ARTICLE Evaluation of Liver Disease in the Pediatric Patient Ian D. D’Agata, MD* and William F. Balistreri, MD† viruses, it is not the same entity as OBJECTIVES the viral hepatitis observed in older After completing this article, readers should be able to: children and adolescents. Under- standing that specific diseases are 1. List the age-specific causes of liver disease in neonates, infants, older more common, if not exclusive, to children, and adolescents. certain age groups is of great help in 2. Explain why fractionation of serum bilirubin is necessary in infants focusing the evaluation and defining who remain jaundiced after 2 weeks of age. the cause of underlying liver dis- 3. Characterize the syndrome of “neonatal hepatitis” and explain how it ease. It is important to remember differs from viral hepatitis. 4. Characterize biliary atresia and identify findings from the history, that despite the long list of disorders physical examination, and laboratory evaluation that may suggest this associated with liver disease in the diagnosis. neonate, most are encountered 5. Describe a quick, cost-effective diagnostic approach to a neonate who rarely. Further, although lists of the presents with cholestasis. various etiologies leading to pediat- ric liver disease are extremely lengthy, about 10 diseases constitute Introduction more successful in infants who approximately 95% of all cases of cholestasis seen, and of these, bili- Because clinicians often do not rec- weigh more than 10 kg at the time of surgery. ary atresia and neonatal hepatitis are ognize the presence of underlying responsible for more than 60%. liver disease, precise documentation Unfortunately, the timely recogni- tion of severe liver disease in the In general, the clinician initially of the disorder can be delayed, suspects liver disease in the neonate which can lead to a subsequent pediatric patient remains a major problem. One contributing factor is who presents with classic signs, delay in the initiation of effective such as persistent jaundice, hepato- therapies. Liver transplantation is a that injury to the pediatric liver manifests in a finite number of megaly, coagulopathy, or failure to reality for pediatric patients who thrive. At other times, incidental have severe or end-stage liver dis- ways; hence, different disorders often have virtually identical initial findings of abnormalities on serum ease, and other therapies also are chemistries may suggest the diagno- now available for treating many presentations. For example, neonates who have liver injury almost always sis. Jaundice, confusion, and coma liver diseases. occur in older children and adoles- The estimated incidence of neo- present with jaundice. Unfortunately, the difference between “physiologic cents who have acute hepatitis or natal liver disease is as high as 1 in following toxin exposure. Pruritus, 2,500 live births. Early recognition hyperbilirubinemia” and hyperbiliru- binemia indicative of severe liver seen in older children who have is particularly important in neonates cholestasis, may manifest as irrita- and infants because a delay in diag- disease often is unappreciated. Data from the United Kingdom have doc- bility in infants. No matter what the nosis may have a negative effect on presentation, a stepwise analysis of the prognosis. For example, it is umented several factors contributing to late referral of infants who have historical data, clinical findings, and well recognized that when biliary laboratory values allows initiation of atresia is diagnosed after 2 months liver disease (Table 1). This also is of age, the success rate of surgical a problem in the United States, where late referrals for biliary atre- repair (Kasai hepatoportoenteros- ABBREVIATIONS tomy) declines sharply. Furthermore, sia and other serious causes of liver because liver dysfunction is progres- dysfunction still occur. AIH: autoimmune hepatitis sive, early recognition allows for ALT: alanine aminotransferase better nutritional support of the AP: alkaline phosphatase patient and a potentially slower Etiology AST: aspartate aminotransferase decline in liver function. The result CT: computed tomography The causes of liver disease in pedi- GGT: gamma glutamyl can be improved growth and fewer atric patients vary with age (Table transpeptidase complications. This is of consider- 2). Some are associated with certain HAV: hepatitis A virus able importance because orthotopic age groups, such as biliary atresia HBV: hepatitis B virus liver transplantation generally is and idiopathic neonatal hepatitis, HCV: hepatitis C virus which are observed only at birth or HDV: hepatitis D virus shortly thereafter. Conversely, alco- HEV: hepatitis E virus *Pediatric Gastroenterology & Liver hol or acetaminophen intoxication Diseases, Valley Children’s Hospital, LFT: liver function test Madera, CA. and Wilson disease are typical of MRI: magnetic resonance imaging †Chief, Division of Gastroenterology & older children, especially adoles- PT: prothrombin time Nutrition, Children’s Hospital Medical cents. Furthermore, although “neo- PTT: partial thromboplastin time Center, Cincinnati, OH. natal hepatitis” may be caused by 376 Pediatrics in Review Vol. 20 No. 11 November 1999 GASTROENTEROLOGY Liver Disease ary atresia occurs more commonly tory of a flu-like illness and sud- TABLE 1. Reasons for a among females of normal weight, denly develops jaundice with ele- Delay in Referral of Infants and the rate of intrafamilial recur- vated aminotransferase values in the Who Have Liver Disease rence approaches zero. Also, an absence of other known hepatotoxic c associated polysplenia syndrome exposures. Hepatitis A is often anic- Lack of follow-up of neonatal favors a diagnosis of biliary atresia. teric in young children (,5y)and jaundice (including failure to Patients who have biliary atresia frequently is unrecognized. fractionate serum bilirubin) experience an earlier onset of jaun- Signs of liver disease in patients c Inadequate investigation of dice and of acholic stools compared who have received tattoos, who use hemorrhagic disease/ with those who have neonatal intravenous drugs, or in whom an coagulopathy hepatitis. underlying condition led to c Misdiagnosis of cholestasis Maternal fever or other signs of increased exposure to parenterally (conjugated hyperbilirubinemia) infection suggest sepsis as the administered blood products (hemo- as human milk jaundice underlying cause of jaundice in the dialysis, hemophilia, surgery) prior (unconjugated neonate. Gram-negative bacteria to widespread screening (1992) can hyperbilirubinemia) (eg, Escherichia coli) causing uri- suggest hepatitis C infection. Teen- nary tract infections are especially agers who become jaundiced always c False security due to a fall in common. should be questioned privately about serum bilirubin concentrations In cholestatic disease, jaundice intravenous drug abuse and exposure or presence of pigmented almost invariably is present in the to crack cocaine, the intranasal use stools first month of life. Unfortunately, of which recently has been shown to jaundice is not recognized in infants be associated with hepatitis C (shar- until the first health supervision ing of glass paraphernalia) and pos- the most appropriate and cost- visit, which leaves little time for sibly hepatitis B infection. If the effective strategy to diagnose and diagnosis and surgical correction of course of a documented hepatitis B treat the underlying condition. biliary atresia, which ideally should infection is particularly severe, coin- occur within the first 2 months of fection or superinfection with hepa- life. The Figure details a rapid step- titis D (delta) should be suspected. History and Signs of Liver wise approach to rule out biliary Male homosexuals are at an Disease atresia in an infant presenting with increased risk to develop viral cholestasis before 2 months of age. hepatitis. NEONATE Acholic stools also are highly It always is important to elicit a Although an infant may have been characteristic of cholestasis in history of exposure to potentially jaundiced at birth (physiologic infancy. In the presence of extra- or hepatotoxic medications, including hyperbilirubinemia) or may be intrahepatic obstruction, little or no isoniazid, nitrofurantoin, sulfon- breastfeeding, it is important not to bilirubin is excreted into the intes- amides, and nonsteroidal anti- attribute jaundice in an infant older tine, resulting in no color to the neo- inflammatory agents, such as acet- than 14 days to one of these causes. formed fecal material. Although aminophen and ibuprofen. If an Jaundice in any infant after 2 weeks some pigment may be present in the overdose or an intoxication is the of age should raise the suspicion of stools of neonates who have biliary cause of liver dysfunction, children liver disease and prompt appropriate obstruction because of desquamation can present with altered mental sta- evaluation. A careful history may of cells containing pigment into the tus and even coma. Confusion and provide clues about the existence stool, these stools usually are much coma suggest liver failure or meta- and type of liver disease. For exam- lighter than those found in healthy bolic disease leading to hyperam- ple, the onset of liver disease associ- infants. Furthermore, breaking the monemia, hypoglycemia, or a com- ated with dietary changes may sug- stool into pieces will show that the bination of both. Female teenagers gest an inborn error of carbohydrate pigment is only superficial,