Jaundice
Evelyn K. Hsu
INTRODUCTION
Jaundice is defined as a yellow discoloration of the skin, mucous membranes, and sclerae caused by increased levels of circulating bilirubin. The term “jaundice” is derived from the French word jaune, which means yellow. Typically, the concentration of bilirubin in the plasma must exceed 1.5 mg/dL to be easily visible. The first step in the evaluation of jaundice is laboratory determination of fractionated bilirubin, as the diagnostic approach differs significantly for unconjugated and conjugated hyperbilirubinemia. In unconjugated hyperbilirubinemia, elevations are due to one of the following:
Increased production of bilirubin from the breakdown of heme proteins (largely hemoglobin)
Decreased conjugation or excretion of bilirubin
Increased enterohepatic circulation of bilirubin (which is less of an issue in an older child)
Conjugated hyperbilirubinemia is largely due to either hepatic dysfunction or obstruction of the biliary system.
Consideration of jaundice in the older child requires a different approach than that of a jaundiced neonate (described in Chapter 46, “Jaundice, Newborn”).
DIFFERENTIAL DIAGNOSIS LISTUnconjugated Hyperbilirubinemia
Increased Production of Bilirubin (Hemolysis)
Red blood cell (RBC) defects
Hemoglobinopathies
Autoimmune hemolytic anemia
Hemolytic uremic syndrome
Decreased Bilirubin Conjugation or Excretion
Gilbert syndrome (GS) and
Crigler-Najjar syndrome (CN)
Mixed Unconjugated/Conjugated Hyperbilirubinemia
Rotor syndrome (RS) and Dubin-Johnson syndrome (DJS)
Hormonal deficiency (hypothyroidism, hypopituitarism)
Conjugated Hyperbilirubinemia
Infectious Causes
Viral hepatitis: A, B, C, D, and E, cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, and echovirus
Bacterial infection: Sepsis and liver abscess
Parasitic infections: Ascariasis
Infection of the biliary tree (cholangitis)
Toxic Causes
Drug-induced liver injury (DILI)
Acetaminophen overdose (and others, including numerous antibiotics and anticonvulsants)
Amanita mushroom ingestion
Disorders of Copper and Iron Storage
Wilson disease
Juvenile hemochromatosis (JHC)
Secondary iron overload (transfusion-related)
Genetic Causes
Alpha-1 antitrypsin deficiency
Cystic fibrosis
Autoimmune Causes
Autoimmune hepatitis (AIH)
Autoimmune sclerosing cholangitis overlap syndrome
Sclerosing cholangitis (primary or secondary)
Obstructive Causes
Cholecystitis
Choledocholithiasis
Tumor (hepatic, biliary, pancreatic, peritoneal, duodenal)
Choledochal cyst
Pancreatic disease
Vascular Causes
Budd-Chiari syndrome
Veno-occlusive disease (VOD) (hepatic sinusoidal obstruction syndrome)
SELECTED DIFFERENTIAL DIAGNOSIS DISCUSSION
Unconjugated Hyperbilirubinemia
Hemolysis can result from hemoglobinopathies, RBC defects, and autoimmune processes. Increased destruction of RBCs releases a heme moiety that is broken down to biliverdin by the heme oxygenase complex, and from biliverdin to unconjugated bilirubin through the activity of biliverdin reductase. Laboratory investigation will often show an increased reticulocyte count, decreased haptoglobin, and increased lactate dehydrogenase levels. In autoimmune processes, patients may be Coombs positive. There is often a positive family history of hemoglobinopathy. Hereditary spherocytosis is the most common congenital RBC membrane disorder, with a frequency of 1 in 5,000 and is inherited in an autosomal dominant fashion. A further discussion of hemoglobinopathies, RBC defects, and autoimmune hemolytic anemia can be found in Chapter 40, “Hemolysis.”
GS is a heterogeneous group of at least four different disorders that all share at least a 50% decrease in hepatic bilirubin UDP-glucuronosyltransferase (BUGT). BUGT acts to conjugate bilirubin, which is then excreted into the enterohepatic circulation. The genetic isoform responsible for bilirubin conjugation is UGT1A1. GS is characterized by recurrent, mild unconjugated hyperbilirubinemia in the presence of otherwise normal liver function tests. Elevation is variable and ranges from 1 to 4 mg/dL. Unless it is coinherited with hemoglobinopathies or RBC defects, it is rarely clinically apparent until after puberty. Large-scale studies have suggested an incidence rate between 3% and 10%, with a strong male predominance. GS is not associated with any negative implications for health or
longevity. There have been reports of associated fatigue or abdominal pain, but studies of larger populations have suggested no significant difference from control populations.
longevity. There have been reports of associated fatigue or abdominal pain, but studies of larger populations have suggested no significant difference from control populations.
CN Types I and II are caused by a profound decrease in BUGT levels. In CN I, unconjugated serum bilirubin levels range from 25 to 35 mg/dL, and affected patients can develop kernicterus even into adulthood, which can be prevented only with lifelong phototherapy, and in some cases, liver transplantation. CN II is more frequent and less severe than CN I, with serum bilirubin levels ranging from 8 to 25 mg/dL. CN I and CN II can be differentiated through phenobarbital treatment; in CN II, treatment leads to a significant decrease in serum bilirubin and increased biliary bilirubin conjugates, there is no change in bilirubin levels pre- and post-phenobarbital treatment.
RS and DJS are two similar but distinct disorders of hyperbilirubinemia. They are rare and inherited in an autosomal recessive fashion. In both syndromes, there is an elevation of both conjugated and unconjugated bilirubin in the presence of other liver function tests that are normal. Both conditions are asymptomatic, unassociated with morbidity or mortality, and require no therapy. DJS is more common than RS, and presents from birth to 40 years of age rather than in early childhood with RS. Liver examination in RS is completely normal, but in DJS, liver pathology shows distinctive brown-black pigmentation with storage located in the lysosomes microscopically.
Thyroid disorders affect bile flow and composition. Hypothyroidism has been shown in animal studies to be associated with decreased bile flow due to a decrease in bile salt-independent flow.
Conjugated Hyperbilirubinemia
Infectious Causes
The most likely cause of acute onset of conjugated hyperbilirubinemia in older infants and children is an acute viral infection. Hepatitis A, B, C, D, and E viruses, in addition to CMV and EBV are the most common causes of jaundice and hepatitis. Other hepatotropic viruses include adenovirus, arbovirus, coxsackievirus, yellow fever, herpes simplex virus, human immunodeficiency virus, paramyxovirus, rubella, and varicella.
Hepatitis A virus is contracted primarily through the fecal-oral route, and is widespread with ˜25,000 cases yearly in the United States. The average incubation period is 28 days; however, fecal shedding can occur for 3 weeks before and for 1 week after the onset of jaundice. Clinically, examination can be significant for jaundice, dehydration, and a mildly enlarged liver. Serum aminotransferase values are usually 20 to 100 times the upper limit of normal, and usually decrease within the first 2 to 3 weeks, remaining abnormal for up to 3 months. Hyperbilirubinemia occurs in 1 of 12 children and often resolves within 4 weeks. Adults are more likely to develop fulminant hepatitis, with a fatality rate of 1% versus 0.1% in children. Active prophylaxis is available in the form of hepatitis A vaccine, a formalin-inactivated virus that induces a protective immune response in 99% of children.
Hepatitis E virus is also spread by the fecal-oral route, and causes high mortality in pregnant women. It is mainly an issue in adults, but isolated childhood infections have been reported.
Hepatitis B virus (HBV) is a major worldwide cause of mortality. It can be transmitted (1) parenterally through contaminated transfused blood products or intravenous drug use, (2) percutaneously or transmucosally from exposure to blood or other contaminated blood fluids, and (3) vertically during childbirth. As many as 350 million individuals are chronically infected, and annually, 250,000 deaths are attributed to chronic hepatitis B and its complications. The presentation of acute HBV infection is dependent upon the age of acquisition. The route of transmission in the pediatric population can be divided into three groups: perinatal, infancy/childhood, and adolescent/young adult. In the adolescent/young adult population, the incubation period ranges from 28 to 180 days, with a prodrome of fever, anorexia, fatigue, malaise, and nausea. Extrahepatic manifestations including migratory arthritis, angioedema, Gianotti-Crosti syndrome (or popular acrodermatitis of childhood) are evident during the prodrome period. Typically, the prodromal symptoms last 1 to 2 weeks, begin to subside, and are followed by symptoms of jaundice, hepatosplenomegaly, and pruritus. Symptoms can persist for 1 to 2 months. In general, 90% will resolve symptoms and 10% will go on to chronic infection. In perinatal, vertically acquired infections, the child is often asymptomatic, with 85% to 90% going on to develop chronic HBV infection. Infants and children who do not become infected perinatally from their mothers still remain at high risk of infection during the first 5 years of life.
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