FORMERLY REFERRED TO AS IDIOPATHIC NEONATAL HEPATITIS (INH)
Definition
Idiopathic neonatal cholestasis is a diagnosis that is applied when a cause for neonatal cholestasis cannot be found despite extensive diagnostic evaluation. The term idiopathic neonatal hepatitis, “INH”, is specifically used when a liver biopsy shows characteristic features, including hepatocyte giant cell transformation, in an infant with idiopathic cholestasis. Cholestasis affects 1 in every 2,500 – 5,000 infants (1,2). In the 1970s, “INH” was responsible for up to 65% of cases of neonatal cholestasis. As new genetic causes of infantile cholestasis have been identified, this figure has decreased over time: only 25 – 30% of cases were designated as idiopathic in the 1980’s (3) and, recently, only about 15% of neonates with cholestasis remain undiagnosed and hence labeled as having idiopathic cholestasis or “INH” (4,5).
Etiology
By definition, idiopathic neonatal cholestasis is of unknown cause or causes.
Pathogenesis
In some infants, it is likely that spontaneously resolving forms of neonatal cholestasis result from perinatal distress leading to hepatic hypoxia or ischemia (6). In other cases, when GGT levels are normal or nearly normal, idiopathic neonatal cholestasis may result from reduced antioxidant protection, decreased bile-acid independent bile flow and/or defects in the hepatocellular canalicular adenosine triphosphate (ATP) dependent transport system involved in bile formation; it is conceivable that some of these infants have unidentified gene variants playing a role in their cholestasis (1,2,7). Likewise, heterozygous mutations in genes associated with bile transport have been identified in association with transient “idiopathic” neonatal cholestasis (1). Because idiopathic neonatal cholestasis is likely due to diverse etiologies, our knowledge of the precise pathogenetic mechanisms is evolving.
Clinical Features
Infants with idiopathic neonatal cholestasis present with protracted jaundice due to direct/conjugated hyperbilirubinemia and may or may not have other symptoms, such as failure to thrive, fat soluble vitamin deficiencies, and acholic stools. In those whose subsequently recover, aminotransferase (AST, ALT, and GGT) levels may rise slightly during the first three months of life before they begin to normalize (2,8).
Diagnosis
There are many causes of infantile cholestasis (1,4,9). Diagnostic evaluation is guided by the clinical context. Typically, biliary atresia, choledochal cyst, alpha-1-antitrypsin deficiency, Alagille syndrome, PFIC and other genetic disorders causing cholestasis, panhypopituitarism, congenital infection, and cystic fibrosis are excluded. If a comprehensive workup fails to reveal a specific cause, a diagnosis of idiopathic neonatal cholestasis is applied. A liver biopsy may show giant cell hepatitis but this finding can also be seen in a number of disorders with specific etiologies such as neonatal panhypopituitarism. Electron microscopy and immunohistochemistry can sometimes direct further metabolic and genetic studies, so consultation with a pathologist prior to liver biopsy can assure proper handling of the specimen. Unlike other specific causes of neonatal cholestasis, there is no universally accepted list of diagnostic tests needed to establish a diagnosis of INH; it is, by definition, a diagnosis of exclusion. Likewise, there are no universally accepted histopathologic features associated with a diagnosis of INH.
Genetics
Since the causes/s are unknown, there is no specific genetic test for this condition, but genetic testing is typically performed to rule out genetic disorders that can cause infantile cholestasis.
Treatment
The treatment is supportive. This may include alimentation with an elemental formula enriched with medium chain triglycerides if exclusive breast feeding does not promote growth, and supplementation with fat soluble vitamins. Many experts (4) would also utilize ursodeoxycholic acid to promote bile flow.
Prognosis
Most infants will normalize bilirubin by 3 – 5 months of age, although some remain jaundiced or have elevated liver enzymes for much longer (2,8). Normalization of AST, ALT, and GGT usually happens after normalization of bilirubin – closer to 7 months of age, although a few infants may exhibit elevated liver enzymes for years after diagnosis (2,8). The ultimate prognosis likely relates to the underlying cause of cholestasis.
References
- Feldman AG, Sokol RJ. Neonatal cholestasis: updates on diagnostics, therapeutics, and prevention (2021). Neoreviews 22(12):e819-e836.
- Wang JS, Tan N, and Dhawan A. Significance of low or normal serum gamma glutamyl transferase level in infants with idiopathic neonatal hepatitis Eur J Pediatr (2006): 165: 795 – 801.
- Mieli-Vergani G, Howard ER, Mowat AP (1991). Liver disease in infancy: a 20 year perspective. Gut 32 (Suppl) S123-S128.
- Balistreri WF, Bezerra JH (2006). Whatever happened to “neonatal cholestasis?” Clin Liver Dis 10 (1):27-53.
- Hoerning A, Raub S, Dechene A et al. Diversity of disorders causing neonatal cholestasis – the experience of a tertiary pediatric center in Germany (2014). Front Pediatr 2:65.
- Herzog D, Chessex P, Martin S et al. Transient cholestasis in newborn infants with perinatal asphyxia Can J Gastroenterol 2003:17:179-82.
- Ballatori N, Truong AT (1995) Multiple canalicular transport mechanisms for glutathione S-conjugates. Transport on both ATP- and voltage-dependent carriers. J Biol chem. 270 (8):3594-3601.
- Hertel PM, Hawthorne K, Kim S, et al (2021). Presentation and outcomes of infants with idiopathic cholestasis: a multicenter prospective study. JPGN 73:478-484.
- Fawaz R, Baumann U, Ekong U, et al. (2017). Guideline for the evaluation of cholestatic jaundice in infants: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition J Pediatr Gastroenterol Nutr 64(1):154-168.
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