ictericia5

Conjugated Hyperbilirubinemia:Screening and Treatment in Older Infants andChildrenRula Harb, MD,* Daniel

W. Thomas, MD†

Author Disclosure

Drs Harb and Thomas

did not disclose any

financial relationships

relevant to this

article.

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.

IntroductionJaundice refers to yellow discoloration of the skin, sclera, mucous membranes, and bodyfluids. It is a common problem that can be the presenting sign for many disorders. Thechallenge for the physician is to identify patients who need additional evaluation. Thedifferential diagnosis for jaundice is age-specific; this review addresses the causativeconditions in infants beyond the newborn period, older children, and adolescents.

Jaundice is caused by elevated serum bilirubin concentrations. It is apparent in infantswhen the serum bilirubin value is greater than 4 to 5 mg/dL (68.4 to 85.5 mcmol/L) andin older children at values greater than 2 to 3 mg/dL (34.2 to 51.3 mmol/L). Serum totalbilirubin is measured in the laboratory as the sum of two components: unconjugated(“indirect”) and conjugated (“direct”) fractions. The terms “direct” and conjugatedhyperbilirubinemia often are used interchangeably. However, this usage is not alwaysaccurate because direct bilirubin may include both the conjugated fraction and bilirubinbound to albumin (delta bilirubin). Delta bilirubin is formed by covalent bonding betweenconjugated bilirubin in the serum and albumin; it is metabolized with albumin and has asimilar half-life of 21 days. The presence of delta bilirubin often prolongs direct hyperbi-lirubinemia while results of the other liver tests are normalizing. Many hospitals continueto 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 thejaundice is prolonged or presenting atypically.

Conjugated hyperbilirubinemia is defined as a conjugated bilirubin concentrationgreater than 2 mg/dL (34.2 mmol/L) or more than 20% of total bilirubin. It is thebiochemical marker of cholestasis used most commonly and defined as perturbation of bileflow. Although jaundice is seen commonly in newborns who have physiologic jaundice,breastfeeding and breast milk jaundice, red blood cell defects, and hemolysis, these areconditions of unconjugated (indirect) hyperbilirubinemia. Causes of unconjugated hyper-bilirubinemia in the older infant/child are not reviewed in this article. Conjugatedhyperbilirubinemia is less common, affecting approximately 1 in 2,500 infants. Thiscondition is never normal at any age, and distinguishing cholestasis from noncholestaticcauses of jaundice is crucial. Prolonged hyperbilirubinemia of greater than 2 to 3 weeks’duration requires additional investigation.

Bilirubin MetabolismThe liver has many functions, many of which depend on its ability to secrete bile. Bilesecretion is the method by which the liver excretes toxins, modulates cholesterol metab-olism, and aids in the intestinal digestion and absorption of lipids and fat-solublevitamins. Bile is composed of water, bile acids (cholic and chenodeoxycholic acids),phospholipids, cholesterol, bile pigment (bilirubin), electrolytes, xenobiotics, andmetabolized drugs. Impairment of bile flow or secretion by the liver results in backup

*Children’s Hospital of Los Angeles, Los Angeles, Calif.†Editorial Board.

Article gastroenterology

Pediatrics in Review Vol.28 No.3 March 2007 83

of its constituents within the liver canaliculi and hepa-tocytes, ultimately creating cholestatic damage to theliver.

Bilirubin is the product of heme breakdown in thereticuloendothelial cells of the spleen and liver (Fig. 1).The end product of this metabolic pathway is water-insoluble unconjugated bilirubin, which is bound toalbumin in the circulation. Unconjugated bilirubin istaken up and metabolized in the liver to conjugatedbilirubin (Fig. 2). Conjugated bilirubin is secreted intothe biliary system by a specific transporter. Defects inbilirubin conjugation cause unconjugated hyperbiliru-binemia (Gilbert syndrome and Crigler-Najjar syn-dromes I and II). Hepatocellular disease can cause amixed unconjugated and conjugated hyperbilirubinemiadue to both impaired bilirubin conjugation and canalic-ular excretion. Defects in conjugated bilirubin excretioncause isolated conjugated hyperbilirubinemia withoutcholestasis (Rotor and Dubin-Johnson syndromes).Other mutations in membrane transporters of other or-ganic anions, such as bile acids, are linked with severaldiseases, including cystic fibrosis, adrenoleukodystrophy,and the familial intrahepatic cholestasis syndromes.

Once bile is excreted from the liver, it is stored in thegallbladder until a meal activates duodenal cholecystoki-nin release and expulsion of gallbladder contents into theintestine. Conjugated bilirubin cannot be reabsorbed byintestinal epithelial cells and is degraded by intestinalflora into stercobilin and urobilinogen, which are ex-creted into stool. A small portion of conjugated bilirubinis deconjugated by intestinal beta-glucuronidase. Theunconjugated bilirubin can be reabsorbed into the circu-lation and returned to the liver, which is known asenterohepatic bilirubin circulation. The amount of bili-rubin reabsorbed normally is very small, but it can be-

come significant in cases of bowelobstruction, where relatively morebilirubin is deconjugated and ab-sorbed, thereby increasing serumbilirubin concentrations and wors-ening jaundice.

Jaundice in the InfantProlonged jaundice in the infant(lasting beyond 2 to 3 weeks afterbirth) is abnormal and requires ad-ditional investigation. It is para-mount to fractionate the bilirubinin infants who have abnormal orprolonged jaundice to identifythose who have conjugated hyper-

bilirubinemia and recognize the disorders that may beamenable to early medical intervention (eg, galac-tosemia, urinary tract infection) or surgery (eg, biliaryatresia, choledochal cyst). In addition, early diagnosisfacilitates the institution of necessary nutritional andmedical support to promote optimal growth and devel-opment.

The causes of cholestatic jaundice in the infant varyand can be divided into two primary categories: obstruc-tive and hepatocellular. A detailed classification is listedin Table 1. The four most common causes of persistentcholestatic jaundice in infants are discussed.

Extrahepatic Biliary Atresia (EHBA)EHBA is the most common and serious cause of pro-longed cholestatic jaundice in infants. It results from aprogressive and destructive inflammatory process thataffects both the extra- and intrahepatic biliary tree. Thecause of EHBA has not been identified clearly. Twoclinical forms have been defined: an embryonic/fetalform, which constitutes 20% of cases, and a perinatal/acquired type, which comprises the remaining 80% ofcases. (1) The embryonic type has an earlier onset, has nojaundice-free interval, and is associated with other non-hepatic anomalies or syndromic features, such as isolatedcardiovascular and gastrointestinal anomalies (intestinalmalrotation, preduodenal portal vein, abdominal situsinversus) and splenic anomalies (polysplenia, asplenia).The acquired type is not associated with other congenitalanomalies, usually occurs in an otherwise healthy terminfant, and has a jaundice-free interval followed by thedevelopment of jaundice in the first few postnatal weeks.Both forms share the cardinal features of cholestaticjaundice, hepatomegaly, and acholic stools.

EHBA was universally fatal before the Kasai hepato-

Figure 1. Bilirubin production in the reticuloendothelial system. RBC�red blood cell

gastroenterology conjugated hyperbilirubinemia

84 Pediatrics in Review Vol.28 No.3 March 2007

portoenterostomy was introduced by Dr Morio Kasai in1959. This procedure establishes bile flow in up to 80%of patients if performed prior to 60 days after birth. Thesuccess rate decreases as the infant’s age increases, withbile flow established in up to 45% of infants 60 to 90 daysof age and 10% of infants 90 to 120 days of age. (1) Theseresults underscore the importance of diagnosing thiscondition early. Approximately one third of patientsrequire liver transplant in the first postnatal year, onethird require it in their teens, and one third live withsome liver function after the Kasai procedure into adult-hood. (1) It is estimated that approximately 50% ofpatients who have good results from the initial Kasaisurgery still become transplant candidates later in life.

“Idiopathic” Neonatal Hepatitis“Idiopathic” neonatal hepatitis, also known as “giantcell” hepatitis, used to be considered the most commoncause of neonatal cholestasis. However, its relative occur-

rence has decreased as specific dis-orders that cause a similar clinicaland histologic picture have beenidentified (eg, alpha-1-antitrypsindeficiency, defective bile acid syn-thesis and transport). The diagno-sis is made in infants who have pro-longed cholestatic jaundice andtypical biopsy findings of disruptedhepatic architecture, multinucle-ated “giant” hepatocytes, focal he-patocyte necrosis, expansion ofportal triads with inflammatory in-filtrate, and extramedullary hema-topoiesis in addition to the absenceof another disorder. Electron mi-croscopy often is useful in diagno-sis.

The prognosis of “idiopathic”hepatitis is variable and depends onwhether a metabolic or infectiouscause ultimately is diagnosed.Jaundice usually resolves by 3 to 4months of age; persistence of jaun-dice beyond this age warrants addi-tional evaluation.

Alagille Syndrome (AGS)AGS also is known as syndromicbile duct paucity or arteriohepaticdysplasia. It is an autosomallydominant inherited with low pen-

etrance disorder of bile duct paucity that occurs in con-junction with syndromic extrahepatic findings.

The defect in AGS is a mutation of the Jagged 1 (JAG1)gene, which is mapped to chromosome 20p12 and en-codes a ligand for the Notch signaling pathway, which isimportant in cell fate determination. The diagnosis canbe made in the patient who has a marked reduction ofintrahepatic bile ducts on liver biopsy in association withother cardiac, ocular, skeletal, and facial abnormalities.The bile duct paucity may not be apparent in earlyinfancy. AGS usually presents in the first 3 postnatalmonths and must be distinguished from biliary atresiaand other causes of nonsyndromic paucity. It may bediagnosed in older children who have persistent choles-tatic jaundice and in adults after diagnosis in a relatedchild.

In the original series described by Alagille in 1975, (2)15 of 30 patients who had cholestatic jaundice andhepatic ductular hypoplasia with intact extrahepatic bile

Figure 2. Bilirubin conjugation. Movement of bilirubin (B) from the circulation into thehepatocyte occurs at the hepatocyte basolateral membrane with the help of a membranecarrier protein. Binding of B to glutathione-S-transferase (GST) facilitates movement intothe rough endoplasmic reticulum (RER), where conjugation with glucuronic acid (GA) isenabled by bilirubin ceridine diphosphate glucuronosyl transferase 1A1 (UGT1A1). Theconjugated bilirubin is excreted into bile at the hepatocyte canalicular membrane througha process mediated by the membrane-bound transporter cMOAT (canalicular multispecificorganic anion transporter). Alb�albumin, cytosol�the fluid within a cell that contains thecell’s oranelles, B-GA�conjugated bilirubin (mono- and di-glucuronides). Adapted fromGourley 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.



ducts had other common features.These included a characteristic fa-cies (prominent forehead, deep-seteyes with mild hypertelorism,straight nose, and small, pointedchin), a systolic murmur caused byperipheral pulmonic stenosis, verte-bral arch defects, growth retarda-tion, mild-to-moderate mental re-tardation, and hypogonadism inboys. Emerick and associates (3)studied 92 patients who had AGSand found cholestasis in 96%, bileduct paucity in 85%, cardiac mur-mur in 97%, vertebral anomalies in51%, characteristic facies in 96%,eye findings (posterior embryo-toxon) in 78%, and renal anomaliesin 40%. Minor features includedgrowth retardation (87%), mentalretardation (2%), developmentaldelay (16%), and pancreatic insuffi-ciency (41%). Alagille and col-leagues (4) have recommended thatthe diagnosis be made by confirm-ing the existence of cholestasis andtwo of the other four abnormalities.Factors that contribute significantlyto mortality in AGS include cardiacdisease (other cardiac defects be-sides peripheral pulmonic stenosissuch as tetralogy of Fallot), intra-cranial hemorrhage, and progres-sive liver disease.

Alpha-1-AntitrypsinDeficiency

Alpha-1-antitrypsin is a member ofthe serine protease inhibitor family(the serpins) that protects the con-nective tissue from degradation byinhibition of neutrophil elastase,cathepsin G, and proteinase 3. Al-though lung disease associated withalpha-1-antitrypsin deficiency is at-tributed to markedly reduced con-centrations, liver disease resultsfrom retention of the abnormallyfolded protein in the endoplasmicreticulum (ER) of the hepatocyte(the site of synthesis of most alpha-

Table 1. Differential Diagnosis of CholestaticJaundice in the InfantObstructive

● 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 theintrahepatic 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

� Tyrosinemia– Disorders of lipid metabolism

� Gaucher disease� Niemann-Pick disease� Cholesterol ester storage disease (Wolman syndrome)

– Disorders of carbohydrate metabolism� Galactosemia� Hereditary fructose intolerance� 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)

� Dubin-Johnson syndrome� 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

� Budd-Chiari syndrome� Hepatoendothelioma/hemangioma

– Cardiac insufficiency and hypoperfusion– Chromosomal abnormalities

� Trisomy 21� Trisomy 18



1-antitrypsin). Alpha-1-antitrypsin is a polymorphic pro-tein that has allelic variants defined by isoelectric focusingof the plasma and classified according to the proteaseinhibitor (Pi) phenotype. Structural variants that havenormal plasma concentrations or functional activity areknown as PiM alpha-1-antitrypsin. Variants in whichalpha-1-antitrypsin is not detected are known as nullallelic variants and when inherited with another nullvariant, are associated with early development of emphy-sema but no liver disease. Variants that have reducedalpha-1-antitrypsin activity include the PiZ and PiS. ThePiZ homozygote is the condition associated most com-monly with liver and lung disease.

Alpha-1-antitrypsin deficiency is the most commongenetic cause of acute and chronic liver disease in chil-

dren and the most common genetically caused disordernecessitating liver transplantation in children. Presenta-tion of liver disease in ZZ homozygotes is variable. In areview of 44 patients, Volpert and colleagues (5) re-ported that the age of diagnosis of alpha-1-antitrypsindeficiency-associated liver disease was younger than 1month in 10 patients, 1 month to 1 year in 21 patients,and older than 1 year in 13 patients. One of every 10patients has prolonged jaundice in infancy, and 1 of 100develops cirrhosis and requires transplantation. (6)Other clinical presentations include neonatal hepatitissyndrome, mild elevation of transaminase values in thetoddler, portal hypertension and cirrhosis in the child oradolescent, chronic hepatitis in the adult, and hepatocel-lular carcinoma in the adult. Diagnosis is made by dem-onstrating an abnormal Pi phenotype (PiZZ) and peri-odic acid-Schiff-positive, diastase-resistant globules inthe ER of hepatocytes.

Jaundice in the Older Child/AdolescentNew-onset cholestatic jaundice in the older child andadolescent always requires additional investigation. It isessential to fractionate the bilirubin to differentiate cho-lestatic jaundice from unconjugated hyperbilirubinemiadue to hemolysis or defective bilirubin conjugation, asoccurs in Gilbert syndrome.

Conjugated hyperbilirubinemia results from obstruc-tive or hepatocellular causes. Biliary stones and sludgecan obstruct the common bile duct and cause subsequentjaundice. Other causes of obstructive jaundice in this agegroup include parasitic infestations (ascaris, liver flukes),primary sclerosing cholangitis, choledochal cyst, and tu-mors. Hepatocellular causes of conjugated hyperbiliru-binemia, such as viral or medication-related hepatitis, canresult in jaundice. Clinically apparent liver disease fromchronic hepatitis B infection has decreased markedly dueto the effective implementation of the vaccine for thisdisorder. Signs of active hepatitis C usually occur inadults and are not discussed in detail in this article.Wilson disease and autoimmune hepatitis are relativelyuncommon causes of hyperbilirubinemia but are two

important entities for thepediatrician to recognizeearly because treatmentthat may prevent progres-sion is available. Otherhepatocellular disordersare detailed in Table 2.

Wilson DiseaseWilson disease is an auto-

somal recessive disorder of copper homeostasis. Theaffected gene is on chromosome 13 and encodes a highlyconserved copper-transporting P-type adenosinetriphosphatase (ATP7b) that excretes copper into bile.Copper is an essential trace element that participates incellular respiration, iron oxidation, pigment formation,and antioxidant defense. It is absorbed from copper-richfoods from the stomach and duodenum, bound to ceru-loplasmin in the circulation, and excreted by the liverinto bile.

The prevalence of Wilson disease is 1 in 30,000 and isequal among all ethnic groups. The condition presents inmost patients as either hepatic or central nervous systeminvolvement. Liver disease occurs at an average age of10 to 13 years in 45% of patients and rarely is seen before3 years of age. Some 35% of patients present with neuro-logic signs (tremor, rigidity, dysarthria) a decade olderthan patients who have hepatic involvement; 10% presentwith psychiatric disturbances (depression, new-onsetschool problems, impulsive behavior); and 10% presentwith other manifestations, including hemolytic anemia,Fanconi syndrome (glycosuria, aminoaciduria), and car-diomyopathy. Thus, patients who have Wilson diseasecan have a mixed conjugated and unconjugated hyperbi-lirubinemia, depending on which disease manifestationsare present.

Alpha-1- antitrypsin deficiency is themost common genetic cause of acute and chronicliver disease in children.



Hepatic involvement ranges from asymptomatictransaminitis to acute liver failure with jaundice, cirrho-sis, hepatic necrosis, and encephalopathy. Liver biopsycan show nonspecific findings of steatosis and glycogendeposition. Micronodular cirrhosis and piecemeal necro-sis also can be seen. Kaiser-Fleischer (KF) rings, repre-senting copper deposition in Descemet’s membrane, arevisible on a slitlamp examination of the eye. Neurologicsymptoms are attributed to copper deposition in the

basal ganglia and include parkinsonian symptoms. KFrings often are present in patients who have neurologicsymptoms, but may be absent in patients who have liverdisease.

Wilson disease is diagnosed in the patient who hassigns and symptoms consistent with the disease in addi-tion to laboratory findings of impaired hepatic coppermetabolism. The serum ceruloplasmin concentration isdecreased because copper is not conjugated to the apo-ceruloplasmin synthesized by the hepatocyte. The un-conjugated apoceruloplasmin is degraded rapidly. Mea-surement of urinary copper in a 24-hour collection isincreased. A liver biopsy quantitating hepatic coppercontent is a helpful diagnostic tool, and a liver that hasnormal copper content excludes the diagnosis. A slitlampexamination can be performed to evaluate for KF rings.Definitive genetic testing is now available for Wilsondisease.

Therapy is geared toward attaining and maintainingnormal copper homeostasis. Oral D-penicillamine andtrientine are copper chelators. Zinc acetate prevents theabsorption of copper from the gastrointestinal tract. Pa-tients are counseled to avoid copper-rich foods such asshellfish, legumes, nuts, chocolate, and liver. Liver trans-plantation is the treatment of choice for selected patientswho have either advanced liver disease or fulminant liverfailure.

Autoimmune Hepatitis (AIH)AIH is an inflammatory hepatitis characterized by thedevelopment of pathologic autoantibodies to normalhost proteins and a dense mononuclear infiltrate in theportal tracts in the absence of another cause. AIH can besubdivided into two general categories classified by thetype of autoantibodies produced: anti-nuclear antibody/anti-smooth muscle antibody (ANA/SMA) AIH, andanti-liver kidney microsomal antibody 1 (LKM1) AIH.

In a study of 52 patients who had AIH, investigatorsfound that the median age at presentation of ANA/SMAAIH was 10.5 years and that for LKM1 AIH was 7.4years. (7) Some 75% of patients were female. Threepatterns of presentation were noted:

1) Acute hepatitis was the pattern in most patientshaving both types, with nausea, vomiting, anorexia, fa-tigue, and abdominal pain, followed by jaundice, darkurine, and pale stools. Duration of illness varied from2 weeks to 2 months in this group.

2) Another group (30%) had the insidious onset ofdisease of longer duration (6 mo to 2 yr), with relapsingjaundice, progressive fatigue, headache, anorexia, andweight loss.

Table 2. Differential Diagnosis ofCholestatic Jaundice in theOlder Child and AdolescentObstructive● 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



3) A small percent of patients, who had no priorhistory of jaundice, had complications of portal hyper-tension.

AIH is suspected on the basis of clinical characteristicsand demonstration of the autoantibodies, as well as anelevated immunoglobulin G value. Definitive diagnosis ismade on liver biopsy, where the typical histologic pictureis a dense mononuclear infiltrate invading the hepaticparenchyma (periportal hepatitis), with periportal necro-sis. In most cases, the disease responds well to immuno-suppressive therapy. Urgent liver transplantation is indi-cated if the patient presents in acute fulminant hepaticfailure.

Evaluation of the Jaundiced PatientAlthough jaundice is relatively common in the first2 weeks after birth and is observed frequently in new-borns, jaundice in the older infant and child always isabnormal and requires more investigation. Additionalevaluation of children who have conjugated hyperbiliru-

binemia and chronic liver disease should involve lookingfor the complications of cholestasis, such as coagulopathy,fat malabsorption, ascites, and encephalopathy, to initiateappropriate therapy. Finally, a child who has conjugatedhyperbilirubinemia or evidence of chronic liver diseaseshould be referred to a pediatric gastroenterologist.

HistoryThe age of the patient and history of presentation giveimportant clues to the cause of the jaundice. Someconditions of infantile cholestasis and conjugated hyper-bilirubinemia present early in life, such as biliary atresia,AGS, and inherited metabolic disorders. Others oftenmanifest beyond infancy, such as AIH and Wilson dis-ease. Diseases such as cystic fibrosis and alpha-1-antitrypsin deficiency can present as either neonatal cho-lestasis or later in life as chronic liver disease.

Signs such as poor feeding, irritability, and vomitingmay be associated with a metabolic condition, such asgalactosemia, or suggest encephalopathy. The presenceof acholic stools suggests an obstructive process such as

biliary atresia, choledochal cyst, or gallstone disease.Additionally, the birth and perinatal histories, past med-ical and surgical histories, family history (including con-sanguinity), medication and dietary histories, social ac-tivity and school performance histories, and travel historyshould be sought.

Physical ExaminationThe clinician should note if the patient is well- or ill-appearing as well as irritable or drowsy. Both signs mayindicate encephalopathy, infection, or metabolic de-rangement. Microcephaly in the infant may indicate con-genital infection. Recognition of dysmorphism is valu-able. Eyes should be examined for posterior embryotoxonor KF rings. The systolic murmur of peripheral pulmonicstenosis, usually heard in the back as well as the front,suggests AGS. Hepatomegaly typically is present, but asmall liver may indicate cirrhosis and end-stage liverdisease. Splenomegaly, ascites, and prominent vascula-ture such as caput medusa suggest portal hypertension

and chronic liver disease.An infant’s diaper shouldbe examined for palestools and dark urine.Neurologic evaluationshould be undertaken forataxia and asterixis.

Laboratory TestsThe key laboratory test to

obtain when evaluating jaundice is fractionation of thebilirubin. Indirect or unconjugated hyperbilirubinemiausually indicates excessive red blood cell destruction atany age. Direct or conjugated hyperbilirubinemia indi-cates a hepatobiliary disorder. Hepatic transaminase con-centrations are elevated in the presence of hepatocellularinjury. The alkaline phosphatase and gamma glutamyltransferase values often are increased with obstructiveconditions. Liver function, including prothrombin time,albumin, and cholesterol, should be measured. The remain-der of the evaluation should be tailored to the specificpatient. Hemolytic anemia can be seen in patients who haveWilson disease. Thyroid function tests can be obtained ifhypothyroidism is suspected. Other age-specific tests maybe considered, including TORCH (toxoplasmosis, rubella,cytomegalovirus, herpes simplex) titers, blood and urinecultures, alpha-1-antitrypsin Pi phenotype, iron profile,chloride sweat test, urine-reducing substances (galac-tosemia), and a metabolic screen in young infants. Testingfor Wilson disease (ceruloplasmin) or for AIH is appropriatein older children.

The key laboratory test to obtain whenevaluating jaundice is fractionation of thebilirubin.



ImagingReal-time ultrasonography is an important diagnostictool in the evaluation of the jaundiced patient. Theabsence of a gallbladder on a fasting examination in aninfant is suggestive but not diagnostic of biliary atresia.Ultrasonography may demonstrate gallstones, chole-dochal cyst, or ascites. A Doppler ultrasonographic studyof the portal circulation may identify portal hypertensionor portal vein thrombosis. Hepatobiliary scintigraphywith technetium-labeled iminodiacetic acid analogs mayhelp differentiate obstructive jaundice from nonobstruc-tive causes. In the case of obstructive jaundice, the he-patic uptake of tracer is normal, but there is no intestinalexcretion. In cases of severe hepatocellular disease, up-take into the liver is delayed, but tracer eventually isexcreted into the intestine. Premedication with pheno-barbital for 3 to 5 days prior to the study enhances biliaryexcretion and imaging of the isotope.

Liver BiopsyUltimately, many patients require a liver biopsy for de-finitive and reliable diagnosis. The liver biopsy can beperformed percutaneously, with or without ultrasono-graphic guidance, or surgically. In addition to evaluationby an experienced pathologist for specific histologic fea-tures, liver tissue can be used to quantify iron and coppercontent and for electron microscopy to detect certainmetabolic conditions.

Management of JaundiceTreatment is directed at the specific underlying disorder,although persistent cholestasis generally can cause reten-tion of bile acids, bilirubin, and cholesterol; decreasedexcretion of bile acids into the intestine with resulting fatmalabsorption; and hepatocellular damage that eventu-ally causes portal hypertension and end-stage liver dis-ease. Some general principles apply to the managementof these consequences independent of the specific cause.These principles include optimizing nutrition by em-ploying the use of medium-chain triglyceride-containingformula or supplements and monitoring fat-soluble vita-

min concentrations with supplementation. Managementof the complications of chronic liver disease and portalhypertension in conjunction with a pediatric gastroenterol-ogist is essential. All children, particularly those who havechronic liver disease, should be immunized, including bothhepatitis A and B, using the guidelines of the AmericanAcademy of Pediatrics. It is appropriate to refer any childwho evidences acute, severe liver disease or a chronic livercondition to a pediatric transplant center for evaluation.

References1. Balistreri WF, Grand R, Hoofhagle JH, et al. Biliary atresia:current concepts and research directions. Hepatology. 1996;23:1682–16922. Alagille D, Odievre M, Gautier M, et al. Hepatic ductularhypoplasia associated with characteristic facies, vertebral malforma-tions, retarded physical growth, mental and sexual development,and cardiac murmur. J Pediatr. 1975;86:63–713. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagillesyndrome in 92 patients: frequency and relation to prognosis.Hepatology. 1999;29:822–8294. Alagille D, Estrada A, Hadchouel M, et al. Syndromic paucity ofinterlobular bile ducts (Alagille syndrome or arteriohepatic dyspla-sia): review of 80 cases. J Pediatr. 1987;110:195–2005. Volpert D, Molleston JP, Perlmutter DH. Alpha-1-antitrypsindeficiency-associated liver disease progresses slowly in some chil-dren. J Pediatr Gastroenterol Nutr. 2000;31:258–2636. Carrell RW, Lomas DA. Alpha1-antitrypsin deficiency: a modelfor conformational diseases. N Engl J Med. 2002;346:45–537. Mieli-Vergani G, Vergani D. Immunological liver diseases inchildren. Semin Liver Dis. 1998;18:271–279

Suggested ReadingGitlin JD. Wilson disease. Gastroenterology. 2003;125:1868–1877McLin VA, Balistreri WF. Approach to neonatal cholestasis. In:

Walker WA, Goulet OJ, Kleinman RE, et al, eds. PediatricGastrointestinal Disease: Pathophysiology, Diagnosis, Manage-ment. 4th ed. Hamilton, Ontario, Canada: BC Decker Inc;2004:1079–1091

Moyer V, Freese DK, Whitington PF, et al. Guideline for theevaluation of cholestatic jaundice in infants: recommendationsof the North American Society for Pediatric Gastroenterology,Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2004;39:115–128



PIR QuizQuiz also available online at www.pedsinreview.org.

1. Conjugated hyperbilirubinemia is:

A. A marker of accelerated hemoglobin breakdown.B. A normal finding in otherwise healthy adolescents.C. Always linked with cholestasis.D. Less common than unconjugated hyperbilirubinemia.E. 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. A complete blood count.B. A reticulocyte count.C. Bilirubin fractionation.D. Gamma glutamyl transferase.E. 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 thehospital. Findings on the physical examination, other than jaundice, are unremarkable. Today, the totalbilirubin concentration is 13 mg/dL (222.3 mmol/L), with a direct fraction of 6 mg/dL (102.6 mmol/L). Ofthe following, the condition that is most likely ruled out by these findings is:

A. Alagille syndrome.B. Alpha-1-antitrypsin deficiency.C. Extrahepatic biliary atresia.D. Neonatal hepatitis.E. Physiologic jaundice.

4. A previously healthy 15-year-old girl develops jaundice and fatigue. She does not complain of colickyabdominal pain associated with meals. She has had no known exposure to hepatotoxins. Aside fromjaundice and appearing mildly ill, findings on her physical examination are unremarkable. Initial laboratoryevaluation 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 Cvirus. As suspected from the history, ultrasonography reveals a normal gallbladder and biliary tree. Serumceruloplasmin and autoantibody results are inconclusive. Pi typing reveals PiMM, and the patient proceedsto liver biopsy. Copper content of the sample is normal. Of the following, the patient is most likely to have:

A. Alpha-1-antitrypsin deficiency.B. Autoimmune hepatitis.C. Choledochal cyst.D. Gilbert syndrome.E. Wilson disease.

5. Wilson disease is diagnosed definitively through:

A. Genetic testing.B. Liver biopsy.C. Serum ceruloplasmin concentrations.D. Slitlamp examination.E. Urinary copper excretion.



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