Inborn Error Of Bile Acid Metabolism Research Articles

Navigating cholestasis: identifying inborn errors of bile acid metabolism for precision diagnosis.

Inborn errors of bile acid metabolism (IEBAM) cause cholestasis during the neonatal period, and 8 types of IEBAM have been reported to date. IEBAM accounts for approximately 2% of cases of cholestasis of unknown cause. As only 10 patients have been identified in Japan, IEBAM presents diagnostic challenges due to the similarity of clinical symptoms with biliary atresia, thus necessitating precise differentiation to avoid unnecessary invasive procedures. Laboratory tests in IEBAM are characterized by normal γ-glutamyltransferase (GGT) and serum total bile acid (STBA) levels despite the presence of cholestasis; therefore, measuring STBA and GGT is essential to distinguishing biliary atresia from IEBAM. With suspected IEBAM, liquid chromatography-mass spectrometry (LC/MS) analysis of urinary bile acids is needed to optimize diagnostic and therapeutic efficacy and avoid open cholangiography and initiate treatment for primary bile acids such as cholic acid or chenodeoxycholic acid. This prospective report aims to increase awareness of IEBAM by highlighting the characteristics of general blood test and bile acid profiles from LC/MS analyses of blood, urine, and stool samples.

AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases

Inborn errors of bile acid metabolism (IEBAM) cause rare but treatable genetic disorders that can present as neonatal cholestasis or neurological diseases. Without timely primary bile acid treatment, patients may develop liver failure early in life. This study aimed to analyze the types and treatment outcomes of IEBAM in Taiwanese infants and document the allele frequency of CYP7B1 hot spot mutations in the population. Urine samples from patients with infantile intrahepatic cholestasis and suspected IEBAM were subjected to urinary bile acid analysis by gas chromatography-mass spectrometry (GC/MS). Genetic diagnoses were made using direct sequencing or next-generation sequencing. We also tested healthy control subjects for a probable hot spot point mutation of CYP7B1. Among the 75 patients with infantile intrahepatic cholestasis tested during 2000 -2016, three had ∆4-3-oxosteroid 5β-reductase deficiency with AKR1D1 mutations, and three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation. Two patients with ∆4-3-oxosteroid 5β-reductase deficiency were successfully treated with cholic acid. The three unrelated infants with oxysterol 7α-hydroxylase deficiencies had the same p.R112X homozygous CYP7B1 mutation. Two had mild renal or neurological involvement. Among 608 healthy control subjects, the allele frequency of the heterozygous mutation for p.R112X was 2/1216 (0.16%). The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age. Distinct types of IEBAM disease were found in the Taiwanese population. Patients with early diagnosis and early treatment had a favorable outcome. IEBAM prevalence rates may be higher than expected due to the presence of heterozygous mutations in the general population.

Diagnostic determination system for high‐risk screening for inborn errors of bile acid metabolism based on an analysis of urinary bile acids using gas chromatography–mass spectrometry: Results for 10 years in Japan

Some patients with cholestasis of unknown cause may have inborn errors of bile acid metabolism (IEBAM) thus causing abnormalities of bile acid biosynthesis. Although seven types of bile acid synthetic defects have thus far been reported for this disorder, no detailed information on its incidence and so on in Japan is yet available. In order to elucidate the current status of IEBAM in Japan, in July 1996 a diagnostic determination system was established for high-risk screening for IEBAM. Urinary bile acids were analyzed on gas chromatography-mass spectrometry (GC-MS) and quantitative analysis was done using selected ion monitoring (SIM). In a total of 576 samples analyzed over the 10 year period prior to June 2005, 159 patients were found with cholestasis of unknown etiology. Of these patients, 10 (6.3%) were found to have IEBAM by this system, while 91 (61.1%) had cholestasis without a definitive diagnosis. This diagnostic determination system with GC-MS of urinary bile acids is therefore considered useful for detecting IEBAM.