Doron D. Kahana, MD, CPNS, and Khalid M. Khan, MD
A 4-week-old boy is brought to the office for a routine weight check because he is breastfeeding. He was the product of a full-term, normal, spontaneous vaginal delivery, with a birth weight of 3,600 g (7 lb, 15 oz). He has been feeding well, exclusively at the breast, with loose stools after each feeding. On physical examination, the infant weighs 4,900 g (10 lb, 13 oz). The examination is normal except that the boy appears jaundiced. On further questioning, the mother states that her son was jaundiced shortly after birth, but she was told that the bilirubin level was all right. She thinks the jaundice may be more noticeable now. His stool is yellow and pasty, although sometimes it appears lighter in color.
1. What are the common causes of unconjugated hyperbilirubinemia in young infants?
2. What are the common causes of conjugated hyperbilirubinemia in young infants?
3. What are the usual causes of jaundice in older children and adolescents?
4. What is the appropriate management of hyperbilirubinemia in breastfed infants?
5. What diagnostic studies are done to determine the etiology of jaundice?
Jaundice occurs when bilirubin reaches a level in the blood that makes it visibly apparent. In newborns, this level is 5 mg/dL. In older children and adolescents, jaundice becomes apparent at serum bilirubin levels of 2 mg/dL. The term physiologic jaundice is used to denote the jaundice that normally occurs after birth. In full-term neonates, bilirubin reaches its peak of approximately 6 mg/dL between the second and fourth days after birth. Levels above 10 mg/dL likely are not physiologic. Typically, bilirubin returns to a normal level (≤1 mg/dL) by 12 days of age. Preterm newborns experience their peak level of bilirubin, which may be up to 10 to 12 mg/dL, between the fifth and seventh days after birth. Levels above 14 mg/dL are probably not physiological. Levels may be elevated in preterm neonates for up to 2 months.
Physiologic jaundice is a benign finding that affects all newborns; however, other, more serious disorders may present with jaundice in the newborn period. The physician must be able to differentiate between physiologic and pathologic causes of jaundice to ensure appropriate intervention and management. New-onset jaundice in older children and adolescents is never physiologic; the natural history is determined by the underlying disorder.
Physiologic jaundice is nearly universal in neonates because of the rapid turnover of red blood cells and the relative immaturity of the liver, which give rise to unconjugated hyperbilirubinemia. The most notable disorder associated with increased levels of unconjugated bilirubin in the newborn period is hemolysis from maternal antibodies to the neonate’s blood group (eg, ABO incompatibility). Breastfeeding jaundice results from inadequate milk intake, mild dehydration, and mild elevation in the level of conjugated bilirubin. The condition should be distinguished from pathologic cholestasis. Breast milk jaundice is different from breastfeeding jaundice and affects approximately 1% of newborns and infants fed breast milk exclusively. Factors in the breast milk as well as the immature neonatal microflora that promote recirculation of bilirubin from the gut (ie, enterohepatic circulation) give rise to unconjugated hyperbilirubinemia. Various illnesses, particularly bacterial infections, also may precipitate jaundice in newborns. Cholestasis, which is defined physiologically as a reduction in canalicular bile flow, manifests as conjugated hyperbilirubinemia. Neonatal cholestasis, which occurs in a small number of patients with neonatal jaundice, may be caused by neonatal hepatitis (often without a discernible cause), extrahepatic biliary atresia (BA), or genetic and metabolic diseases. Jaundice occurs much less frequently in the postneonatal period and is most often secondary to viral hepatitis (see Chapter 127).
Children with jaundice have yellow skin, conjunctiva, and mucous membranes. In newborns, the coloration may not be appreciated by parents or caregivers because of its gradual onset and the inex-perience of the parents or caregivers. The finding may be apparent in otherwise asymptomatic newborns and infants during routine health maintenance visits but may go unappreciated by the examining physician. In addition to the yellow color, the child with jaundice also may present with symptoms related to the cause of the jaundice, including vomiting, anorexia, failure to thrive, acholic (ie, pale, poorly pigmented) stools, dark urine, fatigue, and abdominal pain or fullness, and rickets (Box 126.1).
Box 126.1. Diagnosis of Jaundice in the Pediatric Patient
•Yellow skin, mucous membranes, and conjunctiva
•Tenderness in the right upper quadrant of the abdomen
Bilirubin, a red pigment found primarily in bile, forms from the breakdown of heme-containing compounds, mainly hemoglobin, but also muscle myoglobin, cytochromes, catalases, and tryptophan 2,3-dioxygenase. Disruption along any point in the synthesis and transport of bilirubin or anatomic obstruction in the processing and excretion of bile may result in increased levels of bilirubin and the appearance of jaundice (Figure 126.1). After the breakdown of hemoglobin, unconjugated bilirubin is taken up by the hepatocyte plasma membrane carrier, bilitranslocase, and bound to intracellular proteins (Y proteins or glutathione S-transferase). Uptake depends on hepatic blood flow and the presence of the necessary binding proteins. Once in the liver, unconjugated bilirubin is conjugated by the enzyme glucuronosyltransferase. Conjugated bilirubin, which is water soluble, can be eliminated through the kidneys; unconjugated bilirubin is not water soluble and can be taken up in tissues and stored. After conjugation, bilirubin passes into the bile through the bile canaliculi. It then moves to the gastrointestinal tract, where some of it may be reabsorbed (ie, enterohepatic circulation) or acted on by bacteria to form urobilinogen and stercobilinogen, which may appear in the urine or stool, respectively.
Figure 126.1. The bilirubin pathway.
In neonates, several factors contribute to physiologic jaundice. First, increased destruction of red blood cells occurs, because red blood cell survival in neonates is only 70 to 90 days, compared with 120 days in older children and adults. Second, hepatic uptake is lower, likely a result of decreased levels of hepatic proteins as well as decreased hepatic blood flow. Levels of glucuronosyltransferase do not reach adult values until the second week after birth; as a result, conjugation of bilirubin occurs at a slower rate. Gilbert syndrome is an autosomal recessive disorder characterized by low physiologic levels of glucuronosyltransferase; these individuals remain prone to jaundice at times of illness, stress, and starvation. Prolonged jaundice may occur in some breastfed newborns and infants and is likely related to poor caloric or fluid intake, weight loss and catabolism, slow passage of meconium, or immature intestinal microflora. Breast milk jaundice is different. It is an unconjugated hyperbilirubinemia and is thought to result from milk components such as pregnanetriol, which blocks glucuronosyltransferase. (See Chapter 29 for more information on breastfeeding.) In older children, similar mechanisms may act to cause an increase in the bilirubin level in disease states. Hemolytic anemias (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency, pyruvate kinase deficiency [PKD]) may result in increased red blood cell destruction. Inflammatory or infectious processes involving the liver, such as hepatitis, may impair the ability of the liver to excrete bilirubin. Pharmaceutical and toxicologic agents may also interfere with the ability of the liver to metabolize bilirubin.
The differential diagnosis of jaundice in children involves 3 criteria: age, the type of hyperbilirubinemia (conjugated or unconjugated), and, if the hyperbilirubinemia is conjugated, the nature of the obstruction (intrahepatic or extrahepatic). The latter 2 factors are particularly important in determining the etiology of jaundice in neonates and young infants. A diagrammatic representation of the differential diagnosis of jaundice in children is shown in Figures 126.2, 126.3, and 126.4.
Neonates and Infants Younger Than 8 Weeks
Jaundice occurs universally in all newborns; however, marked elevation of bilirubin levels (≥15 mg/dL) and the presence of jaundice in the first 24 hours after birth or beyond 2 weeks of age warrant assessment. When less than 15% of the total bilirubin is conjugated (direct hyperbilirubinemia), unconjugated hyperbilirubinemia is present. This is determined by measuring the levels of total and direct (ie, conjugated) bilirubin in the blood (bilirubin fractionation). Physiologic jaundice is associated with unconjugated hyperbilirubinemia and typically does not require an evaluation. The hematologic workup of affected newborns and infants is normal. Breastfeeding jaundice secondary to inadequate human milk intake may resemble physiologic jaundice and occurs during the first week after birth. With breast milk jaundice, bilirubin levels rise during the second week after birth when physiologic jaundice is improving. Breast milk jaundice usually peaks by age 4 weeks and can last up to 12 weeks. Levels may reach as high as 25 to 30 mg/dL, possibly posing a threat to the developing brain. In those cases, it may be necessary to stop breastfeeding and introduce formula or phototherapy.
Figure 126.2. Differential diagnosis of jaundice (unconjugated hyperbilirubinemia) in neonates and infants through age 8 weeks.
Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; Hgb, hemoglobin; IDM, infant of diabetic mother; SGA, small for gestational age.
Conditions associated with slow intestinal transit time and increased enterohepatic circulation, such as hypothyroidism, also may result in jaundice. High intestinal obstructions, such as pyloric stenosis, duodenal atresia, annular pancreas, and jejunal atresia, may cause jaundice, perhaps because of starvation and decreased levels of glucuronosyltransferase. Genetic and hematologic disorders should also be considered in the differential diagnosis.
Crigler-Najjar syndrome type 1 is an autosomal recessive disorder characterized by an absence of glucuronosyltransferase and, thus, severe unconjugated hyperbilirubinemia with bilirubin levels approaching 50 mg/dL soon after birth. Crigler-Najjar syndrome type 2 is also autosomal recessive but is characterized by a reduced function of glucuronosyltransferase; bilirubin levels average 20 mg/dL and persist beyond 2 weeks in the absence of hemolysis. Because of very high bilirubin levels, type 1 disease may result in kernicterus unless managed with exchange transfusion. Phototherapy, cholestyramine resin, and eventual liver transplantation are additional therapies that may be necessary. Hematologic problems may also produce jaundice in the neonatal period. Such problems are most often associated with blood group (usually Rh or ABO) incompatibility between mothers and newborns, but some minor blood group antigens can also precipitate jaundice. Jaundice occurs in affected newborns and infants because of the rapid destruction of red blood cells, which release hemoglobin that converts to bilirubin. Hemolytic anemias, such as spherocytosis, result in jaundice, as do conditions that result in polycythemia (ie, increased red blood cells in the circulation), such as maternal-neonate or twin-twin transfusions, neonates who are small for gestational age, delayed clamping of the umbilical cord, infants of diabetic mothers, and neonates with hyperviscosity syndrome.
Figure 126.3. Differential diagnosis of jaundice (conjugated hyperbilirubinemia) in infants (during the first 8 weeks after birth).
Abbreviation: TORCHS, toxoplasmosis, other agents (syphilis, hepatitis B, varicellazoster virus, human immunodeficiency virus, parvovirus B19, enteroviruses, lymphocytic choriomeningitic virus), rubella, cytomegalovirus, and herpes simplex virus.
When more than 15% of the total bilirubin is direct, jaundice is categorized as conjugated (ie, direct) hyperbilirubinemia. This is always pathologic and warrants further investigation. Total parenteral nutrition is the most common cause of conjugated hyperbilirubinemia in the neonatal intensive care unit. It is most likely related to the lipid component of the total parenteral nutrition; however, it does not usually present a diagnostic dilemma. The institution of oral feedings helps reverse the process. In other cases, determining whether the problem is intrahepatic or extrahepatic is paramount. Intrahepatic involvement represents a spectrum of conditions from inflammation (ie, hepatitis), to inadequate formation of the bile ducts (ie, biliary hypoplasia, Alagille syndrome), to the destruction of the bile ducts (ie, BA).
Hepatitis is inflammation of the liver and usually is caused by an infection in the liver, although infection elsewhere in the body (eg, sepsis, urinary tract infection in neonates and young infants) may also cause jaundice. Urinary tract infections are usually caused by Escherichia coli. The hepatic involvement resolves with appropriate antibiotic therapy of the primary infection.
Primary liver infection in the neonatal period may be caused by a number of pathogens, collectively abbreviated as TORCHS (toxoplasmosis, other agents, rubella, cytomegalovirus [CMV], human herpesvirus, HIV, syphilis); the most common culprits are CMV and human herpesvirus. Neonates who are infected prenatally often have low birth weights, hepatosplenomegaly, petechial rashes, and ocular findings, such as cataracts and chorioretinitis. Maternal transmission of hepatitis B is a possible etiology of neonatal cholestasis, but hepatitis C is usually asymptomatic in the neonate. Hepatitis A may cause an acute infection but rarely manifests as jaundice in neonates. Other infectious causes include enteroviruses, reovirus type 3, human parvovirus B19, human herpesvirus 6, human adenovirus 2, Listeria monocytogenes, and tuberculosis. Typically, these conditions are differentiated based on culture, polymerase chain reaction, or serology testing. Certain physical and epidemiologic findings may help distinguish these entities. For example, syphilis is more common in developing nations than in developed nations and jaundice may appear within the first 24 hours after birth or later on in infancy. Infection with L monocytogenes may be associated with the presence of focal granulomas on the posterior pharynx; similar granulomas may be evident in the liver.
Figure 126.4. Differential diagnosis of jaundice in older infants, children, and adolescents.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GGT, γ-glutamyltransferase; HSV, herpes simplex virus.
Metabolic diseases and inborn errors of metabolism may also cause hepatitis. Most of these conditions are inherited in an autosomal recessive manner and are relatively rare. Newborns and infants may present with vomiting, irritability, lethargy, anorexia, hepatomegaly, hypoglycemia, failure to thrive, bleeding, or cataracts in addition to jaundice. Galactosemia may be detected through neonatal screening or may present as E coli sepsis. Newborns and infants with hereditary fructose intolerance present after exposure to fructose, sucrose, or sorbitol, usually past the neonatal period. Depending on the population, α1-antitrypsin deficiency may account for 20% to 30% of cases of idiopathic neonatal liver disease and up to 10% of neonatal cholestatic disease. Inborn errors of metabolism (eg, glycogen storage disease, tyrosinemia) generally present with conjugated (direct) hyperbilirubinemia, whereas inborn errors of erythrocyte metabolism (eg, PKD or G6PD deficiency) present with unconjugated (indirect) hyperbilirubinemia.
Other genetic conditions that cause jaundice in newborns include lysosomal storage disease (eg, type 2 [infantile] Gaucher disease, Niemann-Pick disease, Wolman disease) and cystic fibrosis. The latter can cause cholestatic jaundice because of the presence of inspissated bile in the bile canaliculi. Approximately 50% of newborns and infants with cystic fibrosis have meconium ileus, meconium peritonitis, or intestinal atresia. “Plugged” bile ducts, resulting from bilirubin production overwhelming the drainage system, may occur with severe hemolytic anemia as well. Drugs may also induce intrahepatic cholestasis. Several syndromes are associated with persistent intrahepatic cholestasis. Alagille syndrome (ie, arteriohepatic dysplasia) is characterized by dysmorphic facies, skeletal and cardiovascular anomalies, and a paucity of intralobular bile ducts; the prevalence is 1 in 100,000 live births. Progressive familial intrahepatic cholestasis (which typically results from autosomal recessive defects in bile acid transporters) and bile acid synthesis defect, together with Alagille syndrome (which is autosomal dominant), account for a total of approximately 10% of cases of neonatal cholestasis. Not surprisingly, as the etiologies for more of these cases are identified through genetic and metabolic testing, fewer cases are labeled “idiopathic neonatal hepatitis.”
Extrahepatic BA accounts for approximately 25% of cases of cholestasis in newborns and is characterized by ascending obliteration of the biliary tree. Often, newborns and infants are well until 3 to 6 weeks of age, when they develop conjugated (direct) hyperbilirubinemia. The prevalence is 1 in 14,000 live births, and diagnosis must be prompt for long-term success of surgical correction. Surgery after 2 months of age is associated with liver failure and the future need for transplantation. It has been postulated that some primary insults, such as α1-antitrypsin deficiency, metabolic disorders, or viral infections (eg, CMV, human herpesvirus), may be the inciting event resulting in BA. Choledochal cysts appear as dilatations of the biliary tree and obstruct the passage of bile. They usually present after the perinatal period with bilious emesis.
Older Infants, Children, and Adolescents
The approach to the differential diagnosis of jaundice in older infants and children is similar to that for neonates and young infants. The differential diagnosis is suggested by the total bilirubin level and the fractionated components. Unconjugated hyperbilirubinemia is usually caused by hemolysis, and the level of indirect bilirubin helps clarify the differential diagnosis. Patients with levels below 6 mg/dL may have hemolytic anemia; haptoglobin testing and a peripheral blood smear should help solidify the diagnosis. Patients with an indirect bilirubin level greater than 6 mg/dL may have Crigler-Najjar syndrome type 2; such patients respond favorably to phenobarbital. Congestive heart failure and hypothyroidism may also produce unconjugated hyperbilirubinemia to varying degrees. Gilbert disease is the most common inherited cause of unconjugated hyperbilirubinemia, with a prevalence of 5%; it is caused by reduced activity of the enzyme glucuronosyltransferase, which conjugates bilirubin. Bilirubin levels may rise to approximately 5 mg/dL in response to stress and starvation. Many different drugs, including rifampin and birth control pills, may also be associated with hyperbilirubinemia (usually indirect).
Conjugated (direct) hyperbilirubinemia may result from cholestasis and hepatocellular inflammation or injury. Cholestasis is characterized by high levels of alkaline phosphatase, mild to moderate elevation of transaminase levels, and increased levels of γ-glutamyltransferase. Intrahepatic cholestasis can occur in relation to drugs (ie, estrogens) and alcohol, as well as genetic disorders, such as progressive familial intrahepatic cholestasis (PFIC). This condition is divided into types 1, 2, and 3, depending on gene involvement. In PFIC, the capacity for liver cells to secrete bile is reduced. Extrahepatic cholestasis occurs with cholelithiasis or other obstructions of the biliary tree, such as a cyst. Cholelithiasis may occur in individuals with hemolytic anemia (black or brown pigment gallstones) and in adolescents who are overweight or postpartum (usually cholesterol gallstones). Hepatocellular injury most often results from hepatitis (see Chapter 127), including the infectious, alcoholic, nonalcoholic steatohepatitis, and drug-induced forms. Rarer disorders include Dubin-Johnson and Rotor syndromes. Metabolic diseases, such as Wilson disease, α1-antitrypsin deficiency, and cystic fibrosis, should be considered in the differential diagnosis of every older child who presents with direct (conjugated) hyperbilirubinemia.
A careful history must be obtained, documenting the timing of the onset of jaundice, presence of fever (suggestive of infection), feeding intolerance, pale stools (suggestive of obstruction), and growth and development (Box 126.2).
The patient should be evaluated for evidence of dysmorphism, organomegaly of the liver or spleen, ocular anomalies, developmental delay, abnormal heart sounds (eg, murmur), rash, hearing deficits, or lymphadenopathy. Unique facial features (eg, micrognathia, ocular anomalies) or a cardiac defect may be suggestive of a genetic disorder, such as PFIC or Alagille syndrome. Spleen enlargement is noted in hemolytic disorders and some inborn errors of metabolism, whereas isolated liver enlargement is suggestive of hepatitis. Rashes and lymphadenopathy are associated with certain infectious conditions, including congenital infections (eg, TORCHS) in newborns and infectious mononucleosis in adolescents.
In the newborn nursery, noninvasive methods are used to measure the level of jaundice. The bilirubin meter uses reflectance spectro-photometry to determine the skin color and strongly correlates with serum bilirubin levels. Another noninvasive method is the icterometer, which has an acrylic plastic color chart that is placed against the neonate’s nose.
Box 126.2. What to Ask
•What associated symptoms are present?
•How long have the symptoms been present?
•Does the child have a fever?
•What is the color of the stools?
•Is there a family history of jaundice, hepatitis, or consanguinity?
•What is the child’s diet? If a newborn or an infant, is the child fed mother’s milk or formula?
•When did the parents or caregivers first notice the jaundice?
•Has the child been jaundiced previously?
•Has the child been vaccinated against hepatitis A and B?
•Is there a history of foreign travel or shellfish ingestion?
•Was newborn screening performed, and are the results known?