Jaundice comes from the French word “jaune,” meaning yellow. Jaundice refers to the yellow staining of the sclera, mucous membranes, and skin by bilirubin. It is not a disease by itself but rather a manifestation that accompanies different diseases. Jaundice is caused by elevated serum bilirubin levels with subsequent tissue deposition. In infants, it is usually apparent with bilirubin levels above 4–5 mg/dL (68–86 mmol/L). In older children, jaundice can be noted at levels above 2–3 mg/dL (34–51 mmol/L). The color of the sclera and skin varies depending on the serum bilirubin level. Jaundice involves the head first and progresses caudally with higher levels.

Total serum bilirubin is the sum of the unconjugated (or indirect) and conjugated (or direct) bilirubin fractions. The terms direct and conjugated hyperbilirubinemia are often used interchangeably, but this is not always accurate. Direct bilirubin is measured in the laboratory using a diazo dye-binding assay, and, depending on the method used, can include both conjugated bilirubin and delta bilirubin. Delta bilirubin is formed by covalent bond formation between serum conjugated bilirubin and albumin. Clearance of delta bilirubin can therefore be prolonged, reflecting the half-life of albumin, and may lag behind other signs of clinical improvement.

Cholestasis is defined as diminished bile formation or flow, and is manifested by conjugated hyper-bilirubinemia. The guidelines of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN)1 define an abnormal conjugated bilirubin level as:

• a conjugated bilirubin >1.0 mg/dL, if the total bilirubin is <5 mg/dL, or
  
• a conjugated bilirubin level >20% of the total bilirubin, if the total bilirubin is >5 mg/dL.

Neonatal jaundice is common, observed in the first week of life in about 50% of term infants and 80% of preterm infants. This is usually harmless, often related to physiological jaundice or breastfeeding, and is characterized by unconjugated hyperbilirubinemia. Rarely, however, severe unconjugated hyperbilirubinemia can lead to bilirubin encephalopathy or kernicterus.2 On the contrary, cholestasis (or conjugated hyperbilirubinemia) is much less commonly seen but often results from conditions with serious hepatobiliary dysfunction. Cholestatic jaundice affects approximately 1 in every 2500 infants.3 The challenge for physicians is to identify infants with cholestasis who will need additional evaluation and treatment. Early detection of cholestatic jaundice and accurate diagnosis of its etiology are vital for successful treatment and a favorable prognosis.

Bilirubin is the end product of heme moiety metabolism from hemoglobin and other heme-containing proteins (Figure 7–1). After unconjugated bilirubin is formed, it is transported with albumin in blood to the liver. Inside hepatocytes, unconjugated bilirubin is conjugated with glucuronic acid by uridine diphosphate glucuronosyltransferase (UGT) to increase water solubility. Conjugated bilirubin, along with cholesterol, bile acids, and phospholipids, is transported through the bile canalicular system to the gallbladder and later into the small intestine. Conjugated bilirubin cannot be reabsorbed by enterocytes and is degraded by the intestinal flora into colorless urobilinogen, which is excreted with feces. Urobilinogen is oxidized to urobilin and stercobilin, which are responsible for the brown color of stools. A portion of conjugated bilirubin is deconjugated by beta-glucuronidase and is reabsorbed into the portal circulation and liver, a normal process called the enterohepatic bilirubin circulation. In the liver, this can be conjugated again and excreted into the bile.4

Any disease process that leads to increased bilirubin production and/or limits bilirubin excretion can potentially manifest by visible jaundice from underlying hyperbilirubinemia. Depending on the etiology and pathogenesis, this can lead to unconjugated or conjugated hyperbilirubinemia.

Hyperbilirubinemia in healthy, full-term infants is often attributed to physiological immaturity of bilirubin metabolism, leading to elevated unconjugated bilirubin levels. In actuality, neonatal jaundice is often due to a combination of one or more of the following (Table 7–1):

• increased bilirubin production;
  
• decreased bilirubin clearance;
  
• increased enterohepatic circulation.

Increased bilirubin production is seen with hemolytic disease processes such as ABO incompatibility, inherited membrane defects or enzyme abnormalities of red blood cells, hyperviscosity (polycythemia) -syndrome, or resorption of a large hematoma. Decreased bilirubin conjugation is seen in Crigler–Najjar syndrome and Gilbert’s syndrome that are due to the absence or reduction of UGT activity, leading to unconjugated hyperbilirubinemia.5 Delayed intestinal transit can enhance the enterohepatic circulation of unconjugated bilirubin contributing to unconjugated hyperbilirubinemia. This can be seen in breast milk jaundice, inadequate breastfeeding, and impaired intestinal motility or intestinal obstruction. In neonates, the inadequately developed anaerobic intestinal flora may also enhance the enterohepatic circulation as less bilirubin is converted to urobilinogen for excretion.6

Cholestasis, or conjugated hyperbilirubinemia, results from diminished bile flow or excretion. In infants, the etiologies vary and can be divided into two main categories: obstructive/structural and hepatocellular (Table 7–2). The category of obstructive/structural cholestasis includes biliary atresia and choledochal cysts. The etiology of biliary atresia is unknown, but several mechanisms (infectious, genetic, and immunologic) have been proposed to explain the inflammatory process that leads to bile duct obliteration.7 Biliary atresia is described in more detail in Chapter 23. Choledochal cysts are rare congenital anomalies of the bile ducts characterized by cystic dilatation of the biliary tree.8 Conditions that lead to hepatocellular cholestasis are numerous and include idiopathic neonatal hepatitis, infections, metabolic, genetic, and endocrine disorders.

History

The parents or caregivers should be asked about the onset, duration, and progression of jaundice. Jaundice is considered to be pathologic if it is detected before 24 hours of age or persists beyond 14 days of age. Dark urine color and light or acholic stools are often present with conjugated hyperbilirubinemia and can indicate a serious underlying hepatobiliary disorder. Inspection of a stool sample by the physician may be more accurate rather than solely relying on the parents’ description. However, in some countries parents are given stool color cards as a screening method for obstructive cholestasis. Parents can compare their child’s stool color with examples on the card, and contact their physician, if stools exhibit too light a color. This has led to earlier detection and referral, timely intervention, and better outcome for patients with biliary atresia.9

The physician should inquire about the infant’s feeding pattern, type and amount of milk intake, and the presence of vomiting and irritability. Jaundice should not be attributed to dehydration in an infant who seems to be taking adequate amount of milk (>100 mL/kg/day), so further workup may be needed. Feeding intolerance and irritability can be seen with infections and metabolic disorders. The appearance of a thriving but jaundiced infant beyond 2 weeks of age should not delay evaluation, as a serious condition such as biliary atresia may be present in early life without other obvious signs and symptoms.

The maternal and perinatal history should be reviewed, looking for signs of maternal illness during pregnancy or delivery (fever, skin rashes, and respiratory symptoms), traumatic delivery, and birth asphyxia. The neonate’s size relative to gestational age is important; small-for-gestational-age neonates may have polycythemia, and large-for-gestational-age neonates have an increased incidence of birth trauma that can be accompanied by hematomas. Pertinent family history should be obtained, including that for jaundice, liver diseases, anemia, hemolysis, metabolic disorders, or splenectomy.

Physical Examination

Different etiologies of hyperbilirubinemia can be accompanied by a variety of clinical manifestations. The physical evaluation should focus on confirming the presence of jaundice and looking for risk factors and for associated signs that can help delineate the cause. Evidence of complications such as portal hypertension, coagulopathy, thrombocytopenia, and failure to thrive should be sought.

Jaundice may be the only manifestation of hyperbilirubinemia. It should be assessed with adequate ambient light. Blanching the skin by applying finger pressure over a bony part can help detect jaundice. The extent of body jaundice can provide a rough estimate of bilirubin level. This, however, may not be accurate, especially in infants with dark skin color. Carotenemia, or pseudojaundice, can occur with excessive ingestion of foods rich in beta-carotene (such as squash and carrots). This is common in older infants and toddlers, and is manifested by a yellow-orange skin color without scleral icterus or hyperbilirubinemia. Infants whose jaundice is caused by ongoing hemolysis may also appear pale and lethargic.

The presence of skin rashes can suggest infection, especially those that are perinatally acquired. Clinical manifestations of congenital cytomegalovirus (CMV) can include a petechial rash, jaundice, hepatosplenomegaly, and central nervous system involvement with microcephaly, seizures, and cerebral calcifications. Infants born with congenital toxoplasmosis may have a maculopapular rash, jaundice, fever, hepatosplenomegaly, microcephaly, and seizures. Congenital rubella can present with purpuric skin lesions, growth retardation, and hepatosplenomegaly. Blueberry muffin lesions, described as maculopapular reddish-blue- or magenta-colored lesions related to persistent dermal erythropoiesis, have been reported in neonates with CMV, rubella, and parvovirus. The presence of vesicular skin lesions should raise suspicion for a herpes virus infection.10

Cataracts can be associated with metabolic disorders and congenital infections. Metabolic disorders associated with cataracts and liver diseases include galactosemia and peroxisomal disorders (Zellweger syndrome). Infectious causes include toxoplasmosis, rubella, CMV, herpes, and syphilis.

Liver size and consistency should be assessed. Hepatomegaly can be present with disorders leading to liver damage and with storage diseases. A firm or hard liver can suggest advanced liver disease with cirrhosis. The presence of edema, ascites, coagulopathy, or encephalopathy may also suggest advanced liver disease. Splenomegaly is seen with infections (such as CMV), hematological disorders (such as hereditary elliptocytosis), and storage disorders (such as cholesteryl ester storage disease and glycogen storage diseases).

In certain conditions, if the underlying process is not treated, progression to liver failure can occur, leading to ascites, hypoglycemia, coagulation abnormalities, and encephalopathy. Encephalopathy may not be easily diagnosed in a young infant but should be suspected with poor feeding, irritability, and reversal of day/night sleep patterns.

The differential diagnosis for jaundice is age-specific. This chapter will mostly address conditions associated with jaundice in neonates and infants. Etiologies of jaundice from unconjugated and conjugated hyperbilirubinemia in this population are summarized in Tables 7–1 and 7–2. Causes of cholestatic jaundice occurring in older children and adolescents are briefly summarized in Table 7–3.