Jayne A. Franklyn
Michael D. Gammage
Overt thyroid dysfunction, defined as abnormal serum thyrotropin (TSH) and free thyroxine (T4) concentrations, is common, and subclinical thyroid dysfunction (abnormal serum TSH but normal serum free T4 concentrations) is even more common (see Chapter 19). For example, among 25,863 subjects attending a state-wide health fair in Colorado, the prevalence of overt hypothyroidism was 0.4% and that of overt thyrotoxicosis was 0.1%, and the respective prevalence rates for subclinical hypothyroidism and subclinical thyrotoxicosis were 9.0% and 2.1%, respectively (1). These abnormalities are more common in women, and the rates increase with age.
High serum TSH concentrations are found almost entirely in people with thyroid diseases, but low serum TSH concentrations have multiple causes. They include not only thyroid disease, and treatment for thyroid disease, but also nonthyroidal illness and treatment with drugs such as glucocorticoids and dopamine (see Chapter 13). Also, patients with hypothyroidism are often overtreated with T4 or other thyroid hormone preparations (see Chapter 67) (1,2), and patients with thyrotoxicosis may have low serum TSH concentrations for prolonged periods despite restoration of normal serum T4 and triiodothyronine (T3) concentrations (see Chapter 45).
Most patients with overt thyroid dysfunction have some symptoms and signs (see Chapters 22 and 46), and before the advent of effective therapy they often died, typically from cardiovascular disease. In contrast, most patients with subclinical thyroid dysfunction do not have any more symptoms than do normal subjects (3). Nonetheless, subclinical thyroid dysfunction may be associated with an increase in morbidity and mortality. Cardiovascular disease remains the most important consequence of thyroid dysfunction, particularly thyrotoxicosis, and its treatment today. Other features of thyrotoxicosis, such as osteoporosis, may also result in substantial long-term morbidity. Finally, both thyroid dysfunction and its treatment have been implicated in the development of cancer, most attention focusing on the potential carcinogenic effect of radioiodine (iodine 131) therapy in patients with thyrotoxicosis.
CARDIOVASCULAR MORBIDITY AND MORTALITY IN THYROTOXICOSIS
Overt Thyrotoxicosis
Most patients with thyrotoxicosis have some abnormalities in cardiovascular function (see Chapter 31). Among them, the one most likely to be associated with adverse clinical events is atrial fibrillation. It occurs in approximately 5% to 15% of patients with overt thyrotoxicosis, especially older patients with ischemic heart disease or hypertension. For example, among 462 patients with thyrotoxicosis, 33% of those with coexisting ischemic heart disease and 41% of those with coexisting hypertension had atrial fibrillation (4). Effective treatment of thyrotoxicosis is associated with restoration of sinus rhythm in some, but not all, patients. In those with new-onset atrial fibrillation, spontaneous reversion to sinus rhythm may occur in up to 50%, and it typically does so within a few months after restoration of euthyroidism (5). Reversion to sinus rhythm is, however, much less likely in those with underlying heart disease and those in whom atrial fibrillation antedated thyrotoxicosis (4,5,6).
The main hazard of atrial fibrillation is arterial embolization, especially to the cerebral circulation. Few studies have investigated the rate of arterial embolism in patients with thyrotoxicosis and atrial fibrillation. In one study of 142 patients with thyrotoxicosis, 12 of the 30 patients with atrial fibrillation (40%) had an embolic event, as compared with none of the 112 patients who had a sinus rhythm (7). In another study of 610 patients with thyrotoxicosis, 12 of the 91 patients (13%) who had atrial fibrillation had an embolic event, as compared with 15 of the 519 patients (3%) who did not have atrial fibrillation (8). After adjustment for age, the presence of atrial fibrillation was not a risk factor for cerebrovascular events. However, during the first year after diagnosis of thyrotoxicosis, the frequency of cerebrovascular events among all 610 patients was higher than that expected in the general population. Taken together, the existing data suggest that the frequency of embolism, especially cerebral embolism occurring early in the course of thyrotoxicosis (9), is increased in patients with thyrotoxicosis and atrial fibrillation.
In addition to the association between atrial fibrillation and embolic complications in thyrotoxicosis described above, several studies have examined the relationship between overt thyrotoxicosis and other cardiovascular disease end points, including mortality. A follow-up study of 1,762 patients with thyrotoxicosis treated in the United States from 1946 to 1964 (80% of whom were treated with radioiodine) revealed, during a mean follow-up period of 17 years, an increase in mortality from all causes (standardized mortality ratio 1.3, 95% confidence interval 1.2–1.4), and an increase in mortality from diseases of the circulatory system (standardized mortality ratio 1.4, 95% confidence interval 1.3–1.6) (10). A larger study of 10,552 Swedish patients with overt thyrotoxicosis treated with radioiodine and followed for an average of 15 years revealed a similar increase in mortality from cardiovascular diseases (standardized mortality ratio 1.65, 95% confidence interval 1.59–1.71) (11). Lastly, among 7,209 patients with overt thyrotoxicosis treated with radioiodine between 1950 and 1989 in the United Kingdom, 3,611 had died by 1996, whereas the expected number of deaths was 3,196 ( < 0.001) (12) (Table 77.1). There were significant increases in risk of death for all categories of heart disease (rheumatic heart disease, hypertensive disease, ischemic heart disease; 240 excess deaths), and for cerebrovascular disease (159 excess deaths). The excess in mortality due to cardiovascular and cerebrovascular diseases was most marked in the first year after radioiodine therapy, and was associated with higher doses of radioiodine. There was excess mortality in all age groups; cardiovascular disease mortality was most marked in those over 50 years of age when treated. The excess mortality in this cohort [and the Swedish cohort described above (11)] may have resulted from adverse effects of thyrotoxicosis, radioiodine therapy per se, or radioiodine-induced hypothyroidism or its treatment with Tp4. In the U.K. study, the relationship between death and time after treatment, as well as the relationship between death and dose of radioiodine (an indirect marker of the severity of thyrotoxicosis), suggest that thyrotoxicosis itself was the major cause of the excess mortality. This is probably mediated through the effects of thyrotoxicosis on cardiac rate, rhythm, and function, as well as exacerbation of any underlying heart disease.
TABLE 77.1. OBSERVED AND EXPECTED NUMBERS OF DEATHS AND STANDARDIZED MORTALITY RATIOS FOR CAUSES OF DEATH FOR WHICH THE RISK WAS ALTERED IN A COHORT OF 7, 209 PATIENTS TREATED WITH RADIOIODINE FOR THYROTOXICOSIS
No. of Deaths
Cause of Death
ICD-9 Codes*
Observed
Expected
SMR (95% CI)
P Value
Endocrine and metabolic disease
240–279
159
51
3.1 (2.6–3.6)
< 0.001
Disease of the circulatory system
390–459
1955
1577
1.2 (1.2–1.3)
< 0.001
All cardiovascular disease
1258
1018
1.2 (1.2–1.3)
< 0.001
Rheumatic heart disease
67
21
3.2 (2.5–4.2)
< 0.001
Hypertensive disease
59
28
2.1 (1.6–2.7)
< 0.001
Ischemic heart disease
867
812
1.1 (1.0–1.1)
0.03
Diseases of pulmonary circulation and other heart disease
265
157
1.8 (1.5–1.9)
< 0.001
Cerebrovascular disease
605
446
1.4 (1.2–1.5)
< 0.001
Other diseases of the circulatory system
92
112
0.8 (0.7–1.0)
0.03
Injuries and poisoning
800–999
100
61
1.6 (1.3–2.0)
< 0.001
Fractures
50
26
1.9 (1.4–2.6)
< 0.001
All causes
3611
3186
1.1 (1.1–1.2)
< 0.001
*ICD-9 denotes the ninth revision of the (16); SMR, standardized mortality ratio; and CI, confidence interval. From Franklyn JA, Maisonneuve P, Sheppard MC, et. al. Mortality after the treatement of hyperthyrodism with radioactive iodine. 1998;338:712, with permission.international classification of DiseasesN Engl J Med
Subclinical Thyrotoxicosis
Atrial fibrillation has also been associated with subclinical thyrotoxicosis (see Chapter 79) (13,14,15). In the largest prospective study of this association, which involved 2,007 subjects 60 years of age or older followed for up to 10 years, the cumulative risk for atrial fibrillation was nearly three times higher (28%) in those subjects with a serum TSH concentration ≤ 1 mU/L at baseline than in those with normal serum TSH concentrations (>0.4–5.0 mU/L) (11%) (relative risk 3.1, 95% confidence interval 1.7–5.5; < 0.001) (14) (Fig. 77.1). The incidence of atrial fibrillation in the subjects with slightly low serum TSH concentrations (>0.1–0.4 mU/L) and those with serum TSH concentrations greater than 5.0 mU/L was similar to that in the subjects with normal serum TSH concentrations (16% and 15%, respectively, vs. 11). In a retrospective study ofp 23,638 in- and outpatients in whom serum TSH was measured, 2% of those with normal serum TSH concentrations had atrial fibrillation, as compared with 14% of those with overt thyrotoxicosis, and 13% of those with subclinical thyrotoxicosis (15).
FIGURE 77.1. Cumulative risk of atrial fibrillation in subjects over 60 years of age followed for 10 years and divided according to serum thyrotropin concentration at baseline. (Adapted from Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. 1994;331:1249, with permission.)N Engl J Med
Subclinical thyrotoxicosis may also be associated with alterations in cardiac contractility and heart rate similar to but less marked than occur in overt thyrotoxicosis (see Chapter 31) (16,17). There is little evidence that these changes are associated with clinically important changes in cardiac function (3). In a study of hospital admission rates due to ischemic heart disease, there was an increase in risk for admission among patients taking T4, as compared with those not taking T4, but among those taking T4 there was no difference between those with normal and those with low serum TSH concentrations (18). These results argue against an adverse effect of subclinical thyrotoxicosis secondary to ingestion of T4 (exogenous subclinical thyrotoxicosis).
The risk for all-cause and cardiovascular disease mortality in relation to serum TSH concentration at baseline was studied in a cohort of 1,191 patients 60 years of age or older in the United Kingdom who were followed for 10 years (19,20). Causes of death for those who died during follow-up were compared with age-, sex-, and year-specific data for England and Wales. The all-cause standardized mortality rate for patients with subclinical thyrotoxicosis at year 2 was 2.1 (95% confidence interval 1.0–4.5), and the values for years 3, 4, and 5 were similar. This increase in all-cause mortality was almost completely accounted for by deaths caused by cardiovascular diseases (Fig. 77.2). The causes of the low serum TSH concentrations in this cohort were not determined, although about one third had a goiter on physical examination, and serum free T4 concentrations were higher in the patients with low serum TSH concentrations than in those with normal serum TSH concentrations, suggesting mild thyroid hormone excess as a general cause of TSH suppression. The absence of excess deaths from other common causes such as cancer or respiratory disease in the patients with low serum TSH concentrations suggests that the association of cardiovascular disease mortality with low serum TSH concentrations is not a nonspecific effect of nonthyroidal illnesses on TSH secretion. These results, along with the increased risk for atrial fibrillation cited above, support the view that antithyroid treatment should be considered in patients with persistent subclinical thyrotoxicosis, although evidence that intervention lowers the risk for atrial fibrillation or any other outcome is lacking (3).
FIGURE 77.2. Kaplan-Meier survival plot of cardiovascular deaths in a cohort of 1,191 general practice patients over 60 years of age, subdivided according to their serum thyrotropin concentrations at baseline, followed for 10 years. (Adapted from Parle JV, Maisonneuve P, Sheppard MC, et al. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. 2001;358:861, with permission.)Lancet
CARDIOVASCULAR MORBIDITY AND MORTALITY IN HYPOTHYROIDISM
Overt Hypothyroidism
Severe overt hypothyroidism can lead to fatal myxedema coma (see Chapter 65) (21). Overt hypothyroidism has been reported to be associated with cardiovascular disease, although the evidence for an association is largely confined to older literature reporting findings from relatively small numbers of patients (22,23). Such an association is plausible, however, given the hypercholesterolemia, hyperhomocysteinemia, and diastolic hypertension found in patients with overt hypothyroidism (see Chapter 53).
Subclinical Hypothyroidism
The possibility of an association between subclinical hypothyroidism and cardiovascular disease has also been raised. Serum total and low-density lipoprotein cholesterol concentrations may be slightly high in these patients (see Chapter 78), but the concentrations do not decline consistently during T4 therapy (24). There was an association between serum TSH concentrations and diastolic blood pressure in a study of 57 women with subclinical hypothyroidism and 34 normal women (25). Despite these potential mechanisms for increased cardiovascular risk, the prevalence of angina, myocardial infarction, peripheral arterial disease, and cerebrovascular disease among 3,678 subjects enrolled in the Cardiovascular Health Study was similar in those subjects with subclinical hypothyroidism and those with normal serum TSH concentrations (26). With respect to mortality, there was no increase in all-cause mortality or mortality from ischemic heart disease in subjects with subclinical hypothyroidism in the Whickham cohort followed for up to 20 years (27). These results are in agreement with the results of the 10-year follow-up study of a cohort of 1,191 patients described earlier, in that there was no increase in either all-cause or cardiovascular disease mortality in the patients who had subclinical hypothyroidism at baseline (20).
An association between subclinical hypothyroidism and ischemic heart disease was found in two small studies (28,29), and in a study of elderly subjects in a nursing home 32 of 56 subjects with subclinical hypothyroidism (58%) had coronary artery disease, as compared with 37 of 231 euthyroid subjects (16%) (30). The prevalence of peripheral arterial disease also was increased in these nursing home subjects (31). A study of 1,149 women 55 years of age and older in the Netherlands revealed an association between subclinical hypothyroidism and aortic calcification (odds ratio 1.9) and myocardial infarction (odds ratio 2.3) (32). There was no association with incident myocardial infarction.
FRACTURES AND THYROTOXICOSIS
Overt Thyrotoxicosis
Thyrotoxicosis results in net loss of bone and hence reduction in bone mineral density (see Chapter 40), but the evidence that patients with thyrotoxicosis have an increase in fracture is conflicting.
A large prospective study followed 9,516 white women over 65 years of age for an average of 4.1 years for incident fractures of the femur. There was a 1.8-fold increase in risk for fracture among those women with a history of thyrotoxicosis (95% confidence interval 1.2–2.6) (33). Similarly, there was an increase in mortality from hip fracture among 7,209 patients with thyrotoxicosis treated with radioiodine (standardized mortality ratio 2.9, 95% confidence interval 2.0–3.9) (12). In contrast, there was no association between a history of thyrotoxicosis and fractures of the ankle and foot in a prospective study of over 9,000 postmenopausal women (34). A case control study of the occurrence of fracture before and after diagnosis of thyrotoxicosis found an approximate twofold increased incidence of fracture (of all sites) around the time of diagnosis, with return of the fracture rate to that in the control subjects thereafter (35). A smaller follow-up study of 630 patients who underwent thyroidectomy (only 85 of whom had thyrotoxicosis) revealed no association with fracture of the femur (36).
Subclinical Thyrotoxicosis
Like overt thyrotoxicosis, subclinical thyrotoxicosis (especially that associated with T4 therapy) has been implicated in the development of osteoporosis (see Chapter 40). Most of the studies of subclinical thyrotoxicosis and bone disease have been conducted in patients receiving T4, not patients with endogenous subclinical thyrotoxicosis.
Early studies reported significant reductions in bone mass in patients treated with T4 for prolonged periods of time (37,38). However, several later studies failed to demonstrate any detrimental effect of T4 therapy on bone, even in those taking sufficient T4 to cause subclinical thyrotoxicosis (39,40). Two meta-analyses of the many studies of this topic suggested that T4 therapy was associated with osteopenia in postmenopausal women (41,42), although these analyses are complicated by the heterogeneity of the women who were studied, particularly with respect to their history of thyrotoxicosis and extent of T4therapy. Bone density does increase when patients with subclinical thyrotoxicosis are treated with an antithyroid drug (43).
With respect to fracture, a study of 1,100 patients taking T4 found no significant difference in fracture rate, as compared with the general population (18). In the prospective study of 9,516 white women over 65 years of age described above (33), there was an increased risk for incident fracture of the femur in women taking thyroid hormone (relative risk 1.6, 95% confidence interval 1.1–2.3), but this was no longer significant when adjusted for a history of thyrotoxicosis (present in 36% of those taking T4). A prospective cohort study of 686 women over 65 years of age followed for a mean of 3.7 years revealed that women with baseline serum TSH concentrations < 0.1 mU/L had a threefold increased risk for hip fracture and fourfold increased risk for vertebral fracture, as compared with women with normal serum TSH concentrations (after adjusting for other factors including age, previous thyrotoxicosis, and estrogen therapy) (44). Among 23,183 patients (88% women) in the United Kingdom for whom T
4 had been prescribed, the occurrence of fracture of the femur was not higher than in 92,732 matched control patients (45). Prescription of T4 was not an independent predictor of femoral fracture among the women (adjusted odds ratio 1.0, 95% confidence interval 0.9–1.2), but it was among men (adjusted odds ratio 1.7, 95% confidence interval 1.1–2.6).
Overall, the data regarding osteoporosis and thyroid status support an adverse effect of overt thyrotoxicosis on bone density and fracture risk, and the effect may be sustained despite successful antithyroid therapy. Subclinical thyrotoxicosis has little effect on bone density or fracture risk, except perhaps in patients with low serum TSH concentrations (some of whom may in fact have had overt thyrotoxicosis) and postmenopausal women.
CANCER RISK AND THYROID DYSFUNCTION AND ITS TREATMENT
Several studies have addressed the question of whether thyroid diseases are themselves associated with increased risk for thyroid and other cancers. In a retrospective study of 7,338 women followed on average for more than 15 years, there was a small but significant increase in total cancer deaths in those with nodular goiter, thyroid adenoma, thyrotoxicosis, and Hashimoto's thyroiditis, as compared with the general population, but women in the cohort who did not have thyroid disease also were more likely to die of cancer (46). The risk for cancer was not increased in a cohort of 57,326 patients discharged from a Danish hospital with a diagnosis of thyrotoxicosis, hypothyroidism, or goiter, but there was an increase in thyroid cancer, as well as cancer at some other sites, in all three groups of thyroid disease patients (47). These results may reflect true disease associations, associations between cancer risk and autoimmune disease (as the major underlying cause of thyroid dysfunction), or associations between cancer risk and thyroid hormone or antithyroid therapy.
Several studies have addressed a possible link between risk for breast cancer and thyroid disorders. Several found no association between either thyroid disorders or their treatment and breast cancer risk (48,49), although another study suggested there was a modest association (50). A recent case-control study involving 4,575 women with invasive breast cancer and 4,682 control women revealed that a history of any thyroid disorder was not associated with breast cancer risk (odds ratio 11.2, 95% confidence interval 0.9–1.2) (51). Only parous women with a diagnosis of thyroid cancer had increased risk. The results of similar case-control studies examining risk for other cancers, for example, ovarian cancer, were negative (52).
The introduction of radioiodine therapy for thyrotoxicosis in the 1940s was accompanied by questions concerning its long-term safety, especially in terms of cancer risk (53). These concerns, if anything, increased after recognition that irradiation of the head and neck caused thyroid cancer, whether from x-irradiation or exposure to the products of atomic bomb testing or nuclear power plant accidents (see section Pathogenesis in Chapter 70) (54,55).
Several studies of cancer risk in patients treated with radioiodine for thyrotoxicosis have been reported, with conflicting results. A study of a large cohort of patients in Sweden found no excess risk for leukemia or solid tumors in those exposed to 131I, given either for diagnosis or treatment of thyrotoxicosis or thyroid cancer (56). Overall cancer incidence was increased (standardized incidence ratio 1.06, 95% confidence interval 1.01–1.11), and analysis of a subgroup of 10-year survivors revealed significantly increased risks for cancers of the stomach, kidney, and brain. Furthermore, the risk for stomach cancer has been reported to increase with time and with increasing dose of 131I (57,58). However, a study comparing cancer risk in patients with thyrotoxicosis treated with 131I or thyroidectomy revealed no differences in cancer incidence or mortality at these or other sites (59). In another study the incidence of cancer and mortality was determined in a cohort of 7,417 patients treated with 131I for thyrotoxicosis (60). During 72,073 person-years of follow-up, 634 cancers were diagnosed, as compared with an expected number of 761 (standardized incidence ratio 0.83, 95% confidence interval 0.77–0.90). The risk for cancer mortality was also reduced in the cohort (observed cancer deaths 448; expected 499; standardized mortality ratio 0.90, 95% confidence interval 0.82–0.98). There were significant decreases in the incidence of cancers of the pancreas, bronchus and trachea, bladder, and lymphatic and hematopoietic systems, and mortality from cancers at each of these sites was also reduced. However, there was a small but statistically significant increase in incidence and mortality for cancer of the small bowel and thyroid, although the absolute risk for occurrence or death from these cancers was small.
Because the thyroid is the major site of radiation exposure after radioiodine treatment, attention has focused on risk for thyroid cancer. Patients given 131I for diagnostic imaging have not had an increase in thyroid cancer (61). An analysis of 35,593 patients with thyrotoxicosis treated at 26 centers in the United States and United Kingdom between 1946 and 184, 65% of whom were treated with 131I, did reveal an increase in thyroid cancer mortality (62). The cancer risk was increased in patients treated with 131I and those treated with an antithyroid drug. In the cohort of 7,417 patients mentioned above (60), there was a small but statistically significant increase in incidence and mortality for thyroid cancer (standardized mortality ratio 2.8, 95% confidence interval 1.2–6.7), although the absolute risk for development or death from thyroid cancer was small.
Overall, these findings are reassuring in terms of the overall safety of 131I treatment and cancer risk. The evidence does suggest an increased relative risk for thyroid cancer in patients with thyrotoxicosis treated with 131I, although the absolute risk is small. If there is indeed an increase in risk, it may be caused by the underlying thyroid disease rather than 131I therapy per se.
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