Role of Glitazars in atherogenic dyslipidemia and diabetes: Two birds with one stone?

A triad of high triglycerides, low high-density lipoprotein (HDL) cholesterol, and elevated small dense low-density lipoprotein particles occurring in a patient with type 2 diabetes is referred to atherogenic diabetic dyslipidemia (ADD). Despite statin therapy, a significant residual risk remains potentially attributable to increased triglyceride concentration and low HDL cholesterol, a characteristic hallmark of ADD. Current therapeutic options in reducing this residual risk include nicotinic acid, omega 3 fatty acids, and selective peroxisome proliferator-activated receptor-alpha (PPAR) agonists (fibrates). These drugs are limited in their potential either by lack of evidence to support their role in reducing cardiovascular events or due to their side effects. This review details their current status and also the role of new glitazar, saroglitazar adual PPARα/γ agonist with predominant PPARα activity in the management of ADD.

Risk and outcome of multidrug-resistant tuberculosis: vitamin D receptor polymorphisms and serum 25(OH)D.

SETTING: All India Institute of Medical Sciences and Rajan Babu Institute of Pulmonary Medicine and Tuberculosis, New Delhi, India. OBJECTIVE: To investigate the association of vitamin D receptor (VDR) polymorphisms and serum 25(OH)D with susceptibility to, and response to treatment of, multidrug-resistant tuberculosis (MDR-TB) in comparison with drug-susceptible pulmonary TB (DS-PTB) and healthy controls. DESIGN: Cross-sectional study. METHODS: A total of 897 participants from northern India were consecutively enrolled into three groups (MDR-TB 354, DS-PTB 338, controls 205). Genotypic and allelic frequencies of FokI, BsmI and TaqI VDR polymorphisms, and serum 25(OH)D, calcium and intact parathyroid hormone were measured in all participants. In those with active TB, disease severity, time to sputum smear and culture conversion were correlated with VDR genotype and biochemical parameters. RESULTS: FokI Ff genotype and TaqI t allele correlated positively with MDR-TB; Ff genotype and f allele of FokI frequency were higher in both TB groups. BsmI Bb genotype correlated inversely with MDR-TB. Serum 25(OH)D concentrations were significantly lowest in MDR-TB, correlating inversely with time to sputum smear conversion. CONCLUSIONS: VDR gene polymorphisms and hypovitaminosis D may predispose to MDR-TB. Lower serum 25(OH)D may increase time to MDR-TB sputum smear negativity.

Bone disease in thyrotoxicosis.

Thyrotoxicosis, a clinical syndrome characterized by manifestations of excess thyroid hormone, is one of the commonly-recognised conditions of the thyroid gland. Thyrotoxicosis causes acceleration of bone remodelling and though it is one of the known risk factors for osteoporosis, the metabolic effects of thyroxine on bone are not well discussed. Studies show that thyroid hormones have effects on bone, both in vitro and in vivo. Treatment of thyrotoxicosis leads to reversal of bone loss and metabolic alterations, and decreases the fracture risk. There are limited studies in India as to whether these changes are fully reversible. In this review we discuss about the effects of thyrotoxicosis (endogenous and exogenous) on bone and mineral metabolism, effects of subclinical thyrotoxicosis on bone and mineral metabolism and effects of various forms of treatment in improving the bone mineral density in thyrotoxicosis.

Standardisation of a two-site PTH immunoradiometric assay using various solid phase formats.

BACKGROUND & OBJECTIVES: Estimation of parathyroid hormone (PTH) levels is important in the management of metabolic bone disorders. Here we describe a simple, sensitive and specific second generation immunoradiometric assay (IRMA) to detect intact PTH levels using different solid phase matrices. Different methods for immobilization of antibodies have also been evaluated. METHODS: Experiments were carried out with physical adsorption of antibodies, covalent coupling using 2 per cent glutaraldehyde and N,N`carbonyldiimidazole. In all cases, antibodies raised against C-terminal were used as solid phase agent. Detector antibodies were N terminal antibodies that were radio-iodinated with [125] I followed by gel purification. Several of the antibodies coupled to various solid phase matrices were incubated with PTH standards and the detector antibody as well as the commercially available tracer from DiaSorin kit to identify a suitable match pair. RESULTS: The best pair was polyclonal C-terminal PTH antibody along with the kit tracer from DiaSorin with regards to antibody coated to magnetic cellulose particles. Among the various antibodies and the solid phases evaluated, the best assay was obtained with the matched pair of antibodies (70×G67 and 70×G68) from Fitzgerald immobilized on polystyrene tubes. The polyclonal antibody against C-terminal PTH was chosen as the capture antibody and [125] I labelled polyclonal antibody against N-terminal PTH as the tracer. The sample values obtained in the antibody coated tubes were comparable to those obtained using a commercial kit. INTERPRETATION & CONCLUSIONS: The results indicated the feasibility of adopting this system for further development into a PTH IRMA for regular production as there is no indigenous kit available for intact PTH.

Vitamin D status and bone mineral density in women of reproductive and postmenopausal age groups: a cross-sectional study from south India.

INTRODUCTION: This study documents 25(OH)D status and bone mineral density (BMD) in women of reproductive (WR) and post-menopausal (PMW) age-groups in south India. SUBJECTS AND METHODS: Serum calcium (Ca), phosphorus (iP), albumin, alkaline phosphatase (ALP), creatinine, 25(OH)D and intact parathormone (N-tact PTH) of WR (n = 55) and PMW (n = 136) women were analyzed over a period of one year. Bone mineral Density (BMD) (Hologic, USA) was estimated using Caucasian data as reference. RESULTS: In both, WR and in PMW 25(OH)D deficiency (< 20 ng/ml), insufficiency (20-30 ng/ml) and replete states (> 30 ng/ml) were seen in 76%, 16.5%, 7.5% vs 70%, 23% and 7% respectively. PMW had lower BMD (gm/cm2) than WR at forearm ( P = < 0.001), hip trochanter (P = < 0.0001), lumbar spine antero-posterior (LSAP) (P = < 0.001) and lateral (LS Lateral) (P = < 0.001). Osteoporosis was seen at hip (15% and 28%), forearm (nil and 11%), LSAP (6% and 22%) and LS lateral (0% and 23%) among WR and PMW respectively. BMD did not correlate with any of the biochemical indices but correlated with BMD at other sites. CONCLUSIONS: Vitamin D deficiency coexists with low BMD in our study group. Serum 25(OH)D needs to be documented in women having low BMD. Calcium and vitamin D need to be supplemented as part of therapy in PMW.

High prevalence of associated birth defects in congenital hypothyroidism.

Aim. To identify dysmorphic features and cardiac, skeletal, and urogenital anomalies in patients with congenital hypothyroidism. Patients and Methods. Seventeen children with congenital primary hypothyroidism were recruited. Cause for congenital hypothyroidism was established using ultrasound of thyroid and (99m)Tc radionuclide thyroid scintigraphy. Malformations were identified by clinical examination, echocardiography, X-ray of lumbar spine, and ultrasonography of abdomen. Results. Ten (59%) patients (6 males and 4 females) had congenital malformations. Two had more than one congenital malformation (both spina bifida and ostium secundum atrial septal defect). Five (29%) had cardiac malformations, of whom three had only osteum secundum atrial septal defect (ASD), one had only patent ductus arteriosus (PDA), and one patient had both ASD and PDA. Seven patients (41%) had neural tube defects in the form of spina bifida occulta. Conclusion. Our study indicates the need for routine echocardiography in all patients with congenital hypothyroidism.

The effect of anti epileptic drug therapy on serum 25-hydroxyvitamin D and parameters of calcium and bone metabolism--a longitudinal study.

BACKGROUND: Chronic antiepileptic drug use is associated with bone loss. We sought to assess the longitudinal effect of antiepileptic drug on serum 25-hydroxyvitamin D [25(OH)D] levels and bone mineral metabolism markers. METHODS: Patients in the emergency services or those in neurology outpatient department with history of seizure were characterized and included in the study prospectively. Daily dietary intake of calories, calcium, phosphorus and phytates were characterized by dietary recall method. Base line bone mineral parameters - serum calcium, phosphorus, alkaline phosphatase (SAP), tartrate resistant acid phosphatase (TRACP), 25(OH)D levels, parathyroid hormone (PTH) and urinary calcium creatinine ratio (Ca.Cr), urinary calcium/kg/bodyweight (BW) and phosphate excretion index (PEI) were determined. Patients on AED therapy with normal 25(OH)D levels were followed up and were re-evaluated at the end of 6 months. RESULTS: The daily dietary calcium intake of the subjects was lower than the RDA (Recommended Dietary Allowance) by ICMR (Indian Council of Medical Research). The diet was high in phytates. Two-thirds of the recruited subjects were vitamin D deficient. Subjects with normal 25(OH)D levels at base line showed a significant fall of 25(OH)D levels, urinary calcium, urinary calcium/kg/BW and TRACP levels at the end of 6 months irrespective of the AED used or the plasma level of AED. CONCLUSIONS: Hypovitaminosis D is common in our population. Subjects with normal 25(OH)D levels, irrespective of the type of antiepileptic medications even at sub-therapeutic serum levels of the drug, went into 25(OH)D deficiency and insufficiency states. Theoretically it can be worthwhile to supplement calcium and vitamin D even before initiation of antiepileptic therapy.

Vitamin D status in India--its implications and remedial measures.

Vitamin D deficiency is epidemic in India despite of plenty of sunshine. The interpretation of vitamin D levels should be done with the solar zenith angle, minimal erythemal dose, skintype, UV Index and geographical location. All Indian studies uniformly point to low 25(OH)D levels in the populations studies despite abundant sunshine. All studies have uniformly documented low dietary calcium intake compared to Recommended Daily/Dietary Allowances (RDA) by Indian Council of Medical Research (ICMR). The vitamin D status of children is very low in both urban and rural population studied. Pregnant women and their new born had low vitamin D status. The effect of short course of loading doses of vitamin D doesn't have a lasting effect and a maintenance dose is needed. Low 25(OH)D levels has its implications of lower peak bone mass and lower BMD compared to west. There may be a public health need to fortify Indian foods with vitamin D.

Efficacy of low dose atorvastatin in diabetic dyslipidaemia.

Coronary heart disease (CHD), the commonest cause of morbidity and mortality in patients with type 2 diabetes, requires multipronged approach for management, including especially treating dyslipidaemia with statins. We conducted this study to demonstrate that low dose (10 mg) atorvastatin is effective in reducing LDL cholesterol (LDL-C) to the target levels in patients from Indian subcontinent. Eighty-one subjects with type 2 diabetes mellitus and dyslipidaemia (LDL-C >100 mg/dl in those without coronary artery disease, n=77; LDL-C >70 mg/dl in those with coronary artery disease, n=4) were included. All patients were initiated on 10 mg atorvastatin daily. Serum lipid profile was repeated after 3 months. The mean body mass index among men and women were 25.0 +/- 4 and 26.7 +/- 3.6 kg/m2 respectively. Pretreatment mean HbA(1c) was 7.9 +/- 1.8 % and total cholesterol, triglycerides and HDL cholestrol (HDL-C) and LDL-C was 214 +/- 27 mg/dl, 164 +/- 63 mg/dl, 46 +/- 6 mg/dl and 135 +/- 24 mg/dl respectively. After three months of treatment the mean decrease was 62 +/- 31 mg/dl in total cholesterol (p < 0.001), 31 +/- 57 mg/dl in triglycerides (p < 0.001), 51 +/- 27 mg/dl in LDL-C (p < 0.001) and 4 +/- 8 mg/dl in HDL-C (p < 0.001). The LDL-C level was reduced by 37.6% in these patients, from 135 +/- 24 mg/dl to 84 = 27 mg/dl (p < 0.001) with 10 mg of atorvastatin daily. It was possible to achieve target LDL-C of less than 100 mg/dl in 75.5% (n=58) in subjects without CHD (n=77) and less than 70 mg/dl in 75% (n=3) of those patients with CHD (n=4). The present study showed that in patients with type 2 diabetes mellitus, 10 mg of atorvastatin daily was safe, well tolerated, and effective in reducing LDL-C to target levels.

Vitamin D status in Andhra Pradesh : a population based study.

BACKGROUND & OBJECTIVE: Data on the vitamin D status of the population in a tropical country like India have seldom been documented. Vitamin D deficiency is presumed to be rare. We carried out this study to document the dietary habits, serum calcium, 25(OH)vitamin D [25(OH)D], and parathyroid hormone levels of urban and rural population in a State in south India. METHODS: A total of 943 healthy urban and 205 rural adult subjects and 76 urban and 70 rural healthy children were studied for their dietary pattern, serum calcium, phosphorus, alkaline phosphatase, 25(OH)D, and N-tact parathyroid hormone levels (N-tact PTH). RESULTS: The daily dietary calcium intake of both the urban and rural population was low compared to that of recommended daily/dietary allowances (RDA) issued by Indian Council of Medical Research (ICMR). Dietary calcium and phosphorus were significantly lower(P<0.0001) in both the rural adult and children compared to that of the urban adult and children. The dietary phytate to calcium ratio was significantly (P<0.0001) higher in rural adult and children compared to that of urban adult and children. N-tact PTH levels negatively correlated with 25(OH)D in rural (r=-0.24; P<0.002), in urban adult subjects (r=-0.12; P<0.0001) and in rural and urban children (r=-0.2; P<0.05). The 25(OH)D levels of rural adult subjects were significantly higher (P<0.001) than that of urban adult subjects in both males and female groups. The 25(OH)D levels of both the urban and rural children were low. INTERPRETATION & CONCLUSION: Low dietary calcium intake and 25(OH)D levels were associated with deleterious effect on bone mineral homeostasis. Prospective longitudinal studies are required to assess the effect on bone mineral density, a surrogate marker for fracture risk and fracture rates.

Fluorotoxic metabolic bone disease: an osteo-renal syndrome caused by excess fluoride ingestion in the tropics.

BACKGROUND: There is scant data available on the pathogenetic mechanisms of varied clinical presentation of bone disease in patients with excess fluoride ingestion in the Indian subcontinent. The present study is comprehensive and state of the art, incorporating all essential elements of bone mineral metabolism in patients with excess fluoride ingestion. METHODS: We studied 24 patients (age 31 +/- 16 years) with fluorotoxic metabolic bone disease (FMBD) for their clinical, radiological and biochemical parameters like serum calcium, phosphorous, alkaline phosphatase (SAP), 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, and parathyroid hormone levels, nephrologic parameters that assess renal handling of calcium and phosphorous and skeletal dynamics as revealed by bone histomorphometry. FINDINGS: Major clinical manifestations were bone pain (79%), Tetany (12.5%) and dental mottling (38%). Radiological findings included osteosclerosis (96%), pseudofracture and ligamentous calcification (50%). These patients manifested hypocalcemia and raised SAP with normal serum phosphorus. There was a positive correlation between serum creatinine and phosphorous excretion index (PEI) and a negative correlation between declining endogenous creatinine clearance (Cr.Cl) and increasing renal loss of calcium and phosphorus as indicated by increased calcium to creatinine ratio and PEI. Bone histomorphometry revealed impairment of primary mineralization with hypomineralized lacunae, interstitial mineralization defects and very thick and extended osteoid seams. Autopsy findings in a patient who died of azotemia showed tubular atrophy with secondary glomerular changes. INTERPRETATION: Fluoride intoxication plays an important role in the pathogenesis of the unique osteo-renal syndrome.

Prevalence of vitamin D insufficiency in postmenopausal south Indian women.

AIM: To evaluate the dietary calcium and vitamin D status in south Indian postmenopausal women. METHODS: Postmenopausal women (n = 164) were evaluated for their daily dietary calcium intake, phytate to calcium ratio, and bone mineral parameters. Their serum leutinizing hormone (LH), follicle-stimulating hormone (FSH), 25-hydroxyvitamin D (25[OH]D), and parathyroid hormone levels (PTH) were measured. RESULTS: Their age and BMI were 59.5 +/- 8 years and 27 +/- 5 kg/m2, respectively. Their daily dietary intake of calcium was 323 +/- 66 mg/day; phytate to calcium ratio, 0.56+/-0.1; LH, 26 +/- 13.5 microIU/l; and FSH, 62.6 +/- 30 microIU/l. Their dietary intake of calcium was low compared with the recommended daily/dietary allowance (RDA) of the Indian Council of Medical Research (ICMR) for the Indian population. Of the 164 patients studied, based on population-based reference values, 126 (77%) had normal 25(OH)D levels (9-37.6 ng/ml), and 38 (23%) had 25(OH)D deficiency. Using functional health-based reference values, 30 (18%) patients had normal 25(OH)D levels (> 20 ng/ml), 85 (52%) had 25(OH)D insufficiency (10-20 ng/ml), and 49(30%) had 25(OH)D deficiency (< 10 ng/ml). PTH and serum alkaline phosphatase (SAP) was significantly high in patients with 25(OH)D deficiency (p < 0.05) compared with those with normal 25(OH)D levels. There was a negative correlation between 25(OH)D and PTH (r = -0.2; p < 0.007) and SAP (r = -0.2; p < 0.001). Dietary calcium correlated positively with dietary phosphates (r = 0.8; p < 0.001) and phytate to calcium ratio (r = 0.75; p < 0.001). CONCLUSIONS: Population-based reference values underdiagnosed vitamin D insufficiency and overdiagnosed normal vitamin D status. The diet was insufficient in calcium and high in phytate. About 82% of the study group had varying degrees of low 25-hydroxyvitamin D levels. The quality of diet has to be improved with enrichment/supplementation of calcium and vitamin D to suppress secondary hyperparathyroidism-induced bone loss and risk of fractures.

High prevalence of low dietary calcium and low vitamin D status in healthy south Indians.

Calcium and vitamin D under nutrition can adversely affect the bone mineral metabolism. There is no population-based study from India documenting dietary habits, serum calcium and vitamin D levels. Our study investigated the dietary habits of rural and urban societies in and around Tirupati and their relationship with serum calcium, phosphorous and vitamin D [25(OH)D] levels. Four hundred and seven subjects from 5 villages around Tirupati, (rural population) and 125 asymptomatic staff of our hospital (urban population) were studied. Dietary intakes of calcium, phosphorous and phytates were documented by diet history. Serum calcium, phosphorus and 25 (OH) D levels were estimated in 191 rural subjects and 125 urban subjects. Compared to urban subjects, rural subjects had a significantly lower intake of dietary calcium (P <0.0001) and a significantly higher dietary phytate/calcium ratio and serum calcium and 25 (OH) D levels (P <0.0001). Dietary calcium intake was inadequate in both rural and urban subjects compared to the recommended daily allowances (RDA) for our country. About 31% of the population had normal vitamin D levels, 54% had vitamin D insufficiency and 15% vitamin D deficiency. About two-thirds of the population had low levels of vitamin D. Inadequate dietary calcium intake associated with high phytate/calcium ratio reduces the bioavailable calcium in the gut. Hence, there is a need to fortify food with calcium and to propose new guidelines for 25 (OH) D in Indian subjects. Multicentric studies with large sample populations are required to generate normal standards and nationally relevant guidelines.