis
Chronic viral hepatitis Inherited metabolic liver disease
Hepatitis B Hemochromatosis
Hepatitis C Wilsons disease
Autoimmune hepatitis (Xj, Antitrypsin deficiency
Nonalcoholic steatohepatitis Cystic fibrosis
Biliary cirrhosis Cryptogenic cirrhosis

IBS HARRISON’S 19TH BASED NOTE BOOK
Primary biliary cirrhosis

Primary sclerosing cholangitis
Autoimmune cholangiopathy
USEFUL ONE LINER

• Antimitochondrial antibodies (AMA) are present in about 90% of patients with primary
biliary cirrhosis.
• PRIMARY BILIARY CIRRHOSIS (Pg:2060-6l)

• PRIMARY SCLEROSING CHOLANGITIS(Pg:2061-62)
TABLE CONTRAINDICATIONS LIVER TRANSPLANTATION
SfjraHCTwSraSsI MMiHBMMM
Absolute Relative
Uncontrolled extrahepatobiliary infection Age>70
Active, untreated sepsis Prior extensive hepatobiliary surgery
Uncorrectable, life-limiting congenital anomalies Portal vein thrombosis
Active substance or alcohol abuse Renal failure not attributable to liver
disease
Advanced cardiopulmonary disease Previous extrahepatic malignancy (not
including nonmelanoma skin cancer)
Extrahepatobiliary malignancy (not including non- Severe obesity
melanoma malignancy skin cancer)
Metastatic malignancy to the liver Severe malnutrition/wasting
Cholangiocarcinoma Medical noncompliance
AIDS HIV seropositivity with failure to con
trol HIV viremia or CD4 <100/pl
Life threatening systemic diseases Intrahepatic sepsis
Severe hypoxemia secondary to right to
left intrapulmonary shunts (Po2, <50
mmHg)
Severe pulmonary hypertension (mean
pulmonary artery pressure >35 mmHg)
Uncontrolled psychiatric disorder

USEFUL ONE LINERS
• Strawberry gall bladder is seen in Cholesterolosis.

• The characteristic presentation of acute cholangitis involves biliary pain,jaundice,and
spiking fevers with chills (Charcot’s triad).
TABLE CLINICAL FEATURES OF AUTOIMMUNE PANCREATITIS (AIP)

• Mild symptoms, usually abdominal pain, but without frequent attacks of acute pancre-
atitis
• Diffuse swelling and enlargement of the pancreas
• Two-thirds of patients present with either obstructive jaundice or a “mass” in the head of
the pancreas mimicking carcinoma
• Diffuse irregular narrowing of the pancreatic duct (MRCP or ERCP)
• Increased levels of serum gamma globulins, especially lgG4
• Presence of other autoantibodies (ANA), rheumatoid factor (RF)
• Can occur with other autoimmune diseases: Sjogren’s syndrome, primary sclerosing
cholangitis, ulcerative colitis, rheumatoid arthritis
• Extrapancreatic bile duct changes such as stricture of the common bile duct and intraJ
hepatic ducts
• Pancreatic calcifications (rare)
• Pancreatic biopsies reveal extensive fibrosis and lymphoplasmacytic infiltration
• Glucocorticoids are effective in alleviating symptoms, decreasing size of the pancreas,
and reversing histopathologic changes
USEFUL ONE LINERS
• Gene for hereditary pancreatitis is located on chromosome 7.

• Most common congenital anatomic variant of the human pancreas is pancreas divisum.

CHAPTER 12 DISEASES OF IMMUNITY
CM »
>
t
A 0
,0
31
TABLE COMPLEMENT DEFICIENCIES AND ASSOCIATED DISEASES
Component Associated Diseases

Classic Pathway
Clq, Clr, Cls, C4 Immune-complex syndromes,3 pyogenic infections
C2 Immune-complex syndromes,3 few with pyogenic infections
Cl inhibitor Rare immune-complex disease, few with pyogenic infections
C3 and Alternative Pathway C3
C3 Immune-complex syndromes," pyogenic infections
D Pyogenic infections
Properdin Neisseria infections
I Pyogenic infections
H Hemolytic-uremic syndrome

Membrane Attack Complex
C5, C6, C7, C8 Recurrent Neisseria infections, immune-complex disease
C9 Rare Neisseria infections
"Immune-complex syndromes include systemic lupus erythematosus (SLE) and SLE-like
syndromes, glomerulonephritis, and vasculitis syndromes
TABLE SIGNIFICANT HLA CLASS I AND CLASS II ASSOCIATION WITH DISEASE
Strength of
Marker Gene Association
Spondyloarthropathies
Ankylosing spondylitis B27 Ba27-02,-04,- 05 ++++
Reactive arthritis (Reiter’s) B27 ++++
Acute anterior uveitis B27 +++
Reactive arthritis {Yersnia, Salmonel¬
la, Shigella, Chamydia)
B27 +++
Psoriatic spondylitis B27 +++

Collagen Vascular Diseases
Juvenile arthritis, pauciarticular DR8 ++
DR5 ++
Rheumatoid arthritis DR4 DR81a04- 01,.-04,- 05 +++
Sjogren’s syndrome DR3 ++
White DR3 +
Japanese DR2 ++
Autoimmune Gut and Skin
Gluten sensitive enteropathy (celiac DQ2
disease) DR3 DQAla05:l +++
Chronic active hepatitis DR3 DQBla02:01 ++
Dermatitis herpetiformis Cw6 DRBla04:02 +++
Psoriasis vulgaris DR4 DQBla05:03 ++
Pemphigus vulgaris DQ1 DQBla03:01 +++
Bullous pemphigoid variant DQ7 +

Autoimmune Endocrine
Type 1 diabetes mellitus DQ8 DQBT03:02 +++
DR4 DRBla04:01,-04 ++
DR3
__a
DR2 DQBla06.02
Hyperthyroidism (Graves) BB +
DR3 +
Hyperthyroidism (Japanese) B35 +
Adrenal insufficiency DR3 ++
Autoimmune Neurologic
Myasthenia gravis B8
Multiple sclerosis DR2 DRBla15:01 +
DR2 DRB5a01:01 ++
Other
Behcet’s disease B51 ++
Congenital adrenal hyperplasia B47 21-OH (Cyp 2IB) +++
Narcolepsy DR2 DQBla06.02 ++++
Goodpasture’s syndrome (anti GBM) DR2 ++
Abacavir hypersensitivity B57 5*57:01 ++++
negative association, ie, genetic association with protection from diabetes
USEFUL ONE LINER

• Human Major Histocompatibility Complex is located on chromosome 6p.
• Most common type of Leukocyte Adhesion Deficiency is LAD type 1 caused by mutations
in the 22 integrin gene.
• CHRONIC GRANULOMATOUS DISEASE (Pg: 2106)

• SEVERE COMBINED IMMUNODEFICIENCY (Pg:2107-08)
• HYPER IgM SYNDROME (Pg:2110,2111)
• WISKOTT ALDRICH SYNDROME (Pg:2110)

. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (Pg:2112)
TABLE AUTOANTIBODIES IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Preva- Antigen Recog-

Antibody Clinical Utility
lence, % nized
Antinu¬
Best screening test; repeated negative tests
clear anti- 98 Multiple nuclear make SLE unlikely
bodies
High titers are SLE specific and in some pa¬
An- DNA (double
70 tients correlate with disease activity, nephritis,
ti-dsDNA stranded)
vasculitis
Protein com-
Specific for SLE; no definite clinical correla¬
plexed to 6 tions; most patients also have anti RNP; more
Anti Sm 25
species of nuclear common in blacks and Asians than whites
U1 RNA
Not specific for SLE; high titers associated with
Protein com-
Anti syndromes that have overlap features of several
40 plexed to U1
RNP rheumatic syndromes including SLE; more
RNA
common in blacks than whites
Protein com- Not specific for SLE; associated with sicca
plexed to hY syndrome, predisposes to subacute cutaneous
Anti-Ro
30 RNA, primarily lupus, and to neonatal lupus with congenital
(SS-A)
60 kDa and 52 heart block; associated with decreased risk for
kDa nephritis
47 kDa protein
Anti-La Usually associated with anti Ro; associated
10 complexed to hY
(SS-B) with decreased risk for nephritis
RNA
Histones associ¬
Antihis¬ ated with DNA More frequent in drug induced lupus than in
70 (in nucleosome,
tone SLE
chromatin)
Phospholipids, Three tests available—ELISAs for cardio-
Antiphos¬ P2 glycoprotein 1 lipin and p2Gl, sensitive prothrombin time
50
pholipid (P2G1) cofactor, (DRWT); predisposes to clotting, fetal loss,
prothrombin thrombocytopenia

Ant- Erythrocyte Measured as direct Coombs test; a small pro¬

ierythro- 60
membrane portion develops overt hemolysis
cyte
Surface and Associated with thrombocytopenia, but sensi¬
Antiplate- altered cytoplas¬
tivity and specificity arc not good; this is not a
let mic antigens on
useful clinical test
platelets
Anti¬
neuronal
Neuronal and
(includes In some series, a positive test in CSF correlates-
. ,
antiglu-
60 lymphocyte sur¬
with active CNS lupus
face antigens
tamate
receptor)
In some series, a positive test in serum cor¬
Antiribo- . Protein in ribo¬
relates with depression or psychosis due to CNS
somal P somes
lupus _
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; DRWT, dilute
Russell viper venom time; ELISA, enzyme-linked immunosorbent assay
SYSTEMIC LUPUS INTERNATIONAL COLLABORATING CLINIC CRITERIA
TABLE
FOR CLASSIFICATION OF SYSTEMIC LUPUS ERYTHEMATOSUS
Clinical Manifestations Immunologic Manifestations

Skin ANA > reference negative value
Acute, subacute cutaneous LE Anti-dsDNA
Chronic cutaneous LE Anti Sm
Oral ulcers Antiphospholipid
Alopecia Low serum complement
Synovitis Positive direct Coombs test
Renal
Prot/Cr > 0.5
RBC casts
Biopsy"

Page | 143
Neurologic
Seizures, psychosis, mononeuritis,
myelitis, peripheral or cranial neu¬
ropathies, acute confusional state
Hemolytic anemia
Leukopenia (<4000) or
Lymphopenia (<1000)
Thrombocytopenia (<100,000)
4Renal biopsy read as systemic lupus qualifies for classification as SLE even if none
of the other above features are present
Interpretation: Presence of any 4 criteria (must have at least 1 in each category) qualifies
patient to be classified as having SLE with 93% specificity and 92% sensitivity
USEFUL ONE LINERS
• Most common manifestation of diffuse CNS lupus is cognitive dysfunction.

• Most common pulmonary manifestation of SLE is pleuritis with or without pleural effu¬
sion.
• Most common cardiac manifestation of SLE is pericarditis.
• Most common hematologic manifestation of SLE is anemia, usually normocytic normo¬
chromic.
Drugs Causing Lupus Like Disease
Antiarrhythmics — Procainamide,Disopyramide,Propafenone
Antihypertensive - Hydralazine
Antithyroid — Propylthiouracil
Antipsychotics — Chlorpromazine, Lithium
Anticonvulsant - Carbamazepine.Phenytoin
Antibiotics - Isoniazid, Minocycline,Nitrofurantoin
Antirheumatic — Sulfasalazine
Diuretic — Hydrochlorothiazide
Antihyperlipidemic - Lovastatin,Simvastatin
Several ACE inhibitors and beta blockers

SLE (although half have posi¬
• Only 5% of people with Discoid lupus erythematosus have
ANA); however, among individuals with SLE, as many as 20% have DLE.
tive
HIGH YIELDING TOPIC
• SYSTEMIC LUPUS ERYTHEMATOSUS (Pg:2124-34)

• Catastrophic AntiPhospholipid Syndrome (CAPS) is defined as a rapidly progressive
thromboembolic disease involving simultaneously three or more organs,organ systems,or
tissues leading to corresponding functional defects.
Neurologic: Cervical myelopathy. .5 *3
splenomegaly. Felly's syndrome.

large granular lymphocyte
leukemia, lymphoma / 'Xkf
organtnng pnoumonw
heart* my
; carAomyop&thy. orrhythmui.
mural regulation
nephropathy, secondary
'] X
m
Skin: Rheumatoid nodtiea. purpura.
pyoderma gangranoatan
Extraarticular manifestations of rheumatoid arthritis
USEFUL ONE LINERS

• Most common pulmonary manifestation of rheumatoid arhtritis is pleuritis.
• Most common site of cardiac involvement in rheumatoid arthritis is pericardium.
• Most common hematologic abnormality in rheumatoid arthritis is normocytic normo-
chromic anemia.
• Most common histopathologic type of lymphoma in rheumatoid arthritis is diffuse large
B cell lymphoma.
• Most common cause of death in rheumatoid arthritis is cardiovascular disease.
In 2010 a collaborative effort between the American College of Rheumatology (ACR)
and the European League Against Rheumatism (EULAR) revised the 1987 ACR classifica¬
tion criteria for Rheumatoid Arthritis in an effort to improve early diagnosis with the goal
of identifying patients who would benefit from early introduction of disease-modifying
therapy
• Application of the newly revised criteria yields a score of 0-10, with a score of more than or
equal to 6 fulfilling the requirements for DEFINITE RA.
• The newer classification criteria also do not take into account whether the patient has
rheumatoid nodules or radiographic joint damage because these findings occur rarely in
early RA.
TABLE CLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITIS

Score
Joint involvement 1 large joint (shoulder, elbow, hip, knee, ankle) 0
2-10 large joints 1
1-3 small joints (MCP PIP, thumb IP MTP wrists) 2
4-10 small joints 3
>10 joints (at least 1 small joint) 5
Serology Negative RF and negative ACPA 0
Low-positive RF or low-positive anti-CCP antibodies 2
(<3 times ULN) 3
High-positive RF or high-positive anti-CCP antibodies
(>3 times ULN)
Acute-phase reactants Normal CRP and normal ESR 0
Abnormal CRP or abnormal ESR 1
Duration of symp¬ <6 weeks 0
toms £ 6 weeks 1
Note: These criteria are aimed at classification of newly presenting patients who have at least
one joint with definite clinical synovitis that is not better explained by another disease A
score of >6 fulfills requirements for definite RA

Abbreviations: ACPA, anti-citrullinated peptide antibodies; CCP, cyclic citrullinated pep¬

tides; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IP, interphalangeal joint;
MCR metacarpophalangeal joint; MTP metatarsophalangeal joint; PIP, proximal interpha¬
langeal joint; RF, rheumatoid factor; ULN, upper limit of normal.
• RHEUMATOID ARTHRITIS (Pg:2136-48)

• SYSTEMIC SCLEROSIS (Pg:2154-65)
• SJOGREN’S SYNDROME (Pg:2166-69)
• ANKYLOSING SPONDYLITIS (Pg:2l69-73)
• REACTIVE ARTHRITIS (Pg:2173-75)
SUBSETS OF SYSTEMIC SCLEROSIS (SSC): FEATURES OF LIMITED

TABLE
CUTANEOUS SSC VERSUS DIFFUSE CUTANEOUS SSC
Characteristic Feature Limited Cutaneous SSc Diffuse Cutaneous SSc
Skin involvement Indolent onset. Limited to Rapid onset. Diffuse: fingers,
fingers, distal to elbows, extremities, face, trunk; rapid
face; slow progression progression
Raynaud’s phenomenon Antedates skin involvement, Onset coincident with skin
sometimes by years; may involvement; critical ischemia less
be associated with critical common
ischemia in the digits
Musculoskeletal Mild arthralgia Severe arthralgia, carpal tunnel
syndrome, tendon friction rubs
Interstitial lung disease Slowly progressive, general- Frequent, early onset and pro-
ly mild gression, can be severe
Pulmonary arterial hy¬ Frequent, late, may occur as Often occurs in association with
pertension an isolated complication interstitial lung disease
Scleroderma renal crisis Very rare Occurs in 15%; generally early
(<4 years from disease onset)
Calcinosis cutis Frequent, prominent Less common, mild
Characteristic autoanti¬ Anticentromere Anti-topoisomeraseI(Scl-70),
bodies anti-RNA polymerase III

Page | 147
AUTOANTIBODIES AND ASSOCIATED FEATURES IN SYSTEMIC

TABLE
SCLEROSIS (SSC)
Target Antigen SSc Subset Characteristic Clinical Association
Tendon friction rubs, early ILD, cardiac
Topoisomerase 1 dcSSc involvement, scleroderma renal crisis
Digital ischemic ulcers, calcinosis cutis,
Centromere proteins IcSSc isolated PAH, overlap syndromes; renal
crisis rare
Rapidly progressive skin involvement,
tendon friction rubs, joint contractures,
RNA polymerase III dcSSc
GAVE, renal crisis, contemporaneous
cancers
PAH, ILD, scleroderma renal crisis,
U3 RNP (fibrillarin) dcSSc
myositis
Th/TO IcSSc ILD, PAH
PM/Scl IcSSc Calcinosis cutis, ILD, myositis overlap
Ku Overlap SLE, myositis
Ul-RNP MCTD PAH, arthritis, myositis
Abbreviations:dcSSc, diffuse cutaneous SSc; GAVE, gastric antral vascular ectasia; ILD, in¬
terstitial lung disease; IcSSc, limited cutaneous SSc; MCTD, mixed connective tissue disease;
PAH, pulmonary arterial hypertension; SLE, systemic lupus erythematosus
USEFUL ONE LINER

• Salt and pepper appearance of skin is seen in Scleroderma
PREVALENCE OF EXTRAGLANDULAR MANIFESTATIONS IN I PRIMARY

TABLE
SJOGREN’S SYNDROME
Clinical Manifestation Percent Remarks
Usually non erosive, leading to Jaccoud’s arthrop¬
Arthralgias/arthritis 60
athy.
In one third of patients, precedes sicca manifesta¬
Raynaud’s phenomenon 37
tions.
Lymphadenopathy 14 Lymphoma should be excluded
Lung involvement 14 Small airway disease is the predominant pathology.

The most common clinical manifestation is cutane-

Vasculitis 11
ous palpable purpura.
Interstitial kidney disease is usually asymp tomatic.
Kidney involvement 9 Glomerulonephritis is associated with cryoglobu¬
linemia.
Liver involvement 6 Primary biliary cirrhosis stage 1.
Lymphoma 6
"
Glandular MALT* lymphoma is most common.
Peripheral neuropathy 2 Polyneuropathy, either sensory or sensorimotor.
_ __
Sporadic causes of myositis and inclusion body
Myositis 1
myositis have been reported.
••MucoSa-associated lymphoid tissue
TABLE DIFFERENTIAL DIAGNOSIS OF SJOGREN’S SYNDROME

HIV Infection and Sicca Syndrome Sjogren’s Syndrome Sarcoidosis
Predominant in young males Predominant in mid¬ No age or sex prefer¬
dle-aged women ence
Lack of autoantibodies to Ro/SS-A Presence of autoanti¬ Lack of autoantibodies
and/or La/SS-B bodies to Ro/SS-A and/or La/
SS-B
Lymphoid infiltrates of salivary glands Lymphoid infiltrates Granulomas in salivary
by CD8+T lymphocytes of salivary glands by glands
CD4+ T lymphocytes
Association with HLA-DR5 Association with HLA- Unknown
DR3 and DRw52
Positive serologic tests for HIV Negative serologic tests Negative serologic tests
for HIV for HIV
USEFUL ONE LINERS
• The earliest manifestation of ankylosing spondylitis is sacroilitis.

• Most common extraarticular manifestation is acute anterior uveitis, which occurs in up to
40% of patients and can antedate the spondylitis.
• The characteristic skin lesions in Reactive arthritis is keratoderma blennorrhagica that
consist of vesicles and/or pustules that become hyperkeratotic,
ultimately forming a crust
before disappearing.
Email: mfo@damsdelhi.com | Website: www.damsdelhi.com

Page | 149
• Wright and Moll classification is for psoriatic arthritis.
• Nail changes in the fingers or toes occur in up to 90% of patients with PsA,compared with
40% of psoriatic patients without arthritis.
• The subtype of psoriasis associated with severe arthritis is Pustular psoriasis.
FIGURE Characteristic lesions of psoriatic arthritis. Inflammation is prominent in the distal in-
terphalangeal joints (left 5th, 4th, 2nd, right 2nd, 3rd and 5th) and proximal interphalangeal joints (left 2nd,
right 2nd, 4ÿ and 5th). There is dactylitis in the left 2nd finger and thumb, with pronounced telescoping
of the left 2nd finger. Nail dystrophy (hyperkeratosis and onycholysis) affects each of the finger ex¬
cept the left 3rd finger, the only finger without arthritis.
• WEGENER’S GRANULOMATOSIS (Pg:2182-86)

• EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS (CHURG-
STRAUSS) (Pg:2186-87)
• POLYARTERITIS NODOSA (Pg:2I87-88)
• GIANT CELL ARTERITIS AND POLYMYALGIA RHEUMATICA (Pg:2188-89)
• TAKAYASU ARTERITIS (Pg:2189-90)
• BEHCET’S SYNDROME (Pg:2194)
Page) 150 Email: info@damsdclhi.com | Website: www.damsdelhi.com

USEFUL ONE LINERS
• Wegener’s granulomatosis is also known as granulomatosis with polyangiitis.

with a
• Chronic nasal carriage of Staphylococcus aureus has been reported to be associated
higher relapse rate of WG.
• Highest diagnostic biopsy yield in WG is from pulmonary tissue.
• Polyarteritis nodosa does not involve pulmonary arteries,although bronchial vessels may be
involved; granulomas,significant eosinophilia,and an allergic diathesis are not observed.
• Hairy cell leukemia can be associated with polyarteritis nodosa.
• Most common blood vessel involved in Takayasu arteritis is subclavian artery.
• Drugs that have been implicated in vasculitis include allopurinol, thiazides, gold, sulfon¬
amides, phenytoin, and penicillin.
• IL-6 levels are persistently raised in the CSF of patients with CNS involvement in Behcet s
syndrome.
CLINICAL MANIFESTATIONS RELATED TO ORGAN SYSTEM

TABLE
INVOLVEMENT IN POLYARTERITIS NODOSA
Organ System Percent Incidence Clinical Manifestations
Renal 60 Renal failure, hypertension
Musculoskeletal 64 Arthritis, arthralgia, myalgia
Peripheral nervous system 51 Peripheral neuropathy, mononeuritis
multiplex
Gastrointestinal tract 44 Abdominal pain, nausea and vomiting,
bleeding, bowel infarction and perfo¬
ration, cholecystitis, hepatic infarction,
pancreatic infarction
Skin 43 Rash, purpura, nodules, cutaneous
infarcts, livedo reticularis, Raynaud’s
phenomenon
Cardiac 36 Congestive heart failure, myocardial
infarction, pericarditis
Genitourinary 25 Testicular, ovarian, or epididymal pain
Central nervous system 23 Cerebral vascular accident, altered men-
tal status, seizure
Email: mfo@damsdelhi.com | Website:

TABLE DIAGNOSTIC CRITERIA OF BEHCET’S SYNDROME
Recurrent oral ulceration plus two of the following:

Recurrent genital ulceration
Eye lesions
Skin lesions
Pathergy test _
TABLE FEATURES ASSOCIATED WITH INFLAMMATORY MYOPATHIES
Characteristic Polymyositis Dermatomyositis inclusion Body Myositis
Age at onset >18 years Adulthood and >50 years
childhood
Familial association No No Yes, in some rare cases
Extramuscular mani- Yes Yes Yes
festations
Associated conditions Yes'* Scleroderma and Yes, in up to 20% of cases"
Connective tissue Frequent mixed connective Infrequent
diseases No tissue disease (over- No
Systemic autoim- Yesc lap syndromes) Yesc
mune diseases* Yes Infrequent No
Malignancy Yes Yes, in up to 15% No
Viruses of cases
Drugs'* Unproven
Parasites and bac¬ Yes, rarely
teria' No
USEFUL ONE LINERS
• Most common inflammatory myopathy in patients > 50 years of age is Inclusion body
myositis.
• Most common tumors associated with dermatomyositis are ovarian cancer, breast cancer,
melanoma, colon cancer, and non-Hodgkin’s lymphoma.
• Relapsing polychondritis is an uncommon disorder of unknown cause characterized by
inflammation of cartilage predominantly affecting the ears, nose,and laryngotracheobron-
chial tree.

ill HARRISON’S 19TH BASED NOTE BOOK
TABLE DISORDERS ASSOCIATED WITH RELAPSING POLYCHONDRITIS3

Systemic vasculitis
Rheumatoid arthritis
Overlapping connective tissue disease
Spondyloarthritides
Behcet’s disease
Polymyalgia rheumatica
Primary biliary cirrhosis
Pulmonary fibrosis
Hashimoto’s thyroiditis
Myelodysplastic syndrome
"Systemic vasculitis is the most common association, followed by rheumatoid arthritis and systemic
lupus erythematosus.
HIGH YIELDING TOPIC
• SARCOIDOSIS (Pg:2205-12)
USEFUL ONE LINERS

• A specific complex of dermatologic involvement of the bridge of the nose,the area beneath
the eyes,and the cheeks is referred to as lupus pernio and is diagnostic for chronic form
of sarcoidosis.
• The Kviem-Siltzbach procedure is a specific diagnostic test for sarcoidosis.
ANTINUCLEAR ANTIBODY (ANA) PATTERNS AND CLINICAL
TABLE
ASSOCIATIONS
ANA Pattern Antigen Identified Clinical Correlate
Diffuse Deoxyribonucleoprotein Nonspecific
Histones Drug-induced lupus, lupus
Peripheral (rim) ds-DNA 50% of SLE (specific)

Page | 153
Speckled Ul-RNP >90% of MCTD

Sm 30% of SLE (specific)
Ro (SS-A) Sjogren’s 60%, SCLE, neonatal lupus,
ANA(-) lupus
La (SS-B) 50% of Sjogren’s, 15% lupus
Scl-70 40% of diffuse scleroderma
PM-1 Polymyositis (PM), dermatomyositis
Jo-1 PM w/pneumonitis + arthritis
Nucleolar RNA polymerase 1, others 40% of PSS
Centromere Kinetochore 75% CRFST (limited scleroderma)
Abbreviations: ANA, antinuclear antibody; CREST, calcinosis, itaynaud phenomenon,
esophageal involvement, sclerodactyly, and telangiectasia; MCTD, mixed connective tissue
disease; PSS, progressive systemic sclerosis; SCLE, subacute cutaneous lupus erythematosus;
SLE, systemic lupus erythematosus.
Fy DIP; OA,
psoriactic or
reactive arthritis
mk PIP: OA, SLE,

RA, psoriactic arthritis
w
if
MCP: RA,
pseudogout,
1st CMC: OA hemochromatosis
de Quervain’s Wrist : RA,

tenosynovitis pseudogout,
gonococcal arthritis,
juvenile arthritis,
carpal tunnel syndrome
Figure Sites of hand or wrist involvement and their potential disease association. CMC
Carpometacarpal : DIP,distal interphalangeal; MCP, metacarpophalangeal; OA, osteoarthritis- PIP,’
proximal interphalangeal; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus. (From JJ
Cush eta : Evalution oUmusculoskeletal complaints, in Rheumatology: Diagnosis
and Therapeutics
2nd ed, JJ Cush et al [eds]. Philadelphia, Lippincott Williams & Wikins & 2005, pp
3-20. Used with
permission from Dr. John J Cush.)
Pagej 154 Email: info@damsdelhi.com | Website: www.damsdelhi.com

ANTINUCLEAR ANTIBODY (ANA) PATTERNS AND CLINICAL

TABLE ASSOCIATIONS
ANA Pattern Antigen Identified Clinical Correlate

Diffuse Deoxyribonucleoprotein Nonspecific
Histones Drug-induced lupus, lupus
Peripheral (rim) ds-DNA 50% of SLE (specific)
Speckled Ul-RNP >90% of MCTD
Sm 30% of SLE (specific)
Ro (SS-A) Sjogren’s 60%, SCLE, neonatal lupus,
La (SS-B) ANA(-) lupus
Scl-70 50% of Sjogren’s, 15% lupus
PM-1 40% of diffuse scleroderma
Jo-1 Polymyositis (PM), dermatomyositis
PM w/pneumonitis + arthritis
Nucleolar RNA polymerase 1, others 40% of PSS
Centromere Kinetochore 75% CRFST (limited scleroderma)
Abbreviations: ANA, antinuclear antibody; CREST, calcinosis, Raynaud phenomenon,

esophageal involvement, sclerodactyly, and telangiectasia; MCTD, mixed connective tissue
disease; PSS, progressive systemic sclerosis; SCLE, subacute cutaneous lupus erythematosus;
SLE, systemic lupus erythematosus.
TABLE DISORDERS:ASSOCIATED WITH NEUROPATHIC JOINT DISEASE

Diabetes mellitus Amyloidosis
Tabes dorsalis Leprosy
Meningomyelocele Congenital indifference to pain
Syringomyelia Peroneal muscular atrophy
Email: info@damsdclhi.com | Website:

CHAPTER 13
ENDOCRINOLOGY & METABOLISM
ter
C
I
>CS
Paracrine regulation refers to factors released by one cell that act on an adjacent cell in the
same tissue.
For example, somatostatin secretion by pancreatic islet delta cells inhibits insulin secretion
from nearby beta cells.
• Autocrine regulation describes the action of a factor on the same cell from which it is
produced.
For example, IGF-1 acts on many cells that produce it,including chondrocytes, breast epi¬
thelium, and gonadal cells.

TABLE ANTERIOR PITUITARY HORMONE EXPRESSION AND REGULATION

Cell Corticotrope Somatotrope Lactotrope Thyrotrope Gonadotrope
Tissue-spe¬
cific tran¬ Prop-1, Prop-1, Pit- SF-1, DAX-1
T-Pit Prop-1, Pit-1 Pit-1 1, TEF
scription
factor
Fetal ap¬ 12 weeks
6 weeks 8 weeks 12 weeks 12 weeks
pearance
Hormone POMC GH PRL TSH FSH, LH
Glycopro-
Glycoprotein
Protein Polypeptide Polypeptide Polypeptide tein M4!
subunits
M4!subunits
266(ACTH
Amino acids 199 211 210, 204
1-39)
CRH, AVP,
GHRH, Estrogen, GnRH, activ-
Stimulators gp-130 cyto¬ TRH
ghrelin TRH, VIP ins, estrogen
kines
T3.T4,
Glucocorti¬ Somatostatin,
dopamine,
Sex steroids,
Inhibitors Dopamine somatosta¬
coids IGF-I inhibin
tin, gluco¬
corticoids
Liver, bone, Breast, oth-
Target gland Adrenal Thyroid Ovary, testis
other tissues er tissues
IGF-I produc¬ Sex steroid

tion, growth produc¬
Trophic Steroid pro¬ Milk pro¬ T4 synthesis tion, follicle
induction, and secre¬
effect duction duction growth, germ
insulin antag¬ tion
onism cell matura¬
tion
Normal ACTH, 4-22 M<15ppg/ M, 5-20 IU/L,
range Pg/L
<0.5 pg/L* L;F<20 0.1-5 mU/L F (basal), 5-20
Fg/L IU/L
"Hormone secretion integrated over 24 h.

Page | 157
TRH 5R1F GHRH
CRH
I
GnRH
:°op»Tÿ
Is
Hypothalamus
O
/
/
\
O
Pituitary
mm j
-t,L\\\
if vv
Cortaoi
d* AOrcnai
VT,
Thyrt>d /
/Q
mNbm
0**r**\j
o
A*
orgtQrwrth
IOF-1
Page | 158 Email: info@damsdelhi.com | Website: wwyrtdamsdelhi.com

T-T A PRISON'S 19TH BASED NOTE BOOK
Diagram of Pituitary Axes
Third ventricle
Neuroendocrine
cell nuclei Hypothalamus
r**tv \V,
/
Superior i ?
hypophyseal Stalk
artery
/ Inferior
Long portal // , hypophyseal
vessels / 1 \ artery
Trophic i
hormone /
secreting /
cells
Posterior
pituitary
pituitary
(j v Short portal
*
t Hormone
, vessel
secretion
Figure Diagram of hypothalmic-pituitary vasculature. The hypothalamic nuclei produce hormones
that traverse the portal system and impingeon anterior pituitary cells to regulate pituitary hormone
secretion. Posterior pituitary hormones secretion. Posterior pituitary hormones are derived from
direct neural extension.

M
| AAAJVAAAAJ GnRH pulses
IMAAAAAATÿ
Figure Hypothalamic gonadotropin-releasing hormone (GnRH) pulses induce secretory
pulses of luteinizing hormone (LH).
USEFUL ONE LINERS
• Prolactin is unique among the pituitary hormones in that the predominant central control
mechanism is inhibitory reflecting dopamine mediated suppression of PRL release.
• Most abundant anterior pituitary hormone is growth hormone,and GH-secreting somato-
trope cells constitute up to 50% of the total anterior pituitary cell population.
• Growth hormone receptor antagonist (Pegvisomant) is approved for the treatment of ac¬
romegaly.
• Most common hormone deficiency after cranial irradiation is growth hormone.
• Homozygous or heterozygous mutations of the GH receptor are associated with partial or
complete GH insensitivity and growth failure (Laron’s syndrome).
• Hypogonadism is the most common presenting feature of adult hypopituitarism even
when other pituitary hormones are also deficient.
• Pituitary adenomas are the most common cause of pituitary hormone hypersecretion and
hyposecretion syndromes in adults.
• Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in
both men and women.
Amenorrhea,galactorrhea, and infertility are the hallmarks of hyperprolactinemia in wom-
en.
In men with hyperprolactinemia,diminished libido, infertility,and visual loss (from optic
nerve compression) are the usual presenting
symptoms.

the sex ratio is
• The female-to-male ratio for microprolactinomas (<lcm) is 20:1, whereas
near 1:1 for macroadenomas(>lcm).
TABLE |ETIOLOGY OF HYPOPITUITARISMa
Development/structural
Transcription factor defect
Pituitary dysplasia/aplasia
Congenital central nervous system mass, encephalocele
Primary empty sella
Congenital hypothalamic disorders (septo-optic dysplasia. Prader-Willi syndrome, Lau-
rence-Moon-Biedl syndrome. Kallmann syndrome)
Traumatic
Surgical resection
Radiation damage
Head injuries
Neoplastic
Pituitary adenoma
Parasellar mass (germinoma, ependymoma, glioma)
Rathke’s cyst
Craniopharyngioma
Hypothalamic hamartoma, gangliocytoma
Pituitary metastases (breast, lung, colon carcinoma)
Lymphoma and leukemia
Meningioma
Infiltrative/inflammatory
Lymphocytic hypophysitis
Hemochromatosis
Sarcoidosis
Histiocytosis X
Granulomatous hypophysitis
Transcription factor antibodies
Vascular
Pituitary apoplexy
Pregnancy-related (infarction with diabetes; postpartum necrosis)
Sickle cell disease
Arteritis
Infections
Fungal (histoplasmosis)
Parasitic (toxoplasmosis)
Tuberculosis
pneumocystis carinii

Page | 161
M
KALLMANN SYNDROME
(GnRH) synthesis.
• Results from defective hypothalamic gonadotropin-releasing hormone
• Caused by mutations in the X-linked KAL gene mutations of which impair embryonic
migration migration of GnRH neurons from the hypothalamic olfactory placode to the
hypothalamus. However other genetic abnormalties are also implicated.
• It is associated with anosmia or hyposmia due to olfactory bulb agenesis or hypoplasia.
• Classically the syndrome may also be associated with color blindness,optic atrophy,nerve
deafness,cleft palate,renal abnormalities, cryptorchidism, and neurologic abnormalties
such as mirror movements.
• GnRH deficiency prevents progression through puberty. Males present with delayed pu¬
berty and pronounced hypogonadal features, including micropenis,probably the result of
low testosterone levels during infancy. Females present with primary amenorrhea and fail¬
ure of secondary sexual development.
CRANIOPHARYNGIOMAS
• Benign,suprasellar cystic masses derived from the Rathke’s pouch.

• They are often large, cystic,and locally invasive.
• Many are partially calcified,exhibiting a characteristic appearance on skull x-ray and CT
images.
• More than half of all patients present before age 20,usually with signs of increased intra¬
cranial pressure, including headache, vomiting,papilledema,and hydrocephalus.
• Associated symptoms include visual field abnormalities,personality changes and cognitive
deterioration,cranial nerve damage,sleep difficulties,and weight gain.
• Hypopituitarism can be documented in about 90%,and diabetes insipidus occurs in about
10% of patients.
• About half of affected children present with growth retardation.
• MRI is generally superior to CT for evaluating cystic structure and tissue components of
craniopharyngiomas. CT is useful to define calcifications and evaluate invasion into sur-
rounding bony structures and sinuses.
Keep in mind- Children with GnRH producing hypothalamic hamartomas present with
precocious puberty, psychomotor delay, and laughing-associated sdxures. (gelasric seizures)

TABLE FAMILIAL PITUITARY TUMOR SYNDROMES

Gene Mutated Clinical Features
Multiple endocrine MEN1 Hyperparathyroidism
neoplasia 1 (MEN (llql3) Pancreatic neuroendocrine tumors
1) Foregut carcinoids
Adrenal adenomas
Skin lesions
Pituitary adenomas (40%)
Multiple endocrine CDKNIB Hyperparathyroidism
neoplasia 4 (MEN (12pl3) Pituitary adenomas
4) Other tumors
Carney complex PRKAR1A Pituitary hyperplasia and adenomas (10%)
(17q23-24) Atrial myxomas
Schwannomas
Adrenal hyperplasia
Lentigines
Familial pituitary AIP Acromegaly/gigantism (-15% of afflicted families)
adenomas (llql3.3)
HIGH YIELDING TOPIC
• ACROMEGALY (Pg:2269-71)
DIFFERENTIAL DIAGNOSIS OF ACTH DEPENDENT CUSHING’S
TABLE
SYNDROME*
ACTH Secreting Pitu¬ Ectopic ACTH Secretion

itary Tumor
Etiology Pituitary corticotrope Bronchial, abdominal carci¬
adenoma noid
Plurihormonal adenoma Small cell lung cancer
Thymoma
Sex F>M M>F
Clinical features Slow onset Rapid onset Pigmentation
Severe myopathy
Serum potassium <3.3pg/L < 10% 75%

@1
24-h urinary free Cortisol High High
(UFC)
Basal ACTH level Inappropriately high Very high
Dexamethasone suppression
1 mg overnight
low dose (05 mg q6h) Cortisol >5 p g/dl Cortisol >5 p g/dl
High dose (2 mg q6h) Cortisol <5 p g/dl Cortisol >5 p g/dL
UFC >80% suppressed Microadenomas: 90% 10%
Macroadenomas: 50%
Inferior petrosal sinus sam¬
pling (IPSS)
Basal
IPSS: peripheral >2 <2
CRH induced
IPSS: peripheral >3 <3
aACTH independent causes of Cushing’s syndrome are diagnosed by suppressed ACTH levels and an
adrenal mass in the setting of hyperconisolism. Iatrogenic Cushng’s syndrome is excluded by history
USEFUL ONE LINERS
• Most common cause of Cushingoid features is iatrogenic hypercortisolism.

• Most common pattern of inheritance of pituitary diabetes insipidus is Autosomal domi- -•
nant.
• Most common pattern of inheritance of nephrogenic diabetes insipidus is X-linked semire-

cessive.
CAUSES OF SYNDROME OF INAPPROPRIATE ANTIDIURETIC

TABLE HORMONE (SIADH)
Neoplasms Neurologic
Carcinomas Guillain-Barre syndrome
Lung Multiple sclerosis
Duodenum Delirium tremens
Pancreas Amyotrophic lateral sclerosis
Ovary Hydrocephalus
Bladder, ureter Psychosis
Other neoplasms Peripheral neuropathy

Thymoma Congenital malformations

Mesothelioma Agenesis corpus callosum
Bronchial adenoma Cleft lip/palate
Carcinoid Other midline defects Metabolic
Gangliocytoma Acute intermittent porphyria
Ewing’s sarcoma Pulmonary
Head trauma (closed and penetrating) Asthma
Infections Pneumothorax
Pneumonia, bacterial or viral Abscess, lung Positive pressure respiration
or brain Cavitation (aspergillosis) Drugs
Tuberculosis, lung or brain Meningitis, Vasopressin or desmopressin
bacterial or viral Encephalitis Serotonin reuptake inhibitors
AIDS Oxytocin, high dose
Vascular Vincristine
Cerebrovascular occlusions, hemorrhage Carbamazepine
Cavernous sinus thrombosis Nicotine
Phenothiazines
Cyclophosphamide
Tricyclic antidepressants
Monoamine oxidase inhibitors
TABLE CHARACTERISTICS OF CIRCULATING T4 AND T3

Hormone Property
T4 T3
Serum concentrations
Total hormone 8 pg/dL 0.l4pg/dL
Fraction of total hormone in the unbound form 0.02% 0.3%
Unbound (free) hormone 21 x 10'12M 6 xl0-12M
Serum half-life 7d 2d
Fraction directly from the thyroid 100% 20%
Production rate, including peripheral conversion 90 pg/d 32 pg/d
Intracellular hormone fraction -20% -70%
Relative metabolic potency 0.3 1
Receptor binding 10-10M 10-nM
Email, info@damsdelhi.com
| Website: www.damsdelhi.com
Page | 165
M
USEFUL ONE LINERS
• The iodine transporter,pendrinis located on the apical surface of thyroid cells and mediates
iodine efflux into the lumen. Mutation of the pendrin gene causes Pendred syndrome, a dis¬
order characterized by defective organification of iodine,goiter,and sensorineural deafness.
• Excesss iodide transiently inhibits thyroid iodide organification,by a phenomenon known
as the Wolff Chaikoffeffect.
• Plasma proteins to which thyroid hormones are bound are thyroxine-binding globulin
(TBG), transthyretin (TTR) and albumin out of which TBG has highest affinity for
thyroid hormones.
• HLA-DR polymorphisms are the best documented genetic risk factors for autoimmune hypo¬
thyroidism,especially HLA-DR3, -DR4,and -DR5 in Caucasians. A weak association also exists
between polymorphisms in CTLA-4, a T cell-regulatory gene,and autoimmune hypothyroidism.
• Thyroid acropachy refers to a form of clubbing found in < 1 % of patients with Graves’
disease. It is so strongly associated with thyroid dermopathy.
• Due to the hepatotoxicity of propyl thiouracil, the US Food and Drug Administration
(FDA) has limited indications for its use to the first trimester of pregnancy, the treatment
of thyroid storm,and patients with minor adverse reactions to methimazole.
• Viruses implicated in viral thyroiditis (de Quervain’s thyroiditis, granulomatous thyroid¬
itis) are mumps, coxsackie,influenza,adenoviruses and echoviruses.
• Most common type of lymphoma to develop in the thyroid is diffuse large B cell lymphoma.
• Medullary thyroid carcinoma is more aggressive in MEN 2B than in MEN 2A,and famil¬
ial MTC is more aggressive than sporadic MTC.
SIGNS AND SYMPTOMS OF HYPOTHYROIDISM (DESCENDING ORDER

TABLE
OF FREQUENCY)
Symptoms Signs
Tiredness, weakness Dry coarse skin; cool peripheral extremities
Dry skin Puffy face, hands, and feet (myxedema)
Feeling cold Diffuse alopecia
Hair loss Bradycardia
Difficulty concentrating and poor Peripheral edem
memory Delayed tendon reflex relaxation
Constipation Carpal tunnel syndrome
Weight gain with poor appetite Serous cavity effusions
Dyspnea
Hoarse voice

HD HARRISON’S 19TH BASED NOTE BOOK
Menorrhagia (later oligomenorrhea or

amenorrhea)
Paresthesia
Impaired hearing
SAOTO (DESCENDING ORDER OF

TABLE FREQUENCY)
Symptoms Signs3
Hyperactivity, irritability, dysphoria
Tachycardia; atrial fibrillation in the elderly
Heat intolerance and sweating
Tremor
Palpitations Goiter
Fatigue and weakness Warm, moist skin
Weight loss with increased appetite Muscle weakness, proximal myopathy
Diarrhea
Lid retraction or lag
Polyuria
Gynecomastia
Oligomenorrhea, loss of libido
aExcludes The signs of ophthalmopathy and dermopathy specific for Graves’ disease
5; -
m
pi
’1
FIGU
uE , F®atures of Graves’ disease. A. Ophthalmopathy
are
in Graves’ disease; lid retraction
ma,ked a Thyrold demTOpa,hy over,he

Page | 167
• AUTOIMMUNE HYPOTHYROIDISM (Pg:2290-91)
• TREATMENT OF HYPOTHYROIDISM (Pg:2292-93)
• MYXEDEMA COMA (Pg:2293)
• GRAVE’S DISEASE (Pg:2293-97)
• THYROTOXIC CRISIS (Pg:2297)
• SUBACUTE THYROIDITIS (Pg:2298-99)
• SILENT THYROIDITIS (Pg:2298-99)
• SICK EUTHYROID SYNDROME (Pg:2298-99)
EFFECTS OF AMIODARONE ON THYROID FUNCTION
• Amiodarone is structurally related to thyroid hormone and contains 39% iodine by weight.
• Because amiodarone is stored in adipose tissue,high iodine levels persist for >6 months
after discontinuation of the drug.
• Amiodarone inhibits deiodinase activity,and its metabolites function as weak antagonists
of thyroid hormone action.
• Amiodarone has the following effects on thyroid function:
1. acute,transient suppression of thyroid function;
2. hypothyroidism in patients susceptible to the inhibitory effects of ahigh iodine load; and
3. thyrotoxicosis that may be caused by either a Jod-Basedow effect from the iodine load,
in the setting of MNG or incipient Graves’ disease,or a thyroiditis-like condition.
TABLE SAO
Body Compart- Signs and Symptoms

ment/ System
Body fat Weight gain, central obesity rounded face, fat pad on back of neck
(“buffalo hump”)
Skin Facial plethora, thin and brittle skin, easy bruising, broad and purple
stretch marks, acne, hirsutism
Bone Osteopenia, osteoporosis (vertebral fractures), decreased linear growth
in children

Muscle Weakness, proximal myopathy (prominent atrophy of gluteal and

upper leg muscles with difficulty climb ing stairs a getting up from a
chair)
Cardiovascular Hypertension, hypokalemia, edema, atherosclerosis
system
Metabolism Glucose intolerance/diabetes, dyslipidemia
Reproductive Decreased libido, h women amenorrhea (due to cortisol-mediated inhi¬
system bition of gonadotropin release)
Central nervous Irritability, emotional lability, depression, sometimes cognitive defects;
system in severe cases, paranoid psychosis
Blood and im¬ Increased susceptibility to infections, increased white blood cell count,
mune system eosinopenia, hypercoagulation with increased risk of deep vein throm¬
bosis and pulmonary embolism
Kidney
Renal sodium
retention (and
potassium excretion) Renat porfusionÿflj
(
£(
pressure }
Vasoconstriction
gtomerutarÿÿÿ f
i*100—forM>l colls
\
Activation o(
Angiotensin It receptor
type 1 (AT1 receptor)
\
3 / reteaso
n
Ang
J
'Angiotensin
enzyme (ACE)
Figure Regulation of the renin-angiotensin-aldosterone

(RAA) system.
Email: infog.damsddhi.com | Website:
www.damsddhi.com Page | 169
TABLE CAUSES OF CUSHING’S SYNDROME
Female : Male c/
Causes of Cushing’s Syndrome /o
Ratio
ACTH-Dependent Cushing’s 90
Cushing’s disease (= ACTH-producing pituitary adenoma) 4:1 75
Ectopic ACTH syndrome (due to ACTH secretion by bron¬
chial or pancreatic carcinoid tumors, small-cell lung cancer, 1:1 15
medullary thyroid carcinoma, pheochromocytoma and others)
ACTH-lndependent Cushing’s 4:1 10
Adrenocortical adenoma 5-10
Adrenocortical carcinoma , 1
Rare causes: macronodular adrenal hyperplasia; primary
pigmented nodular adrenal disease (micro- and/or macronod¬ <1
ular); McCune-Albright syndrome
TABLE SIGNS AND SYMPTOMS OF ADRENAL INSUFFICIENCY

Signs and Symptoms Caused by Glucocorticoid Deficiency
TB>Fatigue, lack of energy
Weight loss, anorexia
Myalgia, joint pain
Fever
Normochromic anemia, lymphocytosis, eosinophilia
Slightly increased TSH (due to loss of feedback inhibition of TSH release)
Hypoglycemia (more frequent in children)
Low blood pressure, postural hypotension
Hyponatremia (due to loss of feedback inhibition of AVP release)
Signs and Symptoms Caused by Mineralocorticoid Deficiency (Primary Adrenal
Insufficiency Only)
Abdominal pain, nausea, vomiting
Dizziness, postural hypotension
Salt craving
Low blood pressure, postural hypotension
Increased serum creatinine (due to volume depletion)
Hyponatremia
Hyperkalemia

Signs and Symptoms Caused by Adrenal Androgen Deficiency

Lack of energy
Dry and itchy skin (in women)
Loss of libido (in women)
Loss of axillary and pubic hair (in women)
Other Signs and Symptoms
Hyperpigmentation (primary adrenal insufficiency only) (due to excess of proopiomelano-
cortin [POMC]-derived peptides)
Alabaster colored pale skin (secondary adrenal insufficiency only) (due to deficiency of
POMC derived peptides) _
Abbreviations-. AVP, arginine vasopressin; TSH, thyroid stimulating hormone
• Hyponatremia is the characteristic biochemical feature in primary adrenal insufficiency
and is found in 80% of patients at presentation. Hyperkalemia is present in 40% of pa¬
tients at initial diagnosis.
CLINICAL FEATURES ASSOCIATED WITH PHEOCHROMOCYTOMA,
TABLE
LISTED BY FREQUENCY OF OCCURRENCE
1. Headaches 10. Weight loss

2. Profuse sweating 11. Paradoxical response to antihyper¬
3. Palpitations and tachycardia tensive drugs
4. Hypertension, sustained or paroxysmal 12. Polyuria and polydipsia
5. Anxiety and panic attacks 13. Constipation
6. Pallor 14. Orthostatic hypotension
7. Nausea 15. Dilated cardiomyopathy
8. Abdominal pain 16. Erythrocytosis
9. Weakness 17. Elevated blood sugar
18. Hypercalcemia
-
• The classic “rule of tens” for pheochromocytoma states that -10% are bilateral, 10% are
extraadrenal and -10% are malignant.
• ACUTE ADRENAL INSUFFICIENCY (Pg:2324-27)

• PHEOCHROMOCYTOMA (Pg:2329-35)

Page | 171
HARRISON’S 19TH BASED NOTE BOOK H
X-Linked Adrenoleucodvstrophv
• Caused by mutations in the X-ALD geneencoding peroxisomal membrane transporter

protein ABCD1.
• This results in the accumulation of very long chain (>24 carbon atoms) fatty acids.
• Approximately 50% of cases manifest in early childhood with rapidly progressive white
matter disease(Cerebral ALD).
• 35% present during adolescence or in early adulthood with neurologic features indicative
of myelin and peripheral nervous system development.(Adrenomyeloneuropathy).
• In the remaining 15%, adrenal insufficiency is the sole manifestation of the disease.
Multiple Endocrine Neoplasia
• Four major forms of MEN are recognized and referred to as MEN types 1-4 (MEN 1-4).
• Each type of MEN is inherited as an autosomal dominant syndrome or may occur spo¬
radically.
• In addition to MEN 1-4, at least six other syndromes are associated with multiple endo¬
crine and other organ neoplasias (MEONs).
• These MEONs include the hyperparathyroidism-jaw tumor syndrome,Carney complex,
von Hippel-Lindau disease, neurofibromatosis type 1, Cowden’s syndrome,and Mc-
Cune-Albright syndrome ; all of these are inherited as autosomal dominant disorders,
except for McCune- Albright syndrome,which is caused by mosaic expression of a postzy-
gotic somatic Ml mutation.
Multiple Endocrine Neoplasia Type 1
• Also referred to as Wermer’s syndrome.

• Characterized by the triad of tumors involving the parathyroids, pancreatic islets,and an¬
terior pituitary.
• In addition, adrenal cortical tumors, carcinoid tumors usually of the foregut, meningi¬
omas, facial angiofibromas, collagenomas, and lipomas may also occur in some patients
with MEN 1.
• Primary hyperparathyroidism is the most common feature of MEN1.
• Gastrinoma is the most common pancreatic neuroendocrine tumor in MEN1.
• Most common cause of death is usually a malignant tumor, often from a pancreatic neu¬
roendocrine tumor (NET) or foregut carcinoid.

Multiple Endocrine Neoplasia Type 2 And Type 3
• Also referred to as Sipple’s syndrome.

and
• Characterised by association of medullary thyroid carcinoma, pheochromocytomas
parathyroid tumors.
only.
• Three clinical variants of MEN 2 are recognized :MEN 2A, MEN 2B and MTC
MEN 2A ,which is often referred to as MEN 2 is the most common variant.
• In MEN 2A, MTC is associated with pheochromocytomas in 50% of patients and with
parathyroid tumors in 20 % of patients.
• MEN 2A may rarely occur in association with Hirschsprung’s disease, caused by the ab-
sence of autonomic ganglion cells in the terminal hindgut,resulting in colonic dilatation
severe constipation, and obstruction.
• MEN 2A may also be associated with cutaneous lichen amyloidosis, which is a pruritic
lichenoid lesion that is usually located on the upper back.
• MEN 2B, which is also referred to as MEN 3, represents 5% of all cases of MEN 2 and
is characterized by the occurrence of MTC and pheochromocytoma in association with a
marfanoid habitus; mucosal neuromas of the lips,tongue,and eyelids; medullated corneal
fibers; and intestinal autonomic ganglion dysfunction leading to multiple diverticulae and
megacolon.Parathyroid tumors do not usually occur in MEN 2B.
• MTC only (FMTC) is a variant in which MTC is the sole manifestation of the syndrome.
• MTC is the most common feature of MEN 2A and MEN 2B and occurs in almost all
affected individuals.
Multiple Endocrine Neoplasia Type 4
• Patients with MEN 1 associated tumors such as pituitary adenomas, and pancreatic NETs,
occuring in association with gonadal,adrenal,renal and thyroid tumors have been report¬
ed to have mutations in the gene encoding the 196 amino acid cyclin-dependent kinase
inhibitor (CK1) p27kipl (CDNKIB). Such families with MEN 1 associated tumors and
CDNKIB mutations are designated to have MEN-4.
Von Hippel Lindau Disease
• Autosomal dominant disorder caused by mutations in the VHL gene. VHL gene is located
on chromosome 3p.
Characterised by hemangioblastomas of the retina and CNS ; cysts involving the kid¬
ney,pancreas and epididymis ; renal cell carcinomas ; pheochromocytomas
and pancreatic
islet cell tumors.

Page | 173
involved sites.
• In the CNS,the cerebellum and spinal cord are the most frequently
risk of a renal cell
• The renal abnormalities consist of cysts and carcinomas,and the lifetime
carcinoma (RCC) in VHL is 70%,
• The most frequent pancreatic lesions in VHL are multiple cyst-adenomas.
Neurofibromatosis Type 1
• Also referred to as von Recklinghausen’s disease.
• Autosomal dominent disorder.
• Manifestations include ;
• Neurologic (peripheral and spinal neurofibromas)
• Ophthalmologic (optic gliomas and iris hamartomas such as Lisch nodules)
• Dermatologic (cafe au lait macules)
• Skeletal (scoliosis,macrocephaly,short stature and pseudoarthrosis)
• Vascular (stenoses of renal and intracranial arteries)
• Endocrine (pheochromocytoma,carcinoid tumors and precocious puberty)
Neurofibromatosis Type 2
• Autosomal dominant disorder.
• Characterized by the development of bilateral vestibular schwannomas (acoustic neuro¬
mas) that lead to deafness, tinnitus,or vertigo.
• Some patients with NF2 also develop meningiomas, spinal schwannomas, peripheral nerve
neurofibromas, and cafe au lait macules.
Keep in mindEndocrine abnormalities are not found in NF2 and are associated solely with
NF1.
Cowden’s Syndrome
• Autosomal dominant disorder.
• Caused by mutations of the PTEN gene located on chromsome 10.
Characterised by multiple hamartomatous lesions, especially of the skin, mucous mem-
branes (eg: buccal, intestinal and colonic), breast and thyroid.
Mccune-Albright Syndrome
• Results from postzygotic somatic cell mutations of the G protein Mtimulating subunit (Gs
Mi encoded by the GNASl gene located on chromosome 20q.
• Characterised by the triad of ;

> -polyostotic fibrous dysplasia (which may be associated
with hypophosphatemic rickets)
-cafe au lait skin pigmentation
> -peripheral precious puberty
• It may be associated with other endocrine abnormalties such as thyrotoxicosis, somatotro-
pe tumors and Cushing’s syndrome.
DISEASE ASSOCIATIONS WITH AUTOIMMUNE POLYENDOCRINE

TABLE
SYNDROMES
Autoimmune
Autoimmune Polyendo- Other Autoimmune Polyendocrine
Polyendocrine
crine Syndrome Type 2 Disorders
Syndrome Type 1
IPLX (immune dysfunction polyendocrinopa-
Endocrine Endocrine
thy X-linked)
Addison’s disease Addison’s disease Thymictumors
Hypoparathyroidism TypeI diabetes Anti-insulin receptor antibodies
Graves’s disease or autoimmune
Hypogonadism POEMS syndrome
thyroiditis
Graves’ disease or au¬ Insulin autommune syndrome (Hirata’s
toimmune thyroiditis
Hypogonodism
syndrome)
Adult combined pituitary hormone

Type 1diabetes deficiency (CPHD) with anti-Pit 1
autoantibodies
Kearns-Sayre-syndrome
DIDMOAD syndrome
Nonendocrine Nonendocrine Congenital rubelia associated with
thyroiditis and/or diabetes
Mucocutaneous- Celiac disease, dermatitis
condidiasis herpetiformis
Chronic active
hepatitis Pernicious anemia
Pernicious anemia Vitiligo
Vitiligo Alopecia
Email: mfo@damsdelhi.com | Website: www.damsdelhi.com

Page | 175
M
Asplenism Myasthenia gravis
Ectodermal dys¬ IgA deficiency
plasia
Alopecia Parkinsons disease
Malabsorption
Idiopathic thrombocytopenia
Syndromes
IgA deficiency
Abbreviations: DIDMOAD, diabetes insipidus, diabetes mellitus, propressive bilateral optic atrophy, and
sensorineural deafness, POEMS, polyneuropathy, organomegaly, endocnopathy, M protein, and skin changes.
TABLE COMPARISION OF APS-1 AND APS-2
APS-1 APS-2
Early onset: infancy Later onset
Siblings often affected and at risk Multigenerational
Equivalent sex distribution Females > males affected
Monogenic: AIRE gene, chromosome
Polygenic: HLA, MICA, PTNP22, CTLA4
21, autosomal recessive
Not HLA associated for entire syn¬ DR3/ DR4 associated, other HLA class III gene associations
drome, some specific component risk noted
Autoantibodies to type 1interferons
No autoantibodies to cytokines
and IL-17 and IL-22
Autoantibodies to specific target
Autoantibodies to specific target organs
organs
Asplenism No defined immunodeficiency
Association with other nonendocrine immunologic disorders like
Mucocutaneous candidiasis
myasthenia gravis and idiopathic thrombocytopenic purpura
A COMPARISON OF SYNDROMES OF OBESITY-HYPOGONADISM AND

TABLE
MENTAL RETARDATION
Syndrome
Feature Prader-Willi Laurence-Moon- Ahl-
Biedl Cohen’s Carpenter’s
strom’s
Inheri¬
Sporadic; two- Probably
thirds have Autosomal reces- Autosomal Autosomal
tance sive
autosomal
defect recessive recessive
recessive

Normal;
Normal; infre¬ infre¬ Short or
Stature Short Normal
quently short quently tall
short
Generalized Truncal Truncal
Generalized Early
Moderate to Mid-child- Truncal, gluteal
Obesity Early onset, 1 -2 onset, 2-5
severe Onset hood, age 5
years
1-3 years years
Narrow bifron-
tal diameter High nasal
Al- bridge Acrocephaly
mond-shaped Arched
Flat nasal
Cranio- eyes Not dis¬ palate bridge
Not distinctive
facies Strabismus tinctive Open High-arched
V-shaped mouth
palate
mouth Short phil-
High-arched trum
palate
Hypotonia
Small hands Polydactyly
No abnor- Narrow
Limbs and feet Polydactyly Syndactyly
malities hands and
Hypotonia Genu valgum
feet
Normal
Hypogo- gonadal
Repro- nadism function
ductive
r T Hypogonadism in males or hypogo-
Hypogonadism
status but not in nadotropic Hypogonadism
females hypogonad¬
ism
Enamel hypo¬
plasia Dysplastic
ears
Other Hyperphagia
features Temper tan¬ Delayed
trums
puberty
Nasal speech
Mental Normal
Mild to mod¬
retarda¬ intelli¬ Mild Slight
erate
tion gence
--
MNUHUUCN IVIfc JABULISM AND MU 1 1UN
Bioavailable
Unbound fI Albumin SHBG

(0.5-3.0%) (50-70%) (30-45%)
'ÿ
Excretion
| Testosterone (5 mg/d) I (90%)
:
5a-Reductase Aromatase
(6-8%) (0.3%)
.1 T
Dihydrotestosterone Testosterone | Estradiol
(DHT)
j
i
t T
•External genitalia | •Wolffian duct •Hypothalamic/
•Prostate growth •Bone formation pituitary feedback
•Acne •Muscle mass •Bone resorption
•Facial/body hair •Spermatogenesis •Epiphyseal closure
•Scalp hair loss •Gynecomastia
•Some vascular and
behavioral effects
FIGURE : Androgen metabolism and actions. SHBG, sex hormone-binding globulin.
TABLE ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS

I. Type 1 diabetes (beta cell destruction, usually leading to absolute insulin deficien¬
cy)
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly insulin resistance with relative
insulin deficiency to a predominantly insulin secretory defect with insulin resis¬
tance)
III. Other specific type of diabetes
A. Genetic defects of beta cell development or function characterized by mutations
in:
1. Hepatocyte nuclear transcription factor (HNF) 4M(MODY 1)
2. Glucokinase (MODY 2)
3. HNF-1 M(MODY3)
4. Insulin promoter factor-1 (IPF-lj MODY 4)
5. HNF-14! (MODY 5)

6. NeuroDl (MODY 6)
7. Mitochondrial DNA
8. Subunits of ATP-Sensitive potassium channel
PAX4, BLK, GATA4,
10. Other pancreatic islet regulators/proteins such as KLF11,
GATA6, SLC2A2 (GLUT2), RFX6, GUS3
B. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic
fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl es¬
ter lipase
D. Endocrinopathies — acromegaly, Cushing’s syndrome, glucagonoma, pheochromo-
cytoma, hyperthyroidism, somatostatinorma, aldosteronoma
E. Drug-or chemical-induced—glucocorticoids, vacor (a rodenticide), pentamidine,
nicotinic acid, diazoxide, 4!adrenergic agonists, thiazides, calcineurin and mTOR in¬
hibitors, hydantoins, asparaginase, 4'interferon, protease inhibitors, antipsychotics
(atypicals and others), epinephrine
F. Infections—congenital rubella, cytomegalovirus, coxsackievirus
G. Uncommon forms of immune-mediated diabetes—“stiff-person” syndrome, an¬
ti-insulin receptor antibodies
H. Other genetic syndromes sometimes associated with diabetes—Wolfram’s syn¬
drome, Down’s
syndrome, Klinefelter’s syndrome, Turner’s syndrome,Huntington’s chorea,
Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syn¬
drome
IV. Gestational diabetes mellitus (GDM)
Abbreviations: MODY, maturity-onset diabetes of the young
: Maturity onset diabetes of the young (MODY) and monogenic diabetes are
subtypes of DM characterized by autosomal dominant inheritance, early onset of hypergly-
cemia (usually <25 years; sometimes in neonatal period), and impaired insulin
secretion.

Page | 179
TABLE CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUS
• Symptoms of diabetes plus random blood glucose concentration >11.1 mmol/L (200
mg/dL)" or
• Fasting plasma glucose >7.0 mmol/L (126 mg/dL)ÿ or
• Hemoglobin Alc > 6.5%c or
• 2-h plasma glucose >11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testÿ
"Random is defined as without regard to time since the last meal, Tasting is defined as no caloric intake
for at least 8 h. 'Hemoglobin Au test should be performed in a laboratory using a method approved
by the National Glycohemoglobin Standardization Program and correlated to the reference assay of
the Diabetes Control and Complications Trial. Point of-care hemoglobin A]c should not be used for
diagnostic purposes. ‘The test should be performed using a glucose load containing the equivalent of
75 g anhydrous glucose dissolved in water, not recommended for routine clinical use.
Hyperglycemia
Pre-diabetes* Diabetes Melifrus
*
Impaired fasting Insulin Insulin
Normal glucose or Not required required
Type of glucose impaired glucose insulin for for
tolerance tolerance requiring control survival
Type 1
Type 2 4 4-
Other 4-
specific types
Gestational * 4-
Diabetes
Time (years)
;
FPG <5.6 mmol/L 5.6-69 mmol/L £70 mmol/L
(100 mg/dL) (100-125 mg/dL) (126 mg/dL)
2-h PG <7.8 mmol/L 7.8-11.0 mmol/L £11.1 mmol/L
(140 mg/dL) (140-199 mg/dL) (200 mg/dL)
HbA1C <5.6% 5.7-6.4% £6.5%
USEFUL ONE LINERS
• Most individuals with type 1 DM have the HLA DR3 and/or DR4 haplotype.
• Most common type of MODY is MODY 3.
• MODY 5 is associated with renal cysts.

I IAKIUSON'S I9TH BASED NOTE BOOK
TABLE TREATMENT GOALS FOR ADULTS WITH DEABETESj

Index Goal
Glycemic control*
HbAlc <7.0%c
Preprandial capillary plasma glucose 4.4-7.2 mmol/L (80-130 mg/dL)
Peak postprandial capillary plasma glucoseÿ <10.0 mmol/L(<180mg/dL)
Blood pressure < 140/90 mmHgc
Lipid/
Low-density lipoprotein <2.6 mmol/L (100 mg/dL)6
High-density lipoprotein >1 mmol/L (40 mg/dL) in men
>1.3 mmol/L (50 mg/dL) in women
Triglycerides <1.7 mmol/L (150 mg/dL)
As recommended by the American Diabetes Association; goals should be individualized for
each patient (see text). Goals may be different for certain patient populations. bHbA,c is pri¬
mary goal. cDiabetes Control and Complications Trial-based assay. dl-2h after beginning of
a meal. 'Goal of < 130/80 mmHg may be appropriate for younger individuals Tin decreasing
order of priority. Recent guidelines from the American College of Car-diology and American
Heart Association no longer advocate specific LDL and HDL goals (see Chaps. 291e and 419).
gGoal of < 1.8 mmol/L (70 mg/dL) may be appropriate for individuals with cardiovascular
disease.
TABLE MANIFESTATIONS OF DIABETIC KETOACIDOSIS
Symptoms Physical Findings

Nausea/vomiting Tachycardia
Thirst/polyuria Dehydration/hypotension
Abdominal pain Tachypnea/Kussmaul respirations/ respiratory
Shortness of breath distress
Precipitating events Abdominal tenderness (may resemble acute pan¬
Inadequate insulin administra¬ creatitis or surgical abdomen)
tion Lethargy/obtundation/cerebral edema/possibly
Infection (pneumonia/UTI/ coma
gastro-enteritis/sepsis)
Infarction (cerebral, coronary,
mesenteric, peripheral)
Drugs (cocaine)
Pregnancy

Page | 181
<8
’S
TABLE SECONDARY CAUSES OF DYSLIPIDEMIA
5
S
CO
00
S) LDL HDL O
Lp(a) Elevated
Z
Elevated Reduced Elevated Reduced VLDL Elevated IDL Elevated Chylomicrons Elevated CO
Hypothy- Severe liver Alcohol Smoking Obesity Multiple my- Autoimmune disease Chronic kidney
disease H
roidism disease eloma X
CD
Nephrotic syn¬
drome W
Nephrotic Malabsorp- Exercise DM type DM type 2 Monoclonal DM type 2 Inflammation a
syndrome tion Exposure 2 Glycogen stor- gammopathy Menopause z
o
Cholesta- Malnutri¬ to chlo- Obesity age disease H
sis tion rinated Malnutri¬ m
CD
m Gaucher’s hydrocar¬ tion o
I
rr1
disease bons O
Acute in- Chronic Drugs: Gaucher’s Nephrotic syn- Autoimmune Orchidectomy
5‘ termit-tent infectious estrogen disease drome disease
o’
porphyria disease
i Hepatitis Al¬
cohol
3
M
Anorexia Hyperthy- Cho- Renal failure Hypothyroid- Hypothyroidism
g nervosa roidism lesteryl Sepsis ism Acromegaly
b Hepatoma Drugs: nia- ester Stress
o Drugs: growth
3 Drugs: cin toxicity storage Cushing’s syn¬ hormone, isotreti¬
thiazides, disease drome noin
a cyclospo¬ Drugs: Pregnancy
K rin, carba- anabolic Acromegaly
n mazepine steroids, Lipodystrophy
beta Drugs: estrogen,
blockers beta blockers,
e- glucocor-
1
c_ ti-coids, bile
acid binding
2:
i
n resins, retinoic
3 acid
I NCEP:ATPIIIa 2001 AND HARMONIZING DEFINITION CRITERIA FOR THE

TABLE METABOLIC SYNDROME
NCEP:ATPIII 2001 Harmonizing Definition*
Three or more of the following: Three of the following:
• Central obesity: waist circumfer- #
Waist circumference (cm)
ence >102 cm (M), >88 cm (F)
• Hypertriglyceridemia: triglycer¬ Men Women Ethnicity
ide level > 150 mg/dL or specific > 94 >80 Europid,
medication sub-Sa¬
• Low HDLC cholesterol: <40 mg/ haran
dL and <50 mg/dL for men and African,
women, respectively, or specific Eastern
medication and Middle
Eastern
• Hypertension: blood pressure
> 130 mmHg systolic or > 85 90 > 80 South
mmHg diastolic or specific med¬ Asian,
ication Chinese,
• Fasting plasma glucose level > 100 and ethnic
mg/dL or specific medication or South and
previously diagnosed type 2 dia¬ Central
betes American
>85 >90 Japanese
• Fasting triglyceride level >150 mg/dL or specific
medication
• HDL cholesterol level <40 mg/dL and <50 mg/
dL for men and women, respectively, or specific
medication
• Blood pressure >130 mm systolic or >85 mm
diastolic or previous diagnosis or specific med¬
ication
• Fasting plasma glucose level >100 mg/dL (al¬
ternative indication: drug treatment of elevated
glucose levels)

• VITAMIN D, RICKETS.OSTEOMALACIA (Pg:2463-66)

• FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (Pg:2475)
• JANSEN’S DISEASE
• MILK ALKALI SYNDROME (Pg:2479)
• PSEUDOHYPOPARATHYROIDISM & PSEUDOPSEUDOHYPOPARATHY-
ROIDISM (Pg:2485-86)
USEFUL ONE LINER
• Osteogenesis imperfecta is due to defect in type 1 collagen.
MARFAN’S SYNDROME
• Connective tissue disorder primarily affecting skeleton,cardiovascular system and eyes.

• Autosomal dominant pattern of inheritance.
• 90% of patients have mutation in the gene for the extracellular glycoprotein fibrillin-1
(FBN1) located on chromosome 15q.
• Diagnosis is by GHENT criteria.
Clinical Features
• Skeletal - unusually tall, kyphosis,scoliosis,pectus excavatum/carinatum,high arched pal¬

ate
• Cardiovascular — dilatation of root of aorta and sinuses of valsalva, aortic regurgitation,

dissection of aorta
• Ocular features - Most characteristic is bilateral subluxation or dislocation (ectopia lentis).
Other features include myopic vision,cataract,retinal detachment.
• Propranolol or other 4tadrenergic blocking agents are used to lower blood pressure and
thereby delay or prevent aortic dilation.
Alport’s Syndrome
• There are four forms of AS :

1. Classic AS - X linked dominant disorder with hematuria, sensorineural deafness and
lenticonus.

IS HARRISON’S 19TH BASED NOTE BOOK
2. X linked form - associated with diffuse leiomyomatosis.

3. Autosomal recessive form
4. Autosomal dominant form
Both autosomal recessive and dominant forms can cause renal disease
without deafness o
lenticonus.
80% of AS patients have the classical X-linked variant.
IV collagen
• Most patients have mutations in four of the six genes for the chains of type
(COL4A3,COL4A4,COL4A5,and COL4A6), most commonly COL4A5.
HIGH YIELDING TOPIC
• HEMOCHROMATOSIS (Pg: 2514-18)

Wilson’s Disease
• Autosomal recessive disorder.
• Caused by mutations in the ATP 7B gene which encodes a membrane bound copper
transporting ATPase.
Clinical Features
• Hepatic — hepatitis, cirrhosis, hepatic decompensation.
• Neurologic
> dystonia,incoordination,tremor
> dysarthria,dysphagia
> autonomic disturbances
> memory loss,migraine type headaches,seizures
Sensory Abnormalties and Muscular Weakness Absent

• Psychiatric features
• Hemolytic anaemia
• Sunflower cataract,Kayser Fleisher ring
• Amenorrhea,spontaneous abortions
• Cholelithiasis,nephrolithiasis
Keep in mind MEDNIK syndrome (mental retardation, enteropathy, deafness,neuropa¬
thy, ichthyosis, keratodermia) is a rare multisystem disorder of copper metabolism with both
features of Menkes and Wilson’s disease.

M
TABLE USEFUL TESTS FOR WILSON’S DISEASE
Heterozygous
Test Usefulnessa Normal Value Carriers Wilson’s Disease
Serum
ceru- 180-350 mg/L Low in 20% Low in 90%
loplas- (18-35 mg/dL)
min
Present in >99% if neurologic
or psychiatric symptoms are
Kayser- present
Fleischer ++ Absent Absent
Present in 30-50% in hepatic
rings presentation and presymptom-
atic state
>1.6 pmol (>100 pg) in symp-
Urine tomatic patients; 0.9 to > 1.6
0.3-0.8 pmol Normal to 1.3
copper +++ pmol (60 to > 100 pg) in pre-
(20-50 pg) pmol (80 pg)
(24-h)
symptomatic patients
0.3-0.8 >3.1 pmol (>200 pg) (Obstruc¬
Liver Normal to 2.0
++++ pmol/g (20-50 tive liver disease can cause
copper pmol (125 pg)
pg/g of tissue) false-positive results.)
Hap-
++++ (sib¬ 2 matches
lotype 0 matches 1 match
lings only)
analysis
"Usefulness range: + (somewhat useful) to ++++ (very useful)
,JL.
FIGURE A Kayser-Fleischer ring. Although in this case, the brownish ring rimming the cornea is
clearly visible to the naked eye, confirmation is usually made by slit-lamp examination.
First step in evaluating patients presenting with hepatic decompensation is to establish
disease severity, which can be estimated with the Nazer Prognostic Index. Patients with scores
<7 can usually be managed with medical therapy. Patients with scores >9 should be consid-

between 7 and 9,clinical
ered immediately for liver transplantation. For patients with scores
or medical therapy.
judgment is required in deciding whether to recommend trans plantation
TABLE PROGNOSTIC INDEX OF NAZER
Score (in Points)
1 2 3 4
Laboratory Normal 0
Mearurement Value
Serum bilirubin' 0.2-1.2 mg/dL <5.8 5.8-8.8 8.8-11.7 11.7-17.5 >17.5
Serum aspartate 10-35 IU/L <100 100-150 151-200 201-300 >300
aminotransfer-
ase
Prolongation <4 4-8 9-12 13-20 >20
of prothrombin
time (sec)
"If hemolysis is present, serum billirubin cannot be used as a measure of liver function until
the hemolysis subsides.
TABLE RECOMMENDED ANTICOPPER DRUGS FOR WILSON’S DISEASE
Disease Status First Choice Second Choice
Initial hepatic
Hepatitis or cirrhosis without
Zinca Trientine
decompensation
Hepatic decompensation
Mild Trientineb and zinc Penicillamine’b and zinc
Moderate Trientine and zinc Hepatic transplantation
Severe Hepatic transplantation Trientine and zinc
Initial neurologic/ psychiatric Tetrathiomolybdate0 and zinc Zinc
Maintenance Zinc Trientine
Presymptomatic Zinc Trientine
Pediatric Zinc Trientine
Pregnant Zinc Trientine
Mechanism of action of Zinc in Wilson’s disease ?
• It produces a negative copper balance by blocking intestinal absorption of copper,and it
induces hepatic metallothionein synthesis.thereby sequestering additional toxic
copper.

Page | 187
X
>
'S SuednylCoA Glycine jo
00
X-fc*ed protoporphyria (XLP) - AlAsyrCmae <
7,
C
00 X4nked aidcrobiaskc anemia (XSLA) -- Nogiwo feedback z
c/5
6-AminotevUrtcacid
ALAxilhydrataee ALA-dohydralaso
Oafciancy porphyria (AGP) X
Aorphobanogen
!
!
Acute jntermiaanl porphyria Hydroxymothytbtono synthaso a
(A*>)
L z
Hydroxyrnethytolano Q
CongenM aiyVeopoMc Mon-cnrymjtic
3
UroporphyrinogenIIIayrthaso CO
(CEP)
C
m
I Porphyria cutanea tMk f*CT)
Uroporphyrinogen 111 Uroporphyrinogen I — Uroporphyrin I C
~
5' HapatoerytNcpoiettc porptyia Uroporphyrinogen decarboxybso

o’ I W
Coproporphyrinogen 111 CoproporphyrinogenI — Coproporphyrin I
o-
W
(HCP) Coprpporphymogon oudaso

a.
Proteporphyrnogon IX
n
> - - -1..
3 Variegate porphyria (VP) Pmaopotphyraxyan ondaso
S“ Protoporphyrn IX
s-f! FenocheUiaie
V
Negawe feedback
e- HEHE
I f igurc The human heme biosynthetic pathway indicating in linked boxes the enzyme that, when deficient, causes
£ the respective prophyria. Heptatic porphyrias are shown in yellow boxes and erythropoietic porphyrias in pink boxes.
g
3
'**3B
c
Figure Typical cutaneous lesions in a patient with porphyria cutanea tarda. Chronic, crusted
lesions resulting from blistering due to photosensitivity on the dorsum of the hand of a patient with
porphyria cutanea tarda.
USEFUL ONE LINERS
• Porphyrias areinherited as autosomal dominant, autosomal recessive, or X-linked

traits,with the exception of porphyria cutanea tarda (PCT),which usually is sporadic.
• Most common type of porphyria is Porphyria Cutanea Tarda.
• Patients with PCT characteristically have chronic liver disease and sometimes cirrhosis
and are at risk for hepatocellular carcinoma.
• Most common acute hepatic porphyria is Acute Intermittent Porphyria.
• Most common erythopoietic porphyria in children is Erythropoietic protoporphyria.
• Most common porphyria to cause symptoms before puberty is Erythropoietic protopor¬
phyria.
• Congenital Erythopoietic Porphyria is also known as Gunther’s disease.

Page | 189
p
OQ
CO
VO
o O
CO
VO
TABLE SELECTED LYSOSOMAL STORAGE DISEASES H
X
Clinical Featuraa 03
Disorders Enzyme Deficiency Stored Material Clinical Inheritance Neurologic Liver, Spleen
Enlargement
Skeletal Dysplasia Ophthalmologic Hematologic Unique Features >
CO
[Specific TherapyJ Types
W
(Onset)
a
Mucopolysaccharidoses CTMucopolysacchartdoses (MP8)
MPS IH. Hurter (136) a-L-lduronidase [ET,
BMT]
dermatan
suirate
Infantile
Intermediate
AR Mental
retardation
Corneal clouding Vacuolated lymphocytes Coarse facies; cardiovascular
involvement; joint stiffness o
Heparan sulfate H
MPS IH/8, Hurler/ Adult Mental
tn
Scheie retardation 03
MPS IS, Scheie None O
3
MPS Hunter (136) Iduronate sulfatase
(ET]
Dermatan
sulphate
Severe
Infantile
X-linked Mental
retardation, less
Retinal degeneration, no
corneal clouding
Granulated lymphocytes Coarse facies; cardiovascular
involvement; joint stiffness; o
In mild form distinctive pebbly skin lesions
£2. Heparan sulfate Mild juvenile
MPS III A. SanflUppo Heparan-N-sutfatase Heparan sulfate Late Infantile AR Severe mental + None Granulated lymphocytes Mild coarse facies
A(I3«) retardation
5’ MPSIII B.SanfibppoB N- Acetyl Heparan sulfate Late Infantile AR Severe mental + + None Granulated lymphocytes Mild coarse facies
O (136) o-glucosaminidase retardation
£ MPSIUCSanfilippoC Acetyl-CoA
(136) a glucosamlnide
Heparan sulfate Late Infantile AR 6evere mental
retardation
+ None Granulated lymphocytes Mild coarse facies
1
V) MPS III D. SanWippo
N-acetyttransferase
N-Acetylglucosamine- Heparan sulfate Late Infantile AR Severe mental + + None Granulated lymphocytes Mild coarse facies
O. 0(136) 6-sulfate sulfatase retardation
rt>
tr MPS IV A. Morquio N- Keratan sulfate Childhood AR None Corneal clouding Granulated neutrophils Distinctive
•keletel
h A (136) Acetylgalactosamine Chondroltin-6 delormliy,
O 6-sutfate sulfatase sulfate odonotlood
[ET-Wals]
3 hypoplasia
erotic valva
disease.
MPS IV B Morquo 6 GaJactosidase Childhood AR None t +++ÿ
(136)
n
sr
ft
MPS VI. Maroteaux
Lamyl136)
A/ytsuKaU$e8
(ET.BMT1
Dermatan
sulfate
Late Infantile AR None ++ Corneal clouding Granulated neutrophils and
lymphocytes
Coarse facies;
valvular heart disease
a MPS VII (136) 6 Glucuronidase Dermatan Neonatal AR Mental +++ Corneal clouding Granulated neutrophils Coarse facies; vascular
sulfate Heparan Infantile retardation. involvement; hydrops fetalis
sulfate adult absent In some in neonatal form
adults
h-
1
s
(A
a-
a
zr
o
o
e
m
3
GM2 G*nglio*idoic* None Macrocephaly;
Mental None None Cherry red spot in
GMj, gan- Infantile AR hyperacusis in
Tay-Sachs diseased (153) P -Hexosamini¬ retardation; infantile form
D dase A gliosides Juvenile infantile form
in seizures;
o later juvenile
<§> form Macrocephaly;
± Cherry red spot None
O- AR Mental
Sandhoff disease (153) P Hexosaminidases GM2gan- Infantile hyperacusis
1cn
A and B gliosides retardation;
seizures
o-
a>
Neutral Glycosphlngolipidoses
3T Fabry disease (150) a-Galactosidase Glo- Childhood X-Iinked Painful None None Corneal dystrophy,
vascular lesions
None Cutaneous an¬
giokeratomas;
O A [ET] botriaosyl- acropares¬
hypo-hydrosis
o ccramidc thesias
Gaucher Adult form
3 Gaucher disease (146) Acid P-glucosidase Glucosyt- Type 1 AR None + +++ + ++++++ None
Eye movements cells in highly variable
(ET.SRT) ceramide Type 2
bone
Type 3 Eye movements
marrow;
*5 cytopenias
cr
(/> Niemann-Pick disease (144) Sphingomyelinase Sphingo- Neurone- AR mental ++++ None Osteo¬ Macule degeneration Foam cells Pulmonary
[FT— trials] myelin pathic, retardation porosis in bone infiltrates Lung
A and B failure
n TypeA seizures marrow
•• Nonneu-
ronopathic,
TypeB
Glycoprotcinoses
Fucosidosis(140) ct-fucosidasc Glyco- Infantile AR Mental None Vacuolated Coarse facies;
CL peptides; Juvenile retardation lympho- angiokeratomas
P
oligosac¬ cytes; foam In juvenile
3
C/5 charides cells form
a- a-Mannosidosis (140) ct-Mannosidasc Oligosac¬ Infantile AR Mental +++ +++ Cataracts, corneal Vacuolat- Coarse facies;
n charides Milder retardation clouding ed lympho- enlarged tongue
cr variant cytes,
Granulated
n neutro¬
o \ phils
3
PMannosidosis (140) PMannosidase Oligosac- AR Seizures; None Vacuolated Angiokeratomas
char ides mental lympho¬ GO
retardation cytes, foam
cells o
Aspartyl lucosaminuria (141) Aspartylgluc
osaminidase
Aspar
tylglucos-
Young adult AR Mental
retardation
± ++ None Vacuolated Coarse facies
lympho¬
z
aminc; GO
cytes, foam
giycopcp- cells
tides VO
Sialidosis(I40) Neuraminidase Sialyloligo- Type 1,
saccharides congenital
AR Myoclonus; less in typeI ++.less in Cherry red spot Vacuolated MPS phenotype H
Type II, in¬
mental
retardation
typel lympho-
cytes
in type III I
fantile and CO
Mucolipidoses (ML)
juvenile
>
GO
ML-II, 1-tcJI disease (138) UDP-Af-Acetylglu- Glyco- Infantile AR Mental Corneal clouding Vacuo¬ Coarse facies;
cosamine-I -phos- protein; retardation
phot ransferase glycolipids
lated and absence of O
granulated mucopolysac
neutro¬ chariduria; Z
phils gingival hypo¬
plasia
O
03 ML-HI.pseucdo-Hurler poiydys- UDP-N-Acctytglu- Glyco- Late AR Mild mental None Corneal clouding, H
P
OQ
n
trophy(!38) cosaminc-1 -phos-
photransferasc
protein;
gtycolipkh
infantile retardation mild retinopathy, hy¬
Coarse facies;
stiffness of w
peropic astigmatism hands and CO
VO
shoulders
O
O
*
*3 X
p >
<8
3£
vo
to O
z
Clinical Features C/5
Disorder4 Enzyme Deficiency Stored Clinical Types Inheritance Neuro¬ Liver, Spleen Skel¬ Oph- Hemato- Unique
[Specific Therapy] Material (Onset) logic Enlargement etal thal- logic Features H
Dys¬ mo- X
plasia logic
>
C/3
Leukodystrophies W
Krabbe disease (147) Galactosylceramidase Galactosyl- Infantile AR Mental None None None None White a
[BMT/HSCT] ceramide retardation matter
Galactosyl- globoid o
H
sphingosine cells W
Metachromatic leukodys- ArylsulfataseA Cerebroside Infantile Juve- AR Mental None None Optic None Gait CO
W trophy (148) sulfate nile Adult retardation; atrophy abnormal¬ o
3 dementia; ities in late o
P# psychosis infantile
rr
in adult form
Multiple sulfatase deficien- Active site cysteine to Sulfatides Late infantile AR Mental + ++ Retinal Vacuolated Absent
cy (149) C -formylglycine-con- mucopoly retardation degen- and granu activity of
D-
P verting enzyme saccharides eration lated cells all known
3
GO cellular
CL sulfatases
27 Disorders of Neutral Lipids
h Wolman disease (142) Acid lysosomal lipase Cholesteryl Infantile AR Mild None None
O +++ None Adrenal
3 (ET— trials] esters; mental calcifica¬
triglycerides retardation tion
I
s
Cholesteryl ester storage
disease (142)
Acid lysosomal lipase
(ET—trials)
Cholesteryl Childhood
esters
AR Nne Hepatomegaly None None None Fatty liver
disease;
f* cirrhosis
Farbcr disease (143) Acid ceramidase Ceramide Infantile AR osio ± None Mac- None Arthrop¬
Juvenile mnal ular athy,sub¬
rara degen¬ cutaneous
CL ton
p eration nodules
3&
n
s
h
o
3
m
3
&
s'
s'
B-
i
t
g
3 Disorders of Glycogen
Pompe disease (135) Acid a-glucosidase [FT] Glycogen Infantile, late AR Neuromus- ± None None None Myocardi-
onset cular opathy
g None None None Respirato¬
Variable: Neuromus- None
s-
n
Late -onset GAA
deficiency (135)
Acid a-glucosidase [ET] Glycogen
juvenile to
AR
cular ry insuf¬
adulthood ficiency;
neuro¬
CL muscular
P
3 disease
a. Danon disease (154) LAMP-2 (lysosomal associated Glycogen Variable: X linked Cardiomy- None None None None Myocardi¬
n
membrane protein-2) childhood to (?Domi- opathy al vacuolar
E adulthood nant) Neuromus¬ degenera¬ x
g >
3 cular tion
Inconsis¬ §
oo
tent mental
O
retardation z
in parentheses refer to die chapters n CR Scriveret al: TheMetabolic andMolecular Bases olInherited Disease. 9th ed. New York, McGraw-Hill, wwwommbid- c/5
com. wrhich provide comprehensive reviews LO
Abbreviations: AR, autosomal recessive; BMT/HSCT. bone marrow or stem cel transplantation; ET. enzyme therapy; SRT.substrate reduction therapy H
X
03
>
C/3
tn
O
z
o
03 H
OQ
rt 03
O
VO o
u>
z
irr
i
Figure Mucopolysaccharidosis type IH (Hurler’s syndrome) in a 4-year-old boy. The diag¬

nosis was made at the age of 15 months, at which time he had developmental delay, hepatomeg¬
aly, and skelatal involvement. At the time of the picture, the patient had short stature, an enlarged
tongue, persistent nasal discharge, stiff joints, and hydrocephalus. Verbal language skills consisted
of four or five words. The patient had a severe hearing loss and wore hearing aids.
USEFUL ONE LINERS
• Patients with galactosemia are at increased risk for Escherichia coli neonatal sepsis.
• If maternal phenylalanine levels are not strictly controlled before and during pregnancy,
their offspring are at increased risk for congenital defects and microcephaly (maternal
phenylketonuria).
• An increase in total plasma homocysteine is an independent risk factor for coronary, cere-
brovascular.and peripheral arterial disease as well as for deep vein thrombosis.
• Hyperhomocysteinemia, folate and Vitamin B12 deficiency have been associated with an
increased risk of neural tube defects in pregnant women.
• Nitisone, a drug used in tyrosinemia type 1,reduces urinary excretion of homogentisic acid
and,in conjunction with a low-protein diet, might prevent the long-term complications of
alkaptonuria.
m
Cystinuria
• Autosomal recessive inheritance.

• Defective transporter in the apical brush border of proximal renal tubule and small intes¬
tinal cells.
• There is impaired reabsorption and excessive urinary exretion of the dibasic amino acids
lysine, arginine,ornithine,and cystine.
• Because cystine is poorly soluble, its excess excretion predisposes to the formation of renal,
ureteral, and bladder stones.
• Clinical features - Typical of urolithiasis: hematuria, flank pain, renal colic,obstructive
uropathy and infection.
• Treatment
> High fluid intake
> Pharmacologic therapy : Penicillamine, Tiopronin
Hartnup Disease
• Autosomal recessive inheritance.

• Defect in the neutral amino acid trasnsporter in jejunal mucosa and proximal renal tubule.
• Clinical manifestations are mainly due to deficiency of tryptophan and niacin.
• Clinical features
> Pellagra like skin lesions
> Neurologic manifestations - emotional lability,cerebellar ataxia, frank delirium.
TABLE REDUCING THE INCIDENCE OF POST-LP HEDACHE

Effective Strategies
Use of small-diameter needle (22-gauge or smaller)
Use of atraumatic needle (Sprotte and others)
Replacement of stylet prior to removal of needle
Insertion of needle with bevel oriented in a cephalad to caudad direction (when
using stan-
dard needle)
Ineffective Strategies
Bed rest (up to 4 h) following LP
Supplemental fluids
Minimizing the volume of spinal fluid removed
Immediate mobilization following LP
Page | 195
CHAPTER 14 NEUROLOGY
|
'
I
5
] °
k
Do not confuse between the terms seizure and epilepsy.
•SEIZURE- A paroxysmal event due to abnormal excessive
or synchronous neuronal activity in the brain.
•Epilepsy describes a condition in which a person has recur¬
rent seizures due to a chronic,underlying process.
This definition implies that a person with a single
//; II seizure, or recurrent seizures due to correctable or avoidable

circumstances,does not necessarily have epilepsy
TABLE CLASSIFICATION OF SEIZURES

1. Focal seizures
(Can be further described as having motor, sensory, autonomic, cognitive, or other
features)
2. Generalized seizures
a. Absence
Typical
Atypical
b. Tonic clonic
c. Clonic
d. Tonic
e. Atonic
f. Myoclonic
3. May be focal, generalized, or unclear
Epileptic spasms
• Focal seizure — Originate within networks limited to one cerebral hemisphere.Note that
the term partial seizure is no longer used.
• Generalized seizure — Arise within and rapidly engage networks distributed across both
cerebral hemispheres.
Keep in mind - Focal seizures are usually associated with structural abnormalities of the
brain. In contrast, generalized seizures may result from cellular,biochemical, or structural
abnormalities that have a more widespread distribution. _
• With the new classification system, the subcategories of “simple focal seizures” and “com¬
plex focal seizures” have been eliminated. Instead, depending on the presence of cognitive
impairment, they can be described as focal seizures with or without dyscognitive features.
• Its worthwhile to remember three additional features of focal motor seizures :
1. JACKSONIAN MARCH- Abnormal motor movements may begin in a very restricted
region such as the fingers and gradually progress (overseconds to minutes) to include a
larger portion of the extremity. Thisphenomenon represents the spread of seizure activ¬
ity over a progressively larger region of cerebral cortex.
2. TODD’S PARALYSIS- Localized paresis for minutes to many hours in the involved
region following the seizure.
3. EPILEPSY PARTIALIS CONTINUA- Seizure may continue for severalhours or days.
• ABSENCE SEIZURES
• JUVENILE MYOCLONIC EPILEPSY (Pg:2543-45)
• LENNOX GESTAUT SYNDROME
• MESIAL TEMPORAL LOBE EPILEPSY
HARP ISON’S 19TH BASED NOTE
BOOK
—
I FEATURES THAT DISTINGUISH GENERALIZED TONIC-CLONIC
TABLE
I SEIZURE FROM SYNCOPE Seizure Syncope
Features
Emotional stress, Valsalva,
Immediate precipitating factors Usually none orthostatic hypotension,
cardiac etiologies
None or aura (e.g., odd Tiredness, nausea, diaphore¬
Premonitory symptoms odor) sis, tunneling of vision
Posture at onset Variable Usually erect
Transition to unconsciousness Often immediate Gradual over seconds3
Duration of unconsciousness Minutes Seconds
Duration of tonic or clonic move¬ Never more than 15 s
30-60 s
ments
Cyanosis, frothing at
Facial appearance during event Pallor
month
Disorientation and sleepiness after
Many minutes to hours <5 min
event
Aching of muscles after event Often Sometimes

Biting of tongue Sometimes Rarely
Incontinence Sometimes Sometimes
Headache Sometimes Rarely
FEATURES THAT DISTINGUISH GENERALIZED TONIC-CLONIC

TABLE
SEIZURE FROM SYNCOPE
Features Seizure Syncope
Immediate precipitating Emotional stress, Valsalva, orthostatic
factors Usually none
gypotension, cardiac etiologies
Premonitory symptoms None or aura (e.g., odd Tiredness, nausea, diaphoresis, tun¬
odor) neling of vision
Posture at onset Variable Usually erect
Transition to uncon¬
sciousness Often immediate Gradual over second3
Duration of uncon¬
sciousness Minutes Seconds
Page | 198
mi HARRISON’S 19TH BASED NOTE BOOK
Duration of tonic or 30-60 s Never more than 15 s

clonic movements
Facial appearance Cyanosis, frothing at Pallor
during event month
Disorientation and
Many minutes to hours <5 min
sleepiness after event
Aching of muscles after Often Sometimes
event
Biting of tongue Sometimes Rarely

Incontinence Sometimes Sometimes
Headache Sometimes Rarely
TABLE DRUGS AND OTHER SUBSTANCES THAT CAN CAUSE SEIZURES
Alkylating agents (e.g. busulfan, chlorambucil)

Antimalarials (chloroquine, mefloqunie)
Antimicrobials/antivirals
B-lactam and related compounds
Quinolones
Acyclovir
Isoniazid
Ganciclovir
Anesthetics and analgesics
Meperidine
Fentanyl
Tramadol
Local anesthetics
Dietary supplements
Ephedra (ma huang)
Gingko
Immunomodulatory drugs
Cydosporine
OKT3 (monoclonal antibodies to T cells)
Tacrolimus
Interferons

Psychotropics
Antidepressants (e.g. bupropion)
Antipsychotics (e.g. clozapine)
Lithium
Radiographic contrast agents
Drug withdrawal
Alcohol
Baclofen
Barbiturates (short-acting)
Benzodiazepines (short-acting)
Zolpidem
Drugs of abuse
Amphetamine
Cocaine
Phencyclidine
Cocaine
Phencyclidine
Methylphenidate
Flumazenil"
TABLE SELECTION OF ANTIEPILEPTIC DRUGS

General- Focal Typical Absence Atypical Absence,
ized- Myoclonic, Atonic
Onset To
nic-Clonic
First-Line
Lamotrigine Lamotrigne Valproic acid Valproic acid
Valproic acid Carbamazepine Ethosuximide Lamotrigine
Oxcarbazepine Lamotrigine Topiramate
Phenytoin
Levetiracetam
Alternatives

SSI HARRISON’S 1 9TH BASED NOTE BOOK
Clonazepam
Zonisamide* Topiramate Zonisamide* Lamotrlginc
Phenytoin Valproic acid Clonazepam Felbamate
Carbamaze- Tiagabone" Clobazam
pine Gabapentin* Rufinamide
Oxcarbaze- Lacosamage'
pine Exogabine*
Topiramate Phenobarbital
Phenobar- Primidone
bital Felbamate
Primidone
Felbamate
"As adjunction therapy
Generic Principal Neurologic Adverse Ef¬ Drug Interactions

Name Uses fects Systemic
Carbamaz- Tonic-Cion- Ataxia Aplastic Anemia Level decreased by en¬
epine ic Dizziness Leukopenia zyme-inducing drugs, Level
Focal-onset Diplopia Gastrointestinal Increased by erythromycin,
Vertigo limitation propoxy phene, isoniazid,
Hepatotoxicity cimetidine, fluoxetine
Hyponatremia
Clobazam Len- Fatigue Constipation Level Increased by CY-
nox-Gastaut Sedation Anorexia P2C19 inhibitors
syndrome Ataxia Skin rash
Aggression
Insomnia
Clonaze¬ Absence Ataxia Anorexia Level Decreased by en¬
pam Atypical Sedation zyme-inducing drugs
Absence Lethargy
Myoclonic
Ethosuxi- Absence Ataxia Gastrointestinal Level decreased by en¬
mide Lethargy limitation Skin zyme-inducing drugs
Headache rash Level increased by valproic
Bone marrow acid
suppression

Page | 201
Ezogabine Focal-onset Dizziness Retinal abnor¬ Level decreased by en¬
Fatigue malities Skin zyme-inducing drugs
Sedation discoloration
Confusion Cardiac conduc¬
Vertigo tion (QT interval
Tremor prolongation)
Urinary reten¬
tion
Felbamate Focal-onset
Insomnia Aplastic anemia Increased phenytoin valproic
Len- Dizziness Hapatic Failure acid, active carbamazepine
nox-Gastaut Sedation Weight loss metabolite
syndrome Headache Gastrointestinal
Tonic-clonic limitation
Gabapentin Focal-onset Sedation Gastrointesti¬ No known significant in¬
Dizziness nal limitation tractions
Ataxia Weight gain
Fatigue Edema
Lacosamide Focal-onset Dizziness Gastrointesti¬ Level decreased by en¬
Ataxia nal limitation zyme-inducing drugs
Diplopia Cardiac conduc¬
tion (PR interval
prolongation)
Generic Principal Adverse Effects
Neurologic Drug Interactions
Name Uses Systemic
Focal -
onset Ton¬
ic-clonic Level Decreased
Dizziness Dip¬ By enzyme- in¬
Atypical Skin rash
lopia Sedation cluding drugsb and
Lamotrigine absence Stevens- Johnson
Ataxia oral contraceptives
Myoclonic Syndrome
Headache Level increased by
Lennox-
Gastaut valproic acid
Syndrome
Sedation Fa-
Focal-on- tigue Incoordi¬ No Known Signifi¬
Levetiracetam Anemia Leukopenia
set nation Mood cant interactions
Changes

Fatigue Ataxia Level Decreased by

Focal-on-
Dizziness Dip¬ enzyme- includ¬
Oxcarbaze- set
lopia See Carbarmazepine
pine Ton¬ ing drugsb May
Vertigo Head¬ increase phenytoin
ic-clonic
ache
Sedation Atax¬
Ton¬ Level increased
ia Confusion
ic-clonic by valproic acid,
Phenobarbital Dizziness De- Skin rash
Focal - phenytoin
creased libido
onset
Depression
Level increased by
Gingival Hyperplasia Isoniazid, sulfon¬
Dizziness Dip¬ amides, fluoxetine
Ton¬ Lymphadenopathy
Phenytoin lopia Hirsutism Level decreased by
ic-clonic
(diphenyl- Ataxia Incoor¬
Focal - Osteomalacia Facial enzyme- including
hy-Dantoin) dination
onset Coarsening drugs*5
Confusion Altered folate me¬
Skin Rash
tabolism
Level increased by
Ton¬ valproic acid
Primidone ic-clonic Same as Phe¬ Level decreased by
Focal - nobarbital phenytoin (in¬
onset creased conversion
to Phenobarbital)
Sedation Level decreased by
Gastrointestinal irrita¬
Fatigue enzyme- inducing
Lennox- tion Leukopenia
Dizziness drugs*5
Rufinamide Gastaut Cardiac conduction
Ataxia Level Increased by
syndrome (QT interval shorten¬
Headache valproic acid May
ing)
Diplopia increase phenytoin
Confusion Se¬
dation Depres¬
sion Dizziness Level Decreased by
Focal Gastrointestinal
Tiagabine Speech or enzyme- inducting
-onset Irritation
language Prob¬ drugs*5
lems Paresthe¬
sias, Psychosis

Page | 203
Focal - Psychomotor Renal Stones(avoid

Onset slowing Seda¬ use with other
Tonic tion Level Decreased by
carbonic anhydrase enzyme-inducing
Topiramate -clonic Speech or Lan- inhibitors)
Lennox- guage prob- drugsb
Glaucoma Weight
Gastaut lems Fatigue
Loss Hypohidrosis
Syndrome Paresthesias
Tonic-
clonic
Hepatotoxicity
Absence
Valproic acid Thrombocytopenia
Atypical Ataxia Seda- Level Decreased by
(valproate Gastrointestinal
absence tion enzyme-inducing
sodium, dival¬ irritation Weight gain
Myoclonic Tremor drugs*5
proex sodium) Transient alopecia
Focal -
Hyperammonemia
Onset
Atonic
Focal- on-
Sedation Diz¬ Level Decreased By
set Anorexia renal Stones
Zonisamide ziness enzyme- including
Tonic - Hypohidrosis
Confusion drugs*5
clonic

TABLE DOSAGE AND ADVERSE EFFECTS OF COMMONLY USED ANTIEPILEPTIC DRUGS

Adverse Effects
Generic Trade Principal Uses Typical Dose; Half-Life Therapeu¬ Neurologic Systemic Drug Interac-
Name Dose Interval tic Range tionsa
Name
Carbamaz- Tegre- Tonic-clonic 600-1800 mg/d 10-17 h 4-12pg/mL Ataxia Aplastic Level decreased
epine tolc Focal-onset (15-35 mg/Kg, (variable due Dizziness anemia by enzyme-in-
child); bid (cap to autoinduc¬ Diplopia Leukopenia ducing drugsb
sules or tablets), tion complete Vertigo Gastro- Level increased
tid-qid (oral 3-5 wk after intestinal by erythromy¬
suspension) initiation) irritation cin, propoxy
Hepatotox- phene, isoniazid,
icity cimeridine.
Hyponatre¬ fluoxetine
mia
Clobazam Onfi Lennox-Gastaul 10-40 mg/d 36-42 h Not estab- Fatigue Constipation Level increased
syndrome (5-20 mg/d for (71-82 h for lished Sedation Anorexia by CYP2C19
patients <30 kg less active Ataxia Skinrash inhibitors
body weight); metabolite) Aggression
bid Insomnia
Clonaze¬ Klono- Absence 1-12 mg/d; 24-48 h 10-70 ng/ Ataxia Anorexia Level decreased
pam pin Atypical qd-tid mL Sedation by enzyme-in¬
absence Lethargy ducing drugsb
Myoclonic
Ethosuxi- Zaron- Absence 750-1250 mg/d 60 h. adult 30 40-100 pg/ Ataxia Gastro- Level decreased
mide tin (20-40 mg/kg); h. child mL Lethargy intestinal by enzyme-in¬
qd-bid Headache irritation ducing drugs'5
Skin rash Level increased
Bone by valproic acid
marrow
suppression
Ezogabine Potiga Focal-onset 800-1200 7-11 h Not estab¬ Dizziness Retinal ab¬ Level decreased
mg/d;tid lished Fatigue normalities by enzyme-in¬
Sedation Skin discol¬ ducing drugs'5
Confusion oration
Vertigo Cardiac
Tremor conduction
(QT interval
prolonga¬
tion)
Urinary
retention
Felbamate Felba- Focal-onset 2400-3600 16-22h 30-60 pg/ Insomnia Dizziness Aplastic Increases
tol Lennox-Gastaut mg/d, tid-qid mL Sedation Headache anemia He¬ phenytoin, val¬
syndrome
patic failure proic acid, active
Tonic-clonic
Weight loss carbamazepine
Gastro¬ metabolite
intestinal
irritation
Gabapentin Neu- Focal-onset 900-2400 5-9 h 2-20 pg/mL
tontin
Sedation Gastro¬ No known
mg/d; ikl-qid
Dizziness intestinal significant
Ataxia irritation interactions
Fatigue Weight gain
Edema
Lacosamide vimpat Focal-onset 200-400 mg/d; 13 h Not estab¬ Dizziness Gastro¬
bid Level decreased
lished Ataxia intestinal by enzyme-in¬
Diplopia irritation ducing drugsb
Cardiac
conduction
(PR interval
prolonga¬
tion)
Email: mfo@damsdelhi.com | Website:

HARRISON’S 19TH BASED NOTE BOOK WE
STATUS EPILEPTICUS
• Continuous seizures or repetitive, discrete seizures with impaired consciousness in the

interictal period.
• It has numerous subtypes including generalized convulsive status epilcpticus (GCSE) and
non-convulsive status epilepticus.
• Duration of seizure activity sufficient to meet the definition of status epilepticus has tradi¬
tionally been specified as 15-30 min.
• A more practical definition is to consider status epilepticus as a situation in which the
duration of seizures prompts the acute use of anticonvulsant therapy. For GCSE,this is
typically when seizures last beyond 5 min.
IV beruodiawpinc
t/P 0 or mz 02 tnj*g,
Impending and tarty SE

(5-30 minutes) T
IV antiepiieptic drug
PKrtAmgftearVmiO-JOmgte
«
LEV JO~» rrQ'tg
Generalzed Focatcomptex.
convulsive or
•subtle* SE > myoclonic or
absence SE
/
EstabBshed and
early refractory SE X X
(30 mimjtes-48 hours) IV UOZ 02 mpVg -» 02-0$ mgfcpti
artVcr . Further IV/PO antiepileptic drug
VPA. UEV. tCM. TPM. PGB, or othef
IV PBO 2 mgftg -> 2-10
T
f
Late refractory SE
(>48 hours)
PTBfTHP)
5 roptsg (1 mgVgi .
- i-5mg1igh
! T
Other medication*
Uttocame, wrapami,
Other anesthetic* Other approach* s
magnesun, ketogene det. HoAurane. dcsAjranc. Surgery, WS. iTMS. BCT,
ketamine hypotierrha
mmuncmoduleton
Pharmacologic treatment of generalized tonic-clopic status epilepticus (SE) in adults. CLZ- clonaze¬
pam; ECT-electroconvulsive therapy; LCM- lacosamide; LEV-levetiracetam; LZP- lorazepam; MDZ-
midazolam; PGB- pregabalin; PHT-phenytoin or fos-phenytoin; PRO-propofol; PTB- pentobarbital;
rTMS - repetitive transcranial magnetic stimulation; THP-thiopental; TPM-topiramate; VNS-vagus
nerve stimulation; VPA- valproic acid

HIGH YIELDING TOPIC
• SPECIAL ISSUES RELATED TO WOMEN AND EPILEPSY (Pg:2559)
Cerebrovascular Diseases
• A stroke,or cerebrovascular accident,is defined as an abrupt onset of a neurologic deficit

that is attributable to a focal vascular cause.
• The definition of TIA requires that all neurologic signs and symptoms resolve within 24 h
without evidence of brain infarction on brain imaging.
• Stroke has occurred if the neurologic signs and symptoms last for > 24 h or brain infarc¬
tion is demonstrated.
• A decrease in cerebral blood flow to zero causes death of brain tissue within 4-10 min;
values <16-18 ml/100 g tissue per minute cause infarction within an hour; and values <20
ml/100 g tissue per minute cause ischemia without infarction unless prolonged for several
hours or days.
• Fever dramatically worsens brain injury during ischemia, as doeshyperglycemia.
Management Of Acute Ischaemic Stroke
• First goal is to prevent or reverse brain injury.

• Attend to the patient’s airway,breathing,and circulation (ABCs),and treat hypoglycemiaor
hyperglycemia if identified.
• Perform an emergency NCCT head to differentiate between ischaemic stroke and haem¬
orrhagic stroke.
• Blood pressure should be lowered if there is malignant hypertension or concomitant myo¬
cardial ischemia,or if blood pressure is > 185/110 mmHg and thrombolytic therapy is
anticipated.
• Cerebral edema can be managed with mannitol.
• INTRAVENOUS THROMBOLYSIS

Page | 207
ADMINISTRATION OF INTRAVENOUS RECOMBINANT TISSUE
TABLE PLASMINOGEN ACTIVATOR (rtPA) FOR ACUTE ISCHEMIC STROKE I
(AIS)a
Indication Contraindication
Clinical diagnosis of stroke Sustained BP > 185/110 mmHg despite treat¬
Onset of symptoms to time of drug ment
administration < 4.5 hb Platelets < 100,000; HCT <25%; glucose <50 or
CT scan showing no hemorrhage or >400 mg/dL
edema of > 1/3 of the MCA territory Use of heparin within 48 h and prolonged PTT,
Age 18 > years or elevated INR
Consent by patient or surrogate Rapidly improving symptoms
Prior stroke or head injury within 3 months;
prior intracranial hemorrhage
Major surgery in preceding 14 days
Minor stroke symptoms
Gastrointestinal bleeding in preceding 21 days
Recent myocardial infarction
Coma or stupor
Administration of rtPA
IV access with two peripheral IV lines (avoid arterial or central line placement)
Review eligibility for rtPA
Administer 0.9 mg/kg IV (maximum 90 mg) IV as 10% of total dose by bolus, followed by
remainder of total dose over 1 h
Frequent cuff blood pressure monitoring
No other antithrombotic treatment for 24 h
For decline in neurologic status a uncontrolled blood pressure, stop infusion, give cryopre-
cipitate, and reimage brain emergently
Avoid urethral catheterization for > 2 h
• ENDOVASCULAR REVASCULARIZATION— alternative or adjunctive treatment of

acute stroke in patients who are ineligible for or have contraindications to thrombolytics or
in those who failed to achieve vascular recanalization with ivthrombolytics.
• ANTITHROMBOTIC TREATMENT- Aspirin is the only antiplatelet agent that has
been proven effective for the acute treatment of ischaemic stroke, though there are several
antiplatelet agents proven for the secondary prevention of stroke.
Page l 208 Email: info@damsdeIhi.com | Website: www.damsdelhi.com

USEFUL ONE LINERS
• Non rheumatic atrial fibrillation is the most common cause of cerebral embolism overall.
• Atherosclerosis within the Carotid artery occurs most frequently within the common ca¬
rotid bifurcation and proximal internal carotid artery.
• The term lacunar infarction refers to infarction following athero-thrombotic or lipohyali-
notic occlusion of a small artery in the brain.
• The term small vessel stroke has replaced the term lacunar infarction.
• Drugs, in particular amphetamine and perhaps cocaine may cause stroke on the basis of
acute hypertension or drug-induced vasculopathy.
• Phenylpropanolamine has been linked with intracranial haemorrhage,as has cocaine and
methamphetamine,perhaps related to a drug-induced vasculopathy.
• Risk factors for cerebral venous thrombosis are oral contraceptive use, pregnancy and
the postpartum period,inflammatory bowel disease , intracranial infections (meningitis),
thrombophilias and dehydration.
• Most common site for hypertensive haemorrhage is putamen.
TABLE GRADING SCALES FOR SUBARACHNOID HEMORRHAGE
Grade Hunt-Hess Scale World Federation of Neurosurgical

Societies (WFNS) Scale
1 Mild headache, normal mental status, GCSa score 15, no motor deficits
no cranial nerve or motor findings
2 Severe headache, normal mental status, GCS score 13-14, no motor deficits
may have cranial nerve deficit
3 Somnolent, confused, may have cranial GCS score 13-14, with motor deficits
nerve or mild motor deficit
4 Stupor, moderate to severe motor GCS score 7-12, with or without mo¬
deficit, may have intermittent reflex tor deficits
posturing
5 Coma, reflex posturing or flaccid GCS score 3-6, with or without motor
deficits
aGlasgowae; e &’(*)%)"*!

Moya Moya Disease
• Occlusive disease involving large intracranial arteries, especially the distal internal carotid
artery and the stem of the MCA and ACA.
• Vascular inflammation is absent.
• The lenticulostriate arteries develop a rich collateral circulation around the occlusive le¬
sion which gives the impression of a “puff of smoke” (moyamoya in Japanese) on con¬
ventional x- ray angiography, (see image)
it
SBMI _ __
P
1
m
W‘
tf ;
;
7
M I
M m
• STROKE SYNDROMES (Pg:2572-79)

• DEJERINE ROUSSY SYNDROME (Pg:2583)
• CEREBRAL AMYLOID ANGIOPATHY (Pg:2583-84)
• HYPERTENSIVE ENCEPHALOPATHY (Pg:2584)

TABLE SIMPLIFIED DIAGNOSTIC CRITERIA FOR MIGRAINE

with a normal physical
Repeated attacks of headache lasting 4-72 h in patients
examination, no other reasonable cause for the headache,
and:
At Least 2 of the Follow- p|us gt Least 1 of the Following Features:

ing Features:
Unilateral pain
Throbbing pain Nausea/vomiting
Aggravation by movement Photophobia and phonophobia
Moderate or severe inten¬
sity
• Calcitonin gene related peptide is an important vasoactive neuropeptide implicated in the

pathogenesis of migraine.
• CGRP receptor antagonists(gepants) have now been shown be effective in the acute
to
treatment of migraine, and monoclonal antibodies to CGRP have been shown effective in
two early phase clinical trials.
• Data also support a role for dopamine in the pathophysiology of migraine.

• Most drugs effective in the treatment of migraine are members of one of three major phar¬
macologic classes: nonsteroidal anti-inflammatory drugs,5-HT1B/1D receptor agonists, and
dopamine receptor antagonists.
Trigeminal Autonomic Cephalalgias
• The trigeminal autonomic cephalalgias (TACs) describe a grouping of primary headaches

including cluster headache, paroxysmalhemicranias, SUNCT (short-lasting unilateral
neuralgiform headache attacks with conjunctival injection and tearing)/SUNA (short-last¬
ing unilateral neuralgiform headache attacks with cranial autonomic symptoms) and
hcmicrania continua.
• TACs are characterized by relatively short-lasting attacks of head pain associated with
cranial autonomic symptoms, such as lacrimation, conjunctivalinjection, or nasal con¬
gestion.
TABLE
CLINICAL FEATURES OF THE TRIGEMINAL AUTONOMIC
CEPHALALGIAS
Cluster Head¬ Paroxysmal Hemi-
ache crania SUNCT/SUNA
Gender M>F F=M F-M

Page | 211
t-TARR ISDN’S 19TH BASED NOTE BOOK
B£l
Pain
Throbbing, boring, Burning, stabbing, sharp
Type Stabbing, boring stabbing
Severity Excruciating Excruciating Severe to excruciating
Site Orbit, temple Orbit, temple Periorbital
Attack fre¬ 1-20/d (>5/d for more 3-200/d
1/alternate day-8/d than half the time)
quency
Duration of 5-240 s
15-180 min 2-30 min
attack
Autonomic ,, Yes (prominent conjunctival
Yes Yes
r
features injection and lacrimation)2
Migrainous v Yes Yes

features11
Alcohol ,,
No
Yes No
trigger
Cutaneous
No No Yes
triggers
Indometha-
Yesc
cin effect
Sumatriptan injec¬
Abortive
tion or nasal spray No effective treatment Lidocaine (IV)
treatment
Oxygen
Verapamil Lamotrigine
Prophylactic
Methysergide Indomethacin Topiramate
treatment
Lithium Gabapentin
Alzhemer’s Disease
• Most common cause of dementia in the elderly (though it can manifest as young as the
third decade).
• The most important risk factors are old age and a positive family history.
• The major genetic risk for AD is apolipoprotein E4 (Apo E4).
• Several genes play an important role in the pathogenesis of AD One is the APP gene on
chromosome 21. Adults with trisomy 21 (Down’s syndrome) consistently develop the typ¬
ical neuropathologic hallmarks of AD if they survive beyond age 40 years.

of head trauma, low educational status, dia-
• The other risk factors are female sex, history
betes mellitus.
. Elevated homocysteine and cholesterol levels; hypertension; diminished
folic acid; low dietary intake of fruits,vegetables,and red wine; and
serum levels of
low levels of exercise are
all being explored as potential risk factors for AD.
by a slowly
• Patients most often present with an insidious loss of episodic memory followed
progressive dementia that evolves over years.
• At autopsy, the earliest and most severe degeneration is usually found in the medial tem¬
poral lobe (entorhinal/perirhinal cortex and hippocampus), lateral temporal cortex, and
nucleus basalis of Meynert.
• The characteristic microscopic findings are neuritic plaques and neurofibrillary tangles.
• Increasing evidence suggests that soluble amyloid species called oligomers may cause cel¬
lular dysfunction and represent the early toxic molecule in AD.
• Donepezil, Rivastigmine, Galantamine and Memantine are approved by FDA for treat¬
ment of AD.
Keen in : - ;. -Dementia associated with cerebrovascular disease can be divided into two general
categories: multi-infarct dementia and diffuse white matter disease (also called leukoaraiosis, subcor¬
tical arteriosclerotic leukoencephalopathy, or Binswanger’s disease.
Progressive Supranuclear Palsy
• Also known as Steele - Richardson - Olszewski syndrome

• Degenerative disorder that involves the brainstem, basal ganglia, limbic structures, and
selected areas of cortex.
• Clinical features
• Begins with falls and executive or subtle personalty changes (such as mental rigidity, im-
pulsivity,or apathy)
• Shortly thereafter,a progressive oculomotor syndrome ensues that begins with square wave
jerks, followed by slowed saccades (vertical worse than horizontal) before resulting in pro¬
gressive supranuclearophthalmoparesis.
• Dysarthria,dysphagia,and symmetric axial rigidity can be prominent features that emerge
at any point in the illness.
• A stiff unstable posture with hyperextension of the neck and a slow,jerky,toppling gait are
b
characteristic.
Frequent unexplained and sometimes spectacular falls are common secondary to
a combi¬
nation of axial rigidity, inability to look down,
and poor judgment.

fug
• The dementia overlaps with behavioural FTD,featuring apathy, frontal-executive dysfunc¬
tion,poorjudgment,slowed thought processes,impaired verbal fluency, and difficulty with
sequential actions and with shifting from one task to another.
• Response to L-dopa is limited or absent; no other treatments exist.
• RADIOLOGY GOLDEN POINT - Hummingbird sign and Mickeymouse sign are MRI signs (occurs
due to midbrain atrophy)
r
X
\
.
'V
2
*
• CORTICOBASAL DEGENERATION (Pg:2605)

• DEMENTIA WITH LEWY BODIES (Pg:2605-06)

I® HARRISON’S 19TH BASED NOTE BOOK
TABLE CLINICAL FEATURES Of PARKINSON’S DISEASE
Cardinal Motor Other Motor Features Nonmotor Features

Features
Bradykinesia Micrographia Anosmia
Rest tremor Masked facies (hypo- Sensory disturbances (e.g., pain)
Rigidity mimia) Mood disorders (e.g., depression)
Gait disturbance/ Reduced eye blinking Sleep disturbances (e.g., RBD)
postural instability Soft voice (hypophonia) Autonomic disturbances
Dysphagia Orthostatic hypotension
Freezing Gastrointestinal disturbances
Genitourinal disturbances
Sexual dysfunction
Cognitive impairment (MCI/ demen-
tia)
Abbreviations: RBD, rapid eye movement behavior disorder; MCI, mild cognitive impair¬
ment.
TABLE DIFFERENTIAL DIAGNOSIS OF PARKINSONISM
Parkinson’s Disease Secondary Other Neurodegener-

Atypical Parkinsonism
Parkinsonism ative Disorders
Genetic
Multiple-System atro¬
phy (MSA) Drug induced Wilson’s disease
Cerebellar type
Sporadic Tumor Huntingtons disease
(MSA-c)
Dementia with lewy Parkinson type Neurodegeneration

bodies Infection with brain iron accu¬
(MSA-p)
mulation
Progressive supranucle¬ SCA 3 (spinocerebel¬
ar palsy
Vascular
lar ataxial)
Corticobasal ganglionic Normal-pres¬ Fradile X-associated
sure hydro¬ ataxia-tremor-parkin-
degeneration
cephalus sonism
Frontotemporal demen¬
tia Trauma Prion disease

Dystonia-parkinson¬
Liver failure
ism (DYT3)
Toxins (eg.
Carbon mon¬
oxide, manga¬
nese, MPTP, Alzheimer’s disease
cyanide, hex¬ with parkinsonism
ane, methanol,
carbon disul¬
fide)
FEATURES SUGGESTING AN ATYPICAL OR SECONDARY CAUSE OF

TABLE
PARKINSONISM
Symptoms/Signs Alternative Diagnosis to Consider
History
Early speech and gait impairment (Lack of Atypical parkinsonism
tremor, lack of motor asymmetry) Drug-induced parkinsonism
Exposure to neuroleptics Genetic form of PD
Onset prior to age 40 Wilson’s disease, non-Wilsonian hepato¬
Liver disease lenticular degeneration
Early hallucinations and dementia with later Dementia with Lewy bodies
development of PD fea tures PSP
Diplopia, impaired down gaze Atypical or secondary parkinsonism
Poor or no response to an adequate trial of
levodopa
Physical Exam
Dementia as first or early feature Dementia with Lewy bodies
Prominent orthostatic hypotension MSA-p
Prominent cerebellar signs MSA-c
Slow saccades with impaired down gaze PSP
High-frequency (6-10 Hz) symmetric postural Essential tremor
tremor with a prominent kinetic component
Abbreviations: MSA-c, multiple-system atrophy-cerebellar type; MSA-p, multiple-system at¬

rophy Parkinson’s type; PD, Parkinson’s disease; PSP, progressive supranuclear palsy
USEFUL ONE LINERS

• Commonest cause of familial Parkinson disease is LRRK2 mutation.

• Mutations in the parkin gene should be considered in parkinsonian patients with onset
prior to 40 years of age.
• Atypical and secondary parkinsonism is typically characterized by early speech and gait
impairment,absence of rest tremor,no motor asymmetry, poor or no response to levodopa,
and an aggressive clinical course.
• -synuclein constitutes the major component of Lewy bodies in patients with sporadic PD.
• Mutations in the glucocerebrosidase (GBA) gene associated with Gaucher’s disease numer¬
ically represent the most important risk factor for the development of PD.
• Levodopa remains the most effective symptomatic treatment for PD and the gold stan¬
dard against which new therapies are compared.
• No current medical or surgical treatment provides antiparkinsonian benefits superior to
what can be achieved with levodopa.
• Levodopa benefits the classic motor features of PD, prolongs independence and employ-
ability, improves quality of life, and increases life span.
Keep in mind -When patients initially take levodopa, benefits are long-lasting (many hours) even
though the drug has a relatively short half-life (60-90 min). With continued treatment, however, the
duration of benefit following an individual dose becomes progressively shorter until it approaches
the half-life of the drug. This loss of benefit is known as the wearingoff effect.
• TREATMENT OF PARKINSON DISEASE (Pg:2613-18)

• Hot cross bun sign in MRI is seen in MSA-c.
i
TABLE HYPERKINETIC MOVEMENT DISORDERS
Tremor Rhythmic oscillation of a body part due to intermittent muscle contractions
Dystonia Involuntary, patterned, sustained or repeated muscle con-tractions often asso¬

ciated with twisting movements and abnormal posture
Athetosis Slow, distal, writhing, involuntary movements with a pro-pensity to affect the
arms and hands (this represents a form of dystonia with increased mobility)
Chorea Rapid, semi-purposeful, graceful, dance-like nonpatterned involuntary move-
ments involving distal or proximal muscle groups. When the movements are
of large amplitude and predominant proximal distribution, the term ballism
is used
Myoclonus Sudden, brief (<100 ms), jerk-like, arrhythmic muscle twitches
Tic Brief, repeated, stereotyped muscle contractions that can often be suppressed
for a short time. These can be simple and involve a single muscle group or
complex and affect a range of motor activities.
USEFUL ONE LINERS
• Most common site of lesion in hemiballismus is subthalamic nucleus.

• Huntington’s disease is a progressive, fatal, highly penetrant autosomal dominant disorder
characterized by motor, behavioural, oculomotor, and cognitive dysfunction.
• HD can present as an akinetic-rigid or parkinsonian syndrome (Westphal variant).
• HD is caused by an increase in the number of polyglutamine (CAG) repeats (>40) in the
coding sequence of the huntingtin gene is located in the short arm of chromosome 4.
• HIGH YIELDING TOPICS
• HUNTINGTON’S DISEASE (Pg: 2621-22)
• CHOREA (Pg: 2622-23)
• SPINOCEREBELLAR ATAXIA - ONE LINERS
• Spinocerebellar ataxia type 3 is known as Machado Joseph disease.
• SCA1,SCA2,SCA3,SCA6,SCA7, andSCA17 arecausedby CAG triplet repeat expansionsin
different genes.
• SCA8 is due to an untranslated CTG repeat expansion.
• SCA12 is linked to an untranslated CAG repeat.
• SCA10 is caused by an untranslated pentanucleotide repeat.
i
Friedreich’s Ataxia
• Most common form of inherited ataxia.
• It occurs in two forms
• Classic form
• Associated with Vitamin E deficiency syndrome
• The classic form of Friedreich’s ataxia has been mapped to 9ql3q21.1, and the mutant
gene, frataxin contains expanded GAA triplet repeats in the first intron.
• Presents before 25 years of age with progressive staggering gait, frequentfalling, and ti-
tubation.
• Lower extremities are more severely involved than the upper ones.
• Dysarthria occasionally is the presenting symptom; rarely,progressive scoliosis, foot defor¬
mity,nystagmus,orcardiopathy is the initial sign.
• Extensor plantar responses (with normal tone in trunk and extremities), absence of deep
tendon reflexes and weakness (greater distally than proximally) are usually found.
• Loss of vibratory and proprioceptive sensation occurs.
• The median age of death is 35 years.
• Women have a significantly better prognosis than men.
• Cardiac involvement occurs in 90% of patients. Cardiomegaly, symmetrichy pertrophy,
murmurs,and conduction defects are reported.
• Moderate mental retardation or psychiatric syndromes are present in a small percentage
of patients.
• A high incidence of diabetes mellitus (20%) is found and is associated with insulin resis¬
tance and pancreatic ; -cell dysfunction.
• Musculoskeletal deformities are common and include pes cavus, pes equinovarus,and sco-
liosis.
• MRI of the spinal cord shows atrophy.
• The primary sites of pathology are the spinal cord, dorsal root ganglion cells,and the pe¬
ripheral nerves. Slight atrophy of the cerebellum and cerebral gyri may occur.
• Sclerosis and degeneration occurpredominantly in the spinocerebellar tracts, lateral corti¬
cospinal tracts,and posterior columns.
Ataxia Telangiectasia
• Present in the first decade of life with progressive telangiectatic lesions associated with
deficits in cerebellar function and nystagmus.

• The neurologic manifestations correspond to those in Friedreich’s disease, which should
be included in the differential diagnosis.
• Truncal and limb ataxia, dysarthria, extensor plantar responses,myoclonic jerks, areflexia,
and distal sensory deficits may develop.
• There is a high incidence of recurrent pulmonary infections and neoplasms of the lym¬
phatic and reticuloendothelial system in patients with AT.
• Thymic hypoplasia with Cellular and humoral (IgA and IgG2) immunodeficiencies, pre¬
mature aging,and endocrine disorders such as type 1 diabetes mellitus are described.
• There is an increased incidence of lymphomas, Hodgkin’s disease, acute T cellleuke-

mias,and breast cancer.
• The most common form of progressive motor neuron disease is Amyotrophic Lateral Scle¬
rosis.
Keep in mind World Federation of Neurology has established diagnostic guidelines for
ALS. Essential for the diagnosis is simultaneous upper and lower motor neuron involvement
with progressive weakness and the exclusion of all alternative diagnoses. The disorder is
ranked as: “definite” ALS when three or four of the following are involved: bulbar,cervi-
cal,thoracic, and lumbosacral motor neurons. 'v
When two sites are involved, the diagnosis is “probable” and when only one site is implicated,the
diagnosis is “possible.” _ _
USEFUL ONE LINERS
• In humans, the prion protein gene is located on the short arm of chromosome 20.
• The sporadic form of CJD is the most common prion disorder in humans.
• Dementia with Lewy bodies is the most common disorder to be mistaken for CJD.
• CSF levels of the stress protein 14-3-3 may be elevated in CJD, but it is not specific.
TABLE SOME DRUGS THAT AFFECT AUTONOMIC FUNCTION
Symptom Drug Class Specific Examples

Impotence Opioids Tylenol #3
Anabolic steroids
Some antiarrhythmics Prazosin
Some antihypertensives Clonidine
Some diuretics Benazepril
Some SSRIs Venlafaxine

Opioids Fentanyl
Urinary retention
Decongestants Brompheniramine
Diphenhydramine
Diaphoresis Some antihypertensives Amlodipine
Some SSRIs Citalopram
Opioids Morphine
Hypotension Tricyclics Amitriptyline
Beta blockers Propranolol
Diuretics HCTZ
CCBs Verapamil
SSRIs, selec¬
Abbreviations: CCBs, calcium channel blockers; HCTZ, hydrochlorothiazide;
tive serotonin reuptake inhibitors
• Melkersson-Rosenthal syndrome — consists of recurrent facial paralysis ; recurrent — and
eventually permanent - facial (particularly labial) edema.
USEFUL ONE LINERS
• Most common cause of spinal epidural abscess is Staphylococcus aureus.

• HSV-2 (and less commonly HSV-1) produces a distinctive syndrome of recurrent sacral
cauda equina neuritis in association with outbreaks of genital herpes (Elsberg’s syndrome).
• HIGH YIELDING TOPIC
• BELL’S PALSY (Pg:2647-48)
USEFUL ONE LINERS
• Diagnostic serum autoantibodies against the water channel protein aquaporin-4 are pres¬
ent in 60-70% of patients with NueromyelitisOptica (Devic’s disease).
• Multiple sclerosis is three times more common in women than men.
• Well-established risk factors for MS include vitamin D deficiency, exposure to Epstein-Barr
virus (EBV) after early childhood, and cigarette smoking.
• In MS, the lesions are frequently oriented perpendicular to the ventricular surface, corre-
sponding to the pathologic pattern of perivenous demyelination (Dawson’s fingers).
• The Expanded Disability Status Score (EDSS) is a widely used measure of neurologic
impairment in MS.
• Acute MS (Marburg s variant) is a fulminant demyelinating process that in some cases
progresses inexorably to death within 1-2 years.Typically, there are no remissions.

mi
TABLE DIAGNOSTIC CRITERIA FOR NEUROMYELITIS OPTICA
Required:
1. Optic neuritis
2. Acute transverse myelitis
Supportive (2 of 3 criteria required):
1. Longitudinally extensive cord lesion extending over 3 or more vertebral segments
2. Brain magnetic resonance imaging normal or not meeting criteria for multiple sclerosis
3. Aquaporin-4 seropositivity
HIGH YIELDING TOPIC
• MULTIPLE SCLEROSIS (Pg:2661-73)

• Causes of combined system (sensory + motor) degeneration -Vitamin
• B12 deficiency
• Copper deficiency
• HIV infection
• Severe hepatic disease
• Adrenomyeloneuropathy
USEFUL ONE LINER
• Most common type of hereditary neuropathy is Charcot-Marie-Tooth (CMT) disease.
FABRY’S DISEASE
• Also known as angiokeratomacorporisdiffusum.

• X- linked dominant pattern of inheritance.
• Caused by mutations in the alpha-galactosidase gene that leads to the accumulation of
ceramide trihexoside in nerves and blood vessels.
• Men are more commonly and severely affected.
Angiokeratomas are reddish-purple maculopapular lesions that are usually found around
the umbilicus, scrotum, inguinal region and perineum.
Burning or lancinating pain in the hands and feet often develops in males in late child¬
hood or early adult life.
Page | 222
hypertension, re¬
• Complications can arise from associated premature atherosclerosis (e.g:
nal failure, cardiac disease, and stroke) that often lead to death by the fifth
decade of life.
Some patients also manifest primarily with a dilated cardiomyopathy.
REFSUM’S DISEASE
• Autosomal recessive pattern of inheritance.

• Classical form is caused by mutations in the gene that encodes for phytanoylCoA - hy¬
droxylase (PAHX).
• Can manifest in infancy to early adulthood with the classic tetrad of:
• (1) peripheral neuropathy
• (2) retinitis pigmentosa
• (3) cerebellar ataxia, and
• (4) elevated CSF protein concentration
• Most affected individuals develop progressive distal sensory loss and weakness in the legs
leading to footdrop by their 20s. Subsequently, the proximal leg and arm muscles may
become weak.
• Patients may also develop sensorineural hearing loss, cardiac conduction abnormalities,
ichthyosis, and anosmia.
• Serum phytanic acid levels are elevated. Sensor and motor NCS reveal reduced ampli¬
tudes, prolonged latencies and slowed conduction velocities. Nerve biopsy demonstrates a
loss of myelinated nerve fibers, with remaining axons often thinly myelinated and associ¬
ated with onion bulb formation.
USEFUL ONE LINERS
• Tangier disease is caused by mutations in the ATP-binding cassette transporter 1 (ABCl)

gene, which leads to markedly reduced levels of high-density lipoprotein (HDL) cholester¬
ol levels, whereas triacylglycerol levels are increased. The tonsils may appear swollen and
yellowish-orange in color.
• Most common cause of Familial Amyloid Polyneuropathy is mutation in the gene coding
for transthyretin.
• Distal Symmetric Sensory and Sensorimotor Polyneuropathy (DSPN) is the most com¬
mon form of diabetic neuropathy.
• Most common cranial nerve affected in sarcoidosis is seventh nerve.
• Most common cranial nerve affected in Lyme disease is seventh nerve.
Page | 223
• Distal Symmetric Polyneuropathy (DSP) is the most common form of peripheral neurop¬
athy associated with HIV infection and usually is seen in patients with AIDS.
• Lumbosacral polyradiculoneuropathy in AIDS patients is usually secondary to CMV in¬
fection.
• INH related peripheral neuropathy is more common among the slow acetylators.
• Vitamin B6, or pyridoxine,can produce neuropathic manifestations from both deficiency
and toxicity.
• The neuropathy affecting lateral femoral cutaneous nerve is called Meralgiaparesthetica.
• Immune-Medic ted Brachial Plexus Neuropathy is also known as acute brachial plexitis,
neuralgicamyotrophy or Parsonage-Turner syndrome.
• The most common surgical procedures associated with brachial plexopathy as a compli¬
cation are those that involve median sternotomies (e.g: open-heart surgeries and thoracot¬
omies).
• Polyclonal antineuronal antibodies (IgG) directed against the so callwd “Hu antigen”, are
found in the sera or CSF in the majority of patients with paraneoplastic sensory neurop¬
athy.
TABLE SUBTYPES OF GUILLAIN-BARRE SYNDROME (GBS)
Subtype Features Electrodiag- Pathology

nosis
Acute inflamma- Adults affected more Demyelinating First attack on Schwann
tory demyelinat- than children; 90% cell surface; widespread
ing polyneurop- of cases in Western myelin damage, mac¬
athy (AIDP) world; recovery rapid; rophage activation, and
anti-GMl antibodies lymphocytic infiltration
(<50%) variable secondary axonal
damage
Acutemotor ax- Children and young Axonal First attack motor nodes
onal neuropathy adults; prevalent in of Ranvier; macro phage
(AMAN) China and Mexico; activation, few lympho¬
may be seasonal;recov- frequent periaxonal
cytes,
ery rapid; anti-GDla macrophages; extent of
antibodies axonal damage highly
variable

Acute motor Mostly adults; uncom¬ Axonal Same AMAN, but also
sensory axonal mon; recovery slow, of¬ affects sensory nerves
neuropathy ten incomplete; closely and roots; axonal damage
(AMSAN) related to AMAN usually severe
Miller Fisher Adults and chil- Axonal or de- Few cases examined;
Syndrome (MFS) dren;ophthalmoplegia, myelinating resembles AIDP
ataxia and areflexia;
anti-GQlb antibodies
(90%)
TABLE DIAGNOSIS Of MYASTHENIA GRAVIS (MG)

History
Diplopia, ptosis, dysarthria, dysphagia, dyspnea
Weakness in characteristic distribution: proximal limbs, neck extensors, generalized
Fluctuation and fatigue: worse with repeated activity, improved by rest
Effects of previous treatments
Physical examination
Ptosis, diplopia
Motor power survey: quantitative testing of muscle strength
Forward arm abduction time (5 min)
Vital capacity measurement
Absence of other neurologic signs
Laboratory testing
Anti-AChR radioimmunoassay: -85% positive in generalized MG; 50% in ocular MG;
definite diagnosis if positive; negative result does not exclude MG; -40% of AChR anti-
body-negative patients with generalized MG have anti-MuSK antibodies
Repetitive nerve stimulation: decrement of > 15% at 3 Hz: highly probable
Single-fiber electromyography: blocking and jitter, with normal fiber density; confirmato¬
ry, but not specific
Edrophonium chloride (Enlon) 2 mg + 8 mg IV; highly probable diagnosis if unequivocal¬
ly positive
For ocular or cranial MG: exclude intracranial lesions by CT or MRI
Abbreviations: AChR, acetylcholine receptor; CT, computed tomography; MRI, magnetic

resonance imaging; MuSK, muscle-specific tyrosine kinase

• The thymus is abnormal in -75% of patients ,with acetylcholine receptor antibody-positive
myasthenia gravis; in -65% the thymus is “hyperplastic” with the presence of active ger¬
minal centers detected histologically,although the hyperplastic thymus is not necessarily
enlarged. An additional 10% of patients have thymictumors (thymomas).
• If weakness remains restricted to the extraocular muscles for 3 years, it is likely that it will
not become generalized, and these patients are said to have ocular MG.
TABLE DRUGS WITH INTERACTIONS IN MYASTHENIA GRAVIS (MG)
Drugs That May Exacerbate MG

Antibiotics
Aminoglycosides: e.g., streptomycin, tobramycin, kanamycin
Quinolones: e.g., ciprofloxacin, Ievofloxacin, ofloxacin, gatifloxacin
Macrolides: e.g., erythromycin, azithromycin
Nondepolarizing muscle relaxants for surgery
D-Tubocurarine (curare), pancuronium, vecuronium, atracurium
Beta-blocking agents
Propranolol, atenolol, metoprolol
Local anesthetics and related agents
Procaine, Xylocaine in large amounts
Procainamide (for arrhythmias)
Botulinum toxin
Botox exacerbates weakness
Quinine derivatives
Quinine, quinidine, chloroquine, mefloquine (Lariam)
Magnesium
Decreases acetylcholine release
Penicillamine
May cause MG
Drugs with Important Interactions in MG
Cyclosporine
Broad range of drug interactions, which may raise or lower cyclosporine levels.
Azathioprine
Avoid allopurinol—combination may result in myelosuppression.

MYASTHENIA GRAVIS LAMBERT EATON SYNDROME

Post-synaptic defect Presynaptic defect
Normal reflexes Diminished or absent
No autonomic dysfunction Autonomic changes like dry mouth
Decremental response to repeated nerve Incremental response
stimulation
Ptosis and diplopia Ptosis and diplopia present,but proximal
weakness of legs predominate.
TABLE NEUROMUSCULAR CAUSES OF PTOSIS OR OPHTHALMOPLEGIA
Peripheral Neuropathy
Guillain-Barre syndrome
Miller Fisher syndrome
Neuromuscular Junction
Botulism
Lambert-Eaton syndrome
Myasthenia gravis
Congenital myasthenia
Myopathy
Mitochondrial myopathies
Kearns-Sayre syndrome
Progressive external ophthalmoplegia
Oculopharyngeal and oculopharyngodistal muscular dystrophy
Myotonic dystrophy (ptosis only)
Congenital myopathy
Myotubular
Nemaline (ptosis only)
Hyperthyroidism/Graves’disease (ophthalmoplegia without ptosis)
Hereditary inclusion body myopathy type 3

TABLE DRUGS THAT CAUSE TRUE MYALGIA
Cimetidine
Cocaine
Cyclosporine
Danazol
Emetine
Gold
Heroin
Labetalol
Methadone
D-Penicillamine
Statins and other cholesterol-lowering agents
L-Tryptophan
Zidovudine
TABLE PROGRESSIVE MUSCULAR DYSTROPHIES
Type Inheri- Defective Onset Age Clinical Features Other

tance Gene/ Organ
Protein Systems
Involved
Duchenne XR Dystrophin Before 5 Progressive weak¬ Cardiomyop¬
years ness of girdle athy
muscles Mental im¬
Unable to walk pairment
after age 12
Progressive kypho¬
scoliosis
Respiratory failure
in second or third
decade

Hi HARRISON’S 19TH BASED NOTE BOOK
Becker XR Early child- Progressive weak-

Dystrophin Cardiomyop-
hood to ness of girdle athy
adult muscles
Able to walk after
age 15
Respiratory failure
may develop by
fourth decade
Limb-gir- AD/AR Several (Tables Early child- Slow progressive ± Cardiomy-
dle 462e-6, 462e- hood to weakness of shoul- opathy
7) early adult der and hip girdle
muscles
Em¬ XR/AD Emerin. lamin Childhood Elbow/knee/ankle Cardomyop-
ery-Drei- A/C to adult contractures, hu- athy
fuss Nesprin-1, meral and peroneal
nesprin2, weakness
TMEM43
Congenital AR Several At birth or Hypotonia, con- CNS ab-
within first tractures, delayed normalities
few months milestones (hypomyelin-
Progression to re- ation, mal-
spiratory failure in formation)
some; static course Eye abnor-
in others malities
Myotonic1 AD DM1: Ex¬ Childhood Slowly progressive Cardiac
(DM1, pansion CTG to adult; weakness of face, conduction
DM2) repeat possibly shoulder girdle, defects
DM2: Expan¬ infancy and foot dorsiflex- Mental im¬
sion CCTG if mother ion pairment
repeat affected Preferential prox- Cataracts
(DM1 only) imal weakness in Frontal bald¬
DM2 ness
Gonadal
atrophy
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FSHD1 AD DUX4 4q Childhood Slowly progressive Deafness

to adult weakness of face,
shoulder girdle,
and foot dorsiflex-
ion
FSHD2 AD SMCHD1 Coats’(eye)
disease
Oculopha- AD Expansion, Fifth to Slowly progressive
ryngeal poly A RNA sixth de¬ weakness of extra¬
binding protein cade ocular, pharyngeal,
and limb muscles
“Two forms of myotonic dystrophy. DM1 and DM2, have been identified Many features overlap (see text)
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous
system; XR, X linked recessive
USEFUL ONE LINERS

• Hatchet facies is seen in myotonic dystrophy.
• The most common glycolytic defect associated with exercise intolerance is Me Ardle’s dis¬
ease (myophosphorylase deficiency).
• In McArdle’sdisease,exercise tolerance can be enhanced by a slow induction phase (warm¬
up) or brief periods of rest, allowing for the start of the “second-wind” phenomenon
(switching to utilization of fatty acids).
• Carnitine Palmitoyltransferasell deficiency is the most common recognizable cause of re¬
current myoglobinuria.
• The single most common sign of mitochondrial myopathy is Chronic Progressive External
Ophthalmoplegia seen in >50% of all mitochondrial myopathies.
Keep in mind KEARNS-SAYRE SYNDROME is a widespread multiorgan system disor¬
der with the following triad of clinical findings ;
1. Onset before age 20 years
2. CPEO
3. Pigmentary retinopathy
PLUS one or more of the following features
• Complete Heart Block
• CSF protein >100 mg/di
• Cerebellar ataxia

CLINICAL FEATURES OF PERIODIC PARALYSIS AND NONDYSTROPHIC

TABLE MYOTONIAS
Calcium Potassium Chan-
Sodium Channel nel
Channel
Paramyoto¬
Hypokale- Hyperkale- Andersen-Tawil
Feature nia Congen-
mic PP mic PP Syndrome3
ita
Mode of inheritance AD AD AD AD
Adoles- Early child- Early child- Early childhood
Age of onset
cence hood hood
Myotoniab No Yes Yes No
Episodic weakness Yes Yes Yes Yes
Frequency of attacks of Daily to May be With cold,
Daily to yearly
weakness yearly 2-3/d usually rare
Duration of attacks of From 1-2 h
2-12 h 2-24 h 2-24 h
weakness to >1 d
Serum K+ level during Increased or Usually nor-

Decreased Variable
attacks of weakness normal mal
Increased
myotonia, Increased myo-
Effect of K+ loading No change No change
then weak- tonia
ness
Effect of muscle cool- Increased

increased
No change myotonia, then No change
ing myotonia
weakness
Fixed weakness Yes Yes Yes Yes
“Dysmorphic features and cardiac arrhythmias are distinguishing features (see text). bMay be
paradoxical in paramyotonia congenita
Abbreviations: AD, autosomal dominant; PR, periodic paralysis

Page | 231
HARRISON’S 19TH BASED NOTE BOOK BS
TABLE DRUG-INDUCED MYOPATHIES
Drugs Major Toxic Reaction

Drugs belonging to all three of the major classes of
Lipid-lowering agents
lipid-lowering agents can produce a spectrum of tox¬
Fibric add derivatives
icity. asymptomatic serum creatine kinase elevation,
HMG-CoA reductase inhibitors
Niacin (incotinic acid)
myalgias, exercise-induced pain, rhabdomyolysis, and
myoglobinuria
Acute, high-dose glucocorticoid treatment can cause
acute quadriplegic myopathy. These high doses of
steroids are often combined with nonderolarizing
Glucocorticoids
neuromuscular blocking agents but the weakness can
occur without their use. Chronic steroid administration
produses predominantly proximal weakness
Nondepolazing neuromuscular Acute quadriplegic myopathy can occur with or with¬
blocking agents out concomitant glucocorticoids.
Zidovudine Mitochondrial myopathy with ragged red fibers

Drugs of abuse
Alcohol
All drugs in this group can lead to widespread muscle
Amphetamines breakdown, rabdomyolyisis, and myoglobinauria.
Cocaine
Local injections cause muscle necrosis, skin induration,
Heroin
and limb comtractures
Phencyclidine
Meperidine
Autoimmune toxic myopathy Use of this drug may cause polymyositis and myasthe¬
o-Penicillamine nia gravis.
Amphophilic cationic drugs All amphophilic drugs have the potential to produce
Amiodarone
painless, proximal weakness associated with autophagic
Chloroquine
vacuoles in the muscle biopsy.
Hydroxychloroquine
This drug produces painless, proximal weakness
Antimicrotubular drugs Colchi¬
especially in the setting of renal failure. Muscle biopsy
cine
shows autophagic vacuoles.s

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HARRISON’S 19th Rased

DAMS Faculty’s Perspective

ONE LINEi CONTRIBUTING AUTHORS

FOR PG MEDICAL ENTRANCE EXAMS

On behalf of DAMS, i am proud to introduce before you my humble endeavour “DAMS

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TABLE WELLS CLINICAL PREDICTION RULE FOR PULMONARY EMBOLISM

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• Most commonvalvular disease causing death during pregnancy is mitral stenosis.

HORMONES THAT DECREASE, REMAIN STABLE, AND INCREASE WITH

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Estradiol Glucagon-like peptide 1 Cortisol

PAINFUL CONDITIONS THAT RESPOND TO TRICYCLIC ANTIDEPRES¬

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• The rash of measles typically spares palms and soles.

TABLE FEATURES OF PERIPHERAL AND CENTRAL VERTIGO

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TABLE CAUSES OF EPISODIC GENERALIZED WEAKNESS

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b. Transient global cerebral ischemia

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• Hyperesthesia means pain or increased sensitivity in response to touch.

FEATURES OF CEREBELLAR ATAXIA, SENSORY ATAXIA, AND

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First Symp¬ Neuropsy¬

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Abbreviations: AD-Alzheimer’s disease; CBD-Cortical basal degeneration; CJD-Creutzfeldt-

CLINICAL FEATURES OF APHASIAS AND RELATED CONDITIONS

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• Narcolepsy is a disorder of REM sleep.

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• Most common primary tumor of eye is melanoma.

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TABLE LABORATORY FINDINGS IN ACUTE RENAL FAILURE

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• Oliguria refers to 24 hour urinary output < 400 ml.

HIGH YIELDING TOPICS

• FLUID AND ELECTROLYTE DISTURBANCES (Pg:295-312)

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DIAGNOSTIC APPROACH TO HYPONATREMIA

TABLE CAUSES OF HIGH-ANION GAP METABOLIC ACIDOSIS

TABLE CAUSES OF NON-ANION GAP ACIDOSIS

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B. External pancreatic or small-bowel drainage

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TABLE DRUGS ASSOCIATED WITH ERECTILE DYSFUNCTION

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TABLE DESCRIPTION OF PRIMARY SKIN LESIONS

TABLE SELECTED DERMATOLOGIC CONDITIONS

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Dyshi¬ Palms, soles, Deep vesicles Pityriasis Trunk Symmetric

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Allergic Anywhere Localized Tinea Chest, back, Scaly hyper or

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HIGH YIELDING TOPICS

• ATOPIC DERMATITIS (Pg:344)

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