GI Path: Jaundice

Jaundice is yellowing of the skin, mucous membranes, and sclera due to excess bilirubin; itching is also common. Bilirubin is a pigment in the bile; it is a by-product of heme degradation. Be aware that excess carotene can also cause skin to take on a yellow or orange color, but the sclera is spared. Causes: Accumulation of bilirubin can be due to increased production of the pigment or by impaired excretion – this framework helps us to categories various pathologies that cause jaundice. Normal bilirubin values are approximately 1 mg/dL; jaundice is usually present when levels are 2.5 mg/dL and higher. Be aware that as bilirubin accumulates, jaundice can progress from a yellowish to greenish color. Jaundice is most common in newborns and the elderly due to impaired conjugation in the liver and/or excretion. Diagnosis: Jaundice is a sign of an underlying disorder, so we need to investigate its causes to find the appropriate treatment. We use liver function tests and, when biliary obstruction is suspected, right upper quadrant ultrasound to discover and treat the origins of jaundice. We review the physiology of bilirubin production and excretion, which will help us understand the etiologies of various pathologies. Pre-hepatic phase: Heme is converted to unconjugated bilirubin in the reticuloendothelial cells, primarily in the spleen (also in the bone marrow and liver). Recall that heme is released from senescent red blood cells in hemolysis. Pre-hepatic jaundice is caused by increased hemolysis, which raises unconjugated bilirubin levels.

• This is sometimes called "indirect hyperbilirubinemia."
• This can help us remember the relationship between hemolytic anemia, in which hemolysis is increased, and jaundice.

Hepatic phase: Unconjugated bilirubin travels from the reticuloendothelial cells to the liver, where it is taken up by hepatocytes and conjugated. Liver disorders that interfere with bilirubin conjugation or its excretion from the liver cause "hepatic jaundice," sometimes called "mixed hyperbilirubinemia," in which both unconjugated and conjugated bilirubin are elevated. Post-hepatic phase: Transfer of conjugated bilirubin in the bile through the biliary system; recall that the gallbladder stores most of the bile until cues from the digestive tract trigger its release to the intestines to help break down food. Conjugated bilirubin travels through the common bile duct and sphincter of Oddi to the intestines. Bacterial enzymes in the intestine reduce the conjugated bilirubin, which produces urobilinogens. Most of the urobilinogen is excreted in the feces as stercobilin, which gives the feces its brown color. A small portion is excreted in the urine as urobilin. The rest is "recycled" in the enterohepatic circulation. Post-hepatic jaundice is primarily caused by blockage in the biliary system, which prevents bile excretion and therefore increases conjugated bilirubin in the blood. This is sometimes referred to as "direct hyperbilirubinemia." Keep in mind the mnemonic HOT Liver – Hemolysis, Obstruction, Tumors, and Liver diseases.* # Characterized by elevated levels of unconjugated bilirubin. Unconjugated bilirubin does not appear in the urine; this is because it is not water soluble. We divide cause of causes of indirect hyperbilirubinemia into two broad categories. Situations that produce excess bilirubin in the pre-hepatic phase: Increased hemolysis, which includes disorders like Sickle cell anemia and G6PD deficiency; increased hemolysis is a top cause of jaundice. Inefficient erythropoiesis, as in thalassemia and pernicious anemia. Increased bilirubin production, as we see in massive blood transfusions and hematoma resorption. Intrahepatic situations that impair bilirubin conjugation and uptake: Medications, such as protease inhibitors and Rifampin can reduce hepatic bilirubin uptake. Two autosomal recessive disorders characterized by deficiencies of UDP-glucuronosyltransferase, which is a liver enzyme necessary for bilirubin conjugation and uptake: Gilbert syndrome, in which symptoms are generally mild and intermittent. Crigler-Najjar syndrome, which can be mild or severe, depending on the type. Be aware that Type 1 Crigler-Najjar syndrome is defined by a total lack of UDP- glucuronosyltransferase and, as a result, dangerously high levels of unconjugated bilirubin that can lead to brain damage (this is called kernicterus). # Characterized by elevated levels of conjugated bilirubin. Excess conjugated bilirubin is water soluble and can be excreted in the urine, so these disorders are characterized by urine darkened by bilirubin. Two autosomal recessive disorders characterized by impaired hepatic excretion and/or storage of conjugated bilirubin (by definition, these are intrahepatic causes of jaundice): Dubin-Johnson syndrome, which is often asymptomatic, is caused by defects in bilirubin secretion. Rotor syndrome, which is generally benign and self-limiting, is caused by defects in bile storage that allows bilirubin to leak into the plasma. Be aware that Rotor syndrome may present with elevated levels of both unconjugated and conjugated bilirubin. Cholestasis can have post- and intra-hepatic causes. Cholestasis is the partial or complete blockage of bile flow ("chole" refers to bile, "stasis" refers to inactivity). Cholestasis is another top cause of jaundice. Recall that stercobilin is the form of bilirubin excreted in the feces, and gives the feces its brown color. In cholestasis, the bilirubin is blocked from reaching the intestines and from mixing with the feces, so patients have pale, chalky-colored feces. Post-hepatic causes of cholestasis:

• Gallstone obstruction in the gallbladder or bile duct (note that cholelithiasis is when the gallstones are trapped in the gallbladder, choledocholithiasis is when gallstones are trapped in the common bile duct).
• Biliary system inflammation, atresia, or strictures that narrow the ductal system.
• Ductal compression caused by tumors in the bile system or pancreas, or due to pancreatitis

Intrahepatic causes of cholestasis:

• Cholestatic liver disease (including primary biliary cholangitis and primary sclerosing cholangitis).
• Infiltrative liver diseases (such as amyloidosis, lymphoma, sarcoidosis, and tuberculosis)
• Sepsis
• Pregnancy
• Total parenteral nutrition
• Infectious diseases, including malaria.

# Characterized by increased levels of both unconjugated and conjugated bilirubin. Patients will have abnormal liver functioning tests indicative of liver damage. Hepatocellular injury is a top cause of jaundice. Important causes of liver damage leading to jaundice:

• Hepatitis, including viral, alcoholic, and autoimmune hepatitis, and nonalcoholic steatohepatitis.
• Other viral infections, such as Yellow fever ("yellow" because of the jaundice), EBV, CMV, and HSV;
• Other disorders, including cirrhosis and Wilson's disease, and,
• Drugs and toxins, including estrogen, acetaminophen, and arsenic.

# Very common and generally benign. Newborn jaundice is most often due to the newborn's immature hepatic conjugation process; the jaundice lasts only a couple of weeks and resolves as the infant develops the ability to process and excrete bilirubin. "Breast milk jaundice"* is another form of benign newborn jaundice; the mechanisms are uncertain, but this form of jaundice lasts 3-12 weeks and resolves on its own. In contrast, "breastfeeding jaundice" (aka, breastfeeding failure jaundice) occurs when the infant takes in too little breastmilk to produce sufficient stool and bilirubin excretion is impaired. We need to rule out congenital and hemolytic disorders, such as G6PD deficiency. We need to monitor and treat bilirubin excess promptly because newborns are particularly susceptible to kernicterus, brain damage caused by bilirubin deposits.