White Rose Research Online
TITLE PAGETitleVitamin D and Non-alcoholic Fatty Liver DiseaseAuthorsZixuan Zhang, James L Thorne and J. Bernadette MooreAffiliationSchool of Food Science & Nutrition, University of Leeds, Leeds, LS2 9JT, United KingdomCorresponding authorDr. J Bernadette MooreSchool of Food Science and Nutrition,University of Leeds,Leeds,West YorkshireLS2 9JTT: +44(0)11334 39900E: J.B.Moore@leeds.ac.ukSTRUCTURED ABSTRACTPurpose of reviewVitamin D deficiency may impact disease progression of non-alcoholic fatty liver disease (NAFLD). The aim of this work was to review recent studies examining either vitamin D status or the effects of supplementation in patients with NAFLD, along with investigating the roles of genetic polymorphisms and the gut microbiome.Recent findingsSix heterogeneous observational studies of vitamin D status, and four randomised controlled intervention trials of vitamin D supplementation in NAFLD were conflicting. All studies were hampered by the challenges of diagnosing NAFLD, were underpowered, and lacked data on clinically important outcomes. The results of three cross-sectional studies, including a Mendelian randomisation study, provide limited evidence for a role for genetic modifiers of vitamin D status in NAFLD. Genetic and experimental evidence suggests that vitamin D and the vitamin D receptor (VDR) may influence the gut microbiome in health and disease.SummaryThe evidence relating either lower vitamin D status to the prevalence and severity of NAFLD, or examining vitamin D supplementation in patients with NAFLD is inconclusive. Larger, higher quality trials with relevant endpoints are needed. Further mechanistic studies on the roles of vitamin D and VDR in influencing the gut-liver axis in NAFLD are warranted.KeywordsNAFLD, vitamin D status, supplementation, polymorphisms, microbiomeINTRODUCTIONIn parallel with the increasing epidemics of obesity, diabetes and metabolic syndrome, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of liver disease, with an estimated global prevalence of 24% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Zb3Vub3NzaTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+
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ADDIN EN.CITE.DATA [1]. Defined histologically, NAFLD is a broad spectrum of disease that varies from simple fatty liver to nonalcoholic steatohepatitis (NASH), which can also progress to fibrosis and cirrhosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb29yZTwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [3]. Experimental research has shown that vitamin D has anti-proliferative, anti-inflammatory and anti-fibrotic properties, which might impact disease progression in chronic liver diseases including NAFLD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWNpZmljbzwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+
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ADDIN EN.CITE.DATA [4]. However, mechanisms involving vitamin D and NAFLD pathogenesis have only recently begun to be examined and are not completely understood yet. The aim of this review is to give insights into the association between NAFLD and vitamin D status, describe recent vitamin D supplementation trials in patients with NAFLD, and to discuss the roles of genetic polymorphisms and the gut microbiome in influencing both vitamin D status and NAFLD pathogenesis. The association of low-serum vitamin D status and NAFLDVitamin D from either the diet, or synthesized through sun exposure to skin, is metabolized into its biologically active metabolite, 1α,25-dihydroxyvitamin D [1α,25(OH)2D], through two critical hydroxylation steps. The first step occurs in the liver resulting in 25-hydroxyvitamin D [25(OH)D], the more stable circulating form of vitamin D and its most widely used status indicator; with the second, 1α -hydroxylation step occurring in the kidneys PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWNpZmljbzwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+
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ADDIN EN.CITE.DATA [4]. NAFLD is often considered as the hepatic manifestation of metabolic syndrome ADDIN EN.CITE <EndNote><Cite><Author>Jayakumar</Author><Year>2019</Year><RecNum>93</RecNum><DisplayText>[6]</DisplayText><record><rec-number>93</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1561079818">93</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jayakumar, S.</author><author>Loomba, R.</author></authors></contributors><auth-address>Division of Gastroenterology and Hepatology, Department of Medicine, NAFLD Research Center, University of California at San Diego, La Jolla, California.
Division of Epidemiology, Department of Family Medicine and Public Health, University of California at San Diego, La Jolla, California.</auth-address><titles><title>Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications</title><secondary-title>Aliment Pharmacol Ther</secondary-title><alt-title>Alimentary pharmacology & therapeutics</alt-title></titles><periodical><full-title>Aliment Pharmacol Ther</full-title><abbr-1>Alimentary pharmacology & therapeutics</abbr-1></periodical><alt-periodical><full-title>Aliment Pharmacol Ther</full-title><abbr-1>Alimentary pharmacology & therapeutics</abbr-1></alt-periodical><edition>2019/06/01</edition><dates><year>2019</year><pub-dates><date>May 31</date></pub-dates></dates><isbn>0269-2813</isbn><accession-num>31149745</accession-num><urls></urls><electronic-resource-num>10.1111/apt.15314</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[6], and a growing body of research suggests a relationship between vitamin D deficiency and NAFLD, with low levels of 25(OH)D associated with hepatic inflammation, and the severity and progression of NAFLD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [7, 8]. Whether vitamin D deficiency is a contributing factor to NAFLD, or is symptomatic of associated obesity or impaired liver metabolism capacity in NAFLD remains unclear. Early cross-sectional studies, in two Italian cohorts of 120 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXJnaGVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA [11, 12]. Here we review more recent studies published since the meta-analyses were done. We searched databases including PubMed, Scopus and Cochrane to identify acceptable observational studies reporting vitamin D status and NAFLD. In total six observational studies were identified examining vitamin D status and NAFLD (Table 1). Studies were heterogeneous in terms of NAFLD diagnosis, the populations examined, and sample size. A key challenge in NAFLD is the diagnosis of patients. While liver biopsy is considered the gold standard for staging disease, biopsies are invasive and not practical for large population studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb29yZTwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [13, 14]. Ultrasound, although not completely sensitive, reliably detects fatty liver when steatosis is at least 20% and is more amenable for larger studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaG91PC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaG91PC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj
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b3RlPgB=
ADDIN EN.CITE.DATA [15]. Three studies, with sample sizes ranging from 220-789 individuals, used ultrasound for diagnosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaXBwb25lcmk8L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy
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ADDIN EN.CITE.DATA [16-18]. Elevated liver enzyme levels in blood are readily measured and are therefore often used to define ‘suspected NAFLD’ in large population studies; although it is recognized these are neither sensitive nor specific for NAFLD and significantly underestimate prevalence PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb29yZTwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [2]. Here, the largest population study (n= 3878) used elevated serum alanine transaminase (ALT) levels (ALT > 30 U/L) to diagnose NAFLD in adolescents ADDIN EN.CITE <EndNote><Cite><Author>Cho</Author><Year>2019</Year><RecNum>8</RecNum><DisplayText>[19]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560200101">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cho, Y. H.</author><author>Kim, J. W.</author><author>Shim, J. O.</author><author>Yang, H. R.</author><author>Chang, J. Y.</author><author>Moon, J. S.</author><author>Ko, J. S.</author></authors></contributors><auth-address>Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
Department of Pediatrics, Korea University Medical Center, Seoul, Korea.</auth-address><titles><title>Association between vitamin D deficiency and suspected nonalcoholic fatty liver disease in an adolescent population</title><secondary-title>Pediatr Gastroenterol Hepatol Nutr</secondary-title><alt-title>Pediatric gastroenterology, hepatology & nutrition</alt-title></titles><periodical><full-title>Pediatr Gastroenterol Hepatol Nutr</full-title><abbr-1>Pediatric gastroenterology, hepatology & nutrition</abbr-1></periodical><alt-periodical><full-title>Pediatr Gastroenterol Hepatol Nutr</full-title><abbr-1>Pediatric gastroenterology, hepatology & nutrition</abbr-1></alt-periodical><pages>233-241</pages><volume>22</volume><number>3</number><edition>2019/05/22</edition><keywords><keyword>Adolescent</keyword><keyword>Alanine transaminase</keyword><keyword>Children</keyword><keyword>Nonalcoholic fatty liver disease</keyword><keyword>Obesity</keyword><keyword>Vitamin D deficiency</keyword></keywords><dates><year>2019</year><pub-dates><date>May</date></pub-dates></dates><isbn>2234-8646 (Print)
2234-8840</isbn><accession-num>31110956</accession-num><urls></urls><custom2>PMC6506433</custom2><electronic-resource-num>10.5223/pghn.2019.22.3.233</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[19].All studies showed that vitamin D inadequacy was prevalent in both adolescents and adults with NAFLD. However, conclusions relating the lower vitamin D status to the prevalence and severity of NAFLD were conflicting. Of the three studies that compared status between people with and without NAFLD, two larger population studies: a general Korean adolescent population (n=3878; diagnosis based on ALT levels) ADDIN EN.CITE <EndNote><Cite><Author>Cho</Author><Year>2019</Year><RecNum>8</RecNum><DisplayText>[19]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560200101">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cho, Y. H.</author><author>Kim, J. W.</author><author>Shim, J. O.</author><author>Yang, H. R.</author><author>Chang, J. Y.</author><author>Moon, J. S.</author><author>Ko, J. S.</author></authors></contributors><auth-address>Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
Department of Pediatrics, Korea University Medical Center, Seoul, Korea.</auth-address><titles><title>Association between vitamin D deficiency and suspected nonalcoholic fatty liver disease in an adolescent population</title><secondary-title>Pediatr Gastroenterol Hepatol Nutr</secondary-title><alt-title>Pediatric gastroenterology, hepatology & nutrition</alt-title></titles><periodical><full-title>Pediatr Gastroenterol Hepatol Nutr</full-title><abbr-1>Pediatric gastroenterology, hepatology & nutrition</abbr-1></periodical><alt-periodical><full-title>Pediatr Gastroenterol Hepatol Nutr</full-title><abbr-1>Pediatric gastroenterology, hepatology & nutrition</abbr-1></alt-periodical><pages>233-241</pages><volume>22</volume><number>3</number><edition>2019/05/22</edition><keywords><keyword>Adolescent</keyword><keyword>Alanine transaminase</keyword><keyword>Children</keyword><keyword>Nonalcoholic fatty liver disease</keyword><keyword>Obesity</keyword><keyword>Vitamin D deficiency</keyword></keywords><dates><year>2019</year><pub-dates><date>May</date></pub-dates></dates><isbn>2234-8646 (Print)
2234-8840</isbn><accession-num>31110956</accession-num><urls></urls><custom2>PMC6506433</custom2><electronic-resource-num>10.5223/pghn.2019.22.3.233</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[19] and a Chinese type 2 diabetes population (n=331; diagnosis by ultrasound) ADDIN EN.CITE <EndNote><Cite><Author>He</Author><Year>2018</Year><RecNum>41</RecNum><DisplayText>[18]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560200101">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>He, X.</author><author>Shen, Y.</author><author>Ma, X.</author><author>Ying, L.</author><author>Peng, J.</author><author>Pan, X.</author><author>Bao, Y.</author><author>Zhou, J.</author></authors></contributors><auth-address>Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.</auth-address><titles><title>The association of serum FGF23 and non-alcoholic fatty liver disease is independent of vitamin D in type 2 diabetes patients</title><secondary-title>Clin Exp Pharmacol Physiol</secondary-title><alt-title>Clinical and experimental pharmacology & physiology</alt-title></titles><periodical><full-title>Clin Exp Pharmacol Physiol</full-title><abbr-1>Clinical and experimental pharmacology & physiology</abbr-1></periodical><alt-periodical><full-title>Clin Exp Pharmacol Physiol</full-title><abbr-1>Clinical and experimental pharmacology & physiology</abbr-1></alt-periodical><pages>668-674</pages><volume>45</volume><number>7</number><edition>2018/03/27</edition><keywords><keyword>25-hydroxyvitamin D</keyword><keyword>fibroblast growth factor 23</keyword><keyword>non-alcoholic fatty liver disease</keyword><keyword>type 2 diabetes mellitus</keyword></keywords><dates><year>2018</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0305-1870</isbn><accession-num>29574933</accession-num><urls></urls><electronic-resource-num>10.1111/1440-1681.12933</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[18]; identified significant differences with lower 25(OH)D status in NAFLD. A third study in Italian adults with type 1 diabetes (n=220; diagnosis by ultrasound) found no differences PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaXBwb25lcmk8L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy
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ADDIN EN.CITE.DATA [13, 14, 17].It is a challenge to draw a conclusion from such heterogenous studies. In addition, given the observational nature of these studies a causal relationship between vitamin D deficiency and NALFD can not be concluded.Supplementation of vitamin D in NAFLDAt present, there are no pharmaceutical therapeutic agents specific for NAFLD and clinical care is reliant on dietary and/or physical activity changes aimed at inducing weight loss; however, lifestyle modifications are difficult to implement and sustain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb29yZTwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [2]. A number of compounds are currently being examined in clinical trials including several nutraceuticals, such as vitamin D PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb25lcm1hbjwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+
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ADDIN EN.CITE.DATA [22, 23], and patients with NAFLD ADDIN EN.CITE <EndNote><Cite><Author>Foroughi</Author><Year>2016</Year><RecNum>78</RecNum><DisplayText>[24]</DisplayText><record><rec-number>78</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560257145">78</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Foroughi, M.</author><author>Maghsoudi, Z.</author><author>Askari, G.</author></authors></contributors><auth-address>Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Community Nutrition, School of Nutrition and Food Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.</auth-address><titles><title>The effect of vitamin D supplementation on blood sugar and different indices of insulin resistance in patients with non-alcoholic fatty liver disease (NAFLD)</title><secondary-title>Iran J Nurs Midwifery Res</secondary-title><alt-title>Iranian journal of nursing and midwifery research</alt-title></titles><periodical><full-title>Iran J Nurs Midwifery Res</full-title><abbr-1>Iranian journal of nursing and midwifery research</abbr-1></periodical><alt-periodical><full-title>Iran J Nurs Midwifery Res</full-title><abbr-1>Iranian journal of nursing and midwifery research</abbr-1></alt-periodical><pages>100-4</pages><volume>21</volume><number>1</number><edition>2016/03/18</edition><keywords><keyword>Blood sugar</keyword><keyword>insulin resistance</keyword><keyword>non-alcoholic fatty liver</keyword><keyword>vitamin D</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>1735-9066 (Print)
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ADDIN EN.CITE.DATA [25]. However, the results of vitamin D supplementation trials in patients with NAFLD are inconclusive. In 2017, both a systematic review with meta-analysis that focused exclusively on randomized controlled trials in NAFLD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWJyaXppPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA [27] and Shidfar ADDIN EN.CITE <EndNote><Cite><Author>Shidfar</Author><Year>2019</Year><RecNum>5</RecNum><DisplayText>[28]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1557101746">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shidfar, Farzad</author><author>Mousavi, Seyedeh Neda</author><author>Agah, Shahram</author><author>Hoseini, Sharieh</author><author>Hajimiresmail, Seyed Javad</author></authors></contributors><titles><title>Reduction of some atherogenic indices in patients with non-alcoholic fatty liver by vitamin D and calcium co-supplementation: a double blind randomized controlled clinical trial</title><secondary-title>Iranian Journal of Pharmaceutical Research</secondary-title></titles><periodical><full-title>Iranian Journal of Pharmaceutical Research</full-title></periodical><pages>496-505</pages><volume>18</volume><number>1</number><dates><year>2019</year></dates><publisher>School of Pharmacy, Shahid Beheshti University of Medical Sciences</publisher><isbn>1735-0328</isbn><urls></urls></record></Cite></EndNote>[28] and colleagues reported significant decreases in serum levels of ALT and AST at the post-interventional point, consistent with an earlier study of Lorvand Amiri PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3J2YW5kIEFtaXJpPC9BdXRob3I+PFllYXI+MjAxNzwv
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ADDIN EN.CITE.DATA [30] and Taghvaei ADDIN EN.CITE <EndNote><Cite><Author>Taghvaei</Author><Year>2018</Year><RecNum>6</RecNum><DisplayText>[31]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1557159181">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Taghvaei, T., Akha, O., Mouodi, M., Fakheri, H.T., Kashi, Z., Maleki, I. & Mohammadpour, R.</author></authors></contributors><titles><title>Effects of vitamin d supplementation on patients with non-alcoholic fatty liver disease (NAFLD)</title><secondary-title>Acta Medica Mediterranea</secondary-title></titles><periodical><full-title>Acta Medica Mediterranea</full-title></periodical><pages>415-422</pages><volume>34</volume><number>2</number><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>[31] and colleagues reviewed here (Table 2); but also contrasts to previous studies done by Barchetta PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJjaGV0dGE8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy
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ADDIN EN.CITE.DATA [32], Sharifi ADDIN EN.CITE <EndNote><Cite><Author>Sharifi</Author><Year>2014</Year><RecNum>65</RecNum><DisplayText>[33]</DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560204138">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sharifi, N.</author><author>Amani, R.</author><author>Hajiani, E.</author><author>Cheraghian, B.</author></authors></contributors><auth-address>Department of Nutrition, Faculty of Paramedicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, sharifi.nsr@.</auth-address><titles><title>Does vitamin D improve liver enzymes, oxidative stress, and inflammatory biomarkers in adults with non-alcoholic fatty liver disease? A randomized clinical trial</title><secondary-title>Endocrine</secondary-title><alt-title>Endocrine</alt-title></titles><periodical><full-title>Endocrine</full-title><abbr-1>Endocrine</abbr-1></periodical><alt-periodical><full-title>Endocrine</full-title><abbr-1>Endocrine</abbr-1></alt-periodical><pages>70-80</pages><volume>47</volume><number>1</number><edition>2014/06/28</edition><keywords><keyword>Adult</keyword><keyword>Biomarkers/*metabolism</keyword><keyword>C-Reactive Protein/metabolism</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Inflammation/metabolism</keyword><keyword>Insulin Resistance</keyword><keyword>Liver/enzymology/*metabolism</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Non-alcoholic Fatty Liver Disease/*drug therapy/*metabolism</keyword><keyword>Oxidative Stress/*drug effects</keyword><keyword>Vitamin D/*pharmacology</keyword></keywords><dates><year>2014</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1355-008x</isbn><accession-num>24968737</accession-num><urls></urls><electronic-resource-num>10.1007/s12020-014-0336-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[33], and coworkers that concluded that supplementation with vitamin D did not significantly change ALT and AST levels. Both studies showing a significant effect of vitamin D supplementation on aminotransferases were small. While the trial of Shidfar and collegues ADDIN EN.CITE <EndNote><Cite><Author>Shidfar</Author><Year>2019</Year><RecNum>5</RecNum><DisplayText>[28]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1557101746">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shidfar, Farzad</author><author>Mousavi, Seyedeh Neda</author><author>Agah, Shahram</author><author>Hoseini, Sharieh</author><author>Hajimiresmail, Seyed Javad</author></authors></contributors><titles><title>Reduction of some atherogenic indices in patients with non-alcoholic fatty liver by vitamin D and calcium co-supplementation: a double blind randomized controlled clinical trial</title><secondary-title>Iranian Journal of Pharmaceutical Research</secondary-title></titles><periodical><full-title>Iranian Journal of Pharmaceutical Research</full-title></periodical><pages>496-505</pages><volume>18</volume><number>1</number><dates><year>2019</year></dates><publisher>School of Pharmacy, Shahid Beheshti University of Medical Sciences</publisher><isbn>1735-0328</isbn><urls></urls></record></Cite></EndNote>[28] had n=36-37/arm, in the pilot study of Geier and coworkers PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZWllcjwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [27], who had liver biopsy specimens pre- and post-treatment from only seven patients (four from placebo group and three from the intervention group). Surprisingly, the authors reported that while the NAS improved in all three patients receiving vitamin D (4,000 IU/d for 48 weeks), it also improved in three of the four placebo-treated patients who had both pre- and post-intervention biopsies. In the work by Taghvaei and workers ADDIN EN.CITE <EndNote><Cite><Author>Taghvaei</Author><Year>2018</Year><RecNum>6</RecNum><DisplayText>[31]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1557159181">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Taghvaei, T., Akha, O., Mouodi, M., Fakheri, H.T., Kashi, Z., Maleki, I. & Mohammadpour, R.</author></authors></contributors><titles><title>Effects of vitamin d supplementation on patients with non-alcoholic fatty liver disease (NAFLD)</title><secondary-title>Acta Medica Mediterranea</secondary-title></titles><periodical><full-title>Acta Medica Mediterranea</full-title></periodical><pages>415-422</pages><volume>34</volume><number>2</number><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>[31], steatosis and fibrosis were examined by FibroScan (ultrasound-based transient elastography) and no differences between placebo and vitamin D treated (50,000 IU/wk for 12 weeks; n=20/arm) were observed.In general, while vitamin D treatment in animal and cell models has improved NAFLD-like symptoms, clinical trials of vitamin D supplementation in patients with NAFLD have mostly been under-powered PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWFuZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWFuZTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [25]. Similar to earlier studies previously reviewed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJjaGV0dGE8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJjaGV0dGE8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA [34, 35], the trials reviewed here were heterogeneous in terms of populations examined (adolescents, adults, multiple ethnicities, participants with either obesity, type 1 or type 2 diabetes), the sample size, the type of vitamin D supplementation, duration and dosage used, and the modality used for diagnosis of NAFLD. Cholecalciferol (vitamin D3) raises 25(OH)D levels more than ergocalciferol (calciferol; vitamin D2) and has been primarily the choice of supplement used (Table 2 and PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJjaGV0dGE8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA [35]). However, the dosing regime of supplementation for both NAFLD and other chronic diseases, continues to be debated, with some evidence in favour of loading dose regimes where megadoses, e.g. 100,000 IU, are given to rapidly elevate 25(OH)D [34]. Among the three 12-week RCTs with ultrasound or FibroScan diagnosis, the largest sample size was n=36-37/arm, found in the study by Shidfar and collegues ADDIN EN.CITE <EndNote><Cite><Author>Shidfar</Author><Year>2019</Year><RecNum>5</RecNum><DisplayText>[28]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1557101746">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shidfar, Farzad</author><author>Mousavi, Seyedeh Neda</author><author>Agah, Shahram</author><author>Hoseini, Sharieh</author><author>Hajimiresmail, Seyed Javad</author></authors></contributors><titles><title>Reduction of some atherogenic indices in patients with non-alcoholic fatty liver by vitamin D and calcium co-supplementation: a double blind randomized controlled clinical trial</title><secondary-title>Iranian Journal of Pharmaceutical Research</secondary-title></titles><periodical><full-title>Iranian Journal of Pharmaceutical Research</full-title></periodical><pages>496-505</pages><volume>18</volume><number>1</number><dates><year>2019</year></dates><publisher>School of Pharmacy, Shahid Beheshti University of Medical Sciences</publisher><isbn>1735-0328</isbn><urls></urls></record></Cite></EndNote>[28], which reported significant decreases in ALT levels. Although the study by Geier et al. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZWllcjwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [27] was hampered by sample size, it was notably the longest intervention, giving 4,000 IU/d for 48 weeks, and also reported improved ALT status. Based on the results of the RCTs to date, accurate diagnosis of NAFLD, duration of intervention and sample size are important considerations for the design of future intervention trials.Polymorphisms influencing vitamin D status and NAFLD severityBoth vitamin D status and NAFLD are complex phenotypes that arise from dynamic interactions between dietary, lifestyle and genetic factors PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWNpZmljbzwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+
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ADDIN EN.CITE.DATA [2]. In addition to these environment factors, both NAFLD and vitamin D status are influenced by genetic polymorphisms.Several genetic variants involved in vitamin D metabolism have been found in linkage, candidate gene, and genome-wide association studies (GWAS) to affect circulating vitamin D concentrations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWhyYW1pPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA [37]. Polymorphisms in the NADSYN1 gene have also been associated with vitamin D status; along with variants of the group-specific component (GC) gene, which encodes the vitamin D binding protein (DPB) responsible for transporting vitamin D in serum PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWhyYW1pPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA [36]. Furthermore, polymorphisms in multipe genes encoding for cytochrome P450 (CYP) enzymes involved in the formation of 25(OH)D and 1α,25(OH)2D along with the inactivation of 1α,25(OH)2D (CYP2R1, CYP27B1 and CYP24A1 respectively) have also been associated with vitamin D status PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWhyYW1pPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA [38] found in 106 obese patients with NAFLD and inadequate vitamin D status that VDR SNPs were associated with with altered profibrogenic mRNA expression and liver fibrosis. While a seperate cross-sectional study (control patients n=39, patients with biopsy-proven NAFLD n=244) by Patel and colleagues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRlbDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [39] found no differences in hepatic expression of VDR or other vitamin D-related genes (including CYP24A1 and GC) associated with histological severity of NAFLD.More recently, three recent cross-sectional studies including one mendelian randomization (MR) study have examined the relationship between genetic modifiers of vitamin D status and NAFLD (Table 3). Two of these studies were done in patients with biopsy-proven NAFLD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmFpPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [40]. Separately in an UK paediatric population (n=103), variants of the NADSYN1 (rs12785878, rs 3829251) and VDR (rs2228570) genes were independently associated with increased steatosis, while a GC gene variant (rs 4588) was associated with increased inflammation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaWJzb248L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [37]. On the other hand in a large Chinese population (n=9128) diagnosed by ultrasound, Wang and colleagues notably used bi-directional MR to explore the causal relationship between 25(OH)D and NAFLD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [41]. MR uses SNPs that explain trait variance in the general population to make causal inferences regarding the effect of lifetime exposure to that trait with disease incidence or outcome. MR avoids many of the limitations of conventional epidemiological studies (such as residual confounding and reverse causation) as the populations under investigation are randomized from birth based on their genotype PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1vdTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [42]. In this study, the authors examined four variants related to vitamin D status and eight variants related to NAFLD (Table 3). The results showed three SNPs (GCKR rs780094, PNPLA3 rs738409 and PARVB rs5764455) were significantly associatied with NAFLD, and two SNPs (GC rs2282679 and DHCR7 rs12785878) were significantly associated with serum 25(OH)D status. However, in applying MR utilising polygenetic risk scores (for both vitamin D status and NAFLD) the authors concluded that there was no causal association between vitamin D and NAFLD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj
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ZT5=
ADDIN EN.CITE.DATA [41].Based on the current studies, there is limited evidence for a role for the vitamin D-related polymorphisms in NAFLD. The key limitation of the two biopsy-proven observational studies is sample size. In addition, 25(OH)D levels were measured in serum and bioavailability of the active hormone in liver can not be accounted for. Similarly the hepatic expression of genes responsible for vitamin D metabolism may be altered or switched off in the context of significant liver injury, confounding conclusions. While MR is a valuable tool to assess causality of vitamin D status and NAFLD, done in a single population limits conclusions related to ethnicity and the potential contribution of rare variants related to vitamin D and NAFLD heritability. Therefore, further MR studies examing rare variants and large multi-ethnic populations are likely warranted.The crosstalk between the gastrointestinal microbiome and the VDR in NAFLDThe gastrointestinal microbiome is an additional factor that most likely influences the progression of NAFLD, in the first instance through influencing nutrient uptake from the diet and enterohepatic circulation of nutrients and bile acids PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmlwYXRoaTwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+
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ADDIN EN.CITE.DATA [44, 45]. Endotoxin exposure can trigger the activation of inflammatory cytokines that contribute to NAFLD pathogenesis. While murine studies have found associations between NAFLD and certain bacteria, studies in human reporting differences in the intestinal bacteria between healthy controls and NAFLD have been largel cross-sectional to date ADDIN EN.CITE <EndNote><Cite><Author>Schwenger</Author><Year>2018</Year><RecNum>72</RecNum><DisplayText>[45]</DisplayText><record><rec-number>72</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560206068">72</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schwenger, K. J. P.</author><author>Bolzon, C. M.</author><author>Li, C.</author><author>Allard, J. P.</author></authors></contributors><auth-address>Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada.
Toronto General Hospital, University Health Network, 585 University Avenue, 9-973, Toronto, ON, M5G 2C4, Canada. Dr.Johane.Allard@uhn.ca.
Department of Medicine, University of Toronto, Toronto, Canada. Dr.Johane.Allard@uhn.ca.
Department of Nutritional Sciences, University of Toronto, Toronto, Canada. Dr.Johane.Allard@uhn.ca.</auth-address><titles><title>Non-alcoholic fatty liver disease and obesity: the role of the gut bacteria</title><secondary-title>Eur J Nutr</secondary-title><alt-title>European journal of nutrition</alt-title></titles><periodical><full-title>Eur J Nutr</full-title><abbr-1>European journal of nutrition</abbr-1></periodical><alt-periodical><full-title>Eur J Nutr</full-title><abbr-1>European journal of nutrition</abbr-1></alt-periodical><edition>2018/10/12</edition><keywords><keyword>Fecal transplant</keyword><keyword>Gut bacteria</keyword><keyword>Non-alcoholic fatty liver disease</keyword><keyword>Obesity</keyword><keyword>Prebiotics</keyword></keywords><dates><year>2018</year><pub-dates><date>Oct 10</date></pub-dates></dates><isbn>1436-6207</isbn><accession-num>30306296</accession-num><urls></urls><electronic-resource-num>10.1007/s00394-018-1844-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[45]. Therefore, the causal relationships between NAFLD and gastrointestinal microbiome pathology remains uncertain.However, most interestingly a recent GWAS of the gut microbiota in a German population identified significant associations for overall microbial diversity and individual taxa at multiple genetic loci, including the VDR gene PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [46]. This is consistent with experimental evidence that vitamin D and its receptor VDR play a vital role in regulating microbiome in health and disease ADDIN EN.CITE <EndNote><Cite><Author>Sun</Author><Year>2018</Year><RecNum>74</RecNum><DisplayText>[47]</DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560206345">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sun, J.</author></authors></contributors><auth-address>Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.</auth-address><titles><title>Dietary vitamin D, vitamin D receptor, and microbiome</title><secondary-title>Curr Opin Clin Nutr Metab Care</secondary-title><alt-title>Current opinion in clinical nutrition and metabolic care</alt-title></titles><periodical><full-title>Curr Opin Clin Nutr Metab Care</full-title><abbr-1>Current opinion in clinical nutrition and metabolic care</abbr-1></periodical><alt-periodical><full-title>Curr Opin Clin Nutr Metab Care</full-title><abbr-1>Current opinion in clinical nutrition and metabolic care</abbr-1></alt-periodical><pages>471-474</pages><volume>21</volume><number>6</number><edition>2018/09/01</edition><dates><year>2018</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1363-1950</isbn><accession-num>30169457</accession-num><urls></urls><custom2>PMC6168421</custom2><custom6>NIHMS987380</custom6><electronic-resource-num>10.1097/mco.0000000000000516</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[47]. Genetic deletion of VDR in mice has been shown to influence the intestinal microbiome at both the taxonomic and functional levels, resulting in higher risk of infections, inflammation, cancer and other conditions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [49]. These results suggest that further studies of vitamin D and VDR signaling at the genetic and functional levels and its regulation of microbiome in gut-liver axis will provide novel mechanistic insights and potential therapeutic opportunities for NAFLD.CONCLUSIONRecent studies either examining vitamin D status in patients with NAFLD, or examining the efficacy of vitamin D supplementation for treating NAFLD, are largely inconclusive. However, only a few heterogeneous trials with an insufficient number of participants have been done to date. These were hampered by the challenges of diagnosing NAFLD and lack of data on clinically important outcomes. The overall quality of evidence is very low. There is limited evidence for a role for genetic modifiers of vitamin D status in NAFLD and a recent MR study suggests there is no causal association between vitamin D and NAFLD. However, there is genetic and experimental evidence that vitamin D and the VDR play important roles in regulating the microbiome in health and disease and further mechanistic studies of this pathway influencing the gut-liver axis in NAFLD are warranted. KEY POINTSExperimental research has shown that vitamin D has anti-proliferative, anti-inflammatory and anti-fibrotic properties, which might impact disease progression in chronic liver diseases including NAFLD.Vitamin D supplementation has been shown to improve insulin-sensitivity and glycemic control in people with prediabetes and type 2 diabetes and therefore is of plausible benefit to patients with NAFLD.Vitamin D supplementation trials in patients with NAFLD have been underpowered and are inconclusive.Based on current studies, there is limited evidence for a role for the vitamin D-related polymorphisms in NAFLD.Mechanistic studies on the roles of vitamin D and VDR in influencing the gut-liver axis in NAFLD are warrantedAcknowledgementsNone.Financial Support and SponsorshipNone.Conflicts of InterestThere are no conflicts of interest.References: ADDIN EN.REFLIST [1] Younossi Z, Anstee QM, Marietti M et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018; 15:11-20.**[2] Moore JB. From sugar to liver fat and public health: systems biology driven studies in understanding non-alcoholic fatty liver disease pathogenesis. Proc Nutr Soc 2019; 78:290–304.A comprehensive narrative review of NAFLD and its pathogenesis, thoroughly reviewing the roles of genetics and nutrition in NAFLD development and progression. In addition, the paper introduces the concept of systems biology and reviews recent work utilising genome-scale metabolic networks and developing multi-scale models of liver metabolism relevant to NAFLD. [3] Mendes MM, Darling AL, Hart KH et al. Impact of high latitude, urban living and ethnicity on 25-hydroxyvitamin D status: a need for multidisciplinary action? J Steroid Biochem Mol Biol 2019; 188:95-102.**[4] Pacifico L, Osborn JF, Bonci E et al. Association between vitamin D levels and nonalcoholic fatty liver disease: potential confounding variables. Mini Rev Med Chem 2019; 19:310-332.This comprehensive narrative review included all major cross-sectional studies prior to February 2017 examining the association between vitamin D status and the progression of NAFLD, as well as intervention trials examining effects of vitamin D supplementation. Forty-five studies were reviewed. It usefully discusses key host, environment, and heritability factors that may impact vitamin D status, as well as the conflicting definitions of deficient or optimal vitamin D status and challenges related to the methods of measuring 25(OH)D and the diagnosis of NAFLD.*[5] Bjelakovic G, Nikolova D, Bjelakovic M et al. Vitamin D supplementation for chronic liver diseases in adults. Cochrane Database Syst Rev 2017; 11:Cd011564.This Cochrane review is significant for synthesizing the major randomized controlled trials executed prior to 2017 that assessed the beneficial and harmful effects of vitamin D supplementation in people with chronic liver disease. Four trials that administered vitamin D3 or placebo to patients with NALFD were included. It concluded that there was a paucity of evidence on which to determine the effect of vitamin D supplementation on liver‐related morbidity or mortality.[6] Jayakumar S, Loomba R. Review article: emerging role of the gut microbiome in the progression of nonalcoholic fatty liver disease and potential therapeutic implications. Aliment Pharmacol Ther 2019. [7] Wang X, Li W, Zhang Y et al. Association between vitamin D and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: results from a meta-analysis. Int J Clin Exp Med 2015; 8:17221-17234.[8] Cicero AFG, Colletti A, Bellentani S. Nutraceutical approach to non-alcoholic fatty liver disease (NAFLD): the available clinical evidence. Nutrients 2018; 10:1153.[9] 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.[10] 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.[11] Jaruvongvanich V, Ahuja W, Sanguankeo A et al. Vitamin D and histologic severity of nonalcoholic fatty liver disease: a systematic review and meta-analysis. Dig Liver Dis 2017; 49:618-622.[12] Saberi B, Dadabhai AS, Nanavati J et al. Vitamin D levels do not predict the stage of hepatic fibrosis in patients with non-alcoholic fatty liver disease: A PRISMA compliant systematic review and meta-analysis of pooled data. World J Hepatol 2018; 10:142-154.*[13] Livadariu R, Timofte D, Trifan A et al. Vitamin D deficiency, a noninvasive marker of steatohepatitis in patients with obesity and biopsy proven nonalcoholic fatty liver disease. Acta Endocrinol 2018; 14:76-84.This observational study examined the association between vitamin D deficiency and the severity of NAFLD in 64 adults with biopsy-proven NAFLD. All patients had low levels of 25(OH)D, but a significant relationship between vitamin D deficiency and the severity of NALFD was not established. When patients examined as two groups based on vitamin D insufficiency or deficiency, the results showed that, fibrosis and steatohepatitis were independent predictors of low vitamin D concentration. *[14] Izadi A, Aliasghari F, Gargari BP et al. Strong association between serum vitamin D and vaspin levels, AIP, VAI and liver enzymes in NAFLD patients. Int J Vitam Nutr Res 2019:1-8.This observational study examined the relationship between vitamin D and serum liver enzymes and ultrasound findings in 83 adults with biopsy-proven NAFLD. When divided into two groups, 37 patients with vitamin D deficiency and 46 patients with normal vitamin D levels, serum aspartate transaminase levels were significantly higher in patients with vitamin D deficiency. However, no relationship was identified between 25(OH)D status and NAFLD severity.[15] Zhou JH, Cai JJ, She ZG et al. Noninvasive evaluation of nonalcoholic fatty liver disease: Current evidence and practice. World J Gastroenterol 2019; 25:1307-1326.[16] Cipponeri E, Vitturi N, Mariano V et al. Vitamin D status and non-alcoholic fatty liver disease in patients with type 1 diabetes. J Endocrinol Invest 2019. [17] Leitao J, Carvalhana S, Silva AP et al. No evidence for lower levels of serum vitamin D in the presence of hepatic steatosis. A study on the portuguese general population. Int J Med Sci 2018; 15:1778-1786.[18] He X, Shen Y, Ma X et al. The association of serum FGF23 and non-alcoholic fatty liver disease is independent of vitamin D in type 2 diabetes patients. Clin Exp Pharmacol Physiol 2018; 45:668-674.*[19] Cho YH, Kim JW, Shim JO et al. Association between vitamin D deficiency and suspected nonalcoholic fatty liver disease in an adolescent population. Pediatr Gastroenterol Hepatol Nutr 2019; 22:233-241.This observational study examined the relationship between vitamin D deficiency and NAFLD in 3,878 adolescents in the Korean National Health and Nutrition Survey. It significantly found that adolescents with ‘suspected NAFLD’ based on elevated serum alanine aminotransferase levels had lower 25(OH)D levels in comparison to adolescents with normal serum levels of liver enzymes.*[20] Konerman MA, Jones JC, Harrison SA. Pharmacotherapy for NASH: current and emerging. J Hepatol 2018; 68:362-375.This narrative review highlights the challenges and considerations in clinical trial design for testing potential therapeutic agents for the treatment of non-alcoholic steatohepatitis. and NAFLD. It is an excellent review of existing pharmacological agents and their mechanism of actions that are currently in phase 2 and 3 clinical trials for NAFLD. In addition it notably summarises, the efficacy of those that have been more thoroughly studied (e.g.: vitamin E, pioglitazone, obetocholic acid, elafibranor) and the significant placebo response observed in these trials. *[21] Ilan Y. Future of Treatment for Nonalcoholic Steatohepatitis: Can the Use of Safe, Evidence-Based, Clinically Proven Supplements Provide the Answer to the Unmet Need? Dig Dis Sci 2018; 63:1726-1736.This narrative review discusses the major barriers to drug development for NASH treatment, evidencing the point that natural supplements can improve cardiometabolic parameters and may be of benefit at an earlier stage of disease. Regulatory, intellectual property, manufacturing, and clinical development steps were reviewed. *[22] Li X, Liu Y, Zheng Y et al. The effect of vitamin D supplementation on glycemic control in type 2 diabetes patients: a systematic review and meta-analysis. Nutrients 2018; 10:375.This meta-analysis is significant for including all randomized controlled trials prior to September 2017 that assessed the effects of oral vitamin D supplementation on glycemic control in type 2 diabetes. Twenty trials administered vitamin D or placebo to 2703 participants were synthesized. Conclusions were that vitamin D supplementation resulted in significant improvements to fasting insulin and homeostasis model assessment of insulin resistance as well as serum 25(OH)D levels.*[23] Mirhosseini N, Vatanparast H, Mazidi M et al. Vitamin D supplementation, glycemic control, and insulin resistance in prediabetics: a meta-analysis. J Endocr Soc 2018; 2:687-709.This meta-analysis is significant for including all randomized controlled clinical trials prior to April 2017 that assessed glycemic outcomes in adults with high risk of type 2 diabetes. In synthesizing 28 trials that administered vitamin D with or without calcium or placebo to 3848 participants it concluded that vitamin D supplementation resulted in significant reductions of glycosylated hemoglobin, fasting plasma glucose level and the homeostasis model assessment of insulin resistance.[24] Foroughi M, Maghsoudi Z, Askari G. The effect of vitamin D supplementation on blood sugar and different indices of insulin resistance in patients with non-alcoholic fatty liver disease (NAFLD). Iran J Nurs Midwifery Res 2016; 21:100-104.[25] Keane JT, Elangovan H, Stokes RA et al. Vitamin D and the liver-correlation or cause? Nutrients 2018; 10:496.*[26] Tabrizi R, Moosazadeh M, Lankarani KB et al. The effects of vitamin D supplementation on metabolic profiles and liver function in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Syndr 2017; 11 Suppl 2:S975-S982.This meta-analysis is significant for including all major randomized trials prior to October 2016 where patients with NAFLD were randomized to treatment with vitamin D or placebo. Notably of the 7 studies with 452 individuals that were included, only 4 examined serum aspartate transaminase and alanine aminotransferase levels and the meta-analysis concluded no significant reduction in these from vitamin D treatment.[27] Geier A, Eichinger M, Stirnimann G et al. Treatment of non-alcoholic steatohepatitis patients with vitamin D: a double-blinded, randomized, placebo-controlled pilot study. Scand J Gastroenterol 2018; 53:1114-1120.[28] Shidfar F, Mousavi SN, Agah S et al. Reduction of some atherogenic indices in patients with non-alcoholic fatty liver by vitamin D and calcium co-supplementation: a double blind randomized controlled clinical trial. Iran J Pharm Res 2019; 18:496-505.[29] Lorvand Amiri H, Agah S, Tolouei Azar J et al. Effect of daily calcitriol supplementation with and without calcium on disease regression in non-alcoholic fatty liver patients following an energy-restricted diet: Randomized, controlled, double-blind trial. Clin Nutr 2017; 36:1490-1497.[30] Dabbaghmanesh MH, Danafar F, Eshraghian A et al. Vitamin D supplementation for the treatment of non-alcoholic fatty liver disease: a randomized double blind placebo controlled trial. Diabetes Metab Syndr 2018; 12:513-517.[31] Taghvaei T, Akha, O., Mouodi, M., Fakheri, H.T., Kashi, Z., Maleki, I. & Mohammadpour, R. Effects of vitamin d supplementation on patients with non-alcoholic fatty liver disease (NAFLD). Acta Medica Mediterranea 2018; 34:415-422.[32] Barchetta I, Del Ben M, Angelico F et al. 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. BMC Med 2016; 14:92.[33] 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 2014; 47:70-80.[34] Barchetta I, Cimini FA, Cavallo MG. Vitamin D supplementation and non-alcoholic fatty liver disease: present and future. Nutrients 2017; 9:1015.*This is a useful narrative review that expounds on the evidence in relation to vitamin D dosing regimes in NAFLD.[35] Sharifi N, Amani R. Vitamin D supplementation and non-alcoholic fatty liver disease: a critical and systematic review of clinical trials. Crit Rev Food Sci Nutr 2019; 59:693-703.*[36] Bahrami A, Sadeghnia HR, Tabatabaeizadeh SA et al. Genetic and epigenetic factors influencing vitamin D status. J Cell Physiol 2018; 233:4033-4043.This narrative review focused on four randomised controlled trials and two uncontrolled clinical trials examining the effects of vitamin D supplementation on patients with NAFLD and highlights conflicting results. *[37] Gibson PS, Quaglia A, Dhawan A et al. Vitamin D status and associated genetic polymorphisms in a cohort of UK children with non-alcoholic fatty liver disease. Pediatr Obes 2018; 13:433-441.This cross-sectional study is significant for being the first to examine the relationship between vitamin D status, genetic variants known to affect vitamin D status and NAFLD histological severity in a paediatric population. 103 biopsy-proven paediatric patients with NAFLD had low vitamin D status throughout the year and significantly lower 25(OH)D levels in winter. [38] Beilfuss A, Sowa JP, Sydor S et al. Vitamin D counteracts fibrogenic TGF-beta signalling in human hepatic stellate cells both receptor-dependently and independently. Gut 2015; 64:791-799.[39] Patel YA, Henao R, Moylan CA et al. Vitamin D is not associated with severity in NAFLD: results of a paired clinical and gene expression profile analysis. Am J Gastroenterol 2016; 111:1591-1598.*[40] Arai T, Atsukawa M, Tsubota A et al. Association of vitamin D levels and vitamin D-related gene polymorphisms with liver fibrosis in patients with biopsy-proven nonalcoholic fatty liver disease. Dig Liver Dis 2019; 51:1036-1042.This cross-sectional study of 220 patients with biopsy-proven NAFLD examined select polymorphisms in vitamin D related genes in relationship to histopathological severity, suggesting that the vitamin D receptor rs1544410 polymorphism was associated with advanced liver fibrosis.**[41] Wang N, Chen C, Zhao L et al. Vitamin D and nonalcoholic fatty liver disease: bi-directional mendelian randomization analysis. EBioMedicine 2018; 28:187-193.This study is significant for being the first study to apply bi-directional mendelian randomization (MR) to explore the causal relationship between 25(OH)D and NAFLD. Examining a Chinese population with 9128 participants, although individual single nucleotide polymorphisms associated with NAFLD; when polygenetic risk scores were applied (for both vitamin D status and NAFLD) the authors concluded no causal association between vitamin D and NAFLD. [42] Dimou NL, Tsilidis KK. A Primer in Mendelian Randomization Methodology with a Focus on Utilizing Published Summary Association Data. Methods Mol Biol 2018; 1793:211-230.[43] Tripathi A, Debelius J, Brenner DA et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol 2018; 15:397-411.[44] Safari Z, Gerard P. The links between the gut microbiome and non-alcoholic fatty liver disease (NAFLD). Cell Mol Life Sci 2019; 76:1541-1558.[45] Schwenger KJP, Bolzon CM, Li C et al. Non-alcoholic fatty liver disease and obesity: the role of the gut bacteria. Eur J Nutr 2018.[46] Wang J, Thingholm LB, Skieceviciene J et al. Genome-wide association analysis identifies variation in vitamin D receptor and other host factors influencing the gut microbiota. Nat Genet 2016; 48:1396-1406.[47] Sun J. Dietary vitamin D, vitamin D receptor, and microbiome. Curr Opin Clin Nutr Metab Care 2018; 21:471-474.[48] Jin D, Wu S, Zhang YG et al. Lack of vitamin D receptor causes dysbiosis and changes the functions of the murine intestinal mcrobiome. Clin Ther 2015; 37:996-1009.e1007.[49] Su D, Nie Y, Zhu A et al. Vitamin D signaling through Induction of paneth cell defensins maintains gut microbiota and Improves metabolic disorders and hepatic steatosis in animal models. Front Physiol 2016; 7:498.Table 1 Recent observational studies of vitamin D status in NAFLDReference; CountryDesign; Sample size (NAFLD/NN)Study population; AgeDiagnosis of NAFLDBMI (kg/m2)Vitamin D assay;Definition of inadequacy (nmol/L)Reporting of date or season of blood draw, or sun exposure 25(OH)D status (nmol/L)Cho et al., 2019 ADDIN EN.CITE <EndNote><Cite><Author>Cho</Author><Year>2019</Year><RecNum>8</RecNum><DisplayText>[19]</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560200101">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cho, Y. H.</author><author>Kim, J. W.</author><author>Shim, J. O.</author><author>Yang, H. R.</author><author>Chang, J. Y.</author><author>Moon, J. S.</author><author>Ko, J. S.</author></authors></contributors><auth-address>Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.
Department of Pediatrics, Korea University Medical Center, Seoul, Korea.</auth-address><titles><title>Association between vitamin D deficiency and suspected nonalcoholic fatty liver disease in an adolescent population</title><secondary-title>Pediatr Gastroenterol Hepatol Nutr</secondary-title><alt-title>Pediatric gastroenterology, hepatology & nutrition</alt-title></titles><periodical><full-title>Pediatr Gastroenterol Hepatol Nutr</full-title><abbr-1>Pediatric gastroenterology, hepatology & nutrition</abbr-1></periodical><alt-periodical><full-title>Pediatr Gastroenterol Hepatol Nutr</full-title><abbr-1>Pediatric gastroenterology, hepatology & nutrition</abbr-1></alt-periodical><pages>233-241</pages><volume>22</volume><number>3</number><edition>2019/05/22</edition><keywords><keyword>Adolescent</keyword><keyword>Alanine transaminase</keyword><keyword>Children</keyword><keyword>Nonalcoholic fatty liver disease</keyword><keyword>Obesity</keyword><keyword>Vitamin D deficiency</keyword></keywords><dates><year>2019</year><pub-dates><date>May</date></pub-dates></dates><isbn>2234-8646 (Print)
2234-8840</isbn><accession-num>31110956</accession-num><urls></urls><custom2>PMC6506433</custom2><electronic-resource-num>10.5223/pghn.2019.22.3.233</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[19]; KoreaCross-sectional;3878(215§/3663)Adolescent in general population;12-18ALT>30U/LNAFLD: 26.16±0.34?NN: 20.87±0.07?RIA;Deficiency: <50Season report:2008 to 2014Sun exposure:nrNAFLD*:35.50±0.83?NN: 40.70±0.38?Clipponeri et al., 2019 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaXBwb25lcmk8L0F1dGhvcj48WWVhcj4yMDE5PC9ZZWFy
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ADDIN EN.CITE.DATA [16]; ItalyCross-sectional;220 (57/163)Caucasian adults with type 1 diabetes;18-60UltrasoundNAFLD: 26.6 (24.5-28.5)¤NN: 23.5 (21.5-26.4)¤RIA;Sufficiency: ≥75Insufficiency: 50-75 Deficiency: <50Season report:July 2013 to April 2014Sun exposure:2h/dayNAFLD: 53 (38-70)¤ NN: 50 (34-69)¤He et al., 2018 ADDIN EN.CITE <EndNote><Cite><Author>He</Author><Year>2018</Year><RecNum>41</RecNum><DisplayText>[18]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1560200101">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>He, X.</author><author>Shen, Y.</author><author>Ma, X.</author><author>Ying, L.</author><author>Peng, J.</author><author>Pan, X.</author><author>Bao, Y.</author><author>Zhou, J.</author></authors></contributors><auth-address>Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.</auth-address><titles><title>The association of serum FGF23 and non-alcoholic fatty liver disease is independent of vitamin D in type 2 diabetes patients</title><secondary-title>Clin Exp Pharmacol Physiol</secondary-title><alt-title>Clinical and experimental pharmacology & physiology</alt-title></titles><periodical><full-title>Clin Exp Pharmacol Physiol</full-title><abbr-1>Clinical and experimental pharmacology & physiology</abbr-1></periodical><alt-periodical><full-title>Clin Exp Pharmacol Physiol</full-title><abbr-1>Clinical and experimental pharmacology & physiology</abbr-1></alt-periodical><pages>668-674</pages><volume>45</volume><number>7</number><edition>2018/03/27</edition><keywords><keyword>25-hydroxyvitamin D</keyword><keyword>fibroblast growth factor 23</keyword><keyword>non-alcoholic fatty liver disease</keyword><keyword>type 2 diabetes mellitus</keyword></keywords><dates><year>2018</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0305-1870</isbn><accession-num>29574933</accession-num><urls></urls><electronic-resource-num>10.1111/1440-1681.12933</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[18]; ChinaCross-sectional;331 (209/122)Adults with type 2 diabetes; 20-78UltrasoundNAFLD: 26.83±3.00?NN: 23.27±2.47?ECLIA; nrSeason report: March 2015 to December 2016 Sun exposure: nrNAFLD*: 41.08 (31.75‐53.43)¤NN:48.98 (34.45‐54.65)¤Izadi et al., 2019 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5JemFkaTwvQXV0aG9yPjxZZWFyPjIwMTk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [13];RomaniaCross-sectional;64 (64/0)Adults with obesity;18-60×Biopsy45.06 [35-58]?Steatosis: 44.35±6.82?NASH: 45.82±6.50? NASH+ vanished steatosis: 43.91±7.56?CLIA; Sufficiency: 75-250Insufficiency: 50-75 Deficiency: <50Season report: November 2014 to November 2016Sun exposure: nrSteatosis: 40.48 ±15.63?NASH: 34.45 ±14.80?NASH+ vanished steatosis: 32.00 ±19.08?ALT, alanine aminotransferase; CLIA, chemiluminescence assay; ECLIA, electro-chemiluminescence binding assay; HPLC-UV, high performance liquid chromatography with ultraviolet detector; NAS, NAFLD activity score; NN, non-NAFLD; nr, not reported; NS, no steatosis; RIA, radioimmunoassay ¤Median (Interquartile range); ? Mean ± Standard Deviation; ? Mean [Range] § Adolescent with suspected NAFLD; # Steatosis group includes alcohol (60) and NAFLD (220)× Author communication* Statistic significant relative to 25(OH)D levelTable 2 Recent randomised controlled intervention trials of vitamin D supplementation in NAFLDReference;CountryDesign;Arms (n=)NAFLD diagnosis;Vitamin D cut off;AgeVitamin D assay and status (nmol/L)Liver and vitamin D related outcomesPost-intervention changesDabbaghmanesh et al. 2018PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYWJiYWdobWFuZXNoPC9BdXRob3I+PFllYXI+MjAxODwv
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ADDIN EN.CITE.DATA [30]; Iran12-week 3-arm RCT; G1: placebo (n=31)G2: 0.25 mg/d calcitriol (n=28)G3: 50,000 IU/wk cholecalciferol (n=32)Ultrasound;25(OH)D<70 nmol/L;20-75nr; Before:G1: 52.8±13.0?, G2: 46.5±13.8?, G3: 47.3±15.5?After:G1: 47.0±17.5?, G2: 57.3±49.5?, G3: 80.5±35.3?Liver: ALT, AST, GTT, ALPVitamin D:25(OH)DLiver: ns Vitamin D:25(OH)D↑* Geier et al., 2018PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZWllcjwvQXV0aG9yPjxZZWFyPjIwMTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [27];Switzerland48-week 2-arm RCT (pilot study); G1: placebo (n=10)G2: 4,000 IU/d vitamin D (n=8)ALT and/or biopsy;25(OH)D<70 nmol/L;23-63ECLIA;Before: G1: 50±25?, G2: 52.5±30?After: G1: 40±23?, G2: 98±33?Liver:ALT, AST, GTT, ALP, NAS and CK-18 M30Vitamin D:25(OH)DLiver:ALT↓*, CK-18 M30↓*Vitamin D:25(OH)D↑* Shidfar et al., 2019 ADDIN EN.CITE <EndNote><Cite><Author>Shidfar</Author><Year>2019</Year><RecNum>5</RecNum><DisplayText>[28]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1557101746">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shidfar, Farzad</author><author>Mousavi, Seyedeh Neda</author><author>Agah, Shahram</author><author>Hoseini, Sharieh</author><author>Hajimiresmail, Seyed Javad</author></authors></contributors><titles><title>Reduction of some atherogenic indices in patients with non-alcoholic fatty liver by vitamin D and calcium co-supplementation: a double blind randomized controlled clinical trial</title><secondary-title>Iranian Journal of Pharmaceutical Research</secondary-title></titles><periodical><full-title>Iranian Journal of Pharmaceutical Research</full-title></periodical><pages>496-505</pages><volume>18</volume><number>1</number><dates><year>2019</year></dates><publisher>School of Pharmacy, Shahid Beheshti University of Medical Sciences</publisher><isbn>1735-0328</isbn><urls></urls></record></Cite></EndNote>[28]; Iran12-week 3-arm RCT; G1: placebo (n=36)G2: 1,000 IU/d vitamin D (n=37)G3: 500 mg calcium carbonate+1000 IU/d vitamin D (n=37);All three groups given some advice on physical activity, hypocaloric diet and sun-light exposure.Ultrasound;25(OH)D< 37.5 nmol/L;18-65ELISA; Before: G1: 25.00 ± 1.58?, G2: 24.75 ± 1.60?, G3: 24.75 ± 2.33?After: G1: 27.50 ± 1.95?, G2: 53.50 ± 1.83?, G3: 67.75 ± 2.75?Liver:ALT, AST, ALPVitamin D:25(OH)DLiver:ALT↓*, AST↓* Vitamin D:25(OH)D↑* Taghvaei et al., 2018 ADDIN EN.CITE <EndNote><Cite><Author>Taghvaei</Author><Year>2018</Year><RecNum>6</RecNum><DisplayText>[31]</DisplayText><record><rec-number>6</rec-number><foreign-keys><key app="EN" db-id="trvspwexcdtsdne25ag5ffssdtv2faxwr2fx" timestamp="1557159181">6</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Taghvaei, T., Akha, O., Mouodi, M., Fakheri, H.T., Kashi, Z., Maleki, I. & Mohammadpour, R.</author></authors></contributors><titles><title>Effects of vitamin d supplementation on patients with non-alcoholic fatty liver disease (NAFLD)</title><secondary-title>Acta Medica Mediterranea</secondary-title></titles><periodical><full-title>Acta Medica Mediterranea</full-title></periodical><pages>415-422</pages><volume>34</volume><number>2</number><dates><year>2018</year></dates><urls></urls></record></Cite></EndNote>[31]; Iran12-week 2-arm RCT; G1: placebo (n=20)G2: 50,000 IU/wk vitamin D3 (n=20);Both groups were given lifestyle modification advice.FibroScan;25(OH)D<70nmol/L;30-70ELISA; Before: G1: 49.45 ± 10.88?, G2: 47.90 ± 13.73?After: G1: 52.13 ± 6.23?, G2: 86.00 ± 10.70?Liver:ALT, AST, ALP, CAP score and kPAVitamin D:25(OH)DLiver:nsVitamin D:25(OH)D↑* ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CAP, controlled attenuation parameter; CK-18 M30, cytokeratin?18 M30; ECLIA, electro-chemiluminescence binding assay; ELISA, enzyme-linked immunosorbent assay; GGT, γ-glutamyl transferase; HS, hepatic steatosis; NAS, NAFLD activity score; nr, not reported; ns. not significant; RCT, randomized controlled trial ? Mean±Standard deviation* Statistic significantTable 3 Studies examining genetic polymorphisms related to vitamin D status and NAFLDReference;CountryDesign; Sample Size (NAFLD/NN)Study Population;AgeDiagnosis of NAFLDVitamin D Assay; Definition of Inadequacy;Status (nmol/L)Vitamin D or NAFLD Related PolymorphismsSummary of AssociationsArai et al., 2019PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BcmFpPC9BdXRob3I+PFllYXI+MjAxOTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [40];JapanCross-sectional;220 (220/0)Adults with NAFLD;18-84BiopsyRIA; Sufficiency: ≥75Insufficiency: 50-75Deficiency: <50; 45.0 [17.5-97.5]?Vitamin D related:CYP2R1: rs1993116 rs10741657DHCR7: rs7944926, rs12784878GC: rs2282670CYP27B1: rs10877012VDR: rs2228570, rs1544410, rs7975232, rs731236CYP2R1 rs1993116 genotype non-AA and VDR rs228570 genotype GG associated with VDD; VDR rs1544410 genotype CC associated with advanced liver fibrosisGibson et al., 2018PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaWJzb248L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [37]; United KingdomCross-sectional; 103 (103/0)Children with NAFLD;11-16BiopsyCLIA reported by season;Deficiency: <25Insufficiency: 25-50;Spring: 36.6 [30.5-42.1]*Summer: 41.8 [36.3-47.2]*Autumn: 40.8 [34.2-47.5]*Winter: 26.9 [22.7-31.2]*Vitamin D related:NADSYN1: rs12785878, rs3829251GC: rs2282670, rs7041, rs4588 CYP2R1: rs10741 VDR: rs2228570NADSYN1/DHCR7 rs3829251, CYP2R1 rs10741657 and VDR rs2228570 associated with increased steatosis; GC rs4588 associated with increased inflammation in liver biopsiesWang et al., 2018PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [41]; ChinaCross-sectional, Mendelian Randomization;9128General population;18-93UltrasoundCLIA; nr;VD GRS:Quartile 1: 41.8 ± 12.9?Quartile 2: 40.4 ± 12.3?Quartile 3: 39.6 ± 12.5?Quartile 4: 38.7 ± 11.9?NAFLD GRS:Quartile 1: 40.2 ± 12.4?Quartile 2: 40.3 ± 12.7?Quartile 3: 40.0 ± 12.2?Quartile 4: 40.0 ± 12.4?Vitamin D related:NADSYN1: rs12785878§CYP2R1: rs10741657GC: rs2282679CYP24A1: rs6013897NAFLD related:LYPLAL1: rs12137855PPP1R3B: rs4240624TM6SF2: rs58542926PNPLA3: rs738409 GCKR: rs780094SAMM50: rs738491PARVB: rs5764455 COL13A1: rs1227756GC rs2282679 and DHCR7 rs12785878 were associated with 25(OH)D;GCKR rs780094, PNPLA3 rs738409 and PARVB rs5764455 associated with NAFLDALT, alanine aminotransferase; CLIA, chemiluminescent immunoassays; COL13A1, collagen type XIII alpha 1 chain; CYP24A1, CYP27B1, cytochrome P450 27B1; cytochrome P450 24A1; CYP2R1, cytochrome P450 2R1; DHCR7, 7-dehydrocholesterol reductase; GC, vitamin D binding protein; GCKR, glucokinase regulatory protein; HS, hepatic steatosis; LYPLAL1, lysophospholipase-like 1;NADSYN1, adenine dinucleotide synthetase-1; NN, Non-NAFLD; nr, not reported; PARVB, parvin beta; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPP1R3B, protein phosphatase 1 regulatory subunit 3b; RIA, radioimmunoassay; SAMM50, sorting and assembly machinery component; TM6SF2, transmembrane 6 superfamily member 2; VDD, vitamin D deficiency; VDR, vitamin D receptor§ rs12785878 is an intronic variant in the NADSYN1 gene, which is located immediately proximal to DHCR7; previously rs12785878 has been reported as SNP in DHCR7 [41]. ? Median [Range]; * Mean [95%CI]; ? Mean ± Standard Deviation ................
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