Thyroid hormone indices during illness in six hypothyroid subjects rendered euthyroid with levothyroxine therapy.

PURPOSE: We wanted to evaluate changes in the natural course of serum thyroxine (T4), tri-iodothyronine (T3), reverse tri-iodothyronine (rT3), and thyroid stimulating hormone (TSH) concentrations during hospitalization for an acute illness, in subjects rendered euthyroid with Levothyroxine (LT4) replacement therapy. METHODS: Six male subjects ranging in age 30 - 65 years with a history of primary hypothyroidism were included. They were euthyroid prior to hospitalization. LT4 continued to be administered orally in the same pre-admission daily dose. Serum, T4, T3, rT3, and TSH concentrations were determined on day of admission to the intensive care unit (ICU) for an acute illness. These were repeated during the first week on alternate days and again during a follow-up visit 1 week after discharge. Student's t-test, analysis of variance, and linear regression were used to analyze the data. RESULTS: Serum T4, T3 declined to a nadir and serum rT3 rose to its peak by day 3 of hospitalization before returning to pre admission euthyroid levels. Serum TSH declined initially but rose to supernormal levels on day 7 before normalization. Significant correlations were noted between TSH on one hand and T3/T4 (r = 0.76, p < 0.001) and rT3/T4 (r= - 0.64, p < 0.001) ratios. CONCLUSIONS: Alterations ensuing during a short stay in the hospital due to an acute illness in subjects with primary hypothyroidism rendered euthyroid with appropriate replacement therapy with Levothyroxine (LT4) are almost identical to those in normal subjects. These changes are probably secondary to altered thyroid hormone metabolism. The altered levels of thyroid hormones and TSH noted in these subjects are transient and therefore providers should refrain from initiating frequent changes in daily LT4 replacement dose during the acute illness in these subjects.

Thyrotropin dysregulation during a non-thyroidal illness: transient hypothalamic hypothyroidism?

Both the basal TSH concentration and the TSH response to iv TRH administration are noted to be decreased at the peak of an acute critical illness. Moreover, an impaired release from hypothalamus has been documented in rats with uncontrolled diabetes, suggesting hypothalamic dysfunction in a non-thyroidal illness. However, the exact inference and mechanism of this impaired TSH secretary pattern is not well defined in humans during a non-thyroidal illness. Therefore, this study assessed hypothalamic pituitary thyroid axis by determination by T4, T3, and T3 resin uptake prior to and TSH concentrations, prior to, as well as following, iv TRH administration at an interval of 30 min up to 2 hours on three successive mornings during a severe, critical, fatal illness in five previously known euthyroid subjects. TSH response to iv TRH administration was expressed as a maximal absolute change (delta TSH) and a cumulative response (CR TSH), calculated as the sum of changes from the basal level at each specific time period for up to 120 min. Serum T4, T3 and TSH concentrations on day 1 of the TRH administration were significantly lower than normal values as well as the values documented previously in the same individuals prior to hospitalization. T3 resin uptake was increased simultaneously. Moreover, serum T4, T3, and T3 resin uptake remained significantly unaltered on three successive days of iv TRH administration. However, basal serum TSH rose significantly with a parallel TSH response to iv TRH administration, as reflected by a progressive rise in delta TSH as well as CR TSH over this three-day period, with normalization of the TSH responses by the third day. Therefore, impaired TSH secretary pattern and altered thyroid hormone concentrations noted in subjects with acute critical illness may be attributed to the presence of a transient hypothalamic hypothyroidism.

Serum thyrotropin in primary hypothyroidism: a reliable and accurate predictor of optimal daily levothyroxine dose.

OBJECTIVE: To assess the reliability and accuracy of the predicted optimal daily levothyroxine (LT4) dose based on pretreatment serum thyrotropin (thyroid-stimulating hormone or TSH) level in primary hypothyroidism. METHODS: We examined the relationships between the actual daily LT4 dose required to attain and maintain normal serum TSH concentration and the calculated daily LT4 dose, based on previously established correlations with pretreatment serum TSH concentrations, in 108 consecutive patients with primary hypothyroidism treated in an endocrinology clinic during an 18-month period. RESULTS: Highly significant correlations were noted between the optimal daily LT4 dose and the calculated dose based on either logarithmic regression (r = 0.86; P<0.00001) or linear regression (r = 0.83; P<0.00001). Moreover, the actual mean daily LT4 dose (133 +/- 4 mg) approximated the mean doses predicted by both regression analyses (129 +/- 5 mg and 126 +/- 5 mg, respectively) and was identical in many of the study subjects. CONCLUSION: The predicted optimal daily LT4 dose based on pretreatment serum TSH level provides a reliable and accurate approximation of the final optimal LT4 dose in patients with primary hypothyroidism and therefore may be a more convenient and cost-effective therapeutic approach than the current traditional clinical practice.

Weight gain, improvement in metabolic profile, and CD4 count with insulin administration in an AIDS patient.

Malnutrition with muscle wasting, weight loss, and decreased immunogenicity is a hallmark of Acquired Immune Deficiency Syndrome (AIDS). Several anabolic agents have been utilized for retarding or preventing progressive wasting with limited success. However, insulin, with its most effective anabolic properties, has not been tried in an attempt to prevent or reverse cachexia in AIDS or any other wasting disorders. We report here the effect of using subcutaneous (s.c.) daily administration of insulin 0.3 U/kg (BW) for 6 months in a subject with AIDS. We noted a marked weight gain, improvement in metabolic profiles, that is, lowering of triglyceride, liver enzymes, glycohemoglobin concentrations, as well as 24-hour urinary excretion of urea nitrogen, protein, and creatinine suggestive of positive energy balance. Simultaneously, a marked rise in CD4 counts and an improvement in the thyroid hormone profile were also noted. A deterioration in these parameters occurred during the period of insulin withdrawal following completion of the study protocol. Resumption of insulin administration, on patient's request, once again resulted in the marked improvement similar to that noted during the study period. No adverse effects, including hypoglycemic episodes, were noted during either phase of insulin administration. The possibility that insulin administration may improve the wasting associated with AIDS may warrant further evaluation.

Intractable nausea attributable to isolated deficiency of adrenocorticotropic hormone: prompt resolution after administration of glucocorticoid.

OBJECTIVE: To highlight the vague symptoms of isolated adrenocorticotropic hormone (ACTH) deficiency and suggest helpful diagnostic tests and appropriate management. METHODS: We present a detailed case report, including clinical and laboratory findings, and discuss the diagnostic approach to this rare disorder of isolated ACTH deficiency. RESULTS: A 74-year-old woman had persistent severe nausea and other vague symptoms. Elaborate testing during a period of several weeks failed to determine the cause. Ultimately, isolated ACTH deficiency was diagnosed after documentation of subnormal random serum cortisol and ACTH levels as well as urinary free cortisol concentrations. Moreover, the nausea and other symptoms abated after administration of glucocorticoid. The patient was then maintained on orally administered dexamethasone, 0.5 mg twice daily, for 4 to 6 weeks, at which time the diagnosis was confirmed by a subnormal cortisol response on cosyntropin stimulation testing and an unmeasurable ACTH level after overnight oral administration of metyrapone. Although the cause of this patient's isolated ACTH deficiency remained undetermined, it was thought to be autoimmune in nature because of the presence of Graves' disease. CONCLUSION: This report emphasizes the need for recognition of symptoms, appropriate testing to confirm the diagnosis, and prompt treatment with glucocorticoids in patients with isolated ACTH deficiency.

Effects of carbamazepine on the hypothalamic-pituitary-thyroid axis.

OBJECTIVE: To evaluate the effects of treatment with carbamazepine on the hypothalamic-pituitary-thyroid axis and thyroid hormone concentrations in patients with epilepsy. METHODS: We undertook a prospective study in seven subjects in whom the diagnosis of epilepsy had been established and a regimen of carbamazepine (200 mg three times a day) was initiated. All participants underwent 24-hour 123 I thyroid uptake studies, as well as assessment of the basal thyrotropin concentration and the thyrotropin response to intravenous administration of thyrotropin-releasing hormone. In addition, thyroxine (T(4)), free T(4) index, triiodothyronine (T(3)), free T(3) index, reverse T(3), and T(3) resin uptake were determined before initiation of carbamazepine treatment and again after 3 to 4 months of carbamazepine therapy. RESULTS: Serum T(4), T(3), and free T(4) index decreased significantly (P<0.05) after therapy with carbamazepine, whereas no significant alterations were noted in T(3) resin uptake, free T(3) index, and reverse T(3) concentrations. A significant increase occurred in basal serum thyrotropin level (P<0.05). Moreover, the peak thyrotropin concentration, the absolute change from the basal thyrotropin level, and an integrated thyrotropin response expressed as cumulative response to thyrotropin-releasing hormone stimulation were all significantly increased after carbamazepine therapy in comparison with values documented before initiation of therapy (P<0.05 for all comparisons). Finally, 24-hour 123 I uptake by the thyroid gland increased slightly after carbamazepine therapy, but the change was not statistically significant. All values determined both before and after carbamazepine therapy remained within normal ranges. CONCLUSION: Carbamazepine therapy induces significant alterations in serum thyroid hormone concentrations as well as in the hypothalamic-pituitary-thyroid axis. Nevertheless, patients receiving carbamazepine treatment continue to remain euthyroid despite these significant changes.

Inhibited hypothalamic-pituitary-thyroid axis in type I pseudohypoparathyroidism.

OBJECTIVE: To assess the hypothalamic-pituitary-thyroid axis in two patients with the diagnosis of type I pseudohypoparathyroidism established previously by characteristic clinical features and laboratory findings, including low serum Ca++, high parathyroid hormone concentration, and subnormal urinary cyclic adenosine monophosphate (cAMP) responses to exogenous administration of parathyroid hormone. METHODS: We determined serum thyroxine, triiodothyronine (T(3)), T(3) resin uptake, and 24-hour thyroidal uptake of 123 I before and after subcutaneous administration of thyroid-stimulating hormone (TSH), 10 U daily for 3 days. Serum TSH levels were determined before and again at 15, 30, 45, and 60 minutes after intravenous administration of thyrotropin-releasing hormone (TRH) (400 microg) after an overnight fast. Values noted in the two patients with type I pseudohypoparathyroidism were compared with those obtained in 10 normal volunteer control subjects. RESULTS: Serum thyroxine (T(4)), triiodothyronine (T(3)), T(3) resin uptake, and 24-hour 123 I uptake values for both patients with type I pseudohypoparathyroidism were within the normal ranges (5.5 to 11.5 microg/dL for T(4), 90 to 190 ng/dL for T(3), 35 to 45% for T(3) resin uptake, and 10 to 35% for 24-hour 123I uptake). Their responses to administration of TSH, however, were all significantly lower in comparison with the mean values for the 10 healthy control subjects. Basal TSH was higher in both patients with type I pseudohypoparathyroidism than in normal subjects, but TSH responses after administration of TRH, although not significantly different from normal, were blunted in relationship to the basal concentrations, as expressed as a percentage increase in TSH as well as a cumulative TSH response. CONCLUSION: The responses of pituitary thyrotrophs to TRH and the thyroid gland to TSH were both considerably inhibited in the patients with type I pseudohypoparathyroidism in comparison with normal control subjects. This finding may be yet another evidence of the lack of adequate generation of cAMP, an important second messenger needed for normal functioning of most polypeptide hormones, including TRH and TSH, in this syndrome.

Successful outcome with methimazole and lithium combination therapy for propylthiouracil-induced hepatotoxicity.

OBJECTIVE: To assess the efficacy and safety of combination therapy with methimazole and lithium carbonate in management of severe thyrotoxicosis and propylthiouracil-induced hepatotoxicity. METHODS: We present a case report of a patient with severe thyrotoxicosis and worsening liver dysfunction after propylthiouracil therapy, and we review the pertinent literature. RESULTS: In a 49-year-old man with severe thyrotoxicosis and propylthiouracil-induced hepatotoxicity, indices of liver function continued to increase despite discontinuation of propylthiouracil treatment. Adjunctive therapy with methimazole and lithium resulted in prompt remission of clinical manifestations and normalization of thyroid hormone indices, as well as a gradual reversal of liver dysfunction. CONCLUSION: Adjunctive therapy with methimazole and lithium is synergistic in promptly achieving a euthyroid state. Therefore, this combination therapy provides a safe and effective alternative option in patients with thyrotoxicosis associated with propylthiouracil-induced hepatotoxicity.

Influence of age on optimal daily levothyroxine dosage in patients with primary hypothyroidism grouped according to etiology.

BACKGROUND: Optimal daily levothyroxine (LT4) dosage is reported to be significantly smaller in the elderly with primary hypothyroidism when compared with their younger counterparts. However, this finding has not been studied in different etiologic groups. METHODS: This study assessed the influence of age on optimal daily LT. dosage in 337 patients with primary hypothyroidism grouped according to etiology. RESULTS: Daily LT. dosage declined with increasing age in 99 patients with Hashimoto's thyroiditis, in 73 patients with idiopathic variety, and in 47 patients with hypothyroidism due to radical neck surgery and/or neck radiation for non-thyroidal malignancies. In contrast, daily LT. dosage rose with age in 85 patients who had radioiodine (131I) therapy and/or subtotal thyroidectomy for hyperthyroidism. Finally, daily LT. dosage was not significantly altered in 22 patients with subclinical hypothyroidism or in 11 patients with drug-induced hypothyroidism. CONCLUSION: Optimal daily LT4 dosage does not decline universally in all elderly with primary hypothyroidism: it appears to depend also on the etiology of the disorder.

Pancreatic alpha-cell function in idiopathic reactive hypoglycemia.

Idiopathic reactive hypoglycemia (IRH) is a well-documented but overdiagnosed syndrome. The presence of transient hypoglycemia and enhanced insulin secretion and/or increased insulin sensitivity before the onset of IRH is well documented. However, the data regarding glucagon secretion are sparse. Therefore, this study assessed glucagon and insulin responses to (1) oral ingestion of 100 g glucose oral glucose tolerance test (OGTT) and (2) a 100-g protein meal after an overnight fast in a randomized sequence at intervals of 7 to 10 days in five subjects with previously well-documented IRH and six normal subjects. Basal plasma glucose and insulin levels were not significantly different in both groups. However, basal glucagon was significantly higher (P < .025) in IRH subjects (347 +/- 83 ng/L) compared with normals (135 +/- 20 ng/L). In IRH subjects during the OGTT, hypoglycemia (2.7 +/- 0.11 mmol/L) occurred at 150 +/- 16 minutes and was preceded by a markedly higher (P < .01) peak glucose concentration (11.7 +/- 0.6 mmol/L) at 36 +/- 6 minutes in comparison to normals (8.8 +/- 0.4 mmol/L), indicating the presence of impaired glucose tolerance in these subjects. Similarly, the plasma insulin increase was significantly higher (P < .01) but delayed in IRH subjects compared with normals. In contrast, glucagon suppression was not significantly different in both groups, although glucagon failed to increase following hypoglycemia in IRH. During a protein meal, plasma glucose declined in both groups, with a significantly (P < .05) greater decrease in IRH subjects (-0.8 +/- 0.2 mmol/L) compared with normals (0.5 +/- 0.1 mmol/L). However, the glucagon increase was significantly (P < .01) blunted in IRH subjects (61% +/- 15%) in comparison to normals (152% +/- 39%). Thus, basal hyperglucagonemia with normal glucose concentration may suggest the presence of a hyposensitivity of the glucagon receptor in IRH. Moreover, the lack of appropriate suppression during the OGTT despite marked hyperglycemia, the lack of an increase at the onset of hypoglycemia, and the inhibited response to a protein meal in IRH subjects compared with normals denote altered glucagon secretion in IRH. Therefore, it is likely that glucagon receptor downregulation and impaired glucagon sensitivity and secretion may contribute to postprandial hypoglycemia in IRH.

Normal thyroxine and elevated thyrotropin concentrations: evolving hypothyroidism or persistent euthyroidism with reset thyrostat.

BACKGROUND: The natural course in subjects manifesting normal serum thyroxine (T4), and triiodothyronine (T3), with an elevated thyrotropin (TSH) level demonstrated two distinct outcomes, one progressing to well defined hypothyroidism as expressed by onset of subnormal T4, T3 and a further rise in TSH and the other remaining in the same state. However, thyroid hormone concentrations at the time of diagnosis fail to distinguish between the two groups. Therefore, we examined the influence of alteration in circulating TSH levels on thyroid gland function at the time of diagnosis in subjects with this syndrome to assess the role of pituitary thyroid axis in these different outcomes. METHODS: 24 hour 131I thyroidal uptake was determined in 14 men and 3 women manifesting normal T4, T3 and elevated TSH prior to and again after 1) subcutaneous administration of bovine TSH, 10 units daily for 3 days and 2) daily oral administration of L-triiodothyronine 75 micrograms for 7 days in a randomized sequence at interval of 4 weeks. Subjects were then followed for up to 16 years to assess the natural course. RESULTS: Basal 24 hour 131I uptake values were within the normal range (10-35%) in all subjects and increased on TSH administration and declined following LT3 administration. However, in eight subjects, these responses were markedly lower (< 20%) when compared with the minimum change (50%) noted in normal volunteers. These subjects progressed to manifest hypothyroidism requiring LT4 therapy within two years as reflected by a progressive decrease to subnormal T4 levels with a further rise in serum TSH. The remaining nine subjects, demonstrated normal responses (> 50%) and only one of these became hypothyroid during the follow-up period of 16 years. CONCLUSION: All subjects with normal T4 and T3 with elevated TSH do not manifest "subclinical or evolving hypothyroidism". Two distinct populations seem to exist, one with inhibited pituitary thyroid axis progressing to hypothyroidism or true "subclinical hypothyroidism" at the time of diagnosis and the other with normal pituitary thyroid axis, a state of euthyroidism with "reset thyrostat" at a higher TSH concentration, a state probably persisting for their remaining life span.

Pheochromocytoma.

OBJECTIVE: To characterize the symptoms associated with pheochromocytoma and discuss the diagnosis and management of this tumor. METHODS: We review the clinical manifestations in patients with pheochromocytoma, the biochemical and imaging studies recommended for diagnosis and localization of the tumor, and the available strategies for treatment. RESULTS: Pheochromocytoma is a tumor of chromaffin cells that originates in either the adrenal medulla or the extra-adrenal sympathetic tissues. It is usually unilateral and benign. Frequent initial symptoms include headache, sweating, and palpitations, with or without increased blood pressure. In many patients, hypertension is accelerated during a paroxysm. Pheochromocytoma may also occur as a part of multiple endocrine neoplasia type IIA and B. Several common syndromes, such as panic disorders and hyperthyroidism, may mimic pheochromocytoma; however, pheochromocytoma should be suspected in the presence of hypertension, tachycardia, and throbbing headache, especially occurring as paroxysmal episodes. The physiologic diagnosis of pheochromocytoma is established by biochemical tests of levels of plasma and urinary catecholamines or their metabolites (or both). In most patients, anatomic localization is achieved with computed tomography or magnetic resonance imaging, metaiodobenzylguanidine scintigraphy, labeled somatostatin scans, or positron emission tomography. The management preferentially includes surgical removal of the pheochromocytoma after preparation with appropriate medical therapy to avoid hypertensive crisis during the perioperative period. Patients with contraindications to a major surgical procedure or with malignant pheochromocytoma and metastatic disease, however, may be treated with multiple drugs--for example, alpha- and beta-adrenergic blockers and direct vasodilators to neutralize the effects of high levels of circulating catecholamines and alpha-methyl-metatyrosine to inhibit catecholamine synthesis. CONCLUSION: The presence of suggestive clinical features in patients with hypertension should prompt clinicians to undertake appropriate diagnostic testing because surgical resection of a pheochromocytoma will yield a cure in many cases.

Primary hyperaldosteronism.

OBJECTIVE: To characterize the syndrome of primary aldosteronism and summarize diagnostic and therapeutic strategies. METHODS: We review the mechanisms of action of aldosterone and outline features that distinguish the major subtypes of aldosteronism. RESULTS: The state of aldosterone excess should be suspected in every patient manifesting hypertension and hypokalemia. The documentation of low renin activity and high plasma aldosterone concentration in such patients suggests the presence of primary aldosteronism. Lack of appropriate suppression of plasma aldosterone after saline infusion is thought to be the best maneuver for confirming primary aldosteronism. Nonetheless, a similar lack of aldosterone suppressibility after either oral salt loading for 3 days or oral administration of a single 25-mg dose of captopril may help achieve the same purpose. Once primary aldosteronism has been diagnosed, the distinction between two major subtypes--unilateral adrenal adenoma or Conn's syndrome and bilateral idiopathic adrenal hyperplasia--is important because of the difference in management. Certain physiologic maneuvers, such as change of posture from supine to upright, oral administration of cyproheptadine, and radiologic localization with several techniques including iodocholesterol scanning and adrenal venous sampling, will almost always help distinguish unilateral adenoma from bilateral hyperplasia. CONCLUSION: The distinction between adrenal adenoma and adrenal hyperplasia is critical because of the varied approach to treatment. Most patients with bilateral adrenal hyperplasia are managed medically with an aldosterone antagonist such as spironolactone, whereas most unilateral adenomas are resected after correction of hypertension and hypokalemia with appropriate medical therapy.

Serum thyrotropin determinations: comparison of second- and third-generation assays.

OBJECTIVE: To compare thyrotropin (thyroid-stimulating hormone or TSH) levels determined by second- and third-generation assays in sera extracted from blood samples withdrawn randomly from 34 subjects attending outpatient clinics. METHODS: Serum specimens were separated into two fractions and were frozen and stored at -20 degrees C for subsequent determination of TSH concentrations by second-and third-generation assays. The results were analyzed statistically. RESULTS: Of the 34 serum samples, 23 TSH levels were within normal ranges on both assays, whereas 9 samples showed subnormal TSH concentrations with both second- and third-generation assays. The other two samples revealed mildly increased TSH levels by the third-generation assay but high normal levels with the second-generation assay. Moreover, mean TSH values determined with second- and third-generation assays for all 34 serum samples were not significantly different (1.48 versus 1.66 mU/L; P>0.05). Finally, a highly significant correlation (r = 0.987) was also noted between the two assays on simple linear regression. CONCLUSION: Thus, serum TSH determinations by both the second- and third-generation assays are almost identical, and attempting to achieve greater sensitivity to detect lower levels by further modifications in third-, fourth-, and even later generation assays may be an expensive and fruitless endeavor because of the inability of these methods to discern the thyroid functional state any better than the second-generation assay.

The effect on metabolic control of second-generation sulfonylurea drugs in patients with NIDDM after secondary failure to first-generation agents.

BACKGROUND: The literature contains few data examining the results of therapy with second-generation sulfonylurea drugs in subjects with non-insulin-dependent diabetes mellitus (NIDDM) after the onset of secondary failure to first-generation agents. The present study was undertaken to assess the efficacy of therapy with second-generation sulfonylurea in subjects with NIDDM following secondary failure to first-generation agents. METHODS: The study included 55 subjects with NIDDM who manifested secondary failure to first-generation sulfonylurea therapy. Of these, 29 subjects underwent therapy with the second-generation sulfonylurea glipizide, and 26 subjects were treated with glyburide, both drugs administered in the maximum daily dosage. Before initiation of the second-generation sulfonylurea agents and again at the end of 6 months, metabolic control was assessed by determination of fasting plasma glucose, glycosylated hemoglobin (HbA1c), and the lipid profile. RESULTS: Fasting plasma glucose and HbA1c levels were 209 +/- 31 mg/dL and 12.3 +/- 2.1%, respectively, before initiation of glipizide, and did not significantly change following therapy (fasting plasma glucose, 211 +/- 34 mg/dL; HbA1c, 11.7 +/- 1.8%). Similarly, no significant alteration was noted in these metabolic values in the glyburide group (before glyburide therapy, fasting plasma glucose, 180 +/- 16 mg/dL; HbA1c, 11.2 +/- 1.6%; after glyburide therapy, fasting plasma glucose, 184 +/- 20 mg/dL; HbA1c, 11.0 +/- 1.5%). Lipids also were not significantly altered following therapy with either glipizide or glyburide. Finally, for all subjects, fasting plasma glucose and HbA1c were 200 +/- 27 mg/dL and 11.9 +/- 2.0%, respectively, during treatment with first-generation drugs and did not change significantly following therapy with the second-generation agents (fasting plasma glucose, 205 +/- 20 mg/dL; HbA1c, 11.2 +/- 1.2%). P values were > .60 for all comparisons. CONCLUSIONS: Treatment with second-generation sulfonylurea agents for patients with NIDDM following onset of secondary failure to first-generation sulfonylurea drugs achieves no better metabolic control than treatment with first-generation agents.

Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. A meta-analysis of the randomized placebo-controlled trials.

BACKGROUND: Numerous studies demonstrate the efficacy of the combination therapy of insulin and sulfonylurea in subjects with type II diabetes mellitus. However, two recent meta-analyses of randomized trials during the last decade provided inconsistent conclusions and failed to resolve the controversy. OBJECTIVE: To assess the efficacy of insulin and sulfonylurea combination therapy in type II diabetes mellitus by performing meta-analysis of only the controlled studies selected according to specific strict criteria. METHODS: A computerized literature survey was conducted using the MEDLINE database from January 1980 through March 1992 with the search headings of "sulfonylurea" and "insulin" and "combination therapy in diabetes mellitus. "A manual search was also performed using references from each retrieved report. Case reports, review articles, editorials, and citations reported in non-English-language journals without English translations were excluded. Forty-three citations were obtained. Four strict inclusion criteria were used to select studies: randomized, placebo-controlled trials (oral agent plus insulin vs placebo plus insulin); homogeneous target population (subjects with type II diabetes); intervention using the same sulfonylurea agent in a combination therapy; and uniform outcome measures to evaluate efficacy such as body weight; values for serum glucose, glycohemoglobin, and C peptide; daily insulin dosage; and lipid concentrations. More stringent qualitative subcriteria were then used to eliminate bias in the final unanimous selection by two blinded reviewers. Data were pooled and analyzed using Student's t test and Winer's combined test. RESULTS: Sixteen studies satisfied the inclusion criteria. Metabolic control improved with the combination therapy as reflected by a significant lowering of fasting serum glucose values (P < .01) and glycohemoglobin concentrations (P < .025). Moreover, improved metabolic control was achieved with a significantly smaller daily insulin dose (P < .01) and without a significant change in body weight. Finally, the combination therapy enhanced the endogenous insulin secretion as expressed by an increase in fasting serum C peptide concentration (P < .05). CONCLUSIONS: Combination therapy with insulin and sulfonylurea may be a more appropriate and a suitable option to insulin monotherapy in subjects with non-insulin-dependent diabetes in whom primary or secondary failure to sulfonylurea developed. It may also be a more cost-effective way of long-term management in this group of subjects, especially in the elderly.

Combinations sulfonylurea and insulin therapy in diabetes mellitus.

Management of diabetes mellitus (DM) continues to undergo evolutionary changes with further refinements as a result of enhanced understanding of the pathophysiology, technologic advances in glucose monitoring techniques and equipment, and an abundance of new drugs and insulin administration devices. Clearly, the maintenance of near normal blood glucose levels remains the prime goal of therapy in both noninsulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) especially in the light of the recent diabetes control and complications trial. In addition, the data has always supported the role of sustained hyperglycemia in precipitating diabetic ketosis and hyperglycemic nonketotic state, as well as recurrent infections and changes in lipid levels leading to atherosclerosis in large-sized and medium-sized arteries. Basic therapeutic modalities to achieve euglycemia in NIDDM patients remain the diet, exercise, oral agents, and insulin. Optimal management of associated medical disorders, such as hypertension and obesity, also is important to prevent the onset or progress of angiopathic complications. Combination therapy with insulin and oral agents is a frequently used treatment strategy in the last decade to achieve optimal metabolic control in this population if the therapy with oral agents alone fails to achieve this objective. Furthermore, in patients with IDDM manifesting extreme excursion of diurnal glycemia, this approach deserves trial as suggested in recent studies. However, it is imperative to assess this modality in light of the knowledge of pathophysiology of DM.

More uniform diurnal blood glucose control and a reduction in daily insulin dosage on addition of glibenclamide to insulin in type 1 diabetes mellitus: role of enhanced insulin sensitivity.

Combination therapy with insulin and sulphonylurea has gained acceptance in management of subjects with Type 2 (non-insulin-dependent) diabetes mellitus. However, its role in management of Type 1 (insulin-dependent) diabetes mellitus remains controversial. In this study, the effect of combination therapy with insulin and glibenclamide on metabolic control, daily insulin dosage, and insulin sensitivity was assessed in subjects with Type 1 diabetes mellitus. Ten men with Type 1 diabetes mellitus participated in a randomized, double-blind, crossover, clinical trial with three treatment regimens, namely (1) insulin alone, (2) insulin and placebo, (3) insulin and glibenclamide, each lasting 3 months. Combination therapy induced: (1) reduction in daily insulin dosage; (2) more uniform blood glucose control as reflected by a lower average 24 h blood glucose level, a smaller difference between mean preprandial and 2 h postprandial blood glucose concentrations, decreased 24 h urine glucose excretion, and a decline in number of hypoglycaemic events; (3) improved insulin sensitivity as expressed by more rapid plasma glucose disappearance rate, without a significant alteration in fasting plasma glucagon and 1h postprandial serum C-peptide levels; when compared with treatment with either insulin alone or with insulin and placebo. Therefore, it is apparent that the addition of glibenclamide to insulin reduces daily insulin dosage and renders a greater uniformity to diurnal blood glucose control, most probably secondary to enhancement of insulin sensitivity.

Renal calculi in primary hyperaldosteronism.

Increased urinary calcium (Ca++) excretion and the presence of negative Ca++ balance is well documented in primary hyperaldosteronism. However, renal calculi as a major manifestation of this disorder has not previously been described. This report describes a patient who presented with renal calculi in association with primary hyperaldosteronism. We believe that primary hyperaldosteronism was a major pathogenetic factor in the formation of renal calculi since the increased urinary excretion of Ca++ and uric acid noted at onset declined following a short-term spironolactone administration and remission from renal calculi has persisted following initial nephrolithotomy and continued spironolactone therapy, which also corrected hypertension and hypokalemia, a hallmark of this disorder.