Vitamin D and Vascular Calcification Among Alcoholics
Vitamin D and Vascular Calcification Among Alcoholics
In this study we found an association between low vitamin D levels and low lean mass but we failed to find a correlation with fat mass. The relationship between vitamin D and muscle mass and function has been disentangled in the last decade, especially after the identification of a specific vitamin D receptor in muscle fibers (Bischoff et al., 2001; Girgis et al., 2013). This explains the common observation of proximal muscle atrophy in patients affected by celiac disease, other malabsorptive conditions and osteomalacia (Hall, 1968; Byrne et al., 2002; Glerup et al., 2000). In addition, it has been shown that experimental animals lacking a vitamin D receptor showed reduced muscle mass and fiber size compared with wild-type animals (Endo et al., 2003). These results are in accordance with the observation performed by our group in which vitamin D levels were related to type IIa muscle fiber area (González-Reimers et al., 2010). The results obtained regarding vitamin D levels and lean mass in the present study are full in accordance with these observations. In this sense it is interesting to point out that there was no correlation between vitamin D levels and the amount of fat mass, something which would not have happened if vitamin D deficiency and reduced lean mass were due to malabsorption. In this case, fat mass would have also been reduced and we would have expected to find a correlation with vitamin D levels.
We also found an association between vitamin D levels and liver function. Liver dysfunction may be associated with varying degrees of malabsorption, not only related to the consumption of ethanol itself but also to portal hypertension secondary to liver cirrhosis (Hayashi et al., 2000). Therefore it is not surprising that deranged liver function is accompanied by low levels of liposoluble vitamins, the absorption of which requires the presence of bile salts (Fisher, 2009). Several studies report an association between liver disease and vitamin D deficiency, both in alcoholic and in non-alcoholic liver disease. Some authors have found an independent relationship between low 25-hydroxy vitamin D and non-alcoholic fatty liver disease (Eliades et al., 2013), while other authors report low levels of vitamin D in alcoholic liver dysfunction (Song and Rockey, 2013). The findings of some authors suggest that vitamin D deficiency may be involved in progressive liver fibrous tissue deposition (Abramovitch et al., 2011; Nobili et al., 2014). However, this finding is not shared by other authors and some have failed to find any relationship between liver dysfunction and vitamin D deficiency (Skaaby et al., 2013). In any case, the pathogenetic mechanisms have not been identified. The possible explanation of impaired absorption due to bile salt alteration mentioned above is merely speculative but is a theoretical possibility.
In accordance with studies performed on the general population (Zitterman et al., 2009; Bielakovic et al., 2014), we found a higher mortality among non-cirrhotic alcoholic patients with low vitamin D levels. Recent research has shown that due to the vast distribution of its receptor (VDR), vitamin D deficiency can have protean manifestations (Bouillon et al., 2008). As mentioned earlier, by incompletely understood mechanisms, vitamin D deficiency may be involved in increased cardiovascular risk (Elamin et al., 2011; McGreevy and Williams, 2011; Brøndum-Jacobsen et al., 2012; Liss and Frishman, 2012; Siadat et al., 2012; Tomson et al., 2013) and perhaps in carcinogenesis (Giovannucci, 2005, 2009; Pilz et al., 2013). Some authors have shown that vitamin D levels below 10 ng/ml in older adults are associated with an increased risk of all-cause mortality [HR (95% confidence interval [CI] 2.27 (1.59–3.24)] (Kritchevsky et al., 2012). In our series, although median values of vitamin D levels were low, and a high proportion of patients showed vitamin D values below 30 ng/ml, only three alcoholics showed values below 10 ng/ml, precluding statistical analysis.
It is noteworthy that low vitamin D levels were related to mortality only in the subgroup of non-cirrhotic patients. Although the reason is unclear, it could be speculated that, perhaps, the presence among cirrhotics of several potentially lethal conditions, such as bleeding tendency, liver failure, ascites with possible renal impairment or variceal bleeding, may obscure the eventual importance of low vitamin D levels regarding mortality. In any case, Cox regression analysis reveals that only classical parameters, namely Child score and age, were independently associated with mortality. This is in contrast with the results of a recent study on 2649 patients. In that study vitamin D was found to be an independent prognostic factor, and the authors failed to find a relationship between altered liver enzyme levels and mortality associated with low vitamin D levels (Skaaby et al., 2013). However, that was a population-based study.
A recent meta-analysis of observational studies and randomized controlled trials showed that supplementation with vitamin D significantly reduces overall mortality among older adults (Chowdhury et al., 2014). Other reviews suggest similar results but the validity of the results has been put into question and more randomized controlled trials may be needed (Bielakovic et al., 2014; Theodoratou et al., 2014).
Studies also point out that low vitamin D levels, related to sarcopenia and increased mortality, could be considered a marker of frailty (Bischoff-Ferrari et al., 2004, 2009; Kim et al., 2011). Therefore the association with mortality would not be a direct effect of vitamin D deficiency but it would be a consequence of the fact that vitamin D deficiency itself is a marker of frailty.
In any case we conclude that vitamin D deficiency is common in alcoholic patients and it is associated with liver dysfunction and low lean mass but not with low fat mass. In addition, low vitamin D values are associated with long-term mortality among non-cirrhotic alcoholics, as assessed using Kaplan–Meier curves, although the only variables independently associated with mortality using Cox regression are Child score and age.
Discussion
In this study we found an association between low vitamin D levels and low lean mass but we failed to find a correlation with fat mass. The relationship between vitamin D and muscle mass and function has been disentangled in the last decade, especially after the identification of a specific vitamin D receptor in muscle fibers (Bischoff et al., 2001; Girgis et al., 2013). This explains the common observation of proximal muscle atrophy in patients affected by celiac disease, other malabsorptive conditions and osteomalacia (Hall, 1968; Byrne et al., 2002; Glerup et al., 2000). In addition, it has been shown that experimental animals lacking a vitamin D receptor showed reduced muscle mass and fiber size compared with wild-type animals (Endo et al., 2003). These results are in accordance with the observation performed by our group in which vitamin D levels were related to type IIa muscle fiber area (González-Reimers et al., 2010). The results obtained regarding vitamin D levels and lean mass in the present study are full in accordance with these observations. In this sense it is interesting to point out that there was no correlation between vitamin D levels and the amount of fat mass, something which would not have happened if vitamin D deficiency and reduced lean mass were due to malabsorption. In this case, fat mass would have also been reduced and we would have expected to find a correlation with vitamin D levels.
We also found an association between vitamin D levels and liver function. Liver dysfunction may be associated with varying degrees of malabsorption, not only related to the consumption of ethanol itself but also to portal hypertension secondary to liver cirrhosis (Hayashi et al., 2000). Therefore it is not surprising that deranged liver function is accompanied by low levels of liposoluble vitamins, the absorption of which requires the presence of bile salts (Fisher, 2009). Several studies report an association between liver disease and vitamin D deficiency, both in alcoholic and in non-alcoholic liver disease. Some authors have found an independent relationship between low 25-hydroxy vitamin D and non-alcoholic fatty liver disease (Eliades et al., 2013), while other authors report low levels of vitamin D in alcoholic liver dysfunction (Song and Rockey, 2013). The findings of some authors suggest that vitamin D deficiency may be involved in progressive liver fibrous tissue deposition (Abramovitch et al., 2011; Nobili et al., 2014). However, this finding is not shared by other authors and some have failed to find any relationship between liver dysfunction and vitamin D deficiency (Skaaby et al., 2013). In any case, the pathogenetic mechanisms have not been identified. The possible explanation of impaired absorption due to bile salt alteration mentioned above is merely speculative but is a theoretical possibility.
In accordance with studies performed on the general population (Zitterman et al., 2009; Bielakovic et al., 2014), we found a higher mortality among non-cirrhotic alcoholic patients with low vitamin D levels. Recent research has shown that due to the vast distribution of its receptor (VDR), vitamin D deficiency can have protean manifestations (Bouillon et al., 2008). As mentioned earlier, by incompletely understood mechanisms, vitamin D deficiency may be involved in increased cardiovascular risk (Elamin et al., 2011; McGreevy and Williams, 2011; Brøndum-Jacobsen et al., 2012; Liss and Frishman, 2012; Siadat et al., 2012; Tomson et al., 2013) and perhaps in carcinogenesis (Giovannucci, 2005, 2009; Pilz et al., 2013). Some authors have shown that vitamin D levels below 10 ng/ml in older adults are associated with an increased risk of all-cause mortality [HR (95% confidence interval [CI] 2.27 (1.59–3.24)] (Kritchevsky et al., 2012). In our series, although median values of vitamin D levels were low, and a high proportion of patients showed vitamin D values below 30 ng/ml, only three alcoholics showed values below 10 ng/ml, precluding statistical analysis.
It is noteworthy that low vitamin D levels were related to mortality only in the subgroup of non-cirrhotic patients. Although the reason is unclear, it could be speculated that, perhaps, the presence among cirrhotics of several potentially lethal conditions, such as bleeding tendency, liver failure, ascites with possible renal impairment or variceal bleeding, may obscure the eventual importance of low vitamin D levels regarding mortality. In any case, Cox regression analysis reveals that only classical parameters, namely Child score and age, were independently associated with mortality. This is in contrast with the results of a recent study on 2649 patients. In that study vitamin D was found to be an independent prognostic factor, and the authors failed to find a relationship between altered liver enzyme levels and mortality associated with low vitamin D levels (Skaaby et al., 2013). However, that was a population-based study.
A recent meta-analysis of observational studies and randomized controlled trials showed that supplementation with vitamin D significantly reduces overall mortality among older adults (Chowdhury et al., 2014). Other reviews suggest similar results but the validity of the results has been put into question and more randomized controlled trials may be needed (Bielakovic et al., 2014; Theodoratou et al., 2014).
Studies also point out that low vitamin D levels, related to sarcopenia and increased mortality, could be considered a marker of frailty (Bischoff-Ferrari et al., 2004, 2009; Kim et al., 2011). Therefore the association with mortality would not be a direct effect of vitamin D deficiency but it would be a consequence of the fact that vitamin D deficiency itself is a marker of frailty.
In any case we conclude that vitamin D deficiency is common in alcoholic patients and it is associated with liver dysfunction and low lean mass but not with low fat mass. In addition, low vitamin D values are associated with long-term mortality among non-cirrhotic alcoholics, as assessed using Kaplan–Meier curves, although the only variables independently associated with mortality using Cox regression are Child score and age.
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