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Vitamin D and alcohol: A review of the current literature
Author’s Accepted Manuscript Vitamin D and Alcohol: A Review of the Current Literature V.S. Tardelli, M.P.P. Lago, D.X. Silveira, T.M. Fidalgo www.elsevier.com/locate/psychres
PII: DOI: Reference:
S0165-1781(16)30706-5 http://dx.doi.org/10.1016/j.psychres.2016.10.051 PSY10048
To appear in: Psychiatry Research Received date: 22 April 2016 Revised date: 28 August 2016 Accepted date: 23 October 2016 Cite this article as: V.S. Tardelli, M.P.P. Lago, D.X. Silveira and T.M. Fidalgo, Vitamin D and Alcohol: A Review of the Current Literature, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2016.10.051 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Vitamin D and Alcohol: A Review of the Current Literature Tardelli V.S., Lago M.P.P., Silveira D.X*, Fidalgo T.M. Addiction Unit (PROAD) – Federal University of São Paulo *
Corresponding author: Dartiu Xavier da Silveira Av. Prof. Ascendino Reis 763 – São Paulo – SP [email protected]
Abstract Objectives Vitamin D is associated with bone mineral density, and its deficiency is a global health problem. In psychiatry, low vitamin D levels have been associated with schizophrenia, depression, psychotic symptoms, and, more recently, alcohol use disorders. Alcohol use disorders are among the most prevalent mental disorders worldwide. Therefore, our aim was to evaluate the association between alcohol use and vitamin D serum levels. Methods The PubMed, SCIELO, and Lilacs databases were searched for this systematic review. We assessed all articles published from 1976 to December 2015, and we examined the associated reference lists to retrieve articles that appeared to fulfill our criteria. Results: Of 932 articles, 49 met our inclusion criteria. The majority of the papers (71.4%) were cross-sectional studies. Alcohol intake was found to be positively associated with vitamin D status in 15 articles and negatively associated with vitamin D in 18 articles; no association was found in 16 articles. Discussion Heterogeneous results were found in our review, with a similar number of papers indicating a positive association, a negative association or the absence of any association between alcohol use and vitamin D levels. Nevertheless, it is important to
note that the studies in which a positive association was found were more recent papers that involved considerably larger sample sizes than those in other studies. The older studies compared vitamin D levels in alcoholic and non-alcoholic patients, in contrast to more recent studies, which focused on more specific populations. In addition, most of the selected papers were from high latitude countries, where exposure to sunlight tends to be lower than in tropical countries. Conclusion: The data concerning vitamin D levels in patients with alcohol use disorders remain controversial. Additional research using a standardized methodology is necessary to demonstrate the real impact of alcohol consumption on vitamin D serum levels as well as on the health status of alcohol users. Keywords: Vitamin D, Alcohol, Alcohol Use Disorder
Introduction Recently, vitamin D has been broadly studied because its deficiency or insufficiency is considered a global problem that affects at least one billion people (Bhimani, 2012). Vitamin D is primarily synthesized in the skin through a sunlightdependent reaction that converts 7-dehydrocholesterol into cholecalciferol (Moreira et al., 2004; Premaor and Furlanetto, 2006). Then, cholecalciferol is metabolized to 25hydroxyvitamin D (25OHD) in the liver and, finally, into 1,25-hydroxyvitamin D, its active form (Premaor and Furlanetto, 2006). The essential function of vitamin D is to act in calcium homeostasis (Schneider et al., 2000) by increasing calcium absorption in the intestines (Moreira et al., 2004; Premaor and Furlanetto, 2006). When serum calcium levels decrease, the parathyroid promptly releases parathyroid hormone, which acts by stimulating bone reabsorption and by reducing calcium urinary excretion
(Premaor and Furlanetto, 2006; Moreira et al., 2004). Therefore, vitamin D deficiency is frequently associated with bone disorders, such as rickets, osteomalacia, and osteoporosis (Bhimani, 2012; Premaor and Furlanetto, 2006). Recently, vitamin D receptors have been found in the human brain (Anglin et al., 2013; Eyles et al., 2005), indicating other possible roles for this vitamin. Two recent studies with rat models have shown that vitamin D demonstrated neuroprotective properties (Moore et al., 2005; Wang et al., 2001). In elderly people, vitamin D deficiency may also be associated with low mood disorder and cognitive impairment (Miller et al., 2015), including Alzheimer’s disease (Miller et al., 2015; Wilkins et al., 2006). In psychiatry, low vitamin D levels have been associated with major mental disorders, such as depression (Anglin et al., 2013; Maddock et al., 2013; Schneider et al., 2000), schizophrenia (Bhimani, 2012; Schneider et al., 2000), and psychotic symptoms (Berg et al., 2010; Hedelin et al., 2010), with consistent evidence demonstrating that vitamin supplementation reduces the intensity of symptoms in depression (Bhimani, 2012; Jorde et al., 2008) and other mood disorders (Bhimani, 2012). A recent cohort study found that vitamin D supplementation during the first year of life was associated with a reduced risk of schizophrenia in males (McGrath et al., 2004). Some studies have also associated low vitamin D serum levels with alcohol use disorders (Anglin et al., 2013; Bhimani, 2012; Luisier et al., 1977; Pitts and Van Thiel, 1986; Schneider et al., 2000). Alcohol use disorders are among the most prevalent mental disorders worldwide; they are also associated with many physical and psychiatric comorbid conditions (Grant et al., 2015). According to the World Health Organization, the prevalence of alcohol use disorders may reach 15% in males and approximately 3% in females worldwide (World Health Organization, 2014). In 2013, 56.4% of adults in the
US reported drinking alcohol in the past month (Substance Abuse and Mental Health Services Administration, 2013). In Brazil, 50% of adults reported having used alcohol in the past 12 months, with 10.4% of men and 3.6% of women meeting the diagnostic criteria for alcohol dependence based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (Laranjeira et al., 2014). The one-year prevalence of alcohol dependence in the European Union was estimated at 3.4% among people 18-64 years of age (women, 1.7%; men, 5.2%) (Rehm et al., 2015). Available information about the association between alcohol use and vitamin D is still limited (Naude et al., 2012). Some studies have suggested that low vitamin D serum levels in chronic alcoholics could be caused by malabsorption due to cholestasis or pancreatic insufficiency (Lieber, 2000), poor dietary intake (Lieber, 2000; Moreira et al., 2004; Pitts and Van Thiel, 1986), lack of sunlight exposure (Lieber, 2000; Moreira et al., 2004; Pitts and Van Thiel, 1986) , direct effects on vitamin D metabolism, impaired renal synthesis and/or increased 1,25-dihydroxyvitamin D (1,25OH2D) degradation (Shankar et al., 2008), as well as direct bowel mucosal lesions (Moreira et al., 2004). Concerning the effect of alcohol on vitamin D metabolism, it is believed that alcohol-induced liver damage may decrease the levels of vitamin D-binding proteins and reduce the liver’s ability to hydroxylate vitamin D into its active form (Lee, 2012; Pitts and Van Thiel, 1986). However, other studies have found a positive association between alcohol consumption and vitamin D (Gorter et al., 2016; Jacques et al., 1997; Lee, 2012; McCullough et al., 2010), but the exact biochemical mechanism that explains this phenomenon is unknown (Choi, 2012; Larose et al., 2014; LambergAllardt et al., 2001; Lee, 2012). Alcohol is believed to suppress parathyroid hormone secretion, which is responsible for converting serum 25OHD into 1,25OH2D, thereby increasing the levels of 25OHD, which can be measured. However, this possible
mechanism is highly speculative (Larose et al., 2014). Other studies have found no significant association between alcohol intake and vitamin D levels (Egan et al., 2008). Therefore, the available findings remain controversial, and additional research is necessary to elucidate the different possible mechanisms that may contribute to variations in the serum vitamin D levels related to alcohol consumption. Therefore, we aimed to review the literature concerning the association between vitamin D serum levels and alcohol use disorders.
Methods We screened all articles that cited vitamin D and any information about alcohol use disorders. We searched the PubMed, Lilacs and SCIELO databases for all articles published from 1976 to December 2015. We also examined the reference lists in these reviews and retrieved articles that appeared to fulfill our criteria. Our search strategy included the terms vitamin D and alcohol in order for the search to be as broad as possible. Search Criteria The following inclusion criteria were used: (i) studies written in either English or Portuguese (only these two languages were included because the authors were not fluent in other languages), (ii) human studies, and (iii) studies assessing vitamin D serum levels in alcohol users and non-users. Ninety-seven papers were excluded due to language limitation. Papers that used alcohol intake as a confounding variable were also excluded because the correlation between alcohol intake and vitamin D serum levels was not the main objective of the study. Data Extraction
Data were independently extracted by the authors (V.S.T. and M.P.P.L.) using a structured form. The following variables were considered: (1) the author and publication year, (2) the study design, (3) the number of subjects included, (4) the subject setting, (5) the primary outcome, (6) the available information regarding Vitamin D status and alcohol (7) the details of the evaluated data, (8) the main findings, and (9) the study limitations. Discrepancies were resolved by consensus, and the senior authors (D.X.S and T.M.F.) were consulted when needed. Data concerning alcohol consumption and its relationship with vitamin D were described, when available. It was not possible to describe or standardize alcohol consumption for all papers reviewed, once many of them did not mention drinking patterns and also because articles used very heterogeneous measurement methods. Data Analysis We described the results qualitatively because there was no quantitative information available to perform a meta-analysis. Results We identified 932 references in our preliminary search. Of these references, 863 were excluded in the first analysis because they did not fulfill the inclusion criteria. All 69 remaining articles were reviewed further, and 20 of these were excluded because they assessed populations that differed from those mentioned in the search criteria. The remaining 49 papers, which all met our inclusion criteria, were fully reviewed, and data were extracted from them. All articles were published between 1976 and December 2015. The majority of the papers in our review (71.4%) were cross-sectional studies; the possibility of a meta-analysis was diminished because the remaining articles (eight
cohorts, four case-control papers and one clinical trial) had distinct methods and different outcome evaluations. In 15 of the reviewed articles (30.7%), alcohol intake was found to be positively associated with vitamin D status, indicating that higher alcohol consumption was associated with higher vitamin D levels. In contrast, 18 (36.7%) articles found that alcohol use was negatively associated with vitamin D status, indicating that lower alcohol consumption was associated with higher vitamin D levels. The remaining 16 (32.7%) articles showed no association between alcohol intake and serum vitamin D levels. These data are controversial because the more recent studies tended to find a negative correlation, whereas the older studies tended to find a positive correlation. Detailed information about this discrepancy is presented in Table 1.
Discussion In our analyses, we reviewed 49 studies. We found that in 15 studies, alcohol use was positively associated with vitamin D status, whereas in 18 studies, alcohol use was negatively associated with vitamin D status. Sixteen articles found no association between alcohol use and vitamin D serum levels. Given the equivalent proportion of papers with positive and negative findings, these preliminary results appear to be inconclusive. The first papers comparing vitamin D in alcoholics and non-alcoholics were conducted in high latitude countries, such as Norway and Finland, perhaps because low vitamin D levels were regarded as a public health problem first in these countries compared to tropical regions. In 1980, Devgun studied 129 alcoholics and 32 healthy controls in different seasons in Dundee, UK. The author reported that 25OHD was significantly lower in alcoholics than in controls in all seasons (measured monthly from
August to March). In 1988, Bjorneboe conducted a study in Oslo, Norway, during winter, and he found that 25OHD was 28% lower in alcoholics compared to nonalcoholic controls. These and other papers with data collected in lower temperature settings (Table 1) found that higher alcohol intake was associated with lower serum vitamin D levels, which might be explained by the fact that alcoholic individuals would not leave their houses as frequently as non-alcoholics in such low temperatures. However, it is important to state that these papers had small sample sizes compared to papers that were published later. Fourteen of the included papers (31.1%) found no association between serum vitamin D levels and ethanol intake (Table 1). Overall, these papers had intermediate sample sizes compared to the studies that found negative associations (which had smaller samples) and those in which positive associations were found (which had larger samples). These small sample sizes may partially explain why some papers did not find any association. Moreover, some papers evaluated specific subpopulations, such as the study by Mahabir in 2014, which evaluated 51 postmenopausal women, and that by Venu in 2013, which assessed 63 patients awaiting liver transplantation. This discrepancy could indicate that bias may have affected these results. Larger sample sizes or less specific populations could potentially alter these findings. Recent papers, however, did not confirm the results found in prior papers. After 2000, a greater number of researchers investigated this topic and used larger sample sizes than those used previously. In 2012, Bertrand studied a population of 128,371 nurses who were divided into two different cohorts, and the author found a significant positive association between alcohol intake and serum vitamin D levels. Similarly, Khaw conducted a prospective study of 14,641 individuals in 2014 and found a slight, although significant, positive association between alcohol units per day and vitamin D
serum levels. Moreover, papers that reported that larger alcohol intake was associated with higher vitamin D serum levels had better study designs than did those that found the opposite outcome. In 2014, Steingrimsdottir found that non-alcoholics had lower vitamin D levels than did alcoholics in a cohort study involving 5,764 individuals in Iceland; the study had a 5.4-year mean follow-up period. In a study published in 2014, Knekt also found a positive association in a cohort of 5,010 men and women with a 17year follow-up period. Notably, both studies did not evaluate the association between alcohol intake and vitamin D serum levels as the primary outcome, and they only measured serum vitamin D levels once. Although several papers have reported a positive association between alcohol use and vitamin D serum levels, this association was not the primarily investigated outcome. Many papers used secondary data from population studies, and they investigated many variables and associations, including vitamin D serum levels and alcohol intake. Therefore, this association has not been adequately discussed in more recent papers. However, in the present review, the studies that found positive associations between alcohol intake and vitamin D serum levels were the most consistent in terms of methods and sample size. It is possible that these results might be due to greater exposure to sunlight among alcoholics compared to non-alcoholics because of the homeless status of many alcoholics. Still, the influence of these variables has not been properly addressed, and further studies are needed to better elucidate these findings. The present review has some limitations. Most of the included papers (68.9%) were cross-sectional; therefore, it was not possible to further analyze the data from different studies through meta-analysis. A significant portion of the papers included in this review also had small sample sizes, which may have influenced the final results.
Some papers studied specific populations of alcoholic patients, including the 2014 studies by Anweiller, who investigated 329 community-dwelling older women (average age, 83.3 years), and by Zellner, who assessed patients admitted to an orthopedic surgery service. This difference could also represent a source of bias because conclusions from specific populations of alcoholics could not be generalized to all alcoholics. Conclusion In conclusion, data concerning vitamin D levels in alcoholic patients remain controversial. Therefore, additional research using a standardized methodology is required to demonstrate the real effect of alcohol use on vitamin D serum levels and its impact on the vitamin D-related health status of alcohol users. Standardization includes choosing the metabolite of Vitamin D assessed, once most studies use 25-HydroxyVitamin D, but some studies evaluate 1,25-dihydroxyvitamin D, which impairs comparison between them. Besides that, the measurement of alcohol consumption must also be standardized, once different units or methods for measurement were applied. Finally, several studies do not have the association between alcohol consumption and serum levels of Vitamin D as their primary outcome, which makes discussion of the topic poor.
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Highlights
Association between Alcohol Use Disorders and Vitamin D serum levels is reviewed. Results found by different articles are heterogeneous and controversial. Studies with larges samples showed positive associations between Vitamin D serum levels and alcohol intake; However, papers that evaluated this association as a primary outcome found negative association. Further studies are needed to better elucidate this question.
PII: DOI: Reference:
S0165-1781(16)30706-5 http://dx.doi.org/10.1016/j.psychres.2016.10.051 PSY10048
To appear in: Psychiatry Research Received date: 22 April 2016 Revised date: 28 August 2016 Accepted date: 23 October 2016 Cite this article as: V.S. Tardelli, M.P.P. Lago, D.X. Silveira and T.M. Fidalgo, Vitamin D and Alcohol: A Review of the Current Literature, Psychiatry Research, http://dx.doi.org/10.1016/j.psychres.2016.10.051 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Vitamin D and Alcohol: A Review of the Current Literature Tardelli V.S., Lago M.P.P., Silveira D.X*, Fidalgo T.M. Addiction Unit (PROAD) – Federal University of São Paulo *
Corresponding author: Dartiu Xavier da Silveira Av. Prof. Ascendino Reis 763 – São Paulo – SP [email protected]
Abstract Objectives Vitamin D is associated with bone mineral density, and its deficiency is a global health problem. In psychiatry, low vitamin D levels have been associated with schizophrenia, depression, psychotic symptoms, and, more recently, alcohol use disorders. Alcohol use disorders are among the most prevalent mental disorders worldwide. Therefore, our aim was to evaluate the association between alcohol use and vitamin D serum levels. Methods The PubMed, SCIELO, and Lilacs databases were searched for this systematic review. We assessed all articles published from 1976 to December 2015, and we examined the associated reference lists to retrieve articles that appeared to fulfill our criteria. Results: Of 932 articles, 49 met our inclusion criteria. The majority of the papers (71.4%) were cross-sectional studies. Alcohol intake was found to be positively associated with vitamin D status in 15 articles and negatively associated with vitamin D in 18 articles; no association was found in 16 articles. Discussion Heterogeneous results were found in our review, with a similar number of papers indicating a positive association, a negative association or the absence of any association between alcohol use and vitamin D levels. Nevertheless, it is important to
note that the studies in which a positive association was found were more recent papers that involved considerably larger sample sizes than those in other studies. The older studies compared vitamin D levels in alcoholic and non-alcoholic patients, in contrast to more recent studies, which focused on more specific populations. In addition, most of the selected papers were from high latitude countries, where exposure to sunlight tends to be lower than in tropical countries. Conclusion: The data concerning vitamin D levels in patients with alcohol use disorders remain controversial. Additional research using a standardized methodology is necessary to demonstrate the real impact of alcohol consumption on vitamin D serum levels as well as on the health status of alcohol users. Keywords: Vitamin D, Alcohol, Alcohol Use Disorder
Introduction Recently, vitamin D has been broadly studied because its deficiency or insufficiency is considered a global problem that affects at least one billion people (Bhimani, 2012). Vitamin D is primarily synthesized in the skin through a sunlightdependent reaction that converts 7-dehydrocholesterol into cholecalciferol (Moreira et al., 2004; Premaor and Furlanetto, 2006). Then, cholecalciferol is metabolized to 25hydroxyvitamin D (25OHD) in the liver and, finally, into 1,25-hydroxyvitamin D, its active form (Premaor and Furlanetto, 2006). The essential function of vitamin D is to act in calcium homeostasis (Schneider et al., 2000) by increasing calcium absorption in the intestines (Moreira et al., 2004; Premaor and Furlanetto, 2006). When serum calcium levels decrease, the parathyroid promptly releases parathyroid hormone, which acts by stimulating bone reabsorption and by reducing calcium urinary excretion
(Premaor and Furlanetto, 2006; Moreira et al., 2004). Therefore, vitamin D deficiency is frequently associated with bone disorders, such as rickets, osteomalacia, and osteoporosis (Bhimani, 2012; Premaor and Furlanetto, 2006). Recently, vitamin D receptors have been found in the human brain (Anglin et al., 2013; Eyles et al., 2005), indicating other possible roles for this vitamin. Two recent studies with rat models have shown that vitamin D demonstrated neuroprotective properties (Moore et al., 2005; Wang et al., 2001). In elderly people, vitamin D deficiency may also be associated with low mood disorder and cognitive impairment (Miller et al., 2015), including Alzheimer’s disease (Miller et al., 2015; Wilkins et al., 2006). In psychiatry, low vitamin D levels have been associated with major mental disorders, such as depression (Anglin et al., 2013; Maddock et al., 2013; Schneider et al., 2000), schizophrenia (Bhimani, 2012; Schneider et al., 2000), and psychotic symptoms (Berg et al., 2010; Hedelin et al., 2010), with consistent evidence demonstrating that vitamin supplementation reduces the intensity of symptoms in depression (Bhimani, 2012; Jorde et al., 2008) and other mood disorders (Bhimani, 2012). A recent cohort study found that vitamin D supplementation during the first year of life was associated with a reduced risk of schizophrenia in males (McGrath et al., 2004). Some studies have also associated low vitamin D serum levels with alcohol use disorders (Anglin et al., 2013; Bhimani, 2012; Luisier et al., 1977; Pitts and Van Thiel, 1986; Schneider et al., 2000). Alcohol use disorders are among the most prevalent mental disorders worldwide; they are also associated with many physical and psychiatric comorbid conditions (Grant et al., 2015). According to the World Health Organization, the prevalence of alcohol use disorders may reach 15% in males and approximately 3% in females worldwide (World Health Organization, 2014). In 2013, 56.4% of adults in the
US reported drinking alcohol in the past month (Substance Abuse and Mental Health Services Administration, 2013). In Brazil, 50% of adults reported having used alcohol in the past 12 months, with 10.4% of men and 3.6% of women meeting the diagnostic criteria for alcohol dependence based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) (Laranjeira et al., 2014). The one-year prevalence of alcohol dependence in the European Union was estimated at 3.4% among people 18-64 years of age (women, 1.7%; men, 5.2%) (Rehm et al., 2015). Available information about the association between alcohol use and vitamin D is still limited (Naude et al., 2012). Some studies have suggested that low vitamin D serum levels in chronic alcoholics could be caused by malabsorption due to cholestasis or pancreatic insufficiency (Lieber, 2000), poor dietary intake (Lieber, 2000; Moreira et al., 2004; Pitts and Van Thiel, 1986), lack of sunlight exposure (Lieber, 2000; Moreira et al., 2004; Pitts and Van Thiel, 1986) , direct effects on vitamin D metabolism, impaired renal synthesis and/or increased 1,25-dihydroxyvitamin D (1,25OH2D) degradation (Shankar et al., 2008), as well as direct bowel mucosal lesions (Moreira et al., 2004). Concerning the effect of alcohol on vitamin D metabolism, it is believed that alcohol-induced liver damage may decrease the levels of vitamin D-binding proteins and reduce the liver’s ability to hydroxylate vitamin D into its active form (Lee, 2012; Pitts and Van Thiel, 1986). However, other studies have found a positive association between alcohol consumption and vitamin D (Gorter et al., 2016; Jacques et al., 1997; Lee, 2012; McCullough et al., 2010), but the exact biochemical mechanism that explains this phenomenon is unknown (Choi, 2012; Larose et al., 2014; LambergAllardt et al., 2001; Lee, 2012). Alcohol is believed to suppress parathyroid hormone secretion, which is responsible for converting serum 25OHD into 1,25OH2D, thereby increasing the levels of 25OHD, which can be measured. However, this possible
mechanism is highly speculative (Larose et al., 2014). Other studies have found no significant association between alcohol intake and vitamin D levels (Egan et al., 2008). Therefore, the available findings remain controversial, and additional research is necessary to elucidate the different possible mechanisms that may contribute to variations in the serum vitamin D levels related to alcohol consumption. Therefore, we aimed to review the literature concerning the association between vitamin D serum levels and alcohol use disorders.
Methods We screened all articles that cited vitamin D and any information about alcohol use disorders. We searched the PubMed, Lilacs and SCIELO databases for all articles published from 1976 to December 2015. We also examined the reference lists in these reviews and retrieved articles that appeared to fulfill our criteria. Our search strategy included the terms vitamin D and alcohol in order for the search to be as broad as possible. Search Criteria The following inclusion criteria were used: (i) studies written in either English or Portuguese (only these two languages were included because the authors were not fluent in other languages), (ii) human studies, and (iii) studies assessing vitamin D serum levels in alcohol users and non-users. Ninety-seven papers were excluded due to language limitation. Papers that used alcohol intake as a confounding variable were also excluded because the correlation between alcohol intake and vitamin D serum levels was not the main objective of the study. Data Extraction
Data were independently extracted by the authors (V.S.T. and M.P.P.L.) using a structured form. The following variables were considered: (1) the author and publication year, (2) the study design, (3) the number of subjects included, (4) the subject setting, (5) the primary outcome, (6) the available information regarding Vitamin D status and alcohol (7) the details of the evaluated data, (8) the main findings, and (9) the study limitations. Discrepancies were resolved by consensus, and the senior authors (D.X.S and T.M.F.) were consulted when needed. Data concerning alcohol consumption and its relationship with vitamin D were described, when available. It was not possible to describe or standardize alcohol consumption for all papers reviewed, once many of them did not mention drinking patterns and also because articles used very heterogeneous measurement methods. Data Analysis We described the results qualitatively because there was no quantitative information available to perform a meta-analysis. Results We identified 932 references in our preliminary search. Of these references, 863 were excluded in the first analysis because they did not fulfill the inclusion criteria. All 69 remaining articles were reviewed further, and 20 of these were excluded because they assessed populations that differed from those mentioned in the search criteria. The remaining 49 papers, which all met our inclusion criteria, were fully reviewed, and data were extracted from them. All articles were published between 1976 and December 2015. The majority of the papers in our review (71.4%) were cross-sectional studies; the possibility of a meta-analysis was diminished because the remaining articles (eight
cohorts, four case-control papers and one clinical trial) had distinct methods and different outcome evaluations. In 15 of the reviewed articles (30.7%), alcohol intake was found to be positively associated with vitamin D status, indicating that higher alcohol consumption was associated with higher vitamin D levels. In contrast, 18 (36.7%) articles found that alcohol use was negatively associated with vitamin D status, indicating that lower alcohol consumption was associated with higher vitamin D levels. The remaining 16 (32.7%) articles showed no association between alcohol intake and serum vitamin D levels. These data are controversial because the more recent studies tended to find a negative correlation, whereas the older studies tended to find a positive correlation. Detailed information about this discrepancy is presented in Table 1.
Discussion In our analyses, we reviewed 49 studies. We found that in 15 studies, alcohol use was positively associated with vitamin D status, whereas in 18 studies, alcohol use was negatively associated with vitamin D status. Sixteen articles found no association between alcohol use and vitamin D serum levels. Given the equivalent proportion of papers with positive and negative findings, these preliminary results appear to be inconclusive. The first papers comparing vitamin D in alcoholics and non-alcoholics were conducted in high latitude countries, such as Norway and Finland, perhaps because low vitamin D levels were regarded as a public health problem first in these countries compared to tropical regions. In 1980, Devgun studied 129 alcoholics and 32 healthy controls in different seasons in Dundee, UK. The author reported that 25OHD was significantly lower in alcoholics than in controls in all seasons (measured monthly from
August to March). In 1988, Bjorneboe conducted a study in Oslo, Norway, during winter, and he found that 25OHD was 28% lower in alcoholics compared to nonalcoholic controls. These and other papers with data collected in lower temperature settings (Table 1) found that higher alcohol intake was associated with lower serum vitamin D levels, which might be explained by the fact that alcoholic individuals would not leave their houses as frequently as non-alcoholics in such low temperatures. However, it is important to state that these papers had small sample sizes compared to papers that were published later. Fourteen of the included papers (31.1%) found no association between serum vitamin D levels and ethanol intake (Table 1). Overall, these papers had intermediate sample sizes compared to the studies that found negative associations (which had smaller samples) and those in which positive associations were found (which had larger samples). These small sample sizes may partially explain why some papers did not find any association. Moreover, some papers evaluated specific subpopulations, such as the study by Mahabir in 2014, which evaluated 51 postmenopausal women, and that by Venu in 2013, which assessed 63 patients awaiting liver transplantation. This discrepancy could indicate that bias may have affected these results. Larger sample sizes or less specific populations could potentially alter these findings. Recent papers, however, did not confirm the results found in prior papers. After 2000, a greater number of researchers investigated this topic and used larger sample sizes than those used previously. In 2012, Bertrand studied a population of 128,371 nurses who were divided into two different cohorts, and the author found a significant positive association between alcohol intake and serum vitamin D levels. Similarly, Khaw conducted a prospective study of 14,641 individuals in 2014 and found a slight, although significant, positive association between alcohol units per day and vitamin D
serum levels. Moreover, papers that reported that larger alcohol intake was associated with higher vitamin D serum levels had better study designs than did those that found the opposite outcome. In 2014, Steingrimsdottir found that non-alcoholics had lower vitamin D levels than did alcoholics in a cohort study involving 5,764 individuals in Iceland; the study had a 5.4-year mean follow-up period. In a study published in 2014, Knekt also found a positive association in a cohort of 5,010 men and women with a 17year follow-up period. Notably, both studies did not evaluate the association between alcohol intake and vitamin D serum levels as the primary outcome, and they only measured serum vitamin D levels once. Although several papers have reported a positive association between alcohol use and vitamin D serum levels, this association was not the primarily investigated outcome. Many papers used secondary data from population studies, and they investigated many variables and associations, including vitamin D serum levels and alcohol intake. Therefore, this association has not been adequately discussed in more recent papers. However, in the present review, the studies that found positive associations between alcohol intake and vitamin D serum levels were the most consistent in terms of methods and sample size. It is possible that these results might be due to greater exposure to sunlight among alcoholics compared to non-alcoholics because of the homeless status of many alcoholics. Still, the influence of these variables has not been properly addressed, and further studies are needed to better elucidate these findings. The present review has some limitations. Most of the included papers (68.9%) were cross-sectional; therefore, it was not possible to further analyze the data from different studies through meta-analysis. A significant portion of the papers included in this review also had small sample sizes, which may have influenced the final results.
Some papers studied specific populations of alcoholic patients, including the 2014 studies by Anweiller, who investigated 329 community-dwelling older women (average age, 83.3 years), and by Zellner, who assessed patients admitted to an orthopedic surgery service. This difference could also represent a source of bias because conclusions from specific populations of alcoholics could not be generalized to all alcoholics. Conclusion In conclusion, data concerning vitamin D levels in alcoholic patients remain controversial. Therefore, additional research using a standardized methodology is required to demonstrate the real effect of alcohol use on vitamin D serum levels and its impact on the vitamin D-related health status of alcohol users. Standardization includes choosing the metabolite of Vitamin D assessed, once most studies use 25-HydroxyVitamin D, but some studies evaluate 1,25-dihydroxyvitamin D, which impairs comparison between them. Besides that, the measurement of alcohol consumption must also be standardized, once different units or methods for measurement were applied. Finally, several studies do not have the association between alcohol consumption and serum levels of Vitamin D as their primary outcome, which makes discussion of the topic poor.
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Highlights
Association between Alcohol Use Disorders and Vitamin D serum levels is reviewed. Results found by different articles are heterogeneous and controversial. Studies with larges samples showed positive associations between Vitamin D serum levels and alcohol intake; However, papers that evaluated this association as a primary outcome found negative association. Further studies are needed to better elucidate this question.