Causes of Jaundice

• Hepatic bile has two main functions: emulsifying dietary fat for absorption and eliminating bilirubin, cholesterol, xenobiotics, and trace metals.
• Interference with bile excretion results in jaundice (bilirubin retention) and cholestasis.
• Jaundice can arise from increased bilirubin production, hepatocyte dysfunction, or bile flow obstruction.

Major Causes of Jaundice

• Predominantly unconjugated hyperbilirubinemia is caused by excess bilirubin production through hemolytic anemias, internal hemorrhage resorption, or ineffective erythropoiesis.
• Reduced hepatic uptake can also cause unconjugated hyperbilirubinemia due to drug interference with membrane carrier systems.
• Impaired bilirubin conjugation can cause unconjugated hyperbilirubinemia and presents as physiologic jaundice of the newborn or diffuse hepatocellular disease.
• Predominantly conjugated hyperbilirubinemia is caused by decreased hepatocellular excretion from drug-induced canalicular membrane dysfunction or hepatocellular damage/toxicity.
• Impaired intrahepatic or extrahepatic bile flow leads to conjugated hyperbilirubinemia because of inflammatory destruction of bile ducts, gallstones, or external compression.

Bilirubin and Bile Formation

• Bilirubin metabolism by the liver occurs in several steps beginning with heme degradation.
• About 85% of bilirubin comes from senescent red cell breakdown, and the rest from hepatic heme turnover or red cell precursors.
• Heme oxygenase converts heme to biliverdin, which is then reduced to bilirubin by biliverdin reductase.
• Bilirubin binds to serum albumin for transport because it is water-insoluble and toxic.
• Albumin carries bilirubin to the liver, where it is taken up by hepatocytes.
• In the liver, bilirubin is conjugated with glucuronic acid by UDP-glucuronyltransferase (UGT1A1) and excreted into bile as glucuronides.
• Bilirubin glucuronides are deconjugated in the gut by bacterial B-glucuronidases and degraded to urobilinogens.
• Urobilinogens and intact pigment are excreted in feces.
• Around 20% of urobilinogens are reabsorbed, returned to the liver, and re-excreted into bile, with a small amount excreted in urine.
• Bile salts, formed by conjugating bile acids with taurine or glycine, make up two-thirds of the organic materials in bile.
• Bile acids are water-soluble sterols and function as detergents solubilizing lipids for secretion into bile and dietary lipids in the gut.
• Ninety-five percent of bile acids are reabsorbed and recirculated to the liver (enterohepatic circulation).

Pathophysiology of Jaundice

• Both unconjugated and conjugated bilirubin can accumulate systemically.
• Unconjugated bilirubin is bound to albumin and cannot be excreted in urine.
• Elevated levels of unbound unconjugated bilirubin can diffuse into tissues, especially the brain in infants, causing toxic injury (kernicterus).
• Conjugated bilirubin is water-soluble, nontoxic, loosely bound to albumin, and can be excreted in urine.
• Normal serum bilirubin is between 0.3 and 1.2 mg/dL.
• Jaundice is apparent when bilirubin levels exceed 2 to 2.5 mg/dL.
• Elevated unconjugated bilirubin results from excess production or defective conjugation.
• Elevated conjugated bilirubin results from hepatocellular disease, bile duct injury, or biliary obstruction.

Defects in Hepatocellular Bilirubin Metabolism

• Neonatal jaundice is transient, mild unconjugated hyperbilirubinemia due to immature hepatic conjugation, which typically resolves by 2 weeks of age.
• Hereditary hyperbilirubinemias include Gilbert syndrome, Crigler-Najjar syndrome type I, and Dubin-Johnson syndrome.
• Gilbert syndrome causes fluctuating unconjugated hyperbilirubinemia due to decreased glucuronosyltransferase, whereas Crigler-Najjar syndrome type I is severe glucuronosyltransferase deficiency and is fatal in infancy.
• Dubin-Johnson syndrome is a defect in bilirubin glucuronide transport, causing conjugated hyperbilirubinemia and a darkly pigmented liver.

Cholestasis

• Cholestasis is caused by extrahepatic or intrahepatic obstruction of bile channels or defects in hepatocyte bile secretion.
• Manifestations include jaundice, pruritus, skin xanthomas, and malabsorption of fat-soluble vitamins.
• Elevated serum alkaline phosphatase and γ-glutamyl transpeptidase (GGT) are characteristic laboratory findings.
• Morphologically, cholestasis shows bile pigment accumulation in the hepatic parenchyma, with elongated bile plugs visible in dilated bile canaliculi.

Bile Duct Obstruction and Ascending Cholangitis

• The most common cause of bile duct obstruction in adults is extrahepatic cholelithiasis followed by tumors.
• Obstructive conditions in children include biliary atresia, cystic fibrosis, and choledochal cysts.
• Prolonged obstruction can lead to biliary cirrhosis.
• Ascending cholangitis (bacterial infection of the biliary tree) may complicate duct obstruction, presenting with fever, chills, abdominal pain, and jaundice.

Neonatal Cholestasis

• Prolonged conjugated hyperbilirubinemia in neonates, termed neonatal cholestasis, affects approximately 1 in 2500 live births.
• Major causes are cholangiopathies, mainly biliary atresia, and neonatal hepatitis.
• Neonatal hepatitis is not a specific entity but an indication to search for underlying toxic, metabolic, genetic, and infectious liver diseases; greater of 85% have identifiable causes.
• Differentiation between these two entities needs to occur through liver biopsy analysis.

Biliary Atresia

• Biliary atresia is a complete or partial obstruction of the extrahepatic biliary tree within the first 3 months of life.
• It is the most frequent cause of death from liver disease in early childhood and underlies one-third of neonatal cholestasis cases.
• The fetal form is associated with other developmental anomalies, whereas the perinatal form has unknown etiology.
• Biliary atresia shows inflammation and fibrosing stricture of the hepatic or common bile ducts, leading to progressive destruction of the intrahepatic biliary tree.
• Without surgical intervention, death usually occurs within 2 years of birth.

Autoimmune Cholangiopathies

• Autoimmune cholangiopathies include primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Primary Biliary Cholangitis

• PBC is an autoimmune disease characterized by nonsuppurative, inflammatory destruction of small- and medium-sized intrahepatic bile ducts.
• It affects middle-aged women primarily.
• PBC is thought to result from T lymphocyte-mediated destruction of bile ducts, leading to bile salt retention and hepatocellular injury.
• Antimitochondrial antibodies are present in most patients, but their role is unclear.
• Primary biliary cholangitis causes interlobular bile ducts to be actively destroyed by lymphoplasmacytic inflammation, often called the florid duct lesion.
• Treatment with ursodeoxycholic acid has improved outcomes and slowed disease progression.
• Advanced case may also have dry eyes and mouth (Sjögren syndrome), systemic sclerosis, thyroiditis, rheumatoid arthritis, Raynaud phenomenon, and celiac disease.
• Liver transplantation benefits individuals with advanced liver disease.

Primary Sclerosing Cholangitis

• PSC involves inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts, leading to dilation of preserved segments.
• Ulcerative colitis often coexists with PSC.
• PSC tends to occur in the third through fifth decades of life, exhibiting a 2:1 male predominance.
• PSC appears to be caused by immunologically mediated injury to bile ducts are seen. T cells, autoantibodies, and genetic associations all contribute to this.
• Morpoholgically, large duct inflammation resembles that seen in ulcerative colitis, taking the form of neutrophils infiltrating into the epithelium superimposed on a chronic inflammatory background.
• PSC has no satisfactory medical treatment, and median survival after diagnosis is 10 to 12 years without liver transplantation occurring; though, progression to cholangiocarcinoma may occur.
• Its progression may be detected from elevations of serum alkaline phosphatase in patients with ulcerative colitis.