Albert J Czaja1,2. 1. Mayo Clinic College of Medicine and Science, Rochester, MN, USA. czaja.albert@mayo.edu. 2. Professor Emeritus of Medicine, Mayo Clinic College of Medicine and Science, 200 First Street SW, Rochester, MN, 55905, USA. czaja.albert@mayo.edu.
Abstract
BACKGROUND: Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS: Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS: English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS: Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS: Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
BACKGROUND: Autoimmune hepatitis has an unknown cause and genetic associations that are not disease-specific or always present. Clarification of its missing causality and heritability could improve prevention and management strategies. AIMS: Describe the key epigenetic and genetic mechanisms that could account for missing causality and heritability in autoimmune hepatitis; indicate the prospects of these mechanisms as pivotal factors; and encourage investigations of their pathogenic role and therapeutic potential. METHODS: English abstracts were identified in PubMed using multiple key search phases. Several hundred abstracts and 210 full-length articles were reviewed. RESULTS: Environmental induction of epigenetic changes is the prime candidate for explaining the missing causality of autoimmune hepatitis. Environmental factors (diet, toxic exposures) can alter chromatin structure and the production of micro-ribonucleic acids that affect gene expression. Epistatic interaction between unsuspected genes is the prime candidate for explaining the missing heritability. The non-additive, interactive effects of multiple genes could enhance their impact on the propensity and phenotype of autoimmune hepatitis. Transgenerational inheritance of acquired epigenetic marks constitutes another mechanism of transmitting parental adaptations that could affect susceptibility. Management strategies could range from lifestyle adjustments and nutritional supplements to precision editing of the epigenetic landscape. CONCLUSIONS: Autoimmune hepatitis has a missing causality that might be explained by epigenetic changes induced by environmental factors and a missing heritability that might reflect epistatic gene interactions or transgenerational transmission of acquired epigenetic marks. These unassessed or under-evaluated areas warrant investigation.
Authors: F Alvarez; P A Berg; F B Bianchi; L Bianchi; A K Burroughs; E L Cancado; R W Chapman; W G Cooksley; A J Czaja; V J Desmet; P T Donaldson; A L Eddleston; L Fainboim; J Heathcote; J C Homberg; J H Hoofnagle; S Kakumu; E L Krawitt; I R Mackay; R N MacSween; W C Maddrey; M P Manns; I G McFarlane; K H Meyer zum Büschenfelde; M Zeniya Journal: J Hepatol Date: 1999-11 Impact factor: 25.083
Authors: S Vento; L Guella; F Mirandola; F Cainelli; G Di Perri; M Solbiati; T Ferraro; E Concia Journal: Lancet Date: 1995-09-02 Impact factor: 79.321
Authors: S Magrin; A Craxì; G Fiorentino; C Fabiano; G Provenzano; G B Pinzello; U Palazzo; P Almasio; L Pagliaro Journal: J Hepatol Date: 1991-07 Impact factor: 25.083
Authors: Cara L Mack; David Adams; David N Assis; Nanda Kerkar; Michael P Manns; Marlyn J Mayo; John M Vierling; Mouaz Alsawas; Mohammad H Murad; Albert J Czaja Journal: Hepatology Date: 2020-05-12 Impact factor: 17.425