Thyroxine replacement: a clinical endocrinologist's viewpoint.

BACKGROUND: Hypothyroidism affects 2-5% of the general population. Patients with uncorrected disease suffer significant morbidity and have an increased risk of cardiovascular disease and neurocognitive impairment. Levothyroxine, the treatment of choice, is inexpensive, easy to administer and in most cases restores well-being while normalizing thyroid function. However, 30-50% of individuals on levothyroxine are either over-treated or under-treated and others remain dissatisfied with treatment despite achieving thyroid hormone concentrations within the laboratory reference interval. METHODS: This review is based on a systematic search of the literature for controlled trials, systematic reviews, guideline papers and cohort studies addressing best practice in thyroid hormone replacement. RESULTS: Recent decades have seen improvements in patient management strategies driven by a better appreciation of levothyroxine pharmacokinetics. However, aspects of therapy such as the optimal timing of medication, strategies to overcome treatment non-adherence and target thyroid stimulating hormone concentrations in pregnancy and in patients with differentiated thyroid cancer remain challenging. Furthermore, there is now a substantial body of literature on common genetic variations in the deiodinases and thyroid hormone transporters and their role in the local regulation of thyroid hormone delivery. The benefits of combination therapy with liothyronine and levothyroxine are uncertain, and while it is theoretically probable that subsets of genetically predisposed individuals will benefit from combination therapy the existing evidence is as yet limited. CONCLUSION: Despite the availability of thyroid hormone replacement for more than a century, there are still substantial challenges in practice and opportunities to improve treatment outcomes.

Prognostic significance of thyroglobulin antibody epitopes in differentiated thyroid cancer.

CONTEXT: Thyroglobulin antibodies (TgAbs) are surrogate markers of disease recurrence or persistence in differentiated thyroid cancer (DTC). However, the prognostic significance of TgAb heterogeneity in DTC has not been investigated. OBJECTIVE: To evaluate the relationship between TgAb epitope specificities and clinical outcomes in DTC patients. DESIGN: We studied 61 TgAb-positive patients with DTC, post-thyroidectomy and remnant ablation (7 males, 54 females; age-range 16-80 years, median follow-up duration 8.9 years). TgAb epitope reactivities were mapped using a panel of 10 thyroglobulin (Tg) monoclonal antibodies delineating six antigenic Tg clusters in competitive ELISA studies. Sera from 45 patients with Hashimoto's thyroiditis (HT) and 22 TgAb-positive healthy subjects served as autoimmune and healthy controls. Tg was measured by immunoradiometric assay (IRMA), electrochemiluminescence immunoassay (ECLIA), and RIA, while TgAbs was measured by ELISA and ECLIA methods. RESULTS: Samples from 26 DTC patients showed TgAb epitope restriction similar to HT patients, while 35 patients exhibited nonspecific reactivity comparable to healthy controls. DTC patients with epitope restriction had higher rates of recurrent/persistent disease (81% vs 17%, P < .001), higher median TgAb concentration (887.0 vs 82.0 kIU/L; P < .001), and a higher prevalence of thyroid lymphocytic infiltration (71.4% vs 26.8%; P < .001) compared to patients with nonspecific reactivity. Samples with epitope restriction also had a lower median Tg-IRMA/RIA ratio (3.0% vs 36.0%; P < .001) denoting greater degrees of Tg assay interference. CONCLUSIONS: TgAb epitope restriction is associated with a less favorable prognosis than nonspecific reactivity in DTC patients. TgAb epitope specificities may have prognostic value in DTC.

The utility of radioiodine uptake and thyroid scintigraphy in the diagnosis and management of hyperthyroidism.

BACKGROUND AND OBJECTIVES: The value and practice of thyroid radionuclide imaging in the diagnosis and management of hyperthyroidism is unsettled. Our objectives were to determine the influence of thyroid uptake and scintigraphy on the diagnosis of hyperthyroidism and the prediction of outcome following radioiodine therapy. PATIENTS AND DESIGN: We reviewed records and scintigraphic studies on 881 hyperthyroid patients carried out between 2000 and 2007. The agreement between the clinical and scintigraphic diagnosis was evaluated by kappa statistics. We determined the relationship between 4-h (123)I uptake and the outcome of (131)I treatment in 626 patients. A multiple logistic regression model was used to determine variables influencing treatment outcome in 1 year. RESULTS: The diagnostic categories were Graves' disease (GD, n = 383), toxic multinodular goitre (n = 253), solitary toxic nodule (n = 164) and Graves' disease coexisting with nodules (n = 81). The mean age of the patients was 58 +/- 17, (M:F 160:721). There was good agreement between clinical and scintigraph diagnosis (K = 0.60, 95% CI 0.57-0.64, P < 0.001); and they were correctly matched in 74%; mismatched in 6% and indeterminate in 20% of patients. Treatment outcome was not associated with scintigraph diagnosis (P = 0.98) or radioiodine uptake at 4 h (P = 0.2). The use of antithyroid medications before treatment predicted treatment failure (odds ratio 2.0, 95% CI 1.2-3.6, P = 0.01). CONCLUSION: Thyroid scintigraphy and uptake studies did not influence diagnosis or treatment outcomes in most cases of hyperthyroidism. Our findings in this retrospective study do not justify their routine use. Selective scanning will reduce cost and exposure to radioisotopes without compromising diagnostic accuracy or treatment outcomes.

Peripheral cytokine expression in autoimmune thyroiditis: effects of in vitro modulation by rosiglitazone and dexamethasone.

BACKGROUND: In Hashimoto's thyroiditis (HT), there is evidence for activation of peripheral T-lymphocytes that predominantly express a T helper 1 (T(H)1) cytokine bias. However, the immunomodulatory factors involved in regulating this response have so far received scant attention. In this study, we examine the effects of the glucocorticoid, dexamethasone, and the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, rosiglitazone on the expression of interferon (IFN)-gamma (T(H)1) and interleukin (IL)-4 (T(H)2) by activated peripheral CD4(+) and CD8(+) lymphocytes in patients with HT (n = 10) and healthy control subjects (n = 12). METHODS: Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with phorbolmyristate acetate (PMA) and ionomycin in the presence or absence of varying doses of dexamethasone and rosiglitazone (0.01 microM, 1.0 microM, and 100 microM). Cytokine expression was determined by flow cytometry. RESULTS: CD4(+) and CD8(+) IFN-gamma expression was greater in HT than controls (14.87 versus 9.25; p < 0.05 and 21.34 versus 10.16; p < 0.01, respectively). A dose-dependent inhibition of IFN-gamma expression was seen with dexamethasone and rosiglitazone. Inhibition of CD4(+) and CD8(+) IFN-gamma expression with both dexamethasone and rosiglitazone was greater in control subjects than in patients (p < 0.05). There was no significant difference in IL-4 expression between patients and control groups and its expression remained unaffected by either compound. CONCLUSIONS: We show that CD4(+) and CD8(+) T lymphocytes from HT patients express a type 1 cytokine bias that is significantly more resistant to in vitro modulation by rosiglitazone and dexamethasone. Further studies are needed to clarify if this resistance plays a role in the pathogenesis of autoimmune thyroid disease (AITD).

Diuretic-induced hypokalaemia in patients with hypertension.

We describe a 55 year-old woman with longstanding hypertension who developed hypokalaemia following diuretic treatment. Investigations revealed primary hyperaldosteronism due to an adrenal adenoma, and normal blood pressure was restored after surgical removal of the tumour. Primary hyperaldosteronism is a potentially curable cause of hypertension and should be considered in hypertensive patients who present with diuretic - induced hypokalaemia.

Thyroglobulin epitope recognition in a post iodine-supplemented Sri Lankan population.

OBJECTIVE: We previously reported a high prevalence of raised thyroglobulin autoantibodies (TgAb) in apparently healthy Sri Lankan schoolgirls following salt iodination. To characterize these antibodies further we determined the epitopes on thyroglobulin (Tg) with which they react and compared these with serum obtained from both healthy subjects and established autoimmune thyroid disease (AITD) patients from the UK. To extend our study to a wider population within Sri Lanka, we in addition determined the epitopes recognized by a group of AITD patients selected from a thyroid clinic in Sri Lanka, as well as apparently healthy female Sri Lankan tea workers of distinct ethnicity from the schoolgirls and AITD patients. DESIGN: Sri Lankan schoolgirls (n = 282) and adult female tea estate workers (n = 208) were examined for thyroid autoimmune markers. Sera with high TgAb (> 98 kIU/l) were selected from these two groups (n = 36 and 45, respectively) to study epitope-binding patterns. We also examined the sera from 16 AITD patients attending a thyroid clinic in Colombo, 16 patients with AITD from the thyroid clinic at the University Hospital of Wales and 16 sera from healthy control UK women with no evidence of thyroid disease. To determine the epitopes on Tg recognized by the subjects' TgAb, we employed a panel of Tg mouse monoclonal antibodies labelled with alkaline phosphatase in a competitive enzyme-linked immunosorbent assay reaction with the subjects' serum. RESULTS AND CONCLUSIONS: A majority of the Sri Lankan schoolgirls did not react with the immunodominant epitopes and did not differ significantly from healthy subjects from the UK in their Tg epitope recognition pattern. On the other hand, tea estate workers and Sri Lankan AITD patients recognized typical autoimmune thyroid disease epitopes and, in addition, recognized a separate cluster not previously associated with either the autoimmune state or the healthy state. The significance of this cluster requires further clarification.

Thyroglobulin: current aspects of its role in autoimmune thyroid disease and thyroid cancer.

Thyroglobulin (Tg) is a large glycoprotein (molecular weight: 660000) with 2 polypeptide chains of approximately 2768 amino acids each. It functions both as a pro-hormone and storage hormone for thyroid hormones. The complete Tg gene sequence has been determined for human, rat and bovine species. Tg is one of the thyroid autoantigens recognised in patients with autoimmune thyroid disease (AITD). Antibodies to Tg (TgAb) are present in the serum of patients with AITD and are also sometimes present in healthy euthyroid subjects. Though at least 40 antigenic epitopes on human Tg have been identified, only 2 or 3 of these bind TgAb. Epitope mapping studies suggest that TgAb in AITD patients express a restricted binding pattern while TgAb in the serum of healthy individuals do not show such specific binding. There is evidence to suggest that iodination of Tg may alter these epitope binding patterns. TgAb IgG on the other hand, do not appear to be subclass restricted. Several Tg fragments capable of inducing a T-cell response have been described. Tg is routinely used in the postoperative monitoring of patients with differentiated thyroid cancer. Its use has been limited by problems with assay methods which include poor inter-laboratory standardisation, poor inter-assay variation, low functional sensitivity of the assays, hook effects, and interference from TgAb present in patients serum. The use of rh-TSH in stimulating Tg prior to testing has improved the sensitivity of Tg values in the suppressed state.

Complement activation in postpartum thyroiditis.

BACKGROUND: Postpartum thyroid dysfunction (PPTD) develops in 50% of pregnant women who have raised levels of circulating thyroid peroxidase autoantibodies (TPOAb) at booking. Although these antibodies are able to activate the complement cascade in vitro, it is not known whether complement activation plays any role in the pathogenesis of this disease. AIM: To investigate potential and actual activation of the complement system in women with postpartum thyroiditis. DESIGN: Complement activation was monitored on a weekly basis in 24 postpartum women who had raised TPOAb at 16 weeks gestation, attending an antenatal clinic in Mid-Glamorgan, Wales. METHODS: ELISA procedures were used to measure both in-vitro complement C3 activation by TPOAb and circulating terminal complement complexes (TCC) in serum. RESULTS: Higher levels of bioactive TPOAb activity were seen in women who developed PPTD when compared to those who did not. However, TCC remained undetectable in serum throughout the period of study. CONCLUSIONS: In PPTD, despite the presence of circulating bioactive TPOAbs, the extent of complement activation is inadequate to cause detectable increases in peripheral blood TCC, suggesting that the complement system may not play a major role in PPTD pathogenesis.