JAUNDICE &

CHOLESTATIC LIVER DISEASE

◘ Izatty Lim ◘ 0308188 ◘ 11 April 2014 ◘

Bilirubin Metabolism

Cholestatis• Clinical Features• Lab findings• Morphology• Cholestatic liver

disease

Pathogenesis of Jaundice

Causes of Jaundice

Jaundice yellow discoloration of skin & sclerae systemic retention of bilirubin ( serum level above 2.0mg/dL)

Cholestasis Impaired bile flow systemic retention of not only bilirubin but also other solutes

eliminated in bile ( bile salts & cholesterol)

Introduction

2 major function of hepatic bile:o Constitutes the 1° pathway for elimination of

bilirubin, excess cholesterol & xenobioticso Secreted bile salts and phospholipid molecules

promote emulsification of dietary fat

Bilirubin end product of heme degradation

Daily production 0.2 – 0.3g• Breakdown of senescent red cells within mononuclear phagocytes• Turnover of hepatic hemoproteins

Heme Biliverdin Bilirubin Bilirubin formed outside the liver in cells of mononuclear phagocyte

system is released & bound to serum albumin

Bilirubin & Bile Acids

Hepatocellular processing of bilirubin:1) Carrier-mediated uptake at the sinusoidal membrane2) Cytosolic protein binding and delivery to the endoplasmic reticulum3) Conjugation with one or two molecules of glucuronic acid by bilirubin uridine

diphosphate–glucuronosyltransferase4) Excretion of the water-soluble, nontoxic bilirubin glucuronides into bile.

• Most bilirubin glucuronides deconjugated by gut bacterial β-glucuronidases & degraded to colorless urobilinogens.

• Urobilinogens & the residue of intact pigment are largely excreted in feces. • ≈ 20% of the urobilinogens are reabsorbed in the ileum & colon returned to liver

reexcreted into bile.• Conjugated & unconjugated bile acids also are reabsorbed in the ileum returned to

the liver by enterohepatic circulation.

Bilirubin Metabolism &

Elimination (1) Normal bilirubin production (0.2 to 0.3

g/day) is derived primarily from the breakdown of senescent circulating red cells, with a minor contribution from degradation of tissue heme-containing proteins.

(2) Extrahepatic bilirubin is bound to serum albumin and delivered to the liver.

Hepatocellular uptake (3) and glucuronidation (4) by glucuronosyltransferase in the hepatocytes generate bilirubin monoglucuronides & diglucuronides, which are water-soluble and readily excreted into bile.

(5) Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption & reexcretion into bile.

In the normal adult,

• rate of systemic bilirubin production = rates of hepatic uptake, conjugation, and biliary excretion.

• Equilibrium between bilirubin production and clearance disrupted Jaundice

More than one mechanism may operate to cause jaundice• Especially in hepatitis, when both unconjugated and conjugated

bilirubin may be produced in excess. • In severe disease, bilirubin levels may reach 30 - 40 mg/dL. 

Of these various causes of jaundice, • MC: hepatitis, obstruction to the flow of bile & hemolytic anemia.

Pathogenesis

Neonatal jaundice or physiologic jaundice of the

newborn• almost every newborn develops transient & mild

unconjugated hyperbilirubinemia • hepatic machinery for conjugating & excreting

bilirubin does not fully mature until about 2 weeks of age

Jaundice also may result from inborn errors of metabolism

• Gilbert syndrome, a relatively common (7% of the population), benign, somewhat heterogeneous inherited condition • Manifest as mild, fluctuating unconjugated hyperbilirubinemia. • Primary cause : ↓ hepatic levels of glucuronosyltransferase (mutation in the encoding gene) • Polymorphisms in the gene variable expression of this disease. • not associated with any morbidity.

• Dubin-Johnson syndrome • Result from autosomal recessive defect in the transport protein responsible for

hepatocellular excretion of bilirubin glucuronides across the canalicular membrane.• Affected persons exhibit conjugated hyperbilirubinemia. • Other than having a darkly pigmented liver (from polymerized epinephrine metabolites, not

bilirubin) and hepatomegaly, patients are otherwise without functional problems

Main Causes of Jaundice

Pathologic condition of impaired bile flow, leading to accumulation of bile

pigment in the hepatic parenchyma

Can be caused by extrahepatic or intrahepatic obstruction of bile channels, or by defects in hepatocyte bile secretion

• May manifest as jaundice• Sometimes pruritus• Skin xanthomas (focal accumulations of cholesterol) sometimes appear, the

result of hyperlipidemia and impaired excretion of cholesterol.• Symptoms related to intestinal malabsorption, including nutritional deficiencies

of the fat-soluble vitamins A, D, or K.

Pathogenesis remains obscure

Cholestatis

A characteristic laboratory finding:• ↑ serum alkaline phosphatase (enzyme in bile duct epithelium &

canalicular membrane of hepatocytes reflects the detergent action of retained bile salts on hepatocyte membranes)

• ↑ γ-glutamyl transpeptidase (GGT, canalicular ectoenzyme) reflects the detergent action of bile salts retained in the luminal space of the bile canaliculus on the apical membranes of hepatocytes & bile duct epithelial cells

depend on its severity, duration, and underlying cause Common to both obstructive & non-obstructive cholestasis is the accumulation

of bile pigment within the hepatic parenchyma Elongated green-brown plugs of bile visible in dilated bile canaliculi Rupture of

canaliculi bile extravasation phagocytosed by Kupffer cells. Droplets of bile pigment also accumulate within hepatocytes fine, foamy

appearance (feathery degeneration).

Morphology

In the parenchyma (upper panel), Enlarged cholestatic hepatocytes (1) with dilated canalicular spaces (2). Apoptotic cells (3) Kupffer cells (4) with regurgitated bile pigments.

In the portal tracts of obstructed liver (lower panel), bile ductular proliferation (5), edema, bile pigment retention (6), and eventually neutrophilic inflammation (not shown).Surrounding hepatocytes (7) are swollen & undergoing degeneration.

Obstruction of the biliary tree distention of upstream bile ducts and

ductules by bile.

• The bile stasis and backpressure proliferation of the duct epithelial cells and looping & reduplication of ducts & ductules.

• Unlike the extensive ductular reaction in the setting of massive hepatic necrosis, in obstruction, the ductular proliferation is confined to portal tracts.

• The labyrinthine ductules reabsorb secreted bile salts, serving to protect the downstream obstructed bile ducts from the toxic detergent action of bile salts.

• Associated histologic findings include portal tract edema and periductular infiltrates of neutrophils.

Biliary Obstruction

Extrahepatic biliary obstruction frequently is amenable to surgical correction. By contrast, cholestasis caused by diseases of the intrahepatic biliary tree

cannot be treated surgically (short of transplantation) • the patient's condition may be worsened by an operative procedure. • urgency in identifying the cause of jaundice and cholestasis.

Primary biliary cirrhosis (PBC)

chronic inflammatory intrahepatic liver disorder that slowly destroys the small-to-medium-sized bile ducts. 

When these ducts are damaged, bile builds up in the liver (cholestasis) and over time damages liver tissue.

Primary sclerosing cholangitis (PSC) extrahepatic cholestatic liver disease (affecting the part of the bile duct that is

outside of the liver) that damages the bile ducts both inside and outside of the liver.

In both diseases, inflammation leads to progressive thickening, scarring, and destruction of the

bile ducts. The buildup of bile, bile salts, and cholesterol in the liver causes damage to

cell membranes in the liver, reduced production of bile salts, and fibrosis (development of scar tissue). 

Fibrosis is both a marker of liver damage and a potential contributor to liver failure. Continuing damage causes scarring or cirrhosis (the liver slowly deteriorates and malfunctions), and prevents proper liver function and impaired blood circulation in the intestines.

Cholestatic liver diseases

Robbins Basic Pathology 9th Edition

• By Kumar, Abbas, Aster Robbins and Cotran’s Pathologic Basis of

Disease Seventh Edition• By Kumar, Abbas, Fausto

References

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