Pediatric and Developmental Pathology

, Volume 7, Issue 4, pp 315–334 | Cite as

Bile Acid Synthetic Defects and Liver Disease: A Comprehensive Review

  • Kevin E. Bove
  • James E. Heubi
  • William F. Balistreri
  • Kenneth D.R. Setchell
Original article

Bile acid synthetic defects (BASD), uncommon genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants, are reviewed with emphasis on morphology of associated liver disease. The associated liver diseases may be life threatening, and are treatable, usually by replacement of deficient primary bile acids. Specific diagnosis is made by analysis of body fluids (bile, blood, and urine) using fast atom bombardment-mass spectroscopy (FAB-MS) and gas chromatography-mass spectroscopy (GC-MS). Inborn errors have been demonstrated for four single enzymes involved in modification of the sterol nucleus and in five steps in modification of the side-chain to form cholic and chenodeoxycholic acids, the primary bile acids. With few exceptions, BASD cause liver diseases that vary from severe to mild depending on the defect. In three of four known defects of sterol nucleus modification, liver disease is progressive. Progression of liver disease is most rapid when the defect results in accumulation of toxic monohydroxy and unsaturated oxo-bile acids. Liver disease may be transient, delayed in onset and mild. Reduced bile flow caused by atypical bile acids contributes to cholestasis and may be the dominant factor in defects of side-chain synthesis, peroxisomal abiogenesis and S-L-O syndrome. Pathological findings may include intralobular cholestasis with giant cell transformation, prevalence of necrotic hepatocytes including giant cell forms, and hepatitic injury confined to the portal limiting plate where the smallest bile ductules may be injured and where fibrosis typically develops. Interlobular bile ducts are usually spared. Ultrastructure of liver reveals nonspecific changes with the possible exception of unusual canalicular morphology in some defects. The course of BASD may be modified by replacement of deficient primary bile acids, which produces beneficial feedback inhibition of abnormal bile acid production and enhances choluresis. Giant cell transformation is present in all symptomatic infants with BASD and seems to have a more consistent association with BASD than with the many other liver diseases in infants where it occurs. We hypothesize that immature hepatocytes of infants may fuse to form multinucleate hepatocytes whenever atypical or toxic bile acids are present and the pool of normal bile acids is critically reduced.


Bile acids  enzyme defects  liver disease  giant cells  cholestasis 



This review was supported by NCRR, NIH grant RR-08084.


  1. 1.
    Setchell, K, Street, J 1987Inborn errors of bile acid synthesisSemin Liver Dis78399Google Scholar
  2. 2.
    Setchell, K,  et al. 1990Disorders of bile acid synthesisWaler, WDurie, PHamilton, J. eds. Pediatric Gastrointestinal DiseaseB.C. DeckerPhiladelphia9921013Google Scholar
  3. 3.
    Balistreri, W 1995Inborn errors of bile acid biosynthesis: clinical and therapeutic aspectsHofmann, APaumgartner, GStiehl, A eds. Bile Acids in Gastroenterology—Basic and Clinical AdvancesKluwer AcademicLondon333353Google Scholar
  4. 4.
    Setchell, KD, Heubi, JE, O’Connell, C, Hofmann, A, Lavine, J 1997Identification of a unique inborn error in bile acid conjugation involving a deficiency in amidationPaumgartner, GStrehl, AGerok, W eds. Bile Acids in Hepatobiliary Diseases: Basic Research and Clinical ApplicationKluwer AcademicBostonAUTHOR: Please provide page range for chapter in Ref. 4.CrossRefPubMedGoogle Scholar
  5. 5.
    Bove, KE, Daughtery, CC, Tyson, W,  et al. 2000Bile acid defects and liver diseasePediatr Dev Pathol3116CrossRefPubMedGoogle Scholar
  6. 6.
    Trauner, M, Meier, P, Boyer, J 1998Molecular pathogenesis of cholestasisNew Engl J Med33912171227CrossRefPubMedGoogle Scholar
  7. 7.
    Balistreri, W 1999Liver disease in infancy and childhoodSchiff, ERSorrell, MFMaddrey, WC eds. Schiff’s Diseases of the LiverLippencott-RavenPhiladelphia14151418Google Scholar
  8. 8.
    Stieger, B, Zhang, J, O’Neill, B, Sjorall, J, Meier, P 1997Differential interaction of bile acids from patients with inborn errors of bile acid synthesis with hepatocellular bile acid transportersEur Biochem2443944Google Scholar
  9. 9.
    Russell, D, Setchell, K 1992Bile acid biosynthesisBiochemistry3147374749Google Scholar
  10. 10.
    Setchell, KD 1996Disorders of bile acid synthesis and metabolismWalker, WDuire, PHamilton, JWalker-Smith, JWatkins, J eds. Pediatric Gastrointestinal DiseaseMosbySt. Louis1205AUTHOR: Ref. 10, please confirm city of publication and provide closing page number.Google Scholar
  11. 11.
    Mathis, R, Watkins, J, Szczpanik-van Leeuween, P, Lott, I 1980Liver in the cerebro-hepato-renal syndrome: defective bile acid synthesis and abnormal mitochondriaGastroenterology7913111317PubMedGoogle Scholar
  12. 12.
    Moonens, L, Bakkeren, J, Parmentier, G,  et al. 1980Disturbances in bile acid metabolism of infants with the Zellweger (cerebro-hepato-renal) syndromeEur J Pediatr1333135PubMedGoogle Scholar
  13. 13.
    Dimmick, J, Applegarth, D 1992Pathology of peroxisomal disordersPerspect Pediatr Pathol174598Google Scholar
  14. 14.
    Buchmann, M, Kvittingen, EA, Nazen, H,  et al. 1990Lack of 3β-hydroxy-δ5-C27 steroid dehydrogenase isomerase in fibroblasts from a child with urinary excretion of 3β-hydroxy-δ5 bile acids: a new inborn error of metabolismJ Clin Invest8620342037PubMedGoogle Scholar
  15. 15.
    Setchell, K, Schwarz, M, O’Connell, N,  et al. 1998Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7α-hydroxylase gene causing severe neonatal liver diseaseJ Clin Invest10216901703PubMedGoogle Scholar
  16. 16.
    Wanders, R, Denio, S, Ruiter, J, Schutgeno, R, von Roermund, C, Jacobs, B 1995Measurement of peroxisomal fatty acid beta-oxidation in cultured fibroblastsJ Inherited Metab Dis18113124PubMedGoogle Scholar
  17. 17.
    Pallinger, CR, Eng, C, Salen, G,  et al. 2002Human cholesterol 7alpha-hydroxylase deficiency has a hypercholesterolemic phenotypeJ Clin Invest110109117CrossRefPubMedGoogle Scholar
  18. 18.
    Vlahcevic, Z, Stravitz, D, Heuman, D, Hyleman, P, Pandak, W 1997Quantitative estimations of the contribution of different bile acid pathways to total bile acid synthesis in the ratGastroenterology11319491957PubMedGoogle Scholar
  19. 19.
    Schwarz, M, Lund, E, Setchell, K,  et al. 1996Disruption of cholesterol 7α hydroxy gene in miceJ Biol Chem2711802418031CrossRefPubMedGoogle Scholar
  20. 20.
    Clayton, P, Leonard, J, Lawson, A,  et al. 1987Familial giant cell hepatitis associated with synthesis of 3β, 7 α-dihydroxy and 3β 7 α, 12 α-trihydroxy-5-cholenoic acidsJ Clin Invest7910311038PubMedGoogle Scholar
  21. 21.
    Ichimiya, H, Egestod, B, Nazer, H, Baginski, E, Clayton, PT 1990Treatment of chronic liver disease caused by 3β-hydroxy 5δ-C27 steroid dehydrogenase deficiency with chenodeoxycholic acidArch Dis Child6511211124Google Scholar
  22. 22.
    Witzleben, C, Piccoli, D, Setchell, K 1992A new category of causes of intrahepatic cholestasisPediatr Pathol12269274PubMedGoogle Scholar
  23. 23.
    Horslen, S, Lawson, A, Malone, M, Clayton, P 19923β-hydroxy-δ5-C27 steroid dehydrogenase deficiency: effects of chenodeoxycholic acid therapy on liver histologyJ Inherited Metab Dis153846PubMedGoogle Scholar
  24. 24.
    Jacquemin, E, Setchell, K, O’Connell, N,  et al. 1994A new cause of progressive intrahepatic cholestasis: 3β-hydroxy-C-27-steroid dehydrogenase/isomerase deficiencyJ Pediatr125379384PubMedGoogle Scholar
  25. 25.
    Yamasaki, M, Yamasaki, K 1971Natural occurrence of 3β, 7 α-dihydroxychol-4-en-24 oic acid in hen bileJ Biochem (Tokyo)70235241Google Scholar
  26. 26.
    Kondo, K, Kai, M, Setoguchi, Y,  et al. 1994Cloning and expression of cDNA of human δ-4-3 oxo steroid 5 β reductase and substrate specificity of the expressed enzymeEur J Biochem219357363PubMedGoogle Scholar
  27. 27.
    Setchell, K, Suchy, F, Welsh, M, Zimmer-Nechemias, L, Heubi, J, Balistreri, W 19884-e-Oxysteroid 5β-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesisJ Clin Invest8221352146Google Scholar
  28. 28.
    Schneider, B, Setchell, K, Whitington, P, Nielson, K, Suchy, F 19944-3-Oxosteroid 5-β reductase deficiency causing neonatal liver failure and hemochromatosisJ Pediatr8124133Google Scholar
  29. 29.
    Siafakas, C, Jonas, M, Perez-Atayde, A 1997Abnormal bile acid metabolism and neonatal hemochromatosis: a subset with poor prognosisJ Pediatr Gastroenterol Nutr25321326CrossRefPubMedGoogle Scholar
  30. 30.
    Clayton, P, Johnson, A, Mills, K,  et al. 1996Ataxia associated with increased plasma concentrations of pristanic acid, phytanic acid and C27 bile acids but normal fibroblast branched-chain fatty acid oxidationJ Inherited Metab Dis19761768PubMedGoogle Scholar
  31. 31.
    Daugherty, C, Setchell, K, Heubi, J, Balistreri, W 1993Resolution of hepatic biopsy alterations in 3 siblings with bile acid treatment of an inborn error of metabolism (4-3-oxosteroid 5-β-reductase deficiency)Hepatology1810961101CrossRefPubMedGoogle Scholar
  32. 32.
    Setchell KDR, O’Connell, NC, Russell, DW, Kelly, DA, (2001) “A unique case of cerebrotendinous xanthomatosis presenting in infancy with cholestatic liver disease further highlights bile acid synthetic defects as an important category of metabolic liver disease.” Falk Symposium No.120.XVI International Bile Acid Meeting. Den Haag, Netherlands: Dr. Falk Pharma Gimbh. MTP Press, pp 13–14Google Scholar
  33. 33.
    Clayton, P, Costeels, M, Mieli-Vergani, G, Lawson, A 1995Familial giant cell hepatitis with low bile acid concentrations and increased urinary concentrations of specific bile alcohols: a new inborn error of bile acid synthesisPediatr Res37424431PubMedGoogle Scholar
  34. 34.
    Setchell, KDR, O’Connell, NC 2001Disorders of bile acid synthesis and metabolismSuchy, FJSokol, RJBalistreri, W eds. Liver Diseases in Children 2nd edLippencott Williams and WilkinsPhiladelphia701733Google Scholar
  35. 35.
    van Grunsven, EG, van Berkel, E, Mooijer, AW, Watkins, PA, Moser, HW, Suzuki, Y, Jiang, LL, Hashimoto, T, Hoefler, G, Adamski, J, Wanders, RJA 1999Peroxisomal bifunctional protein deficiency revisited: resolution of its true enzymatic and molecular basisAm J Hum Genet6499107CrossRefPubMedGoogle Scholar
  36. 36.
    Cuebas, DA, Phillips, C, Schmitz, W, Conzelman, E, Novikov, DK 2002The role of α-methylacyl-CoA racemase in bile acid synthesisBiochem J363801807Google Scholar
  37. 37.
    Ferdinandusse, S, van Grunsven, EG, Oostheim, W,  et al. 2002Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of d-bifunctional proteinAm J Hum Genet7015891593CrossRefPubMedGoogle Scholar
  38. 38.
    Watkins, PA, McGuinness, MC, Raymond, GV,  et al. 1995Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficienciesAnn Neurol38472477Google Scholar
  39. 39.
    Ferdinandusse, S, Denis, S, Clayton, PT,  et al. 2000Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathyNat Genet24188191CrossRefPubMedGoogle Scholar
  40. 40.
    Setchell, KDR, O’Connell, NC, Squires, RH, Heubi, JE. 1999Congenital defects in bile acid synthesis cause a spectrum of diseases manifest as severe cholestasis, neurologic disease and fat-soluble vitamin malabsorptionBile Acids and Hepatobiliary DiseaseKluwar Academic PressBoston5765AUTHOR: On Ref. 40, please provide editors and confirm city of publication.Google Scholar
  41. 41.
    Setchell, KDR, Heubi, JE, Bove, KE,  et al. 2003Neonatal liver disease caused by failure to racemize trihydroxycholestanoic acid: identity of gene mutation and effect of bile acid therapyGastroenterology124217232CrossRefPubMedGoogle Scholar
  42. 42.
    Van Veldhoven, PP, Meyhi, E, Squires, RH,  et al. 2001Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorbtion and vitamin K deficiencyEur J Clin Invest8714722CrossRefGoogle Scholar
  43. 43.
    Bowen, P, Lee, C, Zellweger, H, Lindenberg, R 1964A familial syndrome of multiple congenital defectsBull Johns Hopkins Hosp114402414PubMedGoogle Scholar
  44. 44.
    Goldfischer, S, Moore, C, Johnson, A,  et al. 1973Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndromeScience1826264PubMedGoogle Scholar
  45. 45.
    Danks, D, Tippett, P, Adams, C,  et al. 1975Cerebro-hepato-renal syndrome of Zellweger. A report of eight cases with comments upon the incidence, the liver lesion, and a fault in pipecolic acid metabolismJ Pediatr86382387PubMedGoogle Scholar
  46. 46.
    Dimmick, J 1997Pathology of peroxisomal disordersApplegarth, DDimmick, JHall, J eds. Organelle DiseasesChapman and Hall MedicalLondon211232Google Scholar
  47. 47.
    Agamanolis, D, Shehata, B, Waterson, J,  et al. 1988Fetal Zellweger syndrome: report of a casePediatr Pathol6657676Google Scholar
  48. 48.
    Mooi, W, Dingemans, K, Van den Bergh-Weerman, M,  et al. 1983Ultrastructure of the liver in cerebro-hepato-renal syndrome of ZellwegerUltrastruct Pathol5135144PubMedGoogle Scholar
  49. 49.
    Hughs, J, Poulos, A, Robertson, E,  et al. 1990Pathology of hepatic peroxisomes and mitochondria in patients with peroxisomal disordersVirchows Arch [A]416215264Google Scholar
  50. 50.
    Finegold, M, Strohmeyer, W, Noel, A 1998Disruption of bile canalicular tight junctions in Zellweger syndrome (Abstract)Arch Anat Cytol Pathol46510Google Scholar
  51. 51.
    Setchell, KDR, Bragetti, P, Zimmer-Nechemias, L,  et al. 1992Oral bile acid treatment and the patient with Zellweger syndromeHepatology15198207PubMedGoogle Scholar
  52. 52.
    Barbarito E, Batta AK, Salen G, et al. High serum and urinary unconjugated bile acid concentrations are associated with homozygous mutation in bile acid coenzyme A: amino acid N-acyltransferase (BAAT) (Abstract). Gastroenterology 2003; 124 (Suppl): A60.Google Scholar
  53. 53.
    Honda, A, Salen, G, Shefer, S,  et al. 1999Bile acid synthesis in the Smith-Lemli-Opitz syndrome: effects of dehydrocholesterols on cholesterol-7-alpha hydroxylase and 27-hydroxylase in the rat liverJ Lipid Res4015201528PubMedGoogle Scholar
  54. 54.
    Koukoulis, G, Mieli-Vergani, G, Portmann, B 1999Infantile liver giant cells: immunohistological study of their proliferative state and possible mechanisms of their formationPediatr Dev Pathol2353359CrossRefPubMedGoogle Scholar
  55. 55.
    Lemonde, HA, Custard, EJ, Bouquet, J, Duran, M, Overmars, H, Scambler, PJ, Clayton, PT (2003) Mutations in SRD5B1 (AKR1D1), the gene encoding delta (4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 52: 1494–1499Google Scholar

Copyright information

© Society for Pediatric Pathology 2004

Authors and Affiliations

  • Kevin E. Bove
    • 1
    • 2
    • 4
  • James E. Heubi
    • 2
    • 3
    • 4
  • William F. Balistreri
    • 2
    • 3
    • 4
  • Kenneth D.R. Setchell
    • 2
    • 4
  1. 1.Department of Pathology, HT-4Cincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.Department of PediatricsCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  3. 3.Division of Pediatric GastroenterologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  4. 4.University of Cincinnati College of MedicineCincinnatiUSA

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