Skip to main content
SpringerLink
Log in

Diagnosis of inherited disorders of liver metabolism

  • Published:
Journal of Inherited Metabolic Disease

Abstract

Summary: Diagnosis of the metabolic disorder responsible for liver disease can sometimes be straightforward but it can also present a major challenge, particularly if the liver is sufficiently damaged to produce secondary biochemical abnormalities such as galactosuria, hypoglycaemia with hypoketonaemia, or excretion of 3-oxo-Δ4 bile acids. It is important to consider the age of the patient, the nature of the liver disease, any extrahepatic clinical features, the imaging and the first-line laboratory tests when prioritizing diagnostic investigations. This article gives some examples of diagnoses made in our unit for patients with liver disease presenting in utero, in the neonatal period, in infancy and the preschool years, and in the school years. The differential diagnoses that should be considered for different clinical presentations are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Akobeng AK, Clayton PT, Miller V, Super M, Thomas AG (1999) An inborn error of bile acid synthesis (3/f-hydroxy-A5-C27-steroid dehydrogenase deficiency) presenting as malabsorption leading to rickets. Arch Dis Child 80: 463-465.

    Article  PubMed  CAS  Google Scholar 

  • Braverman N, Lin P, Moebius FF, et al (1999) Mutations in the gene encoding 3-/f-hydroxysteroid-A8,A7-isomerase cause X-linked dominant Conradi Hunermann syndrome. Nature Genetics 22 (3): 291 294.

    PubMed  Google Scholar 

  • Brunetti-Pierri N, Corso G, Rossi M, et al (2002) Lathosterolosis, a novel multiple-malformation/mental retardation syndrome due to deficiency of 3-hydroxysteroid-A5-desaturase. Am J Hum Genet 71: 952-958.

    Article  PubMed  Google Scholar 

  • Clayton PT (2002) Inborn errors presenting with liver dysfunction. Semin Neonatol 7: 49-63.

    Article  PubMed  Google Scholar 

  • Clayton PT, Casteels M, Mieli-Vergani G, Lawson AM (1995) 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 37: 424-431.

    PubMed  CAS  Google Scholar 

  • Clayton PT, Mills KA, Johnson AW, Barabino A, Marazzi MG (1996) A4-3-Oxosteroid 5f-reductase deficiency: failure of ursodeoxycholic acid therapy and response to chenodeoxycholic acid plus cholic acid. Gut 38: 623-628.

    PubMed  CAS  Google Scholar 

  • Clayton PT, Verrips A, Sistermans E, Mann A, Mieli-Vergani G, Wevers R (2002) Mutations in the cholesterol 27-hydroxylase gene (CYP27) cause hepatitis of infancy as well as cerebrotendinous xanthomatosis. J Inherit Metab Dis 25: 501-513.

    Article  PubMed  CAS  Google Scholar 

  • Cox PM, Brueton LA, Murphy KW, et al (1999) Early-onset fetal hydrops and muscle degener-ation in siblings due to a novel variant of type IV glycogenosis. Am J Med Genet 86: 187-193.

    Article  PubMed  CAS  Google Scholar 

  • de Lonlay P, Valnot I, Barrientos A, et al (2001) A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure. Nature Genetics 29: 57-60.

    Article  PubMed  CAS  Google Scholar 

  • Derry JM, Gormally E, Means GD, et al (1999) Mutations in a A8-A7sterol isomerase in the tattered mouse and X-linked dominant chondrodysplasia punctata. Nature Genetics 22: 286-290.

    Article  PubMed  CAS  Google Scholar 

  • Dorland L, De Kooning TJ, Toet M, deVries LS, Van Den Berg IET, Poll-The BT (1997) Recurrent non-immune hydrops associated with carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 20(supplement): 88.

    Google Scholar 

  • Duval M, Fenneteau O, Doireau V, et al (1999) Intermittent hemophagocytic lymphohistiocytosis is a regular feature of lysinuric protein intolerance. J Pediatr 134: 236-239.

    Article  PubMed  CAS  Google Scholar 

  • Ferdinandusse S, Denis S, Clayton PT, et al (2000) Mutations in the gene encoding alpha-methyl-CoA racemase cause adult-onset sensory motor neuropathy. Nature Genetics 24: 188-191.

    Article  PubMed  CAS  Google Scholar 

  • Ferreira P, Morais L, Costa R, et al (2000) Hydrops fetalis associated with erythrocyte pyruvate kinase deficiency. Eur J Pediatr 159: 481-482.

    Article  PubMed  CAS  Google Scholar 

  • FitzPatrick DR, Keeling JW, Evans MJ, et al (1998) Clinical phenotype of desmosterolosis. Am J Med Genet 75: 145-152.

    Article  PubMed  CAS  Google Scholar 

  • Gerst N, Ruan B, Pang J, Wilson WK, Schroepfer GJ Jr (1997) An updated look at the analysis of unsaturated C27sterols by gas chromatography and mass spectrometry. J Lipid Res 38: 1685-1701.

    PubMed  CAS  Google Scholar 

  • Gospe SM Jr, Caruso RD, Clegg MS, et al (2000) Paraparesis, hypermanganesaemia, and polycythaemia: a novel presentation of cirrhosis. Arch Dis Child 83: 439-442.

    Article  PubMed  Google Scholar 

  • Hoffmann K, Dreger CK, Olins AL, et al (2002) Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger Huet anomaly). Nature Genetics 31: 410-414.

    PubMed  CAS  Google Scholar 

  • Hyett JA, Clayton PT, Moscoso G, Nicolaides KH (1995) Increased first trimester nuchal translucency as a prenatal manifestation of Smith-Lemli Opitz syndrome. Am J Med Genet 58: 374-376.

    Article  PubMed  CAS  Google Scholar 

  • Jevon GP, Dimmick JE (1998a) Histopathologic approach to metabolic liver disease: Part 1. Pediatr Dev Pathol 1: 179-199.

    Article  PubMed  CAS  Google Scholar 

  • Jevon GP, Dimmick JE (1998b) Histopathologic approach to metabolic liver disease: Part 2. Pediatr Dev Pathol 1: 261-269.

    Article  PubMed  CAS  Google Scholar 

  • Kelley RI, Herman GE (2001) Inborn errors of sterol biosynthesis. Annu Rev Genomics Hum Genet 2: 299-341.

    Article  PubMed  CAS  Google Scholar 

  • Kirk J, Fitzpatrick D, Lyon A, Thomas A, Smith N, Seller A (1996) Pearson's syndrome pre-senting as hydrops fetalis. J Inherit Metab Dis 20 (Suppl. 1): 88 (Abstract).

    Google Scholar 

  • Labrune P, Perignon JL, Rault M, et al (1990) Familial hypermethioninemia partially respon-sive to dietary restriction. J Pediatr 117: 220-226.

    Article  PubMed  CAS  Google Scholar 

  • Lemonde HA, Custard EJ, Marazzi MG, Scambler PJ, Clayton PT (1999) A primary genetic defect of A4-3-oxosteroid-5fl-reductase. J Inherit Metab Dis 22 (supplement 1): 129.

    Google Scholar 

  • Li L, Krantz ID, Deng Y, et al (1997) Alagille syndrome is caused by mutations in human Jaggedl, which encodes a ligand for Notchl. Nature Genetics 16: 243-251.

    Article  PubMed  CAS  Google Scholar 

  • Maichele AJ, Burwinkel B, Maire I, Sovik O, Kilimann MW (1996) Mutations in the testis/liver isoform of the phosphorylase kinase gamma subunit (PHKG2) cause autosomal liver glycogenosis in the gsd rat and in humans. Nature Genetics 14: 337-340.

    Article  PubMed  CAS  Google Scholar 

  • Mandel H, Szargel R, Labay V, et al (2001) The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA. Nature Genetics 29: 337-341.

    Article  PubMed  CAS  Google Scholar 

  • Medicina D, Fabbretti G, Brennan SO, George PM, Kudryk B, Callea F (2001) Genetics and immunological characterization of fibrinogen inclusion bodies in patients with hepatic fibrinogen storage and liver disease. Ann NY Acad Sci 936: 522-525.

    Article  PubMed  CAS  Google Scholar 

  • O'Brien LK, Rinaldo P, Sims HF, et al (2000) Fulminant hepatic failure associated with mutations in the medium and short chain L-3-hydroxyacyl-CoA dehydrogenase gene. J Inherit Metab Dis 23 (supplement 1): 127.

    Google Scholar 

  • Oda T, Elkahloun AG, Pike BL, et al (1997) Mutations in the human Jaggedl gene are respon-sible for Alagille syndrome. Nature Genetics 16: 235-242.

    Article  PubMed  CAS  Google Scholar 

  • Odaib AA, Shneider BL, Bennett MJ, et al (1998) A defect in the transport of long-chain fatty acids associated with acute liver failure. N Engl J Med 339: 1752-1757.

    Article  PubMed  CAS  Google Scholar 

  • Olpin SE, Allen J, Bonham JR, et al (2001) Features of carnitine palmitoyltransferase type I deficiency. J Inherit Metab Dis 24: 35-42.

    Article  PubMed  CAS  Google Scholar 

  • Ravindranath Y, Paglia DE, Warrier I, Valentine W, Nakatani M, Brockway RA (1987) Glucose phosphate isomerase deficiency as a cause of hydrops fetalis. N Engl J Med 316: 258-261.

    Article  PubMed  CAS  Google Scholar 

  • Saudubray JM, Charpentier C (2001) Clinical phenotypes: diagnosis/algorithms. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 1327 1403.

    Google Scholar 

  • Saudubray JM, Martin D, de Lonlay P, et al (1999) Recognition and management of fatty acid oxidation defects: A series of 107 patients. J Inherit Metab Dis 22: 488-502.

    Article  PubMed  CAS  Google Scholar 

  • Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. (2001) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill.

    Google Scholar 

  • Setchell KD, Schwarz M, O'Connell NC, et al (1998) Identification of a new inborn error: in bile acid synthesis: mutation of the oxysterol 7-hydroxylase gene causes severe neonatal liver disease. J Clin Invest 102: 1690-1703.

    Article  PubMed  CAS  Google Scholar 

  • Valnot I, Osmond S, Gigarel N, et al (2000) Mutations of the SCOI gene in mitochondrial cytochrome-c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy. Am J Hum Genet 67: 1104-1109.

    PubMed  CAS  Google Scholar 

  • Van Veldhoven PP, Meyhi E, Squires RH, et al (2001) Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorption and vitamin K deficiency. Eur J Clin Invest 31: 714-722.

    Article  PubMed  CAS  Google Scholar 

  • Verhoeven NM, Huck JH, Roos B, et al (2001) Transaldolase deficiency: liver cirrhosis associ-ated with a new inborn error in the pentose phosphate pathway. Am J Hum Genet 68: 1086-1092.

    Article  PubMed  CAS  Google Scholar 

  • Verstraeten L, Van Regemorter N, Pardou A, et al (1993) Biochemical diagnosis of a fatal case of Gunther's disease in a newborn with hydrops foetalis. Eur J Clin Chem Clin Biochem 31: 121-128.

    PubMed  CAS  Google Scholar 

  • Wraith JE (2002) Lysosomal disorders. Semin Neonatol 7: 75-83.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Child Health, University College London and Great Ormond Street Hospital for Children NHS Trust, London, WCIN 1EH, UK

    P. T. Clayton

Authors
  1. P. T. Clayton
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clayton, P.T. Diagnosis of inherited disorders of liver metabolism. J Inherit Metab Dis 26, 135–146 (2003). https://doi.org/10.1023/A:1024429032116

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1024429032116

Keywords

Search

Navigation