The Epidemiology of Rare Hereditary Metabolic Liver Diseases

Abstract

A rare disease is defined by the European Health Commission as a disorder occurring in less than 5 per 10,000 individuals in the population whereas the United States definition sets a numerical maximum of fewer than 200,000 affected individuals in the country [1, 2]. A disease is defined as ultra-rare if less than 1 person per 50,000 people is affected [2]. The medical and socioeconomic impact of rare diseases is quite significant as there may be as many as 30 million people who live with a rare disease in the US and another 3.5 million in the UK [3, 4]. There are over 100 individual liver diseases, and it is estimated that more than 29 million people in the European Union and more than 30 million Americans suffer from liver disease [5, 6]. This chapter discusses the epidemiology of four rare metabolic liver disorders encountered by gastroenterologists and hepatologists: Wilson disease, lysosomal acid lipase deficiency, α1-antitrypsin deficiency and HFE-related hereditary hemochromatosis. The OMIM database codes (online Mendelian inheritance in man) have been included for each disease as these have been used extensively in the literature especially in relation to genotype-phenotype characterization.

Summary Table of Landmark Literature

Wilson disease
Study title and authors	Study design	Summary results
Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Samuel Alexander Kinnier Wilson, Brain 1912: 34; 295–509	Case series	13 patients with progressive lenticular degeneration with associated liver cirrhosis
La dégénérescence hépato-lenticulaire (Maladie de Wilson—Pseudo-sclérose). Hall HC, Masson, Paris, 1921 Scheinberg IH, Gitlin D. Deficiency of ceruloplasmin in patients with hepatolenticular degeneration (Wilson’s disease). Science 1952, 116:484–5 Biochemical abnormalities in Wilson’s disease. Bearn AG and Kunkel HG, J Clin Invest, 1952, 31:616	Case Control study	Pattern of inheritance described as autosomal recessive Caeruloplasmin deficiency as a phenotypic marker that can be used for disease screening
Assignment of the gene for Wilson disease to chromosome 13: linkage to the esterase D locus. Frydman M et al., Proc Natl Acad Sci U S A. 1985;82(6):1819–21	Linkage analysis	Localization of disease locus to chromosome 13
Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Vulpe C et al., Nat Genet. 1993;3(1):7–13 Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Chelly J et al., Nat Genet. 1993;3(1):14–9	Gene isolation and sequencing	The gene for Menkes disease encodes a copper-transporting P-type ATPase
The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Bull PC et al., Nat Genet. 1993;5(4):327–37	Gene isolation and sequencing	The gene for Wilson disease encodes a copper-transporting P-type ATPase
Isolation of a partial candidate gene for Menkes disease by positional cloning. Mercer JF et al., Nat Genet. 1993;3(1):20–5 Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Petrukhin K et al., Nat Genet. 1993;5(4):338–43 The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Tanzi RE et al., Nat Genet. 1993;5(4):344–50	Gene isolation, sequencing, linkage disequilibrium and haplotype analysis	ATP7B gene is identified as the gene for Wilson disease. Specific mutations begin to be recognised
Isolation and characterization of a human liver cDNA as a candidate gene for Wilson disease. Yamaguchi Y et al., Biochem Biophys Res Commun 1993;197:271–7 Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions. Petrukhin K et al., Hum Mol Genet. 1994;3(9):1647–56	Screening of cDNA clones, genomic organization, alternative splicing	Identification of disease-specific mutations and ATP7B polymorphisms and prediction of structure/function features of WD protein

1. Note: These studies were collectively limited by the small number of patients included due to the rarity of the condition

Α1-Antitrypsin deficiency (A1AD)
Study title and authors	Study design/method	Summary results
The electrophoretic alpha-1-globulin pattern of serum in alpha-1-antitrypsin deficiency. Laurell C-B et al., Scand J Clin Lab Invest 1963, 15:132–140	Serum protein electrophoresis	Absence of the α1-globulin peak in many patients with COPD noticed
Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. Sharp HL et al., J Lab Clin Med 1969, 73:934–939	Observational study	A1AD is associated with liver disease and cirrhosis
Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. Tomas Sveger, N Engl J Med 1976; 294:1316–1321	Prospective study	Liver disease has been associated with the PiZ and PiSZ phenotypes. Approximately 8% of patients developed clinically significant liver disease
α1-Antitrypsin deficiency in 26-year-old subjects. Piitulainen E et al., Chest 2005, 128:2076–2081	Case-control study	Interplay of exogenous and endogenous factors will determine phenotype and outcomes
Performance of enhanced liver fibrosis plasma markers in asymptomatic individuals with ZZ a1-antitrypsin deficiency. Janciauskiene S et al., Eur J Gastroenterol Hepatol 2011, 23:716–720	Case-control study	The enhanced liver fibrosis plasma markers are useful in identifying PiZZ young adults who are at risk of developing significant liver disease
Characteristics of hepatocellular carcinoma in a murine model of alpha-1-antitrypsin deficiency. Marcus NY et al., Hepatol Res. 2010, 40:641–653 Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency. Rudnick DA et al., Hepatology. 2004, 39:1048–1055	Animal studies	Association of the homozygous PiZZ phenotype with HCC

1. Note: These studies were collectively limited by the small number of patients included due to the rarity of the condition
2. Abbreviations: COPD chronic obstructive pulmonary disease, ELF enhanced liver fibrosis, HCC hepatocellular carcinoma

Hereditary haemochromatosis
Study title and authors	Study design/method	Summary results
Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Simon M et al., Gut 1976, 17:332–334	Case series with determination of histocompatibility antigens	Idiopathic haemochromatosis is a genetic condition and the responsible gene may be localized to the region of the histocompatibility complex
A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Feder JN et al. Nat Genet 1996;13:399–408	Disequilibrium and full haplotype analysis	Identification of gene for most common form of hereditary hemochromatosis. Close association of HLA-H (renamed later as HFE) to the locus of HLA-A3 on chromosome 6 and identification of pathogenic mutations of this gene and corresponding change in HFE protein that potentially leads to disease
Hemochromatosis and iron-overload screening in a racially diverse population. Adams PC et al., N Engl J Med 2005;352:1769–1778 Iron-overload-related disease in HFE hereditary hemochromatosis. Allen KJ et al., N Engl J Med 2008, 358:221–230 Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65,238 persons. Asberg A et al., Scand J Gastroenterol 2001, 36:1108–1115 Penetrance of 845G–>A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Beutler E et al., Lancet 2002, 359:211–218	Population studies with a pooled cohort of 235,663 people	The prevalence of C282Y homozygosity in the general population is 1:146–333
European association for the study of the liver. EASL clinical practice guidelines for HFE hemochromatosis. Journal of Hepatology 2010, 53:3–22	Meta-analysis of 2802 patients with phenotypic HH from 32 studies	80.6% of patients are C282Y/C282Y homozygotes and 5.3% compound heterozygotes (C282Y/H63D)

1. Abbreviations: HH hereditary haemochromatosis

Lysosomal acid lipase deficiency
Study title and authors	Study design/method	Summary results/milestone
Primary familial xanthomatosis with involvement and calcification of the adrenals. Report of two more cases in siblings of a previously described infant. Wolman, M. et al., Pediatrics, 1961. 28: p. 742–57	Observational study	Moshe Wolman describes the first case series of three siblings with Wolman disease
Lipid accumulation and acid lipase deficiency in fibroblasts from a family with Wolman’s disease, and their apparent correction in vitro. Kyriakides EC et al., J Lab Clin Med, 1972. 80(6): p. 810–6	Case control study measuring acid lipase activity of cultured fibroblasts	Acid lipase deficiency is demonstrated in fibroblasts
Genomic organization of the human lysosomal acid lipase gene (LIPA). Aslanidis, C et al., Genomics, 1994. 20(2): p. 329–31	Gene isolation, sequencing and linkage	The lipase gene(LIPA) is assigned to locus 10q23.2q23.3
Lysosomal acid lipase/cholesteryl ester hydrolase. Purification and properties of the form secreted by fibroblasts in microcarrier culture. Sando GM et al. J Biol Chem, 1985. 260(28): p. 15186–93	Enzyme purification, structural analysis and ascertainment of catalytic properties of the human enzyme	Human LAL is purified in small amounts
Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice. Du H et al., J Lipid Res, 2008. 49(8): p. 1646–57	Animal study	Enzyme replacement therapy effective in the murine model
Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Balwani M et al., Hepatology, 2013. 58(3): p. 950–7 Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. Valayannopoulos V et al., J Hepatol, 2014. 61(5): p. 1135–42	Phase I–II interventional trial	Enzyme replacement therapy is tried successfully on humans
A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. Burton BK et al., N Engl J Med, 2015. 373(11): p. 1010–20	Phase III interventional trial	Enzyme replacement therapy has been shown to successfully normalise ALT and AST levels, improve LDL and HDL, reduce hepatic steatosis and reduce spleen volume

1. Abbreviations: ALT alanine aminotransferase, AST aspartate aminotransferase, LDL low-density lipoprotein, HDL high-density lipoprotein