Hepatic, biliary and pancreatic pathology

ACEM Primary

August 20, 2021

Table of Contents

Hepatic pathology

General features of hepatic disease

Patterns:

Hepatocyte degeneration and intracellular accumulations
Hepatocyte necrosis and apoptosis
Inflammation
Regeneration
Fibrosis

Evaluation of hepatic disease:

Hepatocyte integrity
- Cytosolic enzymes = AST, ALT, LDH
Hepatocyte function
- Albumin
- Prothrombin time (V, VII and X, prothrombin and fibrinogen)
- Ammonia
Biliary excretion
- Serum BR: Total (conj+unconj), Direct (conj), Delta (unconj, bound to albumin)
- Urine BR
- Plasma membrane enzymes (from damage to bile canaliculus) = serum ALP

Hepatic failure

Fulminant or progressive
80-90% hepatic functional capacity lost
Mortality 80%
3 categories:
- Acute liver failure = within 2 weeks to 6 months
  - Drugs, toxins, viral (hepatitis A/B/autoimmune
  - Massive hepatocyte necrosis
- Chronic liver failure = cirrhosis
- Hepatocyte dysfunction without overt necrosis
  - Viable hepatocytes unable to function
  - Acute fatty liver of pregnancy or tetracycline toxicity
Clinical features:
- Jaundice
- Spider naevi, palmar erythema (hyperoestrogenaemia = local vasodilation)
- Hypogonadism, gynaecomastia
- Hepatic fetor (exhalation of mercaptans due to portosystemic shunting)
- Oedema (hypoalbuminaemia)
- Failure multiple organ systems
- Coagulopathy (failure of clotting factor synthesis) -> bleeding
Complications:
- Hepatic encephalopathy (elevated ammonia levels)
  - Subtle behavioural abnormalities -> confusion -> stupor -> coma
  - Rigidity, hyperreflexia, asterixis
- Hepatorenal Syndrome = development of renal failure with severe chronic liver disease (8% pa)
  - Sodium retention, impaired free water excretion
  - Heralded by drop in urine output, rising BUN and Cr
  - Secondary to decreased renal perfusion pressure due to systemic vasodilation -> vasoconstriction of afferent arterioles -> reduced glomerular filtration
- Hepatopulmonary Syndrome = clinical triad of chronic liver disease + hypoxemia + intrapulmonary vascular dilations (IVPD)
  - Causes of hypoxemia: VQ mismatch, limited diffusion, shunting

Cirrhosis

3 morphological features:
- Bridging fibrous septa
  - Type I and III collagen deposited in space of Disse forming new vascular channels and shunting blood from parenchyma
  - Loss of fenestrations in sinusoids and impaired exchange of solutes
- Parenchymal nodules (remaining hepatocytes encircled with fibrosis)
- Disruption of liver architecture
Pathogenesis:
- Death of hepatocytes + ECM deposition + vascular reorganisation
- Proliferation of hepatic stellate cells -> highly fibrinogenic cells via chronic inflammation, cytokines, disruption of ECM
- Excess collagen from perisinusoidal hepatic stellate cells (Ito cells)
- R lobe bigger and more affected.
- Obliterate biliary tracts = jaundice
Clinical features:
- 40% asymptomatic until late course
- Anorexia, weight loss, weakness
- Sx hepatic failure
- Mortality from progressive liver failure, portal hypertension complication or HCC

Portal hypertension

Increased resistance to portal blood flow
3 categories:
- Prehepatic – obstructive thrombosis in portal vein, splenomegaly
- Intrahepatic – cirrhosis, schistosomiasis, fatty change, infiltrative disease (sarcoid), portal microcirculation diseases
- Posthepatic – severe RV failure, constrictive pericarditis, hepatic vein outflow obstruction
Pathophysiology:
- Vasoconstriction + parenchyma nodules -> increased resistance to portal flow at sinusoids
- Splanchnic vasodilation -> increased venous efflux into portal venous system -> increased blood flow
Consequences:
- Ascites = accumulation of fluid in peritoneal cavity
  - Detectable at 500mL
  - Serous fluid, <3g/dL protein
  - Three mechanisms:
    - Sinusoidal hypertension drives fluid into Space of Disse -> removed by lymph
    - Percolation lymph into peritoneal cavity
    - Splanchnic vasodilation -> reduction arterial BP -> RAAS/ sodium and water retention -> increased perfusion pressure of interstitial capillaries -> drives fluid into abdominal cavity
- Portosystemic shunting = blood flow reversal from portal to systemic via dilation of collateral vessels and angiogenesis
  - Venous bypassing systemic/portal capillary beds
  - Sites: rectum (haemorrhoids), GOJ (varices), retroperitoneum, falciform ligament of liver and abdominal wall (caput medusae)
  - Varices appear ~50% cirrhosis patients -> 25-40% of those bleed -> death in 30% -> 50% who survive first bleed will have another within 1 year. Each episode of bleeding 30% mortality.
- Congestive splenomegaly
  - May result in hypersplenism -> thrombocytopenia, pancytopenia
- Hepatic encephalopathy

Jaundice and Cholestasis

Bilirubin metabolism

Pathophysiology Jaundice:
- Normal serum BR = 0.3-1.2 mg/dL, jaundice evident at 2.0-2.5 mg/dL
- Unconjugated: Insoluble, tightly bound to albumin and cannot be excreted in urine, very small amount present as albumin free anion (toxic)
  - Excess production of BR
    - Haemolytic anaemia
    - Resorption of blood from internal haemorrhage (GIB)
    - Ineffective erythropoiesis (thalassemia, pernicious anaemia)
  - Reduced hepatic uptake
  - Drug interference with membrane carriers
  - Impaired conjugation
    - Crigler- Najjar Syndrome
      - Type I autosomal recessive = absent UGT1A1 (fatal)
      - Type II autosomal dominant with variable penetrance = reduced UGT1A1 (mild, occasional kernicterus)
      - Normal liver morphology
    - Gilbert Syndrome
      - Autosomal recessive, decreased UGT1A1 activity = mild jaundice at high cell takeover and otherwise asymptomatic
      - Normal liver morphology
    - Physiologic jaundice of newborn = decreased UGT1A1 activity + decreased excretion
    - Breastmilk jaundice = b glucuronidases in milk
    - Diffuse hepatocellular disease
- Conjugated: water soluble, non-toxic and can be excreted in urine. Portion may be covalently bound to albumin called bilirubin delta fraction.
  - Deficiency of canaliculi transporters
    - Dubin-Johnson Syndrome = autosomal recessive, mutated MRP2 thus nil bile flow to GIT
      - Liver darkly pigmented due to lysosome pigments
    - Rotor Syndrome = autosomal recessive, ?hepatocyte uptake and excretion BR
  - Cholestasis = impaired bile flow leading
    - Caused by extra or intrahepatic bile duct obstruction or defects in hepatocyte bile secretion
    - Elevated ALP and GGT
    - Morphology:
      - Accumulation of bile pigment in hepatic parenchyma
    - Feathery degeneration – droplets of bile in hepatocytes
    - Causes:
      - Extrahepatic –
        Obstruction due to stone/ stricture/ cancer
      - Intrahepatic –
        Primary sclerosing cholangitis
        Primary biliary cirrhosis
        Biliary atresia
        Medications
        Sepsis
        Acute hepatitis
        Cholestasis of pregnancy
        Progressive Familial Intrahepatic cholestasis (PFIC) = genetic defect impairs bile secretion

Viral hepatitis

	Hepatitis A	Hepatitis B	Hepatitis C	Hepatitis D	Hepatitis E
Virus	ssRNA	Partially dsDNA	ssRNA	ssRNA	ssRNA
Family	Hepatovirus	Hepadnavirus	Flaviviridae	Deltaviridae	Calicivirus
Trans	Faecal-oral (contaminated food or water)	Parenteral Sexual Perinatal	Parenteral	Parenteral	Faecal-oral
IP	2-4 weeks Self limiting	1-4 months	7-8 weeks	Same as HBV	4-5 weeks
Freq CLD	Never	>90% recover<0.5% fulminant5% chronic hepatitis: <2% recover30% carrier state12-20% cirrhosis -> 6-15% develop HCC	~80%	Acute coinfection 5% <70% superinfection with chronic HBV carrier = same as acute hepatitis B, self limiting.	Never High mortality rate in pregnancy ~20%
Dx	IgM Ab	HBsAb Ab to HBcAg Vaccination available	PCR for HCV RNA (persist in chronic hepatitis) ELISA for HCV Ab	IgM, IgG Ab HDV RNA serum HDAg liver	PCR HEV RNA IgM, IgG Ab
Path		Damage secondary to CD8+ T cells	Inhibits IFN mediated cellular activity	Dependent on HBV for life cycle

Hepatitis B serologic markers:

HBsAg = carrier state
- Appears before onset sx, peaks during overt disease and declines to undetectable 3-6 months
HBsAb = indicates immunity
- Does not rise until acute disease is over, may persist for life
HBcAg = Not measured in clinical practice
HBcAb = IgM during window period, IgG indicates prior or current infection
HBeAg, HBV DNA and DNA polymerase = indictator of transmissibility (BEware)
- Signify active viral replication
- Persistance of HBeAg suggestive progression to chronic hepatitis
HBeAb = low transmissibility

Clinicopathologic Syndromes:

Acute asymptomatic infection with recovery
Acute symptomatic infection with recovery
Chronic hepatitis = >6 months, most common with HCV
Carrier state = carry virus but have no liver disease, 90% HBV cases
HIV and chronic viral hepatitis coinfection more common
Fulminant hepatic failure = hepatic insufficiency within 2-3 weeks ~12% cases

Morphology:

Acute hepatitis
- Inflammatory infiltrate including macrophage aggregates
- Periportal necrosis
- Diffuse swelling of hepatocytes = balloon degeneration
- Apoptosis
- Cholestasis
- Fatty change (HCV)
Chronic hepatitis = fibrous tissue resulting in cirrhosis
- Lymphoid aggregates
- Bridging necrosis and fibrosis
- Periportal necrosis and fibrosis
- Ground glass cells (HBV)
Fulminant hepatitis
- Entire liver or random areas
- Necrotic areas with muddy red, mushy appearance with haemorrhage
- Destruction of hepatocytes in contiguous lobules
- Preserved portal tracts

Alcoholic liver disease

	Steatosis	Hepatitis	Cirrhosis
Morphology	Fatty change = vesicular droplets of fat in hepatocytes Perivenular fibrosis Reversible with abstinence.	Hepatocyte necrosis Inflammation Mallory bodies = accumulation of protein, eg. ubiquitin. Fatty change Reversible with abstinence.	Fibrosis Hyperplastic nodules
Pathology	Enzymes in alcohol metabolism (alcohol dehydrogenase, acetaldehyde dehydrogenase) -> generate excess NADH + H+ -> lipid biosynthesis instead of normal catabolism Impaired assembly and secretion of lipoproteins Increased peripheral catabolism of fat	Acetaldehyde -> lipid peroxidation + acetaldehyde-protein adduct formation = disruption of cytoskeletal and membrane function. Cytochrome P450 metabolism -> ROS Impaired metabolism of methionine -> decreased glutathione levels -> more susceptible to oxidative injury Release bacterial endotoxin from gut -> inflammation Release endothelin -> vasoconstriction -> decrease hepatic sinusoidal perfusion -> portal hypertension
Clinical features	Hepatomegaly Mild elevation BR/ ALP	Appears acutely after ETOH binge Minimal to fulminant hepatic failure	Repeated bouts of acute hepatitis

Biliary disease

Cholelithiasis

>80% gallstones are asymptomatic

>90% cholesterol stones and remaining are pigment stones (bilirubin calcium salts)

Risk factors:

Cholesterol stones = fair/ fat/ female/fertile/ forty
- Caucasian, age, female sex hormones, OCP, obesity, rapid weight loss, gallbladder stasis, inborn disorders of bile acid metabolism, hyperlipidaemia
Pigment
- Asian, chronic haemolytic syndromes, biliary infection
- Ileal disease (Crohn’s), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency

Pathogenesis cholesterol stones:

Cholesterol in soluble form via aggregation with detergent lecithins + bile acid salts
Cholesterol concentration exceed solubilizing capacity of bile -> crystals
4 conditions to form stones:
- Supersaturation
- Hypomotility of gallbladder
- Accelerated cholesterol nucleation in bile
- Hypersecretion of mucous in gallbladder traps nucleated crystals

Pathogenesis of pigment stones:

Insoluble calcium salts + unconjugated BR
Infection of biliary tract -> release microbial b glucuronidases -> hydrolyse bilirubin glucuronides -> increase unconjugated BR -> pigment stones
Haemolytic syndromes -> secretion conjugated BR in bile increases -> 1% bilirubin glucuronides are deconjugated in biliary tree -> increase in unconjugated BR

Morphology:

Cholesterol stones are radiolucent, 10-20% contain calcium carbonate = radiopaque
Pigment stones contain calcium thus 50-75% radiopaque

Clinical features:

Biliary colic due to obstructive nature of gallstones in bladder or tree
Inflammation associated with stones (cholecystitis/ cholangitis)
- Cholangitis = bacterial infection of bile ducts, enteric gram negative aerobes such as E. Coli, Klebsiella, Interococcus, Enterobacter -> Charcot triad (fever, RUQ pain, jaundice) -> Reynold’s pentad (altered mental state, shock)
- Choledocolithiasis = presence of stones in biliary tree
Empyema (contains pure pus), perforation, fistulas, obstructive cholestasis, pancreatitis
Gallstone ileus due to stone eroding into adjacent loop of bowel
Increased risk carcinoma

Cholecystitis

Inflammation of gallbladder

Acute calculous cholecystitis = 90% precipitated by obstruction of neck or cystic duct
- Obstruction of chemicals: formation toxic lysolecithins which disrupt protective glycoprotein mucous layer, exposing epithelium to detergent action of bile salts -> inflammation
- Dysmotility: compromises blood flow to mucosa
Acute acalculous cholecystitis = ischaemia
- Cystic artery has no collaterals
- Inflammation + wall oedema -> blood flow compromise
- Risk factors: sepsis, multisystem organ failure, immunosuppression, trauma, burns, diabetes mellitus
Complications
- Chronic cholecystitis (Rokitansky-Aschoff sinuses)
- Gangrenous cholecystitis
- Emphysematous cholecystitis by invasion of gas forming organisms (clostridia/ coliforms)
Clinical features
- RUQ/epigastric pain with mild fever, anorexia, tachycardia, vomiting
- Nil jaundice usually as common bile duct is patent

Pancreas

	Acute pancreatitis	Chronic pancreatitis
Causes	20 per 100 000 people Male to female ratio 1:3 Gallstones (present in 35-60% cases and 5% patients with gallstones develop pancreatits) ETOH Vascular: Shock, vasculitis, atheroembolism Infectious: Mumps, parasites Neoplastic: Pancreatic carcinoma -> obstruction Iatrogenic (10-20%): ERCP Congenital: Mutation in pancreatic enzymes (cationic trypsinogen, trypsin inhibitor genes) Autoimmune Trauma Endocrine/Metabolic: Hypercalcaemia, dyslipidaemia Drugs (azathioprine, frusemide, estrogens)	Irreversible destruction of exocrine parenchyma + fibrosis + late stage destruction of endocrine parenchyma Long term alcohol use Long standing obstruction by tumour, pseudocyst, trauma, pancreas divisum Hereditary causes Cystic fibrosis
Morphology	Microvascular leakage causing oedema Necrosis of fat by lipolytic enzymes Acute inflammation Proteolytic destruction of parenchyma Destruction of blood vessels -> interstitial haemorrhage	Parenchymal fibrosis Dilatation of pancreatic ducts
Pathogenesis	Autodigestion by inappropriately activated pancreatic enzymes: Duct obstruction – cholelithiasis or alcoholism causing ductal concretions = interstitial oedema, impaired blood flow and ischaemia Acinar cell injury – release of intracellular proenzymes, lysosomal hydrolases Defective intracellular transport – delivery of proenzymes to lysosomal compartment and intracellular activation All three lead to acinar cell injury + activated enzymes: Proteolysis Fat necrosis Haemorrhage (elastase) Trypsin -> converts prekallikrein to activated form, initiating kinin system.	Repeated ETOH/ oxidative stress/ injury = chronic inflammation -> profibrogenic cytokines (TGF b, PDGF) -> remodelling ECM -> fibrosis
Clinical features	Epigastric pain Anorexia, nausea, vomiting Serum amylase rises in 6-12 hours, normalises within 3-5 days Lipase rise within 4-8 hrs, peak at 24 and normalise within 8-14 days Glycosuria (10%) Hypocalcaemia (precipitation of calcium in necrotic fat) Metabolic acidosis 5% mortality from shock 40-60% with acute necrotizing pancreatitis develop infection by gram negative organisms	Recurrent attacks mild pain Steatorrhea (malabsorption of fat) Diabetes mellitus Weight loss Hypoalbuminaemic oedema secondary to malnutrition
Complications	DIC ARDS Shock Renal failure Pancreatic abscess Pancreatic pseudocyst = collections of necrotic/ haemorrhagic material rich in pancreatic enzymes. Lack epithelial lining. May spontaneously resolve or become infected.	20-25 year mortality of 50% Hereditary pancreatitis have 40% risk progressing to malignancy Unclear predisposition to pancreatic cancer Pancreatic pseudocyst in 10%

Last Updated on August 20, 2021 by Andrew Crofton

Andrew Crofton, Tanvi Karnik

Andrew Crofton