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Neonatal Cholestasis

by James W. Kendig, MD, Ursula Nawab, MD

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 Jaundice) may result from extrahepatic or intrahepatic disorders, although some conditions overlap.

Extrahepatic

The most common extrahepatic disorder is biliary atresia.

Biliary atresia is obstruction of the biliary tree due to progressive sclerosis of the extrahepatic bile duct. In most cases, biliary atresia manifests 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.

Intrahepatic

Intrahepatic causes can be infectious, alloimmune, metabolic/genetic, or toxic.

Infections can cause cholestasis. Infections may be viral (eg, herpes simplex virus, cytomegalovirus, rubella—see Overview of Neonatal Infections), bacterial (eg, gram-positive and gram-negative bacteremia, UTI caused by Escherichia coli—see Introduction to Miscellaneous Infections in Infants and Children), or parasitic (eg, toxoplasmosis—see Congenital Toxoplasmosis). Sepsis in neonates (see Neonatal Sepsis) receiving parental nutrition can also cause cholestasis.

Gestational alloimmune liver disease involves transplacental passage of maternal IgG that induces a complement-mediated membrane attack complex that injures the fetal liver.

Metabolic causes include numerous inborn errors of metabolism (see also Introduction to Inherited Disorders of Metabolism) such as galactosemia, tyrosinemia, alpha 1-antitrypsin deficiency, disorders of lipid metabolism, mitochondrial disorders, and fatty acid oxidation defects. Genetic defects include Alagille syndrome, cystic fibrosis, and arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. There are also a number of gene mutations that interfere with normal bile production and excretion and cause cholestasis; the resultant disorders are termed progressive familial intrahepatic cholestasis.

Toxic causes are due mainly to the use of prolonged parenteral nutrition in extremely preterm neonates or infants with short bowel syndrome (see Short Bowel Syndrome).

Idiopathic neonatal hepatitis syndrome (giant cell hepatitis) is an inflammatory condition of the neonatal liver. Its incidence has decreased, and it is becoming rare as improved diagnostic studies allow identification of specific causes of 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, inadequate nutrition, 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 resulting from ascites, dilated abdominal veins, and upper GI bleeding resulting from esophageal varices may develop.

Diagnosis

  • Total and direct bilirubin

  • Liver function tests

  • Tests for metabolic, infectious, and genetic causes

  • Liver ultrasonography

  • Hepatobiliary scan

  • Occasionally biopsy of liver or other tissue (eg, lip), operative cholangiography, or genetic testing

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 short-term 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/PTT, and ammonia level. Once cholestasis is confirmed, testing is required to determine etiology (see Table: Diagnostic Evaluation for Neonatal Cholestasis) and evidence of malabsorption (eg, low levels of the fat-soluble vitamins E, D, and A).

Diagnostic Evaluation for Neonatal Cholestasis

Etiology

Test

Hepatic dysfunction

Albumin, ammonia, PT/PTT, AST, ALT, GGT, bilirubin (total and direct)

Infections

Urine cultures, TORCH titers

Endocrinopathy

TSH, thyroxine

Cystic fibrosis

Sweat chloride test

Galactosemia

Newborn screen, reducing substances (eg, galactose) in urine

α 1 -Antitrypsin deficiency

Serum levels of α 1 -antitrypsin, α 1 -antitrypsin phenotype testing

Genetic errors in bile acid synthesis

Bile acid levels in urine and serum

Genetic testing

Inborn errors of metabolism

Urine organic acids, serum ammonia, serum electrolytes

Alloimmune liver disease

Alpha-1antitrypsin, ferritin, lipid profile, tissue iron determined from either lip or liver, liver histology

GGT =γ-glutamyltransferase; TORCH =toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex; TSH =thyroid-stimulating hormone.

Abdominal ultrasonography is often the first test; it is noninvasive and can assess liver size and certain abnormalities of the gallbladder and common bile duct. However, it is nonspecific. 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, severe neonatal hepatitis, and other causes of cholestasis.

When no diagnosis has been made, a liver biopsy is generally done relatively early on, sometimes with operative cholangiography. 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. Alloimmune liver disease is characterized by elevated hepatic iron stores (increased iron may also be demonstrated using lip biopsy if liver biopsy is not otherwise needed).

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 liver failure and death.

Alloimmune liver disease has poor prognosis without early intervention.

Treatment

  • Specific cause treated

  • Vitamin A, D, E, and K supplements

  • Medium-chain triglycerides

  • Sometimes ursodeoxycholic acid

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 short-term prognosis significantly worsens. Postoperatively, many patients have significant chronic problems, including persistent cholestasis, recurrent ascending cholangitis, and failure to thrive. Even with optimal therapy, most infants develop cirrhosis and require liver transplantation.

Because alloimmune liver disease has no definitive marker and/or test, treatment with IVIG or exchange transfusion needs to be considered early to reverse the ongoing liver injury if no definite diagnosis has been made.

Key Points

  • There are numerous inherited and acquired causes of neonatal cholestasis, resulting in failure of bilirubin excretion and thus excess conjugated bilirubin.

  • Neonatal cholestasis typically is noted in the first 2 wk of life; infants are jaundiced and often have dark urine, acholic stools, and hepatomegaly.

  • Begin with laboratory testing of liver function, ultrasonography, and hepatobiliary scan and do tests for causes, sometimes including liver biopsy.

  • Treat specific cause and give supportive care, including supplementation of fat-soluble vitamins and a formula that is high in medium-chain triglycerides and contains sufficient calories.

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