Low serum thyroxine and high serum triiodothyronine in nephrotic rats: etiology and implications for bioavailability of protein-bound hormone

Traditionally, it has been thought that the bioavailable fraction of circulating serum hormones, i.e. that which is available for cellular uptake and is physiologically active, is limited to the free (nonprotein bound) hormone. However, recent evidence, based on acute organ uptake of labeled hormone, suggests that the amount of hormone which is bioavailable in vivo may exceed that which is calculated to be free in vitro. To explore the bioavailability of circulating protein-bound thyroid hormones under steady state conditions in vivo, we altered serum thyroid hormone-binding proteins in rats by inducing nephrotic syndrome with puromycin aminonucleoside. Nephrotic rats (serum albumin, 1.1 g/dl) were found to have a marked reduction in serum T4 [2.1 +/- 0.2 (SEM) vs. 6.5 +/- 0.3 microgram/dl; P less than 0.01] and an elevation of serum T3 [141 +/- 8 vs. 51 +/- 2 ng/dl; P less than 0.01]. Estimated T4 production rate was normal in nephrotic rats, and the 3- to 4-fold increase in T4 MCR appeared to account for the marked reduction in serum T4. By contrast, increased serum T3 levels in nephrotic rats reflected both a reduction (55%) in T3 MCR and an increased rate of peripheral conversion of T4 to T3. A circulating inhibitor of T4 binding to serum proteins appeared to be present in nephrotic rats. The changes in the various serum components of thyroid hormone [T4-binding prealbumin (TBPA)-bound, albumin-bound, free] produced by nephrotic syndrome were compared with the corresponding changes in indices of thyroid hormone bioavailability (MCR, urinary excretion, hepatic content, TSH suppression, single pass extraction by liver). These comparisons suggested that nephrotic syndrome results in increased bioavailability of circulating T4 and decreased bioavailability of circulating T3. The bioavailable fraction of circulating T3 in vivo seemed to include both free T3 and that which is albumin bound in vitro. The bioavailable fraction of circulating T4 resembled free T4 more than non-TBPA-bound T4 (= albumin bound + free), although a nephrosis-induced increase in bioavailability of TBPA-bound T4 was also possible. We conclude that nephrotic rats have low serum T4, which is related to accelerated T4 clearance, and high serum T3, which is related both to decreased T3 clearance and increased peripheral conversion of T4 to T3. Under steady state conditions in vivo, bioavailable circulating T3 appears to include both free T3 and the T3 that is bound to albumin in vitro.     

Prevalence of Vitamin D insufficiency and low bone mineral density in elderly Thai nursing home residents

ABSTRACT: BACKGROUND: Numerous emerging data from research on osteoporosis among Asians found differences from Caucasians. Therefore, the aim of this study was to determine the prevalence of vitamin D insufficiency and osteoporosis in elderly participants from two nursing homes in Thailand, a country located near the equator. METHODS: The subjects of this cross-sectional study comprised 93 elderly Thai women who were living in institutional long-term nursing homes for the aged. Demographic data, daily food and calcium intake, physical activity, and sunlight exposure were measured. Lumbar spine and femoral neck bone mineral density (BMD) and biochemical levels including serum 25 hydroxyvitamin D [25(OH)D] and bone turnover markers were assessed. Vitamin D insufficiency was defined as 25(OH)D level < 70 nmol/l. RESULTS: The mean age of subjects was 75.2 +/- 6.0 (SD) years. Dietary calcium intake was low (322 +/- 158 mg/day) The mean 25(OH)D level was 64.3 +/- 14.9 nmol/L and the prevalence of vitamin D insufficiency was 38.7 % (95 % CI: 28.8 %, 49.4 %). There was no correlation between serum 25(OH)D concentrations and age (r = -.11, p = 0.3). The mean BMD of lumbar spine and femoral neck were 0.92 +/- 0.19 and 0.65 +/- 0.10 g/cm2, respectively. Nearly a half of the subjects had osteopenia (44.1 %, 95 % CI: 33.8 %, 54.8 %) and osteoporosis (47.3 %, 95 % CI: 36.9 %, 57.9 %). Circulating C-terminal telopeptide of type I collagen (CTx) level correlated significantly with both lumbar spine (r = -0.26, p = 0.01) and femoral neck BMD (r = -0.25, p = 0.02). CONCLUSIONS: More than one-third of Thai elderly women residing in nursing homes had vitamin D insufficiency. Almost all nursing home residents had osteoporosis and/or osteopenia.     

Prediction of percentage body fat in rural thai population using simple anthropometric measurements

OBJECTIVE: To develop and validate sex-specific equations for predicting percentage body fat (%BF) in rural Thai population, based on BMI and anthropometric measurements. RESEARCH METHODS AND PROCEDURES: %BF (DXA; GE Lunar Corp., Madison, WI) was measured in 181 men and 255 women who were healthy and between 20 and 84 years old. Anthropometric measures such as weight (kilograms), height (centimeters), BMI (kilograms per meter squared), waist circumference (centimeters), hip circumference (centimeters), thickness at triceps skinfold (millimeters), biceps skinfold (millimeters), subscapular skinfold (millimeters), and suprailiac skinfold (millimeters) were also measured. The sample was randomly divided into a development group (98 men and 125 women) and a validation group (83 men and 130 women). Regression equations of %BF derived from the development group were then evaluated for accuracy in the validation group. RESULTS: The equation for estimating %BF in men was: %BF(men) = 0.42 x subscapular skinfold + 0.62 x BMI - 0.28 x biceps skinfold + 0.17 x waist circumference - 18.47, and in women: %BF(women) = 0.42 x hip circumference + 0.17 x suprailiac skinfold + 0.46 x BMI - 23.75. The coefficient of determination (R2) for both equations was 0.68. Without anthropometric variables, the predictive equation using BMI, age, and sex was: %BF = 1.65 x BMI + 0.06 x age - 15.3 x sex - 10.67 (where sex = 1 for men and sex = 0 for women), with R2 = 0.83. When these equations were applied to the validation sample, the difference between measured and predicted %BF ranged between +/-9%, and the positive predictive values were above 0.9. DISCUSSION: These results suggest that simple, noninvasive, and inexpensive anthropometric variables may provide an accurate estimate of %BF and could potentially aid the diagnosis of obesity in rural Thais.     

A specific haplotype in the 3′ end of estrogen-receptor alpha gene is associated with low bone mineral density in premenopausal women and increased risk of postmenopausal osteoporosis

It is well established that the development of postmenopausal osteoporosis is under genetic influence. We have recently identified a synonymous single nucleotide polymorphism (SNP) in exon 8 of estrogen receptor- (ER) gene in the vicinity of the stop codon (G2014A) that is associated with an increased risk of postmenopausal osteoporosis. In the present study, we attempted to locate SNPs in the 3-unstranslated region (3UTR) of the ER gene that are in linkage disequilibrium with the exon 8 SNP and assessed their utilization in the risk assessment of postmenopausal osteoporosis in 352 Thai postmenopausal women. The association with bone mineral density (BMD) in premenopausal women was also investigated in 202 premenopausal women. A C to A SNP 1,748 nucleotides distal to the end of the stop codon (C3768A) was identified. The C3768A SNP was not overrepresented in subjects with osteoporosis. However, the presence of the A-C haplotype allele based on the A2014 and C3768 alleles was significantly related to the risk of osteoporosis independently of age, body weight, the G2014A and C3768A SNPs (odds ratio 2.36, 95% CI 1.42–3.91). Moreover, the presence of the A-C haplotype allele was associated with lower femoral neck BMD in premenopausal women ( P =0.05). We concluded that a specific haplotype in the 3 end of the ER gene is associated with lower BMD in premenopausal women and is associated with a higher risk of osteoporosis in postmenopausal women. It is likely that the haplotype allele exerts its influence on bone as early as during young adulthood to increase the risk of osteoporosis later in life.     

Exogenous subclinical hyperthyroidism during adolescence: effect on peak bone mass

BACKGROUND: Chronic subclinical hyperthyroidism induced by suppressive doses of L-thyroxine (L-T4) therapy, so-called exogenous subclinical hyperthyroidism, may cause diminished bone mass in postmenopausal women. The effect of subclinical hyperthyroidism during childhood and adolescence on peak bone mass, however, has not been evaluated. OBJECTIVE: To determine whether exogenous subclinical hyperthyroidism during adolescence, the period of critical bone mass acquisition, would reduce peak bone mass. PATIENTS AND METHODS: Eighteen female adolescents and young adults with Hashimoto's thyroiditis and euthyroid goiter (aged 22.4 +/- 4.4 years) who had been treated with suppressive doses of L-T4, 127.5 +/- 23.7 microg/day, during adolescence (age at onset of subclinical hyperthyroidism, 14.2 +/- 1.5 years) for 6.3 +/- 3.4 years were enrolled in the study. Twenty-nine healthy female volunteers matched for age, weight, height and body mass index served as the controls. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. Results: BMD of the lumbar spine, radius, Ward's triangle and total body were comparable in the two groups. In contrast, BMD of the femoral neck, trochanter and shaft of patients was slightly higher than those of controls. There were no correlations between BMD values and clinical parameters. CONCLUSION: Exogenous subclinical hyperthyroidism during adolescence has no demonstrable detrimental effect on peak bone mass attainment.     

Alteration of noncollagenous bone matrix proteins in distal renal tubular acidosis

Our previous report on bone histomorphometry in patients with distal renal tubular acidosis (dRTA) revealed decreased bone formation rate (BFR) when compared to healthy subjects. The abnormality improved significantly after alkaline therapy. The modest increase in osteoblastic surface, after correction of metabolic acidosis, could not explain the striking improvement in bone formation, suggesting additional influence of metabolic acidosis on osteoblast function and/or bone matrix mineralization. Osteoblasts and, to a lesser extent, osteoclasts synthesize and secrete bone matrix including type I collagen and various noncollagenous proteins (NCPs). Substantial evidence suggested diverse functions of NCPs related to bone formation, resorption, and mineralization. Metabolic acidosis, through its effect on bone cells, may result in an alteration in the production of NCPs. Our study examined bone histomorphometry with detailed analysis on the mineralization parameters and NCPs expression within the bone matrix of patients with dRTA before and after treatment with alkaline. Seven dRTA patients underwent bone biopsy at their initial diagnosis and again 12 months after alkaline therapy. Bone mineral density (BMD) and bone histomorphometry were obtained at baseline and after the treatment. The expression of NCPs was examined by immunohistochemistry, quantitated by digital image analysis, and reported as a percentage of area of positive staining or mineralized trabecular bone area. Alkaline therapy normalized the low serum phosphate and PTH during acidosis. The reduction in BMD at baseline improved significantly by the treatment. Bone histomorphometry demonstrated the increase in osteoid surface and volume without significant alteration after acidosis correction. In comparison to the normal subjects, osteoid thickness was slightly but insignificantly elevated. Osteoblast and osteoclast populations and their activities were suppressed. The reduction in mineral apposition rate and adjusted apposition rate were observed in conjunction with the prolongation of mineralization lag time. Alkaline therapy improved the mineralization parameters considerably. In addition to the increase in BFR relative osteoblast number after acidosis correction, osteocalcin expression in the bone matrix increased significantly from 16.7% to 22.3%. Six of seven patients had decreased osteopontin expression. In conclusion, the abnormal bone remodeling in dRTA is characterized by low turnover bone disease with some degree of defective mineralization. Alteration of NCPs expression suggested the effect of metabolic acidosis on bone cells. Alkaline therapy increased bone mass through the restoration of bone mineral balance and, perhaps, improved osteoblast function.     

Physical activity and risk factors for hip fractures in Thai men

To test the hypothesis that hip fracture is associated with physical activity in Thai elderly men, a case-control study was conducted in Bangkok, Thailand. A total of 187 men aged 51 years over, resident in Bangkok, admitted consecutively with a radiologically confirmed first hip fracture were studied. 177 age-matched community controls were randomly recruited from the same neighborhood of the cases. Physical activity was independently associated with reduced risk of hip fracture after controlling for confounding factors. Very active and active past physical activity markedly reduced risk of hip fracture in comparison to subjects with inactive past physical activity. Recent active physical activity was also protective against hip fracture. This prompts a need to identify strategy to promote physical activity among the elderly and at an early age.     

Risk of Calcium Oxalate Nephrolithiasis after Calcium or Combined Calcium and Calcitriol Supplementation in Postmenopausal Women

Although calcium supplementation can cause hypercalciuria, the risk of nephrolithiasis has been shown to decrease rather than increase among subjects who had a higher calcium intake. Hypercalciuria is also a well-established side effect of calcitriol administration. However, the risk of nephrolithiasis is not well defined. The present study was undertaken to prospectively determine the effect of calcium with or without calcitriol on physicochemical risk factors associated with calcium oxalate nephrolithiasis in Thai postmenopausal women with osteoporosis. Subjects consisted of 53 Thai women more than 10 years postmenopausal who were randomly allocated to receive 750 mg of calcium carbonate supplement alone (n= 28) or 750 mg of calcium carbonate plus 0.5 mg calcitriol (n= 25) daily. Mean ± SEM for age was 65.3 ± 1.1 years, body weight 53.5 ± 1.3 kg. Urine samples for biochemical assays were collected at baseline and 3 months after treatment. Supersaturation for calcium oxalate stone formation was assessed from the 24 h urine constituents by the Tiselius’s index, AP(CaOx). Three months of calcium supplement alone resulted in a modest, but not significant, increase in urinary calcium (baseline, 2.90 ± 0.43 mmol/day; after treatment 3.58 ± 0.54 mmol/day) with no change in urinary oxalate, citrate or magnesium. In contrast, calcium together with calcitriol caused a significant increase in urinary calcium (baseline, 2.87 ± 0.41 mmol/day; after treatment, 4.08 ± 0.57 mmol/day; p<0.05). No significant change in other urine constituents after treatment with calcium and calcitriol was detected. Therefore, AP(CaOx) did not significantly increase either after calcium alone (baseline, 1.17 ± 0.39; after treatment, 1.36 ± 0.28) or after calcium plus calcitriol (baseline, 1.09 ± 0.17; after treatment, 1.09 ± 0.19). However, after treatments, 12 subjects (23%) – 6 receiving calcium supplement alone and 6 receiving calcium plus calcitriol supplement – had high AP(CaOx) values (greater than the upper limit of 95% CI for AP(CaOx) derived from non-stone-forming Thai women). The post-treatment/baseline ratio was 3.21 ± 0.74 for urinary calcium, 1.01 ± 0.19 for urinary oxalate, and 2.23 ± 0.42 (median 1.15) for AP(CaOx). The post-treatment/baseline ratio of calcium, but not for urinary oxalate, had a significant correlation with the post-treatment/baseline ratio of AP(CaOx). Our findings suggest that the alteration in the risk of calcium oxalate nephrolithiasis based on urinary composition is related to the alteration in urinary calcium. The risk of calcium oxalate nephrolithiasis does not increase significantly after calcium or combined calcium and calcitriol supplement in the majority of postmenopausal women with osteoporosis. Received: 10 March 1999 / Accepted: 16 November 1999     

Bone histomorphometry in children and adolescents with beta-thalassemia disease: iron-associated focal osteomalacia

Thalassemia/hemoglobinopathy is a hereditary disease that causes chronic anemia and increased erythropoiesis. Consequently, an expansion of bone marrow spaces may contribute to osteopenia/osteoporosis. However, the pathogenesis of bone changes is not yet known. We, therefore, carried out the study on bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated beta-thalassemia disease with the hope of gaining some new insight into the cellular and structural alterations of thalassemic bone. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Bone mineral density (BMD) measurements were performed by dual energy x-ray absorptiometry. Most patients had growth retardation and delayed bone age. BMD was low especially at the lumbar spine. Serum IGF-I levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. Moreover, focal thickened osteoid seams were found together with focal iron deposits. Dynamic bone formation study revealed reduced bone formation rate. These findings indicate that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. Iron deposits in bone and low circulating IGF-I levels may partly contribute to the above findings.