99: Hyperbilirubinemia, Direct (Conjugated Hyperbilirubinemia)

Jaundice is the most common transitional finding in the newborn period, occurring in 60–70% of term and ∼80% of preterm infants. An elevation of serum bilirubin concentration >2 mg/dL is found in virtually all newborns in the first several days of life. Jaundice becomes clinically apparent at serum bilirubin concentration of ≥5 mg/dL.

Bilirubin is the end product of the catabolism of heme derived primarily from the breakdown of red blood cell hemoglobin. The rate-limiting step in this production is the oxidation of heme to form a green pigment called biliverdin, a process controlled by the enzyme heme oxygenase. Each molecule of heme catabolized results in equimolar quantities of bilirubin and carbon monoxide. Other sources of heme include heme-containing proteins such as myoglobin, cytochromes, and nitric oxide synthase. Bilirubin exists in several forms in the blood but is predominantly bound to serum albumin; other compounds, such as drugs and metal ions, may compete with bilirubin for albumin binding sites. Elevated concentration of free unconjugated bilirubin can enter the central nervous system (CNS) and become toxic to neurons. The precise mechanism of toxicity is unknown.

Inside liver cells, unconjugated bilirubin is bound immediately to intracellular proteins, the most important one being ligandin. It is then converted into an excretable and soluble form through the process of conjugation that consists of the transfer of 1 or 2 glucuronic acid residues from uridine diphosphoglucuronic acid (UDPGA) to form a monoglucuronide or diglucuronide conjugate. Uridine diphosphoglucuronyl transferase (UDPGT) is the major enzyme involved in this process. Conjugation is impaired in newborns due to reduced UDPGT activity and a relatively low level of uridine diphosphoglucuronic acid. Conjugated bilirubin is water soluble and can be excreted in the urine, but most of it is rapidly excreted as bile into the intestine. Conjugated bilirubin is further metabolized by bacteria in the intestine and excreted in the feces.

Hyperbilirubinemia presents as either unconjugated hyperbilirubinemia or conjugated hyperbilirubinemia. The 2 forms involve different pathophysiologic causes with distinct potential complications. In contrast to unconjugated hyperbilirubinemia, which can be transient and physiologic in the newborn period, conjugated hyperbilirubinemia is always pathologic. See Chapter 100 for a discussion of unconjugated hyperbilirubinemia.

Conjugated hyperbilirubinemia is defined as a measure of direct reacting bilirubin of >1.0 mg/dL, if the total serum bilirubin (TSB) is ≤5.0 mg/dL, or more than 20% TSB. It is the biochemical marker of cholestasis and a sign of hepatobiliary dysfunction. Unlike physiologic unconjugated hyperbilirubinemia, typically known as “physiologic jaundice of the newborn,” it is important to emphasize that there is no physiologic conjugated hyperbilirubinemia. Chapter 57 provides information for rapid “on-call” assessment and management.

Conjugated hyperbilirubinemia affects ∼1 in every 2500 infants and is much less common than unconjugated hyperbilirubinemia.

Normal bile production involves 2 main processes: bile acid uptake by the hepatocytes from the blood, and bile excretion into the biliary canaliculus. Bile uptake from the blood is an active process facilitated by 2 main receptors at the basolateral membranes, while bile secretion at the canalicular membrane is mediated largely by the bile salt export pump. In healthy newborns, the cellular processes that regulate bile flow are immature and do not function at the normal adult level, making them more susceptible to cholestasis.

Well-known risk factors include congenital infections, sepsis, neonatal hepatitis, ABO incompatibility, trisomy 21, and the use of total parenteral nutrition (TPN).

Prolonged clinical jaundice is the main presenting complaint of conjugated hyperbilirubinemia, along with pale (acholic) stools and dark urine. The Cholestasis Guideline Committee recommends that any infant noted to be jaundiced at 2 weeks of age be evaluated for cholestasis. Breast-fed infants who have a normal history and physical examination and can reliably be monitored should be evaluated for cholestasis at 3 weeks of age, if jaundice is persistent. No single screening test can predict which infant will develop cholestasis.

The differential diagnosis of cholestasis is extensive. It can be classified based on the anatomic location of the pathologic process (extrahepatic vs intrahepatic causes), or it can be categorized into broad etiologic causes, such as infectious, familial, metabolic, toxic, chromosomal, vascular, and bile duct anomalies. Recent understanding in molecular genetics has pointed to new directions of investigations that resulted in identification of the molecular mechanisms of a subset of hepatobiliary diseases that often can lead to ongoing liver dysfunction. The most common differential diagnoses of neonatal cholestasis are listed in Table 99–1.

1. Specific diseases

   1. Biliary atresia. The most common cause of cholestasis in term infants, it remains the single most common reason for liver transplantation in children. It is a progressive idiopathic inflammatory process that leads to chronic cholestasis and fibrosis of both the intrahepatic and extrahepatic bile ducts and subsequent biliary cirrhosis. It has a worldwide estimated incidence of 1 in 15,000 live births, with the highest incidence in Taiwan and French Polynesia (1 in 3000 live births). There are 2 distinct phenotypes identified: the embryonic or fetal form is less common, associated with an earlier onset of cholestasis and multiple congenital anomalies, and the perinatal or acquired form, occurring in 80% of cases, without associated congenital anomalies. In the perinatal or acquired form, infants are presumed to have a normal and patent biliary system at birth that subsequently undergoes progressive inflammation and fibro-obliteration due to a perinatal insult. It is critical to confirm or exclude the diagnosis of biliary atresia as the cause of conjugated hyperbilirubinemia by 45–60 days of age. Evidence suggests that early surgical intervention leads to a better outcome and prognosis.

   2. Genetic intrahepatic cholestasis. There are multiple forms of genetic intrahepatic cholestasis, each with different clinical features and variable clinical presentation and prognosis. Some progressive familial forms (formerly called progressive familial intrahepatic cholestasis [PFIC]) are potentially fatal; the syndromic paucity of intrahepatic bile ducts (Alagille syndrome) tends to have a more favorable prognosis. The pathogenetic mechanisms of this group of disorders have been defined only partially, and the techniques of molecular genetics have only been recently applied. These disorders, although individually rare, are collectively common.

      1. Alagille syndrome. A syndromic condition thought to be due to altered embryogenesis; it is also known as arteriohepatic dysplasia. It is a genetic disorder, transmitted as autosomal dominant inheritance with variable expression. Mutations in JAG1 (protein associated with Alagille syndrome) on chromosome 20p have been identified. Its major clinical features include a paucity of the intrahepatic bile ducts (chronic cholestasis), cardiovascular anomalies (peripheral pulmonic stenosis), skeletal abnormalities (butterfly vertebrae), ophthalmologic findings (posterior embryotoxon), and “typical facies” (facial shape of an inverted triangle, with broad forehead, deep-set eyes, mild hypertelorism, straight nose with flattened tip, prominent chin, and small, low-set, malformed ears). Although it may not be present in 20–40% of young infants, the abnormality of bile ducts is considered to be the most consistent finding in Alagille syndrome; repeat liver biopsies may be needed in patients with a clinically suspected diagnosis but not confirmed on initial histologic diagnosis. Long-term prognosis depends on severity and duration of cholestasis, severity of cardiovascular defect, and liver status as it relates to need for liver transplantation.

      2. Progressive familial intrahepatic cholestasis (PFIC). A group of genetic disorders, with autosomal recessive inheritance and characterized by progressive intrahepatic cholestasis. The predominant mechanism for the intrahepatic cholestasis is altered canalicular transport. Currently, 3 types of PFIC are recognized:

         1. PFIC-1. Originally called Byler disease. It presents with conjugated hyperbilirubinemia early in life, typically within the first 3 months. Diarrhea, pancreatitis, and deficiency of fat-soluble vitamins are seen. Cirrhosis is seen by the first decade of life, and liver transplantation is usually needed by the second decade of life.

         2. PFIC-2. Caused by bile salt export pump (BSEP) deficiency, resulting in altered bile acid transport. It has a presentation similar to PFIC-1 with no evidence of pancreatitis. Serum g-glutamyl transpeptidase (γ-GTP) is not elevated despite cholestasis.

         3. PFIC-3. Due to multidrug resistance protein 3 (MDR3) deficiency, resulting in altered phospholipid transport into the canaliculus. It is clinically similar to PFIC-1 and PFIC-2, except that PFIC-3 has an elevated level of γ-GTP.

   3. Inborn errors of metabolism. (See Chapter 101.) In the neonatal period, several inborn metabolic disorders can result in hepatocellular injury that can give rise to a clinical syndrome of neonatal hepatitis. The most common metabolic disease that presents as cholestasis is α₁-antitrypsin deficiency. Metabolic diseases that can present with rather fulminant liver dysfunction include galactosemia, tyrosinemia, and hereditary fructose intolerance. Hereditary fructose intolerance does not present in the neonatal period unless the infant was exposed to a fructose-containing diet.

      1. Galactosemia. An autosomal recessive disorder of galactose metabolism that is caused by deficiencies in one of 3 enzymes involved in the metabolism of galactose: galactose-1-phosphate uridyltransferase (GALT), galactokinase (GALK), and uridine diphosphate galactose-4-epimerase (GALE).

         Classic galactosemia is the most common and most severe and is caused by deficiency of the galactose-1-phosphate uridyltransferase (GALT) enzyme. It affects ∼1 in 10,000 to 1 in 30,000 live births. Deficiency of the GALT enzyme results in accumulation of galactose-1-phosphate and other metabolites that are thought to be toxic to the liver and other organ systems. The gold standard of diagnosis is measurement of GALT activity in the erythrocytes. Clinical presentation is variable and nonspecific in the neonatal period (occurs after ingestion of galactose-containing formula) and includes vomiting, loose stools, prolonged jaundice, irritability, and poor weight gain. Continued ingestion of galactose results in multiorgan toxicity with hepatomegaly, worsening liver dysfunction, splenomegaly, renal dysfunction, and CNS involvement. These infants, while on lactose-containing formula, have galactose in the urine, resulting in a positive reducing substance in the urine (Clinitest reagent tablets) but negative urine dipstick test for glucose (glucose oxidase). A cataract may be detected on examination. “Oil-drop” cataracts are highly typical of galactosemia and may resolve with treatment if diagnosed early. Neonatal sepsis due to Escherichia coli and other gram-negative organisms is more frequent in galactosemic infants. The reason for this unique predisposition remains unclear. Treatment for galactosemia consists of immediate removal of galactose in the diet as soon as diagnosis is suspected. Liver disease usually improves, but long-term neurodevelopmental complications may develop later despite good dietary control.

         Galactokinase deficiency (GALK) results in accumulation of galactose, galactitol, and galactonate and leads to early onset of juvenile bilateral cataract. Although uncommon, pseudotumor cerebri, mental retardation, hepatosplenomegaly, hypoglycemia, and seizures have been described in GALK-deficient patients.

         The rarest and most poorly understood among the 3 types is epimerase deficiency (GALE). Natural history of epimerase-deficiency galactosemia is limited due to the small number of patients reported to date. When a diet containing lactose is not removed immediately, infants typically present with generalized hypotonia, poor feeding, vomiting, weight loss, progressive cholestatic jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose from their diet resolves or prevents acute symptoms.

      2. Tyrosinemia. Biochemical basis for this disorder is a defect in tyrosine metabolism due to lack of fumarylacetoacetate hydrolase. It is inherited as an autosomal recessive disorder that clinically presents with hepatocellular damage, renal tubular dysfunction, and neuropathy. One characteristic pattern of tyrosinemia is a very high α-fetoprotein. For those patients who survived infancy, they are at high risk of developing hepatocellular carcinoma.

      3. Zellweger or cerebrohepatorenal syndrome. This is a peroxisomal disorder characterized by the absence of peroxisomes and deranged mitochondria. It is inherited as an autosomal recessive trait and presents in the neonatal period with cholestasis, hepatomegaly, profound hypotonia, and dysmorphic features. Diagnosis is confirmed by the presence of abnormal levels of very-long-chain fatty acid in the serum. Most infants die within 1 year. Survivors beyond 1 year of age have severe mental retardation and seizures.

      4. α1-Antitrypsin deficiency. The most common inherited cause of neonatal hepatitis syndrome, with an incidence of 1 in 1600 to 1 in 2000 live births in North American and European populations, α₁-antitrypsin is the most abundant proteinase inhibitor, and it acts by inhibiting destructive proteases. Clinical diagnosis is made by documenting low serum concentration of α₁-antitrypsin and identifying the phenotypic variant based on differences in isoelectric point (Pi), with M being normal and Z being most deficient. There are several phenotypes; however, the homozygous Pi (protease inhibitor) ZZ is the most likely associated with neonatal liver disease and adult emphysema. Despite carrying the same mutation, only 10–15% of newborns present clinically. Treatment is mostly supportive or liver transplantation if cirrhosis is progressive. Outcome is related to severity of neonatal liver disease; 50% of children are clinically normal by 10 years of age, 5–10% require liver transplantation, and in 20–30% of patients, cholestasis resolves with residual evidence of cirrhosis that may eventually require liver transplantation.

      5. Mitochondrial hepatopathies. Usually presents as metabolic crises with associated multiorgan dysfunction. However, mitochondrial disorders can be organ specific with subtle clinical findings to frank liver failure with or without signs of other organ involvement. Infant presenting with features suggestive of liver dysfunction, such as lactic acidosis, hypoglycemia, cholestasis, and coagulopathy should be worked up for mitochondrial hepatopathies. A muscle tissue biopsy or direct enzyme assay of cultured skin fibroblasts may not reveal a diagnosis, especially if the dysfunction is primarily in the liver; 80–95% of patients with clinically suspected mitochondrial disease do not have a detectable pathogenic DNA mutation. Treatment is mainly supportive, and in some cases liver transplantation is necessary.

   4. Idiopathic neonatal hepatitis. A diagnosis given to neonatal hepatitis with liver histology showing giant cell multinucleated hepatocytes where no known infectious or metabolic cause has been found. Diagnosis is one of exclusion. Management is mostly supportive. Overall prognosis is difficult to estimate but generally good for infants whose liver disease resolves in the first year.

   5. Infection

      1. Congenital infections. (TORCH [toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex virus]) Congenitally acquired infections have a spectrum of manifestations but are usually asymptomatic. They share clinical similarities such as hepatosplenomegaly, jaundice, petechial rash, and intrauterine growth restriction. Liver dysfunction is a possible presentation with any of these viral agents, but it is most common with herpes simplex infection. Vertical transmission of hepatitis viruses (B and C) is generally asymptomatic, but clinical hepatitis, including hepatic failure, may develop later.

      2. Bacterial infections. Inflammation-induced cholestasis has been linked predominantly with gram-negative infections (particularly E. coli), although gram-positive infections can also lead to cholestasis. Recent studies point to lipopolysaccharide (LPS) or endotoxin and the subsequent release of cytokines during infections as the major factors in sepsis-associated cholestasis. Disproportionate elevation of serum bilirubin in comparison with serum transaminases should prompt a search for an underlying infection. Infection should be part of the differential diagnosis of new-onset or worsening jaundice in an infant. Urinary tract infection in particular has been reported to be associated with persistent hyperbilirubinemia (both indirect and direct).

   6. Total parenteral nutrition (TPN)-related cholestasis. The frequency, not necessarily the severity, of cholestasis is partly a function of the degree of prematurity. Cholestasis develops in >50% of infants with birthweight of <1000 g and <10% of term infants after prolonged hyperalimentation. Of infants who require long-term TPN for intestinal failure, 40–60% develop TPN-related liver disease. Pathogenesis is unknown but thought to be multifactorial and directly related to prematurity, low birthweight, episodes of sepsis, and duration of TPN use. One of the most important contributing factors is lack of enteral feeding leading to decreased gut hormone secretion, reduction of bile flow, and biliary stasis. Even small oral feedings (continuous or bolus) during hyperalimentation may prevent TPN-related liver disease. The resumption of normal enteral feeds is associated with improvement of cholestasis in 1–3 months, with minimal or no residual fibrosis and normal hepatic function. Hepatic complications are potentially reversible if TPN is discontinued before significant liver damage has ensued. A single component of parenteral nutrition (PN) solution has not been definitely identified as the cause of cholestasis; however, more recent evidence suggests that soy bean lipid emulsion (predominantly omega-6 polyunsaturated fatty acids [PUFAs]) contributes to hepatotoxicity. Studies have demonstrated the benefit of fish oil lipid emulsions (predominantly omega-3 fatty acids [FAs]) in reversing cholestasis and hepatic injury in patients with intestinal failure–associated liver disease.

   7. Inspissated bile. The “inspissated bile syndrome” is the term traditionally used for conjugated hyperbilirubinemia resulting from severe jaundice associated with hemolysis due to Rh or ABO incompatibility, although a multifactorial cause cannot be entirely excluded. Intrahepatic cholestasis is found on liver biopsy, and cholestasis is probably related to direct hepatocellular damage produced by unconjugated hyperbilirubinemia. Prognosis is generally good.

Evaluation of cholestasis can be extensive; therefore, it should be individualized to establish a diagnosis efficiently and promptly. Figure 57–1 provides a concise algorithm for an infant with conjugated hyperbilirubinemia.

1. Laboratory studies

   1. Bilirubin levels (total and direct). The most important initial investigation in a persistently jaundiced infant is determining the fractionated serum bilirubin levels. Presence of direct reacting bilirubin of >1.0 mg/dL, if TSB is ≤5.0 mg/dL, or more than 20% of TSB is consistent with conjugated hyperbilirubinemia.

   2. Liver enzymes. Serum transaminases (alanine transaminase [ALT] and aspartate transaminase [AST]) are sensitive indicators of hepatocellular inflammation but are neither specific nor of any prognostic value. They may be helpful in monitoring the course of the disease. Alkaline phosphatase is nonspecific because it is found in the liver, kidney, and bone.

   3. Prothrombin time and partial thromboplastin time. May be more reliable indicators of liver synthetic function.

   4. γ-Glutamyl transpeptidase (GGT). An enzyme in the biliary epithelium. Elevated levels are a very sensitive marker of biliary obstruction or inflammation. A normal level makes biliary atresia an unlikely diagnosis. Normal levels of GGT in the presence of cholestasis indicate failure of bile excretion at the canalicular level and can be seen in progressive familial hepatic cholestasis.

   5. Complete blood count (CBC), C-reactive protein, blood and urine cultures. Should be considered to screen for any clinical evidence of infection.

   6. Serum cholesterol, triglycerides, and albumin levels. Triglyceride and cholesterol levels may aid in nutritional management and assessment of liver failure. Albumin is a long-term indicator of hepatic function.

   7. Ammonia levels. Should be checked if liver failure is suspected.

   8. Serum glucose levels. Should be checked if the infant appears ill. Metabolic disorders may present with hypoglycemia along with conjugated hyperbilirubinemia.

   9. Urine testing for reducing substances. A simple screening test that should always be performed to screen for metabolic disease, especially for galactosemia. Galactose in the urine results in a positive reducing substance in the urine on a Clinitest reagent tablet but has a negative urine test for glucose (glucose oxidase).

   10. TORCH titers and urine cultures for cytomegalovirus (CMV). The use of TORCH titers is less preferable; direct identification of viral infection or measurement of specific IgM antibodies should be done for rapid diagnosis. Polymerase chain reaction (PCR)-based diagnostic studies are extremely helpful and specific.

   11. Other tests. More specific tests are indicated in the investigation of the specific causes of conjugated hyperbilirubinemia.

       1. Urine organic acid and plasma amino acid. Screens for inborn errors of metabolism as a cause of neonatal liver dysfunction. High concentrations of tyrosine and methionine, and their metabolic derivatives, are seen in the urine in cases of tyrosinemia.

       2. α1-Antitrypsin serum level. Decreased serum α₁-antitrypsin concentration and liver biopsy showing periodic acid–Schiff–positive cytoplasmic granules will reveal variable degrees of hepatic necrosis and fibrosis.

       3. Sweat test. Done for confirmatory diagnosis of cystic fibrosis.

2. Imaging studies

   1. Chest radiograph. Presence of cardiovascular or situs anomalies may be suggestive of biliary atresia. Skeletal abnormalities, such as butterfly vertebrae, may be consistent with a diagnosis of Alagille syndrome.

   2. Ultrasonography. A simple and noninvasive test that should be done in all infants presenting with cholestasis after a 4-hour fast; a small or absent gallbladder is suggestive of biliary atresia, whereas the presence of a normal-looking gallbladder makes this diagnosis unlikely. Ultrasound is a sensitive method for recognizing other surgical causes of neonatal cholestasis, such as a choledochal cyst or structural abnormalities of the biliary tree.

   3. Hepatobiliary scanning. Contrast agents are taken up by the liver and excreted into the bile; they are technetium labeled and provide a clear image of the biliary tree after intravenous injection. Serial images are taken for up to 24 hours or until gut activity is visualized. Nonvisualization of contrast material within the intestine in 24 hours is considered an abnormal finding indicative of biliary obstruction or hepatocellular dysfunction. Sensitivity of this test for biliary atresia is high, but specificity is low because patients without anatomic obstruction may not excrete the tracer. Neonatal hepatitis, hyperalimentation, and septo-optic dysplasia are reported causes of absent gastrointestinal contrast excretion and must be considered in the differential diagnosis. Administration of phenobarbital a few days prior to the study may improve the precision of the test.

   4. Endoscopic retrograde cholangiopancreatography. Sensitivity and specificity are excellent. This procedure can be both diagnostic and therapeutic in cases of cholestasis caused by bile duct stones. It is technically demanding and currently has a limited role in the evaluation of cholestasis in neonates.

3. Other studies

   1. Percutaneous liver biopsy. The single most definitive procedure in the evaluation of neonatal cholestasis; however, biopsy interpretation requires a pathologist with expertise in pediatric liver disease. If a liver biopsy is obtained early in the course of biliary atresia, findings may be indistinguishable from hepatitis. Evidence supports that liver biopsy can be performed safely in young infants; it is therefore recommended that liver biopsy be performed in infants with undiagnosed cholestasis.

   2. Magnetic resonance cholangiopancreatography (MRCP). The few reports available to date regarding the use of MRCP in children are encouraging. The procedure requires deep sedation or general anesthesia. Based on current available data, this modality is not routinely recommended in the evaluation of cholestasis in neonates.

Rapid “on-call” assessment and management is discussed in Chapter 57.

1. Medical management. Few conditions causing neonatal cholestasis are treatable, and these conditions (ie, biliary atresia and choledochal cyst) need timely diagnosis and management. Medical treatment is mostly supportive and should be directed toward promoting growth and development and in treating the other complications of chronic cholestasis, such as pruritus, malabsorption, nutritional deficiencies, and portal hypertension. Management involves dietary manipulation and fat-soluble vitamin support.

   1. Special formula. Elemental formula containing medium-chain triglycerides is preferable because it can be better absorbed regardless of luminal concentration of bile acids.

   2. Medium-chain triglycerides (MCTs). Infants with cholestasis often require a diet that includes MCTs, which can be absorbed without the action of bile salts. Some formulas containing MCTs include Enfaport and Pregestimil. Breast-fed cholestatic infants should be given supplemental MCT.

   3. Vitamin supplementation. Fat malabsorption interferes with maintenance of adequate levels of fat-soluble vitamins. Supplementation of vitamins A, D, E, and K is needed. Extra vitamin K supplementation may be necessary if a bleeding tendency develops.

   4. Dietary restrictions. Removal of galactose and fructose from the diet may prevent the development of cirrhosis and other manifestations of galactosemia and hereditary fructose intolerance, respectively. Dietary restrictions may also be used to treat tyrosinemia but usually are less successful. Most other metabolic causes of cholestatic jaundice have no specific therapy.

2. Pharmacologic management. See Chapter 148 for drug dosages.

   1. Ursodiol (ursodeoxycholic acid [UDCA], Actigall). A naturally occurring dihydroxy bile acid that appears to help cholestasis in 2 ways: substitution in the bile acid pool for more hydrophobic bile acids, and stimulation of bile flow. It was found to lower levels of aminotransferases in patients with viral hepatitis, and to lower biochemical markers and slow the progression of hepatic fibrosis in PFIC. Recommended dose is 20 mg/kg/d in divided doses. The only common side effect is diarrhea, which usually responds to dose reduction.

   2. Phenobarbital. Mode of action is to enhance bile acid synthesis, increase bile flow, and induce hepatic microsomal enzymes. Recommended dose is 3–5 mg/kg/d. Use is limited by its behavioral and sedative side effects.

   3. Cholestyramine. Binds bile acids in the intestinal lumen, thereby decreasing enterohepatic circulation of bile acids, which leads to increased fecal excretion and increased hepatic synthesis of bile acids from cholesterol, which may lower serum cholesterol levels. Side effects include binding of fat-soluble vitamins, metabolic acidosis, and constipation.

   4. Rifampin. Effective in the management of pruritus due to cholestasis, but experience is very limited in neonates. Patients should be monitored for hepatotoxicity and idiosyncratic hypersensitivity reaction, such as renal failure, hemolytic anemia, and thrombocytopenia.

3. Surgical management

   1. Kasai procedure. Surgical procedure such as Kasai portoenterostomy should be done to establish biliary drainage in patients diagnosed with biliary atresia. Optimal results are obtained if the procedure is done before 8 weeks of age. The most significant predictor of long-term outcome is resolution of jaundice. The procedure is used as a bridge to transplantation.

   2. Liver transplantation. When end-stage liver disease is inevitable, liver transplantation is the last resort. Biliary atresia remains the most common indication for liver transplantation in the United States. Overall, the success of liver transplantation has improved significantly. A review of a single-center 9-year experience reports patient survival of 94 and 92% at 1 and 5 years, respectively. Long-term complications include immunosuppression, infection, renal failure, and growth retardation.

Based on individual etiologies (see Section V).