Path Liver Tbl 1

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What is cirrhosis?

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end stage liver damage characterized by disruption of the normal hepatic parenchyma by bands of fibrosis and regenerative nodules of hepatocytes

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Cirrhosis is defined by 3 main morphologic characteristics

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Bridging fibrous septa


Parenchymal nodules

Disruption of the architecture of the entire liver
A diffuse process

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Bridging fibrous septa

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Fibrosis
Key feature of progressive damage to the liver
Dynamic process of collagen deposition & remodeling

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Parenchymal nodules

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Hepatocytes encircled by fibrosis
Cycles of regeneration & scarring

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cirrhosis can be clinically silent until far advanced when it presents with

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anorexia, weight loss, weakness, and debilitation

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Death by cirrhosis occurs due to

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Progressive liver failure
Complications of portal hypertension
Hepatocellular carcinoma

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What causes cirrhosis?

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alcoholic liver disease > viral hepatitis > biliary diseases (5-10%);

Front 8

Describe the role of the hepatic stellate cell in the pathogenesis of cirrhosis

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the hepatocyte stellate cells (HSC) which are the source of fibrosis, are stimulated in chronic inflammation by inflammatory cytokines (TNF, lymphotoxin, interleukin I).

Front 9

Cirrhosis can present with significant clinical changes like

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Portal hypertension
Decreased detoxification
Decreased protein synthesis

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Portal hypertension leads to

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ascites, congestive splenomegaly/hypersplenism.
Esophageal varices, hemoorrhoids, and caput medusae

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Decreseased detoxification results in

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-mental status change, asterixis, and eventual coma (due to T serum ammonia), metabolic hence reversible
-Gynecomastia, spider angiomata and palmar erythema due to hyperestrinism
-jaundice

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Decreased protein synthesis leads to

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-Hypoalbuminemia with edema
-Coagulopathy due to decreased synthesis of clotting factors; degre of deficiency is followed by PT.

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bile formation serves 2 major functions, namely

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1) emulsification of dietary fat by way of detergent action of bile salts and 2) elimination of systemic waste products.

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Bile is the primary pathway for elimination of

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bilirubin, excess cholesterol, and water insoluble xenobiotics

Front 15

Disruption of bile formation is manifested clinically as

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yellowing of skin (or jaundice) and sclerae (referred to as icterus), retention of pigmented bilirubin and also other solutes eliminated in bile.

Front 16

How is bilirubin formed?

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Bilirubin is the end product of heme degradation - majority (0.2 to 0.3 gms) is derived from breakdown of senescent RBCs; remainder is from hepatic heme or hemoproteins (eg p450 cytochromes).

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Bile formation process is 5 steps
1)
2)
3)
4)
5)

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1) Heme oxygenase oxidizes heme to biliverdin which is reduced to bilirubin by biliverdin reductase
2)Bilirubin formed outside the liver is released and bound to serum albumin
3)Carrier mediated uptake of bilirubin into liver.
4) Conjugation with glucuronic acid by bilirubin UDP-uridine diphosphoglucuronyltransferase (UGT1A1) and excretion of water soluble bilirubin glucuronides into bile.
5)Most bilirubin glucuronides are deconjugated by bacterial ß-glucuronides and degraded to colorless urobilinogens which are largely excreted in feces.
*About 20% of urobilinogens are reabsorbed in the ileum and colon, returned to the liver, and re-excreted into bile; and a small amount excreted in urine.

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Jaundice Definition

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Unconjugated bilirubin and conjugated bilirubin glucuronides may accumulate systemically and deposit in tissues giving rise to yellow discoloration of jaundice and yellowing of the sclera (icterus)

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Because hepatic metabolic machinery does not mature until roughly 2 weeks of age, almost every newborn develops transient mild unconjugated hyperbilirubinemia which can be exacerbated by

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breast-feeding due to bilirubin-deconjugated enzymes in breast milk.

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Hereditary hyperbilirubinemias that are unconjugated

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Crigler-Najjar Syndrome
Gilbert syndrome

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conjugated hereditary hyperbilirubinemias

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Dubin Johnson syndrome
Rotor syndrome

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High serum levels of unconjugated bilirubin with a histologically normal liver

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Crigler-Najjar Syndrome type 1 complete loss of UGT1A1. Without liver transplantion, fatal neurological damage (kernicterus)

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UGT1A1 deficiency is less severe hence theres non lethal kernicterus

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Crigler-Najjar Syndrome type 2

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Hyperbilirubinemia and jaundice is exacerbated by infection, stenous exercise or fasting.

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Gilbert syndrome which is a mild, fluctuating unconjugated hyperbilirubinemia due to a reduction in UGT1A1

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Brown liver with accumulated epinephrine pigment granules causes jaundice but patients have normal life expectancy

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Dubin Johnson syndrome due to abscence of MDR2 a bilirubin transporter. Leads to defective hepatocyte secretion of bilirubin conjugates

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Defective hepatocellular bilirubin uptake or excretion and liver is not pigmented

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Rotor syndrome. Pts are jaundice but have normal life expectancy

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Elevated direct bilirubin is caused by

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Dubin Johnson syndrome
Rotor syndrome
viral or alcoholic hepatitis, or posthepatic jaundice, as in biliary obstruction.

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Elevated Indirect bilirubin is caused by

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Crigler-Najjar Syndrome
Gilbert syndrome
prehepatic jaundice, such as hemolytic jaundice

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Patient with jaundice, pruritus, xanthoma (skin accumulations of cholesterol) and intestinal malabsorption. High serum levels of Alkaline phosphatase and gamma glutamyl transpeptidase (GGT)

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Cholestasis which is impaired bile formation or flow, leading to the accumulation of intrahepatic bile pigments.

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Cholestasis can occur in 2 ways

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Intra (hepatocellular dysfunction) or extra (duct obstruction), however both lead to dilated bile canaliculi and hepatocyte degeneration.

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Cholestasis begins in infancy and progresses to liver failure during adulthood. Normal GGT levels, normal canaliculi and biliary trees.

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Progressive familial intrahepatic cholestasis-1 (Byler disease) which involves mutation of ATP8B1 gene leading to impaired bile secretion.

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Cholestasis with extreme pruritus, growth failure and progressive cirrhosis in the first decade. Normal GGT levels

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Progressive familial intrahepatic cholestasis-2 which is a mutation of ABCB11 gene coding for the hepatocyte canalicular bile salt export pump.

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High GGT serum levels and cholestasis

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Progressive familial intrahepatic cholestasis-3 which is mutation of ABCB4 gene coding for MDR3 responsible for phosphaditidylcholine secretion. GGT levels are high due to damaged biliary epithelium.