No approved-drug candidate for congenital bile acid synthesis defect 3 is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Congenital bile acid synthesis defect 3 (CBAS1, 3β-hydroxy-Δ5-C27-steroid dehydrogenase deficiency) accounts for approximately 2% of persistent cholestasis in infants. In a 2015 case report, a one-month-old infant with persistent jaundice, hepatomegaly, and elevated aminotransferases (ALT 174 U/L, AST 195 U/L) had normal γ-glutamyltransferase (24 U/L) and total bile acid (2.2 μmol/L) concentrations. Genetic testing identified two novel compound heterozygous HSD3B7 mutations: a maternally inherited c.503G>A (p.Trp168Ter) causing premature transcription termination, and a paternally inherited c.683G>A (p.Arg228Gln) predicted damaging (PolyPhen score 1, SIFT score 0.05). The patient also carried a single SLC25A13 mutation without citrin deficiency. After initial ursodeoxycholic acid treatment (62.5 mg twice daily) and subsequent switch to chenodeoxycholic acid (41.66 mg twice daily) upon discharge, liver function improved (ALT 34 U/L, AST 143 U/L, TBIL 93.6 μmol/L, DBIL 78.00 μmol/L), and jaundice had completely faded with normalised aminotransferases at two-week telephone follow-up.
A 2024 systematic review of cholic acid treatment for bile acid synthesis defects included 14 publications (162 patients total) covering Zellweger spectrum disorders (n=73), 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency (n=62), cerebrotendinous xanthomatosis (n=22), Δ4-3-oxosteroid 5β-reductase deficiency (n=13), and α-methylacyl-CoA racemase deficiency (n=3). Treatment duration ranged from one week to 16.5 years. The overall risk of bias was critical in one study, serious in four, and moderate in nine. Major issues included missing data (10 studies), generalised data (8 studies), and no wash-out between treatments (4 studies). The review concluded that available data are insufficient to draw definite conclusions on the effectiveness and safety of cholic acid in these patients.
A 2025 case series of three first-degree relatives with congenital bile acid synthesis defect type 2 (AKR1D1 deficiency) reported significant clinical improvement after initiating cholic acid. Earlier literature notes that oral cholic acid has been considered effective in most bile acid synthetic defects, with early diagnosis considered crucial for prognosis. Ursodeoxycholic acid may have limited benefits and can even cause liver damage; once the diagnosis is confirmed, it should be stopped and replaced with primary bile acids. Chenodeoxycholic acid may have toxic effects on hepatic cells at late disease stages, making cholic acid the preferred option.
What is still missing: controlled prospective trials with adequate sample sizes, standardised outcome measures, and independent international disease registries to better utilise existing real-world data. The available evidence consists almost entirely of case reports and small case series with critical or serious risk of bias, and no randomised comparisons of cholic acid against placebo or alternative treatments have been performed.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Clinical Investigation · 1988 · 255 citations · open access
Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis.
AbstractA new inborn error in bile acid synthesis, manifest in identical infant twins as severe intrahepatic cholestasis, is described involving the delta 4-3-oxosteroid 5 beta-reductase catalyzed conversion of the key intermediates, 7 alpha-hydroxy-4-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one for chenodeoxycholic and cholic acid synthesis, to the respective 3 alpha-hydroxy-5 beta (H) products. This defect was detected by fast atom bombardment ionization-mass spectrometry from an elevated excretion and predominance of taurine conjugated unsaturated hydroxy-oxo-bile acids. Gas chromatography-mass spectrometry confirmed these to be 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acids (75-92% of total). Fasting serum bile acid concentrations were greater than 37 mumol/liter; chenodeoxycholic acid was the major bile acid, but significant amounts of allo(5 alpha-H)-bile acids (approximately 30%) were present. Biliary bile acid concentration was less than 2 mumol/liter and consisted of chenodeoxycholic, allo-chenodeoxycholic, and allo-cholic acids. These biochemical findings, which were identical in both infants, indicate a defect in bile acid synthesis involving the conversion of the delta 4-3-oxo-C27 intermediates into the corresponding 3 alpha-hydroxy-5 beta(H)-structures, a reaction that is catalyzed by a delta 4-3-oxosteroid-5 beta reductase enzyme. This defect resulted in markedly reduced primary bile acid synthesis and concomitant accumulation of delta 4-3-oxo-and allo-bile acids. These findings indicate a pathway in bile acid synthesis whereby side chain oxidation can occur despite incomplete alterations to the steroid nucleus, and lend support for an active delta 4-3-oxosteroid 5 alpha-reductase catalyzing the conversion of the delta 4-3-oxosteroid intermediates to the respective 3 alpha-hydroxy-5 alpha(H)-structures.
https://doi.org/10.1172/jci113837Journal of Pediatric Gastroenterology and Nutrition · 2006 · 138 citations
Defects in Bile Acid Biosynthesis‐Diagnosis and Treatment
AbstractBile acid synthetic defects represent a specific category of metabolic liver disease. This article highlights the history and summarizes our analytical approach to the diagnosis and treatment of genetic defects in bile acid synthesis. By the application of mass spectrometry as a screening tool, it is possible to perform rapid diagnosis of potential inborn errors in bile acid synthesis from urinary bile acid analysis. Molecular techniques then afford the identification of specific mutations in genes encoding the enzymes responsible for bile acid synthesis. Using this approach, 6 of the 7 known genetic defects that are causes of progressive cholestatic liver disease, syndromes of fat-soluble vitamin malabsorption, or neurological disease, have been characterized. Bile-acid therapy using oral cholic acid has proven effective in most of these bile acid synthetic defects making early diagnosis crucial to optimum clinical prognosis.
https://doi.org/10.1097/01.mpg.0000226386.79483.7bChinese Medical Journal · 2015 · 19 citations · open access
Novel Mutations in the 3β-hydroxy-Δ5-C27-steroid Dehydrogenase Gene (HSD3B7) in a Patient with Neonatal Cholestasis
AbstractBile acid synthetic defect (BASD) is a rare category of genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants.[1] Until date, four enzymes responsible for congenital defects of bile acid synthesis (CBAS) have been identified. 3β-hydroxy-[INCREMENT]5-C27-steroid dehydrogenase (3β-HSD), the deficiency of which can cause CBAS1 (OMIM No. 607765), is encoded by the gene HSD3B7 and works in the second step of transforming the steroid into primary bile acids. An infant (1 month and 9-day-old) was brought to our hospital by her parents with an indication of lasting jaundice. The baby had been delivered by spontaneous vaginal delivery without complications at the full-term gestation week, weighing 3300 g. Jaundice had appeared just 2 days after birth and persisted after 8 days. Her temperature at that time was normal, the stool sample had a light yellow color, and there was no sign of diarrhea or steatorrhea. After 3 days of treatment in another hospital, the patient was referred to our hospital because of hyperbilirubinemia and liver dysfunction. Initial physical examination on admission showed hepatomegaly (about 4 cm below the rib) and obvious jaundice. After admission, we conducted a thorough examination to determine the cause for cholestasis. The ultrasound scan indicated no particular sign of intrahepatic or extrahepatic bile duct malformation or obstruction. Tests for conventional pathogens in infants had no significant positive findings; these were as follows: Anti-Cytomegalovirus (CMV), anti-Rubella virus, and anti-Herpes simplex virus (HSV) I: IgM−, IgG+; anti-Toxoplasma gondii and anti-HSV II: IgM−, IgG−; anti-Parvovirus B19: IgM−; shell viral assay for urine human CMV detection: –; blood Epstein–Barr virus DNA: –; hepatitis A, B, C, and E virus antibodies: –; human immunodeficiency virus antibody: –; and syphilis antibody: –. Urine sample analysis by gas chromatography-mass spectrometry (GC-MS) ruled out several organic acidurias. Blood sample acylcarnitine and amino acid profiles did not support the diagnosis of fatty acid or amino acid metabolic diseases. Peculiarly, in spite of high aminotransferase (alanine aminotransferase [ALT] 174 U/L, aspartate aminotransferase [AST] 195 U/L) and bilirubin (total bilirubin [TBIL] 106.0 μmol/L, direct bilirubin [DBIL] 78.30 μmol/L) levels, the patient had normal γ-glutamyltransferase (GGT, 24 U/L) and total bile acid (2.2 μmol/L) concentrations, which led us to consider the possibility of BASD. With the parents’ consent, we ran a genetic test of the patient and her parents for a set of genes responsible for neonatal cholestasis. The potential influence of the detected mutations on protein function was estimated using Sorting Intolerant from Tolerant (SIFT) (http://sift.jcvi.org/www/SIFT_BLink_submit.html) and PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) software. Two compound heterozygous HSD3B7 gene mutations and a single SLC25A13 gene mutation were identified in the patient. Sequencing of the patient and parental homologous regions revealed the maternally inherited mutation c.503G>A (p.Trp168Ter) and the paternally inherited mutation c.683G>A (p.Arg228Gln) [Figure 1]. The SLC25A13 mutation c.852-855delTATG (p.Met285fs) was inherited from her mother, but the allele gene was normal.Figure 1: Sequence analysis of exons of the HSD3B7 gene of the patient. Two identified mutations were c.503G>A (p.Trp168Ter) in exon 5 and c.683G>A (p.Arg228Gln) mutation in exon 6. The patient inherited the aforementioned two mutations from her parents as the compound heterozygote. The nucleotide exchange and insertion are marked by arrows.The c.503G>A (p.Trp168Ter) mutation in exon 5 causes an abrupt termination of 3β-HSD transcription. The c.683G>A (p.Arg228Gln) mutation in exon 6 was predicated to have a probable damaging influence on protein function (PolyPhen score 1; SIFT score 0.05). Both HSD3B7 mutations mentioned above have not been identified either in 100 normal subjects studied by us or in Chinese members of the 1000 Genomes Project and other human populations. The SLC25A13 mutation causes neonatal intrahepatic cholestasis due to citrin deficiency (NICCD; MIM No. 605814). The patient inherited the SLC25A13 mutation from her mother and a normal SLC25A13 gene from her father, so she had no aminoacidemia, which is typical for NICCD. The patient's genetic results ultimately led to the diagnosis of CBAS1; however, the parents declined our proposal of liver biopsy. Ursodeoxycholic acid (UDCA) treatment (62.5 mg, b.i.d) had been initiated on the 2nd day of admission to relieve her clinical symptoms. After the establishment of CBAS1 diagnosis, we planned to switch to chenodeoxycholic acid (CDCA) treatment, but the parents demanded an early discharge and received CDCA treatment (41.66 mg, b.i.d) at another hospital. By the time of discharge from our hospital, the patient showed an improvement of liver function (ALT: 34 U/L, AST: 143 U/L, TBIL: 93.6 μmol/L, DBIL: 78.00 μmol/L; decreased aminotransferase and bilirubin; increased albumin, prealbumin, and globulin). At follow-up 2 weeks later by telephone, the parents informed that jaundice had completely faded, and the aminotransferase level had returned to normal. CBAS1 due to HSD3B7 mutations often has an early onset; in rare cases, adults with liver dysfunction turn out to be 3β-HSD deficient. 3β-HSD enzyme dysfunction can lead to bile acid biosynthesis errors, which will cause primary bile acid (cholic acid [CA] and CDCAs) deficiency and atypical bile acid and sterol accumulation. Lack of primary bile acids results in bile acid flow reduction, which in turn leads to fat and fat-soluble vitamin malabsorption. The atypical metabolites can be toxic to liver cells, resulting in liver dysfunction. Although the clinical manifestations in patients (including cholestasis, bleeding tendency, rickets, failure to thrive, etc.)[2] are varied, the GGT and total bile acid concentrations are usually within normal range.[3] Liver biopsy often shows giant cell hepatitis, and at late stages, bridging fibrosis and micronodular cirrhosis can also be seen.[2] Bile acid analysis of serum and urine using GC-MS or fast atom bombardment MS (FAB-MS) is a conventional way to screen BASD, but this test is currently not available in China. CDCA or CA treatments have been recommended by some doctors on the basis of clinical data, where patients who received treatment at an early age remained asymptomatic for many years and could develop normally. CA seems to be a better choice than CDCA, because, at late disease stages, CDCA may have toxic effects on hepatic cells.[3] Gonzales et al. investigated the long-term effect of oral CA for hereditary defects of primary bile acid synthesis and suggested it was safe and effective for 3β-HSD-deficient patients.[4] UDCA treatment can have limited benefits, but it has little effect in reducing the harmful intermediate metabolites in urine[5] and can even cause liver damage. Our patient was admitted for cholestasis, the common causes of which had been excluded after a thorough examination. Her GGT and total bile acid levels stayed normal after admission, which reminded us of BASD. Because serum and urine bile acid analyses by GC-MS and FAB-MS were not available, we tested for cholestasis-related gene mutations instead. We identified two novel HSD3B7 gene mutations in our patient, which could be a new underlying pathogenesis of 3β-HSD deficiency. BASD accounts for about 2% of neonatal cholestasis cases, and early primary bile acid replacement treatment can achieve good results.[5] For cholestasis with normal GGT and total bile acid concentrations, the possibility of BASD should be considered and confirmed with genetic testing. Even though initial UDCA treatment can have some beneficial effects, it is important to investigate further instead of immediately concluding a diagnosis of idiopathic cholestasis. Once confirmed, the UDCA must be stopped immediately and be replaced with primary bile acids. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
https://doi.org/10.4103/0366-6999.172603Orphanet Journal of Rare Diseases · 2024 · 3 citations · open access
The clinical and biochemical effectiveness and safety of cholic acid treatment for bile acid synthesis defects: a systematic review
AbstractAbstract Background Bile acid synthesis defects (BASDs) can be severely disabling involving the liver and nervous system, potentially due to elevated levels of toxic C 27 -bile acid intermediates. Cholic acid (CA) supplementation is hypothesized to decrease bile acid production, stimulate bile secretion and -flow, and slowing down disease progression. This systematic review assesses the clinical and biochemical effectiveness, and safety of CA in BASDs patients. Methods A systematic review of MEDLINE, Embase and clinical trial registries (ClinicalTrials.gov, ICTRP registry) using controlled MeSH- and Emtree terms. Results From 526 articles 70 publications were deemed eligible for inclusion based on title and abstract. 14 publications were included after full-text assessment comprising case reports and -series with 1–35 patients (162 patients in total) receiving 1 week to 16,5 years of CA treatment. All presented data on effectiveness, 8 studies also presented data on safety. The included population concerned patients with Zellweger spectrum disorders ( n = 73), 3β-Hydroxy-Δ5-C 27 -steroid oxidoreductase deficiency ( n = 62), cerebrotendinous xanthomatosis ( n = 22), Δ4-3-oxosteroid 5β-reductase deficiency ( n = 13), and α-methylacyl-CoA racemase deficiency ( n = 3). Main outcomes concerned liver disease (12 studies), general physical examinations, biochemical outcomes, and safety (9 studies), and fat-soluble vitamin absorption (7 studies). The overall risk of bias score was considered to be critical (1 study), serious (4 studies), and moderate (9 studies). Major issues were missing data (10 studies), generalized data (8 studies), and no wash-out between treatments (4 studies). Conclusion More controlled studies are required as the available data is insufficient to draw definite conclusions on the effectiveness and safety of CA treatment in BASD patients. Establishing an independent international disease registry could better utilize existing real-world data.
https://doi.org/10.1186/s13023-024-03449-7Journal of Pediatric Gastroenterology and Nutrition · 1983 · 3 citations
Neonatal Cholestatic Syndromes Associated with Alterations in Bile Acid Synthesis
AbstractIn summary, the conditions discussed above are examples of diseases that result in deficient bile acid synthesis and production of abnormal bile acids. Although the relationship between the production of these abnormal bile acids and the pathogenesis of these diseases remains unknown, they continue to provide us with a better understanding of normal pathways of bile acid production. Clearly, more studies are needed before these interesting metabolic defects and normal infantile bile acid metabolism itself are well understood.
https://doi.org/10.1097/00005176-198302020-00028BMJ Case Reports · 2025 · 0 citations
Varied phenotypic presentation of congenital bile acid synthesis defect type 2 in a set of first-degree relatives with the same genetic mutation
AbstractBile acid synthesis disorders represent a rare subset of cholestatic conditions that, if unrecognised, may progress to end-stage liver disease requiring transplantation. These disorders result from deficiencies in one of the 17 enzymes involved in the conversion of cholesterol into primary bile acids. We present a case series of three first-degree relatives diagnosed with congenital bile acid synthesis defect type 2 (AKR1D1 deficiency), a disorder characterised by impaired steroid 5β-reductase activity. After initiating cholic acid, all patients demonstrated significant clinical improvement.
https://doi.org/10.1136/bcr-2025-266785Institutional Research Information System University of Ferrara (University of Ferrara) · 2018 · 0 citations
L’acido colico nel trattamento degli errori congeniti del metabolismo degli acidi biliari
AbstractInborn errors of primary bile acid synthesis are rare genetic disorders that cause chronic liver disease, steatorrhea and fat-soluble vitamins deficiency in childhood. Absence of itching, normal γGT and serum bile acids suggest the diagnosis, confirmed by urinary mass spectrometry and gene analysis. Oral cholic acid is a safe and effective therapy for the most common defects that if untreated may lead to early cirrhosis and \nliver failure.
https://doi.org/10.19186/ggenp_2018.007Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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