Ravinder Goswami

Prevalence of vitamin D deficiency and its relationship with thyroid autoimmunity in Asian Indians: a community-based survey.

25-Hydroxy vitamin D (25(OH)D) deficiency is linked with predisposition to autoimmune type 1 diabetes and multiple sclerosis. Our objective was to assess the relationship between serum 25(OH)D levels and thyroid autoimmunity. Subjects included students, teachers and staff aged 16-60 years (total 642, 244 males, 398 females). Serum free thyroxine, thyroid-stimulating hormone (TSH), and thyroid peroxidase autoantibodies (TPOAb), intact parathyroid hormone and 25(OH)D were measured by electrochemiluminescence and RIA, respectively. Thyroid dysfunction was defined if (1) serum TSH > or = 5 microU/ml and TPOAb>34 IU/ml or (2) TSH > or = 10 microU/ml but normal TPOAb. The mean serum 25(OH)D of the study subjects was 17.5 (sd 10.2) nmol/l with 87 % having values < or = 25 nmol/l. TPOAb positivity was observed in 21 % of subjects. The relationship between 25(OH)D and TPOAb was assessed with and without controlling for age and showed significant inverse correlation (r - 0.08, P = 0.04) when adjusted for age. The prevalence of TPOAb and thyroid dysfunction were comparable between subjects stratified according to serum 25(OH)D into two groups either at cut-off of < or = 25 or >25 nmol/l or first and second tertiles. Serum 25(OH)D values show only weak inverse correlation with TPOAb titres. The presence of such weak association and narrow range of serum 25(OH)D did not allow us to interpret the present results in terms of quantitative cut-off values of serum 25(OH)D. Further studies in vitamin D-sufficient populations with wider range of serum 25(OH)D levels are required to substantiate the findings of the current study.

Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism

The pathogenesis of basal ganglia calcification (BGC) in hypoparathyroidism is not clear. Its occurrence in hypocalcaemic milieu of hypoparathyroidism is believed to be due to high serum calcium–phosphorus product and poor calcium control.

Prevalence of the triple X syndrome in phenotypically normal women with premature ovarian failure and its association with autoimmune thyroid disorders.

OBJECTIVE To determine the prevalence of triple X females among patients with premature ovarian failure and to describe the clinical features of the syndrome. DESIGN Case report. SETTING Tertiary care hospital. PATIENT(S) Fifty-two consecutive patients with secondary amenorrhea due to premature ovarian failure and no clinical stigmata of Turners syndrome. MAIN OUTCOME MEASURE(S) Triple X syndrome and clinical features, as assessed by karyotype analysis using Giemsa trypsin banding of metaphase chromosomes. RESULT(S) Two of the 52 patients with premature ovarian failure had triple X syndrome. Both cases had associated autoimmune thyroid disorder. One of the women with triple X syndrome had two pregnancies that were complicated by premature birth, idiopathic thrombocytopenia, neonatal death, and occipital encephalocoele. CONCLUSION(S) Among patients with premature ovarian failure, 3.8% have triple X syndrome. The syndrome may be associated with autoimmune thyroid disorder and poor pregnancy outcome due to congenital malformation.

Interaction of Vitamin D Receptor with HLA DRB1*0301 in Type 1 Diabetes Patients from North India

Background Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where interaction and integration of immune response genes along with environmental factors play a role in autoimmune destruction of the insulin producing Pancreatic Beta cells. Methodology/Principal Findings We have studied four single nucleotide polymorphisms (FokI site in Exon 2, BsmI and ApaI sites in Intron 8 and TaqI site in exon 9) in the vitamin D receptor (VDR) gene using PCR-RFLP and HLA-DRB1 alleles using PCR and hybridization with sequence specific oligonucleotide probes and studied their interaction using LD based statistics for non-linked loci followed by sequence analysis of the vitamin D response element (VDRE) present in the promoter region of HLA-DRB1*0301. Haplotypes, constructed using SHEsis program for four single nucleotide polymorphisms in the VDR gene, were studied for their interaction with HLA-DRB1 alleles in 233 T1D patients and 191 healthy controls from North India. A significant increase of haplotypes FBAt and fBAT (p<0.02, OR = 1.44 and p<0.002, OR = 3.23 respectively) was observed in the patients. Both the haplotypes FBAt and fBAT were significantly increased in male patients with age at onset less than 18 years; however, fBAT was significantly increased in female patients irrespective of their age at onset. LD based statistics showed significant interaction between the high producer F and T alleles with HLA-DRB1*0301. F and T alleles of VDR have been shown to contribute to VDR mRNA independently. The promoter sequence analysis of HLA-DRB1*0301 showed presence of VDRE involved in higher expression of HLA-DRB1*030, which was confirmed by flow cytometry and real time PCR analysis. Conclusions/Significance These data suggest that the interaction between VDR and HLA alleles is mediated by VDRE present in the promoter region of HLA-DRB1*0301 allele, which may be detrimental for the manifestation of T1D in the absence of 1,25-(OH)2D3 in early childhood due to poor expression of DRB1*0301 in the thymus resulting in autoimmunity.

Effect of cholecalciferol and calcium supplementation on muscle strength and energy metabolism in vitamin D-deficient Asian Indians: a randomized, controlled trial

Context  Vitamin D deficiency is prevalent worldwide. Vitamin D supplementation has shown variable effect on skeletal muscle strength in the elderly with hypovitaminosis D. There is a paucity of similar data in young individuals.

Prevalence of urinary tract infection and renal scars in patients with diabetes mellitus

In a case control study, we assessed the prevalence of bacterial urinary tract infections (UTI) and renal scarring in 155 consecutive type 1 (n=102) and type 2 (n=53) diabetic individuals and 128 healthy controls. Subjects who received antibiotics during the past 6 months, pregnant women and those with overt renal failure were excluded. In all subjects, urine culture and 99m Technetium (Tc) dimercapto-succinic acid renal scan was performed. UTI was diagnosed if two consecutive urine cultures grew the same organism with at least 10(5) colony forming unit (cfu)/ml in asymptomatic and at least 10(4) cfu/ml in symptomatic subjects, respectively. Renal scan was considered abnormal if focal or multiple tracer uptake defects and/or break in cortical outline were observed. The prevalence of UTI in diabetes mellitus was higher, when compared to that in controls (9% vs. 0.78%, P=0.005). Escherichia coli was the most commonly grown organism (64.3%), followed by Staphyloccocus aureus (21.4%) and Klebsiella pneumoniae (14.3%). Prevalence of renal scarring was higher in patients with diabetes (28/155, 18.0%), when compared to that of controls (7/128, 5.4%, P=0.002). Fifty percent of patients with diabetes and UTI had renal scarring. The prevalence in diabetics with no UTI was also higher, when compared to controls (14.8 vs. 5.5%, P<0.01). The prevalence of UTI as well as renal scarring was significantly higher in females, when compared to male diabetics. No significant difference in vascular events, hypertension, proteinuria, renal function tests and HbA1 was observed in patients with and without renal scar. Thus, patients with diabetes mellitus have 10- and 3-folds increased risk of UTI and renal scarring, respectively. The results could help prioritize protocols for management of UTI among patients with diabetes mellitus.

Skeletal muscle strength in young Asian Indian females after vitamin D and calcium supplementation: a double-blind randomized controlled clinical trial.

CONTEXT Randomized control trials (RCT) of the effect of vitamin D/calcium supplementation on skeletal muscle strength have not shown promising effect in the elderly. OBJECTIVE Our objective was to assess the effect of vitamin D and/or calcium on muscle strength in young adults with vitamin D deficiency. DESIGN AND SETTING We conducted a RCT using a factorial design at a tertiary-care center from September 2010 to April 2011. SUBJECTS A total of 173 healthy females with mean age, body mass index, and 25-hydroxyvitamin D [25(OH)D] of 21.7 ± 4.4 yr, 20.8 ± 2.96 kg/m(2), and 9.3 ± 3.37 ng/ml, respectively, were block randomized to 1) double placebo, 2) calcium/placebo, 3) cholecalciferol/placebo, and 4) cholecalciferol/calcium for 6 months. Cholecalciferol was given at 60,000 IU/wk for 8 wk followed by 60,000 IU/fortnight. Elemental calcium was given in doses of 500 mg twice per day for 6 months. METHODS Assessment included hand grip (primary outcome) and pinch grip strength, distance walked in 6 min, dyspnea score, quality of life by Short Form (36) Health Survey (SP-36), serum 25(OH)D, 1,25-dihydroxyvitamin D, and intact PTH. RESULTS The serum 25(OH)D increased significantly to 29.9 ± 8.35 and 27.0 ± 9.54 ng/ml in two groups on cholecalciferol. The mean hand grip strength (19.4 ± 3.92, 21.1 ± 3.31, 20.6 ± 3.92, and 20.1 ± 4.00 kg) and its increase from baseline (0.3 ± 2.25, 0.3 ± 2.64, -0.3 ± 2.41, and 0.6 ± 2.30 kg) were comparable in four groups at 6 months. Quality of life, urinary calcium/creatinine ratio, and adverse effects were also comparable in groups. CONCLUSION Oral cholecalciferol/calcium supplementation in the dose/schedule used is effective and safe in increasing and maintaining serum 25(OH)D. However, this does not lead to improved skeletal muscle strength in young females.

Pattern of 25-hydroxy vitamin D response at short (2 month) and long (1 year) interval after 8 weeks of oral supplementation with cholecalciferol in Asian Indians with chronic hypovitaminosis D

Hypovitaminosis D is common in Asian Indians. Physicians often prescribe 1500 mug (60 000 IU) cholecalciferol per week for 8 weeks for vitamin D deficiency in India. Its efficacy to increase serum 25-hydroxy vitamin D (25(OH)D) over short (2 months) and long (1 year) term is not known. We supplemented a group of twenty-eight apparently healthy Asian Indians detected to have low serum 25(OH)D (mean 13.5 (sd 3.0) nmol/l) on screening during January-March 2005. Serum parathyroid hormone (PTH) level was supranormal in 30 % of them. Oral supplementation included 1500 mug cholecalciferol per week and 1g elemental Ca daily for 8 weeks. Serum 25(OH)D, total Ca, inorganic P and intact (i) PTH were reassessed in twenty-three subjects (twelve females and eleven males) who had follow up at both 8 weeks and 1 year. At 8 weeks the mean 25(OH)D levels increased to 82.4 (sd 20.7) nmol/l and serum PTH normalized in all. Twenty-two of the twenty-three subjects had 25(OH)D levels>49.9 nmol/l. At 1 year, though the mean 25(OH)D level of 24.7 (sd 10.9) nmol/l was significantly higher than the baseline, all subjects were 25(OH)D deficient. Five subjects with supranormal iPTH at baseline showed recurrence of biochemical hyperparathyroidism. Thus, with 8 weeks of cholecalciferol supplementation in Asian Indians with chronic hypovitaminosis D, mean serum 25(OH)D levels would be normalized and serum PTH value would be reduced to half. However, such quick supplementation would not maintain their 25(OH)D levels in the sufficient range for 1 year. For sustained improvement in 25(OH)D levels vitamin D supplementation has to be ongoing after the initial cholecalciferol loading.

Calcium-Sensing Receptor Autoantibodies and Idiopathic Hypoparathyroidism

CONTEXT Data on calcium-sensing receptor autoantibodies (CaSRAbs) in hypoparathyroidism are variable. OBJECTIVE We assessed the prevalence and significance of CaSRAbs in idiopathic hypoparathyroidism. DESIGN This was a case-control study. SUBJECTS One hundred forty-seven patients with idiopathic hypoparathyroidism treated during 1998-2011 in a tertiary care setting and 348 controls [healthy, n = 199; type 1 diabetes mellitus (T1DM), n = 99; and chronic lymphocytic thyroiditis (CLT), n = 50] participated in the study. METHODS CaSRAb assays included Western blot with CaSR protein expressed in Escherichia coli or human embryonic kidney (HEK)-293 cells, immunoprecipitation (IP) using in vitro-transcribed/translated protein, and indirect immunofluorescence on HEK293-CaSR. Functional significance was assessed by ERK1/2 phosphorylation. PTH and CaSR genes were sequenced for mutations. RESULTS E coli-Western blot assay revealed 16.3% CaSRAb positivity in idiopathic hypoparathyroidism, which was comparable with healthy subjects and CLT but significantly less than the T1DM controls. The prevalence of CaSRAbs on HEK293-Western blot (24.5%) against 150 kDa and/or 168 kDa protein in hypoparathyroidism was significantly higher than the healthy subjects, T1DM, and CLT. IP assay showed CaSRAbs in 12.9% of the hypoparathyroid patients but not in controls. The sensitivity and specificity of CaSRAbs in E coli and HEK-293-CaSR Western blot and IP assays were 16.3% and 83.1%, 24.5% and 88.9%, and 12.9% and 100%, respectively, and 42.1% of the cases detected were common in the IP assay and HEK293-Western blot. Duration of illness and coexistent autoimmunity were similar in patients with and without CaSRAbs. The CaSRAb-positive sera showed no immunofluorescence and phosphorylated ERK1/2 activity. The CaSR gene sequence was normal in all patients. One of the patients showed a novel p.Met1_Asp6del mutation in the signal peptide region of the PTH gene. CONCLUSION IP performed the best in detecting CaSRAbs in 12.9% of hypoparathyroid patients. Although CaSRAbs were functionally inert, its clinical relevance remains due to 100% specificity. Limited prevalence of CaSRAb suggests heterogeneity in the etiology of idiopathic hypoparathyroidism or the presence of CaSR epitopes other than those measured in the current study.

Neuropsychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium

BACKGROUND There is limited information on neuropsychological and neurological dysfunctions in patients with idiopathic hypoparathyroidism (IH). OBJECTIVE To assess neuropsychological and neurological dysfunctions in IH and its associated factors in a cross-sectional design. METHOD Neuropsychological functions were assessed in 62 patients with IH and 70 controls using a battery of cognitive tests. Neurological assessment included extrapyramidal and cerebellar signs. Assessment of intracranial calcification and volume of basal ganglia calcification (BGC) were made on computed tomography and of calcium control by averaging serum total calcium values available during the follow-up. RESULTS A significantly higher proportion of patients with IH showed neuropsychological dysfunctions than controls (32.3 (95% CI: 20.9-45.3) vs 5.7% (95% CI: 1.6-14.0), P<0.001). Neurological signs were present in 35.5% patients (extrapyramidal: 16.1%; cerebellar: 20.9%). Volume of BGC and number of sites with intracranial calcifications including cerebellum/dentate were comparable in patients with and without neuropsychological, extrapyramidal or cerebellar dysfunctions. Cognitive dysfunction score was lower by 1.7 points in males than in females (P=0.02) and increased by 0.21 and 5.5 for each year increase in the duration of illness (P=0.001) and one unit increase in serum calcium-phosphorus product (P=0.01) respectively. The scores improved by 0.27 for every mg% increase in serum calcium (P=0.001). CONCLUSION Neuropsychological dysfunctions are present in up to one-third of patients with IH and correlate with duration of illness, female gender, serum calcium and calcium-phosphorus product during follow-up but not with intracranial calcification. These dysfunctions may affect their daily functions, safety and drug compliance.