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Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood., (© 2023 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Parenteral nutrition (PN) has been strongly associated with intestinal failure-associated liver disease. Cholestasis, liver steatosis, and liver fibrosis are features of this liver injury, which can progress to end stage liver disease. Omega-3 fatty acid rich PN has been shown to alleviate cholestasis and steatosis. There have been reports although suggesting that it may not be able to arrest or reverse the progression to liver fibrosis. In this article, we develop a hypothesis of the mechanism of how Ω-3 fatty acid rich PN may influence the progression of fibrosis.

Objectives: Low γ-glutamyl transpeptidase (GGT) level is an important marker for progressive familial intrahepatic cholestasis, yet the cutoff level and clinical application is not well defined. This study aimed to evaluate the role of GGT as a screening marker among diverse etiologies of infantile cholestasis., Methods: This retrospective study analyzed 256 cholestatic infants admitted to a tertiary referral center between 2000 and 2012. After excluding 121 infants of extrahepatic cholestasis, advanced investigations for 135 infants with intrahepatic cholestasis were performed. The etiologies, outcomes, and correlations with GGT levels were analyzed. Good prognosis was defined as clinical recovery before 1 year of age; poor prognosis as persistent disease, liver transplantation, or death before 1 year., Results: Among 135 patients of intrahepatic cholestasis, >12 different etiologies were found. Neonatal hepatitis (49.6%), progressive familial intrahepatic cholestasis (21.5%), and neonatal cholestasis caused by citrin deficiency (10.4%) were the leading causes. Patients with initial GGT between 75 and 300 U/L had a higher chance of good prognosis (61/74, 82.4%) than those with GGT <75 U/L or >300 U/L (25/61, 41%, P < 0.0001). In the low-GGT group (≤ 100 U/L), 52.6% (30/57) of the patients have good prognosis; and GGT level ≤ 75 U/L has a sensitivity, specificity, and positive predictive value of 100%, 43.3%, and 61.4% in predicting poor prognosis., Conclusions: Patients with GGT levels ≤ 75 or ≥ 300 U/L should receive advanced investigations such as genetic/metabolic assays early; otherwise, the amount of diagnostic workup may be limited if no signs of progressive disease.

Background: Subacute nonsuppurative cholangitis (cholangitis lenta) is an uncommon yet important histological finding in liver biopsies from pediatric liver transplant recipients. The histopathological features include proliferation of bile ductules at the edges of portal tracts, inspissated bile within dilated bile ductules, absence of acute inflammation within ducts or ductules, and normal structure of interlobular bile ducts., Objective: To describe the histopathology and clinical outcomes of pediatric liver transplant recipients with subacute nonsuppurative cholangitis., Materials and Methods: This is a retrospective analysis involving review of medical records and analysis of liver-biopsy specimens by a pathologist blinded to clinical diagnosis. We identified 9 pediatric patients meeting the criteria for nonsuppurative cholangitis. These patients were compared with a control group of patients with biliary obstruction., Results: Liver histopathology clearly distinguishes subacute nonsuppurative cholangitis from biliary obstruction and other causes of posttransplant cholestasis. Clinical biochemistry cannot reliably distinguish between the 2, although statistically significant differences existed in levels of serum total and direct bilirubin, alanine aminotransferase, and alkaline phosphatase. The rate of proven bacterial or fungal infection in the study group was 100% in contrast to a rate of 54.5% in the control group (P < .05). Graft and patient survival were similarly poor., Conclusions: : Finding subacute nonsuppurative cholangitis suggests the presence of severe local or systemic infection in liver-transplant recipients, and its recognition is important for clinical management.

Objective: Lipoprotein metabolism in FIC1 deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency., Patients and Methods: Lipoprotein profile and major lipoprotein regulators such as lecithin:cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation, was also examined., Results: Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotein (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last 1 to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers., Conclusions: The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.

Background: Inborn errors of bile acid synthesis are newly recognized disorders that may cause the phenotypic appearance of neonatal hepatitis or neonatal cholestasis., Methods: This is a clinicopathologic study of two sets of siblings with cholestatic neonatal liver failure., Results: In 3 of the infants, diagnostic evaluation, including analysis of urinary bile salts, revealed a predominance of 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha, 12 alpha-dihydroxy-3-oxo-4-cholenoic acids, a pattern consistent with delta 4-3-oxosteroid 5 beta-reductase deficiency, which could be primary or secondary. The fourth infant died before such testing could be carried out. In addition, all 4 infants had histologically disseminated hemochromatosis and met diagnostic criteria for neonatal hemochromatosis. In the 3 infants studied, histologic examination of the liver disclosed giant cell hepatitis with extensive loss of hepatic parenchyma and rapid progression to cirrhosis. Early treatment with ursodeoxycholic acid and cholic acid, previously reported as effective therapy, was given to 2 siblings; it failed to reverse or halt the liver damage, and both infants died. One infant, with the original diagnosis of neonatal hemochromatosis, was treated with a variety of antioxidants and chelation therapy, as recently reported. No improvement was demonstrated, and he went on to liver transplantation., Conclusions: The presentation of delta 4-3-oxosteroid 5 beta-reductase deficiency as neonatal hemochromatosis may represent a distinct subset of this disorder with an accelerated course, no response to therapy and poor prognosis.

Hypothalamic hypopituitarism was diagnosed in a 3-month-old boy presenting with cholestatic liver disease, which resolved 5 weeks after the start of replacement therapy with hydrocortisone and human growth hormone. Clinical and pathohistological features of liver disease associated with neonatal hypopituitarism in this patient are compared to those of patients reviewed from the literature. Urinary excretion of dopa and 3-methoxytyramine but not of other catecholamine metabolites was elevated during cholestatic liver disease. 3-Methoxytyramine excretion normalized when cholestasis resolved. Altered hepatic metabolism of catecholamines due to growth hormone and cortisol deficiency may explain this observation.

A 4-week-old infant presenting with neonatal cholestasis was found to have congenital toxoplasmosis and biliary atresia. This is the first patient in which their coincidence is reported. Because biliary atresia can coexist with either congenital infection or inborn errors of metabolism, evaluation for an obstructive etiology of jaundice in infants with a recognized cause of intrahepatic cholestasis is necessary.

Three children with surgically corrected extrahepatic biliary atresia developed recurrent cholangitis associated with bile lakes that failed to drain via the hepatoportoenterostomy. Surgical or percutaneous drainage of these cysts was followed by both resolution of the infection and spontaneous internal drainage. We postulate that the ongoing inflammatory process resulted in intrahepatic biliary obstruction, which caused cholangitis and bile cysts. Successful treatment required not only antibiotics but drainage of the bile lakes. Development of bile cysts is a new cause of recurrent cholangitis seen in extrahepatic biliary atresia.