HBP Pathology Flashcards
(43 cards)
Anatomy of the Liver: location, structure, vascular supply, portosystemic anastomoses and clinical significance
Location: right 5th intercostal space to just below the costal margin at the mid clavicular line
Structure: 2 lobes, 8 segments, covered by Glisson’s capsule (contains pain fibres)
Vascular supply: portal vein deO2 (66%), hepatic artery O2 (33%)
Portosystemic anastomoses (clinically significant consequences in portal hypertension)
- oesophageal vein (systemic) – left gastric vein (portal) –> oesophageal varices and bleeding
- inf/middle rectal vein – superior rectal vein –> haemorrhoids (controversial)
- superficial epigastric vein – paraumbilical vein –> caput medusae
Basic histology of the liver: model, 6 features
Lobular model (hexagonal) - centrilobular region (terminal hepatic venule/ central vein) --> least O2 therefore more susceptible to metabolic stress and toxins
- periportal region (portal triad) –> most O2, more susceptible to blood borne infections
- trabeculae –> arrangement of hepatocytes between central vein and portal tracts; in “plates” 1-2 cells thick
- sinusoids between plates where blood traverses to exit at central vein
- bile canaliculi –> 1-2 micrometer channels formed by grooves in membrane of adjacent hepatocytes; drains into periportal bile ductules then terminal bile ducts
- kupffer cell and stellate cell
Functions of the liver (6)
Nutrient metabolism, protein synthesis, drug/ hormone/ toxin metabolism, excretion (bile), storage, immunity (increase acute phase reactants e.g. CRP, SAA, Hepcidin)
Bilirubin metabolism
Haemoglobin –> globin + haem
Haem –> iron + bilirubin
Unconjugated Bilirubin carried by albumin to liver
Bilirubin conjugated and excreted in bile into gut
Gut bacteria convert bilirubin to urobilinogen
Urobilinogen then either
- further converted to stercobilin and ejected in stool
or
- enter portal vein via enterohepatic circulation to return to liver or to go to kidneys to be excreted in urine
Liver biopsy: indications (5), routes (3), complications (3)
Indications:
- Diagnosis
- liver mass with inconclusive imaging (30-60% cases), abnormal LFT with unknown aetiology, pyrexia of unknown origin, multiple possible parenchymal liver diseases (exclude common conditions)
- Prognosis
- staging and grading of known liver disease - Management
- treatment plans based on histological analysis; distinguish between primary and metastatic CA
Route:
- percutaneous (risk of tumour seeding, bleeding, injury to adjacent organs)
- transjugular (IJV-SVC-IVC) – safer
- open wedge (laparoscopy)
Complications:
- bleeding
- puncture of adjacent organs
- tumour seeding along needle track
Hepatocyte Injury: general changes, regeneration, scar formation
Potentially reversible changes e.g. fat and bilirubin accumulation
Irreversible = cells die by apoptosis or necrosis –> widespread death leads to confluent necrosis
Regeneration of hepatocytes is mainly by mitotic replication of hepatocytes adjacent to those that died; stem cell-proliferation and differentiation in long standing CLD
Scar formation by perisinusoidal stellate cells activation
Stigmata of Chronic Liver Disease: general, impaired liver functions, complications
General:
- malaise, fatigue, RUQ pain, hepatomegaly, weight loss
Impaired liver function:
- protein synthesis –> leukonychia + ascites; bruising
- biliary excretion –> jaundice + pruritus
- waste metabolism –> hepatic flap, fetor hepaticus
- estrogen metabolism –> gynaecomastia, spider naevi, palmar erythema, testicular atrophy
Complications:
- liver failure –> encephalopathy, hepatorenal syndrome
- portal hypertension –> formation of portosystemic shunts: haematemesis, varices, splenomegaly (congestive, platelets sequestered in expanded red pulp), caput medusae, ascites
Jaundice: cause, classifications (2)
Hyperbilirubinaemia (normally first presenting as yellow sclera)
Pre-hepatic, hepatic and post-hepatic
Unconjugated vs Conjugated
Unconjugated Hyperbilirubinaemia: presentation (2), causes (2), Gilbert’s syndrome cause/ prevalence/ bilirubin levels
Normal coloured urine and stool
Clinically detectable jaundice at >35 micro mol/L
Pre-hepatic:
- increased production of bilirubin
e. g. Haemolytic Anemia, Ineffective erythropoiesis, resorption of internal bleeding
Hepatic:
- decreased uptake and conjugation of bilirubin
e. g. Gilbert’s syndrome*, physiological jaundice of newborn, drugs such as rifampicin
Gilbert’s syndrome is UGT1A1 mutation causing defective glucuronosyltransferase activity
- common
- mild defect, usually bilirubin <100, rarely clinical jaundice
(vs. Crigler-Najjar with more severe jaundice - type I has absent enzyme, very rare, bilirubin >340, early manifestation, kernicterus; type II bilirubin 100-340, rare, moderately decreased enzyme)
Conjugated Hyperbilirubinaemia: presentation (2), causes
Tea-coloured urine, pale stool
Clinically detectable jaundice at >45 micro mol/L
Hepatic:
- intrahepatic cholestasis (if there is insufficient compensatory drainage)
e. g. inherited hepatocellular injury (hepatitis), intrahepatic bile duct disease (PBC), drugs such as OCP/anabolic steroid/ augmentin
Post-hepatic:
- extra hepatic cholestasis
e. g. intraluminal gallstone, mural cholangiocarcinoma or PSC, extraluminal CA pancreas or lymphoma
Portal hypertension: causes (3 classes), pathogenesis of cirrhosis causing portal HT (2)
Pre-hepatic:
- portal vein thrombosis/ congenital stenosis/ compression by mass
Hepatic:
- cirrhosis
- non cirrhotic schistosomiasis, diffuse granulomatous disease
Post-hepatic:
- heart – right HF or TR (c.f. nutmeg liver)
- IVC thrombosis
- Budd Chiari syndrome (obstruction of >2 hepatic veins)
Portal HT secondary to cirrhosis
- Increased vascular resistance: mechanical obstruction by portal, perisinusoidal and perivenular fibrosis and increased endothelin with decreased NO from sinusoid endothelial cells = vasoconstriction
- Increased blood flow: anastomosis of hepatic arteries and portal veins through fibrous septa and increased splanchnic arteriolar vasodilation by increased NO production in gut (decreased clearance of gut bacteria material by liver)
Liver congestion: pathophysiology, histology (3), clinical presentations (3)
Heart failure increases CVP which is transmitted backwards to IVC and hepatic veins –> dilation of hepatic sinusoids and central veins
Nutmeg appearance (alternating dark sinusoids and pale parenchyma) Centrilobular zone necrosis (red/brown) with atrophy and fatty change, surrounded by uncongested periportal zone (tan-coloured)
Clinical:
- hepatomegaly
- RUQ tenderness
- CCF signs
Ascites: pathophysiology (3), potential treatment
Excessive fluid accumulation in peritoneal cavity
Caused by
- increased hydrostatic pressure in portal HT increasing the venous pressure at peritoneal capillary beds
- decrease in osmotic pressure due to hypoalbuminaemia
- decrease in ECV due ascites and splanchnic vasodilation (decreased CO) leads to activation of RAAS (and ADH) –> increase water retention –> further increase portal HT (and causes dilutional hypoNa)
(liver also unable to metabolise aldosterone)
Aldosterone antagonist (spironolactone) can break vicious cycle
Hepatorenal syndrome: definition, pathophysiology
Pre-renal renal failure due to excessive vasoconstriction of afferent arterioles (decrease renal perfusion pressure and GFR)
Portal HT causes splanchnic arteriolar vasodilation –> decrease ECV –> strong RAAS and SNS activity –> intense renal vasoconstriction overwhelming renal vasodilator system
Hepatic encephalopathy: cause, pathophysiology (2), precipitating factors (1), presentations (5)
Hyperammonaemia
Pathophysiology:
- decrease functional hepatocytes for urea cycle
- portosystemic shunt of ammonia to systemic circulation – physiological, pathological (I.e. portal HT), iatrogenic (trans jugular intrahepatic portosystemic shunt TIPS for portal HT)
Precipitated by variceal bleeding (resorption of internal bleed –> Hb degradation –> protein)
Clinically presents as:
- behavioural abnormalities, insomnia –> confusion/ stupor –> coma, death
- develop over days/wks/mths with fluctuating neurological signs (rigidity, hyperreflexia, asterixis)
Liver failure: definition of acute liver failure, fulminant liver failure, clinical course, histology, biochemical levels, acute-on-chronic examples
Acute liver failure is the presence of encephalopathy within 6 months of disease diagnosis
- usually due to paracetamol overdose, Hep B/E
Fulminant liver failure = encephalopathy within 2 weeks of jaundice onset
Nausea, vomiting, jaundice, fatigue followed by encephalopathy, coagulation defects, portal HT (although more of a chronic feature) and ascites
AST very high, swelling and oedematous liver initially then shrink dramatically and AST decrease
- massive hepatic necrosis with small and shrunken liver; large zones of destruction with loss of architecture microscopically (very pink)
Multiorgan failure eventually
Acute on Chronic liver failure:
- established cirrhosis and extensive vascular shunting/ borderline vascular supply –> liver vulnerable to insults
e.g. Hep D superimposed on Hep B
Ascending bacterial chlangitis in PSC
Primary or metastatic CA
Resistance to medical therapy for viral hepatitis
Definition of Cirrhosis** and classification
**Definition: disrupted architecture of liver with diffuse, regenerative nodules that are separated by bridging fibrous septa
- dynamic and bidirectional (potentially reversible with regression of fibrosis with cure of CLD)
(fibrous septa formed by activation of stellate cells when underlying reticulin collapses in severe injury)
Classified into macro-nodular (e.g. viral hepatitis) and micro-nodular (e.g. AFLD, haemochromatosis) with 3mm as limit – not clinically useful
Cirrhosis: scoring of severity, aetiology (5), complications, lab results (4)
Child-Pugh Score for severity
- Albumin, Bilirubin, Clotting profile (INR), Distended abdomen (ascites), Encephalopathy
- 1-3 points for each category
- Class A (5-6) 95% survival, B (7-9) 75% survival, C (10-15) 50% survival
Aetiologies:
- Infection (viral hep - HBV most common, HCV, non-viral)
- Metabolic (AFLD, NAFLD, Haemochromatosis, Wilsons, alpha-1 antitrypsin deficiency)
- Immune mediated (autoimmune hepatitis, PBC, PSC)
- Drug induced (methotrexate, paracetamol, aspirin)
- Cryptogenic, Idiopathic
Complications (refer to details in other flashcard)
- HCC
- Portal HT
- Synthetic dysfunction
Lab results:
- low platelet, increase PT
- increase ammonia, decrease urea (except after GI bleed)
- reversed A:G ratio – hypoalbuminaemia, increased IgA
- LFT mild to moderate elevation
Infectious Liver Diseases: types (4), duration, clinical presentation, possible disease course
Acute hepatitis
- <6 months
- fever, jaundice, RUQ pain, deranged LFT, malaise
- remit or progress to chronic hepatitis
Chronic hepatitis
- > 6 months
- asymptomatic or deranged LFT
- remit, static, flare-up (acute-on-chronic) or progress to chronic
Fulminant hepatitis
- severe acute hepatitis leading to liver failure within 8 weeks
- high mortality (25-90%)
- usually caused by drugs (isoniazid, rifampicin) + toxins (50%), viral (12%; higher risk in HBV/HDV co-infection or HEV during pregnancy)
Non-viral hepatitis
- bacteria –> pyogenic liver abscess e.g. E.coli, Klebsiella, MTB
- parasites –> amoeba, echinococcus, clonorchis sinensis
Viral hepatitis: causes, presentations, details for each virus (transmission, incubation, risk of fulminant hepatitis, progression to chronic hepatitis or HCC, serology test)
Causative agents: HBV and HCV
(HIV, CMV, EBV in immunocompromised)
Presentation:
- asymptomatic, acute, chronic or fulminant hepatitis
HAV – faecal oral route of transmission, 2-6 weeks incubation, <2% fulminant hepatitis, no progression to chronic hepatitis and no risk of HCC, Anti-HAV IgM serology
HBV – parenteral route of transmission, 4-26 weeks incubation, <1% fulminant hepatitis, 5-10% chronic hepatitis (90% in neonatal), risk of HCC, HBsAg/ Anti-HBc IgM serology, 2% carrier in HK (10% in IVDA)
HCV – parenteral route, 2-26 weeks, <1% fulminant, 80% chronic hepatitis, risk of HCC, Anti-HCV IgM, 0.1% carriers in HK (45% in IVDA)
HDV – parenteral route, 4-7 weeks, 4% fulminant in co-infection; 10% fulminant in superinfection, 5% chronic hepatitis in co-infection; 80% chronic hepatitis in superinfection, risk of HCC same as HBV, Anti-HDV IgM serology
HEV – faecal oral route, 2-8 weeks incubation, 2% fulminant; 15-20% in pregnancy, no chronic hepatitis, no risk of HCC, Anti-HEV IgM serology
Pathology of viral hepatitis: acute (5), chronic (6), grading and staging
Acute viral hepatitis:
- LOBULAR (among hepatocytes) necroinflammatory activity –> cellular damage, spotty necrosis, apoptosis, confluent bridging necrosis if severe
- lobular lymphocyte infiltrate (found in all types of acute hepatitis except for bacterial abscess)
Chronic viral hepatitis:
- PORTAL BASED necroinflammatory activity
- PORTAL BASED fibrosis (Sirius red stain, Trichrome stain)
- Interface hepatitis
- Ground glass hepatocytes (HBsAg cytoplasmic inclusion) – finely granular pink on H&E, can also be seen on orcein stain or IHC cytoplasmic stain
- Sanded nuclei (HBcAg) - IHC nuclear stain
- Mild steatosis and large lymphoid aggregates (HCV)
Grading and Staging (not malignancy!)
- Grade = necroinflammatory activity
- Stage = degree of fibrosis –> stage 1 portal fibrosis, stage 2 periportal fibrosis, stage 3 bridging fibrosis, stage 4 cirrhosis
Alcoholic Fatty Liver Disease: units, pathophysiology (3), manifestations (2) and their definition, presentations, treatment
Standard unit = 10g in Asia (beer 1.8, red wine 1.5)
Prescribed limit for driving = 50mg/dL blood
Male: >2 units per day = significant intake (chronic drinker); >8 units per day = heavy drinker
Female: >1 unit per day = significant intake (chronic drinker); >4 units per day = heavy drinker
Pathophysiology of fatty acid accumulation:
- Ethanol impairs assembly and secretion of lipoproteins
- Increase NADH leads to increased shunting of substrates to lipid biosynthesis
- Acetaldehyde induces lipid per oxidation, disrupts cytoskeleton and membrane to cause hepatitis
- Microsomal ethanol oxidising system has drug interactions
Manifestations:
- Fatty Liver/ Steatosis
- steatosis in >5% hepatocytes
- asymptomatic, hepatomegaly, mildly deranged LFT - Alcoholic Steatohepatitis (10-35% of heavy drinkers)
- steatosis in >5% hepatocytes + ballooning degeneration (hallmark of steatohepatitis) + lobular inflammation
- acute: RUQ pain, fever, jaundice, nausea, vomiting
- chronic: asymptomatic, progress to cirrhosis (8-20%) of which 10-20% HCC
Treatment:
- abstinence from alcohol
Non-alcoholic Fatty Liver Disease: epidemiology, presentation, associations (5), pathophysiology, pathology (6)
27% in HK, MC cause of chronic hepatitis in HK
Asymptomatic, incidental finding (may have hepatomegaly +++)
Associated with metabolic syndrome:
- HT, DM, Hypertriglyceridemia, Low HDL-C (<1.03 mmol/L in male and <1.29 in female), Central obesity (waist circumference >80cm in female, >90 cm in male)
Pathophysiology:
- insulin resistance increases fatty acid mobilisation from adipose tissue to hepatocytes and increases hepatic fatty acid synthesis –> sensitise to toxic effects of infl. cytokines and increase toxic lipid metabolites –> steatohepatitis
Pathology:
- Macroscopically: large, soft, yellow, greasy, distended capsule
- Microscopically (can’t distinguish with ALFD!!!)
- MACROvesicular steatosis –> nucleus displaced (vs microvesicular)
- BALLOONING DEGENERATION with MALLORY DENK bodies –> misfolded and damaged intermediate filament in cytoplasm (deeply eosinophilic)
- LOBULAR necroinflammatory activity (neutrophilic around degenerating hepatocytes)
- PERIVENULAR AND PERISINUSOIDAL fibrosis (distinctive feature of fatty liver, c.f. portal based in chronic viral hep) –> central vein sclerosis – perisinusoidal scarring “chicken wire fence pattern” –> link to portal tract to create central portal fibrous septa –> MICRONODULAR cirrhosis
Drug Induced Liver Injury: onset, presentation, causes, Reye’s syndrome (cause, effect, pathology), Paracetamol overdose (effect, pathology), other possible causes
Variable onset, presentations, pathological features resembling all forms of hepatitis caused by other aetiologies
- direct toxicity, toxic metabolite or immune response e.g. haptens
- intrinsic dose dependent vs idiosyncratic dose independent e.g. isoniazid, rifampicin, halothane
Reye’s syndrome - idiosyncratic
- potentially fatal mitochondrial dysfunction involving mainly liver and brain
- use of aspirin in children (<12 yrs) with viral illness
- pathology: microvesicular steatosis (nucleus not displaced)
Paracetamol Overdose (adult >4gm/day, child >60-90mg/kg/day) - intrinsic
- emergency: potentially causing fulminant hepatitis
- accumulation of NAPQI toxic metabolite due to saturation of conjugation pathways leading to increased CYP450 metabolism and production of NAPQI (which also saturates GSH detox pathway)
- pathology: pan-acinar necrosis (massive hepatic necrosis)
- antidote should be given within 24 hrs
Other causes:
- herbal medicines common, methotrexate (macro vesicular, fibrosis), isoniazid/ rifampicin (massive necrosis), methyldopa (hepatitis), OCP/ Chlorpromazine (cholestasi), allopurinol (granuloma)
