HLA CLASS II DNA GENOTYPES IN GRAVES'' DISEASE: CLUES TO INHERITANCE OF THE HLA-LINKED COMPONENT OF SUSCEPTIBILITY

Restriction fragment length polymorphism analysis using DQ alpha, DQ beta and DR beta cDNA probes was performed in Graves' disease patients and control subjects. The following restriction fragment patterns were increased in frequency in patients compared with control subjects: 10 + 7.0 + 4.0kb DR beta/TaqI fragments (66% vs 32%; P less than 0.01; corrected P less than 0.06), 7.0 + 4.0kb DQ beta/BamHI fragments (55% vs 15%; P less than 0.001; corrected P less than 0.006), and a DQ alpha/TaqI 4.6kb fragment (75% vs 36%; P less than 0.005; corrected P less than 0.02). These associations could be accounted for by the known association of the B8-DR3 haplotype with the disorder. No non-DR3-related restriction fragment pattern was associated with the disease using any of the probes with restriction enzymes TaqI and BamHI. The 10 + 7.0 + 4.0kb DR beta/TaqI restriction pattern was identified in 23 of 35 Graves' disease patients. All 23 subjects were heterozygous for this pattern. This was inconsistent with simple recessive inheritance of the DR3-associated component of disease susceptibility (P = 0.01). The implications of these findings are discussed with reference to models for the inheritance of the HLA-linked component of Graves' disease susceptibility.     

MEASUREMENT OF FREE THYROXINE AND FREE TRIIODOTHYRONINE IN THYROTOXICOSIS AND HYPOTHYROIDISM

Free T4 and free T3 concentrations in thyrotoxic and hypothyroid patients at presentation differentiated those with thyroid disease from euthyroid control subjects and were closely correlated with T4/TBG ratio. A further group of thyrotoxic patients was followed serially during treatment with carbimazole. Measurements of free T4 and free T3 against closely reflected thyroid status with changes in the hormone measurements being paralleled by changes in T4/TBG ratio.     

AMIODARONE AND THYROID HORMONE EFFECTS ON ANTERIOR PITUITARY HORMONE GENE EXPRESSION

Amiodarone therapy results in marked changes in circulating thyroid hormone and TSH concentrations in man. In the present study we have demonstrated that amiodarone treatment of the rat increases serum TSH and pituitary cytoplasmic concentrations of TSH beta and alpha subunit messenger RNAs (mRNAs) and reduces PRL mRNA as measured by cytoplasmic dot hybridization with specific complementary (c) DNA probes. The fall in circulating TSH and TSH mRNA resulting from thyroid hormone treatment was less marked in animals receiving amiodarone in addition to T3 and T4. In contrast, in the hypothyroid state, increases in serum TSH, TSH beta and alpha mRNA, and reductions in PRL and GH mRNA were less marked in rats treated with amiodarone. In studies of rat anterior pituitary cells in primary monolayer culture we demonstrated a direct effect of amiodarone on PRL gene expression which was antagonized by T3. Changes in circulating thyroid hormone concentrations and deiodination of T4 and T3 induced by amiodarone in vivo may be important in the regulation of pituitary hormone gene expression but we have, in addition, shown a direct interaction between amiodarone and T3 effects on the anterior pituitary cell.     

Radioiodine therapy for hyperthyroidism in young patients--perception of risk and use

Although radioiodine is increasingly the treatment of choicein hyperthyroidism, there are regional differences in its usewhich reflect, in part, concerns regarding safety. We investigatedattitudes amongst general practitioners and consultant physiciansto the role of radioiodine therapy, and reviewed our own radioiodineprescribing in patients aged less than 40 to elucidate any influenceof age and/or sex. We surveyed general practitioners in theformer Central Birmingham Health District and consultant physiciansin the West Midlands Region to investigate treatment preferencesin hyperthyroidism and perceived risk from radioiodine of hypothyroidism,carcinogenesis and infertility. Of 230 general practitionerand 130 consultant physician respondents, less than 1% consideredradioiodine the treatment of choice in a 25-year-old femalepresenting with hyperthyroidism. At relapse after antithyroiddrug treatment in a 25-year-old female, only 16.5% of generalpractitioners and 23.9% of physicians advocated radioiodine,the greatest number preferring partial thyroidectomy. For a65-year-old at presentation, 49.1% of general practitionersand 62.3% of physicians considered radioiodine the treatmentof choice. More than 10% failed to note the risk of hypothyroidismfollowing radioiodine, while 11–34% perceived increasedrisk of malignancy or infertility. Review of our own practicedemonstrated that of 100 patients given radioiodine, 94% werecured of hyperthyroidism when reviewed at a mean of 2.4 yearsfrom latest treatment, 70% being hypothyroid. Females givenradioiodine were treated less promptly following diagnosis ofhyperthyroidism than males (2.2 ± 0.26 years vs. 1.6± 0.4) and were more likely to have received a precedingcourse of antithyroid drugs (78% vs. 57%). Doubts regardingthe safety of radioiodine persist amongst doctors and are reflectedin unwillingness to recommend radioiodine therapy in young females,even at relapse of hyperthyroidism. Radioiodine is an effectivetreatment of hyperthyroidism in young patients, although atthe cost of thyroid failure.