Clinical jaundice occurs with bilirubin levels >2–3 mg/dL. The classic presentation is yellow skin (jaundice) and sclera (icterus). Causes of jaundice include overpro-duction of bilirubin, defective hepatic bilirubin uptake, defective conjugation, and defective excretion.
Increased red blood cell (RBC) turnover. RBCs are the major source of bilirubin. Jaundice related to overproduction of bilirubin can be seen in hemolytic anemia and ineffective erythropoiesis (thalassemia, megaloblastic anemia, etc.). Laboratory studies show increased unconjugated bilirubin. Chronic hemolytic anemia patients often develop pigmented bilirubinate gallstones. The most common cause of marked jaundice in the newborn is blood group incompatibility (most commonly ABO) between mother and child, causing hemolytic disease of the newborn.
Physiologic jaundice of the newborn is a transient unconjugated hyperbilirubinemia due to the immaturity of the liver. Risk factors include prematurity and hemolytic disease of the newborn (erythroblastosis fetalis). Physiologic jaundice of the new-born can be complicated by kernicterus; treatment is phototherapy. Jaundice also occurs in newborns who have infections.
When hyperbilirubinemia is prolonged in the newborn, a mutation affecting bili-rubin conjugation enters the differential diagnosis.
• Gilbert syndrome is a common benign inherited disorder that causes uncon-jugated hyperbilirubinemia due to bilirubin UDP-glucuronosyltransferase (UGT) deficiency. Kernicterus rarely occurs and the treatment is phenobar-bital.
• Crigler-Najjar syndrome causes unconjugated hyperbilirubinemia due to bili-rubin glucuronosyltransferase (UGT) absence or deficiency. Treatment for type 1 is gene replacement therapy and liver transplantation. For a milder type 2, phenobarbital is used.
• Dubin-Johnson syndrome is a benign autosomal recessive disorder character-ized by decreased bilirubin excretion due to a defect in the canalicular cationic transport protein. It produces conjugated hyperbilirubinemia and a distinctive black pigmentation of the liver, but has no clinical consequences.
• Rotor syndrome is an autosomal recessive conjugated hyperbilirubinemia that is similar to Dubin-Johnson syndrome, but without liver pigmentation. There are no clinical consequences.
Biliary tract obstruction may have multiple etiologies, including gallstones; tumors (pancreatic, gallbladder, and bile duct); stricture; and parasites (liver flukes—Clo-norchis [Opisthorchis] sinensis). The presentation can include jaundice and icterus; pruritus due to increased plasma levels of bile acids; abdominal pain, fever, and chills; dark urine (bilirubinuria); and pale clay-colored stools. Lab studies show elevated conjugated bilirubin, elevated alkaline phosphatase, and elevated 5´-nucleotidase.
Primary biliary cirrhosis (PBC) is a chronic liver disease that is characterized by inflammation and granulomatous destruction of intrahepatic bile ducts. Females have 10 times the incidence of primary biliary cirrhosis compared to males; the peak incidence is age 40–50.
Presentation includes obstructive jaundice and pruritus; xanthomas, xanthelasmas, and elevated serum cholesterol; fatigue; and cirrhosis (late complication). Most patients have another autoimmune disease (scleroderma, rheumatoid arthritis or systemic lupus erythematosis).
Laboratory studies show elevated conjugated bilirubin, elevated alkaline phos-phatase, and elevated 5´-nucleotidase. Treatment with oral ursodeoxycholic acid slows disease progression. Antimitochondrial autoantibodies (AMA) are present in >90% of cases, which further supports an autoimmune basis. Microscopically, lymphocytic and granulomatous inflammation involves interlobular bile ducts.
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by segmental inflammation and fibrosing destruction of intrahepatic and extrahepatic bile ducts. The exact etiologic mechanism is not known but growing evidence sup-ports an immunologic basis.
The male to female ratio is 2:1; peak age 20–40. Most cases of PSC are associated with ulcerative colitis. The presentation is similar to PBC. Complications include biliary cirrhosis and cholangiocarcinoma.
Microscopically, there is periductal chronic inflammation with concentric fibro-sis around bile ducts and segmental stenosis of bile ducts. Cholangiogram shows “beaded appearance” of bile ducts.
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