Long term antithyroid drug therapy for intractable cases of Graves' disease.

Among the 504 patients with Graves' disease in whom the author initiated antithyroid drug therapy between 1956 and 1968 are 14 to whom the administration of antithyroid drug has been continued for 8 to 21 years because of recurrence shortly after the discontinuation of drugs. During these periods, no side effects were observed and three patients went into complete remission after 8, 9 and 20 years of antithyroid drug administration, respectively. It is suggested therefore that the long term administration of antithryoid drugs can be a useful treatment for intractable cases.     

Delayed Antithyroid Drug-Induced Agranulocytosis

ObjectiveTo demonstrate that drug-induced agranulocytosis can occur after a very prolonged period of lowdose treatment with antithyroid medications.MethodsWe present the history and long-term follow-up of a patient with Graves disease, including clinical and laboratory findings, and provide a brief review of the related literature.ResultsA 53-year-old woman with a history of Graves disease presented with an absolute neutrophil count of zero, body temperature of 38.7°C, and symptoms of an upper respiratory tract infection. She had been treated continuously with low doses of antithyroid drugs for the preceding 11 years—propylthiouracil (100 to 150 mg daily) from February 1998 until July 2003 and methimazole (5 to 30 mg daily) from July 2003 until her presentation with severe neutropenia in March 2009. The daily dose of methimazole had been stable at 15 mg for 1 year before the current presentation. A thorough hematologic evaluation, including bone marrow biopsy, did not reveal an alternative cause for the agranulocytosis. After discontinuation of methimazole treatment and a short course of granulocyte colony-stimulating factor, she responded successfully with clinical improvement of her symptoms and resolved neutropenia.ConclusionAlthough this case is atypical, it reinforces the importance of remaining vigilant for signs of agranulocytosis throughout the course of treatment with antithyroid drugs, even at low doses and after years of continuous administration. (Endocr Pract. 2012;18:e69-e72)     

Results of Treatment of Thyrotoxicosis after Postoperative Relapse

Ninety patients who had a recurrence of thyrotoxicosis after thyroidectomy have been reviewed. All 10 patients who had a second operation and 18 out of 20 patients treated with a full course of antithyroid drugs relapsed. These results differ greatly from the results of treatment of the first episode of thyrotoxicosis, whether by thyroidectomy or antithyroid drugs. Radioiodine is the treatment of choice in this group of patients, despite the high incidence of hypothyroidism.     

Studies on the T3 suppression test with reference to the thyroidal 123I uptake in Graves' disease: comparison of 24-hour and 3-hour uptake

Eighty-three patients with Graves' disease had been treated with methylmercaptoimidazole (MMI). They were prescribed a maintenance dose of antithyroid drug (MMI, 5 mg/day) at the time of a T3 suppression test. The 3-hour and 24-hour thyroidal 123I uptake after T3 administration (75 micrograms/day, 2 weeks) were measured (post T3 uptake). In 38 patients whose post T3 uptake was below 35% in post T3 24-hour uptake, treatment was stopped. The T3 suppression test was then repeated 1 and 3 months later. During a one-year follow up, 26 remained well, while 12 relapsed within 6 to 12 months. We have observed a good correlation between 3-hour uptake and 24-hour uptake of 123I after T3 administration (r = 0.847, p less than 0.001). In 38 patients who showed positive T3 suppression, most patients with MMI withdrawal produced a marked overshoot of post T3 3-hour and 24-hour uptake at one month. Retrospective analysis indicated that there was no significant difference in circulating thyroid hormone levels between remission and relapse groups. The present study provides evidence that 3-hour uptake values are able to be substituted for 24-hour uptake values during a T3 suppression test. In addition, overshoot of thyroidal uptake after antithyroid drug withdrawal was observed in 3-hour values, similar to 24-hour values.     

Does Graves' disease during puberty influence adult bone mineral density?

AIM: To evaluate the bone mineral density at lumbar spine and at femoral neck in a group of young adults in whom Graves' disease developed during childhood and adolescence. PATIENTS AND METHODS: We examined 28 patients (5 male, 23 female, age 20.9 +/- 3.3 years) who were 11.8 +/- 2.9 years old at the onset of Graves' disease. They were treated either with methimazole (14 patients) or with methimazole plus l-thyroxine (14 patients). At the time of the investigation, 13 patients were considered cured following antithyroid treatment, 2 were still on antithyroid drugs, 3 were on replacement therapy with l-thyroxine because of hypothyroidism, and 10, treated either surgically or with (131)I, were on replacement therapy. The bone mineral density was measured at the lumbar spine (L2-L4) and at the femoral neck, using dual-energy X-ray absorptiometry. RESULTS: The spinal bone mineral density SD score was -0.28 +/- 1.02, the femoral neck bone mineral density SD score was 0.36 +/- 1.02, and both were not different from zero (NS). We did not find any correlation between the bone mineral density of the femoral neck and that of the lumbar spine and the clinical parameters. CONCLUSION: Graves' disease, beginning in childhood and adolescence, when appropriately treated, does not affect attainment of peak bone mass.     

Studies on the T3 suppression test by the 24-hour thyroidal 131I uptake in patients with Graves' disease: comparison of the effects of propylthiouracil and methylmercaptoimidazole

The T3 suppression test by the 24-hr thyroidal 131I uptake was reevaluated in patients with Graves' disease before and after withdrawal of antithyroid drug. Fifty patients had been treated with propylthiouracil (PTU) or methylmercaptoimidazole (MMI) for 12 to 70 months. They were prescribed a maintenance dose of antithyroid drug (PTU, 50 mg/day; MMI, 5 mg/day) at the time of investigation and regarded as euthyroid on the basis of serum T3, T4 and TSH levels. Each patient was given 75 micrograms T3 daily for 8 days in conjunction with PTU or MMI. The 24-hr thyroidal 131I uptake was then measured (post T3 uptake). In 30 patients whose post T3 uptake was below 35%, treatment was stopped and the T3 suppression test was repeated at one and 3 months later. During the two-year follow up, 24 remained well, while 6 relapsed within 4 to 12 months. In patients with sustained remission, the post T3 uptake was significantly lower in the MMI-treated group (13 cases, 7.7 +/- 1.0%) than in the PTU-treated group (11 cases, 18.6 +/- 1.9%). MMI withdrawal produced a marked rebound in the post T3 uptake, whereas none of the patients showed the rebound after PTU withdrawal. In patients who relapsed later, there was no difference in the post T3 uptake during treatment and the rebound occurred in the both groups following goitrogen withdrawal. Serum T3, T4 and TSH levels were within normal ranges at one and 3 months after cessation of antithyroid drug. From the results of the present study, it is concluded that criteria for T3 suppressibility by the 24-hr uptake should be determined by the antithyroid drug employed and by the time of investigation. There is a dissociation in the post T3 uptake values following withdrawal of the two different antithyroid drugs.     

Thyroid stimulating immunoglobulins in patients in long-term remission after Graves' disease

Thyroid stimulating antibodies (TSAb) and thyrotropin binding inhibiting immunoglobulins (TBII) were measured in 32 patients with Graves' disease who had been in remission for at least two years after treatment was been stopped. Seventeen patients had been treated with antithyroid drugs, and 15 patients with 131Iodine. In the first group 3 of 17 patients had TSAb and one TBII, whereas in the second group 4 of 15 patients had TSAb and two TBII. One patient from each group had inhibiting TSAb. During the follow-up one patient from each group relapsed, whereas 5 patients from the second group developed myxoedema. No relationship between the clinical outcome and TSAb and TBII was found.     

Risk of agranulocytosis and aplastic anaemia in relation to use of antithyroid drugs. International Agranulocytosis and Aplastic Anaemia Study.

The relation of the use of antithyroid drugs to the risk of developing agranulocytosis and aplastic anaemia was evaluated in a population based case-control study with patients from Israel and seven regions in Europe. Data were obtained from cases and hospital controls by interview. Use of antithyroid drugs in the week before the onset of illness was compared in 262 patients with agranulocytosis and 1771 controls. Forty five patients (17%) and five controls (0.3%) had used antithyroid drugs. The relative risk was estimated to be 102 (95% confidence interval 38 to 275) taking into account confounding by other factors, including the use of other drugs. The excess risk for use of antithyroid drugs in any one week was estimated to be 6.3 cases of agranulocytosis per million users. Use of antithyroid drugs in a five month period ending one month before admission to hospital was compared in 135 patients with aplastic anaemia and 2145 controls. Four patients (3%) and five controls (0.2%) had taken drugs; the estimate of relative risk was 9.2 (95% confidence interval 1.8 to 47) after control for confounding. The estimate of excess risk of agranulocytosis with the use of antithyroid drugs was lower than found previously. Although the excess risk for aplastic anaemia was not calculated, these data suggest that it is very low.     

Effect of alfacalcidol on natural course of renal bone disease in mild to moderate renal failure.

OBJECTIVE--To determine whether alfacalcidol--used in management of overt renal bone disease--may safely prevent renal bone disease when used earlier in course of renal failure. DESIGN--Double blind, prospective, randomised, placebo controlled study. SETTING--17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. SUBJECTS--176 patients aged 18-81 with mild to moderate chronic renal failure (creatinine clearance 15-50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. INTERVENTIONS--Alfacalcidol 0.25 micrograms (titrated according to serum calcium concentration) or placebo given for two years. MAIN OUTCOME MEASURES--Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. RESULTS--132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P < 0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P < 0.001). There was no difference in rate of progression of renal failure between the two groups. CONCLUSION--Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure.     

Thyrotoxicosis: relations between clinical state and biochemical changes during carbimazole treatment.

The relation between clinical and biochemical changes in thyrotoxicosis were studied in 12 patients with Graves''s disease who were being treated with carbimazole. Clinical assessment (using the Crooks-Wayne index) was combined with the measurement of free thyroxine and triiodothyronine indices (FT4I and FT3I) and the assessment of two tissue markers of thyroid hormone action--sex-hormone-binding globulin (SHBG) levels and the thyrotrophin responses to TRH. In general the FT4I and FT3I fell rapidly once treatment was started, and returned to normal in one to four weeks, followed shortly by SHBG levels. The thyrotrophin response returned at this time in two patients, who still had borderline high levels of FT3I and SHBG. The clinical score fell more slowly and variably and was less closely related to any of the biochemical indices than these were to each other. During the early phase of treatment with antithyroid drug the clinical evaluation may be an unreliable indicator of persisting thyroid hormone excess, and when the patient seems clinically but not biochemically thyrotoxic the symptoms should be treated on their own merits with beta-blocking drugs and not with increased doses of antithyroid drugs.     

Thyroid Suppressibility: Follow-up for Two Years after Antithyroid Treatment

In hyperthyroidism suppression and non-suppression of early radioiodine neck uptake by exogenous thyroid hormone after a course of antithyroid drugs does not indicate clearly those patients who will eventually relapse or have a remission. Sixty-four hyperthyroid patients have been followed up for two years after an 18 to 24 months'' course of carbimazole. Twenty-eight patients had suppressed at the end of the carbimazole course and 20 of these remained in remission for two years, and 36 were non-suppressed and 21 of these relapsed.Patients with the highest neck uptakes relapsed soonest after stopping treatment. Pronounced rebound occurred in neck uptakes at one month after stopping treatment, both in patients who relapsed and in those who remained in remission. By one year after stopping treatment those who remained in remission had shown a further fall in early neck uptake. In two patients who relapsed after exposure to stressful events no change in 20-minute radioiodine neck uptakes was found in relation to the supposed stress.     

Rapid improvement of thyroid function by using glucocorticoid indicated for the preoperative preparation of subtotal thyroidectomy in Graves' disease

Glucocorticoid therapy is not considered as an authentic method for obtaining euthyroid in Graves' disease. We tried the administration of prednisolone as a preoperative preparation for subtotal thyroidectomy in 4 hyperthyroid patients with Graves' disease who had suffered adverse effects of thionamide antithyroid drugs, including agranulocytosis, liver damage and skin eruptions. Following oral administration of a 30 mg daily dose of prednisolone, with or without other antithyroid reagents, both serum T4 and T3 concentrations decreased rapidly and reached the normal range within 2 weeks. The clinical signs and symptoms of hyperthyroidism also improved rapidly and subtotal thyroidectomies were performed uneventfully in all cases. These results suggest that 1) glucocorticoid medication can normalize the circulating hormone levels rapidly in Graves' disease, 2) it is a useful method as preoperative preparation for subtotal thyroidectomy, especially when other conventional methods are not available or effective in obtaining euthyroid, and 3) mechanisms other than thyroid stimulation by circulating immunoglobulin seem to play an important role in causing hyperfunction of the gland.     

Changes in thyroid function caused by continuous treatment with thiouracil in rats

Serum concentration evolution of thyroxine and triiodothyronine, and thyrotropin (TSH), have been studied in rats while they were given 6-propylthiouracil (PTU) as antithyroid drug, and during the recovery period after suppression of treatment. In the same way thyroid hypertrophy and plasmatic levels of thyrotropin were correlated. Animals received orally a daily dose of 1 mg/100 g body weight during thirty-five days and had a two week recovery period. Thyroid hormone concentrations in plasma were determined by immunoenzymatic assay ELISA with peroxidase as labelled enzyme. From the results obtained, it can be stated that chronic administration of PTU implies a continuous decrease in thyroid hormone concentrations in plasma, reaching nearly zero values, while after treatment, levels recover their normal values in a week's time. A parallelism exists between thyroid hypertrophy and pituitary TSH hypersecretion, due to a decrease in thyroid hormone levels.     

Comparison of LATS activity and TSH receptor antibody in Graves' disease

TSH-receptor antibody (TRAb) activity and LATS activity of Graves' sera were compared. All of 50 LATS-positive cases were TRAb positive, although only 63% of LATS-negative cases were TRAb positive. Binding of 125I-TSH to the TSH receptors was inhibited dose-dependently by LATS-immunoglobulin. However, no correlation between TRAb activity and LATS activity was observed. TRAb was positive in 2 LATS-positive cases even when the symptoms of hyperthyroidism were controlled by treatment (antithyroid or radioisotope). The positive TRAb was not changed in 4 Graves' disease patients whose LATS activity had disappeared following antithyroid treatment. These clinical studies show that TRAb is more sensitive than LATS and suggest that LATS may be one of a heterogenous population of antibodies to the TSH receptor in Graves' disease.     

Serum concentrations of 3, 3'-diiodothyronine, 3', 5'-diiodothyronine, and 3, 5-diiodothyronine in altered thyroid states

To investigate the thyroid hormone metabolism in altered states of thyroid function, serum concentrations of 3, 3'-diiodothyronine (3, 3'-T2), 3', 5'-T2 and 3, 5-T2 as well as T4, T3 and rT3 were determined by specific radioimmunoassays in 17 hyperthyroid and 10 hypothyroid patients, before and during the treatment. Serum T4, T3, rT3, 3, 3'-T2 and 3', 5'-T2 concentrations were all higher in the hyperthyroid patients than in age-matched controls and decreased to the normal ranges within 3 to 4 months following treatment with antithyroid drugs. In the hypothyroid patients, these iodothyronine concentrations were lower than in age-matched controls and returned to the normal ranges after 2 to 3 months treatment with T4. In contrast, serum 3, 5-T2 concentrations in hyperthyroid patients (mean +/- SE : 4.0 +/- 0.5 ng/dl) were not significantly different from those in controls (3.9 +/ 0.4 ng/dl), although they tended to decrease in 3 of 6 patients after the antithyroid drug therapy. Serum 3, 5-T2 levels in the hypothyroid patients (3.8 +/- 0.6 ng/dl) were also within the normal range and showed no significant change following the T4 replacement therapy. However, serum 3, 5-T2 as well as 3, 3'T2 concentrations rose significantly with a marked rise in serum T3 following T3 administration, 75 micrograms/day for 7 days, in Graves' patients in euthyroid state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antithyroid drug therapy for Graves' hyperthyroidism: is long-term administration of a small maintenance dose necessary?

This retrospective study serves as an inquiry into the common practice of long-term administration of small maintenance doses of either methyl-mercaptoimidazole (MMI) or propylthiouracil (PTU) to Graves' hyperthyroid patients who became euthyroid with primary large doses of the same drugs. One hundred and two patients with Graves' hyperthyroidism treated with antithyroid drug (ATD) were studied. Sixty-one were treated with conventional long term therapy and 41 were treated with short-term therapy. Small maintenance doses of ATDs were not administered to the short-term therapy patients. The duration of long-term therapy was 28.6 +/- 20.2 months (from 12 to 48 months) and that of short-term therapy was 8.4 +/- 1.8 months (from 5 to 11). Post therapy and follow-up observation continued for 19.0 +/- 2.7 months (16-25 months) in both long-term and short-term patients. Of the 61 long-term therapy patients, 20 were relapsed and 41 (67.2%) continue to remain in remission. So too, of the 41 short-term therapy patients, 14 relapsed and 27 (65.9%) still remain in remission. There was no statistical difference between the long-term and short-term therapy group in age, sex, duration of symptoms before diagnosis, antithyroid antibodies, radioactive iodine uptake, free thyroid hormone levels or goiter size before treatment or in TBII levels at cessation of ATD. It is concluded that 'short-term ATD therapy' without a maintenance dose is sufficient and saves several months of the patient's and clinician's time.     

Results of Treatment of Thyrotoxicosis following Relapse after Antithyroid Drug Therapy

One hundred and thirty patients who relapsed after a full course of treatment with antithyroid drugs have been reviewed. Of 22 patients receiving a second course of antithyroid drugs, 17 (77%) relapsed. In contrast, only 2 out of 44 patients treated by surgery relapsed and seven became hypothyroid. Nevertheless, local complications, in particular parathyroid insufficiency, were especially common in this group. Eighty patients received radioiodine, 11 (14%) requiring more than three doses before finally being rendered euthyroid. Postradiation hypothyroidism developed in 39 (49%) patients.     

Five patients with painless thyroiditis simultaneously developed in a nursery school

Painless (silent) thyroiditis (PT) occurred simultaneously in 1 male and 4 females aged 21 to 52 years working at a nursery school. Clinical symptoms did not include goiter, or pain or tenderness of the neck in any of the patients but were characterized by edema of the lower legs as well as palpitation and loss of body weight as observed in subacute thyroiditis. General blood analysis showed that all patients were negative for C-reactive protein (CRP) and 3 had mild impairment of liver function. Examination of thyroid function suggested transient thyrotoxicosis accompanied by a marked reduction in radioactive iodine uptake (RAIU), but antithyroglobulin hemagglutination antibody (TGHA) and antithyroid microsomal hemagglutination antibody (MCHA) were negative in all patients. Examination of various viral antibodies showed no significant changes in their titers. Thyrotoxicosis was transient and disappeared without treatment or by glucocorticoid administration. Our results suggested that PT observed in this study was caused by some environmental factor. The possibility of an unidentified virus as a factor cannot be ruled out.     

Long-term follow-Up of an infant with thyrotoxicosis due to germline mutation of the TSH receptor gene (Met453Thr)

A 18-year clinical follow-up period in a male patient with a germline TSH-R gene mutation (Met453Thr) is described. Nonautoimmune thyrotoxicosis was diagnosed at the age of 7 months. The patient had exophthalmus, failure to thrive, advanced bone age and no goiter. Long-term antithyroid drug treatment (ATD) was necessary during childhood. At the age of 7 years he developed a goiter. Subtotal thyroidectomy was performed at the age of 9 years, followed by repeated ablative radiotherapy at the age of 9.5-13 years due to a toxic multinodular goiter. After 13 years ATD could be discontinued and the patient was euthyroid until 16 years of age, where L-thyroxine substitution had to be started. The exophthalmus diminished, and had disappeared at the age of 18 years, when CT scan of the orbit was performed. Conclusion: TSH-R mutation must be considered in early nonautoimmune thyrotoxicosis. A very aggressive treatment strategy is necessary.     

The expense for one implantation of a banked bone allograft from a cadaveric donor and the issues affecting current advanced medical treatment in the Japanese orthopaedic field

Demand for banked bone allografts is increasing in Japan; however, there are too few bone banks and the bone bank network is not well-established. One reason for this was lack of funding for banks. Bone banks had to bear all material expenses of banked bone allografts themselves because this was not designated a covered expense. In December 2004, the Japanese government started a new “Advanced Medical Treatment” administration system which allowed an approved institution to charge the expense of authorized advanced medical treatments directly to patients. The treatment named “Cryopreserved allogenic bone and ligamentous tissue retrieved from cadaveric donor” was approved as an advanced medical treatment in March 2007. We present the calculation method and the expense per implantation of a banked bone allograft from a cadaveric donor under this treatment and raise issues which affect this advanced medical treatment and remain to be resolved in the Japanese orthopaedic field.