Neonatal liver disease may occur in as many as 1 in 2,500 newborn infants.1,2 The majority of children who eventually develop chronic or life-threatening liver disease first present in the neonatal period.3 Early recognition by the pediatrician of cholestatic jaundice in infants is important for timely diagnosis, successful treatment, and favorable prognosis in infants.
It is critical to differentiate the source of the neonatal liver disease as early as possible, given that strategies for the treatment of infectious or metabolic liver disease and for the surgical correction of biliary abnormalities require early diagnosis. Even in cases where the diagnosed liver disease itself does not have a specific effective treatment, the infants will benefit from medical management of the complications of their liver disease.
This article reviews an approach to the infant with liver disease. We begin by describing the general incidence of the most common causes of infantile liver disease, then defining cholestasis, the predominant pathological process found in these conditions. The unique susceptibility of the immature liver to this process also is explained, and the differential diagnosis and recommended diagnostic evaluation of neonatal liver disease is presented.
Among infants presenting with biochemical or clinical evidence of liver disease, historically the most common diagnosis has been idiopathic neonatal hepatitis, accounting for 30% to 40% of cases.1,4 This condition represents a diagnosis made in the presence of typical histological changes of giant-cell transformation in the absence of evidence of the other common causes of neonatal cholestasis (Sidebar, see page 283). Idiopathic neonatal hepatitis has an incidence between 1 in 4,800 and 1 in 9,000 Uve births.1 It is presumed to be a process caused by an unidentified infectious agent, and the treatment is supportive.
Biliary atresia, a destructive, idiopathic, inflammatory process that leads to fibrosis and obliteration of the biliary tree, is the second most common diagnosis in infants with liver disease, with an incidence that ranges between 1 in 8,000 and 1 in 21,000 live births.4"6 Treatment for this condition is urgent and requires surgical intervention to re-establish bile flow.
Alpha- 1 -antitrypsin deficiency, an autosomal recessive disorder caused by a misfolded protein that cannot traverse the secretory pathway, is the third most common cause of neonatal liver disease, with an incidence of 1 in 1,600 to 1 in 2,000 live births.7 Patients with alpha- 1 -antitrypsin deficiency require supportive care and monitoring for progressive liver disease.
Our best understanding of the distribution of the specific diagnoses in neonatal liver disease comes from reports of consecutive referrals to tertiary care centers serving large populations over decades. A series from Australia reported that of 171 affected infants, 40% had idiopathic neonatal hepatitis and 32% had biliary atresia.1 In a series from England, the distribution of diagnoses in 1,086 infants was biliary atresia 34.7%, idiopathic neonatal hepatitis 30.7%, alpha- 1 -antitrypsin deficiency 17.4%, other hepatitis 8.7%, Alagille syndrome 5.6%, and choledochal cyst 3.1%.5 Newer and more sophisticated diagnostic testing, including genetic testing for the identification of rare congenital disorders (ie, alpha- 1 -antitrypsin deficiency, mitochondrial abnormalities, Alagille syndrome, progressive familial intrahepatic cholestasis) and molecular biological testing for enzymatic defects (ie, in bile acid synthesis and fatty acid oxidation), have led to a marked decrease in the number of infants who are labeled with the nonspecific disorder of idiopathic neonatal hepatitis.
Cholestasis is a principal manifestation of hepatobiliary disease in most age groups. Cholestasis is defined as a pathologic state of reduced bile formation or flow. The clinical definition of cholestasis, therefore, is any condition in which there is retention of substances normally excreted into bile (eg, bilirubin, bile acids, cholesterol). The serum concentrations of conjugated bilirubin and bile salts are measured commonly. The histopathologic definition of cholestasis is the appearance of bile within the elements of the liver, usually associated with secondary cell injury. Most cholestatic conditions can be classified as either obstructive or hepatocellular in origin.
Obstructive cholestasis results from an anatomic or functional obstruction of the biliary system. This can be at the level of the large or extrahepatic bile ducts (ie, cholelithiasis) or smaller intrahepatic ducts (ie, bile duct paucity associated with Alagille syndrome). The principal causes of obstructive cholestasis in children are presented in the Sidebar. Of these, biliary atresia accounts for more than 90% of cases.
The distinguishing histopathologic feature of large-duct obstruction is the presence of bile plugs in interlobular bile ducts. Intrahepatic obstructive cholestasis requires the obstruction or obliteration of enough smaller bile ducts to alter bile flow. Diseases that are associated with ductal paucity express variable degrees of cholestasis, depending on the degree of paucity.
Hepatocellular cholestasis results from impairment of mechanisms of bile formation and implies defective function of most or all hepatocytes. A global defect must be in effect to produce cholestasis. Regardless of the nature of the primary defect, cholestasis, once established, may be amplified by several mechanisms. The typical histopathologic features of hepatocellular cholestasis include the presence of bile within hepatocytes and bile plugs in canalicular spaces. Histological evidence of secondary hepatocellular injury often is severe. In most clinical forms of hepatocellular cholestasis, the molecular mechanism is unknown.
The principal causes of hepatocellular cholestasis in children are listed in the Sidebar. Idiopathic neonatal giant cell hepatitis accounts for the majority of cases, but as noted above, the past decade has brought an improved understanding of the causes of hepatocellular cholestasis in children and a reduction in the percentage of idiopathic cases.
Susceptibility of the Neonatal Liver to Cholestasis
The neonate develops cholestasis in response to a wide variety of insults, both hepatic and systemic, that would not produce cholestasis in adults. Studies of the development of bile formation have shown considerable differences between the mature and immature liver with regard to bile formation, which probably help to establish the infant's sensitivity to a variety of insults, such as gram-negative sepsis, heart failure, metabolic disease, and exposure to minimally toxic substances.8 As a result, the differential diagnosis of cholestasis in the neonate and infant is much broader than in the older child or adult, and it is wise to look beyond the liver for the cause. If no other cause is found and liver disease is suspected, a more focused diagnostic investigation can be undertaken.
The physiologic development of normal hepatic function is characterized by rapid maturation of most processes at the end of gestation.9 However, many other processes are developmentally regulated, and there remains a "physiologic immaturity" for several months after birth. Some of these processes include the transportation and synthesis of bile acids and the metabolism of drugs and toxins.
The knowledge regarding the development of bile formation is based on animal and, when possible, human studies. The enterohepatic circulation in newborn animals of various species is characterized by decreased bile salt secretion,10 decreased bile flow, decreased bile acid synthesis, a smaller bile acid pool size, decreased hepatic uptake of portal bile salts, and inefficient ileal uptake of bile salts.11 All of these factors lead to circulating serum bile salt concentrations equal to those of adults with clinical cholestasis; this condition in infants has been termed physiologic cholestasis.
In addition, there is evidence of different patterns of perinatal hepatic enzymatic activity, which can affect the infant's capacity for normal metabolic processes such as oxidation, reduction, hydrolysis, and conjugation, as well as its ability to metabolize, detoxify, and excrete xenobiotics (foreign particles that may be dangerous or toxic). Some of these differences may have relevance to understanding the susceptibility of infants to liver disease.
Jaundice, presenting with yellow discoloration of the skin or sclerae, is the most common early symptom of neonatal liver disease.12 Jaundice can be present at a serum bilirubin concentration as low as 5.0 mg/dL and often is associated with pale stool and dark urine. In term infants, jaundice is relatively common at age 2 weeks, occurring in 2.4% to 15% of newborns.13"15 However, the possibility of liver disease should be considered in any infant jaundiced beyond age 2 weeks.16'17
The differentiation of cholestatic jaundice from the prolonged jaundice associated with breastfeeding or physiologic hyperbilirubinemia of the neonate is critical and requires fractionation of the bilirubin to determine if conjugated hyperbilirubinemia exists. Most laboratories provide total and direct bilirubin levels instead of total and conjugated fractions. An abnormal direct bilirubin has been designated as greater than 1.0 mg/dL if the total bilirubin is less than 5mg/dL or a value of direct bilirubin that represents more than 20% of the total bilirubin if the total bilirubin is greater than 5 mg/dL.17 These values are considered to represent conjugated hyperbilirubinemia that is pathological, indicates cholestasis, and requires evaluation. In the presence of conjugated hyperbilirubinemia, the most important initial goal of the evaluating physician is to exclude potentially life-threatening disorders such as bacterial infection, endocrine disorders, and metabolic disorders such as galactosemia. Infants presenting with these conditions often appear acutely ill.
On the other hand, the typical infant with the most common form of biliary obstruction, biliary atresia, is thriving, appears well, and has only very mud jaundice during the first 6 to 8 weeks of life. The benign appearance of these infants often reassures the parent or pediatrician into believing that the jaundice is nonsignificant when, in fact, biliary atresia exists. Patients with biliary obstruction frequently develop acholic stools and dark yellow urine. The stools may be intermittently pigmented early on and only become permanently without pigment after 4 to 6 weeks. Significant evidence suggests that earlier diagnosis and surgical repair with a Kasai portoenterostomy lead to a better outcome for this condition.18 The Kasai procedure is associated with greatest likelihood of re-establishment of bile flow and longest survival of the infant's native liver when performed before the age of 45 to 60 days.18"20 This evidence makes early evaluation of neonatal cholestasis imperative.
Some descriptive trends may be helpful to weigh into the differential diagnosis when evaluating infants with liver disease. For example idiopathic neonatal hepatitis occurs more commonly in males, especially premature or low birth-weight babies, and there is a familial incidence of 10% to 15%, while biliary atresia is more common in females of normal birth weight and rarely has a familial association.1,21 Other nonhepatic clinical hints can be useful in helping to determine the etiology of the cholestasis in infants. Infants who have low birth weight, microcephaly, thrombocytopenia, and chorioretinitis may have congenital infections. Unusual or dysmorphic facies may suggest an association with a chromosomal abnormalitiy or syndromic bile duct paucity.22
Other congenital malformations, such as intestinal malrotation, situs abnormalities, cardiac defects, or polysplenia, may be clues to the presence of the syndromic component of biliary atresia, which occurs in one-third of cases. Vomiting, poor feeding, lethargy, and irritability can be signs of an underlying metabolic disorder such as galactosemia or tyrosinemia. Profound coagulopathy at birth or a few days after birth may suggest metabolic liver disease or neonatal iron storage disease. A palpable mass in the right upper quadrant may suggest a choledochal cyst.
One of the major clinical effects of cholestasis, particularly chronic cholestasis, is failure to thrive. The mechanisms of failure to thrive include malabsorption, anorexia, poor nutrient use, hormonal disturbances, and secondary tissue injury. Malabsorption in cholestatic liver disease results from reduced delivery of bile salts to the intestine, which results in inefficient digestion and absorption of fats. Malabsorption of fat results in the loss of a source of calories that is important in infant nutrition. The malabsorption of fat-soluble vitamins can result in vitamin deficiency states. In chronic cholestasis, careful attention must be given to prevent deficiences of fat-soluble vitamins. This is accomplished by administering fat-soluble vitamins and monitoring the response to therapy.
DIFFERENTIAL DIAGNOSIS AND EVALUATION
The differential diagnosis of hepatobiliary disease resulting in neonatal cholestasis is rather limited. Long lists of disorders that potentially produce cholestasis exist; however, fewer than 15 disorders account for greater than 95% of neonatal cholestasis. The limited differential of neonatal cholestasis is presented in the Sidebar. In assessing neonatal liver disease, the first diagnostic concern should be the differentiation of hepatocellular from obstructive cholestasis, because this represents the differential between psysiologic and anatomic disorders and between medical and surgical disease. All disorders that deserve surgical intervention in the first few months of life are obstructive disorders, and their timely identification can improve outcome.
An organized, consistent approach to the recognition and evaluation of an infant with cholestasis is important for the general pediatrician. Pediatricians are the primary providers to infants between ages 2 weeks and 8 weeks and must have a clear understanding of the proper initial evaluation and point for referral to a pediatric gastroenterologist. The recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Committee on the Evaluation of the Cholestatic Infant (Figure, see page 284) are a useful guide for pediatricians and are endorsed by the American Academy of Pediatrics.17 The committee developed this algorithm based on a comprehensive and systematic review of the medical literature, integrated with expert opinion.
The initial recommendation of the committee is that any infant noted to be jaundiced at age 2 weeks should be evaluated for cholestasis with measurement of total and direct serum bilirubin. "However, breast-fed infants who can be reliably monitored and who have an otherwise normal history (no dark urine or light stools) and physical examination may be asked to return at 3 weeks of age and, if jaundice persists, have measurement of total and direct serum bilirubin at that time."17
For infants with only unconjugated hyperbilirubinemia, practioners can refer to previously published guidelines on management of unconjugated hyperbilirubinemia from the American Academy of Pediatrics.23 If the conjugated or direct bilirubin is elevated in an infant older than 2 weeks, then cholestasis is present. One important goal of management is to exclude biliary atresia by age 45 to 60 days.
In an ill-appearing infant, the primary cause of the acute problem is investigated first, and if the cholestasis does not resolve with resolution of the primary problem (ie, bacterial infection, hypothyroidism or metabolic disorder), then further evaluation and referral to a pediatric gastroenterologist is necessary. The subsequent testing should include testing for viral infections and alpha- !-antitrypsin deficiency and ultrasonography of the liver to identify anatomic abnormalities such as a choledochal cyst.
The ultrasound evaluation of an infant with cholestasis is performed most appropriately at the referral center by the most experienced personnel due to the operator dependency of the study. Ultimately, percutaneous liver biopsy has the greatest accuracy for diagnosing the etiology of neonatal liver disease in published articles and is inevitable in most cases to complete an evaluation or confirm a suspected diagnosis.24"26 The liver biopsy is performed by a pediatric gastroenterologist after the initial workup shown in Figure 1 is completed.
Hepatobiliary scintigraphy scans, the injection of radioactive material that normally is excreted into the intestine within a predictable period of time, has been used historically to evaluate for biliary obstruction in infants. The Cholestasis Guideline Committee reviewed the sensitivity and specificity of this testing and concluded that although the sensitivity of this test for detecting biliary atresia is high, the specificity is low, in that many patients without anatomic obstruction do not excrete the tracer.17 Therefore, scintigraphy generally adds little to the evaluation of a cholestatic infant who would undergo a liver biopsy anyway as the gold standard in establishing a specific diagnosis.17'27
Once the diagnosis is established, the patient is either referred to a surgeon for the necessary surgical intervention, such as a Kasai procedure or resection of a choledochal cyst, or is monitored and supported by a pediatric gastroenterologist for their medical disease.
Establishing a rapid and accurate diagnosis of the cause of neonatal liver disease is an urgent matter. The initial detection of this condition relies on the sensitivity of the primary care provider or pediatrician to the signs and symptoms of jaundice and abnormal stool and urine color. It is critical to evaluate jaundice in any infant older than 2 weeks with measurement of fractionated bilirubin, and further assessment is necessary if the direct value is above 1.0 mg/dL in the setting of a total bilirubin of less than 5.0 mg/dL or a direct bilirubin of more than 20% of total if the total is more than 5.0 mg/dL. A diagnostic algorithm for the evaluation of infants who meet these criteria can guide physicians in selecting appropriate and timely diagnostic testing and referral to pediatric gastroenterology for these patients, whose outcome will rely on rapid diagnosis.
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