Association of Vitamin D Serum Levels and Its Common Genetic Determinants, With Severity of Liver Fibrosis in Genotype 1 Chronic Hepatitis C Patients

S. Petta; S. Grimaudo; V. D. Marco; C. Scazzone; F. S. Macaluso; C. Cammà; D. Cabibi; R. Pipitone; A. Craxì

Disclosures

J Viral Hepat. 2013;20(7):486-493. 

In This Article

Discussion

In this study, we have shown that, in a cohort of patients with biopsy-proven G1 CHC, DHCR7 GG genotype, other than being associated with lower vitamin D serum levels, was also independently linked to the severity of liver fibrosis, together with well known risk factors for fibrosis, including lower vitamin D serum levels.

Different lines of evidence showed a relevant role of vitamin D status in patients with CHC patients, and with neoplastic and cardiometabolic disorders,[6,17] prompting genetic, clinical and experimental research on vitamin D metabolism and actions.

In our study we showed that, in G1 CHC patients, lower levels of serum 25(OH)D were independently linked to the DHCR7 GG genotype. Our data are in agreement with the GWAS study of Wong and colleagues on a cohort of about 30 000 subjects that identified the DHCR7 gene as able to affect vitamin D serum levels, with the lowest values in GG patients.[10] In addition, the presence of lower vitamin D serum levels in patients with the DHCR7 GG genotype was also recently reported in a large cohort of Caucasian patients with chronic liver diseases due to different aetiologies.[18] In our study, we did not identify a link between CYP2R1 and GC SNPs, also linked to vitamin D deficiency in the above quoted GWAS study,[10] and vitamin D serum levels. This issue could be related to the demographic, clinical and biochemical characteristics of our studied population, like the very high prevalence of vitamin D deficiency, as well as to the relative low number of included patients.

This study offers the first evidence that the DHCR7 GG genotype, together with lower 25(OH)D serum levels, and with other known risk factors for fibrosis severity, such as older age, low cholesterol and high triglycerides levels, moderate–severe steatosis and high necroinflammatory activity, is independently associated with the presence of severe liver fibrosis in G1 CHC patients. Grünhage and colleagues,[18] in a cohort of more than seven hundred patients with mostly clinically diagnosed chronic liver disease due to different aetiologies (60% HCV related), showed that, among subgroups of patients with liver stiffness measurement (LSM) lower than 7 kPa and lower than 9.5 kPa, the DHCR7 GG genotype was associated with higher LSM values. These data therefore suggested, with limits related to LSM use as surrogate marker of fibrosis, and to subgroups analyses, a potential association between severity of liver disease and the DHCR7 GG genotype. In this line, our study added further and relevant evidence about this issue, demonstrating the association between the DHCR7 GG genotype and severity of histological liver fibrosis, in a cohort of compensated, homogeneous and fully characterized biopsy-proven G1 CHC patients.

Another relevant finding of our study is that both the DHCR7 genotype and vitamin D levels were independently linked to the presence of severe liver fibrosis. This issue suggests that the association between the DHCR7 GG genotype and liver fibrosis is far complex. In fact, on the one hand, it is plausible that DHCR leads to fibrosis via lowering vitamin D serum levels.[10] Experimental evidence in fact suggests that vitamin D, via interaction with VDR, is able to inhibit stellate cell proliferation and their profibrogenic activation.[9] On the other hand, our results suggest that DHCR7 genotype could prompt fibrogenesis also via other direct/indirect mechanisms. However, literature data do not provide us with further help on this issue, and therefore, additional experimental work is needed.

The main limitation of this study lies in the low number of patients carrying the at-risk DHCR7 GG genotype. This issue could affect the interpretation of our results. However, the similar low prevalence of DHCR7 GG genotype reported in other studies,[10,18] then our biologically plausible results[9,10] and the presence in the literature of similar results[10,18] makes us confident about the accuracy of our data, which obviously needs further validation in large cohort studies. Another limitation of our study is its cross-sectional nature and its inability to dissect the temporal relation between DHCR7 genotype, 25(OH)D and fibrosis. A further methodological drawback is the potentially limited external validity of the results for different populations and settings. Another limitation of this study is the lack of data on the potential confounders that may influence the levels of vitamin D, such as exposure to sunshine, dietary intake and the prevalence of osteoporosis. However, all of the subjects involved in this study lived in Sicily, where sunshine is abundant.

In conclusion, this study showed that in a homogeneous cohort of compensated biopsy-proven G1 CHC patients, DHCR7 GG genotype, other than leading to lower vitamin D serum levels, is also associated with the severity of liver fibrosis, suggesting a complex interplay between liver damage, vitamin D and genetic determinants of vitamin D deficiency.

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