Cholestasis occurs in 1/2500 full-term infants. It is defined as direct bilirubin > 1 mg/dL (> 17.1 micromole/L). Cholestasis is never normal and warrants evaluation.
Etiology
Cholestasis (see also Jaundice) may result from extrahepatic or intrahepatic disorders, although some conditions overlap.
Extrahepatic causes of cholestasis
The most common extrahepatic disorder is
-
Biliary atresia (incidence in the US about 1/12,000 live births; 1)
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 several infectious organisms have been implicated, including reovirus type 3 and cytomegalovirus.
Biliary cysts rarely manifest as neonatal cholestasis; these cysts are more common among patients with autosomal recessive polycystic kidney disease (2).
Inspissated bile duct syndrome can also be a cause of extrahepatic neonatal cholestasis and is more common among infants with cystic fibrosis.
Intrahepatic causes of cholestasis
Intrahepatic causes can be infectious, alloimmune, metabolic/genetic, or toxic.
Infections can cause cholestasis. Infections may be viral (eg, herpes simplex virus, cytomegalovirus, rubella), bacterial (eg, gram-positive and gram-negative bacteremia, UTI caused by Escherichia coli), or parasitic (eg, toxoplasmosis). Sepsis in neonates 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 such as galactosemia, tyrosinemia, alpha-1 antitrypsin deficiency, disorders of lipid metabolism, bile acid defects, mitochondrial disorders, and fatty acid oxidation defects. Additional 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.
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.
Etiology references
-
1. Zagory JA, Nguyen MV, Wang KS: Recent advances in the pathogenesis and management of biliary atresia. Curr Opin Pediatr 27(3):389–394, 2015. doi: 10.1097/MOP.0000000000000214.
-
2. Fabris L, Fiorotto R, Spirli C, et al: Pathobiology of inherited biliary diseases: A roadmap to understand acquired liver diseases. Nat Rev Gastroenterol Hepatol 16(8):497–511, 2019. doi: 10.1038/s41575-019-0156-4.
Pathophysiology
In cholestasis, the primary failure is of bilirubin excretion, resulting in excess conjugated bilirubin in the bloodstream and decreased bile salts in the gastrointestinal (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 weeks 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
(See also the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition's guideline for the evaluation of cholestatic jaundice in infants.)
Any infant who is jaundiced after age 2 weeks should be evaluated for cholestasis including with total and direct bilirubin levels. Some experts advocate that breastfed infants who have jaundice do not need to be evaluated until age 3 weeks. 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 the liver include albumin, fractionated serum bilirubin, liver enzymes, prothrombin time/partial thromboplastin time (PT/PTT), and ammonia level (see Tests for Cholestasis). 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, K, and A, or prolonged PT, suggesting a low level of vitamin K).
Diagnostic Evaluation for Neonatal Cholestasis
Etiology |
Test |
|
Hepatic dysfunction |
Albumin, ammonia, PT/PTT, AST, ALT, GGT, total and direct bilirubin (see Tests for Cholestasis) |
|
Infections |
Urine cultures, TORCH titers, HIV screening and other hepatitides (hepatitis A, B, and C) |
|
Endocrinopathy |
|
|
Sweat chloride test, review of newborn screening test |
|
|
Neonatal screen, reducing substances (eg, galactose) in urine (see diagnosis of galactosemia) |
|
|
Serum levels of alpha-1 antitrypsin, alpha-1 antitrypsin phenotype testing |
|
|
Genetic errors in bile acid synthesis |
Bile acid levels in urine and serum |
|
Urine organic acids, serum ammonia, serum electrolytes (see testing of inherited disorders of metabolism) |
|
|
Alloimmune liver disease |
Review of maternal obstetrical history for fetal deaths and/or prior infants with cholestasis Alpha fetoprotein, ferritin, lipid profile |
|
ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma-glutamyl transpeptidase; prothrombin time/partial thromboplastin time = PT/PTT; 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 using hydroxy iminodiacetic acid (HIDA scan) should also be done; excretion of contrast into the intestine rules out biliary atresia, but lack of excretion can occur with biliary atresia, severe neonatal hepatitis, and other causes of cholestasis. Infants with cholestasis are frequently given phenobarbital for 5 days prior to a HIDA scan in an attempt to enhance the excretion.
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.
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 year 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 a poor prognosis without early intervention.
Treatment
(See also the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition's joint position paper on nutritional support of children with chronic liver diseases.)
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 or twice a day 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 months 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. Prophylactic antibiotics (eg, trimethoprim/sulfamethoxazole) are frequently prescribed for a year postoperatively in an attempt to prevent ascending cholangitis. 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 IV immune globulin (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 weeks of life; infants are jaundiced and often have dark urine, acholic stools, and hepatomegaly.
-
Begin with laboratory testing of the liver, 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.
More Information
-
Guideline for the evaluation of cholestatic jaundice in infants from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
-
Joint position paper on nutritional support of children with chronic liver diseases from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition
