Elevated Free Thyroid Hormone Levels Research Articles

Thyroid hormone resistance without mutations in thyroid hormone receptor beta

Resistance to thyroid hormone (RTH) is a rare autosomal dominant disorder that leads to elevated free thyroid hormone levels in the presence of normal or increased serum thyroid-stimulating hormone (TSH) concentrations if it is generalized because both the pituitary and peripheral tissues are then partially resistant. In approximately 85% of patients with RTH, mutations in the thyroid hormone receptor beta (TR beta) gene can be identified. A 68-year-old German man presented for surgical hernia repair. He was found to have elevated free T3 and T4 plasma concentrations in coexistence with goiter, unsuppressed TSH, arterial hypertension, and arthritis urica/gout. An electrocardiogram showed a normal sinus rhythm with 69 beats per minute. There were neither signs or symptoms of hyper- or hypothyroidism nor psychological abnormalities. Generalized RTH was suspected. Generalized RTH should be considered in patients presenting with elevated free thyroid hormone levels and normal or increased TSH concentrations, especially if these patients appear clinically euthyroid. Signs and symptoms of hyper- and hypothyroidism should be evaluated to assure that these patients are candidates for surgical procedures such as hernia repair. Subsequent mutation analysis of the TR beta gene should be conducted to help identify family members. In approximately 15% of patients, mutations in the TR beta gene cannot be identified and raise the possibility of mosaicism.

Treatment of thyrotoxicosis

Thyrotoxicosis is the clinical syndrome resulting from excess circulating free thyroxine (free-T4) and/or free tri-iodothyronine (free-T3) (Figure 1). Thyrotoxicosis is common, with a lifetime incidence of about 2% in women and 0.2% in men. The diagnosis is usually confirmed by the finding of a suppressed serum thyroid stimulating hormone (TSH) concentration in the presence of elevated free thyroid hormone levels. Because free-T3 concentration tends to rise before free-T4, ‘T3 toxicosis’ (elevated free-T3, but normal free-T4) is often the earliest phase of any form of thyrotoxicosis.

Antithyroid therapy improves bony manifestations and bone metabolic markers in patients with Graves' thyrotoxicosis.

Abnormal bone metabolism in patients with Graves' thyrotoxicosis is well documented, but the precise time-course of its recovery remains poorly understood. The present study was undertaken to clarify longitudinal improvement in bony manifestations, especially in cortical bone, and bone metabolic markers in thyrotoxicosis. Two year prospective follow-up study in patients with Graves' disease. Ten consecutive patients with Graves' disease (seven males and three females, of mean (+/-SEM) age 39.3 +/- 3.9 years) were enrolled in the study and treated with antithyroid drugs. Thirteen sex- and age-matched patients with the disease in remission served as controls. Bony manifestations were evaluated both by fine cortical bone striations in the metacarpals on magnified roentgenograms and lumbar bone mineral density (BMD) measurement. Urinary deoxypyridinoline (dPYR) and serum pyridinoline cross-linked telopeptide domain of type I collagen (ICTP) were monitored as markers of bone resorption, as well as serum osteocalcin (OC), carboxy-terminal propeptide of type I procollagen (PICP) and alkaline-phosphatase (ALP) as markers of bone formation. Initial elevated free thyroid hormone levels were normalized within a month of starting therapy. Striation indices of the metacarpals were 1.89 +/- 0.16 before therapy, higher than those of 0.49 +/- 0.12 in the controls (P < 0.0001); the indices gradually decreased to 1.00 +/- 0.20 (12 months) and 0.48 +/- 0.12 (24 months). Lumbar BMD Z-scores increased from -0.22 +/- 0.46 to 0.21 +/- 0.47 (12 months) and 0.68 +/- 0.48 (24 months) (P = 0.0029). Before therapy, urinary dPYR and serum ICTP concentrations were much higher than the control values (dPYR, +553%; ICTP, -396%, P < 0.0001), which declined promptly in the 2nd month. Serum OC, PICP and ALP were also significantly higher than in controls at first (OC, +287%; PICP, +225%; ALP, +196%), and remained elevated until 4 or 8 months. Bone resorption and cortical bone striations occur in untreated patients with Graves' thyrotoxicosis. The bone resorption rapidly ameliorates after normalization of thyroid hormone levels. In contrast, the accelerated bone formation persists for at least 4-8 months, suggesting positive uncoupling of bone remodelling. This dominant bone formation could result in the improvement in cortical bone striations and the increase in bone mineral density of trabecular bone.

Thyroid Nodules in Pregnancy

Thyroid nodules are common in pregnant women. Most of them are benign. Toxic autonomous nodules may be seen infrequently, and the diagnosis is supported by elevated free thyroid hormone levels and undetectable levels of TSH. The most common and most important problem is the diagnosis of thyroid cancer. FNB is the most reliable diagnostic tool. FNB findings also can be used to indicate the urgency for surgery and the appropriate extent of the operation when surgery is indicated. Best use of FNB data requires that the cytopathologist provide tissue diagnoses and that there has been enough experience to permit reasonable inferences of cancer probability for each diagnosis.

Thyroid hormone resistance syndrome. Inhibition of normal receptor function by mutant thyroid hormone receptors.

Thyroid hormone (T3) resistance is inherited in most cases in an autosomal dominant manner. The disorder is characterized by elevated free thyroid hormone levels and partial resistance to thyroid hormone at the cellular level. Distinct single amino acid substitutions in the ligand binding domain of the beta form of the thyroid hormone receptor have been described in two kindreds with this disorder. We used transient expression assays to characterize the functional properties of these receptor mutants, one containing a Gly to Arg change at amino acid 340 (G340R) and the other a Pro to His change at amino acid 448 (P448H). A nine amino acid carboxy terminal deletion (delta 448-456), analogous to an alteration that occurs in v-erbA, was also studied for comparison with the mutations that occur in the T3 resistance syndrome. None of the receptor mutants were able to mediate thyroid hormone dependent activation (TreTKCAT) or repression (TSH alpha CAT) of reporter genes when compared with the wild type receptor. In addition, the mutants inhibited the activity of normal alpha and beta receptor isoforms when examined in coexpression assays. This activity, referred to as dominant negative inhibition, was manifest with respect to both the positively and negatively regulated reporter genes. Although mutant receptor binding to DNA was unaffected, ligand binding studies showed that the G340R and delta 448-456 mutants failed to bind T3, whereas the P448H mutant bound hormone with reduced affinity (approximately 10% of normal) compared to the wild type receptor. Consistent with this finding, the P448H mutant receptor was partially active at higher T3 concentrations. Furthermore, the dominant negative inhibition elicited by the P448H receptor mutant at higher T3 concentrations was reversed in the presence of high doses of T3. These findings indicate that mutant beta receptors in patients with thyroid hormone resistance have reduced affinity for T3 and are functionally deficient, but impair the activity of normal receptors, thereby providing a mechanism for the dominant mode of inheritance in this disorder.