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OBJECTIVE - New in vivo mutations in G protein-coupled receptors open opportunities for insights into the mechanism of receptor activation. Here we describe the molecular mechanism of constitutive TSH receptor (TSHR) activation in an Austrian family with three generations of familial nonautoimmune hyperthyroidism.
PATIENTS - The index patient was diagnosed with hyperthyroidism during her first pregnancy. Her first two children were diagnosed with hyperthyroidism at the age of 11 and 10 years, respectively. TSH suppression was also observed in the third child at the age of 8 years, who has normal free T4 levels until now. TSH suppression in infancy was observed in the fourth child. The mother of the index patient was diagnosed with toxic multinodular goiter at the age of 36 years.
METHODS - DNA was extracted from blood samples from the index patient, her mother, and her four children. Screening for TSHR mutations was performed by high-resolution melting assays and subsequent sequencing. Elucidation of the underlying mechanism of TSHR activation was carried out by generation and structural analysis of TSHR transmembrane homology models and verification of model predictions by functional characterization of receptor mutations.
RESULTS AND CONCLUSIONS - A newly discovered TSHR mutation L665F in transmembrane helix 7 of the receptor was detected in six members of this family. Functional characterization of L665F revealed constitutive activation for the Gs pathway and thus represents the molecular cause for hyperthyroidism in this family. The constitutive activation is possibly linked to a steric clash introduced by the L665F mutation between transmembrane helices 1 and 7.
BACKGROUND - Potassium iodide (KI) has traditionally been used to reduce gland vascularity and diminish blood loss in patients undergoing thyroidectomy for Graves disease (GD). Current American Thyroid Association (ATA) guidelines (Recommendation 22) call for its routine administration in GD but avoidance in toxic multinodular goiter (TMNG).
METHODS - A retrospective review (July 2008-May 2012) of perioperative data was performed on 162 patients undergoing total thyroidectomy without preoperative KI and compared to 102 patients with TMNG. Statistical analysis included Student's t test, χ2 test, and multivariate linear regression.
RESULTS - Compared to TMNG patients, GD patients had a lower mean age (42.7 vs. 49.6 years, p<0.001) and were less likely to be obese (37 vs. 54%, p=0.047). No patients were provided KI in preparation. GD patients did not differ significantly from TMNG patients with respect to mean estimated blood loss (55.4 vs. 51.5 mL, p=0.773) or mean operative time (131.5 vs. 122.6 min, p=0.084). GD patients had a lower rate of transient hypocalcemia (31 vs. 49%, p=0.004), but the two groups did not statistically differ in rates of prolonged hypocalcemia, temporary recurrent laryngeal nerve (RLN) palsy, prolonged RLN paralysis, or hematoma formation.
CONCLUSIONS - Although current ATA recommendations for the management of GD call for routine use of KI before thyroidectomy, this large series demonstrates no appreciable detriment to patient outcomes when this goal is not met.
BACKGROUND - Recent American Thyroid Association guidelines call for thyroidectomy or (131)I (Recommendation 31) in managing hyperthyroidism due to toxic nodular goiter (TNG). Concern for concomitant malignancy favors surgery. A 3 % thyroid cancer incidence in TNG patients has been reported, yet recent studies suggest this rate is underestimated. This multi-institutional study examined cancer incidence in TNG patients referred to surgery.
METHODS - Patients referred for thyroidectomy at three tertiary-care institutions were included (2002-2011). Patients with concurrent indeterminate or malignant diagnosis by fine-needle aspiration (FNA) were excluded. Cancer incidence in TNG patients was determined. Fisher's exact and chi-square tests and nonparametric t tests were used.
RESULTS - Among 2,551 surgically treated patients, 164 had TNG (6.4 %). Median age at presentation was 49.7 years, and 86 % were female. Overall cancer incidence was 18.3 % (30 of 164), and rates were not significantly different between institutions. A significantly greater cancer rate was noted in toxic multinodular goiter versus single toxic nodule patients (21 vs. 4.5 %, P < 0.05). Mean tumor size was 0.71 cm (range 0.1-1.5 cm; 23 % ≥1 cm). Most patients underwent total or near-total thyroidectomy. There were no significant differences in tumor sizes among institutions (P > 0.05). No significant cancer association was noted with age, preoperative dominant nodule size, lymphocytic thyroiditis or preoperative FNA (P > 0.05).
CONCLUSIONS - These data demonstrate a higher than expected incidental cancer rate in TNG patients compared to historical reports (18.3 vs. 3 %). This higher cancer incidence may alter the risk/benefit analysis regarding TNG treatment. This information should be provided to TNG patients before decision making regarding treatment.