Clinical, biochemical and therapeutical aspects of amiodarone-induced hypothyroidism (AIH) in geriatric patients with cardiac arrhythmias

Arch. Gerontol. Geriatr. 38 (2004) 27–36

Clinical, biochemical and therapeutical aspects of amiodarone-induced hypothyroidism (AIH) in geriatric patients with cardiac arrhythmias R.G. Gheri a , P. Pucci a , C. Falsetti a , M.L.E. Luisi a , G.P. Cerisano c , C.F. Gheri a , I. Petruzzi b , P. Pinzani a , B. Salvadori a , E. Petruzzi b,∗ a

c

Endocrinology Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, Florence I-50139, Italy b Gerontology and Geriatrics Unit, Department of Critical Care Medicine and Surgery, University of Florence, Viale Pieraccini 6, Florence I-50139, Italy Cardiac Unit, Azienda Ospedaliera Careggi, Viale Pieraccini 17, Florence I-50139, Italy

Received 2 December 2002; received in revised form 23 June 2003; accepted 8 July 2003

Abstract The clinical features and the laboratory aspects of the amiodarone-induced hypothyroidism (AIH) in the elderly as well as the effects of amiodarone treatment in aged AIH people have not yet been well clarified. In the present paper, we evaluated 18 subjects of both sexes (7 females, 11 males), aged 65–83 years, affected by AIH, recruited in Central Tuscany, Italy. The patients were divided in two subsets on the basis of thyroid stimulating hormone (TSH) values: mild (TSH < 20 mU/l; Group A, n = 11) and severe (TSH > 20 mU/l; Group B, n = 7) hypothyroid patients. On the basis of clinical features, hypothyroidism was diagnosed only in two patients (out of Group B). Concerning the hormonal pattern, we found that free tetraiodothyronine (fT4) levels were significantly lower than the normal range only in Group B subjects; TSH and thyroglobulin were higher than normal in both groups; free triiodothyronine (fT3) were always in the normal range. Thyroid autoantibodies were found positive only in one patient out of Group A and in two patients out of Group B. In 5/18 patients T4 substitutive therapy was rapidly assigned, because of severe degree of hypothyroidism. In the remaining 13/18 patients, we evaluated the clinical behavior of AIH. After additional cardiac evaluation, amiodarone was withdrawn in 5/13 patients: during follow-up period (4–10 months) four patients became quickly euthyroid while one worsened. In 8/13 patients, amiodarone treatment had

∗

Corresponding author. Tel.: +39-055-427-1471; fax: +39-055-427-1413. E-mail address: [email protected] (E. Petruzzi).

0167-4943/$ – see front matter © 2003 Published by Elsevier Ireland Ltd. doi:10.1016/S0167-4943(03)00080-3

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to be carried on; during follow-up (2–48 months), four patients remained mildly hypothyroid, while other four patients became severely hypothyroid. In conclusion, in amiodarone treated elderly people, diagnosis of hypothyroidism is reliable only on the basis of high values of TSH; clinical features and fT3 serum levels never enable diagnosis. © 2003 Published by Elsevier Ireland Ltd. Keywords: Amiodarone; Hypothyroidism; Elderly subjects

1. Introduction Several changes in thyroid function have been described in the elderly and largely attributed to concomitant nonthyroidal illness (Mariotti et al., 1993, 1998, 1999; Chiovato et al., 1997). Actually aged persons are considered ≥65 years of age, but this step is certainly undergoing a change, due to the projected increase of the average life expectancy, as it results from the WHO 11 Countries Study (Grundy, 1992). On the other hand, health is an elusive concept, difficult to define and measure. Recently it has been applied in the EURAGE SENIEUR protocol (Ligthart et al., 1984, 1990) what might be representative for the successful aging, as opposed to usual aging (Rowe and Kahn, 1987). The extent to which aging per se contributes to thyroid function changes remains to be completely elucidated, and the hypothyroid state is worsened when extremely old subjects are considered (Mariotti et al., 1993). It has also been reported that age-related thyroid function alterations are absent in healthy aged individuals, if careful exclusion criteria are applied (Mariotti et al., 1993). The clinical features of senile hypothyroidism differ from the general characteristic of these conditions (Robuschi et al., 1987). In fact there are in the elderly, in comparison with young patients, fewer classical signs or symptoms (Doucet et al., 1994). This may be explained primarily by the changed response of peripheral tissues to thyroid hormones. Because of the atypical clinical symptoms, the recognition of these conditions is difficult and, in general, occurs late (Leovey et al., 1991). The help of the laboratory seems to be essential in making the diagnosis of the thyroid disease, but the interpretation of laboratory tests in the elderly may be different (Hurwitz, 1993; Vandenberghe, 1993; Faulkner and Demers, 1994). Amiodarone is an iodine-rich drug used in the treatment of resistant cardiac arrhythmias. Amiodarone-induced hypothyroidism (AIH) is a particular aspect of such treatment (Martino et al., 1987, 2001; Loh, 2000; Bogazzi et al., 2001). Many in-depth study have been performed in order to determine the incidence and predictability (Gheri et al., 1990; Sandhu and Davies, 2001) and to elucidate the pathogenesis of AIH (Trip et al., 1991). Nevertheless, the clinical features, the laboratory data and the therapeutic aspects of the AIH in aged people have not yet been well examined. The goals of the present paper are: (1) to determine the main clinical and laboratory features for the diagnosis of AIH in the elderly; (2) to investigate the effects of further amiodarone administration in AIH aged cardiac patients and to determine practical therapeutical aspects.

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Table 1 Age and sex, amiodarone dose per day and length of treatment, in the patients undergone the study, at the diagnosis of AIH Patient number

Name

Age (year)

Sex

Amiodarone dose (mg/day)

Length of amiodarone treatment (months)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

BM LL DO BM CAM MB PD CA GU MM SE ML GV MG BG PL GB LA

67 79 77 76 71 70 65 77 69 83 70 71 73 73 70 72 73 80

F F F F F F F M M M M M M M M M M M

200 200 140 200 200 140 100 100 200 140 140 140 140 140 100 140 140 200

60 2 1 6 5 2 12 1 1 7 48 39 6 1 72 5 5 1

2. Subjects and methods Eighteen subjects of both sexes (7 females, 11 males) aged 65–83 years, suffering from AIH, recruited in Central Tuscany, Italy, were included in the study (Table 1). None had a previous history of hyper/hypothyroidism, or 131 Iodine therapy or subtotal thyroidectomy, before amiodarone administration. All subjects have been judged euthyroid before amiodarone administration on the basis of TSH evaluation. All patients, suffering from tachyarrhythmias, underwent 100–200 mg amiodarone treatment per day throughout 1–72 months. They were referred to us from the Cardiovascular Unit (Careggi General Hospital, Florence University, Italy) because of high TSH serum level (range 5–100 mU/l). To evaluate the relationship between clinical and biochemical features of AIH, the patients were divided in two groups, on the basis of TSH values: Group A (TSH < 20 mU/l, “mild hypothyroidism”, n = 11) (Table 2) and Group B (TSH > 20 mU/l, “severe hypothyroidism”, n = 7) (Table 3). In each patient, typical signs and/or symptoms of hypothyroidism were evaluated by the same clinician (R.G.G.), in order to avoid clinical bias. Serum TSH, free T4 (fT4 ), and free T3 (fT3 ) levels were determined by means of commercial kits (MEIA® Abbott, Chicago, USA). Thyroglobulin, anti-thyroglobulin (TGAb), and anti-microsomal/TPO antibodies (TPOAb) in serum were detected by RIA method (RIA Henning, Berlin, Germany). Goiter presence and size were evaluated in all subjects, according to the Pan American Health Organization (PAHO) criteria and methods (Delange et al., 1986).

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Table 2 Clinical features, thyroid hormone serum concentrations (fT3, fT4), TSH, thyroglobulin (TG) and thyroid antibodies (TGAb, TPOAb) values in patients with mild (TSH <20 mU/l) AIH Patient number

Clinical features of hypothyroidism

Goiter

fT3 (pmol/l)

fT4 (pmol/l)

TSH (mU/l)

TGAb (U/l)

TPOAb (U/l)

TG (ng/ml)

1 2 4 5 7 8 9 11 12 17 18

No No No No No No No No No No No

No No No No No No No Yes No No No

4.5 2.92 4.4 2.3 4.1 2.3 3.6 2.64 2.1 4.11 n.d.

8.6 14.3 7.8 14 12.4 12.1 17.4 16.1 10.5 6.8 10.1

6.04 14 17.9 5.2 10.6 7.7 6.04 12.2 12.9 17.3 9.9

0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 829

102 18.6 299 14.7 55 273 42 117 148 n.d. 138

Table 3 Clinical features, thyroid hormone serum concentrations, TSH, thyroglobulin (TG) and thyroid antibodies values (TGAb, TPOAb) in patients with severe (TSH >20 mU/l) AIH Partient number

Clinical features of hypothyroidism

Goiter

FT3 (pmol/l)

FT4 (pmol/l)

TSH (mU/l)

TGAb (U/l)

TPOAb (U/l)

TG (ng/ml)

3 6 10 13 14 15 16

No Yes Yes No No No No

Yes No No No Yes No No

2.9 2.2 1.2 2.76 1.9 3.2 3.2

6.7 5 0.9 2.85 3 5.4 0.5

27.5 100 91 100 100 100 57

0 175 0 0 0 0 0

0 0 0 0 377 0 0

n.d. 62 171 151 55 309 458

The effects of carrying on amiodarone treatment in AIH subjects have been evaluated by means of a retrospective analysis of their clinical follow-up. Five severely AIH affected patients (patient number: 3, 6, 13, 14, 16 (Group B)) have been excluded from the evaluation because T4 therapy has been administered immediately. The remaining 13 patients have been divided in two subsets, on the basis of further cardiac evaluation. Five patients (patient number: 2, 4, and 11 (Group A); patient number: 10 and 15 (Group B)) could stop amiodarone treatment, while eight patients (patient number: 1, 5, 7, 8, 9, 12, 17, 18 (Group A)) suffering from severe tachyarrythmias, had to carry on the treatment, at the pre-established dosage. All the results are expressed as mean ± standard error mean (mean ± S.E.M.). Student’s two-tailed t-test for independent samples was used as appropriate. 3. Results Patient sex distribution, age, amiodarone dose per day and treatment length (mean ± S.E.M.) were not significantly different in the two groups under investigation (Table 4).

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Table 4 Patients sex and age, amiodarone dose per day and treatment length before diagnosis of hypothyroidism in the two groups studied (mean ± S.E.M.)

Group Aa Group Bb P a b

Sex

Age (years)

Amiodarone dose per day (mg)

Amiodarone treatment length (months)

5F/6M 2F/5M

72.5 ± 1.55 74 ± 1.89 0.551

160 ± 12 134 ± 6 0.122

16.36 ±6.87 13.43 ± 10.59 0.811

Mild hypothyroid, n = 11. Severe hypothyroid, n = 7.

Goiter was present both in one patient out of Group A (Table 2) and in two patients out of Group B (Table 3). Only two patients out of Group B (Table 3) showed clinical signs and symptoms of hypothyroidism (mixedematous faces, weight gain, hypersomnia, poor memory, large tongue, tiredness, weakness, depression). In the remaining patients, both of Groups A and B, physical endocrinological examination did not reveal any evidence of hypothyroidism; only specific symptoms, that could be considered aging-dependent, were present. Thyroglobulin and/or TPO antibodies were identified both in one out of Group A (Table 2) and in two out of Group B (Table 3) patients. The prevalence of thyroid antibodies in the two groups of subjects studied was not statistically different (P = 0.665; χ2 = 0.187; d.f. = 1). In one patient (patient number: 14), goiter and presence of thyroid antibodies were concomitant. Mean TSH serum level were, by definition, higher than normal in both group and, obviously, significantly higher in Group B than in Group A (Table 5). No significant difference was found in fT3 serum concentration between Groups A and B subjects. Mean fT4 serum level was in the normal range in Group A patients, while in the Group B subjects was lower than the normal range and significantly lower (P < 0.001) than the one of Group A (Table 5). TG serum concentration was more than double in both groups under investigation, in comparison to the normal upper limit, without any significant difference between the two groups (Table 5). Five patients (patient number: 3, 6, 13, 14, 16 (Group B)), because of severe degree of hypothyroidism, started T4 substitutive therapy, obtaining euthyroidism; so they were excluded from follow-up. In remaining 13 patients, retrospective clinical follow-up was Table 5 TSH, TG, fT4 and fT3 serum levels in the two groups of patients under investigation (mean ± S.E.M.) at diagnosis of AIH

Aa

Group Group Bb P a b

TSH (mU/l)

fT4 (pmol/l)

fT3 (pmol/l)

TG (ng/ml)

10.89 ± 1.4 (n = 11) 82.21 ± 11.75 (n =7) <0.0001

11.83 ±1.08 (n = 11) 3.48 ± 0.95 (n = 7) <0.0001

3.3 ± 0.32 (n = 10) 2.48 ± 0.3 (n = 7) 0.094

120.73 ± 33.7 (n = 10) 201 ± 69.79 (n = 6) 0.259

Mild hypothyroid. Severe hypothyroid.

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achieved. After cardiac re-evaluation, in five patients out of this subset, amiodarone treatment could be stopped. Four patients (patient number: 4 and 11 (Group A); patient number: 10 and 15 (Group B)) became euthyroid in 4–10 months; one patient (patient number: 2 (Group A)) remained mildly hypothyroid for 4 months but, later on, without any assessed cause, developed a severe hypothyroidism. In the other eight patients, amiodarone treatment had to be continued. Four (patient number: 1, 5, 7, 9 (Group A)) out of these patients did not show any clinical or biochemical significant variation of mild hypothyroidism (follow-up: 12–48 months). On the contrary, the remaining four patients (patient number: 8, 12, 17, 18 (Group A)) showed a clinically severe worsening of hypothyroidism in 2–12 months and had to undergo T4 substitutive therapy.

4. Discussion Hypothyroidism is a relatively common disease in general population and shows a clear relationship with female sex and advanced age. In the aged patient, hypothyroidism may be mild or severe, but usually no clinical signs or symptoms are detectable. Therefore, it is always difficult to diagnose hypothyroidism on the basis of clinical evaluation. The prevalence of high TSH serum levels was found to be 17.4 and 6.9% in women and men over 65 years, respectively (Tunbridge et al., 1977); several other studies on population, carried out in different countries, confirm the high frequency of hypothyroidism its predominance in women, and its progressive increase with advancing age (Helfand and Crapo, 1990). The most frequent causes of primary hypothyroidism, in aged patients, are autoimmune thyroiditis (Blumenthal and Perlstein, 1987; Tomer and Shonfeld, 1988; Mariotti et al., 1992; Diez, 2002) and previous treatments with radio iodine or thyroid surgery; among the uncommon causes, there is an increasing evidence that also iodine rich drug can induce thyroid hypofunction. Amiodarone, an antiarrythmic iodine rich drug, is frequently used in cardiac patients. The relationship between Amiodarone and thyroid function has been reviewed (Unger et al., 1993; Martino et al., 1994, 2001; Hilleman et al., 1998; Bogazzi et al., 2001; Nakajima et al., 2001). In the present series, only two AIH aged patients were diagnosed as hypothyroid on the basis of clinical examination by the presence of typical symptoms and/or signs; the two patients belonged to the severe hypothyroid group. It is difficult to recognize typical clinical signs of hypothyroidism in the elderly patients and difficulty increases in the case of cardiac aged patients; for this reason, it is essential to search laboratory support about thyroid status in aged cardiac patients chronically amiodarone treated. Serum concentration of fT4 in aged subjects has been studied by several groups (Hermann et al., 1981), and no age-induced change was reported. On the contrary, serum fT3 level seems to decrease with old age, even excluding patients with non thyroidal illness (Hermann et al., 1981; Harman et al., 1984). Basal TSH serum concentrations do not change with age (Ordene et al., 1983). The finding of increased TSH levels in elderly subjects appears to be a consequence of the reduced secretion of thyroid hormones, suggesting the diagnosis of primary hypothyroidism. In all the investigated patients, we observed higher than normal TSH serum concentrations; fT4 serum mean concentration was found significantly decreased

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only in severely affected group, while both groups showed fT3 mean serum concentration in the normal range, without any significant difference. Thus, these observations strongly suggest that in subjects aged above 65 years and treated with amiodarone, hypothyroidism cannot be diagnosed until elevated TSH serum concentrations are found, since typical clinical features of hypothyroidism are frequently absent. Low fT4 levels are usually found only in severely affected hypothyroid patients, suggesting that fT4 determination alone may not be useful in screening for hypothyroidism in geriatric population. fT3 determination is not useful to make the diagnosis, since it has been always found within the normal range and, moreover, it is frequently physiologically slightly reduced in aged subjects. Serum TG levels were found increased in 13/16 of evaluated patients; this result is similar to the one obtained by Martino et al. (1987) and it could be due to TSH stimulation (Belfiore et al., 1984) or inflammatory destruction of the thyroid gland (Leung et al., 1989). However, in our experience, TSH was significantly different in the two groups while TG concentrations were similar. Moreover, we were unable to find any significant linear correlation between TSH and TG values (P = 0.472, d.f. = 14, t = 0.739, r = 0.194). It has been demonstrated that amiodarone and its major metabolite, desethylamiodarone, exert direct cytotoxic effect on human follicular cells (Ordene et al., 1983; Cappiello et al., 1995); furthermore, excess of iodine administration can induce follicular cell necrosis (Wollman et al., 1990; Gerber et al., 1994). However, increased RAIU (Radio Active Iodine Uptake) values have been observed in patients affected by AIH and this seems to be due to maximal TSH stimulation of the thyroid, rather than to thyroiditis (Hawthorne et al., 1985; Wiersinga et al., 1985). According to our study, the length and the dose of amiodarone appear to have no influence in the development of hypothyroidism. In fact hypothyroidism was detected after 1–72 months from the start of the amiodarone treatment. By clustering the observed patients in two series, we found that severe hypothyroidism was present in patients treated for a time course and with amiodarone dose similar to that used in the group presenting mild hypothyroidism. It is well known that AIH can be linked to the presence of thyroid autoantibodies (Martino et al., 1987); it has been suggested that Hashimoto’s thyroiditis could be a risk factor for the development and for the outcome of AIH, for patients undergo a persistent glandular hypofunction (Martino et al., 1987). Iodine, by itself, might induce an autoimmune response (Mc Gregor et al., 1985; Monteiro et al., 1986) and/or non-specific damage of the thyroid follicles (Allen et al., 1986). In the present series, only few patients (3/18) with AIH presented circulating anti-thyroid antibodies. In the great majority of patients of this report, thyroid gland was clinically normal, without thyroid autoantibodies. However, we cannot exclude subtle defects in thyroid hormonogenesis, resulting in an enhanced susceptibility to the inhibitory effect of iodine on hormone synthesis and/or a failure to escape from the acute Wolff–Chaicoff effect (Martino et al., 1987). The hypothesis of subtle thyroid defects is confirmed by the positive iodide perchlorate discharge test observed in elderly subjects (Inada et al., 1983). Up to date, few prospective follow-up studies on the outcome of patients with AIH have been carried out (Nademanee et al., 1986; Martino et al., 1987; Trip et al., 1991). In the series shown by Martino et al. (1987), 70% of patients with thyroid autoimmunity had persistent hypothyroidism, while hypothyroidism spontaneously remitted within 2–4 months after withdrawal of amiodarone in 90% of patients without circulating thyroid

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antibodies. According to this observation, we found that, after amiodarone withdrawal, only one patient (with mild hypothyroidism and without thyroid antibodies) showed a severe worsening of hypothyroidism, while the others obtained a prompt recovery. On the contrary, carrying on amiodarone treatment in mild AIH patients, a severe worsening of hypothyroidism in about 50% of subjects was observed. In conclusion, the identification of hypothyroid status in cardiac geriatric patients chronically treated with amiodarone is clinically very difficult and needs laboratory help. TSH (elevated) and fT4 (decreased only in severe hypothyroidism) are the two discriminating parameters permitting the identification of hypothyroidism. Subtle thyroid defects of hormonogenesis, frequently found in elderly people, could be important prognostic factors beside thyroid antibodies. Amiodarone withdrawal may not always induce euthyroidism in mildly AIH aged patients; on the contrary, the prosecution of amiodarone therapy seem to worse the thyroid clinical status only in about 50% of patients. If, in mildly AIH patients, evaluated on the basis of the cardiac function, amiodarone withdrawal is possible, the follow-up of the thyroid function must be observed for some months, as sometimes we have found, instead of a recovery of the thyroid function, a severe worsening of the same. Nevertheless, in AIH cardiac aged patients on chronical amiodarone therapy, precocious substitutive T4 therapy seems to be absolutely necessary, only in case of severe hypothyroidism. In the mild form of AIH, it is recommended to follow-up the thyroid function before starting the T4 therapy, since about half of the patients do not develop severe hypofunction.

Acknowledgements This research was supported by a grant from Ente Cassa di Risparmio di Firenze. The authors gratefully acknowledge Prof. Mario Serio and Prof. Francesco M. Antonini, University of Florence, Italy, for their suggestions and criticism during the preparation of the manuscript. The authors also thank Mrs. Claudia Moro for her technical and secretarial assistance.

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