Conjugated Hyperbilirubinemia: Screening and Treatment in Older Infants and Children Rula Harb and Daniel W. Thomas Pediatr. Rev. 2007;28;83-91 DOI: 10.1542/pir.28-3-83 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/28/3/83 Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2007 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347. Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 Article gastroenterology Conjugated Hyperbilirubinemia: Screening and Treatment in Older Infants and Children Rula Harb, MD,* Daniel W. Thomas, MD† Author Disclosure Objectives After completing this article, readers should be able to: 1. Describe the metabolism of bilirubin. 2. Evaluate a child of any age who has conjugated hyperbilirubinemia. 3. Recognize the signs and symptoms of Wilson disease. Drs Harb and Thomas did not disclose any financial relationships relevant to this article. Introduction Jaundice refers to yellow discoloration of the skin, sclera, mucous membranes, and body fluids. It is a common problem that can be the presenting sign for many disorders. The challenge for the physician is to identify patients who need additional evaluation. The differential diagnosis for jaundice is age-specific; this review addresses the causative conditions in infants beyond the newborn period, older children, and adolescents. Jaundice is caused by elevated serum bilirubin concentrations. It is apparent in infants when the serum bilirubin value is greater than 4 to 5 mg/dL (68.4 to 85.5 mcmol/L) and in older children at values greater than 2 to 3 mg/dL (34.2 to 51.3 mmol/L). Serum total bilirubin is measured in the laboratory as the sum of two components: unconjugated (“indirect”) and conjugated (“direct”) fractions. The terms “direct” and conjugated hyperbilirubinemia often are used interchangeably. However, this usage is not always accurate because direct bilirubin may include both the conjugated fraction and bilirubin bound to albumin (delta bilirubin). Delta bilirubin is formed by covalent bonding between conjugated bilirubin in the serum and albumin; it is metabolized with albumin and has a similar half-life of 21 days. The presence of delta bilirubin often prolongs direct hyperbilirubinemia while results of the other liver tests are normalizing. Many hospitals continue to measure direct bilirubin by a method that includes both direct and delta bilirubin. Clinicians should consider asking for a breakdown of the direct bilirubin fraction if the jaundice is prolonged or presenting atypically. Conjugated hyperbilirubinemia is defined as a conjugated bilirubin concentration greater than 2 mg/dL (34.2 mmol/L) or more than 20% of total bilirubin. It is the biochemical marker of cholestasis used most commonly and defined as perturbation of bile flow. Although jaundice is seen commonly in newborns who have physiologic jaundice, breastfeeding and breast milk jaundice, red blood cell defects, and hemolysis, these are conditions of unconjugated (indirect) hyperbilirubinemia. Causes of unconjugated hyperbilirubinemia in the older infant/child are not reviewed in this article. Conjugated hyperbilirubinemia is less common, affecting approximately 1 in 2,500 infants. This condition is never normal at any age, and distinguishing cholestasis from noncholestatic causes of jaundice is crucial. Prolonged hyperbilirubinemia of greater than 2 to 3 weeks’ duration requires additional investigation. Bilirubin Metabolism The liver has many functions, many of which depend on its ability to secrete bile. Bile secretion is the method by which the liver excretes toxins, modulates cholesterol metabolism, and aids in the intestinal digestion and absorption of lipids and fat-soluble vitamins. Bile is composed of water, bile acids (cholic and chenodeoxycholic acids), phospholipids, cholesterol, bile pigment (bilirubin), electrolytes, xenobiotics, and metabolized drugs. Impairment of bile flow or secretion by the liver results in backup *Children’s Hospital of Los Angeles, Los Angeles, Calif. † Editorial Board. Pediatrics in Review Vol.28 No.3 March 2007 83 Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology conjugated hyperbilirubinemia come significant in cases of bowel obstruction, where relatively more bilirubin is deconjugated and absorbed, thereby increasing serum bilirubin concentrations and worsening jaundice. Jaundice in the Infant Prolonged jaundice in the infant (lasting beyond 2 to 3 weeks after birth) is abnormal and requires additional investigation. It is paramount to fractionate the bilirubin in infants who have abnormal or Figure 1. Bilirubin production in the reticuloendothelial system. RBCⴝred blood cell prolonged jaundice to identify those who have conjugated hyperof its constituents within the liver canaliculi and hepabilirubinemia and recognize the disorders that may be tocytes, ultimately creating cholestatic damage to the amenable to early medical intervention (eg, galacliver. tosemia, urinary tract infection) or surgery (eg, biliary Bilirubin is the product of heme breakdown in the atresia, choledochal cyst). In addition, early diagnosis reticuloendothelial cells of the spleen and liver (Fig. 1). facilitates the institution of necessary nutritional and The end product of this metabolic pathway is watermedical support to promote optimal growth and develinsoluble unconjugated bilirubin, which is bound to opment. albumin in the circulation. Unconjugated bilirubin is The causes of cholestatic jaundice in the infant vary taken up and metabolized in the liver to conjugated and can be divided into two primary categories: obstrucbilirubin (Fig. 2). Conjugated bilirubin is secreted into tive and hepatocellular. A detailed classification is listed the biliary system by a specific transporter. Defects in in Table 1. The four most common causes of persistent bilirubin conjugation cause unconjugated hyperbilirucholestatic jaundice in infants are discussed. binemia (Gilbert syndrome and Crigler-Najjar syndromes I and II). Hepatocellular disease can cause a Extrahepatic Biliary Atresia (EHBA) mixed unconjugated and conjugated hyperbilirubinemia EHBA is the most common and serious cause of produe to both impaired bilirubin conjugation and canaliclonged cholestatic jaundice in infants. It results from a ular excretion. Defects in conjugated bilirubin excretion progressive and destructive inflammatory process that cause isolated conjugated hyperbilirubinemia without affects both the extra- and intrahepatic biliary tree. The cholestasis (Rotor and Dubin-Johnson syndromes). cause of EHBA has not been identified clearly. Two Other mutations in membrane transporters of other orclinical forms have been defined: an embryonic/fetal ganic anions, such as bile acids, are linked with several form, which constitutes 20% of cases, and a perinatal/ diseases, including cystic fibrosis, adrenoleukodystrophy, acquired type, which comprises the remaining 80% of and the familial intrahepatic cholestasis syndromes. cases. (1) The embryonic type has an earlier onset, has no Once bile is excreted from the liver, it is stored in the jaundice-free interval, and is associated with other nongallbladder until a meal activates duodenal cholecystokihepatic anomalies or syndromic features, such as isolated nin release and expulsion of gallbladder contents into the cardiovascular and gastrointestinal anomalies (intestinal intestine. Conjugated bilirubin cannot be reabsorbed by malrotation, preduodenal portal vein, abdominal situs intestinal epithelial cells and is degraded by intestinal inversus) and splenic anomalies (polysplenia, asplenia). flora into stercobilin and urobilinogen, which are exThe acquired type is not associated with other congenital creted into stool. A small portion of conjugated bilirubin anomalies, usually occurs in an otherwise healthy term is deconjugated by intestinal beta-glucuronidase. The infant, and has a jaundice-free interval followed by the unconjugated bilirubin can be reabsorbed into the circudevelopment of jaundice in the first few postnatal weeks. lation and returned to the liver, which is known as Both forms share the cardinal features of cholestatic enterohepatic bilirubin circulation. The amount of bilijaundice, hepatomegaly, and acholic stools. rubin reabsorbed normally is very small, but it can beEHBA was universally fatal before the Kasai hepato84 Pediatrics in Review Vol.28 No.3 March 2007 Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology Figure 2. Bilirubin conjugation. Movement of bilirubin (B) from the circulation into the hepatocyte occurs at the hepatocyte basolateral membrane with the help of a membrane carrier protein. Binding of B to glutathione-S-transferase (GST) facilitates movement into the rough endoplasmic reticulum (RER), where conjugation with glucuronic acid (GA) is enabled by bilirubin ceridine diphosphate glucuronosyl transferase 1A1 (UGT1A1). The conjugated bilirubin is excreted into bile at the hepatocyte canalicular membrane through a process mediated by the membrane-bound transporter cMOAT (canalicular multispecific organic anion transporter). Albⴝalbumin, cytosolⴝthe fluid within a cell that contains the cell’s oranelles, B-GAⴝconjugated bilirubin (mono- and di-glucuronides). Adapted from Gourley GR. Bilirubin metabolism. In: Walker WA, Goulet OJ, Kleinman RE, et al, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 4th ed. Hamilton, Ontario, Canada: BC Decker, Inc; 2004:1344 –1362. portoenterostomy was introduced by Dr Morio Kasai in 1959. This procedure establishes bile flow in up to 80% of patients if performed prior to 60 days after birth. The success rate decreases as the infant’s age increases, with bile flow established in up to 45% of infants 60 to 90 days of age and 10% of infants 90 to 120 days of age. (1) These results underscore the importance of diagnosing this condition early. Approximately one third of patients require liver transplant in the first postnatal year, one third require it in their teens, and one third live with some liver function after the Kasai procedure into adulthood. (1) It is estimated that approximately 50% of patients who have good results from the initial Kasai surgery still become transplant candidates later in life. “Idiopathic” Neonatal Hepatitis “Idiopathic” neonatal hepatitis, also known as “giant cell” hepatitis, used to be considered the most common cause of neonatal cholestasis. However, its relative occur- conjugated hyperbilirubinemia rence has decreased as specific disorders that cause a similar clinical and histologic picture have been identified (eg, alpha-1-antitrypsin deficiency, defective bile acid synthesis and transport). The diagnosis is made in infants who have prolonged cholestatic jaundice and typical biopsy findings of disrupted hepatic architecture, multinucleated “giant” hepatocytes, focal hepatocyte necrosis, expansion of portal triads with inflammatory infiltrate, and extramedullary hematopoiesis in addition to the absence of another disorder. Electron microscopy often is useful in diagnosis. The prognosis of “idiopathic” hepatitis is variable and depends on whether a metabolic or infectious cause ultimately is diagnosed. Jaundice usually resolves by 3 to 4 months of age; persistence of jaundice beyond this age warrants additional evaluation. Alagille Syndrome (AGS) AGS also is known as syndromic bile duct paucity or arteriohepatic dysplasia. It is an autosomally dominant inherited with low penetrance disorder of bile duct paucity that occurs in conjunction with syndromic extrahepatic findings. The defect in AGS is a mutation of the Jagged 1 (JAG1) gene, which is mapped to chromosome 20p12 and encodes a ligand for the Notch signaling pathway, which is important in cell fate determination. The diagnosis can be made in the patient who has a marked reduction of intrahepatic bile ducts on liver biopsy in association with other cardiac, ocular, skeletal, and facial abnormalities. The bile duct paucity may not be apparent in early infancy. AGS usually presents in the first 3 postnatal months and must be distinguished from biliary atresia and other causes of nonsyndromic paucity. It may be diagnosed in older children who have persistent cholestatic jaundice and in adults after diagnosis in a related child. In the original series described by Alagille in 1975, (2) 15 of 30 patients who had cholestatic jaundice and hepatic ductular hypoplasia with intact extrahepatic bile Pediatrics in Review Vol.28 No.3 March 2007 85 Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology conjugated hyperbilirubinemia Differential Diagnosis of Cholestatic Jaundice in the Infant Table 1. Obstructive ● ● ● ● ● Extrahepatic biliary atresia Choledochal cyst Spontaneous perforation of the bile duct Inspissated bile Mass: stone, tumor Hepatocellular ● ● Idiopathic neonatal hepatitis Disorders of the intrahepatic bile ducts – Alagille syndrome (arteriohepatic dysplasia/syndromic paucity of the intrahepatic bile ducts) – Nonsyndromic paucity of the intrahepatic bile ducts – Congenital hepatic fibrosis with bile duct cysts (Caroli disease) ● Metabolic disorders – Disorders of amino acid metabolism 䡲 Tyrosinemia – Disorders of lipid metabolism 䡲 Gaucher disease 䡲 Niemann-Pick disease 䡲 Cholesterol ester storage disease (Wolman syndrome) – Disorders of carbohydrate metabolism 䡲 Galactosemia 䡲 Hereditary fructose intolerance 䡲 Glycogen storage disease – Disorders of bile acid metabolism and transport excretion – Zellweger syndrome and other disorders of peroxisomal metabolism – Disorders of bilirubin transport (do not cause cholestatic liver injury) 䡲 Dubin-Johnson syndrome 䡲 Rotor syndrome – Mitochondrial disorders – Alpha-1-antitrypsin deficiency – Cystic fibrosis – Neonatal iron storage disease ● Endocrine disorders – Hypothyroidism – Hypopituitarism and septo-optic dysplasia ● Infectious – Sepsis (urinary tract infection, endotoxemia, enterocolitis) – TORCH infections (toxoplasmosis, cytomegalovirus, herpesvirus, rubella, syphilis) – Hepatitis B, non-typeable hepatitis – Human immunodeficiency virus ● Drugs and Toxins – Total parenteral nutrition – Medications – Fetal alcohol syndrome ● Other – Vascular anomalies 䡲 Budd-Chiari syndrome 䡲 Hepatoendothelioma/hemangioma – Cardiac insufficiency and hypoperfusion – Chromosomal abnormalities 䡲 Trisomy 21 䡲 Trisomy 18 86 Pediatrics in Review Vol.28 No.3 March 2007 ducts had other common features. These included a characteristic facies (prominent forehead, deep-set eyes with mild hypertelorism, straight nose, and small, pointed chin), a systolic murmur caused by peripheral pulmonic stenosis, vertebral arch defects, growth retardation, mild-to-moderate mental retardation, and hypogonadism in boys. Emerick and associates (3) studied 92 patients who had AGS and found cholestasis in 96%, bile duct paucity in 85%, cardiac murmur in 97%, vertebral anomalies in 51%, characteristic facies in 96%, eye findings (posterior embryotoxon) in 78%, and renal anomalies in 40%. Minor features included growth retardation (87%), mental retardation (2%), developmental delay (16%), and pancreatic insufficiency (41%). Alagille and colleagues (4) have recommended that the diagnosis be made by confirming the existence of cholestasis and two of the other four abnormalities. Factors that contribute significantly to mortality in AGS include cardiac disease (other cardiac defects besides peripheral pulmonic stenosis such as tetralogy of Fallot), intracranial hemorrhage, and progressive liver disease. Alpha-1-Antitrypsin Deficiency Alpha-1-antitrypsin is a member of the serine protease inhibitor family (the serpins) that protects the connective tissue from degradation by inhibition of neutrophil elastase, cathepsin G, and proteinase 3. Although lung disease associated with alpha-1-antitrypsin deficiency is attributed to markedly reduced concentrations, liver disease results from retention of the abnormally folded protein in the endoplasmic reticulum (ER) of the hepatocyte (the site of synthesis of most alpha- Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology 1-antitrypsin). Alpha-1-antitrypsin is a polymorphic protein that has allelic variants defined by isoelectric focusing of the plasma and classified according to the protease inhibitor (Pi) phenotype. Structural variants that have normal plasma concentrations or functional activity are known as PiM alpha-1-antitrypsin. Variants in which alpha-1-antitrypsin is not detected are known as null allelic variants and when inherited with another null variant, are associated with early development of emphysema but no liver disease. Variants that have reduced alpha-1-antitrypsin activity include the PiZ and PiS. The PiZ homozygote is the condition associated most commonly with liver and lung disease. Alpha-1-antitrypsin deficiency is the most common genetic cause of acute and chronic liver disease in chil- conjugated hyperbilirubinemia Conjugated hyperbilirubinemia results from obstructive or hepatocellular causes. Biliary stones and sludge can obstruct the common bile duct and cause subsequent jaundice. Other causes of obstructive jaundice in this age group include parasitic infestations (ascaris, liver flukes), primary sclerosing cholangitis, choledochal cyst, and tumors. Hepatocellular causes of conjugated hyperbilirubinemia, such as viral or medication-related hepatitis, can result in jaundice. Clinically apparent liver disease from chronic hepatitis B infection has decreased markedly due to the effective implementation of the vaccine for this disorder. Signs of active hepatitis C usually occur in adults and are not discussed in detail in this article. Wilson disease and autoimmune hepatitis are relatively uncommon causes of hyperbilirubinemia but are two important entities for the pediatrician to recognize early because treatment that may prevent progression is available. Other hepatocellular disorders are detailed in Table 2. Alpha-1antitrypsin deficiency is the most common genetic cause of acute and chronic liver disease in children. Wilson Disease dren and the most common genetically caused disorder necessitating liver transplantation in children. Presentation of liver disease in ZZ homozygotes is variable. In a review of 44 patients, Volpert and colleagues (5) reported that the age of diagnosis of alpha-1-antitrypsin deficiency-associated liver disease was younger than 1 month in 10 patients, 1 month to 1 year in 21 patients, and older than 1 year in 13 patients. One of every 10 patients has prolonged jaundice in infancy, and 1 of 100 develops cirrhosis and requires transplantation. (6) Other clinical presentations include neonatal hepatitis syndrome, mild elevation of transaminase values in the toddler, portal hypertension and cirrhosis in the child or adolescent, chronic hepatitis in the adult, and hepatocellular carcinoma in the adult. Diagnosis is made by demonstrating an abnormal Pi phenotype (PiZZ) and periodic acid-Schiff-positive, diastase-resistant globules in the ER of hepatocytes. Jaundice in the Older Child/Adolescent New-onset cholestatic jaundice in the older child and adolescent always requires additional investigation. It is essential to fractionate the bilirubin to differentiate cholestatic jaundice from unconjugated hyperbilirubinemia due to hemolysis or defective bilirubin conjugation, as occurs in Gilbert syndrome. Wilson disease is an autosomal recessive disorder of copper homeostasis. The affected gene is on chromosome 13 and encodes a highly conserved copper-transporting P-type adenosine triphosphatase (ATP7b) that excretes copper into bile. Copper is an essential trace element that participates in cellular respiration, iron oxidation, pigment formation, and antioxidant defense. It is absorbed from copper-rich foods from the stomach and duodenum, bound to ceruloplasmin in the circulation, and excreted by the liver into bile. The prevalence of Wilson disease is 1 in 30,000 and is equal among all ethnic groups. The condition presents in most patients as either hepatic or central nervous system involvement. Liver disease occurs at an average age of 10 to 13 years in 45% of patients and rarely is seen before 3 years of age. Some 35% of patients present with neurologic signs (tremor, rigidity, dysarthria) a decade older than patients who have hepatic involvement; 10% present with psychiatric disturbances (depression, new-onset school problems, impulsive behavior); and 10% present with other manifestations, including hemolytic anemia, Fanconi syndrome (glycosuria, aminoaciduria), and cardiomyopathy. Thus, patients who have Wilson disease can have a mixed conjugated and unconjugated hyperbilirubinemia, depending on which disease manifestations are present. Pediatrics in Review Vol.28 No.3 March 2007 87 Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology conjugated hyperbilirubinemia Differential Diagnosis of Cholestatic Jaundice in the Older Child and Adolescent Table 2. Obstructive ● ● Choledochal cyst Mass: stone, tumor, parasite Hepatocellular ● Autoimmune – Autoimmune hepatitis – Primary sclerosing cholangitis – Primary biliary cirrhosis ● Disorders of the intrahepatic bile ducts – Alagille syndrome (arteriohepatic dysplasia/ syndromic paucity of the intrahepatic bile ducts) – Nonsyndromic paucity of the intrahepatic bile ducts – Congenital hepatic fibrosis/Caroli disease ● Metabolic disorders – Wilson Disease – Disorders of bilirubin transport – Dubin-Johnson syndrome – Rotor syndrome – Mitochondrial disorders – Alpha-1-antitrypsin deficiency – Cystic fibrosis – Hemochromatosis ● Endocrine disorders – Hypothyroidism ● Infectious – Sepsis (endotoxemia, enterocolitis) – Hepatitis A, B, C, E, non-typeable hepatitis – Human immunodeficiency virus ● Drugs and toxins – Total parenteral nutrition – Medications ● Other – Vascular anomalies – Budd-Chiari syndrome – Hemangioma – Cardiac insufficiency and hypoperfusion – Chromosomal abnormalities – Trisomy 21 Hepatic involvement ranges from asymptomatic transaminitis to acute liver failure with jaundice, cirrhosis, hepatic necrosis, and encephalopathy. Liver biopsy can show nonspecific findings of steatosis and glycogen deposition. Micronodular cirrhosis and piecemeal necrosis also can be seen. Kaiser-Fleischer (KF) rings, representing copper deposition in Descemet’s membrane, are visible on a slitlamp examination of the eye. Neurologic symptoms are attributed to copper deposition in the 88 Pediatrics in Review Vol.28 No.3 March 2007 basal ganglia and include parkinsonian symptoms. KF rings often are present in patients who have neurologic symptoms, but may be absent in patients who have liver disease. Wilson disease is diagnosed in the patient who has signs and symptoms consistent with the disease in addition to laboratory findings of impaired hepatic copper metabolism. The serum ceruloplasmin concentration is decreased because copper is not conjugated to the apoceruloplasmin synthesized by the hepatocyte. The unconjugated apoceruloplasmin is degraded rapidly. Measurement of urinary copper in a 24-hour collection is increased. A liver biopsy quantitating hepatic copper content is a helpful diagnostic tool, and a liver that has normal copper content excludes the diagnosis. A slitlamp examination can be performed to evaluate for KF rings. Definitive genetic testing is now available for Wilson disease. Therapy is geared toward attaining and maintaining normal copper homeostasis. Oral D-penicillamine and trientine are copper chelators. Zinc acetate prevents the absorption of copper from the gastrointestinal tract. Patients are counseled to avoid copper-rich foods such as shellfish, legumes, nuts, chocolate, and liver. Liver transplantation is the treatment of choice for selected patients who have either advanced liver disease or fulminant liver failure. Autoimmune Hepatitis (AIH) AIH is an inflammatory hepatitis characterized by the development of pathologic autoantibodies to normal host proteins and a dense mononuclear infiltrate in the portal tracts in the absence of another cause. AIH can be subdivided into two general categories classified by the type of autoantibodies produced: anti-nuclear antibody/ anti-smooth muscle antibody (ANA/SMA) AIH, and anti-liver kidney microsomal antibody 1 (LKM1) AIH. In a study of 52 patients who had AIH, investigators found that the median age at presentation of ANA/SMA AIH was 10.5 years and that for LKM1 AIH was 7.4 years. (7) Some 75% of patients were female. Three patterns of presentation were noted: 1) Acute hepatitis was the pattern in most patients having both types, with nausea, vomiting, anorexia, fatigue, and abdominal pain, followed by jaundice, dark urine, and pale stools. Duration of illness varied from 2 weeks to 2 months in this group. 2) Another group (30%) had the insidious onset of disease of longer duration (6 mo to 2 yr), with relapsing jaundice, progressive fatigue, headache, anorexia, and weight loss. Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology 3) A small percent of patients, who had no prior history of jaundice, had complications of portal hypertension. AIH is suspected on the basis of clinical characteristics and demonstration of the autoantibodies, as well as an elevated immunoglobulin G value. Definitive diagnosis is made on liver biopsy, where the typical histologic picture is a dense mononuclear infiltrate invading the hepatic parenchyma (periportal hepatitis), with periportal necrosis. In most cases, the disease responds well to immunosuppressive therapy. Urgent liver transplantation is indicated if the patient presents in acute fulminant hepatic failure. Evaluation of the Jaundiced Patient Although jaundice is relatively common in the first 2 weeks after birth and is observed frequently in newborns, jaundice in the older infant and child always is abnormal and requires more investigation. Additional evaluation of children who have conjugated hyperbiliru- conjugated hyperbilirubinemia biliary atresia, choledochal cyst, or gallstone disease. Additionally, the birth and perinatal histories, past medical and surgical histories, family history (including consanguinity), medication and dietary histories, social activity and school performance histories, and travel history should be sought. Physical Examination The clinician should note if the patient is well- or illappearing as well as irritable or drowsy. Both signs may indicate encephalopathy, infection, or metabolic derangement. Microcephaly in the infant may indicate congenital infection. Recognition of dysmorphism is valuable. Eyes should be examined for posterior embryotoxon or KF rings. The systolic murmur of peripheral pulmonic stenosis, usually heard in the back as well as the front, suggests AGS. Hepatomegaly typically is present, but a small liver may indicate cirrhosis and end-stage liver disease. Splenomegaly, ascites, and prominent vasculature such as caput medusa suggest portal hypertension and chronic liver disease. An infant’s diaper should be examined for pale stools and dark urine. Neurologic evaluation should be undertaken for ataxia and asterixis. The key laboratory test to obtain when evaluating jaundice is fractionation of the bilirubin. Laboratory Tests binemia and chronic liver disease should involve looking for the complications of cholestasis, such as coagulopathy, fat malabsorption, ascites, and encephalopathy, to initiate appropriate therapy. Finally, a child who has conjugated hyperbilirubinemia or evidence of chronic liver disease should be referred to a pediatric gastroenterologist. History The age of the patient and history of presentation give important clues to the cause of the jaundice. Some conditions of infantile cholestasis and conjugated hyperbilirubinemia present early in life, such as biliary atresia, AGS, and inherited metabolic disorders. Others often manifest beyond infancy, such as AIH and Wilson disease. Diseases such as cystic fibrosis and alpha-1antitrypsin deficiency can present as either neonatal cholestasis or later in life as chronic liver disease. Signs such as poor feeding, irritability, and vomiting may be associated with a metabolic condition, such as galactosemia, or suggest encephalopathy. The presence of acholic stools suggests an obstructive process such as The key laboratory test to obtain when evaluating jaundice is fractionation of the bilirubin. Indirect or unconjugated hyperbilirubinemia usually indicates excessive red blood cell destruction at any age. Direct or conjugated hyperbilirubinemia indicates a hepatobiliary disorder. Hepatic transaminase concentrations are elevated in the presence of hepatocellular injury. The alkaline phosphatase and gamma glutamyl transferase values often are increased with obstructive conditions. Liver function, including prothrombin time, albumin, and cholesterol, should be measured. The remainder of the evaluation should be tailored to the specific patient. Hemolytic anemia can be seen in patients who have Wilson disease. Thyroid function tests can be obtained if hypothyroidism is suspected. Other age-specific tests may be considered, including TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex) titers, blood and urine cultures, alpha-1-antitrypsin Pi phenotype, iron profile, chloride sweat test, urine-reducing substances (galactosemia), and a metabolic screen in young infants. Testing for Wilson disease (ceruloplasmin) or for AIH is appropriate in older children. Pediatrics in Review Vol.28 No.3 March 2007 89 Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology conjugated hyperbilirubinemia Imaging Real-time ultrasonography is an important diagnostic tool in the evaluation of the jaundiced patient. The absence of a gallbladder on a fasting examination in an infant is suggestive but not diagnostic of biliary atresia. Ultrasonography may demonstrate gallstones, choledochal cyst, or ascites. A Doppler ultrasonographic study of the portal circulation may identify portal hypertension or portal vein thrombosis. Hepatobiliary scintigraphy with technetium-labeled iminodiacetic acid analogs may help differentiate obstructive jaundice from nonobstructive causes. In the case of obstructive jaundice, the hepatic uptake of tracer is normal, but there is no intestinal excretion. In cases of severe hepatocellular disease, uptake into the liver is delayed, but tracer eventually is excreted into the intestine. Premedication with phenobarbital for 3 to 5 days prior to the study enhances biliary excretion and imaging of the isotope. Liver Biopsy Ultimately, many patients require a liver biopsy for definitive and reliable diagnosis. The liver biopsy can be performed percutaneously, with or without ultrasonographic guidance, or surgically. In addition to evaluation by an experienced pathologist for specific histologic features, liver tissue can be used to quantify iron and copper content and for electron microscopy to detect certain metabolic conditions. min concentrations with supplementation. Management of the complications of chronic liver disease and portal hypertension in conjunction with a pediatric gastroenterologist is essential. All children, particularly those who have chronic liver disease, should be immunized, including both hepatitis A and B, using the guidelines of the American Academy of Pediatrics. It is appropriate to refer any child who evidences acute, severe liver disease or a chronic liver condition to a pediatric transplant center for evaluation. References 1. Balistreri WF, Grand R, Hoofhagle JH, et al. Biliary atresia: current concepts and research directions. Hepatology. 1996;23: 1682–1692 2. Alagille D, Odie`vre M, Gautier M, et al. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical growth, mental and sexual development, and cardiac murmur. J Pediatr. 1975;86:63–71 3. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29:822– 829 4. Alagille D, Estrada A, Hadchouel M, et al. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987;110:195–200 5. Volpert D, Molleston JP, Perlmutter DH. Alpha-1-antitrypsin deficiency-associated liver disease progresses slowly in some children. J Pediatr Gastroenterol Nutr. 2000;31:258 –263 6. Carrell RW, Lomas DA. Alpha1-antitrypsin deficiency: a model for conformational diseases. N Engl J Med. 2002;346:45–53 7. Mieli-Vergani G, Vergani D. Immunological liver diseases in children. Semin Liver Dis. 1998;18:271–279 Management of Jaundice Treatment is directed at the specific underlying disorder, although persistent cholestasis generally can cause retention of bile acids, bilirubin, and cholesterol; decreased excretion of bile acids into the intestine with resulting fat malabsorption; and hepatocellular damage that eventually causes portal hypertension and end-stage liver disease. Some general principles apply to the management of these consequences independent of the specific cause. These principles include optimizing nutrition by employing the use of medium-chain triglyceride-containing formula or supplements and monitoring fat-soluble vita- 90 Pediatrics in Review Vol.28 No.3 March 2007 Suggested Reading Gitlin JD. Wilson disease. Gastroenterology. 2003;125:1868 –1877 McLin VA, Balistreri WF. Approach to neonatal cholestasis. In: Walker WA, Goulet OJ, Kleinman RE, et al, eds. Pediatric Gastrointestinal Disease: Pathophysiology, Diagnosis, Management. 4th ed. Hamilton, Ontario, Canada: BC Decker Inc; 2004:1079 –1091 Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004; 39:115–128 Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 gastroenterology conjugated hyperbilirubinemia PIR Quiz Quiz also available online at www.pedsinreview.org. 1. Conjugated hyperbilirubinemia is: A. B. C. D. E. A marker of accelerated hemoglobin breakdown. A normal finding in otherwise healthy adolescents. Always linked with cholestasis. Less common than unconjugated hyperbilirubinemia. Synonymous with direct hyperbilirubinemia. 2. A 4-week-old breastfeeding boy is jaundiced and has a total bilirubin concentration of 13 mg/dL (222.3 mmol/L). The laboratory test that maximizes diagnostic efficiency is: A. B. C. D. E. A complete blood count. A reticulocyte count. Bilirubin fractionation. Gamma glutamyl transferase. Hepatic transaminase. 3. A 4-week-old breastfeeding boy has become increasingly jaundiced. The pregnancy was unremarkable. Delivery was at term, and the infant was appropriate for gestational age. The jaundice was not noted in the hospital. Findings on the physical examination, other than jaundice, are unremarkable. Today, the total bilirubin concentration is 13 mg/dL (222.3 mmol/L), with a direct fraction of 6 mg/dL (102.6 mmol/L). Of the following, the condition that is most likely ruled out by these findings is: A. B. C. D. E. Alagille syndrome. Alpha-1-antitrypsin deficiency. Extrahepatic biliary atresia. Neonatal hepatitis. Physiologic jaundice. 4. A previously healthy 15-year-old girl develops jaundice and fatigue. She does not complain of colicky abdominal pain associated with meals. She has had no known exposure to hepatotoxins. Aside from jaundice and appearing mildly ill, findings on her physical examination are unremarkable. Initial laboratory evaluation reveals a bilirubin concentration of 11 mg/dL (188.1 mmol/L) with a direct fraction of 4 mg/dL (68.4 mmol/L), and elevated hepatic transaminases, but no evidence of Epstein-Barr or hepatitis A, B, or C virus. As suspected from the history, ultrasonography reveals a normal gallbladder and biliary tree. Serum ceruloplasmin and autoantibody results are inconclusive. Pi typing reveals PiMM, and the patient proceeds to liver biopsy. Copper content of the sample is normal. Of the following, the patient is most likely to have: A. B. C. D. E. Alpha-1-antitrypsin deficiency. Autoimmune hepatitis. Choledochal cyst. Gilbert syndrome. Wilson disease. 5. Wilson disease is diagnosed definitively through: A. B. C. D. E. Genetic testing. Liver biopsy. Serum ceruloplasmin concentrations. Slitlamp examination. Urinary copper excretion. Pediatrics in Review Vol.28 No.3 March 2007 91 Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009 Conjugated Hyperbilirubinemia: Screening and Treatment in Older Infants and Children Rula Harb and Daniel W. Thomas Pediatr. Rev. 2007;28;83-91 DOI: 10.1542/pir.28-3-83 Updated Information & Services including high-resolution figures, can be found at: http://pedsinreview.aappublications.org/cgi/content/full/28/3/83 Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pedsinreview.aappublications.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://pedsinreview.aappublications.org/misc/reprints.shtml Downloaded from http://pedsinreview.aappublications.org. Provided by Univ Of North Carolina on December 8, 2009