The relationship among homocysteine, creatinine clearance, and albuminuria in patients with type 2 diabetes.

OBJECTIVE: Although it is accepted that elevated plasma homocysteine (tHcy) levels occur in end-stage renal disease and type 2 diabetes, the changes with milder renal dysfunction (e.g., microalbuminuria) are less clearly established. This study explores the relationship among tHcy, creatinine clearance (Ccr), and albumin excretion rate (AER) in a population with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 260 patients with type 2 diabetes were screened in our outpatient clinic during 10 months. Fasting blood samples were collected, and AER was calculated from an overnight timed urine sample. Ccr was calculated using the Cockroft-Gault formula. RESULTS: A total of 198 subjects (76%) had normoalbuminuria (<20 microg/min), 50 subjects (19%) had microalbuminuria (20-200 microg/min), and 12 subjects (5%) had macroalbuminuria (>or=200 microg/min). Those with microalbuminuria had higher levels of tHcy than those with normoalbuminuria (13.2 +/- 7.8 vs. 11.3 +/- 4.6 micromol/l, P < 0.05). Patients were then subdivided based on low Ccr (<80 ml x min(-1) x 1.73 m(-2)) and normal Ccr (>or=80 x min(-1) x 1.73 m(-2)). None of the patients with macroalbuminuria had normal Ccr. In those with normoalbuminuria, tHcy levels were higher than in those with low Ccr than in those with normal Ccr (12.0 +/- 4.6 vs. 10.0 +/- 4.4 micromol/l, P < 0.01). The same was found for those with microalbuminuria (low Ccr versus normal Ccr: 14.6 +/- 9.0 vs. 10.2 +/- 2.8 micromol/l, P < 0.02). For normal Ccr, tHcy was similar irrespective of AER (normoalbuminuria versus microalbuminuria: 10.0 +/- 4.4 vs. 10.2 +/- 2.8 micromol/l, NS). For low Ccr, tHcy was higher in those with microalbuminuria versus normoalbuminuria (14.6 +/- 9.0 vs. 12.0 +/- 4.6 micromol/l, P = 0.01). Using multivariate regression, Ccr, but neither AER nor the presence of albuminuria, was an independent predictor of tHcy. CONCLUSIONS: These data strongly suggest that in patients with type 2 diabetes, the relationship between plasma tHcy and AER is largely due to associated changes in renal function, as defined by Ccr.

Red clover isoflavones enriched with formononetin lower serum LDL cholesterol-a randomized, double-blind, placebo-controlled study.

BACKGROUND: Although postmenopausal combined hormone replacement therapy reduces the risk of hip fracture, long-term use may be associated with an increased risk of breast cancer, and in women more than 10 years after menopause it is associated with an increased risk of cardiovascular disease. Isoflavones, because of preferential binding to estrogen receptor beta, may retain the beneficial effects on bone but lessen the adverse effects on the breast. OBJECTIVE: The objective of this study was to study the effects of an isoflavone obtained from red clover (Rimostil) on bone mineral density, and on low-density lipoprotein (LDL) cholesterol. DESIGN: In a double-blind, randomized, placebo-controlled trial, 50 mg of Rimostil was given to women who were menopausal for at least 1 year. Bone mineral density of the spine, femoral neck and forearm and serum LDL cholesterol were measured at baseline and at 6-month intervals. The duration of follow-up was 2 years. RESULTS: There was no beneficial effect of Rimostil on bone density at any site. There was a 12% fall in serum LDL cholesterol in the Rimostil-treated arm, which was significantly greater than the 2% drop seen in the control arm (P=0.005).

Mortality associated with primary hyperparathyroidism.

561 patients with primary hyperparathyroidism were followed between 1961 and 1994. Relative survival was compared to that of the Australian population studied during the same time interval. Mortality was significantly greater in the hyperparathyroid population (P<0.001). Mortality was not greater in the patients with serum calcium levels >3.00 mmol/L compared to those with a serum calcium levels <3.00 mmol/L. 113 patients did not have parathyroid surgery. Their relative survival was not significantly different from those who had surgery but their mean serum calcium and parathyroid hormone (PTH) levels were significantly lower than those who had surgery. A re-analysis of the 453 patients followed between 1972 and 2011 was carried out and a 20-year survival analysis made of those diagnosed between 1972 and 1981 and those diagnosed between 1982 and 1991. The latter group had significantly worse relative mortality than the former group (P<0.001) but was significantly older at the time of diagnosis (56.94 ± 14.83 vs 52.01 ± 13.58, P<0.001). The serum calcium and serum PTH levels were not significantly different between these two groups.

Longitudinal changes in forearm bone mineral content in primary hyperparathyroidism.

Forearm bone mineral content was measured in 28 patients with primary hyperparathyroidism before and 1 year after successful parathyroidectomy. The forearm bone mineral content rose from a mean value of 1.068 to 1.092 g/cm (P less than 0.05, paired t-test). Those patients with the lower initial values had the largest rise. In an additional study, the forearm bone mineral content was measured in 10 women over the age of 40 years (mean age 58.6 +/- 7.9SD years) with hyperparathyroidism before and for 2 years after successful parathyroidectomy and compared with the forearm bone mineral content measured over 2 years in 12 women (mean age 56.3 +/- 5.5SD years) with continuing hyperparathyroidism and with the forearm bone mineral content of 12 eucalcemic control women (mean age 58.8 +/- 8.2SD years), also measured over 2 years. The parathyroidectomized group gained bone, whereas the ongoing hyperparathyroid group and the eucalcemic control group lost bone. The difference between the parathyroidectomized group and the ongoing hyperparathyroid group was significant after 2 years (P less than 0.05). The percentage loss of forearm bone mineral in the eucalcemic control subjects was not significantly different from the percentage loss of forearm bone mineral in the ongoing hyperparathyroid group, although the initial mean bone mineral content in the eucalcemic group was significantly higher than in the ongoing hyperparathyroid group, suggesting that a possible determinant of bone mineral loss in women in this age group is the initial bone mineral content.

Does Graves' disease or thyrotoxicosis affect the prognosis of thyroid cancer.

Twenty-one patients who underwent surgical treatment for thyrotoxicosis and who were found at operation to have thyroid cancer are presented. Sixteen had Graves' disease and 5 had toxic nodular goiter. The group with Graves' is compared with 110 euthyroid patients with thyroid cancer who underwent their initial surgery in the same time period and who were of the same age (+/- 1 yr) and sex as the patients with Graves' disease. None of the thyrotoxic patients died during follow-up of 2-24 yr or developed subsequent metastases. The 1 patient with a local lymph node metastasis has not shown evidence of recurrence. Hypoparathyroidism appeared as a complication in only 1 patient. The size of tumors in the patients with Graves' disease was significantly smaller than in the euthyroid group. The course of the disease in both the patients with Graves' disease and the thyrotoxic group as a whole was relatively benign. This series does not support the recent suggestions that thyroid cancer in patients with Graves' disease is more aggressive than in either patients with toxic nodular goiter or euthyroid subjects. Patients with Graves' disease and thyroid cancer should be treated identically to other patients with thyroid cancer. Therapy should consist of total thyroidectomy followed by a postoperative 131I scan. Residual tissue or metastases found on the scan should be ablated with 6 GBq 131I. The patient should receive a suppressive dose of T4.

Relationships between plasma lipoprotein cholesterol concentrations and the pool size and metabolism of cholesterol in man.

The plasma concentration of unesterified and esterified cholesterol within very low density (VLDL), low density (LDL) and high density (HDL) lipoproteins have been examined in relation to the metabolism and pool size of cholesterol in normal and hyperlipidaemic subjects. Cholesterol metabolism was assessed as faecal endogenous neutral and acidic steroid excretion, a 2-pool model of cholesterol turnover, and in vitro plasma cholesterol esterifying activity. VLDL total cholesterol (TC) concentration was positively correlated with cholesterol turnover, endogenous neutral steroid excretion, bile acid excretion and the absolute rate of plasma cholestrol esterification. The correlations with cholesterol turnover and neutral steroid excretion, but not that with bile acid excretion, remained significant when these were corrected for their relationships to body weight. LDL-TC was negatively correlated with the fractional rate of plasma cholesterol esterification and, in subjects with primary type IIa hyperlipoproteinaemia, also with the rate constant for cholesterol elimination from the rapidly exchanging cholesterol pool. No correlation was found between LDL-TC concentration and bile acid excretion. HDL-TC concentration was negatively correlated with both the rapidly and slowly exchanging pools of tissue cholesterol, after correction for their relationships to body weight and adiposity. In contrast, cholesterol pool sizes were not correlated with the concentration of VLDL or LDL-TC; nor was there any relationship to plasma cholesterol esterifying activity. No correlation was found between the relative proportions of unesterified cholesterol within any lipoprotein fraction and either the pool size or metabolism of cholesterol. These findings accord with previous reports of enhanced cholesterol metabolism in subjects with elevated VLDL concentrations and of impaired plasma LDL and cholesterol clearance in patients with primary type IIa hyperlipoproteinaemia. The demonstration that HDL-TC concentration is negatively correlated with body cholesterol pool size supports in vitro evidence for a role of HDL IN TISSUE CHOLESTEROL CLEARENCE.

Single-day intravenous pamidronate in Paget's disease.

Although the efficacy of pamidronate (APD) in Paget's disease is established, the optimal dose and regimen are not known. In this article, further findings using a single-day intravenous infusion are reported, comparing the responses of 114 subjects treated with doses of 20 mg (n = 35), 30 mg (n = 26), 45 mg (n = 29), and 60 mg (n = 24). Assessments of clinical and biochemical response were made at 2, 4, 8, 12, and 24 weeks. Patients with persistent disease activity were retreated after 24 weeks. The single-day infusion of APD was followed by a rapid and sustained biochemical response, but in only 24% of patients did alkaline phosphatase (AP) levels normalize. Of patients in whom the serum AP level normalized, 93% had initial values less than three times the upper limit of normal. Although there was no significant difference in response between the lower dosage groups, there was a greater response in patients treated with a higher dose of APD. The percentage decrease in AP from baseline was similar after the first and second infusions. These findings show that a single-day infusion of APD is effective in the treatment of Paget's disease and that a dose-response relationship exists.

Prevalence of positive anti-neutrophil cytoplasmic antibody (ANCA) in patients receiving anti-thyroid medication.

OBJECTIVE: Vasculitis is a rare complication of anti-thyroid medications. There are 32 cases of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis in association with anti-thyroid medication reported in the English literature. The objectives of this study were to assess the frequency of positive ANCA in patients on long-term anti-thyroid medication, and to follow patients prospectively from commencement of medication to determine whether they became ANCA-positive after therapy. DESIGN: Prospectively collected cross-sectional study of two groups of patients: (i) who had received long-term (>18 months) anti-thyroid medication, and (ii) newly diagnosed thyrotoxicosis before commencement of anti-thyroid medication attending clinic between 28 April 1998 and 30 September 1998. Data were collected for age, sex, ethnicity, underlying thyroid disease, medication and duration, and symptomatology. RESULTS: Eight of 30 patients on long-term anti-thyroid medication (26.7%) were ANCA-positive. All ANCA-positive patients were female, seven were taking propylthiouracil (PTU) at the time of testing. ANCA-positive patients had taken PTU for a mean +/- s.d. of 7.9+/-10.2 years, compared with 0.8+/-2.2 years in ANCA-negative patients (Mann-Whitney, P<0.0001). The ten patients with newly diagnosed thyrotoxicosis were ANCA-negative before commencement of carbimazole. One (10%) became ANCA-positive within 8 months of therapy. CONCLUSIONS: In our population, ANCA-positivity in association with long-term anti-thyroid medication is common (26.7%). One patient who was ANCA-negative prior to anti-thyroid therapy has become ANCA-positive. ANCA should be tested in patients receiving long-term anti-thyroid medications, and in patients with adverse reactions. As PTU is more commonly associated with vasculitis and positive ANCA, carbimazole may be the preferred medication for long-term use. Patients with positive ANCA should be followed, and considered for definitive anti-thyroid therapy, to allow cessation of medication. ANCA-positivity may resolve after cessation of anti-thyroid medication.

The effect of isoflavones extracted from red clover (Rimostil) on lipid and bone metabolism.

OBJECTIVE: This study was undertaken to evaluate the effects of varying doses of phytoestrogens on lipid and bone metabolism in postmenopausal women. DESIGN: A novel red clover isoflavone preparation (Rimostil) containing genistein, daidzein, formononetin, and biochanin was administered to 46 postmenopausal women in a double-blind protocol after a single-blind placebo phase and followed by a single-blind washout phase. Patients were randomized to receive either 28.5 mg, 57 mg, or 85.5 mg of phytoestrogens daily for a 6-month period. RESULTS: At 6 months, the serum high-density lipoprotein cholesterol had risen significantly by 15.7-28.6% with different doses (p = 0.007, p = 0.002, p = 0.027), although the magnitude of the response was independent of the dose used. The serum apolipoprotein B fell significantly by 11.5-17.0% with different doses (p = 0.005, p = 0.043, p = 0.007) and the magnitude of the response was independent of the dose used. The bone mineral density of the proximal radius and ulna rose significantly by 4.1% over 6 months with 57 mg/day (p = 0.002) and by 3.0% with 85.5 mg/day (p = 0.023) of isoflavones. The response with 28.5 mg/day of isoflavones was not significant. There was no significant increase in endometrial thickness with any of the doses of isoflavone used. CONCLUSION: These results show that the administration of an isoflavone combination extracted from red clover was associated with a significant increase in high-density lipoprotein cholesterol, a significant fall in apolipoprotein B, and a significant increase in the predominantly cortical bone of the proximal radius and ulna after 6 months of treatment. Interpretation of the results is undertaken cautiously because of the absence of a simultaneously studied control group.

Pathology of Tangier disease.

Two cases of Tangier disease are described in children from families unrelated to each other. Necropsy in one case, the first to be reported in this condition, showed large collections of cholesterol-laden macrophages in tonsils, thymus, lymph nodes, and colon, and moderate numbers in pyelonephritic scars and ureter. As the storage cells may be scanty in marrow, jejunum, and liver, the rectum is suggested as the site of choice for biopsy. The diagnosis was confirmed by demonstrating the absence of alpha-lipoproteins from the plasma of the living child, and by finding low plasma levels in both parents of both cases. The disease can be distinguished from other lipidoses by differences in the predominant sites of storage, staining reactions, and serum lipid studies.

Effects of high-dose inhaled corticosteroids on bone metabolism in prepubertal children with asthma.

We studied the effect of inhaled corticosteroids on the increase in bone mineral content in prepubertal children with asthma. Forty-eight asthmatic, prepubertal children receiving either inhaled beclomethasone dipropionate or budesonide were evaluated. Nine children of similar age not receiving inhaled steroids served as controls. The average age of corticosteroid-treated children was 7.8 +/- 2.4 years, and of control children, 8.4 +/- 2.1 years (NS). The average dose of inhaled corticosteroids in the treated children was 0.67 +/- 0.48 mg/m(2)/day, and they were followed over a 9-20-month period. Total bone mineral content (TBMC) was measured at baseline and after 9-20 months. A derived value for 12 months' TBMC was calculated, assuming that changes in TBMC were linear with the passage of time. The change in TBMC over a 12-month period was 264 +/- 68 mg for the corticosteroid-treated children and 330 +/- 84 mg for control children (P < 0.025). In a multiple regression analysis in which adjustments were made for the effects of age, height, and weight, the change in TBMC in corticosteroid-treated children was inversely related to the inhaled steroid dose/m(2)/day (P = 0.016). The increase in the lumbar vertebral bone mineral density in control children was also significantly greater than in the corticosteroid-treated children (P < 0.025). We conclude that inhaled steroids, at an average dose of 0.67 mg/m(2)/day, when used in the treatment of asthma reduce the acquisition of bone mineral in prepubertal children.

The relationship of prorenin values to microvascular complications in patients with insulin-dependent diabetes mellitus.

We have performed a cross-sectional analysis of the relationship between prorenin values and the microvascular complications of diabetes in a well controlled population of insulin-dependent diabetes mellitus (IDDM) subjects. One hundred and thirty-nine subjects (75 men, 64 women, age 44 +/- 17 years; duration of diabetes 19 +/- 15 years), formed the study group. Sixty-seven subjects (48.2%) had no complications, 55 (39.6%) had retinopathy alone, and 17 (12.2%) had retinopathy and albuminuria. Patients with no complications had lower prorenin values than those with microvascular complications (p < 0.001), whilst patients with both albuminuria and retinopathy had higher values than those with retinopathy alone (p < 0.05). Retinopathy was associated with duration of diabetes (p < 0.0001), diastolic blood pressure (p < 0.02) and albuminuria (p < 0.0001) while albuminuria was associated with prorenin (p < 0.02), serum triglyceride (p < 0.01) and retinopathy (p < 0.001). Patients with albuminuria were 5.5 times more likely to have raised prorenin values (>80 ng/mL/h) than those with normal albumin excretion [95% confidence interval (CI): 1.48-20.12] and those with retinopathy alone were 2.5 times as likely (95% CI: 1.19-5.15). Eighty patients with IDDM (40 males, 40 females; age: 47 +/- 17 years; duration of diabetes: 20 +/- 15 years), had retinal photography performed to determine the association between the severity of retinopathy and prorenin values. Retinopathy was more severe in patients with retinopathy and albuminuria than in those with retinopathy alone (p < 0.002). When the prorenin values of patients with more marked retinopathy (eye grade greater than 3) were compared, prorenin values of those with retinopathy and albuminuria were greater than those of patients with retinopathy alone [269 (139-1406) versus 91 (41-273) ng/mL/h: geometric mean (range); p < 0.05]. Furthermore, when patients without albuminuria were considered, there was no significant difference between the prorenin levels of patients with more severe retinopathy (eye grade >3) when compared to patients with lesser degrees of retinopathy [91 (41-273) versus 69 (23-375). In patients with microvascular complications, prorenin values were independently predicted by albuminuria (p < 0.0001) and diastolic blood pressure (p < 0.02) but not the severity of retinopathy. In conclusion, prorenin values are significantly associated with the presence of microvascular complications in patients with IDDM. The association with albuminuria may be stronger than the association with retinopathy.

Testing for disorders of calcium metabolism.

Assays of serum immunoreactive parathyroid hormone are clinically useful in the differential diagnosis of hypercalcaemic states and in the assessment of the severity of parathyroid bone disease in uraemic patients. Serum immunoreactive calcitonin measurements are essential in the investigation of individuals who might be suffering from medullary carcinoma, and such measurements may be used in the detection of metastases. Serum 25-hydroxyvitamin D assays are useful in patients receiving pharmacological doses of vitamin D, to monitor patient compliance and to prevent the occurrence of vitamin D intoxication. Low values in patients with renal failure and in patients with malabsorption and highly suggestive of the presence of osteomalacia. The measurement of serum levels of dihydroxylated vitamin D metabolites is currently of doubtful clinical relevance, though such measurements may become useful in monitoring patients receiving these compounds therapeutically.