Low 25-OH Research Articles

Is vitamin D status a predictor glycaemic regulation and cardiac complication in type 2 diabetes mellitus patients?

ObjectiveTo evaluate vitamin D as a predictor of glycaemic regulation in type 2 diabetes mellitus patients. Research design and methodsIn observational study 171 type 2 diabetic patients who are followed for median (range) of 10.15 (3–18) years. Mean±SD age was 56±10. Plasma 25-hydroxyvitamin D3 levels were determined by high-performance liquid chromatography/tandem mass spectrometry on baseline samples. Vitamin D deficiency was defined as a 25-OHD level of less than 20ng/ml. Vitamin D levels between 20 and 30ng/ml are termed ‘insufficient’. Vitamin D levels greater than 30ng/ml are termed ‘optimal’. Results125 patients have vitamin D deficiency, 14 patients have insufficient and the others have optimal. Vitamin D levels were not associated with sex, age, BMI, HDL, LDL, kreatinin, hypertension and smoking. But vitamin D deficiency patients had more longer duration (p=0.011), more higher uric acid (p=0.021), fasting glucose (p=0.037), postprandial glucose (p=0.001) and HbA1c (p=0.026). ConclusionsIn our study type 2 diabetic patients have 73% of vitamin D deficiency. Vitamin D deficiency predicts higher fasting and postprandial blood glucose and diabetes disregulation. Type 2 DM patients and low 25-OH vitamin D levels could increased cardiovascular disease directly or indirectly (low HDL and high uric acid in 25-OH vitamin D <20ng/ml). Whether vitamin D substitution improves prognosis remains to be investigated.

Combined effect of 25‐OH vitamin D plasma levels and genetic Vitamin DReceptor (NR 1I1) variants on fibrosis progression rate in HCV patients

Decreased vitamin D levels have been described in various forms of chronic liver disease and associated with advanced fibrosis. Whether this association is a cause or consequence of advanced fibrosis remains unclear to date. To analyse combined effects of 25-OH vitamin D plasma levels and vitamin D receptor gene (VDR; NR1I1) polymorphisms on fibrosis progression rate in HCV patients. 251 HCV patients underwent VDR genotyping (bat-haplotype: BsmI rs1544410 C, ApaI rs7975232 A and TaqI rs731236 A). Plasma 25-OH vitamin D levels were quantified in a subgroup of 97 patients without advanced fibrosis. The VDR haplotype and genotypes as well as plasma 25-OH vitamin D levels were associated with fibrosis progression. The bAt[CCA]-haplotype was significantly associated with fibrosis progression >0.101 U/year (P = 0.007; OR = 2.02) and with cirrhosis (P = 0.022; OR = 1.84). Forty-five percent of bAt[CCA]-haplotype patients were rapid fibrosers, 21.1% were cirrhotic. Likewise, ApaI rs7975232 CC genotype was significantly associated with fibrosis progression and cirrhosis. Lower plasma 25-OH vitamin D levels were significantly associated with fibrosis progression >0.101 U/year in F0-2 patients (P = 0.013). Combined analysis of both variables revealed a highly significant additive effect on fibrosis progression with 45.5% rapid fibrosers for bAt[CCA]-haplotype and 25-OH vitamin D < 20 μg/L compared with only 9.1% for the most favourable combination (P = 0.006). In multivariate analysis, the bAt-haplotype was an independent risk factor for fibrosis progression (P = 0.001; OR = 2.83). Low 25-OH vitamin D plasma levels and the unfavourable VDR bAt[CCA]-haplotype are associated with rapid fibrosis progression in chronic HCV patients. In combination, both variables exert significant additive effects on fibrosis progression.

Niveles séricos de 25 Hidroxivitamina D en mujeres no menopáusicas, menopáusicas y posmenopáusicas

Objetivo: evaluar los niveles séricos de 25 hidroxivitamina D (25-OH vitamina D) en mujeres no menopáusicas, menopáusicas y posmenopáusicas, y su relación con algunos factores de riesgo.Materiales y métodos: estudio analítico de cohorte transversal, realizado en 113 mujeres elegidas consecutivamente en la consulta externa de una institución de tercer nivel de complejidad. Se conformaron tres grupos: grupo A, premenopáusicas de 20 a 30 años (n=40); grupo B, menopáusicas de 45 a 55 años (n=40); y grupo C, posmenopáusicas &gt;65 años (n=33). Se comparó el nivel de 25-OH vitamina D en suero a través del estudio ELISA, y su relación con factores como tabaquismo, exposición solar y actividad física en los últimos tres meses.Resultados: el 76% de las mujeres tenían niveles bajos de 25-OH vitamina D (&lt;25 nmol/L). En el 80% de las mujeres del grupo A, se encontraron niveles bajos de esta vitamina comparado con el 77,5% del grupo B y el 69,7% del grupo C (p=0,57). Hubo diferencias significativas entre las medianas de los valores de 25-OH vitamina D en el grupo B al compararlas con el grupo A y C. El análisis de factores de riesgo para una disminución de los niveles séricos de 25-OH vitamina D no mostró diferencias significativas.Conclusiones: a pesar de estar ubicados en un área geográfica tropical, existen niveles séricos bajos de 25-OH vitamina D en las mujeres de los grupos de edad evaluados.

The Vitamin D Receptor Gene Bat (Cca) Haplotype Impairs the Response to Pegylated-Interferon/ Ribavirin-Based Therapy in Chronic Hepatitis C Patients

Chronic hepatitis C infection is a major cause of end-stage liver disease. Therapy outcome is influenced by 25-OH vitamin D deficiency. To further address this observation, our study investigates the impact of the vitamin D receptor (NR1I1) haplotype and combined effects of plasma vitamin D levels in a well-described cohort of hepatitis C patients. A total of 155 chronic hepatitis C patients were recruited from the Swiss Hepatitis C Cohort Study for NR1I1 genotyping and plasma 25-OH vitamin D level measurement. NR1I1 genotype data and combined effects of plasma 25-OH vitamin D level were analysed regarding therapy response (sustained virological response). A strong association was observed between therapy non-response and the NR1I1 CCA (bAt) haplotype consisting of rs1544410 (BsmI) C, rs7975232 (ApaI) C and rs731236 (TaqI) A alleles. Of the HCV patients carrying the CCA haplotype, 50.3% were non-responders (odds ratio [OR] 1.69, 95% CI 1.07, 2.67; P=0.028). A similar association was observed for the combinational CCCCAA genotype (OR 2.94, 95% CI 1.36, 6.37; P=0.007). The combinational CCCCAA genotype was confirmed as an independent risk factor for non-response in multivariate analysis (OR 2.50, 95% CI 1.07, 5.87; P=0.034). Analysing combined effects, a significant impact of low 25-OH vitamin D levels on sustained virological response were only seen in patients with the unfavourable NR1I1 CCA (bAt) haplotype (OR for non-SVR 3.55; 95% CI 1.005, 12.57; P=0.049). NR1I1 vitamin D receptor polymorphisms influence response to pegylated-interferon/ribavirin-based therapy in chronic hepatitis C and exert an additive genetic predisposition to previously described low 25-OH vitamin D serum levels.

The Association between Prognostic Demographic and Tumor Characteristics of Breast Carcinomas with Serum 25-OH Vitamin D Levels

Abstract Objective: Epidemiologic studies show that women with low 25-OH vitamin D levels have an increased risk of breast cancer incidence and mortality. However, there is a lack of research examining vitamin D levels and prognostic variables in breast cancer patients. The aim of this study is to identify the associations between 25-OH vitamin D levels, demographic variables, and prognostic pathological and genetic characteristics of breast cancers. Method: This study cohort consists of 155 women who underwent breast cancer surgery at the University of Rochester between 1/2009 and 9/2010. Vitamin D levels were obtained in the 1-year period before and after surgery (74% of vitamin D levels within 6 months). Prognostic variables included age, race, menopausal status, Oncotype DX score, TNM staging, ER/PR status, and HER2 expression. ANCOVA, linear regression, and logistic regression were used to determine the association between prognostic variables and 25-OH vitamin D levels, while controlling for relevant covariates (age, race, and month of blood draw). Results: Non-Caucasian (OR = 3.8; P &amp;lt; 0.01) and premenopausal (OR = 3.5; P &amp;lt; 0.01) breast cancer patients were significantly more likely to have suboptimal 25-OH vitamin D levels than Caucasian and postmenopausal patients, respectively. Women with invasive breast tumors were more likely to have suboptimal vitamin D levels (invasive OR = 2.4; P = 0.10) and lower mean 25-OH vitamin D levels (invasive: 30.5 ng/mL vs. in situ: 36.9 ng/mL; P = 0.04). A significant correlation (r = −0.42; P = 0.04) between decreasing vitamin D levels and increasing Oncotype score was noted. Breast cancer patients who had ER- and triple-negative breast tumors were more likely to have suboptimal levels of 25-OH vitamin D (ER-OR = 2.4; P = 0.07; triple-negative OR = 2.6; P = 0.09). Conclusions: Breast cancer patients with suboptimal vitamin D levels were more likely to have tumors with more aggressive tumor profiles, worse prognostic markers (ER- and triple-negative tumors), and higher recurrence risk (Oncotype scores), lending support to previous research that found decreased breast cancer survival among vitamin D deficient individuals. Further research is needed to elucidate the biological relationship between vitamin D and prognostic breast cancer markers.

2235 SHOULD 25-OH VITAMIN D BE CHECKED IN ALL STONE-FORMERS WITH HYPERCALCIURIA AND ELEVATED PTH?

INTRODUCTION AND OBJECTIVES: Secondary hyperparathyroidism (i.e. elevated parathyroid hormone NOT due to a parathyroid adenoma or hyperplasia) may occur in patients with renal leak hypercalciuria and also in patients with low 25-OH vitamin D. Patients with the former condition may benefit from treatment with a thiazide diuretic, while those with the latter may also benefit from vitamin D repletion. METHODS: A retrospective review was performed of patients with hypercalciuria. Patients evaluated in two metabolic stone clinics were included for analysis. Serum 25-OH Vitamin D, PTH, and calcium values were normalized to account for variations in laboratory assays. RESULTS: 79 patients were included in the study. F:M ratio was 40:39, mean age was 48.4 years (SD 13.1) and mean BMI was 26.8 (SD 6.8). Vitamin D deficiency (i.e. vitamin D level lower than the lower limit of normal for a given laboratory) was present in 38/79 patients (48.1%). Mean 24-hour urine calcium was 242.3 mg/day (SD 117.6). In total, 11/79 patients (13.9%) demonstrated PTH values above normal limits and 5 of these 11 patients (45.4%) demonstrated vitamin D deficiency. CONCLUSIONS: In nearly half of stone-patients with elevated PTH, 25-OH vitamin D was below normal. For those patients, the source of secondary hyperparathyroidism may be renal leak hypercalciuria or vitamin D deficiency. We believe it is worthwhile to check vitamin D in stone-formers with elevated PTH as this may lead to the unanticipated diagnosis of vitamin D deficiency.

Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV-HCV co-infected patients with chronic hepatitis

Recent findings in hepatitis C virus (HCV)-monoinfected patients have shown a correlation between low serum levels of 25-OH vitamin D3 [25(OH)D3] and severe liver fibrosis and low sustained virologic response to therapy. Data are lacking in HIV-HCV coinfected patients. One hundred and eighty nine HIV-HCV coinfected patients, who received ≥80% of interferon (IFN) plus ribavirin therapy, were analyzed for baseline serum 25(OH)D3 levels. Correlations between serum 25(OH)D3 levels, chronic hepatitis C features, HCV virologic response to antiviral therapy, and HIV infection characteristics were analyzed. Mean serum 25(OH)D3 level was 18.5 ± 9.8 ng/ml, including 162 (85%) patients with level ≤30 ng/ml. Serum 25(OH)D3 levels were significantly correlated with the histological Metavir fibrosis score (r = -0.16; p = 0.027). Patients with severe fibrosis (Metavir F3/F4) had lower serum 25(OH)D3 levels compared to F2 and F1 patients (16.2 ± 10.0 vs. 18.9 ± 8.5 and 20.9 ± 11.1 ng/ml, respectively; p = 0.06). In multivariate analysis, low serum 25(OH)D levels were independently associated with severe liver fibrosis (p = 0.04) and cold season (p = 0.0002). Serum levels of 25(OH)D3 were also significantly correlated with liver fibrosis as assessed by FibroTest® (r = -0.22; p = 0.008) and serum α2-macroglobulin levels (r = -0.23; p = 0.006). In contrast, no correlation was found between 25(OH)D3 levels and HCV sustained virologic response to IFN-based therapy [OR 0.98 (0.95-1.01); p = 0.22]. No association was found between 25(OH)D3 levels and markers of HIV-related immunodeficiency. In HIV-HCV coinfected patients, low serum 25(OH)D3 levels correlate with severe liver fibrosis. In contrast, serum 25(OH)D3 levels are not linked to HCV virologic response to therapy or severity of immunodeficiency.

25-OH Vitamin D: Is It the Universal Panacea for Metabolic Syndrome and Type 2 Diabetes?

Obesity has become a global epidemic. Consequently, thereareincreasingratesofobesity-relateddiseases such as diabetes, cardiovascular diseases, sleep disorders, andassociatedmorbidityandmortality.Althoughthereis growing debate on the etiopathogenesis of the global pandemic of obesity, there is no question that increasing calories, concomitant decreases in physical activity, and increasingsedentarylifestylearemajorcontributors.Typically, obesity is associated with insulin resistance/hyperinsulinemia, which has been implicated in the increased cardiovascular diseases, metabolic syndrome, and type 2 diabetes.Metabolically,obesityisassociatedwithreduced high-densitylipoproteincholesterolandhightriglycerides and increases in serum total cholesterol, low-density lipoprotein, and small, dense, low-density lipoprotein cholesterol particles. In addition, obesity is regarded as a proinflammatory state with increases in the oxidative stress burden, free oxygen radicals, and F2-isoprostanes. However,theassociationsofobesityandmetabolicderangements are very complex. Although there are direct causal relationships of some of these metabolic derangements with obesity, in some situations, the metabolic change can be a consequence of the obesity per se. Recently, several epidemiological studies have reported increasing prevalence of low serum 25-hydroxy vitamin D (25-OH vitamin D) levels in several communities around the globe. In contrast to old literature, where specific demographic populations such as elderly patients living in higherlatitudesandaltitudes,geographicalareaswithlow sun exposure, religious practices, etc. posed greater risk, there are alarming rates of low serum 25-OH vitamin D levels among seemingly healthy populations, especially in the elderly in the Western industrialized world. This has

Recessive versus imprinted disorder: consanguinity can impede establishing the diagnosis of autosomal dominant pseudohypoparathyroidism type Ib

Hypocalcemia and hyperphosphatemia with low/normal parathyroid hormone (PTH) levels can be observed in hypoparathyroidism (HP), a disorder that may follow an autosomal dominant (AD) or autosomal recessive (AR) mode of inheritance. Similar biochemical changes are also observed in pseudohypoparathyroidism (PHP) type Ia and Ib, but affected patients usually show elevated PTH levels indicative of hormonal resistance. Features of Albright's hereditary osteodystrophy (AHO) are typically not observed in patients affected by familial forms of PHP-Ib, which are most frequently caused by maternally inherited, heterozygous microdeletions within STX16 and are associated with isolated loss of methylation at GNAS exon A/B. We established the molecular defect in two children of consanguineous Turkish parents, who presented with hypocalcemia, hyperphosphatemia, and low 25-OH vitamin D levels, but initially normal or only mildly elevated PTH levels, i.e. findings that do not readily exclude HP. After normalizing serum magnesium levels, hypocalcemia and hyperphosphatemia persisted, and PTH levels increased, suggesting PTH resistance rather than PTH deficiency. Because of the absence of AHO and parental consanguinity, an AR form of PHP-Ib appeared plausible, which had previously been suggested for sporadic cases. However, loss of GNAS methylation was restricted to exon A/B, which led to the identification of the 3-kb STX16 microdeletion. The same mutation was also detected in the healthy mother, who did not show any GNAS methylation abnormality, indicating that her deletion resides on the paternal allele. Our findings emphasize the importance of considering a parentally imprinted, AD disorder even if consanguinity suggests an AR mode of inheritance.

Acute Pseudogout Following Intravenous Neridronate for Osteoporosis

To the Editor: An 84-year-old woman with a history of surgical menopause at the age of 37 years, gastroesophageal reflux disease, and prolonged corticosteroid use (prescribed by her general pratictioner for osteoarthritis-related pain), sustained a low-trauma vertebral fracture at L3 level. Radiographs showed previous L2 fracture. Other investigations were unremarkable, except for low 25-OH vitamin D levels (22.1 ng/ml) and elevated plasma parathyroid hormone (144 pg/ml). She was then diagnosed with osteoporosis, supplemented with 300,000 IU of oral cholecalciferol, and started therapy with neridronic acid (NA), 100 mg intravenously1. Corticosteroids had been tapered before starting NA. The day after her first NA dose, she noticed polyarthralgia, myalgia, and fever (to 38°C). Over the subsequent 5 days, symptoms eased, but she experienced progressive pain and swelling … Address correspondence to Dr. S. Carda, Physical and Rehabilitative Medicine Department, AUO Maggiore della Carità, v. le Piazza d’Armi 1, 28100 Novara, Italy. E-mail: stefano.carda{at}virgilio.it

Relationship of vitamin D and parathyroid hormone with obesity and body composition in African Americans

Obesity disproportionately affects African Americans (AA) (especially women), and is linked to depressed 25-hydroxyvitamin D (25-OH D) and elevated parathyroid hormone (PTH). The relationship of 25-OH D and PTH with body composition and size in AA is not well known. To determine the relationship of 25-OH D and PTH levels with body composition and anthropometric measures. A cross-sectional study was conducted in 98 healthy, overweight, adult AA enrolled in an NIH/NIEHS-sponsored weight loss/salt-sensitivity trial. Multivariable linear regression analyses were used to explore the relationship of 25-OH D and PTH with body composition, determined by dual-energy X-ray absorptiometry, and anthropometric measures. Body composition and size were contrasted across vitamin D/PTH groups using general linear models: (i) normal (25-OH D >50 nmol/l, PTH <or=65 pg/ml), (ii) low 25-OH D and normal PTH and (iii) low 25-OH D and high PTH. Age, gender and season-adjusted regression analyses showed that PTH was directly correlated with total (P = 0.02), truncal (P = 0.03) and extremity (P = 0.03) fat mass, while 25-OH D was inversely related to truncal fat mass (P = 0.02). Total fat mass in groups 1-3, respectively, was 30.0, 34.0 and 37.4 kg (P = 0.008); truncal fat mass was 13.4, 15.9 and 17.6 kg (P = 0.006) and extremity fat mass was 15.8, 16.9 and 19.7 kg (P = 0.02). Lean mass did not differ across the three groups. Our findings show that lower 25-OH D and raised PTH are both correlated, though in opposite directions, with fat mass, fat distribution and anthropometric measures in adult AA.

Should the Concentration of Vitamin D Be Measured in All Patients With Hypertension?

The importance of vitamin D in a variety of health areas has led to increased interest about the prevalence, etiologies and associated morbidities of hypovitaminosis D. The role of vitamin D in absorption of calcium and bone health is well known, but recent data support additional effects on the immune system, cancer, neuromuscular function, and cardiovascular system, including hypertension [1,2]. Vitamin D is converted to 25-hydroxyvitamin D (25-OH D) in the liver and then again to 1,25 dihydroxyvitamin D (1,25-OH D) in the kidney. While 1,25-OH D is the biologically active form of vitamin D, 25-OH D is considered the best indicator of vitamin D status in the body because it circulates in a higher concentration, has a long half-life and is the substrate for 1,25-OH D production [1]. There are several etiologies of vitamin D deficiency and insufficiency (Table 1). The lack of ultraviolet B radiation from sunlight is the most common reason for vitamin D deficiency - northern latitudes, the winter season, sun protection factors (SPF) in lotions to prevent skin exposure to the sun all contribute to this form of vitamin D deficiency or insufficiency. The most common biochemical definition of vitamin D deficiency is a 25-OH D level less than 20 ng/ml (50 nmol/L) while levels from 21 to 29 ng/ml are considered insufficiency [3]. Surveys show that large minorities (40-45%) of elderly Americans and approximately 50% of post-menopausal women in American are deficient or insufficient in Vitamin D [4]. Prevalence rates go up with increasing age due to lesser quantities of the vitamin D precursor in the skin, 7-dehydrocholesterol and in populations with high levels of melanin in the skin (e.g African-Americans and dark-skinned Hispanic populations) since melanin also impairs the absorption of ultraviolet B radiation (Table 1). Table 1 Common Causes of Vitamin D Deficiency Vitamin D and Cardiovascular Disease Vitamin D deficiency is associated with diabetes, obesity, metabolic syndrome and hypertension [5]. In addition, low 25-OH D levels (< 15 to 20 ng/ml) have been associated with the development of hypertension (6) and cardiovascular events (7). In the Framingham Offspring Study participants followed for a median interval of 5.4 years demonstrated a higher relative risk for a cardiovascular event with lower vitamin D levels (Figure 1). The risk of an event increased by 2.13 in subjects with hypertension with 25-OH D levels less than 15 ng/ml [7]. It is impressive that the general risk for cardiovascular disease associated with vitamin D deficiency is comparable to the Framingham-derived risk ratios if the patient has metabolic syndrome (relative risk of 2.1), hypertension (relative risk of 1.7), dyslipidemia (relative risk of 1.8), increased fibrinogen levels (relative risk of 2.42) and homocysteinemia (relative risk of 1.6) [8-11]. Figure 1 Five-year cardiovascular event rates (%) according to varying levels of 25-hydroxyvitamin D in the Framingham Offspring Study. Rates were adjusted for age and sex and grouped according to the presence or absence of hypertension. Modified from reference ... Vitamin D and Hypertension Epidemiologic association between Vitamin D deficiency and hypertension Data from the INTERSALT study suggest a rise in BP is proportional to distance from the equator [12] while seasonal variations in BP have also been reported in temperate climates [13]. Population studies have shown an inverse relationship between vitamin D levels and hypertension, with increasing incidence of hypertension as Vitamin D levels decrease [6, 14]. The largest database is from Forman and colleagues (6) using 117,730 subjects from the Health Professional follow-up study and the Nurse's Health Studies in which there was a median follow-up period of 4 years for the development of incident hypertension. When comparing those individuals whose 25-0H D levels were 30 ng/ml, the relative risk of developing hypertension was 3.18, with a marked gender difference (6.13 in men and 2.67 in women). Hence, a significant inverse relationship exists between vitamin D and development of hypertension.

Variable Clinical Spectrum of the Most Common Inborn Error of Bile Acid Metabolism—3β‐hydroxy‐Δ5‐C27‐steroid Dehydrogenase Deficiency

We studied the clinical features of children with 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase (3beta-HSDH) deficiency presenting to King's College and Great Ormond Street hospitals between 1989 and 2005. The diagnosis was made biochemically by detection of sulphated dihydroxycholenoic acids and trihydroxycholenoic acids in urine by fast atom bombardment mass spectrometry or electrospray ionisation tandem mass spectrophotometry and a plasma bile acid profile showing absent or low cholic and chenodeoxycholic acid levels and high concentrations of 3beta-7 alpha-dihydroxy-5-cholenoic acid and 3beta-7 alpha-12 alpha-trihydroxy-5-cholenoic acid. Eighteen children (12 male) with 3beta-HSDH deficiency were identified and diagnosed at a median age of 1.35 years (range 8 weeks-11 years). The presenting features included neonatal cholestasis (n = 11), rickets (n = 8, 1 of whom also had hypocalcaemic tetany, seizures, and normal liver biochemical markers), hepatomegaly (n = 7), pruritus (n = 3), and steatorrhoea and failure to thrive (n = 3). Ten children had low serum 25-OH vitamin D levels, of whom 8 also had low vitamin E and 6 had low vitamin A serum levels. Liver histology showed giant cell change and hepatocyte disarray in all with added features of cholestasis in 11, bridging fibrosis in 6, micronodular cirrhosis in 1, fatty change in 1, and active lobular and portal inflammation in 1. Five patients were treated with cholic acid and chenodeoxycholic acid (7 mg x kg(-1) x day(-1) of each), 7 with chenodeoxycholic acid only (7-18 mg x kg(-1) x day(-1)), and 1 with cholic acid (8 mg x kg(-1) x day(-1)) only. Repeated liver biopsies performed in 4 patients 6 months after starting replacement therapy showed improved histological changes. Three children died untreated before 5 years of age. After a median follow-up of 5.5 years (range 1-17 years) 12 out of 13 treated children have no clinical signs of liver disease or of fat-soluble vitamin deficiency. 3beta-HSDH deficiency is a rare inborn error of metabolism with diverse clinical features. Early replacement treatment leads to clinical and biochemical control and prevents chronic liver and bone disease, at least in the medium term.

Treat the bones and get less rejection!

Known since antiquity, rickets was a common disease until the beginning of the 20th century. It took many years and the collaborative effort of several laboratories to identify the compound present in cod liver oil responsible for the therapeutic effect against rickets. The vitamin D structure was finally described in 1936 by the German chemist Adolf Windaus (1876–1959). Since then, we have come to understand the synthesis of 1α,25(OH)2-vitamin D3 (calcitriol) and its mechanism of action through a nuclear receptor, VDR, to regulate calcium homeostasis and bone mineralization. VDR is expressed not only in intestinal cells and osteoblasts but also constitutively in monocytes and in activated macrophages, dendritic cells, natural killer cells, T and B cells, which suggests immunomodulatory functions for calcitriol. Calcitriol acts as an inhibitor of the adaptive immune system. It has inhibitory effects on macrophages and dendritic cells. Calcitriol enables dendritic cells with tolerogenic properties (1) and acts directly in Th cells to enhance the development of a Th2 phenotype (2). These features could be of benefit in the transplantation setting. In retrospective studies, the administration of calcitriol to kidney transplant recipients improved graft function, graft survival and decreased episodes of acute rejection (3–5). Similar results have been published for heart transplantation. Low post-operative calcitriol serum concentrations are independently associated with high 1-year mortality in cardiac transplant recipients (6). Patients receiving low-dose calcitriol after cardiac transplantation required substantially lower cumulative doses of cyclosporin for organ rejection without any detectable change in the episodes of rejection (7). What about liver transplantation and calcitriol? We investigated the effect of calcitriol as an immunosuppressive agent in an experimental model for liver transplantation (8). Calcitriol increased the survival of vascularized liver allografts in rats when compared with controls. Vitamin D reduced the concentration of interleukin (IL)-2 and IL-12 in serum and in grafts, and increased IL-4 and IL-10 in the grafts. The rejection activity after transplantation was significantly lower in treated rats compared with vehicle-treated controls. In this issue of Liver International, Bitetto et al. (9) present a highly anticipated clinical study that investigates whether vitamin D has beneficial immune properties after liver transplantation. Based on a collection of 133 liver transplantation recipients, the authors report that a low pretransplant serum 25-OH vitamin D is independently associated with rejection episodes (Banff score ≥6) in the first 2 months following liver transplantation and that the introduction of vitamin D3 supplementation in the first month after liver transplantation is associated with a decreased risk for acute rejection (Banff score ≥3) in the following 3–8 months. These results are not surprising, but are important nonetheless. It is estimated that two-third of patients with cirrhosis and 96% of patients awaiting liver transplantation have low serum vitamin D levels (10) and the present study found optimal vitamin D levels (>30 ng/ml) in only 7.5% of the patients tested. Osteoporosis, which increases the risk of vertebral fractures, occurs in 12–55% of patients with cirrhosis (10). In the months following liver transplantation, further bone loss occurs in most liver recipients and exacerbates pre-existing osteopenia with a high incidence of fracturing (10). Patients listed for a liver transplantation should then receive vitamin D before and after transplantation. This supplementation is safe, well tolerated and appears to have additional non-negligible immune effects. Acute rejection is rarely a serious issue after liver transplantation today. Nevertheless, immunosuppressive drugs have side effects, which limit the long-term benefit of liver transplantation. Calcineurin inhibitors impair renal function and every large liver transplantation centre must provide dialysis for some of their transplant recipients and some even receive kidney transplantation. The hope that mTOR inhibitors could serve as renal protective immunosuppressors is vanishing. A retrospective, controlled study showed that the administration of sirolimus after orthotopic liver transplantation did not protect against renal dysfunction (11). Another case–control retrospective series suggested that the choice of sirolimus for liver transplant patients with chronic renal insufficiency is associated with the stabilization of renal function but conferred no additional benefit over low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of <30 ml/min (12). In this context, vitamin D as a calcineurin inhibitor sparing immunosuppressant in liver transplantation is an attractive option. The retrospective nature of the work of Bitetto is a disadvantage as are the arbitrarily chosen endpoints. It is imperative that prospective randomized studies be designed in the liver transplantation field to establish definitively the immunosuppressive role of vitamin D as it is already the case in the renal transplantation field (13). We should not miss the opportunity to treat the bones and get less rejection!

The Prevalence of 25-Hydroxyvitamin D Deficiency in Post-HSCT Pediatric Patients.

Children undergoing HSCT are at risk for vitamin D deficiency due to lack of sun exposure, the recommended use of sunscreen, dietary insufficiency, and the effects of medications such as glucocorticoids and calcineurin inhibitors. We assessed the prevalence of 25-hydroxyvitamin D (25-OH vitamin D) deficiency in pediatric post-HSCT patients in an outpatient oncology clinic during 4 weeks in May 2008. Patients found to have low 25-OH vitamin D levels were referred for dietary counseling and given supplementation or repletion as needed. 25-OH vitamin D and parathyroid hormone (PTH) levels were measured in 62 (88.6%) of 70 eligible patients. 83.8% of patients had a 25-OH vitamin D level less than the institutional lower limit of normal, 30 ng/mL. 29% of patients were 25-OH vitamin D insufficient with levels 20–29 ng/mL (range of 20–29). 54.8% of patients were 25-OH vitamin D deficient with levels <20 ng/mL (range 5–19). The prevalence of insufficiency and deficiency was similar between male (87.8%; 57.6%) and female patients (57.6%; 55.2%).The mean duration of days following transplant was 532.6 days (median 251.5 days). The mean age at transplant was 3.7 years (median 3.5 years). 47% of patients were female. 75.8% were Caucasian. 90.3% received allogeneic transplants. The underlying diseases were as follows: ALL (27.4%), AML/MDS (24.2%), bone marrow failure (11.3%), nonmalignant hematologic diagnosis (8.1%), solid tumor (8.1%), immunodeficiency (6.5%), lymphoma (6.5%), and other diagnoses (8.1%). 8 patients regularly took either an over-the-counter multivitamin or vitamin D supplement and all 8 patients had 25-OH levels less than 30 ng/mL. There was a negative inverse correlation of (r= −0.3, p=0.029) between PTH and 25-OH vitamin D. There were no significant associations between 25-OH vitamin D level and any of the following: corticosteroid or calcineurin inhibitor use in the preceding year, time from transplant, age at transplant, current age, or graft-versus-host disease. 25-OH vitamin D insufficiency and deficiency are common following pediatric HSCT. We recommend vitamin D screening for all post-HSCT pediatric patients. Further investigation is needed to identify potential risk factors for vitamin D deficiency and the long-term effects of deficiency on bone health and development.

Chemotherapy is linked to severe vitamin D deficiency in patients with colorectal cancer

Preclinical and clinical evidence support an association between vitamin D deficiency and an increased risk of colorectal cancer. Normal vitamin D status has been linked to favorable health outcomes ranging from decreased risk of osteoporosis to improved cancer mortality. We performed a retrospective study to assess the impact of metastatic disease and chemotherapy treatment on vitamin D status in patients with colorectal cancer residing in Western New York. Patients, 315, with colorectal cancer treated in a single institute were assayed for 25-OH vitamin D. The association of age, gender, primary disease site and stage, body mass index, and chemotherapy with vitamin D status was investigated. Vitamin D deficiency was common among participants with a median 25-OH vitamin D level of 21.3 ng/ml (optimal range 32-100 ng/ml). Primary site of disease and chemotherapy status were associated with very low 25-OH vitamin D levels (< or =15 ng/ml) on multivariate analysis. Patients receiving chemotherapy and patients with a rectal primary were 3.7 and 2.6-fold more likely to have severe vitamin D deficiency on multivariate analysis than nonchemotherapy patients and colon cancer primary patients, respectively. Chemotherapy is associated with a significant increase in the risk of severe vitamin D deficiency. Patients with colorectal cancer, especially those receiving chemotherapy, should be considered for aggressive vitamin D replacement strategies.

Calcium, Parathormone, and Vitamin D Abnormalities among Roux-en-Y Gastric Bypass Patients

Background: Malabsorption of vitamin D and calcium is a known side effect of laparoscopic gastric bypass (LGB). Our objective was to identify the prevalence of abnormalities in calcium, parathormone (PTH), and 25-OH vitamin D levels in patients undergoing LGB, and the correlation of reported compliance with supplementation, and seasonal variation on vitamin D levels. Methods: Patients undergoing LGB from September 2003 through June 2004 were included. Calcium and PTH levels were obtained preoperatively. At 1 year postoperatively, calcium, PTH, and vitamin D levels were obtained. Laboratory values were classified as low, normal, or high, based on standard reference ranges. Results were analyzed using the exact binomial test. Results: One-year follow-up laboratory data were available for 70 patients: 10 males and 60 females with a mean age of 44.7 years. The mean preoperative body mass index was 47.4 kg/m2. Mean percent excess weight loss at 1 year was 73.4%. Nine patients (14.3%) had elevated PTH levels preoperatively, and seven patients (10.3%) had elevated PTH postoperatively (p ≤ 0.001). The incidence of low 25-OH vitamin D levels postoperatively was 40.4%. Conclusions: A significant percentage of patients undergoing LGB present with an abnormally high PTH level. Abnormally low vitamin D levels are quite prevalent 1 year after LGB, despite normal serum calcium levels. The month of surgery (summer vs. winter) did not have an impact on PTH, calcium, or vitamin D levels. Patients' self-reported compliance or noncompliance with recommended supplementation did not correlate with their vitamin D levels.

Review: Vitamin D, immunity and lupus

The identification of vitamin D receptor in cells involved in the immune response and the discovery that activated dendritic cells produce vitamin D hormone suggested that vitamin D could exert immunoregulatory effects. Patients with autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus (SLE) show low 25-OH vitamin D serum levels. In particular, SLE patients have multiple risk factors for vitamin D deficiency and disease severity seems correlated with lower 25-OH vitamin D serum levels. Treatment of vitamin D deficiency could be particularly important in SLE patients due to concomitant insults on their tissues such as bone, and in view of the possible immunomodulatory effects exerted by vitamin D.

Vitamin D Supplementation and Cardiovascular Disease Risk

Many studies,1,2 but not all, have shown that low bone density is associated with increased cardiovascular disease (CVD) risk. Vitamin D deficiency is common in the elderly and is associated with osteoporosis; however, the association of endogenous 25-OH vitamin D (25-OH D) levels with CVD events is controversial.3,4 CVD rates are higher during winter seasons and at increased geographic latitudes where average serum vitamin D levels are lowest.5 Low 25-OH D levels have been found in stroke6 and heart failure patients.7 Moreover, 25-OH D deficiency is associated with hypertension, obesity,8 glucose intolerance,8 and the metabolic syndrome,9 which may be responsible, at least in part, for its association with increased CVD risk. Article p 846 Although vitamin D supplementation improves bone strength, elevated serum vitamin D levels may be associated with lower levels of vascular calcification. In subjects at moderately high risk for coronary heart disease, endogenous serum vitamin D levels were inversely correlated with the extent of coronary artery calcification as determined by cardiac computed tomography.10 Vitamin D also has intriguing antiinflammatory properties11 that have potential therapeutic benefit in several autoimmune diseases and allograft rejection. In 2 small clinical trials,12,13 vitamin D supplementation lowered C-reactive protein levels. Additionally, 1,25(OH)2D induces relaxation of vascular smooth muscle cells …

Long-Term Vitamin D Supplementation Improves Bone Mineral Density (BMD) in Patients with Sickle Cell Disease.

Among the many complications of sickle cell disease (SCD) are osteopenia and osteoporosis. We and others have previously documented a high prevalence of low serum 25-OH vitamin D level with accompanying osteopenia and osteoporosis in patients with SCD; however the long-term effects of treatment on BMD have not been reported. We hypothesized that supplementation with oral vitamin D and calcium will result in an improvement in BMD and accordingly, treated 6 adult subjects with SCD for 12 months with oral supplementation with vitamin D and calcium and studied the effects of treatment on BMD. Subjects with serum 25-OH D levels <20 ng/ml were placed on 50,000 IU of oral vitamin D weekly for 8 weeks, followed by 50,000 IU every other week for 44 weeks; subjects also received 1000 mg of elemental calcium daily. We evaluated BMD at weeks 1 and 52. Subjects had a mean pre-treatment plasma 25-OH vitamin D of 9.1 ng/ml. BMD was abnormal in all subjects; 4 subjects had osteoporosis with a Z-score <-2.5, and 2 subjects had osteopenia with a Z-score −1.9 to −2.5 (in the lumbo-sacral vertebrae). All subjects had mildly elevated intact PTH levels which were within the reference range but declined further post-treatment. Following one year of treatment with vitamin D and calcium, we observed a mean post-treatment increase in BMD of 5.4% (p value <0.02) and a 176% increase in plasma 25-OH D level (from 9.1ng/ml to 28ng/ml; p value <0.009). All patients with SCD we have studied have hypovitaminosis D that in adults is associated with low BMD. In patients followed for one year who received supplementation with calcium and vitamin D, 25-OH D level increased in all and BMD improved in four of six subjects. These results suggest that this treatment regimen can be effective is restoring BMD. The reasons for apparent unresponsiveness in some patients must be further evaluated. Clinical trials to document the effectiveness of treatment for this ubiquitous problem should be instituted. [Display omitted] [Display omitted]