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Cholestasis is failure of bilirubin secretion, resulting in conjugated hyperbilirubinemia and jaundice. There are numerous causes, which are identified by laboratory testing, hepatobiliary scan, and, sometimes, liver biopsy and surgery. Treatment depends on cause.
Etiology
Cholestasis (see also Approach to the Patient With Liver Disease: Jaundice) may result from extrahepatic or intrahepatic disorders, although some conditions overlap. The most common extrahepatic disorder is biliary atresia. There are numerous intrahepatic disorders, collectively termed the neonatal hepatitis syndrome.
Biliary atresia is obstruction of the biliary tree due to progressive sclerosis of the extrahepatic bile duct. In most cases, biliary atresia develops several weeks after birth, probably after inflammation and scarring of the extrahepatic (and sometimes intrahepatic) bile ducts. It is rarely present in premature infants or in neonates at birth. The cause of the inflammatory response is unknown, but infectious organisms have been implicated.
Neonatal hepatitis syndrome (giant cell hepatitis) is an inflammatory condition of the neonatal liver. It has numerous metabolic, infectious, and genetic causes; some cases are idiopathic. Metabolic diseases include α1-antitrypsin deficiency, cystic fibrosis, neonatal iron storage disease, respiratory chain defects, and fatty acid oxidation defects. Infectious causes include congenital syphilis, echovirus, and some herpesviruses (simplex and cytomegalovirus); the classic hepatitis viruses (A, B, and C) are less common causes. There are also a number of less common genetic defects, such as Alagille syndrome and progressive familial intrahepatic cholestasis.
Pathophysiology
In cholestasis, the primary failure is of bilirubin excretion, resulting in excess conjugated bilirubin in the bloodstream and decreased bile salts in the GI tract. As a result of inadequate bile in the GI tract, there is malabsorption of fat and fat-soluble vitamins (A, D, E, and K), leading to vitamin deficiency, undernutrition, and growth failure.
Symptoms and Signs
Cholestasis typically is noted in the first 2 wk of life. Infants are jaundiced and often have dark urine (containing conjugated bilirubin), acholic stools, and hepatomegaly. If cholestasis persists, chronic pruritus is common, as are symptoms and signs of fat-soluble vitamin deficiency; progression on growth charts may show a decline. If the underlying disorder causes hepatic fibrosis and cirrhosis, portal hypertension with subsequent abdominal distention from ascites, dilated abdominal veins, and upper GI bleeding from esophageal varices may develop.
Diagnosis
Any infant who is jaundiced after age 2 wk should be evaluated for cholestasis. The initial approach should be directed at diagnosing treatable conditions (eg, extrahepatic biliary atresia, in which early surgical intervention improves outcome).
Cholestasis is identified by an elevation in both total and direct bilirubin. Tests that are needed to further evaluate liver function include albumin, fractionated serum bilirubin, liver enzymes, PT, and PTT. Once cholestasis is confirmed, testing is required to determine etiology (see Table 1: Gastrointestinal Disorders in Neonates and Infants: Diagnostic Evaluation for Neonatal Cholestasis ).
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Table 1
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| Diagnostic Evaluation for Neonatal Cholestasis |
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Etiology
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Test
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Hepatic dysfunction
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Albumin, PT/PTT, AST, ALT, GGT, bilirubin (total and direct)
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Infections
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Urine cultures, TORCH titers
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Endocrinopathy
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TSH, thyroxine
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Cystic fibrosis
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Sweat chloride test
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Galactosemia
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Reducing substances (eg, galactose) in urine
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α 1-Antitrypsin deficiency
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Serum levels of α1-antitrypsin, α1-antitrypsin phenotype testing
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Genetic errors in bile acid synthesis
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Bile acid levels in urine and serum
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Inborn errors of metabolism
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Urine organic acids, serum ammonia, serum electrolytes
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GGT =
γ-glutamyltransferase; TORCH = toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex; TSH = thyroid-stimulating hormone.
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A hepatobiliary scan should also be done; excretion of contrast into the intestine rules out biliary atresia, but lack of excretion can occur with both biliary atresia and severe neonatal hepatitis. An abdominal ultrasound can aid in assessing liver size and in attempting to visualize the gallbladder and common bile duct but is nonspecific. When no diagnosis has been made, a liver biopsy is generally performed relatively early on. Patients with biliary atresia typically have enlarged portal triads, bile duct proliferation, and increased fibrosis. Neonatal hepatitis is characterized by lobular disarray with multinucleated giant cells. Sometimes diagnosis remains unclear, and surgical exploration with operative cholangiography is required.
Prognosis
Biliary atresia is progressive and, if untreated, results in liver failure, cirrhosis with portal hypertension by several months of age, and death by 1 yr of age.
Prognosis of cholestasis due to specific disorders (eg, metabolic disease) is variable, ranging from a completely benign course to a progressive disease resulting in cirrhosis.
Idiopathic neonatal hepatitis syndrome usually resolves slowly, but permanent liver damage may result and lead to death.
Treatment
Specific treatment is directed at the cause. If there is no specific therapy, treatment is supportive and consists primarily of nutritional therapy, including supplements of vitamins A, D, E, and K. For formula-fed infants, a formula that is high in medium-chain triglycerides should be used because it is absorbed better in the presence of bile salt deficiency. Adequate calories are required; infants may need > 130 calories/kg day. In infants with some bile flow, ursodeoxycholic acid 10 to 15 mg/kg once/day or bid may relieve itching.
Infants with presumed biliary atresia require surgical exploration with an intraoperative cholangiogram. If biliary atresia is confirmed, a portoenterostomy (Kasai procedure) should be done. Ideally, this procedure should be done in the first 1 to 2 mo of life. After this period, the prognosis significantly worsens. Postoperatively, many patients have significant chronic problems, including persistent cholestasis, recurrent ascending cholangitis, and failure to thrive. Even with optimal therapy, many infants develop cirrhosis and require liver transplantation.
Last full review/revision November 2007 by William J. Cochran, MD
Content last modified February 2012
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