Vitamin D deficiency in patients with liver cirrhosis

Abstract

There is ongoing evidence that vitamin D is related to the pathophysiology of cirrhosis. Although the incidence of vitamin D deficiency in chronic liver diseases and cirrhosis is strongly documented, its pathogenic association with advanced liver fibrosis remains controversial. There is evidence of a significant relation of 25(OH)D levels with the degree of liver dysfunction, considering that an inverse correlation of 25(OH)D levels with both Child-Pugh score and Model for End-Stage Liver Disease has been reported. In addition, vitamin D deficiency has been shown to increase the risk for overall mortality and infections in patients with cirrhosis. Vitamin D deficiency has been also associated with advanced stages of hepatocellular carcinoma and poor prognosis. Finally, there are studies suggesting that patients with chronic hepatitis C and normal vitamin D levels have higher virological response to treatment. However, there are not enough studies conducted in cirrhotic-only populations. The association between vitamin D and cirrhosis demonstrates a great potential for clinical application. The relation between vitamin D deficiency and the degree of liver function, degree of fibrosis and infectious complications could support its use as a prognostic index and a diagnostic tool.

Keywords: Vitamin D; liver cirrhosis; prognosis; vitamin D deficiency; vitamin D insufficiency.

Figure 1

Vitamin D and liver fibrosis. Dietary sources provide vitamin D₂ and vitamin D₃, which are absorbed in the intestine. The main source of vitamin D is biosynthesis from epidermal cells as a result of exposure to sunlight. Vitamin D₃ is transferred to the liver, where 25-hydroxylation takes place. 25(OH)D is transported to the kidney where it is again enzymatically hydroxylated to form 1,25(OH)D₃ or calcitriol (the active form of vitamin D₃). Calcitriol through its receptor, VDR, exerts its systemic (endocrine – purple axis) regulatory effects on many different target organs. A second 1,25(OH)D₃ pool is proposed (paracrine - yellow axis), that involves the immune system and the local production of calcitriol by immune cells, which could contribute to immune regulation The complex interplay between environmental, genetic, cell signaling and other host factors that drive the inflammatory process and fibrogenesis remains a topic of research. ‘’Key players’’ of this process are presented in this figure

1. DHCR7 genotype / polymorphisms = The DHCR7 gene has been proposed to be able to affect vitamin D serum levels. A link with the severity of fibrosis has been suggest, namely with the (GG) homozygote of the DHCR7 gene. A stronger association of the susceptible DHCR7 SNPs (single nucleotide polymorphisms) with fibrosis initiation rather than progression has been suggested

2. Collagen promoter = There is evidence that 1,25-(OH)2D₃ inhibits type I collagen formation in stellate cells, mainly by binding to specific sites. At least two sites have been identified, with the proximal Sp 1-1 site being the most recognizable

3. VDR variants = VDR polymorphisms have been associated with liver fibrosis

4. Signaling mechanisms = A host of enzymes, growth factors and other physiologically active compounds are in complex interaction, resulting in the regulation of liver inflammation and fibrosis

UVB, ultraviolet B; VitD, vitamin D; Cyp27A1, cytochrome P450, family 27, subfamily A, polypeptide 1; Cyp27B1, cytochrome P450, family 27, subfamily B, polypeptide 1; VDR, vitamin D receptor; TLRs, toll-like receptors; HLA, human leukocyte antigen system; ApoE, apolipoprotein E; Nramp1, natural resistance-associated macrophage protein one; CTLA-4, cytotoxic T lymphocyte antigen-4; DHCR7, 7-dehydrocholesterol reductase; MMPs, matrix metalloproteinases; ROS, reactive oxygen species; PGs, prostaglandins; BMP7, bone morphogenetic protein 7; TGF-β, transforming growth factor-β; TIMPs, tissue inhibitor metalloproteinases.