eMedicine Specialties > Gastroenterology > Systemic Disease
Hyperbilirubinemia, Unconjugated
Updated: May 14, 2008
Introduction
Background
Increased production of bilirubin
Hemolysis generally induces a modest elevation in plasma levels of unconjugated bilirubin (1-4 mg/dL). During acute hemolytic crises, such as those occurring in sickle cell disease or paroxysmal nocturnal hemoglobinuria, bilirubin production and plasma bilirubin may transiently exceed these levels. Although the plasma bilirubin level increases linearly in relation to bilirubin production, the bilirubin concentration may still be near the reference range in patients with a 50% reduction in red blood cell survival if hepatic bilirubin clearance is within the reference range.
Ineffective erythropoiesis (early labeled bilirubin [ELB] production) that is markedly increased is the basis of a rare disorder known as primary shunt hyperbilirubinemia or idiopathic dyserythropoietic jaundice.
Impaired hepatic bilirubin uptake
- Congestive heart failure
- Surgical/naturally occurring shunts
- Drugs/contrast agents: Unconjugated hyperbilirubinemia due to drugs/contrast agent resolves within 48 hours of discontinuing the drug
- Rifampicin
- Rifamycin
- Probenecid
- Flavaspidic acid
- Bunamiodyl (cholecystographic agent)
Neonatal jaundice
- Physiologic jaundice: All newborns have higher bilirubin levels (mainly unconjugated bilirubin) compared to adults.
- Nonphysiologic jaundice
- Breast milk jaundice (maternal milk jaundice): Breastfed infants have higher mean bilirubin levels compared to formula-fed infants.
- Lucey-Driscoll syndrome (maternal serum jaundice)
- Hemolysis
- Metabolic/endocrine disorders
- Galactosemia
- Fructosemia
- Hypoglycemia
- Hypoalbuminemia
- Hypothyroidism
- Sepsis
- Hypoxia
- Hypertrophic pyloric stenosis
- Increased bilirubin load
- ABO/Rh incompatibility
- Inherited RBC disorders - Sickle cell disease, hereditary spherocytosis/elliptocytosis
- Drug reactions
- Ineffective erythropoiesis - Thalassemia, vitamin B-12 deficiency, congenital dyserythropoietic anemia
Impaired conjugation of bilirubin
Three degrees of inherited defects of bilirubin conjugation are known to exist in humans (ie, Crigler-Najjar syndrome type I and type II, Gilbert syndrome). Gilbert syndrome, also called constitutional hepatic dysfunction or familial nonhemolytic jaundice, is the mildest form of inherited nonhemolytic unconjugated hyperbilirubinemia.
Pathophysiology
Increased production of bilirubin
Ineffective erythropoiesis (ELB production): In a review of 11 such cases, evidence existed of rapid heme and hemoglobin turnover within the bone marrow, possibly due to premature destruction of red blood cell precursors. These patients also had erythroid hyperplasia of bone marrow, reticulocytosis, increased iron turnover with diminished red blood cell incorporation, and hemosiderosis of hepatic parenchymal cells and Kupffer cells. The underlying defect responsible for the high rate of heme turnover within the marrow remains unknown.
Neonatal jaundice
- Physiologic jaundice: Several factors contribute to the development of physiologic jaundice.
- Inefficient hepatic excretion of unconjugated bilirubin
- Portal venous shunting through a patent ductus venosus
- Shortened red blood cell survival leading to an increased bilirubin load
- Low levels of bilirubin uridine diphosphate (UDP)–glucuronosyltransferase (UGT) activity
- Hydrolysis of conjugated bilirubin by intestinal beta-glucuronidase resulting in the release of unconjugated bilirubin in the intestine: In neonates, bacterial degradation of bilirubin is reduced because intestinal flora is not fully developed. This may lead to increased absorption of unconjugated bilirubin.
- Epidemiology: Hyperbilirubinemia may reach or exceed 10 mg/dL in approximately 16% of newborns.
- Nonphysiologic jaundice
- Immaturity of hepatic bilirubin clearance: Bilirubin-UGT activity is only 1% of normal adult levels at birth, regardless of gestational age. Enzyme activity increases to adult levels by the 14th week of life. The main precipitant factors are decreased energy intake and delayed closure of the ductus venosus.
- Maternal milk jaundice: An undefined substance, present in maternal milk, inhibits bilirubin UGT activity. This inhibitory effect of breast milk increases during storage but is destroyed by heating to 56°C.
- Maternal serum jaundice (Lucey-Driscoll syndrome): This may result from the presence of an unidentified inhibitor of UGT, which enters the fetus through maternal serum.
Impaired conjugation of bilirubin
- Crigler-Najjar syndrome type I: Hepatic bilirubin UGT activity is undetectable.
- Crigler-Najjar syndrome type II (Arias syndrome): The reduction of hepatic bilirubin UGT activity is incomplete.
- Servedio et al reported patients with Crigler-Najjar types I and II may also possess mutations in the promoter region of the UGT1A1 gene.1 This gene codes for the bilirubin-UGT enzyme that is impaired in Gilbert syndrome.
- Gilbert syndrome
- Hepatic bilirubin UGT activity is consistently decreased to approximately 30% of normal in individuals with Gilbert syndrome. Decreased bilirubin UGT activity has been attributed to an expansion of thymine-adenine (TA) repeats in the promoter region of the UGT-1TA gene, the principal gene encoding this enzyme. Racial variation in the number of TA repeats and a correlation with enzyme activity suggest that these polymorphisms contribute to variations in bilirubin metabolism. An increased proportion of the bilirubin monoconjugates in bile reflects reduced transferase activity.
- Investigators have discovered that Gilbert syndrome may coexist with other liver diseases, such as nonalcoholic steatohepatitis; unconjugated hyperbilirubinemia in these patients may be due to Gilbert syndrome and should not always be attributed to the underlying liver disease.
- A case report from the Czech Republic also reported the simultaneous occurrence of mutations causing Gilbert syndrome and Dubin-Johnson syndrome in a 3-year-old boy.
- Huang et al reported that adults with certain haplotypes in UGT1A1, OATP2, and G6PD genes are at a higher risk of developing unconjugated hyperbilirubinemia.2
Frequency
United States
Regarding unconjugated hyperbilirubinemia caused by increased production of bilirubin, ineffective erythropoiesis (ELB production) is associated with a heterogeneous group of disorders that is frequently familial. Regarding unconjugated hyperbilirubinemia caused by impaired conjugation of bilirubin, Crigler-Najjar syndrome type I occurs in persons of all ethnic groups and is inherited as an autosomal recessive trait. Gilbert syndrome affects 4-13% of the population.
Mortality/Morbidity
Nonphysiological causes of unconjugated hyperbilirubinemia, such as Rhesus incompatibility, can lead to kernicterus, a potentially fatal disorder affecting the basal ganglia and other parts of the central nervous system if left untreated. Activation of astrocytes by unconjugated hyperbilirubinemia is believed to play a major part in brain toxicity via the production of inflammatory cytokines.
- Increased production of bilirubin, ineffective erythropoiesis (ELB production): Morbidity and mortality appear to be minimal. The disease is rare and is associated with an excellent prognosis.
- Neonatal jaundice, nonphysiologic: Morbidity and mortality appear to be relatively minimal. Regarding maternal milk jaundice, the jaundice may continue for 4 weeks but resolves promptly when breastfeeding is stopped. The prognosis is excellent. Regarding maternal serum jaundice (Lucey-Driscoll syndrome), jaundice can persist for several weeks, but the prognosis is good.
- Impaired conjugation of bilirubin: For Crigler-Najjar syndrome type I, unless treated vigorously (ie, orthotopic liver transplant, segmental transplantation), most affected patients die by 15 months of life. Fortunately, more patients are surviving to adulthood because of advances in the treatment of hyperbilirubinemia. For Crigler-Najjar syndrome type II (Arias syndrome), although type II runs a more benign clinical course than type I, several cases of bilirubin-induced brain damage have been reported. For Gilbert syndrome, once the diagnosis is established, only reassurance is necessary because of the excellent prognosis.
Sex
- Gilbert syndrome is diagnosed more commonly in boys after puberty than in girls. The apparent sex difference is due to the fact that daily bilirubin production is lower in women compared to men, and the residual bilirubin UGT activity may be sufficient for excreting the daily bilirubin load.
Age
- Increased production of bilirubin: Onset of ineffective erythropoiesis (ELB production) usually occurs at age 20-30 years.
- Impaired conjugation of bilirubin: Crigler-Najjar syndrome type I manifests during the first days of life.
Clinical
History
- Increased production of bilirubin: Ineffective erythropoiesis (ELB production) is characterized by the onset of asymptomatic jaundice.
- Neonatal jaundice, physiologic: Physiologic jaundice is clinically obvious in 50% of neonates during the first 5 days of life.
- Neonatal jaundice, nonphysiologic
- Maternal milk jaundice: Bilirubin levels in breastfed babies can occasionally reach 15-24 mg/dL by 10-19 days of life.
- Maternal serum jaundice (Lucey-Driscoll syndrome): Jaundice occurs during the first 4 days of life, with serum bilirubin concentrations reported at 8.9-65 mg/dL and reached within 7 days of birth.
- Impaired conjugation of bilirubin
- Crigler-Najjar syndrome type II (Arias syndrome): During surgery or intercurrent illnesses, the levels may increase to as much as 40 mg/dL.
- Gilbert syndrome: Serum bilirubin fluctuates with time and increases during fasting, intercurrent illness, emotional stress, or menstruation. Apart from mild jaundice, physical examination findings in people with Gilbert syndrome are normal.
Physical
- Increased production of bilirubin
- Ineffective erythropoiesis (ELB production): Patients with these diseases, which are characterized by abnormalities in heme biosynthesis within the developing normoblast, do not exhibit evidence of increased red blood cell destruction but they have significant increases in total bile pigment turnover. However, red blood cell destruction is increased, together with an absolute (but not relative) increase in erythroid ELB production in paroxysmal nocturnal hemoglobinuria and sickle cell anemia or following hemorrhage.
- Hemolysis is characterized by unconjugated hyperbilirubinemia, although significant levels of conjugated bilirubin may be observed in the presence of underlying liver disease, sepsis, drugs, or when the amount of bilirubin generated and conjugated exceeds the biliary transport limit for conjugated bilirubin, as may occur in acute hemolytic crises or with multiple blood transfusions. Hemolysis due to hereditary abnormalities of erythrocytes (eg, hereditary spherocytosis/elliptocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, sickle cell disease) generally produces a milder degree of jaundice, which may manifest within a few days of birth or as recurrent episodes during later life, and frequently in association with febrile illnesses.
Causes
- Increased bilirubin production
- Hemolysis
- Dyserythropoiesis
- Hematoma
- Impaired hepatic bilirubin uptake
- Congestive heart failure
- Portosystemic shunts
- Drugs - Rifamycin, rifampin, probenecid, flavaspidic acid, bunamiodyl
- Impaired bilirubin conjugation
- Crigler-Najjar syndrome types I and II
- Gilbert syndrome (decreased uptake and/or conjugation)
- Neonatal physiologic jaundice
- Breast milk jaundice
- Maternal serum jaundice
- Hypothyroidism/hyperthyroidism
- Ethinyl estradiol
- Liver diseases - Chronic hepatitis, cirrhosis, Wilson disease (decreased uptake and conjugation)
- Fasting hyperbilirubinemia - Contributed to by increased enterohepatic circulation of bilirubin and genetic factors
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References
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Further Reading
Keywords
hemolysis, acute hemolytic crisis, sickle cell disease, sickle cell anemia, paroxysmal nocturnal hemoglobinuria, primary shunt hyperbilirubinemia, idiopathic dyserythropoietic jaundice, ineffective erythropoiesis, Crigler-Najjar syndrome, Arias syndrome, Gilbert syndrome, constitutional hepatic dysfunction, familial nonhemolytic jaundice, dyserythropoiesis, hematoma, congestive heart failure, CHF, portosystemic shunts, drug interactions, neonatal physiologic jaundice, breast milk jaundice, maternal serum jaundice, hypothyroidism, hyperthyroidism, liver disease, chronic hepatitis, cirrhosis, Wilson disease, fasting hyperbilirubinemia, liver dysfunction, hepatic dysfunction, hepatic disease
