Endocrine

1
 Index
1. Pituitary gland
2. DM
3. Thyroid gland
4. Adrenal gland

2
Pituitary gland

3
 Anatomy
• Lies in the base of the skull in a portion
of sphenoid bone called sella torsica.
• 2 lobes:
– Anterior lobe 2/3 (adenohypophysis)
– Posterior lobe 1/3(neurohypophysis)
(supraoptic and paraventricular nuclei)
• It measures 15X10X6 mml wt 500-900
mg
• It may double(2-3 X) in size during
pregnancy
• Blood supply:
– Richly vascularized Hypothalamic
-Hypophyseal
– 0.8 ml/min from portal circulation
Portal System
– It supply by middle inferior & superior
hypophysial arteries from the internal
carotid arteries

4
 Histology of anterior pituitary(6 hormon)
1. Somatotrophs cells (about 50%)
– GH secreting cells
– Acidophilic stained
2. Lactotrophic (10-15%)
– Prolactin secreting cells
– Acidophilic stained
3. Thyrotrophis (< 10%)
– TSH secreting cells
– Basophilic cells
4. Corticotrophs (15-20%)
– ACTH secretary cells
– Basophilic cells
5. Gonadotrophs (10-15%)
– LH,FSH secretary cells
– Basophilic staining

5
6
 Hypopituitarism
• Slow & gradual in onset
• Single or multiple hormone deficiency.
• Cause:
– 10: destruction of APG
– 20: deficiency of hypothalamic stimulating factors
• Treatment and prognosis depend on
– The extent of hypofunction
– Underlying cause
– location of the lesion

7
• GH deficiency
– children lead to short stature
– Adult lead to vague non specific symptoms
• Fatigue & malaise
• Decrease muscle mass
• Loss of libido
• Increase risk of IHD
• Gonadotrophin deficiency (hypogonadism)
– Women
• before puberty primary amenorrhea and failure of puberty development
• After puberty 2ndary amenorrhea and regression of 2ndary sexual
characteristic
• Infertility
– Men
• before puberty failure of puberty development
• After puberty decrease libido or impotence
• Loss of 2ndary sexual characteristic
• Infertility

8
 TSH deficiency
(20 hypothyroidism)
• Mental dullness
• Puffiness of the face
• Dry skin, loss of hair
• cold intolerance
• Hoarseness of voice
• Bradycardia & HTN
• Constipation & inc. in wt
• Slow reflexes
ACTH deficiency
(20 adrenocortical
insufficiency)
• Weakness
• Anorexia & wt loss
• Nausea & vomiting
• Postural hypotension
9
 Causes of hypopituitarism
1. Infarction
6. Aneurysm of internal carotid artery
– Postpartum necrosis (Sheehan
syndrome) 7. Hemochromatosis
– Vascular disease 8. Idiopathic or genetic deficient
production of pituitary hormone
– Head trauma
synthesis of abnormal hormone
2. Infections
9. Iatrogenic
– TB, fungi
– Stalk section
– Pyogenic, syphilis
– Radiation
– Toxoplasmosis
– Hypophysectomy
3. Granulomas 10. Primary hypothalamic disorders
– Sarcoidosis – Tumor (craniopharyngioma)
– Histiocytosis – Granulomas (histiocytosis x)
4. Autoimmune lymphocytic hypophysitis – Genetic or idiopathic releasing H.D
5. Neoplasm's involving pituitary – Head trauma
– Pituitary adenoma – Structural anomalies of
hypothalamus
– Craniopharyngioma
– Metastasis or primary carcinoma (rare)
10
 Diagnosis by stimulation test
Hormone Test agent N response
GH IHT 0.1 uint Serum GH > 10ng/ml at
L-dopa 250-500 any time
Arginine 0.5 gm
Clonidine test
Glucagon test
Prl TRH 100-500 Doubling of baseline
metoclopramide
TSH TRH 500 ng Peak value >5 mu/ml

LH & FSH GnRH 100mmg IV Doubling of the base line

LH & FSH
ACTH IHT (short ACTH stimulation Peak serum cortisol >20
test cosyntropin test) ng/dl
Metyrapone test 2-3 gm po Serum 11-deoxycortisol
level >8 ng/dl 11
 Treatment of hypopituitrism
Deficient Therapy
hormone
TSH L-thyroxin .05-.02 mg/d PO

ACTH Hydrocortisone 20 mg/ m-10mg /e

LH & FSH Men :testosterone

Women :cyclic estrogen and progesterone
For fertility HCG,HMG
GH GH 0.05 mg/kg

12
• Always benign
• 10% of intracranial neoplasm
– Pituitary microaadenoma is
Pituitary tumors
• Intrasellar adenoma
• Less than 1 cm in diameter
– Pituitary macroadenoma
• larger than 1 cm in diameter
• Clinical
• Hormone hypersecretion
• Space occupying lesion
– Headaches
– Visual loss (field defect: bitemporal hemianopia)
• Hormone deficiency states
– Interference with surrounding normal pituitary
– Treatment
– Surgical (Transfrontal or transsphenoidal)
– Radiological (Conventional irradiation/heavy particle I)
– Medicall
• Dopamine agonist (bromocriptin)
• Somastatin analog (octreotide) 13
 Type of pituitary tumors
Type of tumor Frequency Syndromes of
hormone excess
Prl secreting 26% Prolactinoma

nonfunctioning 23%

ACTH secreting 15% Cushing’s disease

GH-secreting 14% Acromegaly

plurihormonal 12%

LH or FSH secreting 8% (Non-functioning

pituitary tumour)
TSH-secreting 1% 20 thyrotoxicosis
14
 Acromegaly & gigantism
• GH secreting adenoma • Diagnosis
– Childhood & adolescence – Glucose suppression test
lead to gigantism – IGF-1
– Adult lead to acromegaly – Tumor localization MRI
• Most frequently in middle age, • Treatment
M=F – Surgical ( transsphenoidal/
• Laboratory finding transfrontal)
– Radiotherapy (successful in
– Elevated GH
60-80%)
– Plasma glucose may be – Medical
elevated
• Octreotide effective in
– Increase serum insulin 65%
– Elevated serum phosphate • Bromocriptine is less
– Hypercalciuria effective
• Pegvisomat GH recptor
15
antagonists
 Clinical feature
Symptoms % • Glucose intolerance 50
• Acralenlargement 100 • Hyperinsulinemia 70
• Hyperhidrosis 100 • Irregular menses 60
• Hypertrichosis 33 • Decrease libido or impotence 46
• Lethargy or fatigue 88 • Galactorrhea 13
• Weight gain 87 • Gynecomastia 8
• Paresthesia (CTS) 70 • Goiter 32
• Headache 65 • Hypothyroidism 13
• Joint pain 69 • Hypertension 24
• Papillomas 45 • Cardiomegaly 16
• Photophobia 46 • Renal calculi 11
• Visual deficit 20 • Hypoadrenalism 4

16
GIGANTISM

ACROMEGALY

17
• 50 year old male
• Chief complaints:
– Increasing shoe size
– sweating of hands and feet
– Fatigue
– Headache
– Joint pains
– No family history of
• Pituitary tumors
• Hypercalcemia
• Pancreatic tumors
• Past medical history
– s/p carpal tunnel surgery
• Physical finding
– Frontal Bossing
– Chin Protrusion
– Large nose
– Macroglossia
– Spider hands
– Soft tissue swelling

18
Acromegaly:
Large Hands

Bone and Soft Tissue

Manifestations
of Acromegaly

19
Acromegaly: marked macroglossia, can
cause:
• Severe sleep apnea
• Cardiac arrhythmias
• Sudden death

Skin Tags

20
Acromegaly: Slow changes over
years

21
 Prolactinomas
• The most common functional pituitary adenoma
• F>M
• In women 90% are microadenoma
• In men 60% are macroadenoma
• Laboratory finding:
– Elevated serum prolactin
– Decrease plasma gonadotropin
– Liver function test
– Kidney function test DDx
– TFT
• Treatment
– Surgical (transsphenoidal/transfrontal)
– Medical
• Dopamine agonist (bromocriptine)
• Cabergoline 22
 Clinical features
In women In men
• menstrual disorder • Decrease libido
– Amenorrhea • Impotence
– Oligomenorrhea • Infertility
– Infertility
• Galactorrhea (rare)
• Galactorrhea in 70%

23
 Causes of hyperprolactinemia
Physiological causes Disease states
Sleep Prolactinomas
Stress Hypothalamic & pituitary stalk disease
Pregnancy Granuloma
Craniopharyngioma
Nipple stimulation Primary hypothyroidism
Nursing Chronic renal failure
Coitus Cirrhosis
Chest wall trauma
Drugs • Dopamine depleting agent
• Dopamine receptor antagonist – Methyldopa
– Phenothiazenes – Reserpine
– Butyrophenones – Estrogen
– Metoclopramide – Antiandrogens
– Sulpiride – Opiates
– Verapamil

24
 ADH (vasopressin)
• 2 receptors
– V1 receptors mediate
• Vascular smooth muscle
contraction
• Stimulate prostaglandin
synthesis
– V2 receptors produce renal
action by increase the water
permeability of the luminal
membrane of collecting duct
epithelium
• Absence of ADH permeability of the
epithelium is decrease leading to
polyuria

25
 Diabetes insipidus (DI)
• Laboratory finding
• Deficient ADH or it is actions – Serum ADH
• Passage of large amount of diluted • Low in CDI
urine
• High or normal ADH in NDI
• 2 type
– A large urinary volume >3 l /day
– Central DI due to deficiency of
– Urine osmolality <200 mosm/kg
ADH
– Slightly elevated plasma
– Nephrogenic DI due to resistant
osmolality
to ADH
• Diagnosis
• Clinical
– Water deprivation test ( for 4-18)
– Polyuria
• >30 ml/kg/day
• < 300 mosm/kg
– Polydipsia
– Thirst

26
 Causes
Central DI
• Familial (AD)
• Idiopathic Nephrogenic DI
• Trauma or surgery • Familial (x-linked)
• Tumors • Renal disease (pyelonephritis)
– Craniopharyngioma • Hypercalcemia
– Meningioma • Hypokalemia
• Infection • Sickle cell disease
– Encephalitis • Amyloidosis
– Meningitis • Drugs
• Granulomatous disease – Lithium
– Sarcoidosis – Demeclocycline
– Histocytosis
• Vascular disorders
– Aneurysm
– Sheehan syndrome 27
 Interpretation of WDT
CDI NDI psychogenic

Urine osmol No change No change Increase

after wdt <300 <300 >750
Urine osmol increase No change increase
after
vasopressin
Plasma ADH low Normal or low
high
28
 Treatment
CDI NDI
• Desmopressin (intra – • Treatment of the underlying
nasally/SC) disorder
• Chlorpropamide (enhance • Thiazide diuretic & mild salt
AVP action & secretion) depletion
• PG inhibitor
– Ibuprofen
– Indomethaacin

29
 SIADH
• Disease / agent that enhances ADH release or action
• Most common cause of hyponatremia in hospitalized
patients
• Characterized by
– Hyponatremia (dilution)
– Submaximal urinary dilution
• Features
– Hyponatremia & hypotonicity of plasma
– Urine osmolality > plasma osmol
– Absence of edema or volume depletion
– Normal renal & adrenal functionExcessive renal
excretion of the Na

30
 Clinical manifestation
• Sx & Sx of water intoxication
• Depending on
– Degree of hyponatremia
– Rate of development
• Acute hyponatremia (Na < 120 mml/l)
– Seizures
– Coma
• Chronic hyponatremia (Na reach 115-120 mmol/l)
– Anorexia
– Nausea & vomiting
– Abdominal cramps
– Headache

31
 Causes
• Neoplastic diseases • CNS disorders
– Lung, pancreas, prostate – Trauma: head injury
carcinoma – Infection: meningitis,
– Lymphoma / leukemia encephalitis, abscess
– Ewing sarcoma – Brain tumor
– Mesothelioma – Epilepsy
– Thymoma – CVA
– Carcinoid – Peripheral neuropathy
• Pulmonary disorders • Drugs
– Pneumonia – Desmopressin, oxytocin
– TB – Chloropopamide
– Asthma – Cytotoxic drugs
– Pneumothorax – Tranquilizer & antidepressant
– Abscess, empyema – Thiazide diuretics
– CF
– Positive pressure breathing

32
 Treatment of SIADH
Acute symptomatic
hyponatremia is medical
emergency
• Hypertonic saline infusion
3% at a rate of 0.1 ml/kg/m
in combination with
furosemide to increase the
Na in a rate 0.5-1 mmol/h
Chronic symptomatic
hyponatremia
• Correction of the underlying
cause
• Fluid restriction to 800-1000
ml/day
• Induction of NDI with
demeclocycline in 1-2 gm/d
or lithium
• Vasopessin V2 receptor
antagonist (Talvapton)
33
DM

34
 DM
• Group of metabolic diseases
characterized by hyperglycemia
• Resulting from defects in
– Insulin secretion
– Insulin action
– Both
• Classification
– Type 1
– Type 2
– Impaired glucose tolerance
– Gestational diabetes
• Etiologic Classification
• Genetic defects of
– B-cell function
– Insulin action
• Diseases of the exocrine
pancreas
• Endocrinopathies
• Drug / chemical induced
• Physiologic stress (eg, infection)
• Uncommon forms of immune-
mediated diabetes
• Other genetic syndromes
sometimes associated with
diabetes
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 Diabetes Mellitus in the US:
Health Impact of the Disease
6th leading cause of
death
Renal Life expectancy
failure* 5 to 10 yr

Blindness* CVD 2X to 4X
Diabetes

Nerve damage in
Amputation* 60% to 70% of patients

36
Criteria for the diagnosis of diabetes
1. FPG ≥ 126 mg/dl (7.0 mmol/L)
2. Symptoms of hyperglycemia (polyuria, polydipsia or unexplained wt.
loss) & a casual plasma glucose ≥ 200mg/l) (11.1 mmol/L)
OR
3. 2 hr plasma glucose ≥ 200 mg/dl (11.1) during an OGTT
Indications for OGTT
1. Patients with Impaired Fasting Glycemia (IFG)
2. Pregnant women and postpartum (in women with GDM
• OGTT is performed using a 75 oral glucose load in the morning after a
noncaloric 8hr fast. Water is allowed but not coffee or smoking.

37
Criteria for the Diagnosis of Diabetes: 1997
ADA Guidelines

Plasma Glucose Level (mg/dL)

Stage of Fasting Plasma OGTT
Glycemic Control Glucose (2-hr Postload Glucose)

Normal <100 <140

IFG 100 – 125

or
IGT 140 – 199

Diabetes* ³126 ³200

*Third criterion: ³200 mg/dL casual plasma glucose (regardless of time since
last meal) plus symptoms of diabetes (polyuria, polydipsia, unexplained
weight loss)
38
ADA. Diabetes Care.1997;20:1183-1197.
Pathogenesis of Type I DM
Genetic Environment ?
HLA-DR3/DR4 Viral infe..??

Autoimmune Insulitis

ß cell Destruction

Severe Insulin deficiency

Type I DM
39
 Pathogenesis of Type II DM
ß cell defect Environment
Genetic Obesity ???

Abnormal Secretion Insulin resistance

Relative Insulin Def.

ß cell
exhaustion Type II DM IDDM

40
 Type-I
• Age: < 40 Years
• Duration: Weeks
• Ketonuria: Common
• Insulin- Dependent
• Autoantibody: Yes
• Family History: No
• Insulin levels: very low
• Islets: Insulitis
• Complications:
– Acute & Metabolic
Type-II
• > 40 Years
• Months to years
• Rare
• Independent *
• No
• Yes
• Normal or high *
• Normal / Exhaustion
• Complications
– Late and vascular.
41
 Clinical Feature
• Asymptomatic
• Polyuria & thirst
• Nocturnal enuresis
• Polyphagia & weight loss
• Weakness or fatigue
• Blurring of vision
• Vulvovaginitis or pruritus
• May presented with acute complication
• May presented with late complications
42
 Treatment of Type 2 Diabetes
1. Diet and exercise (inc. insulin sensitivity)
2. OHA (monotherapy / combination)
– Insulin secretagogues
• Sulfonylureas
• Repaglinide
• Nateglinide
– Insulin sensitizers
• Biguanides
• Thiazolidinediones
– Inhibitors of CHO absorption
• Acarbose
• Miglitol
3. Insulin & OHA (20-30%)

43
 Sulfonylureas
• Metabolized in the liver
• Second generation: significant
fecal excretion
– Glyburide -50%
– Glimeperide - 40%
• Hypoglycemic agents for Type 2
DM
• Act by increasing endogenous
insulin secretion
• Favors lipogenesis (non- or mildly
obese)
• Adverse effects
– Severe hypoglycemia
(Overdose / Early in treatment
/ glyburide)
– Weight gain
– Erythema, skin reactions
– Blood dyscrasias
– Hepatic dysfunction
– GI disturbances
• Contraindication (insulin used)
– Pregnancy
– Surgery
– Severe infections
– Severe stress or trauma
– Severe hepatic or renal failure
44
 Repaglinide (Meglitinides)

• Mode of Action: Stimulating • Adverse effects:

release of insulin
• Benzoic acid derivatives
• Greater effect postprandially
• Fast onset & offset action
– Hypoglycemia
– Weight gain
– Hypersensitivity
• Contraindication:
– DKA - Type 1 diabetes
– Hypersensitivity

45
 Metformin (biguanide)
• Monotherapy or combination • Adverse Effects:
• Mode of action – Anorexia, Nausea, Diarrhea
– Decreases hepatic glucose – Lactic acidosis (very rare)
production • No
– Enhances muscle glucose uptake – Weight gain
• Useful in obese pationts with – Hypoglycemia
dyslipedemia – Hyperinsulinemia
• Contraindications:
– Renal failure - Cr>1.5 mg/dl
– Liver failure
– Congestive heart failure
– DKA
– Sepsis
– Dye procedures
– Alcoholism
46
 Rosiglitazone (thiazolindendione)

• Mode of Action:
– Binds to peroxisome profilerator
– Activated receptor gamma
– Regulation of glucose and fatty acid metabolism
• Significantly improved FBS & HbA1C in type 2 diabetics
• Adverse effects: Rosiglitazone = placebo
– Minor anemia
– Fluid retention
– Weight gain

47
 Acarbose (alpha – Glucosidase inhibitor)
• Monotherapy or combination with sulfonylurea
• Mode of Action:
– Inhibiting alpha-glucosidase locally in small intestine
– Slows intestinal absorption of carbohydrates
– Reduces postprandial hyperglycemia
• Most useful in exaggerated postprandial hyperglycemia
• Adverse Effects:
– Flatulence
– Bloating
– Diarrhea
• Contraindications:
– IBD
– Ulcer
– Malabsorption
– Partial intestinal obstruction
• Monitoring of transaminase / 3 months 48
Insulin
• Units: 1 U = 36 µg
• 2 chains connected by disulphide bridges
• A-chain containing 21 amino acids
• B-chain containing 30 amino acids
• Secreted into portal circulation
• Degradation
• 50% in liver
• 50% in other target tissues & kidney
• Enzymatic degradation follows receptor-mediated endocytosis
• Plasma half-life: 3 - 5 min.
• Circulates as free monomer
• Insulin deficiency
• Hyperglycemia
• Increased lipolysis, plasma triglycerides & LDL; decreased HDL
• Acidosis
• Osmotic diuresis (dehydration, hypovolemia, polydipsia)
• Depletion of intracellular and whole-body K+
49
 Effects of insulin
Stimulate Inhibits
Liver Glycogen synthesis Glycogenolysis
Triglyceride synthesis Ketogenesis
Gluconeogenesis
Skeletal muscle Glucose uptake
Protein synthesis Protein degradation
Glycogen synthesis Glycogenolysis
Adipose tissue Glucose uptake Lipolysis
Triglyceride storage
Promotes anabolic Inhibits catabolic
processes processes

50
 Insulin onset peak dura
Rapid-acting < 0.5 h 1-3 h 3-5 h
Short acting 0.5-1 h 2-4 h 5-8 h
Intermediate 3-4 h 6-15 h 18-24 h
Long acting 2-4 h 4-12 h 12-24 h
ultralente 4-8 h 12-24 h 20-30 h
Insulin glargine 0.15 h 1-3 h 24 h
Insulin detemir 0.15 h 1-3 h 24 h

51
 Insulin treatment regimens
• Conventional insulin treatment
– 1 or 2 daily subcutaneous injections
– Mixture of short & intermediate or long-acting insulin
• Intensive insulin treatment
– Frequent monitoring of blood glucose
– 3 or more daily injections of insulin
– Some regular alone, some combined regular and intermediate- or
long-acting
– Adjusted to needs of individual patient
• Continuous subcutaneous insulin infusion
– Insulin pump with lispro or regular insulin
– Programmed basal delivery
 Allows control of “dawn phenomenon”
– Patient-triggered bolus before meals

52
 Treatment
Insulin dosage depends on
• Age
• Weight
• Duration of diabetes
• Stage of puberty
• Nutritional intake
• Exercise patterns
• Results of BG monit
• Intercurrent illness
Adverse effects
• Hypoglycemia
• Allergy and resistance to
insulin
• Lipohypertrophy
• Lipoatrophy
• Insulin edema

53
Lipohypertrophy Lipoatrophy

54
55
 Diabetic complication
Acute complication Late complication
• Hypoglycemic coma • Macrovascular compliction
• DKA – IHD
• Nonketotic hyperosmolar – CVD
coma • Microvascular compliction
– Diabetic retinopathy
– Diabetic nephropathy
Significant because: – Diabetic neuropathy
1. Reduces the quality of life and at worst – Diabetic foot (15%)
is fatal (e.g. ketoacidosis)
2. Damage to several tissues
– Dermopathy

56
 Diabetic ketoacidosis
• The most frequent endocrine emergency
• May be the 1st presentation of type 1 DM
• Result from
– Absolute insulin deficiency
– Increase requirement
• Mortality rate around 5%
• Diagnosis
– Hyperglycemia
– Ketonuria and ketonemia
– Acidosis (PH< 7.3 or bica < 15 mmol/l)
• Laboratory finding
– Serum glucose
– Keton
– Serum electrolyte
– Blood urea
– Serum amylase (10X & abdominal pain)
– ABG (acidosis)
– Septic work-up 57
 Precipitating causes Complication
• Infection • Metabolic abnormality
• Trauma – Sever acidosis
• Surgery – Hypo/hyperkalemia
• MI – Hypoglycemia
• Stroke • Cerebral edema
• Emotional stress • Vascular thrombosis
• Inadequate intake or poor • Infection
compliance • MI
• Increase secretion of • Acute gastric dilatation
counter regulatory • Respiratory distress
hormones syndrome
58
 Clinical presentation
• Polyuria &polydipsia
• Anorexia, Nausea,
vomiting & abdominal
pain
• Fruity odor of the breath
• Sign of dehydration
• Tachycardia
• Kussmaul breathing
• Hypotonia, stupor &
coma
Treatment
• Fluid replacement
• Insulin therapy for
hyperglycemia
• Electrolyte correction
• Acidosis correction
• Treatment of ppt cause
59
 Hypoglycemic coma
• Hypoglycemia
– the most frequent acute complications in type 1 diabetes
– No agreed definition of hypoglycemia
– the level of blood glucose at which physiological neurological
dysfunction begins
• Predisposing factors
– Missed meal
– Change in physical activity
– Alterations or errors in insulin dosage
– Defective in counter regulatory hormones
– Alcohol ingestion
• Treatment
– In mild cases oral rapidly absorbed carbohydrate
– In sever cases (comatose patient) IV hyper tonic glucose 50% or
25% concentration
– Glucagons injection 60
 Clinical manifestation
• Autonomic activation • Neuroglycopenia
1. Hunger 1. Impaired thinking
2. Pallor 2. Change of mood
3. Tremor 3. Irritability
4. Palpitation 4. Headache
5. Sweating 5. Convulsion
6. Anxiety 6. Coma

61
 Diabetic retinopathy
• The leading cause of blindness • Treatment
in adult – Glycemic control
• 5% of patients progress to – Control of BP
sever visual acuity loss
– Control of blood lipid
• 10-18% of NPRDR progress to
– Drug therapy
PDR
• Aldose reductase inhibitor
• 50% with PDR progress to
• Pentoxifylline
blindness in 5y
• Platelets inhibitors
• Risk
– Laser therapy
– 98% in type 1 DM after 15y
– Vitrectomy surgery
– 78% in type 2 DM after 15y

62
 Classification
• Non proliferative DR • Proliferative DR
1. Increased capillary 1. New vessels
permeability 2. Vitreous hemorrhage
2. Micro aneurysms 3. Retinal detachment
3. Retinal hemorrhage 4. New viscualization of
the iris (Rubeosis iridis)
(dot & blots)
5. Scar (retinitis
4. Hard exudates proliferanse)
5. Venous beading
6. Diabetic macular
edema

63
Normal Retina

Fluorescein angiogram
• Early retinopathy
• Leaky blood vessels
• Aneurysems

64
Cotton wool spots
• New blood vessels
• Very weak & easy ruptured
• Laser therapy

Proliferative Retinitis
• Neovascularization
• Haemorrhagia
• Fibroplasia
• Retinal detachment
• Laser cauterization
65
Red dots & blots
• Micro aneurysms
• Haemorrhages
• Exudates

Proliferative retinopathy
• Abnormal capillaries
• Haemorrhages

Maculopathy (NIDDM)
• Ring of leaked material
(exudates) around the macula
region
66
 Diabetic Nephropathy

• Microalbuminuria • Pathological pattern

– Diffuse form
proteinuria 30–300 mg/day
• More common
• 20X higher risk of • Widening GBM
nephropathy • Generalized mesangial
thickenings
• Persistent proteinuria >500
– Nodular form
mg/day resulting in ESRD • Accumulation of periodic
• 25-50% of diabetes acid schiff positive
material are deposit in
cases the periphery of
• Mortality 20-40X higher glomerular tufts
than without renal (Kimmelstiel-Wilson
lesion)
dysfunction
67
 Staging
• Stage 1 (0-2y)
– Increase in the GFR
– Hyper functioning & hypertrophy
• Stage 2 (2-3y) characterized
histological by
– Glomerular mesingial expansion
– Glomerular sclerosis
– BM thickenings
– Without clinically apparent
disease
• Stage 3 (7-15y)
– Stage of incipient nephropathy
– Microalbumnuria
– The earliest lab evidence of DN
• Stage 4 (overt nephropathy)
– Protienuria
– Normal or decrease GFR
– Intervention can slow but not
reserve the progression to RF
– The decline in renal function
occur in rate 1mml/per month
• Stag 5 (20-40y)
– Continuing decline in GFR
– Increase in BP
– 50-75% progress to ESRD within
10-15y
68
 Risk factors Treatment
• Hyperglycemia
• Glycemic control
• HTN
• BP control
• Microalbuminuria
• Duration of DM • Smoking cessation
• Family Hx of • Proteins restriction
– HTN • Lipid reduction
– CVD • ACE inhibitor
– Nephropathy (microalbuminuria)
• Ethnicity
• Male gender
• Cigarette smoking
• Genetics

69
 Diabetic Neuropathy

• Slowly progressive affecting the • Treatment

long axons
– Simple analgesia
• Exact etiology unknown
– Tricyclics antidepressants
• Peripheral symptoms:
– Anticonvulsants
– Numbness/tingling in the feet
– Cramps – Other measure
– Sensitivity/insensitivity to • Mexilitine
touch • Gamma linolenic acid
– Loss of balance/coordination • Capsaicin
• Autonomic symptoms:
– Orthostatic hypotension
– Gastric stasis
– Urinary incontinence
– Loss of sexual response

70
 Classification of DN
Peripheral neuropathy Autonomic neuropathy
• Distal symmetrical sensory – Postural hypotension
loss – Resting tachycardia
• Motor neuropathy – Loss of sweating
– Foot drop – Gastrointestinal
– Wrist drop neuropathy
– Diabetic amyotrophy • Gastroparesis
Cranial neuropathy • Diabetic diarrhea
• III, IV, VI, VII – Urinary bladder atony
– Erectile dysfunction

71
 Foot ulceration
Risk factors
• Male sex
• Age
• Peripheral vascular disease
• Neuropathy
• Low socioeconomic status
• Limited joint mobility
• Poor education of patient
Treatment
• Infection
– Surgical drainage
– Appropriate antibiotic
• Vascular component
– consider
revascularization
• Neuropathic ulcers protect
foot from stress by:
– Casting
– Footwear

72
• Due to nerve damage
• Callus (hard skin)
around the ulcer,
indicating excess
pressure.

Diabetic Gangrene

73
Thyroid gland

74
Thyroid gland
• The largest endocrine organ
• Promote
– Normal growth & development
– Regulate energy & heat production
• Anatomy
– 2 lobe, pear in shaped
– 2.4-4 cm length, 1.5-2 cm in width, 1-1.5 cm in thickness, wt 10-20 g
– Blood flow about 5ml/g/min
• Diseases
– Goiter
– Thyrotoxicosis
– Hypothyroidism
– Thyroiditis
– Thyroid neoplasia

75
 Thyroid Hormone Synthesis
1. Iodide trapping
2. Oxidation of iodide and
iodination of
thyroglobulin
3. Coupling of iodotyrosine
molecules within
thyroglobulin
(formation of T3 and T4)
4. Proteolysis of
thyroglobulin
5. Deiodination of
iodotyrosines
6. Intrathyroidal
deiodination of T4 to T3
Total thyroidectomy &
thyroglobulin in blood 
ectopic thyroid tissue
76
 Effects of Thyroid Hormone
• Fetal brain and skeletal
maturation
• Increase in basal metabolic rate
• Inotropic and chronotropic
effects on heart
• Stimulates gut motility
• Increase bone turnover
• Increases sensitivity to
catecholamines
• Increase in serum glucose
• Decrease in serum cholesterol
Laboratory investigation
• Thyroid hormone concentration
T3,T4,TSH
• Thyroid radioiodine uptake
• Thyroid scan
• Thyroid U/S
• Anti-thyroid antibodies
• Thyroid biopsy
• Thyroid stimulation and
suppression test

77
 Thyrotoxicosis
• Definintion
– Biochemical and physiological complex that result when
tissues are presented with excessive quantities of thyroid
hormone
• Diagnosis
– T3, T4, TSH
– RAIU
– Thyroid antibodies

78
 Causes
Associated with sustained Not Associated with
hormone over production hyperthyriodism
(hyperthyroidism) 1. Thyrotoxic factitia
1. Graves disease 2. Subacute thyroiditis
2. Toxic multinodular 3. Ectopic thyroid Tissue
goiter 1. Struma ovarii
3. Toxic adenoma 2. Functioninig metastatic
4. Iodine-induced (Jod- 3. Thyroid cancer
basedow)
5. Trophoblastic tumor
6. Increased TSH secretion
79
Treatment
Antithyroid drugsThionamides
• Propylthiouracil (Fulminant
Hepatitis)
• Methamazole (Cholestatic
jaundice)
• Carbimazole
• Iodine and iodine containing
agent
• Beta-bloching agents
• Side effects
– Agranulocytosis
– Hepatotoxicity
– Rash (erythema to an
exfoliative dermatitis)
Radioactive iodine therapy
• Complication
– Hypothyroidism
• Contraindication
– Pregnancy
– Sever exophthalmos
Surgery
• nodule for Graves’ Disease
• I131 is contraindicated
(pregnancy)
• Large Goiters less likely to
respond to ATD or I131
• Before surgery
– Be euthyroid to decrease risk
of arrhythmias.
– Give PTU +/- beta-blocker.
PTU blocks peripheral 80
conversion of T4 to T3.
 Symptoms and signs
1. Nervousness 99 1. Tachycardia 100
2. Increased sweating 91 2. Goiter 100
3. Heat intolerance 89 3. Skin changes 97
4. Palpitation 89 4. Tremor 97
5. Dyspnea 75 5. Bruit 77
6. Fatigue 88 6. Eye sign 71
7. Weakness 70 7. Gynecomastia 10
8. Increased appetite 65 8. Splenomegaly 10
9. Wt loss 82 9. Atrial fibrillation 10
10. diarrhea 23 10. Palmar erythema 8

81
 Graves thyrotoxicosis
• The common cause of thyrotoxicosis
• F:M 10:1
• Age 30-40
• Characterized by:
– Diffuse goiter
– Thyrotoxicosis
– Ophthalmopathy
– Dermopathy
– Achropathy

82
 Graves’ Ophthalmopathy

1. Class one: spasm of upper lids with thyrotoxicosis

2. Class two: periorbital edema and chemosis
3. Class three: proptosis
4. Class four: extraocular muscle involvement
5. Class five: corneal involvement
6. Class six: loss of vision due to optic nerve involvement
83
A 40 year old white female complains of
• Nervousness
• Fatigue
• Weight loss which became apparent one
year ago. she has lost 14 pounds over this
period
• Denies anorexia
Recently she has been unable to perform
routine household activities because of
• Fatigue
• Palpitations
• Exertional dyspnea.
She has been extremely uncomfortable this
summer, and perspires excessively. She is on
oral contraceptives.

84
 THYROID EYE DISEASE

• Lid retraction
– Sympathetic overactivity
infiltration of levator / SR
complex. Infiltration
• Hypotropia Soft tissue involvement:-
– Retraction disappears on
• Chemosis
downgaze
• SIGNS:- • Conjunctival injection
over the recti
– Lid retraction
insertions
– Lid lag
– Staring appearance • Puffy lids
85
 Thyroid Storm
• High levels of thyroid hormone
• Usually preceded by stress:
– Infection
– Surgery
– RAI ablation
• PE:
– HF, AF
– Hyperthermia
– Coma
• Tx:
– IV steroids
– PTU
– Propanolol
– Ice baths
86
 Thyroiditis
• Thyroid disorders marked by infiltration of
– Leukocytes
– Fibrosis
– Both
• Types:
– Acute suppurative
– Painful (de Quervain’s)
– Postpartum
– Hashimoto’s
– Fibrous (Reidel’s)

87
• Acute Suppurative Thyroiditis
– Bacterial infection (S. aureus or S. pneumo.)
– Usually preceded by trauma
– Tx:
• IV abx
• I and D if abscess
• Painful Thyroiditis (de Quervain’s)
– Unknown virus
– Painful thyroid following URI
– Hyperthyroidism followed by hypothyroidism
– Lasts 2 months
– Tx:
• Beta blockers/thyroxine
• Supportive
• Postpartum Thyroiditis
– “Silent” thyroiditis of pregnancy and first few postpartum
months
– Associated with Graves’ and other autoimmune diseases
– Tx:
• Beta blockers/syn -throid as needed
• Usually self limiting, but high titers of antibodies heralds long term
disease
88
• Hashimoto’s Thyroiditis
– Most common thyroiditis
– Antimicrosomal and antithyroglobulin antibodies, but anti TSH
receptor Abs seen
– Associated with other autoimmune diseases
– Pts usually euthyroid
– 60-80 time increase in lymphoma
• Histology:
– Predominant lymphocytes with germinal centers.
– Scant follicles
• Tx:
– Hypothyroid patients: synthroid
– Hyperthyroid: antithyroid medications
– Surgery reserved for failure of suppression or suspicion of
lymphoma
89
 Hypothyroidism
Clinical condition associated with
decreased
• Function of the thyroid gland
• Circulating level of thyroid
hormones
Labs:
• Free T4
• TSH
• Thyroid antibodies
– Thyroid peroxidase antibodies
– Thyroglobulin antibodies
Treatment:
• Oral L-thyroxine therapy
– 5-10 ug/kg in newborns
– 1-2 ug/kg in adults
Cause
• Primary hypothyroidism
permanent loss or atrophy of
thyroid tissue
• Goitrous hypothyroidism
compensatory thyroid
enlargement due to transient
or progressive impairment of
hormone biosynthesis
• Secondary hypothyroidism
insufficient stimulation of a
normal gland as a result of
hypothalamic or pituitary
disease
90
Primary Atrophic
Hypothyroidism
• Autoimmune thyroiditis
(Hashimoto’s disease)
• Postablative I 131 or surgery
• Athyreotic (Development
defects)
– Complete absence
(agenesis)
– Failure of thyroid to
descend
• Unresponsivenes to TSH
Goitrous Hypothryoidism
• Hashimoto’s thyroiditis
(iodine sufficient areas)
• Endemic iodine deficiency
(mountainous areas)
• Iodine-induced
• Antithyroid agents
• Central Hypothyroidism
Secondary hypothyroidism
• Panhypopituitarism
• Isolated TSH deficiency
• Abnormal TSH synthesis or
receptor defect
• Hypothalamic
91
hypothyroidism
Autoimmune Thyroiditis
• More common in women
• Thyroid autoantibodies
present
– autoantibodies to thyroid
peroxidase (TPOAB)
– autoantibodies to
thyroglobulin (TgAb)
• May be associated with
other autoimmune
diseases
Postablative
Hypothyroidism
• Common cause of thyroid
failure in the adult
• Follows total
thyroidectomy secondary
to thyroid cancer or
subtotal thyroidectomy
for Graves’ disease
• Following treatment with
radioactive iodine
92
Iodine-induced Antithyroid Agents
• Chronic administration • Lithium
of large doses of iodine • Para-aminosalicylic acid
– Potassium iodide (KI) • Phenylbutazone
– Radiographic contrast
• Topically applied
– Amiodarone
resorcinol
• May occur in newborns
• Ethionamide
when women given
large quantities of • Soybean in infant
iodine during pregnancy formulas

93
 Central Hypothyroidism
• Due to hypothalamic or pituitary disease
• May be associated with other pituitary
hormone deficiencies
• May precipitate adrenal crises if thyroid
hormone is replaced before hydrocortisone

94
 Clinical Features
• Symptom Cases
• Thick tongue 82
• Weakness 99%
• Coarseness of hair 76
• Lethargy 91% • Hair loss 57
• Dry & Coarse skin 97% • Pallor of skin 67
• Edema of eyelids 90 • Pallor of lips 57
• Facial Edema 79 • Memory impairment 66
• Anorexia & Weight gain 59
• Slow speech 90%
• Constipation 61
• Hoarseness of voice 52 • Dyspnea 55
• Sensation of cold 89 • Galactorrhea
• Decreased sweating 89 • Diminished libido
• Cold skin 83 • menorrhagia

95
 Signs
• Cardiomegaly • Hyponatremia
• Bradycardia • Normocytic
• HTN normochromic anemia
• Hung-up reflexes • High incidence of
pernicious anemia

96
• Gland enlargement
• Goiterous iodine deficiency

• Look apathetic
• Hair is very dry and brittle
• Puffiness around the eyelids
• Skin may be very thick and appear to
be yellow
• Tongue enlargement 97
Cardiovascular
• Cardiomegaly
• Bradycardia
• HTN
• Peripheral vascular Pericardial infusion
resistance is increased
• Cardiac output is
decreased
• Blood volume is
reduced
• Elevated cholesterol
After treatment 98
Alimentary System CNS
• Decreased appetite • Slowing of intellectual
• Modest weight gain functions
• Constipation • Psychiatric disorders
• Myxedema coma
• Hearing loss (Pinred
Syndrome)
• “hung-up reflexes”
(Delay in relaxation
phase)

99
MusculoSkeletal System Fluids/Electrolytes
• Muscle aches and • Decreased renal blood
stiffness flow
• Increased muscle mass • Delay in water excretion
• Growth failure in • Hyponatremia
children
• Delayed maturation of
bone

100
Hematopoietic System Reproductive Function
• Normocytic • Sexual immaturity
normochromic anemia • Delayed or precocious
• High incidence of puberty
pernicious anemia • Galactorrhea
associated with • Diminished libido
hypothyroidism
• menorrhagia

101
 Primary Hypothyroidism
TSH T4 TPO Diagnosis
Inc. Dec. + Autoimmune
Inc. Dec. - Post surgery /
irradiation

TBG Deficiency
T4 T3RU TSH
Dec. Inc. Normal

102
Adrenal gland

103
 Hormones
• Cortex
• Aldosterone
• Cortisol
• DHEA, DHEAS,
androstenedione
• Medulla
• Epinephrine
• Norepinephrine
• Dopamine

GFR:
• Zona glomerulosa: aldosterone
• Zona fasciculata: glucocorticoids (cortisol)
• Zona reticularis: androgens (DHEA and androstenedione)
104
 Actions of hormones
Cortisol
• Essential for response to stress
– Stimulation of gluconeogenesis
• Increases protein and lipid
catabolism
• Decreases glucose utilization
– Anti-inflammatory effects
– Suppression of immune response
• Inhibits production of IL-2
and T lymphocytes
– Maintenance of vascular
responsiveness to
cathecholamines
• Required for vasoconstrictor
effect of norepinephrine
Aldosterone
• Helps maintain water & salt
balance
– Increases Na reabsorption
(distal tubules)
– Increases K+ & H+ secretion
– Production falls too low,
causing blood volume & BP to
drop
• Stimulated by
– Angiotensin II
– Hyperkalemia
• Suppressed by hypernatremia

105
 Anatomy
• Paired retroperitoneal organs
• Up to 5 cm long, 3 cm wide
• About 5 grams
– Larger at birth (5-10g)
– Susceptible to hemorrhage
– Regresses over 6 weeks
• Arterial supply (enters
circumferentially)
– Inferior phrenic (main)
– Aorta and renal arteries
– Gonadal (in fetus 60% of
time)
• Venous return
– Right: directly into
posterior IVC
– Left: to renal vein
• Inferior phrenic vein
• Lymphatics
– Paraaortic nodes
• Nerve supply
– Mainly sympathetic from
T10-L1
– No cortex innervation
106
 Histology
• Cortex (90%) • Medulla
– Derived from mesoderm – Derived from
• Begins during 5th week of neuroectoderm
development • Neural crest cell
• Mesothelial cell migration migration
– Glomerulosa, fasciculata, • Begins during 7th week of
reticularis development
• Primitive medulla by 20th
– Zonation occurs until week
about 18 months of age
– Continues growth until
cortex atrophy (18
months)

107
 Hyperaldosteronism
• 10 (Conn syndrome) – Symptoms (HTN &
– High aldosterone & low hypokalemia):
renin • Polyuria & polydipsia
(NDI)
• 20
• Visual disturbances
– High renin & aldosterone • Postural hypotension
• Usually young with: • HA
– HTN (1% of HTN • Muscle weakness
patients) • Cramps
– High Na+ • Paralysis

– Low K+ <3.0 (20%

normal)
– Alkalosis 108
• Mineralocorticoid escape
– Due to breakdown of distal tubules
• Sodium retention decreases
• Limits K+ loss
– About 1.5kg of excess fluid absorption
• No edema
• Limits HTN
– Worse with adenoma
– Better with hyperplasia

109
• Causes
– Adenoma (most common)
• F>M
• 4th-5th decades of life
– Bilateral adrenal hyperplasia
– Adrenocortical carcinoma
(rare)
– Glucocorticoid remedial
aldosteronism
• Aldosterone producing
adenoma
• Responsive to renin
• Treatment
– Medical: spironolactone,
amiloride
• Better for bilateral adrenal
hyperplasia
• Prepare for surgical treatment
• Gynecomastia
(spironolactone)
– Control HTN with medicine
– Correct electrolytes
– Surgical
• Localize lesion
• Removal of
adenoma/carcinoma
• 90% of patients have a
decrease in HTN

110
 Hyperaldosteronism
• Diagnosis
– History, HTN, symptoms
– Laboratory
• Serum K+ (<3.0)
• Serum aldosterone
– Level >14 micrograms/d
diagnostic of primary
hyperaldosteronism
• Serum renin
– If >1.0 then unlikely
primary
– Localization
• CT scan with thin cuts
through adrenal
• MRI (less sensitive)
• Adrenal scintigraphy (less
accurate)
• Adrenal vein sampling
– Gold standard
– Measure selective
aldosterone levels
» Elevated on side of
adenoma
» Suppressed
contralateral side
111
 Cortex Hormones
• Cogenital adrenal • Cushing’s Syndrome
hyperplasia (Excess Cortisol)
– AR – Protein catabolic state
– Enzyme deficiency (11, 17, 21 – Liberation of amino acids
hydroxylase) by muscle
– 21 – hydroxylase deficiency – Weakened muscles and
elastic tissues
(95%)
– AA are transformed into
• Virilization glucose and glycogen and
• Salt loss without HTN then transformed into fat
– 11 – hydroxylase deficiency – Loss of calcium in urine
(5%) • Addison’s disease
• Virilization & HTN (deficiency)

112
 Actions of Cortisol
• Increases plasma glucose
levels
– Inc gluconeogenesis
– Dec glucose utilisation
– Increases glycogenesis
– Inc glycogen storage
• Increases lipolysis
– Provides energy
• Proteins are catabolised
– Releases Amino Acids
• Na+ and H2O Retention
– Maintains BP
• Anti inflammatory
• Increased gastric acid
production
113
 Cushing’s Syndrome
• Cushing’s Syndrome
– Excess cortisol in the blood
• Cushing’s Disease
– Excess cortisol in the blood due to an ACTH
secreting pituitary tumour
• F:M 3-15:1
• Onset at 20-40y.

114
 Cushing’s Syndrome

• Changes in protein, fat, glucose & • changes in sex hormones

CA metabolism – Hirsutism, excess hair growth
– Moon face – Irregular periods
– Buffalo hump – Problems conceiving
– Central obesity – Impotence
– Diabetes
– Muscle atrophy & weakness • Salt & water retention
– Osteoporosis – High BP
– Thin skin, easy bruising, striae – Fluid retention

115
116
117
 Investigation
1. Screening
2. Confirmation
– Urinary free cortisol
– Diurnal Rhythm
– Over night Dexamethasone suppression testing
• Cortisol is measured at 8am
• Dexamethasone 1mg is given at 11pm
• Cortisol is measured at 8am the next morning
• Cortisol suppression to <50 nmol/l is normal
3. Differentiation of the Cause
– ACTH
– High dose Dexamethasone Suppression testing
– Localization of the ACTH source
• Imaging ,MRI ...pit>>>ct :chest:ectopic” and abd.
• IPSS 118
Cortisol: Circadian Rhythm

25

600

0
0800 2000 h
119
 Dexamethasone Suppression Test
• LOW DOSE
– 0.5 mg Dexamethasone 6-h,
48 hrs
– Result
• Complete suppression in
normal subject
• If cortisol detectable then
patient has Cushing’s
syndrome
• HIGH DOSE
– 2 mg Dexamethasone 6-h for
48 hrs
• Result
– Suppresses to < 50% of
baseline then the patient has
Pituitary dependent Cushing’s
Disease
– Not suppress then the
patient has ectopic ACTH
production or an adrenal
tumour
120
 DDx
• Exogenous steroids
• True Cushing’s Syndrome
• Pseudocushing’s Syndrome
– Mimic clinical signs and symptoms
– Non-endocrine causes
• Alcoholism
• Major depression
• Morbid obesity
• Acute illness

121
 Laboratory Features
• Very elevated plasma & urinary cortisol
• Very raised plasma ACTH (>110 pmol/l)
• Non-suppression with dexamethosone
• Flat CRH response
• Hyperglycaemia
• Hypokalaemia
• Metabolic Alkalosis
• Increased Plasma LDH
122
 Cushing’s Syndrome causes
• Exogenous steroid use
– PO or topical
– Most common cause (overall)
• Cushing’s Disease
– Pituitary adenoma (95%)
• Basophilic or
chromophobe
– Bilateral adrenocortical
hyperplasia
– 70% of endogenous cases
– F>M (3:1)
• Ectopic source (produce ACTH or
CRH)
– Small cell lung CA (most
common)
– Small-cell CA of prostate
– Carcinoid tumors
– Medullary thyroid
– Pancreas
– Ovarian
– Pheochromocytoma
– 15% of endogenous causes
• Adrenal adenomas (10%)
• Adrenal carcinoma (5%)
Most common cause in children123
 Radiographic Localization
• MRI of sella turcica
• CT of chest/abdomen with 3mm
cuts through adrenal
– Adrenal hyperplasia
• Thickening and elongation
of adrenal rami bilaterally
• Multinodularity of cortex
bilaterally
• CT of adrenal glands
– Adenomas- usually >2cm but
<5cm
• Low attenuation (lipid
content)
• Atrophy of opposite gland
– Carcinoma- indistinguishable
from adenomas
• >5cm
• Necrosis, calcifications,
irregularity, invasion
• MRI of adrenal- usually not needed
– Signal intensity much higher than
in spleen = carcinoma
– Adjacent organ and/or vascular
involvement
124
 Treatment: Surgical
• Cushing’s disease
• Nelson’s syndrome
– Transphenoidal hypophysectomy – Rapid post-operative enlargment of
• >90% cure rate 1st time pituitary adenomas that can be
• Transient post-op diabetes invasive
insipidus, adrenal – Hyperpigementation
insufficiency, CSF rhinorrhea, – Preoperative irradiation decreases
meningitis incidence
– Transphenoidal irradiation • Adrenal lesions/carcinoma
– Removal of primary lesion
• High success rate in kids
– Survival based on underlying disease
(80%)
• Ectopic ACTH lesions
• Low success in adults (20%)
– Remove lesion
– Bilateral adrenalectomy
– Survival based on primary disease
• If failed pituitary surgery
• Nelson’s syndrome (10-20%)
• Life-long steroid
125
replacement
 Treatment: Medical
– Used as prep for surgery or poor operative candidate
• Metyrapone- inhibits conversion of deoxycortisol to cortisol
• Aminoglutethimide-inhibits desmolase
– Cholesterol to pregnenolone
– Blocks synthesis of all 3 corticosteroids
– Side effects: N/V, anorexia, lethargy
• Ketoconazole- an imidazole that blocks cholesterol synthesis
• Mitotane (O-P-DDD)-inhibits conversion to pregnenolone
– Inhibits final step in cortisol synthesis
– Destroys adrenocortical cells (spares glomerulosa cells)

126
 ADRENAL INSUFFICIENCY
CLASSIFICATION
• Primary (Addison’s disease):
– Destruction or impairment of the adrenal cortex
– Usually affects all zones of the adrenal cortex
– Decreased production of cortisol, aldosterone, and adrenal androgens.
– Mean age of diagnosis: 40 years
• Secondary (Central):
– Reduced ACTH secretion or production
– Subsequent adrenal atrophy
• Tertiary
– Failure of the hypothalamus to produce CRH
– Mostly result of suppression from the pharmacologic use of
glucocorticoids

127
 Etiologies – Primary Insufficiency
• Autoimmune (Autoimmune
Polyglandular Syndrome)
– Type I:
• Addison's disease
• Chronic mucocutaneous
candidiasis
• Hypoparathyroidism
– Type II (Schmidt's syndrome):
• Addison's disease
• Primary hypothyroidism
• Primary hypogonadism
• Insulin-dependent diabetes
• Infection
– TB, HIV, Fungal
• Infiltrative
– Amyloidosis, Sarcoidosis,
Hemochromatosis,
Adrenoleukodystrophy
• Neoplasm
– Adrenal metastases (lung and
breast)
– Lymphoma
• Hemorrhage or infarct
– Meningococcemia (Waterhouse-
Friderichsen)
– DIC
– Lupus (antiphospholipid
antibody)
– Anticoagulation
• Iatrogenic
– Bilateral adrenalectomy
– Drugs that inhibit P-450 enzymes
(ketoconazole, etomidate)
• Congenital adrenal hypoplasia
• ACTH resistance syndromes 128
 Etiologies – Secondary Insufficiency
• Cessation of exogenous
glucocorticoid therapy
– Such therapy suppresses HPA
axis with adrenal atrophy
– Taking
• > 30mg/d hydrocortisone
• 7.5mg/d prednisone
• 0.75mg/d dexamethasone
for >3 weeks
• Failure to give stress
steroids
• Removal of ACTH-secreting
pituitary adenoma
– Function of ‘normal’
corticotrophs suppressed
• Inadequate ACTH production
– Usually other pituitary
hormones deficient
– Partial or complete
hypopituitarism
– Isolated ACTH deficiency rare
• Lymphocytic hypophysitis
• Abnormal post-
translational processing
of POMC to ACTH, may
have more generalized
defects in peptide
processing (e.g., cleavage
of proinsulin to insulin)
giving rise to DM.
129
 Clinical manifestations

• 10 & 20 Insufficiency
– Anorexia, weight loss
– Weakness, fatigue
– Nausea, vomiting, diarrhea
– Postural dizziness, hypotension, mental depression
– Lab
• Hyponatremia
• Hypoglycemia
• Mild normocytic anemia
• Lymphocytosis
• Eosinophilia

130
• Primary Insufficiency
– Hyperpigmentation
– Vitiligo
– Autoimmune thyroid
disease
– Salt craving
– CNS symptoms in
adrenomyeloneuropathy
– Lab
• Hyperkalemia
• Acidosis
• Elevated creatinine

131
 •Adrenal Crisis
– Dehydration, hypotension, or
• Secondary insufficiency shock
– Pallor without marked – Anorexia, weight loss
anemia – Nausea, vomiting
– Headaches, visual – Acute abdomen, abdominal
symptoms pain
TSH – Secondary hypothyroidism
– Unexplained hypoglycemia &
ADH – Diabetes insipidus fever
Gonadotropin – Amenorrhea, decreased
libido – Hyperpigmentation or vitiligo
– Scant axillary & pubic hair – Lab:
– Small testicles • Hyponatremia
– Prepubertal growth deficit • Hyperkalemia
– Delayed puberty • Hypercalcemia
• Azotemia
• Eosinophilia 132
 DIAGNOSIS

• Basal Cortisol Level

– Random cortisol levels: (less sensitive)
• < 15ug/dl: insufficiency likely
• > 34ug/dl: insufficiency unlikely
• 15-34ug/dl: perform Cosyntropin, increment <9 likely
insufficient
– Check morning cortisol
• > 18 µg/dL indicates an intact axis
• < 3 µg/dL strongly suggests insufficiency
• 3 – 18: perform cosyntropin stimulation test

133
 DIAGNOSIS
High-Dose Cosyntropin Stimulation
Test
• IM or IV of 250 µg of
cosyntropin (exogenous ACTH)
• Plasma cortisol levels are
measured at 30 and 60 minutes
– Normal response: > 18
µg/dL
– Subnormal response: < 18
• After positive test
– Primary adrenal
insufficiency: elevated ACTH
level
– Secondary insufficiency:
normal or low plasma ACTH
levels
Low-Dose Cosyntropin Test
• 0.5 – 1 ug will give a maximal
response within 15 to 30 mins
• diagnosing secondary
insufficiency because ACTH
level closer to physiologic level
• Normal response: peak plasma
cortisol level > 18 µg/dL
• Like high-dose test, low
sensitivity when ruling out mild
or recent secondary
insufficiency; confirm with more
sensitive tests (insulin
tolerance, metyrapone)
134
 DIAGNOSIS
Insulin Tolerance Test
• Hypoglycemia induced by the IV
injection of reg insulin
stimulates the entire HPA axis.
• Plasma glucose and cortisol are
measured after injection of
insulin.
– Normal response: cortisol
increases to at least 18ug
per dL
• Expensive and contraindicated
in patients with coronary heart
disease or seizures
• Metyrapone Test
– Inhibits conversion of
11-deoxycortisol to cortisol
– Give at midnight
– Measure the concentration of
11-deoxycortisol and cortisol
at 8am
– In normal subjects, the
plasma 11-deoxycortisol
concentration increases to at
least 7ug/dL.
– In patients with adrenal
insufficiency, the increase is
smaller and is related to the
severity of the corticotropin
135
deficiency
136
 Treatment

Acute replacement therapy

• IV hydrocortisone 100mg q6h
• Normal saline in the shocked patient
• Usually D5% because of possible hypoglycemia
• Clinical improvement should be seen in 4-6 hrs
• After the first 24 hours the dose of hydrocortisone can be
reduced, usually to 50 mg IM q6h
• Then, if the patient can take it by mouth, to oral
hydrocortisone, 40 mg in the morning and 20 mg at 6 PM

137
 CHRONIC REPLACEMENT THERAPY
• Mimic the normal cortisol secretion rate
• Hydrocortisone (15 – 25 mg/day in divided doses)
• Doses are largely based on end points such as
– Weight
– Well-being
– BP
• Fludrocortisone (0.05 – 0.2 mg/day), in primary adrenal
failure
• Adequacy assessed by measuring
– Electrolytes
– Orthostatics
– Plasma renin activity 138
 CHRONIC REPLACEMENT THERAPY
• Double the daily dose in:
– Febrile illness
– Accident
– Mental stress
• Surgery
– 50 to 100 mg of hydrocortisone hemisuccinate with premedication
• Pregnancy
– Increased (5 – 10 mg/day) in the last trimester
– During labor, patients should be well hydrated with a saline drip and
receive hydrocortisone at 50 mg intramuscularly every 6 hours until
delivery.
• Adrenal androgen replacement therapy
– DHEA at 25 to 50 mg/day in both primary and secondary insufficiency
– To date, the reported benefit is principally confined to female patients
139
and includes improvement in sexual function and well-being.
 Pheochromocytoma
• Originate from • 10% bilateral
– Adrenal medulla • 10% extraadrenal
– Extraadrenal paraganglia
cells • 10% malignant
• Secrete • 10% familial
– Norepinephrine (neuroectodermal
– Epinephrine disorders or MEN2)
– Rarely dopamine and • 10% occur in children
other
• 10% multifocal
• 10% normotensive
140
 Pheochromocytoma, Presentation
• Episodic headaches, tachycardia, diaphoresis
• HTN
– Sustained HTN
– Sustained HTN with paroxysm
– Paroxysmal HTN with intermittent normotension
• Nausea/vomiting
• Flushing
• Raynaud’s phenomenon
• 10% present in “pheocrisis”
• 50% found as incidentaloma

141
 Diagnosis
• 24hr urinary
– Catecholamines (NE, Epi,
Dop)
– Metabolites (metanephrine,
normetanephrine, VMA)
• Plasma catecholamine or
metabolites during episode
• Elevated serum epinephrine
suggests pheo in medulla or
Organ of Zukerkandl
• NO FNA! (can precipitate
hypertensive crisis)
• Localizing studies:
– Thin cut CT detects most
lesions: 97% intraabdominal
– MRI: 90% pheos bright on T2
weighted scan
– MIBG: used for extraadrenal,
recurrent, multifocal, malignant
disease
• Malignant disease
– Local invasion, disease outside
of adrenal/paraganglionic
tissue
– No histological or clinical
criteria can differentiate
malignant disease
142
 Treatment
• Surgery
• Avoid anesthetic agents that
• Must medically optimize prior to
precipitate catecholamine secretion.
surgery
– Induce with thiopental/isoflurane
– Treat HTN
– Expand intravascular volume
– Phentolamine (short acting α-
blocker)
– Control cardiac arrhythmias
– Sodium nitroprusside for BP
• Phenoxybenzamine (α-adrenergic
control
antagonist)
– Norepinephrine if needed for
• PO salt and fluid repletion
hypotension
• May need β-blocker as
– Lidocaine and esmolol to control
antiarrhythmic. Do not start until
arrhythmias.
after pt α-blocked
• Medical options: chemo, high dose
• Metyrosine – decreases
I131 MIBG, XRT – symptomatic relief
catecholamine synthesis 143