Outcomes of Graves' Disease Patients Following Antithyroid Drugs, Radioactive Iodine, or Thyroidectomy as the First-line Treatment.

BACKGROUND: The long-term outcomes of first-line choice among ATD, RAI, and thyroidectomy for GD patients remain unclear. OBJECTIVE: To compare the long-term morbidity, mortality, relapse, and costs of GD patients receiving first-line treatment. METHODS: A population-based retrospective cohort of GD patients initiating first-line treatment with ATD, RAI, or thyroidectomy as a first-line primary treatment between 2006 and 2018 from Hong Kong Hospital Authority was analyzed. Risks of all-cause mortality, CVD, AF, psychological disease, diabetes, and hypertension were estimated using Cox proportional hazards regression models. The 10-year healthcare costs, change of comorbidities, and risk of relapse were compared across treatments. RESULTS: Over a median follow-up of 90 months with 47,470 person-years, 6385 patients (ATD, 74.93%; RAI, 19.95%; thyroidectomy, 5.12%) who received first-line treatment for GD were analyzed. Compared with ATD group, patients who had undergone surgery had significantly lower risks of all-cause mortality [hazard ratio (HR) = 0.363, 95% confidence interval (CI) = 0.332-0.396], CVD (HR = 0.216, 95% CI = 0.195-0.239), AF (HR = 0.103, 95% CI = 0.085-0.124), psychological disease (HR = 0.279, 95% CI = 0.258-0.301), diabetes (HR = 0.341, 95% CI = 0.305-0.381), and hypertension (HR = 0.673, 95% CI = 0.632-0.718). Meanwhile, RAI group was also associated with decreased risks of all-cause mortality (HR = 0.931, 95% CI = 0.882-0.982), CVD (HR = 0.784, 95% CI = 0.742-0.828), AF (HR = 0.622, 95% CI = 0.578-0.67), and psychological disease (HR = 0.895, 95% CI = 0.855-0.937). The relapse rate was 2.41% in surgery, 75.60% in ATD, and 19.53% in RAI group. The surgery group was observed with a significant lower Charlson Comorbidity Index score than the other 2 groups at the tenth-year follow-up. The mean 10-year cumulative healthcare costs in ATD, RAI, and surgery group was US$23915, US$24260, and US$20202, respectively. CONCLUSIONS: GD patients who received surgery as an initial treatment appeared to have lower chances of all-cause mortality, CVD, AF, psychological disease, diabetes, and hypertension in the long-term when compared to those treated with ATD or RAI. The surgery group had the lowest relapse and direct healthcare costs among the 3 treatment modalities. This long-term cohort study suggested surgery may have a larger role to play as an initial treatment for GD patients.

Increased Cardiovascular Mortality and Morbidity in Patients Treated for Toxic Nodular Goiter Compared to Graves' Disease and Nontoxic Goiter.

BACKGROUND: Previous research has suggested an increased risk of death and cardiovascular disease in patients treated for hyperthyroidism. However, studies on this subject are heterogeneous, often based on old data, or have not considered the impact that treatment for hyperthyroidism might have on cardiovascular risk. It is also unclear whether long-term prognosis differs between Graves' disease and toxic nodular goiter. The aim of this study was to use a very large cohort built on recent data to assess whether improvements in cardiovascular care might have changed the prognosis over time. The study also investigated the impact of different etiologies of hyperthyroidism. METHODS: This was an observational register study for the period 1976-2012, with subjects followed for a median period of 18.4 years. Study patients were Stockholm residents treated for Graves' disease or toxic nodular goiter with either radioactive iodine or surgery (N = 12,239). This group was compared to Stockholm residents treated for nontoxic goiter (N = 3685), with adjustments made for age, sex, comorbidities, and time of treatment. Comparisons were also made to the general population of Stockholm. Outcomes were assessed in terms of all-cause and cardiovascular mortality as well as cardiovascular morbidity. RESULTS: The hazard ratios (HR) for all-cause mortality and for cardiovascular mortality were 1.27 [confidence interval (CI) 1.20-1.35] and 1.29 [CI 1.17-1.42], respectively, for hyperthyroid patients compared to those with nontoxic goiter. For cardiovascular morbidity, the HR was 1.12 [CI 1.06-1.18]. Patients aged ≥45 years who were treated for toxic nodular goiter were generally at greater risk than others, and those included from the year 1990 and onwards were at greater risk than those included earlier. Increased all-cause mortality, as well as cardiovascular mortality and morbidity, were also seen in comparisons with the general population. CONCLUSIONS: This is the first large study to indicate that the long-term risk of death and cardiovascular disease in hyperthyroid subjects is due to the hyperthyroidism itself and not an effect of confounding introduced by its treatment. Much of the excess risk is confined to individuals treated for toxic nodular goiter. Despite advances in cardiovascular care during recent decades, hyperthyroidism is still a diagnosis associated with increased cardiovascular morbidity and mortality.

Mortality in Graves' orbitopathy is increased and influenced by gender, age and pre-existing morbidity: a nationwide Danish register study.

INTRODUCTION: It is unclear whether the excess mortality associated with Graves' disease differs between individuals with Graves' orbitopathy (GO) or without (GD). SUBJECTS AND METHODS: A nationwide, register-based cohort study in which all adult Danes diagnosed with GD (n = 28 461) and GO (n = 3965) between 1995 and 2012 were matched for age and gender with four control subjects. Median follow-up time was 7.9 years (range 0-17.5). Mortality risk in GO patients compared to the control population and compared to GD patients was calculated using Cox regression analyses, adjusting for pre-existing morbidity using the Charlson score. RESULTS: Adjusted mortality in Graves' disease overall (GD + GO) was significantly increased compared to that in the background population (HR = 1.18 (95% confidence interval: 1.15-1.21)). In GD and GO separately, adjusted mortality was also significantly higher than that in their respective control populations (HR: 1.19 (1.16-1.22) and HR: 1.23 (1.12-1.35) respectively). However, mortality in GO compared to that in GD was decreased (HR: 0.64 (0.59-0.69)), although this difference attenuated after adjustment for pre-existing morbidity, age and gender. Both GD and GO males had a significantly higher mortality than those in females. For GO, but not for GD, mortality risk was the highest in the youngest and decreased with increasing age. CONCLUSIONS: GD and GO were associated with increased mortality, especially in males. In GO, but not in GD patients, there was an inverse relationship between age and mortality. Surprisingly, and in need of further study, mortality was not higher in GO than that in GD individuals.

MiR-346 and TRAb as Predicative Factors for Relapse in Graves' Disease Within One Year.

Despite the efficacy and safety, antithyroid drug (ATD) therapy for Graves' disease (GD) is associated with a high risk of relapse, especially within the first year. The inability to predict whether and when relapse may occur is a major problem for ATD therapy. This study was aimed to investigate potential predicative factors for GD patients after ATD withdrawal. Consecutive patients newly diagnosed with GD and treated with ATD [methimazole (MMI)] were enrolled in this study. Univariate and multivariate Cox proportional hazard analyses were used for the analysis of predicative parameters for GD relapse after MMI withdrawal. Kaplan-Meier survival analysis and log-rank test were utilized for presenting the risk of relapse. Of the 103 patients included, 67 (65.0%) remained in remission and 36 (35.0%) had a relapse within 1 year after the MMI withdrawal. The multivariate analysis suggested significant predictive factors for GD relapse: patients with higher miR-346 expressions (≥median value) at diagnosis and at cessation, and lower TRAb levels at cessation. MiR-346 at diagnosis and cessation, and TRAb at cessation could serve as predictive factors for GD relapse within 1 year after drug withdrawal.

Total thyroidectomy as primary definitive treatment for Graves' hyperthyroidism.

The objective of this study was to compare the results of total thyroidectomy (TT) for hyperthyroidism secondary to Graves' disease (GD) with TT for other benign thyroid diseases to determine if TT should be considered more often as first-line therapy for GD. Seven hundred eighty patients underwent TT for benign disease: 203 for GD, 56 for other hyperthyroidisms, and 521 for other benign diseases from March 1, 2003, to December 31, 2009. The perioperative results of these three groups were compared for demographics, blood loss, operative time, complications, and hospitalization. There were no significant differences among the three groups except the patients with GD were more likely to be younger (42 vs 56 vs 57 years; P < 0.001), have more blood loss (154 vs 99 vs 110 mL; P = 0.05), and were more likely to develop permanent hypoparathyroidism (1.0 vs 1.8 vs 0%; P = 0.03) when compared with other causes of hyperthyroidism and other benign thyroid diseases. Permanent recurrent laryngeal nerve injury did not occur in the GD group (0 vs 0 vs 0.4% nerves at risk; P = 0.69) with transient recurrent laryngeal nerve injury occurring in 1.7 versus 2.7 versus 3.1 per cent nerves at risk (P = 0.35). The lack of a euthyroid state preoperatively had no influence on surgical outcomes or complications. Eighty percent of the TTs for GD were done as same-day outpatient procedures. TT offers a safe, low-risk, and rapid cure for GD to justifiably be considered as a reasonable first-line therapy in selected patients with Graves' hyperthyroidism.

Increased mortality in patients with differentiated thyroid cancer associated with Graves' disease.

CONTEXT: We previously reported that differentiated thyroid cancer (DTC) has higher aggressiveness and poorer prognosis in patients with Graves' disease (GD) than DTC in euthyroid control patients. Subsequent studies on this issue reached controversial conclusions. Genetic and environmental factors, as well as the lack of appropriate control subjects and/or inadequate patient follow-up, may account for these discrepancies. OBJECTIVE: The aim of this study was to investigate the long-term disease-specific mortality of nonoccult DTCs occurring in patients with GD compared with DTCs in matched euthyroid control patients. PATIENTS AND DESIGN: The previously described cohorts of nonoccult DTCs occurring in either patients with GD (DTC-GD, n = 21) or matched euthyroid DTC control patients (n = 70) were compared again after a longer follow-up (50-363.6 months; median, 165.6 months) to compare the major clinical endpoints of persistent/recurrent disease and overall survival. Both cohorts were recruited in 1982-1994 at a single institution. All patients had undergone total thyroidectomy and were followed up according to a standardized protocol. RESULTS: Persistent/recurrent disease was more frequent in DTC-GD patients than in control patients (P = .0119). Disease-specific mortality was also significantly higher in DTC-GD patients (6 of 21, 28.6%) than in euthyroid control patients (2 of 70, 2.9%) (P = .0001). At the last visit, the percentage of disease-free patients was 57.1% (12 of 21) in the DTC-GD group vs 87.1% (61 of 70) in the control group (P = .0025). CONCLUSIONS: Nonoccult DTCs occurring in patients with GD cause increased disease-specific mortality compared with DTCs in matched euthyroid control patients. These findings emphasize the need for early diagnosis and aggressive treatment of nonoccult DTCs in patients with GD.

Graves' disease and toxic nodular goiter are both associated with increased mortality but differ with respect to the cause of death: a Danish population-based register study.

BACKGROUND: Hyperthyroidism has been associated with increased all-cause mortality. Whether the underlying cause of hyperthyroidism influences this association is unclear. Our objectives were to explore whether mortality risk and cause of death differ between Graves' disease (GD) and toxic nodular goiter (TNG). METHODS: This is an observational cohort study, using record-linkage data from nationwide Danish health registers. A total of 1291 subjects with GD and 861 with TNG, treated in a hospital setting, were identified and followed for a mean period of 11 years. Cases were matched 1:4 with nonhyperthyroid controls with respect to age and sex. The hazard ratio (HR) for mortality was calculated using Cox regression analyses. All analyses were adjusted for comorbidity using the Charlson score. RESULTS: Both GD (HR=1.42 [95% confidence interval (CI) 1.25-1.60]) and TNG (HR=1.22 [CI 1.07-1.40]) were associated with increased all-cause mortality. After stratification for the cause of death, GD was associated with increased mortality due to cardiovascular diseases (HR=1.49 [CI 1.25-1.77]) and lung diseases (HR=1.91 [CI 1.37-2.65]), whereas TNG was associated with increased cancer mortality (HR=1.36 [CI 1.06-1.75]). When analyzing mortality in GD using TNG individuals as controls, there was no significant difference in all-cause mortality between GD and TNG. However, GD was clearly associated with a higher cardiovascular mortality (HR=1.39 [CI 1.10-1.76]) compared to TNG. CONCLUSION: Both GD and TNG, treated in a hospital setting, are associated with increased all-cause mortality. The causes of death differ between the two phenotypes, with cardiovascular mortality being significantly higher in GD.

(131)I therapy in patients with benign thyroid disease does not conclusively lead to a higher risk of subsequent malignancies.

UNLABELLED: Due to its excellent tolerability and low incidence of side effects, 131I therapy has been the treatment of choice for benign thyroid diseases for over 60 years. A potentially increased risk of malignancies due to this therapy is however still subject of debate. AIM: To review the literature pertaining to 131I therapy of benign thyroid diseases in order to establish whether there is an increased incidence of, or increased mortality due to malignancies of the thyroid or other organs. METHODS: In order to allow for sufficient long-term follow-up time after 131I therapy, only literature after 1990 was reviewed. Two criteria were applied to consider an increased incidence of malignancies linked to 131I therapy: a) there should be a latency period of at least 5 years between 131I therapy and the observation of an increased risk b) an elevated risk should increase with increasing radiation exposure. RESULTS: A total of 7 studies reporting cancer incidence and / or mortality in 4 different patient collectives spanning a total of 54510 patients over an observation period varying from 2-49 years were found. Although some studies detected a slightly increased risk for malignancies of the thyroid or the digestive system, others did not find these effects - while other studies even reported a slightly lower risk of malignant (thyroid) disease after 131I therapy for benign thyroid diseases. CONCLUSION: As over 60 years of experience has thus far failed to produce conclusive evidence to the contrary, it can be concluded that there is no increased risk of malignancies after 131I therapy for benign thyroid disease.

Surgical management of Graves disease in childhood and adolescence: an institutional experience.

BACKGROUND: Graves disease is the most common cause of hyperthyroidism in children. Medical therapy, radioiodine ablation, and thyroidectomy are all treatment options. To evaluate the safety and efficacy of operative therapy, we updated our operative experience with pediatric Graves disease at a single tertiary care center. METHODS: The medical records of children <18 years old who underwent thyroidectomy for Graves disease between 1986-2003 were reviewed. RESULTS: We identified 78 patients (median age, 13.8 years; 87% female). The most common presenting signs and symptoms included heat intolerance (61%), decreased academic performance (50%), tremor (49%), and ophthalmopathy (43%). All patients had clinical and laboratory evidence of autoimmune thyrotoxicosis. Sixty-nine percent chose operative therapy because of failure of medical therapy or adverse drug reactions. Near-total thyroidectomy was the most common surgical procedure performed (65%). Pathology demonstrated previously unrecognized thyroid malignancies in 4 (5%) patients. Operative morbidities were transient and included hypoparathyroidism (6%) and recurrent laryngeal nerve neuropraxia (1%). Three (4%) patients who underwent subtotal thyroidectomy developed recurrent hyperthyroidism; all were treated successfully with radioiodine ablation. Of patients presenting with ophthalmopathy, 85% noted improvement postoperatively, while 1 (3%) patient experienced worsening of symptoms. Only 5% developed new-onset Graves ophthalmopathy after operation. CONCLUSIONS: Near-total thyroidectomy for Graves disease in children is safe and effective when performed by experienced thyroid surgeons. In addition to relief of systemic symptoms, the majority of patients presenting with Graves ophthalmopathy experienced improvement of their ocular disease after operation. In 5% of patients, surgical management allowed for detection and treatment of clinically occult thyroid malignancies.

Extensive thyroidectomy in Graves' disease.

BACKGROUND: The best surgical treatment for hyperthyroidism caused by Graves' disease remains a controversial subject. METHODS: Seven hundred fourteen consecutive patients underwent total or near-total thyroidectomy for Graves' disease in a 13-year period. In a first analysis, postoperative rates of suffocating hematoma, wound infection, recurrent laryngeal nerve (RLN) palsy, hypoparathyroidism, and persistence or recurrence of hyperthyroidism, were studied and compared with the same parameters in 4,426 patients who underwent bilateral thyroid gland resection for other conditions. A second analysis identified factors associated with postoperative complications among Graves' disease patients. RESULTS: Comparing Graves' disease patients with patients who had bilateral thyroid resection for other conditions, the transient morbidity rate was 13.3% versus 8.2% (p < 0.0001), with 10.2% versus 5.0% (p < 0.0001) hypoparathyroidism, 2.2% versus 1.7% (p = 0.35) RLN palsy, 1.7% versus 0.9% (p < 0.05) suffocating hematoma, and 0.3% versus 0.4% (p = 0.67) wound infection, respectively. Permanent morbidity rate was 2% versus 2.2% (p = 0.72), including 0.4% versus 0.6% RLN palsy and 1.5% versus 1.7% hypoparathyroidism. Among the Graves' disease patients, univariate analysis revealed that those who experienced postoperative complications had a higher weight resected thyroid gland (odds ratio = 1.5; 95% CI, 1.0-2.3) and a higher rate of total thyroidectomy (24.4% versus 19.5%, odds ratio = 2.2; 95% CI, 1.4-3.4) than patients without complications. In the multivariable model, these two factors remained independent. There was no recurrence of hyperthyroidism with a median followup of 6.7 years (interquartile range 4.1 to 10.1 years). Persistent hyperthyroidism developed in three patients. CONCLUSIONS: Total or near-total thyroidectomy is an effective and safe treatment for Graves' disease when performed by an experienced surgeon.

Amiodarone-induced thyrotoxicosis: left ventricular dysfunction is associated with increased mortality.

OBJECTIVE: Amiodarone-induced thyrotoxicosis (AIT) is a challenging management problem, since patients treated with amiodarone invariably have underlying heart disease. Consequently, thyrotoxicosis can significantly contribute to increased morbidity and mortality. The aim of this study was to compare the clinical outcome and hormone profiles of patients with AIT (n = 60) with those with Graves' thyrotoxicosis (n = 49) and toxic multinodular goitre (MNG, n = 40). DESIGN: A retrospective study of patients with AIT in a single institution was conducted. METHODS: Data from patients with AIT over 12 years were collected. RESULTS: Mean TSH levels were significantly suppressed in all three groups. However, there was no intergroup significant difference. Free thyroxine (T4) levels were significantly higher in AIT (45.6 +/- 3.5 pmol/l) and Graves' disease (44.6 +/- 4.0 pmol/l) compared with toxic MNG (31.5 +/- 5.1 pmol/l, P < 0.05). In contrast, free triiodothyronine (T3) levels were only significantly higher in Graves' disease (14.7 +/- 1.5 pmol/l, P = 0.002) compared with AIT (8.6 +/- 0.7 pmol/l) and toxic MNG (7.4 +/- 0.5 pmol/l). Six deaths occurred in the patients with AIT (10.0%, P < 0.01) and no deaths occurred in the other groups. Amiodarone treatment (P = 0.002) was the most significant predictor of death, whereas free T4, free T3 and age did not affect outcome. Within the amiodarone-treated group severe left ventricular dysfunction (P = 0.0001) was significantly associated with death. CONCLUSIONS: (i) AIT differs from other forms of thyrotoxicosis, and (ii) severe left ventricular dysfunction is associated with increased mortality in AIT.

Prognosis of small thyroid cancer in patients with Graves' disease.

BACKGROUND: To find the best ways to follow up patients with small thyroid cancer (STC; 1 cm or less in diameter) and concomitant Graves' disease, this study examined whether such patients had the same excellent prognosis as those with STC without Graves' disease. METHODS: Between 1970 and 1996, 2199 patients were diagnosed as having STC by pathology after thyroidectomy. Of those, 509 patients (33 males and 476 females, mean age 43.5 years) underwent thyroidectomy for Graves' disease. Control patients with STC without Graves' disease were matched for age, sex, treatment year and tumour size (33 males and 476 females, mean age 44.0 years). RESULTS: Patients with STC and Graves' disease had a longer disease-free survival than those with STC alone (99 and 93 per cent at 20 years' follow-up, respectively; P < 0.001). The Cox's proportional hazard analysis showed that concomitant Graves' disease and age at surgery are more significant factors for predicting disease-free survival than surgical procedures. CONCLUSION: Patients who undergo thyroidectomy for Graves' disease and are found to have STC have an excellent prognosis and longer disease-free survival than patients with STC alone.

Thyroid disease and increased cardiovascular risk.

The effects of thyroid dysfunction are thought to be reversible on restoration of euthyroidism, but postmortem and epidemiologic data suggest that subclinical or treated thyroid disease is associated with increased vascular risk. In order to determine the extent of this risk, and to explore whether the nature and/or treatment of thyroid disease are critical in this relationship, we used medical record linkage to match patients with treated thyroid disease of various etiologies with routinely collected national inpatient and daycase hospital discharge records and death records, and assessed the number of hospitalizations from cardiovascular or cerebrovascular disease or death in patients with thyroid disease and control patients. Patients treated for Graves' disease had more hospitalizations from cardiovascular disease than controls (relative risk, 1.42; 95% confidence interval, 1.20 to 1.67; p < 0.001). Toxic multinodular goiter was also associated with significantly higher rates of cardiovascular disease (relative risk, 1.50; 95% confidence interval, 1.11 to 2.02; p = 0.008). Patients with Hashimoto's thyroiditis aged over 50 years had a threefold increase in cardiovascular admissions compared to controls (23.5% and 6.5%, respectively; 95% confidence interval for difference, 6.0% to 27.9%; p = 0.003). Thus, different forms of thyroid disease were associated with increased long-term vascular risk despite restoration of euthyroidism. The mechanisms that mediate this risk are unclear but may not involve thyroid hormone abnormality.

[Clinical evolution of a cohort of patients with Graves-Basedow disease treated with metimazole]. / Evolución clínica de una cohorte de pacientes con enfermedad de Graves-Basedow tratados con metimazol.

BACKGROUND: Prospective studies of Graves-Basedow disease in Spain are scarce. Our objective was to evaluate the clinical and biochemical evolution of a cohort of patients with Graves-Basedow disease. PATIENTS AND METHOD: 202 patients with Graves-Basedow disease diagnosed between January 1997 and June 1999. RESULTS: 5.9% of patients received 131I and 2.5% underwent surgery after treatment with methimazole. A relapse was observed in 23.3% patients. In the survival analysis, significant differences with regard to the rate of relapse were observed according to the goitre degree. CONCLUSIONS: In our study, all patients reached remission with methimazole. There was a high rate of relapse following discontinuation of therapy within the first months. Goitre size at the time of diagnosis was a significant determining factor of relapse.

A long-term follow-up study after retro-orbital irradiation for Graves' ophthalmopathy.

PURPOSE: The aim of this retrospective analysis was to find out whether low-dose radiation, which is used in the treatment of Graves' ophthalmopathy, could cause radiation-induced cancer, which would in turn adversely affect the survival of the irradiated population and cause an increase in the cancer-specific death rate. METHODS AND MATERIALS: From 1963 to 1978, 250 patients received bilateral orbital irradiation for a progressive Graves' ophthalmopathy. Median age was 49 years. Overall survival and causes of death were evaluated with the help of patients still living, registration offices, medical records, referring physicians, and relatives. Survival curves were calculated with the Kaplan-Meier method. The outcome for each patient was compared with data from life tables regarding gender, age, and calendar period-specific person-years at risk. In addition, treatment outcome for living patients was evaluated with a questionnaire. RESULTS: After a median follow-up of 31 years, 102 patients are still alive, 123 patients have died, and 25 patients have been lost to follow-up. The 10-year, 20-year, and 30-year survival rates were 89%, 68%, and 49%, compared with the age-adapted survival rate of the normal population of 92%, 76%, and 52%. Evaluation of cancer-specific survival was possible in 166 cases. The 10-year, 20-year, and 30-year cancer-specific survival rates were 98%, 92%, and 88%, compared with 97%, 93%, and 87% in the normal population. Treatment response was evaluable in 94 cases. A complete response was reported in 41 patients, a partial response in 39 patients, and no change in 14 patients. CONCLUSIONS: No significant evidence of radiation-induced cancer death was seen in this small cohort of patients treated with radiotherapy for Graves' ophthalmopathy. The long-term treatment results seem to be satisfactory. Studies with greater numbers of patients are necessary to examine the risks and benefits more precisely.