International Journal of Cardiology, 0 1991 Elsevier Science Publishers ADONIS 016752739100079U
CARD10
30 (1991) 309-313 B.V. 0167-5273/91/$03.50
309
01210
Is idiopathic atria1 fibrillation caused by occult thyrotoxicosis? A study of one hundred consecutive patients with atria1 fibrillation Michael
Giladi
‘, Dan Aderka
*, Lilach
Zeligman-Melatzki and Yoram
I, Ariel Finkelstein
r, Daniel
Ayalon
’
Levo 1
’ Department of Medicine T and 2 The Timsit Institute of Reproductive Enducri~oio~l, Irhiiov Hospital, Tel Aviv Medical Center, The Sackler Faculty of Medicine,Tel Aviv University, Tel Aviv. Israel (Received
11 July 1990; revision
accepted
23 October
1990)
Giladi M, Aderka D, Zeligman-Melatzki L, Finkelstein A, Ayalon D, Levo Y. Is idiopathic atria1 fibrillation caused by occult thyrotoxicosis? A study of one hundred consecutive patients with atria1 fibrillation. Int J Cardiol 1991;30:309-313. In this study we evaluated the possible relationship between idiopathic atrial fibrillation and occult thyrotoxicosis, diagnosed by lack of response of thyroid stimulating hormone to administration of thyrotropin releasing hormone. Three groups were comparedz 25 patients with idiopathic atrial fibrillation 52 with cardiovascular atrial fibrillation; and 27 with sinus rhythm. Patients were excluded with any clinical evidence of thyrotoxicosis or with elevated serum IT, level, as well as those with diseases or on medications known to be associated with a diminished response to administration of the releasing hormone. A flat test (lack of response) was found in only 4% of the patients. There was no si~ifi~nt difference among the 3 groups. Based on these data we believe that there is no relationship between idiopathic atrial fibrillation or any other type of atrial fibrillation and occult thyrotoxicosis. Key words: Atria1 fib~llation;
Thyrotoxicosis;
Thyrotropin
Introduction The incidence of atria1 fibrillation is about 2% in the general adult population and may reach 4-14% in elderly patients [l-5]. Thyrotoxicosis is the second most important etiology of atria1 fibrillation, the first being cardiovascular diseases. Atria1 fibrillation occurs in 10-E% of patients with thyrotoxicosis and even more frequently in
Correspondence to: Y. Levo, M.D., Dept. of Medicine T, Ichilov Hospital, 6 Weizman Street, Tel Aviv, 64239. Israel.
releasing hormone test
the aged [6-g]. Atria1 fibrillation due to thyrotoxicosis is associated with a high incidence, up to 10%. of systemic embolic events and responds to antithyroidal therapy [6,9,10]. The diagnosis of thyrotoxicosis is sometimes difficult especially in the absence of the typical clinical characteristics and elevated serum levels of ?; and T4 [ll-131. These difficulties have led to the use of administration of thyrotropin releasing hormone as a means of distinguis~ng euthyroidism from thyrotoxicosis [14,15]. Atria1 fibrillation with no identifiable cause is known as idiopathic or lone atria1 fibrillation and its incidence has been estimated as 3-314 of all atria1 fibrillation cases [2,16].
310
On the one hand, thyrotoxicosis is an important cause of atria1 fib~llation which might occasionally be missed. On the other hand, a considerable proportion of patients with atria1 fibrillation do not have any identifiable cause for this arrhythmia. Hence, the inevitable question arises: do some or all patients with idiopathic atria1 fib~llation have occult thyroto~cosis missed by routine laboratory tests? Several studies have tried to answer this question. The results, however, have been either controversial or inconclusive [1720]. In the present study we tried to compare the incidence of occult thyrotoxicosis, diagnosed by administration of thyrotropin releasing hormone, in the following three groups: patients with idiopathic atria1 fib~llation, patients with atria1 fibrillation secondary to cardiovascular diseases, and patients with sinus rhythm.
Patients and Methods Study design This study included 100 consecutive patients with paroxysmal or chronic atria1 fibrillation. All were initially evaluated for symptoms and signs of thyrotoxicosis and for elevated levels of free thyroxin in the serum. Patients with clinical symptoms of thyrotoxicosis or with an elevated level of free thyroxin were excluded (8 patients with atrial fib~llation). Patients with a severe illness such as sepsis or ketoacidosis, terminal disease, severe depression, schizophrenia, severe renal failure, malnutrition and those receiving corticosteroids, high doses of aspirin or verapamil were also excluded from the study (14 patients with atria1 fib~llation). One other patient was excluded due to equivocal results of ad~~stration of the releasing hormone. The remaining 77 patients were divided into two groups: the first included 25 patients with idiopathic atria1 fibrillation and the second included 52 with cardiovascular atria1 fibrillation. The control group included 27 hospitalized patients with a negative present or past history of atria1 fib~llation. The exclusion criteria for the control group were similar to those applied to the other groups. All patients were further evaluated by levels of T3 in the serum and by administration of
thyrotropin releasing hormone. The latter consisted of measuring the levels of thyrotropin in the serum before and 20 minutes after the intravenous administration of 200 pg of releasing hormone. The study was approved by the institutional committee on human research, and an informed consent was obtained from each of the participating individuals. Definitions
Idiopathic atrial fibrillation was diagnosed in the absence of: thyrotoxicosis; ischemic heart disease; hypertensive heart disease, with echo or electrocardiographic evidence of left ventricular hypertrophy; valvar heart disease; congestive heart failure; cardiomyopathy; sick sinus syndrome; and chronic lung disease with car pulmonale (diagnosed by history, physical examination and echocardiography). Cardiovascular atrial fibrillation was diagnosed in the absence of thyrotoxicosis and in the presence of at least one of the following: ischemic; hypertensive or valvar heart disease; congestive heart failure; cardiomyopathy; sick sinus syndrome or car pulmonale. Diagnosis of thyrotoxicosis and hypothyroidism: for the purpose of this study, thyrotoxicosis was diagnosed in the presence of an inadequate release of thyroid stimulating hormone in response to administration of thyrotropin releasing hormone namely, a 20 minute increase in the level of stimulating hormone of less than 1.0 @J/ml (flat test). Hypothyroidism was diagnosed in the presence of subnormal serum levels of T3 and/or free thyroxin and abnormally high levels of stimulating hormone. In cases of equivocal results, an exaggerated response was taken as another criterion for hypothyroidism. Statistical analysis: The Fisher’s exact test was used to compare sample proportions and the Student t-test to compare sample means. A two-tailed P value below 0.05 was considered statistically significant.
Results Relevant parameters
characteristics, including age, sex, and of kidney function, as well as the
311 TABLE
1
Patients’
characteristics,
and prevalence
Age (years) Male:female ratio BUN (mg/dl) Creatinine (pmol/l) No. of patients with
of thyrotoxicosis
and hypothyroidism.
Idiopathic atria1 fibrillation (n = 25)
Cardiovascular atria1 fibrillation (n = 52)
Controls (n = 27)
P
63.8 k 17.0 * 1.1 16.6 + 4.5 1.07 + 0.26
72.4 + 9.2 0.9 19.6 + 1.4 1.23 f 0.42
69.5 + 10.1 1.4 18.7 & 6.7 1.32 & 0.33
< 0.01 a NS NS < 0.01 b
values
thyrotoxicosis (%) No. of patients with
1 (4.0)
2 (3.8)
1 (3.7)
NS
hypothyroidism
3 (12.0)
3 (5.8)
0 (0.0)
NS
(Cg)
* Data presented as means f SD. NS = not significant. a Comparison between patients with idiopathic atria1 fibrillation b Comparison between patients with idiopathic atrial fibrillation
and patients with cardiovascular and controls.
prevalence of occult thyrotoxicosis and hypothyroidism in each of the study groups are presented in Table 1. Patients with idiopathic atria1 fibrillation were younger and had a lower mean serum creatinine level. Thyrotoxicosis was found in 4 patients only and hypothyroidism in 6, without significant differences among the three groups. Table 2 presents in detail all thyroid function tests in the 4 thyrotoxic patients diagnosed by the test.
as the underlying etiology of idiopathic atria1 fibrillation. In 1979, Forfar et al. [17] performed tests using releasing hormone on 75 patients with atria1 fibrillation which could not be attributed to a cardiovascular disease. Ten of these patients (13%) were subsequently diagnosed as thyrotoxicosis based on a flat test. The main criticism regarding this study stems from the fact that there was no control group and that in 9 out of the 10 patients with a flat test, abnormally high serum levels of thyroidal hormones were found, hence they could have been diagnosed as thyrotoxicosis without the supporting evidence of the test [21,22]. In spite of these deficiencies, Forfar and Toft, in a later editorial in 1982, reiterated their conclusion
Discussion Several addressed
studies over the possibility
TABLE
2
Thyroid
function
No.
the past 10 years have of occult thyrotoxicosis
tests of patients
Study
with occult
thyrotoxicosis.
Age
Sex
group
atria1 fibrillation.
m4
T3
TSH,
(ng/dl)
(ng/ml)
@J/ml
TSH,, &)/ml
Idiopathic atria1 fibrillation Cardiovascular atria1
55
M
1.6
93
2.0
2.0
fibrillation Cardiovascular atria1
57
F
1.0
85
0.5
0.5
fibrillation Control
74 74
M M
1.3 0.9
101 80
1.0 5.0
1.0 4.0
TSH,, TSH,: levels of thyroid stimulating hormone (TSH) levels before and 20 minutes thyrotropin releasing hormone. Normal values: FT4 = 0.7 - 2.2 ng/dl; Ts = 80 - 20 ng/ml;
after the i.v. administration TSH = 1 - 7 nU/ml.
of 20 pg of
312
that all idiopathic atria1 fibrillation patients should be subjected to a hormonal test [6]. In 1984, Ciaccheri et al. [18] reported on 5 patients with a flat test out of 40 with idiopathic atria1 fibrillation (12.5%). None of the 12 control patients with palpitations but no atria1 fibrillation had a flat test. The results in the study group were not statistically significant, possibly due to the small number of controls. A year later, in 1985, Davis et al. [19] published their results on 75 patients with atria1 fibrillation of various causes, and 73 patients with sinus rhythm. None of their patients had any clinical evidence of thyrotoxicosis. Ten patients in the first group (13%) and 5 (7%) in the second, had a flat test, (P insignificant). Only 13 patients of the atria1 fibrillation group, however, had idiopathic atria1 fibrillation and a few of them could have been diagnosed as thyrotoxicosis on the basis of abnormally elevated serum thyroidal hormones. In 1987, Bruce et al. [20] described 24 clinically euthyroid elderly patients with idiopathic atrial fibrillation with normal serum levels of T3 and T4. Patients with other underlying conditions known to be associated with a diminished response of stimulating to releasing hormone were not included. Four patients (17%) had a flat test. Once again, this study did not include a control group which is of utmost importance when such an elderly population is studied. Nevertheless, the authors concluded that the hormonal test should always be included in the workup of patients with idiopathic atrial fibrillation. The study presented herein was designed more rigorously than most previous ones. A group of 25 patients with idiopathic atria1 fibrillation was studied with 2 control groups: one consisting of 52 patients with cardiovascular atria1 fibrillation, and the other of 27 patients without atria1 fibrillation. Patients were excluded with clinical evidence of thyrotoxicosis or with a high level of free thyroxin in the serum. The prevalence of a flat hormonal test was approximately 4% in all three groups. The fact that only 4% of the patients in this study had a flat test, as compared to 8-17% in previous studies, should be noted. We believe that this stems from the strict inclusion criteria of our study group. All patients with clinical or laboratory evi-
dence of thyrotoxicosis were excluded from the study. According to this criteria, 9 out of the 10 patients with a flat test in Forfar’s study [17], and some of the patients in the study of Davies et al. [19], would not have been included in our study. In addition, patients with conditions or on medications which might influence the test were also excluded from our study. Severe illnesses, psychiatric disorders, advanced renal failure, anorexia nervosa, ketoacidosis, Cushing’s disease, and, medications such as corticosteroids, verapamil, dopamine antagonists, high doses of aspirin and oral contraceptives, have all been associated with a diminished response to administration of releasing hormone [23-281. In accordance with this criterion, 14 patients with atria1 fibrillation were excluded from our study. In three of the four abovementioned studies [17-191, such exclusion criteria have not been applied and therefore patients with a flat test unrelated to occult thyrotoxicosis, could have been included. In view of our data, and in contrast to previous studies, we believe that a flat hormonal test, reflecting occult thyrotoxicosis, is relatively uncommon among patients with idiopathic atrial fibrillation, once overt thyrotoxicosis and other conditions leading to a diminished response to administration of thyrotropin releasing hormone have been ruled out. Hence, our data do not support a relationship between occult thyrotoxicosis and idiopathic atria1 fibrillation or any other form of atria1 fibrillation.
References Rubenstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of the Sick Sinus Syndrome. Circulation 1972;45:5-13. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation - The Framingham study. N Engl J Med 1982;306:1018-1022. Camm AJ, Evans KE, Ward DE, Martin A. The rhythm of the heart in active elderly subjects. Am Heart J 1980;99: 598-603. Wosika PH, Feldman E, Chesrow EJ, Myers GB. Unipolar precordial limb lead electrocardiogram in the aged. Geriatrics 1950;5:131-141. Mihahck MJ, Fisher C. Electrocardiographic findings in the aged. Am Heart J 1974;87:117-128.
313 6 Forfar JC, Toft AD. Thyrotoxic atrial fibrillation: an underdiagnosed condition? Br Med J 1982;285:909-912. 7 Campbell M. The paroxysmal atria1 tachycardia. Lancet 1941;2:641-647. 8 Sandler G, Wilson GM. The nature and prognosis of heart disease in thyrotoxicosis. A review of 150 patients treated with I-131. Q J Med 1959;28:347-369. 9 Nakazawa HK, Sakurai K, Momotani N, Hamada N, Ito K. Timing of cardioversion application in thyrotoxic atria1 fibrillation. Circulation 1984;62:296-299. IO Staffurth JS, Gibberd MC, Tang Fui SNG. Atria1 embolism in thyrotoxicosis with atria1 fibrillation. Br Med J 1977:2:688-690. 11 Levin RM. Thyrotoxicosis in the elderly. J Am Geriatr Sot 1987;35:587-589. 12 Davis PJ, Davis FB. H~rth~oidism in patients over the age of 60 years. Medicine 1974;53:161. 13 Tibaldi JM, Barzel US, Alben J et al. Thyrotoxicosis in the very old. Am J Med 1986;81:619-622. 14 Ormston BJ, Garry R, Cryer RJ, Besser GM, Hall R. Thyrotropin releasing hormone as a thyroid function test. Lancet 1971;2:10-14. 15 Editorial. Thyroid function tests: progress and problems. Lancet 1983;1:164-165. 16 Kopecky SL, Gersh BJ, McGoon MD et al. The natural history of lone atria1 fibrillation. N Engl J Med 1987;317:669-674. 17 Forfar JC, Miller HC, Toft AD. Occult thyrotoxicosis: a correctable cause of “Idiopathic” atria1 fibrillation. Am J Cardiol 1979;44:9-12. 18 Ciaccheri M, Cecchi F, Arcangeli C, Dolara A, Zuppiroli A. Pieroni C. Occult thyrotoxicosis in patients with chronic and paroxysmal isolated atria1 fibrillation. Clin Cardiol 1984;7:413-416.
19 Davies AB, Williams I, John R, Hall R, Scanlon MF. Diagnostic value of thyrotropin releasing hormone tests in elderly patients with atria1 fibrillation. Br Med J 1985;291:773-776. 20 Bruce SA. Rangedara DC, Lewis RR, Corless D. Hyperthyroid&m in elderly patients with atria1 fibrillation and normal thyroid hormone measurements. J R Sot Med 1987;80:74-76. 21 Daly JG, Greenwood R, Himsworth RI. Thyrotoxic atria1 fibrillation (letter). Br Med J 1982;285:1574. 22 Mardell R, Gamlen TR. Indication for thyroid function screening (letter). Lancet 1983;1:363. 23 Kolesnick RN, Gershengorn MC. Thyrotropin releasing hormone and the pituitary. Am J Med 1985:79:729-739. 24 McGrath PJ, Quitkin FM, Stewart JW, Asnis G, Novacenko H, Puig-Antich J. A comparative study of the pituitary TSH response to thyrotropin in outpatient depressives. Psychiat Res 1984;12:185-193. 25 Naeije R, Goldstein J, Clumeck N, Meinhold H, Wenzel KW, Vanhaelst L. A low T3 syndrome in diabetic ketoacidosis. Clin Endocrinol 1978;8:467-472. 26 Barlarino A, Demarinis L. Calcium antagonist and hormone release. Effect of verapamil on basal. gonadotropin-releasing hormone and thyrotropin-releasing hormone, induced pituitary hormone release in normal subjects. J Clin Endocrinol Metab 1980;51:749-753. 27 Dussault JH, Turcotte R, Guyda H. The effect of acetylsalicylic acid on TSH and PRL secretion after TRH stimulation in the human. J Clin Endocrinol Metab 1976;43: 232-235. 28 Otsoki M, Dakoda M, Bara S. Influence of glucocorticoids on TRF-induced TSH response in man. J Clin Endocrinol Metab 1973:36:95-102.
CARD10
30 (1991) 309-313 B.V. 0167-5273/91/$03.50
309
01210
Is idiopathic atria1 fibrillation caused by occult thyrotoxicosis? A study of one hundred consecutive patients with atria1 fibrillation Michael
Giladi
‘, Dan Aderka
*, Lilach
Zeligman-Melatzki and Yoram
I, Ariel Finkelstein
r, Daniel
Ayalon
’
Levo 1
’ Department of Medicine T and 2 The Timsit Institute of Reproductive Enducri~oio~l, Irhiiov Hospital, Tel Aviv Medical Center, The Sackler Faculty of Medicine,Tel Aviv University, Tel Aviv. Israel (Received
11 July 1990; revision
accepted
23 October
1990)
Giladi M, Aderka D, Zeligman-Melatzki L, Finkelstein A, Ayalon D, Levo Y. Is idiopathic atria1 fibrillation caused by occult thyrotoxicosis? A study of one hundred consecutive patients with atria1 fibrillation. Int J Cardiol 1991;30:309-313. In this study we evaluated the possible relationship between idiopathic atrial fibrillation and occult thyrotoxicosis, diagnosed by lack of response of thyroid stimulating hormone to administration of thyrotropin releasing hormone. Three groups were comparedz 25 patients with idiopathic atrial fibrillation 52 with cardiovascular atrial fibrillation; and 27 with sinus rhythm. Patients were excluded with any clinical evidence of thyrotoxicosis or with elevated serum IT, level, as well as those with diseases or on medications known to be associated with a diminished response to administration of the releasing hormone. A flat test (lack of response) was found in only 4% of the patients. There was no si~ifi~nt difference among the 3 groups. Based on these data we believe that there is no relationship between idiopathic atrial fibrillation or any other type of atrial fibrillation and occult thyrotoxicosis. Key words: Atria1 fib~llation;
Thyrotoxicosis;
Thyrotropin
Introduction The incidence of atria1 fibrillation is about 2% in the general adult population and may reach 4-14% in elderly patients [l-5]. Thyrotoxicosis is the second most important etiology of atria1 fibrillation, the first being cardiovascular diseases. Atria1 fibrillation occurs in 10-E% of patients with thyrotoxicosis and even more frequently in
Correspondence to: Y. Levo, M.D., Dept. of Medicine T, Ichilov Hospital, 6 Weizman Street, Tel Aviv, 64239. Israel.
releasing hormone test
the aged [6-g]. Atria1 fibrillation due to thyrotoxicosis is associated with a high incidence, up to 10%. of systemic embolic events and responds to antithyroidal therapy [6,9,10]. The diagnosis of thyrotoxicosis is sometimes difficult especially in the absence of the typical clinical characteristics and elevated serum levels of ?; and T4 [ll-131. These difficulties have led to the use of administration of thyrotropin releasing hormone as a means of distinguis~ng euthyroidism from thyrotoxicosis [14,15]. Atria1 fibrillation with no identifiable cause is known as idiopathic or lone atria1 fibrillation and its incidence has been estimated as 3-314 of all atria1 fibrillation cases [2,16].
310
On the one hand, thyrotoxicosis is an important cause of atria1 fib~llation which might occasionally be missed. On the other hand, a considerable proportion of patients with atria1 fibrillation do not have any identifiable cause for this arrhythmia. Hence, the inevitable question arises: do some or all patients with idiopathic atria1 fib~llation have occult thyroto~cosis missed by routine laboratory tests? Several studies have tried to answer this question. The results, however, have been either controversial or inconclusive [1720]. In the present study we tried to compare the incidence of occult thyrotoxicosis, diagnosed by administration of thyrotropin releasing hormone, in the following three groups: patients with idiopathic atria1 fib~llation, patients with atria1 fibrillation secondary to cardiovascular diseases, and patients with sinus rhythm.
Patients and Methods Study design This study included 100 consecutive patients with paroxysmal or chronic atria1 fibrillation. All were initially evaluated for symptoms and signs of thyrotoxicosis and for elevated levels of free thyroxin in the serum. Patients with clinical symptoms of thyrotoxicosis or with an elevated level of free thyroxin were excluded (8 patients with atrial fib~llation). Patients with a severe illness such as sepsis or ketoacidosis, terminal disease, severe depression, schizophrenia, severe renal failure, malnutrition and those receiving corticosteroids, high doses of aspirin or verapamil were also excluded from the study (14 patients with atria1 fib~llation). One other patient was excluded due to equivocal results of ad~~stration of the releasing hormone. The remaining 77 patients were divided into two groups: the first included 25 patients with idiopathic atria1 fibrillation and the second included 52 with cardiovascular atria1 fibrillation. The control group included 27 hospitalized patients with a negative present or past history of atria1 fib~llation. The exclusion criteria for the control group were similar to those applied to the other groups. All patients were further evaluated by levels of T3 in the serum and by administration of
thyrotropin releasing hormone. The latter consisted of measuring the levels of thyrotropin in the serum before and 20 minutes after the intravenous administration of 200 pg of releasing hormone. The study was approved by the institutional committee on human research, and an informed consent was obtained from each of the participating individuals. Definitions
Idiopathic atrial fibrillation was diagnosed in the absence of: thyrotoxicosis; ischemic heart disease; hypertensive heart disease, with echo or electrocardiographic evidence of left ventricular hypertrophy; valvar heart disease; congestive heart failure; cardiomyopathy; sick sinus syndrome; and chronic lung disease with car pulmonale (diagnosed by history, physical examination and echocardiography). Cardiovascular atrial fibrillation was diagnosed in the absence of thyrotoxicosis and in the presence of at least one of the following: ischemic; hypertensive or valvar heart disease; congestive heart failure; cardiomyopathy; sick sinus syndrome or car pulmonale. Diagnosis of thyrotoxicosis and hypothyroidism: for the purpose of this study, thyrotoxicosis was diagnosed in the presence of an inadequate release of thyroid stimulating hormone in response to administration of thyrotropin releasing hormone namely, a 20 minute increase in the level of stimulating hormone of less than 1.0 @J/ml (flat test). Hypothyroidism was diagnosed in the presence of subnormal serum levels of T3 and/or free thyroxin and abnormally high levels of stimulating hormone. In cases of equivocal results, an exaggerated response was taken as another criterion for hypothyroidism. Statistical analysis: The Fisher’s exact test was used to compare sample proportions and the Student t-test to compare sample means. A two-tailed P value below 0.05 was considered statistically significant.
Results Relevant parameters
characteristics, including age, sex, and of kidney function, as well as the
311 TABLE
1
Patients’
characteristics,
and prevalence
Age (years) Male:female ratio BUN (mg/dl) Creatinine (pmol/l) No. of patients with
of thyrotoxicosis
and hypothyroidism.
Idiopathic atria1 fibrillation (n = 25)
Cardiovascular atria1 fibrillation (n = 52)
Controls (n = 27)
P
63.8 k 17.0 * 1.1 16.6 + 4.5 1.07 + 0.26
72.4 + 9.2 0.9 19.6 + 1.4 1.23 f 0.42
69.5 + 10.1 1.4 18.7 & 6.7 1.32 & 0.33
< 0.01 a NS NS < 0.01 b
values
thyrotoxicosis (%) No. of patients with
1 (4.0)
2 (3.8)
1 (3.7)
NS
hypothyroidism
3 (12.0)
3 (5.8)
0 (0.0)
NS
(Cg)
* Data presented as means f SD. NS = not significant. a Comparison between patients with idiopathic atria1 fibrillation b Comparison between patients with idiopathic atrial fibrillation
and patients with cardiovascular and controls.
prevalence of occult thyrotoxicosis and hypothyroidism in each of the study groups are presented in Table 1. Patients with idiopathic atria1 fibrillation were younger and had a lower mean serum creatinine level. Thyrotoxicosis was found in 4 patients only and hypothyroidism in 6, without significant differences among the three groups. Table 2 presents in detail all thyroid function tests in the 4 thyrotoxic patients diagnosed by the test.
as the underlying etiology of idiopathic atria1 fibrillation. In 1979, Forfar et al. [17] performed tests using releasing hormone on 75 patients with atria1 fibrillation which could not be attributed to a cardiovascular disease. Ten of these patients (13%) were subsequently diagnosed as thyrotoxicosis based on a flat test. The main criticism regarding this study stems from the fact that there was no control group and that in 9 out of the 10 patients with a flat test, abnormally high serum levels of thyroidal hormones were found, hence they could have been diagnosed as thyrotoxicosis without the supporting evidence of the test [21,22]. In spite of these deficiencies, Forfar and Toft, in a later editorial in 1982, reiterated their conclusion
Discussion Several addressed
studies over the possibility
TABLE
2
Thyroid
function
No.
the past 10 years have of occult thyrotoxicosis
tests of patients
Study
with occult
thyrotoxicosis.
Age
Sex
group
atria1 fibrillation.
m4
T3
TSH,
(ng/dl)
(ng/ml)
@J/ml
TSH,, &)/ml
Idiopathic atria1 fibrillation Cardiovascular atria1
55
M
1.6
93
2.0
2.0
fibrillation Cardiovascular atria1
57
F
1.0
85
0.5
0.5
fibrillation Control
74 74
M M
1.3 0.9
101 80
1.0 5.0
1.0 4.0
TSH,, TSH,: levels of thyroid stimulating hormone (TSH) levels before and 20 minutes thyrotropin releasing hormone. Normal values: FT4 = 0.7 - 2.2 ng/dl; Ts = 80 - 20 ng/ml;
after the i.v. administration TSH = 1 - 7 nU/ml.
of 20 pg of
312
that all idiopathic atria1 fibrillation patients should be subjected to a hormonal test [6]. In 1984, Ciaccheri et al. [18] reported on 5 patients with a flat test out of 40 with idiopathic atria1 fibrillation (12.5%). None of the 12 control patients with palpitations but no atria1 fibrillation had a flat test. The results in the study group were not statistically significant, possibly due to the small number of controls. A year later, in 1985, Davis et al. [19] published their results on 75 patients with atria1 fibrillation of various causes, and 73 patients with sinus rhythm. None of their patients had any clinical evidence of thyrotoxicosis. Ten patients in the first group (13%) and 5 (7%) in the second, had a flat test, (P insignificant). Only 13 patients of the atria1 fibrillation group, however, had idiopathic atria1 fibrillation and a few of them could have been diagnosed as thyrotoxicosis on the basis of abnormally elevated serum thyroidal hormones. In 1987, Bruce et al. [20] described 24 clinically euthyroid elderly patients with idiopathic atrial fibrillation with normal serum levels of T3 and T4. Patients with other underlying conditions known to be associated with a diminished response of stimulating to releasing hormone were not included. Four patients (17%) had a flat test. Once again, this study did not include a control group which is of utmost importance when such an elderly population is studied. Nevertheless, the authors concluded that the hormonal test should always be included in the workup of patients with idiopathic atrial fibrillation. The study presented herein was designed more rigorously than most previous ones. A group of 25 patients with idiopathic atria1 fibrillation was studied with 2 control groups: one consisting of 52 patients with cardiovascular atria1 fibrillation, and the other of 27 patients without atria1 fibrillation. Patients were excluded with clinical evidence of thyrotoxicosis or with a high level of free thyroxin in the serum. The prevalence of a flat hormonal test was approximately 4% in all three groups. The fact that only 4% of the patients in this study had a flat test, as compared to 8-17% in previous studies, should be noted. We believe that this stems from the strict inclusion criteria of our study group. All patients with clinical or laboratory evi-
dence of thyrotoxicosis were excluded from the study. According to this criteria, 9 out of the 10 patients with a flat test in Forfar’s study [17], and some of the patients in the study of Davies et al. [19], would not have been included in our study. In addition, patients with conditions or on medications which might influence the test were also excluded from our study. Severe illnesses, psychiatric disorders, advanced renal failure, anorexia nervosa, ketoacidosis, Cushing’s disease, and, medications such as corticosteroids, verapamil, dopamine antagonists, high doses of aspirin and oral contraceptives, have all been associated with a diminished response to administration of releasing hormone [23-281. In accordance with this criterion, 14 patients with atria1 fibrillation were excluded from our study. In three of the four abovementioned studies [17-191, such exclusion criteria have not been applied and therefore patients with a flat test unrelated to occult thyrotoxicosis, could have been included. In view of our data, and in contrast to previous studies, we believe that a flat hormonal test, reflecting occult thyrotoxicosis, is relatively uncommon among patients with idiopathic atrial fibrillation, once overt thyrotoxicosis and other conditions leading to a diminished response to administration of thyrotropin releasing hormone have been ruled out. Hence, our data do not support a relationship between occult thyrotoxicosis and idiopathic atria1 fibrillation or any other form of atria1 fibrillation.
References Rubenstein JJ, Schulman CL, Yurchak PM, DeSanctis RW. Clinical spectrum of the Sick Sinus Syndrome. Circulation 1972;45:5-13. Kannel WB, Abbott RD, Savage DD, McNamara PM. Epidemiologic features of chronic atrial fibrillation - The Framingham study. N Engl J Med 1982;306:1018-1022. Camm AJ, Evans KE, Ward DE, Martin A. The rhythm of the heart in active elderly subjects. Am Heart J 1980;99: 598-603. Wosika PH, Feldman E, Chesrow EJ, Myers GB. Unipolar precordial limb lead electrocardiogram in the aged. Geriatrics 1950;5:131-141. Mihahck MJ, Fisher C. Electrocardiographic findings in the aged. Am Heart J 1974;87:117-128.
313 6 Forfar JC, Toft AD. Thyrotoxic atrial fibrillation: an underdiagnosed condition? Br Med J 1982;285:909-912. 7 Campbell M. The paroxysmal atria1 tachycardia. Lancet 1941;2:641-647. 8 Sandler G, Wilson GM. The nature and prognosis of heart disease in thyrotoxicosis. A review of 150 patients treated with I-131. Q J Med 1959;28:347-369. 9 Nakazawa HK, Sakurai K, Momotani N, Hamada N, Ito K. Timing of cardioversion application in thyrotoxic atria1 fibrillation. Circulation 1984;62:296-299. IO Staffurth JS, Gibberd MC, Tang Fui SNG. Atria1 embolism in thyrotoxicosis with atria1 fibrillation. Br Med J 1977:2:688-690. 11 Levin RM. Thyrotoxicosis in the elderly. J Am Geriatr Sot 1987;35:587-589. 12 Davis PJ, Davis FB. H~rth~oidism in patients over the age of 60 years. Medicine 1974;53:161. 13 Tibaldi JM, Barzel US, Alben J et al. Thyrotoxicosis in the very old. Am J Med 1986;81:619-622. 14 Ormston BJ, Garry R, Cryer RJ, Besser GM, Hall R. Thyrotropin releasing hormone as a thyroid function test. Lancet 1971;2:10-14. 15 Editorial. Thyroid function tests: progress and problems. Lancet 1983;1:164-165. 16 Kopecky SL, Gersh BJ, McGoon MD et al. The natural history of lone atria1 fibrillation. N Engl J Med 1987;317:669-674. 17 Forfar JC, Miller HC, Toft AD. Occult thyrotoxicosis: a correctable cause of “Idiopathic” atria1 fibrillation. Am J Cardiol 1979;44:9-12. 18 Ciaccheri M, Cecchi F, Arcangeli C, Dolara A, Zuppiroli A. Pieroni C. Occult thyrotoxicosis in patients with chronic and paroxysmal isolated atria1 fibrillation. Clin Cardiol 1984;7:413-416.
19 Davies AB, Williams I, John R, Hall R, Scanlon MF. Diagnostic value of thyrotropin releasing hormone tests in elderly patients with atria1 fibrillation. Br Med J 1985;291:773-776. 20 Bruce SA. Rangedara DC, Lewis RR, Corless D. Hyperthyroid&m in elderly patients with atria1 fibrillation and normal thyroid hormone measurements. J R Sot Med 1987;80:74-76. 21 Daly JG, Greenwood R, Himsworth RI. Thyrotoxic atria1 fibrillation (letter). Br Med J 1982;285:1574. 22 Mardell R, Gamlen TR. Indication for thyroid function screening (letter). Lancet 1983;1:363. 23 Kolesnick RN, Gershengorn MC. Thyrotropin releasing hormone and the pituitary. Am J Med 1985:79:729-739. 24 McGrath PJ, Quitkin FM, Stewart JW, Asnis G, Novacenko H, Puig-Antich J. A comparative study of the pituitary TSH response to thyrotropin in outpatient depressives. Psychiat Res 1984;12:185-193. 25 Naeije R, Goldstein J, Clumeck N, Meinhold H, Wenzel KW, Vanhaelst L. A low T3 syndrome in diabetic ketoacidosis. Clin Endocrinol 1978;8:467-472. 26 Barlarino A, Demarinis L. Calcium antagonist and hormone release. Effect of verapamil on basal. gonadotropin-releasing hormone and thyrotropin-releasing hormone, induced pituitary hormone release in normal subjects. J Clin Endocrinol Metab 1980;51:749-753. 27 Dussault JH, Turcotte R, Guyda H. The effect of acetylsalicylic acid on TSH and PRL secretion after TRH stimulation in the human. J Clin Endocrinol Metab 1976;43: 232-235. 28 Otsoki M, Dakoda M, Bara S. Influence of glucocorticoids on TRF-induced TSH response in man. J Clin Endocrinol Metab 1973:36:95-102.
