Bilirubin Metabolism and Disorders

Increased Bilirubin Production

• Dyserythropoiesis can lead to an increase in unconjugated bilirubin production, reaching up to 70% in cases of thalassemia major, megaloblastic anemia, congenital erythropoietic porphyria, and lead poisoning.
• Prolonged production of unconjugated bilirubin can lead to bilirubin salt precipitation and subsequent gallstone formation.

Decreased Hepatic Clearance

• Congestive heart failure, cirrhosis/portosystemic shunts, and certain drugs can cause decreased hepatic clearance of bilirubin.
• Congestive heart failure or portosystemic shunts can impair bilirubin delivery to the liver, reducing hepatic uptake.
• Cirrhosis can result in unconjugated hyperbilirubinemia due to capillarization of sinusoids, affecting bilirubin uptake by hepatocytes.
• Drugs like rifamycin, rifampin, probenecid, flavaspidic acid, and bunamiodyl can inhibit bilirubin uptake, but this effect is reversible upon cessation of these medications.

Defective Bilirubin Conjugation

• Inherited conditions like Crigler-Najjar syndrome types I and II, and Gilbert syndrome are associated with defective bilirubin conjugation.
• Ethinyl estradiol and hyperthyroidism can also contribute to defective conjugation.
• Crigler-Najjar syndrome, a rare autosomal-recessive disorder, involves an alteration in the bilirubin-UGT gene responsible for bilirubin conjugation.
• Type I Crigler-Najjar syndrome results in a complete or near-complete loss of UGT function, while Type II presents with low UGT activity.
• Type I Crigler-Najjar syndrome typically presents with high unconjugated bilirubin levels at birth, leading to kernicterus. Treatment involves plasma exchange and phototherapy.
• Type II Crigler-Najjar syndrome may not require treatment or can be managed with phenobarbital, which induces UGT expression.
• Type I Crigler-Najjar syndrome does not respond to phenobarbital due to the loss-of-function mutation.

Other Causes of Conjugated Hyperbilirubinemia

• Drugs like isoniazid, chlorpromazine, erythromycin, and anabolic steroids can cause conjugated hyperbilirubinemia.
• Sepsis, shock, and hemochromatosis are also associated with conjugated hyperbilirubinemia.

Bilirubin Testing

• Plasma (heparin) or serum samples are used for bilirubin testing.
• Bilirubin is a breakdown product of heme, primarily derived from hemoglobin degradation.
• Unconjugated bilirubin is water-insoluble and binds to albumin in the plasma.
• Hepatocytes take up unconjugated bilirubin and conjugate it via uridine diphosphoglucuronate glucuronosyltransferase (UGT), creating a water-soluble form.
• Conjugated bilirubin is excreted into bile and delivered to the small intestine.
• Intestinal bacteria convert bilirubin into urobilinogens.
• Urobilinogens are reabsorbed and circulated back to the liver (enterohepatic circulation) or excreted in urine and stool.
• Elevated Total Bilirubin levels (>2.5-3 mg/dL) indicate jaundice and can be classified into prehepatic, hepatic, or posthepatic causes.
• Unconjugated hyperbilirubinemia is common in newborns due to high hematocrit and decreased UGT activity.

Common causes of Unconjugated and Conjugated Hyperbilirubinemia

• Unconjugated hyperbilirubinemia:*

• Increased bilirubin production from hemolysis and dyserythropoiesis: Hemolysis leads to increased red blood cell destruction and bilirubin production.

• Conjugated hyperbilirubinemia:*

• Hepatocellular injuries: Conditions affecting liver cells can lead to impaired conjugation and bile excretion.

• Biliary obstruction: Obstruction of bile ducts can prevent bilirubin flow to the intestines.

Normal bilirubin values:

• Adults/elderly/children: Total bilirubin: 0.3 - 1.0 mg/dL or 5.1 - 17 μmol/L (SI units); Indirect bilirubin: 0.2 - 0.8 mg/dL or 3.4 - 12.0 μmol/L (SI units); Direct bilirubin: 0.1 - 0.3 mg/dL or 1.7 - 5.1 μmol/L (SI units).
• Newborns: Total bilirubin: 1.0 - 12.0 mg/dL or 17.1 - 205 μmol/L (SI units)

Possible critical values:

• Adults: Total Bilirubin > 12 mg/dL
• Newborns: Total Bilirubin > 15 mg/dL