Jaundice

Did You Know?

• The word jaundice comes from the French jaunisse, meaning 'yellow disease'.
• The medical term icterus is from the Greek word ikteros.
• The yellow-breasted chat (Icteria virens) was believed to cure jaundice by its sight.

Signs and symptoms

The most common signs in adults are yellowish discoloration of the sclera and skin; scleral icterus indicates a serum bilirubin of at least 3 mg/dl. Dark urine (bilirubinuria) and pale fatty stool (acholia with steatorrhea) are also frequent. Severe itchiness commonly accompanies jaundice because bilirubin irritates the skin. The conjunctiva has high elastin content, making it particularly prone to bilirubin deposition; thus yellowing of the eye is detected early. Although traditionally called scleral icterus, the proper term is conjunctival icterus, as deposition occurs in the conjunctival membranes overlying the avascular sclera. In individuals with darker skin tones, jaundice may be less apparent on the skin and is more reliably observed in the sclera, palms, soles, and oral mucosa. A rare sign in childhood is yellowish or greenish teeth from bilirubin deposition during tooth calcification; this does not occur in adult-onset liver disease.

Pathophysiology

Jaundice arises from an underlying pathological process along the normal heme metabolism pathway. Red blood cells rupture after about 120 days in the reticuloendothelial system; macrophages phagocytose free hemoglobin and split it into heme and globin. Heme oxygenase catalyzes oxidation of heme to biliverdin (green), iron, and carbon monoxide. Biliverdin reductase then reduces biliverdin to unconjugated (indirect) bilirubin, a yellow pigment. About 4 mg of bilirubin per kg of blood is produced daily, mostly from expired red blood cells, with roughly 20% from other heme sources such as ineffective erythropoiesis and breakdown of myoglobin and cytochromes. Unconjugated bilirubin travels to the liver bound to serum albumin. In the liver, UDP-glucuronyl transferase conjugates bilirubin with glucuronic acid to form water-soluble bilirubin diglucuronide (conjugated bilirubin), which is excreted into the gallbladder.

Diagnosis

Most people with jaundice show predictable patterns of liver panel abnormalities, though variation exists. The typical panel includes aminotransferases (ALT, AST), alkaline phosphatase (ALP), bilirubin, total protein, and albumin; additional tests include gamma glutamyl transpeptidase (GGT) and prothrombin time. No single test differentiates classifications of jaundice; a combination of liver function tests and physical examination is essential. First, GGT levels (elevated only in liver conditions) help distinguish liver from bone or heart disorders. Second, if ALP and GGT rise proportionately with AST and ALT, a cholestatic problem is indicated; if AST and ALT rise significantly higher, a liver problem is indicated. In most liver disorders AST is higher than ALT, except in hepatitis (viral or hepatotoxic) where ALT exceeds AST. Alcoholic liver damage may show fairly normal ALT with AST ten times higher. Rapid drops from very high ALT/AST levels can indicate severe necrosis. Low albumin suggests a chronic condition, while normal levels occur in hepatitis and cholestasis.

Special populations

Jaundice in infants presents with yellowed skin and icteral sclerae, spreading in a cephalocaudal pattern from face and neck to trunk and lower extremities in severe cases. Other symptoms include drowsiness, poor feeding, and in severe cases unconjugated bilirubin crossing the blood-brain barrier causing kernicterus (permanent neurological damage). The most common cause is normal physiologic jaundice; pathologic causes include hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, ABO/Rh autoantibodies, alpha 1-antitrypsin deficiency, Alagille syndrome, progressive familial intrahepatic cholestasis, pyknocytosis, cretinism, sepsis, and others. Transient neonatal jaundice occurs in over 80% of newborns, defined as total serum bilirubin greater than 5 mg/dL. Physiologic jaundice results from immaturity of liver enzymes, immature gut microbiota, and increased breakdown of fetal hemoglobin. Breast milk jaundice, caused by β-glucuronidase in breast milk, begins within 2 weeks after birth and lasts 4–13 weeks. High bilirubin levels can cause kernicterus, especially in newborns due to increased blood-brain barrier permeability.