Microvascular abnormalities in the bulbar conjunctiva of patients with type 2 diabetes mellitus.

OBJECTIVE: To study and quantify microvascular abnormalities objectively in vivo in patients with type 2 diabetes mellitus (T2DM). METHODS: The conjunctival microcirculation in 14 patients with T2DM and in age-matched healthy control subjects without diabetes was videotaped and objectively studied by using computer-assisted intravital microscopy (CAIM), a novel and quantitative real-time technology. RESULTS: Patients with T2DM (N = 14) had significantly (P<0.01) wider conjunctival vessel diameters (71.9 +/- 5.2 mm) than did healthy nondiabetic control subjects (54.0 +/- 4.4 mm). In the study patients, microvascular distribution was significantly (P<0.01) abnormal (36.7 +/- 18.2 versus 45.3 +/- 9.6 cm per unit area, patients versus control subjects), and vessel distribution was uneven on the surface of the bulbar conjunctiva. The arteriole:venule (A:V) ratio in patients with T2DM was extremely variable and differed significantly (P<0.01) from that in the nondiabetic control subjects (A:V approximately 1:2). In addition, a unique sinusoidal (hypertensive) vascular pattern frequently existed in some of the large veins of all study patients with T2DM but in none of the nondiabetic control subjects. CONCLUSION: We identified the presence of microvascular changes (abnormalities) in the conjunctival microcirculation of patients with T2DM. Although all these abnormalities did not appear in the same patient at the same time, the sum total of their presence in each patient correlated significantly with disease severity, as noted in the medical records. The severity of microvascular abnormalities, however, did not correlate with the duration of the disease since diagnosis. CAIM may be a useful objective and quantitative technique for assessing microangiopathy in patients with T2DM. The easy noninvasive accessibility of the conjunctival vessels and the ability to identify and locate the same vessels repeatedly for longitudinal evaluations further emphasize the usefulness of this real-time technology.

Lack of effect of thyroxine administration on elevated thyroid stimulating hormone receptor antibody levels in treated Graves' disease patients.

Increased levels of antibodies to TSH receptors are thought to be a major cause of active Graves' disease or recurrence following therapy. It was recently reported that T4 administration during antithyroid drug treatment for Graves' disease resulted in a significant decrease of TSH receptor antibodies compared to drug therapy alone. It is known that these antibodies may remain elevated long after patients become euthyroid, so a large number of patients whose antibodies remained significantly elevated after 1 year of methimazole therapy were evaluated in the study. A total of 330 Graves' disease patients were treated with methimazole for 1 year. TSH receptor antibody titers remained persistently elevated in 195 patients. Thirty-five randomly selected patients were continued on maintenance doses of methimazole for a second year, and 160 patients were treated with a combination of methimazole and thyroxine for a second year. T4 doses needed ranged from 75-100 micrograms/day to maintain serum-free T4 and free T3 within the normal range. After 6 months of combined therapy, 35 patients were found to have suppressed serum TSH levels. The patients were divided after 18 months into three groups: A, B, and C. Group C, consisting of 35 randomly selected patients (8 males and 27 females) whose ages ranged from 12-62 years and who had been maintained on methimazole alone, served as controls. Group B, whose serum TSH levels were suppressed after 6 months of combined therapy, consisted of 9 males and 26 females whose ages were 15-66 years. Group A, 35 randomly selected patients with normal serum TSH levels after methimazole and thyroxine therapy for 6 months, consisted of 8 males and 27 females whose ages were 10-63 years. TSH receptor antibody titers gradually decreased in all three groups with drug therapy, and there was no significant difference in the titers at corresponding times, i.e. 0, 1.0, 1.5, and 2.0 years. After treatment for 2.0 years, all patients of the three groups were followed for a further 12 months. Rates of recurrence among the above three groups were not significantly different during the observation period. In the present study, T4 administration in combination with antithyroidal drugs had no effect on levels of antibodies to TSH receptors and no effect on rates of recurrence. The reason for the discrepant results in the present study from previous reports is not known.

Treatment of methimazole-induced agranulocytosis using recombinant human granulocyte colony-stimulating factor (rhG-CSF).

Agranulocytosis, although extremely infrequent, is a serious complication of antithyroidal drug therapy in patients with hyperthyroidism. Presently, there is no specific therapy for this life-threatening complication, and recovery time is highly variable. Recently, recombinant human granulocyte colony-stimulating factor (rhG-CSF) was reported to be effective in shortening the recovery time of the neutropenia in patients undergoing chemotherapy. The present study was undertaken to determine the efficacy of rhG-CSF administration in patients with methimazole-induced (MMI) agranulocytosis. Thirty-four patients (7 males and 27 females, ages 16-68 yr) with MMI agranulocytosis were divided into 3 groups: group A (n = 11) was treated with antibiotics only; group B (n = 11) received antibiotics and dexamethasone, 8 mg/day; and group C (n = 12) was treated with antibiotics and im injections of rhG-CSF, 75 micrograms/day. Patients in groups A and B were studied retrospectively. When rhG-CSF became available, patients in group C were studied prospectively. Bone marrow sternal punctures were performed in all group C patients who were then divided into 2 subgroups according to the granulocyte to erythrocyte count ratio (G:E). Group C1 (n = 6) had a G:E ratio of less than 0.5, and group C2 (n = 6) had a ratio of more than or equal to 0.5. Recovery time in all groups was defined as the number of days required for the peripheral granulocyte count to be greater than 1.0 x 10(9)/L. There was no significant difference in recovery time between groups A and B: 10.1 +/- 2.2 and 12.3 +/- 1.9 days (mean +/- SE), respectively. P was not significant; the administration of dexamethasone proved to be ineffective in shortening the time for recovery from peripheral granulocytes. On the other hand, recovery time was significantly shorter in group C (6.8 +/- 1.2 days mean +/- SE) compared with groups A and B (P < 0.05). Group C2 recovered in 2.2 +/- 0.6 days whereas group C1 took much longer, 9.8 +/- 1.3 days (P < 0.001). There was a direct correlation between the G:E ratio and the peripheral leucocyte count, r = 0.806, P < 0.01. Furthermore, rhG-CSF significantly shortened recovery time when the peripheral granulocyte count was greater than 0.1 x 10(9)/L (group C2) compared with patients whose counts were less than 0.1 x 10(9)/L (group C1), 2.2 +/- 0.4 vs. 8.6 +/- 1.3 days, respectively (P < 0.001). These data indicate that administration of steroids is ineffective in shortening the duration of recovery in patients with MMI agranulocytosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Thyroid histology of hyperthyroid Graves' disease with undetectable thyrotropin receptor antibodies.

To determine the histological characteristics of hyperthyroid Graves' disease with undetectable TSH receptor antibodies (TRAb), we examined the thyroid histological findings of patients with hyperthyroidism who were referred for subtotal thyroidectomy and who lacked circulatory TRAb. Four patients had undetectable TRAb (6.4 +/- 4.2%) before treatment (group A). Their pathological and clinical findings were compared with those of four patients who had hyperthyroid Graves' disease with detectable TRAb (83.8 +/- 8.3%) before treatment (group B). The groups were matched for sex, age, duration of antithyroidal drug therapy, anti-Tg antibody, and antimicrosomal antibody levels. All patients were in a euthyroid state just before operation. Papillate hyperplastic epithelia in group A were significantly less severe than in group B. Enlarged colloids were not observed in two of the four patients in group A but were observed in all four patients in group B. Moderate or marked lymphocytic infiltrations were observed in all patients in group A but were virtually absent in group B. Based on these results, it is probable that hyperthyroid Graves' disease with undetectable TRAb titers represents an early stage or subtype of usual hyperthyroid Graves' disease in which there is marked or moderate lymphocytic infiltration.

Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus.

An important defect in insulin-dependent diabetes mellitus (IDDM) is that the liver does not meet its full fuel-processing function, because many of the enzymes involved depend on high insulin concentrations in the portal vein. We tried to reactivate the liver by long-term treatment of IDDM patients with intravenous insulin in pulses, with the aim of achieving high portal-vein concentrations during and after a glucose meal. We studied 20 IDDM patients with brittle disease; despite use of a four-injection regimen with manipulation of insulin doses, diet, and physical activity, and frequent clinic visits for at least a year, these patients still had wide swings in blood glucose and frequent hypoglycaemic reactions. The intermittent therapy consisted of 7-10 pulses of intravenous insulin, infused while the patient was ingesting carbohydrate, primarily glucose, during the first hour of a 3 h treatment; three treatments were given in a day. After 2 consecutive days' treatment, patients were treated for 1 day per week. No patient was withdrawn from the study. At the time of this analysis the duration of intermittent treatment ranged from 7 to 71 months (mean 41 [SE 5] months). Haemoglobin A1C concentrations declined from 8.5 (0.4)% at the end of the stabilisation phase to 7.0 (0.2)% at the analysis point (p = 0.0003). During the same time the frequencies of major and minor hypoglycaemic events also fell significantly (major 3.0 [1.1] to 0.1 [0], minor 13.0 [2.6] to 2.4 [0.8] per month; both p < 0.0001). Because the use of saline rather than insulin pulses would have led to unacceptable hyperglycaemia we opted for a historical control design. The absence of a true control group limits the interpretation of these preliminary results, but we believe further studies of hepatic and muscle metabolism before and after long-term intermittent intravenous insulin therapy would be worth while.

Alterations in endothelium-associated proteins and serum thyroid hormone concentrations in anorexia nervosa.

Plasma concentrations of endothelium-associated proteins (EAP) (plasma fibronectin (PFN), angiotensin-converting enzyme, factor VIII-related antigen (F VIII-R:Ag)) and tissue plasminogen activator and serum thyroid hormone concentrations were studied in nine patients with anorexia nervosa (AN), before and after weight gain. Before weight gain (-35.9 (SE 2.3)% of standard body-weight) PFN was significantly reduced and F VIII-R:Ag was significantly increased in AN patients compared with the concentrations in control subjects (211.5 (SE 14.9) v. 274.7 (SE 16.6) micrograms/ml, P < 0.05; 129.2 (SE 14.1) v. 88.2 (SE 9.7) %, P < 0.05 respectively). Serum triiodothyronine (T3) and free T3 levels were also significantly lower before weight gain in AN patients (0.85 (SE 0.07) v. 1.53 (SE 0.08) nmol/l, P < 0.001; 2.57 (SE 0.23) v. 5.31 (SE 0.34) pmol/l, P < 0.001 respectively), although serum thyroxine (T4), free T4, and thyrotropin concentrations were within the normal range throughout the study periods. Following weight gain, PFN and F VIII-R:Ag concentrations normalized as did the thyroid hormone levels. The incremental changes in PFN levels correlated significantly with those in serum thyroid hormone concentrations (T3, r 0.79, P < 0.01; free T3, r 0.84, P < 0.01). These findings suggest that PFN levels may be directly related to serum T3 concentrations in AN patients.

Heterogeneity of serum prolactin in patients with menstrual disorder in conjunction with hyperthyroxinemia.

Since the secretion of PRL is regulated by the hypothalamic-pituitary axis, an increase in large molecular size PRL in the serum is most likely due to secretion by the pituitary itself. The present study was performed to investigate the possible occurrence of PRL heterogeneity in 128 subjects with menstrual disorder in conjunction with hyperthyroxinemia (88 with untreated Graves' disease, 40 with subacute thyroiditis) and 50 age- and sex-matched healthy controls. All 128 patients in this study were suffering from amenorrhea or oligomenorrhea at the time of their initial visit. PRL heterogeneity was found in the sera of 5 of 88 (5.7%) patients with untreated Graves' disease, in 2 of 40 (5.0%) patients with subacute thyroiditis, but in none of the normal controls. PRL heterogeneity remained essentially unchanged in patients with Graves' disease over 6 months of treatment; however, in patients with subacute thyroiditis, either big-big PRL or big PRL decreased significantly along with a corresponding increase in little PRL associated with recovery from the illness within 6 months. The menstrual disorders in all patients were restored to normal after restoration to a euthyroid state. The underlying cause of the occurrence of PRL heterogeneity in patients with menstrual disorder in conjunction with hyperthyroxinemia is not known.

The incidence of thyroid stimulating blocking antibodies during the hypothyroid phase in patients with subacute thyroiditis.

The etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain, although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses. It has been suggested that nonimmune processes are involved in SAT patients who have negative autoantibody titers. The disease has a variable course; although it is self-limited in most cases, some patients develop transient hypothyroidism, and others do not during the recovery period. The present study was performed to evaluate the occurrence of TSH receptor antibody (TRAb), measured by RRA (TSH binding inhibitor), TRAb measured by stimulation assay (thyroid-stimulating antibody), and TRAb measured by blocking assay [TSH-blocking antibody (TSH-BAb)] activity in 68 patients with SAT who had negative autoantibody titers. The patients were divided into 2 groups: group I, 31 patients who developed hypothyroidism during the recovery period; and group II, 37 patients who remained euthyroid during recovery. Positive immunoglobulin activity occurred in about 20% of group I patients during follow-up, but in only 3% of group II patients. About 20% of group I patients developed positive TSH-BAb activity and were hypothyroid, requiring exogenous hormone therapy for 1.2-3.5 yr, whereas hypothyroidism was relatively transient in group I patients who had negative TSH-BAb activity (2-6 months). Although increased TSH-BAb activity may account for hypothyroidism in some patients with SAT, the precise mechanism for the development of transient hypothyroidism in SAT remains enigmatic.

Responses of growth hormone and cortisol to intravenous glucose loading test in patients with anorexia nervosa.

The hypothalamic satiety and hunger centers appear to be affected by changes in circulating blood glucose concentrations. The response of the centers, in turn, is reflected by alterations in growth hormone (GH) and cortisol levels. There are no studies attempting to relate blood glucose and GH and cortisol changes in patients with anorexia nervosa (AN) during an intravenous glucose tolerance test (IVGTT). In the present inquiry, IVGTT (10 g) were performed on AN patients to characterize the satiety and hunger centers' responses to changes in glucose and insulin levels as reflected by GH and cortisol levels. Study participants were 15 female AN patients and eight healthy female volunteers. No significant differences in blood glucose levels were observed between the two groups. However, immunoreactive insulin (IRI) levels in AN patients were significantly lower than those in the control group. Although GH and cortisol concentrations were significantly suppressed after the infusion in the control group, the AN patients' GH levels paradoxically increased, and cortisol levels did not change. Moreover, a negative correlation was observed between delta GH and delta IRI in all individuals in this study (r = -.61, P less than .01). In conclusion, abnormal GH and cortisol responses to a 10-g IVGTT were found in patients with AN. delta GH levels correlated negatively with delta IRI levels. These data suggest that hypothalamic satiety and hunger centers in AN respond abnormally to change in blood glucose levels.

Sensitivity of thyroids to endogenous thyrotrophin in patients with Graves' disease.

T3 nonsuppressibility and TSH nonresponsiveness to TRH are characteristics of untreated hyperthyroid Graves' disease. Although the tests are commonly restored to normal during antithyroidal drug therapy, dissociation of TRH and T3 suppression tests have been observed in euthyroid Graves' disease and during drug therapy. Abnormalities of pituitary-thyroidal regulation and persistence of thyroid autoimmune disease have been found in Graves' patients following various modalities of therapy. The present study investigated in vivo sensitivity to endogenous TSH of thyroids in 144 Graves' disease patients following treatment with subtotal thyroidectomy, 131I, or antithyroidal drugs. After administration of TRH, thyroidal sensitivity to TSH was determined by the following: delta T3 (peak T3 minus basal T3), % increase in T3 (peak over basal), and the ratio of delta T3 to delta TSH. Significant differences in sensitivity to TSH in T3 nonsuppressible patients were found compared to suppressible patients regardless of their TSH responses to TRH or modality of therapy. These data suggest that measurements of serum T3 and TSH following TRH administration to determine in vivo thyroidal sensitivity may be substituted for the T3 suppression test as a confirmatory test for Graves' disease or as a prognosticator of relapse following therapy.

Follow-up study of thyroid stimulating-blocking antibodies in hypothyroid patients.

It has been shown that hypothyroidism of some patients may be associated with increased activity of thyroid stimulating-blocking antibodies (TSBAb). The present study was undertaken to follow the course of thyroid blocking, stimulating immunoglobulins and TSH-binding inhibitor immunoglobulins (TBII) in six hypothyroid patients who had elevated TSBAb and were treated with T4. Four of the six had Graves' disease previously treated with antithyroidal drugs, one had Graves' disease treated with 131I and one had subacute thyroiditis and subsequently became hypothyroid. The patients were followed for 1-5 years. Blocking activity and TBII normalized in four of the six during T4 therapy, so T4 was discontinued and they remained euthyroid. These data indicate that it is important to monitor carefully thyroid function in hypothyroid patients treated with a fixed amount of T4 to avoid subclinical hyperthyroidism and its consequence, e.g. osteoporosis.

Prolactin responses in dexamethasone suppression test in patients with anorexia nervosa.

In anorexia nervosa (AN), abnormalities are present in the hypothalamic-pituitary-adrenal axis, but the prolactin (PRL) response to dexamethasone suppression test (DST) has not yet been studied. In order to study the interrelationships between the various endocrine abnormalities, we investigated the responses of PRL and cortisol to DST (1 mg of dexamethasone at 2300) in AN patients. The subjects were 12 female inpatients with AN and 8 age- and sex-matched healthy controls. The percentage suppression and absolute change in PRL levels before and after dexamethasone administration were significantly different in the 2 groups. In the control group PRL levels suppressed to 36.5 +/- 3.7% of basal, while AN levels declined to 79.4 +/- 8.9% of basal. When the percentage suppression of PRL was compared between patients with and without cortisol suppression, the mean PRL level was 68.9 +/- 7.8% of the basal level for the cortisol-suppressed patients and 100.4 +/- 19.1% for the nonsuppressed patients. Hence in both groups, the percentage PRL suppression was significantly reduced compared with the control group, and indeed nonexistent in cortisol-nonsuppressed patients. The finding that there was less PRL suppression in the cortisol-suppressed patients than in the controls suggests that, in AN, there may be an abnormality in PRL secretion not related to the hypothalamic-pituitary-adrenal axis. Further work is needed to distinguish between the PRL response to stress and potential hypothalamic abnormality.

The occurrence of thyrotropin binding-inhibiting immunoglobulins and thyroid-stimulating antibodies in patients with silent thyroiditis.

Silent (painless) thyroiditis has been recognized as a clinical entity for over a decade and is characterized by spontaneously resolving thyrotoxicosis. Its etiology is uncertain; however, a few reports have indicated the occurrence of TSH binding-inhibiting immunoglobulins (TBII) and thyroid-stimulating antibodies (TSAb) in some of the patients. The present study was undertaken to evaluate thyroid function and the occurrence of TBII and TSAb and thyroid autoantibodies (antithyroglobulin and antimicrosomal) in 53 patients with silent thyroiditis during the course of their disease. The patients were divided into 2 major groups: I) those who developed transient hypothyroidism and II) those who did not. All patients initially had significantly increased concentrations of serum T4, free T4, and free T3, suppressed TSH levels, and decreased thyroid radioiodine uptake. TBII and TSAb were initially positive in 8 (15.1%) and 10 patients (18.9%), respectively. Forty patients were available for follow-up. TBII was positive in 6 of 24 (25.0%), and TSAb was positive in 8 of 24 (33.3%) of the patients who developed transient hypothyroidism during the course of their disease. Among the patients who did not become hypothyroid at any time, TBII was positive in only 2 of 16 (12.5%), and none of the patients became TSAb positive. The findings indicate that increased TSAb and TBII activity may be detected in patients with silent thyroiditis and, when present, are associated with transient hypothyroidism during the course of the disease.

Thyroid response, especially to thyrotropin-binding inhibitory immunoglobulins, in euthyroid relatives of patients with Graves' disease: a clinical follow-up.

Three hundred and fifty-three euthyroid relatives of Graves' disease patients were tested for TSH binding inhibitory immunoglobulins (TBII). Eighteen had elevated levels of TBII, and 232 who had negative TBII levels also agreed to be followed for a period of 6-30 months. TBII was chosen as the critical screening measurement for this study, rather than thyroid-stimulating antibodies (TSAb) and thyroid-stimulating blocking antibodies (TSBAb), because of the availability and ease of use of TBII RIA kits. Eleven of the 18 subjects with elevated TBII were T3 nonsuppressible (group I), and 10 of the 11 were TRH unresponsive. Nine of these 10 subjects showed TSH levels below 0.05 mU/L. The remaining 7 subjects were T3 suppressible and TRH responsive (group II). Alterations in thyroid status occurred in 8 of the 11 subjects in group I during follow-up. One developed hypothyroidism, and 7 became hyperthyroid. The hypothyroid subject had initial titers of TBII, TSAb, and TSBAb that were markedly elevated, and TSAb disappeared when she became hypothyroid. Six of the 7 subjects who developed hyperthyroidism had elevated TSAb and negative TSBAb titers while they were euthyroid. All 7 subjects in group II remained euthyroid during the follow-up period. Only 2 of the 232 relatives who initially had negative TBII titers became hyperthyroid during the follow-up period. The results indicate that euthyroid relatives with a family history of Graves' disease who have elevated TBII levels and suppressed basal serum TSH concentrations have a much higher potential to develop hyperthyroidism than those who have normal or negative TBII levels.

Thyroid-stimulating antibody and thyrotropin-binding inhibitory immunoglobulin activity in hypothyroid patients who subsequently developed thyrotoxicosis.

Although abnormal thyroid-stimulating and -blocking antibodies have been demonstrated in hyperthyroid and hypothyroid patients with autoimmune thyroid disorders, a direct correlation is not always observed. Thyroid-stimulating antibody, thyrotropin-binding inhibitory immunoglobulin, and thyroid-stimulating blocking antibody levels were determined in three hypothyroid patients who subsequently developed hyperthyroidism. Thyroid-stimulating antibodies levels were normal in one, elevated in another, and unmeasured in the third hypothyroid patient, but became elevated in all patients with the onset of hyperthyroidism. There was discordance, however, in one patient who had markedly elevated thyroid-stimulating antibodies and TSH-binding inhibitory immunoglobulin levels when she was hypothyroid. The data indicate that thyroidal responses to the abnormal stimulating antibodies may differ among patients with autoimmune thyroid disease.

Effect of cholinergic muscarinic receptor blockade on human growth hormone (GH)-releasing hormone-(1-44)-induced GH secretion in anorexia nervosa.

The presence of hypothalamic disturbances affecting GH secretion in anorexia nervosa has been suggested, although a normal GH response to GH-releasing hormone (GHRH) administration has been shown in these patients. The present study was performed to investigate the role of acetylcholine in regulating GH secretion by using pirenzepine, which selectively blocks muscarinic cholinergic receptors. Paired tests were performed in nine anorexia nervosa patients (age +/- SEM, 19.1 +/- 1.2 yr; percent ideal body weight, -32.7 +/- 2.2%) and in six normal controls (20.1 +/- 0.3 yr; -3.1 +/- 1.8%). GHRH-(1-44) (1 microgram/kg) was infused iv with and without pirenzepine pretreatment (0.6 mg/kg, iv). Basal levels of GH were not different in anorexia nervosa compared to normal controls, whereas, somatomedin-C levels were significantly lower in anorexia nervosa patients. However, after pirenzepine administration, the GHRH-stimulated GH responses were completely blocked in normal controls, but not in anorexia nervosa patients. These results suggested that altered muscarinic cholinergic mechanism are involved in the modulation of GH secretion in patients with anorexia nervosa.

The clinical efficacy of a 5-HT1A agonist, SM-3997, in the treatment of bulimia.

Psychotherapeutic and pharmacological treatment of bulimia and vomiting require long duration and frequently entail considerable obstacles in patience compliance, making such regimens difficult to pursue. The regulating mechanism of the appetite center is recognized to be complex and recently an important role of serotonin (5-HT), a neurotransmitter, has been shown in rats. In the present study a newly developed 5-HT1A agonist, SM-3997, was administered to 12 patients with bulimia and its clinical efficacy was evaluated. The patients were treated on an open basis with SM-3997, 30-40 mg/day, for 6-15 weeks. Bulimic behavior stopped completely in 4 patients, was improved in 4 others and was unchanged in the remaining 4. These results suggest that the administration of a 5-HT1A agonist, SM-3997, may be effective in the treatment of bulimia and vomiting and that further investigation is warranted.

Decreased thyroidal triiodothyronine secretion in patients with anorexia nervosa: influence of weight recovery.

Basal thyroxin (T4), triiodothyronine (T3), and thyrotropin (TSH) concentrations were significantly lower before weight recovery in 10 patients with anorexia nervosa (AN) than they were in control subjects. After weight recovery, basal T4 and TSH levels were unchanged and significantly lower in AN patients than in control subjects. Basal T3 concentrations increased significantly after weight gain: however, concentrations remained lower than those in the control subjects. The maximum increase in T3 and T3 net secretory response to thyrotropin-releasing hormone (TRH), obtained before and after weight recovery, appeared significantly lower than that in control subjects: however, the increases in TSH responses were not different from those of control subjects. Thus, low T3 concentrations in AN patients may be due not only to impaired peripheral conversion of T4 to T3 associated with the altered nutritional state, but also to decreased thyroidal T3 secretion in response to endogenous TSH, which is indicative of hypothalamic-pituitary-thyroidal dysfunction.

Development of spontaneous hypothyroidism in patients with Graves' disease treated with antithyroidal drugs: clinical, immunological, and histological findings in 26 patients.

Graves' disease may result eventually in hypothyroidism in approximately 5-20% of patients. In a few such patients hypothyroidism was associated with TSH-blocking antibodies, but whether the frequency of TSH-blocking antibodies in such patients is as high as it is (21%) in patients with primary myxedema is not known. This study was undertaken to determine the presence of various immunoglobulins [TSH binding inhibitor immunoglobulins, thyroid-stimulating antibodies (TSAb), and TSH-blocking antibodies] in 26 patients with Graves' disease who developed hypothyroidism from 0.5-10 yr or more after discontinuation of antithyroid drug therapy. Eight of the 26 patients (31%) had TSH-blocking antibodies, 16 (61%) had TSAb, and 14 (54%) had thyroid hormone binding inhibitor immunoglobulins. Thyroid needle biopsies were performed in 9 patients. Three of 5 patients who had subclinical hypothyroidism had chronic lymphocytic thyroiditis, and all had positive TSAb titers. Three patients had the fibrous variant of chronic lymphocytic thyroiditis; their TSAb values were 902%, 431%, and 1290%. One patient had follicular hyperplasia. We conclude that TSH-blocking antibodies may account for hypothyroidism in approximately one third of patients with Graves' disease who were previously treated with antithyroid drugs, and that autoimmune thyroiditis is comparable for the hypothyroidism in the remaining two thirds of Graves' disease patients.

Methimazole-induced agranulocytosis in Japanese patients with Graves' disease.

We reviewed the records of approximately 7000 Japanese patients whose hyperthyroidism was treated with methimazole (MMI) alone. Four patients (Group I) developed agranulocytosis during a second course of MMI therapy and eight patients (Group II) during an initial course. Six patients (three in each group) received less than 30 mg MMI daily. Agranulocytosis occurred after more than 2 months of therapy (12 weeks-1 year) in five patients. Seven patients were less than 40 years of age. One patient displayed a gradual protracted development of agranulocytosis. These results indicate that agranulocytosis after MMI may occur irrespective of dose, age, duration of treatment, and with a second exposure.