Advertisement
Mayo Clinic Proceedings Home

In reply

      Vitamin D and its relationship to nonalcoholic fatty liver disease (NAFLD) has become of recent interest as studies have linked low serum 25(OH)D levels with NAFLD. The potential therapeutic role of vitamin D supplementation in NAFLD is an intriguing concept given its safety profile, its important role in modifying cardiometabolic outcomes, and the fact that many NAFLD patients have hypovitaminosis D. Mascitelli et al recommend that serum vitamin D levels should be assessed in all patients with NAFLD and metabolic syndrome. We agree that assessment of serum 25(OH)D levels should be performed in NAFLD patients. A study by Targher et al
      • Targher G.
      • Bertolini L.
      • Scala L.
      • et al.
      Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease.
      evaluated serum 25(OH)D levels in 60 patients with biopsy-proven NAFLD and showed that serum 25(OH)D concentrations were significantly lower in patients with NAFLD than in controls. In addition, serum vitamin D concentrations were lower in individuals with more severe liver histology after adjustment for many potential confounders. The authors caution about making a causal inference because low serum concentrations of vitamin D may only be a reflection of an unhealthy lifestyle, since NAFLD is often accompanied by the metabolic syndrome.
      • Ford E.S.
      • Ajani U.A.
      • McGuire L.C.
      • Liu S.
      Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults.
      However, it is possible that low vitamin D levels are driving the progression of NAFLD, since this study found an inverse association with vitamin D levels and worsening histological features of NAFLD.
      • Targher G.
      • Bertolini L.
      • Scala L.
      • et al.
      Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease.
      No other study to date has looked specifically at vitamin D levels in biopsy-proven NAFLD. In a larger cohort study aimed at investigating the relationship between NAFLD and hypovitaminosis D in patients with different stages of insulin resistance and no previously diagnosed liver disease, an association was found between low levels of vitamin D and early ultrasonography-diagnosed NAFLD.
      • Barchetta I.
      • Angelico F.
      • Del Ben M.
      • et al.
      Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes.
      This study further supports the association between low serum vitamin D levels and NAFLD.
      The role of vitamin D in NAFLD may be associated with its known anti-inflammatory actions. It has been shown to dose-dependently suppress the release of tumor necrosis factor α and interleukin 6 and also up-regulate synthesis of the anti-inflammatory cytokine interleukin 10.
      • Schleithoff S.S.
      • Zittermann A.
      • Tenderich G.
      • Berthold H.K.
      • Stehle P.
      • Koerfer R.
      Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
      • Canning M.O.
      • Grotenhuis K.
      • de Wit H.
      • Ruwhof C.
      • Drexhage H.A.
      1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes.
      A group of investigators have also shown that the addition of vitamin D to differentiated mesenchymal multipotent cells displayed a decreased profibrotic signaling pathway and gene expression, leading to decrease in collagen deposition.
      • Artaza J.N.
      • Norris K.C.
      Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.
      This pathway may provide the mechanism by which vitamin D can improve fibrosis in NAFLD. In addition, it may have a potential role in other liver diseases. Recently, it was found that vitamin D deficiency predicted an unfavorable response to antiviral treatment of recurrent hepatitis C. Vitamin D supplementation improved the probability of achieving a sustained viral response following antiviral treatment.
      • Bitetto D.
      • Fabris C.
      • Fornasiere E.
      • et al.
      Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C.
      However, another more recent case-control study spanning more than 4 years found no difference in vitamin D levels between patients with and without progression of hepatitis C liver disease; hence, the authors concluded that there was no role for vitamin D supplementation in patients with advanced chronic hepatitis C.
      • Corey K.E.
      • Zheng H.
      • Mendez-Navarro J.
      • Delgado-Borrego A.
      • Dienstag J.L.
      • Chung R.T.
      HALT-C Trial Group
      Serum vitamin D levels are not predictive of the progression of chronic liver disease in hepatitis C patients with advanced fibrosis.
      Although therapeutic trials related to vitamin D in other disease states have been disappointing,
      • Wejse C.
      • Gomes V.F.
      • Rabna P.
      • et al.
      Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
      • Lehouck A.
      • Mathieu C.
      • Carremans C.
      • et al.
      High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
      a recent randomized study showed that improving vitamin D status in insulin-resistant women resulted in decreased insulin resistance and improved insulin sensitivity; however, these changes were not evident until higher serum levels of vitamin D were reached.
      • von Hurst P.R.
      • Stonehouse W.
      • Coad J.
      Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient—a randomised, placebo-controlled trial.
      Interventional studies are necessary to determine whether vitamin D deficiency predicts incident NAFLD, whether vitamin D supplementation will be protective against NAFLD, and what mechanisms might account for such protection. In the interim, it is reasonable to recommend that patients with NAFLD receive 1000 IU of vitamin D3 per day.
      • Assy N.
      Nutritional recommendations for patients with non-alcoholic fatty liver diseases.
      We agree that the serum vitamin D level should have been assessed in our patient
      • Nelsen E.M.
      • Newman D.B.
      • Sweetser S.
      52-Year-old man with liver enzyme abnormalities and elevated ferritin level.
      given the prevalence of hypovitaminosis in NAFLD. We have contacted the patient and are arranging testing and clinic visitation for discussion of the potential benefit of vitamin D supplementation.

      References

        • Targher G.
        • Bertolini L.
        • Scala L.
        • et al.
        Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease.
        Nutr Metab Cardiovasc Dis. 2007; 17: 517-524
        • Ford E.S.
        • Ajani U.A.
        • McGuire L.C.
        • Liu S.
        Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults.
        Diabetes Care. 2005; 28: 1228-1230
        • Barchetta I.
        • Angelico F.
        • Del Ben M.
        • et al.
        Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes.
        BMC Med. 2011; 9: 85
        • Schleithoff S.S.
        • Zittermann A.
        • Tenderich G.
        • Berthold H.K.
        • Stehle P.
        • Koerfer R.
        Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
        Am J Clin Nutr. 2006; 83: 754-759
        • Canning M.O.
        • Grotenhuis K.
        • de Wit H.
        • Ruwhof C.
        • Drexhage H.A.
        1-alpha,25-Dihydroxyvitamin D3 (1,25(OH)(2)D(3)) hampers the maturation of fully active immature dendritic cells from monocytes.
        Eur J Endocrinol. 2001; 145: 351-357
        • Artaza J.N.
        • Norris K.C.
        Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells.
        J Endocrinol. 2009; 200: 207-221
        • Bitetto D.
        • Fabris C.
        • Fornasiere E.
        • et al.
        Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C.
        Transpl Int. 2011; 24: 43-50
        • Corey K.E.
        • Zheng H.
        • Mendez-Navarro J.
        • Delgado-Borrego A.
        • Dienstag J.L.
        • Chung R.T.
        • HALT-C Trial Group
        Serum vitamin D levels are not predictive of the progression of chronic liver disease in hepatitis C patients with advanced fibrosis.
        PloS One. 2012; 7: e27144
        • Wejse C.
        • Gomes V.F.
        • Rabna P.
        • et al.
        Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial.
        Am J Respir Crit Care Med. 2009; 179: 843-850
        • Lehouck A.
        • Mathieu C.
        • Carremans C.
        • et al.
        High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial.
        Ann Intern Med. 2012; 156: 105-114
        • von Hurst P.R.
        • Stonehouse W.
        • Coad J.
        Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient—a randomised, placebo-controlled trial.
        Br J Nutr. 2010; 103: 549-555
        • Assy N.
        Nutritional recommendations for patients with non-alcoholic fatty liver diseases.
        World J Gastroenterol. 2011; 17: 3375-3376
        • Nelsen E.M.
        • Newman D.B.
        • Sweetser S.
        52-Year-old man with liver enzyme abnormalities and elevated ferritin level.
        Mayo Clin Proc. 2012; 87: 94-97

      Linked Article