Jaundice is a medical condition characterized by yellowing of the skin and the whites of the eyes. This discoloration occurs due to an accumulation of bilirubin, a pigment, in the bloodstream. Bilirubin is a natural byproduct formed when red blood cells reach the end of their lifespan and are broken down. Normally, the liver processes this bilirubin, converting it into a form that can be excreted from the body, primarily through bile and then into stool. Jaundice arises when this process of bilirubin metabolism and excretion is disrupted.
Common Causes of Jaundice
Many instances of jaundice stem from acquired conditions rather than inherited genetic factors. Physiological jaundice, common in newborns, arises because an infant’s liver is still developing and may not yet efficiently process bilirubin. This temporary condition appears a few days after birth and resolves without intervention as the liver matures.
In older children and adults, jaundice often results from issues affecting liver function or bile flow. Liver inflammation, such as viral hepatitis A, B, or C, can impair the liver’s ability to process bilirubin. Obstructions in the bile ducts, which transport bilirubin from the liver to the intestines, can also lead to its buildup. Examples include gallstones or tumors. Certain medications, excessive alcohol consumption, or severe infections can also damage liver cells and contribute to jaundice.
Inherited Conditions Causing Jaundice
Several genetic disorders can cause jaundice by affecting how the body handles bilirubin. Gilbert syndrome is a common, benign inherited condition where individuals have reduced activity of the UGT1A1 enzyme, which conjugates bilirubin in the liver. This leads to intermittent, mild increases in unconjugated bilirubin, often noticeable during periods of stress, fasting, or illness. Crigler-Najjar syndrome is a rarer, more severe genetic disorder involving mutations in the UGT1A1 gene, resulting in a profound deficiency or complete absence of the UGT1A1 enzyme. This severe impairment can lead to dangerously high levels of unconjugated bilirubin, particularly in newborns, posing a risk of brain damage.
Other inherited conditions affect bilirubin transport after liver processing. Dubin-Johnson syndrome is an autosomal recessive disorder caused by a mutation in the ABCC2 gene, which encodes a protein transporting conjugated bilirubin out of liver cells into the bile ducts. This defect leads to conjugated bilirubin accumulation within the liver and its leakage into the bloodstream. Rotor syndrome, another rare autosomal recessive disorder, similarly involves impaired transport of conjugated bilirubin from liver cells. Its specific genetic defects are less clearly defined than in Dubin-Johnson syndrome, often involving genes related to hepatic uptake and storage.
Conditions causing increased red blood cell breakdown can also lead to jaundice by overwhelming the liver’s capacity to process bilirubin. Hereditary spherocytosis is a genetic disorder where red blood cells are abnormally shaped and fragile, breaking down prematurely in the spleen. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder that makes red blood cells vulnerable to oxidative stress, leading to hemolysis and bilirubin release. Pyruvate kinase deficiency, an autosomal recessive disorder, affects an enzyme crucial for red blood cell metabolism, leading to premature destruction of cells and elevated bilirubin levels.
Genetic Influence on Newborn Jaundice
Genetic factors play a role in a newborn’s susceptibility to jaundice, even physiological jaundice. Variations in genes can influence how efficiently an infant’s liver processes bilirubin, leading to higher or more prolonged jaundice. The UGT1A1 gene is important as it codes for the enzyme uridine diphosphate glucuronosyltransferase (UGT), which converts unconjugated bilirubin into a water-soluble, excretable form.
Some infants inherit UGT1A1 gene variations that reduce enzyme activity, making them more prone to elevated bilirubin levels shortly after birth. For instance, common polymorphisms, like the UGT1A128 allele, are associated with decreased enzyme activity, increasing the risk of more pronounced or prolonged physiological jaundice in healthy newborns. While most newborn jaundice resolves without issue, elevated and sustained bilirubin levels, especially in genetically susceptible infants, can lead to kernicterus. This neurological condition involves bilirubin deposition in the brain, potentially causing long-term developmental problems.