No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial
Background:
Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder worldwide, reaching prevalence up to 90 % in obese patients with type 2 diabetes (T2D), and representing an independent risk factor for cardiovascular mortality. Furthermore, the coexistence of T2D and NAFLD leads to higher incidence of diabetes’ complications and additive detrimental liver outcomes. The existence of a close association between NAFLD and hypovitaminosis D, along with the anti-inflammatory and insulin-sensitizing properties of vitamin D, have been largely described, but vitamin D effects on hepatic fat content have never been tested in a randomized controlled trial. We assessed the efficacy and safety of 24-week oral high-dose vitamin D supplementation in T2D patients with NAFLD.
Methods:
This randomized, double-blind, placebo-controlled trial was carried out at the Diabetes Centre of Sapienza University, Rome, Italy, to assess oral treatment with cholecalciferol (2000 IU/day) or placebo in T2D patients with NAFLD. The primary endpoint was reduction of hepatic fat fraction (HFF) measured by magnetic resonance; as hepatic outcomes, we also investigated changes in serum transaminases, CK18-M30, N-terminal Procollagen III Propeptide (P3NP) levels, and Fatty Liver Index (FLI). Secondary endpoints were improvement in metabolic (fasting glycaemia, HbA1c, lipids, HOMA-IR, HOMA-β, ADIPO-IR, body fat distribution) and cardiovascular (ankle-brachial index, intima-media thickness, flow-mediated dilatation) parameters from baseline to end of treatment.
Results:
Sixty-five patients were randomized, 26 (cholecalciferol) and 29 (placebo) subjects completed the study. 25(OH) vitamin D significantly increased in the active treated group (48.15 ± 23.7 to 89.80 ± 23.6 nmol/L, P < 0.001); however, no group differences were found in HFF, transaminases, CK18-M30, P3NP levels or FLI after 24 weeks. Vitamin D neither changed the metabolic profile nor the cardiovascular parameters.
Conclusions:
Oral high-dose vitamin D supplementation over 24 weeks did not improve hepatic steatosis or metabolic/cardiovascular parameters in T2D patients with NAFLD. Studies with a longer intervention period are warranted for exploring the effect of long time exposure to vitamin D.
Trial registration:
This trial was approved on July 2011 by the Ethics Committee of Policlinico Umberto I, Sapienza University of Rome, Italy, and registered at www.clinicaltrialsregister.eu number 2011-003010-17.
Keywords:
Fatty liver NAFLD Vitamin D supplementation Type 2 diabetes
Autoři:
Ilaria Barchetta 1; Maria Del Ben 1; Francesco Angelico 1; Michele Di Martino 2; Antonio Fraioli 1; Giuseppe La Torre 3; Rosella Saulle 3; Ludovica Perri 1; Sergio Morini 4; Claudio Tiberti 5; Laura Bertoccini 5; Flavia Agata Cimini 1; Francesca Panimolle 5; Carlo Catalano 2; Marco Giorgio Baroni 5,6; Maria Gisella Cavallo 1*
Působiště autorů:
Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 1 , 001 1 Rome, Italy.
1; Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Rome, Italy.
2; Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy.
3; Microscopic and Ultrastructural Anatomy (CIR), University Campus Bio-Medico, Rome, Italy.
4; Endocrinology and Diabetes, Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
5; Department of Medical Sciences, Endocrinology and Diabetes, University of Cagliari, Cagliari, Italy.
6
Vyšlo v časopise:
BMC Medicine 2016, 14:92
Kategorie:
Research article
prolekare.web.journal.doi_sk:
https://doi.org/10.1186/s12916-016-0638-y
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
The electronic version of this article is the complete one and can be found online at: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0638-y
Souhrn
Background:
Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder worldwide, reaching prevalence up to 90 % in obese patients with type 2 diabetes (T2D), and representing an independent risk factor for cardiovascular mortality. Furthermore, the coexistence of T2D and NAFLD leads to higher incidence of diabetes’ complications and additive detrimental liver outcomes. The existence of a close association between NAFLD and hypovitaminosis D, along with the anti-inflammatory and insulin-sensitizing properties of vitamin D, have been largely described, but vitamin D effects on hepatic fat content have never been tested in a randomized controlled trial. We assessed the efficacy and safety of 24-week oral high-dose vitamin D supplementation in T2D patients with NAFLD.
Methods:
This randomized, double-blind, placebo-controlled trial was carried out at the Diabetes Centre of Sapienza University, Rome, Italy, to assess oral treatment with cholecalciferol (2000 IU/day) or placebo in T2D patients with NAFLD. The primary endpoint was reduction of hepatic fat fraction (HFF) measured by magnetic resonance; as hepatic outcomes, we also investigated changes in serum transaminases, CK18-M30, N-terminal Procollagen III Propeptide (P3NP) levels, and Fatty Liver Index (FLI). Secondary endpoints were improvement in metabolic (fasting glycaemia, HbA1c, lipids, HOMA-IR, HOMA-β, ADIPO-IR, body fat distribution) and cardiovascular (ankle-brachial index, intima-media thickness, flow-mediated dilatation) parameters from baseline to end of treatment.
Results:
Sixty-five patients were randomized, 26 (cholecalciferol) and 29 (placebo) subjects completed the study. 25(OH) vitamin D significantly increased in the active treated group (48.15 ± 23.7 to 89.80 ± 23.6 nmol/L, P < 0.001); however, no group differences were found in HFF, transaminases, CK18-M30, P3NP levels or FLI after 24 weeks. Vitamin D neither changed the metabolic profile nor the cardiovascular parameters.
Conclusions:
Oral high-dose vitamin D supplementation over 24 weeks did not improve hepatic steatosis or metabolic/cardiovascular parameters in T2D patients with NAFLD. Studies with a longer intervention period are warranted for exploring the effect of long time exposure to vitamin D.
Trial registration:
This trial was approved on July 2011 by the Ethics Committee of Policlinico Umberto I, Sapienza University of Rome, Italy, and registered at www.clinicaltrialsregister.eu number 2011-003010-17.
Keywords:
Fatty liver NAFLD Vitamin D supplementation Type 2 diabetes
Zdroje
1. Clark JM, Brancati FL, Diehl AME. Nonalcoholic fatty liver disease: the most common cause of abnormal liver enzymes in the US population. Gastroenterology. 2011;120(5 Suppl 1):A65.
2. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005–23.
3. Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes Care. 2007;30:734–43.
4. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 2015;62(5):1148–55.
5. Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–8.
6. Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, et al. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012;130(7):1639–48.
7. Raff EJ, Kakati D, Bloomer JR, Shoreibah M, Rasheed K, Singal AK. Diabetes mellitus predicts occurrence of cirrhosis and hepatocellular cancer in alcoholic liver and non-alcoholic fatty liver diseases. J Clin Transl Hepatol. 2015;3(1):9–16.
8. Lomonaco R, Bril F, Portillo-Sanchez P, Ortiz-Lopez C, Orsak B, Biernacki D, Lo M, Suman A, Weber MH, Cusi K. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care. 2016; 39(4):632–8.
9. Mantovani A, Pernigo M, Bergamini C, Bonapace S, Lipari P, Pichiri I, et al. Nonalcoholic fatty liver disease is independently associated with early left ventricular diastolic dysfunction in patients with type 2 diabetes. PLoS One. 2015;10(8):e0135329.
10. Jia G, Di F, Wang Q, Shao J, Gao L, Wang L, et al. Non-alcoholic fatty liver disease is a risk factor for the development of diabetic nephropathy in patients with type 2 diabetes mellitus. PLoS One. 2015;10(11):e0142808.
11. Targher G, Bertolini L, Rodella S, Zoppini G, Lippi G, Day C, et al. Nonalcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia. 2008;51(3):444–50.
12. Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2007;30(5):1212–8.
13. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341–50.
14. Del Ben M, Polimeni L, Baratta F, Pastori D, Loffredo L, Angelico F. Modern approach to the clinical management of non-alcoholic fatty liver disease. World J Gastroenterol. 2014;20(26):8341–50.
15. Hypponen E, Boucher BJ, Berry DJ, Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age. Diabetes. 2008;57(2):298–305.
16. Forouhi NG, Luan J, Cooper A, Boucher BJ, Wareham NJ. Baseline serum 25-hydroxy vitamin d is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990-2000. Diabetes. 2008;57:2619–25.
17. Barchetta I, De Bernardinis M, Capoccia D, Baroni MG, Fontana M, Fraioli A, et al. Hypovitaminosis D is independently associated with metabolic syndrome in obese patients. PLoS One. 2013;8(7):e68689.
18. Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G, 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(7):517–24.
19. Barchetta I, Angelico F, Del Ben M, Baroni MG, Pozzilli P, Morini S, et al. Strong association between nonalcoholic 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.
20. Eliades M, Spyrou E, Agrawal N, Lazo M, Brancati FL, Potter JJ, et al. Meta-analysis: vitamin D and non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2013;38:246–54.
21. Mutt SJ, Hyppönen E, Saarnio J, Järvelin MR, Herzig KH. Vitamin D and adipose tissue-more than storage. Front Physiol. 2014;5:228.
22. Barchetta I, Carotti S, Labbadia G, Gentilucci UV, Muda AO, Angelico F, et al. Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus. Hepatology. 2012;56(6):2180–7.
23. Zhou QG, Hou FF, Guo ZJ, Liang M, Wang GB, Zhang X. 1,25- Dihydroxyvitamin D improved the free fatty-acid-induced insulin resistance in cultured C2C12 cells. Diab Metab Res Rev. 2004;24:459–64.
24. Abramovitch S, Dahan-Bachar L, Sharvit E, Weisman Y, Tov AB, Brazowski E, et al. Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats. Gut. 2011;60:1728–37.
25. Kitson MT, Roberts SK. D-livering the message: the importance of vitamin D status in chronic liver disease. J Hepatol. 2012;57(4):897–909.
26. Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology. 2009;50:1072–8.
27. Joka D, Wahl K, Moeller S, Schlue J, Vaske B, Bahr MJ, et al. Prospective biopsy-controlled evaluation of cell death biomarkers for prediction of liver fibrosis and nonalcoholic steatohepatitis. Hepatology. 2012;55:455–64.
28. Han H, Cui M, You X, Chen M, Piao X, Jin G. A role of 1,25(OH)2D3 supplementation in rats with nonalcoholic steatohepatitis induced by choline-deficient diet. Nutr Metab Cardiovasc Dis. 2015;25(6):556–61.
29. Kitson MT, Pham A, Gordon A, Kemp W, Roberts SK. High-dose vitamin D supplementation and liver histology in NASH. Gut. 2016;65(4):717–8.
30. American Diabetes Association. Standards of medical care in diabetes–2009. Diabetes Care. 2009;32:S13–61.
31. Tanwar S, Trembling PM, Guha IN, Parkes J, Kaye P, Burt AD, et al. Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease. Hepatology. 2013;57(1):103–11.
32. Brouwer-Brolsma EM, Bischoff-Ferrari HA, Bouillon R, Feskens EJ, Gallagher CJ, Hypponen E, et al. Vitamin D: do we get enough? A discussion between vitamin D experts in order to make a step towards the harmonisation of dietary reference intakes for vitamin D across Europe. Osteoporos Int. 2013;24(5):1567–77.
33. Deleskog A, Hilding A, Brismar K, Hamsten A, Efendic S, Östenson CG. Low serum 25-hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance. Diabetologia. 2012;55(6):1668–78.
34. Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–70.
35. Gastaldelli A, Harrison SA, Belfort-Aguilar R, Hardies LJ, Balas B, Schenker S, et al. Importance of changes in adipose tissue insulin resistance to histological response during thiazolidinedione treatment of patients with nonalcoholic steatohepatitis. Hepatology. 2009;50(4):1087–93.
36. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.
37. Yokoo T, Bydder M, Hamilton G, Middleton MS, Gamst AC, Wolfson T, et al. Nonalcoholic fatty liver disease: diagnostic and fat-grading accuracy of lowflip-angle multiecho gradient-recalled-echo MR imaging at 1.5 T. Radiology. 2009;251(1):67–76.
38. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int. 2005;16(7):713–6.
39. Sharifi N, Amani R, Hajiani E, Cheraghian B. Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial. Endocrine. 2014;47(1):70–80.
40. Bril F, Maximos M, Portillo-Sanchez P, Biernacki D, Lomonaco R, Subbarayan S, et al. Relationship of vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis. J Hepatol. 2015;62(2):405–11.
41. Anty R, Hastier A, Canivet CM, Patouraux S, Schneck AS, Ferrari-Panaia P, Ben-Amor I, Saint-Paul MC, Gugenheim J, Gual P, Iannelli A, Tran A. Severe vitamin D deficiency is not associated with liver damage in morbidly obese patients. Obes Surg. 2016. [Epub ahead of print].
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