Real-life Data on the Effect of Medical Therapy for Amiodarone-induced Thyrotoxicosis on CV Events and Hospitalizations.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) often receive initial therapy for thyrotoxicosis in several different medical settings before admission to a referral center. OBJECTIVE: This work aimed to determine whether first-line medical therapy (ie, therapies for thyrotoxicosis at first diagnosis of AIT) affects the outcome of AIT patients. METHODS: A single-center historical-prospective cohort study was conducted on 313 AIT patients. Clinical and biochemical data were collected at first diagnosis, at a referral center, and during the course of AIT. Primary outcomes were cardiovascular (CV) events and hospitalizations. First-line therapies were considered appropriate when they included glucocorticoids for type 2 AIT and methimazole for type 1 AIT at the approved dose, either alone (optimal medical therapy, OMT) or in combination (right-dose combination therapy, RCT). Other therapies were considered not appropriate, including no therapy. Duration of exposure to thyrotoxicosis was the time from first diagnosis of AIT to its remission. RESULTS: A total of 34.5% patients received appropriate therapies (28.1% OMT, 6.4% RCT), whereas the remaining (65.5%) received inappropriate therapies. CV events and hospitalizations were more frequent in patients who received inappropriate therapies (33.2% vs 4.5%, and 24.9% vs 6.5%, respectively; P < .0001 for both). Appropriate therapies reduced serum thyroid hormone concentrations (P = .018) from first diagnosis to referral, unlike the inappropriate therapies. The duration of exposure to thyrotoxicosis was longer in patients receiving inappropriate therapies and was a risk factor for arrhythmias (hazard ratio [HR] 1.004; P = .0008), major acute CV events (HR 1.004; P = .020), and hospitalizations (HR 1.006; P < .0001). CONCLUSION: The first medical therapy of AIT influences the exposure time to thyrotoxicosis and the occurrence of CV events and hospitalizations.

Identification of Two Different Phenotypes of Patients with Amiodarone-Induced Thyrotoxicosis and Positive Thyrotropin Receptor Antibody Tests.

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AIT1) due to Graves' disease (GD). However, the TRAb role and function in AIT have not been clarified. Methods: A retrospective cohort study of 309 AIT patients followed at a single academic center over a 30-year period. AIT TRAb-positive patients (n = 21, 7% of all cases) constituted the study group; control groups consisted of type 2 AIT (AIT2) TRAb-negative patients (n = 233), and 100 non-AIT patients with GD. Clinical and biochemical data at diagnosis and during the course of disease were compared. Histological samples of patients who had total thyroidectomy were reviewed. Stored serum samples were used for a functional assay of TRAb class G immunoglobulins (IgGs) in Chinese hamster ovary (CHO) cells stably transfected with complementary DNA encoding for the TSH receptor. Results: TRAb-positive patients were grouped according to color flow Doppler sonography, radioactive iodine thyroid uptake, and duration of amiodarone therapy before thyrotoxicosis in type 1 (n = 9, 43%; TRAb1) or type 2 (n = 12, 57%; TRAb2) AIT. TRAb1 patients had clinical and biochemical features indistinguishable from GD controls, and were responsive to methimazole. Conversely, TRAb2 patients had clinical features similar to AIT2 controls, and were responsive to glucocorticoids, but not to methimazole. The CHO cell functional assay demonstrated that TRAb1 IgGs had a stimulatory effect on cyclic AMP production, which was absent in TRAb2 IgGs. Pathology in TRAb1 showed hyperplastic thyroid follicles and mild lymphocyte infiltration, reflecting thyroid stimulation. On the contrary, TRAb2 samples revealed follicle destruction, macrophage infiltration, and sometimes fibrosis, consistent with a destructive process. Conclusions: Almost 60% of TRAb-positive AIT patients had a destructive thyroiditis. TRAb-positive tests in AIT patients do thus not necessarily imply a diagnosis of GD and AIT1, and should be evaluated in the clinical and biochemical setting of each AIT patient and confirmed by measuring thyroid-stimulating immunoglobulins.

PCB153 reduces apoptosis in primary cultures of murine pituitary cells through the activation of NF-κB mediated by PI3K/Akt.

Polychlorinated biphenyls (PCBs) are persistent pollutants involved in human tumorigenesis. PCB153 is a ubiquitous non-dioxin-like PCB with proliferative and anti-apoptotic effects. To explore the impact of PCB153 in the survival of pituitary cells, we exposed murine pituitary primary cells to PCB153 10 µM for 24 h. Apoptosis was assessed by RT-qPCR, Western-blot, immunoprecipitation, caspase activity, and immunofluorescence. We found that PCB153 decreased pituitary apoptosis through both the extrinsic and intrinsic pathways. PCB153 reduced the level of the pro-apoptotic protein p38-MAPK. Otherwise, PCB153 activated PI3K/Akt and Erk1/2 pathways and enhanced the expression and nuclear translocation of NF-κB. Cotreatments with specific inhibitors revealed that only PI3K/Akt changed the caspase-3 expression and NF-κB activation induced by PCB153. Also, PCB153 decreased the expression of the pro-apoptotic and pro-senescent cyclins p53 and p21. In summary, exposure to PCB153 leads to a downregulation of apoptosis in the pituitary driven by a PI3K/Akt-mediated activation of NF-κB.

Duration of Exposure to Thyrotoxicosis Increases Mortality of Compromised AIT Patients: the Role of Early Thyroidectomy.

CONTEXT: Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism has not yet been settled. OBJECTIVES: Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis. METHODS: Retrospective cohort study of 64 consecutive patients with AIT selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF <40%), Group 2 (thyrotoxic, LVEF ≥40%), Group 3 (euthyroid, LVEF < 40%), Group 4 (euthyroid, LVEF ≥40%). RESULTS: Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% versus 0%, respectively (P = .048), whereas 5-year cardiovascular mortality rates were 53.3% versus 12.3%, respectively (P = .081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, interquartile range [IQR] 82.5-140, vs 76 days, IQR 24.8-88.5, P = .021). Survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% versus 4% (P = .741) and 5-year cardiovascular mortality rates were 12.5% and 20% (P = .685), respectively. Age (hazard ratio [HR] 1.104, P = .029) and duration of exposure to thyrotoxicosis (HR 1.004, P = .039), but not presurgical serum thyroid hormone concentrations (P = .577 for free thyroxine, P = .217 for free triiodothyronine), were independent predictors of death. CONCLUSIONS: A prolonged exposure to thyrotoxicosis resulted in increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.

Comparison Between Total Thyroidectomy and Medical Therapy for Amiodarone-Induced Thyrotoxicosis.

CONTEXT: It is not known whether total thyroidectomy is more favorable than medical therapy for patients with amiodarone-induced thyrotoxicosis (AIT). OBJECTIVE: To compare total thyroidectomy with medical therapy on survival and cardiac function in AIT patients. METHODS: Observational longitudinal cohort study involving 207 AIT patients that had received total thyroidectomy (surgery group, n = 51) or medical therapy (medical therapy group, n = 156) over a 20-year period. AIT types and left ventricular ejection fraction (LVEF) classes were determined at diagnosis of AIT. Cardiac and thyroid function were reevaluated during the study period. Survival was estimated using the Kaplan-Meier method. RESULTS: Overall mortality and cardiac-specific mortality at 10 and 5 years, respectively, were lower in the surgery group than in the medical therapy group (P = 0.04 and P = 0.01, respectively). The lower mortality rate of the surgery group was due to patients with moderate to severely compromised LVEF (P = 0.005 vs medical therapy group). In contrast, mortality of patients with normal or mildly reduced LVEF did not differ between the 2 groups (P = 0.281 and P = 0.135, respectively). Death of patients with moderate to severe LV systolic dysfunction in the medical therapy group occurred after 82 days (interquartile range, 56-99), a period longer than that necessary to restore euthyroidism in the surgery group (26 days; interquartile range, 15-95; P = 0.038). Risk factors for mortality were age (hazard ratio [HR] = 1.036) and LVEF (HR = 0.964), whereas total thyroidectomy was shown to be a protective factor (HR = 0.210). LVEF increased in both groups after restoration of euthyroidism, above all in the most compromised patients in the surgery group. CONCLUSIONS: Total thyroidectomy could be considered the therapeutic choice for AIT patients with severe systolic dysfunction, whereas it is not superior to medical therapy in those with normal or mildly reduced LVEF.

Diabetes mellitus induced by somatostatin analogue therapy is not permanent in acromegalic patients.

CONTEXT: Therapy with somatostatin analogues (SSAs) may have deleterious effects on glucose metabolism in patients with acromegaly, often leading to the development of diabetes mellitus (DM). AIM: The aim of the study was to evaluate whether DM, developed during therapy with SSAs, may revert after drug withdrawal and cure of acromegaly with pituitary adenomectomy. DESIGN: Retrospective cohort study, in a tertiary referral centre. PATIENTS: Eighteen acromegalic patients without DM at the diagnosis of acromegaly treated with SSAs as a primary therapy, and then cured by pituitary adenomectomy. METHODS: Endocrine status and glucose homeostasis were evaluated at diagnosis of acromegaly and at least every 6 months during SSA therapy. At each visit, patients were classified into one of the following classes: normal glucose tolerance, prediabetes, overt diabetes. RESULTS: Median follow-up after starting SSAs therapy was 69 months (IQR 54.75-132.25). During SSA therapy, all patients had controlled acromegaly defined by normal serum IGF1 concentrations for the age. Of the 13 euglycaemic patients at diagnosis, three developed prediabetes and three diabetes, whereas, of the five prediabetic patients at diagnosis, two worsened to overt diabetes and three remained in the prediabetic range (P = 0.04). After curing acromegaly with pituitary adenomectomy and subsequent SSA withdrawal, prediabetes reverted in five of six patients, and diabetes in all five patients (three reverted to euglycaemia, while two reverted to prediabetes) (P = 0.01). CONCLUSIONS: In acromegalic patients with controlled disease, changes in glycaemic status induced by SSAs are not permanent.

Disease activity and lifestyle influence comorbidities and cardiovascular events in patients with acromegaly.

OBJECTIVE: The primary objective of this study is to identify the predictors of comorbidities and major adverse cardiovascular events (MACE) that can develop after diagnosis of acromegaly. The role of therapy for acromegaly in the event of such complications was also evaluated. DESIGN AND METHODS: Retrospective cohort study was conducted on 200 consecutive acromegalic patients in a tertiary referral center. The following outcomes were evaluated: diabetes, hypertension and MACE. Each patient was included in the analysis of a specific outcome, unless they were affected when acromegaly was diagnosed, and further classified as follows: (i) in remission after adenomectomy (Hx), (ii) controlled by somatostatin analogues (SSA) (SSAc) or (iii) not controlled by SSA (SSAnc). Data were evaluated using Cox regression analysis. RESULTS: After diagnosis of acromegaly, diabetes occurred in 40.8% of patients. The SSAnc group had a three-fold higher risk of diabetes (HR: 3.32, P = 0.006), whereas the SSAc group had a 1.4-fold higher risk of diabetes (HR: 1.43, P = 0.38) compared with the Hx group. Hypertension occurred in 35.5% of patients, after diagnosis. The determinants of hypertension were age (HR: 1.06, P = 0.01) and BMI (HR: 1.05, P = 0.01). MACE occurred in 11.8% of patients, after diagnosis. Age (HR: 1.09, P = 0.005) and smoking habit (HR: 5.95, P = 0.01) were predictors of MACE. Conversely, therapy for acromegaly did not influence hypertension or MACE. CONCLUSION: After diagnosis of acromegaly, control of the disease (irrespective of the type of treatment) and lifestyle are predictors of comorbidities and major adverse cardiovascular events.

Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series.

BACKGROUND: Approximately 60% of sporadic medullary thyroid carcinomas (sMTC) remain orphan of a recognized genetic cause. Recently, a high percentage of RAS point mutations have been described in RET-negative sMTC. The aim of this study was to assess the prevalence of RAS point mutations in a large series of MTC collected in four Italian centers. METHODS: For this purpose, we studied codons 12, 13, and 61 of H-, K-, and N-RAS genes in 188 MTC samples, either hereditary or sporadic, by direct sequencing. Correlations between the RAS mutational status and the clinical-pathological features of MTC patients as well as a meta-analysis of all published data were performed. RESULTS: The prevalence of RAS mutations in the present series of MTC was 10.1%, and 17.6% when considering only RET-negative cases. RAS mutations were found in MTC tumoral tissue, but not in peripheral blood indicating their somatic origin. A novel mutation in codon 72 (M72I) was found, but with a low or null transforming potential. No association was found between the presence of RAS mutations and the clinical-pathological features of the patients. Although not statistically significant, a positive association between the presence of RAS mutations and a better outcome was observed. The meta-analysis of all published studies confirmed a prevalence of 8.8% for RAS mutations in MTC. CONCLUSIONS: The prevalence of RAS mutations in our MTC series was relatively low and consistent with the meta-analysis data. Only somatic RAS mutations were found and only in RET-negative sMTC. Likewise, MTCs that harbor a RAS mutation identify a subgroup of tumors with less aggressive behavior. To our knowledge, this is the largest series of MTCs studied for the presence of mutations in RAS genes and the first meta-analysis on this specific topic.