icterus

**Definition:** Icterus (Greek *ikteros*) is the same as jaundice. Bilirubin deposits in tissues, especially those rich in elastin (sclera, skin, sublingual mucosa). Scleral icterus is usually the first place it appears. It is detectable at a total bilirubin of about 2-3 mg/dL (normal is under 1.2 mg/dL).

**Bilirubin metabolism (high-yield):** - Heme is converted to biliverdin by heme oxygenase, then to unconjugated (indirect) bilirubin by biliverdin reductase. - Unconjugated bilirubin is lipophilic and travels bound to albumin. - In the hepatocyte, UDP-glucuronosyltransferase (UGT1A1) conjugates it to form conjugated (direct) bilirubin, which is water soluble. - Conjugated bilirubin is excreted in bile. Gut bacteria convert it to urobilinogen. Most urobilinogen is excreted as stercobilin (brown stool), and some is reabsorbed and excreted in urine as urobilin (yellow urine).

**Classification by mechanism:** 1. **Prehepatic (unconjugated hyperbilirubinemia):** Caused by hemolysis (hereditary spherocytosis, sickle cell disease, G6PD deficiency, autoimmune hemolytic anemia) and ineffective erythropoiesis. Urine bilirubin is absent (acholuric jaundice) because unconjugated bilirubin is albumin-bound and not filtered. Urine urobilinogen is increased. 2. **Hepatic:** - Unconjugated: Gilbert syndrome (mild UGT1A1 reduction, unmasked by fasting, stress, or illness), Crigler-Najjar types I and II (type I has absent UGT1A1 and risks kernicterus; type II responds to phenobarbital), and physiologic neonatal jaundice. - Conjugated: Dubin-Johnson syndrome (MRP2 defect, black liver) and Rotor syndrome (OATP1B1/1B3 defect, normal-appearing liver). - Mixed: Hepatitis, cirrhosis, and drug or toxin injury. 3. **Posthepatic (obstructive/cholestatic, conjugated hyperbilirubinemia):** Causes include choledocholithiasis, pancreatic head carcinoma, cholangiocarcinoma, primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia. Findings are dark urine (bilirubinuria), pale or clay-colored stools, pruritus (bile salts), and elevated ALP and GGT. Painless jaundice with a palpable gallbladder suggests pancreatic cancer (Courvoisier sign).

**Clinical pearls:** - Carotenemia causes yellow skin but spares the sclera, which distinguishes it from icterus. - Neonatal jaundice in the first 24 hours is pathologic (think hemolysis such as ABO or Rh incompatibility). Kernicterus is bilirubin deposition in the basal ganglia, and unconjugated bilirubin crosses the blood-brain barrier. - Treatment of neonatal hyperbilirubinemia is phototherapy, which converts bilirubin to water-soluble isomers. Exchange transfusion is used for severe cases. - Workup: fractionate bilirubin (direct vs. indirect), check AST/ALT, ALP/GGT, and CBC with reticulocytes and LDH/haptoglobin if hemolysis is suspected. Use ultrasound as first-line imaging for biliary obstruction. - Charcot triad (fever, RUQ pain, jaundice) indicates ascending cholangitis. Reynolds pentad adds hypotension and altered mental status. - Conjugated bilirubin greater than 20-50% of total suggests a hepatobiliary cause. Isolated unconjugated elevation with otherwise normal liver tests suggests hemolysis or Gilbert syndrome. - In veterinary and older pathology usage, "icteric" also describes yellow serum or plasma.