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Radioiodine and the treatment of hyperthyroidism: the early history.

Little was known about iodine metabolism in the mid-1930s, but when Saul Hertz and his chief, J. Howard Means, at the Massachusetts General Hospital (MGH) realized in 1936 that radioiodine could be made and used as a tracer, they arranged with physicists Robley Evans and Arthur Roberts at the Massachusetts Institute of Technology (MIT) to make the short-lived 128I and study its physiology in rabbits. By 1938, they showed that the rabbit's thyroid gland rapidly took up 128I, especially when there was only a little non-radioactive iodine present. There was, however, no hope of using 128I as a treatment because of its brief half-life (25 minutes). In 1939, Joseph Hamilton and Mayo Soley, working with Ernest Lawrence's cyclotron in Berkeley, California, were able to make several radioiodines; one was 130I (12-hour half-life) and another 131I (8-day half-life). They were the first to give these radioiodines to humans to study iodine physiology. The MGH-MIT group also built a cyclotron and by 1940 had generated these two new radioiodines. One of the goals of both groups was the treatment of hyperthyroidism. Hertz and Roberts were the first to do so on March 31, 1941; Hamilton and John Lawrence, Ernest's brother, began on October 12, 1941. By 1942, the United States was actively fighting in World War II. That year both Boston and Berkeley groups have preliminary data on the treatment of hyperthyroidism in Atlantic City; both showed that it was effective and went on to treat more patients. In Berkeley the therapy was viewed cautiously, and, in many case, the physicists were mainly occupied with work for the Manhattan District. In Boston Hertz used the therapy as often as he could, emphasizing the use of 130I, until he joined the U.S. Navy in 1943. Earle Chapman, a clinician on the voluntary staff of the MGH, took over Hertz's practice in 1943; their later differences over the precise treatment and who was in charge led to their falling out. After Hertz's release from the Navy he was not permitted to return to the MGH and became quite bitter; Chapman stayed on at the MGH. After the war was over, both had acquired a sufficient number of patients--there was then no such thing as a controlled trial--and wrote up the results for publication. Each wrote a different physicist, Hertz with Roberts and Chapman with Evans. When Hertz learned that Chapman's paper was being considered by the Journal of the American Medical Associations, he quickly sent his manuscript to JAMA as well. Although the editor of JAMA was puzzled by two papers on the same topic from the same institution, both papers appeared in the same issue of JAMA on May 11, 1964, and announced the new therapy was effective treatment for hyperthyroidism.

Animals↗

Circulating telopeptide type I is a peripheral marker of thyroid hormone action in hyperthyroidism and during levothyroxine suppressive therapy.

The aim of the present investigation was to evaluate the clinical performance of serum carboxy-terminal-1-telopeptide (ICTP), a new marker of bone resorption, in identifying peripheral overexposure to thyroid hormones, as compared with serum osteocalcin (OC) and serum sex hormone binding globulin (SHBG). Serum ICTP, SHBG, and OC were assayed by specific radioassays in three study groups. Group 1: 50 perimenopausal women on long-term levothyroxine (LT4) suppressive treatment; group 2: 29 women with untreated hyperthyroidism; group 3: 36 normal euthyroid women matched with group 1 patients for age, alcohol, smoking habits, and lifestyle. Serum concentrations of SHBG, ICTP, and OC were markedly increased in hyperthyroid patients, whereas only serum ICTP was slightly but significantly increased in LT4 treated patients. Serum ICTP had higher diagnostic value for hyperthyroidism when compared with SHBG and to OC (sensitivity: 100%, 71%, 55%; accuracy: 97%, 88%, and 76%, respectively). In group 1, increased serum ICTP was observed in 30 of 50 patients, whereas increased SHBG and OC were found only in 11 of 50 (p < .001). Serum free thyroid hormone concentrations correlated with circulating ICTP and SHBG, and the correlation with serum OC was of lower significance. In conclusion, serum ICTP is a sensitive and reliable marker of peripheral thyroid hormone activity at the bone level; its clinical performance is higher than OC and even better than SHBG. Thus, serum ICTP is better than other peripheral markers in monitoring LT4 suppressive therapy in patients at increased risk for osteoporosis such as perimenopausal women.

Adult↗

Autoimmune hyperthyroidism in prepubertal children and adolescents: comparison of clinical and biochemical features at diagnosis and responses to medical therapy.

We explored our clinical impression that young children with autoimmune hyperthyroidism are more thyrotoxic at presentation and require a longer course of medical therapy than do adolescents to achieve remission. A retrospective chart review of clinical and biochemical data at presentation and response to therapy in 32 prepubertal (PREPUB) and 68 pubertal (PUB) children and adolescents with autoimmune hyperthyroidism was undertaken. Initial therapy included prophylthiouracil or methimazole in all but 11 patients who chose radioactive iodine (131I); 30 additional patients ultimately chose 131I or surgery after an initial period of medical therapy. In PREPUB children there were significantly longer duration of symptoms (7.8+/-7.7 months) and higher serum concentrations of triiodothyronine (T3) 708+/-330 ng/dL) at presentation than in the PUB group (4.7+/-3.4 months; p < .05) (537+/-197 ng/dL; p < .01). Duration of symptoms correlated negatively with chronologic age (r = -0.24; p < .02) but not with T3 or thyroxine (T4) levels (p = .1). PUB children had significantly higher titers of thyroid microsomal antibodies (positive dilution factor 1:6022+/-14572) than did PREPUB children (1:592+/-1226; p < .05). There was a higher familial incidence of thyroid disease in boys (80%) than in girls (64%) (p < .02). The duration of medical therapy was significantly longer (3.5+/-2.9 years) in PREPUB children compared to the PUB group (2.2+/-1.8 years) (p < .05). Only 17% of PREPUB treated 5.9+/-2.8 years compared with 30% of PUB treated 2.8+/-1.1 years achieved a 1-year remission after stopping antithyroid medication (percentage between groups, p < .01; years of treatment, p < .05). The median time to remission after medical therapy was 8 years in PREPUB and 4 years in PUB (p < .02). PREPUB children continued to remit after prolonged medical therapy (>6 years) whereas PUB patients did not. Total treatment length correlated negatively with chronological age (r = -0.26; p < .05) and positively with T4 and T3 concentrations at diagnosis (r = 0.31; p < .01). The diagnosis of hyperthyroidism is delayed in prepubertal children compared to adolescents. This delay may contribute to the higher T3 levels observed in this group at presentation. Prepubertal children also appear to require longer medical therapy to achieve a lower rate of remission, but do continue to remit after prolonged treatment. These differences in response to therapy should be considered when discussing therapeutic options with the family.

Adolescent↗

Subclinical hyperthyroidism.

Subclinical hyperthyroidism is defined as a situation where the levels of the peripheral thyroid hormones are normal but serum thyrotropin (TSH) is low. It is not a rare finding; rates between 0.2% and 11.8% have been reported in different groups, according to age, sex, etc. The etiology is usually the same as that of overt hyperthyroidism. The health implications include general symptoms, effects on the cardiovascular system, and decreased bone density. The increased frequency of atrial fibrillation and the increased mortality reported are especially serious. It is not clear whether subclinical hyperthyroidism should be treated or not. Most authors conclude that treatment is required in selected cases or in special circumstances.

Bone Diseases↗

Risks of iodine-induced hyperthyroidism after correction of iodine deficiency by iodized salt.

Biochemical signs of hyperthyroidism, or even overt and possibly lethal clinical hyperthyroidism were reported in 2 severely iodine-deficient African countries (Zimbabwe and Democratic Republic of Congo, RDC) soon after the introduction of iodized salt. The 2 countries had access to iodized salt produced in Botswana, as well as 5 other countries in the region, namely Cameroon, Nigeria, Kenya, Tanzania, and Zambia. Therefore, a multicenter study was conducted in these 7 countries to evaluate whether the occurrence of iodine-induced hyperthyroidism (IIH) after the introduction of iodized salt was a general phenomenon or corresponded to specific local situations in the 2 affected countries. Two or 3 areas with a past history of severe iodine deficiency that had recently been supplemented with iodized salt were selected in each of the 7 countries. The prevalence of goiter was determined in 4423 schoolchildren in these areas and the concentration of urinary iodine in 2258. Salt factories and health structures were visited for the evaluation of the quality of iodized salt and the possible occurrence of IIH. The study showed that iodine deficiency had been eliminated in all areas investigated, and that the prevalence of goiter had markedly decreased since the introduction of iodized salt. This is a remarkable achievement in terms of public health. However, some areas were now exposed to iodine excess due mostly to a poor monitoring of the quality of the iodized salt and of the iodine intake of the population. In these areas or countries, IIH occurred only when the introduction of iodized salt had been of recent onset (<2 years), namely in Zimbabwe and RDC. In conclusion, the risk of IIH after correction of iodine deficiency is closely related to a recent excessive increment of iodine supply.

Africa↗

Successful treatment of hyperthyroidism with amiodarone in a patient with propylthiouracil-induced acute hepatic failure.

Acute hepatic failure is a rare and potentially lethal complication of propylthiouracil (PTU) use for hyperthyroidism. We present a 20-year-old woman with Basedow-Graves' disease who developed PTU-induced fulminant hepatitis, which progressed to acute hepatic failure with grade III hepatic encephalopathy. Laboratory evaluation ruled out the most common causes of fulminant hepatitis. We treated her hyperthyroidism with amiodarone (average daily dose, 200 mg) for 3 weeks, achieving rapid and persistent euthyroidism, (triiodothyronine [T(3)] levels ranged between 64 and 109 ng/dL) without side effects. Amiodarone treatment did not abolish the thyroid radioactive iodine uptake (RAIU), allowing for subsequent treatment with radioactive iodine. The clinical course was favorable and the patient achieved full hepatic recovery 3 months after the hepatic failure was detected. After an extensive review of the literature, we believe that this is the first communication of the successful use of amiodarone to control hyperthyroidism in a patient with PTU-induced fulminant hepatitis.

Adult↗

Novel thyrotropin receptor germline mutation (Ile568Val) in a Saxonian family with hereditary nonautoimmune hyperthyroidism.

OBJECTIVE: Hereditary nonautoimmune hyperthyroidism is caused by activating thyrotropin receptor (TSHR) germline mutations. We describe a family from Saxony, Germany, with this condition. Recurrent thyrotoxicosis and goiter were prevalent in three generations, affecting in addition to the 16-year-old index patient, her father and late paternal grandmother. Hyperthyroidism in the girl was remarkable for its poor response to methimazole (40-60 mg/d) treatment. METHODS AND RESULTS: Molecular analysis of genomic DNA extracted from peripheral blood leucocytes showed a TSHR germline mutation in the girl and her father. This mutation results in a new amino acid exchange of valine for isoleucine in TSHR codon 568 (Ile568Val). Only the wild-type TSHR sequence was found in the girl's mother. On functional characterization in COS-7 cells, the novel Ile568Val TSHR mutation conferred constitutive activation of the cAMP pathway (2- to 3-fold increase of basal cyclic adenosine monophosphate [cAMP]), but not of the inositol phosphate cascade. As a consequence of the molecular findings, total thyroidectomy has been performed in the girl. She is now euthyroid on levothyroxine replacement therapy. CONCLUSION: This is the second Saxonian family with autosomal-dominant nonautoimmune hyperthyroidism, adding to a total of 13 families and 11 individuals with activating TSHR germline mutations worldwide. We suggest that the condition may indeed be more frequent than previously thought and that consequent assessment of a family history in children as well as adults with thyroid autonomy will contribute to ensure correct diagnosis and adequate treatment of patients with activating TSHR germline mutations.

Adolescent↗

Thyrotropin-stimulated DNA synthesis and thyroglobulin expression in normal and hyperthyroid feline thyrocytes in monolayer culture.

Feline hyperthyroidism is a common, spontaneous disease in older cats that is similar clinically and histopathologically to human toxic multinodular goiter (TNG). In this study, the functional response of feline normal thyroid (NT) and hyperthyroid (HT) cells grown in monolayer culture to thyrotropin (TSH) was determined. Basal levels of DNA synthesis were similar in NT and HT cells. TSH stimulated concentration-dependent DNA synthesis in NT and HT cells, with maximal stimulation seen at 1 and 10 mU/mL TSH in NT and HT cells, respectively. HT cells had higher basal levels of thyroglobulin (Tg) expression. TSH stimulated Tg expression in NT and HT cells in a concentration-dependent fashion, with maximal activity at 0.5 and 5 mU/mL TSH, respectively. These results demonstrate that NT and HT cells in monolayer culture exhibit growth and functional responses to TSH. HT cells have higher basal Tg expression than NT cells and require higher TSH concentrations to stimulate DNA synthesis and Tg expression, two measures of thyroid cell activation. These data support the idea that feline hyperthyroidism is caused by cell abnormalities, resulting in dysregulated growth and hormone synthesis, and emphasize its importance as an animal model for TNG.

Animals↗

Radioiodine therapy for thyroid cancer and hyperthyroidism in patients with end-stage renal disease on hemodialysis.

Treatment with radioactive iodine ((131)I) may be necessary for thyroid cancer or for hyperthyroidism in patients with end-stage renal disease who require hemodialysis. Because (131)I is cleared mainly by the kidneys in patients with normal renal function, many issues arise in patients who require (131)I treatment but who are on hemodialysis. This paper presents a case report of a patient on dialysis who required treatment with (131)I for thyroid cancer. We describe a mathematical model, which suggests that the treatment dose of (131)I for a patient with thyroid cancer on hemodialysis would be approximately 13%-28% of a typical empiric dose of (131)I for a patient with normal renal function. Also, we present a comprehensive review and discussion of the literature on patients who are receiving hemodialysis who were treated with (131)I for either thyroid cancer or hyperthyroidism. Using a multidisciplinary approach and special precautions, (131)I therapy can be administered safely and effectively for patients with thyroid cancer or hyperthyroidism who are receiving hemodialysis.

Adult↗

Hyperthyroidism induced by potassium iodide given in the course of 125I-fibrinogen test.

Hyperthyroidism developed in three patients during the administration of potassium iodide given for the purpose of blocking the thyroid uptake of radioactive iodine liberated in the course of the 125I-fibrinogen test. In a consecutive series of 31 geriatric patients, who received potassium iodide for the same reason, biochemical hyperthyroidism developed in three instances and significant depression of thyroid function was observed in 10. The performance and the interpretation of the 125I-fibrinogen test are unaffected if iodide is not administered to the patient. The possible hazards to some patients of either induced hyperthyroidism or faulty assessment of thyroid function may be greater than the risk of thyroid irradiation. It is suggested that for the performance of the 125I-fibrinogen test potassium iodide need not be given to the elderly and should be given in a dose of 30 mg daily for two weeks to younger patients. Under certain circumstances potassium perchlorate may be a preferable drug for preventing the accumulation of radioactive iodine by the thyroid.

Aged↗

Cardiac angiotensin receptors in experimental hyperthyroidism in dogs.

OBJECTIVE: The aim was to define the changes in angiotensin II receptors and the plasma renin-angiotensin system in experimental hyperthyroidism in dogs. METHODS: Hyperthyroidism was induced in dogs by subcutaneous injection of triiodothyronine (T3; 1 mg.kg-1 x d-1 for 14 d; group T); control dogs received saline (group C). Plasma angiotensin II (AII), angiotensinogen, renin activity and concentration, and angiotensin II receptors in left ventricle, right atrium, thoracic aorta, adrenal gland, and liver were measured. RESULTS: T3 treatment caused tachycardia, increased heart weight, hypertrophy of the circumflex and septal coronary arteries, increased plasma renin activity [C = 1.6(SEM 0.2), T = 9.8(2.8) ng angiotensin I.ml-1 x h-1], plasma renin concentration [C = 13.0(3.7), T = 34.5(5.6) ng angiotensin I.ml-1 x h-1], and plasma AII [C = 23(3), T = 104(5) pg.ml-1], while plasma angiotensinogen did not change. There were no significant changes in adrenal gland and right atrial angiotensin II receptor densities; increases were measured in the left ventricle [C = 0.33(0.06), T = 0.75(0.12) pmol.g-1 tissue], thoracic aorta [C = 0.19(0.02), T = 0.28(0.03) pmol.g-1 tissue], and liver [C = 8.4(1.2), T = 12.9(1.7) pmol.g-1 tissue]. The relative affinities of the left ventricular angiotensin II receptor for angiotensin peptides (obtained from displacement assays) were: Sar1, Ile8-AII > AII > angiotensin III > angiotensin I > hexapeptide > pentapeptide. CONCLUSIONS: Experimental hyperthyroidism in dogs results in activation of the plasma renin-angiotensin system and up regulation of left ventricular, aortic, and liver angiotensin II receptors.

Animals↗

Renal hypophosphatemic osteomalacia unmasked by hyperthyroidism.

A case of renal hypophosphatemic osteomalacia (RHO) that was unmasked by hyperthyroidism is presented. The patient presented at age 64 with pathologic leg fractures. There was no family history of osteomalacia or rickets. Initial evaluation revealed hyperthyroidism, which was treated with radioactive iodine. Despite control of thyroid function, the patient had recurrent pathologic fractures. Further evaluation revealed histologically proven osteomalacia and the biochemical findings of RHO: elevated serum alkaline phosphatase, decreased serum phosphate and tubular resorption of phosphate, and normal serum calcium, parathyroid hormone, and vitamin D levels. Other causes of osteomalacia were excluded. Treatment with phosphate and calcitriol reversed the osteomalacia. This case demonstrates that hyperthyroidism, and possibly other illnesses that affect vitamin D or bone metabolism, may unmask metabolic bone disease and that physicians should be alert for the subtle clinical and biochemical indicators of unrecognized metabolic bone disease in adults.

Bone and Bones↗

Hyperthyroidism in the setting of gestational trophoblastic disease.

We report the case of a 27-year-old woman who presented with palpitations, hyperemesis, and weight loss. The patient was found to have laboratory values consistent with hyperthyroidism. A serum pregnancy test was positive for an estimated 8-week gestation. After an ultrasound diagnosis of a molar pregnancy, the patient underwent a uterine evacuation with subsequent resolution of her hyperthyroid status. We provide herein the details of this rarely documented presentation of hyperthyroidism in the setting of gestational trophoblastic disease.

Adult↗

Tc-99m pertechnetate thyroid images in hyperthyroidism. Size, distribution, and presence of a pyramidal lobe.

One hundred consecutive thyroid images obtained by use of Tc-99m pertechnetate, in authenticated cases of hyperthyroidism, were reviewed. Calibrated images showed that only 42 of the 200 thyroid lobes (21%) were greater than 5 cm in length. The enlarged lobes occurred in 29 patients. Of these, only 4 had a multinodular appearance (and 7 patients with smaller lobes also had multinodular glands). Neither thyromegaly (by length) nor multinodular appearance are common features of hyperthyroidism in this area. There were 12 instances of pyramidal lobes in the hyperthyroid men (12 of 26 = 46%) and 24 cases in women (24 of 74 = 32%). The site of origin of the pyramidal lobe was from the left in 17, from right in 16, and from the midline in 3 cases. During the period of review of all thyroid images, only one other case of a pyramidal lobe was found (a case of multinodular goiter).

Adolescent↗

Timing for repeated treatment of hyperthyroid disease with radioactive iodine after initial treatment failure.

PURPOSE: It has been reported that the effect of radioactive iodine (RAI) treatment is complete in 4 to 6 months. This retrospective study evaluated the appropriate time for repeated treatment of hyperthyroid disease with RAI after initial treatment failure. METHODS: Outcomes of 128 patients treated with RAI for hyperthyroid disease were reviewed retrospectively at 3 and 6 months. RESULTS: Eighty patients (group A) were treated successfully with a single dose of RAI. Twenty patients (group B) required a second treatment dose. Twenty-eight patients were lost to follow-up. All patients in group A were clinically improved to various degrees at 3 months and continued to improve at 6 months. All eight patients in group B who showed no improvement at 3 months remained the same at 6 months. The difference between the two groups was statistically significant. CONCLUSION: Patients with hyperthyroid disease who are unimproved at 3 months can be retreated with RAI without further delay.

Adolescent↗

Liver tests in hyperthyroidism: effect of antithyroid therapy.

Changes in liver biochemical test results have been described in hyperthyroid patients before and after antithyroid therapy. In the present study, we analyzed liver tests at diagnosis and after 6 weeks of treatment with propylthiouracil (PTU) in 43 patients with hyperthyroidism. At diagnosis, 60.5% of the patients had at least one liver abnormality. Elevations of alkaline phosphatase, alanine and aspartate aminotransferase, and gamma-glutamyl transpeptidase levels were observed in 19 (44.2%), 10 (23.3%), six (14%), and six (14%) of the patients, respectively. At the end of the 6-week treatment with PTU, elevations in liver test values, possibly induced by PTU, were found in seven (16.3%) patients. Age, sex, type of goiter (either diffuse or multinodular), and presence or absence of abnormal liver biochemical tests at diagnosis were not significant in determining the possibility of PTU-induced elevations in liver tests. These data suggest that liver test abnormalities are frequently found at the time of diagnosis of hyperthyroidism. However, the presence or absence of these abnormalities does not predict elevations in liver test results, which are possibly induced by PTU during therapy.

Adult↗

Autonomic contribution to the blood pressure and heart rate variability changes in early experimental hyperthyroidism.

OBJECTIVE: To study the interaction between autonomic nervous activity and thyroid hormones in the control of heart rate (HR) and blood pressure (BP). DESIGN AND METHODS: Thyrotoxicosis was produced by injections of L-thyroxine (0.5 mg/kg/day for five days). Blockers were atropine (0.5 mg/kg), atenolol (1 mg/kg) or prazosin (1 mg/kg). Eight animals were studied in each group. Spectral analyses was performed using continuous BP time series obtained in conscious rats. RESULTS: Thyroxine treatment was sufficient to induce a significant degree of tachycardia (423+/-6 vs 353+/-4 bpm, P < 0.001, unpaired Student's t test), systolic BP elevation (142+/-3 vs 127+/-2 mmHg, P < 0.001) and cardiac hypertrophy (1.165+/-0.017 vs 1.006+/-0.012 g, P < 0.001). The intrinsic HR was markedly increased after treatment with thyroxine (497+/-16 vs 373+/-10 bpm, P < 0.05). Vagal tone was positively linearly related to intrinsic HR (r = 0.84, P< 0.01). Atenolol neither modified HR nor BP variability in rats with hyperthyroidism. The thyrotoxicosis was associated with a reduction of the 0.4 Hz component of BP variability (modulus 1.10+/-0.07 vs 1.41+/-0.06 mmHg, P < 0.01). Prazosin was without effect on this 0.4 Hz component in hyperthyroid animals. CONCLUSIONS: These data show a functional diminution of the vascular and cardiac sympathetic tone in early experimental hyperthyroidism. The marked rise in the intrinsic HR could be the main determinant of tachycardia. The BP elevation may reflexly induce vagal activation and sympathetic (vascular and cardiac) inhibition.

Animals↗

Pharmacokinetics of bisoprolol and influence on serum thyroid hormones in hyperthyroid patients.

Nine hyperthyroid patients (FT4 greater than or equal to 20 ng/L; FT3 greater than or equal to 6 ng/L) were given 1 X 10 mg bisoprolol/day p.o. for a period of 7 days. Pharmacokinetic data were derived from measurements of plasma bisoprolol concentrations after the first dose and at steady state after 7 days treatment. The thyroid hormones FT4, FT3, and rT3 were determined in the serum before and after bisoprolol treatment. In addition, subjective and objective parameters of thyroid function were recorded during the course of the therapy. The maximum bisoprolol concentrations measured after the first dose and after 7 days were 54.3 +/- 2.1 and 70.3 +/- 3.8 ng/ml, respectively, the minimum concentrations being 9.6 +/- 1.0 ng/ml and 11.9 +/- 1.7 ng/ml, respectively. This yields an accumulation factor of 1.2. At steady state, the plasma elimination half-life of bisoprolol was 9.8 +/- 0.9 h. No significant changes in serum thyroid hormones were observed during bisoprolol treatment. There was, however, an improvement in the subjective and objective clinical symptoms of hyperthyroidism. In comparison with the findings in healthy volunteers, the pharmacokinetics of bisoprolol remained unaltered in mild to moderate hyperthyroid patients. After oral application of bisoprolol, only small variations in the plasma concentration were observed inter- and also intraindividually in the course of treatment. This finding reflects the high absolute bioavailability of bisoprolol.

Adrenergic beta-Antagonists↗