A screening test to identify aldosterone-producing adenoma by measuring plasma renin activity. Results in hypertensive patients.

In an attempt to devise a screening test for aldosterone-producing adenoma (APA) among hypertensive patients, the serum sodium and potassium levels, plasma renin activity (PRA), plasma aldosterone concentration, and aldosterone-PRA ratio were measured in 348 patients with hypertension. Nine patients with a substantially elevated aldosterone-PRA ratio were selected and hospitalized for further investigations. All nine patients were then recognized by scintigraphy with labeled cholesterol, venography, and surgical excision as having APA. The serum concentration of potassium was subnormal in three of nine patients with APA. In patients with APA, administration of diuretics and salt restriction significantly elevated PRA. However, even under notable diurnal and day-to-day variations of plasma aldosterone concentrations, the aldosterone-PRA ratio was always elevated inappropriately (more than 400) in patients with APA. In contrast, after administration of diuretics, both the PRA and aldosterone levels increased significantly in patients with essential hypertension, but the aldosterone-PRA ratio was less than 200. Since the renin-angiotensin system seems to be a major factor controlling aldosterone secretion in normal subjects, it is suggested that an elevation of aldosterone-PRA ratio more than 400 is a useful screening tool for the prediction of APA among hypertensive patients.

Diabetic complications and their relationships to risk factors in a Japanese population.

The relationship between diabetic complications and age, sex, duration, mode of therapy, body weight, control of blood glucose, blood pressure, and serum triglyceride and cholesterol was analyzed in a population with non-insulin-dependent diabetes in Japan. The prevalences of complications in the subjects varied from 6.5% for cerebrovascular strokes to 85.1% for sclerotic changes in retinal vessels; 35.8% of the patients had diabetic retinopathy and 19.8% had proteinuria. Univariate and multivariate analyses revealed that control of diabetes (blood glucose, mode of therapy, and duration) was closely correlated with retinopathy and proteinuria. However, blood glucose did not correlate with coronary insufficiency or cerebrovascular strokes. These macrovascular complications were related to aging and blood pressure. The data suggested that not only good glycemic control but also sufficient antihypertensive therapy was necessary for treating diabetic patients. The coefficient of determination of the risk factors was calculated for each diabetic complication. Except for sclerotic changes in retinal vessels, the coefficients were too small to fully explain the development of diabetic complications, especially for macrovascular diseases. The current data suggest that susceptibility of the individual patients to the diabetic complications is an important determinant.

High blood pressure as risk factor in diabetic retinopathy development in NIDDM patients.

The correlation between diabetic retinopathy and blood pressure was analyzed in 742 type II diabetic patients. Systolic and pulse blood pressures were significantly higher in the patients with retinopathy than in those without (mean systolic pressure 142 vs. 139 mmHg, P less than .01; mean pulse pressure 60.5 vs. 56.4 mmHg, P less than .001). There was no difference in the diastolic blood pressure between these two groups. The correlation between blood pressure and the components of retinopathy (including microaneurysms, hemorrhages, and exudates) was also analyzed. Even when the patient with microaneurysms or dot hemorrhages, blot hemorrhages, or hard or soft exudates were separately evaluated, systolic and pulse blood pressures were higher in those with one of these diabetic changes than in patients without them. To avoid the influence of nephropathy, the patients were divided into nonproteinuric or proteinuric groups. In the nonproteinuric group, pulse blood pressure was higher in patients with retinopathy than in those without. In the proteinuric group, systolic blood pressure was also higher in patients with retinopathy than in those without. However, these observed differences in blood pressure were slight after the division of the patients. With respect to the components of retinopathy, systolic and pulse blood pressures were significantly higher in the patient with blot hemorrhages than in those without in both nonproteinuric and proteinuric groups (nonproteinuric: systolic pressure 142 vs. 137 mmHg, P less than .005, and pulse pressure 60.4 vs. 55.5 mmHg, P less than .001; proteinuric: systolic pressure 155 vs. 146 mmHg, P less than 0.01, and pulse pressure 69.0 vs. 63.5 mmHg, P less than .05).

Some effects of adrenalectomy in the fatty rat.

Function of the pituitary-adrenal axis was examined in lean and genetically obese fatty (Zucker) rats. The diurnal rhythms of plasma corticosterone and plasma ACTH were similar in both groups. The secretion of corticosterone by adrenal glands incubated in vitro with graded doses of ACTH was also comparable in lean and fatty rats. Adrenalectomy reduced food intake and weight gain in the fatty rats to levels similar to those in the lean animals and raised plasma ACTH to the same level. The injection of corticosterone (2 and 10 mg/day) increased food intake more in adrenalectomized fatty rats than in the corresponding lean ones. Progesterone increased food intake similarly in both groups. The enhanced responsiveness to corticosterone could account for many of the metabolical defects in the fatty rat.

Effects of excess iodide and other anions on thyroid hormone secretion in normal or hypophysectomized rats treated with graded doses of thyroid hormone.

In order to obtain further information about the stimulatory action of excess iodide on thyroid hormone secretion in thyroxine (T4)-treated rats, experiments were performed in hypophysectomized rats, or rats treated with graded doses of T4 or triiodothyronine (T3).T3 as well as T4 played a permissive role in the production of the iodide effect in normal animals, but T3 was more effective than T4. Excess iodide stimulated thyroid hormone secretion in hypophysectomized animals, this finding being compatible with the hypothesis that, by inhibiting TSH secretion, T3 and T4 produced a condition in which excess iodide stimulated thyroid hormone secretion in intact rats. However, T4 played an additional role in thyroid hormone secretion by acting directly on the thyroid. In hypophysectomized animals, small doses of T4 stimulated thyroid hormone secretion, and this action was additive to that of excess iodide, whereas large doses of T4 were inhibitory and reduced the effectiveness of excess iodide. The stimulatory action on thyroid hormone secretion was specific for iodide and was not shared by other anions. The action of excess iodide was blocked by methimazole. We suggest that excess iodide stimulates thyroid hormone secretion by increasing intrathyroidal concentrations of cyclic AMP in the absence of TSH, and that this increase in cyclic AMP concentration is blocked by methimazole.

An increase of plasma triiodothyronine concentration in man in a cold environment.

In an attempt to study an effect of cold on endocrine function in man, plasma thyroxine (T4), triiodothyronine (T3), TSH, and cortisol concentrations were studied in 24 healthy men who worked in a cold environment (4 to 6C) for 3 h for the culture of mushrooms and 56 healthy men who lived in cold environment in winter. For comparison, similar measurements were made on 47 university employees who lived in rooms with air-conditioning. In 24 adult men, acute exposure to cold for 3 h failed to affect plasma concentrations of T4, T3, and TSH. In 56 adult men, no significant difference was found in the concentrations of T4, TSH, and cortisol between summer and winter. However, plasma T3 concentration increased significantly in winter, suggesting seasonal variation of T3. In contrast, no such seasonal variation was found in 47 university employees who lived in rooms with air-conditioning.

Volume of sella turcica in normal subjects and in patients with primary hypothyroidism and hyperthyroidism.

In an attempt to assess a possible relationship between pituitary size and TSH secretion, the volume of sella turcica was measured in 570 subjects, 26 primary hypothyroid patients, and 34 thyrotoxic patients. The volume of sella turcica, measured by a 3-dimensional approach, increased progressively with age until 20 years of age and was rather constant thereafter in normal subjects. In thyrotoxic patients, the volume of sella turcica was normal in spite of decreased plasma TSH concentration. In contrast, 81% of primary hypothyroid patients had an abnormal enlargement of the sella turcica. The magnitude of an increase of sella turcica inversely related with a decrease in serum T4 and T3 concentrations. On the other hand, the magnitude of an increase of sella turcica correlated well with an increase of circulating TSH. We suggest that an increase of sella turcica indirectly reflects an increase in pituitary size and TSH-secreting capacity, possibly due to hypertrophy and hyperplasia of TSH cells in primary hypothyroid patients.

Pituitary unresponsiveness to thyrotropin-releasing hormone in thyrotoxic patients during chronic anti-thyroid drug therapy and in rats previously treated with excess thyroid hormone.

In an attempt to study pituitary-thyroid feedback control in thyrotoxic patients, TRH tests were performed in 10 thyrotoxic patients who were treated for varying intervals with propylthiouracil. Plasma TSH was undetectable before and after administration of 500 mug TRH in 7 patients (euthyroid or hypothyroid) after therapy for 1 to 4 months. Also, plasma TSH was undetectable before and after TRH in 3 patients who had been euthyroid for at least 6 months. To explore this abnormality, rats were made thyrotoxic by administering large doses of thyroxine or desiccated thyroid for 3 to 28 days. Discontinuation of thyroid hormone administration was followed by a significant but temporary fall of plasma thyroxine and triiodothyronine concentration below control levels. Duration of the low plasma thyroxine and triiodothyronine concentration was longer with the prolonged administration of thyroid hormone. Despite low plasma thyroxine and triiodothyronine concentrations, plasma TSH was below normal before and after administration of TRH. This unresponsiveness of the pituitary to TRH may be comparable to that found in thyrotoxic patients receiving antithyroid drugs for a certain period. Since this pituitary unresponsiveness to TRH in rats is due to a depletion of pituitary TSH content, it is suggested that depletion of pituitary TSH in thyrotoxic patients during antithyroid therapy is the cause of pituitary unresponsiveness to TRH.

Presence of antideoxyribonucleic acid antibody in patients with hyperthyroidism of Graves' disease.

In 16 untreated patients with hyperthyroidism due to Graves' disease, serum antidouble stranded DNA antibody, measured by RIA, was positive (greater than 20 U/ml) in 14. In methimazole-treated patients with T3-suppressible thyroid uptake, anti-DNA antibody was found in 9% (3 of 35). The frequency of positive tests in methimazole-treated patients with T3-nonsuppressible thyroid uptake and in surgically treated patients was 24% (5 of 21) and 57% (4 of 7), respectively. Among anti-DNA antibody-negative (less than 9 U/ml) and weakly positive (10-19 U/ml) patients, those with T3-suppressible thyroid uptake had lower anti-DNA antibody titers than those with T3-nonsuppressible thyroid uptake. Among 32 patients with Hashimoto's thyroiditis, anti-DNA antibody was positive in 7. None of the patients with simple goiter had positive or weakly positive anti-DNA antibody results. Although the quantity of antibodies did not correlate well in individual patients, the rates of positive TSH binding-inhibiting immunoglobulin and anti-DNA antibody tests were roughly comparable in these patient groups. None of these patients with thyroid disease associated with anti-DNA antibody had clinical or other serological evidence suggestive of systemic lupus erythematosus or related collagen vascular disorders. The finding of anti-DNA antibody provides a new aspect of immunological abnormality associated with hyperthyroidism of Graves' disease.

Effects of adrenalectomy on body weight and the size and number of fat cells in the Zucker (fatty) rat.

Adrenalectomy reduced food intake and the rate of weight gain in the Zucker (fatty) rat to levels indistinguishable from normal. The size of adipocytes in the retroperitoneal and perimetrial fat pads also decreased after adrenalectomy but the number of fat cells in each of these depots increased to reach levels not different from those in the sham-operated fatty rat. Fat accretion in the intact fatty rat was characterized by both hyperplasia and hypertrophy of the fat cells, but in the adrenalectomized Zucker rats, weight gain was accompanied by hyperplasia and decreased fat cell size. These data show that adrenalectomy can prevent most of the phenotypic expression of the genetic defect in the fatty rat and challenge the concept that reduced food intake can prevent hyperplasia of fat cells.

An enzymatic defect in the obese (ob/ob) mouse: loss of thyroid-induced sodium- and potassium-dependent adenosinetriphosphatase.

Genetically obese (ob/ob) mice, mice that became obese after treatment with gold thioglucose, and lean animals were studied in the euthyroid state, after induction of hypothyroidism, and after treatment with triiodothyronine. The activity of glycerol 3-phosphate dehydrogenase (sn-glycerol-3-phosphate:(acceptor) oxidoreductase; EC 1.1.99.5] was reduced in the livers from hypothyroid animals and was increased by treatment with triiodothyronine in all groups. The activity of the ouabain-suppressible sodium- and potassium-dependent ATPase (ATP phosphohydrolase; EC 3.6.1.3) was increased by triiodothyronine and reduced by hypothyroidism in the lean and gold thioglucose-treated obese animals. In the obese (ob/ob) mice, on the other hand, treatment with triiodothyronine did not increase the activity of this enzyme, which remained at the level found in hypothyroid animals. This enzymatic activity was reduced in both liver and kidney. Adenylate cyclase [ATP pyrophosphate-lyase (cyclizing); EC 4.6.1.1] activity in liver membranes, however, was similar in all three groups of mice. This enzyme complex was activated by glucagon and was unaffected by treatment with thyroid hormones. The lack of a thyroid-dependent ouabain-suppressible (Na(+) + K(+))-ATPase in the tissues of the obese (ob/ob) mouse could explain most, if not all, of the abnormalities that have been described in this animal.

Thyroidal response to an increase or decrease of endogenous TSH in patients with hyperthyroidism and its correlation with TSH binding inhibiting immunoglobulin.

One hundred and twenty-one patients with hyperthyroidism of Graves' disease were treated with antithyroid drugs for 3 years and thyroidal response to an increase or decrease of TSH and the serum thyroid stimulating immunoglobulin (TSI) activity were studied in relation to the presence or absence of TSH binding inhibiting immunoglobulin (TBII). TBII activity was positive in 83% of untreated patients but decreased gradually with time during antithyroid drug therapy. Thyroidal radioactive iodine uptake (RAIU) was suppressed by T3 in 86 of 121 treated patients but 16% of suppressible patients had TBII activity. Thyroidal RAIU was not suppressed by T3 in 35 treated patients, and 19 of 35 unsuppressible patients had TBII activity but other 16 patients did not. When suppressible and unsuppressible patients were combined, suppression of serum T4 and thyroidal RAIU by T3 tended to be less in the presence of TBII activity. TSI activity was detected in the sera of untreated patients but did not correlate with TBII activity. TSI activity was undetectable after treatment for 3 years irrespective of presence or absence of TBII activity and T3-suppressibility. TSH, T4 and T3 elevation in response to 500 micrograms thyrotropin releasing hormone (TRH) was normal in all treated patients irrespective of presence or absence of TBII activity and T3-suppressibility. It is suggested that in vivo thyroidal responsiveness to an increase or decrease of endogenous TSH did not correlate with the presence or absence of TBII activity after long-term therapy with antithyroid drugs.

Unusual clinical presentation of malignant histiocytosis in a 70-year-old woman.

A 70-year-old woman was admitted for evaluation of hepatosplenomegaly, fever and elevated serum LDH levels. A biopsy specimen of the liver revealed histiocytic proliferation at the portal triad, and a mild degree of hepatitis. A bone marrow biopsy specimen showed proliferation of histiocytes with minimal immaturity and atypism, and haemophagocytosis by the proliferated histiocytes. Fever, hepatosplenomegaly and elevation of LDH levels all disappeared spontaneously, and presumptive diagnosis of benign reticulosis with haemophagocytosis was made. One year later, fever, hepatosplenomegaly and elevation of LDH levels redeveloped, and the liver and bone marrow biopsy specimen showed proliferation of unequivocally malignant histiocytes. The patient died as a result of disseminated intravascular coagulation with shock 20 d later. We concluded that, in this case, malignant histiocytosis first presented as benign haemophagocytic reticulosis and, 1 year later, there was a typical malignant presentation.