1. General features of hepatic disease

Question 1

4 main common syndromes that result as a consequence of many different diseases affecting the hepatobiliary system

Answer 1

1. Hepatic failure
2. Cirrhosis
3. Portal hypertension
4. Jaundice & Cholestasis

Question 2

Definition of hepatic failure

Answer 2

Hepatocellular insufficiency due to various insults, leading to a decreased ability of the liver to carry out normal physiological functions

Question 3

Classification of hepatic failure

Answer 3

1. Acute liver failure
   - Acute liver illness associated with encephalopathy within 6 months after initial diagnosis
   - If encephalopathy sets in within 2 weeks of onset of jaundice, known as fulminant liver failure
   - Caused by drugs, HAV, HBV, toxins & chemicals
2. Chronic liver disease
   - Most common route to liver failure
   - Ends in eventual cirrhosis
3. Hepatic dysfunction without overt necrosis
   - Hepatocytes remain viable but are unable to perform normal metabolic functions
   - Caused by tetracycline toxicity & acute fatty liver of pregnancy

Question 4

Pathological Effects of Hepatic Failure

Answer 4

1. Impaired bilirubin metabolism → jaundice
2. Impaired protein synthesis → hypoalbuminemia which predisposes to peripheral edema & ascites
3. Impaired clotting factor synthesis → coagulopathy with increasing bleeding tendencies
4. Impaired hormone inactivation → hyperestrinism (elevated estrogen levels) → manifests clinically as spider naevi, palmar erythema, gynaecomastia
5. Impaired detoxification → hyperammonemia (which can cause hepatic encephalopathy) → Fetor hepaticus (characteristic musty body odour due to mercaptans formed by GI bacteria action on methionine being shunted into systemic circulation)

Question 5

Complications of Hepatic Failure

Answer 5

1. Hepatic Encephalopathy
   - Disorder of neurotransmission in CNS & neuromuscular system
   - Due to elevated blood levels of ammonia which impairs neuronal function
   - Neurological signs: rigidity, hyperreflexia, asterixis (liver flap)
2. Hepatorenal Syndrome
   - Appearance of renal failure in individuals with serve chronic liver disease in whom there are no intrinsic morphologic or functional causes for renal failure
   - Due to systemic vasodilation & activation of renal sympathetic which constricts afferent renal blood supply, decreasing renal perfusion
3. Hepatopulmonary Syndrome
   - Clinical triad of chronic liver disease, hypoxemia & intrapulmonary vascular dilations
   - Due to enhanced nitric oxide production by the lung

Question 6

Definition of cirrhosis

Answer 6

End stage of chronic liver disease, defined by 3 main morphologic characteristics: bridging fibrous septa, parenchymal nodules & disruption of the architecture of the entire liver

Question 7

Causes of Cirrhosis

Answer 7

1. Alcoholic liver disease
2. Chronic viral hepatitis
   - Chronic hepatitis B virus infection
   - Chronic hepatitis C virus infection
3. Intrahepatic biliary disease (biliary cirrhosis)
   - Primary biliary cirrhosis
   - Secondary biliary cirrhosis
   - Primary sclerosing cholangitis
4. Metabolic liver diseases
   - Hemochromatosis (pigment cirrhosis)
   - Wilson disease
   - alpha1-antitrypsin deficiency
   - Non-alcoholic fatty liver disease (NAFLD)

Question 8

Pathogenesis of cirrhosis

Answer 8

1. Chronic liver disease with chronic inflammation results in progressive fibrosis of the liver
   - Major player: hepatic stellate cells aka Ito cells (found in space of Disse, normally stores Vitamin A)
   - Under stress, Ito cells get converted to myoepithelial cells which lay down interstitial collagen (types I & III) in the space of Disse
   - This creates fibrous septal tracts
2. Fibrous septal tracts impairs solute exchange between hepatocytes & plasma
   - Deposition of collagen in space of Disse causes “capillarization” of hepatic sinusoids due to loss of fenestrations
   - New vascular channels develop within the fibrous septa which further shunts blood away from the liver parenchyma
3. Hepatocyte death & regeneration within the confines of the bridging fibrous septa
   - Forms parenchymal nodules without normal hepatic lobular architecture
4. On the whole, the aforementioned processes occur diffusely throughout the liver, resulting in an architectural disruption of the entire liver

Question 9

Morphology of cirrhosis

Answer 9

Grossly:
1. Enlarged in early stage, shrunken in late stage

2. Nodular surface texture
3. Variety of colours may be seen (yellow in fatty change, grey in viral hepatitis, green in jaundice, brown in hemochromatosis)

Histologically:
1. Bridging fibrous septa

2. Parenchymal nodules comprising hepatocytes
   - Micronodular (<3mm): alcoholic cirrhosis
   - Macronodular (>3mm): viral hepatitis cirrhosis
   - Irregular nodules: biliary cirrhosis
3. Inflammatory infiltrate
4. Ductular proliferation within fibrous septa
5. Cholestasis
6. Piecemeal necrosis/interface hepatitis (necrosis of the limiting plate of the first row of hepatocytes)
7. Other specific features of specific etiologies:
   - Mallory bodies (reticular eosinophilic depositions in liver cells due to intermediate filament damage) → Alcoholic cirrhosis, Wilson disease
   - Groundglass hepatocytes (due to intracellular accumulation of HBsAg): → HBV cirrhosis
   - Hemosiderin (use Perl’s stain or Prussian blue): → Pigment cirrhosis
   - Aggregated copper within lysosomes principally in the periphery of the nodule (use rhodamine stain): → Wilson disease
   - alpha1-antitrypsin globules in cytoplasm of hepatocytes (PAS positive, diastase resistant): → alpha1-antitrypsin deficiency cirrhosis

Question 10

Pathological Effects & Complications of cirrhosis

Answer 10

1. Progressive hepatic failure
2. Development of portal hypertension
3. Hepatocellular carcinoma

Question 11

Definition of portal hypertension

Answer 11

Raised blood pressure within the portal venous system

Question 12

Causes of Portal Hypertension

Answer 12

1. Prehepatic causes
   - Obstructive thrombosis of portal vein
   - Massive splenomegaly with consequent splenic vein blood flow
2. Intrahepatic causes
   - Cirrhosis (causes most cases of portal hypertension)
   - Schistosomiasis
   - Massive fatty change
   - Caroli disease
   - Sarcoidosis
3. Posthepatic causes
   - Severe right-sided heart failure
   - Constrictive pericarditis
   - Hepatic vein outflow obstruction (Budd Chiari syndrome)

Question 13

Pathogenesis of Portal Hypertension in Cirrhosis

Answer 13

1. Increase in resistance to portal blood flow at level of hepatic sinusoids
   - Parenchymal nodules compress sinusoids
   - Contraction of vascular smooth muscle cells & myofibroblasts
2. Hepatic artery-portal vein shunt formation
   - Anastomoses form between branches of the hepatic artery & portal vein within the fibrous septa
   - In turn imposes high arterial pressures of hepatic artery on low pressure portal venous system
3. Increased portal blood flow (hyperdynamic circulation)
   - Reduced clearance of bacterial DNA absorbed from gut & carried to liver (due to impaired solute exchange between hepatocytes & plasma in cirrhosis)
   - Stimulates increased nitric oxide production
   - In turn causes splanchnic arterial vasodilation

Question 14

Pathological effects & complications of cirrhosis

Answer 14

1. Ascites
   - Increased fluid shift into space of Disse from intravascular compartment due to increased sinusoidal hydrostatic pressure in portal hypertension
   - Often accompanied by decreased plasma oncotic pressure due to hypoalbuminemia & water/sodium retention
   - Increased fluid shift leading to increased lymphatic drainage from the liver overwhelms thoracic duct capacity, resulting in percolation of hepatic lymph into peritoneal cavity
2. Formation of portosystemic shunts
   - Increased portal venous pressures causes dilation of anastomotic channels between portal veins & systemic veins, allowing collateral flow of portal blood into systemic veins
   i. Periumbilical veins & superficial abdominal veins (when dilated → caput medusae)
   ii. Gastric veins & lower esophageal veins (when dilated → esophageal varices)
   iii. Superior rectal veins & inferior rectal veins (when dilated → hemorrhoids)
   - Portosystemic shunting exacerbates problems associated with shunting of blood through liver (e.g. hyperammonemia)
   - Rupture of esophageal varices can result in potentially fatal hematemesis
3. Congestive splenomegaly
   - Splenomegaly secondary to hypertension
   - Results in pathological effects of hypersplenism (anemia, thrombocytopenia, leukocytopenia)
4. Hepatic encephalopathy
   - Due to hyperammonemia portosystemic shunting

Question 15

Definition of jaundice & cholestasis

Answer 15

1. Jaundice: yellow pigmentation of skin due to hyperbilirubinemia
2. Cholestasis: accumulation of bile pigment within hepatic parenchyma

Question 16

Causes of hyperbilirubinemia

Answer 16

1. Prehepatic (hemolytic) causes
   - Hemolytic anemias
   - Resorption of blood from large internal hemorrhages
   - Ineffective erythropoiesis
2. Hepatic (hepatocellular) causes
   - Widespread hepatocellular diseases (hepatitis, cirrhosis)

• Physiologic jaundice of the newborn (due to immaturity of hepatic conjugation enzymes before 2nd week of life)
• Gilbert syndrome
  i. AR inheritance
  ii. Mildly decreased glucuronyl transferase activity (30% of normal)
  iii. Causes mild fluctuating hyperbilirubinemia
• Crigler-Najjar syndrome type I
  i. AR inheritance
  ii. Complete absence of glucuronyl transferase
  iii. Invariably fatal by 18 months without liver transplantation
• Crigler-Najjar syndrome type II
  i. AD inheritance
  ii. Greatly decreased glucuronyl transferase activity (can only form monoglucuronidated bilirubin)
  iii. Causes very yellow skin
• Dubin-Johnson syndrome
  i. AR inheritance
  ii. Absence of MDR2 transporter resulting in failure to transport conjugated bilirubin out of hepatocytes into bile canaliculi
  iii. Generally innocuous
• Rotor syndrome
  i. AR inheritance
  ii. Multiple defects in uptake & excretion of bilirubin into & out of hepatocytes
  iii. Generally innocuous

3. Posthepatic (obstructive) causes
   - Gallstones
   - Carcinomas of head of pancreas, bile duct carcinoma, tumours of ampulla of Vater
   - Extrahepatic biliary atresia

Question 17

Pathophysiologic Classification of Hyperbilirubinemias

Answer 17

1. Predominantly unconjugated hyperbilirubinemia
   - Due to prehepatic & some hepatic causes of hyperbilirubinemia (those affecting uptake & conjugation of bilirubin)
   - Unconjugated bilirubin is insoluble in water, hence complexed to albumin in blood
   - Cannot be excreted in urine (not filtered when albumin-bound)
   - Can cross blood-brain-barrier, causing kernicterus (severe neurologic damage) in young children
2. Predominantly conjugated hyperbilirubinemia
   - Due to posthepatic & some hepatic causes of hyperbilirubinemia (those affecting excretion of bilirubin)
   - Conjugated bilirubin in water-soluble, only loosely bound to albumin in blood
   - Excreted in urine
   - Cannot cross blood-brain-barrier

Question 18

Clinical features of Prehepatic Jaundice

Answer 18

1. Jaundice
   i. Unconjugated hyperbilirubinemia
   ii. Lemon yellow
2. Stools: dark in colour (increased stercobilin)
3. Urine: normal colour (unconjugated bilirubin cannot be filtered into urine)
4. No pruritis (no bile accumulation)
5. Anemia with reticulocytosis
6. Splenomegaly
7. Liver function test:
   i. ALT & AST: normal
   ii. Alkaline phosphatase & GGT: normal
   iii. Liver proteins: normal

Question 19

Clinical features of Hepatic Jaundice

Answer 19

1. Jaundice
   i. Conjugated hyperbilirubinemia
   ii. Orange tint
2. Stools: normal colour
3. Urine: tea colour
4. Anorexia
5. Hepatic tenderness
6. Spleen is normal size or enlarged
7. Liver function test:
   i. ALT & AST: raised
   AST>ALT → toxins (AST in mitochondria)
   ALT>AST → viral (ALT in cytoplasm)
   ii. Alkaline phosphatase & GGT: raised (in cholestatic phase)
   iii. Liver proteins: reduced (in chronic liver failure)

Question 20

Clinical features of Posthepatic Jaundice

Answer 20

1. Jaundice
   i. Conjugated hyperbilirubinemia
   ii. Greenish tinge
2. Stools: pale (no bile pigments)
3. Urine: dark in colour (bilirubinuria, no urobilin)
4. Pruritis & scratch marks (bile accumulation)
5. Enlarged gallbladder
6. Liver function test:
   i. ALT & AST: mildly elevated
   ii. Alkaline phosphatase & GGT: raised
   iii. Liver proteins: normal