Hereditary hyperbilirubinemia

Overview

Hereditary hyperbilirubinemia refers to a group of inherited disorders characterized by elevated levels of bilirubin in the blood. Bilirubin is a yellow pigment produced during the normal breakdown of red blood cells. Normally, it is processed in the liver and excreted in bile. In hereditary hyperbilirubinemia, genetic mutations disrupt this process, leading to accumulation of bilirubin, often causing jaundice (yellowing of the skin and eyes). These conditions are typically benign but can vary in severity and type depending on the specific genetic defect.

Causes

Hereditary hyperbilirubinemia is caused by mutations in genes that affect bilirubin metabolism, transport, or conjugation in the liver. The major types include:

• Gilbert syndrome: Caused by a mutation in the UGT1A1 gene, leading to reduced activity of the enzyme UDP-glucuronosyltransferase

• Crigler–Najjar syndrome: Also due to UGT1A1 mutations, but in more severe forms; classified into:

  • Type I: Complete absence of enzyme activity (severe)

  • Type II: Partial deficiency (less severe)

• Dubin–Johnson syndrome: Caused by mutations in the ABCC2 gene, impairing bilirubin excretion

• Rotor syndrome: Caused by mutations in SLCO1B1 and SLCO1B3 genes, leading to impaired bilirubin reuptake by liver cells

Symptoms

Symptoms vary depending on the specific syndrome and the degree of bilirubin elevation. Common features include:

• Jaundice: Yellowing of the skin and sclera (whites of the eyes), often intermittent in mild forms like Gilbert syndrome

• Dark urine: Especially in Dubin–Johnson and Rotor syndromes

• Fatigue or mild abdominal discomfort: Occasionally reported in some individuals

• Normal liver enzymes: Despite elevated bilirubin in many cases

Severe forms, such as Crigler–Najjar type I, can lead to dangerous bilirubin buildup in the brain (kernicterus) if left untreated, especially in newborns.

Diagnosis

Diagnosis involves a combination of clinical evaluation, lab tests, and sometimes genetic testing. Key steps include:

• Blood tests: Total and direct bilirubin levels help distinguish between conjugated and unconjugated hyperbilirubinemia

• Liver function tests: Usually normal in hereditary forms

• Urinalysis: May show bilirubin in conjugated hyperbilirubinemia (e.g., Dubin–Johnson)

• Genetic testing: Confirms specific mutations in relevant genes

• Liver biopsy (rarely needed): May show dark pigmentation in Dubin–Johnson syndrome

Other causes of jaundice (e.g., hepatitis, hemolysis, bile duct obstruction) must be ruled out to confirm a hereditary origin.

Treatment

Treatment depends on the type and severity of the syndrome:

• Gilbert syndrome: No treatment required; patients are advised to avoid fasting and excessive stress, which can trigger episodes

• Crigler–Najjar syndrome:

  • Type I: Requires phototherapy, liver transplantation may be necessary

  • Type II: May be treated with phenobarbital to enhance bilirubin metabolism

• Dubin–Johnson and Rotor syndromes: No specific treatment; management is supportive as these conditions are typically benign

Regular monitoring and patient education are essential in managing these lifelong conditions.

Prognosis

The prognosis for most hereditary hyperbilirubinemia syndromes is excellent, especially for Gilbert syndrome, which is entirely benign. Dubin–Johnson and Rotor syndromes also do not lead to liver damage or other complications. Crigler–Najjar syndrome type I carries a higher risk due to severe hyperbilirubinemia, but with appropriate treatment, many patients can avoid neurological damage. Early diagnosis and intervention are key to preventing complications in severe cases.