Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns

Stefan Bittmann *

Department of Pediatrics, Ped Mind Institute (PMI), Germany and Department of Pediatrics, Hindenburgring 4, D-48599 Gronau, Germany and Shangluo Vocational and Technical College, Shangluo, 726000, Shaanxi, China.

*Author to whom correspondence should be addressed.


Abstract

Primary bile acid disorders (BASD) in newborns are rarely found with a prevalence of 1-9/1,000,000 and include 1-2 % of all cases with neonatal cholestasis. Causes are different gene defects, which lead to liver enzyme defects, which play a major role in both cholic acid pathways, the classical with production of cholic acid and the alternative one with chenodeoxycholic acid. They are found in both genders in the same distribution. Early diagnosis is very important to introduce a bile acid replacement therapy as soon as possible as the treatment of choice to date. Diagnosis will be confirmed by molecular trsting, liver biopsy and different forms of mass spectrometry methods. Differential diagnosis includes progressive familial intrahepatic cholestasis, neonatal hepatitis and biliary atresia. Further gene therapy approaches must be developed, like CRISP Cas9 technology, to repair the spontaneous point mutations on DNA of these patients to cure and not to treat them their whole life finally.

Keywords: BASD, children, cholestasis, bile acid


How to Cite

Bittmann , S. (2024). Primary Bile Acid Disorders: A Largely Unknown Group of Rare Genetic Diseases in Newborns. Asian Journal of Pediatric Research, 14(5), 1–7. https://doi.org/10.9734/ajpr/2024/v14i5340

Downloads

Download data is not yet available.

References

Ichimiya H, et al. Treatment of chronic liver disease caused by 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase deficiency with chenodeoxycholic acid. Arch Dis Child. 1990;65:1121–1124.

Setchell KD, et al. Identification of a new inborn error in bile acid synthesis: Mutation of the oxysterol 7α-hydroxylase gene causes severe neonatal liver disease. J Clin Invest. 1998;102:1690–1703.

Schwarz M, et al. Disruption of cholesterol 7alpha-hydroxylase gene in mice: II. bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase. J Biol Chem. 1996;271:18024–18031.

Schwarz M, et al. Identification and characterization of a mouse oxysterol 7alpha-hydroxylase cDNA. J Biol Chem. 1997;272:23995–24001.

Axelson M, Sjovall J. Potential bile acid precursors in plasma—Possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man. J Steroid Biochem. 1990;36:631–640.

Shoda J, et al. Formation of 7 alpha- and 7-beta-hydroxylated bile acid precursors from 27-hydroxycholesterol in human liver microsomes and mitochondria. Hepatology. 1993;17:395–403.

Ishibashi S, et al. Disruption of cholesterol 7alpha-hydroxylase gene in mice: I. postnatal lethality reversed by bile acid and vitamin supplementation. J Biol Chem. 1996;271:18017–18023.

Gonzales E, et al. SRD5B1 (AKR1D1) gene analysis in delta(4)-3-oxosteroid 5beta-reductase deficiency: evidence for primary genetic defect. J Hepatol. 2004; 40:716–718.

Lemonde HA, et al. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003; 52:1494–1499.

Setchell KD, et al. Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis: A new inborn error of bile acid synthesis. J Clin Invest. 1988;82:2148–2157.

Heubi JE, et al. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007; 27:282–294.

Siafakas CG, et al. Abnormal bile acid metabolism and neonatal hemochromatosis: A subset with poor prognosis. J Pediatr Gastroenterol Nutr. 1997;25:321–326.

Shneider BL, et al. Delta 4-3-oxosteroid 5 beta-reductase deficiency causing neonatal liver failure and hemochromatosis. J Pediatr. 1994;124: 234–238.

Clayton PT, et al. Delta 4-3-oxosteroid 5 beta-reductase deficiency: Failure of ursodeoxycholic acid treatment and response to chenodeoxycholic acid plus cholic acid. Gut. 1996;38:623–628.

Levy P, et al. Acute infusions of bile salts increase biliary excretion of iron in iron-loaded rats. Gastroenterology. 1991;101: 1673–1679.

Clayton PT, et al. 3-Oxo-delta 4 bile acids in liver disease. Lancet. 1988;1: 1283–1284.

Sumazaki R, et al. Gene analysis in delta 4-3-oxosteroid 5 beta-reductase deficiency. Lancet. 1997;349:329.

Bove KE, et al. Bile acid synthetic defects and liver disease. Pediatr Dev Pathol. 2000;3:1–16.

Daugherty CC, et al. Resolution of liver biopsy alterations in three siblings with bile acid treatment of an inborn error of bile acid metabolism (delta 4-3-oxosteroid 5 beta-reductase deficiency) Hepatology. 1993;18:1096–1101.

Bazzoli F, et al. Relationship between serum and biliary bile acids as an indicator of chenodeoxycholic and ursodeoxycholic acid-induced hepatotoxicity in the rhesus monkey. Dig Dis Sci. 1982;27:417–424.

Sarva RP, et al. Comparison of the effects between ursodeoxycholic and chenodeoxycholic acids on liver function and structure and bile acid composition in the Rhesus Monkey. Gastroenterology. 1980;79:629–636.

Wikvall K. Purification and properties of a 3 beta-hydroxy-delta 5-C27-steroid oxidoreductase from rabbit liver microsomes. J Biol Chem. 1981;256: 3376–3380.

Clayton PT, et al. Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and 3 beta,7 alpha, 12 alpha-trihydroxy-5-cholenoic acids. J Clin Invest. 1987;79:1031–1038.

Stieger B, et al. Differential interaction of bile acids from patients with inborn errors of bile acid synthesis with hepatocellular bile acid transporters. Eur J Biochem. 1997;244:39–44.

Buchmann MS, et al. Lack of 3 beta- hydroxy- delta 5-C27-steroid dehydrogenase/isomerase in fibroblasts from a child with urinary excretion of 3 beta-hydroxy-delta 5-bile acids: a new inborn error of metabolism. J Clin Invest. 1990;86:2034–2037.

Schwarz M, et al. The bile acid synthetic gene 3beta-hydroxy-delta(5)-C(27)-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis. J Clin Invest. 2000;106:1175–1184.

Cheng JB, et al. Molecular genetics of 3beta-hydroxy-delta5-C27-steroid oxidoreductase deficiency in 16 patients with loss of bile acid synthesis and liver disease. J Clin Endocrinol Metab. 2003; 88:1833–1841.

Jacquemin E, et al. A new cause of progressive intrahepatic cholestasis: 3 beta-hydroxy-C27-steroid dehydrogenase/isomerase deficiency. J Pediatr. 1994;125:379–384.

Horslen SP, et al. 3Beta-hydroxy-delta 5-C27-steroid dehydrogenase deficiency; effect of chenodeoxycholic acid therapy on liver histology. J Inherit Metab Dis. 1992; 15:38–46.

Witzleben CL, et al. A new category of causes of intrahepatic cholestasis. Pediatr Pathol. 1992;12:269–274.

Yamato Y, et al. 3Beta-hydroxy-delta5-C27-steroid dehydrogenase deficiency: Diagnosis and treatment. J Paediatr Child Health. 2001;37:516519.

Moghadasian MH, et al. Cerebrotendinous xanthomatosis: A rare disease with diverse manifestations. Arch Neurol. 2002;59: 527–529.

Gallus GN, et al. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci. 2006;27:143–149.

Verrips A, et al. Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis. Brain. 2000;123:908–919.

Setchell KDR, Street JM. Inborn errors of bile acid synthesis. Semin Liver Dis. 1987; 7:85–99.

Clayton PT, et al. Familial giant cell hepatitis with low bile acid concentrations and increased urinary excretion of specific bile alcohols: A new inborn error of bile acid synthesis? Pediatr Res. 1995;37: 424–431.

Cruysberg JR, et al. Juvenile cataract associated with chronic diarrhea in pediatric cerebrotendinous xanthomatosis. Am J Ophthal. 1991;112:606–607.

Wevers RA, et al. Paediatric cerebrotendinous xanthomatosis. J Inherit Metab Dis. 1992;15:374–376.

Setchell KDR, et al. Disorders of bile acid synthesis and metabolism: A metabolic basis for liver disease. In: Suchy FJ, et al., editors. Liver Disease in Children. New York: Cambridge University Press; 2007. pp. 736–766.

Bove KE, et al. Bile acid synthetic defects and liver disease: A comprehensive review. Pediatr Dev Pathol. 2004;7:315–334.

Westin S, et al. FXR, a therapeutic target for bile acid and lipid disorders. Mini Rev Med Chem. 2005;5:719–727.

Edwards PA, et al. BAREing it all: The adoption of LXR and FXR and their roles in lipid homeostasis. J Lipid Res. 2002;43: 2–12.

Otte K, et al. Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol. Mol Cell Biol. 2003;23:864–872.

Makishima M, et al. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–1365.

Parks DJ, et al. Bile acids: Natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–1368.

Wang H, et al. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3:543–553.

Goodwin B, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell. 2000;6:517–526.

Kuipers F, et al. The farnesoid X receptor (FXR) as modulator of bile acid metabolism. Rev Endocr Metab Disord. 2004;5:319–326.

Vlahcevic ZR, et al. Regulation of bile acid biosynthesis. Gastroenterol Clin North Am. 1999;28:1–25.

Russell DW, et al. Bile acid biosynthesis. Biochemistry. 1992;31:4737–4749.

Ichimiya H, et al. Bile acids and bile alcohols in a child with hepatic 3 beta- hydroxy- delta 5-C27-steroid dehydrogenase deficiency: Effects of chenodeoxycholic acid treatment. J Lipid Res. 1991;32:829–841.

Chiang JYL, Ferrell JM. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. Am J Physiol Gastrointest Liver Physiol. 2020 Mar 1;318(3):G554-G573.

DOI: 10.1152/ajpgi.00223.2019

Epub 2020 Jan 27.

PMID: 31984784;

PMCID: PMC7099488.

Jiao N, Baker SS, Chapa-Rodriguez A, Liu W, Nugent CA, Tsompana M, Mastrandrea L, Buck MJ, Baker RD, Genco RJ, Zhu R, Zhu L. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut. 2018 Oct;67(10):1881-1891.

DOI: 10.1136/gutjnl-2017-314307

Epub 2017 Aug 3.

PMID: 28774887.

Chiang JYL, Ferrell JM. Discovery of farnesoid X receptor and its role in bile acid metabolism. Mol Cell Endocrinol. 2022 May 15;548:111618.

DOI: 10.1016/j.mce.2022.111618.

Epub 2022 Mar 11.

PMID: 35283218;

PMCID: PMC9038687.

Chen HL, Wu SH, Hsu SH, Liou BY, Chen HL, Chang MH. Jaundice revisited: Recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J Biomed Sci. 2018 Oct 26;25(1):75.

DOI: 10.1186/s12929-018-0475-8

PMID: 30367658;

PMCID: PMC6203212.

Feldman AG, Sokol RJ. Neonatal cholestasis: Updates on diagnostics, therapeutics, and prevention. Neoreviews. 2021 Dec 1;22(12):e819-e836.

DOI: 10.1542/neo.22-12-e819

PMID: 34850148; PMCID:

PMC10103174.

Farooqui N, Elhence A, Shalimar. A current understanding of bile acids in chronic liver disease. J Clin Exp Hepatol. 2022 Jan-Feb;12(1):155-173.

DOI: 10.1016/j.jceh.2021.08.017

Epub 2021 Aug 23.

PMID: 35068796;

PMCID: PMC8766695.

Bove KE. Liver disease caused by disorders of bile acid synthesis. Clin Liver Dis. 2000 Nov;4(4):831-48.

DOI: 10.1016/s1089-3261(05)70144-6

PMID: 11232360.

Amendola M, Squires JE. Pediatric Genetic Cholestatic Liver Disease Overview. 2022 Sep 15 [updated 2023 May 25]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 36108118.

Vasavan T, Ferraro E, Ibrahim E, Dixon P, Gorelik J, Williamson C. Heart and bile acids - Clinical consequences of altered bile acid metabolism. Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864 (4 Pt B):1345-1355

DOI: 10.1016/j.bbadis.2017.12.039

Epub 2018 Jan 6.

PMID: 29317337.

Potter CJ. Cholestasis in the premature infant. Clin Perinatol. 2020 Jun;47(2):341-354.

DOI: 10.1016/j.clp.2020.02.009

Epub 2020 Mar 4.

PMID: 32439115.

Heubi JE, Bove KE, Setchell KDR. Oral cholic acid is efficacious and well tolerated in patients with bile acid synthesis and zellweger spectrum disorders. J Pediatr Gastroenterol Nutr. 2017 Sep;65(3):321-326.

DOI: 10.1097/MPG.0000000000001657

PMID: 28644367;

PMCID: PMC5559188.

Baumann U, Sturm E, Lacaille F, Gonzalès E, Arnell H, Fischler B, Jørgensen MH, Thompson RJ, Mattsson JP, Ekelund M, Lindström E, Gillberg PG, Torfgård K, Soni PN. Effects of odevixibat on pruritus and bile acids in children with cholestatic liver disease: Phase 2 study. Clin Res Hepatol Gastroenterol. 2021 Sep;45(5): 101751.

DOI: 10.1016/j.clinre.2021.101751.

Epub 2021 Jun 26.

PMID: 34182185.

Kriegermeier A, Green R. Pediatric cholestatic liver disease: Review of bile acid metabolism and discussion of current and emerging therapies. Front Med (Lausanne). 2020 May 5;7:149.

DOI: 10.3389/fmed.2020.00149

PMID: 32432119;

PMCID: PMC7214672.

Bedoyan SM, Lovell OT, Horslen SP, Squires JE. Odevixibat: A promising new treatment for progressive familial intrahepatic cholestasis. Expert Opin Pharmacother. 2022 Nov; 23(16): 1771-1779.

DOI: 10.1080/14656566.2022.2140040

Epub 2022 Oct 30.

PMID: 36278881;

PMCID: PMC10074157

Fagan EA. Intrahepatic cholestasis of pregnancy. Clin Liver Dis. 1999 Aug;3(3):603-32.

DOI: 10.1016/s1089-3261(05)70087-8

PMID: 11291241.

Heubi JE, Setchell KDR. Open-label Phase 3 Continuation Study of Cholic Acid in Patients With Inborn Errors of Bile Acid Synthesis. J Pediatr Gastroenterol Nutr. 2020 Apr;70(4):423-429.

DOI: 10.1097/MPG.0000000000002618

PMID: 31899729.

Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: Inborn errors of bile acid synthesis. Nature Clinical Practice Gastroenterology & Hepatology. 2008 Aug;5(8):456-68.