The Role of Vitamin D in Autoimmune Hepatitis

Abstract

Autoimmune hepatitis is an inflammation of the liver characterized by the presence of peri-portal hepatitis, hypergammaglobulinemia, and the serum autoantibodies. The disease is classified into 2 distinct types according to the nature of auto-antibodies. Disturbances of the calcium-parathyroid hormone-vitamin D axis are frequently associated with chronic liver disease. Patients with AIH have a high prevalence of vitamin D deficiency. Genetic studies have provided the opportunity to determine which proteins link vitamin D to AIH pathology, namely, the major histocompatibility complex class II molecules, vitamin D receptors, toll-like receptors, cytotoxic T lymphocyte antigen-4, cytochrome P450 CYP2D6, regulatory T cells (Tregs) and the forkhead/winged helix transcription factor 3. Vitamin D also exerts its effect on AIH through non-genomic factors, namely, mitogen-activated protein kinase signaling pathways, γδT cells, interferon-gamma nitric oxide synthase, and reactive oxygen stress. In conclusion, vitamin D may have a beneficial role in AIH and improves liver function in concanavalin A-induced mouse AIH. Calcitriol is best used for AIH because it is the active form of a vitamin D3 metabolite and its receptors are present in sinusoidal endothelial cells, Kupffer cells, stellate cells of normal livers, and the biliary cell line.

Epigenetic changes and their implications in autoimmune hepatitis

“…Vitamin D deficiency in chronic liver disease most likely reflects progressive hepatic fibrosis and impaired vitamin D3 hydroxylation , but reduced exposure to sunlight, malabsorption, dietary deficiency, and drug effects on vitamin D metabolism may also contribute . Diverse immune regulatory and antifibrotic effects have been ascribed to 1, 25‐dihydroxyvitamin D , and the serum 25‐hydroxy‐vitamin D level may be a biomarker of epigenetic modifications in autoimmune hepatitis .…”

“…Tobacco smoke [41] Aerosolized particles [172,173] Tobacco smoke induces deimination [41] Aerosolized matter induces demethylation [172] Heavy metals Arsenic, mercury, nickel, chromium, cadmium [41,174] Mainly DNA hypermethylation [174] Variable transcriptional activity [174] Toxins Trichloroethylene [41,175] DNA hypermethylation [175] Reduced transcriptional activity [175] Infections Epstein-Barr virus [41,176] Hypomethylated virus genome [176] Virus-encoded transcription factors [177,178] Activates genes for cell proliferation [177,178] Diet Isoflavones (pregnancy) [180] Methyl groups (pregnancy) [181] High energy diets (pregnancy) [182] Vitamin D deficiency [198] Genistein induces DNA hypermethylation [180] Methyl donors prevent heritable obesity [159] High energy diet alters DNA methylation [182] Vitamin D deficiency increases immune and fibrotic responses [201] Supplements S-adenosylmethionine [70,249] Reduces demethylase activity [249] Inhibits MBD2 activity [249] DNA, deoxyribonucleic acid; DNMTs, deoxyribonucleic acid methyltransferases; MBD2, methyl-DNA-binding domain protein 2; mRNA, messenger ribonucleic acid. Numbers in brackets are references.…”

“…Low circulating levels of 25-hydroxy-vitamin D have been described in most patients with noncholestatic chronic liver diseases, including autoimmune hepatitis [197][198][199][200][201][202]. Vitamin D3 is the natural skin-derived form of vitamin D, and it is hydroxylated in the liver to 25-hydroxy-vitamin D [203].…”

“…Vitamin D deficiency in chronic liver disease most likely reflects progressive hepatic fibrosis and impaired vitamin D3 hydroxylation [197,198,200], but reduced exposure to sunlight, malabsorption, dietary deficiency, and drug effects on vitamin D metabolism may also contribute [198,204]. Diverse immune regulatory and antifibrotic effects have been ascribed to 1, 25-dihydroxyvitamin D [201], and the serum 25-hydroxy-vitamin D level may be a biomarker of epigenetic modifications in autoimmune hepatitis [202]. The immune regulatory effects of 1, 25-dihydroxyvitamin D include modulation of nuclear DNA polymerase and protein kinase activity affecting cell proliferation [205,206], regulation of FOXP3 expression in CD4 + T cells by activating the FOXP3 gene [207,208], stimulation of cytotoxic T lymphocyte antigen-4 (CTLA-4) and IL-10 production in experimental colitis [209] and downregulation of intracellular expression of Toll-like receptors in human monocytes [210].…”

The ROS-generating and antioxidant systems in the liver of rats treated with prednisolone and vitamin D(3)

“…Це корелює зі встановленим у цій роботі фактом підвищення вмісту низькомолекулярних тіолів у печінці за дії холекальциферолу, переважну частину яких становить власне глутатіон. Крім того, ефек-ти вітаміну можуть опосередковуватись його протизапальною дією, зокрема інгібуванням спричиненої гідроксильними радикалами ЕКСПЕриМЕНТАЛьНІ рОБОТи активації NF-kB-залежної транскрипції генів численних прозапальних цитокінів [56,57]. З іншого боку, у дослідженнях на моделях неопластичних клітин, було виявлено, навпаки, прооксидантні ефекти вітаміну D 3 [58].…”