Impact of Teprotumumab on Clinical Practice in Thyroid Eye Disease.

BACKGROUND: Following its FDA approval in January 2020, we examined the impact of teprotumumab on thyroid eye disease (TED) clinical practices. METHODS: Across three referral centers from January 1, 2018, to December 30, 2022, we retrospectively analyzed demographics, clinical features, treatment choices, and insurance status of patients with active, moderate to severe TED. RESULTS: Of 74 patients recommended for medical therapy, 53% received collaborative recommendations from endocrinologists and ophthalmologists in a TED clinic. Prior to teprotumumab availability, 19 patients were recommended medical therapy, and all received medical therapy (100%), which consists of corticosteroids (14, 73.7%) or tocilizumab (5, 26.3%). After teprotumumab became available, out of 55 patients that were recommended medical therapy, only 41 (74.6%) received medical therapy, mostly teprotumumab (33, 60%), followed by corticosteroids (5, 9.1%) or tocilizumab (3, 5.4%), while 14 (25.4%) did not receive medical therapy. Discordance between physicians' recommendations and therapy received or lack thereof was explained by patients' refusal (9, 64.3%), mostly due to side effect concerns (8, 88.9%), and insurance denial (5, 35.7%). Teprotumumab use was mostly associated with otic changes (10, 30.3%), weight loss (9, 27.3%), and hyperglycemia (6, 18.2%), but 2 (6.1%) patients developed serious infections. Corticosteroids were associated with insomnia (4, 21.1%), and one patient in the tocilizumab group had an infusion reaction requiring hospitalization. CONCLUSION: Teprotumumab introduction increased TED therapy evaluations, yet not all received recommended treatment due to safety concerns or accessibility issues. Enhancing collaborative care, medication accessibility, and adverse effect management is crucial.

Alemtuzumab-Induced Thyroid Eye Disease: A Comprehensive Case Series and Review of the Literature.

PURPOSE: To present 5 cases of alemtuzumab-induced thyroid eye disease (AI-TED) and review the literature to highlight the natural history, severity, and outcomes as compared with conventional thyroid eye disease (TED). METHODS: A multi-institutional retrospective case series of patients with AI-TED was compiled. Chart review evaluated for clinical characteristics, imaging findings, and treatment for AI-TED. Additionally, a comprehensive review of the literature identified all previously published cases of AI-TED. RESULTS: Five new patients with AI-TED were included in this series. The average clinical activity score on presentation was 2.8 (range 1-4) and reached an average peak of 5.0 during the active phase of the disease (4-7). Patients were treated medically with selenium (40%) or monoclonal antibodies including teprotumumab or tocilizumab (40%). Surgical treatment with orbital decompression for compressive optic neuropathy was performed on 2 (40%) patients. Combined with 11 previously reported cases, these 16 patients with AI-TED had an average clinical activity score on presentation of 3.3. The average length of the AI-TED phase was 14.0 months, and all patients were treated with medical and/or surgical interventions for their disease. CONCLUSIONS: Clinical and imaging findings in AI-TED mirror that of conventional TED, however, AI-TED may present with greater severity. AI-TED may develop many months after Graves' disease; therefore, providers should be aware of this association and monitor patients for the development of severe TED.

Radiofrequency Ablation of Benign and Malignant Thyroid Nodules.

Thyroid nodule treatment has significantly evolved over recent years with attempts to individualize treatment on the basis of the cause of the nodule and patient performance status. The risks and complications associated with surgery and radioactive iodine have promoted interest in additional therapies such as radiofrequency ablation (RFA). RFA creates an electrical current through a target tissue (thyroid nodule) with resultant tissue heating causing coagulative necrosis. National and international groups are beginning to recognize the role of RFA as a viable therapeutic option in the treatment of thyroid nodules. Based on numerous guidelines, RFA is indicated in the treatment of symptomatic benign nodules and autonomously functioning nodules when surgery is refused or when the patient would not tolerate surgery. The treatment of thyroid malignancy with RFA is controversial, with some groups advocating for its use in the treatment of small papillary thyroid cancers in specific scenarios. The most important aspect of RFA is the preprocedural workup and adequate patient selection. Procedural technique varies among centers. However, RFA is typically performed as a single-day-admission outpatient procedure. Methods such as hydrodissection and a moving shot technique are employed to ensure adequate coverage of the nodule without overtreating the peripheries and damaging sensitive structures. As a result, the procedure is well tolerated, and major complications such as recurrent laryngeal nerve injury and nodule rupture are very rare. In the proper patient cohort, thyroid RFA offers an efficacious and safe option in the management of thyroid nodules. An invited commentary by Filippiadis and Vrachliotis is available online. ©RSNA, 2022.

American Association of Clinical Endocrinology Disease State Clinical Review: The Clinical Utility of Minimally Invasive Interventional Procedures in the Management of Benign and Malignant Thyroid Lesions.

OBJECTIVE: The objective of this disease state clinical review is to provide clinicians with a summary of the nonsurgical, minimally invasive approaches to managing thyroid nodules/malignancy, including their indications, efficacy, side effects, and outcomes. METHODS: A literature search was conducted using PubMed and appropriate key words. Relevant publications on minimally invasive thyroid techniques were used to create this clinical review. RESULTS: Minimally invasive thyroid techniques are effective and safe when performed by experienced centers. To date, percutaneous ethanol injection therapy is recommended for recurrent benign thyroid cysts. Both ultrasound-guided laser and radiofrequency ablation can be safely used for symptomatic solid nodules, both toxic and nontoxic. Microwave ablation and high-intensity focused ultrasound are newer approaches that need further clinical evaluation. Despite limited data, encouraging results suggest that minimally invasive techniques can also be used in small-size primary and locally recurrent thyroid cancer. CONCLUSION: Surgery and radioiodine treatment remain the conventional and established treatments for nodular goiters. However, the new image-guided minimally invasive approaches appear safe and effective alternatives when used appropriately and by trained professionals to treat symptomatic or enlarging thyroid masses.

Comparison of long-term antithyroid drugs versus radioactive iodine or surgery for Graves' disease: A review of the literature.

BACKGROUND: The management of Graves' disease (GD) in the US is shifting towards increased use of anti-thyroid drugs (ATD). If patients fail to achieve remission after a standard course of therapy of 12-18 months, long-term treatment with ATD (≥24 months) may be chosen over definitive therapy with radioiodine (RAI) or surgery. Clinicians will need to contrast this strategy to ablative therapies as they help patients in decision making. SUMMARY: Review of the literature illustrates that long-term ATD delivers euthyroidism with minimal complications, low financial cost and with an advantageous profile regarding quality of life (QoL) and other biological outcomes. CONCLUSIONS: Long-term ATD is a viable alternative to ablative therapies in the management of GD offering advantages across multiple patient centred outcomes. Decision making must factor differences in this approach compared to ablative therapies and ultimately be tailored to individualized patient situations.

The "Quiet TED"-A Special Subgroup of Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) or Graves' orbitopathy starts with an active inflammatory stage (active disease) followed by resolution of inflammation and progression to a fibrotic, inactive stage. In our practice, we have encountered cases that have not had active disease despite presence of fibrotic sequelae and disease progression. We aim to delineate the clinical characteristic of this unique group of patients. METHODS: We conducted a single-center (Mayo Clinic Rochester) retrospective chart review of TED patients who throughout the course of their disease had only evidence for inactive TED, defined as clinical activity score <3. RESULTS: Median age in the cohort (n = 19) was 54 years (IQR 47-61). 58% had a prior diagnosis of Graves' disease (GD) before referral. 80% (n = 15) were euthyroid at the time of TED onset (median thyroid-stimulating hormone 1.7 mIU/L). The most common finding was diplopia (100%, n = 19) followed by proptosis (63%, n = 12). Interestingly the disease was asymmetric in 42% of cases. Overall median clinical activity score on presentation was 1 (IQR 0-1). Severity wise, 85% (n = 16) of patients were classified as moderate-to-severe during follow up. Orbital decompression was performed in only 1 case, while extraocular muscle surgery was performed in 13 cases. CONCLUSIONS: Quiet TED is a subgroup of TED patients that defies the classic disease paradigm. It presents primarily with diplopia and proptosis. Further evaluation of this group might identify useful insights in TED pathophysiology and help optimize therapeutic choices.

Drivers of the Decision to Biopsy and Follow-Up of Small Suspicious Thyroid Nodules.

OBJECTIVE: In 2015, the updated American Thyroid Association (ATA) guidelines recommended observation for suspicious subcentimeter thyroid nodules, based on their indolent course. We aimed to evaluate the frequency of biopsy in suspicious thyroid nodules since the introduction of these guidelines, including factors contributing to clinical decision-making in a tertiary care center. METHODS: We conducted a retrospective study of patients in the Mayo Clinic, Rochester, Minnesota, with new, subcentimeter suspicious thyroid nodules (by report or by sonographic features) between March, 2015, and November, 2017, not previously biopsied. RESULTS: We identified 141 nodules in 129 patients: mean age 58.1±14.1 years, 74% female, 87% Caucasian. The frequency of biopsy in suspicious thyroid nodules was 39%. Ultrasound features that were the strongest predictors for biopsy on multivariate analysis included: nodule volume (odds ratio [OR] 37.3 [7.5-188.7]), radiology recommendation for biopsy (OR 2.6 [1.8-3.9]) and radiology report of the nodule as "suspicious" (OR 2.1 [1.4-3.2]). Patient's age and degree of comorbidities did not change the likelihood for biopsy, nor did it vary by clinician type or how the nodule was initially found (incidentally or not incidentally). Among 86 nodules that were not biopsied, 41% had no specific follow-up recommendations. CONCLUSION: One third of suspicious thyroid nodules underwent biopsy since the release of updated ATA guidelines. Factors driving thyroid biopsy seem to be associated with nodule characteristics but not with patient factors including age and comorbidities. Further studies and development of decision aides may be helpful in providing individualized approaches for suspicious thyroid nodules. ABBREVIATIONS: ATA = American Thyroid Association; OR = odds ratio.

Patient Discomfort in Relation to Thyroid Nodule Fine-Needle Aspiration (FNA) Performed with or without Parenteral and/or Topical Anesthetic.

OBJECTIVE: There is much reported variation in the impact of local anesthesia on thyroid fine-needle aspiration (FNA) related discomfort. We compare patients undergoing thyroid FNA with subcutaneous injection or topical anesthetic to no anesthetic. METHODS: We conducted a retrospective review of 585 sequential ultrasound guided thyroid FNA procedures in Mayo Clinic. Group 1 (n = 200), no anesthetic; Group 2 (n = 185), subcutaneous injection anesthetic; and Group 3 (n = 200), topical anesthetic. Patient demographics, number of FNA passes, needle gauge, and cytopathology were recorded plus a discomfort score (0 to 10) before and immediately post procedure in all 3 groups and peak discomfort during the FNA in Groups 1 and 2. RESULTS: There were no differences among the 3 groups in age, sex, FNA sufficiency rate, cytopathology, and FNA passes number. There was no significant difference between Groups 1 and 2 in peak discomfort score during the FNA: 0 (45%, 42.2%), 1 to 2 (19%, 24.9%), 3 to 5 (23.5%, 20.5%), 6 to 8 (9.5%, 10.8%), 9 to 10 (3%, 1.6%), respectively. Discomfort score post procedure: 0 (78.5%, 77.8%, 53.5%), 1 to 2 (13%, 13%, 36.5%), 3 to 5 (7%, 7%, 9%), 6 to 8 (1.5%, 2.2%, 1%), 9 to 10 (0%, 0%, 0%) for groups 1, 2, and 3, respectively. There were no significant differences among the 3 groups for a discomfort score ≥3. CONCLUSION: FNA associated patient discomfort was comparable during and after the procedure regardless of the use of anesthetic or the type utilized. Approximately 90% of patients experienced mild to moderate discomfort during the procedure. And 90% reported no more than a level 2 discomfort post procedure. ABBREVIATIONS: End = endocrinology; FNA = fine-needle aspiration; MCF = Mayo Clinic Florida; MCR = Mayo Clinic Rochester.

Riedel's thyroiditis association with IgG4-related disease.

CONTEXT: IgG4-positive (+) plasma cells have been reported in both Riedel's thyroiditis (RT) and Hashimoto's thyroiditis (HT). These cells are the hallmark of IgG4-related disease (IgG4-RD). OBJECTIVE: We sought to determine whether RT is part of IgG4-RD spectrum. DESIGN, SETTING AND PATIENTS: This was a case-control study performed at a tertiary medical centre. We included RT cases from the period 1958 to 2008 that had sufficient paraffin-embedded tissue for IgG4 immunostaining. Controls were patients with HT, age and gender matched, with similar pathology criteria. MAIN OUTCOME MEASURE: The main outcome measures were the intensity of the IgG4 staining and the clinical and histological correlates with IgG4-RD. RESULTS: Six pairs of RT and HT were analysed. The mean age was 44·7 years. In both groups, 5/6 cases had positive IgG4 staining. The mean number of IgG4 + cells/ HPF, normalized to the degree of inflammation, was 3·2 ± 3·0 SD (RT) vs 0·9 ± 0·7 (HT), P = 0·15, for fibrotic areas and 2·1 ± 2·3 SD vs 1·0 ± 0·8 (P = 0·39) for areas with lymphoid aggregates. We found the number of IgG4 +  cells in RT to be inversely correlated with the duration of disease (P = 0·046). Three RT cases had associated comorbidities from the IgG4-RD spectrum while none of the HT cases had such conditions. CONCLUSIONS: Riedel's thyroiditis is a component of IgG4-RD with the density of the IgG4 +  lymphocytic infiltrate being time dependent. In this small study, we did not identify differences in IgG4 infiltration between RT and HT, minimizing the utility of this marker in RT diagnosis.

Amiodarone-induced thyrotoxicosis in adults with congenital heart disease--clinical presentation and response to therapy.

OBJECTIVE: The development of amiodarone-induced thyrotoxicosis (AIT) can threaten the hemodynamic stability of adult patients with congenital heart disease (CHD). Here, we describe the natural history and treatment response of AIT 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. Subjects were identified from the cohort of adults with CHD who were treated at the Mayo Clinic Adult CHD clinic between 1987 and 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 of 23, 74%), with arrhythmia and weight loss as the most common symptoms. The majority (12 of 23, 52%) were initially observed; 10 patients (43%) were treated medically and 1 patient (5%) underwent thyroidectomy. Four patients from the observation group eventually required active treatment and 3 patients from the medical group required surgery. Asymptomatic patients tended to resolve under observation (5 of 7, 71.4%) rather than progress to active treatment (0 of 4) (P = .06). Discontinuation of amiodarone, AIT type, or use of perchlorate did not impact AIT duration. CONCLUSION: AIT in CHD patients exhibits a wide range of severity and sensitivity to medical therapy. Asymptomatic patients display a trend toward 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 toward better disease prevention and treatment.

PAPP-A as a Potential Target in Thyroid Eye Disease.

CONTEXT: Proptosis in Thyroid Eye Disease (TED) can result in facial disfigurement and visual dysfunction. Treatment with Insulin-like growth factor I receptor (IGF-IR) inhibitors has been shown to be effective in reducing proptosis but with side effects. OBJECTIVE: To test the hypothesis that inhibition of IGF-IR indirectly and more selectively with PAPP-A inhibitors attenuates IGF-IR signaling in TED. DESIGN: Informed consent was obtained from TED patients undergoing surgery, and retro-orbital tissue collected for fibroblast isolation and culture. SETTING: Surgeries were performed in Mayo Clinic operating suites. Cell culture was performed in a sterile tissue culture facility. PATIENT SAMPLES: Retro-orbital tissue was collected from 19 TED patients. INTERVENTIONS: Treatment of TED fibroblasts with pro-inflammatory cytokines. Flow separation of CD34- and CD34+ orbital fibroblasts, the latter representing infiltrating fibrocytes into the orbit in TED. MAIN OUTCOME MEASURES: PAPP-A expression and proteolytic activity, IGF-I stimulation of phosphatidylinositol 3 kinase/Akt pathway and inhibition by immuno-neutralizing antibodies against PAPP-A, CD34+ status and associated PAPP-A and IGF-IR expression. RESULTS: Pro-inflammatory cytokines markedly increased PAPP-A expression in TED fibroblasts. IGF-IR expression was not affected by cytokine treatment. Inhibition of PAPP-A's proteolytic activity suppressed IGF-IR activation in orbital fibroblasts from TED patients. TED fibroblasts that were CD34+ represented ∼80% of the cells in culture and accounted for ∼70% of PAPP-A and IGF-IR expressing cells. CONCLUSIONS: These results support a role for PAPP-A in TED pathogenesis and indicate the potential for novel therapeutic targeting of the IGF axis.

Clinician feedback using a shared decision-making tool for the evaluation of patients with thyroid nodules-an observational study.

BACKGROUND: We pilot-tested an encounter conversation aid to support shared decision making (SDM) between patients with thyroid nodules and their clinicians. OBJECTIVE: Characterize the clinician feedback after providing care to patients with thyroid nodules using a tool to promote SDM conversations during the clinical encounter, and evaluate how clinicians used the tool during the visit. METHODS: Mixed method study in two academic centers in the U.S., including adult patients presenting for evaluation of thyroid nodules and their clinicians. We thematically analyzed interviews with clinicians after they used the SDM tool in at least three visits to characterize their feedback. Additionally, investigators evaluated visits recordings to determine the extent to which clinicians engaged patients in the decision-making process (OPTION score, scale 0 to 100, higher levels indicating higher involvement), the tool's components used (fidelity), and encounter duration. Using a post-visit survey, we evaluated the extent to which clinicians felt the tool was easy to use, helpful, and supportive of the patient-clinician collaboration. RESULTS: Thirteen clinicians participated in the study and used the SDM tool in the care of 53 patients. Clinicians thought the tool was well-organized and beneficial to patients and clinicians. Clinicians noticed a change in their routine with the use of the conversation aid and suggested it needed to be more flexible to better support varying conversations. The median OPTION score was 34, the fidelity of use 75%, and the median visit duration 17 min. In most encounters, clinicians agreed or strongly agreed the tool was easy to use (86%), helpful (65%), and supported collaboration (62%). CONCLUSION: Clinicians were able to use a SDM tool in the care of patients with thyroid nodules. Although they wished it were more flexible, they found on the whole that its use in the clinical encounter was beneficial to patients and clinicians.

The Adverse Effects Profile of Teprotumumab.

CONTEXT: Teprotumumab therapy for thyroid eye disease (TED) patients represents a major step forward. It targets and inhibits the insulin-like growth factor-1 receptor (IGF-1R), and its effectiveness is based on its interconnectedness with the thyrotropin receptor. However, IGF-1R has a ubiquitous expression and several adverse effects have been reported with teprotumumab use. OBJECTIVE: Describing these adverse effects for better understanding is the purpose of this review. METHODS: We reviewed the oncological studies in which teprotumumab was initially used. Subsequently we reviewed the clinical trials for TED and then the case series and case reports associated with teprotumumab use since it is US Food and Drug Administration approval (January 2020). We focused on common and/or serious adverse effects reported with the use of teprotumumab. RESULTS: We described the common occurrence of hyperglycemia (10%-30% incidence), its risk factors and suggested management. Hearing changes are described, a broad spectrum from mild ear pressure to hearing loss (sensorineural mechanism). Risk factors, suggested monitoring, and possible upcoming therapies are reviewed. We also reviewed data on fatigue, muscle spasms, hair loss, weight loss, gastrointestinal disturbances, menstrual changes, and infusion reactions. We noted some discrepancies between adverse effects in oncological studies vs studies focused on TED, and we aimed to explain these differences. CONCLUSION: The use of teprotumumab should consider patient's values and preferences in balancing the expected benefit with these potential risks. Future drugs targeting IGF-1R should investigate these adverse effects for a possible class effect. Combination therapies with different agents hopefully will be identified that maximize benefits and minimize risks.

Incidence, Risk Factors, and Outcomes of Incident Atrial Fibrillation in Patients With Graves Disease.

OBJECTIVE: To describe the incidence, risk factors, and outcomes of incident atrial fibrillation (AF) in Graves disease (GD). PATIENTS AND METHODS: Patients with GD between January 1, 2009, and December 31, 2019, were included retrospectively. We defined GD-related AF as AF diagnosed less than or equal to 30 days before or any time after GD. Late-onset AF was defined as incident AF diagnosed more than 90 days after GD. RESULTS: Of 1371 patients with GD, AF occurred in 139 patients. Late-onset AF occurred in 32 (23.0%) of AF cases, of which 16 (50.0%) had attained euthyroidism. Independent risk factors were age (HR, 1.05; 95% CI, 1.03-1.06 per year), overt hyperthyroidism (free T4 >1.7 ng/dL; HR, 2.75; 95% CI, 1.38 to 5.46), and male sex (HR, 2.30; 95% CI, 1.54 to 3.43) for early AF. These were age (HR, 1.08; 95% CI, 1.05 to 1.119 per year), chronic obstructive pulmonary disease (HR, 3.47; 95% CI, 1.36 to 5.54), and heart failure (HR, 5.86; 95% CI, 2.39 to 14.38) for late AF. Atrial fibrillation in GD was associated with higher mortality (HR, 16.32; 95% CI, 4.66 to 56.58), acute coronary syndrome/stable angina events (HR, 3.89; 95% CI, 1.23 to 12.31), and cardiac hospitalizations (HR, 15.39; 95% CI, 8.17 to 29.00) when adjusted to age, sex, and pre-existing AF. CONCLUSION: Late-onset AF comprised one-quarter of GD-related AF cases requiring surveillance even after restoring euthyroidism. Risk factors for AF in GD are similar to those in the general population although overt hyperthyroidism conferred the highest risk, especially for early AF. Treatment with thionamide was associated with late AF.

Medical Therapy in Patients with Moderate to Severe, Steroid-Resistant, Thyroid Eye Disease.

Background: Corticosteroid therapy is often employed in thyroid eye disease (TED), but its efficacy is variable. Teprotumumab and tocilizumab have been considered as effective alternatives. This study aims to evaluate their clinical outcomes and safety in patients with steroid-resistant TED. Methods: A retrospective case-control study was conducted between 2018 and 2022 within a national multicenter health system. Thirty-seven patients with moderate to severe steroid-resistant TED treated with teprotumumab or tocilizumab (cases) were compared with steroid-naïve patients treated with similar therapy (controls). Due to lack of steroid-naïve patients treated with tocilizumab, a control subgroup for tocilizumab was not included in the analysis. Demographic and clinical characteristics were described. Proptosis, diplopia, clinical activity score (CAS), and disease severity (European Group on Graves' orbitopathy classification) were evaluated at weeks 0, 12, 24, and 52 after therapy initiation. Results: Thirty-one patients received teprotumumab (13 cases and 18 controls) and 6 received tocilizumab (cases). The mean age was 57 years (standard deviation ±14.3), median duration of TED was 11.5 months (interquartile range [IQR]: 7.2-17.7), and median excess proptosis was 4 mm (IQR: 2-8) above the upper limit of normal for sex and race. At week 24, in the teprotumumab cases, 81% had proptosis response (reduction of ≥2 mm), 45.5% resolution of diplopia, 85.7% disease inactivation (CAS <3), and 58.3% reverted to mild disease severity. There were comparable results in teprotumumab controls, with no significant differences between subgroups. In the tocilizumab cases, 50% had a proptosis response, 16.7% resolution of diplopia, 100% disease inactivation, and 75% returned to mild disease. In the teprotumumab cases, there was a trend toward worsening proptosis and diplopia between weeks 24 and 52. In the same time frame, the tocilizumab cases had a trend toward worsening diplopia, disease activity, and severity. In the teprotumumab subgroup, 46.2% experienced otic changes and 23.1% hyperglycemia. In the tocilizumab subgroup, there were no reported adverse events. Conclusions: Teprotumumab and tocilizumab improved inflammation in patients with moderate to severe TED who had failed previous steroid therapy. Additionally, the teprotumumab cases demonstrated similar improvement in proptosis and diplopia to the teprotumumab controls. Further evaluation, particularly regarding the long-term response and side effect profile, of these medications in steroid-resistant TED is needed.

Effect of the Fetal THRB Genotype on the Placenta.

CONTEXT: Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators. OBJECTIVE: To investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. METHODS: Sections of placentas were collected and frozen at -80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. RESULTS: The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA. CONCLUSION: We present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.

The Association Between Thyroid Stimulating Hormone and Depression: A Historical Cohort Study.

OBJECTIVE: To investigate the association between thyroid-stimulating hormone (TSH) and clinically relevant depression (CRD) in a population-based study. PATIENTS AND METHODS: Adult patients (≥18 years of age) who received care at Mayo Clinic in Rochester, Minnesota, and completed a TSH and Patient Health Questionnaire - 9 (PHQ-9) within 6 months of each other, between July 8, 2017, and August 31, 2021, were included. Demographics, medical comorbidities, thyroid function laboratory data, psychotropic medications, presence of primary thyroid disorder, thyroid hormone replacement (T4 and/or T3), and mood disorder diagnoses (using International Classification of Diseases, 10th version, Clinical Modifications codes) were extracted electronically. The primary outcome, CRD, was defined as a PHQ-9 score greater than or equal to 10. Logistic regression analysis was conducted to assess the association between TSH categories (low ≤0.3 mIU/L; normal >0.3-4.2 mIU/L; high >4.2 mIU/L) and CRD. RESULTS: The cohort included 29,034 patients, mean age 51.4 years, 65% females, 89.9% White, and a mean body mass index of 29.9 kg/m2. The mean ± standard deviation for TSH was 3.0±8.5 mIU/L, and the mean PHQ-9 score was 6.3±6.2. After adjustment, the odds of CRD were significantly higher among the low TSH category (odds ratio, 1.37; 95% CI, 1.18-1.57; P<.001) compared with the normal TSH category, especially in people 70 years of age or younger compared with people older than 70 years of age. Subgroup analysis did not show an increase in odds of CRD among patients with subclinical/overt hypothyroidism/hyperthyroidism (after adjustment). CONCLUSION: In this large population-based cross-sectional study, we report that low TSH was associated with higher odds of depression. Future longitudinal cohort studies are needed to investigate the relationship between thyroid dysfunction and depression as well as sex differences.

Efficacy and Safety of Teprotumumab in Patients With Thyroid Eye Disease of Long Duration and Low Disease Activity.

CONTEXT: Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials. OBJECTIVE: We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED. METHODS: This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed. RESULTS: A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (-2.41 [0.228]) than with placebo (-0.92 [0.323]), difference -1.48 (95% CI -2.28, -0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths. CONCLUSION: Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.

Long-Term Lithium Therapy and Thyroid Disorders in Bipolar Disorder: A Historical Cohort Study.

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders.