Pathology Notes
Year 5
Corrections
Osteomalacia lowest calcium over a long time,
osteoporosis normal calcium. Often low after
pregnancy and the child ends up with rickets.
Primary HPT high Ca, carcinoma is highest Ca
Severe long standing CCF results in transudate
pleural effusion and ascites, diabetes makes it
more likely. Ascites and effusion are not part of
septicemia. Low albumin low oncotic pressure,
secondary hyperaldosteronism, retain fluid.
Nephrotic syndrome same mechanism. Lung Ca
primary and mets making fluid is common
Heroin, alcohol, crystal meth, acute liver failure,
brain hemorrhage in 24y drug dealer
Iron deficiency, RhA, alcohol, folate 4m to run
out, B12 (more extreme grows before anemia
manifests) largest
Normal, oedema/inflame, necrosis, granulation,
dense fibrosis
Pseudomembranous colitis: metronidazole PO,
vanc PO, gentamicin PO, gentamicin IV,
cephalexin PO (CAUSES IT)
Phos, Ca, K, Cl, Na
HONKC (440), DKA, DI, pneumonia, SIADH (260)
Lecture 1: Calcium metabolism
Ca 2.2-2.6 low Ca --> NMJ disruption, seizures.
Detection by parathyroid, PTH released to increase
Ca. 1% calcium in serum
Free ionised 50% biologically active
Protein bound 40% by albumin
Complexed 10% with citrate/phosphate
Total Ca 2.2-2.6, report corrected calcium if albumin is
different (adjusted to what the Ca would be if albumin
were normal). Ionised Ca 1.1 measured with blood gas
machine. Low albumin results in low bound Ca but
free Ca is normal
Ca is essential for normal nerve and muscle function,
plasma concentration is maintained through bone
turnover, despite Ca/VD deficiency
Alice Tang
2017-2018
Parathyroid detects low Ca, releases PTH, increases Ca
from bone, gut absorption, kidney resorption and
renal 1 alpha hydroxylase activation
Ca homeostasis relies on VitD and PTH
PTH 84aa from parathyroids. Causes bone and renal
Ca resorption, stimulates vitD 1,25 (OH)2 vitD
synthesis from 1 alpha OHase, stimulates renal Pi
wasting
Measured VD3 is 25-OH D3, inactive. PTH turns on 1
alpha hydroxylase to initiate conversion to 1,25 (OH)2
D3 active form, more Ca absorption
VD2 ergocalciferol is a plant product, VD3
colecalciferol is made in the skin, both are active
Synthesis of VD: all absorbed VD is hydroxylated at 25
position by 25 hydroxylase in the liver, 25 OH VD is
inactive, this is the stored and measured for, of VD.
Activation happens in kidney, rarely expressed in lung
sarcoid tissue - unexplained hyperCa due to ectopic 1a
hydroxylase
1,25 (OH)2 VD calcitriol causes: intestinal Ca
absorption ,intestinal Pi absorption. Needed for bone
formation. VDR controls genes for cell proliferation,
immunity. Deficiency is associated with poverty
Osteoclasts release ALP with increased bone turnover.
Bone is the main reservoir of Ca, Phos, Mg with a
metabolic role. Clinically important for osteoporosis,
osteomalacia, Paget's disease, PTH bone disease,
renal osteodystrophy
Vitamin D deficiency
Pathology Notes
Year 5
Defective bone mineralisation, cannot add calcium to
the osteoid
Children, epiphyseal widening at the wrist and
rickets. Bowed legs, costochondral swelling,
myopathy. Anticonvulsant rickets liver inducer,
increased breakdown and excretion of VD.
Adult osteomalacia: bone/muscle pain, increase
risk of fracture, low Ca, low Phos, high ALP,
Looser's zones of pseudofractures (partial).
Demineralised bone. Caused also by renal
failure resulting in failure of 1aOHase. Chappati
unleavened flour phytic acid reduces VD
absorption
>50% VitD deficient in the UK, 16% severe in winter
and spring. Risks include lack of sun, dark skin, diet,
malabsorption. Results in secondary hyperPTH (high
PTH). In pregnancy, baby takes even more Ca away
from mother
Osteoporosis
Bone chemistry is all normal, due to loss of bone mass
with normal mineralisation Ca. Causes pathologic
fracture, lost after age 20. Residual bone is normal.
Low Ca intake, deficient sex steroids, low use,
Cushing, hyperthyroid, cirrhosis. No symptoms until a
fracture occurs. Fracture of neck of femur or Colles
wrist fracture.
Diagnosis with DEXA scan, hip and lumbar spine T-
score, SD from mean of a young healthy population to
determine fracture risk. Z score SD from mean of age
matched controls, to see accelerated bone loss in
younger Pt.
Osteopenia -1 to -2.5
Osteoporosis <-2.5
Fracture causes death in elderly much faster. More
bone mass loss after menopause. Childhood illness
prevents peak being rached, early menopause also
increases rapid bone loss
Osteoporosis is also caused by sedentary lifestyle,
smoking, EtOH, low BMI, hyperPRL, thyrotoxicosis,
Cushings, steroids, genetics, prolonged illnesses. More
rapid bone loss
Treat with weight bearing exercise, stop
smoking/EtOH. Treat with VitD/Ca, bisphosphonates
like alendronate to decrease bone resorption as we
don't have enzymes to break C-N bond, but
nausea/gastric irritation. Teriparatide is a PTH
derivative (anabolic), strontium anabolic and anti-
resorptive but not as good as normal bone, estrogen
HRT but increases breast cancer risk, SERM raloxifene
prevents BC but results in hot flushes
Alice Tang
2017-2018
Normal bone is 2/3 mineralised
HyperCa polyuria/polydipsia, constipation, neuro
confusion, seizure, coma if Ca>3, overlaps with
hyperPTH. Should result in PTH = 0
High Ca, suppressed PTH = appropriate
response. Malignancy, sarcoid, VitD excess,
thyrotoxicosis, milk alkali syndrome
High Ca, not suppressed PTH = primary HPT
single adenoma (hyperplasia, carcinoma),
familial hypocalciuric hypercalcemia.
Parathyroid hyperplasia associated with MEN1.
F>M
Primary HPT
Commonest cause of high Ca: parathyroid adenoma,
hyperplasia (MEN1), carcinoma. F>M
Increased Ca, increased PTH, low Phos, high urine Ca.
Bones weak (PTH bone disease), kidney stones,
abdominal moans (constipation, pancreatitis),
psychiatric groans (confusion)
Familial hypocalciuric hypercalcemia RARE higher set
point for Ca
Gene defect in CaSR ca sensing receptor. Low urine Ca
= FHH, high = primary HPT
Cancer causes hyperCa in 3 ways:
1. Humoral hyperCa of malignancy (small cell lung
cancer), PTHrP baby makes this to steal Ca
(overrides maternal). Death in 6m
2. Bone metastasis (breast Ca) local bone
osteolysis
3. Haem malignancy (myeloma) cytokines
Other causes of non-PTH driven hyperCa
1. Sarcoid (non renal 1 a hydroxylase)
2. Thyrotoxicosis (thyroxine increases bone
resorption)
3. Hypoadrenalism (reduced renal Ca transport)
4. Thiazidess (renal Ca transport)
5. Excess VitD (sunbeds)
Treat by giving saline, saline, frusemide if HF,
bisphosphonates if cause is cancer. Treat underlying
cause
Hypocalcemia shows neuromuscular
irritability/excitability. Treat with Ca and VitD
activated forms. Trousseau carpal spasm, Chvostek
cheek spasm, convulsion
Pathology Notes Alice Tang
Year 5 2017-2018

Repeat and adjust for albumin Lecture 2: Diabetes Clinical Cases

1. Low PTH: surgical post thyroidectomy, AI
hypoPTH, congenital absence (DiGeorge), Mg
deficiency (PTH regulation)
2. Non-PTH driven: VitD deficiency (diet,
malabsorption, sunlight lacking), CKD
(1aOHase), PTH resistance (pseudohypoPTH)

Can progress to tertiary hyperPTH, same as primary

biochemistry, after extended period

Paget's disease
Focal bone remodelling from osteoclasts. PAIN,
warmth, high output cardiac failure (blood shunting),
deformity, fracture, malignancy of bone risk. High
ALP, treat with bisphosphonates for pain. Affects
pelvis, femur, skull, tibia. Investigate with nuclear med Normal = pH 7.4, H+ 50, pCO2 4.2
scan/XR. Active OB and OC
1. pH 6.85, pCO2 2.4, pO2 15, Na 145, K 5, U 10,
Primary hyperPTH loss of cortical bone results in glucose 25, Cl 95, bicarb 4. Metabolic acidosis,
fracture risk, long term results in osteitis fibrosa unconscious as brain enzymes cannot
cystica, cysts in bones function at this acidic pH

Renal osteodystrophy in CKD or dialysis patients long Osmolality = charged + uncharged

term. Secondary hyperPTH, retention of Al from = 2(Na+K) + U + G
dialysate
=335

Assume cations (Na, K) = anions (Cl, bicarb,

others) others = anion gap = Na + K - Cl - bicarb

Lactate or ketones present, or hyperchloremic.

Normal AG = 18, in this patient 145+5-95-4=51
high suggesting extra anions (ketones). Diabetic
ketoacidosis

2. 19 year old known T1DM for several years

unconscious, pH 7.65, pCO2 2.8, bicarb 24
normal, pO2 15. Respiratory alkalosis, primary
hyperventilation (anxiety, hypo) Ca binds
protein more strongly, they become
hypocalcemic, giving tetany, breathe slowly
and shallowly
3. 60M unconscious in casualty, polyuria,
polydipsia. Na 160, K 6, U 50, pH 7.3, glucose
60. Osmolality = 2(Na+K) + U + G = 442
unconscious due to dehydration. Unknown
diabetic, pee out lots of free water due to
high Na and high glucose. HHS hyperosmolar
hyperglycaemic state (HONK) no ketones as
enough insulin is present to switch off
ketogenesis
Pathology Notes
Year 5
4. 59M T2DM known, good diet on metformin,
unconscious, urine negative for ketones. Na
140, K 4, U 4, pH 7.1, glucose 4, PCO2 1.3 Cl
90, bicarb 4. Osmolality = 296, AG = 50,
metabolic acidosis. High anion gap not due to
ketones methanol, ethanol, lactate.
Metformin blocks lactate to glucose
conversion and can cause lactic acidosis. Cori
cycle: glucose in circulation goes to muscle,
used to produce lactate, enters circulation to
the liver, converted back to glucose.
Metformin overdose or in kidney failure
(metformin is renally excreted)
Fasting glucose > 7 (plasma), IFG 6.1-7
Glucose tolerance test (75g) plasma glucose
>11.1 at 2h (IGT at 7.8-11.1)
Lecture 3: Liver Pathology
Liver 1500g, dual blood supply from hepatic
artery and portal vein, unlikely to get ischemic
damage
Hepatocytes, cholangiocytes, BV, endothelium,
Kupffer cells, stellate cells (store VitA, when
activated make collagen in the liver as
myofibroblasts)
Normal structure 1: periportal, 2: midzone, 3:
perivenous. Born in 1, mature in 2, end in 3. Zone
3 most enzymes (alcohol dehydrogenase), drug
induced damage occurs most in zone 3, PO2
lower in zone 3. If hypermetabolic, PO2 below
critical level (alcohol) greatest damage
Portal tract: artery, vein, bile duct (if no bile duct
= disease going on)
Alice Tang
2017-2018
Normal sinusoid is lined by endothelium with
Kupffer cells inside, stellate cells in the space of
Disse and hepatocytes outside
Endothelial cells do not sit on BM (unique in
body)
Discontinuous endothelium to contact
hepatocytes
With stellate cell activation in liver injury the
Kupffer cells are activated, gaps disappear, loss of
fenestrae, deposition of collagen by SoD,
hepatocytes lose their microvilli
Cirrhosis: whole liver involved, fibrosis, nodules
of regenerating hepatocytes, distorted vascular
architecture. Intra and extra hepatic shunting of
blood. Classified as micro or macronodular (larger
than normal lobule). Aetiology: alcohol/insulin
resistance fatty liver disease, viral hepatitis
Portal HTN, hepatic encephalopathy, liver cell
cancer are complications (cirrhosis is the top
western cause of HCC)
Passive splenomegaly from portal HTN. Cirrhosis
may be reversible if underlying cause is
aggressively treated
Acute hepatitis: viruses, drugs spotty necrosis
small foci of necrosis
Chronic hepatitis: viruses (not A/E), drugs, AI (6
months LFTs elevated)
Severity of inflammation = grade
Severity of fibrosis = stage (most important for
diagnosis)
Piecemeal necrosis (interface hepatitis) between
portal tract and parenchyma. Apoptosis from
CTLs. Fibrosis bridging to portal tract intrahepatic
shunting
Alcoholic liver disease: fatty liver, alcoholic
hepatitis, cirrhosis
Fatty liver is a metabolic problem, pale and
greasy. Droplets of fat. Acute and reversible
Alcoholic hepatitis. Ballooning of hepatocytes.
Acetaldehyde binds and cross linkes lysine
Pathology Notes
Year 5
residues binding and clumping IF
cytoskeleton. Affects transport of
proteins/water: increases protein and water
accumulation. Mallory-Denk bodies are
formed from the clumping of IFs (hyaline =
pink) collagen blue. Neutrophils present.
Macronodular almost always due to alcohol
Cirrhosis small nodules
NAFLD/NASH looks like alcoholic liver disease but
isnt. due to IR, high BMI, DM. Commonest liver
disease (middle east 30%, Americans 4 million)
PBC bile duct loss due to chronic inflammation
with granulomas. Anti mitochondrial Abs, often
middle aged women
PSC periductal bile duct fibrosis leading to loss
(not granuloma). Associated with UC, increased
risk of cholangiocarcinoma. ERCP diagnostic.
Concentric fibrosis onion skinning
Hemochromatosis increased gut iron absorption
(2mg instead of 1mg), chromosome 6, 60% have
mutation in HFE1. Parenchymal damage
secondary to iron deposition (bronze diabetes)
deposition and destruction of parenchymal
tissues. Multi organ disease to heart, adrenals.
Brown liver on histology
Hemosiderosis is the accumulation of iron in
macrophages (Kupffer) often due to blood
transfusion. No significant liver disease due to
macrophage handling iron well
Wilson disease accumulation of copper due to
failed excretion, gene C13 accumulates in liver
and CNS. Compound heterozygotes, difficult to
diagnose genetically. Rhodanine stain
Autoimmune hepatitis interface hepatitis with
plasma cells, anti-smooth muscle actin Ab,
responds to steroids, more in women
Alpha 1 antitrypsin deficiency failure to secrete
(although made and even causes damage), intra-
cytoplasmic inclusions, hepatitis and cirrhosis
Alice Tang
2017-2018
Drug related injury can cause any kind of liver
disease
Paracetamol toxicity. Alcohol metabolized by
zone 3 cells, also in paracetamol.
Hepatic granuloma: organized collection of
activated macrophages, no longer phagocytic but
predominantly secretory. PBC, drugs, TB, sarcoid.
Giant cells
Liver tumours benign: liver cell adenoma, bile
duct adenoma, hemangioma. Sharply defined
Liver tumours malignant: secondary (far more
common) and primary. Commonest biopsy
reason is metastatic cancer, multiple mets
Portal venous system is where many BV enter: L
gastric, SMA, IMA, splenic vein. Stomach, SI/LI,
pancreas first vascular bed is liver
Primary tumours: HCC, hepatoblastoma (fetal),
cholangiocarcinoma, hemangiosarcoma. Usuaully
associated with cirrhosis in the West
Cholangiocarcinoma associated with PSC, worm
infections (Thailand), cirrhosis. Arises from intra
and extrahepatic ducts (including GB)
Hepatitis B not associated with fatty change.
Genotype 3 HCV is associated with some fatty
change
Lecture 4: Antimicrobials
If sensitive, penicillin is still the strongest. 5%
given Abx experience adverse event: GIT upset,
fever, rash, renal dysfunction (amikacin,
gentamicin), acute anaphylaxis, hepatitis
1. PtG cell wall (beta lactams: penicillins,
cephalosporins, carbapenems;
glycopeptides: vancomycin, teicoplanin)
2. Ribosomes smaller
3. DNA gyrase
Pathology Notes Alice Tang
Year 5 2017-2018

Cephalosporins are also BLase resistant,

increasing generation has more effectiveness
against G- and lose G+ cover
First gen: cephalexin
Second gen: cefuroxime less active against
anaerobes than co-amoxiclav
Third gen: cefotaxime, ceftriaxone (associated
with C diff), ceftazidime (anti-Pseudomonas,
G+ thick PtG cell wall (NAG+NAM). G- thin cell
no G+)
wall
ESBLs resistant to all cephalosporins.
Beta-lactams inactivate transpeptidases (pbp)
Carbapenems are stable to ESBL enzymes
terminal cell wall synthesis steps, structural
(meropenem, imipenem, ertapenem) but
analog of the enzyme substrate. Bactericidal,
carbapenemases are becoming more widespread.
active against rapidly dividing bacteria,
MDR Acinetobacter, Klebsiella
ineffective against non-PtG cell walls
(Mycoplasma, chlamydia). Prevent peptide cross
BLs are non toxic, renally excreted, short half life,
links from being formed
dont cross BBB (but meningitis crossed), cross
reactivity and cover most bugs empirically. Cross
allergy, 10% with cephs/carbs must clarify nature
of allergy

Glycopeptides are large, cannot penetrate outer

cell walls of G-, inhibit cell wall synthesis,
treatment of serious MRSA IV route, oral vanc for
C diff, slow bactericidal, nephrotoxic. Bind
peptide chain to prevent glycosidic bonds and
peptide cross links D-Ala D-Ala

Protein synthesis inhibitors include

aminoglycosides (gentamicin, amikacin,
tobramycin), tetracyclines, macrolides
Defective PtG cell walls cause lysis and death.
(erythromycin), lincosamides (clindamycin),
Bacteria arent always dividing biofilms or not in
streptogramins (synercid) (MSL group),
right stage of cell cycle
chloramphenicol, oxazolidinones (linezolid)
Derivatives
Aminoglycosides bind the amino-acyl site of 30S
1. Penicillin good for G+ Strep, CLosrtidia,
ribosomal subunits. Rapid, concentration
however broken down by beta-lactamases
dependent bactericidal action. Needs specific
made by S aureus 90% resistance
transport mechanism to enter cells hence some
2. Amoxicilin broad spectrum extending
intrinsic resistance. Ototoxic, nephrotoxic, need
coverage to Enterococci and G-
to monitor levels. Gentamicin/tobramycin
3. Flucloxacilin is less active but more stable to
especially active against P aeruginosa. Synergistic
beta-lactamases
with B-lactams, no activity in anaerobes. Prevent
4. Piperacilin extended to Pseudomonas and
elongation of polypeptide chain, cause
non coliform enteric G- broken down by
misreading of codons along mRNA
BLases, take with clavulanic acid and
tazobactam (co-amoxiclav, tazocin)
Pathology Notes
Year 5
Tetracyclines are broad spectrum agents with
lots of resistance. Activity against intracellular
pathogens (chlamydia, rickettsia, mycoplasma),
bacteriostatic, not for children or pregnant
women, light sensitive rash. Reversibly binds 30S
subunit to prevent binding of aminoacyl-tRNA to
ribosomal acceptor site, inhibiting protein
synthesis
Macrolides are bacteriostatic, minimal G- activity
(erythromycin is a better G- drug, used for S
typhi), CAP for Staph/Strep in pen allergic. Active
against Campylobacter, Legionella, Pneumophila.
Newer clarithromycin, azithromycin better
properties. Bind 50S subunit interfering with
translocation and stimulate dissociation of
peptidyl-tRNA. Toxins or Nec Fasc needs to inhibit
toxin production
Chloramphenicol bacteriostatic broad
antibacterial activity but rising drug resistance.
Rarely used except for eyes and special
indications due to risk of aplastic anemia (1/25k-
45k) and grey baby syndrome in neonates due to
an inability to metabolise the drug. Pen allergy
for pneumonia. Binds peptidyl transferase of 50S
subunit, inhibits formation of peptide bonds in
translation
Linezolid due to MRSA highly active against G+
MRSA/VRE but not against G-, binds 23S
component of 50S subunit to prevent formation
of functional 70S initiation complex for
translation to start. Expensive and can cause
thrombocytopenia, use only with ID approval.
Completely synthetic, 18m to develop resistance
DNA synthesis inhibitors: fluoroquinolones,
nitroimidazoles
Fluoroquinolones act on alpha-subunit of DNA
gyrase, bactericidal, broad spectrum G-
Pseudomonas. Levofloxacin and moxifloxacin
newer agents increased activity against G+ and
intracellular bacteria chlamydia (lose G-). Oral
absorption is high, used for UTI, pneumonia,
atypical pneumonia (legionella), bacterial
gastroenteritis. Lots of resistance, especially in
gonorrhea
Alice Tang
2017-2018
Nitroimidazoles include metronidazole and
tinidazole, great against anaerobes and protozoa
(Giardia). Intermediate breaks DNA strands, rapid
bactericidal. Nitrofurans are related;
nitrofurantoin to treat simple UTI (E coli)
Inhibitors of RNA synthesis: rifampicin, rifabutin
Rifampicin inhibits protein synthesis binding
DNA-dependent RNA polymerase, inhibits
initiation. Active against Mycobacteria, Brucella,
chlamydia. Monitor LFTs, interact with OCP and
hepatic metabolized drugs. Can turn urine and
tears orange. High resistance, single aa change in
beta subunit of RNA pol, fails to bind rifampicin.
Except for short term prophylaxis
(meningococcal) never use as a single agent due
to resistance
Cell membrane toxins
Daptomycin cyclic lipopeptide G+ MRSA, VRE
instead of linezolid/synercid
Colistin polymyxin G- Pseudomonas,
Acinetobacter, Klebsiella. Not orally absorbed,
nephrotoxic, reserved for use against MDR bugs
as a lastline drug. Some resistance present
Folate inhibitors: sulphonamides and
diaminopyrimidines (trimethoprim). Act indirectly
on DNA through interface with folic acid
metabolism, synergy between these classes due
to sequential action on the same pathway.
Sulphonamide resistance is common but
sulfamethoxazole and trimethoprim (co-
trimoxazole) is useful for PCP pneumonia.
Trimethoprim for community acquired UTI
Resistance due to chemical modification,
inactivation, modification/replacement of target,
reduced accumulation (impaired uptake or
enhanced efflux), bypass Abx sensitive step
(trimethoprim/sulphonamides in enterococci)
Pathology Notes
Year 5
B-lactam inactivation by b-lactamases in S aureus
and G- coliforms, not the same in MRSA,
pneumococci. Penicillin resistance not reported
in Group A, B, C, G, beta hemolytic Strep
MRSA mecA gene oncodes a new PBP2a with low
affinity for b-lactam binding
Pneumococcus pen resistance due to acquisition
of stepwise mutations in PBP, low resistance
increase dose. Causes meningitis, poor
penetrance so bacteria may not respond. Add
vancomycin to get high concentrations in CNS
ESBLs able to break down cephalosporins
(cefotaxime, ceftazidime, cefuroxime),
commoner in E coli/Klebsiella, treatment failure
with BL/BLI (augmentin, tazocin). Lower response
than expected.
>10% resistance = cannot use for empiric
therapy. 10% E coli resistant to first line drugs
Encode resistance to many classes MDR in one
genetic package
Carbapenem use has increased (C diff) big groups
of distribution and epidemiology are: NDM, VIM,
IMP, KPC, OXA-48. Treatment is difficult only with
polymyxins, tigecycline, fosfomycin
Altered targets: macrolide adenine N6
methyltransferase modifies 23srRNA, reduces
binding of MLS Abx, erm genes. Erythromycin
resistance induces clindamycin resistance =
blunting. Antimicrobial stewardship, good
prescribing, encourage handwashing, send
samples
Alice Tang
2017-2018
Flucloxacilin resistance in S aureus is mediated by
alteration of target. Cannot use carbapenem as
mechanism is the same
ESBL is resistant to ceftriaxone through enzymatic
inactivation of antibiotic. Can use carbapenem
instead
Lecture 5: Lymphoma
Link cancer cell with normal counterpart
B cell ALL is the earliest one, B MM is the latest
one
1. Rapid cell proliferation risking DNA replication
error
2. Depends on apoptosis, 90% of normal
lymphocytes die in germinal centers, Ab
specificity to prevent AI disease, apoptosis
switched off in germinal centers, acquire DNA
utation in pro-apoptotic genes
3. DNA molecules are cut and rejoined, undergo
point mutation to result in TCR/Ig diversity.
New point mutations and recombination
errors
Ig gene recombination:
VDJ recombination in BM, RAG1/2 enzyme,
TdT
Class switch recombination, somatic
hypermutation, adenosine induced
deaminase enzyme
Chromosomal translocations associated with
lymphoma involve Ig locus, promoter highly
active in B cells. Bring intact oncogenes close
together to Ig promoter. Anti-
apoptotic/proliferative genes including bcl2, bcl6,
Myc, cycD1
Fusion gene vs deregulated protooncogene.
Mostly there is no identifiable risk factor.
Constant Ag stimulation, infection, loss of T cell
function
Chronic Ag stimulation can cause lymphoma;
initially Ag dependent and eventually
autonomous (malignant)
Pathology Notes
Year 5
H pylori, gastric MALT, marginal zone NHL
stomach
Sjogren: marginal NHL of parotid
Coeliac small bowel T cell lymphoma EATL
(enteropathy associated T cell NHL)
HTLV1 infects T cells by vertical transmission,
chronic lifelong Caribbean and Japanese carriers
causing adult T cell leukemia lymphoma 2.5% at
70y
Immunosuppression and EBV; infects B cells,
healthy carrier state maintained by T cells
recognizing EBV Ag on B cells, suppression or loss
of T cels increases risk of B cell lymphoma. HIV,
60 fold increase, iatrogenic transplant, PTLD post
transplant lymphoproliferative disorder
Pathogenesis
BM production, enter lymph node to form mantle
cell where nave unstimulated B cells are, follicle
where B cells and DC interact, forms germinal
centres. T cells in paracortex. T cell area interact
with APC
Normal architecture lost in lymphoma
IHC stains using CD markers CD20 B, CD3 B
Neoplastic proliferation of lymphoid cells forming
discrete tissue masses. Arise in and involve
lymphoid tissue (acquired lymphoid tissue,
extranodal lymphoma)
Alice Tang
2017-2018
Hodgkin and non-Hodgkin lymphoma. NHLs are
either B cell type (commonest; low and high
grade), T cell type, other
Combination clinical, histological, IHC, molecular
data. Treatment and prognostic implications
Clonal neoplasm due to mutation in genes
allowing uncontrolled cell growth. Normal
lymphocytes instability produces mutations.
Inherited genomic instability, viral EBV/HIV,
environmental mutagens, H pylori, iatrogenic
radio/chemoTx, immunosuppression (infection
and loss of surveillance)
HIV takes away T cell function, releasing B cell
malignancy from normal control
EBV drives B cell proliferation
BL in HIV driven EBV infection
Hodgkin classic and lymphocyte predominant
subtypes. NHL B cell precursor/peripheral (low
and high grade), T cell precursor/peripheral
B NHL commonest 80-85% different stages
resembles normal counterpoint. Disseminated at
presentation (except HL or early NHL), may also
disrupt normal immune system and develop
immunodeficiency
Architecture: nodular/diffuse, small round or
cleaved (ALL), large centroblastic, immunoblastic,
plasmablastic
IHC used to identify proteins on cells in tissue
sections, labelled Ab to cell surface receptor
visible under LM section. T cell CD3, CD5; B cell
CD20. Cell distribution, loss of normal surface
proteins in neoplastic T cells, abnormal protein
expression secondary to specific chromosomal
abnormalities CycD1, B cell clonality light chain
expression
FISH to find translocations, PCR clonal TCR or Ig
gene rearrangement
Mantle cell lymphoma t11;14
Prognostic anaplastic large cell lymphoma
t2;5
Pathology Notes
Year 5
Histological grading, IHC, molecular studies
Common B cell NHL: low grade slow indolent
(follicular, small lymphocytic lymphoma/chronic
lymphocytic leukemia, marginal zone, mantle
zone
High graded diffuse large B cell lymphoma
Intermediate Burkitts lymphoma
Follicular lymphoma
Clinical LAD, elderly
Follicular pattern, germinal centers CD10,
bcl6
Molecular t14;18 bcl-2 gene brown staining in
follicle
Indolent but can transform to high grade
lymphoma (large rapid progressing)
Small lymphocytic lymphoma/CLL
Elderly, nodes or blood
Small lymphocytes sheets, nave/post
germinal center memory B cell, CD5, CD23
(abnormal) from nave B cells
Multiple genetic abnormalities
Indolent but can transform into high grade
lymphoma by Richter transformation
MALT lymphoma/marginal zone
Arise at extranodal sites (gut, lung, spleen)
In response to chronic Ag stimulation e.g. H
pylori in stomach
Alice Tang
2017-2018
Post germinal center memory B cell
Indolent but can transform into high grade
lymphoma
Treat low grade disease with non-chemo
modalities such as removing the Ag in H pylori
Mantle cell lymphoma
Male middle aged, LN, GIT, disseminated
disease at presentation
Mantle cell zone pre germinal ceter cell.
Aberrant CD5, cycD1 expression
Molecular t11;14 cycD1 overexpression
3-5y median survival
Burkitt lymphoma
Jaw/abdominal mass in children/YA
Endemic, sporadic, immunodeficiency
EBV associated, germinal center cell origin
with starry sky appearance; macrophages
with debris
Molecular c-myc translocation 8;14, 2;8, 8;22
Aggressive disease high mitotic rate
Diffuse large B cell lymphoma
Elderly, LAD, high grade, germinal center/post
Sheets of large lymphoid cells, mitotic figures
Germinal center phenotype = good prognosis
(IHC)
High proliferation fraction = poor prognosis,
p53 + good prognosis
T cell lymphoma (rare)
NOS, elderly, LAD, extranodal disease.
Background cells negative, brown stain for T
cells of different sizes
Large T cells associated with a reactive cell
population especially eosinophils
Aggressive
Pathology Notes
Year 5
Adult T cell lymphoma in the Caribbean and
Japan, HTLV-1 reaction
Enteropathy associated T cell lymphoma, some
patients with longstanding coeliac disease
Cutaneous T cell lymphomas mycosis fungoides
CD4 Th cells
Anaplastic large cell lymphoma in children/YA,
LAD, large epithelioid lymphocytes, bean shaped
nuclei, T cell or null phenotype. Molecular t2;5,
Alk-1 protein expression (better prognosis if
positive). Aggressive
Hodgkin lymphoma often at a single nodal site
spreading contiguously to adjacent LN
Nodular sclerosing
Mixed cellularity
Lymphocyte rich/depleted (some
relationship to NHL in lymphocyte
predominant)
Classic HL presents in young/MA involving single
LN group, germinal ceter/post germinal center B
cell origin, EBV associated, sclerosis, mixed cell
population with scattered Reed-Sternberg cells,
Hodgkin cells with eosinophils. Moderately
aggressive. Orphan Annie owl eye nuclei CD13,
CD15
NHL multiple LN sites, spreading discontinuously
Nodular LP Hodgkin lymphoma isolated LAD,
germinal center B cell, no EBV association,
histopathology B cell rich nodules with scattered
L&H cells, indolent, can transform to high grade B
cell lymphoma. Negative for CD13/15
Lymphoma practice: histology, anatomical stage
(CT, MRI, PET, BM biopsy), prognosis LDH, B2M,
albumin, kidney/BM function, prognosis,
cure/palliative
Classic HLL 1% of all cancer 3/100k, commoner in
males. Bimodal age incidence, 20-29 commonest,
young women commonly have the NS nodular
sclerosing subtype. Second smaller peak >60y
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2017-2018
elderly. Painless enlargement of LN, obstruction,
constitutional B symptoms of fever, sweats,
weight loss >10% in 6m, pruritus, alcohol induced
pain
Nodular sclerosing 80% good prognosis in
young women
Mixed cellularity 17% good prognosis
Lymphocyte rich (rare) good prognosis
Lymphocyte depleted (rare) poor prognosis
Nodular lymphocyte 5% elderly multiple
recurrences
Staging follows pathological diagnosis of LN
biopsy, stages have prognostic significance, best
approach for therapy. FDG-PET/CT scan, biopsy of
other infiltrated sites
Staging (Ann Arbor)
1. One group of notes
2. >1 group of nodes above same side of
diaphragm
3. Nodes above and below diaphragm (spleen is
considered a lymph organ)
4. Extranodal
Suffix A if none, B if any B symptoms: fever,
unexplained wt loss >10% in 6m, night sweats
FDG-PET CT stage dye is filtered but not excreted,
shows metabolically active groups of cells
Chemotherapy combination of drugs. HL is highly
responsive to radiotherapy, end of chemo to
involve a small area to target diseased nodes less
toxic to normal tissue. Combination treatment
ABVD Adriamycin, bleomycin, vinblastine, DTIC
At 4-weekly intervals, effective, preserves fertility
unlike MOPP, can cause long term pulmonary
fibrosis, cardiomyopathy. Chemo for ALL cases,
cure with chemo only is optimal, 2-6 cycles
Pathology Notes
Year 5
RTx involved smaller field low risk of relapse,
collateral damage to normal tissue. Breast Ca risk
1:4 after 25y, leukemia 3% at 10y, lung + skin
cancer
Combination treatment leads to greatest risk of
secondary malignancy, two mechanisms of DNA
damage. High dose rescue chemotherapy or
radiotherapy for relapse
Commonest cause of death is due to relapse,
however after 10 years of no relapse, causes of
death are related to treatment: second
malignancy (breast Ca) and cardiovascular events.
80% cure. Intensify will kill people with the
management
Lecture: Hematology of systemic disease
Jaundice and anemia, raised LDH in a patient with
lymphoma could be:
Lymphoma stage 4 with BM/liver involvement
Lymphoma with nodes compressing bile duct
with ACD
Lymphoma with acquired AIHA (indolent)
Anemia in cancer/systemic disease: Fe
deficiency, ACD, leucoerythroblastic anemia, HA,
secondary polycythemia (renal cell and liver
cancer)
Fe deficiency: occult blood loss in GIT, urinary
tract cancer (renal cell carcinoma, bladder
cancer), laboratory findings (low ferritin,
transferrin saturation, raised TIBC), bleed until
proven otherwise
Leucoerythroblastic anemia: variable degree of
anemia, teardrop RBC (anisopoikilocytosis),
nucleated RBC, immature myeloid cells
Lecture 6: Hospital acquired infections
Enormous social/clinical/economic impact,
around 1bn a year GBP, 15-30% preventable
C diff superbug large outbreaks, perception is due
to poor staff practice and dirty hospitals but
particularly virulent strain of C diff, 20x more
Alice Tang
2017-2018
toxin produced, resistant to rugs. Frail and elderly
patients
3.5-10.5% of hospitalized patients in
industrialised countries develop HAI
C diff and UTI are the commonest infections.
MRSA bacteremia, C diff diarrhea account for
15% of HAI. Consider by syndrome as well as by
organism
Hospital microbiome project: Acinetobacter and
pseudomonas were replaced by human skin
associated corynebacteria, staph, strep. 24h from
the patient to the room colonisation
Surveillance to find baseline rate, reduce HAI.
Reduced infection causes measuring, analysis,
feedback altering practice, improved infection
control practices
C diff is a G+ commensal anaerobe, even when
clean, patients are still more likely to get C diff if
they occupy that room afterwards
E coli bacteremia G- rod, catheters, not
handwashing, elderly care. Different issues in
different areas
Health and social care act, clean appropriate
environment, isolation, lab support, appropriate
treatment, adhered to policies/monitored,
standard to healthcare workers being free of
infection
Sterilize equipment, cleaning does not eradicate.
On patient, washing/skin prep and prophylaxis
for contaminated procedures, hand cleaning
Screen for MRSA, give topical suppression to
reduce carriage on skin. Reduce transmission of
bugs, better design of surfaces, prevent
adherence, using hand clearning products,
environment
Surgical site infections: wound envirnonment,
host defence, pathogens affect SSIs. Staph aureus
is commonest cause, certain cases use
prophylaxis Abx
Pathology Notes
Year 5
Influences on practice and behaviour: ward
layout, responsibility for cleaning, staff ratios,
clarity of roles, organization
Case 1: T2DM, HTN, hyperchol, IHD, PVD with L
below knee amputation, excess EtOH,
osteomyelitis, PICC line long vascular access,
urinary catheter, Abx induced thrombocytopenia.
3 MRSA bacteremias, uncontrolled source of
infection somewhere in the body. R groin
vascular graft remnant. MRSA 7 times more likely
to die
Case 2: CPE resistance, rapid spread, high
mortality. Carbapenemase producing
enterobactericae, increasing number. Outbreak
with Kleb NDM. Screen all patients on that ward.
Meropenem. Optimal management not known,
dose, polypharmacy, drug monitoring,
penetration. Adherence monitors, quick
discharge to remove reservoir from hospital
Upper Gastro-Intestinal Disease
Stratified squamous epithelium (oesophagus or
anus) at the top, muscularis mucosa, submucosa,
submucosal glands, muscularis propria (externa)
Normal esophagus Z line = gastroesophageal
junction/squamo-columnar junction. Irregular
and Z shaped. Pemphigoid and all skin diseases
can affect esophagus
Normal stomach has fundus and body specialized
mucosa, antral non-specialised mucosa. Surface
lined by mucous secreting gastric mucosa
columnar epithelium. No goblet cells, only
foveolar cells (mucin secreting). Specialized
glands in lamina propria (chief cells), muscularis
mucosa
Duodenum glandular epithelium with goblet cells
intestinal type epithelium. Villi to crypt height >
2:1, crypts get larger to try and generate more
villi
Disease of the esophagus
Inflammation (GORD mostly and Barretts),
neoplasia (carcinoma), varices
Alice Tang
2017-2018
Acute esophagitis: red, neutrophilic
inflammation, spongiosus oedema, like acute
eczema. Caused by reflux or NaOH
swallowing/chemical esophagitis. Reflux of acid
AND BILE SALTS (pH probe and endoscope),
ulceration (removal of mucosa, through
muscularis mucosae. Erosions are superficial)
causing necrotic slough, inflammatory exudate,
granulation tissue, results in fibrosis. Chronic
ulcer = when fibrosis occurs. Complications
include hemorrhage, perforation, stricture,
Barretts
Barretts: re-epithelialisation by metaplastic
columnar epothelium with goblet cells. Intestinal
type epithelium. Columnar lined esophagus (CLO)
Gastric metaplasia (non specialized)
+ goblet cells in esophagus = intestinal
metaplasia, more likely to become cancer (US
only this is diagnosed as BO)
Treat reflux to make metaplasia regress.
Dysplasia is the next step, changes and features
of Ca but no BM invasion. Adenocarcinoma =
invaded through BM. Low grade = treat
metaplasia and it will regress, high grade = must
follow up or intervene
Esophageal adenocarcinoma is the commonest
type in the UK. Forms glands, makes mucin,
mostly near GOJ bottom
Squamous cell carcinoma of esophagus,
associated with alcohol/smoking (all head and
neck squamous cancers). Commoner in the rest
of the world, mid
(commoner) or lower oesophagus, invades
submucosa
(keratin and intercellular bridges)
Prognosis is poor, diagnose quickly at pre invasive
stage
Esophageal varices commonest cause portal
HTN, then portal vein thrombosis. Enlarged
Pathology Notes
Year 5
thrombosed variceal focus. Little ulceration
needed to bleed, kills
Eosinophilic oesophagitis
Allergy, asthma spasm to food. Give steroids or
allergen removal
Stomach
Gastritis inflammation acute (acute insult,
aspirin/NSAID, HP, corrosives, shock
hypoperfusion, EtOH) neutrophils. Chronic
gastritis persistent insult (bile reflux, NSAIDs, HP,
chemical gastritis is in the antrum, AI is in the
body antiparietal), lymphocytes and neutrophils
Gastric cancer, MALToma, H pylori. No follicles
unless HP infection, induces follicles and germinal
centers. Lymphoma
HP spiral bacteria, motile. Chronic gastritis and
activity/acute inflammation. Results in CLO-IM-
dysplasia, adenocarcinoma, lymphoma
MALToma. Increased 8x risk of non cardia distal
antral gastric cancer, cag-A toxin+ HP needle like
appendage injects into intercellular junctions,
block apoptosis, bacteria attach easily, more
chronic inflammation. Teat with Abx to reduce
cancer
CMV, strongyloides immunosuppression. Ibd
Flat or polyp (adenoma-carcinoma sequence)
pathway. Flat pathway (metaplasia/dysplasia)
most important in stomach and upper GIT.
Chronic gastritis, intestinal metaplasia, dysplasia,
cancer (ulcer)
Acute ulcers due to infection or to cancer. All
ulcers biopsied to exclude Ca
Complications of ulcers include bleeding, anemia,
shock and massive hemorrhage. Perforation and
peritonitis
Intestinal metaplasia in response to LT damage,
increased risk of cancer. Gastric epithelial
dysplasia, abnormal growth, no invasion through
BM. Host genetic factors (Marshall Hall one acute
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2017-2018
one chronic), cagA toxic HP, environmental
smoking/diet, cancer phenotypes
Gastric cancer commoner in Japan, Chile, Italy,
China, Portugal, Russia, commoner in men, 95%
of stomach malignant tumours are
adenocarcinomas
Intestinal well differentiated
Diffuse poorly differentiated single cells with
no glands, signet ring cell carcinoma. Linitis
plastic
5% SCC, lymphoma/MALToma (treat HP if
infectious and MALToma will go away
otherwise progresses to large cell cancers),
GIST gastrointestinal stromal tumor like a
leiomyoma, but from interstitial cells of
Kerhull spindle cell tumor, neuroendocrine
tumors (anywhere in GIT)
15% survival
MALToma chronic immune stimulation in B cell
marginal zones, treat with HP eradication if
limited to stomach and HP is present
Duodenum
Inflammation duodenitis, HP, other pathogens
Duodenitis increased acid production driven by
HP spilling to duodenum. Chronic inflammation,
gastric metaplasia with HP infection. GASTRIC
metaplasia (loss of goblet cells) then get HP in
duodenum. DU correlation between zendoscopy
and biopsy pathology, 73.5% progress to ulcer,
erosive duodenitis with neutrophils
Others: CMV, cryptosporidium (children), Giardia
lamblia (Russia), Whipple disease Tropheyma
whippelii (macrophages)
Malabsorption partial villous atrophy, crypst
hyperplasia, increased intraepithelial
lymphocytes, normally 20 lymphocytes/ 100
enterocytes
Commonest cause is coeliac disease: needs
endomysial Ab, tTG Ab, biopsy of duodenum on
gluten rich diet shows villous atrophy, off gluten
shows normal. Other causes of villous atrophy
(nonspecific) tropical sprue (Zimbabwe)
Pathology Notes
Year 5
Duodenal MALToma/lymphoma associated with
coeliac, EATL T cell lymphoma
Malabsorption pernicious anemia
Lecture: Surgical Site Infections, Bone and
Joint Infections
Septic arthritis
Spinal osteomyelitis/epidural abscess
Epidemiology of SSI: 15.7% HAI were SSI, costs
$600m on knee/hip infections. Increased length
of stay (11d)
SSI major pathogens are S aureus (MSSA, MRSA),
E coli, P aeruginosa (bowel)
Contamination of wound at operation, depends
on virulence of bacteria (GAS>S epi) and host
immune response (DM, steroids)
Contaimination with over 10^5 per gram
increased risk of SSI, dose required is lower if
there is foreign material such as silk suture
Superficial incisional (skin, SC)
Deep incisional (fascia, muscle)
Organ/space (to joint space or organ)
SAH/SDH after a fall, decompressive craniectomy,
cranioplasty with titanium plate. Large subdural
collection, midline shift, abscess evacuation,
plates removed, severe infection with thick pus
1.5cm (G+ cocci) yellow colony on blood agar
hemolytic MRSA, start on IV linezolid
Prevention pre-op, intra-op, post-op
Pre-op: age independent risk factor, linear trend
until 65, treat remote infections, may require
postponement of op, underlying illness ASA 3+,
DM (2-3 times increased risk, post op
hyperglycemia, control glucose HbA1c<7),
malnutrition, low serum albumin, radioTx,
steroid/RhA DMARDs stop 4w pre-op, 8w post-
op, obesity adipose poorly vascularized with poor
tissue O2 and immune functioning. Smoking
duration/number, nicotine stop primary wound
healing, PVD, poor blood supply, pre-op
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2017-2018
showering , hair removal cardiothoracics shaving
increases SSI microabrasions, use electric clippers
with single use head. Nasal decontaomination
after screening (20-30%+), Abx prophylaxis at
induction, bactericidal in serum and tissues at
incision, additional doses if significant blood loss
or prolonged operation
Intra-op manage infected surgeons, low theatre
traffic, decrease bacterial load, ventilation PPV
towards outside to prevent contaminated air.
Dilute bacteria, 20 air changes per hour, 3 must
be fresh air, keep OR doors closed, laminar flow
for ortho implant surgery, skin prep chlorhexidine
70% EtOH, good technique, gentle handling,
eradiate dead space, adhere to asepsis placing
catheters or intravascular device. Normothermia.
Hypothermia increases SSI due to low O2, poor
neutrophil function, vascoconstriction, forced air
warming if below 36C. O2 >95%, higher inspired
O2 reduces SSIs
Septic arthritis 2-10/100,000. RhA, higher 28-38,
7-15% mortality. Risks include RhA, OA, crystal
arthritis, joint prosthesis, IVDU, DM, renal diease,
liver disease, trauma, immunosuppression
Organisms adhere to synovial membrane,
bacteria proliferate in synovial fluid, host
inflammatory response, exposure
Bacterial factors: S aureus fibronectin binding
protein receptors recognize proteins. Kingella has
pili. S aureus makes PVL toxin causes fulminant
infections (panton valentine leucocidin)
Host factors: leucocyte proteases/cytokines
degrade cartilage/bone loss, high pressure worse
flow, ischemia/necrosis. Deletion of MP cytokines
reduces host response, no IL-10 increases
severity of staph
Causes: S aureus (46%), Streo, G-
1-2w red, painful, swollen, restricted joint. 90%
monoarticular, 50% knee, culture before Abx,
synovial fluid aspiration for MCS, ESR, CRP, >50k
WBC suggests septic arthritis. USS effusion
needle guided aspiration, contiguous
Pathology Notes
Year 5
osteomyelitis MRI, CT. Abx no data on duration,
usually 4-6w IV Abx, OPAT, joint washout
Vertebral osteomyelitis acute hematogenous,
exogenous after disc surgery, implant associated.
S aureus commonest, CNS, GNR, strep. At the
lumbar spine usually, or cervical. Back pain, fever,
neuro impairment. Diagnose with 90% sensitive
MRI, blood culture, CT/open biopsy, 6w Tx longer
if undrained abscess/implant
76M 4/12 back pain, down L leg, 25kg weight loss
6m, R femur fracture with metal plate, R knee
arthritis, HTN, discitis L2/3, biopsy, tissue culture
showed CNS vague granuloma, empirical anti TB
R+E, empirical ceftriaxone IV, debrided and
stabilized, PCR serology showed Brucella start
rifampicin, Cipro, doxy. Less well defined Brucella
granuloma silver colonies on culture
Patient febrile fell off ladder, Salmonella, Cipro,
readmiteed fever, loss of appetite, Cipro
resistant, discitis L1/2, paravertebral collection,
azithro 6m, fever HTN, Salmonella. Given azithro
and mero, then switched to ceftriaxone
(sensitive), debride and stabilize
Chronic osteomyelitis causes pain, Brodies
abscess, sinus tract. Dead bone and new bone
formation. Diagnose with MRI, bone biopsy.
Radical debridement down to libing bone,
remove all infected bone and soft tissue.
Lautenback technique. Remove all internal
fixation, double ended reaming, double lumen
irrigation Abx in central lumen, Hartmans infused
through drain, fluid sent for culture, oral Abx for
6w post discharge, at 101 months, 26/35 cured
Papineau technique, excise, open cancellous
bone fraft, skin graft for wound closure, 93%
success
Prosthetic joint infections
Pain, joint was never right since op, early failure,
sinus tract. CNS > S aureus, G- possible
Radiology loosening, bone loss next to prosthesis,
CRP >13.5 knee >5 hips suggests infection.
Alice Tang
2017-2018
Aspiration, >1700 WBC, hips 4200 suggests
infection, lab for culture
Intra-op micro sampling, tissue from 5 sites
around implant, histo >5 neut per high power
field. 3+ identical organisms = infection
Single stage revision to remove all foreign
material/dead bone. Change gloves/drapes,
reimplant new prosthesis with Abx impregnated
cement, IV Abx
Endo Klinik single stage, aspirate, excise, Abx,
implant with Abx loaded cement, IV Abx
Two stage revision: remove prosthesis, samples
for micro, spacer in joint IV Abx 6w, stop for 2w/
redebride and sample, reimplant with Abx
impregnated cement, no further Abx if samples
clear, OPAT
70F R-THR, revision later on, XR lysis around
distal femoral component, DM
Lecture: Introduction to MPD, CML
Dr Donald MacDonald
Myeloproliferative disorders
Polycythemia and raised Hb
Hct relative nonmalignant (lack of plasma) or true
(excess RBC) secondary non-malignant or primary
myeloproliferative
MPD neoplasm Ph chromosome negative
(polycythemia vera, essential thrombocythemia,
primary myelofibrosis), Ph+ CML
FBC Hb 135-175g/l, Hct 0.56 (0.41-0.53)
N 40% plasma 60% RBC
High RBC mass true: elevated EPO, primary
low EPO
Low plasma volume relative: alcohol,
obesity, diuretics
True secondary poly: appropriate/inappropriate
Appropriate to improve O2 carrying capacity
of the lung: altitude, hypoxic lung disease,
Pathology Notes
Year 5
cyanotic heart disease (Eisenmengers shunt),
high affinity Hb
Inappropriate: renal disease (cyst, tumor,
inflammation), uterine myoma, other
tumours (liver, lung). No hypoxia, but excess
EPO is produced
Myeloid
AML blasts >20%
Myelodysplasia 5-19% blasts
Myeloproflierative disorders
o ET (megakaryocyte)
o PV (erythroid)
o Primary myelofibrosis
CML
Mutation will impair cell differentiation (type 2),
cell proliferation (type 1), prolong cell survival
(anti apoptosis). Mutations include point or
chromosomal translocation forming fusion gene
or disrupted protooncogene. Myeloproliferative
neoplasia favours proliferation of mature cells.
Differentiation pathways unaffected; increased
numbers of mature cells. In contrast, acute
myeloid leukemia excess of immature cells due to
loss of differentiation capacity, failure of
maturation
MPD Philadelphia chromosome+
JAK2 calreticulin and MPL (PV, ET, PMF)
comstitutively active signal
PV 2-3/100k more in males, mean age 60y, 5%
below 40, incidental raised Hb on FBC routine
test. Increased hyperviscosity headache, light
headedness, stroke, visual change, fatigue, SOB.
Increased HA release causing aquagenic pruritus,
peptic ulceration.
Variable splenomegaly, plethora,
erythromelalgia, thrombosis, retinal vein
engorgement, gout
Treat with venesection, cytoreduction
hydroxycarbamide reduce risk of stroke. If frail,
give aspirin, keep plt low
ET MPM involving MGC plt >600, incidence
1.5/100k
Alice Tang
2017-2018
Primary myelofibrosis
JAK2+, BM aspirate dry tap due to intense
fibrosis, weight loss, abdo pain,
hepatosplenomegaly, Hb low, WBC high, plt low.
Leukerythroblastic (can be mets BC) infiltrated
BM
CML: more in males, 40-60y weight loss, lethargy,
night sweats, splenomegaly, features of anemia,
bruise/bleed, gout. High RBC, granulocytes,
basophilia. Blindness in one eye CVA thrombosis
from hypermetabolism. Hepatomegaly
Blood film shows leukocytosis 50-500x10^9,
mature myeloid cells, biphasic peak slightly older,
neutrophils and myelocytes, basophils, no excess
myeloblasts <5%, plt raised
Natural history chornic phase, 80% chronic phase
4-5y, nearly 80% progress to accelerated phase,
10-19% blasts, blast crisis >20% blasts in blood
and bone, marrow blast cells
Ph t(9,22) smaller than normal bcr-abl only in
malignancy, expresses fusion oncoprotein with
RTK activity, only in BM occurs in introns, identify
on FISH. RT-PCR can quantify bcr-abl to
determine response to therapy 5 bcr 3 abl
normal = cannot amplify in these cells. In CML,
fusion transcript cDNA contains 5 bcr and 3 abl
so the fusion gene will be produced
Measure residual leukemia markers: haem
response leucocyte count drops (200
hydroxycarbamide to normal 10), reduce
perceptange of Ph metaphases with cytogenetics
response, Ph+ 0.001 residual leukemia cells, RT-
PCR effectiveness monitoring to undetectable
(log reduction bcr-abl to abl ratio) molecular
response 3 log reduction <0.1%
Oral active TKI abl kinase inhibitors: 1st
generation imatinib (glivec), 2nd generation
dasatanib, nilotinib. Allogenic BM transplant 20%
mortality 80% survival at 5y on imatinib with
complete molecular response. Sfx fluid retention,
pleural effusion, resistance or stem cell Tx
Pathology Notes Alice Tang
Year 5 2017-2018

Myelodysplastic Syndrome (MDS) and

Idiopathic/Inherited Aplastic Anemia

MDS group of acquired haematopoietic stem cell

disorders 4/100k, clones of marrow stem cells
with abnormal maturation resulting in
functionally defective cells AND a numerical
reduction (low neutrophils in particular poor
function). Large workload for hematology due to
ongoing care needed.
cytopenia, qualitative abnormalities of
erythroid, myeloid, megakaryocyte maturation,
increased risk of transformation to leukemia
Disorder of the elderly, general marrow failure,
develops over weeks and months
Pelger-Huet anomaly abnormally bilobed
nucleus (usually many)
Dysgranulopoiesies of neutrophils
Dyserythrpoiesis of RBC, still joined by a small
bridge suggesting dysplasia, cytoplasmic
blebs, ringed sideroblasts (Fe Prussian blue
stain for hemosiderin accumulated in
mitochondria)
Dysplastic megakaryocytes (micro-MKC)
Increased proportion of blasts in marrow
(normal <5%), myeloblasts with Auer rods =
leukemia, nucleolus also seen. Allowed a few
blasts <5%. >20% blasts = AML
Myelokathexis neoframentation of lobes of
nucleus (rare)
Some drugs can only be justified because of
objective criteria rather than clinical judgment
Evolution: deterioration of blood count, develop
AML in poor cases (<1y), extremely poor
prognosis, usually not curable. 1/3 die from
infection, 1/3 die from bleeding, 1/3 die from
acute leukemia
Treatment: allogeneic stem cell transplant OR
intensive chemotherapy, only a minority benefit
due to age related comorbidities
1. Supportive care blood products
2. Biological modifiers: immunosuppressants,
azacytidine, lenalidomide, decitabine
3. Oral chemotherapy:
hydroxyurea/hydroxycarbamide, low dose
cytarabine, intensive chemo/SCT AML
regimen, reduced intensity/allo
Aplastic anemia (idiopathic)

WHO classification of MDS pre-2016 FAB

classification based on number of blasts in BM.
<5% refractory anemia +/- sideroblasts (5q-
syndrome responds well to treatment), 5-9%, 10-
19% more likely to get to AML, cytogenetic
abnormalities goes up with the increased number
of blast cells except 5q- deletion (by definition)

Revised international prognostic scoring system

(IPSS-R) in MDS BM failure can be primary or secondary
(commoner)
Primary causes:
1. Congenital: Fanconi anemia (multipotent
stem cell)
2. Diamond-Blackfan anemia (RBC precursor)
3. Kostmanns syndrome (neutrophil progenitor)
Pathology Notes
Year 5
4. Acquired: idiopathic AA (multipotent stem
cell)
Secondary causes:
1. Marrow infiltration
2. Haem/non haem solid tumours
3. Radiation
4. Drugs: cytotoxics, phenylbutazone, gold salts,
antibiotics (chloramphenicol, sulphonamide),
diuretics (thiazide), antithyroid (carbimazole).
Chemicals
5. AI, infection
Primary BM failure damage of stem/progenitor
cells: pluripotent or committed progenitor (uni/bi
cytopenia)
Idiopathic AA is very rare 2-5/million/year
Bimodal age incidence, 15-24 and >60y
Vast majority 70-80% idiopathic
Inherited: DC, Fanconi anemia, Shwachman-
Diamond syndrome
Immune mediated BM failure due to clonal
hematopoiesis, immune attack through CTLs,
most have somatic mutations or structural
chromosomal abnormalities
Triad of BM failure:
Anemia, fatigue, SOB, palpitations (better
indicator)
Leukopenia increased infection
Platelets easy bruise/bleed
Blood cytopenia, hypocellular BM. Classified as
severe or non severe (SAA/NSAA)
Alice Tang
2017-2018
Replaced by fat, few cells (mostly lymphocytes
and stem cells). 50% cellular
Differential diagnoses of
pancytopenia/hypocellular marrow: hypoplastic
MDS/AML, hypocellular ALL, hairy cell leukemia,
mycobacterial infection, anorexia, ITP
Severe AA
2/3 peripheral blood features. Low reticulocytes
<1%, low neutrophils <0.5 (<0.2 very severe), plt
<20, BM <25% cellularity
Management of BM failure:
Seek a cause (benzene)
Supportive blood transfusions
(leucodepleted, CMV neg, irradiated), Abx,
iron chelation therapy when ferritin>1000,
250mg Fe builds up (heart, liver, pancreas,
parathyroids)
Marrow recovery with androgens
(oxymetholone, danazol), growth factors.
Immunosuppression (CTL AI response
reduction), stem cell transplant, gene
therapy?
Specific treatment based on severity (older =
antilymphocyte globulin ALG, cyclosporine),
adnreogens. Younger patient with donor 80%
cure by sibling, VUD/MUD>40y 50% survival.
Late complications
Relapse AA 35% 15y, clonal disorders: MDS
leukemia, PNH, Solid tumours 3% risk
Pathology Notes
Year 5
Inherited AA
Fanconi anemia commonest form of inherited
AA, AR or X-linked, heterozygote may be 1:300,
multiple mutated genes, cell repair of broken
DNA, chromosomal fragility increased in presence
of in vitro mitomycin/diepoxybutane
Normal count at birth, BM
failure/pancytopenia slowly from 5-10
onwards
10% acute leukemia
Supportive/androgen treatment )but hepatic
toxicity)
Short stature, hypopigmented spots, caf au
lait spots, abnormal thumbs, microcephaly,
hydrocephaly, hypogonadism, developmental
delay
30% normal
90% end up with AA
Dyskeratosis congenita telomeric shortening. BM
failure, predisposed to cancer, somatic
abnormalities in skin pigmentation, nails,
leukoplakia. Supportive, marrow recovery
(oxymetholone/GF), SCT, gene therapy
3 patterns of inheritance, abnormal
structure and function
telomeres at the end of chromosomes to
prevent fusion/rearrangement, protect
genes from degradation
Reduced in BM failure disease DC
Many AD TERC/XLR DKC1, AR
Postmortem Study Day
Inspection and evisceration (Mike Osborne)
Inspect as if alive, check nametag, measure and
document scars (CABG), look at vein harvest
saphenous vein bilateral scars. Hip replacement
scar. Incision from adams apple to pubis. Bloody
ascites and pleural effusions, visceral and parietal
pleura fills with fluid
Bowel perforation feculant, tumours would
see/feel, ischemia. Diverticular disease in this
patient
Pericardium becomes adherent to the heart with
any CABG/surgery/myocarditis on the heart.
Usually like a bag and comes off easily. Grafts are
Alice Tang
2017-2018
prone to atheroma, but this healthy looking graft
doesnt seem to be the cause of death (radial
artery, internal mammary artery also used for
grafts)
Very large heart, LV down graft. LV circular, some
fibrosis and some hemorrhage occurring with
ischemic damage. RV is crescentic. Dilated LV,
HTN disease, no valvulopathy. Hypertrophy and
thickens to work harder, then ventricle dilates
and wall thins. End stage HTN heart disease and
IHD (550g) normal mans heart 350g white pale
fibrosis with infarction
Nutmeg liver shows congestive cardiac failure,
ruptured MI
Lungs/brain ripe for metastasis huge blood
supply, especially LN, tumour, embolism?
Damage to lung parenchyma, pneumonia,
abscess, tumor, pulmonary edema
Mesothelioma thickened pleura. Malignant.
Primary hilar LAD. Breast/colon primaries. Many
small = mets, pulmonary embolus. Millary TB
pockets of infection small abscesses
Fibrosis, infection, inflammation, perforation,
adhesions to bladder, vagina leading to fistulae.
Low fiber western diet
Esophageal varices at the gastroesophageal
junction. Cancers mostly here. H pylori and ulcers
in antrum (bleed, perforate)
Pancreas: commonest cause gallstones and
alcohol, scorpion. Melanoma mets everywhere.
Liver cirrhosis, fatty change
Mets also to bone, commonest cause of #NOF is
osteoporosis in elderly women. Breast and
prostate cancer result in tumour deposits
weakening bone --> pathological fracture
White wedge shaped ischemia, any stones in
kidney collecting duct, tumours of TCC. HTN
scarring in kidney parenchyma, IHD, benign cystic
change
Pathology Notes
Year 5
Postmenopausal women, poor prognosis. Tumors
with late presentation ruptured pregnancy in
ectopic
Teratoma commoner in younger people
Bell clapper test spermatic cord, horseriders
EDH lucid period then dies 6h alter, arterial bleed
over time and pressure makes them go
unconscious
SAH berry aneurysm
Mets in brain commonest cancer: breast, lung,
gut. Primary tumors uncommon, never met
outside the brain. Melanoma black tumor
Completing the medical certificate of cause of
death
Section 1a actual immediate cause of death, 1b
led to 1a, 1c led to 1b, 2 contributing factor but
did not directly cause the death
1a MI
1b Coronary artery atheroma
2 Diabetes, HTN
1a PE
1b DVT
1c #NOF
1a Hypertensive and ischemic heart disease
1b HTN, coronary artery atheroma
Mode of death: X failure (crem forms: cardiac,
respiratory, renal failure), avoid modes of death
on death certificate on its own
Underlying cause, there are a myriad of
causes of cardiac failure, doesnt tell you
anything
Respiratory failure: T1 or T2 is a 1a cause,
specific mechanisms of dying with different
underlying causes of lung disease. Or just
leave the failure out
Renal failure: SLE, AKI/CKD due to diabetes,
need to give underlying cause
Alice Tang
2017-2018
86F T2DM, dementia, fall #NOF, surgical Tx, good
recovery, collapsed post-op
1a PE
1b DVT
1c
76M T1DM, AS, sudden collapse at home
1a Stroke
1b Embolus from MI
64M boiler maintenance, smoker, cough 2y,
haemoptysis at home 1L
1a Hypovolaemic shock
1b Lung cancer
2 Asbestos and smoking
Asbestos increases risk of lung cancer too,
multiplicative effect with smoking. It needs to be
referred to the coroners court
78F SLE, L weakness and paralysis, poor swallow,
paralysis, deteriorates with tachypnea,
tachycardia, dies
1a Aspiration pneumonia
2a Stroke
Haem-Onc diagnosis
NHL: neoplastic lymphoid cells in lymphoid tissue,
200/million, Burkitt lymphoma is the most
aggressive (rate of disease progression 24h
doubling rate). Indolent disease 25y survival
Presents with painless LAD, compression, B
symptoms (splenomegaly)
Stage the disease (Hodgkin lymphoma) CT, PET,
BM biopsy, LP if risk of CNS involvement
Prognostic markers: LDH (intracellular rapid
turnover high), HIV/HTLV1/HepB may reactivate
if B cell depletion is given
Urgent chemo, monitor. Subtypes include
follicular, SLL, marginal, diffuse large B cell, BL,
BLL, mantle cell. Different frequencies (HTLV1
Japan Caribbean) HTLV1 transverse myelitis
tropical sprue
Pathology Notes
Year 5
Histology predicts clinical course
BL, T/B LL very aggressive (high grade), diffuse
large B cell, (high grade) mantle aggressive,
follicular, CLL, gastric, parotid, thyroid MALT
indolent (low grade)
Without treatment, 2-5w survival without
treatment if very aggressive (curable)
Aggressive 3-12m
Indolent 10-15y (incurable)
Very aggressive treat as an acute leukemia with
chemotherapy protocols
DLBCL aggressive B cell NHL, 30-40%, histological
diagnosis, stage, international prognostic index
IPI age>60, serum LDH, performance
status, stage , 1+ extranodal site
predicts 5 year survival
Same Ann Arbor scoring for stage
Cure 60% of all patients
Combination chemotherapy (different
mechanisms): rituximab-CHOP, include
anthracycline (doxy)
Cyclophosphamide
Adriamycin
Vincristine
Prednisolone
Immunotherapy antiCD20 rituximab, 50%
curative, in relapse autologous stem cell
transplant salvage 25%
Follicular NHL indolent 35%, t(14,18)
overexpresses bcl2 constitutive expression anti-
apoptosis. FLIPI score (IPI mod), incurable 12-15y
survival, 2-3 chemo schedules over this time
period. Block SVC obstructive symptoms, each
response is shorter and less responsive to chemo
MALT lymphoma is a marginal zone NHL with
extranodal lymphoid tissue 8%, chronic Ag
stimulation
Sjogrens parotid (MZL)
H pylori gastric MALT (MZL)
Hashimoto thyroid (MZL)
Lacrimal gland (Psittaci infection)
Presents 55-60, in stomach with
dyspepsia/epigastric pain, at stage Ie, B
Alice Tang
2017-2018
symptoms are rare. Methylation of p15, p16
t(11,18) resulting in transformed cells Abx
sensitive MALT, Ag independent = Abx
insensitive. Breath test at 2m, repeat endoscopy
6m for 2y, then annually, 75% remission,
response may take a year
CLL chronic lymphocytic leukemia (SLL)
Proliferation of mature B cells, commonest
leukemia in west, Caucasians, 4.2/100k in UK at
72y median, relatives 7x increased incidence
Lymphocytosis 5-300 x 10^9, smear cells (fragile
and break open on smear), normocytic
normochromic anemia, thrombocytopenia, BM
lymphocytic replacement of normal marrow
B cells are always HLA-DR+, some Ag: CD 19, 22
present through most of B cell life
TdT lymphoblast. Enzyme causes nucleotide
substitution, somatic hypermutation at VD
joining point, changes aa to refine specificity
of Ab. EARLY LIFE
Cy-Ig pre-B cell
CD5 intermediate B cell
Normal B cell CD19+CD5-
CD5 T cell, CD5+CD19-
1. High WBC TdT+ ALL immature blasts
2. Small mature/smear cell
a. Mature B, C5+ mantle
b. CLL
Clinical Rai/Binet staging, CD38 bad prognosis,
cytogenetics with FISH, IgH mutated VH
44%/unmutated VH 56%. Class switching, somatic
hypermutation. Unmutated worse survival (8y)
whereas postgerminal center mutated better
25y. Powerful prognostic factor
FISH cytogenetic panel normal, 13q del, trisomy
12, 11q del (ATM), 17p del (TP53) worsening
survival in these common aberrations
Lack of health Ig increased risk of infection,
sinusitis, pharyngitis (sinopulmonary infections),
BM effacement and failure. Circulation to nodes,
spleen, blood. High grade Richter transformation
1% treat with CHOP-R. if more mutations are
Pathology Notes
Year 5
acquired. Disease of immune cells relating to AI
complications (HA)
Commonest leuk in west: supportive, specific,
treatment: vaccinate against pneumococcus, flu.
NOT against VZV live vaccine. Anti infection
prophylaxis
Aciclovir prophylaxis
PCP for those on fludarabine,
alemtuzumab
Hpogammaglobulinemia sinopulmonary,
give IVIG
AI 1st line steroids, 2nd line rituximab, irradiated
blood products if risk of TA GVHD
Treatment for CLL
Not to treat stage A, incurable by chemo; go-go
(55) or no-go (90) years. Aim to obtain
response/remission, disease will relapse, 2nd line
therapy. Young cured with allogenic SCT
Watch and wait unless progressive
lymphocytosis doubling time <6m,
progressive BM failure Hb<100, plt <100, neut
<1, splenomegaly/LAD, B symptoms, AI
cytopenia (steroid treatment)
1st line chemo (tp53 intact)
FCR most intensive fludarabine,
cyclophosphamide, rituximab
R-bendamustine
Obinutuzumab anti CD20 + chlorambucil
Supportive only
High risk case: tp53/17p deletion,
refractory/early relapse <24m, failed 2 lines
chemo. New agents: ibrutinib, (Bruton TKI),
idelalisib (PI3K), benetoclax anti bcl2 oral
MALT NHL marginal zone subtype
Potassium Handling
Dr Amir Sam
Most abundant intracellular cation, 3.5-
5.0mmol/L in serum. Haemolysis very high K,
aldosterone stimulates K loss
Alice Tang
2017-2018
Renin made in JG cells, cleave angiotensinogen to
make AT1, to AT2 by ACE in lung capillaries. AT2
stimulates aldosterone release from adrenals,
stimulates K excretion in urine/Na retention
HyperK is a stimulus for aldosterone release
Principal cells of cortical collecting tubule; Na
enters, K lost. Aldosterone binds MCR, increases
Na channel expression, more Na reabsorption,
makes lumen negative. K moves down electrical
gradient secreted into lumen
MR increases expression of SGK (serum
glucocorticoid kinase), to Nedd4 (Na channel
degradation), inhibition increases Na channels
(ubiquitination), more K loss
Aldosterone is stimulated by AT2 and K
Main causes of hyperK:
Reduced GFR, renal failure, not excreting
K. Hyponatremia (not excreting water)
Low renin (type 4 renal tubular acidosis,
diabetic nephropathy, NSAIDs)
ACEi/ARBs (amiloride)
Addison disease
Aldosterone antagonists (eplerenone)
Rhabdomyolysis
Acidosis (H/K exchange) H enter to correct
acidosis so K moves out
1. Renal impairment (U, Cr)
2. Drugs
3. Low aldosterone/Addisons
4. Release from cells (rhabdo, acidosis)
Tented T waves on ECG, not specific, can be high
takeoff, broad QRS, arrhythmia, VT
Management:
1. 10ml 10% calcium gluconate
2. 50ml 50% dextrose + 10u insulin
3. Nebulised salbutamol (b-agonist)
4. Treat underlying cause
Hypokalemia causes:
GI loss D+V
Pathology Notes
Year 5
Renal loss: hyperaldosteronism (excess
cortisol Cushings), increased Na delivery
to distal nephron, osmotic diuresis
(uncontrolled DM)
Redistribution into cells: insulin, beta
agonists, alkalosis. Driving K into cells.
Refeeding syndrome drives K back into
cells (feed slowly, monitor)
Renal tubular acidosis type 1, 2, Mg
Clinical features hypoK
Muscle weakness, cardiac arrhythmia, polyuria,
polydipsia due to nephrogenic DI
Primary aldosteronism suppresses renin, use A:R
ratio. HTN and hyperkalemia in a patient
Management hypoK
Serum K 3-3.5 oral KCl (2 SandoK tablets tds
48h), recheck serum K
Serum K <3 give IV KCl max rate 10mmol/h rates
higher than 20 irritate the peripheral veins, need
to be given centrally
Treat underlying cause (spironolactone)
LoH Na K Cl absorption, Na delivered distally
more in the DCT enters cells, K moves out. Bartter
syndrome (mutation), loop diuretics. Give
amiloride to lock Na absorption. Thiazide and
Gitelman syndrome
High aldosterone increases K loss
Hypovolemia ADH hyponatremia, excess
water retention (dilutional) . Hypovolemic
hyponatremia. Manage case 1 with 0.9% saline,
stop diuretic
HF baroreceptors stimulated from low CO. fluid
restriction, treat cause
Vasodilated, low BP, stimulates ADH release.
Excess NO in cirrhosis. Treat with fluid restriction,
treat underlying cause
Hypothyroid low cardiac contractility euvolemia,
give thyroxine
Alice Tang
2017-2018
Addisons low aldosterone, losing volume
Secondary (cortisol deficiency) cortisol inhibits
ADH so if cortisol deficient, increases.
Hyperkalemia (low aldosterone less Na
absorption)
Aldosterone doesnt change concentration
(absorb Na and water, will not have
hypernatremia with hyperaldosterone)
Short Synachtn test, give fludro
SIADH no hypovolemia, no adrenal insufficiency,
reduced plasma osmo, increased urine osmo
>100: CNS, lung, drugs, tumor, surgery. SSRI, TCA,
opiate, PPI, CBZ
DI ADH deficient
Hypernatremia:
Unreplaced water loss: GIT loss and not drinking,
sweat (marathon runners, drink loads, make
more ADH), renal losses osmotic diuresis low ADH
release/action (DI). Check serum glucose DM is
commoner, high Ca/K resistant to ADH
nephrogenic ADH (less action), plasma/urine
osmolality, water deprivation test
High K renal failure low GFR and ACEi
High BP, low K A:R ratio
Metabolic Bone Disease
Mechanical support/muscle attachment,
protective, metabolic (Ca store). Difficult to
biopsy, need to decalcify bone to look at the
components
Inorganic 65%, organic 35%
Site predilection: which bone and where
Epiphysics (growth plate to end of bone),
wide part is metaphysis, diaphysis long
tubularbone
Periosteum blood supply delivery on the
outside, damage = necrosis
Ill defined lytic lesion in humerus
Well circumscribed, soap bubble expanding bone
Pathology Notes
Year 5
Cancellous bone high surface area no BV
Cortical bone microanatomy strengthened
concentric lamellae. Inside is trabecular
Cortical bone with BV
Osteoblast builds bone down osteoid
Osteoclasts multinucleate chew bone
Osteocyte communicate between the two,
canaliculi
React in response to
hormones/vitamins/mechanical stimuli.
Osteoprogenitor cells: RANKL/OPG complex. OPG
competes with RANK to turn off bone resorption
at menopause, estrogen and OPG fall, increasing
bone resorption. Tumors take advantage, GF to
cause bone resorption. Prostate Ca forms
cytokines to cause bone formation
Immature or mature, woven/lamellae, flat or long
bones (intramembranous ossification)
Mature lamellar and immature woven indicating
bone destruction and remodeling (only at base of
tooth), otherwise pathological
Disordered bone turnover due to imbalance of
chemicals, loss of bone mass (osteopenia)
fractures with little trauma, cannot get out of
seat, bone pain, inflammation
1. Non endocrine (age related OP)
2. Endocrine (VitD, PTH)
3. Disuse osteopenia, low movement
localized or generalized
Bone biopsy from iliac crest usually, cortical
thickness, porosity, trabecular bone volume,
thickness, number/separation of trabeculae.
Usually added to acid, this removes calcium
morphology (need to be undecalcified)
Goldman stain = mineralized or osteoid bone,
tetracycline labelling normal bone shows tram
track at mineralization front. When disrupted
there is a problem with mineralization. Immature
bone in children turns teeth black,
contraindicated
Alice Tang
2017-2018
Osteoporosis
Primary: age, post menopause
Secondary: drugs, (epilepsy, thyroid), systemic
disease
Reduced bone mass, high turnover increased
bone resorption, low turnover from low bone
formation
Nutrition/social factors; EtOH, smoking,
malabsorption, VitC/D deficiency
Endocrine abnormality hyperT, hyperPTH,
Cushing, DM
Immobilisation
Iatrogenic drugs
Risks include: age, female, smoking, EtOH,
menocause, immobility, low T, thyroid, steroids
(osteonecrosis and fracture)
1/3 women, 1/12 men >50, 50% cannot live
independently, 20% die with fractures
Nonspecific back pain, compression fracture
through vertebrae/NOF, Colles fracture FOOSH,
60% dont know they have a vertical fracture
T11/L2 area
HOLES IN THE BONE
Lab: serum Ca, Phos, ALP (N), urine Ca, collagen
breakdown products. DEXA >2.5SD below
Mineralisation is normal
PTH bone, kidney, SI
VD hydroxylation liver/kidney problem with
metabolism and get hyperPTH. Bone breakdown,
GIT increase Ca and kidney excretion
Osteomalacia defective bone mineralization,
deficiency of VD OR Phos. Too much osteoid, thin
bones on X-ray because it cannot be seen if it is
undermineralised. Bone pain and tenderness,
fracture, proximal weakness, bone deformity.
Rickets bowed legs. Horizontal fracture in Looser
zone pseudofracture
Pathology Notes
Year 5
HyperPTH increased Ca/phos excretion in urine,
hyperCa, hypoPhos in blood, skeletal osteitis
fibrosa cystica. Bones feel hot and swollen
Stones
Bones
Groans
Moans
Renal osteodystrophy
Skeletal changes of CKD AND increased bone
resorption (OFC), OM, osteosclerosis, growth
retardation, OP. Or a combination
OFC holes in the bones
Pagets osteolytic, then osteosclerotic eventually.
OC first breakdown, then OB fight back, then
crazy paving mosaic biopsy
Onset >40y, equal gender, rare in Asians/Africans
monoostotic 15%, remainder poly. Unknown
aetiology, familial autosomal incomplete
penetrance 5q35 mutation sequestosome gene
Site predilection bone pain in back, pelvis, skull.
Pain, microfractures, nerve compression SN/cord,
medulla at risk with skull changes, hemodynamic
changes/CO enters abnormal bone with HF.
Sarcoma in 1% in young people <20 normally, but
Pagets anyone, deformation of the bone doesnt
respond to gravity normally
Bone biopsy if suspected OM, diagnostic
classification of renal osteodystrophy, osteopenia
in young <50, or abnormal Ca metabolism,
hereditary childhood bone disease. Evaluate Tx
Allergy
Oral route promotes immune tolerance, skin
induces IgE sensitization
Disruption of skin: atopic dermatitis in children,
or pellagrin gene mutation, more leaky skin.
Allergen can access dermis, DCs in skin tend to be
more effective than other subsets in making T
cells secrete IL-4,5
Alice Tang
2017-2018
LEAP study 2015 showed in children at high risk
of peanut allergy (atopic dermatitis) early
introduction led to a reduction in peanut IgE
sensitization and allergy. Gut and tolerance,
exposure in the skin and IgE Ab to peanut
IL-33 is not a target for drugs
Onset for allergic disease:
Infant atopic dermatitis, good allergy
Childhood asthma, allergic rhinitis
Adult drug, bee, oral allergy, occupational
Prevalence increasing in eczema, asthma, food
allergy, anaphylaxis, hospital admission. More
fast food consumed, high fructose, obesity
associated with allergy. High in glycated
proteins/sugars seen as harmful by the immune
system, cause harm IgE
Hygiene hypothesis, lack of VitD in infancy
increases risk of food allergy, low omega/linoleic
fatty acids, diet advanced glycated end products
Clinical features of IgE allergic responses
Minutes to 3h after exposure
Angioedema, urticarial wheals/hives,
flush, itch, cough, SOB, sneeze, D+V,
hypotension, doom
2+ organ systems involved
Reproducible, triggered by exercise,
alcohol, infection
Skin prick or blood tests
Not associated with fatigue, migraine, abdominal
pain/D/C/bloat, hyperactivity, depression,
variation with dose
Investigations: skin prick test, lab measure
allergen specific IgE, component resolved
diagnostics, challenge test with supervised
exposure. Acutely, evidence of mast cell
degranulation with serum mast cell tryptase
levels
Skin prick test exposure patient to standardised
solution of allergen to the forearm, use a positive
control (HA) and negative control (diluent)
measure local wheal and flare responses. Positive
Pathology Notes Alice Tang
Year 5 2017-2018

if wheal >3mm over negative control. Stop NEUROPSYCHIATRIC: Anxiety or panic disorder
antihistamines for 48h beforehand, more specific
and sensitive than blood tests. ENDOCRINE: carcinoid and phaechromocytoma

Rapid, cheap, easy, high NPV >95%, large wheal = TOXIC: Scromboid toxicity (Histamine poisoning )
more allergy, patient can see the response. Small
risk anaphylaxis, high false positives. Track IgE IMMUNE: Systemic mastocytosis
allergy concentrations, outgrow allergy? Safe for
oral food challenge? Monitor response to anti IgE

Component resolved diagnostics, peanutallergy,

reduced need for food challenge, heat labile Ag
food challenge

Mast cell tryptase is a biomarker for anaphylaxis.

Tryptase is a preformed protein in mast cell
granules, systemic degranulation of mast cells in
anaphylaxis increase serum tryptase. Peaks at 1-
2h, returns to baseline 6-12h, failure = systemic
mastocytosis, useful if diagnosis is unclear (GA
hypotension and rash), less sensitivity for food-
induced anaphylaxis

Anaphylaxis severe systemic HS reaction. ABC
problems, skin and mucosal changes. 0.3% of
population mostly in skin, CVS, resp. resp more
in children. Acute onset, resp compromise, or low
BP
Idiopathic anaphylaxis seen in 20% cases
IgE mast, basophil: HA and PAF. Food, insect
venom, ticks, penicillin
IgG MP, neut: HA/PAF, biologicals, blood, IgG
transfusion. Systemic high doses of Ag
Complement mast/MP:PAF, HA. Lipid
excipients, liposomes, dialyses, PEG
Pharmacological mast: leukotriene, HA.
NSAID, aspirin, opiates, neuromuscular,
quinolone drugs
Rise in tryptase is directly proportional to the fall
in BP. Treat with adrenaline
Alpha 1 receptors: peripheral
vascoconstriction to reverse hypotension,
mucosal edema
B1/2 HR, BP, relax SM
IM adrenaline outerthigh,repeat, sit
up/supine, 100% O2, fluid replacement,
inhaled bronchodilators,
chlorpheniramine
Refer to allergy clinic, investigate cause, avoid
cause. Emergency anaphylaxis kit
C milk and egg allergy grow out of it. Adults rarely
grow up of personal and tree nut allergy

Mimics include +ve skin prick = sensitization, ?allergy. higher IgE

SKIN: Chronic urticaria and angioedema (ACE
inhibitors)
CARDIOVASCULAR: Myocardial infarction and PE
RESPIRATORY: Very severe asthma, vocal cord
dysfunction, inhaled FB
levels = greater chance of allergy
Avoidance, education , nutritional input, mental
health. Anaphylaxis guidelines, control allergic
asthma. Breast feeding
IgE mediated food allergy syndromes
Pathology Notes
Year 5
Food associated exercise induced anaphylaxis
within 4-6h of ingestion. Common triggers are
wheat, shellfish, celery
Delayed food induced anaphylaxis to beef, pork,
lamb. 3-6h after eating red meat and gelatin, due
to tick bites.
Oral allergy syndrome. Oral swelling and itch,
1%to anaphylaxis. Sensitization to inhaled pollen
cross reactive IgE to food. Adults more than
young children. Birch/stone fruid, veg, nuts.
Cooked = no symptoms
CNS Infections
Dr Luke Moore
Wide variety of presentations, life-threatening,
time to presentation/speed of progression varies
4 routes of entry:
1. Haematogenous spread (pneumococcus
20% of us are carriers), viruses
(enterovirus, herpes)
2. Commonest route of entry
3. Direct implantation, ear infection, trauma
4. Local extension (rabies)
5. PNS into CNS
Meningitis
Meninges inflammation: fever, headache, stiff
neck. Meningoencephalitis crossover
Neuro damage via direct bacterial toxicity,
indirect inflammatory process, cytokine release,
oedema, shock, seizure, cerebral hypoperfusion.
10% mortality
Acute a few hours, chronic (days to weeks),
aseptic (acute or chronic, no pus)
N men, S pneumo, H flu in acute meningitis
N men A, B, B serotypes. We are vaccinated
against C
S pneumo biphasic young and older 65
(vaccine prevents pneumonia and meningitis)
Hib vaccine common, other serotypes
increase
Listeria present in some foods (and France
especially) causing meningoencephalitis, GBS
(30% in vagina normal flora, babies pass
Alice Tang
2017-2018
through birth canal and can cause neonatal
meningitis. Screening programme GBS
colonisation), E coli biphasic (older
bacteremias, neonates)
N men: childhood death, person to person
(colonized) from asymptomatic carriers,
pathogenic strains in only 1% of carriers,
nasopharyngeal mucosa in a susceptible person,
incubation in <10d
Non-blanching rash petechial/purpuric 80%
children, maculopapular 13%, no rash 7%
50% meningitis, 10% septicemia, 40% BOTH
BOTH = capillary leak of albumin leading to
hypovolemia, coagulopathy
bleed/thrombosis, metabolic acidosis, heart
failure and multiorgan failure
Extremity gangrene
Chronic meningitis
TB leptomeningeal enhancement, fever,
headache, neck stiffness over weeks. 544/100k in
Africa, commoner in immunosuppressed, 5.5
mortality, Meninges and basal cisterns of brain
and spinal cord
Aseptic meningitis commonest CNS infection,
headache, stiff neck, photophobia, rash.
Coxsackievirus group B, echovirus 80% cases
Encephalitis
Transmission person to person or via vectors.
Geospecific due to movement of humans and
arthropods. WNV is a leading cause
internationally (East Africa) transmitted by
mosquitos biting birds. Increased in US
significantly. Italy, Greece because birds fly south
for the winter
Amoeba: Naegleria fowleri in warm water
(BATH!) local invasion process Acanthamoeba
species, Balamuthia mandrillaris brain abscess
Cats toxoplasmosis
Focal CNS infections
Brain abscess mostly by local extension from
otitis media, IE, paranasal sinuses, mastoiditis.
Strep, Staph
Pathology Notes Alice Tang
Year 5 2017-2018

Brain encephalitis: disturbed brain function.

Spinal infection: pyogenic vertebral osteomyelitis, Rabies, arbovirus, Trypanosoma, prions, amoeba
mainly IE Myelitis spinal cord

Risks include age, DM, IVDU, steroids, transplant Immune modulation

Diagnostics Vaccination
MRI better than CT for parenchymal
abnormalitiessuch as abscesses and infarctions. Removal
More discerning but difficult to get, long. CSF,
brain sample
Transplant patients, EBV persists for life in B cell,
CSF studies: MUST LEARN with potential for B cell transformation

Normal CMV pneumonitis or retinitis. Can take own T

Purulent cells (autologous) expand in vitro and reinfuse.
Aseptic Donor HLA T cells expanded in vitro and infused,
or banks of HLA matched
Strep pneumo a-hemolysis
ZN red blue red TB Cytokine therapy aimed to modify the immune
response
Normal opening pressure 20smmH2O, in MSM its 1. IFN alpha to boost immune response,
India ink stain Cryptococcus yeast capsule treat HCV, HBV, Kaposi sarcoma, hairy cell
around, HIV immunocompromised leukemia, CML, MM
2. IFN beta for Behcets and relapsing MS in
MRI oedema, PCR expensive the past (less). Immunomodulatory rather
than immune boosting. Visual loss
Management is iterative especially
30 mins clinical assessment 3. IFN gamma for chronic granulomatous
1-2h CSF analysis disease
24-48h CSF culture
Immune checkpoint inhibitor ipilimumab for
Meningitis ceftriaxone (Pneumo, Strep, H, CTLA4 inhibitory signal, CD 28 activating.
doesnt kill listeria hence add amoxi) 2g IV BD. CD80/CD86 ligand on APC. Blockade of inhibition
>50/IC add amoxicillin 2g IV 4hourly allows T cell activation for advanced melanoma.
Inflammatory arthritis and IBD as a side effect
Meningoencephalitis acyclovir 10mg/kg IV TDS,
ceftriaxone 2g IV BD PD-1 pembrolizumab/nivolumab antibodies
activated in T cells, negative signal. PD-1/2 are on
Moderate and treat exactly what you have with APCs and tumour cells. Remove negative signal to
specific therapy enhance T cell response (advanced melanoma)

Adjunctive therapy: level of care, steroids, LP, X linked SCID BM transplant

public health. Steroids to reduce inflammation, EBV specific T cells lymphoproliferation
coning and death Normal human Ig X linked hyper IgM syndrome
VZV immunosuppressed seronegative indivual
after chicken pox exposure
Pathology Notes Alice Tang
Year 5 2017-2018

Pancreas and Gall Bladder Pathology Chronic pancreatitis: relapsing or persistent,

Microanatomy acini exocrine with ducts.
Endocrine component
Acute pancreatitis
Acute inflammation due to aberrant release of
enzymes, common with increasing incidence
Causes include:
1. Duct obstruction
a. Gallstones 50%
b. Trauma
c. Tumours, cause pancreatitis (A+C)
2. Metabotoxic
a. Alcohol 33% (5% alcoholics)
b. Drugs (thiazides)
c. HyperCa (fat necrosis in pancreatitis causes
low Ca)
d. Hyperlipidemia
3. Poor blood supply
a. Shock
b. Hypothermia
4. Infection/inflammation
a. Viruses (mumps) parotids and pancreas
similar
b. AI/idiopathic
5. Direct acinar damage
Duct obstruction; gallstone stuck distal to CBD
and pancreatic ducts join leads to reflux up
pancreatic duct, damage acini, release of
proenzymes. Alcohol spasm of Sphincter of Oddi,
forms a protein rich pancreatic fluid, obstructing
ducts
Patterns of injury: periductal necrosis of acinar
cells near duct (usually obstruction), perilobular
necrosis at the edges of the lobules (poor blood
supply), panlobular from
Pancreatic complications include pseudocyst
(lack epithelial lining, just inflamed granulation
tissue, like an ulcer) or abscess (infected
pseudocyst), shock, hypoglycemia/Ca/ 50%
mortality for hemorrhagic pancreatitis. Blue
calcium
acute pancreatitis present in 50% of cases,
uncommon, 3% mortality per year
Alcohol 80%, hemochromatosis (exocrine
and endocrine failure)
Gallstones abnormal pancreatic duct
anatomy (dorsal and ventral fusion), cystic
fibrosis (mucoviscoidosis)
Tumours
AI/idiopathic
Pathogenesis pattern of injury parenchymal
fibrosis, loss of parenchyma, atrophy. Duct
strictures with calcified stones, secondary
dilatations
Malabsorption, DM, pseudocyst and carcinoma
can result from chronic pancreatitis (underlying
duct obstruction may look like cancer, very
painful). Pale and firm due to atrophy of acini,
dilated ducts, difficult to see acini, filled with
mucous. Mostly fibrosis in chronic disease.
Pseudocyst associated with acute or chronic,
connect with pancreatic ducts, lined with fibrous
tissue (not epithelium) necrotic material/ fluid
with enzymes. Can resolve, compress, infect,
perforate
AI pancreatitis IgG4 positive plasma cells,
involves pancreas, bile ducts, any other part =
IgG4 disease, stains brown
Tumours of the pancreas mostly ductal
carcinomas 85%, 5% cancer deaths with poor
prognosis 5% 5 year survival, commoner with age
and males, mets to liver, the rest are acinar.
Cystic neoplasms include serous cystadenoma
(benign glandular) or mucinous cystic neoplasms
(benign/malignant difficult to tell). Pancreatic
neuroendocrine tumours (islet cell tumor)
Risks
Smoking, BMI, diet, chronic pancreatitis, DM
Ductal carcinoma arise from dysplastic ductal
lesions: pancreatic intraductal neoplasia (PanIN)
high or low grade. K-ras mutations in 95% cases
Pathology Notes
Year 5
Intraductal mucinous neoplasm is also another
risk factor.
Appearance macroscopic: gritty and grey, invades
adjacent structures, tumours in head present
earlier due to obstructive symptoms
Microscopic appearance adenocarcinomas mucin
secreting glands in desmoplastic stroma
Chronic pancreatitis. Venous thrombosis
(migratory thrombophlebitis), often go around
nerves hence pain
Cystic pancreas tumours are usually multilocular,
serous or mucin secreting epithelium, usually
benign
Pancreatic endocrine neoplasms are usually non-
secretory, contain neuroendocrine markers
(chromogranin granule for neurosecretion),
difficult to predict behaviour. MEN1 associated
1. Insulinoma hypoglycemia presentation,
uniform tumor. Packets of cells uniform
nuclei
Gall bladder: gallstones, inflammation, cancer
Gallstones cholelithiasis in 20% of adults in the
West, even higher in native americans. Most are
asymptomatic
Risk factors: age and females, ethnic, hereditary
disorders of bile metabolism, OCP drugs, rapid
weight loss liberating cholesterol from peripheral
fat and excretion in GB.
1. Cholesterol stones (50%), single, radiolucent
(solitaires, pale, cannot see on XR)
2. Pigment (Ca salts of unconjugated BR),
multiple, radiopaque (hemolytic anemia)
Gallstones complications include bile duct
obstruction, acute/chronic cholecystitis, GB
cancer, pancreatitis
Acute cholecystitis
Acute inflammation (neutrophil polymorphs)
Chronic cholecystitis
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2017-2018
Chronic inflammation (lymphocytes and fibrosis)
diverticula Rokitansky-Aschoff sinuses, 90%
gallstones
GB cancer adenocarcinoma 90% associated with
gallstones
Lecture Meeran
65M previous MI BP 140/80 atenolol, LDL 3 on
atorvastatin 80mg. SPRINT study, 9000
randomised to tight BP control or not. Optimum
medical therapy, protocol encouraged thiazide or
BB. Intensive group survived better, thiazides are
cheap
10% falls to 8% with intensive treatment, ARR 2%,
RRR 20% reduce 2 events
Optimal medical therapy: intensive lifestyle
modification, aspirin, high dose statin, BP
Statin intolerance: niacin (no longer used),
ezetimibe
PCSK9 inhibition (protein on LDLR) degradation
and recycling LDLR. Antibody slows the recycling,
more active receptors. Evolocumab, atheroma
reduced in size. No difference in death rate,
reduced risk of non-fatal MI. No clear benefit.
May be useful in FH patients, uncontrolled lipids
Empagliflozin SGLT2 inhibitor (EMPA-REG)
reduces renal Na/glucose reabsorption from PCT.
Pee glucose to bring down blood sugar. EMPA
10/25 change in MACE. Improve 4years HbA1c,
weight, waist circumference, sysBP, diaBP, HR no
change. Many effects right at the start. HF
especially did well. Diuretic with no side effects.
GFR renal function is maintained compared to
placebo. Not cheap at 48k to prevent 1 drug
Liraglutide GLP-1 agonist stimulates insulin
release, reduction in primary outcomes (LEADER).
Semaglutide, reduce death early
Start with metformin (UKPDS most data),
consider empagliflozin/liraglutide, prevent death
earlier
Pathology Notes
Year 5
Meeran Liver
Portal triad with large central vein, periphery to
center
Causes of high BR
1. Pre-hepatic unconjugated: hemolysis, do
FBC + film
2. Hepatic disease: repeat LFTs
3. Post hepatic obstructive jaundice
Van den Bergh reaction measures serum BR via
fractionation. Direct reaction measures
conjugated BR (high unconjugated BR in
neonates, need to pick up liver disease but
commonly benign)
Add methanol to cause a complete
reaction, the difference
Direct = conjugated (liver is working)
Indirect = unconjugated
Pediatric jaundice might be normal, need to look
for hypothyroid, hemolysis, indirect BR (DAT,
Coombes). BR usually unconjugated due to liver
immaturity and fall in Hb early in life
Mostly settles with phototherapy, converts BR to
lumirubin and photobilirubin = isomers that dont
need conjugation for excretion
Film normal = unlikely to have hemolysis. Normal
ALP = unlikely to be obstructive jaundice
Case 2: chronic EtOH, drunk, alcoholic hepatitis =
hepatic jaundice
HepA immune after first infection, 1 month after
and clear virus. Kills those who are malnourished
HepB immunize give HBsAg ONLY, produce anti-
HBs (if only anti-HBs immunized) if anti-HBc
present, they have recovered
HBV carriers never clear the virus completely,
may have it congenitally at a young age. eAg
cleared after 2 years but keep on expressing
sAg. Remain infectious but often look healthy
Alcoholic hepatitis looks the same as NASH hence
need history. Liver cell damage shows ballooning
degeneration and Mallory Denk bodies. Obese in
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2017-2018
NASH but same pathology. Supportive treatment,
give nutrition, vitamins (thiamine B1),
occasionally steroids
Chronic stable liver disease palmar erythema,
spider naevi, dupuytrens contracture,
gynaecomastia
Increased pressure in umbilical vein hence
causing a visible vein in the anterior abdominal
wall. Usually 1-2 show direction of flow by
putting finger on, squeeze, release. Blood from
umbilicus. Splenomegaly in portal HTN; pressure
in portal system is high
Nodules of regeneration grow and blood needs to
move around the nodules of cirrhosis
Portal HTN: visible veins, splenomegaly, ascites
(shifting dullness). Low albumin, low oncotic
pressure, high aldosterone, block aldosterone to
prevent ascites slight dehydration, GI bleed =
worry. Pressure too high so little blood enters
liver = high varices veins no muscular wall, can
bleed to death
Sengstar tube NG tube with balloon in fridge,
swallow tube and blow balloon up and pull to
block varices
Drill hole in central vein TIPSS enter needle in
internal jugular vein. Portal pressure enters
hepatic vein, bypass liver. More unclean blood in
central vein. Risk of encephalopathy increases
whilst risk of bleed decreases (GI bleed 3x risk but
lets them survive). Beta blocker (bleeding on BB
is worse). Prophylactic endoscopy, sclerotherapy
each 3m
Portosystemic anastomosis: oesophageal, rectal,
umbilical vein recanalising, spleno-renal shunt
Scratch marks due to obstructed bile ducts,
increased bile salts circulating. Colorless but skin
irritants. Normal liver with post-hepatic
obstruction. Gut bacteria metabolise BR to
urobilinogen/stercobilinogen. Normal
enterohepatic recirculation. Physical obstruction
of biliary tree = gone from urine. Urine dip
Pathology Notes
Year 5
negative for uro/poo neg for stercobilinogen =
obstruction. If positive = hepatitis
Courvoisiers law: palpable GB, jaundice, painless
= pancreatic Ca, dilated bile ducts. Liver mets,
each grows into nodules hepatocyte ducts
growing as there are bits of pancreas in the liver
Obstetric hematology
Mild anemia: RBC mass increases 120-130%,
plasma volume rises 150%, macrocytosis
physiological folate/B12 deficiecny. Neutrophilia,
thrombocytopenia increased size
Fetal 300mg Fe, 500mg maternal. RNA 30mg
increase daily absorption 1-2 to 6mg (5-fold),
homeostasis is controlled due to lack of
excretion
Folate requirement increases for growth and
cell division, 200mcg/day more
IDA can cause mat+neo problems: IUGR,
premature, postpartum hemorrhage
Hepcidin decreae ferritin increase
60mg Fe, 400mcg folate, no effects on outcome
Folate reduces risk of neural tube defects,
pre-conception and 12w into gestation 1st
trimester, dose 400mcg/day
No routine Fe supplementation in UK
10% lower platelets, non pregnant 225-249,
pregnant 175-199 (50 = sufficient for delivery,
>70 for epidural) small but potentially
devastating from spinal hematoma. Dilution and
increased consumption of plts, baby not affected
with normal plt count, rises 2-5h post delivery.
Fall is mostly in 3rd trimester when all volume
change has already happened. Larger plts but
better function.
Thrombocytopenia in pregnancy causes
Immune thrombocytopenia, suppression may
unmask AI (peripheral destruction)
Pre-eclampsia
HELLP, other MAHA
Risks and causes depends on patient, plus all
other causes like hematology causes in non-
pregnant (leukemia, BM failure, hypersplenism,
DIC). Mostly gestational. In women with lower
Alice Tang
2017-2018
counts <100 likely to be pathological, more and
more immune ITP causes
Preeclampsia severity correlates with plt count,
50% get low plts, increased
activation/consumption, coagulation activation,
remits after delivery usually. Some DIC present
ITP may precede or early onset. Treat with IVIG (2
infusions, consecutive days), steroids, anti-D if
RhD+ block splenic MP for delivery of bleed.
Baby may be affected and this is
unpredictable, few have a count <20 in 5%
Check cord blood, check daily, may fall 5d
after delivery
Bleed in 25% severely affected IVIG if low
Usually normal delivery, avoid some forceps
or suction
MAHA plt rich thrombi deposited in small BV,
thrombocytopenia, fragment and destroy RBC in
vasculature = shearing, RBC fragments, organ
damage in kidney, CNS, placenta
TTP/HUS course not changed by delivery. TTP
plasma exchange to remove multimers of vWF.
Atypical HUS (renal disorders)
Coagulation changes in pregnancy decrease
chance of bleed, but result in a leading cause of
maternal mortality = VTE, commoner in high BMI
F8, vWF increases 3-5 fold, fibrinogen increases 2
fold, F7, F10. Protein S falls to half basal
hypercoagulable state. PAI-1 increase 5 fold,
inhibitor of fibrinolysis, PAI-2 only made by
placenta rapid control of bleed from placental
site (700ml/min) at delivery, uterus must contract
Net procoagulant state increased thrombin,
increased fibrin cleavage, low fibrinolysis,
interacts with other maternal factors. Increased
rate of thrombosis. More PE deaths in last 6w.
Returns to normal by 2m, over 1/3 pre-2w, need
greater awareness of pregnancy
Hypofibrinolytic BUT D-Dimer increased in
pregnancy due to inflammation, endothelial
activation. Not used
Pathology Notes
Year 5
All pregnant women: change in coagulation,
reduces venous return, vessel wall. Variable:
dehydration, immobile, obese, pre-eclampsia,
operative delivery, SCD, nephrotic, parity,
multiples, HbSS, IVF hyperstimulation, previous
clot/FH, age
VTE and inherited thrombophilia increased.
LMWH doesnt cross placenta, use once or twice
daily. Do not convert to warfarin as it crosses the
placenta (6-12w teratogenic, only in high risk
metallic valve patients), would not use the
NOACs. Stop for labour or planned delivery for
epidural 24h after treatment, 12h after
prophylactic
Complications
Increased risk of thrombosis especially in
placenta, causing IUGR, miscarriage, late fetal
loss, placental abruption, severe pre-eclampsia
(PET) plausible but not proven
Antiphospholipid syndrome (APLS) recurrent
miscarriage, persistent lupus anticoagulant
(LA, pro-coagulant) or anticardiolipin Ab
(ACL), 3+ consecutive Ab pre-10w, 1+ preterm
needs investigation
Aspirin + heparin improves outcome, greater
live birth rate
Placenta praevia, accrete hysterectomy, major
hemorrhage, previous C-section
Postpartum hemorrhage 500ml normal, 5% have
loss >1l at delivery. Factors = atony and trauma,
heme factors minor except dilutional
coagulopathy after resus, DIC in abruption,
embolism
Amniotic fluid embolism catastrophic but rare,
shivers, vomiting, shock, DIC, 86% mortality, TF in
amniotic fluid usually 3rd trimester
Hbopathy avoid birth of children with a0 Hb Barts
death in utero hydrops fetalis, b0 thalassemia
transfusion dependent. HbSS 43y life expectancy,
compound HbS syndromes. Screening program
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2017-2018
HPLC Hb variants, HbA2 delta chain beware of
IDA, >3.5% Bthal, test partner, proceed, prenatal
diagnosis
CVS sampling 10-12w
Amniocentesis 15-17w, fetal blood sample
USS hydrops
Renal function
GFR is the best measure of kidney function,
filtration via glomerulus, normal is 120ml/min
GFR dereases with age, 1ml/min per year
Clearance is used to find GFR, vol plasma cleared
per unit time, not serum protein bound, freely
filtered, not secreted or reabsorbed CL = GFR
C = (UV)/P
Inulin clearance gold standard for GFR, plant
based 5.2kDa fructose polymer, neutral charge,
freely filtered, not processed by tubular cells,
steady state infusion, difficult to measure
research only
Single injection of Cr-EDTA/Tc-DTPA/Iohexol
radiolabeled molecule. Direct CL from urine
collection or indirect plasma regression curve
Endogenous marker needed; urea first
endogenous marker byproduct of ptotein
metabolism, freely filtered, 20-60% reabsorption
by tubular cells, depends on nutritional state,
hepatic function, GI bleed, limited clinical value.
Some hydration status or increase before Cr
Cr is related to muscle mass and turnover, intake
of protein. Higher in blacks, secreted by renal
tubules. Some from intestinal absorption, freely
filtered, actively secreted into ruine. Generation
depends on muscle, age, sex, ethnicity. High GFR
= lower Cr but not linear
Cockcroft Gault eCCr = 1.23 x (140-age) x weight /
serum Cr adjust by 0.85 if female estimating Cr CL
not GFR, may overestimate especially when
<30ml/min
Pathology Notes
Year 5
MDRD need age, sex, Cr, ethnicity.
Underestimate if younger but better fit, currently
used at Imperial (Cr + eGFR given)
NICE use CKD-EPI same variables but different
modelling, reduces bias at higher GFR
Cystatin C protein cysteine protease inhibitor
made by nucleated cells, constant rate
generation, freely filtered, almost completely
reabsorbed and catabolized by tubular cells. Poor
assay
Serial levels of GFR, insensitive GFR marker but
trend is important
Urine results
Spot urine measurement to quantify proteinuria
can be done instead of 24h urinary collection,
good correlation, use Cr to correct for urine
concentration. 24h urine collection is difficult and
messy, inaccurate without specific education.
Urine PCR
Urine single sample for sip, microscopic,
proteinuria, electrolyte. 24h for Cr CL, stone
forming elements
Urine dip negative for blood reliably excludes
hematuria
pH 4.5-8.0 (renal tubular acidosis, high pH
urine = low systemically)
Specific gravity 1.003-1.035
Protein (albumin)
Blood
Leucocyte esterase, negative is significant
Nitrites G-
Urine microscopy centrifuge 5-10 min 3000rpm,
crystal, casts, bacteria, RBC/WBC
Ethylene glycol poisoning with calcium oxalate
crystals. Metabolized to glycolic acid to oxalate
acid, binds Ca, sediments in kidneys. Need
dialysis
CT KUB first line (or plain KUB otherwise). Renal
biopsy gold standard (USS or CT guided)
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2017-2018
AKI vs CKD
SKI rapid decline GFR, potentially reversible,
precise diagnosis and reversal whilst CKD
longstanding, irreversible, aim to prevent
progression.
Inability ro maintain electrolyte, acid base, fluid
homeostasis, rapid reduction in kidney function.
Medical emergency
1. Stage 1 increase sCr 26+ or 1.5-1.9x
reference sCr
2. Stage 2 increase 2-2.9x
3. Stage 3 increase by 3x or 354+ micromolar
May not have a baseline Cr, new/old? Need to do
other tests to find out if this is longstanding
Pre-renal, intrinsic or post-renal
1. Pre-renal low renal perfusion due to
generalized tissue low perfusion, renal
ischemia, fluid loss, bleed. No structural
abnormality
Normal response to reduced circulating volume,
activate central baroreceptors, RAS, AVP, SNS,
vasoconstrict, increase CO. failure = pre-renal AKI
True volume depletion (blood/fluid)
Hypotension
Edema (HF wrong compartment, liver
failure)
Selective renal ischemia
Drugs affect GFR
Underlying renal artery stenosis = selective cause
of renal ischemia. Drugs causing AKI include:
NSAIDs, calcineurin inhibitor (ciclosporin)
decrease afferent dilatation, ACEi/ARB
decrease efferent constriction, diuretics true
volume depletion
Acute tubular necrosis (ATN)
AKI not associated with structural renal damage,
responds to restored circulating volume,
prolonged insult ischemic injury, ATN doesnt
respond to restoring circulating volume. Variable
long term effects
Post-renal AKI benign prostatic hypertrophy,
hydronephrosis seen in both kidneys back
Pathology Notes
Year 5
pressure. Physical obstruction to urine flow.
Intra-renal, ureteric (bilateral), prostatic/urethral,
blocked catheter. Severe hydronephrosis needs
decompression nephrostomy otherwise it can be
infected and lost
GFR depends on pressure gradient, increased
tubular pressure reducing GFR due to
obstruction. Immediate relief restores GFR fully
with no structural damage. Prolonged
obstruction causes damage = glomerular
ischemia, tubular damage, long term interstitial
scarring
Intrinsic renal AKI more diverse, abnormal parts
of any nephron: vascular, GN, tubular, interstitial
1. Direct tubular injury commonly ischemia
(prerenal), endogenous toxins (myoglobin
crush/statins, immunoglobulins myeloma and
paraprotein), exogenous toxins (contrast,
drugs aminoglycosides, acyclovir)
2. Immune dysfunction GN/vasculitis on renal
biopsy, can target treatment
3. Infiltration: amyloid, lymphoid, myeloma.
Systemic vasculitis purpuric rash to both legs,
nonblanching
The important causes are pre-renal and ATN
AKI some resolve and some dont, imbalance
between scarring and remodeling chronic
disease
CKD treat to prevent complications. Stages based
on GFR
1. >90
2. 60-89
eGFR + A:Cr determine risk of adverse outcome.
Incidence is increasing, more elderly population
on dialysis so increased point prevalence too
DM
Atherosclerotic renal disease
HTN
Chronic GN
Infective/obstructive uropathy
PCKD
Results in metabolic acidosis from failure to
excrete H+ causing muscle and protein
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2017-2018
degradation, osteopenia, cardiac dysfunction.
Treat with oral bicarb when serum bicarb <22.
CKD hyperkalemia, flat P and tented T, NSAIDs
increase K, hyperaldosterone loss K, CKD diet
intake causes high K
K major intracellular cation membrane
depolarization, cardiac and muscle function.
Common in DM, med, ACEI, spironolactone and K
sparing diuretics, broad complex tachycardia and
cardiac arrest afterwards
Progressive hormonal failure, decline EPO
production, loss of renal parenchyma when
GFR<30, normochromic, normocytic anemia
ESA stimulating agents incrase Hb in a dose
dependent manner, change in QoL debatable.
May not respond on CKD due to IDA, TB, Ca,
B12/folate def, HPT
Renal bone disease complex due to low bone
density, bone pain, fractures: osteitis fibrosa
cystica, osteomalacia, adynamic bone disease,
mixed osteodystrophy
HyperPTG in CKD phosphate retention causing
increase FGF23 (pee out phosphate), lowers
1,25,OHVitD. hypoCa and high PTH, leading to
resistance to PTH in bone, decreased Ca sensing
receptor and VitD receptor
OF: osteoclastic resorption of calcified bone,
replacement by fibrous tissue hyperPTH
tertiary adenoma autonomous. Resorption of
calcified bone, larger trabeculae, black on XR
Osteomalacia lack of VitD active = poor
mineralization of bone osteoid
Adynamic bone disease excess suppression of
PTH low turnover, low osteoid. Calcium
binders to rid excess phosphate
Treat with phos control: diet, binders. VitD
activators: 1-a-calcidol, paricalcitol. Direct PTH
suppression cinacalcet (CaSR but ABD if excess)
Pathology Notes
Year 5
Cardiovascular disease in CKD, low GFR =
increased risk of event. 20% excess risk CVA,
normal risk factors are less well defined in renal
disease (cholesterol, HTN). Heavily calcified
plaques rather than traditional lipid rich
atheroma
Uraemic cardiomyopathy: 3 phases: LV
hypertrophy, dilatation, dysfunction
Uraemia and death
HIV, obesity is not a contraindication to
transplant, well controlled now, no cancer within
the last 2 years
Stem cell transplantation
CML best stem cell transplant originally
Maximum tolerated dose (MTD), further away
from bomb = lower dose from bomb epicenter.
BM is the first organ to be seriously affected by
radiation, then GIT, nervous system. BM/spleen
protected against irradiation and restore blood
count hematopoietic stem cell
Temporary change in blood group with stem cell
transplant
Autologous transplant: growth factor, collect
stem cells and freeze (acute leukemia,
lymphoma, solid tumor), thaw and reinfuse after
high dose chemo. Also for myeloma, lymphoma,
CLL
BM is the dose limiting organ. Older patient less
likely to receive other persons transplant. May
have a clean BM (lymphoma) treat to remission,
take blood stem cells, freeze, chemo/radioTx
dose in normal doses would destroy BM capacity,
larger dose than normal and then replace into
patient
Allogeneic transplant: healthy stem cells from
another person, can give even larger doses of
chemo/radioTx (AML, ALL, CML BM based
disease), aplastic anemia, congenital immune
deficiency. If treatment is stopped after no cells
are present, leukemia would return. High dose
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2017-2018
chemo +/- total body irradiation. Infuse stem cells
from well matched donor, produce progeny.
Complete replacement whole immune system
from another person.
From treatment potentially pancytopenic,
accommodate in single room, en suite, positive
pressure environment (air flows out to you),
rooms all have lobbies, airflow all outwards to
hospital, dont allow hospital air into the unit.
Remain there until fully regenerated 4-5w, some
visitors
Rejection, inflammatory reaction, destroy kidney.
In BMT, can still reject. When BM progeny are
established, wrong place, reject whole body
GVHD maculopapular erythematous rash in
whole body (skin first), kills patient
Class 2 DR
Class 1 BCEAGF
Also match 10/10 or 12/12 with DQ
HLA-ABDR typing, chance identical HLA with
siblings. Serology alone low resolution,
sequencing higher resolution
A2 common AA at certain sequences, can be
recognized by Ab, all seen as A2, but aa changes
at different places along this sequence GVHD.
Unrelated donors
Depends on ethnicity, some HLA are common
irrespective of donor
Most expensive, highest risk. Non-related 150-
200k success at 40%
BM, PB (G-CSF), UC sources, cannot find stem cell
on histology vol of harvest depends on per Kg of
recipient weight (2x10^6/kg to get a successful
graft). Multiple sites and multiple depths, several
punctures. G-CSF infection increases this, higher
so CD34 turnover and BM makes more cells, hook
patient up to blood centrifuge middle WBC
siphoned off, other cells are returned, takes 3h.
process 15L total
Pathology Notes
Year 5
CD34 1% of cells in sample, 1.5L BM 10L in blood,
more in PB donation than BM, barely get 200ml
from cord. Cord blood Tx in children, so need
fewer cells
Outcome: age, disease phase, gender of R/D,
time to BMT, donor (patient male and donor
female NO Y chromosome proteins never seen
before, compounded if female pregnant with
male child already seen those proteins,
compounded)
Deaths due to graft failure 1%, infection, GVHD in
allograft, relapse
Invasive aspergillus 92% mortality
CMV in transplant, 20% of T cells stop us from
dying from CMV pneumo gastro nephr, retin
Serology
Allogeneoic
Killing lining of gut, testicles and so on
cytokine storm, everything is activated, donors
cells enter, responses heightened, go on to
damage
GVHD worse with HLA disparity, age,
conditioning, F/M, stem cell source (PB worse
lymphocytes), disease phase advanced, viral
infection stimulate lymphocytes
Gvhd treated with steroids, ciclosporin A, FK506,
mycophenylate mofetil, Mab
Prevent GVHD with immunosuppression
Methotrexate
Steroids
Ciclosporin A
CsA + MTX better leukemia free survival
than T cell depletion
FK506
T cell depletion
Graft vs leukemia, no allogenic = may as well
remove stem cells. Infuse more lymphocytes to
treat leukemia relapse. Balance relapse with CMV
disease and GVHD
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2017-2018
Non-neoplastic Bone Disease
Acquired diseases in adults
Trauma fractures in bone, type of fracture
influences how it should be treated and how it
will heal, can heal without scarring if properly
aligned
Complete or incomplete (greenstick in
child)
Soft tissue intact
Splintered, comminuted
Compound, pierced soft tissue into air
Simple, compound, greenstick (not fully broken),
comminuted malaligned and need to piece,
impacted compression injury after crush. Poor
healing = shorter, functional impairment
Fracture repair
1. Organization of hematoma at fracture site
(pro-callus) clotted hemorrhage, periosteal
proliferation
2. Formation of fibrocartilaginous callus, can still
move
3. Mineralization, set, bone forms through
cartilage
4. Remodeling of bone along weightbearing
lines
Biopsy fracture site, many atypical looking new
cells, could look like tumor. Clinical information is
imperative, can have complete repair
Cancellous trabecular bone with high surface
area
Fracture healing factors:
Type of fracture (compound fracture =
soil, grit, bugs)
Presence of infection
Comorbidities: neoplasm, metabolic
disorder (cannot mineralize), drugs,
vitamin deficiency (VitD)
Pseudarthrosis may impair function
Ill defined process, broken through and confined,
metastatic breast cancer, spinal repair and
removal
Pathology Notes
Year 5
Infection osteomyelitis
Adults often occur in vertebrae, jaw (dental
abscess), toe (diabetic skin ulcer). In children,
commoner in long bone metaphysis (femur, tibia)
General malaise, fever, chills, leukocytosis, local
pain, swell, red. 60% +bloods, XR mixed picture,
eventually lytic. Almost always bacterial, S aureus
in adults H flu/strep in children. Rarely fungal, can
be blood borne, direct extension,
traumatic/surgery/theatre, difficult to get Abx in
high levels to the bone. 6w min on Abx
Adults: salmonella in SCD, Pseudomonas IVDU,
Kleb, E coli enterics
Neonates: H flu, GBS, Enterobacter
Core biopsy for cultures for micro to define.
Inflammation. Lytic, mottled rarefaction,
involucrum new bone after 1 week. If untreated
can be necrotic and fall off (sequestra) 6w
1. Stage 1 medullary
2. Stage 2 superficial
3. Stae 3 localised
4. Stage 4 diffuse
Host A normal, B local/systemic, C treatment
worse than disease
Deformation of surface of bone, necrotic
sequestrum has fallen off
TB can cause OM 3-5% extrapulmonary TB,
affects immunocompromised, destructive and
resistant, spinal dsiase 50%, psoas abscess, Potts
disease severe skeletal deformity. Systemic
amyloid. Langhans type giant cells in TB OM.
Syphilis can cause OM congenital or acquired,
late skeletal lesions cause non-gummatous
periostitis, gummatous inflammation of
bone/koint, neuropathic joint tabes dorsalis
Lyme disease; inflammatory arthropathy from
tick bite, prevalent vector bone disease in
Northern hemisphere. Borrelia burgdorferi in
Ixodes ticks. Arthritis in young people with
erythema migrans. Affects both sexes, May to
Nov
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2017-2018
1. Early localized in a week, can be large on
thigh, groin, axilla, earlobe
2. Stage 2 early disseminated cardiac,
arthritis, brain issues
3. Stage 3 late arthritic
Prevention, vaccines are available, Abx for proven
disease, no prophylaxis, clinical diagnosis
Degeneration (vs inflammatory)
OA primary age, secondary due to previously
damaged or congenitally abnormal joint
Irregular contours
Loss of joint space
Cartilage loss, fissuring, collapse
subchondral bone, cyst formation
Abnormal matric calcification
Osteophytes
Hips, knees, vertebra
Doesnt affect wrists/ankles
Ligamentum teres blood supply, trauma to the
hip, steroid, thyroid and radiation. Blood is
compromised causing avascular necrosis. Wedge
shaped death of bone, OA. Biomechanical,
biochemical, age, genetic
Nonspecific chronic inflammatory infiltrate of the
synovium
RhA synovitis, severe chronic and relapsing.
Unpredictable, 1% of world population, prone in
native americans. More females and younger 30-
40
AI most likely 80% RhF+ (IgM), forms complexes
with IgG, lodges in organs to cause liver, lung
systemic disease
Genetic disposition: HLA DR4, DR1 (C6), higher
incidence in 1st degree relatives
Nonspecific initially, diagnose early and treat
inflammation to prevent joint destruction. Raised
ESR/CRP, Rh nodules in elbows and fingers in
25%, RhF+
Radial deviation of wrist
Ulnar deviation of fingers
Swan neck/boutonniere
Pathology Notes
Year 5
Symmetrical painful swollen joints
Fusing joints: extension PIP, extension of
DIP swan neck
PIP flex, DIP extend Boutonniere
Spare DIP. Affect wrist, ankle, knee
Eventually destructive arthropathy, similar
to OA
Thickening villous proliferation of synovial
membrane, hyperplastic synoviocytes, intense
inflammatory cell infiltrate, fibrin deposition and
necrosis. Pannus is on the surface. Upregulation
of IL1, IL6 induce MMP to cause joint destruction.
TNFa and CRP made by liver. Circadian rhythm
disturbed
Hyperplastic synoviocytes are Grimley-
Sokoloff cells
Fibrinous Reiss bodies filling the joint
RhA stages
1. Unknown Ag reaches synovial membrane
2. T and B cell proliferation, incrased
angiogenesis
3. Chronic inflammation
4. Pannus
5. Cartilage/bone destruction
Metabolic bone disease
Gout needle shaped crystals, would not take fluid
unless septic. Affects any joint but usually great
toe 90%, lower extremities, precipitate crystals
into joint, forms tophus in elbows. Common in
leukemia/cancer nuclei, high urate
Pseudogout calcium pyrophosphate or
hydroxyapatite crystal deposition degenerative.
Grey areas of Ca deposition. Polarized light non
needle shaped rhomboid/hexagonal
1. Sporadic 8% 75-85
2. Metabolic (hemochromatosis, low
Mg/phos, primary HPT)
3. Genetic AD ANKH mutn, 5p
4. Trauma to joint
Autoinflammatory and AI disease
Fever/malaise in EBV due to cytokines, abscess
due to neutrophils, sacroiliac joint inflammation
in AS cyotkines, AIHA from Ab
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2017-2018
Auto-inflammatory (innate) usually localized with
increased MP/neut e.g. CD; autoimmune
(adaptive) or mixed, T/B cell in primary and
secondary lymphoid organs, loss of tolerance,
reactive to self Ag, auto-Ab
1. Monogenic auto-inflam: TRAPS, familial
med fever
2. Polygenic CD, UC, OA, GCA, TA
3. Mixed: AS, psoriatic arthritis, Behcets
4. Polygenic AI RhA, MG
5. Rare monogenic AI: IPEX
Monogenic autoinflammatory: mutn in IL-1,
TNFa: Muckle Wells, familial cold auto-
inflammatory syndrome. Cryopyrin. Familial med
fever commonest inflammosome
Urate activates cryopyrin, increase procaspase 1,
IL1, NFkB, apoptosis. Gain of function
exaggerates inflammation. Loss of function in
negative modulator pyrin-marenostrin.
Commoner in Armenians. Fevers 48-96h,
peritonitis, pleurisy, pericarditis, arthritis, long
term risk amyloid, nephrotic, renal failure. MEFV
gene serositis
Treat FMF with colchicine binds neutrophil
tubulin to disrupt function (migration,c ytokine
secretion), IL1-R antaogonist Anakinra, TNFa
inhibitor Etanercept
Rare monogenic AI disease. Mutn in adaptive
response; tolerance, Treg, lymphocyte apoptosis
APS1 APECED AI polyendocrinopathy, candida,
ectodermal, dystrophy. AIRE defect, develop T
tolerance upregulate self Ag, promotes apoptosis.
Enhanced Ab against parathyroid and adrenal
hypoPTH, Addisons, Ab IL17, IL22 result in
candidiasis
IPEX immune dysreg, polyendocrinopathy,
enteropathy, XL, FoxP3 Treg cell development
fails, early death. Endocrine: DM, IBD, thyroid,
diarrhea, skin eczema dermatitis (DM, dermatitis,
diarrhea), need transplant
Pathology Notes
Year 5
ALPS (AI lymphoproliferative syndrome) FAS
mutation, TNFRSF6 heterogeneous mix,
lymphocytes dont die, failure of tolerance and
homeostasis. AI disease cytopenia. Thymus and
periphery problem. Thymus, no tolerance. Large
spleen, LN, lymphoma
Polygenic autoinflammatory disease
Localized pathology HLA less strong, no auto-Ab
Crohns familial, linkage analysis shows 8 regions
associated with susceptibility (loci 1-10)
IBD1 on C16 is an NOD2/CARD15, 3
mutations associated with CD, strong
evidence
NOD2 mutations in 30% patients, not
necessary. Abnormal allele increases risk
of CD 1.5-3x, 44x if homozygous but not
sufficient
Mutations also in Blau syndrome, sarcoid
NOD2 in myeloid cells (MP, neut, DC) microbial
sensor stimulating inflammatory response with
NFkB muramyl dipeptide. Loss of function
mutation, short protein cant recognize bacteria.
Local inflammation, gramuloma, tissue damage
1. Pain, diarrhea (blood), fever/malaise
2. Treat with steroids, aza, anti-TNFa, anti IL-
12/23
Mixed pattern in the middle ank spond
HLA may be present, auto-Ab not usually a
feature. HLA-B27 (<50% overall risk genetic)
other inherited risks: IL23R, ERAP1, ANTXR2, ILR2.
Inflammation localized at enthuses with high
tensile forces (sacroiliac inflammation), erosion,
damage, fusion. Inflammation at spine,
calcification and fusion. Achilles tendon, plantar
fascia. Low back pain and stiffness
1. Large joints, uveitis
2. NSAIDs, anti-TNFa very effective, anti-
IL17/12/23
Polygenic AI disease HLA common, auto-Ab found
1. Goodpasture disease antiGBM HLA-DR15
2. Graves disase HLA-DR3
3. SLE HLA-DR3
4. T1DM HLA-DR3/4
5. RhA HLA-DR4
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PTPN 22 negative regulator of T cells, present on
lymphocytes. Mutation causes increase in range
of AI disease. SLE, RhA, T1DM. not enough
negative suppression
CTLA4 negative regulator of T cells, aberrant in
SLE, RhA, T1DM, thyroid
Gender: mostly in women especially Sjogrens,
SLE, scleroderma, RhA. Basis of gender
association is poorly known: X/Y, imprinting,
hormones, reproductive function
Loss of tolerance, auto-reactive T/B cells with
autoAb, failure of self tolerance: central and
peripheral. Inappropriate survival of auto-
reactive, peripheral failure of costimulatory
molecules, Tregs or immune-privileged site
damage
Pre-T BM to thymus, death if no recognition and
bind too strongly also die
Nave T cells need costimulation for full
activation. APC express: CD40 (CD40L), CD80/86
(CD28). Without costim mols T cells become
anergised, do not respond to subsequent
challenge
Populations of Treg cells, CD25+FoxP3+CD4+
secrete TGFb, IL10. Deficiency = IPEX, abnormal in
many AI diseases. Tr1 IL10 CD4 T cells, CD8 Tregs
Immune privilege: eye, testes, CNS. Protected
from immune-damage
Immunopathology Gel/Coombs skin test HS
effector mechanisms via Ab or T cell. Very
incomplete
1. Type I in allergy, IgE release on mast cell
and basophil causing cell degranulation.
Release inflammatory mediators
(preformed HA, 5HT, synthesized LT, PG)
usually foreign materials. Possible self in
eczema
2. Type II Ab binds cell associated Ag, ADCC
NK cells, phagocyte Fc, complement
classical pathway. Modify with receptor
activation/blockade (Type V). AIHA,
Pathology Notes
Year 5
Goodpasture, pemphigus vulgaris, Graves,
MG
3. Type III immune complexes soluble Ag,
complexes deposit in BV to cause
inflammation. Complement, NK cells, MP,
neutrophils. Skin binding
vasculitis/purpura, nephritis, arthritis.
Cryoglobulinemia (Fc of IgG, HepC Ag,
precipitate in cold periphery), SLE (anti-
dsDNA, histones, RNP), RhA (Fc of IgG)
4. Type IV T cell response HLA I to CD8
enhanced cytotoxicity, or HLA II to CD4
high IFNy, MP, TNFa. T1DM pancreatic B
cell Ag destruction by T cells, RhA, MS,
EAE CD4 brain infiltration (myelin basic
protein)
Gel and Coombs:
1. Anaphylaxis (rare AI)
2. Cytotoxic HS (common AI)
3. Immune complex (sometimes or serum
sickness)
4. Delayed HS (sometimes)
Neoplastic Bone Disease
Amputation when unable to get clearance of
margins or when large vessels/nerves are
involved. Chemo, radio, surgery. Need to get
diagnosis right. Treat in specialist centers
(Marsden, RNOH), very rare, benign or malignant
60x less common than lung Ca. Commoner in
younger (except chondrosarcoma)
Age and site predilection, consider preexisting
conditions and bone geography. Commonest
around knee, distal femur, fibula
Presents with pain, swelling, deformity, fracture.
Elderly more likely to be a metastasis.
Uncommon primaries in hands/feet. Trauma
history, multiple lesions likely to be
mets/lymphoid/MM. Associated previous
radioTx, older people may get primary bone
sarcoma
Investigate with XR, size, discrete margin, soft
tissue extension, broken through bone, infection,
mets. Early referral to specialist center (Bristol,
Leeds, Newcastle, Glasgow). Soft tissue extension
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Biopsy (NOT OPEN, periosteum and fascial layers
are good barriers to tumor spread, no option but
to amputate when opened). Needle core biopsy
of non-necrotic tissue by radiologist with
Jamshidi needle with US/CT guidance. Open
biopsy if sclerotic/inaccessible. Imprint cytology
preparations are useful
4 x 1cm cores
Malignant tumor. Blood forming cells, not full of
little bits of bone, tumor in BM spaces, form pale
cartilage, bits of bone, mesenchymal cells
Tumour like conditions
Fibrous dysplasia
Fibroma
Reparative giant cell granuloma
Ossifying fibroma
Simple bone cyst
Fibrous dysplasia commoner in women, young,
one bone affected more than multiples. Soap
bubble osteolysis on XR, low risk Ca. McCune-
Albright. Pain in hip, pelvis/femur soap bubbles
well circumscribed multiples. Histology curly
trabecular bone, some cartilage, overall non-
malignant Chinese letter shapes, remove with
minimal margin and patient doesnt need
chemo/radio. Shepherds crook deformity of
femur
Benign make cartilage OR bone
1. Cartilage: osteochondroma,
enchondroma, chondrobalstoma
2. Bone: osteoid osteoma, osteoblastoma,
osteoma
Osteochondroma common in young males.
Mushrooms or sessile. Benign.
Enchondromas are benign in the bone, older in
hands and feet, pathological fractures. Patchy
calcification in cartilaginous tumours. Pushes
bone apart rather than permeating bone. Treat
conservatively, cartilage enters marrow spaces.
Giant cell tumor unpredictable, can enter lungs
and BV but dont often die of this, epiphysis to
Pathology Notes
Year 5
metaphysis in young people, lytic but sharp
cutoff, locally aggressive, recur, mets possible
often in the knee. Osteoclasts, multinucleate
(osteoblast one nucleus on surface, osteoclast in
matrix one nucleus)
Commonly malignant bone tumor is mets
1. Adults: breast, prostate, lung, kidney, thyroid
(+adrenal)
2. Children: neuroblastoma, Wilms,
osteosarcoma, Ewings, rhabdomyosarcoma
IHC stains prostate carcinoma prominent nucleoli
Malignant
Osteosarcoma mostly knee <20y males (older in
jaw), pelvis, humerus, poor prognosis, 6w chemo
and limb salvage surgery (Codmans triable)
malignant mesenchymal cells, cartilage (different
amounts of each)
Site: cortical, intramedullary
Differentiation cytology high/low grade
Multicentric
Metastatic
Break through cortex, push through periosteum,
Codman triangle = osteosarcoma. Stain malignant
for ALP
Chondrosarcoma in pelvis and axial skeleton,
proximal femur/tibia, 40_, lytic with fluffy
calcification. Low to high grade. Prognosis
depends on differentiation and accessibility,
difficult to treat with chemo due to poor
vascularization
Site
Histology conventional (myxoid, hyaline),
dedifferentiated
Islands of cartilage pushed through bone to
muscle. Atypical chondrocytes
Ewings/PNET primitive peripheral
neuroectodermal tumor, usually <20y diaphysis,
metaphysis of long bones. Onion skinning of
periosteum, lytic sclerotic. Sheets of small round
cells, t11;22 on FISH. Rosettes. Need to exclude
SCO, no ALP, CD99+ immunostain
Soft tissue mesenchymal proliferations of fat,
muscle, stem cells, BV. Occur anywhere, mostly in
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2017-2018
large muscles of extremeties in older patients, no
race variation, but some are rare in some
populations (Ewings not in Afro)
Unknown aetiology or linked factors
Liposarcoma myxoid: balloon cell, mucinous
adenoma
Spindle cell sarcoma (nerve sheath): fibroblast,
nerve, SM, skeletal muscle, fat
Pleomorphic sarcoma (stem cell)
Synovial sarcoma: epithelial and mesenchymal,
CK immune recognizable. Otherwise need FISH,
EM, SKY, CGH, PCR, RT-PCR
Tumour specific chromosome translocations
Ewings t11,22
Desmoplastic round cell tumor t11;22
Molecular diagnosis increasing
Good prognosis: small, low grade, superficial,
clear margin, no vascular invasion, diploid (no
aneuploidy), slow proliferation, TS present,
tumour promoter gene absent
3 good prognostic = stage 0
2 good 1 bad = 1
1 good 2 bad = 2
3+ bad = 3
mets = 4
Form bone, slower, hence segmental resection,
can still be optimistic
Transplant
Solid organs: kidney, liver, heart, lung, pancreas.
Small bowel, free cells (BMSC, pancreatic islets),
blood, skin, cornea, bone, cartilage, tendon,
nerve, hands/face
Half life of a transplanted kidney depends on
living or deceased donor, roughly 10-12y.
improved post-op care, technique, management,
transplant immunology (immunosuppressants
and GVHD)
Transplant rejection, 3 phases of rejection
1. Recognition of foreign Ag
2. Activation of Ag specific lymphocytes
Pathology Notes
Year 5
3. Effector phase damage and dysfunction
HLA causes recognition of foreign Ag on C6, and
ABO group (less likely now). Minor HC genes also
play a part. T cell and Ab mediated rejection,
there is a lot of crosstalk, but management is
different
Cell surface Ag presenting to T cells; HLA I (ABC
constitutively active), HLA II (DR, DQ, DP on APC,
or upregulated with danger signals). These HLA
proteins are highly variable, with hundreds of
alleles at each locus
Peptide binding groove on their surface, similar
looking due to similar function. Variability due to
the peptide binding groove, allows us to present
peptides from bacterial Ag. TCR/CD3 highly
variable, needs APC to present Ag
HLA in infection and neoplasia is important. In
transplantation, immunization against the
transplanted organ, recognizing HLA of the donor
HLA A, B, DR are the most important in
transplantation as they are the most variable,
highly polymorphic
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Number of mismatches between a pair based on
A, B, DR
1:1:0 mismatch (shortcut as we dont look at all
of the HLA loci), minimizing differences improves
transplant outcome. Fair AND best use, thus
living donation is encouraged due to less ischemic
damage and family members are likely to share
some alleles
T cell mediated rejection, needs APC to activate
alloreactive T cells. Costimulatory molecules
present. Production of IL-2 to amplify T cell
proliferation. CD4 activation recruits other cells
(cytotoxic T cells, B cell Ab, MP)
Rejection happens systemically, APC move to
lymphoid organs, activated in LN, return to
grafted organ and invade
Granzyme B, eprforin release from CTLs, local
recruitment, interstitial infiltration of T cells
Graft biopsy, high Cr interstitial inflammation
(small blue CD4, CD8, MP) disrupt and infiltrate
tubules, tubulitis
B cell mediated rejection (Ab)
1. Exposure to foreign Ag
2. Proliferation and maturation of B cells, Ab
production
3. Effector phase Ab binds endothelium of
graft )capillaries of glomerulus, arterial)
Natural anti-A or anti-B can cause Ab med
rejection. No natural anti-HLA, only if exposed to
another persons tissues (pregnancy, transfusion,
prior transplant). De novo post-formed after
transplantation. May also activate complement
Complement activated lysis after HLA on donor
epithelial cell binds Ab. Slow attack sub-lytic
complement or cross linking can lead to
proliferation of endothelial cells/hypertrophy,
new BM formation leading to slow organ damage
Recruitment to microcirculation peritubular
capillaries, different histological picture.
Pathology Notes
Year 5
Glomerulitis in Ab-mediated rejection.
Peritubuluar capillaries full of inflammatory cells
C4d stain for Ab on endothelium and local
complement activation, brown staining
ABO glycoproteins in RBC surface and endothelial
lining on BV of transplanted organ, in the past the
new organ would not perfuse due to immediate
thrombosis, immediate failure, remove these
with plasma exchange and patients do well
Prevention of rejection with AB/HLA matching
encourage donation from relatives in kidney
and BM. Determine with PCR-DNA sequence
analysis to find geneotype
Screen for anti-HLA, find if Pt is sensitized. How
many and which Ab they have. The more they
have = more difficult to transplant. Then new
ones will arise, try to monitor and treat
1. Cytotoxicity assays: serum, donor
lymphocytes, complement, viability stain
2. Flow cytometry: donor lymphocytes with
recipient serum, can add anti-human IgG
with FITC label, count and find negative or
positive flow crossmatch/intensity of
reaction
3. Solid phase assays: recombinant Ag HLA
on surface of beads mixed together, mix
serum with beads to look for fixing of Ab
on surface, more precise quantification
for each HLA specificity
Transplant with sons kidney, rise in anti-
DQ5/DR1 titre and Cr, treat with plasma
exchange and IVIG, titres reduced, slow graft
dysfunction and is unlikely to last long. Still
functional
Xenotransplantation or stem cell research in the
future
Treatment
Immunosuppression to dampen immune system.
Targeting T or B cells
T cell activation inhibited with:
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Mab against anti-CD3 (OKT3, ATG) T cell
depleting agents, fix on surface
Alemtuzumab anti-CD52 mAb
Calcineurin inhibitors downstream
pathway after TCR activation: ciclosporin,
tacrolimus
Cell cycle inhibitor azathioprine,
mycophenolate mofetil
IL-2R anti-CD25 mAb daclizumab
Targeting Ab new drugs:
Plasma exchange to remove the Ab from
circulation
IVIG targeting Ab in T cells via negative
feedback with flooding body with Ig, shut
down production of Ab against graft
Anti-CD20 B cell depletion
Proteasome inhibitors prevent plasma cell
Ab production
Complement inhibitor: eculizumab
Regime: prepare with induction agent T cell
OKT3/ATG, (campath) anti-CD52, anti-CD25 (anti-
IL2R or), then baseline immunosuppression CNII +
MMF or Aza, possibly with steroids. Acute
rejection add steroids methylprednisolone IV
then oral, ATG/OKT3 in cellular. Ab mediated
with IVIG, plasma exchange, anti-C5, anti-Cd20
(late graft failure, often resistant to treatment)
Hematopoietic stem cell transplant: blood cancer,
BM deficiency. Eliminate host immune system
with total body irradiation, replace with
autologous or allogeneic BM. Donor lymphocytes
will mount reaction against host tissues. Depends
on HLA-incompatibility, graft vs tumour effect is
positive. GVHD MTX/CIC
GVHD: skin, liver, gut. Injury induced by
cytotoxics in the gut. Reaction of donor against
host tissues
Post transplant malignancy especially viral:
HHV8 Kaposi, lymphoproliferative disease (EBV),
skin cancer, lung, colon
UTI
Urine and bladder should be sterile until urethra,
cystitis and ascending infection to kidney.
Pathology Notes
Year 5
Bacteriuria is the presence of bacteria in the
urine, but this is not too important especially due
to sampling method
Coliforms in pregnancy, dangerous. Doesnt need
treatment in elderly or in normal people without
symptoms
Cystitis inflammation of bladder often due to
infection
Uncomplicated UTI in a structurally and
neurologically normal tract, whilst complicated
UTI in functional/structural abnormalities
(catheter, calculi, posterior valves in children,
men longer tract, pregnant women gravid uterus
compress, children, hospitalised)
Bacteremia in young nonpregnant women 1-3%,
40-50% females experience UTI with symptoms in
their life, dont always treat. Very common
UTI 95% caused usually by single species of
bacteria; E coli. Only a few serotypes;
O1/2/4/6/7/8/75/150/18ab virulence factors
such as fimbriae adhere to epithelium to prevent
washing out and help ascend
Other organisms: CNS S saprophyticus in young
women especially attaching to urothelium.
Proteus, Klebsiella (neuro/anatomical
abnormalities), S epidermidis rare cause except in
prosthesis (procedure, longterm indwelling
catheter)
Recurrent and structural abnormalities increases
relative frequency of atypicals. Resistant to host
defence, urine osmolality, pH, organic acids, urine
flow, micturition, mucosa bactericidal activity,
cytokines
Ascending UTI, urethra usually colonized with
bacteria, female is short, proximal to
vulvar/perianal areas, likely for contamination.
Organisms causing UTI in women colonise vaginal
introitus/periurethral area before UTI. Massage
urethra/sec can force bacteria into bladder.
Multiply and enter ureters/vesicoureteric reflux
present to renal pelvis/parenchyma. Some E coli
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2017-2018
more associated with ascension but others stay
lower down due to different virulence factors
Abnormality of renal tract/urine flow obstruction.
Stasis increases susceptibility to infection
1. Mechanical extrarenal: BPH, stenosis,
valves, calculi, PCKD
2. Neurogenic: DM, spinal cord, tabes
dorsalis, poliomyelitis
3. Vesicoureteral reflux in children by
maintaining residual pool of infected urine
in bladder after voiding. Scarring and
chronic kidney problems
Hematogenous spread is also possible to the
kidney, site of abscess in S aureus
bacteremia/endocarditis. G- bacilli rare by
hematogenous
Symptoms different in varying age groups
1. Children <2 failure to thrive, vomiting,
fever
2. Children >2 frequency, dysuria, abdominal
pain/flank pain, burning. More localized
Lower UTI symptoms, irritation of urethral,
vesical mucosa. Frequent and painful urination of
small amounts of turbid urine. Some suprapubic
pain/heaviness, some blood at the end of
micturition if severe. Fever absent in lower UTI
Upper UTI symptoms: rigors and fever (G-
bacteremia rigors), flank pain, lower tract
symptoms (freq, urg, dysuria) earlier by 1-2 days
Older patients are often asymptomatic, often not
diagnostic due to high prevalence of freq,
dysuria, hesitancy, incontinence. Symptoms often
abdominal pain, change in mental status
Investigation if uncomplicated: urine dip, MSU for
MCS, bloods with FBC/UE/CRP
Complicated UTI renal USS, IVU. Perinephric
abscess, structural abnormalities in children
Dipstick leukocyte esterase made by WBC,
nitrites made by coliforms which we cannot
Pathology Notes
Year 5
absorb. Positive nitrites more suggestive of UTI.
N-/L+ could be atypical
MCS in pregnancy due to associated with
pyelonephritis and early delivery, catheter,
children, resistance with ESBLs
Pure growth single organism 10^4 generally
diagnostic, lower if typical. Pyuria may be absent
in child UTI
TB, taking Abx can give a false negative.
Squamous epithelium lining urethra, if we see
this, implies early stream urine reducing
significance (not sterile)
Positive catheter specimen dont treat unless
symptomatic
Urine dip leukocytes + nitrites; white cell pyuria
showing infection, squamous cell shows
contamination (look like fried eggs)
Sterile pyuria: prior Tx with Abx, calculi,
catheterization, bladder neoplasm, TB, STI
Count colonies on plated agar; 10^5 but can be
positive if sterile bladder urine, with proper
collection
Empirical treatment in community lower UTI,
follow local guidelines TMP high resistance
Uncomplicated female: cephalexin or
nitrofurantoin 3d
Anaphylaxis use nitrofurantoin
Men longer 7d, prostatitis ciprofloxacin
Systemic complicated upper UTI: co-amoxiclav +
aminoglycoside to cover resistant ESBLs
Systemic unwell AND C diff use just
gentamicin/amikacin aminoglycoside
Catheter often causative and colonized, treat
only with clinical reason, biofilm wrong cell cycle.
Fungi usually on catheter, can cure UTI,
Candida+catheter. No benefit in treating
Alice Tang
2017-2018
asymptomatic, dont treat unless
immunocompromised, transplants, or elective
urinary tract surgery (introduce camera), often
from untreated thrush (similar)
Pyelonephritis infection of the kidney, greater
number of organisms to kidney increases risk.
More with sepsis, aggressive treatment with
broad spectrums, more systemically unwell: co-
amoxiclav and gentamicin. Less Cipro due to
association with C diff and resistance. Image to
investigate structural/calculi reasons
Complications: perinephric abscess, chronic leads
to renal impairment and scarring, septic shock,
acute papillary necrosis
Prophylaxis controversial, promotes resistance,
adverse effects. Not advised
1. E coli
2. S saprophyticus in young women
Immunology of HIV
37M living with HIV,39M have died of AIDS, 5000
infected per day, 10% are children, mostly die
within 20y without access to ART, orphaned 13M
children, kills more people worldwide than any
other infectious disease
Retrovirus, RNA replicates with RT and integrates
DNA into host genes, infects CD4+ cells,
icosahedral shell protein (20 faces)
CD4 T cells and CD4 monocytic/follicular DC
germinal center of LN, cells are host targets, slow
developing 10y, dipoid +ssRNA, each RNA
associated with RT enzyme. 9 genes (structure:
env, gag, pol, regulatory: tat, rev, nef, auxillary:
vif, vpr, vpu) encodes 15 structural, regulatory,
auxillary proteins.
Env gp120/gp41 surface for vaccine
development
Gag p17, p24, p9, p7 therapy HLA-specific
T response and replication
Pol RT, IN, PR integrase, protease
enzymes for drugs
Pathology Notes
Year 5
HIV-1 uses cells to replicateand move cell to cell,
selective loss of CD4 T helper cells, changes the
function of these cells. Immunity needs Ab (B
cells) prevent infection, neutralize virus, enough
CD8 CTL to kill latent infection
CD4+ Th provide help for B cell, CD8, APC main
cell, hence immune failure. Progressive decline in
function before number. Progressive; HIV-specific
CD4 then lack of recall responses (vaccines,
opportunistic), allo responses and mitogen
responses lost. IL-2 also lost, strongest stimulator
of T cells
Entry needs CD4 and co-receptor CCR5, CXCR4
(chemokine receptor). Blocking chemokine
receptor prevents infection
Transmission: sexually via mucosal surfaces
(increased in damage such as other STI), CD4 and
DC in mucosa which bind and carry virus to local
LN or other cells. Infected blood transfusion,
products, sharing needles. Mother to child
vertical transmission before or during birth, via
breast milk
Natural immunity within hours of infection
involves: inflammation, nonspecific MP
activation, NK, complement,
cytokines/chemokines, stimulation of pDC
plasmacytoid via TLR (can secrete IFNa)
Humoral B cell responses with neutralizing Ab
made later, with anti-gp120, anti-gp41, virus has
already proliferated and mutated to espace. Non-
neutralising anti-p24 gag IgG also made (?role).
HIV infectious even when Ab-coated
CD4 orchestrate response, recognize gag p24
peptides in HLA II, selectively lost
CD8 kill HIV/cancer cells, suppress viral
replication, prevent viral entry to other cells due
to secretion of soluble mediators (antiviral
cytokines, IFNg, TNFa, MIP1a, MIP1b, RANTES
CCR5 blockade prevent entry)
CD4 longer peptides on APC, CD8 shorter
peptides on target cell
Alice Tang
2017-2018
HIV-1 interferes at CD8 T cell activation several
key points, from nave to effector cells as it
depends on CD4 and APC (MO/DC)
Lysis of infected cells, cytokine and
chemokine production
Anergised CD4 by virus, cannot prime CD8, no
APC activation, diminished CD8/B cell memory
and responses. Infected MO/DC killed by
virus/CTL
HIV accumulates mutations/variants/quasispecies
due to RT lacking proof reading mechanisms, low
fidelity of viral RNA to cDNA and transcription of
DNA to RNA
Escape from neutralizing Ab, escape from specific
T cells, resistance and escape from ARVs:
1. Attachment/entry
2. RT and DNA synthesis
3. Integration
4. Viral transcription
5. Viral protein synthesis
6. Assembly and release
7. Maturation
HAART = 2NRTIs + PI (or NNRTI)
RTI (NRTI are incorporated, NNRTI binding
agents)
Attachment inhibitor (maraviroc CCR5i)
Fusion inhibitor
Integrase inhibitor
Protease inhibitor
Median time to AIDS 8-10y, viral burden set point
predicts disease progression after peak viraemia,
if left untreated. Rapid progressors 10% 2-3y,
LTMP <5% stable CD4 no symptoms after 10y.
ESN exposed seronegative (1 partner exposed but
other still seronegative after years unprotected),
HAART changes course of disease
LTNP genetic, immune and virologic factors:
1. HLA-B57 non/slow progression, MBL
alleles, CCR5 deletion, TNFc2
2. Effective CTL/HTL responses
3. Attenuated strains
Pathology Notes
Year 5
Testing: anti-HIV Ab on ELISA or PCR-viral RNA
(VL) this is more sensitive when immunology is
low
HIV Ab ELISA screening test, but Western blot is
confirmatory. Baseline plasma VL good predictor
of time taken for disease to appear. Flow
cytometry whole blood anti-human
CD3/4/8/18/56/57/158b
HAART increase CD4, decrease VL, lower
opportunistic infections and AIDS deaths.
Reservoir of cells remain
Initial CD4 rise in Tmem redistribution, later CD4
thymic nave T cells
Many regimens, 40 drugs from different classes.
Dropped: zalcitabine, amprenavir
Initiate treatment with HAART when patient is
symptomatic, CD4 200-350, all offered
immediate treatment
Vaccination
Measles is very contagious; the number of people
that one sick person will infect on average (R0) if
effective R0 <1, transmission is halted R0 measles
= 18
Herd immunity threshold HIT = 1 1/R0
Percent of fully immune people needed to stop
the spread of disease. Measure of protection for
people who are not immune. Immunity isnt
conferred in 100% of vaccines
Memory cells to vaccine Ag, robust response post
vaccination. Increase immunogenicity by adding
adjuvants
Live vaccines single dose enough for immunity,
strong response, local and systemic immunity.
However, may revert to virulence so not for
immunosuppressed, interference by
viruses/passive Ab, poor stability, may be
contaminated
Alice Tang
2017-2018
Inactivated vaccines more stable, clearer
constituents, cannot cause infection. Several
doses, local reactions common, need adjuvant
Other vaccine components include: active,
adjuvants (AlOH, phosphates), Abx/formaldehyde
trace components, preservatives, stabilisers
Serious reactions
1. DTP encephalopathy, shock, anaphylaxis
2. OPV/IPV GBS, polio
3. Measles ana, thrombocytopenia
4. Rubella acute arthritis
5. T GBS, ana
6. HepB ana
Give vaccine before age of peak incidence,
targeted vs widespread, catch u-p campaign,
endemic vs epidemic
Eradication: no animal reservoir, antigenically
stable with few strains, no latent reservoir, or
integration, lasting, high coverage
Measles live vaccine, deaths in
immunosuppressed. More older children got
measles, change in epidemiology. MMR trivalent
1998 second dose to induce immunity in those
who havent responded to the first dose
Haem
RhA ACD, IDA from NSIADs,
neutropenia/thrombocytopenia from drug
toxicity, Felty syndrome (large spleen in RhA
causing pancytopenia), increased ESR
Prolonged aPTT haemophilia A, mixing test
deficiency
TTP ADAMTS13 Ab, treat with plasma exchange,
remove Ab and replace protease. In emergency
give plasma infusion. Steroids later on despite it
being immune. Do not give platelet transfusions
Splenic rupture high mortality 30%, may be trivial
trauma (turning over in bed). 50% large spleen in
Pathology Notes
Year 5
Vaccinate against pneumonoccus, H flu,
meningococcus, dog bites, malaria, lifelong
penicillin, splenectomy card
Nodular sclerosing Hodgkin lymphoma, CT
needed earlier for diagnosis as node was behind
the heart. ACD low RBC lifespan. Release of IFNg,
IL1, TNF, low proliferation, low EPO, poor iron
utilization. Treat underlying disease, EPO
1% cancers HL: adolescence and old age. Painless
LAD above diaphragm, 1/3 B symptoms, familial,
EBV in >50, histopathology needed, ESR for
monitoring, CT/MRI/PET staging
Blood Transfusion
ABO incompatible transfusion results in
intravascular hemolysis, naturally occurring IgM
antibodies in plasma (e.g. group O has anti A and
anti B)
RhD (85%+) on RBC + or -, RhD- can make anti-D if
exposed to RhD+ RBC, these are IgG and do not
cause direct agglutination of RBC, not immediate
but delayed hemolytic transfusion reaction.
Others include CcEe, Kell 90%+, Duffy, Kidd, M, N,
S only match if they have the corresponding Ab
or other situations SCD (more likely to make Ab
due to lifelong transfusions). RhD- can be given to
anyone but short supply no problem first time
RhD+ to RhD- but next time needs RhD-. In
pregnancy can result in severe fetal anemia/HF
hydrops fetalis if mother is RhD- and fetus is
RhD+ (exposure to positive blood makes the
immune Ab)
Test ABO/RhD use known anti-A/B, D against Pt
RBC and reverse group against their plasma (IgM
Ab) positive = agglutination clumping, before
every transfusion. Column agglutination
technology; positive cells stay at the top, fast.
100s of RBC Ag but cannot test for all of them, 1-
3% have immune RBC to 1+ RBC Ag due to
transfusion/pregnancy. Immune Ab are IgG, find
clinically significant RBC, transfuse negatives to
prevent delayed reaction. Dont worry about this
in major hemorrhage
Alice Tang
2017-2018
Ab screen on patient plasma, use 2-3 reagent RBC
with all Ag using IAT technique (indirect Ag)
clump before every transfusion, no manual steps
Add antiglobulin reagent, spin to detect ABO
incompatibility for serological crossmatch. IgG
binds but no crosslink, IgM anti-A/B fix
complement and lyse cell
Electronic crossmatch, compatibility determined
by IT not physical testing, faster, fewer people, no
need to have blood around, better stock
management, only possible if the patient has no
Ab
F: 11.5-13.5 normal Hb, if 10, transfuse if
symptomatic and actively bleeding
Must inform patient if transfused in an
emergency, valid consent needed for transfusion,
give alternatives if possible, right blood needed
RBC stored at 4C for 35d, move from fridge needs
to transfuse in 4h, 1 unit over 2-3h
Plts weak expression of Ah, should be D
compatible, but not in emergency, store at 22C
for 7d, 1 unit over 20-30min. Irradiation (prevent
GVHD) or washed plts. O plts to A/B/AB need
high titre negative, more likely to get bacteria
Plasma, group D doesnt matter, MB treated
plasma to children (1996, non UK sourced, reduce
risk of vCJD), AB universal donor given to all
groups with no anti-A/B short supply, no need to
cross match, but 30-40 mins to thaw 1 unit over
20-30min
Indications
Major blood loss >30% blood volume
Peri-operative critical care <70g/L
Post chemo <80g/L
Symptomatic anemia, IHD, ECG changes
Hb>10
Check Hb pre transfusion and every 1-2 units,
increment 1 unit increases 10g/L in 75kg person,
transfuse to above 100g/L rarely needed unless
severe disease. Children based on weight to
prevent overloading
Pathology Notes
Year 5
Maximum surgical blood ordering schedule, if not
used, they are taken back until they expire,
predictable blood loss, rarely need blood for GB.
Some always need blood = AAA repair
Elective surgery G+S, if Ab present then
crossmatch
Intra-operative cell salvage, collect lost blood,
centrifuge, filter, wash, re-infuse
Post-op cell salvage into wound drain, filter,
reinfuse for ortho, all CF/plts removed in cell
salvage methods
CMV- for intrauterine/neonatal, elective in
pregnant women to prevent fetal exposure
Irradiated blood for immunosuppressed, cannot
destroy donor lymphocytes
Washed if severe allergic reaction to some
plasma proteins
Platelet transfusion
Major transfusion >75
Post chemo prevent bleed <10 (<20 if
sepsis)
Surgery <50 (H/N<100)
Platelet dysfunction or immune cause if
active bleeding and no alternative/life
threatening
FFP if blood loss >150ml.min, DIC with bleeding,
liver disease and risk PT>1.5 N, beriplex in
warfarin reversal. Adult dose 15mL/kg, 1 unit
250mL 4-6units for adults
CPC Ca
Low Ca = fits
High Ca = depression
Smith fracture flexed fracture, Colles extended
Potts fracture ankle tibia and fibula
Microscopic hematuria in IE
Severe renal colic, may pass the stone, painful
but then its gone
Alice Tang
2017-2018
GN painless microscopic hematuria
Hypercalcemia = stones, bones, groans,
polydipsia/polyuria (nephrogenic DI osmotic
diuresis just like glucose). Band keratopathy on
the eye calcification of iris. Renal stones,
pancreatitis, PUD, skeletal changes (fractures,
bone loss, lytic lesions in the skull)
Malignancy, hyperparathyroidism, sarcoidosis
Use PTH to differentiate these three causes.
Often history of chest sarcoid in sarcoidosis. In
hospital commonly Ca, previous Ca is Ca,
normally healthy. In HIGH Ca, PTH should be 0,
but can appear normal because of elevation living
6m with hyperCa is almost 0
PTH 1.1-6.8
Ca 2.2-2.6
85% parathyroid adenoma uncontrolled release
PTH, bone, kidney, intestine, increases Ca in
blood
1a hydroxylase is regulated by PTH, increased,
conversion to calcitriol (1,25,(OH)2D3) can result
in hypercalcemia. PTH regulates Ca
HyperPTH normal/high PTH, high Ca, low Phos,
high/N ALP, normal VitD consumed by
1ahydroxylase
Renal stones
Uric acid radiolucent
Struvite staghorn
Cystine radiopaque (mild)
FH, dehydration, hyperCalciuria >6, hyperCa,
HPTH, Proteus recurrent UTI, colic, hematuria,
renal failure nephrocalcinosis. CTKUB, measure
urine and serum biochemistry. Most stones pass,
some are study lithotripsy, cystoscopy,
lithotomy. Drink water, treat hypercalciuria
(thiazides to reduce urine Ca, increase serum Ca)
or hyperCa
Single adenoma 85%, lose Ca from bones slowly,
with osteoporosis, lytic after many years,
overactive VD
Pathology Notes
Year 5
Tumours, 4 gland hyperplasia genetic
MEN1(pituitary, parathyroid, pancreas) from age
of 15 onwards (MEN2 less common HPTH),
carcinoma very hyperCa. Painless
nephrocalcinosis/lithiasis. Salt and pepper skull,
periosteal resorption
IV saline for hyperCa, rehydrate patient, medical
emergency if Ca >3 (arrhythmias at risk) 4L/day,
lost Na need to replace, give frusemide if
HF/elderly
Bisphosphonates in cancer to reduce Ca
Surgery to remove PTH in HPTH
Ca>3 dehydrated, confused, drowsy, coma,
seizures, renal failure, IV, catheter, rehydrate
0.9% saline, plus frusemide. IV pamidronate 30-
60mg hold off as you cannot make a diagnosis as
PTH will be high and we dont know why, reduces
pain too when cancer grows into the bone
(activates osteoclasts, stop bone turnover) C=N
OB use pamidronate to make bone, not able to
turnover so cancer mets cannot enter bone, pain
stops
USS and sestaMIBI Tc scan = concordant, then
find out which is the tumor, remove the largest.
Gene MEN1 remove
Hyperplasia in MEN1/2, look at gland to decide if
it is adenoma or MEN
PHPTH multinucleated giant cells
CPC Malabsorption
32F TATT, muscle aches, loss of energy, weight
loss deliberate, stress ++, eczema as a child,
moderate folate deficiency
FBC, U+E, LFT, glucose, thyroid
Microcytic anemia
IDA: low Hb, low Fe, high RIBC/transferrin, low
transferrin saturation, low ferritin
Normal peripheral blood film
Alice Tang
2017-2018
IDA increased central pallor, poikilocytes (tear
drop cells, elliptocytes) oval macrocytes
Bthal aggregated ribosomal material basophilic
stippling RNA remnants, seen also in lead
poisoning, sideroblastic anemia
WBC hypersegmented neutrophil megaloblastic
anemia, poor DNA synthesis B12, folate, drugs
(hydroxycarbamide, methotrexate)
Codocytes (target cells) high SA:vol, in IDA, thal,
hypoplenism, liver disease
Howell jolly bodies nuclear remnants in RBC =
hyposplenism, reduced function
IDA causes: blood loss, poor diet, malabsorption,
combination
Megaloblastic: B12/folate, poor diet,
malabsorption, pernicious anemia
Hyposplenism: no spleen (therapeutic, trauma),
poor function (IBD, celiac, SCD, SLE)
Low Ca, high ALP, VD low, PTH high
SHPTH. VD deficiency (poor diet), B12/folate,
hyposplenism. Bowel disease with malabsorption
refer for 2ndary care
Anemia should not ignore
Bacterial overgrowth (poor motility in gut),
tropical sprue (uncommon)
1. Coeliac lacking Fe, B12, folate, fat, Ca
2. CD (Fe more due to blood loss) B12, bile
salts
3. Pancreatic disease fat, Ca, B12
4. Bacterial overgrowth fat, folate
Inflammatory markers CRP/(ESR), 10% with CD
dont produce CRP response. Serological tests,
UG endoscopy, distal duodenal biopsy waiting
list, fecal elastase (pancreatic malabsorption
mod-sev), CT, MRI small bowel (CD)
Pathology Notes
Year 5
Polygenic AI, monozygotic 75% concordance at
MHC. 90% HLA DQ2/DQ8 association
Gliadin deamindated by TTG, T cell response, HLA
presentation to CD4 T cells make IFN-y and APC
are activated, production of IL-15. Activate
intraepithelial lymphocytes, NKG2D (recognize
MICA stress), kill and damage epithelium
B cell with surface receptors for gliadin, presents
to primed CD4, helps B cell germinal center
reaction, isotype switching to IgG/A, affinity
maturation (high affinity), anti-gliadin Ab. IgA
more sensitive than IgG but low sp/sens and
outdated
T cells for gliadin TTG complex
Anti-endomysial and anti-TTG Ab
Anti-TTG IgA best test, most sen/sp. Some people
are IgA deficient, need to check Ig too!
Anti-gliadin persists for 12m on gluten free diet
whilst others disappear quickly
Can also investigate under endoscopy, under
magnification. Patchy, so take multiple biopsies
(6 ideal, 4 min)
Subtotal villous atrophy
Increased intraepithelial lymphocytes present in
dermatitis herpetiformis, lymphoma, sprue
Villous atropgy: diardia, sprue, CD, radiotherapy,
GVHD
Complications include osteomalacia/porosis,
epilepsy/cerebral calcification, lymphoma,
hyposplenism
1. Lymphoma
2. Not sticking to the diet
3. Resistant celiac
DQ2 on the end of the chromosome, thyroid
PLUS coeliac AI correlation. Results in chronic Fe,
folate, B12, D, K deficiency, malignancy
Alice Tang
2017-2018
lymphoma, feel better physically and
psychologically when treated
Recurrent mouth ulcers, IBS, infertile, epilepsy,
short stature, peripheral neuropathy can
present
Blood
Low ferritin AND low transferrin saturation = IDA
Reticulocyte count shows BM is working
Reticulocytes absent = inadequate haematinics,
acute major hemorrhage (takes a few hours), BM
failure
Blood film IDA shows pencil cells, these are
pathognomic, anisopokilocytosis, hypochromic
Normal WBC do not clump, can see Auer rod
AML (otherwise just AL)
APML many Auer rods
MDS abnormal blasts in BM
ALL children, CLL old, CML middle aged, AML any
age
HIV commonest cause of low plts in a young man
Meeran 2
Wrist DEXA for HPT
Spine and femur for other types, Cushings and
steroids
Operate if they are young, with stones or low
bone density, severe
PHPTH radial aspect cystic changes (lytic). Looser
zones in vitamin D deficiency pseudofractures
where bone has been lost (weak from
osteomalacia/VDD)
CXR/bloods
In sarcoid, steroids will normalize the Ca and
treat the bilateral hilar LAD, macrophages express
1a hydroxylase, seasonal due to sun and vitD
E coli meningitis ONLY in <1 neonates
Pathology Notes
Year 5
Mycoplasma second commonest pneumonia,
cold agglutinins positive: give macrolide to cover
atypicals (co-amoxiclav AND erythromycin)
Anti-staph = flucloxacillin, S aureus abscess/boils
but NOT cellulitis. Strep = cellulitis, more
dangerous and can invade with hyaluronidase
flesh eating bugs
Strep just penicillin
S viridans PUO teeth, settles on a damaged valve
due to MS or MR from RhF. Indolent, subacute IE
S aureus endocarditis is acute and aggressive IE
from IVDU. Septicemia and kills you in 3w, no
clubbing or peripheral signs
Mycobacterial Diseases
33% of the worlds population is infected with TB
NTM non-tuberculous mycobacteria are
ubiquitous in the environment, often grow in
water and soil (hot tubs), difficult to eradicate.
Cellulitis in warm water/shower heads, some like
cold water (M marinum in fishing)
MTB complex causing most human disease (M
bovis BCG, MTB), MAC (M avium, intracellulare),
M leprae
Non-motile, rod shaped, slow growing bacteria.
Long-chain, waxy, fatty acids (mycolic) culture for
6-8w holds onto acid (AFB)
ZN Ziehl Neelsen stain purple against blue
Auramine fluorescent stain (yellow on
black, more sensitive test)
NTM have varying pathogenicity, no
person to person transmission, commonly
resistant to anti-TB treatments, regular
colonisers
MAI (M avium intracellulare)/MAC
immunocomputent ronchial tree in
bronchiectasis/cavities. Immunosuppressed
results in disseminated infection. M marinum
swimming pool granuloma cutaneous, M ulcerans
Alice Tang
2017-2018
skin lesions W Africa, Bairnsdale ulcer, Buruli
ulcer (large, chronic, progressive painless ulcer)
Rapid growing NTM = M abscessus, chelonae,
fortuitum. Skin and soft tissue infections in
hospital settings, catheters and devices. Easier to
treat
Changing epidemiology: increasing age, airway
disease, previous TB (cavitating disease)
Diagnosis: BTS guidelines, clinical and micro. Lung
disease with pulmonary symptoms, nodular
opacity, bronchiectasis, multiple small nodules,
positive culture >1 sputum sample or +BAL, +
biopsy with granuloma
Difficult to treat:
MAI macrolide, rifampicin, ethambutol,
(amikacin, streptomycin) rapid growers often
resistant. Susceptibility testing, but usually
macrolides
M leprae multibacillary lepromatous, leonoid
facies huge Ab response, shed many bacilli whilst
paucibacillary tuberculoid losing limbs do not
shed much, anti-TNFa increases risk of
reactivation
HIV combination results in multisystem disease
extrapulmonary, 2nd commonest cause of
infectious deaths, 2m a year, increased incidence
in UK due to immigration and opportunistic
infection in HIV, 9000/year, sanitation
10/100k is high, US is around 2, Delhi 110, some
areas of London is similar. Lifetime risk of close
contact with smear positive pulmonary TB is 10%
risk (greatest in first 6m) of active TB
Disease states:
1. Cleared disease IGRA
2. Exposed but not infected IGRA
3. Primary active TB (low CD4, TNF block)
4. Contained disease (localized) IGRA
5. Latent TB (able to control, large
population) IGRA/TST+ but can move to
active phase (age, alcohol, renal failure,
steroids)
Pathology Notes
Year 5
MTB complex: MTB, M bovis (contaminated
milk), M africanum (7 species) obligate aerobe
15-20h generation time
Transmission droplet/airborne suspended tiny
particles in the air negative pressure rooms
needed. Reach lower airway macrophages, 1-10
infectious dose 1-10 bacilli very few, 3000
infectious nuclei in 1 cough or talking 5 mins,
remains for 30 mins
Prevention: detect cases, treat index case,
prevent transmission using PPE/negative
pressure isolation
Optimise susceptible contacts: risk factors and
vaccination with BCG live attenuated M bovis,
babies in high prevalence communities only 70-
80% effective to prevent severe childhood TB,
protection wanes with little evidence in adults
Notifiable disease, treat the vulnerable
population and get them into hospital
Ghon focus/complex in primary TB cell mediated
immunity, granuloma formed, erythema
nodosum and some disseminated/military TB.
Latent TB/reactivation in 10%
Post-primary (reactivation) TB commonly seen 5y
later, 5-10% risk in lifetime, risks include
immunosuppression, chronic alcohol excess,
malnutrition, ageing, pulmonary/extra-
pulmonary. Less effective immune response
Caseating granuloma in lung parenchyma,
mediastinal LN
Upper lobe common, walled off
Extrapulmonary: TB lymphadenitis (scrofula,
Kings disease), cervical LN commonest, abscess,
sinus, GI swallow tubercles, peritoneal
ascetic/adhesive, genitourinary slow progression
to renal disease, spread to lower urinary tract,
hydronephrosis
Bone and joint via hematogenous spread
commonest spinal TB Potts disease hunchbacks,
typically thoracic, military TB progressive and
Alice Tang
2017-2018
increasing from HIV, progressive disseminated
hematogenous TB
Risks: South Asia, SSA, HIV. Fever, weight loss,
night sweat, cough, anorexia, hemoptysis
Investigate with CXR, radiology, sputum 3x
(induced with saline), bronchoscopy, biopsy, EMU
genital, AAFB smear, culture, NAAT PCR,
histology, tuberculin skin test (Mantoux, dont
help in diagnosing active TB), IGRA
LN ring enhancing and central necrosis for
mediastinal LN
Gastric aspirates in kids, centrifuge, rapid but
operator dependent smear
PCR will reveal drug sensitivity too. RPO
rifampicin resistance on this gene
Mantoux only tells us about exposure to MTB,
not active disease. IGRA finds IFNy production,
doesnt differentiate active disease
Anti-TB (RHZE) rifampicin interacts with many
drugs orange secretion, isoniazid H peripheral
neuropathy, hepatotoxic, pyrazinamide Z
hepatotoxic, ethambutol
drusg for 6m, then RH 4 months, upload video
to take drug = video or direct observed
MDR TB (RH resistance) especially in USSR 20%,
very transmissible. XDR (RH + fluoroquinolones,
use moxifloxacin) increased risk with previous
treatment, HIV, known contact, failure to
respond, smear positive after 4m. longer regimen
18-24m, toxic medication, 50% new diagnoses in
some areas HIV+TB
Shorter course regimen 7 drugs, 9-12m for MDR-
TB, lower cost 90%+ cure rate
Challenges in TB-HIV coepidemics, drug
epidemics, more likely to have normal XR and
smear -, TST (as T cell mediated and these are
damaged), detection is later.
Pathology Notes
Year 5
Enzymes
Enzymes mostly measured to detect tissue injury,
intracellular, some are released as a result of
normal cell turnover. Cytosolic or subcellular;
tissue injury cause cytosolic leakage increasing
plasma concentration. More extensive damage
causes breakdown of cells and release of
subcellular organelle enzymes
Different isoenzymes are specific to particular
tissues: ALP is produced by intestines, bone, liver,
placenta. Increases are mostly in liver and bone
disease, increase in bone = increased OB activity.
GGT liver production distinguishes bone and liver
ALP, muscles also have AST (nonspecific for liver).
Can also use electrophoretic separation, bone
specific ALP immunoassay
Raised ALP in pregnancy 3rd trimester and
childhood growth spurt
Pathological high ALP
1. >5x upper limit of normal
a. Bone Pagets osteomalacia
b. Liver cholestasis, cirrhosis
2. <5x
a. Bone tumour, fracture,
osteomyelitis
b. Liver infiltration, hepatitis
Raised ALP NOT in OP unless there are fractures
too
Amylase exocrine pancreas, high in acute
pancreatitis, 10x upper limit of normal or small
increases in acute abdomen (PUD). Salivary
isoenzyme (parotid mumps). Lipase more specific
marker of pancreatitis
CK muscle damage, 3 forms with M/B dimers
1. CK-MM skeletal muscles
2. CK-MB (1/2) cardiac <5% circulating
3. CK-BB brain minimal even in severe
damage
Statin myopathy myalgia to rhabdomyolysis,
raised CK. Risks include polypharmacy (fibrates
gemfibrozil, cyclosporine, CYP3A4), high dose,
Alice Tang
2017-2018
genetics, previous history. Less likely in
rosuvastatin or newer ones (lower dose/MOA)
Increased CK in exercise, IM injection, cocaine.
Inherited myopathies (DMD), MI, Afro-
Caribbeans, hyperthyroidism
TPMT activity for thiopurines: aza,6MP,6TG (6
thioguanine) drug toxicity markers
ACS necrosis leads to rise in cardiac troponin,
myoglobin, CK-MB (CK, AST, LDH used before)
Troponin some bound some free, some of the
cyto pool leaks out. In more severe injury MI, the
bound form also leaks, higher release of troponin.
rise 4-6h, peak 12h, raised 3d. no biomarkers rise
quickly enough to aid in thrombolysis decision.
presentation and 12h later troponin, 3-10 days
raised. CK would have fallen after a while
ANP/BNP (atria/ventricles) ventricular function
and heart failure markers clinically
Viral Infections in Pregnancy
Teratogens: VZV, Zika
IUGR/premature: rubella, CMV
Congenital disease: CMV, HSV
Persistent infection: HIV, HepB/C
Rashes: VZV, EBV, HSV, CMV, PB19 (fifth disease),
enterovirus, measles, rubella
Herpes DNA viruses, infection for life, serology
shows exposure and can reactivate to cause
shingles, cold sores, herpes in genitals.
HSV 1+2 close contact transmission short latency
in days, dorsal root ganglion latency.
Asymptomatic, painful vesicular rash, LAD, fever.
Direct contact with secretions, oral herpes at
delivery. Primary genital infection in 3rd trimester
greatest risk, GUM clnic, acyclovir, type specific,
C-section if infected in final 6w. maternal Ab
protection but does not prevent transmission,
PROM and invasive monitoring should be avoided
Pathology Notes
Year 5
Neurological disease 2-6w worst (+lesions at a
week), disseminated disease in brain at a week.
Mortality 80% if untreated, swab baby
VZV respiratory transmission 70% attack rate in
susceptible, higher in a household, infectious
from 48h until all crusty, prodromal fever,
myalgia worse in adults, maculopapular rash to
vesicles in trunk to extremeties, can scar
Clinical diagnosis or EM/PCR (not serology)
10-20% women of childbearing age still
susceptible especially in tropical country, 2000
cases/year, common exposure in pregnancy in 2nd
exposure (12-20) 2% risk, congenital varicella
syndrome scar, limb hypoplasia, muscle
atropgy, rudimentary digits, cortical atrophy,
psychomotor retardation, choreoretinitis,
cataracts, reactivation and fetal zoster with poor
fetal cell mediated immunity
Primary VZV in 3rd trimester complications are
commoner, pneumonia (smoker), transmit at
delivery, severe disseminated hemorrhagic
purpura fulminans, encephalitis
VZV Ig, treatment if confirmed, vaccination
CMV asymptomatic early childhood, may get a
rash or IM-like, shed in urine
Perinatal, transplacental, postnatal. Commonest
cause of viral congenital infection 3/1000
asymptomatic initially then hearing defects and
poor intellectual performance, heel prick test
possible
IUGR, jaundice, HSM, chorioretinitis,
thrombocytopenia, encephalitis, microcephaly,
ventriculomegaly, calcification, deaf, learning
disability, ganciclovir if positive seroconversion
PCR urine/saliva
Rubella rogavirus RNA, respiratory 12-21 days,
fine macular rash, LAD, prodrome in adult, cirus
isolation/serology
HHV6
Alice Tang
2017-2018
Measles rubeola conjunctivitis paramyxovirus
extremely infectious, respiratory, koplik spots,
face behind ears, then spreads to forehead. Can
cause fetal loss, preterm delivery, increased at
death, no congenital abnormalities
Rubella fine rash down the body, spots on palate
with sore throat
Roseola infantum (exanthema subitum)
Parvovirus B19 fifth disease, erythema
infectiosum, slapped cheek, asymptomatic,
respiratory, transient aplastic risus,
polyarthropathy. Red face after fever, speckled
lacy rash
Hydrops fetalis (oedema) ascites,
effusions in first 20w, USS. High output
cardiac failure due to anemia, IU-
transfusion
No vaccine or Ig
Enterovirus picornavirus RNA, polio, coxsackie,
echovirus. Hand foot mouth disease, rash,
encephalitis, myocarditis, very common in young
toddlers
Zika flavivirus RNA: Antigua, Barbados, Grenada,
Jamaica, St Lucia, T+T, avoid bites and travel to
areas with transmission, avoid conception for 2-
6m after travel (viral shedding in semen), test if
symptomatic or abnormalities on antenatal USS
Nutrition
Fat soluble ADEK can cause toxicity, deficiency is
unlikely
Vitamin A retinol deficiency
colorblindness, excess hepatitis and skin
problems
Vitamin C cholecalciferol deficiency
osteomalacia/rickets, excess hyperCa
Vitamin E tocopherol, vitamin K (aPTT
prothrombin) phytomenadione
anemia, neuropathy, malignancy, IHD,
poor clotting
Cannot store water soluble vitamins
Thiamine B1 beri-beri (wet cardiovascular
pulm edema, dry neuropathy), Wernicke
Pathology Notes
Year 5
(confusion, ophthalmoplegia, ataxia),
glossitis. Give Pabrinex to alcoholics, test with
RBC transketolase
VB2 riboflavin glossitis
B6 pyridoxine dermatitis/anemia (excess =
neuropathy). RBC glutathione reductase ASR
activation
B12 cobalamin pernicious anemia (serum B12
measurement)
VitC scurvy (excess renal stones)
Folate, neural tube defect
Niacin pellagra
Fe anemia/hemochromatosis (pituitary,
testicular deposition)
Iodine goiter/hypothyroid (cereals fortified)
Zinc dermatitis
Copper anemia/Wilsons
Fluoride caries/fluorosis
Ideal: half carb, fat, rest protein
Mostly white adipose tissue, hypothalamus
signals satiety and thermogenesis, controlled by
insulin. Adipose makes adiponectin (deficiency
results in insulin resistance biomarker), adipose
makes leptin satiety hormone preventing eating
more. Low ghrelin when fed (hunger), eaten meal
release PYY high. Obese = dysregulation at any
point, less chance of losing weight in the future
Normal weight:60-70% water, 10-35% fat, 10-
15% protein, 2-5% minerals
Obesity is better measured by waist-hip ratio at
the umbilicus for cardiovascular and DM risk.
Lower BMI cutoffs in the South Asian population
(2.5)
M>94/>102
F>80/>88
Protein 84g M, 64g women, indispensable
leucine, conditional cysteine cannot be made in
neonates
PUFA GOOD, EFA included
Dietary fat determines LDL-C (correlates with CVS
risk), increased satfat increases cholesterol, PUFA
lowers cholesterol
Alice Tang
2017-2018
HDL associated with reduced IHD risk (women,
alcohol, obese) women higher HDL than men
(oestrogen effect?)
Linoleic>oleic>palmitic for IHD risk (polyunsat,
monounsat, sat), transmonounsaturates are bad,
high risk of CVS disease
Increased fat, decreased carbohydrate, change in
lifestyle
GLP-1 agonists, orlistat to treat obesity, improves
PCOS, oesophagitis, CHD, OA, liver, pregnancy,
reduce mortality 20%, HbA1c with 10kg loss
Bariatic surgery; adjustable band above fundus,
port is in the abdomen, can add a needle to
introduce fluid to tighten, sleeve gastrectomy
(2/3 stomach removed), gastric bypass (best
metabolically bypass first 150cm of duodenum,
sever many vagal fibers, no pylorus, bile doesnt
interact with the food 20-30% weight loss
improve DM, OSA, pregnant). Dont need insulin
often after operation, weight independent
Duodenal/jejunal sleeve to prevent bile coming
into contact with food
Protein energy malnutrition
1. Marasmus no subcut fat
2. Kwashiorkor calories ok but protein lost.
Oedema, scaly/ulcerated, lethargic
Cerebrovascular Disease + Trauma
Oedema, excess fluid in brain parenchyma
increasing ICP
Vasogenic disrupted BBB: tight junctions
lost (perivascular edema) AQP4
Cytotoxic secondary to cellular injury
(hypoxia, ischemia), cell death and release
of solutes into tissue from dying cells
Reduce ICP with steroids, close TJ, astrocytes
pump water out of parenchyma, release fluid into
subarachnoid space, reverse flow into ventricles
Lost definition on non-contrast CT, localized
edema around a lesion
Pathology Notes
Year 5
Hydrocephalus blockage in normal CSF flow
choroid plexus from lateral ventricles to
interventricular foramina of Monroe to 3rd
ventricle (thalamus/hypothalamus), cerebral
aqueduct in midbrain into 4th ventricle (roof
cerebellum, floor pons). 2 apertures: foramen of
magendie, noushka x2 (3 total), central canal of
spinal cord
Arachnoid granulations, pierces dura, recycle CSF
to superior sagittal sinus, 500ml a day produced.
Non-communicating in neonates often, choroid
plexus stuck at the top of the aqueduct, use a
stent (obstructed flow), expansion, neonates
head will increase in size as bones have not
fused. Palpate the foramen to see ICP
Communicating no obstruction but difficulty in
reabsorbing CSF. Meningitis and scarred
meninges
Raised ICP 7-15mmHg at rest supine adult,
herniation occurs
Flax of dura mater; subfalcine herniation.
Cingulate cortex, midline shift
Transtentorial herniation; medial
temporal lobes around tentorium into
posterior cranial fossa (uncal) on
brainstem cardiorespiratory centers
Tonsillar herniation; foramen magnum
cerebellum medullary centers (coning
after LP)
Stroke
Cerebral infarct, primary hemorrhage,
intraventricular, SAH. Exclude SDH, EDH,
ICH/infarct from infection/tumor
TIA warning stroke due to temporary clot,
average 1 minute usually <5m, no permanent
injury to brain, 1/3 get a significant infarct within
5y, important predictor of future infarct. Funny
turn in an older person
Intraparenchymal hemorrhage commonest in
basal ganglia due to HTN commonly, severe
headache, vomiting, rapid LOC, focal neurology
Alice Tang
2017-2018
AVMs symptomatic in 2-5th decade with
hemorrhage, seizure, headache, focal neurology
high pressure massive bleeding on angiography.
High morbidity after rupture and mortality. Treat
with surgery, embolization, radiosurgery
Flows without the capillary bed. Inappropriate
vasculature. Fibrotic vessel wall and hemorrhage
into the parenchyma
Cavernous angioma well defined congenital
lesion, closely packed vessels with no
parenchyma between vascular spaces. Low
pressure recurrent bleeds, headache, seizure,
focal neurology, hemorrhage, Tx surgery
Ruptured berry aneurysm causing SAH, anterior
circle of Willis MCA ICA bifurcation, 20%
vertebrobasilar circulation, 30% multiple
aneurysms. 6-10mm diameter risk of rupture.
Thunderclap severe headache, vomiting, LOC
surgical emergency. Clip aneurysm effective but
invasive with craniotomy. Interventional
radiology femoral artery endovascular coil
treatments
Infarct death due to ischemia, commonest form
of disease 70-80% strokes, due to cerebral
atherosclerosis. HTN, DM, smoking. Focal in a
defined vascular territory or global systemic
circulation failure
At risk at watershed areas between perfusion
fields (smaller vessels further from origin, least
overlap if impaired flow resulting in ischemia)
Infarct no recovery with permanent damage.
Hemorrhage dissection of parenchyma, fewer
macrophages, limited tissue damage and possible
partial recovery
TBI
19% high morbidity, 31% good recovery. Non-
missile/missile, acceleration/deceleration,
rotation stressing midline structures, RTA, fall,
assault, focal/diffuse
Fractures to base of skull middle ear/anterior
cranial fossa CSF leakage, ororrhea, rhinorrhea,
Pathology Notes
Year 5
infection risk into cranial cavity. Battle sign and
raccoon eyes periorbital hematoma
Contusions in collision with skull causing surface
bruising. Pia mater tear = laceration, lateral
surfaces of hemispheres, interior
frontal/temporal lobe. Coup or contrecoup
(frontal hit plus rebound, occiput)
Diffuse axonal injury at moment of injury, shear
and tensile forces, commonest cause of coma
without bleed, midline structures affected:
corpus callosum, rostral brainstem, septum
pellucidum (fenestrated between ventricles) in
boxers
Microglial activation in TBI, longer term
degenerative injury CTE
Brain tumours
Supratentorial focal neurolocy, seizure,
headache, change in mental status, personality
change
Subtentorial cerebellar atacia, long tract signs, CN
palsy
MRI if possible for neuroimaging T1, T2 contrast
and perfusion, spectroscopy, fMRI, PET-scan for
research
Manage with radical surgery (subtotal), radioTx
(fractionated, stereotactic, whole brain),
chemoTx high grade glioma (temozolamide)
Open biopsy is more accurate, stereotactic 0.5cm
tissue may not be representative. Craniotomy for
debulking
Tumor type cell of origin, grade, genetic profile,
no staging except medulloblastoma
Glial tumours need genetic profiling
Grade = how differentiated a tumor is, degree of
malignancy, histopathology. Only natural history,
not prognosis
Alice Tang
2017-2018
Grade I long term survival/cure
Grade II death in 5+ years
III Death in 5y
IV death in 1y
III/IV high grade tumors
Glial tumors are the commonest primary CNS
tumours in adults and children
1. Adult diffuse gliomas: astrocytoma,
oligodendroma. Never grade I, will always
recur. IDH mutation
2. Pediatric circumscribed tumors. Compressive
margins, grade !-!! do not infiltrate with rare
malignant transformation. Pilocytic
astrocytoma (I), pleomorphic
xanthoastrocytoma, subependymal
astrocytoma. MAPK pathway mutation (B-RAF
commonest)
Pilocytic astrocytoma children and teens in the
cerebellum, optic/hypothalamic. Piloid hairy cells,
Rosenthal fibers, granular bodies, slow growing,
low mitoses 50% BRAF mutation
Diffuse glioma Grade II+, cerebral hemispheres
commonest site, mostly start as grade IV,
glioblastoma aggressive and frequent.
Progression to higher grade is the rule, becoming
more malignant in 5-7y. Secondaries IDH
mutation (not GBM). Low grade tumor with few
mitoses, no pathological vascular proliferation in
diffuse astrocytoma (IDH+), nonenhancing with
contrast
GBM grade IV, older 50+ primary, secondary turn
into GBM IDH mutant. High cellularity, high
mitotic activity, endothelial proliferation, necrosis
Multilayered vascular proliferation in GBM
Necrosis varied, microscopic
Oligodendroma IDH mutation codeletion 1p/19q
(correlates with morphology), seizure, round cells
with clear cytoplasm (fried eggs) chemo/radio
response
Pathology Notes
Year 5
Meningioma after glioma, commoner in older,
any site of craniospinal axis, slow growth, late
symptoms seizure/compression. Anywhere
where there is dura. Grade I/II/III mostly I with
recurrence. Onion bulbs on histology, grade on
histology only, mitoses for grade. Extraaxial but
close to parenchyma, can growh into the space,
then harder to remove completely. Interface
examine, pseudoinvasion in Virchows Robin
space
Medulloblastoma grade IV embryonal tumor
from neuroepithelial precursor of cerebellum,
dorsal brainstem, rare but 2nd commonest in
children. Small blue round cell tumor. WNT
activated, SHH activated, non-WNT, non-SHH,
better with radio-chemoTx. Poor prognosis with
non-WNT/SHH tumors/. Nodular/desmoplastic.
Children vermis, adults hemisphere
CNS mets increasing, multiple, lung, melanoma,
breast, renal, colon. Very poor prognosis
Steroids favor a glioblastoma (short history high
grade), vascular proliferation high grade glioma
producing growth factor
Infection CPC
Branching Gram+ rods = Actinomyces, Grocott
stain. Atypicals are not picked up on a normal
test, need to inform micro of suspicions.
Washout and debridement needed for deep
infections, grew S aureus from tissue and bone +
rifampicin to disrupt biofilms. OPAT, discharged,
then returned 11d later with erythema. Further
debridement with Taylor Spatial frame. Unhealed
fractures, distal fibula resection, septic arthritis of
ankle joint. Grew same organisms with same
sensitivities (no problem with Abx) PICC line,
another 6w therapy with plaster of Paris for 6w
(10m total treatment)
Osteomyelitis often not cured by antimicrobials
alone, continuous drug will lessen discharge but it
will not cure the disease as it cannot sterilize
dead bone, cavities with necrosis and dead walls
Alice Tang
2017-2018
Ensure sufficient debridement with healthy flaps
to prevent infection. Removal of prosthesis and
adequate debridement is most important,
truncated secondary role of Abx, mostly
aggressive surgery
Fibrous capsule, dead necrotic tissue, immune
system cannot enter here, PTH changes Abx
MOA, Abx cannot enter. Source control?
Catheter? Line? Debridement? Ongoing source
such as nec fasc need to debride first
Other implants: venflon, central line, PICC line,
portacath, prosthetic cardiac valves, prosthetic
implant (cosmetic/reconstructive) contribute to
treatment failure
C diff isolate patient. Must wash hands with soap
and water before and after each patient contact
(gloves and aprons) 1b spores per gram of feces.
C diff care pathway, fluid balance chart, Bristol
stool chart
T>38.5
HR>90
WCC>15
Rising Cr
Clinical severe colitis, or on radiology
Failure to respond to therapy at 72h
1+ = early surgical/gastro review. Megacolon in
emergency, dont pass any diarrhea (hence not a
marker of severity)
Non-severe metronidazole, consider changing
to vancomycin
Severe vancomycin + metronidazole consider
Severe + colonic dilatation vancomycin +
metronidazole, ?colectomy
Severe + ileus/vomiting intracolonic
vancomycin, ?colectomy
Ribotype 027 severe C diff, mortality increased,
more toxin A + B. Quinolones most likely to
induce C diff in this population
Feco-oral spore spread; risk includes
multiple/long course Abx, age>65, long hospital
Pathology Notes
Year 5
stay 4w, severe underlying diseases disrupted
bowel flora, overgrowth. 5% colonized with C diff
normally, but 4w 50% colonized. PPIs higher
stomach pH (recommend stopping this), also for
antacids or cytotoxics. Even 1 dose may be
enough to disrupt, several weeks later. Abrupt,
watery, foul smelling diarrhea (green mucoid)
Pseudomembranous colitis
Cytotoxin damaging epithelium and other TJ.
Destruction of cells leading to fluid loss
AGGRESSIVE inflammation. Plaque with high
neutrophils look like membranes remain,
destroyed colonic architecture WCC high, CRP
low (C diff!)
Cleanliness and hygiene, restrict Abx prescribing,
only use narrow spectrum if possible, increase
cleaning, isolate infected patients, use PPE
Multiple Myeloma
Paraprotein monoclonal Ig, osteolytic bone
lesions, anemia due to pushing aside normal
erythropoiesis, reduction in normal polyclonal Ig
(increased infection), kidney failure from clogged
PCT
Transformed plasma cells, due to
numeric/structural genetic aberrations from
MGUS premalignant
Charateristic complications: cancer/TME bone
disease and large scale Ig secretion causing renal
failure. 2nd commonest blood cancer after B cell
lymphomas, 4-5k/y, debilitating, incurable 4-7y
depending on age 65-70 median age of diagnosis,
-15y life expectancy
Huge RER/golgi, pushing nucleus to one side,
secreting many proteins
MGUS harmless and common
N-RAS, K-RAS, p53 mutations, secondary
mutations cause aggressive cancers, changes in
TME increased angiogenesis
Different subclones will respond differently to
different treatments
Alice Tang
2017-2018
MM symptoms: CRAB (Ca elevated, renal failure,
anemia, bone lesions + monoclonal protein)
Back and bone pain = commonest symptom,
worsens FAST, osteolytic lesions,
pathological/microfractures. Paralysis and cord
compression. Infections, renal failure, abnormal
routine lab test, fatigue, pneumonia
Serum protein electrophoresis (cheap), able to
see gammaopathy: Ig many clones migrate
differently giving a smear, monoclonal will spike
(paraprotein). Large albumin fraction. MM cells
look like normal plasma cells on BM aspirate.
Clumped heterochromatin, low N:C ratio (huge
RER), abundant cytoplasma, nucleoli,
dedifferentiation to plasmablast less compact
chromatin in nucleus
MGUS similar changes: serum monoclonal
paraprotein, BM plasma cells low
Immunophenotype: v mature but no B cell
markers on lymphoma such as CD19/20, surface
Ig (internalized) NEGATIVE. POSITIVE CD38,
CD138 (also in normal plasma cells). MM stains
for EITHER kappa or lambda light chains,
polyclonal normal 50%, normal up to 5% plasma
cells. MM 40-70% plasma cells only K+ or L+
Myeloma bone disease lytic lesions or low bone
density, 20% pathological fracture at diagnosis,
60% at some point. Spinal cord compression
(paralysis), hypercalcemia leading to renal failure,
bone pain
Cell interactions between tumor and bone. MM
secretes factors for stimulation of OC
differentiation and inhibit OB differentiation
causing this imbalance
MM bone disease detected by MRI/CT whole
body low dose CT scan to find lytic lesions in skull
and knees (rare below knees). PET-CT is also used
to find active disease
Nephropathy PCT necrosis, Fanconi syndrome,
cast nephropathy. Free light chains Bence-Jones
clog up tubule
Pathology Notes
Year 5
Treatment options
1. Steroids
2. Cytostatic chemotherapy:
cyclophosphamide, melphalan (low dose)
3. Proteasome inhibitors
4. IMIDs immunomodulatory drugs:
thalidomide, lenalidomide
Melphalan nitrogen mustard alkylating agent,
adds alkyl to guanine, crosslinking and blocking
DNA replication. WW2 lymphopenia in victims,
derivatives used to treat lymphoma. Related to
cyclophosphamide, chlorambucil, ifosphamide
Autologous hematopoietic stem cell
transplantation most effective single
treatment for MM. Collect stem cells from
blood and store, high dose melphalan to kill
myeloma, reinfuse stem cells to rescue blood
formation 24h later
Proteasome inhibitors, dont have proteins to
make Ig (secretory protein)
Thalidomide MDS/MM protein turnover
Diabetes Meeran
Cushing endogenous = ectopic ACTH, adrenal,
pituitary
Low and high dose dexamethasone test fail to
suppress. High dose dex is not used anymore, as
imaging is a better test
Hypotensive from osmotic diuresis from
hypokalemia from tumor ectopic releasing ACTH
causing alkalosis from chronic hypokalemia. 380
osmolality, rehydrate cautiously, replace
potassium slowly (hyperkalemia will kill). Give
fluid, she doesnt pass urine, Cr very high
Find the source, possibly a small lesion in hilum
close to mediastinum (inoperable), probably very
slow growing mets
Huge adrenals, bilateral adrenalectomy. STEMI
Cushings cured, neuro signs, known mets,
Alice Tang
2017-2018
coronary thrombosis at post mortem. Fibrosis on
inferior wall, brain
Opportunistic Viral Infections
HPV/EVER1 or 2 associated with
epidermodysplasia verruciformis (virus and
genetic lesion)
HIV/SIV lentivirus, high VL drives down CD4,
some CD8 control, CD4<200 many infections.
AIDS defining (viral): cervical cancer invasive HPV,
CMV retinitis, encephalopathy, HSV ulcers,
bronchitis, pneumonitis, esophagitis, KS (HHV8),
BL (EBV), PML (JC), oral hairy leukoplakia (EBV)
cannot scrape off
DMARD/steroid, cytotoxics, MABs, solid organ
transplant, advanced HIV, stem cell allogenic Tx
(increased risk of opportunistic viral infection)
Transplant acquired virus from donor graft, host
reactivation, novel infection. Screen serostatus
risk assessment, prophylaxis, isolation barrier
nursing, advice, PEP, vaccinate contacts, diet
control
CMV/EBV commonly monitored in transplants,
adeno/HSV in paeds. Serology is not as useful in
immunosuppressed use molecular testing,
extended screen. Increased drug resistance
Herpesviruses: HSV, VZV, CMV, EBV, HHV6/8.
DNA viruses, latent infection with a small subset
of expressed genes, reactivation leads to
expression of viral genes, production of progeny
virus, destruction of host cells (250 genes, large,
avoid immune surveillance). Reactivation under
immune suppression
HSV cold sores, stomatitis, ulcers, genital disease,
cutaneous, oesophagitis, hepatitis, viremia. Treat
with aciclovier/valacyclovir, foscarnet (ganciclovir
sensitive but usually not used). Prophylaxis in
pre-graft needed
VZV increased risk of pneumonitis, encephalitis,
hepatitis, purpura fulminans in neonates.
Shingles late complication post transplant, early
sign of HIV infection (need testing)
Pathology Notes
Year 5
multidermatomal/disseminated zoster = high
mortality. Acute retinal necrosis (ARN),
progressive outer retinal necrosis (PORN),
cerebral vasculopathy (stenosis and dilation in
arteries, associated with infarction in brain).
Acyclovir prophylaxis protection, PEP with VZIg
passively (test for IgG and give Ig). Acyclovir first
line, then valacyclovir. Fos/Gan also work but
more toxic
CMV encephalitis, retinitis (+HIV), pneumonitis
(transplant), gastroenteritis/colitis on biopsy.
Owls eye nuclear inclusion (viral replication).
Solid organ D+/R- risk reactivation, BMT D-/R+
risk reactivation. Valgancyclovir prophylaxis solid
organ, preemptive therapy in BMT. Treat with IV
ganciclovir, oral valganciclovir, IV foscarnet
(nephrotoxic), cidofovir (nephrotoxic, use for
CMV retinitis), IVIg pneumonitis. Letermovir,
maribavir, brincidofocir, fomiversin
EBV predisposes to cancers: lymphoma, latent
infection of B cells, rising VL, confirm with LN
biopsy, reduce immunosuppression and give anti-
CD20 rituximab B cell (PTLD post transplant
lymphoproliferative disease)
Kaposi sarcoma HHV8 preHIV epidemic,
brown/purple vascular lesion. Cutaneous or
visceral. Spindle cell proliferation,
neoangiogenesis, inflammation, edema, biopsy.
Treat with chemo and ART. Primary effusion
lymphoma (PEL), multicentric Castleman disease
JC virus polyomavirus causing PML, high mortality
in AIDS 5% dementia, incidence decreased. Also
seen in other immunocompromised hosts:
natalizumab for MS humanized MAbs. Acquired
in childhood via tonsils, latent in kidney/BM.
Immunosuppression crosses BBB. Cognitive
disturbance, insidious personality change,motor
deficits, focal neurology. White matter
demyelination. MRI/PCR CSF to diagnose, brain
biopsy
BK virus BK cystitis (polyomavirus)
hemorrhagic cystitis post transplant, dsDNA, BK
nephropathy after renal transplant. Fever,
cystitis, blood clots, hematuria. Blood PCR/NAAT.
Alice Tang
2017-2018
Bladder irrigation or modulate
immunosuppression. Cidofovir
Adenovirus post-BMT (paeds in particular),
exogenous or reactivation of persistent
endogenous. Fever, encephalitis, pneumonitis,
colitis. High mortality in disseminated infection,
need high suspicion. Screen in adults
urine/resp/stool, blood if disseminated (stage).
Cidofovir, probenecid, CTLs
HepB serology
1. HBsAg rises first
2. Core IgM increases (actue infection)
3. IgG core increases
4. Clearing infection = surface disappears
and surface Ab appears
When persistent, no seroconversion, surface Ag
appears high, anti-core appears and EAg
increases, IgM increases and decreases. No
surface Ab, in immunocompromised carriers flare
disease, reactivate especially in B cell depleting
therapies (rituximab), prevent with nucleoside
analogues (lamivudine, tenofovir, entecavir)
Sag, core Ab, sAb current ++-, past -++,
vaccination --+
HEV endemic UK,enteric transmitted viral hep,
zoonosis in genotype 3 virus from pigs
(undercooked meat), developing countries
waterborne genotype 1 high mortality in
pregnant women. Uncommon in organ
donation/blood transfusion. Chronic infection,
increased transaminitis, HEV RNA increase,
immunomodulation, ribavirin
Immunology cases
Anaphylaxis systemic HS reaction, overwhelming
T1HS crosslinking IgE on mast cell surfaces
causing mast cell degranulation. Release of
specific biological mediators (HA, LT)
Oedema
Urticaria
Flushing
Bronchoconstriction/wheeze
Dyspnea
Pathology Notes
Year 5
Conjunctival injection, angioedema,
rhinorrhea
Impending doom
Hypotension
Tachycardia
Increased bronchial secretions
Treat with adrenaline 0.5mg for adult IM, B2
arterial SM constriction, IV antihistamines
(Chlorphenimine), nebulized bronchodilators, IV
steroids (200mg hydrocortisone preventing
rebound anaphylaxis)
Latex allergy T1 common in multiple urological
procedures, preterm infants,indwelling latex
devices (ventriculoperitoneal shunts) or T4 not
responsive to antihistamines, in HCW, OT,
industry workers
Latex fruit syndrome cross reactivity with
avocado, apricot, banana, chestnut, kiwi,
passionfruit, papaya, pear, pineapple
Confirm diagnosis skin prick test, commercial
extracts at a range of concentrations. Non-
standard tests at some places
T4HS test with patch test, leave for 24-48h, with
moistened blotting paper, eczema seen with
infiltrating T cells, granuloma
Refer to allergist, avoidance with occupational
health. Desensitization only works for insect
venoms and aeroallergens (pollen)
Meningococcal meningitis need: antibody (many
URTIs), complement deficiency results in
encapsulated oragnisms (N men, Ngon, HfluB,
pneumococcus), disrupted BBB (fracture)
Hx infection: SPUR serious, persistent, unusual,
recurrent. PMHx,
Complement C3, C4 (classical), CH50, AP50
functional tests for classical pathway. Ig serum
electrophoresis
CH50: classical pathway C1, 4, 2 actiate C3, final
C5-9. Lysis 50% in the assay testing classical
Alice Tang
2017-2018
pathway (time taken) compare to standard
serum. Sheep RBC
AP50 tests alternative pathway activation with
bacterial cell wall properdin, factor B/H/I, all
components needed to give positive normal
result. Guinea pig RBC
Normal C3/4, absent AP50, CH50 shows
deficiency in final common pathway C5-9
complete deficiency of C7. Manage with
meningovax, pneumovax, HIB. Daily penicillin
prophylaxis
Meningococcal especially common in
alternative/final common pathway. Sporadic
disease should screen for complement deficiency.
Giving complement wouldnt really work due to
short half life. Gene therapy may work
SLE: anti-dsDNA
If ANA+ need to look at dsDNA, ENA soluble
nuclear extracted, cytoplasmic
1. dsDNA SLE
2. ENA Ro La Sm RNP SLE/sjogrens, Scl70,
RNA pol, fibrillarin diffuse cutaneous
scleroderma
Lupus immune complexes activate classical
pathway, low C3/4 used up hence SLE active.
ESR/dsDNA Ab titre reflect activity of disease
Urinalysis proteinuria, microscopic hematuria,
RBC, casts, diffuse progressive GN, immune
deposition. T3HS: Treat with prednisolone, aza,
hydroxychloroquine, rituximab, IVIG,
mycophenolate, cyclophosphamide
Anti-TNFa adalimumab
S pneumo confirmed on sputum culture. IgG
response to penicillin, reaction immune complex
formation resulting in nephropathy: rash,
deposition, high WCC, CRP, ESR. Serum sickness
penicillin stimulates more IgG, complement
activation small vessel vasculitis
Pathology Notes
Year 5
Low serum C3/4 classical activation, specific IgG
to penicillin but slow test. Biopsy skin/kidney
infiltration
Small vessel vasculitis in the brain causing
encephalitis
Purpura local hemorrhage, inflammation.
Manage with steroids, dont give penicillin
Recurrent URTI/LRTI with failure to thrive,
hospitalisations, courses of Abx, otitis media.
Severe infections, ercurrent minor infections with
failure to respond to Abx. Unusual Burkholderia
cepacia, opportunistic CMV, Candida,
pneumocystic, aspergillus, unusual sites,
concomitant problems. Low B cells, caused by
BTK mutation failure of pre-B maturation, no Ig
made. Treat with IVIg every 3w, indefinitely
MM punched out lytic lesions, proliferation of
plasma cells producing Ab, pathological fractures
ESR RBC due to change in plasma abnormal
proteins. Rouleaux seen in MM
Autologous stem cell transplant
RhA
Peripheral, symmetrical, polyarthritis stiffness,
change in pregnancy of Th1/2 profiles, Th2
dominates in pregnancy then switches back.RH,
anti-CCP, 6+ weeks
RhF IgM against Fc of IgG, some also have IgG and
IfA, 60-70% sensitive/specific (found in other
diseases)
Anti-CCP arginine deiminated to form citrulline by
PADI (peptidyl arginine deminiase),
polymorphism increases this in RAs, lose
tolerance to residues to make anti-CCPs, 60%
sensitive, 95% specific
HLA-DR1,4, twin concordance (genetic). Common
HLA II common sequence 70-74 positions, in
alpha helix forming wall of peptide binding
groove, peptide presentation in disease
pathogenesis. PADI type 2, 4 polymorphisms
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2017-2018
influence development, loss of B tolerance.
PTPN22 tyrosine phosphatase suppress T cell
activation
Treat with DMARDs MTX, sulphasalazine,
hydroxychloroquine, leflunomide. TNFa
antagonist rituximab CD20 deplete B cells (not
plasma), abatacept CTLA4 Ig fusion protein binds
CD28 ligands, tocilizumab IL-6R. Screen for TB
due to antiTNF reactivation TB (CXR, TB ELISPOT),
hepB, C, HIV
Infectious diseases tutorial
Cavity within the RUL
Auramine stain rather than ZN fluorescent,
greater sensitivity. ZN able to see morphology
Modified ZN Nocardia/Actinomyces weaker acid,
less acid fast
2w of culture but keep up to 6w. R cavitating
lesion MTB pulmonary. Infection control
public health England, tell the TB team, treat with
ID, resp, TB nurses etc, dont just RIPE. Involve
early, infection control/occupational health.
Isolate to prevent further infection
MTB/MAC sort of G+ with thick mycolic acid wall,
indolent. Droplet from pulmonary TB, invades
parenchyma hemoptysis. Positive microscopy
= infectious (60-70% sensitive) often treat on
clinical suspicion before culture returns. 3
sputum samples for microscopy. Morning sputum
5ml ideally
1. Immunocompetent child Ghon complex
with inflamed LN, typically in the apices,
calcification in the apices (previous TB).
Caseous necrosis. Infiltration of
macrophages = cheese like. 90% of first
exposure is controlled, flu-like or mild
illness. May clear or latent TB. 10% clinical
TB. Resolution is commonest, Ghon will
scar and calcify (RUL especially previous
TB) spectrum. Mild symptoms in this child,
controlled Ghon focus Ghon complex
(LN draining apices)
Pathology Notes
Year 5
Immunocompromise, HIV co-infection, 10-15%
lifetime risk of clinical to a 10% yearly risk. Test
IFN-y for latent TB then treat with prophylactic
isoniazid. Age is a risk factor, malnutrition and
alcoholics
2. Extensive caseous necrosis
3. Tuberculoma in the brainstem
Extrapulmonary is bad, TB men, TB osteomyelitis,
scrofula LN neck. Presents atypically and may not
have typical responses due to
immunocompromised, distant multiple sites.
Miliary TB in lungs only disseminated TB.
Hematogenous spread to pons
Case 2
Cellulitis, nec fasc, osteomyelitis. Swab ulcer as
deep as possible as skin surface will colonise the
ulcer. Tissue viability or vascular/ortho to
debride, DM team
Lucent lytic lesion, swelling around the bone
irregular and thickened tibia
G+ cocci in clusters = S aureus (can be Strep,
anaerobes in DM). broken skin to allow
organisms to invade
Local direct invasion into bone common routes,
hematogenous
Children no anastomosis in sinusoids so sluggish
blood flow, local infection commoner long
bones femur osteomyelitis. Spinal OM
commonest in adults, due to torturous route of
spinal artery, bacteremia will enter here. Treat
bacteremia for 2w to prevent these sequelae
Direct inoculation from surgery/trauma
Fibrous capsule with dead necrotic tissue inside,
not all Abx penetrate bone and fibrous capsule
with no blood supply, debride and get back to
healthy tissue back to bleeding, and Abx 6w
for treatment but must be surgical. Sequestrum
with dead organisms inside. Inadequate
debridement (vs maintain function) especially
vascular/DM
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2017-2018
Dehiscence between tendon of muscle and
eyelid, can happen with age. Trauma, sunk back
in socket, muscles weak
Horners just a little droop, small segment of
muscle. Oculomotor nerve palsy much worse
(MG worsening fatiguing weakness)
Mydriasis in oculomotor nerve palsy, early, due
to compression. Surgical or medical CN3 palsy
(external, versus DM blood supply compromised
whole nerve function affected) PNS outside with
nerve inside
Sudden pain = surgical cause (not medical
usually) CT head to investigate, transverse
horizontal axis at the eye, round oval with a tail,
well circumscribed, hyperdense (lighter) relative
to the surrounding brain (hypointense on MRI)
Berry aneurysm well circumscribed with an
artery coming off of it, same density, same
streaks above = ICAs = anterior communicating
artery (commonest), posterior communicating
artery, typically at the branching points of the
circle of Willis. Focal weakness, dilatation, middle
media layer has less elastic tissue and SM hence
weaker
SAH from rupture 50% mortality, over 50% of
survivors have persistent deficits. <60 common
Reduced cerebral perfusion
Raised ICP
Irritant leading to vasospasm, narrowing
and further reducing blood supply to the
brain
85% from Berries, 15% from AVM
Check collateral supply to the brain
Allens test in the hand
Raised ICP waking up at night. White fluid and
midline shift. Glioblastoma 15m from
presentation
Heart, septal cusp of mitral valve, chordae
tendinae are destroyed, ruptured. Mural
endocarditis. Copper tinge blood clots IE
subacute due to S viridans. Acute commonest = S
Pathology Notes
Year 5
aureus. Fever systemic infection increased
cytokines, loud systolic murmur MR to axilla,
cough from pulmonary HTN from LHF to RHF
pulmonary edema. Septic emboli, stroke,
Janeway lesions, Roth spots, Osler nodes,
deposition of circulation immune complexes.
Infarcted region in the kidney. Pain lower
abdomen, hematuria, proteinuria. Adhesions to
pancreas, wedge shaped infarct
DM, HIV, valve replacement/prolapse, IVDU, Ca,
immune status, IE acute. 90% L, introduce drugs
to veins to RH TR reduced immune system, raised
JVP, RHF, peripheral edema, fever, pneumonia
throwing emboli off to the lung empyema
ECG, echo, FBC, inflammatory markers,
renal/liver, urine dip, blood cultures from 2 sites
History for RhF
Pulmonary valve homograft, thrombogenic
(anticoagulation needed) prevent vegetations,
damage to RBC mechanical HA, increased risk
IE due to foreign body. Lifelong prophylaxis for
dental/surgical procedures
Case 2: concentric LVH, luminal volume reduced
due to compression banana shape = HOCM
genetic sarcomeric protein defective filling in
diastole. LV outflow. Asymmetric usually of
septum, but this is overall, everywhere
LOW SV, CO, low ventricular volume. Diastolic
filling impaired, reduced compliance.
Asymptomatic, SOB, syncope, chest pain needs
more O2 to supply, ischemia/AF abnormal
conduction pathways, sudden cardiac death in
athletes
O/E displaced apex beat, harsh systolic ejection
murmur obstruction. Echo structural damage,
MRI, genetic tests
Relaxation of ventricle, HTN with BB, CCB,
antiarrhythmic, diuretics, surgery
pacemaker/defib. Family screening due to AD
condition
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2017-2018
Bullae in the lung anterior and apex, R dilatation,
L hypertrophy. Smoking. Pneumonia exacerbation
of COPD due to mucopurulent, PE SOB, HTN and
chronic bronchitis cor pulmonale RHF, RHTN,
pulmonary edema, SOB and peripheral edema
Large cysts, no parenchyma ADPCKD. Congenital
AR, cystic renal dysplasia, acquired simple cysts,
medullary sponge kidney disease, VHL, tuberous
sclerosis, cystic renal cell carcinoma
Flank pain ADPKD in 4th decade referred from
kidney due to cyst enlargement, infection, stones,
hematuria due to hemorrhage, trauma, last <1w.
Palpable masses, HTN, RAAS. Decline in renal
function. Hypoperfusion, ischemia of tissue, low
volume of blood. Results in RAAS activation,
increased Na retention, hyperconstrict vessels
(A+V) causing more problems, BP high
Variable prognosis
1. 53y
2. 68y
PKD HTN, renal failure, replacement needed by
60. GFR for kidney function, hypokalemia, low
phos, hyperPTH, hypoCa, metabolic acidosis. VitD
activation decreased, low Ca, PTH increases
Osteomalacia, osteoporosis, increase fractures
and bone pain. HTN CHF, atherosclerosis, anemia
ADPKD hepatic cysts, berry aneurysm, liver
function usually normal, MVP, UTI, colonic
damage
Breast 1: darker = solid, well circumscribed,
nodularity at the edges (lobulation).
Fibroadenoma, sometimes can be painful in
trauma but generally this is normal
H+E, imaging, biopsy (core needs to LA take a
chunk and 24h processing histology formalin to
fix and embed in wax to take thin sections, FNA
much quicker cytology dragging cells out into
syringe and place onto a slide, smear, add stain
and check microscope however no architecture)
CT guided for deeper things too
Pathology Notes
Year 5
Fibrous stromal pink with glandular epithelium
GOOD organization with equal parts of each
Watchful waiting if small and asymptomatic.
Large/symptoms surgical removal, shell it out, no
need for WLE, never really recur. No malignant
potential at all. Commonest benign tumor of the
breast
Breast 2: postmenopausal should shrink, size
large, pain. Phyllodes tumor fibroepithelial tumor
of the breast (similar, fibro and epi) BUT large,
stromal part proliferates and overgrows, more
stromal fibro component, 10% malignant, most
are still benign. Stromal sarcoma when malignant
much rarer (tend to go to visceral organs rather
than carcinoma to LN) often has cystic change
(may bleed), variable appearance, large
Smooth edge but stromal expansion, projections.
Variable look compared to fibroadenoma. Nature
of the overgrowth, fewer cells in benign,
malignant is more cellular with large,
pleomorphic, mitotically active. Always excise
Phylloides tumor, 1-2cm wide local excision.
Benign types high risk recurrence locally if WLE
not done
Breast 3: 52F bloody discharge R nipple.
Cytological look at the discharge. Cancer near
duct near nipple, duct inflammation. Duct
ectasia, intraductal papilloma of the breast
(second commonest benign breast tumor)
anywhere in the duct but commoner in the nipple
centrally (symptomatic)
Tumour frondlike branchlike fashion from
epithelial surface into lumen like a tree, benign
epithelial growth. Fronds will detach and this
comes out in the discharge
Papilloma can become infected pain, abscess
formation. Malignant transformation <10%,
generally removed, duct is surgically removed no
need for WLE, narrow is fine
Breast 4: dimpling, drawn in skin inverted nipple,
irregular tumor with strands. Irregular stellate
mass with extensions, breast carcinoma.
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2017-2018
Ductal/lobular (microscopy), in situ (in ducts) or
invasive (able to break out) worse due to
metastatic spread capacity
Pulls duct, scarring reaction hence feels hard,
converge on nipple hence it retracts. To the
axillary LN and the rest goes to internal
mammary/thoracic inside the chest, some drain
to contralateral LN (rare but anatomical
difference)
Sarcoma to lung and liver
Grade invasive BrCa 1 better 3 poorly
differentiated down microscope
Stain for 3 receptors: ER, PR, Her2 (IHC) prognosis
and treatment
Wiped out normal architecture of the breast,
deregulated fashion destroying tissue. Invasive
ductal cancer solid nests and loops
WLE breast conserving, radiotherapy to surgical
site. Sentinel LN biopsy, inject blue stain
radioactive into cancer site, track this to the
drainage to find the first LN in the axilla that the
tissue drains to. If theres no cancer, the rest will
be fine, otherwise if + then more treatment
Chemo high risk high grade large tumor, risk of
mets, then give systemic chemo. ER+ good, Her2-
good
Haem 1: LDH cell death, high in HA and
aggressive rapid lymphomas/leukemias, high cell
turnover. Inherited = RBC failure, hereditary
spherocytosis/elliptocytosis. Hb = sickle cell,
thalassemia imbalance of chains. Enzyme greek
children eating fava beans G6PD
Acquired = environment
AIHA Coombes test RBC in saline, add antibody
targets human. Inject human Ag into
mouse/rabbit, sera, causes agglutination if
human Ag present
Anti-RBC, anemia, low Hb, hemolysis (reticolu)
DAT+ AIHA, destructive or mechanical
Pathology Notes
Year 5
Treat with steroids DO NOT transfuse, rituximab
second line
Wide mediastinum owl eye Reed Sternberg large
binucleate cell Hodgkin lymphoma. Few
malignant cells but A LOT OF INFLAMMATION
with fibrosis bands
PET-CT active disease glucose UPTAKE but not
BREAKDOWN. Bladder, ureter and renal
collecting duct is normal to stain
Stage IIb, multiple spread above diaphragm (I/II)
III both sides, II = more than 1 group of nodes, b =
B symptoms (fever, night sweat) (weight loss,
pruritis, alcohol induced pain)
Cure 80% 5y survival (depends on stage) with
chemo. Surgery is out due to so many LN ABVD
regimen cures HL (fertility), avoid radiotherapy if
possible due to secondary cancer (breast, BM,
skin), fibrosis, damage
Leukemia, BM fail in acute severe drop in WBC,
Hb, plt. Neutropenic sepsis. Chronic leukemia
hyperactive expansion, months and years of
hepatosplenomegaly
Increased basophils and eosinophils, CML
FISH protein or PCR product
Imatinib = kinase inhibitor
Lecture 1: Hyperuricemia and Gout
Purines are ubiquitous biomolecules: adenosine,
guanosine, inosine. Genetic code, second messengers
for hormone action, energy transfer molecules
Purine catabolism
(Underlies gout, 3% of males in lifetime)
Purines are broken down to hypoxanthine (XO) to
xanthine (XO) to urate (uricase) to allantoin. Allantoin
is highly soluble and freely excreted in the urine.
Human uricase inactive, hence urate builds up and
this is relatively insoluble, circulating at the limit of
solubility
Monosodium urate plasma concentrations:
Male 0.12-0.42 mmol/l
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2017-2018
Female 0.12-0.36 mmol/l
Solubility at 37C = 0.4mmol/l, cooler temperatures
lower solubility, also pH dependent. Urate is more
likely to precipitate at extremities where temperature
is cooler
Renal urate handling
Freely filtered at glomerulus into PCT, reabsorbed and
re-secreted (may be due to anti-oxidant properties).
10% of urate is in the fractional excretion of uric acid
(FEUA), 90% is reabsorbed to keep the serum urate up
De novo purine synthesis is highly energy intensive
and only used in metabolically demanding situations.
Dominates in bone marrow only (salvage pathway
alone is insufficient). PAT enzyme is the RLS
(phosphoribosyl amidotransferase) negative feedback
by AMP, GMP, IMP. Subject to feedforward effect
from PPRP too
Purine salvage pathway is highly energy efficient, this
is used where possible. HGPRT transfers hypoxanthine
back to IMP and guanine to GMP
HGPRT deficiency
Complete = Lesch Nyhan syndrome. Normal at birth,
developmental delay at 6/12. XLR disease affecting
boys mostly. Hyperuricemia and gout (rare),
choreiform movements (basal ganglia) at 1y, spasticity
(UMN rigidity), mental retardation, self mutilation
(85%). No negative feedback on PAT, so de novo
pathway goes into overdrive, forming more urate.
PPRP increases, more feedforward mechanism too
Classification of disorders of urate homeostasis
Increased urate production from primary causes
include LNS, partial HGPRT deficiency, glycogen
storage disorders, fructose intolerance, PRPP
synthetase overactivity. Secondary causes due to
increased cell turnover resulting in high urate levels
such as myeloproliferative/lymphoproliferative
disorders, carcinomatosis, chronic HA, Gaucher
disease, severe psoriasis
Decreased urate excretion primary causes include
FJHN. Secondary causes include CRF, Bartter
syndrome, Down syndrome, saturnine gout lead
poisoning, diuretics, aspirin
Causes of hypouricemia due to decreased urate
production: XO deficiency, allopurinol, severe hepatic
disease. Increased urate excretion idiopathic, Fanconi
syndrome, cystinosis, myeloma, URAT1 inactivation
Pathology Notes
Year 5
Gout
Monosodium urate crystals. Acute podagra, chronic
tophaceous (tophi in earlobes and joints. Cottage
cheese/chalky); males 0.5-3%, females 0.1-0.6%
prevalence. Inflammatory reaction in joint synovium
for joint crystallopathy. Males post-pubertal, females
post-menopausal
1st MTP, skin tight and shiny, red. Periosteal erosion
due to tophus. Monosodium urate needle shaped
birefringent crystals
Acute gout: rapid pain, exquisite, red/hot/swollen, 1st
MTP in 50%, this joint in involved in 90% overall
Management: clear the inflammation
Paradoxical acute change of urate concentration can
cause further precipitation, do not change plasma
urate acutely
NSAIDs: diclofenac, not for CKD, asthmatics
Colchicine, inhibits tubulin assembly (mitosis)
suppress cell turnover reduced neutrophil
motility, cannot set up inflammatory reaction
Glucocorticoids, injection or pred tablets
systemically
Manage hyperuricemia long term
Hydrate, not beer or port (dietary purines)
Reverse factors increasing urate (thiazide
diuretics)
Reduce synthesis with allopurinol, Xoi
Increase FEUA with probenecid, increased renal
excretion of urate (uricosuric)
Allopurinol interacts with azathioprine, increasing BM
toxicity. AZA prodrug is metabolized to MP, then to
thioinosinate (active drug) interfering with purine
metabolism. Allopurinol makes MP last longer. XO
metabolizes MP and causes the dose to increase,
making it toxic (neutropenia)
TMP and methotrexate should also not be prescribed
together
Diagnosis of gout: tap effusion, view under polarized
light, with red filter compensator. Birefringence = able
to rotate the plane of polarization. Urate crystals are
negatively birefringent; blue 90 degrees to the red
compensator and yellow parallel to the filter
Pseudogout
Alice Tang
2017-2018
Calcium pyrophosphate dihydrate crystals are
positively birefringent. Occurs in patients with
osteoarthritis, self limiting 1-3w. Parallel to axis blue
Lecture 2: Immunology
Constitutive barriers to infection via skin or mucosal
surfaces
Physical contact: Trichophyton, athletes foot
Minor skin abrasion: Bacillus anthracis, cutaneous
anthrax
Puncture: C tetani, tetanus
Handling infected animals: Francisella tularensis,
tularemia
Mosquito bite (Aedes aegypti): Flavivirus, Yellow
Fever
Mosquito bite (Anopheles): Plasmodium, malaria
Deer tick bite: Borrelia burgdorferi, Lyme disease
Inhaled droplet: influenza, flu
Spores: N meningitides, meningitis. B anthracis,
pulmonary anthrax
Contaminated food/water: S typhi, typhoid fever.
Rotavirus, diarrhea
Physical contact: T pallidum, syphilis. HIV, AIDS
Skin consists of tightly packed keratinized cells,
physically limiting colonization. Low pH and low O2
tension. Sebaceous glands with hydrophobic oils
repelling water and microorganisms, lysozyme
destroys structural integrity of cell wall, ammonia and
defensins anti-bacterial
Secreted mucus traps pathogens, IgA prevents
attachment and penetration of epithelial cells.
Lactoferrin starves invading bacteria of iron
Cilia trap pathogens and remove mucus through
sneezes and coughs
100 trillion commensal bacteria at surfaces compete
with pathogenic bacteria for resources, produce fatty
acids and bactericidins to inhibit the growth of many
pathogens
intracellular pathogens include viruses, mycobacteria,
yeasts, whilst others are extracellular
Innate immune system
1. Cells include PMN (NEB),
monocytes/macrophages, NK cells, dendritic cells
2. Soluble components include complement, acute
phase proteins, cytokines and chemokines
Pathology Notes
Year 5
Cells have identical responses in all people, express
receptors to detect sites of infection, pathogens,
phagocytic capacity and secrete
chemokines/cytokines
PMN (NEB) made in bone marrow and migrate rapidly
to injury site, express receptors to detect
inflammation and express pattern recognition
receptors to detect pathogens. Phagocytosis/non-
oxidative killing, secrete enzymes, HA, lipid mediators.
Express Fc for Ig to detect immune complexes
Monocyte/macrophage made in BM and enter blood
to tissues: Kupffer cell, mesangial, osteoclast,
sinusoidal lining cell, alveolar macrophage, microglia,
histiocyte, Langerhans cell. Receptors to detect
pathogens and inflammation, Fc receptors for Ig to
detect immune complexes. Phagocytosis, non-
oxidative killing, present processed antigen to T cell
Phagocyte recruitment from cellular damage and
bacterial products
Chemokines attract phagocytes
Cytokines increase endothelial vascular
permeability
TLRs and mannose receptors recognize PAMPs (sugar,
DNA, RNA of bacteria), bind Fc of Ig
Opsonisation facilitates endocytosis, bridge pathogen
to phagocyte, to coat, enters phagosome, fuses
with lysosome to form phagolysosome.
Oxidative/non-oxidative killing
NAPDH oxidase complex converts O2 to reactive
oxygen species superoxide and H2O2,
myeloperoxidase catalyses the production of
hydrochlorous acid from H2O2 and chloride, good
oxidant and anti-microbial
Non-oxidative killing with lysozyme and lactoferrin
Phagocytosis depletes neutrophil glycogen reserves,
causing cell death. Residual enzymes are released,
liquefaction of adjacent tissue, accumulation of dead
neutrophils in infected tissue makes pus. Extensive
local pus formation forms an abscess
Phagocyte mobilized, expression of endothelial
activation markers, increased adhesion and migration
into tissues from blood. Phagocytosis, killing,
macrophages survive and communicate with T cells
Alice Tang
2017-2018
Natural killer cells are lymphocytes, inhibitory
receptors for self-HLA molecules prevent
inappropriate activation by normal self. Natural
cytotoxicity receptors (activatory receptors) for
heparin sulphate proteoglycans. Kill altered self in
malignancy or virus infected cells. Promote DC
function. Downregulate HLA cause NK killing
DC in peripheral tissues, express Fc receptors,
pathogen and cytokine recognition receptors. After
phagocytosis they mature, increase MHCI (HLA),
costimulatory molecules, migrate to LN (CCR7),
present processed Ag to T cells in LN to prime
adaptive immune response
Adaptive immune system
Wide repertoire of Ag receptors, not entirely
genetically encoded. Gene segment rearrangement,
nucleic acids added/deleted randomly, create 10^12
receptors, likely to make some autoreactive cells but
these must be deleted/tolerised. T cell receptor: a and
b chain with VDJ segments
Exquisite specificity, discriminate small
differences
Clonal expansion, proliferates with appropriate
specificity
Immunological memory, residual pool for
response in reinfection
Primary lymphoid organs: BM generates
hematopoietic stem cells. Site of B cell maturation,
thymus is site of T cell maturation. Most active as
fetal/neonate
Secondary lymphoid organs are where nave
lymphocytes and pathogens interact: spleen, LN,
MALT
T cells express CD3, TCR recognizes HLA/peptide from
APC. CD8 HLA I, CD4 HLA II
Thymus low affinity T cells not selected. High affinity
negative selection, deleted. Intermediate affinity
positive selection 10%
CD4 helper T cells recognize peptides from
extracellular proteins HLA-DR, DP, DQ. Provide help
for full B/T response, regulate cell-cell interactions
IL12, IFNy Th1 IL2, IFNy, TNFa, IL10 CD8, MP
IL6, TGFb Th17 IL17, IL21, IL11 neutrophil
TGFb Treg (neg) IL10, FoxP3, CD25 IL10, TGFb
Pathology Notes
Year 5
IL6, IL1b, TNFa TFh IL2, IL10, IL21 follicular Th
germinal centre B cell responses
IL4, IL6 Th2 IL4,5,13,10 Th cells
CD8 for cytotoxicity via cell to cell contacts with
perforin forming pores and granzymes, or the
expression of Fas ligand. Recognise peptides with HLA
I (HLA-A, B, C). Secrete cytokines IFNy, TNFa, defence
against viruses and tumors (intracellular)
T cell memory, delay, peak and enhanced repeat
B cells from lymphoid progenitors: Pro B, Pre B, IgM B
or plasma cells (GEA) with germinal centre reaction.
Self recognition is deleted, no intermediate reaction.
Early IgM response if it engages an antigen to become
a plasma cell
Or germinal centre reaction dependent on DC primed
CD4 cell requiring CD40/CD40L, B cells proliferate,
somatic hypermutation and isotype switching,
editing receptor until it is high affinity, switched to A
or E
Plasma cells make immunoglobulins, soluble proteins
made of 2 heavy + 2 light chains
Heavy chain determines class (GAMDE with GA
subclasses)
Recognised by Ag binding regions (Fab) of heavy
and light
Effector function determined by constant region
of heavy chain (Fc)
A dimer, M pentamer
Fab identifies pathogens/toxins, interacts with other
components to remove pathogens via Fc
(complement, phagocyte, NK), especially for bacteria
Alice Tang
2017-2018
Initial B cell response is IgM with IgG increasing over
time. With memory, IgG increases much faster. B cell
memory high affinity
Complement 20 proteins made by liver in circulation
as inactive molecules, enzymatically activate other
proteins in a biological cascade when triggered. Rapid,
amplified response
Classical pathway involves C1, 2, 4 activated by
the formation of Ab-Ag immune complexes
MBL pathway involves C4, 2 dont need adaptive
immune system engagement here, binds cell
surface carbohydrates
Alternative pathway binds C3 with bacterial
LPS/teichoic acid directly, involving factors BIP
Converge on C3 the major amplification step to final
common pathway C5-9, forming MAC membrane
attack complex, making holes in membranes
Complement fragments released also:
Increase vascular permeability and cell trafficking
Opsonisation of immune complexes to keep them
soluble
Promote phagocytosis
Activate phagocytes
Promote mast cell/basophil degranulation
Punches holes in bacterial membranes
Cytokines are autocrine or paracrine small protein
messengers with immunomodulatory functions.
IL2,6,10,12, TNFa, TGFb
Chemokines are chemoattractants directly
recruiting/homing leukocytes. CCL19, CCL21 are
ligands for CCR7, direct DC trafficking to LN. IL8,
RANTES, MIP1. Can act as coreceptors for HIV
Lecture 3: Histology
Neutrophils are associated with acute
inflammation
Lymphocytes and plasma cells are associated
with chronic inflammation (lymphoma), MM, AI
disease. H pylori sheets of lymphocytes
Eosinophil red granules, bilobed nucleus.
Associated with allergic reactions (drugs or
external), parasitic infections (schistosomiasis),
tumours e.g. Hodgkins disease reaction
Pathology Notes
Year 5
Oesophagus feline contractions; eosinophilic
oesophagitis. Asthma of the oesophagus
Mast cell urticarial reaction
Macrophage lots of cytoplasm. Associated with
late acute inflammation, chronic inflammation,
granulomas (organized collection of activated
macrophages, become secretory, like epithelial
cells). Caseous necrosis in TB, epithelioid
macrophages. Fungal, idiopathic sarcoid, cat
scratch disease granuloma
ZN Ziehl Neelson stain for TB (AFB)
Tumours ontological classification
Carcinoma, sarcoma, lymphoma, melanoma
Carcinoma (epithelial cell)
Squamous cell: keratin producing,
intercellular bridges
Adenocarcinoma: mucin producing, glands.
Mucin stain blue
Transitional cell
Originates from skin, head and neck, oesophagus,
anus, cervix, vagina
Melanoma fontana stain for melanin
Stains: histochemical, immunohistochemical
H+E
Prussian blue iron stain positive for Fe overload,
hemochromatosis
Glomerulus congo red positive amyloid. Apple
green birefringence in polarized light
Immunofluorescence
Immunoperoxidase
Tumours
Cytokeratin epithelial marker carcinoma
CD45 lymphoid marker
CK20+ cytokeratin, CK7- large bowel cancer
primary
Infections
HSV multiple-nuclei in cells, IHC
Lecture 4: Haemolytic anemia
Normal RBC survives 120d, hemolysis is shorted
RBC survival. Intra or extravascular by RES.
Inherited or acquired
Alice Tang
2017-2018
Intravascular: malaria, G6PDD, blood transfusion
mismatch, cold Ab hemolysis, drugs, MAHA,
HUS/TTP, PNH
Hereditary HA: membrane (proteins,
permeability), RBC metabolism, Hb (thal, SCD,
unstable Hb). FH important e.g. hereditary
spherocytosis AD neonatal jaundice
Anemia may be present in hemolysis but not
invariable. Increased erythroid hyperplasia with
increased RBC production and reticulocytes.
Increased folate demand, susceptible to
parvovirus B19 arrest maturation of developing
RBC. Self limiting but may need transfusion.
Reticulocytes from and may have aplastic crisis.
Propensity to gallstones (cholelithiasis), iron
overload, osteoporosis. Early forms with no
differentiation, immune lifelong after
PK deficiency, hepatic siderosis, increased iron,
Perl stain
Gilbert syndrome, poor BR conjugation, high
unconjugated BR, increased risk of gallstones
UGT 1A1 TA7/TA7 extra dinucleotide on TATA,
reduced UGT transcription, less enzyme
Pallor, jaundice, splenomegaly, pigmenturia
(coca cola), FH
Anemia, reticulocytosis (except B19),
polychromasia (reticulocytes), high BR,
increased LDH intravascular hemolysis,
reduced haptoglobin. Hburia,
hemosiderinuria (intravascular hemolysis)
Link lipid bilayer to spectrin A (band 3)
GPI anchor (PNH) complement regulatory
proteins prevent damage by complement
RBC membrane defects: hereditary spherocytosis
(vertical interaction) or hereditary elliptocytosis
(horizontal interaction)
HS vertical: band 3, protein 4.2, Ankyrin, b-
spectrin
HE horizontal: a-spectrin, b-spectrin, protein
4.1
Hereditary spherocytosis
Pathology Notes
Year 5
Commonest genetic defect in RBC
cytoskeleton, lack area of central pallor
Increased MCHC hyperchromic
Polychromasia young RBC population
FH in 75%, AD. 25% recessive or de novo
Increased sensitivity to lysis in hypotonic saline,
osmotic fragility test. Reduced binding of dye eosin-5-
maleimide (flow cytometry dye binding test)
Hereditary elliptocytosis
No polychromasia, not much hemolysis. Hereditary
pyropoikilocytosis is the homozygous form, more
serious
G6PD deficiency
Affects 400m worldwide, mostly where malaria is
endemic, selection. X-linked, clinically seen in
hemizygous M, homozygous F
Catalyses first step of pentose phosphate pathway
(hexose monophosphate)to generate NADPH to
maintain intracellular GSH glutathione. Protect cell
from oxidative stress
Acute HA triggered by oxidants, infection, fava
bean, napthalene. Steady state asymptomatic
Neonatal jaundice
Commonest cause of kernicterus
Chronic HA rare
Hemighosts, Heinz bodies peripheral inclusions
denatured Hb oxidative hemolysis methylviolet, bite
cells. Unremarkable in steady state
Antimalarials, primaquine, dapsone
Sulphonamides, ciprofloxacin, nitrofurantoin
Vitamin K
Fava bean, mothballs (even via breastfeeding)
Alice Tang
2017-2018
Other pathways for hemolysis include the Embden-
Meyerhof pathway, Rapoport-Luebering shuttle and
the nucleotide/glutathione metabolism pathways
Pyruvate kinase deficiency commonest glycolytic
pathway defect. Echinocytes shrink in size from
dehydration. Increased post-splenectomy. Defect in
nucleotide synthesis. Pyrimidine 5-nucleotidase
deficiency results in basophilic stippling (also seen in
lead poisoning, but less hemolysis). Age of onset,
pattern, inheritance and other somatic defects
Investigations in hemolysis: DAT (direct antiglobulin
test) detect Ig for AIHA. Look for intravascular
hemolysis with urinary hemosiderin/Hb/LDH
high/haptoglobin low. Osmotic fragility test/eosin-5-
maleimide dye binding test. G6PD +/- PK activity, Hb
separation A/F%, Heinz body stain, PNH diagnosed
with Hams test or flow cytometry of GPI linked
proteins, thick/thin blood film
Management
Folate supplement
Avoid precipitating factor
RBC transfusion
Immunisation against BBV (hepB especially, hepA)
Monitor for gallstones/cholecystectomy if
symptomatic, chronic symptoms
Splenectomy if indicated
Splenectomy indications
PK deficiency, enzymopathies
Hereditary spherocytosis
Severe elliptocytosis/pyropoikilocytosis
Thalassemia
Immune HA
Pathology Notes
Year 5
However greater risk for overwhelming sepsis,
encapsulated organisms (Pneumococcus,
Haemophilus) avoid with immunization and penicillin
prophylaxis
Criteria: transfusion dependent, growth delay,
physically limited Hb<8, hypersplenism, age <3, before
10 years to maximize pre-pubertal growth
Case history: 18m female infant from UAE, presented
at 6m with anemia, jaundice, pigmenturia, sudden
onset after respiratory illness, chronic hemolysis,
parents (1st cousins) and 2 siblings well. Pale, icteric,
palpable spleen tip. Hb 7, reticulocytes 880 (37.4%).
Irregularly contracted cells and supravital methyl-
violet showed Heinz bodies (denatured Hb)
Hb stability test with heat and isopropanol strongly
positive, compared to parental and control samples.
Unstable Hb variant. On electrophoresis and HPLC
none detected as it didnt separate. Late eluting
fractions on HPLC
Electrospray ionization mass spec (ESI-MS) molecular
mass resolving difference, RBC ideal single protein at
high concentration, fast and cheap
Hb Hammersmith disrupts haem contact, reduced
O2 affinity, Heinz body HA seen
Lecture 5: Prion Diseases
75M retired businessman returned from Ghana
c/o paraesthesia, ataxia, tremor. Gradual onset
over 3/52 ascending tingling, jerky tremor left
hand, walking with a stick
PMH: R hemisphere stroke with no residual
deficit, HTN, obese, syphilis treated, falciparum
malaria treated
DH: perindopril, simvastatin, clopidogrel
FH: sister died from MND
SH: lives alone, 20U alcohol/week, non-smoker,
MSM
Normal general exam. Neuro exam shows jerky
tremor, nystagmus on left. Unremarkable
investigations.
MRI DWI diffusion weighted imaging picks up
recent infarcts well, nil acute ischemia changes.
Alice Tang
2017-2018
TPPA+ (past Treponema infection), RPR- (no
current infection)
Continual relentless deterioration: more
tremulous, dysarthria, ataxia, fully orientated,
diplopia, bedbound
Neurological differential diagnosis: CJD, rare
neuro diagnosis
14-3-3 marker of rapid neuronal
degeneration (negative)
S100
NSE
DWI MRI repeat increased signal in cortex seen in CJD
Day 30: oculomotor signs, anarthric, myoclonus
severe, ataxic breathing, orientated where intelligible
Planned transfer to QS for brain biopsy, rapid
deterioration with no response to Abx or high dose
steroids, died D41, sporadic CJD (FAST, 6m max
survival)
Prion diseases = protein only infections agent. Do
contain DNA but protein only, rare transmissible
spongiform encephalopathies in humans/animals with
rapid neurodegeneration. Untreatable. Cascade,
develop abnormal protein
Normal prion gene making prion protein, unknown
function but involved in copper metabolism. Found on
C20, codon 129 has 3 polymorphisms MM, MV, VV.
MM associated with prion disease
PrP normal alpha helix, protease sensitive
PrP(Sc) beta sheet, protease and radiation resistant.
Unable to get rid of this (wash, radiate, autoclave)
surgical instruments. Template seed, rapid and
irreversible conversion to abnormal isoform. Trigger is
unclear. Some genetic forms predisposing
1. Sporadic is commonest: CJD (80%) in old people
2. Acquired (<5%) Kuru (cannibalism), vCJD (BSE) in
young people, iatrogenic CJD GH, blood, surgery.
Long incubation times
3. Genetic (15%) PRNP mutations
a. Gerstmann-Staussler-Sheinker syndrome
b. Familial Fatal Insomnia (3m death)
Sporadic CJD
Rapid dementia with myoclonus, cortical blindness
(occipital cortex problem), akinetic mutism (anarthria
Pathology Notes
Year 5
and bedbound), LMN signs (anterior horn cells). 65y
mean onset 1 in a million/year, death in 6 months
uncertain cause
Diagnosis of S-CJD
EEG periodic triphasic complexes (nonspecific),
also in hepatic encephalopathy and lithium
toxicity, 2/3 abnormal
MRI increased signal in basal ganglia,
cortical/striatal signal change on DWI MRI
CSF 14-3-3, S100 markers of rapid
neurodegeneration may be raised
Neurogenetics rule out genetic cause
Tonsillar biopsy not useful (vCJD only)
Brain biopsy/autopsy spongiform vacuolation in
the basal ganglia and cortex. Increased tissue
water
PrP amyloid plaques (differed to AD)
Differentials include AD 5-10y (sometimes 1y),
vascular dementia, mixed dementia, CNS neoplasm
(glioma, mets), cerebral vasculitis, paraneoplastic
syndrome, familial CJD, vCJD
BSE/vCJD atypical in young people, 26y with median
14m survival. 1995/1996. Psychiatric onset dysphoria,
anxiety, paranoia, hallucinations. Neurological
symptoms with peripheral sensory symptoms, ataxia,
chorea, dementia, myoclonus
Diagnosis vCJD
MRI pulvinar sign, seen also post-brain
transfusion
Putamen/posterior thalamus
Alice Tang
2017-2018
Nonspecific slow waves on EEG
14-3-3, S100 normal
Almost 100% MM codon 129+
Tonsil biopsy 100% sensitive/specific, prions enter
lymphoid tissue, no need for brain biopsy. Early
clinical diagnosis. Important for therapeutic trials.
May be positive in incubation period. Autopsy
may still be performed but less important
PrP(Sc) type 4t detectable in CNS, lymphoreticular
tissue
Florid plaques and vacuolation present
Iatrogenic CJD inoculation by treatment or surgery,
originally from corneal transplants, human cadaveric
GH, neurosurgery (dural graft), transfusions/IVIG 3
cases, other procedures. No current blood test
Leads to progressive ataxia, dementia and myoclonus
later on, depends on route
Codon 129 MM methionine/methionine (or valine),
30 specific mutations so far all dominant. FH crucial
dementia, MS, ataxia, psychiatric illness. EEG non-
specific, neurogenetics crucial, MRI basal ganglia high,
spinocerebellar ataxia, Huntingtons, autopsy
Gerstman-Straussler-Scheinker (GSS) slowly
progressive ataxia, hyporeflexia, dementia, 30-70,
survival 2-10 years, PRNP P102L mutation
Fatal familial insomnia (FFI) untreatable insomnia,
dysautonomia, tachy/bradycardia, ataxia, thalamic
degeneration. EPS, pyramidal signs, late cognitive
decline. Rare
Kuru in PNG cannibals, ingestion of neural tissue
infected with prion disease. Fore tribes encouraged in
women/children, fountains of knowledge. Incubation
up to 45 years, no MMs left, progressive cerebellar
syndrome death within 2 years, dementia late/absent.
Rapid once it occurs
Treatment is only symptomatic with clonazepam,
VPA, LEV for myoclonus. Delaying prion conversion
with quinacrine (FAILED), pentosan intra-ventricular
(IVH) survived in PVS, tetracycline. Difficult to run
trials. Anti-prion Ab preventing peripheral replication,
blocks progression in mice but doesnt enter CNS.
Depletion in neuronal cellular prion protein prevents
onset of disease in mice and blocks cell loss, reversal
of early spongiosis
Pathology Notes
Year 5
Report cases to National Prion Clinic at QS, UCL,
London, NCJDSU in Edinburgh
Lecture 6: HIV in African Children
3.3m children <15 living with HIV, borne mostly
by SSA, 1 in 10. Under-5 mortality is an indicator
of child health, large contribution. Many are
teenagers with perinatally acquired HIV
Most are mother to child vertical transmission,
but some for sexual abuse
Clinical features
Suppurative ear infection
Enlarged parotids/LN, usually in mumps
(immune activation)
Enlarged liver/spleen
Clubbing
Herpes zoster infection, atypicals, shingles in
more than one dermatome or the eye
CMV retinitis
Progressive encephalopathy
Anemia
Frequent nose bleeds
Severe oral thrush, esophagitis, pain to
swallow
Caries, URTI, otitis media
Failure to thrive
Severe pneumonia, TB, LIP lymphoid
interstitial pneumonitis due to EBV
coinfection, pneumocystis carinii
Severe nappy rash, skin rashes
Easy bruising
Recurrent diarrhea
Molluscum contagiosum in the face
Basal ganglia calcification, white matter
changes, atrophy, vasculopathy/stroke from
immune changes in vascular endothelium
Kaposi sarcoma due to HHV8 coinfection.
Usually children dont have time to get the
malignancies
Growth curves important to measure failure to
thrive. Length, weight, head circumference. Not
meant to cross the lines
Pre-HAART, 85% dead by 3
Alice Tang
2017-2018
1/3 children born to infected mothers will be
infected, the rest affected. 16m lost their
parents. HIV transmitted perinatally via maternal
plasma viral load. Breastfeeding, in utero,
intrapartum. Low maternal viral load at delivery
reduces risk of HIV
Much higher risk if she delivers at the peak.
Healthy placenta is an effective barrier to HIV
transmission. Less healthy with malaria/toxo
anything causing chorioamnionitis
Firstborn twin is more likely to be infected than
the second due to slower delivery. Increased risk
of MTCT increases by 2% for every hour of post-
rupture of membranes. Halved risk of
transmission with C-section
At 6w (intrapartum) large differences between
breast and formula fed babies. 16% excess risk in
the breastfed group, mortality was not very
different (study in Nairobi slums, formula fed
were getting diarrhea) but following up for more
years means that mortality would change
Risk from drinking 1L of breast milk = risk from 1
episode of unprotected sex
ARV, 1 in 2000 risk. Prevent HIV, prevent
unintended pregnancies, prevent transmission
MTCT, care and support. Rates have decreased
everywhere
All pregnant/BF women initiate triple ARVs
tenofovir, 3TC lamivudine, efavirenz. BF infants
daily nevirapine (NVP) 6w. maintain for duration
Pathology Notes
Year 5
of MTCT risk, lifelong if CD4<500 or conditional
prgrams. Uninfected infants BF exclusively for
6m, continue to 12m
Challenges include severe malnutrition, multiple
coinfections (TB), risk of IRIS immune
reconstitution inflammatory syndrome, family
disruption, stigma, depression, poverty
Lecture 7: Zoonoses and Arthropod-Borne
Infections
Pathogens cause disease in animals, there must
be a vertebrate intermediate (e.g. babesiosis
animal-tick-human)
Infection from vertebrate animals by direct
contact, indirect vector, indirect environmental
contamination. Inhale, ingest, bites, arthropod,
person to person (blood transfusion babesiosis
and tularemia). Pets, lab, household animal, wild
animal
Bubonic plague from Yersinia pestis colonizing
fleas of rats and prairie dogs
Brucella (Crimean fever), goat. Fever, spondylitis,
personality changes
Mechanical transmission: dysentery, cholera,
typhoid
Arthropod-borne: plague, Rickettsia, Ehrlichia,
Anaplasma, relapsing fever, Lyme borreliosis,
Leishmania, arboviruses
Birds: Psitticosis, Q fever. Other pets: brucellosis,
salmonellosis, Bartonella, Lyme, Rickettsia,
Leishmaniasis, Echinococcosis, rabies. Cats:
Bartonella, leptospirosis, Q fever, toxoplasmosis
(protozoa, pregnant women worry), rabies. Dogs:
hydatid disease, leptospirosis, brucellosis, Q fever
Mice and rats: Hantan, Lyme, Ehrlichia, Bartonella
Cattle: anthrax (heroin from Afghanistan animal
hides) , brucellosis, Q fever listeria (over 50 with
meningitis), E coli, toxo, anaplasmosis, TB
Pigs: brucellosis, leptospirosis, Trichinella, HepE,
flu A, Japanese encephalitis
Alice Tang
2017-2018
Emerging diseases, 75% of new bugs are
zoonoses. Mixing of multiple hosts, potential to
cross species barrier, adaptation of pathogen and
vector. Reassortment in host. Travel, food, exotic
pets, food, environments encroachment of
natural habitats
Recreation: leptospirosis (plumber, water), HepA,
giardia, toxo, Mycobacterium marinum/ulcerans,
Burkholderia, E coli
Food associated, bushmeat
Fever in a returning traveler, PUO, 3 negative
blood films if fever within a week of holiday
return, travel history, occupation, exposure to
risk factors, timing
Leishmaniasis in Europe and S America
Any mammal can carry rabies, contact with
infected animal with slow migration to CNS. IFA
for rabies Ag in brain tissue, serial frozen skin
sections, isolate virus in murine neuroblastoma
cells/mouse intracerebral inoculation. RT-PCR,
serology IgM ELISA. Pre-exposure vaccine is
important, rapid access to post exposure vaccine,
IgG
Brucella is a G- facultative intracellular bacteria, 9
species, different host specificity. Lives in WBC
transmitted by pigs and ruminants. 3-4w
incubation, nonspecific
osteomyelitis/meningoencephalitis, serverely
debilitating, 90% positive BM culture, 70%
positive blood culture with extended incubation.
Treat with doxycycline, tetracycline with
streptomycin 4-6w course
Borrelia spiral
Africa Louse-borne relapsing fever. Lice living in
clothing, mostly in Africa. Fever, rigors
Lyme borreliosis, UK Ixodes tick early erythema
migrans, flu-like, palsy, carditis, arthritis, late
encephalopathy. Treat with doxycycline
Global warming, changing habitats, wars,
population growth, breakdown of infrastructure
Pathology Notes
Year 5
Lecture 8: Hepatitis
HAV feco-oral, MSM, poor sanitation 2-6 weeks,
often subclinical in chidren. Notifiable,
occupational risk, GUM clinic. Plumbers, sewage,
chefs. Hand-washing is important
Shanghai blood clams
New Zealand blueberries. Consumption of
soft fruit. Virus present in urine
Transaminitis 2-6w, high ALT, anti-HAV IgM
diagnostic. IgG = previous infection or
vaccination. HAV in stool
Anti-HAV IgM recent infection/vaccine
Anti-HAV IgG previous infection/vaccine
Vaccine given to travelers
HBV and HIV same transmission: mother to baby,
blood, sexual (MSM), needlestick. 30% chance of
catching it from needlestick, HCV 3%, HIV 0.8%.
prevalent in SSA, SEA, SA, different genotypes
respond differently. Some horizontal
transmission positive in children
Dane particles, tubules and spheres surface Ag
screening test (Australian antigen). DNA virus
with 4 overlapping reading frames: surface
protein, replicative polymerase (RT), pre-core E/
core, X gene. Mutation can change sensitivity.
Hepadnavirus, affects snow leopards, Peking
ducks, woodchucks, ground squirrel
Adult 5-10% chance of becoming chronic
Neonate 95% change of chronicity, worse in male
40% chance of dying
Chronic = 6m or more
2-6m incubation period LONGER
Anti-HBc diagnostic
HBV natural course results in fibrosis, cirrhosis,
HCC (1-4% chance each year), often multifocal.
Transplantation or radioablation, chemotherapy
REVEAL showed a much higher risk of cirrhosis
with high baseline viral load
Treatment initially with IFNa in 30-40% of adult
disease, nothing for neonates, with sweat,
Alice Tang
2017-2018
autoimmune disease and bad side effects.
Antiviral but proinflammatory enhance HLA
Long-term suppression: lamivudine, tenofovir,
entecavir. HIV coinfection: tenofovir,
emtricitabine
HepB Ig to prevent graft reinfection. Treat with
nucleoside analogs in transplanted organ
Decompensated HepB, give antivirals to improve
liver. HBV vaccines, 5% may not respond, no
boosters needed (HBsAg). Anti-HBs for protection
HCV mostly blood products, drug use, not much
sex or MTCT. High in Egypt, schistosomiasis
treatments. Flavivirus (Dengue, JEV, WNV, YFV).
60-80% chronicity higher in men, fibrosis,
scarring, brain effects
20-40% clears, 60-80% chronic, 6-8w incubation.
Anti-HCV Ab 2 weeks after ALT increases. No
vaccine, HCV RNA is for diagnostic, treat with
IFNa and ribavirin, or peginterferon alfa-2b
(polyethylene glycol), better AUC. 90% cure.
Usually genotype 1, 2, 3
SVR12 IFN free shorter treatment. Telepravir,
bocepravir, sofosbuvir (not for genotype 3)
expensive tablets. Liver transplant consideration
HDV small virus, plant satellite, needs HBV to
replicate mainly in middle east. Coinfection IgM
anti-HDV, however superinfection is worse when
HBV is already present cirrhosis in 2-3y. Different
treatment to HBV
HEV Hepeviridae rare in Britain, in sewage
contaminated water, enteric. Zoonoses (pork),
genotype 1, 2 human. 3, 4 swine. High mortality
in pregnant women. Shellfish, sausages, pigs,
blood transfusions 3-8w incubation. Bells palsy,
Guillain Barre, chronic infection, effective
vaccine, ribavirin to treat
HFV? HGV? Less of a liver virus reclassified as
pegivirus, simian virus. Higher CD4
Pathology Notes
Year 5
Lecture 9: Pyrexia of Unknown Origin and
Endocarditis (PUO)
1/3 are infection
Fever > 38.3 on several occasions persisting
without diagnosis for at least 3 weeks in spite of 1
week investigation in hospital. CTD common,
neoplasm, 23% unknown
Subclasses: classical PUO, healthcare associated
PUO, immune deficient PUO (renal, transplant,
rheumatoid), HIV related
Classical PUO abscesses, (hydatid cyst), IE, TB,
complicated UTI, returning traveler
58M 3w fever, chills, back pain. Diabetic, WCC 36,
neut 33.7, CRP 169, risk spinal TB. Initial negative
blood cultures, eventual endocarditis, discitis
with epidural abscess. MSSA bacteremia,
metastatic staphylococcal disease
Fever in the returned traveler
Malaria, dengue, typhoid bacterial diarrhea
present in 7-10 days. Rashes
Brucella 3w
Rickettsia
Viral hemorrhagic fever, Congo, Angola rare
60F 3d headache, fever, nausea, 10d trip to India,
past history of dengue, previously treated TB,
purpuric rash on trunk
Rash possible in malaria, dengue, typhoid,
rickettsia IgM/G present. Treat rickettsia with
doxycycline, tick/mite/fleaborne zoonosis,
emerging pathogen. Small G- bacteria, Rocky
Mountains, spotted fever in India. Serology
Healthcare associated PUO, dont start sepsis
unless sepsis: rash, C diff, resistance risk. Post
surgical collections and infections, catheter
related UTI, line related, ventilator associated
(VAP), bed sores, C diff colitis WBC increased
HAPs increased colonization with G-, gentle
aspiration and get older aspirate more. Legionella
is rare, iatrogenic from staff and relatives
Immune deficient PUO
Alice Tang
2017-2018
Neutropenic fever, <0.5 BMT often, mucositis
common, line biofilms. Fungal infections, GVHD
increased risk of molds, higher risk in acute
leukemia, allograft. Drug fever
HIV related PUO depends on CD4. Seroconversion
illness or IVDU, abroad transfusion. Can present
with MAI or PCP, Cryptococcus. Strep pneumo is
independent, must offer HIV test. Lymphoma,
histo, leish
PCP cough, hypoxic, desaturation with exercise.
Haem patients worsen quickly. Deep respiratory
samples (renamed as Pneumocystic jirovecii)
Workup: admit, observe fever, medical history,
physical, lab tests 3 blood cultures, HIV test,
inflammatory markers (pro-calcitonin, WBC, CRP),
lag is possible
Recent/old travel filarial and histo can stay for life
until immunocompromised. Sepsis source
control. Water: lepto, FH familial Mediterranean
fever
Syphilis rash, bone pain
Eosinophilia think of worms, reactivation of
strongyloides, filarial, schisto
Brucella indolent fever, small, G- coccobacillus,
unpasteurized milk, bone pain, headache
Skin biopsy, BM, endoscopy samples
Witthold therapy unless septic. In febrile
neutropenia, empiric Abx immediately after
samples
Vasculitis screen Bence-Jones urinary protein
electrophoresis, urine casts/dip, MM, ANCA, Rho,
La
31F renal transplant, 1m fever, steroids started.
SOB, yeast grew, widespread CT chest
consolidation. Histoplasmosis from skin, Malaysia
travel, donor kidney from mother, dimorphic
fungus
Pathology Notes
Year 5
IE 1.7/100k, 58y median age, greater in men,
native v prosthetic valve, structural heart disease
is a risk factor, RhF (GAS), MV, AV commonest,
poor dentition, instrumentation (endoscopy,
cystoscopy), bowel lesion, lines, prior bacteremia
especially S aureus, Enterococcus, G-
Valvular endothelium experiences trauma, clu,ps
of platelet-fibrin deposition, non-bacterial
thrombotic endocarditis. Adherence,
colonization, vegetation. Difficult for Abx to
penetrate vegetation >20mm worry, biofilms.
Fever, chills, weakness, SOB. Clubbing, murmur,
carditis PR changes on ECG
78F, DM, MVR, 4d fever, PSM, TTE MV mass.
Strep oralis dental work. IV benpen+gent, aortic
root abscess, urgent valve replacement. Splenic
infarct, renal abscess, infarct, GN, cerebral
abscess in L sided IE. Drug addicts TV S aureus
commonest, IVDU with HIV, polymicrobial
infection commoner. S viridans, Enterococci, S
aureus, G-, fungi. Multiple blood cultures needed
Duke criteria: pathologic criteria bugs
grown/embolised vegetation, intracardiac
abscess. Clinical criteria: 2 major/1 maj + 3 min/5
min
MSSA IE: flucloxacillin for 4-6w, wath for abscess,
early cardiosurg referral. MRSA endocarditis
vancomycin, gentamicin or rifampicin/fucidin
Surgery if: more than 1 serious systemic emboli,
uncontrolled infection, significant valve
dysfunction, lack of response to Abx, local
suppurative complication, CHF
Lecture 10: Child/Neonatal Infections
Congenital = born with infection vertical
transmission at any time. Generally, earlier =
more significant fetal damage
Screen for rubella, syphilis, HepB (HepC), HIV,
some toxo, VZV. Can do things to attenuate or
vaccinate
Varied presentation with non-specific signs,
febrile rash. TORCHES (toxo, rubella, CMV, HSV,
syphilis, HSV, HIV)
Alice Tang
2017-2018
Mild maternal infection, wide range of severity in
baby, serological diagnosis. Long term sequelae if
untreated
Eye/ear deafness in rubella, cataracts
Rash
Thrombocytopenia
Cerebral abnormalities: microcephaly,
meningoencephalitis
Hepatitis, jaundice
Congenital toxoplasmosis. Asymptomatic at birth
but 60% go on to suffer long term deafness, low
IQ, microcephaly. 40% symptomatic at birth with
choroidoretinitis, microcephaly, hydrocephalus,
intracranial calcification, seizures, jaundice,
hepatosplenomegaly
Congenital rubella syndrome
Effect on fetus depends on time of infection.
Mitotic arrest of cells, angiopathy, growth
inhibitor effect
Cataracts, microphthalmia, glaucoma,
retinopathy
CVS: PDA, PAS, ASD/VSD
Ears: deafness
Brain: microcephaly, meningoencephalitis,
developmental delay
Other: growth retardation, bone disease,
hepatosplenomegaly, thrombocytopenia,
rash
First trimester, infection less likely but damage
more likely
CMV, HSV (during delivery HSV2) florid vesicular
rash
HepB, C, HIV, listeria G+ rod, GBS, syphilis,
chlamydia (during delivery, neonatal
conjunctivitis, erythromycin), mycoplasma
(hominis, ureaplasma), parvovirus (slapped cheek
syndrome, fifth disease) hydrops
fetalis/miscarriage
Neonatal = first 6w of life, if premature, neonatal
is longer. Higher incidence of infection, can
become ill rapidly and seriously unlike
adults/older children. Treat with antibiotics more
Pathology Notes
Year 5
readily, lower threshold. Immature host defence,
premature = less material IgG, NICU long lines
and IV access, exposure to bugs
colonization/infection
Early onset = 48h life GBS, E coli, listeria. Other
strep, H flu, anaerobes
Late onset = after 48h
GBS G+ coccus catalase negative, beta-hemolysis,
Lancefield Group B. Bacteremia, meningitis,
disseminated joint infection
E coli G- rod, neonates bacteremia, meningitis,
UTI
Listeria G+ rod hemolysis on blood agar, grows
well. Amoxicillin or ampicillin
Early onset sepsis risk factors:
Maternal PROM/premature labour, fever,
fetal distress, meconium distress (aspirated
during delivery), previous history
Baby respiratory distress/asphyxia, low BP,
acidosis, hypoglycemia, neutropenia, rash,
hepatosplenomegaly, jaundice
Investigate with FBC, CRP, culture, deep ear swab
GBS surface, CSF LP more readily, surface swab,
CXR
Support
Ventilate, circulatory support, TPN, benpen
(GBS)+gent (E coli)
Coagulase negative staph (CNS) in long lines
G- Klebsiella, Citrobacter in neonates,
Enterobacter, Pseudomonas, Candida
Late onset sepsis: bradycardia, apnoea, poor
feeding, irritable, convulsions, jaundice, increased
CRP, sudden changes, focal inflammation
Treat early, review and stop Abx if cultures
negative and clinically stable
1st line flucloxacillin + gentamicin (CNS)
2nd line tazocin (pip/taz) + vancomycin
Alice Tang
2017-2018
community acquired late onset: cefotaxime,
amoxicillin, gentamicin
Childhood: consider age. Viral common HSV, VZV,
HHV6/8, EBV, CMV, RSV. Bacterial infections are
commoner post-viral infections such as iGAS
Fever and abdominal pain are common
nonspecific symptoms. Routine bloods, urine,
sputum, swabs
Meningitis is the most important pediatric cause
of morbidity and mortality. Clinical headache,
neck stiffness, photophobia. Cultures, swab, (CT
head) LP CSF, rapid Ag screen agglutination test
GBS, N men, S pneumo (good specificity, but poor
sensitivity), EDTA blood PCR
Raised WCC polymorphs in bacterial. G stain
organisms, high protein/low glucose, RAT CSF
may be +, PCR more readily done
N men = G- diplococcus, commonest cause of
meningitis in childhood. Non-blanching rash
petechial. Central necrosis
S pneumo G+ diplococci. Leading cause of
morbidity and mortality in under 2s, alpha partial
hemolysis. Meningitis (2nd commonest),
bacteremia, pneumonia (empyema), 90+ capsular
serotypes, increasing penicillin resistance.
Optochin sensitive
Pneumococcal conjugate vaccines: 23 capsular
types polysaccharide vaccine <2y poor
responders. Conjugate polysaccharide to protein
CRM increased immune response down to 2m. 7
serotypes 80% disease in Prevenar. Serotype
replacement with less common serotypes,
Prevenar 13 used increased serotypes
H flu G- diplococcus (Hib), non-typable causes
respiratory infection, grows on chocolate agar
<3 months N men, S pneumo, Hib, GBS, E coli,
Listeria
3-12m N men, S pneumo, Hib
Pathology Notes Alice Tang
Year 5 2017-2018

>6y N men, S pneumo

URTI 1/3 childhood illnesses, mostly viral, empiric

treatment. S penumo commonest bacterial URTI,
UK strains sensitive to penicillin/amoxicillin.
Mycoplasma pneumonia older >4 children,
macrolides (azithromycin) fried egg appearance.
If no response, consider whooping cough
(Bordetella pertussis), TB

UTI common in chidren 3% girls, 1% boys at 11.

Pure growth 10^5 cfu/ml, pyuria pus in urine on
urine microscopy, can affect renal tract
development. E coli, coliforms (Proteus, Kleb),
Enterococcus, CNS. Early diagnosis, renal tract
imaging, Abx prophylaxis trimethoprim

Recurrent/persistent infections, sign of

congenital/acquired immunodeficiency (HIV,
SCID), pediatric ID

2m (8w): DTaP, IPV, Hib, PCV

3m: DTap, IPV, Hib, PCV, Men C
4m: DTap, IPV, Hib, PCV, MenC
1y: Hib, Men C booster

13m: MMR, PCV

3y: MMR, DTaP, IPV
13+: tetanus, diphtheria, IPV, HPV 16/18