OVERVIEW: What every practitioner needs to know

Are you sure your patient has cholestasis? What are the typical findings for cholestasis?

The typical findings in an infant with cholestasis due to conjugated hyperbilirubinemia include jaundice and scleral icterus. Infants may also have acholic stools, dark yellow urine, and hepatosplenomegaly.

What other disease/condition shares some of these symptoms?

Physiologic jaundice, unconjugated hyperbilirubinemia, breast-feeding jaundice, and breast milk jaundice can all present with symptoms similar to conjugated hyperbilirubinemia. However, they all present with elevation of indirect bilirubin and do not have acholic stools or hepatosplenomegaly.

Physiologic jaundice, a temporary elevation of indirect bilirubin during the first few days of life, is due to increased bilirubin production, decreased ability to eliminate bilirubin, and significant enterohepatic circulation of bilirubin.

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Unconjugated hyperbilirubinemia is an elevation of indirect bilirubin resulting from hemolysis, birth trauma, polycythemia, ileus, or hypothyroidism.

Breast-feeding jaundice is an elevation of indirect bilirubin secondary to dehydration from insufficient milk production or intake.

Breast milk jaundice is an elevation of indirect bilirubin in some breast-fed infants due to a yet undefined component of breast milk.

What caused this disease to develop at this time?

A broad spectrum of etiologies are responsible for conjugated hyperbilirubinemia in the infant. Infectious causes include viruses (adenovirus, cytomegalovirus, coxsackie virus, Epstein-Barr virus, echovirus, hepatitis A/B/C, herpes virus, human immunodeficiency virus, enterovirus, parvovirus B19, reovirus) and bacterial/parasitic infections including sepsis, urinary tract infections, and uncommonly, liver abscess. Infection with rubella, syphilis, histoplasmosis, leptospirosis, listeriosis, toxocariasis, toxoplasmosis, and tuberculosis also may cause conjugated hyperbilirubinemia.

Conjugated hyperbilirubinemia occurs in several disorders associated with bile duct obstruction, with subsequent obstruction of biliary flow. These include biliary atresia, choledochal cyst, biliary sludge or cholelithiasis, congenital hepatic fibrosis, inspissated bile syndrome, perforation of the bile duct, an intrinsic or extrinsic obstructing mass, and neonatal sclerosing cholangitis.

Endocrinopathies, including hypothyroidism, hypopituitarism, septooptic dysplasia, and McCune-Albright syndrome may result in conjugated hyperbilirubinemia.

Genetic/metabolic causes of conjugated hyperbilirubinemia include alpha-1-antitrypsin deficiency, Alagille syndrome, cystic fibrosis, tyrosinemia, galactosemia, bile acid synthesis defects, mitochondrial disorders, urea cycle defects, peroxisomal disorders (including Zellweger syndrome), progressive familial intrahepatic cholestasis (PFIC; types 1, 2, and 3), respiratory chain defects, neonatal iron storage disease, Dubin-Johnson syndrome, Rotor syndrome, trisomy 18, and trisomy 21.

Storage disorders, including Niemann-Pick, Gaucher syndrome, Wolman disease, Farber disease, glycogen storage diseases, cholesterol ester storage disease, and mucolipidoses, although extremely rare, may also present as conjugated hyperbilirubinemia.

Exposure to several drugs, such as ceftriaxone, erythromycin, ethanol, isoniazid, methotrexate, rifampin, sulfa-containing products, tetracycline, and parenteral nutrition may also cause conjugated hyperbilirubinemia.

Patients with congestive heart failure, hypoperfusion, shock, perinatal asphyxia, venoocclusive disorder, and Budd Chiari syndrome may develop conjugated hyperbilirubinemia. Finally, patients with histiocytosis, neonatal lupus, and neonatal leukemia may have conjugated hyperbilirubinemia.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Evaluation of a jaundiced infant should begin with fractionation of serum bilirubin into total and direct bilirubin. Infants with pathologic cholestasis will have a direct bilirubin greater than 1.0 mg/dL if the total bilirubin is less than 5 mg/dL. Alternatively, if the total bilirubin is greater than 5 mg/dL, at least 20% of the total serum bilirubin will be conjugated.

Liver function tests (alanine transaminase, aspartate aminotransferase, gamma-glutamyl transferase [GGT]) in most infants with conjugated hyperbilirubinemia are three to five times the upper limits of normal. Alkaline phosphatase levels may be raised, but cautious interpretation is required, as normal values vary by age. A low or normal GGT in the setting of conjugated hyperbilirubinemia suggests PFIC type 1 (Byler disease), PFIC type 2, an inborn error of bile acid metabolism, or panhypopituitarism.

Tests of liver synthetic function are also useful. A low albumin level may suggest inadequate hepatic synthesis or loss into stool or urine. A low glucose concentration suggests failure of critical liver function, suggesting metabolic diseases or congenital infections. A prolonged prothrombin time/international normalized ratio suggests liver synthetic dysfunction, but also occurs with vitamin K deficiency.

A complete blood count with differential can also provide useful diagnostic clues. An abnormal white blood cell count might suggest infection. A low hemoglobin value can suggest anemia from hemolysis. An elevated platelet count suggests inflammation, whereas thrombocytopenia might suggest hypersplenism associated with portal hypertension.

Infants with urinary tract infections may present with cholestasis, and a urinalysis and urine culture in all such babies is necessary. In the appropriate clinical context, blood cultures may identify a source of infection. Acholic stools should raise the clinical suspicion of biliary atresia.

The newborn screen should detect galactosemia, tyrosinemia, hypothyroidism, and cystic fibrosis (in states where such screening occurs), but may occasionally miss an affected infant. A positive urine reducing substance test (while the patient is receiving galactose) suggests galactosemia, with testing for galactose-1-phosphatase uridyl transferase necessary for confirmation. Urine succinylacetone is used to test for tyrosinemia. A sweat chloride test should be performed if clinical suspicion for cystic fibrosis is high, as some mutations are not detected on newborn screening.

A serum alpha-1-antitrypsin level (with a low value being abnormal) and phenotype (with PiZZ and PiSZ being abnormal) are used to evaluate for alpha-1-anti-trypsin deficiency. Isolated use of a level risks missing an affected patient, as the alpha-1-antitrypsin level can be elevated as an acute-phase reactant.

Thyroid-stimulating hormone and thyroxine levels are used to evaluate for hypothyroidism and may also suggest hypopituitarism. A total serum bile acid level (while the patient is not taking any choleretic agents, such as ursodeoxycholic acid), should also be performed in cholestatic infants. Infants who are cholestatic should have elevated total bile acid levels. Low or normal serum bile acid levels in the context of cholestasis suggests a bile acid synthetic defect and requires subsequent urine bile acid testing.

After evaluation by a specialist, a percutaneous liver biopsy can assess for a wide variety of disorders, including infections (such as herpes simplex virus, cytomegalovirus), Alagille syndrome (bile duct paucity), alpha-1-anti-trypsin deficiency (periodic Acid–Schiff–positive diastase-resistant granules), storage and mitochondrial disease (with specific electron microscopic findings), or biliary atresia (bile duct plugs, bile duct proliferation, portal tract edema, and fibrosis). Biliary atresia can most definitively be diagnosed with an exploratory laparotomy and intraoperative cholangiogram, with characteristic findings seen on imaging.

Would imaging studies be helpful? If so, which ones?

Radiologic assessment of a child with cholestasis should begin with an abdominal ultrasonogram to look at hepatic structure, size, and composition. The presence of a choledochal cyst, obstructing mass, gallstones, biliary sludge, or ascites will be detected. A triangular cord sign (cone-shaped fibrotic mass cranial to the bifurcation of the portal vein) or absent gallbladder may suggest biliary atresia, but neither sign is sensitive or specific. Abdominal ultrasonography will also provide information about extrahepatic organs, including polysplenia or asplenia, which are known associations with the fetal/embryonic form of biliary atresia.

If a cardiac murmur is appreciated on physical examination, a cardiac echocardiogram should be obtained to assess for cardiac abnormalities. Up to 24% of patients with Alagille syndrome will have structural heart disease, as will some patients with biliary atresia. Echocardiography will also assess for abnormal cardiac function, which may contribute to cholestasis.

Cardiomegaly and butterfly vertebrae seen in Alagille syndrome may be detected on chest radiography. Consider radiographs of the long bones and skull if there is suspicion for a congenital cytomegalovirus infection.

Hepatobiliary scintigraphy with technetium-labeled iminodiacetic acid analog (HIDA) can suggest biliary obstruction. Injected radionucleotide is normally taken up by hepatocytes, secreted into the biliary system, and then travels to the small intestine. Slow uptake of tracer into the liver suggests severe hepatocellular disease, whereas lack of excretion into the small intestine suggests biliary obstruction.

An intraoperative cholangiogram is necessary in all infants suspected to have biliary atresia to delineate biliary anatomy and localize the area of obstruction.

Confirming the diagnosis

An algorithm is presented in Figure 1.

Figure 1.

Guideline for the evaluation of cholestatic jaundice in infants. Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

If you are able to confirm that the patient has this disease, what treatment should be initiated?

It is crucial to quickly identify infants with medically treatable forms of cholestasis.
Table I gives medical treatments for cholestasis produced by various causes.

Table I.
Cause of Cholestasis Treatment
Infection (viral or bacterial) Intravenous antiviral agents/antibiotics
Galactosemia Galactose-free diet
Tyrosinemia Low tyrosine/phenylalanine diet, NTBC
Hereditary fructosemia Fructose/sucrose ree diet
Hypothyroidism Thyroid hormone replacement therapy
Hypopituitarism Thyroid hormone, growth hormone, and cortisol replacement
Bile acid synthetic defect Ursodeoxycholic acid or cholic acid supplementation
Alpha-1-antitryspin deficiency Avoidance of cigarette smoke and respiratory environmental pollutants

NTBC = 2-nitro-4-trifluoromethylbenzoyl-1,3-cyclohexanedione

It is important to delineate causes of cholestasis that require surgical intervention. Surgical interventions corresponding to various causes of cholestasis are shown in
Table II.

Table II
Cause of Cholestasis Surgical Intervention
Biliary atresia Hepatoportoenterostomy (Kasai procedure)
Choledochal cyst Choledochoenterostomy
Spontaneous perforation of the common bile duct Surgical drainage
Inspissated bile in the common bile duct Biliary tract irrigation

The timing of hepatoportoenterostomy in patients with biliary atresia is critical. The greatest chance of reestablishing bile flow occurs if hepatoportoenterostomy is performed before 60 days of life (80% success rate). Only 20% of infants reestablish bile flow if hepatoportoenterostomy occurs after 90 days of life.

In all infants with cholestasis, nutritional support is the cornerstone of therapy. Decreased bile flow results in decreased bile acid delivery to the small intestine, resulting in decreased formation of mixed micelles, which are central to fat and fat-soluble vitamin absorption. Patients with cholestasis also have abnormal metabolism of protein and carbohydrates. Patients with cholestasis may also have increased metabolic demands secondary to inflammation and infection. Finally, as a result of organomegaly and/or ascites, affected patients may have reflux, early satiety, and vomiting, with resultant anorexia and decreased calorie consumption.

Infants with cholestasis should receive medium-chain triglyceride containing formulas (such as Pregestimil and Alimentum), in which 50%-60% of fat calories are medium-chain triglycerides. Unlike long-chain triglycerides, which require bile acids for absorption, medium-chain triglycerides are absorbed directly from the intestine. In addition, infants with cholestasis often have increased caloric needs and may require up to 125% of the recommended dietary allowance plus additional calories for catch-up growth. If they are unable to consume the necessary calories orally, nasogastric drip feeds should be initiated.

Intestinal absorption of fat-soluble vitamins (A, D, E, and K) is also impaired and levels should be monitored to avoid deficiencies. For some infants, supplementation with a combination preparation, such as AquaADEK, will suffice. However, more severe deficiencies require supplementation with individual vitamins. Vitamin A deficiency, which can lead to vision impairment, occurs when the retinol–retinol binding protein ratio is less than 0.8 and requires supplementation either orally or intramuscularly.

Vitamin D deficiency can lead to rickets and osteomalacia and occurs when serum levels of 25,OH vitamin D are less than 14 ng/mL. If deficiency occurs, oral vitamin D should be prescribed. Vitamin E deficiency can lead to neurologic changes and hemolysis, and occurs when the vitamin E to total serum lipid ratio falls to less than 0.6 mg/g-0.8 mg/dL and should be treated with oral alpha tocopherol. Vitamin K deficiency can lead to a coagulopathy and is evident when the PT becomes prolonged. Depending on the severity of deficiency, vitamin K may be supplemented orally or intramuscularly.

Ursodiol can be used to stimulate bile flow in children with cholestasis. Nonabsorbable ion exchange resins (cholestyramine and colestipol) may be used in patients with PFIC to treat diarrhea. Patients with Alagille syndrome and PFIC may experience disabling pruritus. Some relief can be provided with rifampin; however, patients with severe pruritus may require a surgical biliary diversion to redirect flow of bile salts from the enterohepatic recirculation. Patients with Alagille syndrome often manifest hyperlipidemia and xanthomas that do not respond to diets low in cholesterol and saturated fats.

For patients with cholestasis in whom end-stage liver disease develops, liver transplantation may also be a treatment option.

What are the adverse effects associated with each treatment option?

Some infants find formulas containing medium-chain triglycerides less palatable than either breast milk or standard formulas. Ursodeoxycholic acid can lead to diarrhea or constipation. Bile acid binding agents such as cholestyramine and colestipol can cause constipation, diarrhea, hyperchloremic acidosis, and binding of other drugs. Excess vitamin A can lead to hepatotoxicity, pseudotumor cerebri, bone lesions, and hypercalcemia. Excess vitamin D can lead to hypercalcemia and kidney stones. Excess vitamin E can lead to headache, weakness, diarrhea, blurry vision, and elevated creatinine kinase levels.

What are the possible outcomes of cholestasis?

Idiopathic neonatal hepatitis, one of the common reasons cited for conjugated hyperbilirubinemia, is a histologic diagnosis in which patients have extensive giant cell transformation of hepatocytes. Conjugated hyperbilirubinemia will resolve in approximately 90% of affected infants by 1 year of age. Persistent conjugated hyperbilirubinemia in these infants may reflect yet undefined cellular defects in metabolism or substrate transport pathways.

The outcome of infants with biliary atresia is dictated by several factors, all related to the reestablishment of bile flow. Age at time of hepatoportoenterostomy is likely the single most important factor, with 80% success in reestablishing bile flow if the operation occurs at less than 60 days of life. In contrast, only 20% success occurs if the operation occurs at more than 90 days of life.

The size of bile ducts present at the porta hepatis, the extent of cirrhosis at the time of surgery, and the experience and technical expertise of the surgeon performing the operation also impact outcome. If jaundice successfully clears after hepatoportoenterostomy, the 10-year transplant-free survival rate ranges from 75%-90%; conversely, if jaundice remains after a Kasai procedure, the 3-year transplant-free survival rate is 20%. Eventually, the vast majority of patients with biliary atresia have progressive disease, with at least 80% requiring liver transplantation by 20 years of age.

The outcome of Alagille syndrome is largely dependent on an individual’s particular clinical manifestations. For patients with liver disease in infancy, 20%-50% will require liver transplantation by 20 years of age. Patients who have intracardiac disease have much higher mortality rates than do patients without intracardiac lesions (40% survival rate at 6 years compared with 95% survival rate at 6 years). Children with Alagille syndrome are also at risk for hepatocellular carcinoma and their alpha fetoprotein levels should be screened on an annual basis. The overall 20-year survival rate for patients with Alagille syndrome is 75%. Survival rates are lower (60%) for patients who undergo liver transplantation.

In alpha-1-antitrypsin deficiency, 8%-10% of patients will manifest clinically significant liver disease during the first 40 years of life. A small percentage of these patients develop end-stage liver disease in infancy. Although not usually present until adulthood, 60%-65% of patients will have clinically significant lung disease. Cigarette smoking accelerates lung damage and greatly increases mortality in alpha-1-antitrypsin deficiency.

What causes this disease and how frequent is it?

Neonatal cholestasis affects approximately 1/2500 live births each year. The three most common causes of neonatal cholestasis are biliary atresia, idiopathic neonatal hepatitis, and alpha-1-antitrypsin deficiency.

Biliary atresia occurs in 1/8-12,000 live births, with a slight female predominance. A higher incidence has been described in nonwhites.

Alagille syndrome, an autosomal dominant disorder, occurs in approximately 1/70,000 live births. This frequency may be an underestimate, as some affected patients do not have neonatal cholestasis.

Alpha-1-antitrypsin deficiency, an autosomal dominant disorder, affects approximately 1/2000 live births, with slightly higher rates occurring in those of northern European descent.

How do these pathogens/genes/exposures cause the disease?

Several cholestatic disorders have known genetic associations, with clinical genetic testing available.

Alpha-1-antitrypsin is a serine protease inhibitor that targets elastase, cathepsin G, and proteinase 3. Patients with a normal phenotype (PiMM) have normal serum alpha-1-antitrypsin levels. A single nucleotide substitution (Lys for Glu), however, results in abnormally folded protein that cannot be secreted from the liver. Patients with the PiZZ and PiSZ phenotypes have very low alpha-1-antitrypsin levels, and 10%-15% of these patients will have liver disease.

Patients with the PiMZ phenotype have intermediate alpha-1-antitrypsin levels without resultant liver disease. They are, however, predisposed to more severe liver disease in conjunction with other conditions such as viral hepatitis or cystic fibrosis. More than 100 allelic variants exist, not all of which are associated with clinical disease.

Mutations in the JAG1 gene, which encodes a Notch signaling pathway, are identified in more than 90% of patients with Alagille syndrome, half of which are de novo mutations. JAG1 is crucial in liver, bile duct, cardiovascular, and kidney development. Tremendous clinical variability exists among individuals with the same
JAG1 mutation, with no genotype-phenotype correlation identified.

The PFIC disorders are autosomal recessive and are caused by mutations that impact cannalicular bile acid transporters. PFIC type 1 is caused by mutations in FIC1; PFIC type 2 is caused by mutations in BSEP; and PFIC type 3 is caused by mutations in MDR3.

The pathogenesis of many of the other causes of cholestasis, including biliary atresia, remain unknown. Proposed theories to explain the pathogenesis of biliary atresia include viral infections, autoimmune-mediated bile duct destruction, and abnormal bile duct development.

Other clinical manifestations that might help with diagnosis and management

Biliary atresia is a progressive fibroobliterative disease of the extrahepatic and intrahepatic biliary tree that leads to cirrhosis. The classic affected infant appears to be well and thriving at 4-6 weeks of age, with only mild jaundice and acholic stools. This reassuring clinical picture may delay the diagnosis of biliary atresia, unless the clinical suspicion is high.

The less common fetal/embryonic form of biliary atresia presents with cholestasis at birth, with a high frequency of associated malformations, including asplenia or polysplenia, preduodenal portal vein, malrotation, situs inversus, and cardiovascular defects. As disease progresses, more severe manifestations, including ascites, liver synthetic dysfunction, and failure to thrive occur.

Alagille syndrome, or arteriohepatic dysplasia, is a multisystem disorder. The traditional diagnosis is made in patients with bile duct paucity, plus three of five clinical criteria, including cholestasis, cardiac abnormalities (most commonly peripheral pulmonic stenosis), butterfly vertebrae, posterior embryotoxon, and characteristic facial features (triangular face, broad forehead, pointed chin, elongated nose with bulbous tip).

Splenomegaly may suggest cirrhosis and portal hypertension, a storage disease, or hemolysis. Profound coagulopathy, out of proportion to presetning hepatocellular injury, within the first days of life suggests neonatal hemochromatosis. Neurologic abnormalities can suggest Zellweger syndrome, mitochondrial disease, metabolic disease, or severe hepatic dysfunction leading to hyperammonemia and encephalopathy. Cataracts and brain calcifications suggest perinatal infection.

What complications might you expect from the disease or treatment of the disease?

Failure to excrete bilirubin and bile acids can lead to pruritus. Decreased delivery of bile salts to the intestine can lead to fat and fat-soluble vitamin malabsorption, which in turn can lead to growth failure and bone fractures. Hepatocellular damage can lead to portal hypertension (with concurrent splenomegaly, thrombocytopenia, ascites, and risk of variceal bleeding), cirrhosis, and liver failure. In addition, children with cholestatic disorders are at increased risk of hepatocellular carcinoma (HCC) over time. Children with PFIC type 2 are at particular risk, even within the first 2 years of life, and should be screened for HCC every 6 months.

Children with choledochal cysts are at increased risk of cholangiocarcinoma. Ascending cholangitis after hepatoportoenterostomy can develop in patients with biliary atresia, presenting with right upper quadrant abdominal pain, worsening jaundice, fever, acholic stools, and increased cholestatic markers and aminotransferase levels.

Patients with Alagille syndrome often have cholesterol levels greater than 1000 mg/dL, with xanthomas commonly appearing after cholesterol levels reach 500 mg/dL. They may also experience severe and disabling pruritus that interrupts daily activities, sleep, and overall quality of life. Intracranial bleeding from cerebrovascular disease such as internal carotid aneurysms or moyamoya disease is a significant cause of morbidity and mortality in patients with Alagille syndrome.

Are additional laboratory studies available; even some that are not widely available?

Serologic tests for specific infections (hepatitis B surface antigen, TORCH (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex), Epstein-Barr virus, cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza, human immunodeficiency virus, syphilis can be used in the appropriate clinical setting. Serum and urine amino acids, urine organic acids, and serum ammonia levels are used to evaluate for metabolic disease.

How can this disease be prevented?

Any infant who is jaundiced at 2 weeks of age should be evaluated for cholestasis with measurement of total and direct serum bilirubin. Breast-fed infants who can be reliably monitored and who do not have dark urine, light stools, or failure to thrive may return at 3 weeks of age, and if jaundice persists bilirubin can be fractionated at that time.

What is the evidence?

Davenport, M, Stringer, MD, Tizzard, SA. “Randomized double-blind, placebo controlled trial of corticosteroids after Kasai portoenterostomy for biliary atresia”. Hepatology. vol. 46. 2007. pp. 1821-7. (This randomized placebo-controlled trial of oral corticosteroids after Kasai procedure for biliary atresia in 73 infants showed a greater decrease in bilirubin levels 1 month after the procedure in infants who received steroids. However, this difference disappeared at 6 and 12 months after the Kasai operation, with no long-term benefit regarding progression to transplantation.)

Davit-Spraul, A, Fabre, M, Branchereau, S. “ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotype differences between PFIC1 and PFIC2 and natural history”. Hepatology. vol. 51. 2010. pp. 1645-55. (This study of 62 children with PFIC and normal GGT levels revealed that patients with PFIC type 2 were more likely to have neonatal cholestasis; higher aminotransferase and alpha fetoprotein levels and progression to early liver failure and HCC compared with patients with PFIC type 1 This study also showed that a combination of ursodeoxycholic acid, biliary diversion, and liver transplantation allowed 87% of patients to survive, at a median age of 10.5 years, half with their native livers.)

DeRusso, P, Ye, W, Shepherd, R. “Growth failure and outcomes in infants with biliary atresia: a report from the Biliary Atresia Report Consortium”. Hepatology. vol. 46. 2007. pp. 1632-8. (This multicenter study of children with biliary atresia demonstrated poor outcomes, defined as liver transplantation or death by 24 months of age, in 46 children with poor growth after Kasai operation (growth velocity and weight z scores), compared with 54 children who did not have poor growth after the Kasai procedure.)

Emond, JC, Whitington, PF. “Selective surgical management of progressive familial intrahepatic cholestasis (Byler's Disease)”. J Pediatr Surg. vol. 30. 1995. pp. 1635-41. (This study describes the use of partial external biliary diversion as primary therapy for PFIC in eight children, six of whom had complete resolution of clinical symptoms, whereas two patients with histologic bridging/cirrhosis derived no benefit and required liver transplantation.)

McElhinney, DB, Krantz, ID, Bason, L. “Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome”. Circulation. vol. 106. 2002. pp. 267-74. (This study indicates that 94% (187) of 200 individuals with a JAG mutation/Alagille syndrome had evidence of cardiovascular involvement, 111 of whom had stenosis/hypoplasia of the branch pulmonary arteries and 23 of whom had tetralogy of Fallot.)

Moyer, V, Freese, DK, Whitington, PE. “Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition”. J Pediatr Gastroenterol Nutr. vol. 39. 2004. pp. 115-28. (This clinically important paper provides guidelines for evaluating cholestatic jaundice based on a combination of scientific literature and expert opinion in cases in which the literature is lacking.)

Setchell, KD, Suchy, FJ, Welsh, MB. “Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis”. J Clin Invest. vol. 82. 198. pp. 2148-57. (This report delineates the discovery of what is now recognized as the most common inborn error of bile acid synthesis presenting as infantile cholestasis.)

Shneider, BL, Brown, MB, Haber, B. “A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000”. J Pediatr. vol. 148. 2006. pp. 467-74. (This multicenter study of 104 patients with biliary atresia who underwent a Kasai operation at an average age of 61 days demonstrated that transplant-free survival in those with a bilirubin level less than 2 mg/dL at 3 months after the Kasai procedure was 84% compared with 16% in those in whom the bilirubin level remained elevated after 3 months.)

Sokol, RJ, Mack, C. “Etiopathogenesis of biliary atresia”. Semin Liver Dis. vol. 21. 2001. pp. 517-24. (This review discusses potential causes for biliary atresia, including viral infections such as reovirus and rotavirus, immune-mediated bile duct injury, and autoimmune disease, with the additional potential contributions of an immature neonatal immune system and genetic factors.)

Strautnieks, SS, Byrne, JA, Pawlikowska, L. “Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families”. Gastroenterology. vol. 134. 2008. pp. 1203-14. (This study identified 82 new mutations in 109 families with intrahepatic cholestasis suggestive of PFIC type 2.)

Sveger, T, Eriksson, S. “The liver in adolescents with alpha-1-antitrypsin deficiency”. Hepatology. vol. 22. 1995. pp. 514-7. (This study details the long-term follow-up of 184 Swedish children with alpha-1-antitrypsin deficiency identified by screening. None of these patients had clinically evident liver disease at 16-18 years of age, although 12%-15% had abnormal liver test results. Of the 22 patients with a PiZZ phenotype and clinically evident liver disease in infancy, 2 died in early childhood of cirrhosis and 2 died of unrelated causes. The remaining children are well.)

Ongoing controversies regarding etiology, diagnosis, treatment

The role of corticosteroids in patients with biliary atresia is controversial. Steroids are postulated to stimulate bile flow independent of bile salts, provide an antiinflammatory effect, and provide an immunomodulatory effect on bile duct injury. Steroids may also suppress the immune system, increasing the likelihood of cholangitis. In the current medical literature, studies can be found that both support and refute the use of steroids in biliary atresia, leaving most clinicians conflicted. A large multicentered prospective placebo-controlled trial of steroids in biliary atresia, sponsored by the National Institutes of Health, is nearing completion and may provide definitive data to resolve this ongoing debate.