doi:10.1002/jgh3.12010
O R I GI N AL A R T IC L E
Vitamin D supplementation in patients with nonalcoholic fatty liver disease: A randomized controlled trial Mallikarjun Sakpal,* Sandeep Satsangi,* Manu Mehta,* Ajay Duseja,* Radha K Dhiman* and Yogesh K Chawla*
Sanjay Bhadada,† Ashim Das,‡
Departments of *Hepatology, †Endocrinology and ‡Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Key words cytokines, nonalcoholic fatty liver disease, vitamin D. Accepted for publication 12 August 2017. Correspondence Dr Professor Ajay Duseja, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, 160012, India. Email:
[email protected] Declaration of conflict of interest: None.
Abstract Background and Aim: Deficiency of vitamin D may be related to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the effect of vitamin D supplementation in patients with NAFLD. Methods: A total of 81 patients with NAFLD with normal or raised (n = 47) serum alanine aminotransferase (ALT) having vitamin D deficiency were randomized prospectively. Group 1 (n = 51) received lifestyle modifications and a single injection of vitamin D (600 000 U) (standard medical treatment [SMT] + vitamin D) and group 2 (n = 30) received lifestyle modifications (SMT) for 6 months. The primary objective of this study was to assess the improvement in insulin resistance (IR) and serum ALT (in patients with raised ALT) and the secondary objective was to assess the change in cytokine profile in the SMT + vitamin D group. Results: After 6 months, significant improvement in serum levels of ALT was observed in the SMT + vitamin D group when compared to the SMT group (ALT [87 48 and 59 32 IU/mL, P < 0.001] vs [64 35 and 62 24 IU/mL, P = 0.70]). Mean insulin levels and homeostasis model assessment-IR remained unchanged at 6 months in the SMT + vitamin D group while there was a significant increase in mean insulin and homeostasis model assessment-IR in the SMT group. SMT + vitamin D group had significant increase in mean serum levels of adiponectin (836 309 and 908 312 (pg/mL), P = 0.018) compared with the baseline; tumor necrosis factor-α levels decreased from baseline but the change was not significant. Conclusion: Patients with NAFLD given vitamin D in addition to lifestyle modifications have significant improvement in serum ALT and serum adiponectin levels.
Nonalcoholic fatty liver disease (NAFLD) is a constellation of conditions histologically characterized by macrovesicular hepatic steatosis in individuals who do not consume alcohol in amounts generally considered to be harmful to the liver.1 It is a broad term consisting of patients with simple steatosis or nonalcoholic fatty liver (NAFL) at one end of the spectrum, nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC) at the other end.2–4 Even though NAFLD is considered a hepatic manifestation of metabolic syndrome (MS), pathogenesis of NAFLD is still ill understood with involvement of various environmental and genetic factors in the pathogenesis. Recent evidence also points to the role of small intestinal bacterial overgrowth, altered gut microbiota, and endotoxemia in patients with NAFLD.5,6 Vitamin D is a lipophilic molecule essential to maintain calcium and phosphate balance and osteometabolic system regulation. In adult population, the prevalence of hypovitaminosis D
ranges from 5% to 30%,7 but it reaches a peak of 75% in patients with MS.8 Vitamin D-deficient individuals are more likely to develop alterations in glucose metabolism, such as impaired glucose tolerance, MS, and type 2 diabetes mellitus (DM).9 Low serum vitamin D has been shown to predispose to intrahepatic lipid accumulation leading to NAFLD, and vitamin D is capable of reducing free fatty acid (FFA) induced insulin resistance (IR) both in peripheral tissues and in hepatocytes.10 Understanding the complex interplay between vitamin D signals and lipid/glucose metabolism and differentiating specific metabolic effects from nonspecific anti-inflammatory properties in fatty liver disease have opened a new therapeutic intervention for patients with NAFLD. Therapeutic potency of sunlight therapy and vitamin D in an animal model of fatty liver disease has clearly shown benefit.11 Vitamin D substitution thus may represent a simple, cheap, and almost side effect-free candidate approach to reduce the burden of end-stage liver failure and liver cancer in this frequent disease entity for which medical interventions with proven longterm efficacy are still lacking. Till now there is no randomized
JGH Open: An open access journal of gastroenterology and hepatology (2017) 1–6
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Introduction
© 2017 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Vitamin D supplementation in NAFLD
controlled trial of vitamin D supplementation in patients with NAFLD. Hence, we planned to study the efficacy of vitamin D supplementation in patients with NAFLD.
Methods A total of 81 consecutive patients with NAFLD with normal or raised serum alanine aminotransferase (ALT), attending liver clinic of Postgraduate Institute of Medical Education and Research, Chandigarh, India, were enrolled in the study over a period of 1.5 years, after obtaining an informed consent. The study had the approval of the institute’s ethics committee. Inclusion criteria for patients with NAFLD included age more than 12 years, nonalcoholic individuals defined as either total abstainers or individuals who consumed less than 20 g of alcohol per day, ultrasound showing features of steatosis, with or without raised ALT (>40 IU/L), and negative viral markers (Hepatitis B surface antigen (HBsAg) and anti-hepatitis C virus [HCV]). Patients with raised ALT in addition had negative autoimmune markers (antinuclear antibody [ANA], anti-smooth muscle antibody [ASMA], anti-liver kidney microsomal antibody [LKM], and antimitochondrial antibody [AMA]) and normal ceruloplasmin/negative Kayser–Fleischer (KF) ring with normal iron work up (serum iron, total iron-binding capacity [TIBC], ferritin, and transferrin saturation). Pregnant females, patients with history of drug intake likely to cause NAFLD, patients with jejunoileal bypass or extensive small bowel resection or total parenteral nutrition at the time of liver biopsy, and those with clinical, laboratory, and imaging features of cirrhosis of liver and patients with renal, hepatic, respiratory, or congestive cardiac failure were excluded from the study. All patients underwent anthropometric measurements including height, weight, body mass index (BMI) (measured as weight in kg divided by height in m2), waist and hip circumference, and waist–hip ratio (WHR). Body weight was measured to the nearest 0.5 kg in erect position without footwear, wearing light indoor clothes. Overweight was defined using Asian criteria as BMI ≥23 but < 25 kg/m2, obesity as BMI ≥25 kg/m2 but 1.64 was taken as abnormal.16 MS was defined as per the National Cholesterol Education Program—Adult treatment panel III criteria17 with waist circumference modified as per the Asia Pacific criteria.13 Three of the following five criteria had to be satisfied for a diagnosis of MS. 1. Abdominal obesity: Waist circumference ≥ 90 cm in males and ≥80 cm in female (Asian-specific cut-offs). 2. Blood pressure ≥ 130/85 mm Hg. 3. A fasting plasma glucose > 110 mg/dL or a diagnosed case of diabetes mellitus. 4. Serum triglycerides ≥ 150 mg/dL. 5. High-density lipoprotein cholesterol 8.7 as advanced fibrosis (≥F3).18 Serum 25(OH) vitamin D levels were measured in all patients by a validated colorimetric method on sera frozen immediately after separation and stored at −20 C for 6 months. Patients were classified as vitamin D deficient if 25(OH) D3 level was
