Jaundice is the yellowish discoloration of the skin and the whites of the eyes, caused by an excessive accumulation of the pigment bilirubin in the bloodstream. This condition is not a disease itself but a symptom of an underlying issue with how the body processes this pigment. While the vast majority of cases, particularly in newborns, are not directly inherited, a specific set of genetic disorders permanently impair the body’s ability to handle bilirubin. This makes certain types of chronic or recurring jaundice directly traceable to inherited genes.
How the Body Processes Bilirubin
Bilirubin production begins with the natural breakdown of old or damaged red blood cells, primarily in the spleen. During this process, hemoglobin is broken down, and its heme component is converted into unconjugated bilirubin. This unconjugated form is lipid-soluble, meaning it cannot dissolve in water and cannot be easily excreted by the kidneys.
To travel through the bloodstream, unconjugated bilirubin binds to albumin, which transports it to the liver. Inside the liver cells, the enzyme UDP-glucuronosyltransferase (UGT1A1) chemically attaches it to glucuronic acid in a process called conjugation. This transformation makes the bilirubin water-soluble, or conjugated, allowing it to be secreted into the bile. The conjugated bilirubin then travels through the bile ducts into the small intestine, where it is modified by gut bacteria and ultimately excreted.
Physiological Jaundice and Familial Risk Factors
Physiological neonatal jaundice is the most common form, occurring in an estimated 60% to 80% of newborns. This temporary condition results from the infant’s normal transitional physiology. A newborn’s liver enzyme system, including the UGT1A1 enzyme, is immature and inefficient at conjugating bilirubin. Simultaneously, newborns have a higher volume of red blood cells and a shorter lifespan, resulting in a bilirubin load the immature liver cannot clear quickly.
While the cause is not genetic inheritance, certain familial factors increase a newborn’s risk of developing significant jaundice. Having a sibling who required treatment, such as phototherapy, is a recognized risk factor. Blood type incompatibilities between mother and infant, such as Rh or ABO incompatibility, cause increased red blood cell breakdown. This often occurs in subsequent pregnancies and follows a familial pattern.
Inherited red blood cell disorders, such as Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency, are genetic conditions. These disorders lead to accelerated red blood cell destruction, drastically increasing the bilirubin load and elevating the risk for severe neonatal jaundice.
Jaundice Caused by Specific Inherited Conditions
Specific, chronic types of jaundice are directly inherited due to permanent defects in the liver’s bilirubin processing machinery. The most prevalent inherited disorder is Gilbert’s Syndrome, affecting an estimated 3% to 10% of the population. This condition involves a genetic variation in the UGT1A1 gene, leading to a reduced level of the UGT1A1 enzyme.
This impairs the liver’s ability to conjugate bilirubin, resulting in mild, fluctuating unconjugated hyperbilirubinemia. Symptoms often present only during periods of stress, fasting, or illness, and the condition is generally considered harmless.
Severe Inherited Syndromes
Rarer, more severe inherited conditions result from defects in other parts of the bilirubin pathway. Crigler-Najjar Syndrome is caused by UGT1A1 gene mutations that lead to a near-total or complete absence of the conjugating enzyme. Type I of this syndrome is life-threatening, as the massive buildup of unconjugated bilirubin can cross the blood-brain barrier and cause permanent neurological damage.
Other syndromes affect the excretion of conjugated bilirubin from the liver cell into the bile duct. Dubin-Johnson Syndrome is caused by a defect in the MRP2 transport protein, impairing the transport of conjugated bilirubin. Rotor Syndrome is caused by mutations in the OATP1B1 and OATP1B3 genes, which affect the liver’s uptake and storage of bilirubin.
Clinical Evaluation and Genetic Testing
Clinical evaluation is necessary to distinguish between temporary, acquired causes of jaundice and inherited conditions. The initial diagnostic step involves a blood test to measure the total bilirubin level and fractionate it into unconjugated and conjugated components. An elevated unconjugated fraction points toward issues with production or conjugation (e.g., Gilbert’s or Crigler-Najjar syndrome). An elevated conjugated fraction suggests a problem with excretion (e.g., Dubin-Johnson or Rotor syndrome).
Liver function tests (measuring enzymes like ALT and AST) help rule out liver damage from non-genetic causes like hepatitis. If the pattern of hyperbilirubinemia suggests an inherited disorder, genetic testing provides a definitive diagnosis. This testing analyzes specific genes, such as UGT1A1 or MRP2. Confirming a genetic diagnosis is important because conditions like Gilbert’s Syndrome require no treatment, while severe genetic forms necessitate specialized, lifelong medical management.