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 of Neonatal Cholestasis
Cholestasis ( see also Jaundice Jaundice Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 micromol/L)... read more ) 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 1/8,000 to 1/18,000 live births; 1 Etiology references Cholestasis is failure of bilirubin secretion, resulting in conjugated hyperbilirubinemia and jaundice. There are numerous causes, which are identified by laboratory testing, hepatobiliary scan... read more )
Biliary atresia Biliary Atresia Biliary atresia is obstruction of the biliary tree due to progressive sclerosis of the extrahepatic bile duct. Diagnosis is by blood tests, ultrasonography, liver biopsy, and hepatobiliary scan... read more 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 Congenital and Perinatal Cytomegalovirus Infection (CMV) Cytomegalovirus infection may be acquired prenatally or perinatally and is the most common congenital viral infection. Signs at birth, if present, are intrauterine growth restriction, prematurity... read more .
Biliary cysts rarely manifest as neonatal cholestasis; these cysts are more common among patients with autosomal recessive polycystic kidney disease Autosomal Dominant Polycystic Kidney Disease (ADPKD) Polycystic kidney disease (PKD) is a hereditary disorder of renal cyst formation causing gradual enlargement of both kidneys, sometimes with progression to renal failure. Almost all forms are... read more ( 2 Etiology references Cholestasis is failure of bilirubin secretion, resulting in conjugated hyperbilirubinemia and jaundice. There are numerous causes, which are identified by laboratory testing, hepatobiliary scan... read more ).
Inspissated bile duct syndrome can also be a cause of extrahepatic neonatal cholestasis and is more common among infants with cystic fibrosis Gastrointestinal Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more .
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 Neonatal Herpes Simplex Virus (HSV) Infection Neonatal herpes simplex virus infection is usually transmitted during delivery. A typical sign is vesicular eruption, which may be accompanied by or progress to disseminated disease. Diagnosis... read more , cytomegalovirus Congenital and Perinatal Cytomegalovirus Infection (CMV) Cytomegalovirus infection may be acquired prenatally or perinatally and is the most common congenital viral infection. Signs at birth, if present, are intrauterine growth restriction, prematurity... read more , rubella Congenital Rubella Congenital rubella is a viral infection acquired from the mother during pregnancy. Signs are multiple congenital anomalies that can result in fetal death. Diagnosis is by serology and viral... read more ), bacterial (eg, gram-positive and gram-negative bacteremia Occult Bacteremia and Fever Without Apparent Source in Infants and Young Children Occult bacteremia is the presence of bacteria in the bloodstream of febrile young children who have no apparent foci of infection and look well. Diagnosis is by blood culture and exclusion of... read more , UTI Urinary Tract Infection (UTI) in Children Urinary tract infection (UTI) is defined by ≥ 5 × 104 colonies/mL in a catheterized urine specimen or, in older children, by repeated voided specimens with ≥ 105 colonies/mL... read more caused by Escherichia coli), or parasitic (eg, toxoplasmosis Congenital Toxoplasmosis Congenital toxoplasmosis is caused by transplacental acquisition of Toxoplasma gondii. Manifestations, if present, are prematurity, intrauterine growth restriction, jaundice, hepatosplenomegaly... read more ). Sepsis Neonatal Sepsis Neonatal sepsis is invasive infection, usually bacterial, occurring during the neonatal period. Signs are multiple, nonspecific, and include diminished spontaneous activity, less vigorous sucking... read more 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 Introduction to Inherited Disorders of Metabolism Most inherited disorders of metabolism (also called inborn errors of metabolism) are caused by mutations in genes that code for enzymes; enzyme deficiency or inactivity leads to Accumulation... read more such as galactosemia Galactosemia Galactosemia is a carbohydrate metabolism disorder caused by inherited deficiencies in enzymes that convert galactose to glucose. Symptoms and signs include hepatic and renal dysfunction, cognitive... read more , tyrosinemia Tyrosine Metabolism Disorders Tyrosine is an amino acid that is a precursor of several neurotransmitters (eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and melanin; deficiencies of enzymes involved... read more , alpha-1 antitrypsin deficiency Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin deficiency is congenital lack of a primary lung antiprotease, alpha-1 antitrypsin, which leads to increased protease-mediated tissue destruction and emphysema in adults.... read more , disorders of lipid metabolism, bile acid defects, mitochondrial disorders Mitochondrial Oxidative Phosphorylation Disorders Impairment of oxidative phosphorylation often, but not always, causes lactic acidosis, particularly affecting the central nervous system, retina, and muscle. See also Approach to the Patient... read more , and fatty acid oxidation defects Overview of Fatty Acid and Glycerol Metabolism Disorders Fatty acids are the preferred energy source for the heart and an important energy source for skeletal muscle during prolonged exertion. Also, during fasting, the bulk of the body’s energy needs... read more . Additional genetic defects include Alagille syndrome, cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency... read more , 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 Short Bowel Syndrome Short bowel syndrome is malabsorption resulting from extensive resection of the small bowel (usually more than two thirds the length of the small intestine). Symptoms depend on the length and... read more .
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.
1. Harpavat S, Garcia-Prats JA, Anaya C, et al: Diagnostic yield of newborn screening for biliary atresia using direct or conjugated bilirubin measurements. JAMA 323(12):1141–1150, 2020. doi: 10.1001/jama.2020.0837
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 of Neonatal Cholestasis
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 Overview of Malabsorption Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more of fat and fat-soluble vitamins (A, D, E, and K), leading to vitamin deficiency, inadequate nutrition, and growth failure.
Symptoms and Signs of Neonatal Cholestasis
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 of Neonatal Cholestasis
Total and direct bilirubin
Tests for metabolic, infectious, and genetic causes
Occasionally biopsy of liver, operative cholangiography, or genetic testing
(See also the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition's 2017 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 Diagnosis Biliary atresia is obstruction of the biliary tree due to progressive sclerosis of the extrahepatic bile duct. Diagnosis is by blood tests, ultrasonography, liver biopsy, and hepatobiliary scan... read more , 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 Tests for Cholestasis Laboratory tests are generally effective for the following: Detecting hepatic dysfunction Assessing the severity of liver injury Monitoring the course of liver diseases and the response to treatment... read more ). Once cholestasis is confirmed, testing is required to determine etiology ( see Table: Diagnostic Evaluation for Neonatal Cholestasis Diagnostic Evaluation for Neonatal Cholestasis ) and evidence of malabsorption Overview of Malabsorption Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more (eg, low levels of the fat-soluble vitamins E, D, K, and A, or prolonged PT, suggesting a low level of vitamin K).
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 Cholescintigraphy Imaging is essential for accurately diagnosing biliary tract disorders and is important for detecting focal liver lesions (eg, abscess, tumor). It is limited in detecting and diagnosing diffuse... read more ) 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 for Neonatal Cholestasis
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.
Gestational alloimmune liver disease has a poor prognosis without early intervention.
Treatment of Neonatal Cholestasis
Specific cause treated
Vitamin A, D, E, and K supplements
Sometimes ursodeoxycholic acid
(See also the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition's 2019 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 gestational 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 ( 1 Treatment reference Cholestasis is failure of bilirubin secretion, resulting in conjugated hyperbilirubinemia and jaundice. There are numerous causes, which are identified by laboratory testing, hepatobiliary scan... read more ).
1. Fischer HS, Staufner C, Sallmon H, et al: Early exchange transfusion to treat neonates with gestational alloimmune liver disease: An 11-year cohort study. J Pediatr Gastroenterol Nutr 70(4):444–449, 2020. doi: 10.1097/MPG.0000000000002593
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.
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition: 2017 Guideline for the evaluation of cholestatic jaundice in infants
North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition: 2019 Joint position paper on nutritional support of children with chronic liver diseases
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