A study of the relationship between vitamin D status and the severity and outcomes of chronic hepatitis C infection and nonalcoholic steatohepatitis

Vitamin D is an important secosteroid hormone with pleiotropic effects that influence downstream transcription of >200 target genes, endowing vitamin D with anti-inflammatory and anti-fibrotic properties, and immunomodulatory effects that influence both innate and adaptive immunity. The liver is a pivotal organ in the synthesis of vitamin D and it is hypothesized that the non-classical extra-skeletal effects of vitamin D may be relevant in the pathogenesis and treatment of chronic liver disease, influencing disease severity and outcomes. Since 2010, a number of retrospective and prospective studies have produced conflicting data about any association between baseline vitamin D status and sustained virologic response to interferon-based antiviral therapy in chronic hepatitis C (CHC) infection, with some studies suggesting that a lower 25-hydroxyvitamin D level is associated with poorer treatment outcomes. Furthermore, a lower 25-hydroxyvitamin D level has been associated with a more advanced fibrosis stage on liver biopsy in CHC infection, raising the possibility that vitamin D status may influence fibrosis progression. Vitamin D deficiency is associated with insulin resistance, a key factor in the development of nonalcoholic fatty liver disease (NAFLD), which is the most prevalent cause of liver disease in developed countries. Those with nonalcoholic steatohepatitis (NASH) have a more severe phenotype of NAFLD. Vitamin D has also been reported to be independently associated with the histologic severity of NASH, with a lower 25-hydroxyvitamin D level associated with more inflammation and fibrosis. Animal studies have also suggested that vitamin D supplementation may improve the severity of inflammation in NASH and protect against the development of liver fibrosis. The general aim of this work is to evaluate any association between vitamin D status and the severity of disease and treatment outcomes in both CHC infection and NASH. First, any association between baseline vitamin D level, liver fibrosis stage assessed by histology, and sustained virologic response in CHC was studied. This was followed by a prospective evaluation of any association between vitamin D status and liver fibrosis, assessed by measurement of liver stiffness. Finally, any effect of high-dose vitamin D supplementation on the metabolic profile and liver histology in patients with NASH was studied. The work in this thesis has not found any association between vitamin D status and the severity and outcomes of liver disease in either CHC or NASH. These findings are in keeping with recent systematic and umbrella reviews, and cast doubt on any causal link between vitamin D deficiency and non-skeletal health outcomes, suggesting that vitamin D deficiency is a marker of ill-health rather than an important factor implicated in the pathogenesis of disease.