Humoral hypercalcemia of hepatocellular carcinoma associated with elevated levels of parathyroid-hormone-related-peptide.

Parathyroid-hormone-related-peptide (PTHrP) has been shown to be important in the pathogenesis of hypercalcemia of malignancy. The malignancies most commonly associated with hypersecretion of PTHrP include squamous cell carcinoma and breast cancer. The pathogenesis of hypercalcemia associated with hepatocellular carcinoma was evaluated in this study. Two male patients with hepatocellular carcinoma were found to have severe hypercalcemia at initial presentation. PTHrP was measured with radioimmunoassay in these two patients before treatment as well as in nine other patients with hepatocellular carcinoma but without hypercalcemia. The levels were markedly elevated in the two patients with hypercalcemia (29.3 and 32.1 pM), but were less than 5 pM in the nine patients without hypercalcemia. These results suggest that PTHrP was important in the pathogenesis of hypercalcemia associated with hepatocellular carcinoma in these men.

Cultural differences in attitudes, values, and beliefs about osteoporosis in first and second generation Japanese-American women.

This study examines attitudinal differences related to osteoporosis between first and second generation Japanese-American women. In an interview, the women completed a battery of tests assessing their attitudes, values, and beliefs about the diagnosis, treatment, and follow-up care of osteoporosis. The groups differed in their general knowledge of osteoporosis, perceptions of the disease, attributions of its causes, anticipated and preferred support mechanisms for care, and anticipated areas of concern for self-or other-care. There were also considerable differences in treatment compliance and feelings toward physicians. The findings were discussed in relation to the effects of culture on health-care attitudes and behaviors.

Parathyroid hormone-activated phosphoinositide degradation and calcium channels in human dermal fibroblasts.

Previous studies have shown that there are two types of parathyroid hormone (PTH) receptors on human dermal fibroblasts. We evaluate the effects of PTH on intracellular cyclic AMP, calcium and phosphoinositides in order to define the effector systems of the PTH receptors. The results show that PTH stimulates cyclic AMP accumulation in the human dermal fibroblasts with half-maximal effect at 1-5 nM. PTH also increases intracellular calcium as measured by the technique using Fura-2 fluorescent dye and stimulates phosphoinositide degradation as evaluated by column chromatography. The half-maximal effect on AMP occurred at 5 nM, while those effect on calcium and phosphoinositide turnover occurred at 500 nM of PTH. The results show that cyclic AMP, intracellular calcium and phosphoinositides are second messengers for PTH in human dermal fibroblasts. These results provide further evidence to support the concept of heterogeneity of the PTH receptor and its effector system.

Total and regional bone mineral densities in women with Colles' fractures: a comparative study with normal matched controls.

Total body and regional bone mineral densities (BMDs) were measured in 34 women with past Colles' fracture and 34 age- and sex-matched controls using the Norland XR-26 dual energy X-ray bone densitometer. The results showed that in patients with Colles' fracture affecting the left forearms, the BMD at the ultradistal 2.5 cm region was significantly lower in the right forearm when compared with the left. This difference was not statistically significant among patients with fractures affecting the right or both forearms. The patients were also found to have lower BMDs in the femoral regions (0.600 +/- 0.010 g/cm2 in patients versus 0.655 +/- 0.019 g/cm2 in controls), pelvis (0.679 +/- 0.009 g/cm2 in patients versus 0.728 +/- 0.020 g/cm2 in controls) and spine (0.710 +/- 0.018 g/cm2 in patients versus 0.780 +/- 0.030 g/cm2 in controls) when compared with the controls. No such difference could be demonstrated in the head, trunks or arms. These data suggested that women with past Colles' fracture might be more prone to fractures of spine and femoral regions. Bone mineral densities in the weight-bearing regions, including femur and spine correlated strongly with each other (femoral neck versus lumbar spine, r = 0.64, p < 0.0001). Sites from the same anatomic regions, namely the femoral regions had highly correlated BMD values (femoral neck versus Ward's triangle, r = 0.91, SEE = 0.05, p < 0.0001), while poorer correlation was found among unrelated regions, such as between left ultradistal forearm and femoral neck (r = 0.43, SEE = 0.10, p < 0.05).

Loss of bone mass in patients with Klinefelter's syndrome despite sufficient testosterone replacement.

To determine whether testosterone replacement therapy reverses the detrimental effects of hypogonadism on bone density, we measured the total body, lumbar spine and proximal femur bone mineral density (BMD) by dual-energy X-ray absorptiometry in 14 patients with Klinefelter's syndrome on long-term testosterone replacement therapy and compared the results with 14 age- and sex-matched normal controls. Seven of the patients were receiving oral testosterone undecanoate thrice daily (240 mg/day) and the others were having intramuscular testosterone enanthate injections once every 3 weeks (250 mg/injection). Their serum testosterone levels were maintained within the normal limits (10-40 nmol/l). We showed that patients on testosterone replacement had decreased amount of bone density in the left femoral neck when compared with the controls (p < 0.01). Similar decreases were also observed in the left Ward's triangle (p < 0.01) and in the left trochanter (p < 0.05). There were no significant differences in the total body and the lumbar spine measurements in these two groups of subjects. No correlation was found between the BMD values of femur and the duration of testosterone treatment in the patients with Klinefelter's syndrome. The type of testosterone treatment was also not associated with significant differences in BMD. In conclusion, sufficient testosterone replacement with currently available methods does not reverse the decrease in bone mass associated with hypogonadism in patients with Klinefelter's syndrome.

Total and regional bone densities in dialysis patients.

Total and regional bone mineral densities (BMD) of ten male haemodialysis (HD) patients and ten male patients on continuous ambulatory peritoneal dialysis (CAPD) were measured using dual-energy X-ray absorptiometry (DEXA), and compared with that of age- and sex-matched controls. Our data showed that patients with renal failure on dialysis had reduced bone densities as manifested by a reduction in total body BMD, femoral neck BMD, and Ward's triangle BMD. In addition, head BMD and femoral trochanter BMD were also reduced in HD patients. Among HD patients, the length of the period of dialysis correlated with serum level of parathyroid hormone and the reductions in total body BMD and head BMD. Furthermore, there was a strong negative correlation between bone density of the skull and serum parathyroid hormone. Our results demonstrated regional variations in the reduction of bone density in patients with asymptomatic renal bone disease. DEXA bone scan is a useful adjunct in the early assessment of renal osteodystrophy and bone density of the skull can be used as a monitor in hyperparathyroid bone disease.

Idiopathic hypercalciuria causing osteoporosis and hypocalcemia.

Idiopathic hypercalciuria, though a common cause of nephrolithiasis, has not been recognized to cause hypocalcemia and severe bone disease. We describe an adolescent with idiopathic hypercalciuria who presented initially with severe hypocalcemia and osteoporosis and this was later complicated by recurrent renal calculi formation after calcium and vitamin D supplement. After treatment with thiazide, hypercalciuria was controlled and serum biochemistry normalized. While idiopathic renal hypercalciuria may cause a negative calcium balance in adults, a variant of this syndrome with severe renal calcium leak occurring in a growing subject could lead to severe hypocalcemia and osteoporosis.

Rhabdomyolysis associated with cranial diabetes insipidus.

Rhabdomyolysis has been reported to be associated with hyperosmolality in diabetic ketoacidosis and non-ketotic hyperosmolal state. Whether the rhabdomyolysis was due to hyperosmolality per se or whether hyperglycaemia also played a role is not clear. We hereby report a case of cranial diabetes insipidus with hypernatraemia and hyperosmolality complicated by rhabdomyolysis. None of the known risk factors, such as coma, hypokalaemia, hypophosphataemia, diabetic ketoacidosis or non-ketotic hyperosmolality, were present in this patient. We believe that severe hyperosmolality per se is an important predisposing factor for non-traumatic rhabdomyolysis, and serum muscle enzymes should be closely monitored in the management of patients with diabetes insipidus.

Bone mineral density in premenopausal women receiving long-term physiological doses of levothyroxine.

Total body and regional bone mineral density (BMD) levels were determined in 26 premenopausal women with Hashimoto's thyroiditis receiving long-term physiological doses of levothyroxine sodium replacement therapy. The BMD levels of each patient were compared with the mean of the BMD levels of age-matched normal controls. The mean levothyroxine sodium dose was 111 +/- 6 micrograms/d, and the mean duration of treatment was 7.5 +/- 5.3 years (range, 1 to 24 years). Dietary calcium intake was similar in both groups, as were serum thyroxine, triiodothyronine, free thyroxine index, and thyrotropin levels. Women receiving the levothyroxine treatment had normal total body BMD levels but had significantly lower BMD levels at the femoral neck (-5.7%), femoral trochanter (-7.0%), Ward's triangle (-10.6%), both arms (right, -7.8%; left, -8.9%), and pelvis (-4.9%). In contrast, lumbar spine BMD levels were similar in the two groups. There was no correlation between the total body or different regional BMD levels and the duration or dosage of levothyroxine treatment or thyroid function test results. However, the z score of the femoral neck of these patients showed a significant negative correlation with their serum free thyroxine index levels. We conclude that patients receiving physiological doses of levothyroxine may have decreased bone density. Thyroid functions in patients receiving long-term levothyroxine treatment should be closely monitored and bone densitometry should be performed in patients at risk for osteoporosis.

Rapid postmenopausal loss of total body and regional bone mass in normal southern Chinese females in Hong Kong.

Osteoporosis is a major health problem in Hong Kong, affecting about 200,000 patients among a population of 6 million. To evaluate the rate of bone loss and determinants of low bone mass among the Southern Chinese, we measured the total body and regional bone mass with the XR-26 dual-energy X-ray absorptiometry in 90 normal females. The results show that the total and regional bone densities were stable before menopause, with a change of around 0.5% every year. After menopause, a rapid loss is evident for total body and regional bone mass. The rate of bone loss varies from 1.2% for the pelvis to 3.1% for the Ward's triangle per year. Thus, by the age of 70, most Southern Chinese females would have lost at least 25% of their bone. Age, body weight, and skeletal area are important determinants for the total body bone mass. Bone densities in weight-bearing regions, including hip, pelvis, spine and legs correlate strongly with each other (r = 0.68, P less than 0.001). Correlation is poor among unrelated regions, such as between head and arms (r = 0.39, P greater than 0.5). To conclude, normal Chinese women in Hong Kong lose bone rapidly after menopause at a rate of about 2% per year. This may account for the major incidence of osteoporosis-related complications in Hong Kong.

Dietary calcium intake and other risk factors: study of the fractured patients in Hong Kong.

Osteoporosis has become a major health problem among the elderly in Hong Kong. This study compares the level of dietary calcium intake and the differences in various risk factors among elderly fracture patients and elderly without fractures. Furthermore, this study identifies the relationship between the risk factors and the amount of calcium intake; and classifies the fracture patients and the low calcium intake group. Although the design of the present study precludes testing causal hypotheses, the findings are suggestive of factors that are likely to be important in a program to reduce fractures among elderly populations.

1,25-Dihydroxycholecalciferol and peritoneal macrophage chemotaxis in patients on continuous ambulatory peritoneal dialysis.

Single graded doses of 1,25-dihydroxycholecalciferol of 2 and 4 micrograms were added intraperitoneally into the overnight 1.5% glucose dialysate of 6 patients on continuous ambulatory peritoneal dialysis. The effect on peritoneal macrophage chemotaxis and random migration was studied and compared with the baseline when no 1,25-(OH)2D3 was added. No consistent effect on peritoneal macrophage chemotaxis was observed. Random migration was significantly depressed at 4 micrograms when compared with baseline (5.4 +/- 1.9 vs. 12.2 +/- 3.7 cells/high-power field, p less than 0.05). The potential clinical role of 1,25-(OH)2D3 as an immune modulator requires further study.

Propylthiouracil hypersensitivity with circumstantial evidence for drug-induced reversible sensorineural deafness: a case report.

Severe adverse reactions to propylthiouracil occur in 1-5% of patients. Three major side effects, namely agranulocytosis, hepatotoxicity and drug-induced hypersensitivity, have been described though these syndromes are not distinct entities and there can be overlaps in the clinical manifestations. The drug-induced hypersensitivity may be an immune-mediated reaction with multiorgan involvement in which a combination of polyarthritis, cutaneous vasculitis and fever is common. We report a patient with propylthiouracil-induced hypersensitivity with an unusual combination of high spiking fever, migratory polyarthritis, reversible sensorineural deafness, normochromic normocytic anaemia, leucocytosis and hepatotoxicity associated with polyclonal activation of multiple autoantibodies. This case illustrates the highly variable clinical manifestations of the syndrome. The prompt recovery upon withdrawal of the drug indicates the importance of early diagnosis.

Desensitization of parathyroid hormone receptors on cultured bone cells.

Administration of excessive amounts of parathyroid hormone (PTH) in the treatment of osteoporosis can reverse the beneficial effects of a low-dose, intermittent regime. To investigate the direct actions and the possible cellular mechanisms of PTH in inducing desensitization of PTH receptors, we studied the effects of desensitization on rat osteoblastic UMR-106 cells. When the osteoblasts were preincubated with bPTH-(1-34), complete refractoriness to a subsequent challenge with the hormone developed within 1 h and at hormone concentrations as low as 5 nM. When osteoblasts thus desensitized were incubated in hormone-free medium, recovery of the cAMP responses began within 2 h and reached maximum after 16 h. Cycloheximide did not affect the process of desensitization. [Nle8,Nle18,Tyr34]bPTH-(3-34)amide significantly impaired the desensitization process by PTH-(1-34) but did not have stimulatory effect on cAMP responses. No significant heterologous desensitization was obvious after preincubation with isoprenaline (50 microM), prostaglandin E1 (50 microM), or prostaglandin E2 (50 microM) for 2 h. Binding experiments with [125I]PLP-(1-36)amide after desensitization revealed that there was an approximate twofold decrease in receptor affinities as analyzed by Scatchard analysis, showing that the decrease in affinity was prominent in the process of desensitization. When the cells were treated with monensin during desensitization, PTH challenge after desensitization produced significantly lower cyclic AMP responses. Recovery after desensitization occurred over a period of 16 h. Inclusion of monensin, but not cycloheximide, impaired the recovery. The results show that homologous desensitization of rat osteoblasts to PTH is brought about by the occupancy of receptors by PTH-(1-34) but not by cAMP generation itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed decline in plasma atrial natriuretic peptide levels after an abrupt reduction in atrial pressures: observation in patients with dual-chamber pacing.

The effect of an abrupt reduction in atrial pressures on atrial natriuretic peptide (ANP) secretion was studied in four patients with complete atrioventricular block with a dual-chamber pacemaker when the pacing mode was changed from the VVI to the DVI mode at an equal rate of 70/min. Simultaneous continuous hemodynamic monitoring was performed using a balloon-tipped thermodilution catheter. With DVI pacing, there was an immediate decrease of right atrial pressure from 4.5 +/- 0.9 to 1.8 +/- 1.1 mm Hg, and a reduction of pulmonary arterial wedge pressure from 7 +/- 0.8 to 4.5 +/- 0.9 mm Hg, together with a rise in cardiac output from 3.1 +/- 0.2 to 3.7 +/- 0.2 L/min. However, despite a constant hemodynamic status after dual-chamber pacing, the arterial ANP level steadily decreased from 151 +/- 26 pg/ml to a steady low level of 78 +/- 15 pg/ml after 20 minutes of dual-chamber pacing (percentage reduction- 48 +/- 8%, p less than 0.05). This persisted until the end of the study at 60 minutes. The time-dependent decay in ANP secretion after an abrupt and constant change in hemodynamic status should be considered when interpreting ANP levels.

Long-term results following 131I treatment for Graves' disease in Hong Kong Chinese--discriminant factors predicting hypothyroidism.

The clinical outcome of 1028 Hong Kong Chinese patients with Graves' disease treated with radioiodine therapy and followed for a mean of 9.85 +/- 4.84 years (range 2-20) was analysed. Retreatment was required by 413 patients (40.2 per cent), with 134 patients (13.0 per cent) requiring more than two 131I doses. One hundred and eighty-nine patients received carbimazole after 131I until euthyroidism was achieved. The cumulative incidence of hypothyroidism at one, five, 10 and 15 years was 9.6 per cent, 31.4 per cent, 53.8 per cent and 65.8 per cent, respectively. The average incidence of hypothyroidism after the first two years was 3.3 per cent per annum. Stepwise logistic regression analysis of pretreatment variables suggested that a combination of adjunctive carbimazole therapy, absence of ophthalmopathy and longer effective half-lives of 131I were of value in predicting which patients were less likely to develop permanent hypothyroidism. However, the probability of accurately predicting permanent hypothyroidism based on the present model was only 60 per cent. We believe that no single pretreatment variable, or combination of variables, predicts long-term hypothyroidism with sufficient confidence to justify the use of a 'formula' approach for prescribing 131I therapy for Graves' disease.

Importance of measurement of bone density in the management of osteoporosis.

Bone mass is the primary, although not the only, determinant of fracture. Over the past few years a number of noninvasive techniques have been developed to more sensitively quantitate bone mass. These include radiogrammetry (RG) and radiographic photodensitometry (RD), single and dual photon absorptiometry (SPA and DPA), quantitative computed tomography (QCT), and single and dual-energy X-ray absorptiometry (SEXA and DEXA). These techniques provide bone mass quantitation at the spine, wrist, hip and total body skeletal sites that are the principal areas usually involved in osteoporosis. The evaluation of the aetiology, progression, and treatment of osteoporosis has been clearly improved with the use of these methods. It is the intent of this review to discuss the pros and cons of these techniques, in particular their applications to the detection and management of osteoporosis.

Discriminant factors affecting early outcome of radioiodine treatment for Graves' disease.

Pretreatment clinical, biochemical, iodine-131 (131I) scan and tracer-kinetic parameters were studied in 827 Chinese patients with Graves' disease treated with radioactive iodine. One year after 131I therapy, 56.7% were euthyroid, 33.9% were still thyrotoxic and 9.4% were hypothyroid. Discriminant analysis of all pretreatment variables identified thyroid mass, presenting free thyroxine index and 4 h 131I uptake as the three variables most helpful in discriminating the early outcome group of 131I therapy. The findings suggest that patients with large goitres and severe disease may require higher doses of 131I for treatment of Graves' disease.