Low Vitamin D Levels And High Liver Enzymes

Low Vitamin D Levels And High Liver Enzymes

Vitamin D deficiency is common among patients with liver diseases. Both cholestatic and non-cholestatic liver diseases can cause vitamin D deficiency. Whether vitamin D status can also affect liver function is poorly understood. To investigate the association between vitamin D status, liver enzymes, and incident liver disease, we included a total of 2,649 individuals from the Monica10 study conducted in 1993-1994. Vitamin D status as assessed by serum 25-hydroxyvitamin, serum alanine transaminase (ALT), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) were measured at baseline. Information on fatal and non-fatal liver disease was obtained from the Danish National Patient Register and The Danish Registry of Causes of Death, respectively. Median follow-up time was 16.5 years, and there were 62 incident cases of fatal and non-fatal liver disease. Multivariable Cox regression analyses with age as underlying time axis and delayed entry showed a statistically significant inverse association between vitamin D status and incident liver disease with a hazard ratio = 0.88 (95 % confidence interval 0.79-0.99) per 10 nmol/l higher vitamin D status at baseline (adjusted for gender, season, alcohol consumption, smoking, physical activity, dietary habits, education, body mass index, and ALT). The risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, although not statistically significant. In this general population study, vitamin D status was inversely associated with incident liver disease. Further studies are needed to determine whether patients in risk of developing impaired liver function should be screened for vitamin D deficiency for preventive purposes.

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... Most cases of HCC are attributable to CLDs, particularly chronic hepatitis B (CHB) and chronic hepatitis C (CHC), and the related cirrhoses [3]. In the past decade, increasing evidence has demonstrated that vitamin D levels are significantly associated with incident liver disease and the risk of CLD mortality [13,56,57]. The first prospective study reported by Skaaby et al. [56] enrolled 2649 individuals, had a median follow-up time of 16.5 years, and found that vitamin D levels were inversely correlated with the incidences of fatal and nonfatal liver diseases [56]. ...

... In the past decade, increasing evidence has demonstrated that vitamin D levels are significantly associated with incident liver disease and the risk of CLD mortality [13,56,57]. The first prospective study reported by Skaaby et al. [56] enrolled 2649 individuals, had a median follow-up time of 16.5 years, and found that vitamin D levels were inversely correlated with the incidences of fatal and nonfatal liver diseases [56]. Another nested case-control study in the Linxian Nutrition Intervention Trials also demonstrated that an increased vitamin D level was associated with a lower risk of CLD death [13]. ...

... In the past decade, increasing evidence has demonstrated that vitamin D levels are significantly associated with incident liver disease and the risk of CLD mortality [13,56,57]. The first prospective study reported by Skaaby et al. [56] enrolled 2649 individuals, had a median follow-up time of 16.5 years, and found that vitamin D levels were inversely correlated with the incidences of fatal and nonfatal liver diseases [56]. Another nested case-control study in the Linxian Nutrition Intervention Trials also demonstrated that an increased vitamin D level was associated with a lower risk of CLD death [13]. ...

Introduction: In addition to being crucial for host immune defense, vitamin D is involved in cell proliferation, apoptosis, differentiation, inflammation, invasion and metastasis, angiogenesis and micro-RNA modulation. To date, clinical studies have demonstrated that vitamin D deficiency is common not only in patients with chronic liver diseases but also in those with hepatocellular carcinoma (HCC). Experimental studies have also demonstrated that vitamin D and its receptors are related to the occurrence of HCC and the prognoses of patients with HCC. Areas covered: In this review, we discuss the potential anti-tumor role of vitamin D in HCC based on current findings from epidemiological studies, basic science, and clinical studies and provide new insights into the pathogenesis and treatment of HCC. Expert commentary: Recent studies have revealed the anti-tumor effects of vitamin D to a certain degree. Vitamin D and its analogs may provide new treatment targets and prognostic factors for HCC that might be essential for the primary or secondary prevention of HCC and the monitoring of its progression.

... [23][24][25] It is not well defined whether Vitamin D deficiency could contribute to liver dysfunction or is just result from the reduced liver function; however, a previous longitudinal study revealed an inverse association between Vitamin D status and incidence of liver disease. [26] Current research about the relationship between 25(OH)D levels and liver function tests is mostly conducted among the adult population, [27] and limited evidence is available in the pediatric age group. [28] The aim of this study is to determine the association of serum 25(OH)D with liver enzymes among adolescents. ...

... It is worth noting that no previous studies have explored the association between Vitamin D status and liver enzymes in the adolescents' population, except for only one study that has investigated this association with the development of liver disease in a general adult population. [26] Our findings are in line with a previous study that revealed that the risk of having a greater value of liver enzymes tended to be more for lower serum 25(OH)D status although not statistically significant. They also found an inverse association between Vitamin D status and the prevalence of hepatic disorders. ...

... They also found an inverse association between Vitamin D status and the prevalence of hepatic disorders. [26] In our study, we found a relatively high frequency of Vitamin D deficiency among adolescents (77.3% boys vs. 80.6% girls). In line with these findings, increasing rate of Vitamin D deficiency has been reported among children and adolescents as well as adult population from other parts of the country. ...

Background Hypovitaminosis D is highly prevalent and has several adverse health effects. This study aims to assess the relationship of serum concentrations of 25-hydroxyvitamin D (25[OH] D) and liver enzymes in adolescents. Methods This population-based cross-sectional survey was conducted among a nationally representative multistage sample of 1095 adolescents (52% boys), aged 10–18 years, living in different provinces of Iran. Serum 25(OH)D concentration <30 ng/mL was considered as hypovitaminosis D, and liver enzymes (alanine aminotransaminase [ALT] and aspartate aminotransaminase [AST]) of >40 U/L was considered as high level. To determine the association between serum 25(OH)D categories and elevated levels of liver enzymes, multiple regression models and linear regression analysis were applied, after adjustment for potential confounders. Odds ratios (95% confidence interval) of serum 25(OH)D and elevated liver enzymes were assessed by logistic regression analysis. Results Higher rates of Vitamin D deficiency were documented among individuals with increased levels of liver enzymes. Compared to boys, median of 25(OH)D was lower in girls with elevated levels of liver function tests (12.75 vs. 25.60 ng/mL for ALT and 13 vs. 14.10 ng/mL for AST), with marginally significant gender differences regarding AST. Conclusions We found a relatively high frequency of hypovitaminosis D among adolescents with abnormal liver function. Further prospective studies are needed to examine these associations from early life.

... The risk for advanced liver disease started to increase substantially at vitamin D levels below 40-50 nmol/L, which resembles the cut-off for inadequate levels according to Institute of Medicine [12] (Figure 1). Our findings were in line with one previous Danish populationbased study, where the authors studied the association between vitamin D status and incident liver disease [13]. However, we focused on clinically more relevant advanced liver diseases (e.g. ...

... However, we focused on clinically more relevant advanced liver diseases (e.g. cirrhosis, liver failure and HCC), whereas the Danish study included also milder liver diseases, including for example fatty liver [13]. We adjusted our analyses for multiple social, lifestyle and metabolic-health factors. ...

... We adjusted our analyses for multiple social, lifestyle and metabolic-health factors. We did not adjust for vitamin D supply from diet, but the previous study did not find confounding effect from unhealthy diet (based on Healthy Food Index) to the association between vitamin D and liver disease [13]. Vitamin D levels have been associated with several health indicators [11], and therefore, despite our adjustments for various confounders, residual confounding cannot be excluded. ...

Background Vitamin D deficiency is a common finding in chronic liver disease. It has also been linked to the pathogenesis of non-alcoholic fatty liver disease, hepatic fibrogenesis, decompensation and hepatocellular carcinoma. Aims We analyzed whether serum vitamin D is associated with incident advanced liver disease in the general population. Methods Serum 25-hydroxyvitamin D was measured in 13807 individuals participating in the Finnish population-based health examination surveys FINRISK 1997 and Health 2000. Data were linked with incident advanced liver disease (hospitalization, cancer or death related to liver disease). During a follow-up of 201444 person-years 148 severe liver events occurred. Analyses were performed using multivariable Cox regression analyses. Results Vitamin D level associated with incident advanced liver disease with the hazard ratio of 0.972 (95% confidence interval 0.943-0.976, p < .001), when adjusted for age, sex, blood sampling season and stratified by cohort.The association remained robust and significant in multiple different adjustment models adjusting sequentially for 22 potential confounders. Conclusion Low vitamin D level is linked to incident advanced liver disease at population level.

... Moreover, suboptimal vitamin D status has been associated with lower efficacy of anti-resorptive therapy for osteoporosis [12][13][14]. Finally, extrarenal production of 1,25-dihydroxyvitamin D has been involved in the control of the immune response [15], cell proliferation [5], mortality [16,17], and many other extraskeletal effects [18]. ...

... All participants underwent a medical interview in order to exclude subjects taking vitamin D supplements, drug interfering with vitamin D metabolism, as well as subjects with severe kidney and liver disorders. To what extent a subclinical liver disorder could affect the predictive value of our questionnaire remains to be established [16]. Informed consent was obtained from all participants. ...

Sun exposure is the main determinant of vitamin D production. The aim of this study was to develop an algorithm to assess individual vitamin D status, independently of serum 25(OHD) measurement, using a simple questionnaire, mostly relying upon sunlight exposure, which might help select subjects requiring serum 25(OHD) measurement. Six hundred and twenty adult subjects living in a mountain village in Southern Italy, located at 954 m above the sea level and at a latitude of 40°50′11″76N, were asked to fill the questionnaire in two different periods of the year: August 2010 and March 2011. Seven predictors were considered: month of investigation, age, sex, BMI, average daily sunlight exposure, beach holidays in the past 12 months, and frequency of going outdoors. The statistical model assumes four classes of serum 25(OHD) concentrations: ≤10, 10–19.9, 20–29.9, and ≥30 ng/ml. The algorithm was developed using a two-step procedure. In Step 1, the linear regression equation was defined in 385 randomly selected subjects. In Step 2, the predictive ability of the regression model was tested in the remaining 235 subjects. Seasonality, daily sunlight exposure and beach holidays in the past 12 months accounted for 27.9, 13.5, and 6.4 % of the explained variance in predicting vitamin D status, respectively. The algorithm performed extremely well: 212 of 235 (90.2 %) subjects were assigned to the correct vitamin D status. In conclusion, our pilot study demonstrates that an algorithm to estimate the vitamin D status can be developed using a simple questionnaire based on sunlight exposure.

... An early study demonstrated that low serum 25(OH)D was associated with the severity of liver fibrosis in HIV/ HCV co-infected patients [31]. Additional report showed that low serum 25(OH)D status was associated with hepatic dysfunction [32,33]. According to a recent report from Non-alcoholic Steatohepatitis Clinical Research Network Note LN natural logarithm, IL-8 interleukin-8, TGF-β transforming growth factor-β (NASH CRN) cohort, low vitamin D status was associated with an increased risk of non-alcoholic steatohepatitis in NAFLD patients [34]. ...

... Vitamin D is converted to 25(OH)D by hepatic cytochrome P450 (CYP)2R1 and is then converted into 1,25(OH)2D3, the active form of vitamin D, by CYP27B1 in the kidney [49,50]. Several studies indicated that serum 25(OH)D level was reduced among patients with liver and kidney diseases [33,51,52]. Thus, a prospective study is needed to establish causal relationship between vitamin D deficiency and advanced liver fibrosis in patients with NAFLD. ...

Several studies explored the association between vitamin D status and nonalcoholic fatty liver disease with contradictory results. We aimed to investigate the association between vitamin D status, inflammatory cytokines and liver fibrosis in nonalcoholic fatty liver disease patients. Two hundred nineteen nonalcoholic fatty liver disease patients and 166 age- and gender- matched healthy controls were recruited for this study. Serum 25(OH)D was measured by radioimmunoassay. Serum interleukin-8 and transforming growth factor-β1 were measured using ELISA. Serum 25(OH)D was only marginally decreased in nonalcoholic fatty liver disease patients. Interestingly, serum 25(OH)D was markedly reduced in nonalcoholic fatty liver disease patients with advanced liver fibrosis compared to nonalcoholic fatty liver disease patients with indeterminate liver fibrosis and no advanced fibrosis. Logistic regression analysis showed that there was an inverse association between serum 25(OH)D and severity of liver fibrosis in nonalcoholic fatty liver disease patients. Further analysis showed that serum interleukin-8 was elevated in nonalcoholic fatty liver disease patients, the highest interleukin-8 in patients with advanced fibrosis. An inverse correlation between serum 25(OH)D and interleukin-8 was observed in nonalcoholic fatty liver disease patients with and without liver fibrosis. Although serum transforming growth factor-β1 was slightly elevated in nonalcoholic fatty liver disease patients, serum transforming growth factor-β1 was reduced in nonalcoholic fatty liver disease patients with advanced fibrosis. Unexpectedly, a positive correlation between serum 25(OH)D and transforming growth factor-β1 was observed in nonalcoholic fatty liver disease patients with advanced fibrosis. In conclusion, low vitamin D status is associated with advanced liver fibrosis in nonalcoholic fatty liver disease patients. Interleukin-8 may be an important mediator for hepatic fibrosis in nonalcoholic fatty liver disease patients with low vitamin D status.

... In a general population study, individuals with lower vitamin D levels had a higher risk of having increased levels of ALT, AST, or GGT, liver enzymes, Although the association was not statistically significant. In Skaaby et al. study, liver disease incidence was higher in poor vitamin D status [9]. According to some evidence, adipokines expression and secretion in adipocytes may be directly influenced by vitamin D3 [1]. ...

... There is evidence of a significant association between serum levels of 25(OH)D3 and hepatic enzymes [8,29]. In a recent population study (n = 2,649) [9] after adjusting for confounding variables, the higher levels of hepatic enzymes were observed for lower levels of vitamin D, although not statistically significant. ...

Some studies indicated poor vitamin D level in NAFLD which is independently correlated with severity of steatosis. Low 25(OH) D3 levels are associated with an impaired lipid profile. Impaired levels and function of vaspin and omentin, which are adipokines, have been demonstrated in NAFLD patients. This study determined the relationship between vitamin D and serum liver enzymes, ultrasound findings, some adipokines, atherogenic index of plasma (AIP) and visceral adiposity index (VAI) in patients with NAFLD in a cross-sectional study. This study was a cross-sectional study in eighty-three NAFLD patients (57 males and 26 females). Plasma levels of omentin-1e-1, vaspin were measured. Anthropometric indices metabolic status was assessed. Visceral adiposity index and atherogenic index of plasma were calculated according to suggested formula. Anthropometric indices, lipid profiles, liver enzymes as well as abdominal ultrasonography and the status of vitamin D were assessed. The results showed that aspartate aminotransferase (AST) (44.22 ± 8.5 IU/L vs. 40.19 ± 8.75 IU/L, p-value = 0.039) AIP (0.767 ± 0.142 vs. 0.6417 ± 0.139, p < 0.001) and VAI (9.28 ± 3.25 vs. 7.048 ± 2.415, p = 0.001) were significantly higher in patients with vitamin D deficiency compared to those with vitamin D sufficiency. The positive correlations between Vaspin levels and vitamin D were found to be remarkably significant in both males and females (r = 0.437; P = 0.004; P < 0.001, r = -0.709, respectively. In both males and females serum vitamin D concentrations were negatively associated with AIP. Partial correlations controlling for age and sex showed that vitamin D is significantly and inversely associated with AIP, VAI, AST, and ALT. Additionally, vitamin D levels correlated directly with vaspin.

... Recent reports on the association between vitamin D and its risk on stroke have been inconclusive. A report showed that insufficient levels of vitamin D increases the risk of stroke (Zhou R. et al., 2018) while some reports showed no effect of low levels vitamin D as a risk factor of stroke (Perna et al., 2013;Skaaby et al., 2014). Nonetheless, it has been reported that 78% of patients with ischemic stroke have vitamin D deficiency in China (Si et al., 2019). ...

... Our current report is congruent with previous reports which showed that vitamin D deficiency is associated with the severity of ischemic stroke (Tu et al., 2014;Li et al., 2018). Reports on the association between vitamin D and stroke have been varying due to several explanations (Skaaby et al., 2014;Zhou R. et al., 2018). To start with, most studies used different cut-off values of serum 25(OH) D in their analyses and this may have swayed their findings. ...

• Hanpei Miao
• Hanyu Zhu
• Xiaoqian Luan
• Zhen Wang

Purpose Lower serum vitamin D has been reported to be associated with stroke. This study aimed to analyze the risk factors of vitamin deficiency in Chinese stroke patients, and further analyze its impact in different gender and their clinical variables. Methods 982 stroke patients were enrolled. Laboratory parameters such as serum vitamin D, apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), ApoA-I/ApoB, cholesterol (CH), fibrinogen (FIB), blood glucose (Glu), high-density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were collected and recorded. The severity of stroke was assessed by National Institute of Health Stroke Scale (NIHSS) score. Based on their serum vitamin D level, patients were divided into three groups: Vitamin D deficiency (<50 nmol/L), vitamin D insufficiency (≥50–75 nmol/L) and vitamin D sufficiency (≥75 nmol/L) and differences were compared among the three groups. Statistical analyses were done to assess the risk factors for serum vitamin D deficiency in our ischemic stroke patients. Results Gender, NIHSS, and FIB showed significant differences among the vitamin D groups ( P < 0.001 ∼ P = 0.002). The female gender (OR = 2.422, P < 0.001), severity of stroke using NIHSS (OR = 1.055, P = 0.008) and FIB (OR = 1.256, P = 0.005) were risk factors of vitamin D deficiency in ischemic stroke patients. In subgroup analysis, NIHSS was significantly associated with vitamin D deficiency in the male group (OR = 1.087, P = 0.002) and higher FIB group (OR = 1.078, P = 0.001). Conclusions The female gender, severity of stroke using NIHSS and FIB were risk factors for vitamin D deficiency in our incident stroke patients. NIHSS was more sensitive to vitamin D deficiency in male ischemic stroke patients. Besides, under higher FIB circumstance, the increasing NIHSS score was more related to the vitamin D deficiency. Levels of vitamin D in patients with ischemic stroke should be well monitored during the disease cascade.

... The results of some cross-sectional studies revealed a significant association between serum levels of 25(OH)D 3 and hepatic enzymes [13,51]. In a recent population study (n = 2,649) after adjusting for confounding variables, the risk of having a high level of hepatic enzymes was higher for lower levels of vitamin D, although not statistically significant [52]. ...

... Vitamin D deficiency has been often described in persons with chronic liver diseases. [7] The existing evidence on the beneficial and harmful effects of vitamin D supplementation in individuals with chronic liver diseases is not sufficient and contrasting. [8] One meta-analysis research of observational and interventional studies in persons with HCV infection reported a positive relation between sustained virological response and high levels vitamin D. [9] On the other hand, one study reported association between vitamin D levels and chronic liver disease progression. ...

• Mayada Noori Iqbal
• Abdul Hussein Leith
• Ammar Hamza Abbas

Background: The interleukin 17 is usually linked to tissue damage in autoimmune disorders and bacterial and fungal infections. In both chronic Hepatitis B and Hepatitis C Virus infections, some reports show a close relationship between activation of Th17 lymphocytes and the extent of hepatic damage instigated by the antiviral immune response. Vitamin D deficiency has been often described in persons with chronic liver diseases. The strong Immunomodulatory effects of Calcitriol (active form of vitamin D) in vitro, suggested a possible therapeutic benefit in chronic hepatitis B infection and chronic hepatitis C cases. Aims: to investigate the sera levels of Interleukin-17 and Vitamin D3 (as Calcitriol) in viral hepatitis patients and determine the relationships between these biomarkers. Methods: Blood samples were taken from 70 chronic viral hepatitis patients and 35 healthy controls. The patients group consisted of 34 chronic HBV cases and 36 chronic HCV cases. All samples were quantified for (interleukin-17 and calcitriol) by sandwich Enzyme-linked immunosorbent assay. Non-parametric statistical tests (Kolmogorov-Smirnov test and Mann–Whitney test) were used by employing SPSS statistical software. Results: Results revealed that the mean of interleukin-17 sera of patients was (64.74ng/L) while it was (90.9ng/L) in controls with significant difference at (P<0.05). Furthermore, there was a highly significant difference (P<0.01) between the HBV and HCV groups, with means of (36.9ng/L and 70.1 ng/L) respectively. The mean of patients' serum calcitriol was significantly lower (P<0.01) than the controls' (79.05 and 113.3 pmol/L, respectively). The mean of calcitriol levels in HBV group was (44.88pmol/L), which is significantly lower (P<0.01) than the mean of HCV group (92.2pmol/L). There was a highlysignificant positive relationship between 1,25 (OH)2D3 (Calcitriol) and interleukin-17 at pvalue (p< 0.01). Conclusion: serum levels of interleukin-17 were low in patients but were higher in HCV patients than in HBV patients. Calcitriol and interleukin-17 are strongly correlated in a positive manner, which implies that Vitamin D3 had a suppressive effect on interleukin-17

... In epidemiologic studies, VDD has been demonstrated to be a predictor of liver disease morbidity and mortality. In a Danish population-based sample of over 2500 middle-aged subjects followed prospectively for a median followup period of 16.5 years, lower serum 25(OH)D levels were independently associated with higher incidence of fatal and non-fatal liver disease [51] . Similarly, in another prospective study with 22 years follow-up [52] , those with a higher serum 25(OH) vitamin D had lower chronic liver disease mortality. ...

Obesity and metabolic syndrome are considered as responsible for a condition known as the non-alcoholic fatty liver disease that goes from simple accumulation of triglycerides to hepatic inflammation and may progress to cirrhosis. Patients with obesity also have an increased risk of primary liver malignancies and increased body mass index is a predictor of decompensation of liver cirrhosis. Sarcopenic obesity confers a risk of physical impairment and disability that is significantly higher than the risk induced by each of the two conditions alone as it has been shown to be an independent risk factor for chronic liver disease in patients with obesity and a prognostic negative marker for the evolution of liver cirrhosis and the results of liver transplantation. Cirrhotic patients with obesity are at high risk for depletion of various fat-soluble, water-soluble vitamins and trace elements and should be supplemented appropriately. Diet, physical activity and protein intake should be carefully monitored in these fragile patients according to recent recommendations. Bariatric surgery is sporadically used in patients with morbid obesity and cirrhosis also in the setting of liver transplantation. The risk of sarcopenia, micronutrient status, and the recommended supplementation in patients with obesity and cirrhosis are discussed in this review. Furthermore, the indications and contraindications of bariatric surgery-induced weight loss in the cirrhotic patient with obesity are discussed.

... In this study, low 25 (OH)D concentration was associated with high AST and cholesterol total value. Skaaby et al [37] investigate the association between vitamin D status, liver enzymes, and incident liver disease in 2649 individuals and found that the risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, in accordance with our results. ...

Potential relationship of vitamin D, vitamin D receptor (VDR), and vitamin D binding protein (DBP) have been suggested in the pathophysiology of hepatitis C virus (HCV) infection. The aim of this observational study is to determine vitamin D levels, and VDR and DBP genetic polymorphism according demographic and laboratory data in chronic HCV patients (CHC). A total of 148 CHC patients gave serum samples for testing 25-hydroxyvitamin D (25 (OH)D) level by immunochemiluminometric assay (<20 ng/mL defined as deficient) and donated blood samples to allelic discrimination analysis using TaqMan assays. Analyzed single nucleotide polymorphisms (SNPs) were: VDR-rs7975232 (ApaI) C>A, rs731236 A>G (TaqI), rs1544410 C>T (BsmI), rs10735810 T>C (FokI) and carrier globulin/binding protein (GC)-rs4588 and rs7041 and the haplotype bAt [CCA]. Hepatic fibrosis was assessed using Fib-4 and Forns index. Eighty-two (54.40%) patients demonstrated deficiency of vitamin D and this was associated to AST (P = .019 [CI: 1.003–1.034]), total cholesterol (P = .038 [CI: 1.004–1.164]), fibrosis grade (P < .001 [CI: 0.000–0.844]), and FokI (P = .028) allele T presence. Association was found between VDR polymorphism and fibrosis (BsmI andTaqI), triglycerides (TaqI), and HDL (FokI). DBP polymorphism was associated to HCV genotype (GC rs7041), previous HCV treatment, and GGT (GC rs4588). In conclusion, low frequency of vitamin D deficiency was found, but VDR polymorphisms were frequently associated to fibrosis grade suggesting that they could be used as disease evaluation markers to understand the mechanisms underlying the virus–host interaction.

... The positive association between alcohol intake and vitamin D status has been described in many studies [53][54][55]. However, these results should be regarded with caution since excessive alcohol intake may have a negative effect on vitamin D status due to changes in vitamin D metabolism [56]. It has also been described in an animal model that alcohol treatment may 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 The high prevalence in 25(OH)D inadequacy/deficiency observed in our study, even when using the IOM´s conservative cut-off points, highlights the urgency to define strategies for the improvement of vitamin D status in Portuguese older adults. ...

... The role of inflammation on vitamin D status in IBD was noted in our previous study which showed a significantly lower 25(OH)D concentration in IBD patients with elevated ESR compared to controls [6]. The lack of a significant relationship between 25(OH)D and albumin in IBS is similar to the findings of a study on albumin and 25(OH)D in inflammatory bowel disease [37]; and the absence of a significant relationship between ALT and 25(OH)D in IBS is also consistent with a report that characterized the relationship between vitamin D and liver enzymes in adult patients with liver disease [38]. The seasonal variations in 25(OH)D in IBS subjects is similar to the pattern described in published reports [36,39,40]. ...

IMPORTANCE: Irritable bowel syndrome (IBS) is associated with significant morbidity in children and adolescents, and the therapeutic efficacy of available treatment options is limited. The role of vitamin D supplementation in pediatric IBS is unclear as the vitamin D status of pediatric patients with IBS is unknown. Equally, the relationship of vitamin D status with psychosomatic symptoms in children and adolescents is unclear. AIM: To characterize the vitamin D status of pediatric patients with IBS using a case-control study design. HYPOTHESIS: Serum 25-hydroxyvitamin D [25(OH)D] concentration will be similar between patients with IBS and controls. SUBJECTS AND METHODS: A retrospective case-controlled study of 116 controls (age 14.6 ± 4.3 y), female (n = 67; 58%) and 55 subjects with IBS (age 16.5 ± 3.1y), female (n = 44; 80%). Overweight was defined as BMI of ≥85th but <95th >percentile, and obesity as BMI ≥95th percentile. Vitamin D deficiency was defined as 25(OH)D of/L, while seasons of vitamin D draw were categorized as summer, winter, spring, and fall. Major psychosomatic manifestations included in the analysis were depression, anxiety, and migraine. RESULTS: More than 50% of IBS subjects had vitamin D deficiency at a cut-off point of/L (53% vs. 27%, p = 0.001); and >90% of IBS subjects had vitamin D deficiency at a cut-off point of/L (93% vs. 75%, p = 0.006). IBS subjects had significantly lower mean 25(OH)D: 53.2 ± 15.8 nmol/L vs. 65.2 ± 28.0 nmol/L, p = 0.003; and albumin: 6.2 ± 0.6 vs. 6.5 ± 0.6 μmol/L, p = 0.0.01. IBS subjects with migraine had significantly lower mean 25(OH)D concentration compared to controls (p = 0.01). BMI z-score was similar between the controls and IBS subjects (0.5 ± 1.4 vs. 1.2 ± 2.9, p = 0.11). CONCLUSIONS: Pediatric patients with IBS had significantly lower 25(OH)D concentration compared to controls despite having similar mean BMI values as controls. Only 7% of the children and adolescents with IBS were vitamin D sufficient, and >50% of the subjects with IBS had vitamin D deficiency. This is a much higher prevalence of vitamin D deficiency compared to IBD and other malabsorption syndromes. Monitoring for vitamin D deficiency should be part of the routine care for patients with IBS. Randomized control trials are warranted to determine the role of adjunctive vitamin D therapy in pediatric IBS.

... [53][54][55] However, these results should be regarded with caution since excessive alcohol intake may have a negative effect on vitamin D status due to changes in vitamin D metabolism. 56 It has also been described in an animal model that alcohol treatment may decrease the serum levels of its active metabolite (1,25-dihydroxycholecalciferol) while 25(OH)D levels remained unchanged. This may limit the interest of using 25(OH)D when studying the effects of alcohol on vitamin D status. ...

Objectives To evaluate vitamin D status and its associated factors in Portuguese older adults from the Nutrition UP 65 study. Design Cross-sectional observational study. Participants and methods Nationwide cluster sample of 1500 Portuguese subjects ≥65 years old. Participants were classified, according to US Institute of Medicine cut-offs, as presenting normal 25-hydroxyvitamin D (25(OH)D) levels (≥50.0 nmol/L), at risk of inadequacy (30.0–49.9 nmol/L) or at risk of deficiency (<30 nmol/L). The association between individuals' characteristics and 25(OH)D levels was analysed through multinomial logistic regression analysis. Results Median 25(OH)D serum value was 36.1 (interquartile range (IQR): 35.5) nmol/L. According to the used cut-offs, 39.6% of participants were at risk of 25(OH)D deficiency and 29.4% were at risk of 25(OH)D inadequacy. In the adjusted model, having higher skin pigmentation and waist circumference >88 cm for women and >102 cm for men were associated with higher odds of 25(OH)D deficiency. Otherwise, living in Lisbon Metropolitan Area and in Madeira, 1–12 years of schooling, being married or in a common-law marriage, monthly income ≥€1000, alcohol consumption, medication or supplements with vitamin D supplement use, and blood samples collected in spring or summer were associated with lower odds of being at risk of 25(OH)D deficiency. In this model, season of blood sample collection, medication or supplements use, and waist circumference were the factors more strongly associated with 25(OH)D levels. Conclusions Despite using the conservative Institute of Medicine cut-offs, over two-thirds of these study participants presented inadequate 25(OH)D levels, warranting the implementation of corrective measures. Potentially modifiable factors were strongly associated with 25(OH)D levels in this study. These findings may be particularly relevant to the development of public health policies in southern European countries.

... Vitamin D deficiency has been often described in persons with chronic liver diseases. [7] The existing evidence on the beneficial and harmful effects of vitamin D supplementation in individuals with chronic liver diseases is not sufficient and contrasting. [8] One meta-analysis research of observational and interventional studies in persons with HCV infection reported a positive relation between sustained virological response and high levels vitamin D. [9] On the other hand, one study reported association between vitamin D levels and chronic liver disease progression. ...

... The role of inflammation on vitamin D status in IBD was noted in our previous study which showed a significantly lower 25(OH)D concentration in IBD patients with elevated ESR compared to controls [6]. The lack of a significant relationship between 25(OH)D and albumin in IBS is similar to the findings of a study on albumin and 25(OH)D in inflammatory bowel disease [37]; and the absence of a significant relationship between ALT and 25(OH)D in IBS is also consistent with a report that characterized the relationship between vitamin D and liver enzymes in adult patients with liver disease [38]. The seasonal variations in 25(OH)D in IBS subjects is similar to the pattern described in published reports [36,39,40]. ...

• Benjamin U Nwosu
• Louise Maranda
• Ninfa Candela

Importance: Irritable bowel syndrome (IBS) is associated with significant morbidity in children and adolescents, and the therapeutic efficacy of available treatment options is limited. The role of vitamin D supplementation in pediatric IBS is unclear as the vitamin D status of pediatric patients with IBS is unknown. Equally, the relationship of vitamin D status with psychosomatic symptoms in children and adolescents is unclear. Aim: To characterize the vitamin D status of pediatric patients with IBS using a case-control study design. Hypothesis: Serum 25-hydroxyvitamin D [25(OH)D] concentration will be similar between patients with IBS and controls. Subjects and methods: A retrospective case-controlled study of 116 controls (age 14.6 ± 4.3 y), female (n = 67; 58%) and 55 subjects with IBS (age 16.5 ± 3.1y), female (n = 44; 80%). Overweight was defined as BMI of ≥85th but <95th percentile, and obesity as BMI ≥95th percentile. Vitamin D deficiency was defined as 25(OH)D of <50 nmol/L, while seasons of vitamin D draw were categorized as summer, winter, spring, and fall. Major psychosomatic manifestations included in the analysis were depression, anxiety, and migraine. Results: More than 50% of IBS subjects had vitamin D deficiency at a cut-off point of <50 nmol/L (53% vs. 27%, p = 0.001); and >90% of IBS subjects had vitamin D deficiency at a cut-off point of <75 nmol/L (93% vs. 75%, p = 0.006). IBS subjects had significantly lower mean 25(OH)D: 53.2 ± 15.8 nmol/L vs. 65.2 ± 28.0 nmol/L, p = 0.003; and albumin: 6.2 ± 0.6 vs. 6.5 ± 0.6 μmol/L, p = 0.0.01. IBS subjects with migraine had significantly lower mean 25(OH)D concentration compared to controls (p = 0.01). BMI z-score was similar between the controls and IBS subjects (0.5 ± 1.4 vs. 1.2 ± 2.9, p = 0.11). Conclusions: Pediatric patients with IBS had significantly lower 25(OH)D concentration compared to controls despite having similar mean BMI values as controls. Only 7% of the children and adolescents with IBS were vitamin D sufficient, and >50% of the subjects with IBS had vitamin D deficiency. This is a much higher prevalence of vitamin D deficiency compared to IBD and other malabsorption syndromes. Monitoring for vitamin D deficiency should be part of the routine care for patients with IBS. Randomized control trials are warranted to determine the role of adjunctive vitamin D therapy in pediatric IBS.

... • Human studies which reported as (і) Increased urinary excretion of bone resorption markers in parallel with urinary GGT levels in postmenopausal women [6], (іі) Correlation between serum GGT and ferritin levels in the adult population [26], as well as in patients with chronic hepatitis C [27] and DM [28], and (ііі) An inverse association between 25(OH)D and GGT activity [29]. ...

Purpose: To examine serum levels of GGT activity and biomarkers of iron metabolism in relation to parameters of bone and mineral metabolism in elderly patients with and without osteoporotic bone fractures in the absence of overt liver diseases. Methods: In a cross-sectional study of 416 older (>60 years) patients (168 subjects with hip fracture, 89 with other fractures of the peripheral skeleton and 160 without any fracture; mean age 78.9 ± 8.7 years; 282 women) we simultaneously measured serum levels of two bone formation markers (osteocalcin, OC; procollagen type 1 Nterminal propeptide, P1NP), bone resorption marker (β- isomerised carboxy-terminal cross-linking telopeptide of type I collagen, βCTX), their ratios (PINP/OC, PINP/βCTX, OC/βCTX), 25(OH) vitamin D, PTH, calcium, phosphate, magnesium, GGT activity, other liver function tests and indices of iron metabolism (serum ferritin, iron, transferrin and transferrin saturation [TSAT]). Results: Multivariate regression analyses demonstrated significant bidirectional links between P1NP and GGT, P1NP/OC ratio and GGT, P1NP and TSAT, OC and ferritin, GGT and ferritin. GGT, ferritin and TSAT were independent indicators of βCTX, while ferritin and TSAT were also independent predictors of the P1NP/OC ratio, and TSAT was an independent predictor of the P1NP/βCTX ratio. In multivariate regression, P1NP, βCTX, P1NP/βCTX ratio, ferritin, magnesium and age were independent indicators of fracture. Conclusions: The study highlighted the bidirectional links between serum GGT activity, indices of iron and bone metabolism and the role of GGT and iron homeostasis in maintaining bone health and identified indicators for osteoporotic fractures. The GGT- and iron-related factors contributing to bone integrity warrant further investigations.

... Reflecting the in vivo mechanisms of vitamin D production, a number of factors have been associated with levels of circulating 25-OH-D. Low levels of 25-OH-D have been associated to high levels of hepatic function tests [7], renal failure [8], and low daily exposure to ultraviolet B radiation [9]. Body mass index and a number of lifestyle factors such as physical activity level, diet, smoking, and alcohol consumption have also been associated to circulating levels of 25-OH-D [9,10]. ...

Gallstone disease is highly prevalent in the general population and is a major gastrointestinal cause of hospital admissions. The objectives were to determine whether circulating levels of 25-hydroxyvitamin D were associated to ultrasound proven gallstones or cholecystectomy in a general population sample. Determinants of vitamin D status were also explored. A random sample of 4130 people from the population of Copenhagen with ages 41–71 years were invited (N = 4130) and 2650 participants were included. Ultrasound examinations were performed to assess gallstone status and blood samples were drawn to assess 25-hydroxyvitamin D and biomarkers of renal and hepatic function. Gallstone disease was found in 422 participants. Associations were estimated by logistic regression models. Levels of 25-hydroxyvitamin D was not significantly associated with gallstone disease. Time of birth during low vitamin D exposure was associated with gallstone disease (gallstone prevalence 18.0 versus 14.4 %, odds ratio 1.33, 95 % confidence interval [1.07; 1.65]). Highest quartile of cystatin C was significantly associated with gallstone disease (gallstone prevalence 22.1 versus 12.0 %, odds ratio 1.53, 95 % confidence interval [1.08; 2.18]). Serum levels of creatinine and alanine amino transferase were not associated with gallstone disease. Sensitivity analyses excluding participants with cholecystectomy did not alter results significantly. No association between 25-hydroxyvitamin D and gallstone disease was identified. Findings suggest gallstones to be associated to low vitamin D exposure in utero and to renal failure suggesting that vitamin D might have an impact on gallstone disease. Future studies should explore associations for vitamin D and gallstone disease prospectively.

... 43 In addition, individuals with elevated serum ALT had lower calcidiol than those with normal ALT. 44 However, it is debatable whether vitamin D deficiency is the precursor or the consequence of liver diseases. Patients with vitamin D deficiency, measured by serum level of calcitriol, were also shown to have a higher grade of hepatic necroinflammation, more advanced fibrosis stage, and more rapid fibrosis progression. ...

The incidence of non-alcoholic fatty liver disease (NAFLD) is rising rapidly in parallel with obesity rates. The underlying pathogenesis of NAFLD remains an enigma but is largely influenced by individual lifestyle choices involving diet and exercise. Therefore, studies have highlighted the importance of calorie reduction and macronutrient composition (eg, carbohydrate and fat) in modifying disease outcomes. Micronutrients are also believed to play a role in disease progression. There are now an increasing number of studies linking vitamins with NAFLD, particularly vitamin E, and the supplementation of several different vitamins has been demonstrated as a promising therapeutic option in the treatment of NAFLD. This review provides a broad overview of the potential role of vitamins in NAFLD development and disease management.

... This is supported by a study conducted by Skaaby et al. that found a statistically significant inverse association between vitamin D level and incident liver disease. These investigators found that the risk of having a higher plasma level of ALT, AST or GGT (gamma-glutamyl transferase) tended to be increased with lower nutritional vitamin D levels [25,26]. Given the abundance of evidence connecting nutritional vitamin D deficiency to mortality, low vitamin D levels can be a potential mechanism by which elevated AST levels may be linked with increased risk of mortality [27][28][29]. ...

Liver disease is a common comorbid condition in maintenance hemodialysis (MHD) patients and may be associated with poor survival. The relationship between aspartate aminotransferase (AST) and survival has not yet been addressed in these patients. We hypothesized that higher AST level is associated with higher death risk in MHD patients. A 5-year (January 2007-December 2011) cohort of 109 718 MHD patients was studied in the USA in dialysis clinics where AST was measured in at least 50% of all outpatients in the baseline calendar quarter. Survival models were adjusted for demographic variables, and available clinical and laboratory surrogates of malnutrition-inflammation complex, and cubic survival splines were plotted. A linear association existed between baseline serum AST levels and mortality. Increasing AST of >20 IU/L was incrementally and almost linearly associated with higher death risk at all levels of adjustment. In fully adjusted models, AST levels of ≥40 IU/L were associated with the highest risk of mortality (hazard ratio: 1.46, 95% CI: 1.38-1.54). Low AST levels (<15 IU/L) were associated with increased death risk only in fully adjusted models examining hepatitis C virus-positive patients. Higher AST level of >20 IU/L is incrementally associated with higher mortality in MHD patients whereas AST in the 15-20 IU/L range is associated with the greatest survival. These findings suggest that the assessment of liver function and improving liver disease may confer survival benefit to MHD patients. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

... A limited number of studies have examined the effects of Vitamin D supplementation on liver enzymes and severity of steatosis in NAFLD patients. The results of some cross-sectional studies have shown that there is a correlation between serum 25(OH)D and liver enzymes (5,34). In a clinical study, the supplementation with Vitamin D did not significantly change serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and grade of fatty liver (28). ...

... Vitamin D intake is estimated to be 50% lower in NAFLD patients than in non-NAFLD patients, 49 and low vitamin D levels are associated with incident liver disease risk (some of whom develop NAFLD). 99 Levels of vitamin D have been associated inconsistently with NAFLD, NAFLD severity, and insulin resistance, 25,100-105 a condition commonly shared by both obese and NAFLD patients. In addition, several genes involved in vitamin D metabolism have shown no differential regulation in NAFLD patients compared with controls. ...

• Octavia Pickett-Blakely
• Kimberly Young
• Rotonya M Carr

Micronutrients include electrolytes, minerals, vitamins, and carotenoids, and are required in microgram or milligram quantities for cellular metabolism. The liver plays an important role in micronutrient metabolism and this metabolism often is altered in chronic liver diseases. Here, we review how the liver contributes to micronutrient metabolism; how impaired micronutrient metabolism may be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a systemic disorder of energy, glucose, and lipid homeostasis; and how insights gained from micronutrient biology have informed NAFLD therapeutics. Finally, we highlight some of the challenges and opportunities that remain with investigating the contribution of micronutrients to NAFLD pathology and suggest strategies to incorporate our understanding into the care of NAFLD patients.

... How vitamin D status can affect liver function is poorly understood. Skaaby et al., [19] from a general population based study suggested that the risk of having a high level of ALT, AST, or GGT tended to be higher for lower vitamin D levels, although this was not statistically significant. However in another study [20] Vitamin D insufficiency was not associated with the presence of NAFLD as assessed by validated non-invasive prediction models. ...

Context: Biochemical Vitamin D deficiency is said to be present universally in recent times. However, its effect is more profound in modulation of anthropometric and biochemical risk factors of various chronic metabolic disorders rather than its influence on bone mineral abnormalities. The present study was undertaken to compare various anthropometric and biochemical parameters including basic bone mineral biochemistry in various strata of Vitamin D status. Materials and methods: A population based study was done in the rural area of West Bengal comprising 405 people (initially targeted 400) to look for various anthropometric and biochemical parameters. Results: Anthropometric metabolic markers like BMI, WC, waist to height ratio and biochemical parameters like total cholesterol, LDL, TG, insulin, ALT, FPG were statistically significantly higher in vitamin D deficient (<20 ng/ml) (n = 228) subjects compared to Vitamin D non-deficient subjects (≥20 ng/ml) (n = 177) which persisted even after adjustment for BMI except for FPG. The difference was similarly present when severely Vitamin D deficient (<10 ng/ml) (n = 39) subjects were compared to Vitamin D sufficient subjects (≥30 ng/ml) (n = 38) and persisted after adjustment for BMI except for FPG. However, WHR, blood pressure (both systolic and diastolic), HbA1c, HDL, AST, Uric acid, freeT4, TSH, HOMA-IR were not different in both the above-mentioned comparisons. Metabolic syndrome was statistically significantly lower in vitamin D non-deficient subjects. Though iPTH was statistically significantly higher in the low vitamin D cohorts in both the comparisons, bone mineral markers like serum calcium, phosphorus and alkaline phosphatase were not different even when severely vitamin D deficient subjects were compared to vitamin D sufficient subjects. Conclusion: Pandemic of vitamin D deficiency is more likely to be associated with cardio-metabolic risk factors than biochemical bone mineral abnormality.

... In addition, vitamin D deficiency is very common in patients with liver disease. Both cholestatic and non-cholestatic liver disease can lead to vitamin D deficiency [13]. Physical activity and exercise can reduce the fat of liver tissue in patients with non-alcoholic fatty liver, and the prevalence of fatty liver is lower in people with high physical activity [14]. ...

• Seyyed Javad Hashemi Sangatrashani
• Masoumeh Habibian
• Seyyed Jafar Moosavi

Background Deficiency or insufficient level of vitamin D is very common in patients with liver disease, and is closely related to musculoskeletal pains, including low back pain. Objective The current study aims to investigate of the activity of liver enzymes in women with chronic low back pain following core stability exercises and vitamin D intake. Methods This clinical trial was conducted on 48 women (Mean±SD of age=36.59±5.50 years) in 2019 selected by using a convenience sampling method. They were randomly divided into four groups of control, vitamin D, exercise and combined (exercise +vitamin D). The last two exercise groups performed 8 weeks of core stability exercises with different intensities. The vitamin D and combined groups received 50,000 IU/week of vitamin D for 8 weeks. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Alkaline phosphatase (ALP) activities were measured before and after the interventions. Data were analyzed by using paired t-test and one-way ANOVA. Findings Eight weeks of core stability exercises, vitamin D intake, and the combined exercise and vitamin D supplementation caused a significant reduction in the activity of AST, ALT, and ALP enzymes. The combined intervention induced more reduction in the AST and ALP activities compared to other two groups received exercise and supplementation alone, and the decrease in ALT activity following the combined intervention was higher compared to the exercise group. Conclusion It seems that the core stability exercises, vitamin D intake, and combination of exercise and vitamin D supplementation can improve liver function in women with chronic low back pain who have vitamin D deficiency by reducing the activity of liver enzymes. The combined intervention has greater effectiveness in improving liver function.

... Hepatic damages result in increased blood concentration of ALP, ALT, and AST [52]. In the present study, extended period of exposure to FO and/or CT did not influence the serum ALP level. ...

Reproductive attributes, expression of TRAP6 and TGF-β mRNA in the mucosa of the utero-vaginal junction (UVJ) of oviduct, and liver function were evaluated in Chukar partridge (Alectoris chukar) breeders subjected to long-term oral administration of fish oil (FO) and/or calcitriol (CT). A total of forty-eight 1.5-year-old laying Chukar partridges and 16 age-matched males (female:male ratio of 3:1) were randomly allocated to four groups (4 replicates of 3 female birds and one male bird each). Breeder females in groups 1, 2, and 3 were orally administered daily with 0.2 mL/500 g body weight FO, 0.2 mL solution containing 10 μg CT, or their combination (FO + CT) for 42 successive days, respectively. Pure crystalline calcitriol was dissolved in ethanol (30%) prior to administration. The control group (CON), received a similar volume of a 30% solution of ethanol only. Eggs were collected and incubated to evaluate the reproductive performance. Blood samples were taken on days 0, 21, and 42 of the trial for the quantification of serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). On day 43, one bird per replicate was killed by cervical dislocation to assess the expression of TRAP6 and TGF-β genes in the UVJ mucosa. Administration of CT or FO + CT increased the egg production rate, fertility rate, and hatchability rate of the set eggs. Fertility duration and sperm penetration rate were higher in partridges receiving FO and (or) CT, but chick quality, and embryonic mortality were not affected by the treatment effect. Administration of CT or FO + CT decreased the serum ALT and AST levels. Administration of FO or CT was associated with a lower expression of TGF-β mRNA in the UVJ mucosa. Oral administration of FO resulted in a reduction in the expression of TRAP6 in the UVJ mucosa. However, the birds fed CT or FO + CT recorded a higher mRNA expression for TRAP6. Although the reproductive performance and TRAP6 expression were higher following the feeding of FO or FO + CT, expression of TGF-β was decreased, suggesting plausibly that TGF-β may not have a determinant effect on the reproductive attributes in female Chukar partridges. Further studies are required to understand the mechanisms underlying the effects of TRAP6 and TGF-β on other reproductive criteria in partridges.

... Several inflammatory cytokines, such as interleukin (IL)-6, tumor necrosis factor alpha (TNF-α) and IL-1β, and adipokines, such as adiponectin and leptin, may participate in these reactions [19,20]. Because NAFLD and vitamin D deficiency engender similar risks for cardiovascular disease, insulin resistance and MS in epidemiologic studies, there have been many reports debating a potential association between NAFLD and vitamin D deficiency [19][20][21][22][23]. However, most studies have lacked information on serum cytokines or adipokines and had small sample sizes. ...

• Li-Wei Chen
• Cheng-Hung Chien
• Sheng-Fong Kuo
• Rong-Nan Chien

Background: This study aimed to evaluate the association between serum vitamin D levels and nonalcoholic fatty liver disease (NAFLD) parameters, such as metabolic syndrome (MS), inflammatory cytokines (tumor necrosis factor, high sensitive C-reactive protein) and adipokines (adiponectin, leptin). Methods: From August 2013 to August 2016, a community-based study was performed in the north-eastern region of Taiwan. All subjects received a demographic survey, blood testing and abdominal ultrasonography (US). The vitamin D level was evaluated by quartile divide or used the classification of deficiency (< 20 ng/ml), insufficiency (20-30 ng/ml) and sufficiency (> 30 ng/ml). Results: Subjects were divided into NAFLD group and normal control (subjects number = 564 in each group) following abdominal US study and matching age and gender. The mean age was 57.1 years in NAFLD group and 57.5 in control group. Subjects in NAFLD group had a lower mean vitamin D than those in the control group (28.5 ± 9.5 ng/ml vs. 29.9 ± 10.2 ng/ml, P = 0.018). Subjects with serum vitamin D deficiency or insufficiency had higher odds for MS than those with sufficient vitamin D levels [deficiency vs. sufficiency, adjusted odds ratio (aOR) =1.860 (95% CI = 1.234-2.804), P = 0.003; insufficiency vs. sufficiency, aOR = 1.669 (95% CI = 1.237-2.251), P = 0.001]. Similarly, subjects in the lowest quartile of vitamin D had higher odds for MS than those in the highest quartile of vitamin D (aOR = 2.792, 95% CI = 1.719-4.538, P < 0.001). Vitamin D level was positively correlated with age and male, but negatively correlated with serum leptin level. Conclusion: Subjects with low vitamin D level had higher odds for MS, but higher levels of leptin, compared to those with high vitamin D levels.

... liver can increase liver enzymes such as ALT and AST 50 . It has been shown that the reduced levels of 25-OHD3 can increase the likelihood of raising ALT and AST levels in β-thalassemia patients 51 . In a study, the elevated levels of ALT (> 50 IU/L) were significantly connected to Vit-D insufficiency in patients with β-thalassemia (OR 9.7, 95% CI 4.0-23.5; ...

Numerous problematic disorders such as vitamin D (Vit-D) deficiency subsequent to large iron loading can be developed in patients with β-thalassemia. The study aimed to estimate Vit-D insufficiency and its risk factors in patients with β-thalassemia. In this multicenter and observational study, all β-thalassemia patients, who referred to 14 hospital-based thalassemia divisions or clinics in Mazandaran province, Iran were included in the study. The data belong to December 2015 until December 2019. The study population was made of transfusion dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) patients. Serum levels of 25-OHD3 have been measured by high performance liquid chromatography (HPLC) method as ng/mL. Demographic and clinical information along with some biological tests, as well as the results of T2*-weighted magnetic resonance imaging were analyzed. Of 1959 registered patients, 487 (24.9%) patients had Vit-D-related data. The prevalence of Vit-D insufficiency (< 30 ng/mL) was 41.9, 95% CI 37.5–46.3. The adjusted risks of moderate to severe liver siderosis and raised AST (aspartate aminotransferase) for Vit-D insufficiency (< 30 ng/mL) were 2.31, 95% CI 1.38–3.89 and 2.62, 95% CI 1.43–4.79, respectively. The receiver operating characteristic (ROC) curve analysis showed that the predictive accuracy of ferritin for Vit-D insufficiency status was 0.61, 95% CI 0.54–0.68 with a cutoff point of 1,078 ng/mL (P = 0.03, sensitivity 67%, specificity 49%, positive predictive value [PPV] 47% and negative predictive value [NPV] 68%). In spite of the national programs for treating Vit-D deficiency and our previous efforts for giving supplements to all patients, Vit-D insufficiency/deficiency is still common in our patients. Also, moderate to severe liver siderosis and raised AST were the independent risk factors for the Vit-D insufficiency.

... The risk of having a high level of LFT tended to be higher for lower the vitamin D with not significantly. Vitamin D deficiency is frequently present in chronic liver disease and may predict non-response to antiviral therapy in chronic hepatitis C [9][10]. ...

Background: Vitamin D deficiency is related to substandard health. The frequency of vitamin D deficiency may be rising, however populace based patterns are uncertain.

... In this study, there were statistically significant differences between both normal and different degrees of depression regarding serum level of 25-OH-vitamin D as it decreased with increasing severity of depression; also, there was a statistically significant negative correlation between 25-OH-vitamin D and ALT, AST, FI, HAI and depression score. These findings are supported by Skaaby et al. [25] who reported a statistically significant inverse association between vitamin D status and incident liver disease with a hazard ratio = 0.88 (95% confidence interval 0.79-0.99) per 10 nmol/L higher vitamin D status at baseline. ...

• Ola Galal
• Al Rawhaa A. Abo Amer
• Amira Ibrahim Mansour
• Karim I. Mohamed

Background Deficiency of vitamin D and depression are commonly occurring in patients with chronic liver diseases. This study aimed to determine the association between 25-OH-vitamin D status and depressive symptoms among children with chronic liver diseases. Eighty children were enrolled and divided into 2 groups: the patients' group (60 children with chronic hepatitis) and the control group (20 healthy children). All children have been analyzed for their clinical, biochemical features, histological profile, serum 25-OH-vitamin D levels, and assessment of childhood depression using Arabic form based on Kovacs Children's Depression Inventory. Results Serum level of 25(OH) D was significantly lower in the hepatic group than the control group [17 (5–52) ng/ml, 45 (13–95) ng/ml, p = <0001 respectively]. Depression score was significantly higher in the hepatic group as 30% of the control group had mild depression, while 36.7% of the hepatic group had mild depression, 16.7% had moderate depression, and 10% had severe depression. There was a statistically significant difference between children with depressive symptoms and non-depressive symptoms as regards the level of serum vitamin D as it was lower in children with depressive symptoms [median (range) 17 (5–40) ng/ml, 27.5 (8–52) ng/ml, p = 0.04 respectively]. There were statistically significant differences between the serum level of 25(OH) D and depression as it decreases with increasing severity of depression. Conclusion Children with chronic liver disease who had depressive symptoms showed significantly lower levels of vitamin D when compared with those without depressive symptoms; also, vitamin D had an inverse correlation with depression scores in these children.

... Serum samples were collected at each examination round. GDF15, CRP, cystatin C, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), and highsensitivity cardiac troponin I (hs-cTnI) levels were measured on the Abbott ARCHITECT platform (Abbot Laboratories, Abbott Park, Illinois, USA) in the MORGAM/BiomarCaRE laboratory (Hamburg, Germany) as previously described [43,51,52]. Over half (61.2%) of the ALT measurements were below the lower limit of detection (6 U/L), and therefore, ALT was not included in the analyses. ...

Growth differentiation 15 (GDF15) is a potential novel biomarker of biological aging. To separate the effects of chronological age and birth cohort from biological age, longitudinal studies investigating the associations of GDF15 levels with adverse health outcomes are needed. We investigated changes in GDF15 levels over 10 years in an age-stratified sample of the general population and their relation to the risk of acute hospitalization and death. Serum levels of GDF15 were measured three times in 5-year intervals in 2176 participants aged 30, 40, 50, or 60 years from the Danish population-based DAN-MONICA cohort. We assessed the association of single and repeated GDF15 measurements with the risk of non-traumatic acute hospitalizations. We tested whether changes in GDF15 levels over 10 years differed according to the frequency of hospitalizations within 2 years or survival within 20 years, after the last GDF15 measurement. The change in GDF15 levels over time was dependent on age and sex. Higher GDF15 levels and a greater increase in GDF15 levels were associated with an increased risk of acute hospitalization in adjusted Cox regression analyses. Participants with more frequent admissions within 2 years, and those who died within 20 years, after the last GDF15 measurement already had elevated GDF15 levels at baseline and experienced greater increases in GDF15 levels during the study. The change in GDF15 levels was associated with changes in C-reactive protein and biomarkers of kidney, liver, and cardiac function. Monitoring of GDF15 starting in middle-aged could be valuable for the prediction of adverse health outcomes.

... Vitamin D deficiency is also prevalent among chronic liver and kidney disease patients (14)(15)(16)(17) . It is not clearly defined whether the reduced liver function contributes to vitamin D deficiency or if vitamin D deficiency leads to liver dysfunction; however, previous studies found an inverse association between the 25(OH)D levels and the incidence of liver disease and liver enzymes (18,19) . ...

The objective of this study was to evaluate the effect of vitamin D 3 on total homocysteine (tHcy) and C-reactive protein (CRP) levels and liver and kidney function tests in overweight women with vitamin D deficiency. Therefore, a randomized double-blind placebo controlled clinical trial was conducted on one hundred eligible women. Subjects were randomly divided into two groups: the placebo ( n = 50) and the vitamin D ( n = 50) which received 50,000 IU vitamin D 3 per week for 2 months. The participants' 25- hydroxyvitamin D (25 (OH)D), tHcy, CRP, aspartate and alanine aminotransferases (AST, ALT), urea, creatinine and estimated glomerular filtration rate (eGFR) were measured and compared before and after treatment. Results showed that the tHcy, CRP, AST, ALT, and eGFR levels after the second month of vitamin D 3 intervention were significantly ( p < 0.001) decreased and the 25(OH)D, urea, and creatinine levels were significantly ( p < 0.001) increased in the treatment group. In the placebo group, no significant changes were identified throughout the follow up period. In conclusion, vitamin D 3 intervention with a treatment dose of 50,000 IU per week for at least 2 months may help in lowering homocysteine and CRP levels and may improve liver function tests, which in turn might help in minimizing the risk of CVD and liver diseases among overweight women but negatively affect kidney function.

... 12 A population-based study on 2,649 individuals carried out by Skaaby et al showed that low serum vitamin D was associated with a higher risk of both fatal and non-fatal liver diseases with a hazard ratio of 0.88 (95% confidence interval, 0.79-0.99). 13 In another cross-sectional study involving 6,055 health check-up subjects, low serum vitamin D status was associated with higher severity of NAFLD. 14 However, considering our review of the literature, evaluating the therapeutic role of vitamin D in the health of liver abnormalities is a neglected factor. ...

The current study aimed to investigate the effects of vitamin D administration on the markers of inflammation and metabolic damages in the liver of high-fat diet-induced obese rats. Forty male Wistar rats were divided into two groups of control receiving a normal diet (ND) and intervention receiving a high-fat diet (HFD). After 16 weeks, each group was divided into two groups including ND, ND + vitamin D, HFD, and HFD + vitamin D. Vitamin D was administered by oral gavage for five weeks at the dose of 500 IU/kg. Hepatic MCP-1, TGF-β, and NF-κB levels, serum liver enzymes, and serum lipids, and histological and structural changes in the liver were determined. Vitamin D administration significantly reduced the monocyte chemoattractant protein (MCP)-1 concentrations in the HFD + vitamin D group compared with the HFD group and reduced liver Transforming growth factor beta (TGF-β) levels in both vitamin D-treated groups (p<0.05). Moreover, a significant reduction in the serum levels of aspartate amino transferase (AST) and alanine amino transferase (ALT) in vitamin D treated groups was identified (p<0.05). A significant improvement in lipids and a pronounced improvement in the markers of liver histology damage including fat accumulation, aggregation of inflammatory cells, pre-apoptotic changes, hepatic sinusoidal dilatation, and necrotic pyknosis in the Kupffer cells were also identified. Our results demonstrated that vitamin D has potential effects in ameliorating the inflammatory, metabolic, and histologic changes in the liver of these animals.

... Probably the most difficult is to explain the positive association of vitamin D with the level of adiposity, triglycerides, and liver enzymes indicative of fatty liver disease, and the negative association with HDL-cholesterol. Most literature data contrast with these findings and show the negative association with the level of adiposity (3), blood lipids (80,81), and liver enzymes (82), even though there are also some conflicting findings (1)(2)(3)(4)83). ...

The status of vitamin D in underground working coal miners and its association with their cardiometabolic health is rarely studied. This study aimed to examine vitamin D (VitD) status in Serbian underground coal miners and to correlate it with anthropometric and laboratory indicators of cardiometabolic risk. Nutritional data (food frequency questionnaire, FFQ, and two times repeated 24 h recall), anthropometric data (including segmental analysis by bio-impedance analyzer TANITA BC-545N), arterial tension, and biochemical and hematological data of 103 coal miners (aged 22–63 years) were correlated with their late summer (early September) serum 25 (OH)D levels (measured by HPLC). 68.9% of the studied coal miners were overweight/obese, and 48.5% had metabolic syndrome. Their mean VitD nutritional intakes were low: 5.3 ± 3.8 μg/day (FFQ) and 4.9 ± 8 μg/day (24 h recalls), but their mean serum 25 (OH)D levels were surprisingly high (143.7 ± 41.4 nmol/L). Only 2.9% of the coal miners had 25(OH)D levels lower than 75 nmol/L (indicating an insufficient/deficient status), while 63.2% had values above 125 nmol/L (upper optimal limit), and even 10.7% had values above 200 nmol/L. There were no statistical differences in 25 (OH)D levels in the coal miners with or without metabolic syndrome (or overweight/obesity). Interestingly, 25(OH)D levels had significant positive correlations with body mass index (BMI), fat mass (FM), fat mass percentage (FM%), limbs FM%, serum triglycerides, GGT, AST, ALT, and ALT/AST ratio, and had significant negative correlations with serum HDL-cholesterol and age. All these correlations were lost after corrections for age, FM, FM%, and legs FM%. In Serbian coal miners, high levels of early September VitD levels were observed, indicating sufficient non-working-hour sun exposure during the summer period. Furthermore, the unexpected positive correlations of VitD levels with anthropometric and biochemical parameters indicative of obesity, metabolic syndrome, and fatty liver disease were found. More research is needed on the VitD status of coal miners (particularly in the winter period) and its relationship with their cardiometabolic status.

• Shira Zelber-Sagi
• Dana Ivancovsky-Wajcman
• Liane Rabinowich
• Liat Deutsch

Malnutrition and sarcopenia that lead to functional deterioration, frailty, and increased risk for complications and mortality are common in cirrhosis. Sarcopenic obesity, which is associated with worse outcomes than either condition alone, may be overlooked. Lifestyle intervention aiming for moderate weight reduction can be offered to obese compensated cirrhotic patients, with diet consisting of reduced caloric intake, achieved by reduction of carbohydrate and fat intake, while maintaining high protein intake. Dietary and moderate exercise interventions in patients with cirrhosis are beneficial. Cirrhotic patients with malnutrition should have nutritional counseling, and all patients should be encouraged to avoid a sedentary lifestyle.

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the beneficial and harmful effects of vitamin D supplementation in people with chronic liver diseases.

Vitamin D deficiency is common among children and adolescents and can be affected by several factors such as puberty and obesity. The aim of this study was to evaluate vitamin D status in children and adolescents and to analyse the influence of puberty and obesity on its level. Method: A cross-sectional study was carried-out, in which clinical and biochemical data were gathered from 384 healthy children and adolescents between May 2019 to May 2020. Results: 220 females and 164 males were enrolled (aged 7-16 years; mean ± SD: 11 ± 2.5). Vitamin D deficiency was found in 49% of the total cases and was significantly more prevalent in females than males (33.1% in female; 15.9% in male, P < .001). Mean vitamin D level was lower in obese children compared with non-obese (P < .001). Non-obese group had significantly higher levels of vitamin D in Tanner stage IV of puberty than obese individuals (20.1 ± 17.0 vs 5.4 ± 2.0) (P = .03). Vitamin D levels were significantly lower in females than males only in Tanner stage II (12.3 ± 9.0 vs 19.6 ± 16.6) (P = .005). The lowest level of Vitamin D was in Tanner stage Ⅳ-Ⅴ in boys and in Tanner stage Ⅱ-Ⅲ in girls (P < .001). Conclusion: Puberty is an additional risk factor for vitamin D deficiency especially in girls and obese children. This increased risk, together with the fact that most important time for building a proper skeleton is during childhood and adolescent, makes it essential to monitor vitamin D in these age groups.

• Elaine A. Shehata
• Rehan Qayyum

Background: Several studies have examined the relationship between vitamin D (VD) and liver disease but none have explored this relationship in adults with normal liver enzymes. Our aim was to explore an independent association of VD with alanine aminotransferase (ALT) in a large sample of the US adults with liver enzymes in normal range (≤39 U/L). Methods: We used the continuous National Health and Nutrition Examination Survey from 2001 to 2006. We excluded individuals with serum ALT>39 U/L. We built linear regression models to estimate unadjusted and adjusted (age, sex, race, diabetes, hypertension, alcohol use, smoking, and body mass index) effect sizes, taking into account the complex probability survey design. Results: Of the 12,155 participants, 6635 (54.6%) were women, mean±SD age was 49.9±19.4 years, VD was 21.9±9.2 ng/mL, and ALT was 20.9±6.9 U/L. In unadjusted analysis, VD was significantly associated with serum ALT (0.02 U/L/ng/mL of VD, P=0.007). After adjustment for confounders, VD remained statistically significantly associated with serum ALT levels (0.04 U/L, P<0.001). Similarly, individuals in the highest quartile of VD had significantly higher serum levels of ALT than those in the lowest quartile (unadjusted difference=0.98 U/L, P<0.001; adjusted difference=1.21 U/L, P<0.001). Conclusions: We found a positive association between VD and ALT after excluding individuals with suspected active liver injury (ALT>39 U/L). The underlying mechanisms for this association are not known and needs further study.

• Leila Baniadam

Background Vitamin D deficiency is common among children and adolescents and can be affected by several factors such as puberty and obesity. Objective The aim of this study was to evaluate vitamin D status in children and adolescents and to analyse the influence of puberty and obesity on its level. Method A cross-sectional study was carried-out, in which clinical and biochemical data were gathered from 384 healthy children and adolescents between May 2019 to May 2020. Results 220 females and 164 males were enrolled (aged 7-16 years; mean ± SD: 11 ± 2.5). Vitamin D deficiency was found in 49% of the total cases and was significantly more prevalent in females than males (33.1% in female; 15.9% in male, P < .001). Mean vitamin D level was lower in obese children compared with non-obese ( P < .001). Non-obese group had significantly higher levels of vitamin D in Tanner stage IV of puberty than obese individuals (20.1 ± 17.0 vs 5.4 ± 2.0) ( P = .03). Vitamin D levels were significantly lower in females than males only in Tanner stage II (12.3 ± 9.0 vs 19.6 ± 16.6) ( P = .005). The lowest level of Vitamin D was in Tanner stage Ⅳ-Ⅴ in boys and in Tanner stage Ⅱ-Ⅲ in girls ( P < .001). Conclusion Puberty is an additional risk factor for vitamin D deficiency especially in girls and obese children. This increased risk, together with the fact that most important time for building a proper skeleton is during childhood and adolescent, makes it essential to monitor vitamin D in these age groups.

• Ke-Ping JIAO
• Shao-Min LI
• Wen-Yan LV
• Hai-Yan HE

Vitamin D3 has been reported to be an immunity modulator and high levels of vitamin D3 are correlated with a decreased risk for developing diseases in the central nervous system. Astrocytes are important immune cells and contribute toward inflammation during neurological diseases. The vitamin D receptor has been reported to be expressed in astrocytes; however, the effect of vitamin D3 on astrocyte activation has not been studied. Here, we found that lipopolysaccharide stimulation in astrocytes could enhance the expression of vitamin D receptor and Cyp27B1, which encodes the enzyme for converting vitamin D3 into its active form. Vitamin D3 suppressed the expression of proinflammatory cytokines tumour necrosis factor-α, interleukin-1β, vascular endothelial growth factor, and also TLR4 in activated astrocytes. Astrocyte activation was further found to be suppressed after the administration of vitamin D3 in neonatal rats injected with lipopolysaccharide in vivo. We demonstrated the antiactivation effect of vitamin D3 in astrocytes after lipopolysaccharide stimulation. Considering the function of reactive astrocytes in augmenting inflammatory response in neurodegeneration and brain injury, the finding that vitamin D3 administration may inhibit astrocyte activation may be potentially useful for the treatment of central nervous system disorders.

Background & Aims Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed disease category that derived from non-alcoholic fatty liver disease. The impact of MAFLD on health events has not been investigated. Methods UK Biobank participants were diagnosed for whether MAFLD presented at baseline. Five genetic variants (PNPLA3 rs738409 C/G, TM6SF2 rs58542926 C/T, GCKR rs1260326 T/C, MBOAT7 rs641738 C/T, and HSD17B13 rs72613567 T/TA) were integrated into a genetic risk score (GRS). Cox proportional hazard model was used to examine the association of MAFLD with incident diseases. Results A total of 160 979 (38.0%, 95% confidence interval [CI] 37.9%, 38.2%) participants out of 423 252 were diagnosed as MAFLD. Compared with participants without MAFLD, MAFLD cases had multivariate adjusted hazard ratio (HR) for liver cancer of 1.59 (95% CI 1.28, 1.98), cirrhosis of 2.77 (2.29, 3.36), other liver diseases of 2.09 (1.95, 2.24), cardiovascular diseases of 1.39 (1.34, 1.44), renal diseases of 1.56 (1.48, 1.65), and cancers of 1.07 (1.05, 1.10). The impact of MAFLD, especially on hepatic events, was amplified by high GRS, of which the genetic variations in PNPLA3, TM6SF2, and MBOAT7 play the principal roles. MAFLD case with normal body weight is also associated with an increased risk of hepatic outcomes, but the genetic factor seems do not influence the risk in this subpopulation. Conclusions MAFLD is independently associated with an increased risk of both intrahepatic and extrahepatic events. Fatty liver disease related genetic variants amplify the effect of MAFLD on disease outcomes.

Background: Vitamin D deficiency is often reported in people with chronic liver diseases. Therefore, improving vitamin D status could have a beneficial effect on people with chronic liver diseases. Objectives: To assess the beneficial and harmful effects of vitamin D supplementation in people with chronic liver diseases. Search methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science. We also searched databases of ongoing trials and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and asked experts and pharmaceutical companies for additional trials. All searches were up to January 2017. Selection criteria: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). Data collection and analysis: We used standard methodological procedures expected by The Cochrane Collaboration. We contacted authors of the trials to ask for missing information. We conducted random-effects and fixed-effect meta-analyses. For dichotomous outcomes, we calculated risk ratios (RRs), and for continuous outcomes, we calculated mean differences (MD), both with 95% confidence intervals (CI) and Trial Sequential Analyses-adjusted CIs. We calculated Peto odds ratio (OR) for rare events. We considered risk of bias in domains to assess the risk of systematic errors. We conducted Trial Sequential Analyses to control the risk of random errors. We assessed the quality of the evidence with GRADE. Main results: We included 15 randomised clinical trials with 1034 participants randomised. All trials had a parallel group design. Nine trials were conducted in high-income countries and six trials in middle-income countries. All trials were at high risk of bias. Six trials included participants with chronic hepatitis C, four trials included participants with liver cirrhosis, four trials included participants with non-alcoholic fatty liver disease, and one trial included liver transplant recipients. All included trials reported the baseline vitamin D status of participants. Participants in six trials had baseline 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), while participants in the remaining nine trials were vitamin D insufficient (less than 20 ng/mL). All trials administered vitamin D orally. Mean duration of vitamin D supplementation was 0.5 years and follow-up was 0.6 years. Eleven trials (831 participants; 40% women; mean age 52 years) tested vitamin D3, one trial (18 men; mean age 61 years) with three intervention groups tested vitamin D2 and 25-dihydroxyvitamin D in separate groups, and three trials (185 participants; 55% women; mean age 55 years) tested 1,25-dihydroxyvitamin D. Seven trials used placebo, and eight trials used no intervention in the control group.The effect of vitamin D on all-cause mortality at the end of follow-up is uncertain because the results were imprecise (Peto OR 0.70, 95% CI 0.09 to 5.38; I(2) = 32%; 15 trials; 1034 participants; very low quality evidence). Trial Sequential Analysis on all-cause mortality was performed based on a mortality rate in the control group of 10%, a relative risk reduction of 28% in the experimental intervention group, a type I error of 2.5%, and type II error of 10% (90% power). There was no diversity. The required information size was 6396 participants. The cumulative Z-curve did not cross the trial sequential monitoring boundary for benefit or harm after the 15th trial, and the Trial Sequential Analyses-adjusted CI was 0.00 to 2534.The effect of vitamin D on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) and on serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants), myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants), and thyroiditis (RR 0.33 95% CI 0.01 to 7.91; 1 trial; 68 participants) is uncertain because the results were imprecise. The evidence on all these outcomes is of very low quality. The effect of vitamin D3 on non-serious adverse events such as glossitis (RR 3.70, 95% CI 0.16 to 87.6; 1 trial; 65 participants; very low quality of evidence) is uncertain because the result was imprecise.Due to few data, we did not conduct Trial Sequential Analysis on liver-related mortality, and serious and non-serious adverse events.We found no data on liver-related morbidity and health-related quality of life in the randomised trials included in this review. Authors' conclusions: We are uncertain as to whether vitamin D supplements in the form of vitamin D3, vitamin D2, 1,25-dihydroxyvitamin D, or 25-dihydroxyvitamin D have important effect on all-cause mortality, liver-related mortality, or on serious or non-serious adverse events because the results were imprecise. There is no evidence on the effect of vitamin D supplementation on liver-related morbidity and health-related quality of life. Our conclusions are based on few trials with an insufficient number of participants and on lack of data on clinically important outcomes. In addition, the analysed trials are at high risk of bias with significant intertrial heterogeneity. The overall quality of evidence is very low.

Observational studies have suggested a possible protective role of vitamin D on the cardiovascular system. The available evidence does not support either cardiovascular benefits or harms of vitamin D supplementation. This chapter provides an overview and discussion of the current knowledge of vitamin D effects from a cardiovascular health perspective. It focuses on vitamin D in relation to cardiovascular disease, i.e. ischemic heart disease, and stroke; the traditional cardiovascular risk factors hypertension, abnormal blood lipids, obesity; and the emerging risk factors hyperparathyroidism, microalbuminuria, chronic obstructive pulmonary diseases, and non-alcoholic fatty liver disease. Meta-analyses of observational studies have largely found vitamin D levels to be inversely associated with cardiovascular risk and disease. However, Mendelian randomization studies and randomized, controlled trials (RCTs) have not been able to consistently replicate the observational findings. Several RCTs are ongoing, and the results from these are needed to clarify whether vitamin D deficiency is a causal and reversible factor to prevent cardiovascular disease.

Background: Nonalcoholic fatty liver disease (NAFLD) presents high incidence throughout the world and has been progressively increasing in prevalence. This disease has a heterogeneous natural history, including simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis. The factors that determine its evolution to more severe forms of the disease are still poorly understood, and micronutrients with antioxidant potential may be involved in the pathophysiology of the disease. Aim: To evaluate the relationship between serum levels of micronutrients and the severity of NAFLD. Methods: A retrospective, observational and cross-sectional study was conducted. This study included all patients undergoing bariatric surgery who experienced liver biopsy during the procedure, and had serum levels of micronutrients (vitamin D, vitamin B12, zinc, iron, and magnesium), which was assessed in a preoperative evaluation conducted at a reference center in southern Brazil. Results: A total of 614 patients were analyzed, of which 93% had steatosis, 70.7% had NASH, and 49.3% had some degree of fibrosis. Serum levels of vitamin D were negatively correlated with the severity of steatosis and NASH, and serum levels of vitamin B12 were positively correlated with the severity of steatosis and fibrosis. The other micronutrients showed no association with NAFLD staging. Conclusion: Serum levels of vitamin D are inversely related to the severity of steatosis and NASH, and serum levels of vitamin B12 are higher in more advanced stages of simple steatosis and liver fibrosis. Serum levels of zinc, iron, and magnesium were not associated with NAFLD severity.

The objective of this work is to assess the nutritional status of HIV-positive patients and to correlate it to the response to treatment and to certain parameters such as age, gender, socio-economic level, etc. to validate the various tools for assessing the nutritional status of the HIV-positive population. This prospective observational study was extended over a 6-month period and included 220 HIV-positive patients. The nutritional status of each patient was evaluated according to the following tools: exploitation sheet, anthropometric analysis, food survey and calculation of dietary intake, nutritional risk index and nutritional risk stratification. The sex ratio was 52.78, where 144 (65.46%) were women, the average age was 41.60 ± 11.05 years. The evaluation of energy intake showed that 82% of patients had a deficiency in intake relative to nutritional needs. The study population presented vitamin, mineral and micronutrient deficiencies. According to the nutritional risk stratification table we designed, 53% of patients were in grade 7 and 2% were in grade 12. Undernutrition among HIV-positive people was prevalent in the study population, which had a negative impact on the health status and well-being of patients. Correcting undernutrition states would correct anthropometric parameters and biological markers, thus reducing and/or stabilizing viral load and improving CD-ratio.The trial registration number (TRN) is 354 on February 23, 2017.

Background: Vitamin D deficiency is often reported in people with chronic liver diseases. Improving vitamin D status could therefore be beneficial for people with chronic liver diseases. Objectives: To assess the beneficial and harmful effects of vitamin D supplementation in adults with chronic liver diseases. Search methods: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We also searched ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. We scanned bibliographies of relevant publications and enquired experts and pharmaceutical companies as to additional trials. All searches were up to November 2020. Selection criteria: Randomised clinical trials that compared vitamin D at any dose, duration, and route of administration versus placebo or no intervention in adults with chronic liver diseases. Vitamin D could have been administered as supplemental vitamin D (vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol)), or an active form of vitamin D (1α-hydroxyvitamin D (alfacalcidol), 25-hydroxyvitamin D (calcidiol), or 1,25-dihydroxyvitamin D (calcitriol)). Data collection and analysis: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of evidence. Main results: We included 27 randomised clinical trials with 1979 adult participants. This review update added 12 trials with 945 participants. We assessed all trials as at high risk of bias. All trials had a parallel-group design. Eleven trials were conducted in high-income countries and 16 trials in middle-income countries. Ten trials included participants with chronic hepatitis C, five trials participants with liver cirrhosis, 11 trials participants with non-alcoholic fatty liver disease, and one trial liver transplant recipients. All of the included trials reported the baseline vitamin D status of participants. Participants in nine trials had baseline serum 25-hydroxyvitamin D levels at or above vitamin D adequacy (20 ng/mL), whilst participants in the remaining 18 trials were vitamin D insufficient (less than 20 ng/mL). Twenty-four trials administered vitamin D orally, two trials intramuscularly, and one trial intramuscularly and orally. In all 27 trials, the mean duration of vitamin D supplementation was 6 months, and the mean follow-up of participants from randomisation was 7 months. Twenty trials (1592 participants; 44% women; mean age 48 years) tested vitamin D3 (cholecalciferol); three trials (156 participants; 28% women; mean age 54 years) tested vitamin D2; four trials (291 participants; 60% women; mean age 52 years) tested 1,25-dihydroxyvitamin D; and one trial (18 participants; 0% women; mean age 52 years) tested 25-hydroxyvitamin D. One trial did not report the form of vitamin D. Twelve trials used a placebo, whilst the other 15 trials used no intervention in the control group. Fourteen trials appeared to be free of vested interest. Eleven trials did not provide any information on clinical trial support or sponsorship. Two trials were funded by industry. We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on all-cause mortality (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.51 to 1.45; 27 trials; 1979 participants). The mean follow-up was 7 months (range 1 to 18 months). We are very uncertain regarding the effect of vitamin D versus placebo or no intervention on liver-related mortality (RR 1.62, 95% CI 0.08 to 34.66; 1 trial; 18 participants) (follow-up: 12 months); serious adverse events such as hypercalcaemia (RR 5.00, 95% CI 0.25 to 100.8; 1 trial; 76 participants); myocardial infarction (RR 0.75, 95% CI 0.08 to 6.81; 2 trials; 86 participants); thyroiditis (RR 0.33, 95% CI 0.01 to 7.91; 1 trial; 68 participants); circular haemorrhoidal prolapse (RR 3.00, 95% CI 0.14 to 65.9; 1 trial; 20 participants); bronchopneumonia (RR 0.33, 95% CI 0.02 to 7.32; 1 trial 20 participants); and non-serious adverse events. The certainty of evidence for all outcomes is very low. We found no data on liver-related morbidity such as gastrointestinal bleeding, hepatic encephalopathy, hepatorenal syndrome, ascites, or liver cancer. There were also no data on health-related quality of life. The evidence is also very uncertain regarding the effect of vitamin D versus placebo or no intervention on rapid, early, and sustained virological response in people with chronic hepatitis C. Authors' conclusions: Given the high risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, vitamin D supplementation versus placebo or no intervention may increase or reduce all-cause mortality, liver-related mortality, serious adverse events, or non-serious adverse events in adults with chronic liver diseases. There is a lack of data on liver-related morbidity and health-related quality of life. Further evidence on clinically important outcomes analysed in this review is needed.

This study was carried out to evaluate the level of vitamin D3 with liver and kidney function between the students of the Education of Education-University of Samarra. The 90 samples were collected (52 male and 38 female) aged between (20-30) years in (12.1.2018-12.2.2018). This study concluded the measurement of (Vitamin D3, Urea, Uric acid, Creatinine, AST and ALT). Each parameters has been classified according to vitamin D3 status into two groups ‫لــض‬o groupsto vitamin D3 (PTH , Vit.ed between (2030-) years in 2018-12/1/ ‫خ‬ ‫فــي‬ /2018. The first group G1 refers to samples that have a sufficient level of vitamin D3, and the second group G2 refers to samples that have a deficient level of vitamin. Results showed the following: A high significant decrease of Vitamin D3 among deficient subjects (P≤0.05) compared with the sufficient subjects. The prevalence of vitamin D3 deficiency was higher in females than males and among rural subjects rather than urbans. There was a significant increase in ALT enzyme among G2 samples compared to G, while no significant difference was observed in ALT level as compared with G1 and G2. No significant differences in Creatinine, Urea, and Uric acid were noted between two groups.

• Ruairidh Nicoll
• Konstantinos Gerasimidis
• Ewan Forrest

Aims Chronic alcohol consumption may result in liver injury and chronic liver disease, but other factors are likely to influence disease progression. Malnutrition, specifically micronutrient deficiency, is frequently associated with both alcohol use disorder and chronic liver disease. We hypothesize that micronutrient deficiencies may affect the progression of liver disease in this population. Methods Systematic integrative review of the medical literature; electronic search of MEDLINE 1950–2021; studies investigating role of any micronutrient in the acceleration of alcohol-related liver injury in humans or animals. Studies which specifically related to alcoholic hepatitis were excluded. Outcomes were extracted and recorded in tabulated form and discussed narratively. Results We identified 46 studies investigating the role of micronutrient deficiencies in the pathogenesis of alcohol-related liver disease. Specific micronutrients which were identified included folic acid or related B vitamins (n = 9 studies), Vitamin D (n = 9 studies), magnesium (n = 8 studies), zinc (n = 8 studies) and selenium (n = 12 including one systematic review). Observational evidence suggests a potential role of magnesium deficiency in accelerating alcohol-related liver injury with weak or negative evidence for other micronutrients. Conclusions Magnesium deficiency may increase the risk of alcohol-related liver injury and adverse liver outcomes. However, currently, there is insufficient evidence to support magnesium supplementation except for clinically relevant magnesium deficiency. Long-term prospective cohort studies assessing the impact of micronutrients on liver disease progression in patients with alcohol use disorder are lacking and may help determine whether there is a causal role for micronutrient deficiencies in alcohol-related liver injury.

• Melonie Heron

Objectives—This report presents final 2004 data on the 10 leading causes of death in the United States by age, race, sex, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements the annual report of final mortality statistics. Methods—Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2004. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD–10) are ranked according to the number of deaths assigned to rankable causes. Results—In 2004, the 10 leading causes of death were (in rank order) Diseases of heart; Malignant neoplasms; Cerebrovascular diseases; Chronic lower respiratory diseases; Accidents (unintentional injuries); Diabetes mellitus; Alzheimer's disease; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Septicemia and accounted for about 78 percent of all deaths occurring in the United States. Differences in the ranking are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2004 were (in rank order) Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Respiratory distress of newborn; Bacterial sepsis of newborn; Neonatal hemorrhage; and Diseases of the circulatory system. Important variation in the leading causes of infant death is noted for the neonatal and postneonatal periods.

• Melonie Heron

Objectives—This report presents final 2010 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements the Division of Vital Statistics' annual report of final mortality statistics. Methods—Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2010. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD–10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. Results—In 2010, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Cerebrovascular diseases; Accidents (unintentional injuries); Alzheimer's disease; Diabetes mellitus; Nephritis, nephrotic syndrome and nephrosis; Influenza and pneumonia; and Intentional self-harm (suicide). These 10 causes accounted for 75% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2010 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Necrotizing enterocolitis of newborn. Important variations in the leading causes of infant death are noted for the neonatal and post-neonatal periods.

• Donna L. White
• Shahriar Tavakoli Tabasi
• Fasiha Kanwal
• Hashem B. El-Serag

Vitamin D may affect the severity of HCV-related liver disease. To examine the association between serum vitamin D levels and advanced liver disease in a multiethnic US cohort of HCV patients, and account for dietary and supplemental intake. We measured serum 25-hydroxyvitamin D levels and used FibroSURE-ActiTest to assess hepatic pathology in a cohort of HCV-infected male veterans. We estimated and adjusted for daily intake of vitamin D from diet using a Dietary History Questionnaire, and dispensed prescriptions prior to study enrolment. We used race-stratified logistic regression analyses to evaluate the relationship between serum vitamin D levels and risk of advanced fibrosis (F3/F4–F4) and advanced inflammation (A2/A3–A3). A total of 163 African American (AA) and 126 White non-Hispanics were studied. Overall, ~44% of AAs and 15% of Whites were vitamin D deficient (<12 ng/mL) or insufficient (12–19 ng/mL); 4% of AAs and 9% of White patients had an elevated level (>50 ng/mL). Among AAs, patients with elevated serum vitamin D levels had significantly higher odds of advanced fibrosis (OR = 12.91, P = 0.03) than those with normal levels. In contrast, AAs with insufficient or deficient levels had > two-fold excess risk of advanced inflammation (P = 0.06). Among White males there was no association between vitamin D levels and advanced fibrosis (F3/F4–F4) or inflammation (A2/A3–A3) risk. We observed potential differences in the association between vitamin D levels and degree of HCV-related hepatic fibrosis between White and African American males. Additional research is necessary to confirm that high serum vitamin D levels may be associated with advanced fibrosis risk in African American males, and to evaluate whether racial differences exist in HCV-infected females.

Vitamin D deficiency is associated with increased cardiovascular disease risk in observational studies. Whether these associations are causal is not clear. Loss-of-function mutations in the filaggrin gene result in up to 10% higher serum vitamin D concentrations, supposedly due to a decreased UV-protection of the keratinocytes. We used a Mendelian randomization approach to estimate the causal effect of vitamin D status on serum lipids, blood pressure, body mass index, waist circumference, and the metabolic syndrome. Three population based studies were included, Monica10 (2,656 individuals aged 40-71 years), Inter99 (6,784 individuals aged 30-60 years), and Health2006 (3,471 individuals aged 18-69 years) conducted in 1993-94, 1999-2001, and 2006-2008, respectively. Participants were genotyped for the two most common filaggrin gene mutations in European descendants R501X and 2282del4, in all three studies and further for the R2447X mutation in the Inter99 and Health2006 studies. Filaggrin genotype was used as instrumental variable for vitamin D status. Baseline measurements of serum 25-hydroxyvitamin D were performed in all three studies. Instrumental variable analyses showed a 23.8% (95% confidence interval, CI 3.0, 48.6) higher HDL cholesterol level and a 30.5% (95% CI: 0.8, 51.3) lower serum level of triglycerides per doubling of vitamin D. These associations were, however, not statistically significant when applying the Bonferroni adjusted significance level. The remaining lipids showed non-significant changes in a favorable direction. Doubling of vitamin D gave a non-significantly lower odds ratio = 0.26 (95% CI: 0.06, 1.17) of the metabolic syndrome. There were no statistically significant causal effects of vitamin D status on blood pressure, body mass index, or waist circumference. Our results support a causal effect of higher vitamin D status on a more favorable lipid profile, although more studies in other populations are needed to confirm our results.

Vitamin D deficiency is associated with an increased risk of all-cause mortality in observational studies. The specific causes of death underlying this association lack clarity. We investigated the association between vitamin D status and cause-specific mortality. We included a total of 9,146 individuals from the two population-based studies, Monica10 and Inter99, conducted in 1993-94 and 1999-2001, respectively. Vitamin D status was assessed as serum 25-hydroxyvitamin D. Information on causes of death was obtained from The Danish Register of Causes of Death until 31 December 2009. There were a total of 832 deaths (median follow-up 10.3 years). Multivariable Cox regression analyses with age as underlying time axis and vitamin D quartiles showed significant associations between vitamin D status and death caused by diseases of the respiratory system, the digestive system, and endocrine, nutritional and metabolic diseases with hazard ratios (HRs) 0.26 (p(trend) = 0.0042), 0.28 (p(trend) = 0.0040), and 0.21 (p(trend) = 0.035), respectively, for the fourth vitamin D quartile compared to the first. We found non-significantly lower HRs for death caused by mental and behavioural diseases and diseases of the nervous system, but no association between vitamin D status and death caused by neoplasms or diseases of the circulatory system. The associations of vitamin D status and cause-specific mortality suggest that we also look elsewhere (than to cardiovascular disease and cancer) to explain the inverse association between vitamin D status and mortality.

African Americans with genotype 1 chronic hepatitis C attain a sustained virologic response (SVR) at only approximately one-half the rate of whites after peginterferon and ribavirin treatment. The serum concentration of 25-hydroxyvitamin D [25(OH)D] has recently been established as a predictor of treatment response. Therefore, the low serum concentrations of 25(OH)D found among African Americans may contribute to the low response rate; however, to our knowledge, none of the studies of vitamin D in chronic hepatitis C treatment have included a significant number of black patients. The objective was to compare the relation between the 25(OH)D concentration and genotype 1 chronic hepatitis C treatment response in African Americans with that in whites. This cross-sectional analysis included 106 African American and 65 white patients with genotype 1 chronic hepatitis C. Consistent with previous studies, we found that the SVR rate in the white patients increased significantly with an increasing serum concentration of 25(OH)D [SVR rates were 20%, 46%, and 70% for 25(OH)D serum concentrations <20, 20-35, and >35 ng/mL, respectively; P-trend = 0.008]; however, there was no relation between the SVR rate and 25(OH)D serum concentration in the African American patients [SVR rates were 32%, 28%, and 33% for 25(OH)D serum concentrations <20, 20-35, and >35 ng/mL, respectively; P-trend = 0.832]. We also found an analogous racial difference in the relation between the extent of liver fibrosis and the 25(OH)D concentration. Racial differences in vitamin D physiology or race-specific factors that modify the effects of vitamin D may affect the immune response to genotype 1 hepatitis C virus.

• William Burgess Grant

Evidence continues to mount that vitamin D reduces the risk and mortality rates of many types of disease. However, evidence from prospective cohort studies is sometimes weaker than that from case-control and ecological studies. A suggested reason for this discrepancy is that, because serum levels of 25-hydroxyvitamin D [25(OH)D] change over time, a single 25(OH)D concentration measurement taken at study enrollment does not reliably indicate 25(OH)D concentration related to the health outcome. To evaluate this suggestion further, this paper plots results from 12 prospective cohort studies of all-cause mortality rate vs. follow-up time. The regression fit to the hazard ratio per 20-nmol/l increase in serum 25(OH)D concentration vs. time increased from 0.82 (95% CI, 0.67-1.02) for 6 y to 0.96 (95% CI, 0.90-1.01) for 14 y. The value extrapolated for zero follow-up time was 0.72 (95% CI, 0.50-1.03), giving a hazard ratio reduction 3.5 times higher than the standard result from the meta-analysis [0.92 (95% CI, 0.89-0.95)]. Using the example of the Vitamin D Pooling Project of Rarer Cancers, this paper also discusses follow-up time's effect in interpreting prospective cohort studies of cancer outcome. This paper recommends that meta-analyses of prospective cohort studies account for follow-up time and, if possible, that studies measure serum 25(OH)D concentration every 2-4 y.

In this study, we aimed to evaluate the endothelial functions in patients with nonalcoholic fatty liver disease (NAFLD). In this observational case-control study, a total of 51 patients with NAFLD in study group and a total of 21 with age- and sex-equivalent individuals in control group were enrolled. In both patients and control groups, levels of asymmetric dimethylarginine (ADMA), systemic endothelial function (brachial artery flow-mediated dilation) (FMD) and carotid artery intima-media thickness (C-IMT) were measured. FMD and C-IMT were evaluated by vascular ultrasound. Plasma levels of ADMA were measured by ELISA. C-IMT was significantly higher in patients with NAFLD group than control group (0.67 ± 0.09 vs. 0.52 ± 0.11 mm, P < 0.001). The average C-IMT measurements were found in groups of control, simple steatosis, and NAFLD with (borderline and definite) NASH as 0.52 ± 0.11, 0.63 ± 0.07, and 0.68 ± 0.1 mm, respectively. The differences between groups were significant (P < 0.001). Measurement of brachial artery FMD was significantly lower in patients with NAFLD group compared to control group (7.3 ± 4.8 vs. 12.5 ± 7.1 %, P < 0.001). FMD measurements in groups of control, the simple steatosis, and NAFLD with NASH as 12.5 ± 7.1, 9.64 ± 6.63, and 7.03 ± 4.57 %, respectively, and the differences were statistically significant (P < 0.001). The increase in C-IMT and decrease in FMD was independent from metabolic syndrome and it was also more evident in patients with simple steatosis and NASH compared to control group. There was no significant difference between the control and NAFLD groups in terms of plasma ADMA levels (0.61 ± 0.11 vs. 0.69 ± 0.37 μmol/L, P = 0.209). Our data suggested that NAFLD is associated with endothelial dysfunction and increased earlier in patients with atherosclerosis compared to control subjects.

In animal models and human cross-sectional studies, vitamin D deficiency has been associated with liver disease progression. Vitamin D supplementation has been suggested as a treatment to prevent disease progression. We sought to evaluate the role of vitamin D levels in predicting chronic liver disease development. We conducted a nested case-control study of vitamin D levels in subjects with (cases) and without (controls) liver histologic progression or clinical decompensation over the course of the HALT-C Trial. Vitamin D levels were measured at 4 points over 45 months. 129 cases and 129 aged-matched controls were included. No difference in baseline vitamin D levels were found between cases and controls. (44.8 ng/mL vs. 44.0 ng/mL, P = 0.74). Vitamin D levels declined in cases and controls over time (P = 0.0005), however, there was no difference in the level of decline (P = 0.37). Among study subjects with diabetes mellitius, baseline vitamin D levels were higher in cases, 49.9 ng/mL, than controls, 36.3 ng/mL. (P = 0.03) In addition, baseline vitamin D levels were higher in black case subjects, 32.7 ng/mL, than in black control subjects, 25.2 ng/mL (P = 0.08) No difference in vitamin D levels was found between patients with and without progression of hepatitis C-associated liver disease over 4 years. Our data do not suggest any role for vitamin D supplementation in patients with advanced chronic hepatitis C and raise the possibility that higher vitamin D levels may be associated with disease progression.

• William Burgess Grant

Ecological studies have reported strong inverse correlations between indices of solar ultraviolet-B (UVB) doses and incidence and/or mortality rates for many types of cancer. Case-control studies (CCS) generally find inverse correlations between serum 25-hydroxyvitamin D [25(OH)D] concentration measured at time of diagnosis for cancer incidence, whereas nested case-control studies (NCCS), which involve a several-year follow-up time after serum sampling, generally do not. This paper examines the relation between follow-up interval and relative risk (RR) for breast, colorectal, and prostate cancer. I plot the RR versus serum 25(OH)D data as a function of follow-up time from the literature for each type of cancer. For breast cancer, RRs were significantly reduced only for follow-up periods less than 3 years. For colorectal cancer, RRs were generally significantly reduced for follow-up periods up to 12 years. For prostate cancer, RRs were not statistically significant from 4 years to 28 years. This study included no CCS. Follow-up periods after serum sampling should not be too long for breast cancer because once a tumor reaches a diameter of 1-3 mm, it requires angiogenesis to continue growing, and vitamin D reduces angiogenesis around tumors. Breast cancer diagnoses are more common in spring and fall than in summer or winter, indicating that they can grow rapidly if circulating 25(OH)D drops in the fall or melatonin levels drop in spring. Serum sampling should be conducted during the study, perhaps every 2 years, to overcome the problem of change of 25(OH)D concentration during cohort studies.

Hypovitaminosis D has been recently recognized as a worldwide epidemic. Since vitamin D exerts significant metabolic activities, comprising free fatty acids (FFA) flux regulation from the periphery to the liver, its deficiency may promote fat deposition into the hepatocytes. Aim of our study was to test the hypothesis of a direct association between hypovitaminosis D and the presence of NAFLD in subjects with various degree of insulin-resistance and related metabolic disorders. We studied 262 consecutive subjects referred to the Diabetes and Metabolic Diseases clinics for metabolic evaluation. NAFLD (non-alcoholic fatty liver disease) was diagnosed by upper abdomen ultrasonography, metabolic syndrome was identified according to the Third Report of National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATPIII) modified criteria. Insulin-resistance was evaluated by means of HOMA-IR. Fatty-Liver-Index, a recently identified correlate of NAFLD, was also estimated. Serum 25(OH)vitamin D was measured by colorimetric method. Patients with NAFLD (n=162,61.8%) had reduced serum 25(OH) vitamin D levels compared to subjects without NAFLD (14.8±9.2 vs 20.5±9.7 ng/ml, p<0.001, OR 0.95, IC 95% 0.92-0.98). The relationship between NAFLD and reduced 25(OH)vitamin D levels was independent from age, sex, triglycerides, high density lipoproteins (HDL) and glycaemia (p<0.005) and Fatty Liver Index inversely correlated with low 25(OH) vitamin D regardless sex, age and HOMA-IR (p<0.007). Low 25(OH)vitamin D levels are associated with the presence of NAFLD independently from metabolic syndrome, diabetes and insulin-resistance profile.

To examine the vitamin D status in patients with alcoholic cirrhosis compared to those with primary biliary cirrhosis. Our retrospective case series comprised 89 patients with alcoholic cirrhosis and 34 patients with primary biliary cirrhosis who visited our outpatient clinic in 2005 and underwent a serum vitamin D status assessment. Among the patients with alcoholic cirrhosis, 85% had serum vitamin D levels below 50 nmol/L and 55% had levels below 25 nmol/L, as compared to 60% and 16% of the patients with primary biliary cirrhosis, respectively (P < 0.001). In both groups, serum vitamin D levels decreased with increasing liver disease severity, as determined by the Child-Pugh score. Vitamin D deficiency in cirrhosis relates to liver dysfunction rather than aetiology, with lower levels of vitamin D in alcoholic cirrhosis than in primary biliary cirrhosis.

Low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with risk factors for cardiovascular disease, and they also appear to predict later development of type 2 diabetes, cancer, and an increased mortality rate. These predictions are all based on a single 25(OH)D measurement, but so far there are no known reports on tracking of serum 25(OH)D levels. In the present Norwegian study, serum 25(OH)D levels were measured 1) in 2,668 subjects in the 1994 and 2008 Tromsø surveys and 2) every third month for 1 year in 94 subjects randomly assigned to placebo in a vitamin D intervention study. There was a marked seasonal variation in 25(OH)D, and, depending on the method of adjusting for season, the correlation coefficient between serum 25(OH)D measurements from 1994 and 2008 ranged from 0.42 to 0.52. In the 1-year intervention study, the correlation between baseline and 12-month values was 0.80. Apart from the effect of season, changes in weight, intake of vitamin D, and physical activity were related to change in serum 25(OH)D levels. Tracking of serum 25(OH)D appears similar to that for blood pressure and serum lipids, and it provides some support for the use of a single 25(OH)D measurement to predict future health outcomes.

The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)2D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1α-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype. The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)2D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1α-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.

To examine whether self rated health confounds or modifies the relation between a prudent food intake pattern and mortality and to study whether the prudent food intake pattern predicts subsequent changes in self rated health. A prospective cohort study with follow up of total mortality and changes in self rated health. Food intake patterns were identified by principal component analysis from a 28 item food frequency questionnaire, collected at baseline. MONICA surveys, Copenhagen County, Denmark. A random sample of 3698 men and 3618 women aged 30-70 years were followed up from 1982 to 1998 (median 15 years). Among participants with complete information on all variables 18% had rated their health as poor (average or bad) at the baseline examination. Poor self rated health was related to a low score on the prudent food intake pattern, which was characterised by a frequent intake of wholemeal bread, fruit and vegetables. Three hundred and seventy six men and 210 women died during follow up. Poor self rated health and a low prudent food score were associated with increased mortality in both men and women. Self rated health did not modify the relation between diet and mortality. Of the 1098 men and 1048 women with good self rated health at baseline, 243 men and 297 women reported poor health during follow up. Low prudent food score, smoking, and high BMI increased the risk of developing poor health in both men and women, but in multivariate analysis the associations attenuated and were only significant for BMI. Both prudent food intake pattern and self reported health are independent predictors of mortality. Self rated health does not seem to modify the relation between diet and mortality.

A recent report highlighted the interlaboratory variability in serum 25-hydroxyvitamin D (25OHD) results (1). Concerns have also been raised about the apparent inability of some 25OHD assays to reliably measure 25-hydroxyvitamin D2 (25OHD2) (2)(3)(4). The accurate measurement of this metabolite is essential for the monitoring of vitamin-D-deficient patients receiving ergocalciferol, which is the only supplement used in the United States (5) and widely used elsewhere. The international Vitamin D Quality Assessment Scheme (DEQAS) has been monitoring the performance of 25OHD assays since 1989 and now has >100 registered participants in 18 countries. In essence, DEQAS is an ongoing, multicenter trial of the methods used by its participants and provides a unique opportunity to assess the accuracy and specificity of 25OHD methods as well as the analytical performance of a large number of their users. The organization of DEQAS has been described elsewhere (6), and details are available on the DEQAS website (www.deqas.org). In brief, five samples of normal human sera are sent out at 3-month intervals. Participants are asked to measure the total 25OHD concentration in each and return their results within 6 weeks. After statistical analysis of results (7), participants receive a report giving an All-Laboratory Trimmed Mean (ALTM) and Standard Deviation (SD) for each sample. A small study conducted in 1997 (8) showed that the ALTM was a good surrogate for the "true" (target) value produced by gas chromatography–mass spectrometry. The accuracy of each result is defined by its percentage bias from the ALTM. Results for each sample are also grouped by method, and a method mean (MM) is produced. The overall accuracy of each method can be assessed from the percentage bias of the method mean from the ALTM: {[(MM − ALTM)/ALTM] × 100}. The …

To explore the relationship between serum liver enzymes and both the glucose tolerance status and insulin secretion in young obese patients. A total of 734 young obese patients (BMI ≥ 25 kg m(-2)) and 231 lean healthy volunteers matched in age (BMI < 23 kg m(-2)) were enrolled in this cross-sectional observational study. The 734 obese patients were subdivided to three groups (OB-NGR, OB-IGR, and OB-DM) according to their glucose tolerance status. FSIVGTT was performed to assess the degree of insulin sensitivity (SI) and islet secretion function (AIRg). The disposition index (DI; product of SI and AIRg) was calculated as an integrated measurement of insulin secretion and insulin action after compensating for insulin resistance. The extent and distribution of hepatic fat infiltration was assessed using the liver/spleen ratio (L/S ratio) with CT scan. ALT and GGT levels in OB-NGR, OB-IGR, and OB-DM groups were significantly increased compared to the normal controls, and were incrementally increased in turn in the three groups, whereas DI decreased at the same time. One standard deviation increment in ALT and GGT increased the risk of β-cell dysfunction after controlling for potential confounders such as sex, age, BMI, waist-hip ratio, and blood pressure. Even after the adjustment of the serum lipid profile and L/S ratio, the odds ratio of ALT remained statistically significant (OR, 1.603; 95 % CI, 1.225-2.096). Serum levels of liver enzymes showed an independent close relationship with insulin secretion capacity. Excluding the impact of a fatty liver, increased ALT and GGT levels indicated a significant association with the attenuation of pancreatic β-cell function. This study provides the possibility that elevated liver enzymes might be treated as simple biomarkers of early insulin secretion deficit in type 2 diabetes, especially in young obese patients.

Background: Vitamin D deficiency is common in chronic liver disease particularly in those with severe liver fibrosis. Aims: To determine the effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ) on the human α(1) (I) collagen promoter and collagen formation by human stellate LX-2 cells and the mechanism of the effect of the vitamin D receptor (VDR) on the promoter. Methods: Type I collagen was assessed by measurements of collagen mRNA and collagen protein and by transfection experiments. Binding of VDR to the α(1) (I) collagen promoter was determined by EMSA and ChIP assays. Results: 1,25-(OH)2 D3 decreased human α(1) (I) collagen mRNA and protein and the secretion of type I collagen by stellate cells after exposure to TGFβ1. Furthermore, 1,25-(OH)2 D3 inhibited TGFβ1-induced activation of the α(1) (I) collagen promoter in transfected LX-2 cells. The effect of 1,25-(OH)2 D3 is mediated by the VDR, which binds at a proximal Sp1 site and also at a newly identified distal site on the collagen promoter. A VDR expression vector reduced the activities of the collagen promoter in transfected LX-2 cells. Conclusions: 1,25-(OH)2 D3 inhibits type I collagen formation in human stellate cells. The effect of 1,25-(OH)2 D3 is mediated by its receptor which binds at a proximal Sp1.1 site and at a newly identified distal site on the collagen promoter. Correction of vitamin D deficiency in patients with chronic liver disease is a potential therapy to inhibit progression of fibrosis.

Vitamin D is associated with cardiovascular disease and renal function but the mechanisms are as yet unexplained. Microalbuminuria is associated with a higher risk of kidney function loss, cardiovascular disease, and mortality. Parathyroid hormone is a predictor of cardiovascular mortality and negatively correlated with glomerular filtration rate. We investigated the association between vitamin D status and 5-year changes in urine albumin creatinine ratio (UACR) and parathyroid hormone (PTH). A random sample of 6,784 individuals aged 30-60 years from a general population participated in the Inter99 study in 1999-2001. Vitamin D (serum-25-hydroxyvitamin D) was measured at baseline by high-performance liquid chromatography. UACR and PTH were measured at baseline and follow-up. Increased UACR was defined as UACR >4.0 mg/g reflecting the upper quartile at baseline. We included 4,330 individuals who participated at 5-year follow-up. In multivariable linear regression analysis, a 10-nmol/l higher baseline level of vitamin D was associated with a 5-year decrease in UACR by 0.92 % (95 % confidence interval, CI 0.13, 1.71). In multivariable logistic regression analysis, the odds ratio of developing increased UACR during follow-up was 0.96 (95 % CI 0.92, 0.98) per 10 nmol/l higher baseline vitamin D level. We found a significant inverse cross-sectional (p < 0.0001) but no prospective association (p = 0.6) between baseline vitamin D status and parathyroid hormone. We found low vitamin D status to be a predictor of long-term development of increased UACR. It remains to be proven whether vitamin D deficiency is a causal and reversible factor in the development of albuminuria.

Background/objectives: Mild to moderate vitamin D insufficiency has been proposed as a risk factor for several common chronic diseases including type 2 diabetes. This study aimed to examine the association between serum 25-hydroxy vitamin D (25(OH)D) and incident diabetes. Subjects/methods: The MONICA10 cohort consists of 2656 participants (men and women aged 41-71 years) who participated in a 10-year follow-up examination during 1993-1994 as part of the MONICA 1 population survey. A total of 2571 participants free of diabetes at baseline and with successful measurement of serum 25(OH)D were included in the current study. The Danish National Diabetes register enabled identification of 288 cases of incident diabetes during follow-up (median: 16.4 years). Data were analysed by Cox proportional hazard models and associations were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Results: Serum 25(OH)D was inversely associated with incident diabetes adjusted for potential confounders (HR per 25 nmol/l=0.83; 95% CI: 0.72-0.95; P=0.009). A statistically significant interaction was observed between 25(OH)D and waist circumference (WC) (P(interaction)=0.042) suggesting an association in persons with a high WC (HR (95%CI) per 25 nmol/l=0.74 (0.63-0.88), 218 incident cases) and not in persons with a normal WC (HR (95%CI) per 25 nmol/l=0.98 (0.78-1.24), 70 incident cases). Conclusions: Low serum 25(OH)D was associated independently with incident diabetes. The inverse association was only found in overweight-obese and not in normal weight individuals, suggesting that obesity may modify the effect of vitamin D status on the risk of diabetes.

Low vitamin D status has been associated with cardiovascular disease (CVD) and mortality primarily in selected groups, smaller studies, or with self-reported vitamin D intake. We investigated the association of serum vitamin D status with the incidence of a registry-based diagnosis of ischemic heart disease (IHD), stroke, and all-cause mortality in a large sample of the general population. A total of 9,146 individuals from the two population-based studies, Monica10 and Inter99, were included. Measurements of serum 25-hydroxyvitamin D at baseline were carried out using the IDS ISYS immunoassay system in Monica10 and High-performance liquid chromatography in Inter99. Information on CVDs and causes of death was obtained from Danish registries until 31 December 2008. There were 478 cases of IHD, 316 cases of stroke, and 633 deaths during follow-up (mean follow-up 10 years). Cox regression analyses with age as underlying time axis showed a significant association between vitamin D status and all-cause mortality with a HR = 0.95 (P = 0.005) per 10 nmol/l higher vitamin D level. We found no association between vitamin D status and incidence of IHD or stroke (HR = 1.01, P = 0.442 and HR = 1.00, P = 0.920, respectively). In this large general population study, the observed inverse association between serum vitamin D status and all-cause mortality was not explained by a similar inverse association with IHD or stroke.

Objectives: A low vitamin D level has been associated with increased cardiovascular disease risk but possible mechanisms remain unclear. We investigated the association between vitamin D levels and 5-year changes in blood pressure, lipid profile and incidence of the metabolic syndrome, hypertension and hypercholesterolemia. Methods: A random sample of 6,784 individuals aged 30-60 years from a general population was investigated in the Inter99 study in 1999-2001. Vitamin D (serum 25-hydroxyvitamin D) was measured at baseline by high-performance liquid chromatography, and 4,330 individuals participated at the 5-year follow-up and were included in the present study. Results: The median baseline vitamin D concentration was 48.0 nmol/l. In multivariable linear regression analyses, a 10 nmol/l higher baseline level of vitamin D was associated with a decrease in triglycerides and very low density lipoprotein cholesterol by 0.52 (p = 0.03) and 0.66% (p = 0.005), respectively. In multivariable logistic regression analyses, the odds ratios per 10 nmol/l higher baseline vitamin D level were 0.95 (p < 0.05) and 0.94 (p = 0.01) for the development of the metabolic syndrome and hypercholesterolemia, respectively. There was no association between vitamin D and blood pressure. Conclusions: An optimal vitamin D status may influence cardiovascular health by changing the lipid profile in a favorable direction and decreasing the incidence of the metabolic syndrome.

Background and aims: Danish legislation regarding food fortification has been very restrictive and vitamin D deficiency is thought to be common in Denmark due to inadequate dietary intakes and the fact that in Denmark (latitude 56°N) vitamin D is only synthesized in the skin after exposure to solar radiation during summertime (April-September). The purpose of this study was to evaluate the vitamin D status of a general adult population in Denmark and, in addition, associations between vitamin D status and distinct lifestyle factors were studied. Methods: A random sample of 6784 persons from a general population aged 30-60 years participated in a health examination in 1999-2001. Serum samples from all participants were stored and levels of 25-hydroxyvitamin D (25(OH)D) were measured by HPLC in 2009. The method was compared to another HPLC method. Information on dietary intake of vitamin D and other lifestyle factors were obtained by questionnaires. A total of 6146 persons defined as ethnic Danes and with successful measurements of 25(OH)D were included in the analyses. Results: The overall prevalence of vitamin D deficiency (25(OH)D<25 nmol/l) and insufficiency (25(OH)D<50 nmol/l) were 13.8% and 52.2%, respectively. A marked seasonal fluctuation was seen in serum levels of 25(OH)D - median values of 25(OH)D were lowest in February and highest in August. In multiple logistic regression models (n=5506), low vitamin D status was significantly associated with obesity (BMI≥30), daily smoking and a sedentary lifestyle. However, measurements of 25(OH)D were not associated with the estimated dietary intake of vitamin D. Comparison of two HPLC methods demonstrated considerable differences in accuracy. Discussion and conclusions: Our results suggest that poor vitamin D status is common among adults in a Northern European country without food fortification with vitamin D. Methodological issues are, however, of great importance when using cut-off values to define poor vitamin D status. In addition, we demonstrated that low serum levels of 25(OH)D were associated with several lifestyle factors.

Previous studies suggest that chronic liver disease may be related to vitamin D deficiency. It is, however, not known whether 25(OH)D levels are associated with incident hepatic decompensation and mortality in chronic liver failure. We aimed to evaluate whether 25(OH)D serum levels are associated with Child-Pugh (CP) score, model for end-stage liver disease (MELD) score, occurrence of hepatic decompensation, and survival in patients with cirrhosis. We enrolled 75 consecutive cirrhotic patients admitted to our outpatient liver clinic (32% females; age: 58 ± 11 years; aetiology alcohol in 61%). At baseline, 25(OH)D was determined and the degree of liver dysfunction was estimated by CP and MELD score. Thereafter patients were followed-up with respect to hepatic decompensation and mortality. 25(OH)D levels averaged 16.0 ± 9.2 ng/ml and were inversely correlated with MELD score (r = -0.34, P = 0.003) and CP score (r = -0.21, P = 0.080). Thirty-seven patients developed hepatic decompensation and 24 patients died during a median follow-up of 3.6 years. Age- and gender-adjusted relative risk (with 95% confidence interval) was 6.37 (1.75-23.2; P = 0.005) for hepatic decompensation and 4.31 (1.38-13.5; P = 0.012) for mortality within the first vs the third 25(OH)D tertile but these associations were largely attenuated towards non-significant trends after additional adjustments for CP or MELD score. Our findings show a significant association of 25(OH)D with the degree of liver dysfunction and suggest that low 25(OH)D levels may predict hepatic decompensation and mortality in patients with chronic liver failure.

Non-alcoholic fatty liver disease (NAFLD) is usually a silent disease that occurs in a very high proportion of people with features of the metabolic syndrome, including overweight, insulin resistance and type 2 diabetes. Because obesity and type 2 diabetes are now extremely common in Westernised societies, it is likely that the prevalence of NAFLD increases markedly in the future. Although previously it was thought that NAFLD was harmless, it is now recognised that NAFLD can be a progressive liver condition that increases risk of cirrhosis, end-stage liver disease and hepatocellular carcinoma. Additionally, liver fat accumulation causes insulin resistance and increases risk of type 2 diabetes. Increasing evidence now shows NAFLD is a risk factor for cardiovascular disease (CVD). The purpose of this review is to briefly discuss the pathogenesis of NAFLD, to describe the relationship between NAFLD and CVD and the mechanisms linking both conditions and to discuss some of the treatment options (including lifestyle, nutrition and drugs) that may influence both NAFLD and risk of CVD.

Vitamin D through the vitamin D nuclear receptor (VDR) plays a key role in mineral ion homeostasis. The liver is central in vitamin D synthesis, however the direct involvement of the vitamin D-VDR axis on the liver remains to be evaluated. In this review, we will describe vitamin D metabolism and the mechanisms of homeostatic control. We will also address the associations between the vitamin D-VDR axis and pathological liver entities, such as non-alcoholic fatty liver disease, autoimmune liver disease, viral hepatitis and liver cancer. The link between liver diseases and the vitamin D-VDR axis will be discussed in light of evidences arising from in vitro and in vivo studies. Finally, we will consider the therapeutic potential of the vitamin D-VDR axis in liver diseases.

End-stage chronic liver disease is associated with vitamin D deficiency but the prevalence across a broad-spectrum of liver disease is unknown. This study prospectively examines prevalence of vitamin D deficiency and response to replacement in chronic liver disease. One hundred and fifty-eight outpatients with chronic liver disease were enrolled. Serum 25-hydroxyvitamin D (25[OH]D) levels were classified as: severely deficient less than 25 nmol/l, deficient 25-54 nmol/l or replete greater than 54 nmol/l. Sixty-five of 158 (41%) had cirrhosis. 25[OH]D was suboptimal in 101/158 (64%), including severe deficiency in 24 patients (15%). Vitamin D deficiency occurred in liver disease of all aetiologies, including patients with only mild liver disease. 25[OH]D increased by 60.0% (19.11 ± 13.20 nmol/l) in patients with deficiency after vitamin D replacement and decreased by 25.2% (-18.33 ± 12.02 nmol/l) in non-treated initially replete patients over a median of 4 months. Vitamin D deficiency improves with oral vitamin D supplementation and levels fall without supplementation. Chronic liver disease patients are at very high risk of vitamin D deficiency regardless of etiology or severity.

Unlabelled: 25-Hydroxyvitamin D (25[OH]D) can potentially interfere with inflammatory response and fibrogenesis. Its role in disease progression in chronic hepatitis C (CHC) and its relation with histological and sustained virological response (SVR) to therapy are unknown. One hundred ninety-seven patients with biopsy-proven genotype 1 (G1) CHC and 49 healthy subjects matched by age and sex were consecutively evaluated. One hundred sixty-seven patients underwent antiviral therapy with pegylated interferon plus ribavirin. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. Tissue expression of cytochrome (CY) P27A1 and CYP2R1, liver 25-hydroxylating enzymes, were assessed by immunochemistry in 34 patients with CHC, and in eight controls. The 25(OH)D serum levels were significantly lower in CHC than in controls (25.07 +/- 9.92 microg/L versus 43.06 +/- 10.19; P < 0.001). Lower levels of 25(OH)D were independently linked to female sex (P = 0.007) and necroinflammation (P = 0.04) by linear regression analysis. CYP27A1, but not CYP2R1, was directly related to 25(OH)D levels (P = 0.01), and inversely to necroinflammation (P = 0.01). Low 25(OH)D (odds ratio [OR], 0.942; 95% confidence interval [CI], 0.893-0.994) and cholesterol (OR, 0.981; 95%CI, 0.969-0.992) levels, older age (OR, 1.043; 95%CI, 1.002-1.085), high ferritin (OR, 1.003; 95%CI, 1.001-1.005), and necroinflammation (OR, 2.235; 95%CI, 1.014-4.929) were independently associated with severe fibrosis (F3-F4) by multivariate logistic analysis. Seventy patients (41%) achieved SVR. By multivariate analysis, hepatic steatosis (OR, 0.971; 95%CI, 0.944-0.999), lower cholesterol (OR, 1.009; 95% CI, 1.000-1.018), and 25(OH)D levels (OR, 1.039; 95%CI, 1.002-1.077) were independently associated with no SVR. Conclusion: G1 CHC patients had low 25(OH)D serum levels, possibly because of reduced CYP27A1 expression. Low vitamin D is linked to severe fibrosis and low SVR on interferon (IFN)-based therapy.

• Jihad Arteh
• SriLakshmi Narra
• Satheesh Nair

Vitamin D deficiency has been associated with cholestatic liver disease such as primary biliary cirrhosis. Some studies have suggested that cirrhosis can predispose patients to development of osteoporosis because of altered calcium and vitamin D homeostasis. The aim of this study was to determine the prevalence of vitamin D deficiency in patients with chronic liver disease. One hundred and eighteen consecutive patients (43 with hepatitis C cirrhosis, 57 with hepatitis C but no cirrhosis, 18 with nonhepatitis C-related cirrhosis) attending the University of Tennessee Hepatology Clinic had their 25-hydroxyvitamin D level measured. Severity of vitamin D deficiency was graded as mild (20-32 ng/ml), moderate (7-19 ng/ml) or severe (<7 ng/ml), normal being >32 ng/ml. Of patients, 109/118 (92.4%) had some degree of vitamin D deficiency. In the hepatitis C cirrhosis group, 16.3% (7/43) had mild, 48.8% (21/43) had moderate, and 30.2% (13/43) had severe vitamin D deficiency. In the hepatitis C noncirrhotic group, 22.8% (19/57) had mild, 52.6% (30/57) had moderate, and 14% (8/57) had severe vitamin D deficiency. In the nonhepatitis C-related cirrhosis group, 38.9% (7/18) had mild, 27.8% (5/18) had moderate, and 27.8% (5/18) had severe vitamin D deficiency. Severe vitamin D deficiency (<7 ng/ml) was more common among patients with cirrhosis compared with noncirrhotics (29.5% versus 14.1%, P value=0.05). Female gender, African American race, and cirrhosis were independent predictors of severe vitamin D deficiency in chronic liver disease. Vitamin D deficiency is universal (92%) among patients with chronic liver disease, and at least one-third of them suffer from severe vitamin D deficiency. African American females are at highest risk of vitamin D deficiency.

• Constance E Ruhl
• James E Everhart

Elevated serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) activities are markers of liver injury, but may also be associated with other diseases and death. In a prospective, national, population-based sample, we examined whether elevated ALT and GGT were associated with increased risk of all-cause and disease-specific mortality. Death certificate-based 12-year mortality was analyzed among 14,950 adult participants in the third US National Health and Nutrition Examination Survey, 1988-1994, who were negative for markers of viral hepatitis B and C. Abnormal ALT was defined as >30 U/L in men or >19 U/L in women, and abnormal GGT as >51 U/L in men or >33 U/L in women. Cumulative mortality was 13.9% from all causes, including 4.2% from cardiovascular disease, 4.2% from neoplasms, 0.44% from diabetes, and 0.13% from liver disease. In multivariate-adjusted analyses, elevated ALT was not associated with all-cause mortality (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.88-1.6). ALT elevation was associated with deaths from liver disease (HR, 8.2; 95% CI, 2.1-31.9), but not from cardiovascular disease (HR, 0.90; 95% CI, 0.56-1.4), neoplasms (HR, 1.0; 95% CI, 0.65-1.5), or diabetes (HR, 2.4; 95% CI, 0.65-9.1). All-cause mortality increased with elevated GGT (HR, 1.5; 95% CI, 1.2-1.8), as did mortality from liver disease (HR, 13.0; 95% CI, 2.4-71.5), neoplasms (HR, 1.5; 95% CI, 1.01-2.2), and diabetes (HR, 3.3; 95% CI, 1.4-7.6), but not from cardiovascular disease (HR, 1.3; 95% CI, 0.80-2.0). In the US population, elevated GGT was associated with mortality from all causes, liver disease, cancer, and diabetes, while ALT was associated only with liver disease mortality.

Morbidity and mortality due to liver disease and cirrhosis vary significantly by race/ethnicity in the United States. We examined the prevalence of liver disease risk factors among blacks, Mexican Americans, and whites, including elevated aspartate aminotransferase and alanine aminotransferase activity, infection with viral hepatitis B or hepatitis C, alcohol intake, obesity, diabetes, and metabolic syndrome. Data were obtained from the Fourth National Health and Nutrition Examination Survey (NHANES IV). A logistic regression was used to examine the association of race/ethnicity to liver disease risk factors, controlling for the demographic and socioeconomic variables. Mexican-American men and women are the most likely to have elevated aminotransferase activity. Among men, Mexican Americans are more likely than whites to be heavy/binge drinkers, and blacks are more likely to have hepatitis B or hepatitis C. Among women, Mexican Americans are more likely than whites to be obese and diabetic, and less likely to be heavy/binge drinkers; blacks are more likely than whites to have hepatitis B or hepatitis C, be obese or diabetic, and less likely to be heavy/binge drinkers. In this national sample, the prevalence of risk factors for liver disease varies by race/ethnicity. Mexican Americans and blacks have a greater risk of developing liver disease than their white counterparts. These findings are consistent with the observed racial/ethnic disparities in morbidity and mortality due to chronic liver disease and contribute to the efforts to identify the causes of these disparities. This information can be used by health professionals to tailor screening and intervention programs.

• T.F. Andersen
• M Madsen
• J Jørgensen
• J H Olsen

The Danish National Hospital Register (LPR) has collected nationwide data on all somatic hospital admissions since 1977, and since 1995 data on outpatients and emergency patients have been included as well. Numerous research projects have been undertaken in the national Danish context as well as in collaboration with international teams, and the LPR is truly a valuable source of data for health sciences, especially in epidemiology, health services research and clinical research. Nearly complete registration of somatic hospital events in Denmark is combined with ideal conditions for longterm follow-up due to the existence of a national system of unique person identification in a population of relative demographic stability. Examples of studies are provided for illustration within three main areas: I: Using LPR for surveillance of the occurrence of diseases and of surgical procedures, II: Using the Register as a sampling frame for longitudinal population based and clinical research, and III: Using the Register as a data source for monitoring outcomes. Data available from the Register as well as studies of the validity of the data are mentioned, and it is described how researchers may get access to the Register. The Danish National Hospital Register is well suited to contribute to international comparative studies with relevance for evidence-based medicine.

In 1875 registration of causes of death in Denmark was established by the National Board of Health, and annual statistics of death have since been published. Until 1970 the national statistics were based upon punched cards with data collected from the death certificates. Since then the register has been fully computerized and includes individual based data of all deaths occurring among all residents in Denmark dying in Denmark. Furthermore, a microfilm of all death certificates from 1943 and onward is kept in the National Board of Health. The Danish Institute for Clinical Epidemiology (DICE) has established a computerized register of individual records of deaths in Denmark from 1943 and onwards. No other country covers computerized individual based data of death registration for such a long period, now 54 years. This paper describes the history of the registers, the data sources and access to data, and the research based upon the registers, presenting some examples of research activities.

• Fedja A. Rochling

Serum liver tests are important but often problematic in evaluating patients with and without symptoms of hepatic disease. The common term "liver function tests" is misleading because most tests used in clinical practice measure hepatocellular damage not function. True liver function tests are those that measure synthesis of proteins made by the liver (albumin, clotting factors) or the liver's capacity to metabolize drugs. A commonly ordered panel of automated tests includes bilirubin, aminotransferases, alkaline phosphatase, and gamma-glutamyl transpeptidase. This article reviews patterns of elevated enzyme values encountered in liver diseases and their diagnostic limitations and provides an algorithm for evaluating abnormal liver test results.

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are immune-mediated chronic inflammatory diseases of the liver of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. 1,25-Dihydroxyvitamin D(3) has been implicated as an immunomodulator, which acts through its own receptor (VDR). Polymorphisms of the VDR have been linked to a variety of autoimmune diseases. In this study VDR polymorphisms were analyzed in 123 patients with AIH, 74 patients with PBC, and 214 controls. VDR polymorphisms were assessed by BsmI, TaqI, ApaI, and Fok endonuclease digestion after specific polymerase chain reaction (PCR) amplification. We found a significant association between the BsmI polymorphisms in PBC patients in comparison with controls (chi(2) = 9.49, P =.009). Furthermore we detected a significant association of the Fok polymorphims in AIH patients in comparison to controls (chi(2) = 9.71, P =.008) indicating a genetic link of VDR polymorphisms to autoimmune liver diseases such as PBC and AIH in German patients. These findings contribute to the knowledge of the complex events determining immunologic tolerance in the liver. Further studies are needed to elucidate the mechanisms by which the vitamin D receptor contributes to the development of autoimmune diseases.

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are two autoimmune diseases of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. Vitamin D has been shown to exert multiple immunomodulatory effects, which acts through its own receptor (VDR). Polymorphisms of VDR had been implicated in several autoimmune diseases. In the present study, the association between Chinese patients with AIH, PBC and the polymorphisms in exon 2, intron 8 and exon 9 of vitamin D receptor genes was studied. Four candidate gene loci were investigated in 49 patients with AIH, 58 patients with PBC, and 160 healthy controls. The VDR polymorphisms were assessed by FokI, BsmI, ApaI, and TaqI endonuclease digestion after specific polymerase chain reaction (PCR) amplification. The result show a significant difference in FokI polymorphism between AIH patients and controls (chi(2) = 5.47, P = 0.019), and a significant association in BsmI polymorphisms between PBC patients and controls (chi(2) = 6.52, P = 0.01). Furthermore the distribution of FokI, BsmI, ApaI, and TaqI gene types differed between Chinese healthy controls and Caucasian healthy controls. It is suggested that there is a genetic link of VDR polymorphisms to autoimmune liver diseases such as AIH and PBC in Chinese patients. Further studies are needed to elucidate the mechanisms by which VDR polymorphisms contribute to the lose of immune tolerance in autoimmune diseases.

• Giovanni Targher
• Lorenzo Bertolini
• Luca Scala
• Guido Arcaro

To explore associations between serum 25-hydroxyvitamin D(3) [25(OH)D] concentrations and liver histology in patients with non-alcoholic fatty liver disease (NAFLD). We studied 60 consecutive patients with biopsy-proven NAFLD, and 60 healthy controls of comparable age, sex and body mass index (BMI). NAFLD patients had a marked decrease in winter serum 25(OH)D concentrations (51.0+/-22 vs. 74.5+/-15 nmol/L, P<0.001) compared with controls. Metabolic syndrome (MetS; as defined by the Adult Treatment Panel III criteria) and its individual components occurred more frequently among NAFLD patients. The marked differences in 25(OH)D concentrations observed between the groups were little affected by adjustment for age, sex, BMI, creatinine, calcium, homeostasis model assessment (HOMA)-insulin resistance, and the presence of the MetS. Interestingly, among NAFLD patients, decreased 25(OH)D concentrations were closely associated with the histological severity of hepatic steatosis, necroinflammation and fibrosis (P<0.001 for all) independent of age, sex, BMI, creatinine, calcium, HOMA-insulin resistance, and presence of the MetS. Compared with controls, NAFLD patients have a marked decrease in serum 25(OH)D concentrations, which is closely associated with histopathological features of NAFLD. Further investigation into whether vitamin D(3) may play a role in the development and progression of NAFLD appears to be warranted.

The liver plays a central role in vitamin D metabolism. Our aim was to determine the prevalence and type of vitamin D-parathyroid hormone (PTH) disturbance in ambulatory patients with noncholestatic chronic liver disease (CLD) and its relationship with disease severity and liver function. We studied 100 consecutive outpatients (63 men, 37 women; mean age, 49.0 +/- 12.1 [SD] y) with noncholestatic CLD caused by alcohol (n = 40), hepatitis C (n = 38), hepatitis B (n = 12), autoimmune hepatitis (n = 4), hemochromatosis (n = 4), and nonalcoholic steatohepatitis (n = 2); 51 patients had cirrhosis. Serum concentrations of 25-hydroxyvitamin D (25[OH]D), PTH, calcium, phosphate, magnesium, creatinine, and liver function tests were determined. Serum 25(OH)D levels were inadequate in 91 patients: vitamin D deficiency (<50 nmol/L) was found in 68 patients and vitamin D insufficiency (50-80 nmol/L) was found in 23 patients. Secondary hyperparathyroidism (serum PTH, >6.8 pmol/L) was present in 16 patients. The prevalence of vitamin D deficiency was significantly higher in cirrhotic vs noncirrhotic patients (86.3% vs 49.0%; P = .0001). In Child-Pugh class C patients, 25(OH)D levels were significantly lower than in class A patients (22.7 +/- 10.0 nmol/L vs 45.8 +/- 16.8 nmol/L; P < .001). Serum 25(OH)D independently correlated with international normalized ratio (negatively; P = .018) and serum albumin (positively; P = .007). Serum 25(OH)D levels of less than 25 nmol/L predicted coagulopathy, hyperbilirubinemia, hypoalbuminemia, increased alkaline phosphatase, and anemia and thrombocytopenia. Vitamin D inadequacy is common in noncholestatic CLD and correlates with disease severity, but secondary hyperparathyroidism is relatively infrequent. Management of CLD should include assessment of vitamin D status in all patients and replacement when necessary.

• Daniel Bikle

Vitamin D and calcium are critical for skeletal health. Their absorption from the intestine is negatively impacted by a number of gastrointestinal diseases and surgical procedures, leading to osteoporosis and/or osteomalacia. Diseases of the liver can impact the metabolism of vitamin D to its circulating form, 25(OH)D, as well as the production of carrier proteins, albumin and vitamin D-binding protein, that may alter the delivery of 25(OH)D and its active metabolite 1,25(OH)(2)D to target tissues, including the skeleton, again leading to bone disease. The clinician evaluating a patient with apparent osteoporosis and vitamin D deficiency/ insufficiency needs to consider a gastrointestinal etiology. Similarly, the clinician evaluating a patient with a gastrointestinal disorder needs to evaluate that patient for vitamin D deficiency and bone disease. Treatment involves adequate vitamin D and calcium supplementation to achieve normal serum 25(OH)D, PTH, and serum and urine calcium levels.

• Helen M Pappa
• Elana Bern
• Daniel Kamin
• Richard J. Grand

The purpose of this review is to report on the vitamin D status and its relationship with bone health in individuals with gastrointestinal and liver disorders. In addition, recommendations regarding replacement and maintenance of optimal vitamin D stores, as well as the state of knowledge regarding its effect on the disease through its actions on the immune system, will be reviewed. The scientific community has revised upward the serum levels of vitamin D considered optimal, and doses of vitamin D much larger than those currently recommended may be needed to maintain these levels, especially in individuals with gastrointestinal and liver disorders. The relationship between vitamin D and bone health in this population is controversial. The role of vitamin D in the regulation of the immune system continues to be elucidated. Hypovitaminosis D is prevalent among individuals with gastrointestinal and liver disease. Although replacement and supplementation guidelines have not been well defined, practitioners should aim for a serum 25-hydroxyvitamin D level of at least 32 ng/ml. The contribution of vitamin D to the bone health of these individuals and its role in altering disease course through its actions on the immune system remain to be elucidated.

Tracking of serum 25-hydroxyvitamin D levels during 41 Schechtman, Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response

• R Jorde
• M Sneve
• M Hutchinson
• N Emaus
• Y Figenschau
• G Grimnes
• S J Weintraub
• J F Fleckenstein
• T N Marion
• M A Madey
• T M Mahmoudi

R. Jorde, M. Sneve, M. Hutchinson, N. Emaus, Y. Figenschau, G. Grimnes, Tracking of serum 25-hydroxyvitamin D levels during 41. S.J. Weintraub, J.F. Fleckenstein, T.N. Marion, M.A. Madey, T.M. Mahmoudi, K.B. Schechtman, Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response. Am. J. Clin. Nutr. 96(5), 1025–1031 (2012)

Low Vitamin D Levels And High Liver Enzymes

Source: https://www.researchgate.net/publication/258856408_Vitamin_D_status_liver_enzymes_and_incident_liver_disease_and_mortality_A_general_population_study