Thyroid hormone resistance: the role of mutational analysis.

The finding of increased thyroxine (T4) and tri-iodothyronine (T3) levels in a patient with normal or increased thyroid-stimulating hormone is unexpected and presents a differential diagnosis between a thyroid-stimulating hormone-secreting pituitary adenoma, generalized resistance to thyroid hormone (RTH) and laboratory artefact. Without careful clinical and biochemical evaluation, errors may occur in patient diagnosis and treatment. In the case of RTH, mutation of the thyroid hormone receptor beta gene results in generalized tissue resistance to thyroid hormone. As the pituitary gland shares in this tissue resistance, euthyroidism with a normal thyroid-stimulating hormone is usually maintained by increased thyroid hormones. To date, we have identified eight pedigrees in New Zealand with mutations in the thyroid hormone receptor beta gene, including two novel mutations. Mutational analysis of the thyroid hormone receptor beta gene allows definitive diagnosis of RTH, potentially avoiding the need for protracted and expensive pituitary function testing and imaging. Mutational analysis also enables family screening and may help to avoid potential misdiagnosis and inappropriate treatment.

Psychoses associated with thyrotoxicosis - 'thyrotoxic psychosis.' A report of 18 cases, with statistical analysis of incidence.

OBJECTIVE: To report a series of newly diagnosed thyrotoxic patients with concurrent acute psychosis, and to assess the association between the two disorders. DESIGN: Retrospective study of thyrotoxic patients with associated psychosis ('thyrotoxic psychosis'; TP) requiring inpatient psychiatric care. New Zealand thyrotoxicosis annual incidence figures and first psychiatric admission rates for affective psychosis were utilised to statistically assess the co-occurrence of thyrotoxicosis and affective psychosis. PATIENTS AND METHODS: During the 20-year study period, 18 inpatients (16 women and 2 men), mean age 54 years, with TP were identified. No patient had a past history of thyrotoxicosis, but four had required psychiatric inpatient care many years earlier. Thyrotoxicosis was documented by radioimmunoassay of thyroid hormone levels, and thyroid scintiscan. Psychiatric manifestations were classified using ICD9 criteria. RESULTS: Thyroid hormone levels were markedly elevated in more than half of our TP patients. All younger patients had Graves' disease, and most older patients toxic nodular goitre. All patients were treated with antithyroid drugs, and all but one subsequently received (131)I therapy. Two patients were not mentally ill when thyrotoxicosis was diagnosed, but suffered major mood swings when thyroid hormone levels were falling. There was no specific psychiatric clinical picture but affective psychoses were commonest - seven depression, seven mania. The other diagnoses were two schizophreniform, one paranoid, and one delirium. Initially, neuroleptic medication was used in all but one patient, and during long-term follow-up (median 11 years) more than half our series had remained well with no further psychiatric problems. Statistical analysis was restricted to thyrotoxic patients with first psychiatric hospital admission for affective psychosis. During the 20-year period, there were nine thyrotoxic patients (95% confidence interval 4.5-17.1) with concurrent affective psychosis requiring first admission, and the calculated expected number was only 0.36. These findings indicate a clear association well above chance co-occurrence. CONCLUSION: TP is not a specific clinical picture, but affective psychoses are commonest. Statistical analysis of thyrotoxic patients with concurrent affective psychoses showed an incidence well above chance co-occurrence. It appears that thyrotoxicosis may be a precipitant of acute affective psychosis.

Primary thyroid lymphoma: clinical features, treatment and outcome: a report of 8 cases.

AIM: To assess the clinical findings and response to treatment of patients with primary thyroid lymphoma. METHODS: Patients with primary thyroid lymphoma were identified by reviewing the diagnoses of all patients with thyroid malignancies diagnosed at Christchurch Hospital between 1980-91. The records of patients with primary thyroid lymphoma were abstracted. RESULTS: During the 12 year period eight patients (6 females, 2 males) with primary thyroid lymphoma were diagnosed and treated. The median age was 78 years (range 18-90 yr). All patients presented with recent thyroid masses and obstructive symptoms were prominent. Two patients were initially referred with endocrine dysfunction--one thyrotoxic and one hypothyroid. Six patients had nonHodgkin lymphoma and two Hodgkin's disease, with all having stage IA disease. Two patients were treated by thyroidectomy, and in the remaining six patients the thyroid lymphoma masses regressed following radiotherapy with the two youngest patients also receiving chemotherapy. At follow up all five elderly patients have since died--two of disseminated lymphoma, two of concurrent cancers and one of vascular disease, and the three younger patients remain in remission after 4.5, 6.5 and 10.5 years. CONCLUSION: Primary thyroid lymphoma usually presents with obstructive symptoms, but there may be associated thyroid dysfunction. Thyroid lymphoma masses respond well to radiotherapy.

Lithium associated thyrotoxicosis: a report of 14 cases, with statistical analysis of incidence.

OBJECTIVE: Lithium is known to cause goitre and hypothyroidism, and has been associated less commonly with hyperthyroidism. We report a series of 14 patients with lithium associated thyrotoxicosis (LiAT), and have used epidemiological data to assess the association between long-term lithium treatment and the development of thyrotoxicosis. DESIGN: Information for this retrospective study was obtained from records of patients attending the thyroid clinic between 1973 and 1991. Statistical analysis of the association between long-term lithium treatment and incidence of thyrotoxicosis was made using local thyrotoxicosis incidence figures and lithium prescription data. MEASUREMENTS: Investigations included 99mTc pertechnetate thyroid scans, and blood analyses to measure serum T4, serum T3, free T4 index, and thyroid microsomal and thyroglobulin antibody titres. RESULTS: During the 18-year period there were 14 patients with LiAT. This number of cases of thyrotoxicosis occurring in patients on lithium was more than three times greater than that predicted from local thyrotoxicosis incidence rates (P < 0.05). Scintiscans were obtained for 13 patients: 8 had toxic diffuse goitre, 2 toxic multinodular goitre, 1 toxic uninodular goitre, and 2 had a lack of visualization consistent with 'painless thyroiditis'. Nine patients received a course of carbimazole and 6 of these remain in remission. Six patients have received 131I therapy. Eight patients have become hypothyroid at follow-up (5 post 131I, 1 following a course of carbimazole, and the 2 with 'painless thyroiditis'). CONCLUSIONS: Statistical analysis has shown that long-term lithium therapy is associated with an increased risk of thyrotoxicosis. LiAT is a heterogeneous condition with differing underlying thyroid pathologies and the mechanisms remain uncertain. The management of LiAT should initially be with antithyroid medication, and 131I therapy should be given only to patients who do not obtain long-term remission.

Bone mineral density in patients receiving suppressive doses of thyroxine for thyroid carcinoma.

AIMS: Studies of the effect of thyroxine therapy on skeletal integrity have given conflicting results; the reductions in bone mass reported by some have prompted recommendations that the prescribed replacement doses of thyroxine should be reduced. We have examined bone mineral density in a group of patients with differentiated thyroid carcinoma receiving high doses of thyroxine to suppress thyroid stimulating hormone (TSH). METHODS: The 44 patients (6 male, 38 female) had a median age of 49 years (range 27-75) with median duration of thyroxine therapy of 9.0 years (range 3 to 42) and mean dose of thyroxine 0.167 mg/day (range 0.125-0.3). TSH levels were chronically suppressed in 39 subjects. Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) in all subjects at the femoral neck and lumbar spine and compared with previously established local reference ranges. RESULTS: There was no reduction in bone mineral density in the thyroxine treated group compared with the local reference population at both lumbar spine and femoral neck, and no correlation with duration of therapy. CONCLUSIONS: These negative findings, that thyroxine in suppressive doses does not significantly reduce bone mineral density in New Zealand patients suggest that thyroxine therapy alone is not a major risk factor for the development of osteoporosis.

The epidemiology of thyrotoxicosis in New Zealand: incidence and geographical distribution in north Canterbury, 1983-1985.

In a 3-year (1983-1985) epidemiological study of thyrotoxicosis in North Canterbury, New Zealand, the annual incidence was 25.8 per 100,000 (female 40.7, male 10.5). Thyroid scintiscanning showed that 64% had diffuse hyperplasia (DH), 27% toxic multinodular goitre (TMG), 7% toxic uninodular goitre (TUG), and 2% zero uptake. The calculated annual incidence of toxic diffuse goitre (DH) was 15 per 100,000, and for toxic nodular goitre (TMG and TUG combined) was 8 per 100,000. The age-related incidence for toxic diffuse goitre peaked in middle life whereas toxic nodular goitre showed an increasing incidence with age. There was no significant seasonal variation or rural/urban difference in incidence. Analysis of geocoded addresses did not identify areas of high incidence. The variable duration of symptoms prior to diagnosis limits the search for possible environmental trigger factors. North Canterbury was an endemic goitre area prior to the introduction of iodized salt 50 years ago, and the incidence of toxic nodular goitre is likely to fall in future.

Thyrotropin results in euthyroid patients with a past history of hyperthyroidism.

Sensitive TSH levels were measured in 93 euthyroid patients with a past history of hyperthyroidism. Subnormal TSH values were found in 18 out of 75 (24%) patients previously treated with a course of antithyroid drugs, and in 3 out of 18 (17%) post-thyroidectomy patients. These subnormal TSH results are a limitation to the general application of the TSH-first strategy. Twelve months follow-up showed that subnormal TSH values are associated with increased risk of relapse in the antithyroid drug treated group (p less than 0.001). Longer follow-up varies in duration and some late relapses have occurred in drug treated patients with normal baseline TSH levels. To date relapses have occurred in 3 out of 56 normal TSH patients compared with in 6 out of 16 suppressed TSH patients; no thyroidectomy patients have relapsed. Prospective studies are needed to confirm the predictive value of sensitive TSH measurements.

Outcome following standardized 185 MBq dose 131I therapy for Graves' disease.

The clinical outcome of 199 patients with Graves' disease treated with standardized 185MBq 131I therapy doses has been analysed. Most patients were controlled with antithyroid drugs prior to the 131I therapy, and also received antithyroid drugs for several months following 131I. The median follow-up period was 5.5 years. The single 185MBq 131I dose successfully treated 72.4% of patients. The 1, 2 and 5 year hypothyroid figures were 15.5%, 19.3% and 27.3%, respectively. Previous thyroidectomy was associated with an increased hypothyroid rate. Retreatment was required by 25.6%, with 3.5% requiring more than two 131I doses. Discriminant analysis of pretreatment variables suggests that patients with large goitres or severe disease (serum T3 greater than 10nmol/l) should be treated with higher doses of 131I.

Hypertension in hypothyroidism: arterial pressure and hormone relationships.

To investigate the regulation of arterial pressure and vasoactive hormones in hypothyroidism associated with hypertension, we measured intra-arterial pressure and hourly venous hormones (renin, angiotensin II, aldosterone, catecholamines and cortisol) for 24 hours in five hypertensive patients with primary hypothyroidism before commencing treatment, and again after three to six months of thyroxine replacement therapy. Arterial pressure fell significantly after thyroxine replacement in four patients. Thyroxine treatment was associated with a fall in plasma norepinephrine levels together with a decline in slopes of norepinephrine/arterial pressure regression lines which suggests that the sympathetic system may contribute to the hypertension in hypothyroidism. Variability of heart rate, blood pressure and plasma norepinephrine fell with thyroxine replacement consistent with impaired damping of swings in sympathetic activity in the untreated state. Reciprocal changes in arterial pressure and renin-angiotensin-aldosterone system activity suggested that this system was not the mediator of hypertension in hypothyroidism.

The peripheral blood picture in thyrotoxicosis.

The haematological results of 200 patients with uncomplicated thyrotoxicosis is reviewed. Although more than half of the patients showed a normal blood picture, several abnormalities were detected. In 37 percent of patients the erythrocytes showed microcytosis, and 8.5 percent were mildly anaemic. An absolute lymphocytosis was found in 11 percent and neutropenia was present in 2.5 percent of patients. The prevalence of treated pernicious anaemia was 1.5 percent.

Conjugal thyroid disease--six couples with thyrotoxicosis, one couple with hypothyroidism, and one couple with thyroid cancer.

Six married couples with thyrotoxicosis, one couple with primary hypothyroidism, and one couple with well differentiated thyroid cancer are reported. The occurrence of conjugal thyroid disease raises the possibility that environmental factors may have played an aetiological role.

Lithium associated thyroid cancer.

This report documents papillary cell carcinoma of the thyroid occurring in a 55-year-old woman after three-and-a-half years of lithium therapy. She presented with unilateral thyroid enlargement causing tracheal deviation. There was no clinical suspicion of malignancy and the histological findings were totally unexpected.

A screening programme for congenital hypothyroidism: preliminary results.

Highly sensitive and precise radioimmunoassays for thyroxine (T4) and thyrotropin (TSH) in dried blood spots on filter paper cards have been developed and are used to screen newborn infants for congenital hypothyroidism. Blood spot TSH levels are measured in samples for which blood spot T4 levels fall in the lower 10 to 15 percent. There was a low recall rate of approximately one infant in every 550 screened. During a 17-month period 5225 infants have been screened for congenital hypothyroidism and two cretins have been detected. Due to very early diagnosis, both infants were commenced on T4 replacement therapy before the age of three weeks.

Results of lithium- 131I treatment of thyrotoxicosis.

The role of lithium as an adjunct to 131I therapy of thyrotoxicosis has been assessed. Seventeen lithium- 131I treated patients and 16 control- 131I treated patients have been followed for almost three years. Five lithium- 131I and 3 control- 131I patients have become hypothyroid with the lithium treated patients developing earlier thyroid failure. Ten lithium and 10 control patients remain clinically and biochemically euthyroid. Two lithium- 131I and 2 control- 131I patients remain on low dose antithyroid drugs.

Low dose lithium-carbimazole in the treatment of thyrotoxicosis.

Fifteen patients with thyrotoxicosis were treated with low dose sustained release lithium carbonate 400 mg, combined with carbimazole 40 mg daily, and the therapeutic response was followed over a two week period. This response was compared with that obtained in a similar group of patient treated with carbimazole alone. Li-carbimazole treatment brought about a fall in the mean total serum T4 of 57.4% compared with a drop of 32.8% in patients treated with carbimazole alone. The mean serum T3 fell by 69.4% in the Li-carbimazole group compared with 47.3% in the group treated with carbimazole only. No lithium adverse effects were encountered.

Unilateral breast-feeding: a new clue to the diagnosis of thyrotoxicosis.

Two thyrotoxic women who had breast-fed exclusively at the right breast are reported. This phenomenon may prove to be a useful clue to undiagnosed thyrotoxicosis in the postpartum period.