Coincidence of multiple endocrine neoplasia types 1 and 2: mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism.

CONTEXT: Primary hyperparathyroidism (HPT) presents as a part of inherited syndromes such as multiple endocrine neoplasia (MEN) types 1 and 2. In patients with MEN1, parathyroid hyperplasia or multiple adenomas occur in approximately 90-95%. MEN2A-related HPT is characterized by a mild hypercalcemia, which is mostly asymptomatic. OBJECTIVE: Here we present a family with coexistence of MEN1 gene mutation and RET mutation. RESULTS: Six family members carrying MEN1 gene mutation IVS5 + 1G>A only, one family member with RET mutation Y791F, and three family members with both MEN1 gene and RET mutation were studied. The key to diagnosis was recurrent HPT in a young male carrying RET mutation Y791F, a mutation not likely to give rise to recurrent HPT. CONCLUSION: MEN1 gene mutation and RET codon 791 mutation in the same patient did not affect the typical phenotype of MEN1 or MEN2, and also the course of diseases seems to be unchanged. The reason may be that both mutations, although contributing to tumor pathogenesis, do not interact and induce a worsening of the cancer syndromes.

Reference intervals of serum thyroid function tests in a previously iodine-deficient area.

AIM: We undertook the present study to establish reference data for serum thyroid function tests in a previously iodine-deficient area. METHODS: Data from 4298 individuals, 20-79 years of age were available for the present analysis. Thyroid function (thyrotropin [TSH], free triiodothyronine [FT(3)], and free thyroxine [FT(4)]) and serum autoantibodies to thyroperoxidase (anti-TPOAb) were evaluated from blood samples. Thyroid structure and size were measured by ultrasound. RESULTS: A reference population was selected comprising 1488 persons (825 men) by excluding subjects with known thyroid diseases, and with yet unknown thyroid disorders such as goitre, inhomogeneous thyroid pattern, nodules, hypoechogenicity and anti-TPOAb seropositivity. Reference intervals for serum TSH, FT(3), and FT(4) were 0.25-2.12 mIU/L, 3.8-7.0 pmol/L, and 8.3-18.9 pmol/L, respectively. Reference serum TSH levels were not comparable to the reference values that were recently established for the U.S. population and most reference values slightly differed from the reference values provided by the manufacturers. CONCLUSIONS: The reference ranges of thyroid function tests in this formerly iodine-deficient region are distinct from the reference ranges that were established in areas with iodine sufficiency. Creating a reference population in the present setting should include thyroid ultrasound in order to exclude yet undiagnosed thyroid disorders.

The association of thyroid function with cardiac mass and left ventricular hypertrophy.

Decreased serum TSH levels predict cardiovascular mortality, which could be explained by left ventricular hypertrophy (LVH). The aim of this analysis was to investigate the association between thyroid function and LVH. The population-based Study of Health in Pomerania was conducted in a previously iodine-deficient area. Data of 1510 individuals at least 45 yr of age with echocardiography and without thyroid disorders were analyzed. LVH was defined as a left ventricular mass index (LVMI) exceeding 150 g/m(2) (men) or 120 g/m(2) (women). Overt hyperthyroidism was associated with LVMI (P < 0.01), whereas euthyroid subjects and those with elevated TSH levels did not significantly differ with regard to LVMI. LVH was observed in three (15.0%) subjects with elevated serum TSH levels, in 127 (10.5%) euthyroid persons, in 24 (12.5%) individuals with decreased serum TSH levels, and in four (57.1%) subjects with hyperthyroidism (P < 0.01). Logistic regression analysis identified overt hyperthyroidism as an independent risk factor for LVH (odds ratio, 13.65; 95% confidence interval, 2.83-65.75; P < 0.01). There is an association between thyroid function status, cardiac mass, and LVH. Hyperthyroidism is an independent risk factor for LVH.

[Carl Adolph von Basedow--150th anniversary of his death]. / Carl Adolph von Basedow-- Zu seinem 150. Todestag.

Carl Adolph von Basedow was the son of an aristocratic family and was born 1799 in Dessau. He was the grandson of the famous pedagogue Johann Bernhard Basedow. He studied medicine at the university of Halle and spent two years in the surgical service of Paris hospitals--the Charité and the Hôtel Dieu. In 1822, he settled in Merseburg as a physician. He was soon acclaimed as a genial and skilled helper in all branches of medical practice. He performed his own post-mortem examinations and published findings on a number of different diseases. His famous contribution in the thyroid field appeared in 1840 entitled "Exophthalmos due to hypertrophy of the cellular tissue in the orbit". Exophthalmos, goiter and palpitation of the heart have become known as the Merseburg Triad. In 1848, he published the autopsy findings on a patient who died from "exophthalmic cachexia". In Germany and some other countries, the disease was named as Morbus Basedow since 1858. In 1854 he pricked in his finger in the postmortem room when examining a patient who had died of typhus and he succumbed to septicemia at the early age of fifty-five. The date of his death was April 11, 1854. On April 14, he was laid in the Sixtus Cemetery in Merseburg. Basedow postulated that a wrong mixing of the blood manifested in cell tissue congestion and glandular vegetation cause the manifestations of disease. If we abstract our modern knowledge and accept circulating antibodies and disturbance of the immune balance as a dyscrasia as well as the proliferation of lymphocytic clones and local cellulary infiltration in terms of immune thyroiditis and autoimmune orbitopathy as cell tissue congestion and glandular vegetations, then doubt arise whether we have indeed made much progress in the last 150 years. At least, respect for the genius of the general physician Carl Adolph von Basedow is becoming greater. We may all hope that in the contributions and the discussions, we shall learn where we stand at the end of the century and what new avenues of research are appearing on the horizon.

Thyroid function and carotid wall thickness.

Decreased serum TSH levels predict vascular mortality in older people. There is a need to investigate mechanisms that could explain this association. This study was designed to investigate the relationship between thyroid function and the carotid intima-media thickness (IMT). The Study of Health in Pomerania is a population-based survey in Germany. Data from 2086 individuals at least 45 yr old with carotid ultrasound and without known thyroid disorders were analyzed. Twenty-nine participants (1.4%) had elevated serum TSH levels, 300 (14.4%) had decreased serum TSH levels, and 12 (0.6%) participants were hyperthyroid. A linear relationship between thyroid function and IMT was found. The highest IMT values were observed in participants with hyperthyroidism, the lowest in subjects with elevated serum TSH levels (P < 0.01). A multivariable regression analysis identified thyroid function as an independent risk factor for increased IMT. Other risk factors for increased IMT included male gender, advanced age, diabetes mellitus, current smoking, and the use of antihypertensive medication; increased pulse pressure, serum low-density cholesterol, and total cholesterol/high-density lipoprotein ratio; as well as a decreased heart rate and a positive history of myocardial infarction. We conclude that there is an independent association between thyroid function and the IMT of the carotid artery.

The prevalence of undiagnosed thyroid disorders in a previously iodine-deficient area.

OBJECTIVE: The aim of the present study was to analyze the current status of morphologic and functional thyroid abnormalities in a previously iodine-deficient area. METHODS: The population based Study of Health in Pomerania (SHIP) comprised 4310 participants, aged 20-79 years. Thyroid function (thyrotropin [TSH] free triiodothyronine [FT(3)], and free thyroxine [FT(4)]) and serum autoantibodies to thyroperoxidase (TPOAb) were evaluated from blood samples. Thyroid structure and size were measured by ultrasound. Data from 3941 participants with no known thyroid disorders were analyzed. RESULTS: The median iodine urine excretion was 12.4 microg/dL. The rate of decreased serum TSH levels (<0.3 mIU/L) was 11.3%; 2.2% of participants had suppressed serum TSH levels (<0.1 mIU/L). The prevalence of subclinical hyperthyroidism was 1.8%, the prevalence of overt hyperthyroidism 0.4%. Elevated TSH levels were found in 1.2% of individuals. Subclinical hypothyroidism was observed in 0.5%, overt hypothyroidism in 0.7% of the sample. Elevated TPOAb were detected in 7% of subjects, 4.1% of participants had TPOAb greater than 200 IU/mL. The prevalence of goiter was 35.9%. An inhomogeneous echo pattern was detected in 35.2% and nodules in 20.2% of participants. Diffuse autoimmune thyroiditis was diagnosed in 47 subjects (1.2%). CONCLUSION: There are a number of thyroid disorders in this previously iodine-deficient region. Further studies are required to investigate the change of thyroid disorders during iodine supplementation programs.

Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition.

OBJECTIVE: Thyroid function alters the pharmacokinetics of many drugs; one example is the cardiac glycoside digoxin. Because digoxin disposition is affected by intestinal expression of P-glycoprotein, we hypothesized that thyroid hormones may regulate P-glycoprotein and influence disposition of P-glycoprotein substrates. METHODS: Duodenal expression of P-glycoprotein measured by reverse transcriptase-polymerase chain reaction of MDR1 messenger ribonucleic acid (mRNA) and by immunohistochemical examination was studied in 8 healthy volunteers (4 men and 4 women; age range, 22-29 years; body weight, 59-89 kg) before and after coadministration with levothyroxine (200 microg orally for 17 days), which resulted in suppression of thyroid-stimulating hormone. The pharmacokinetics of the P-glycoprotein substrate talinolol was assessed after intravenous (30 mg) and oral (100 mg) administration. RESULTS: Duodenal MDR1 mRNA expression and immunoreactive P-glycoprotein were increased 1.4-fold (not significant; P =.078) and 3.8-fold (P <.01), respectively, after administration of levothyroxine. The changes in P-glycoprotein expression were associated with minor alterations in talinolol half-life after both oral and intravenous administration. CONCLUSIONS: Expression of intestinal P-glycoprotein in humans appears to be influenced by thyroid hormones. The functional consequences need to be addressed in patients with hyperthyroidism.

Relapse of Graves' disease after successful outcome of antithyroid drug therapy: results of a prospective randomized study on the use of levothyroxine.

Antithyroid drugs are effective in restoring euthyroidism in Graves' disease, but many patients experience relapse after withdrawal. Prevention of recurrence would therefore be a desirable goal. In a prospective study, patients with successful outcome of 12 to 15 months antithyroid drug therapy were stratified for risk factors and randomly assigned to receive levothyroxine in a variable thyrotropin (TSH)-suppressive dose for 2 years or no treatment. The levothyroxine group was randomized to continue or discontinue levothyroxine after 1 year. End points included relapse of overt hyperthyroidism. Of 346 patients with Graves' disease enrolled 225 were euthyroid 4 weeks after antithyroid drug withdrawal and were randomly assigned to receive levothyroxine (114 patients) or no treatment (controls, 111 patients). Of those not randomized, 39 patients showed early relapse within 4 weeks, 61 endogenous TSH suppression, 7 TSH elevation, and 14 had to be excluded. Dropout rate during the study were 13.3%. Kaplan-Meier analyses showed relapse rates to be similar in the levothyroxine group (20% after 1 year, 32% after 2 years) and the randomized controls (18%, 24%), whereas relapses were significantly more frequent in the follow-up group of patients with endogenously suppressed TSH (33%, 49%). Levothyroxine therapy did not influence TSH-receptor antibody, nor did it reduce goiter size. The best prognostic marker available was basal TSH determined 4 weeks after withdrawal of antithyroid drugs (posttreatment TSH). The study demonstrates that levothyroxine does not prevent relapse of hyperthyroidism after successful restoration of euthyroid function by antithyroid drugs and characterizes posttreatment TSH as a main prognostic marker.