The early effects of radioiodine therapy for hyperthyroidism on biochemical indices of bone turnover.

OBJECTIVE: We investigated the early changes following radioiodine therapy for hyperthyroidism, in biochemical indices of bone synthesis and degradation, and their relationship to circulating thyroid hormone concentrations. DESIGN: Prospective follow-up over the first 12 weeks after radioiodine therapy. PATIENTS: Six women with clinical and biochemical evidence of hyperthyroidism. MEASUREMENTS: Serum concentrations of T4, free T3 and osteocalcin, and urinary excretion of the pyridinium cross-links, pyridinaline and deoxypyridinaline, measured before and weekly for 12 weeks after administration of radioiodine therapy. RESULTS: Biochemical indices of bone metabolism were elevated prior to treatment. There was a brisk reduction in circulating thyroid hormones levels paralleled by a similar fall in pyridinium cross-link excretion, which had returned to normal in five patients by the end of the study. There was a positive correlation between pyridinium cross-link excretion and thyroid hormone concentrations. There was no significant change in serum osteocalcin. CONCLUSIONS: Treatment of hyperthyroidism results in prompt correction of the associated increased rate of bone collagen degradation suggesting that effective early correction of hyperthyroidism is desirable to limit its detrimental effect on skeletal mass.

Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium cross-links as specific urinary markers.

UNLABELLED: Urinary excretion of the bone collagen derived pyridinium cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) was measured in 19 patients (4 M:15 F) with untreated thyrotoxicosis, and 20 pre-, and 20 postmenopausal women taking T4 100-200 micrograms daily for autoimmune hypothyroidism. Both PYD and DPD excretion (nanomoles per mmol creatinine) was elevated in the thyrotoxic patients compared to 287 controls; median 131 vs. 26 and 37.5 vs. 7.2, respectively, P less than 0.0001. In premenopausal women mean urinary pyridinium cross-link excretion and serum osteocalcin levels were similar in both T4-treated and matched control groups, despite suppression of serum TSH concentrations to below 0.1 mU/L in 14 of the 20 taking T4. In postmenopausal women mean (+/- 1 SE) urinary PYD excretion (nanomoles per mmol creatinine) was raised in those taking T4, relative to euthyroid controls; 40.0 +/- 2.7 vs. 32.1 +/- 2.3, P less than 0.05. DPD excretion and serum osteocalcin levels were also higher, but not significantly. When only the T4-treated women with a subnormal serum TSH were considered the difference in PYD excretion was more marked, and mean DPD excretion was also significantly elevated; 13.7 +/- 1.3 vs. 10.1 +/- 0.8, P less than 0.05. CONCLUSION: bone collagen breakdown is increased in thyrotoxicosis, and in postmenopausal women taking sufficient T4 to suppress serum TSH. Similarly treated premenopausal women appear to be at lower risk.

Clinical outcome and costs of care in radioiodine treatment of hyperthyroidism.

The long-term clinical outcome and costs of treatment of hyperthyroidism with radioiodine have been examined in two cohorts of patients from Sheffield and Scotland. The majority of patients in both series were considered to have Graves' disease. The Sheffield patients (660) were included in a trial of three radioiodine dose regimens of 3,500 (312), 7,000 (323) and 14,000 (25) rad determined using a formula for accurate dosimetry. The Scottish patients (3,920) drawn from five centres in Aberdeen, Dundee, Edinburgh, Glasgow and Inverness were treated using an arbitrary scale, for the activity of radioiodine administered, related to goitre size. Their results are grouped into five MBq 'dose' bands: 37-185, 186-370, 371-555, 556-740 and 741+. The proportion of patients with persistent hyperthyroidism was higher in both cohorts for low-dose radioiodine regimens, but 15-25% of patients who received high doses showed persistent hyperthyroidism. Early and late onset hypothyroidism was lower after low doses but differences between the treatment groups were small in terms of clinical benefit. Total morbidity at 10 years follow-up, in terms of hyperthyroidism, and hypothyroidism, was highest after low-dose therapy. There was little variation in total costs, but patient costs were lowest for the Scottish regimen and highest for low-dose therapy. A dose of at least 370-555 MBq which will ensure early elimination of hyperthyroidism will also limit the medical workload and total costs.

Antithyroid drugs in the treatment of hyperthyroidism of Graves' disease: long-term follow-up of 434 patients. Scottish Automated Follow-Up Register Group.

A study of antithyroid drug (ATD) therapy with a mean follow-up period of 10 years (range 2-25) in 434 patients with Graves' disease has been made by linking hospital records with those of a central follow-up register. The majority (89%) were treated with carbimazole and 87% received combined therapy with triiodothyronine (T3) (73%) or thyroxine (T4) (14%). Sixty-one per cent were assessed for T3 suppression tests on completion of treatment, of whom 61% (95% CL, 55-67%) suppressed. The overall 5-year cumulative proportion developing recurrent hyperthyroidism was 54-62% with rates of 26-44% in suppressed patients and 65-79% in those not suppressed. In unsuppressed patients, most (72%) of the recurrences occurred within 1 year with only an additional 10% predicted up to 10 years. In suppressed patients 30% of recurrences occurred in the first year, 60% between 1 and 5 years and a further 10% between 5 and 10 years. Suppression with T3 is probably the best and cheapest predictor of outcome but has an accuracy of only 70% for both positive and negative tests which limits its usefulness in planning long-term follow-up and surveillance. A standard format should be adopted for the analysis and reporting of follow-up studies, based on actuarial methods of estimating the cumulative proportion with recurrences or other events, to facilitate comparisons between different centres.

Effects of widespread dermatitis and topical steroid therapy on thyroid function tests.

Five patients with extensive dermatitis and 5 normal subjects were treated with topical betamethasone valerate 0.1% (Betnovate, Glaxo) 19-34 g daily for 4 days. Thyroid functions tests were not affected by the treatment but some patients with widespread inflamed skin demonstrated altered serum thyroid hormone levels as a result of the euthyroid sick syndrome.

Serum levels of pregnancy associated alpha 2-glycoprotein (alpha 2-PAG) during pregnancy in autoimmune thyroid disease: relationship to disease activity.

Serum concentrations of pregnancy associated alpha 2-glycoprotein (alpha 2-PAG) were measured serially by an enzyme linked immunosorbent assay during 24 pregnancies in 18 patients with Graves' disease and four with Hashimoto's thyroiditis. During each trimester, alpha 2-PAG levels were significantly higher than in normal pregnant controls, matched for week of gestation. Patients showing remission of disease activity had progressively higher alpha 2-PAG levels throughout pregnancy than those with active disease. The data support the idea that alpha 2-PAG may play an important role in inducing and maintaining the clinical remissions observed in some women with autoimmune thyroid disease during pregnancy.

Age and the daily dose of thyroxine replacement therapy for hypothyroidism.

The initial prescriptions and later adjustments of thyroxine (T4) replacement have been analysed in 2246 hypothyroid patients who have been monitored by a thyroid follow-up register for a mean period of 6 years (range 1-13 years). In 465 (21%) patients of 65 years or over, initial T4 doses were on average only 20 micrograms lower than in younger patients. However, only 40% of the elderly were taking 200 micrograms of T4/day or more, compared with 60% of the younger patients. Over 10 years, the predicted proportion of patients who have a downward adjustment of their T4 prescription is 3%, but there is no difference in recognized overtreatment between older and younger patients. The findings suggest that the majority of the elderly may receive larger doses of T4 than are required for optimal replacement. There are strong reasons for the standardization of thyroxine prescribing in the elderly and for the provision of routine surveillance of thyroxine replacement through the type of follow-up system used in this study.

Oxazepam pharmacokinetics in thyroid disease.

The pharmacokinetics of oxazepam, a drug mainly eliminated by a single step glucuronidation reaction, were studied in seven hyperthyroid and six hypothyroid patients before and after treatment. Oxazepam elimination half-life was shorter and apparent oral clearance higher in untreated hyperthyroid patients than after treatment. There was no significant change in oxazepam elimination in hypothyroid subjects. Time to peak concentration (tmax) was reduced in the hyperthyroid state. Hypothyroidism had no significant effect on tmax. Serum bilirubin concentration was lower in the patients while hyperthyroid before treatment than when euthyroid and also lower than in the hypothyroid patients. There was no significant correlation between serum bilirubin concentrations and oxazepam elimination. These results suggest that glucuronyl transferase activity is increased in hyperthyroidism but is not altered in most patients with hypothyroidism. The extent of increase in glucuronyl transferase activity is similar to that produced by enzyme inducing drugs.

A search for the mechanism underlying the altered MCV in thyroid dysfunction: a study of serum and red cell membrane lipids.

The mean red cell volume (MCV) is increased in hypo- and decreased in hyperthyroidism but the underlying cause(s) is unknown. In view of the well recognised alterations in serum lipids in thyroid dysfunction, we have examined the possibility that a corresponding alteration in the amount or distribution of lipids in the red cell membrane may account for the red cell volume changes. Our findings however do not support this hypothesis.

Late onset hypothyroidism after subtotal thyroidectomy for hyperthyroidism: implications for long term follow-up.

A follow-up register has been used in Aberdeen and Dundee to record early and late onset hypothyroidism occurring in a large population of post-thyroidectomy patients treated for hyperthyroidism. In one centre, in a total of 1170 patients, the prevalence of postoperative hypothyroidism, at the time of entry to the register, was 41 per cent. Of these early cases of hypothyroidism 93 per cent occurred within 18 months of operation. Results are presented from a 12-year prospective study of patients treated in two centres, who were euthyroid when entered on the follow-up register. In one centre, based on 683 patients, the 10-year incidence of late onset hypothyroidism estimated by actuarial methods was 7.4 per cent (95 per cent confidence limits, 3.8-11.1); in the other centre with 156 patients the 5-year incidence was 10.8 per cent (95 per cent confidence limits, 3-18.6). The minimum predicted annual incidence is 1 per cent. Large thyroid remnants do not protect some patients against early or late postoperative hypothyroidism but do lead to an increased risk of recurrent hyperthyroidism. Hypothyroidism after subtotal thyroidectomy for hyperthyroidism shows a bimodal pattern and this study emphasizes the need to maintain life-long follow-up.

Successful pregnancy after cyproheptadine treatment for Cushing's disease.

A patient with active Cushing's disease who became pregnant following treatment with cyproheptadine is described. Despite stopping the cyproheptadine treatment at 3 mth gestation, the previous amelioration of the clinical and biochemical features of the adrenal hyperfunction was maintained and the pregnancy progressed satisfactorily. Moreover, serial evaluation of maternal glucose tolerance proved to be normal and it is suggested that this matabolic aspect is an important determinant in the outcome of pregnancies occurring in patients with Cushing's syndrome.

Do we need thyroid follow-up registers? A cost-effective study.

Patients who had received radioiodine treatment for hyperthyroidism were followed up by two different methods. 576 patients (group 1) were followed up conventionally by their general practitioners and as hospital outpatients. 609 similarly treated patients (group 2) were followed up by a computer-assisted system, the Scottish Automated Follow-up Register (S.A.F.U.R.). Follow-up in the two groups were compared on the basis of cost-effectiveness. On average, patients were seen for follow-up about once every 8 months if in group 1 and every 14 1/2 months in group 2. The overall cost of follow-up and treatment for group 2 patients was less than 60% of that for group 1 patients. A central follow-up register is reliable and cost-effective, particularly so when patients are dispersed over a wide area.

Breast cancer in thyroid disease: fact or fallacy?

The incidence of breast cancer was examined prospectively in 2523 patients registered in a thyroid follow-up system. No significant differences were found between the observed and expected numbers of cases in any of the sub-groups defined by age, underlying pathology, or type of treatment. These results provide no indication that the risk of breast cancer is increased in patients treated for thyroid disease.