What causes cholestasis in neonates with elevated International Normalized Ratio (INR) and normal gamma-glutamyltransferase (GGT) levels?

From the Guidelines

Neonatal cholestasis with deranged INR and normal gamma-GGT suggests progressive familial intrahepatic cholestasis (PFIC) types 1 or 2, or potentially biliary atresia in early stages, and immediate management should include vitamin K administration and referral to pediatric hepatology for further evaluation and potential surgical intervention. The management of neonatal cholestasis involves a multidisciplinary approach to prevent long-term liver damage and other complications.

Key Management Steps

• Immediate vitamin K administration (1-2 mg IV or IM) to correct coagulopathy, followed by oral supplementation of fat-soluble vitamins: vitamin K (2.5-5 mg daily), vitamin D (800-1200 IU daily), vitamin E (25-50 IU/kg daily), and vitamin A (5000-10000 IU daily) 1.
• Ursodeoxycholic acid (15-30 mg/kg/day divided in 2-3 doses) should be started to improve bile flow.
• The infant requires urgent referral to pediatric hepatology for further evaluation including liver biopsy, genetic testing, and potential surgical intervention if biliary atresia is suspected.
• Nutritional support with medium-chain triglyceride (MCT) formula and adequate caloric intake (120-150 kcal/kg/day) is essential.
• Monitor liver function tests, coagulation parameters, and fat-soluble vitamin levels regularly.

Importance of Early Intervention

Early intervention is critical as untreated cholestasis can rapidly progress to liver failure, with some conditions like biliary atresia requiring surgical intervention (Kasai procedure) within the first 60 days of life for optimal outcomes. The normal gamma-GGT in the setting of cholestasis is particularly concerning for genetic disorders affecting bile acid transport proteins rather than obstructive causes 1.

Recent Guidelines and Recommendations

Recent guidelines suggest that liver transplantation currently remains the standard of care for progressive cholestasis in certain genetic disorders, and referral to a liver transplant centre is strongly encouraged for patients with substantial liver involvement 1.

From the Research

Cholestasis in Neonates with Deranged INR and Normal Gamma-GGT

• Cholestasis in neonates is characterized by conjugated hyperbilirubinemia and can be a sign of over 100 hepatobiliary and/or metabolic disorders 2, 3.
• A timely evaluation of the etiology of cholestasis is critical to identify treatable causes, such as biliary atresia, and to optimize outcomes for all infants 2, 3, 4.
• The diagnostic approach to neonatal cholestasis involves a step-wise evaluation, including serum bilirubin level fractionation, to rapidly identify the underlying etiology 5.
• Genetic testing panels are increasingly used to help identify causes of cholestasis, and next-generation sequencing has transformed the ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks 2, 3, 4.
• Current therapies for cholestasis focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, but do not address the underlying cause of cholestasis in most instances 2, 3.
• Ursodeoxycholic acid (UDCA) is a therapeutic agent commonly used in the treatment of cholestatic hepatopathies, with multiple mechanisms of action, including stabilizing plasma membranes, halting apoptosis, and inducing changes in the expression of metabolizing enzymes and transporters 6.

Laboratory Findings

• Deranged INR and normal gamma-GGT levels can be seen in neonates with cholestasis, but the exact cause and optimal therapy for biliary atresia remain elusive 2, 3.
• Serum matrix metalloproteinase-7 has been studied as a potential diagnostic marker for biliary atresia, with excellent diagnostic performance characteristics 4.
• Genetic testing can identify a definite or possible genetic diagnosis in a subset of cholestatic infants, highlighting the importance of genetic testing in the diagnostic workup 4.

Treatment and Management

• Early recognition and treatment of neonatal cholestasis are essential to ensure timely treatment and optimal prognosis, even when specific treatment is not available 5.
• UDCA is a commonly used therapeutic agent in the treatment of cholestatic hepatopathies, with a long-lasting use predicted due to its multiple hepatoprotective effects 6.
• New emerging therapies, such as ileal bile acid transport inhibitors, are being studied for the treatment of pruritus in Alagille syndrome and progressive familial intrahepatic cholestasis 4.