Rebecca S Bahn

Mayo Clinic - Rochester, Рочестер, Minnesota, United States

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Publications (145)757.74 Total impact


  • No preview · Article · Jan 2016 · Endocrine Practice
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    ABSTRACT: Context: The best treatment option for patients with Graves Disease (GD) depends on each person's situation and how the differences between the treatment options matter to them in bringing resolution to their illness. Our objective was to develop and test an encounter decision tool (GD Choice) for patients and clinicians to engage in shared decision making about the treatment of GD Methods: GD Choice was developed using an iterative process based on the principles of interaction design and participatory action research. To evaluate the impact of the tool we conducted a controlled before-and-after study assessing the use of GD Choice vs. usual care (UC). Results: We enrolled 68 patients, 37 to UC and 31 to GD Choice. At baseline, the groups were similar. Treatment discussion length was similar in both arms. After their visit, patients in both groups had similar knowledge about the options, except for GD Choice patients knowing significantly more about the complications of treatment (correctly answered by 83% vs. 55%, p=0.04). Compared to UC, patients in the GD Choice arm had greater involvement in decision making observed on video recordings of clinical encounters (mean OPTION scale score, 35% vs. 30%, p=.02), but reported similar levels of decisional comfort and participation in shared decision making. Conclusions: GD Choice increases engagement in the decision-making process and knowledge regarding intervention complications without increasing the length of consultation. These promising results support the conduct of a randomized trial of GD choice vs. UC in a large multicenter trial. Clinical trial registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02107794.
    No preview · Article · Sep 2015 · Thyroid: official journal of the American Thyroid Association
  • R S Bahn
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    ABSTRACT: Environmental, genetic, and immune factors are at play in the development of the variable clinical manifestations of Graves' ophthalmopathy (GO). Among the environmental contributions, smoking is the risk factor most consistently linked to the development or worsening of the disease. The close temporal relationship between the diagnoses of Graves' hyperthyroidism and GO have long suggested that these 2 autoimmune conditions may share pathophysiologic features. The finding that the thyrotropin receptor (TSHR) is expressed in orbital fibroblasts, the target cells in GO, supported the notion of a common autoantigen. Both cellular and humeral immunity directed against TSHR expressed on orbital fibroblasts likely initiate the disease process. Activation of helper T cells recognizing TSHR peptides and ligation of TSHR by TRAb lead to the secretion of inflammatory cytokines and chemokines, and enhanced hyaluronic acid (HA) production and adipogenesis. The resulting connective tissue remodeling results in varying degrees extraocular muscle enlargement and orbital fat expansion. A subset of orbital fibroblasts express CD34, are bone-marrow derived, and circulate as fibrocytes that infiltrate connective tissues at sites of injury or inflammation. As these express high levels of TSHR and are capable of producing copious cytokines and chemokines, they may represent an orbital fibroblast population that plays a central role in GO development. In addition to TSHR, orbital fibroblasts from patients with GO express high levels of IGF-1R. Recent studies suggest that these receptors engage in cross-talk induced by TSHR ligation to synergistically enhance TSHR signaling, HA production, and the secretion of inflammatory mediators.
    No preview · Article · Sep 2015 · Hormone and Metabolic Research
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    ABSTRACT: Activation of thyrotropin receptor (TSHR) and/or insulin-like growth factor (IGF-1) receptor (IGF-1R) enhances HA production and adipogenesis in orbital fibroblasts from patients with Graves' ophthalmopathy (GO) and recapitulates the tissue remodeling characteristic of the orbit in GO. A functional relationship between TSHR and IGF-1R has long been postulated and recently bi-directional cross-talk between the receptors in GO fibroblasts was demonstrated. Because the transcription factor Forkhead box O-1 (FoxO1) was recently shown to be a critical downstream mediator of TSH and IGF-1 effects on thyrocyte proliferation, we designed studies to determine whether FoxO1 might similarly act as a common mediator of M22, a stimulatory TSHR antibody (TSAb), and IGF-1 in GO orbital fibroblasts. FOXO1 mRNA and protein were measured in orbital tissue specimens derived from normal individuals and patients with GO. In addition, we investigated the control of FoxO1 cellular localization using quantitative Western blotting of fractionated cell lysates from orbital fibroblasts treated with M22 and/or IGF-1 with or without specific TSHR, IGF-1R, or PI3K/Akt1/2 inhibitors. We found significantly lower levels of both FOXO1 mRNA and protein in GO orbital tissue specimens compared with normal orbital tissues (mean 39%; p=0.043 and 46.4%; p=0.028, respectively). In addition, treatment of GO orbital cultures with M22, IGF-1 or M22 plus IGF-1 increased cytoplasmic Fox-O1 compared with control (1.63 fold, p=0.008; 1.68, p=0.001; 1.61, p=<0.001, respectively) and decreased nuclear Fox-O1 (mean 28%, p=0.002; 38%, p=<0.001; 35%, p=0.007, respectively). These effects were inhibited by co-treatment with the respective, but not the opposite, receptor antagonist. Akt inhibition of M22 or IGF-1 treated cultures was found to increase nuclear (1.4 fold; p=0.026 and (1.3 fold; p=0.001, respectively) and decrease cytoplasmic (24.2%; p=0.001 and 36%; p=0.004, respectively) Fox-O1 localization. These data point to FoxO1 as an important mediator of TSAb and IGF-1 action via their cognate receptors in GO orbital fibroblasts. These findings provide a link between the low FoxO1 protein levels demonstrated in GO orbital tissue and the tissue remodeling characteristic of GO, and suggest novel therapy for GO aimed at increasing nuclear expression of FoxO1 in GO target cells.
    No preview · Article · Jul 2015 · Thyroid: official journal of the American Thyroid Association
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    ABSTRACT: Context: Graves' orbitopathy (GO) is a potentially sight-threatening disease for which available medical therapy is not uniformly successful. Multiple case series suggest that rituximab (RTX) may be effective therapy for GO patients. Objective: To determine the efficacy of RTX in GO. Design: It is a prospective, randomized, double-masked, placebo-controlled trial. Setting: The study was conducted at a large academic private practice. Patients: Twenty five patients with active moderate to severe GO were enrolled, and 21 completed the study to the primary endpoint. There were four adverse events (AE) in 3/12 placebo patients and 11 AE in 8/13 RTX-treated patients; 5/6 moderate or severe AE occurred in the RTX group. Interventions: Two RTX infusions (1000 mg each) or two saline infusions were given 2 weeks apart. Main Outcome Measures: The primary endpoint was a reduction in clinical activity score (CAS) assessed as a continuum and separately as improvement by ≥2 points at 24 weeks. Secondary endpoints included success and failure rates, proportions showing clinically significant improvement in proptosis, lid fissure width, diplopia score, lagophthalmos and disease severity, and changes in those parameters, orbital fat/ muscle volume and quality-of-life. Results: The treatment groups were similar in all parameters at baseline. The last observation was carried forward if the patient discontinued prematurely. No differences were found in the proportions of patients showing CAS improvement at 24 weeks (25% placebo; 31% RTX, p = 0.75) or in CAS decrease from baseline to 24 or 52 weeks [mean 1.5 points (1.8 SD) placebo; 1.2 (2 SD) RTX at 24 weeks, p = 0.73]. Similarly, there were no differences between groups in any of the secondary endpoints at either 24 or 52 weeks. Conclusion: RTX offered no additional benefit over placebo to our patients with active and moderate to severe GO and carried with it non-negligible adverse effects.
    No preview · Article · Oct 2014 · Journal of Clinical Endocrinology & Metabolism
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    ABSTRACT: Objective: The development of amiodarone-induced thyrotoxicosis (AIT) can threaten the hemodynamic stability of adult patients with congenital heart disease (CHD). We aim to describe its natural history and treatment response in this at risk population.Methods: We studied retrospectively all cases of AIT that occurred in CHD patients at our institution after a minimum of 3 months on amiodarone. They were identified from the cohort of adults with CHD who were treated at Mayo Clinic Adult CHD clinic between 1987-2009.Results: We identified 23 cases of AIT: 7 were type 1, 13 were type 2, and 3 were undefined due to insufficient data. Most patients were symptomatic (17/23, 74%) with arrhythmia and weight loss as the most common symptoms. The majority (12/23, 52%) were initially observed, 10 were treated medically (43%) and one underwent thyroidectomy (5%). Four patients from the observation group eventually required active treatment and 3 from the medical group required surgery. Asymptomatic patients tended to resolve under observation (5/7, 71.4%) rather than progress to active treatment (0/4) for p=0.06. Discontinuation of amiodarone, AIT type or use of perchlorate did not impact AIT duration.Conclusions: AIT in CHD patients exhibits a wide range of severity and sensitivity to medical therapy. Asymptomatic patients display a trend towards AIT resolution with observation alone. Amiodarone continuation does not appear to impact management outcome or disease duration. Additional studies in this high-risk population could identify elements of pathophysiology that would point towards better disease prevention and treatment.
    No preview · Article · Sep 2013 · Endocrine Practice
  • Rebecca S Bahn

    No preview · Article · Sep 2013 · Endocrinology
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    ABSTRACT: Context:Several treatment options are available for Graves' disease (GD) including antithyroid drugs (ATDs), radioactive iodine (RAI), and thyroidectomy.Objective:The primary outcome was to determine the relapse rates of various treatment options. The secondary outcome was to present data regarding adverse effects of ATDs.Data Sources:We searched multiple databases through March 2012.Study Selection:Eligible studies were randomized clinical trials (RCTs) and comparative cohort studies in adults that included two or more treatment options for GD.Data Extraction:Two reviewers independently selected studies, appraised study quality, extracted outcome data, and determined adverse effect profiles.Data Synthesis:We found 8 studies with 1402 patients from 5 continents. Mean follow up duration in months was: ATDs: 57, RAI: 64, Surgery: 59. Studies were at moderate to high risk of bias. Network meta-analysis suggested higher relapse rates with ATDs (52.7%, 352/667) than RAI (15%, 46/304) [odds ratio (OR) =6.25; 95 % confidence interval (CI), 2.40-16.67] and with ATDs than surgery (10%, 39/387) [OR=9.09; 95% CI, 4.65-19.23]. There was no significant difference in relapse between RAI and surgery. Examination of 31 cohort studies identified adverse effects of ATDs in 692/5136 (13%) patients. These were more common with methimazole, mainly owing to dermatologic complications, while hepatic effects were more common with propylthiouracil use.Conclusion:We confirm the relatively high relapse rate of ATD therapy in comparison with RAI or surgery, along with a significant side-effect profile for these drugs. These data can inform discussion between physician and patients regarding choice of therapy for GD. The limited quality of the evidence in the literature underlines the need for future RCTs in this area.
    No preview · Article · Jul 2013 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Objective Bioidentical compounded hormone therapy is popular among patients, but providers do not have pharmacokinetic information or dosing guidelines for these preparations. Our objective was to compare the pharmacokinetics of the commonly used compounded preparations with conventional hormonal preparations that are considered bioequivalent in practice.Methods We conducted a randomized, blinded, four-arm 16-day clinical trial of forty postmenopausal women assigned to one of three doses of a compounded estrogen cream (Bi-est (80:20); 2.0, 2.5, or 3.0 mg) + compounded oral progesterone 100 mg, or to a conventional estradiol patch (Vivelle-Dot™ 0.05 mg) + Prometrium™ 100 mg. Serum levels of estrone, estradiol, estriol, and progesterone were obtained at multiple time intervals during the first 24-h, and at steady-state.ResultsResults were analyzable for 37/40 women. Study medications were well tolerated. The AUC at 24 h and at steady-state for estrogens remained consistently lower for all doses of Bi-est tested relative to the patch. The difference was statistically significant for Bi-est 2.0 mg (AUC-estradiol = 181 vs. 956; p < 0.001) and 2.5 mg (AUC-estradiol = 286 vs. 917; p < 0.001). Estriol levels remained low in all study arms. Serum progesterone levels were comparable in conventional vs. compounded groups.Conclusions This pharmacokinetic trial showed that the currently used doses of compounded hormones yield lower levels of estrogen compared to the standard-dose estradiol patch. To find comparable doses, further studies are needed. This successfully conducted randomized controlled study attests to the feasibility of using a similar design in the setting of a larger clinical trial.
    No preview · Article · Apr 2013 · Maturitas
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    ABSTRACT: Context:Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction.Objective:The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH).Design:Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling.Main Outcome Measures:cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed.Results:Compound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production.Conclusions:Because cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.
    No preview · Article · Mar 2013 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Background: Graves' ophthalmopathy (GO) develops or worsens in up to one-third of patients treated with radioactive iodine (RAI) for Graves' hyperthyroidism. We sought to identify the prevalence of development or worsening of GO in patients treated with RAI for Graves' hyperthyroidism and to identify the risk factors associated with that outcome. Methods: We identified a retrospective cohort of consecutive patients treated with RAI at Mayo Clinic (Rochester, MN) between 2005 and 2006. We assessed their medical records for evidence of hypothyroidism and development or worsening of GO in the year after therapy. Hypothyroidism was defined as thyrotropin >3.0 mIU/L or free thyroxine <0.8 ng/dL. Results: We identified 291 consecutive patients who received RAI therapy during the study period, with 195 out of 291 having complete follow-up data for a one-year period. GO was present in 46 out of 195 patients (23.6%) at baseline. After RAI treatment, GO developed or worsened in 25 out of 195 patients (12.8%) and it was associated with hypothyroidism at first follow-up (p=0.011) with an odds ratio (OR) of 3.3 [95% confidence interval (CI) 1.3-8.7]. More smokers than nonsmokers developed new or worse GO (17.7% vs. 11.8%), but that difference did not reach statistical significance (p=0.35). Preexisting GO (24% of patients) was associated with a higher risk for negative GO outcome compared with patients who had no GO at baseline (11%; p=0.021). Both development of hypothyroidism by the first visit after RAI therapy (OR 3.6) and preexistent GO (OR 2.8) remained significant in a multivariate analysis. Development of hypothyroidism was more likely in patients with longer duration to first follow-up (p<0.001). By 6-8 weeks after RAI treatment, the prevalence of hypothyroidism was ∼40%, while that of hyperthyroidism was only 20%. Conclusions: The presence of hypothyroidism at the first assessment of thyroid function after RAI administration is a strong predictor for adverse GO outcome. This risk is highest in patients with preexisting GO. We suggest that in order to prevent clinical hypothyroidism and the associated risk for GO, the optimal time for first measurement of fT4 is before 6 weeks after RAI therapy.
    No preview · Article · Dec 2012 · Thyroid: official journal of the American Thyroid Association
  • Rebecca S Bahn

    No preview · Article · Nov 2012 · Expert Review of Clinical Pharmacology
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    ABSTRACT: Fibroblasts (FIBs) within the retro-orbital space of patients with Graves' disease (GOFs) express thyrotropin receptors (TSHRs) and are thought to be an orbital target of TSHR-stimulating autoantibodies in Graves' ophthalmopathy (GO). Recently, we developed a low molecular weight, drug-like TSHR antagonist (NCGC00229600) that inhibited TSHR activation in a model cell system overexpressing TSHRs and in normal human thyrocytes expressing endogenous TSHRs. Herein, we test the hypothesis that NCGC00229600 will inhibit activation of TSHRs endogenously expressed in GOFs. Three strains of GOFs, previously obtained from patients with GO, were studied as undifferentiated FIBs and after differentiation into adipocytes (ADIPs), and another seven strains were studied only as FIBs. ADIP differentiation was monitored by morphology and measurement of adiponectin mRNA. FIBs and ADIPs were treated with the TSH- or TSHR-stimulating antibody M22 in the absence or presence of NCGC00229600 and TSHR activation was monitored by cAMP production. FIBs contained few if any lipid vesicles and undetectable levels of adiponectin mRNA, whereas ADIPs exhibited abundant lipid vesicles and levels of adiponectin mRNA more than 250,000 times greater than FIBs; TSHR mRNA levels were 10-fold higher in ADIPs than FIBs. FIBs exhibited higher absolute levels of basal and forskolin-stimulated cAMP production than ADIPs. Consistent with previous findings, TSH stimulated cAMP production in the majority of ADIP strains and less consistently in FIBs. Most importantly, NCGC00229600 reduced both TSH- and M22-stimulated cAMP production in GOFs. These data confirm previous findings that TSHR activation may cause increased cAMP production in GOFs and show that NCGC00229600 can inhibit TSHR activation in GOFs. These findings suggest that drug-like TSHR antagonists may have a role in treatment of GO.
    No preview · Article · Jul 2012 · Thyroid: official journal of the American Thyroid Association
  • Xiaoming Yin · Rauf Latif · Rebecca Bahn · Terry F Davies
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    ABSTRACT: Graves' disease (GD), including Graves' ophthalmopathy or orbitopathy (GO), is an autoimmune disease with an environmental and genetic component to its etiology. The genetic contribution to the GO clinical phenotype remains unclear. Previous data from our laboratory and others have suggested that GO has no specific genetic component distinct from GD itself, while other reports have occasionally appeared suggesting that polymorphisms in genes such as CTLA4 and IL23R specifically increase the risk for GO. One of the criticisms of all these reports has been the clinical definition of the GO phenotype as distinct from hyperthyroid GD devoid of clinically significant eye involvement. The objective of this study was to take advantage of a phenotypically pure group of GD patients with GO and examine a series of genes associated with GD to determine if any were more definitively associated with GO rather than Graves' thyroid disease itself. To further examine whether specific susceptibility genes are associated with GO, we have performed further genetic association studies using highly characterized GO patients, many of whom had undergone orbital decompression surgery for their exophthalmos. We genotyped HLA, CTLA4, IL23R, and TSHR genes in a group of 256 Caucasian patients with severe GO (n=199) and less severe GO (n=57), and 90 patients with GD but no clinically apparent GO. We found that the allele and genotype frequencies were not statistically different between GO and non-GO patients for any of the genes and gene combinations assessed. These results provide further evidence that patients with GO do not have a distinct genetic susceptibility to their eye disease and again suggest that environmental and/or epigenetic influences are at play.
    No preview · Article · Jul 2012 · Thyroid: official journal of the American Thyroid Association
  • Source
    Seethalakshmi Iyer · Rebecca Bahn
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    ABSTRACT: Graves' ophthalmopathy is an inflammatory autoimmune disorder of the orbit. The close clinical and temporal relationships between Graves' hyperthyroidism and ophthalmopathy have long suggested that both conditions derive from a single systemic process and share the thyrotropin receptor as a common autoantigen. This receptor is expressed not only in thyroid follicular cells, but also in orbital fibroblasts with higher levels measured in orbital cells from ophthalmopathy patients than in cells from normal individuals. Recent studies from several laboratories have shown that thyrotropin receptor activation in orbital fibroblasts enhances hyaluronic acid synthesis and adipogenesis, both cellular functions that appear to be upregulated in the diseased orbit. The phosphoinositide 3-kinase/Akt signaling cascade, along with other effector pathways including adenylyl cyclase/cAMP, appears to mediate these processes. Future therapies for this condition may involve inhibition of thyrotropin receptor signaling in orbital fibroblasts.
    Preview · Article · Jun 2012 · Best Practice & Research: Clinical Endocrinology & Metabolism
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    ABSTRACT: Background: Fibroblasts within the retro-orbital space of patients with Graves' disease (GOFs) express TSH receptors (TSHRs) and are thought to be an orbital target of TSHR-stimulating autoantibodies in Graves' ophthalmopathy (GO). Recently, we developed a low molecular weight, drug-like TSHR antagonist (NCGC00229600) that inhibited TSHR activation in a model cell system over-expressing TSHRs and in normal human thyrocytes expressing endogenous TSHRs. Herein, we test the hypothesis that NCGC00229600 will inhibit activation of TSHRs endogenously expressed in GOFs. Methods: Three strains of GOFs, previously obtained from patients with GO, were studied as undifferentiated fibroblasts (FIBs) and after differentiation into adipocytes (ADIPs), and another 7 strains were studied only as FIBs. ADIP differentiation was monitored by morphology and measurement of adiponectin mRNA. FIBs and ADIPs were treated with TSH or TSHR stimulating antibody M22 in the absence or presence of NCGC00229600 and TSHR activation was monitored by cAMP production. Results: FIBs contained few if any lipid vesicles and undetectable levels of adiponectin mRNA whereas ADIPs exhibited abundant lipid vesicles and levels of adiponectin mRNA more than 250,000 times greater than FIBs; TSHR mRNA levels were 10-fold higher in ADIPs than FIBs. FIBs exhibited higher absolute levels of basal and forskolin-stimulated cAMP production than ADIPs. Consistent with previous findings, TSH stimulated cAMP production in the majority of ADIP strains and less consistently in FIBs. Most importantly, NCGC00229600 reduced both TSH- and M22-stimulated cAMP production in GOFs. Conclusions: These data confirm previous findings that TSHR activation may cause increased cAMP production in GOFs and show that NCGC00229600 can inhibit TSHR activation in GOFs. These findings suggest that drug-like TSHR antagonists may have a role in treatment of GO.
    No preview · Article · May 2012 · Thyroid: official journal of the American Thyroid Association
  • Source
    Xiaoming Yin · Rauf Latif · Rebecca S Bahn · Terry F Davies
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    ABSTRACT: Background: Graves' disease (GD), including Graves' ophthalmopathy or orbitopathy (GO), is an autoimmune disease with an environmental and genetic component to its etiology. The genetic contribution to the GO clinical phenotype remains unclear. Previous data from our laboratory and others have suggested that GO has no specific genetic component distinct from GD itself while other reports have occasionally appeared suggesting that polymorphisms in genes such as CTLA4 and the IL23R specifically increase the risk for GO. One of the criticisms of all these reports has been the clinical definition of the GO phenotype as distinct from hyperthyroid GD devoid of clinically significant eye involvement. The objective of this study was to take advantage of a phenotypically pure group of GD patients with GO and examine a series of genes associated with GD to determine if any were more definitively associated with GO rather than Graves' thyroid disease itself. Methods: In order to further examine whether specific susceptibility genes are associated with GO, we have performed further genetic association studies using highly characterized GO patients, many of whom had undergone orbital decompression surgery for their exophthalmos. We genotyped HLA, CTLA4, IL23R and TSHR genes in a group of 256 Caucasian patients with severe GO (n = 199) and less severe GO (n = 57), and 90 patients with GD but no clinically apparent GO. Results: We found that the allele and genotype frequencies were not statistically different between GO and non-GO patients for any of the genes and gene combinations assessed. Conclusions: These results provide further evidence that patients with GO do not have a distinct genetic susceptibility to their eye disease and again suggests that environmental and/or epigenetic influences are at play.
    Full-text · Article · Apr 2012 · Thyroid: official journal of the American Thyroid Association
  • R S Bahn
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    ABSTRACT: Current treatment options for Graves' hyperthyroidism and the related ophthalmopathy (GO) are not uniformly effective and carry with them potentially serious side effects. As a result, efforts have been focused on the development of novel therapies. Progress has been made, particularly in the production of thyroid-stimulating hormone receptor (TSHR) antagonists, as either monoclonal blocking antibodies or small-molecule ligands. In addition, rituximab (RTX) is the first targeted biological therapy to be studied as treatment for these conditions.
    No preview · Article · Apr 2012 · Clinical Pharmacology &#38 Therapeutics
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    ABSTRACT: Graves' ophthalmopathy (GO) is characterized by expanded volume of the orbital fat and extraocular muscle tissues and elevated levels of TSH receptor autoantibodies (TRAb). The expansion of orbital tissues involves accumulation of hyaluronic acid (HA) within the orbit. The objective of the study was to determine whether a monoclonal stimulatory TRAb (M22) impacts HA synthesis in GO orbital cells and, if so, whether this might be blocked by an IGF-I receptor (IGF-IR)-blocking antibody (1H7) or inhibitors of various downstream signaling cascades. GO orbital fibroblast cultures (n = 6) were treated with M22, bovine TSH (bTSH), or IGF-I in serum-free medium. Some cultures also received 1H7, LY294002, rapamycin, or protein kinase A inhibitor. HA production and phosphorylated Akt levels in media or immunoblotting for phosphorylated Akt were measured. M22 or bTSH stimulated HA synthesis (2.1-fold with 100 ng/ml M22 and 1.9-fold with 10 U/liter bTSH; P < 0.05 each). M22-induced HA synthesis was inhibited by LY294002 or rapamycin but not by protein kinase inhibitor. HA synthesis stimulated by M22 or IGF-I was inhibited by 1H7 (mean 36.6 ± 5.6% and mean 45.8 ± 7.6%, respectively; P < 0.05 each). Similarly, M22- or IGF-I-stimulated Akt phosphorylation was inhibited by 1H7 (mean 54 ± 9.6 and 36.1 ± 8.8%, respectively; P = 0.01 each). The stimulatory TRAb M22 increases HA production in undifferentiated GO orbital fibroblasts via phosphoinositide 3-kinase/phosphorylated AKT/mammalian target of rapamycin activation. Blockade of IGF-IR inhibits both HA synthesis and Akt phosphorylation induced by M22 or IGF-I in these cells, suggesting that TSH receptor and IGF-IR signaling may be closely linked in the GO orbit.
    No preview · Article · Mar 2012 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: INTRODUCTION: Amiodarone-induced thyrotoxicosis (AIT) is a recognized complication of amiodarone treatment with limited management options. Its predisposing factors are incompletely defined yet a higher prevalence was reported in adults with congenital heart disease (CHD). Therefore we sought to determine the incidence and risk factors for AIT in adults with CHD. METHODS: At a tertiary care center we followed a historical cohort of amiodarone-treated CHD patients for the period 1987-2009. Follow-up concluded at AIT diagnosis or with last thyroid assessment on amiodarone. Cumulative incidence of AIT was calculated. AIT association with nutritional status was hypothesized a priori. RESULTS: AIT developed in 23/169 patients or 13.6%. The AIT incidence peaked in the 3rd year at 7.7%. AIT patients had a lower body mass index (BMI) at AMIO initiation compared with the rest of the cohort (mean±standard deviation: 21.9±2.9 vs. 25.1±5.0; p<0.001). Patients with BMI<21 were more likely to develop thyrotoxicosis (RR=6.1) compared to those with BMI>25 (p<0.001). Presence of goiter was strongly associated with AIT (RR 3.6, p=0.002). Affected patients had a trend for higher cyanotic heart disease prevalence (34.8% vs. 17.8%, p=0.059). On multivariate analysis body mass index and goiter remained independent predictors of outcome. CONCLUSIONS: BMI<21 at initiation of amiodarone therapy and presence of goiter are strong predictors of AIT in this population. Its incidence is time dependent. These predictors can be used clinically in assessing overall impact of amiodarone therapy in congenital heart disease patients.
    No preview · Article · Mar 2012 · International journal of cardiology

Publication Stats

6k Citations
757.74 Total Impact Points

Institutions

  • 1986-2015
    • Mayo Clinic - Rochester
      • • Department of Ophthalmology
      • • Department of Internal Medicine
      • • Department of Endocrinology, Diabetes, Metabolism and Nutrition
      Рочестер, Minnesota, United States
  • 2002-2010
    • Mayo Foundation for Medical Education and Research
      • • Division of Endocrinology, Diabetes, Metabolism, and Nutrition
      • • Department of Ophthalmology
      Scottsdale, AZ, United States
  • 2004
    • University of Illinois at Chicago
      • Department of Microbiology and Immunology (Chicago)
      Chicago, IL, United States
    • Albert Einstein College of Medicine
      • Department of Cell Biology
      New York, New York, United States
  • 1998
    • Washington Hospital Center
      Washington, Washington, D.C., United States
  • 1994-1995
    • Ludwig-Maximilian-University of Munich
      • Department of Internal Medicine II
      München, Bavaria, Germany
  • 1989
    • University at Buffalo, The State University of New York
      • Department of Medicine
      Buffalo, NY, United States