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NORD gratefully acknowledges William F. Balistreri, MD, Director, Pediatric Liver Care Center, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital, for assistance in the preparation of this report.
Neonatal cholestasis refers to impaired flow of bile at any point from the liver cells into the intestine of a newborn.
Neonatal cholestasis may be caused by viruses, metabolic disease or genetic disorders, as well as other rare diseases that affect or impair the function of the liver. In a small percent of patients, the cause of liver injury is unknown – these cases are referred to as idiopathic neonatal hepatitis (INH). The incidence of neonatal cholestasis is estimated to be ~1:2500 live births worldwide, and 25% to 50% are now known to be associated with changes (variants or mutations) in specific genes.
The symptoms of neonatal cholestasis may vary from one individual to another. Symptoms of liver disease include yellowing of the whites of the eyes and the skin (jaundice), enlargement of the liver (hepatomegaly), unusually dark urine and poor growth. Some individuals with neonatal cholestasis fully recover from the condition (sporadic or transient forms); however, some will progress to chronic liver disease (persistent or progressive forms).
The liver is located on the right side of the abdominal cavity just under the rib cage. The liver has many different functions including filtering harmful substances (toxins, including bilirubin) out of the bloodstream, synthesizing proteins, storing essential vitamins, helping to breakdown (metabolize) food to use as energy, creating components that help the blood form clots in response to injury and producing bile, a liquid that plays an essential role in breaking down fats in the small intestine.
Neonatal cholestasis can range from a mild, temporary (transient) disease that improves without treatment to more serious forms that cause additional complications. The common symptoms of liver disease may appear anytime during the first few weeks of life. By the age of 2 to 3 months, it becomes clear that an infant with neonatal cholestasis is not gaining weight and is growing at a slower than normal rate (failure to thrive). The infant may be irritable because of excessively itchy skin (pruritus). Other symptoms may include enlargement of the spleen (splenomegaly).
In more serious forms of neonatal cholestasis additional symptoms can occur including easy bruising, prolonged bleeding, infection (sepsis) and/or the accumulation of body fluids within the abdomen (ascites) in the later stages of chronic liver injury. Liver (hepatic) failure may eventually develop in some individuals with severe forms of neonatal cholestasis.
Neonatal cholestasis, in general, has many different causes including several viruses including cytomegalovirus and the herpes viruses, various metabolic liver diseases or genetic disorders such as alpha-1-antitrypsin deficiency, PFIC and Alagille syndrome. Other rare disorders may also impair the function of the liver. All of these disorders should be diagnosed promptly. According to the medical literature, 15-20% of cases of neonatal cholestasis run in families (familial form) – and in recent years multiple studies have shown that genetic factors play a role in its development.
The incidence of neonatal cholestasis in the general population is unknown. The proportion of cases classified as “idiopathic” has diminished as advanced diagnostic techniques and a better molecular understanding of cholestatic diseases in general have allowed physicians to diagnose many infants as being affected with specific syndromes. In the past, these infants would have been included as having idiopathic neonatal hepatitis.
Neonatal cholestasis is a diagnosis made by excluding other conditions.
The key to diagnosis is early recognition of neonatal jaundice (elevated levels of conjugated bilirubin in the blood – hyperbilirubinemia). This allows the timely initiation of a diagnostic evaluation to identify treatable disorders. Therefore, any infant jaundiced beyond 14 days of life should have blood tests done to determine if the jaundice is due to cholestasis (elevated conjugated bilirubin levels) or is associated with elevated unconjugated bilirubin levels. The latter is normal (“physiologic jaundice”) or related to breast milk feeding.
The structure of the liver and the surrounding ducts and blood vessels can be examined by ultrasonography. In some patients, a liver biopsy may be necessary. During a biopsy, a needle and syringe are used to remove a small piece of liver tissue. This sample is studied under a microscope. A liver biopsy may be able to rule out other liver disorders such as those that affect the inside of the liver (intrahepatic disorders) and extrahepatic disease (biliary atresia).
The current gold standard for the diagnosis of inherited syndromes of neonatal cholestasis is genetic testing. Typically, patients with otherwise unexplained cholestasis despite extensive diagnostic work-up (laboratory assessment and liver biopsy) undergo a search for mutations in genes associated with liver disease.
There is no specific treatment available for infants with neonatal cholestasis. Treatment is directed toward the specific symptoms that are apparent in each individual.
Careful attention to nutritional needs and diet are essential for infants with this disorder. Special supplements (i.e., fat-soluble vitamins), formulas, and/or dietary restrictions may be suggested by the physician. Special infant formulas may be prescribed, for example, malabsorption of long-chain triglycerides may be corrected with formulas that contain medium-chain triglycerides.
If itching (pruritus) becomes a problem, drug that have been used to treat itching associated with cholestasis include ursodeoxycholic acid and inhibitors of the ileal bile acid transporter.
A surgical choice of last resort for infants who develop end-stage liver disease is liver transplantation.
Emerging novel treatment strategies based on the understanding of the specific genetic variants present in a patient will allow a “personalized medicine” approach that will offer the promise for significantly improved quality of life and overall patient care in the near future.
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Contact for additional information about neonatal cholestasis:
William F. Balistreri, M.D.
Director, Pediatric Liver Care Center
Division of Pediatric Gastroenterology,
Hepatology and Nutrition
Cincinnati Children’s Hospital
3333 Burnet Avenue
Cincinnati, Ohio 45229-3039
Behrman RE, Kliegman RM, Jenson HB. Eds. Nelson Textbook of Pediatrics. 20th Edition. Elsevier Saunders. Philadelphia, PA; 2016.
Suchy F, Sokol R, Balistreri WF, eds. Liver Disease in Children, 5th Edition. Cambridge University Press, 2021.
Patrinos ME, Harrigan R. Idiopathic Neonatal Hepatitis. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:288.
Balistreri WF, Bezerra JA. Whatever happened to neonatal hepatitis? Clin Liver Dis. 2006;10:27-53.
The Merck Manuals Online Medical Library. Neonatal Cholestasis. Last Update: Sept 2023. Available at: https://www.merckmanuals.com/professional/pediatrics/gastrointestinal-disorders-in-neonates-and-infants/neonatal-cholestasis Accessed Jan 25, 2024.
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