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Cardiothyreosis: Prevalence and risk factors
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Annales d’Endocrinologie 80 (2019) 211–215
Original article
Cardiothyreosis: Prevalence and risk factors La cardiothyréose : prévalence et facteurs de risque Meriem Yazidi a,∗ , Mélika Chihaoui a , Hiba Oueslati a , Fatma Chaker a , Ons Rjeb a , Salsabil Rjaibi b , Sana Ouali c , Hédia Slimane a a
Université de Tunis El Manar, faculté de médecine de Tunis, department of Endocrinology, La Rabta hospital, 1007 Tunis, Tunisia b Université de Tunis El Manar, faculté de médecine de Tunis, Department of Epidemiology, 1007 Tunis, Tunisia c Université de Tunis El Manar, faculté de médecine de Tunis, La Rabta Hospital, Cardiology department, 1007 Tunis, Tunisia
Abstract Cardiothyreosis (CT) or thyrotoxic heart disease is associated with higher morbidity and mortality than the other forms of hyperthyroidism. Its risk factors have been analyzed in a limited number of studies. The aims of our study were to investigate the prevalence of CT and its risk factors in patients with hyperthyroidism. Methods. – We identified 538 patients with a hospital discharge diagnosis of hyperthyroidism from January 2000 to December 2015. Among them, 35 patients were diagnosed as having CT. Their demographic, clinical and biological characteristics were studied and compared with those of 72 controls (patients admitted for hyperthyroidism without CT) randomly selected using univariate and multivariate analysis. Results. – The prevalence of CT in patients hospitalized with overt hyperthyroidism was 6.5%. The cardiac complications seen were atrial fibrillation (AF) in 33 cases (6.1%) and cardiac heart failure (CHF) in 11 cases (2%). The risk factors of CT were age greater than 50 years (OR = 13.1; 95% CI [4.9–34.4]), low socioeconomic status (OR = 2.8; 95% CI [1.2–6.7]), low educational level (OR = 3.1; 95% CI [1.2–8.3]), personal history of hypertension (OR = 3.5; 95% CI [1.1–11.2]) and a multinodular toxic goiter as the etiology of hyperthyroidism (OR = 4.6; 95% CI [1.6–13.9]). After multivariate analysis, age greater than 50 years was the only independent risk factor of CT (adjusted OR = 11.6; 95% CI [2.7–49.5]). Severe biological hyperthyroidism (FT4 > 3 times normal) was associated with a lower risk of CT (adjusted OR = 0.2; 95% CI [0.1–0.9]). Conclusions. – The prevalence of CT in patients with overt hyperthyroidism was relatively low. Cardiac complications were AF and CHF with a clear predominance of AF. Advanced age was the only independent risk factor of CT. Cardiac complications may be seen even if hyperthyroidism is not biologically severe. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Hyperthyroidism; Complication; Atrial fibrillation; Heart failure
Résumé La cardiothyréose (CT) ou cardiopathie thyrotoxique est associée à une plus lourde morbi-mortalité que les autres formes d’hyperthyroïdie. Ses facteurs de risque n’ont été analysés que par un nombre restreint d’études. Les objectifs de notre travail étaient de déterminer la prévalence de la CT et de ses facteurs de risque chez les patients qui présentent une hyperthyroïdie. Méthodes. – Nous avons colligé 538 cas d’hyperthyroïdie hospitalisés entre janvier 2000 et décembre 2015. Parmi eux, 35 cas de CT ont été identifiés. Nous avons comparé, par analyses univariée et multivariée, les caractéristiques démographiques, cliniques et biologiques de ces patients à celles de 72 témoins (patients admis pour hyperthyroïdie non compliquée de CT) tirés au sort. Résultats. – La prévalence de la CT chez les patients hospitalisés pour hyperthyroïdie était de 6,5 %. Les complications cardiaques observées étaient l’arythmie complète par fibrillation auriculaire (ACFA) dans 33 cas (6,1 %) et l’insuffisance cardiaque dans 11 cas (2 %). Les facteurs de risque de CT étaient l’âge supérieur à 50 ans (OR = 13,1 ; IC 95 % [4,9–34,4]), le bas niveau socioéconomique (OR = 2,8 ; IC 95 % [1,2–6,7]) et d’instruction (OR = 3,1 ; IC 95 % [1,2–8,3]), les antécédents personnels d’hypertension artérielle (OR = 3,5 IC 95 % [1,1–11,2]) et l’étiologie multinodulaire toxique de l’hyperthyroïdie (OR = 4,6 ; IC 95 % [1,6–13,9]). Après analyse multivariée, l’âge supérieur à 50 ans était le seul facteur de risque de CT (OR ajusté = 11,6 [IC 95 %, 2,7–49,5]). Une hyperthyroïdie sévère sur le plan biologique (FT4 > 3 fois la normale) était associée à un moindre risque de cardiothyréose (OR ajusté = 0,2 [IC 95 %, 0,1–0,9]).
∗
Corresponding author. E-mail addresses: [email protected] (M. Yazidi), [email protected] (M. Chihaoui), [email protected] (F. Chaker), [email protected] (O. Rjeb), [email protected] (H. Slimane). https://doi.org/10.1016/j.ando.2017.11.004 0003-4266/© 2017 Elsevier Masson SAS. All rights reserved.
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Conclusions. – La prévalence de la CT au cours de l’hyperthyroïdie était relativement faible. Les complications cardiaques de l’hyperthyroïdie étaient représentées par l’ACFA et l’insuffisance cardiaque avec une nette prédominance de l’ACFA. L’âge avancé était le seul facteur de risque indépendant de CT. Une hyperthyroïdie non sévère sur le plan biologique n’élimine pas le risque de complications cardiaques. © 2017 Elsevier Masson SAS. Tous droits r´eserv´es. Mots clés : Hyperthyroïdie ; Complications ; ACFA ; Insuffisance cardiaque
1. Introduction Overt hyperthyroidism is a common disorder with prominent cardiovascular effects. It creates a hyperdynamic cardiovascular state because of enhanced left ventricular function, increased heart rate and marked fall in systemic vascular resistance [1–4]. Because of its multiple effects on the cardiovascular system, hyperthyroidism can lead to severe heart complications. Since 1995, hyperthyroidism is considered as an etiology of cardiomyopathy in the WHO classification [5]. Cardiothyreosis (CT), or thyrotoxic heart disease, is defined as an association of hyperthyroidism with one or more heart complications [5–7]. It is a not well-defined disease entity given the lack of diagnostic criteria regarding the type of cardiac complication. Traditionally, CT includes rhythmic troubles, congestive heart failure and coronary insufficiency [1,7–9]. Some authors also include atrioventricular blocks, left ventricular hypertrophy, diastolic dysfunction and more recently pulmonary hypertension [7,9–13]. Atrial fibrillation (AF) is the best known and the most studied cardiac complication. CT frequency varies widely according to the type of population studied and the used diagnostic criteria. It is associated with higher morbidity and mortality than the other forms of hyperthyroidism. Early diagnosis and management of thyrotoxicosis may prevent and improve the prognosis of cardiac complications [14–17]. Factors associated with CT have been analyzed in a limited number of studies. An advanced age and a preexisting cardiac disease are the most known risk factors. Conflicting data exist with respect to other factors, such as male gender, thyrotoxicosis severity, duration of the thyrotoxic state and the etiology of hyperthyroidism. We therefore carried out this study to determine the prevalence and risk factors of CT among patients with overt hyperthyroidism.
2. Methods It was a retrospective case control study conducted at the department of Endocrinology of the university hospital La Rabta in Tunis (Tunisia). We identified all patients with a hospital discharge diagnosis of hyperthyroidism from January 2000 to December 2015. Hyperthyroidism was defined as an increased serum-free thyroxine (FT4) concentration and a concomitant suppressed thyroid-stimulating hormone level (TSH). Patients with subclinical hyperthyroidism (low level of TSH with normal level of FT4) were excluded. A total of 538 patients were included. FT4 and TSH levels were measured by the chemiluminescent microparticle immunoassay (CMIA) method on
Abbott Architect ci8200 analyzer using the Architect/Abbott kit (Chicago, USA). 2.1. Definition of cases and controls Cases were patients with CT defined as an association of hyperthyroidism with one of the following heart complications: heart rhythm disorder (other than sinus tachycardia), congestive heart failure (CHF) or coronary insufficiency. Patients with documented preexisting heart rhythm disorder, CHF or coronary artery disease were excluded. Patient who developed hyperthyroidism after treatment with amiodarone for heart rhythm disorder were also excluded. Thirty-five patients with CT were identified. Seventy-two controls were randomly selected from patients admitted for hyperthyroidism without CT during the same study period. 2.2. Data collection Demographic characteristics, clinical and paraclinical data were retrospectively collected from the medical records. 2.3. Diagnostic criteria of the studied parameters Illiterate patients or patients with a primary school education were classified as having a low level of education. Indigent patients receiving free medical care were classified as having a low socioeconomic status. Smoking status was documented as non-smoker or current smoker. Etiology of hyperthyroidism was categorized by clinical, immunologic, sonographic and scintigraphic criteria into five diagnostic groups: Graves’ disease (hyperthyroidism with three of the following: Graves’ ophthalmopathy, significant titer of TSH-receptor antibodies or overall increased uptake on Tcm99 thyroid scanning), toxic multinodular goiter (multiple hyperfunctioning nodules in scintigraphy), toxic adenoma (a solitary hyperfunctioning thyroid nodule in scintigraphy), thyroiditis (low Tcm99 uptake scan) and hyperthyroidism of indeterminate etiology. Hyperthyroidism was considered as biologically severe when the FT4 level was higher than 3 times the upper normal value. 2.4. Statistical analysis All data were analyzed using SPSS for Windows version 21.0. Continuous variables were expressed as means ± SEM and categorical variables were expressed as numbers with percentages. Statistical comparisons were performed using Student’s t test or
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Table 1 Comparison of clinical and paraclinical parameters between patients with cardiothyreosis and controls.
Age at diagnosis of hyperthyroidism > 50 years Male gender Low level of education Low socioeconomic status Current smoker History of hypertension Diabetes mellitus Graves’ disease Toxic multinodular goiter Toxic adenoma Thyroiditis Severe biological hyperthyroidism
26 (74) 14 (40) 25 (71) 20 (57) 12 (34) 8 (23) 2 (6) 18 (51) 10 (28) 1 (3) 1 (3) 7 (20)
13 (18) 21 (29) 37 (51) 25 (35) 15 (21) 6 (8) 2 (3) 60 (83) 7 (10) 2 (3) 2 (3) 32 (44)
P
OR [CI 95%]
< 0.001 0.26 0.015 0.013 0.11 0.02 0.43 0.005 0.004 0.88 0.88 0.014
13.1 [4.9–34.4] 0.6 [0.2–1.4] 3.1 [1.2–8.3] 2.8 [1.2–6.7] 2.1 [0.8–5.1] 3.5 [1.1–11.2] 2.2 [0.3–16.2] 0.2 [0.1–0.7] 4.6 [1.6–13.9] 1.2 [0.1–13.7] 1.2 [0.1–13.7] 0.3 [0.3–0.9]
Values are in n (%). CT: cardiothyreosis, OR: odds ratio, CI: confidence interval.
Fisher’s exact test, as appropriate. Statistical significance was posted at level P < 0.05. We used univariate logistic regression analysis to calculate odds ratios (OR) and to identify which factors were potentially associated with CT. All factors with a P < 0.2 on the univariate analysis were included in a multivariate logistic regression model. Adjusted OR was calculated to identify independent risk factors for CT. The study was approved by our hospital ethics committee.
3. Results Among the 538 patients admitted for hyperthyroidism during the study period, 6.5% (n = 35) were diagnosed as having CT. The cardiac complications were AF in 33 cases (6.1%) and CHF in 11 cases (2%). AF and CHF were associated in 9 patients (1.7%). No case of coronary heart disease was diagnosed. The comparison of the different parameters between the patients with CT and the controls is represented in Table 1. Patients with CT were significantly older (57 ± 14 vs. 35 ± 14 years, P < 0.001), had more frequently a low educational and socioeconomic levels and had a higher prevalence of hypertension history compared with controls. Toxic multinodular goiter was more prevalent among patients with CT whereas Graves’ disease was more prevalent among controls. Severe biological hyperthyroidism was associated with a lower risk of CT. Serum FT4 level was lower in patients with CT (3.6 ± 1.3 vs. 4.4 ± 1.6 ng/dL, P = 0.01). No difference was found between cases and controls for the TSH level (0.027 ± 0.02 vs. 0.018 ± 0.03 UI/mL, P = 0.09). There was no significant difference in the duration of hyperthyroidism symptoms between cases and controls (10.5 ± 13.5 vs. 12.3 ± 14.4 months; P = 0.57). No difference was found in the mean number of signs of thyrotoxicosis (4.6 ± 1.8 vs. 4.8 ± 3.7 signs; P = 0.72). Results of multiple logistic regression analysis are shown in Table 2. In multivariate analysis, an age over 50 years at diagnosis was the only independent risk factor of CT. Severe biological hyperthyroidism remained a protective factor of CT.
Table 2 Results of multivariate analysis. P value adjusted; OR [CI 95%] Age at diagnosis of hyperthyroidism > 50: 0.001; 11.6 [2.7–49.5] years Male gender: 0.33; 2.9 [0.3–27.1] Low level of education: 0.53; 1.6 [0.3–7.8] Low socioeconomic status: 0.9; 1.1 [0.2–5.0] Current smoker: 0.12; 4.9 [0.6–37.4] History of hypertension: 0.35; 2.2 [0.4–12.0] Graves’ disease: 0.78; 0.7 [0.1–8.7] Toxic multinodular goiter; 0.69; 0.5 [0.1–10.1] Severe biological; 0.04; 0.2 [0.1–0.9] Hyperthyroidism OR: odd ratio; CI: confidence interval.
4. Discussion The prevalence of CT in our study was relatively low: 6.5% of patients admitted for overt hyperthyroidism. The two types of cardiac disease observed were CHF and AF with a clear predominance of the latter. Age above 50 years was the only independent risk factor of CT. Severe biological hyperthyroidism was a protective factor of CT. Our study confirms that age is independently associated with a higher risk of AF and CHF in hyperthyroid patients [8,18–22]. Actually, the risks of AF and CHF increase with age regardless of the presence of hyperthyroidism or not [23,24]. These risks are however higher in case of hyperthyroidism [20,22]. Several reasons may explain the increased risk of CT with age. First, hyperthyroidism is usually associated with mild and nonspecific symptoms in the elderly [19,22] leading to a delayed diagnosis and the occurrence of complications. Second, hyperthyroidism is associated with shortened repolarization time in the atrium; this may cause AF in a population that is already prone to arrhythmias such as the elderly [19,25]. Finally, the prevalence of hypertensive, ischemic and degenerative heart diseases are increased with age leading to a greater susceptibility to hemodynamic changes induced by hyperthyroidism [18]. Regarding the gender, some studies showed that cardiac complications in hyperthyroid patients were more common in men [19,20]. This was not the case in our study.
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Only few studies analyzed the involvement of socioeconomic and educational level in CT risk. The higher risk patients with low socioeconomic status or low educational level could be explained by the difficulties to reach health care centers. This may result in a delayed diagnosis and treatment. However, in multivariate analysis, low educational level and poor socioeconomic status were not independently associated with the risk of CT. The implication of cardiovascular risk factors in the occurrence of CT is controversial [8,19,20]. Age is probably a confounding factor for diabetes and hypertension whose prevalence increase with aging. According to Frost et al., hypertension and diabetes were not associated with a higher risk of AF in patients with hyperthyroidism [19]. Similarly, in our study, smoking, diabetes and hypertension were not associated with a higher risk of CT after multivariate analysis. On the other hand, the association between the etiology of hyperthyroidism and CT reflects more an age difference between cases and controls than a pathophysiological mechanism related to a specific etiology [26]. Indeed, after univariate analysis, Graves’ disease was significantly more frequent in controls while toxic multinodular goiter was more frequent in patients with CT. However after adjustment, toxic multinodular goiter no longer appeared as an independent risk factor of CT. Few studies investigated the relationship between CT and thyrotoxicosis duration [20,27]. In the study of Ruiz et al., patients with longer disease duration had more severe myocardial damage [27]. However, in the study of Siu et al., there was no difference in the duration of thyrotoxicosis between patients with or without left ventricular systolic dysfunction [20]. Similarly in our study, the duration of hyperthyroidism symptoms was similar between cases and controls. It should be noted that the exact disease duration is difficult to identify. Patients with CT could have had a longer duration of the disease and particularly a long period of subclinical hyperthyroidism. Although usually asymptomatic, it was established that persistent subclinical hyperthyroidism was associated with AF and CHF especially in elderly patients [16,20]. Interestingly, severe biological hyperthyroidism was independently associated with a lower risk of CT. This result, which may seem paradoxical at first sight, has also been reported by other authors [7,20,28,29]. The higher frequency of toxic multinodular goiter in patients with CT might explain this finding. Indeed, there is often a delay in the diagnosis of toxic multinodular goiter as overt hyperthyroidism occurs after a longstanding period of subclinical hyperthyroidism [30,31]. The FT4 level increases thereafter gradually. On the other hand, the lower T4 levels in patients with cardiothyreosis could also be explained by the presence of an “euthyroid sick syndrome” in these patients with a complicated disease. In fact, in severe systemic illness, changes in thyroid function may occur leading to a decrease in T4 levels. Indeed, some patients with CHF have been described with an “euthyroid sick syndrome” [32,33]. In conclusion, a direct causal link between hyperthyroidism and cardiac complications cannot be asserted. It seems more likely that hyperthyroidism by increasing the workload on the heart and basal metabolism precipitated the onset of these
complications especially in frail and elderly subjects. This observation is in coherence with a recent consensus on hyperthyroidism status [34]. Our study has some methodological limitations. As cases, controls were selected among hospitalized patients who usually have more severe forms of hyperthyroidism than ambulatory patients. We also acknowledge the inability of the study to evaluate some contributing factors such as a pre-existing heart disease as echocardiography was only performed in patients with clinical or electrical signs of cardiac disease. Thus, the prevalence of subclinical heart disease in hyperthyroid patients remains unknown. Multivariate analysis, exclusion of patients with documented preexisting arrhythmia or CHF and exclusion of subjects who developed hyperthyroidism after treatment with amiodarone are strong points and allow us to relate with more certainty cardiac complications to hyperthyroidism. Disclosure of interest The authors declare that they have no competing interest. References [1] Dahl P, Danzi S, Klein I. Thyrotoxic cardiac disease. Curr Heart Fail Rep 2008;5:170–6. [2] Klein I, Ojamaa K. Thyrotoxicosis and the heart. Endocrinol Metab Clin North Am 1998;27:51–62. [3] Desforges JF, Woeber KA. Thyrotoxicosis and the Heart. N Engl J Med 1992;327:94–8. [4] Epstein FH, Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501–9. [5] Richardson P, McKenna RW, Bristow M, Maisch B, Mautner B, O’connell J, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 1996;93:841–2. [6] Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies an American heart association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. Circulation 2006;113:1807–16. [7] Babenko AY, Bairamov AA, Grineva EN, Ulupova EO. Thyrotoxic cardiomyopathy; 2012 [From basic research to clinical management, Prof. Josef Veselka (Ed.), ISBN: 978-953-307-834-2, InTech, Available from: http://www.intechopen.com/books/cardiomyopathies-from-basic-researchto-clinical-management/cardiomyopathy-at-ddysfunction-of-thyroid]. [8] Biondi B. Mechanisms in endocrinology: heart failure and thyroid dysfunction. Eur J Endocrinol 2012;167:609–18. [9] Siu C-W, Tse H-F, Lau C-P. Thyrotoxic heart disease. J HK Coll Cardiol 2005;13:16–20. [10] Li JH, Safford RE, Aduen JF, Heckman MG, Crook JE, Burger CD. Pulmonary hypertension and thyroid disease. Chest 2007;132:793–7. [11] Yue W-S, Chong B-H, Zhang X-H, Liao S-Y, Jim M-H, Kung AW, et al. Hyperthyroidism-induced left ventricular diastolic dysfunction: implication in hyperthyroidism-related heart failure. Clin Endocrinol 2011;74:636–43. [12] Dörr M, Wolff B, Robinson DM, John U, Lüdemann J, Meng W, et al. The association of thyroid function with cardiac mass and left ventricular hypertrophy. J Clin Endocrinol Metab 2005;90:673–7. [13] Sideris S, Benetos G, Gatzoulis K, Kallikazaros I. Atrioventricular conduction disturbances in hyperthyroidism. Hospital Chronicles 2014;9:275.
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ScienceDirect www.sciencedirect.com
Annales d’Endocrinologie 80 (2019) 211–215
Original article
Cardiothyreosis: Prevalence and risk factors La cardiothyréose : prévalence et facteurs de risque Meriem Yazidi a,∗ , Mélika Chihaoui a , Hiba Oueslati a , Fatma Chaker a , Ons Rjeb a , Salsabil Rjaibi b , Sana Ouali c , Hédia Slimane a a
Université de Tunis El Manar, faculté de médecine de Tunis, department of Endocrinology, La Rabta hospital, 1007 Tunis, Tunisia b Université de Tunis El Manar, faculté de médecine de Tunis, Department of Epidemiology, 1007 Tunis, Tunisia c Université de Tunis El Manar, faculté de médecine de Tunis, La Rabta Hospital, Cardiology department, 1007 Tunis, Tunisia
Abstract Cardiothyreosis (CT) or thyrotoxic heart disease is associated with higher morbidity and mortality than the other forms of hyperthyroidism. Its risk factors have been analyzed in a limited number of studies. The aims of our study were to investigate the prevalence of CT and its risk factors in patients with hyperthyroidism. Methods. – We identified 538 patients with a hospital discharge diagnosis of hyperthyroidism from January 2000 to December 2015. Among them, 35 patients were diagnosed as having CT. Their demographic, clinical and biological characteristics were studied and compared with those of 72 controls (patients admitted for hyperthyroidism without CT) randomly selected using univariate and multivariate analysis. Results. – The prevalence of CT in patients hospitalized with overt hyperthyroidism was 6.5%. The cardiac complications seen were atrial fibrillation (AF) in 33 cases (6.1%) and cardiac heart failure (CHF) in 11 cases (2%). The risk factors of CT were age greater than 50 years (OR = 13.1; 95% CI [4.9–34.4]), low socioeconomic status (OR = 2.8; 95% CI [1.2–6.7]), low educational level (OR = 3.1; 95% CI [1.2–8.3]), personal history of hypertension (OR = 3.5; 95% CI [1.1–11.2]) and a multinodular toxic goiter as the etiology of hyperthyroidism (OR = 4.6; 95% CI [1.6–13.9]). After multivariate analysis, age greater than 50 years was the only independent risk factor of CT (adjusted OR = 11.6; 95% CI [2.7–49.5]). Severe biological hyperthyroidism (FT4 > 3 times normal) was associated with a lower risk of CT (adjusted OR = 0.2; 95% CI [0.1–0.9]). Conclusions. – The prevalence of CT in patients with overt hyperthyroidism was relatively low. Cardiac complications were AF and CHF with a clear predominance of AF. Advanced age was the only independent risk factor of CT. Cardiac complications may be seen even if hyperthyroidism is not biologically severe. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Hyperthyroidism; Complication; Atrial fibrillation; Heart failure
Résumé La cardiothyréose (CT) ou cardiopathie thyrotoxique est associée à une plus lourde morbi-mortalité que les autres formes d’hyperthyroïdie. Ses facteurs de risque n’ont été analysés que par un nombre restreint d’études. Les objectifs de notre travail étaient de déterminer la prévalence de la CT et de ses facteurs de risque chez les patients qui présentent une hyperthyroïdie. Méthodes. – Nous avons colligé 538 cas d’hyperthyroïdie hospitalisés entre janvier 2000 et décembre 2015. Parmi eux, 35 cas de CT ont été identifiés. Nous avons comparé, par analyses univariée et multivariée, les caractéristiques démographiques, cliniques et biologiques de ces patients à celles de 72 témoins (patients admis pour hyperthyroïdie non compliquée de CT) tirés au sort. Résultats. – La prévalence de la CT chez les patients hospitalisés pour hyperthyroïdie était de 6,5 %. Les complications cardiaques observées étaient l’arythmie complète par fibrillation auriculaire (ACFA) dans 33 cas (6,1 %) et l’insuffisance cardiaque dans 11 cas (2 %). Les facteurs de risque de CT étaient l’âge supérieur à 50 ans (OR = 13,1 ; IC 95 % [4,9–34,4]), le bas niveau socioéconomique (OR = 2,8 ; IC 95 % [1,2–6,7]) et d’instruction (OR = 3,1 ; IC 95 % [1,2–8,3]), les antécédents personnels d’hypertension artérielle (OR = 3,5 IC 95 % [1,1–11,2]) et l’étiologie multinodulaire toxique de l’hyperthyroïdie (OR = 4,6 ; IC 95 % [1,6–13,9]). Après analyse multivariée, l’âge supérieur à 50 ans était le seul facteur de risque de CT (OR ajusté = 11,6 [IC 95 %, 2,7–49,5]). Une hyperthyroïdie sévère sur le plan biologique (FT4 > 3 fois la normale) était associée à un moindre risque de cardiothyréose (OR ajusté = 0,2 [IC 95 %, 0,1–0,9]).
∗
Corresponding author. E-mail addresses: [email protected] (M. Yazidi), [email protected] (M. Chihaoui), [email protected] (F. Chaker), [email protected] (O. Rjeb), [email protected] (H. Slimane). https://doi.org/10.1016/j.ando.2017.11.004 0003-4266/© 2017 Elsevier Masson SAS. All rights reserved.
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Conclusions. – La prévalence de la CT au cours de l’hyperthyroïdie était relativement faible. Les complications cardiaques de l’hyperthyroïdie étaient représentées par l’ACFA et l’insuffisance cardiaque avec une nette prédominance de l’ACFA. L’âge avancé était le seul facteur de risque indépendant de CT. Une hyperthyroïdie non sévère sur le plan biologique n’élimine pas le risque de complications cardiaques. © 2017 Elsevier Masson SAS. Tous droits r´eserv´es. Mots clés : Hyperthyroïdie ; Complications ; ACFA ; Insuffisance cardiaque
1. Introduction Overt hyperthyroidism is a common disorder with prominent cardiovascular effects. It creates a hyperdynamic cardiovascular state because of enhanced left ventricular function, increased heart rate and marked fall in systemic vascular resistance [1–4]. Because of its multiple effects on the cardiovascular system, hyperthyroidism can lead to severe heart complications. Since 1995, hyperthyroidism is considered as an etiology of cardiomyopathy in the WHO classification [5]. Cardiothyreosis (CT), or thyrotoxic heart disease, is defined as an association of hyperthyroidism with one or more heart complications [5–7]. It is a not well-defined disease entity given the lack of diagnostic criteria regarding the type of cardiac complication. Traditionally, CT includes rhythmic troubles, congestive heart failure and coronary insufficiency [1,7–9]. Some authors also include atrioventricular blocks, left ventricular hypertrophy, diastolic dysfunction and more recently pulmonary hypertension [7,9–13]. Atrial fibrillation (AF) is the best known and the most studied cardiac complication. CT frequency varies widely according to the type of population studied and the used diagnostic criteria. It is associated with higher morbidity and mortality than the other forms of hyperthyroidism. Early diagnosis and management of thyrotoxicosis may prevent and improve the prognosis of cardiac complications [14–17]. Factors associated with CT have been analyzed in a limited number of studies. An advanced age and a preexisting cardiac disease are the most known risk factors. Conflicting data exist with respect to other factors, such as male gender, thyrotoxicosis severity, duration of the thyrotoxic state and the etiology of hyperthyroidism. We therefore carried out this study to determine the prevalence and risk factors of CT among patients with overt hyperthyroidism.
2. Methods It was a retrospective case control study conducted at the department of Endocrinology of the university hospital La Rabta in Tunis (Tunisia). We identified all patients with a hospital discharge diagnosis of hyperthyroidism from January 2000 to December 2015. Hyperthyroidism was defined as an increased serum-free thyroxine (FT4) concentration and a concomitant suppressed thyroid-stimulating hormone level (TSH). Patients with subclinical hyperthyroidism (low level of TSH with normal level of FT4) were excluded. A total of 538 patients were included. FT4 and TSH levels were measured by the chemiluminescent microparticle immunoassay (CMIA) method on
Abbott Architect ci8200 analyzer using the Architect/Abbott kit (Chicago, USA). 2.1. Definition of cases and controls Cases were patients with CT defined as an association of hyperthyroidism with one of the following heart complications: heart rhythm disorder (other than sinus tachycardia), congestive heart failure (CHF) or coronary insufficiency. Patients with documented preexisting heart rhythm disorder, CHF or coronary artery disease were excluded. Patient who developed hyperthyroidism after treatment with amiodarone for heart rhythm disorder were also excluded. Thirty-five patients with CT were identified. Seventy-two controls were randomly selected from patients admitted for hyperthyroidism without CT during the same study period. 2.2. Data collection Demographic characteristics, clinical and paraclinical data were retrospectively collected from the medical records. 2.3. Diagnostic criteria of the studied parameters Illiterate patients or patients with a primary school education were classified as having a low level of education. Indigent patients receiving free medical care were classified as having a low socioeconomic status. Smoking status was documented as non-smoker or current smoker. Etiology of hyperthyroidism was categorized by clinical, immunologic, sonographic and scintigraphic criteria into five diagnostic groups: Graves’ disease (hyperthyroidism with three of the following: Graves’ ophthalmopathy, significant titer of TSH-receptor antibodies or overall increased uptake on Tcm99 thyroid scanning), toxic multinodular goiter (multiple hyperfunctioning nodules in scintigraphy), toxic adenoma (a solitary hyperfunctioning thyroid nodule in scintigraphy), thyroiditis (low Tcm99 uptake scan) and hyperthyroidism of indeterminate etiology. Hyperthyroidism was considered as biologically severe when the FT4 level was higher than 3 times the upper normal value. 2.4. Statistical analysis All data were analyzed using SPSS for Windows version 21.0. Continuous variables were expressed as means ± SEM and categorical variables were expressed as numbers with percentages. Statistical comparisons were performed using Student’s t test or
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Table 1 Comparison of clinical and paraclinical parameters between patients with cardiothyreosis and controls.
Age at diagnosis of hyperthyroidism > 50 years Male gender Low level of education Low socioeconomic status Current smoker History of hypertension Diabetes mellitus Graves’ disease Toxic multinodular goiter Toxic adenoma Thyroiditis Severe biological hyperthyroidism
26 (74) 14 (40) 25 (71) 20 (57) 12 (34) 8 (23) 2 (6) 18 (51) 10 (28) 1 (3) 1 (3) 7 (20)
13 (18) 21 (29) 37 (51) 25 (35) 15 (21) 6 (8) 2 (3) 60 (83) 7 (10) 2 (3) 2 (3) 32 (44)
P
OR [CI 95%]
< 0.001 0.26 0.015 0.013 0.11 0.02 0.43 0.005 0.004 0.88 0.88 0.014
13.1 [4.9–34.4] 0.6 [0.2–1.4] 3.1 [1.2–8.3] 2.8 [1.2–6.7] 2.1 [0.8–5.1] 3.5 [1.1–11.2] 2.2 [0.3–16.2] 0.2 [0.1–0.7] 4.6 [1.6–13.9] 1.2 [0.1–13.7] 1.2 [0.1–13.7] 0.3 [0.3–0.9]
Values are in n (%). CT: cardiothyreosis, OR: odds ratio, CI: confidence interval.
Fisher’s exact test, as appropriate. Statistical significance was posted at level P < 0.05. We used univariate logistic regression analysis to calculate odds ratios (OR) and to identify which factors were potentially associated with CT. All factors with a P < 0.2 on the univariate analysis were included in a multivariate logistic regression model. Adjusted OR was calculated to identify independent risk factors for CT. The study was approved by our hospital ethics committee.
3. Results Among the 538 patients admitted for hyperthyroidism during the study period, 6.5% (n = 35) were diagnosed as having CT. The cardiac complications were AF in 33 cases (6.1%) and CHF in 11 cases (2%). AF and CHF were associated in 9 patients (1.7%). No case of coronary heart disease was diagnosed. The comparison of the different parameters between the patients with CT and the controls is represented in Table 1. Patients with CT were significantly older (57 ± 14 vs. 35 ± 14 years, P < 0.001), had more frequently a low educational and socioeconomic levels and had a higher prevalence of hypertension history compared with controls. Toxic multinodular goiter was more prevalent among patients with CT whereas Graves’ disease was more prevalent among controls. Severe biological hyperthyroidism was associated with a lower risk of CT. Serum FT4 level was lower in patients with CT (3.6 ± 1.3 vs. 4.4 ± 1.6 ng/dL, P = 0.01). No difference was found between cases and controls for the TSH level (0.027 ± 0.02 vs. 0.018 ± 0.03 UI/mL, P = 0.09). There was no significant difference in the duration of hyperthyroidism symptoms between cases and controls (10.5 ± 13.5 vs. 12.3 ± 14.4 months; P = 0.57). No difference was found in the mean number of signs of thyrotoxicosis (4.6 ± 1.8 vs. 4.8 ± 3.7 signs; P = 0.72). Results of multiple logistic regression analysis are shown in Table 2. In multivariate analysis, an age over 50 years at diagnosis was the only independent risk factor of CT. Severe biological hyperthyroidism remained a protective factor of CT.
Table 2 Results of multivariate analysis. P value adjusted; OR [CI 95%] Age at diagnosis of hyperthyroidism > 50: 0.001; 11.6 [2.7–49.5] years Male gender: 0.33; 2.9 [0.3–27.1] Low level of education: 0.53; 1.6 [0.3–7.8] Low socioeconomic status: 0.9; 1.1 [0.2–5.0] Current smoker: 0.12; 4.9 [0.6–37.4] History of hypertension: 0.35; 2.2 [0.4–12.0] Graves’ disease: 0.78; 0.7 [0.1–8.7] Toxic multinodular goiter; 0.69; 0.5 [0.1–10.1] Severe biological; 0.04; 0.2 [0.1–0.9] Hyperthyroidism OR: odd ratio; CI: confidence interval.
4. Discussion The prevalence of CT in our study was relatively low: 6.5% of patients admitted for overt hyperthyroidism. The two types of cardiac disease observed were CHF and AF with a clear predominance of the latter. Age above 50 years was the only independent risk factor of CT. Severe biological hyperthyroidism was a protective factor of CT. Our study confirms that age is independently associated with a higher risk of AF and CHF in hyperthyroid patients [8,18–22]. Actually, the risks of AF and CHF increase with age regardless of the presence of hyperthyroidism or not [23,24]. These risks are however higher in case of hyperthyroidism [20,22]. Several reasons may explain the increased risk of CT with age. First, hyperthyroidism is usually associated with mild and nonspecific symptoms in the elderly [19,22] leading to a delayed diagnosis and the occurrence of complications. Second, hyperthyroidism is associated with shortened repolarization time in the atrium; this may cause AF in a population that is already prone to arrhythmias such as the elderly [19,25]. Finally, the prevalence of hypertensive, ischemic and degenerative heart diseases are increased with age leading to a greater susceptibility to hemodynamic changes induced by hyperthyroidism [18]. Regarding the gender, some studies showed that cardiac complications in hyperthyroid patients were more common in men [19,20]. This was not the case in our study.
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Only few studies analyzed the involvement of socioeconomic and educational level in CT risk. The higher risk patients with low socioeconomic status or low educational level could be explained by the difficulties to reach health care centers. This may result in a delayed diagnosis and treatment. However, in multivariate analysis, low educational level and poor socioeconomic status were not independently associated with the risk of CT. The implication of cardiovascular risk factors in the occurrence of CT is controversial [8,19,20]. Age is probably a confounding factor for diabetes and hypertension whose prevalence increase with aging. According to Frost et al., hypertension and diabetes were not associated with a higher risk of AF in patients with hyperthyroidism [19]. Similarly, in our study, smoking, diabetes and hypertension were not associated with a higher risk of CT after multivariate analysis. On the other hand, the association between the etiology of hyperthyroidism and CT reflects more an age difference between cases and controls than a pathophysiological mechanism related to a specific etiology [26]. Indeed, after univariate analysis, Graves’ disease was significantly more frequent in controls while toxic multinodular goiter was more frequent in patients with CT. However after adjustment, toxic multinodular goiter no longer appeared as an independent risk factor of CT. Few studies investigated the relationship between CT and thyrotoxicosis duration [20,27]. In the study of Ruiz et al., patients with longer disease duration had more severe myocardial damage [27]. However, in the study of Siu et al., there was no difference in the duration of thyrotoxicosis between patients with or without left ventricular systolic dysfunction [20]. Similarly in our study, the duration of hyperthyroidism symptoms was similar between cases and controls. It should be noted that the exact disease duration is difficult to identify. Patients with CT could have had a longer duration of the disease and particularly a long period of subclinical hyperthyroidism. Although usually asymptomatic, it was established that persistent subclinical hyperthyroidism was associated with AF and CHF especially in elderly patients [16,20]. Interestingly, severe biological hyperthyroidism was independently associated with a lower risk of CT. This result, which may seem paradoxical at first sight, has also been reported by other authors [7,20,28,29]. The higher frequency of toxic multinodular goiter in patients with CT might explain this finding. Indeed, there is often a delay in the diagnosis of toxic multinodular goiter as overt hyperthyroidism occurs after a longstanding period of subclinical hyperthyroidism [30,31]. The FT4 level increases thereafter gradually. On the other hand, the lower T4 levels in patients with cardiothyreosis could also be explained by the presence of an “euthyroid sick syndrome” in these patients with a complicated disease. In fact, in severe systemic illness, changes in thyroid function may occur leading to a decrease in T4 levels. Indeed, some patients with CHF have been described with an “euthyroid sick syndrome” [32,33]. In conclusion, a direct causal link between hyperthyroidism and cardiac complications cannot be asserted. It seems more likely that hyperthyroidism by increasing the workload on the heart and basal metabolism precipitated the onset of these
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