Hyperthyroidism is a clinical situation where there is excess thyroid hormones in the circulation due to increased synthesis of hormone from a hyperactive thyroid gland. Common causes are Graves’ disease, toxic multinodular goitre and toxic solitary nodule. Excess thyroid hormones in the circulation are also found in thyroiditis (hormone leakage) and excess exogenous thyroxine intake. Thyrotoxicosis is the term applied when there is excess thyroid hormone in the circulation due to any cause. Thyrotoxicosis can be easily diagnosed by high serum level of thyroxine (T4) and triiodothyronine (T3) and low serum level of thyroid stimulating hormone (TSH). Hyperthyroidism is confirmed by high isotope (I 131 or Tc99) uptake by the thyroid gland, while in thyroiditis it will be low. Treatment of hyperthyroidism depends on the underlying cause. Antithyroid drugs, 1131 therapy and surgery are the options of treatment of hyperthyroidism. Surgery is the preferred treatment for toxic adenoma and toxic multinodular goitre, while 1131 therapy may be suitable in some cases. Antithyroid drugs and 1131 therapy are mostly preferred for Graves’ disease. Beta-adrenergic blockers are used for symptomatic relief in most patients of thyrotoxicosis due to any cause. Other rare causes of hyperthyroidism like, amiodarone induced thyrotoxicosis, choriocarcinoma, thyrotropin secreting pituitary tumour are difficult to diagnose as well as to treat.
J Indian Med Assoc. 2006 Oct;104(10):563-4, 566-7
Autoimmune thyroid diseases.
PURPOSE OF REVIEW: Interesting clinical and basic studies have been published in the field of autoimmune thyroiditis (represented by Graves’ disease and Hashimoto’s thyroiditis) since January 2005. The review is organized into four main areas: genetics, environment, adaptive immune system, and innate immune system. RECENT FINDINGS: The quest continues for the identification of susceptibility genes for autoimmune thyroiditis. In addition to the classical major histocompatibility complex class II genes and cytotoxic T cell antigen-4, new studies have appeared on CD40 the protein tyrosine phosphatase-22. Too much iodine increases the incidence of Hashimoto’s thyroiditis, perhaps by augmenting the antigenicity of thyroglobulin. T regulatory cells, Toll-like receptors and presentation of lipid antigens by CD1 molecules are new areas of basic immunological investigation that have been applied to autoimmune thyroiditis. SUMMARY: Overall, the studies have greatly expanded our understanding of the pathogenesis of thyroiditis. They have opened new lines of investigations that will ultimately result in a better clinical practice.
Curr Opin Rheumatol. 2007 Jan;19(1):44-8
Muscle carnitine in hypo- and hyperthyroidism.
Weakness is common in both hyper- and hypothyroidism, and skeletal muscle L-carnitine may play a role in this regard, as suggested by studies indicating abnormal levels of carnitine in serum and urine of patients with thyroid dysfunction. Skeletal muscle samples were obtained for carnitine analysis from control subjects, and from hyperthyroid and hypothyroid patients before and after treatment. There was a significant reduction in carnitine, especially the esterified portion, in hyperthyroid individuals, with a return to normal as euthyroid status was regained. In hypothyroid patients, there was a trend for carnitine to be lower than normal and for improvement once euthyroid status was attained. Our data indicate that muscle carnitine levels are affected by both hypo- and hyperthyroidism. A decrease in muscle carnitine in both conditions may contribute to thyroid myopathy.
Muscle Nerve. 2005 Sep;32(3):357-9
Thyrotoxicosis and thyroid storm.
Thyroid storm represents the extreme manifestation of thyrotoxicosis as a true endocrine emergency. Although Grave’s disease is the most common underlying disorder in thyroid storm, there is usually a precipitating event or condition that transform the patient into life-threatening thyrotoxicosis. Treatment of thyroid storm involves decreasing new hormone synthesis, inhibiting the release of thyroid hormone, and blocking the peripheral effects of thyroid hormone. This multidrug, therapeutic approach uses thionamides, iodine, beta-adrenergic receptor antagonists, corticosteroids in certain circumstances, and supportive therapy. Certain conditions may warrant the use of alternative therapy with cholestyramine, lithium carbonate, or potassium perchlorate. After the critical illness of thyroid storm subsides, definitive treatment of the underlying thyrotoxicosis can be planned.
Endocrinol Metab Clin North Am. 2006 Dec;35(4):663-86
Carnitine is a naturally occurring inhibitor of thyroid hormone nuclear uptake.
Carnitine (3-hydroxy-4N-trimethylammoniumbutanoate) is a naturally occurring quaternary amine that is ubiquitous in mammalian tissues (concentrations in the order of mM). Based on limited studies of approximately 40 years ago, carnitine was considered to be a peripheral antagonist of thyroid hormone (TH) action. These interesting observations have not been explored. To study the biologic basis of this effect, we tested the following possibilities in three TH-responsive cell lines: (1) inhibition of TH entry into cells; (2) inhibition of TH entry into the nucleus; (3) inhibition of TH interaction with the isolated nuclei; and (4) facilitated efflux of TH from cells. On a preliminary basis we had verified that these cell lines (human skin fibroblasts, human hepatoma cells HepG2, and mouse neuroblastoma cells NB 41A3) take up 14Ccarnitine; however, there was no 14Ccarnitine uptake into the nuclei. Concentrations of unlabeled carnitine as high as 100 mM did not affect (125I)T3 binding to isolated nuclei or exit of TH from cells, thus excluding possibilities numbered 3 and 4. At 10 mM camitine, (125I)T3 and (125I)T4 whole-cell uptake was inhibited by approximately 20% in fibroblasts and in HepG2, but by approximately 5% in NB 41A3 cells. Inhibition of T3 nuclear uptake was evaluated in HepG2 and NB 41A3 cells. At 10 mM carnitine, inhibition of T3 nuclear uptake was disproportionately higher, namely approximately 25% in neurons and 35% in hepatocytes. At 50 mM carnitine, there was a minimal additional decrease in whole-cell uptake of either hormone but a marked decrease in T3 nuclear uptake. The latter inhibition was approximately 60% in neurons and 70% in hepatocytes. We are aware of no inhibitor of TH uptake that has such a markedly different effect on the nuclear versus whole-cell uptake. Our data are consistent with carnitine being a peripheral antagonist of TH action, and they indicate a site of inhibition at or before the nuclear envelope.
Thyroid. 2000 Dec;10(12):1043-50
Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial.
Old studies in animals and unblinded studies in a few hyperthyroid patients suggested that L -carnitine is a periferal antagonist of thyroid hormone action at least in some tissues. This conclusion was substantiated by our recent observation that carnitine inhibits thyroid hormone entry into the nucleus of hepatocytes, neurons, and fibroblasts. In the randomized, double-blind, placebo-controlled 6-month trial reported here, we assessed whether 2 or 4 g/d oral L-carnitine were able to both reverse and prevent/minimize nine hyperthyroidism- related symptoms. We also evaluated changes on nine thyroid hormone-sensitive biochemical parameters and on vertebral and hip mineral density (bone mineral density). Fifty women under a fixed TSH-suppressive dose of L -T(4) for all 6 months were randomly allocated to five groups of 10 subjects each. Group 0 associated placebo for 6 months; groups A2 and A4 started associating placebo (first bimester), substituted placebo with 2 or 4 g/d carnitine (second bimester), and then returned to the association with placebo. Groups B2 and B4 started associating 2 and 4 g/d carnitine for the first two bimesters, and then substituted carnitine with placebo (third bimester). Symptoms and biochemical parameters worsened in group 0. In group A, symptoms and biochemical parameters worsened during the first bimester, returned to baseline or increased minimally during the second bimester (except osteocalcin and urinary OH-proline), and worsened again in the third bimester. In group B, symptoms and biochemical parameters (except osteocalcin and urinary OH-proline) did not worsen or even improved over the first 4 months; they tended to worsen in the third bimester. In both the A and B groups, the two doses of carnitine were similarly effective. At the end of the trial, bone mineral density tended to increase in groups B and A (B > A). In conclusion, L-carnitine is effective in both reversing and preventing symptoms of hyperthyroidism and has a beneficial effect on bone mineralization. Because hyperthyroidism depletes the body deposits of carnitine and since carnitine has no toxicity, teratogenicity, contraindications and interactions with drugs, carnitine can be of clinical use.
J Clin Endocrinol Metab. 2001 Aug;86(8):3579-94
Effects of carnitine on thyroid hormone action.
By experiments on cells (neurons, hepatocytes, and fibroblasts) that are targets for thyroid hormones and a randomized clinical trial on iatrogenic hyperthyroidism, we validated the concept that L-carnitine is a peripheral antagonist of thyroid hormone action. In particular, L-carnitine inhibits both triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei. This is relevant because thyroid hormone action is mainly mediated by specific nuclear receptors. In the randomized trial, we showed that 2 and 4 grams per day of oral L-carnitine are capable of reversing hyperthyroid symptoms (and biochemical changes in the hyperthyroid direction) as well as preventing (or minimizing) the appearance of hyperthyroid symptoms (or biochemical changes in the hyperthyroid direction). It is noteworthy that some biochemical parameters (thyrotropin and urine hydroxyproline) were refractory to the L-carnitine inhibition of thyroid hormone action, while osteocalcin changed in the hyperthyroid direction, but with a beneficial end result on bone. A very recent clinical observation proved the usefulness of L-carnitine in the most serious form of hyperthyroidism: thyroid storm. Since hyperthyroidism impoverishes the tissue deposits of carnitine, there is a rationale for using L-carnitine at least in certain clinical settings.
Ann N Y Acad Sci. 2004 Nov;1033:158-67
Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies.
PURPOSE: To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer. PATIENTS AND METHODS: Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks. RESULTS: Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m(2). Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m(2). No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m(2) and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m(2). Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma. CONCLUSION: Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m(2) without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.
J Clin Oncol. 2005 Nov 1;23(31):7871-80