Skip to main content
Log in

Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial

  • Endocrine Trials
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

The aim of this study was to investigate the effects of vitamin D supplementation on serum aminotransferases, insulin resistance, oxidative stress, and inflammatory biomarkers in adult patients with non-alcoholic fatty liver disease (NAFLD). Fifty-three patients with NAFLD were enrolled in a parallel, double-blind, placebo-controlled study. The patients were randomly allocated to receive either one oral pearl consisting of 50,000 IU vitamin D3 (n = 27) or a placebo (n = 26), every 14 days for 4 months. Serum aminotransferases, high-sensitive C-reactive protein (hs-CRP), tumor necrosis factor α, malondialdehyde (MDA), total antioxidant capacity, transforming growth factor β1, as well as grade of hepatic steatosis and homeostasis model assessment of insulin resistance were assessed pre- and post-intervention. In patients who received vitamin D supplement compared to the controls, the median of serum 25(OH)D3 significantly increased (16.2 vs. 1.6 ng/ml, P < 0.001). This increase accompanied by significant decrease in serum MDA (−2.09 vs. −1.23 ng/ml, P = 0.03) and near significant changes in serum hs-CRP (−0.25 vs. 0.22 mg/l, P = 0.06). These between-group differences remained significant even after controlling for baseline covariates. Other variables showed no significant changes. Improved vitamin D status led to amelioration in serum hs-CRP and MDA in patients with NAFLD. This might be considered as an adjunctive therapy to attenuate systemic inflammation and lipid peroxidation alongside other treatments for NAFLD patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. E.A. Yetley, Assessing the vitamin D status of the US population. Am. J. Clin. Nutr. 88(2), 558S–564S (2008)

    CAS  PubMed  Google Scholar 

  2. M.F. Holick, Vitamin D deficiency. N. Engl. J. Med. 357(3), 266–281 (2007)

    Article  CAS  PubMed  Google Scholar 

  3. J.S. Adams, M. Hewison, Update in vitamin D. J. Clin. Endocrinol. Metab. 95(2), 471–478 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  4. G. Musso, Non-alcoholic fatty liver, adipose tissue, and the bone: a new triumvirate on the block. Endocrine 42, 237–239 (2012)

    Article  CAS  PubMed  Google Scholar 

  5. E. Hyppönen, B.J. Boucher, D.J. Berry, C. Power, 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age. Diabetes 57(2), 298–305 (2008)

    Article  PubMed  Google Scholar 

  6. J.P. Reis, D. von Mühlen, D. Kritz-Silverstein, D.L. Wingard, E. Barrett-Connor, Vitamin D, parathyroid hormone levels, and the prevalence of metabolic syndrome in community-dwelling older adults. Diabetes Care 30(6), 1549–1555 (2007)

    Article  CAS  PubMed  Google Scholar 

  7. L.-H. Li, X.-Y. Yin, C.-Y. Yao, X.-C. Zhu, X.-H. Wu, Serum 25-hydroxyvitamin D, parathyroid hormone, and their association with metabolic syndrome in Chinese. Endocrine 44(2), 465–472 (2013)

    Article  CAS  PubMed  Google Scholar 

  8. N.C. Bozkurt, E. Cakal, M. Sahin, E.C. Ozkaya, H. Firat, T. Delibasi, The relation of serum 25-hydroxyvitamin-D levels with severity of obstructive sleep apnea and glucose metabolism abnormalities. Endocrine 41(3), 518–525 (2012)

    Article  CAS  PubMed  Google Scholar 

  9. G. Targher, L. Bertolini, L. Scala, M. Cigolini, L. Zenari, G. Falezza, G. Arcaro, Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutr. Metab. Cardiovasc. Dis 17(7), 517–524 (2007)

    Article  CAS  PubMed  Google Scholar 

  10. J.M. Clark, F.L. Brancati, A.M. Diehl, Nonalcoholic fatty liver disease. Gastroenterology 122(6), 1649–1657 (2002)

    Article  PubMed  Google Scholar 

  11. I. Barchetta, F. Angelico, M.D. Ben, M.G. Baroni, P. Pozzilli, S. Morini, M.G. Cavallo, 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. 9(1), 85 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. T. Nakano, Y.F. Cheng, C.Y. Lai, L.W. Hsu, Y.C. Chang, J.Y. Deng, Y.Z. Huang, H. Honda, K.D. Chen, C.C. Wang, Impact of artificial sunlight therapy on the progress of non-alcoholic fatty liver disease in rats. J. Hepatol. 55(2), 415–425 (2011)

    Article  CAS  PubMed  Google Scholar 

  13. E. Rhee, M. Kim, S. Park, C. Park, K. Baek, W. Lee, M. Kang, S. Park, S. Kim, K. Oh, High serum vitamin D levels reduce the risk for nonalcoholic fatty liver disease in healthy men independent of metabolic syndrome. Endocr. J. 60(6), 743–752 (2013)

    Article  CAS  PubMed  Google Scholar 

  14. G. Targher, C. Byrne, Lower 25-hydroxyvitamin D3 levels and increased risk of liver diseases: is there a causal link? Endocrine (2014). doi:10.1007/s12020-014-0220-3

    PubMed  Google Scholar 

  15. C.L. Roth, C.T. Elfers, D.P. Figlewicz, S.J. Melhorn, G.J. Morton, A. Hoofnagle, M.M. Yeh, J.E. Nelson, K.V. Kowdley, Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and toll-like receptor activation. Hepatology 55(4), 1103–1111 (2012)

    Article  CAS  PubMed  Google Scholar 

  16. D. Prati, E. Taioli, A. Zanella, E. Della Torre, S. Butelli, E. Del Vecchio, L. Vianello, F. Zanuso, F. Mozzi, S. Milani, Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann. Intern. Med. 137(1), 1–10 (2002)

    Article  CAS  PubMed  Google Scholar 

  17. S. Abu-Mouch, Z. Fireman, J. Jarchovsky, A.R. Zeina, N. Assy, Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J. Gastroenterol. 17(47), 5184–5190 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. C.L. Craig, A.L. Marshall, M. Sjöström, A.E. Bauman, M.L. Booth, B.E. Ainsworth, M. Pratt, U. Ekelund, A. Yngve, J.F. Sallis, International physical activity questionnaire: 12-country reliability and validity. Med. Sci. Sports Exerc. 85(3), 1381–1395 (2003)

    Article  Google Scholar 

  19. N.A. Botsoglou, D.J. Fletouris, G.E. Papageorgiou, V.N. Vassilopoulos, A.J. Mantis, A.G. Trakatellis, Rapid, sensitive, and specific thiobarbituric acid method for measuring lipid peroxidation in animal tissue, food, and feedstuff samples. J. Agric. Food Chem. 42(9), 1931–1937 (1994)

    Article  CAS  Google Scholar 

  20. A. Khosrowbeygi, N. Zarghami, Y. Deldar, Correlation between sperm quality parameters and seminal plasma antioxidants status. Iran. J. Reprod. Med. 2(2), 58–64 (2012)

    Google Scholar 

  21. J. Jou, S.S. Choi, A.M. Diehl, Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin. Liver Dis. 28(04), 370–379 (2008)

    Article  CAS  PubMed  Google Scholar 

  22. J.W. Haukeland, J.K. Damås, Z. Konopski, E.M. Løberg, T. Haaland, I. Goverud, P.A. Torjesen, K. Birkeland, K. Bjøro, P. Aukrust, Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J. Hepatol. 44(6), 1167–1174 (2006)

    Article  CAS  PubMed  Google Scholar 

  23. G. Targher, Relationship between high-sensitivity C-reactive protein levels and liver histology in subjects with non-alcoholic fatty liver disease. J. Hepatol. 45(6), 879–881 (2006)

    Article  CAS  PubMed  Google Scholar 

  24. G. Targher, G. Arcaro, Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 191(2), 235–240 (2007)

    Article  CAS  PubMed  Google Scholar 

  25. M.T. Cantorna, Y. Zhu, M. Froicu, A. Wittke, Vitamin D status, 1, 25-dihydroxyvitamin D3, and the immune system. Am. J. Clin. Nutr. 80(6), 1717S–1720S (2004)

    CAS  PubMed  Google Scholar 

  26. S. Zúñiga, D. Firrincieli, C. Housset, N. Chignard, Vitamin D and the vitamin D receptor in liver pathophysiology. Clin. Res. Hepatol. Gastroenterol. 35, 295–302 (2011)

    Article  PubMed  Google Scholar 

  27. A. Zittermann, S. Frisch, H.K. Berthold, C. Götting, J. Kuhn, K. Kleesiek, P. Stehle, H. Koertke, R. Koerfer, Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am. J. Clin. Nutr. 89(5), 1321–1327 (2009)

    Article  CAS  PubMed  Google Scholar 

  28. S.S. Schleithoff, A. Zittermann, G. Tenderich, H.K. Berthold, P. Stehle, R. Koerfer, Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am. J. Clin. Nutr. 83(4), 754–759 (2006)

    CAS  PubMed  Google Scholar 

  29. J. Beilfuss, V. Berg, M. Sneve, R. Jorde, E. Kamycheva, Effects of a 1-year supplementation with cholecalciferol on interleukin-6, tumor necrosis factor-alpha and insulin resistance in overweight and obese subjects. Cytokine 60(3), 870–874 (2012)

    Article  CAS  PubMed  Google Scholar 

  30. Y. Karim, C. Turner, N. Dalton, R. Roplekar, A. Sankaralingam, M. Ewang, I. Fogelman, G. Hampson, The relationship between pro-resorptive inflammatory cytokines and the effect of high dose vitamin D supplementation on their circulating concentrations. Int. Immunopharmacol. 17(3), 693–697 (2013)

    Article  CAS  PubMed  Google Scholar 

  31. S. Shab-Bidar, T.R. Neyestani, A. Djazayery, M.R. Eshraghian, A. Houshiarrad, A. Kalayi, N. Shariatzadeh, N. Khalaji, Improvement of vitamin D status resulted in amelioration of biomarkers of systemic inflammation in the subjects with type 2 diabetes. Diabetes Metab. Res. Rev. 28(5), 424–430 (2012)

    Article  CAS  PubMed  Google Scholar 

  32. M.J. Czaja, F.R. Weiner, K.C. Flanders, M.-A. Giambrone, R. Wind, L. Biempica, M.A. Zern, In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J. Cell Biol. 108(6), 2477–2482 (1989)

    Article  CAS  PubMed  Google Scholar 

  33. F.H. Epstein, G.C. Blobe, W.P. Schiemann, H.F. Lodish, Role of transforming growth factor β in human disease. N. Engl. J. Med. 342(18), 1350–1358 (2000)

    Article  Google Scholar 

  34. T. Hasegawa, M. Yoneda, K. Nakamura, I. Makino, A. Terano, Plasma transforming growth factor-β1 level and efficacy of α-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study. Aliment Pharmacol. Ther. 15(10), 1667–1672 (2001)

    Article  CAS  PubMed  Google Scholar 

  35. S. Isik, U. Ozuguz, Y. Ates Tutuncu, G. Erden, D. Berker, K. Acar, Y. Aydin, G. Akbaba, N. Helvaci, S. Guler, Serum transforming growth factor-beta levels in patients with vitamin D deficiency. Eur. J. Intern. Med. 23(1), 93–97 (2012)

    Article  CAS  PubMed  Google Scholar 

  36. A.A. Mahmoud, A.S. Bakir, S.S. Shabana, Serum TGF-β, Serum MMP-1, and HOMA-IR as non-invasive predictors of fibrosis in Egyptian patients with NAFLD. Saudi J. Gastroenterol. 18(5), 327 (2012)

    Article  PubMed Central  PubMed  Google Scholar 

  37. L. Malaguarnera, R. Madeddu, E. Palio, N. Arena, M. Malaguarnera, Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. J. Hepatol. 42(4), 585–591 (2005)

    Article  CAS  PubMed  Google Scholar 

  38. H. Wiseman, Vitamin D is a membrane antioxidant Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action. FEBS Lett. 326(1), 285–288 (1993)

    Article  CAS  PubMed  Google Scholar 

  39. O. Tarcin, D.G. Yavuz, B. Ozben, A. Telli, A.V. Ogunc, M. Yuksel, A. Toprak, D. Yazici, S. Sancak, O. Deyneli, Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. J. Clin. Endocrinol. Metab. 94(10), 4023–4030 (2009)

    Article  CAS  PubMed  Google Scholar 

  40. M.C. Banakar, S.K. Paramasivan, M.B. Chattopadhyay, S. Datta, P. Chakraborty, M. Chatterjee, K. Kannan, E. Thyagarajan, 1,25-Dihydroxyvitamin D3 prevents DNA damage and restores antioxidant enzymes in rat hepatocarcinogenesis induced by diethylnitrosamine and promoted by phenobarbital. World J. Gasteroenterol. 10, 1268–1275 (2004)

    CAS  Google Scholar 

  41. A.G. Pittas, S.S. Harris, P.C. Stark, B. Dawson-Hughes, The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 30(4), 980–986 (2007)

    Article  CAS  PubMed  Google Scholar 

  42. P.R. von Hurst, W. Stonehouse, J. Coad, 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. 103(4), 549 (2010)

    Article  Google Scholar 

  43. E. Kamycheva, V. Berg, R. Jorde, Insulin-like growth factor I, growth hormone, and insulin sensitivity: the effects of a one-year cholecalciferol supplementation in middle-aged overweight and obese subjects. Endocrine 43(2), 412–418 (2013)

    Article  CAS  PubMed  Google Scholar 

  44. H.R. Ardabili, B.P. Gargari, L. Farzadi, Vitamin D supplementation has no effect on insulin resistance assessment in women with polycystic ovary syndrome and vitamin D deficiency. Nutr. Res. 32(3), 195–201 (2012)

    Article  CAS  PubMed  Google Scholar 

  45. I.H. de Boer, L.F. Tinker, S. Connelly, J.D. Curb, B.V. Howard, B. Kestenbaum, J.C. Larson, J.E. Manson, K.L. Margolis, D.S. Siscovick, Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care 31(4), 701–707 (2008)

    Article  PubMed Central  PubMed  Google Scholar 

  46. R. Jorde, Y. Figenschau, Supplementation with cholecalciferol does not improve glycaemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels. Eur. J. Nutr. 48(6), 349–354 (2009)

    Article  CAS  PubMed  Google Scholar 

  47. A.G. Pittas, B. Dawson-Hughes, Vitamin D and diabetes. J. Steroid Biochem. Mol. Biol. 121(1), 425–429 (2010)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. A.G. Pittas, J. Lau, F.B. Hu, B. Dawson-Hughes, The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 92(6), 2017–2029 (2007)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. R.A. DeFronzo, J.D. Tobin, R. Andres, Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am. J. Physiol. Endocrinol. Metab. 237(3), E214 (1979)

    CAS  Google Scholar 

  50. S.H. Ipekci, M. Basaranoglu, A. Sonsuz, The fluctuation of serum levels of aminotransferase in patients with nonalcoholic steatohepatitis. J. Clin. Gastroenterol. 36(4), 371 (2003)

    Article  PubMed  Google Scholar 

  51. S. Liangpunsakul, N. Chalasani, Serum vitamin D concentrations and unexplained elevation in ALT among US adults. Dig. Dis. Sci. 56(7), 2124–2129 (2011)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. T. Skaaby, L. Husemoen, A. Borglykke, T. Jørgensen, B. Thuesen, C. Pisinger, L. Schmidt, A. Linneberg, Vitamin D status, liver enzymes, and incident liver disease and mortality: a general population study. Endocrine (2013). doi:10.1007/s12020-013-0107-8

    Google Scholar 

  53. H.A. Saleh, A.H. Abu-Rashed, Liver biopsy remains the gold standard for evaluation of chronic hepatitis and fibrosis. J. Gastrointest. Liver. Dis. 16(4), 425 (2007)

    Google Scholar 

  54. J.F. Cobbold, D. Patel, S.D. Taylor-Robinson, Assessment of inflammation and fibrosis in non-alcoholic fatty liver disease by imaging-based techniques. J. Gastroenterol. Hepatol. 27(8), 1281–1292 (2012)

    Article  PubMed  Google Scholar 

  55. G. Ligabue, G. Besutti, R. Scaglioni, C. Stentarelli, G. Guaraldi, MR quantitative biomarkers of non-alcoholic fatty liver disease: technical evolutions and future trends. Quant. Imaging Med. Surg. 3(4), 192 (2013)

    PubMed Central  PubMed  Google Scholar 

  56. M. Manco, P. Ciampalini, V. Nobili, Low levels of 25-hydroxyvitamin D3 in children with biopsy-proven nonalcoholic fatty liver disease. Hepatology 51(6), 2229 (2010)

    Article  PubMed  Google Scholar 

  57. M. Eliades, E. Spyrou, N. Agrawal, M. Lazo, F. Brancati, J. Potter, A. Koteish, J. Clark, E. Guallar, R. Hernaez, Meta-analysis: vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol. Ther. 38(3), 246–254 (2013)

    Article  CAS  PubMed  Google Scholar 

  58. A. Geier, Shedding new light on vitamin D and fatty liver disease. J. Hepatol. 55(2), 273–275 (2011)

    Article  PubMed  Google Scholar 

  59. G. Targher, E. Scorletti, A. Mantovani, C.D. Byrne, Nonalcoholic fatty liver disease and reduced serum vitamin D3 levels. Metab. Syndr. Relat. Disord. 11(4), 217–228 (2013)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by a Grant (No. RDC-9105) from Vice-Chancellor for Research Affairs of Jundishapur University of Medical Sciences and approved by the Research Institute for Infectious Diseases of the Digestive System, Jundishapur University of Medical Sciences, Ahvaz, Iran. Also, it was a part of PhD thesis of Nasrin Sharifi, student of Jundishapur University of Medical Sciences. The authors wish to thank Dr. Amir Hossein Sina from Danesh Lab in Ahvaz for his kind help in laboratory test assessment. We also thank Mr. Amir Mansour Vatankhah, and Dr. Mehran Messgari for their cooperation in measuring biochemical factors.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Reza Amani.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharifi, N., Amani, R., Hajiani, E. et al. Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial. Endocrine 47, 70–80 (2014). https://doi.org/10.1007/s12020-014-0336-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-014-0336-5

Keywords

Navigation