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Mortality and Vascular Outcomes in Patients Treated for Thyroid Dysfunction

Medicines Monitoring Unit (R.W.V.F., T.M.M., A.D.M.), Division of Medicine and Therapeutics (A.D.M.), and Wards 1 and 2 (R.T.J., G.P.L.), Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom

Address all correspondence and requests for reprints to: G. P. Leese, Wards 1 and 2, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom. E-mail: graham.leese{at}tuht.scot.nhs.uk.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: There are limited studies describing mortality and morbidity in patients treated for hyperthyroidism, and no data exist for people with treated hypothyroidism.

Objective: The objective of the study was to describe all-cause mortality and vascular mortality and morbidity in patients after treatment for hyperthyroidism and hypothyroidism.

Design: This was a population-based cohort study from 1994 to 2001.

Setting: The study was conducted in Tayside, Scotland.

Patients: All patients were treated for thyroid dysfunction.

Intervention(s): Event rates among patients with thyroid dysfunction were compared with rates in the general population. We measured standardized mortality ratio and standardized incidence ratio (SIR).

Main Outcome Measure(s): The primary outcome was all-cause mortality. The secondary outcome was serious vascular event, the composite end point of nonfatal myocardial infarction, nonfatal stroke, or vascular death.

Results: There were 15,889 primary hypothyroid and 3,888 hyperthyroid patients. There were 3,116,719 patient-years of follow-up in 524,152 subjects in the general population. No increase was found in all-cause mortality or serious vascular events in patients with treated hypothyroidism or hyperthyroidism. Nonfatal ischemic heart disease [SIR 1.23, 95% confidence interval (CI) 1.10–1.36] and dysrhythmias (SIR 1.32, 95% CI 1.11–1.57) were increased in treated hypothyroidism when adjusted for age, sex, diabetic status, and previous vascular disease. In treated stabilized hyperthyroidism, only the risk of dysrhythmias was increased (SIR 2.71, 95% CI 1.63–4.24). Risk of heart failure or cerebrovascular disease was not increased in either patient group.

Conclusions: We found no increase in all-cause mortality in subjects with treated thyroid disease. However, there was increased risk of cardiovascular morbidity in patients with treated primary hypothyroidism and dysrhythmias in treated hyperthyroidism.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
THERE IS A high prevalence of thyroid dysfunction in some Western populations, with up to 3% of the general population being affected (1, 2, 3, 4). Although untreated thyroid disease is associated with increased rates of cardiovascular disease (5), there are fewer data describing mortality and vascular events in subjects after treatment and stabilization of thyroid disease. Previous studies have investigated mortality in patients treated with radioactive iodine (6), the incidence of cancer in patients treated for hyperthyroidism (7, 8), and mortality in older patients after abnormal TSH measurements in nonthyroid-treated patients (9). There is a marked absence of data relating to subjects with treated hypothyroidism. This may be attributed to the difficulty of following up subjects whose condition is routinely managed in a primary care setting (1, 4).

The Thyroid Epidemiology, Audit, and Research Study (TEARS) has used record linkage technology to define incident and prevalent cohorts of subjects who have been treated for thyroid dysfunction from a complete and representative population base (1). The present study used the same methodology to establish the rates of all-cause mortality and serious vascular events in patients who have been treated for thyroid dysfunction through the linkage of the TEARS data set to outcome data available from routinely collated sources (10). We used this approach to explore in detail the different outcomes observed between people with treated hyperthyroidism and treated hypothyroidism.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This was an observational cohort study using data from the TEARS data set and the record linkage technologies of the Medicines Monitoring Unit (MEMO) and Health Informatics Centre at the University of Dundee. MEMO uses record-linkage technology to conduct epidemiological and pharmacoepidemiological studies and has been described in detail elsewhere (1, 10). In brief, a unique patient identifier, the community health number (CHNo), is used to link patient-level data from routinely collated population-based data sets. Every person registered with a general practitioner in Scotland is assigned a CHNo, and in Tayside this is used as the patient identifier for all contacts with health care activity. In this case the TEARS data set was linked to outcome data to establish relative mortalities and morbidities in the thyroid population.

Study population

This study used anonymized patient-level data from the general population of Tayside, Scotland. We used a dynamic population that included all subjects that were registered with a general practitioner in Tayside from January 1, 1994, to December 31, 2001.

Databases

CHNo master patient index. This index provided data on registered Tayside general practitioners, dates registered with general practitioners, date of birth, and date of death. It was used to define the study population from which subjects were identified.

The TEARS data set. The data set originally covered the period from 1993 to 1997 but is now extended to 2001. It links records from all dispensed prescriptions in Tayside, the thyroid follow-up register, the radioactive iodine database, biochemistry results, and Scottish Morbidity Records (SMR1) hospital admission data for all thyroid operations (see text below). It determined whether patients originally had primary hypothyroidism or hyperthyroidism and identified all new cases of thyroid disease. We used data from the TEARS data set to describe disease type; this has been shown to be 98% sensitive in predicting cases of hyperthyroidism and 96% for hypothyroidism (1). Subjects known to have thyroid cancer and those receiving T₄ for euthyroid goitre were excluded from the analysis a priori.

Death certification data. An electronic database was available from the General Register Office, Scotland. Data used included date of death and underlying cause of death, coded according to the International Classification of Diseases, ninth (ICD-9) or 10th (ICD-10) revisions (11, 12). These data were supplied with names and addresses of the deceased, so CHNos were assigned using the validated MEMO methodology and were then record linked and anonymized (10).

SMR1 records. These data are routinely validated and collated by the Information and Statistics Division (ISD) of the National Health Service in Scotland and were available for Tayside from January 1, 1980, to December 31, 2001. These contained diagnostic codes relating to all hospital in-patient episodes of care and also used the ICD-9 or ICD-10 revisions. These data were used to provide details on nonfatal events that resulted in hospital admission.

Diabetes Audit and Research in Tayside, Scotland data. This data set includes validated information on all people with types 1 and 2 diabetes in Tayside and provided data on date of diagnosis (13). This was included because of known associations between diabetes and thyroid dysfunction and diabetes and cardiovascular disease.

Outcomes

The primary outcome was all-cause mortality. The secondary outcome was serious vascular event as defined by the Antithrombotic Trialists’ Collaboration (14). We selected this composite end point of nonfatal myocardial infarction (ICD-9 codes 410; ICD-10 codes I21), nonfatal stroke (ICD-9 codes 431, 434.9, 436; ICD-10 codes I61, I63, I64), or vascular death (ICD-9 codes 390–459; ICD-10 codes I00-I99). Details of fatal events were derived from the General Register Office death certification data, whereas details of nonfatal events were derived from SMR1 inpatient data. Further end points were explored. Circulatory diseases consisted of diseases of the circulatory system (ICD-9 codes 390–459; ICD-10 codes I00-I99). Two subcategories of this were cardiovascular disease (ICD-9 390–429; ICD-10 I00-I52) and cerebrovascular disease (ICD-9 430–438; ICD-10 I60-I69). Cardiovascular disease consisted of ischemic heart disease (ICD-9 410–414; ICD-10 I20-I25), heart failure (ICD-9 428; ICD-10 I50), and dysrhythmias (ICD-9 427; ICD-10 I47-I49). Ischemic heart disease has as subcategories myocardial infarction (ICD-9 410; ICD-10 I21) and angina (ICD-9 413; ICD-10 I20).

Statistical analysis

The observed values were the total number of events for patients who had been treated for thyroid dysfunction. The expected values were calculated by applying the event rate in the general Tayside population to the number of subjects in the thyroid dysfunction population. The general population event rates were calculated by dividing the number of persons suffering events in the Tayside population by total population of Tayside taken from census-based data. This was calculated on a yearly basis from 1994 to 2001 and was stratified by age (5-yr groupings), sex (males or female), and diabetic status (diabetic or not diabetic). Analyses were also conducted that stratified by preexisting vascular disease as identified by inpatient admission records. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated by dividing observed by expected events, and 95% confidence interval limits for SMRs and SIRs were constructed assuming a poisson distribution.

We analyzed two subcategories of thyroid dysfunction. Patients were classified as hyperthyroid if they had been treated for hyperthyroidism by surgery, radioactive iodine, or medication or they had a history of hyperthyroidism on the thyroid register. These patients had been successfully treated and stabilized with or without the need for thyroid replacement therapy (1). The subgroup of incident hyperthyroid patients consisted of new treated cases arising between 1994 and 2001 that had been successfully treated. Patients were classified as primary hypothyroid if they were on continuous long-term thyroid replacement therapy because of an underactive thyroid. The subgroup incident hypothyroid cohort consisted of new cases of hypothyroidism that had been diagnosed and stabilized between 1994 and 2001. The definitions of primary hypothyroidism and hyperthyroidism were mutually exclusive. Those with any form of thyroid cancer or those treated with T₄ for euthyroid goitre were excluded.

Ethics approval

The databases used were anonymized and registered under the Data Protection Act for purposes of research and audit. At all times, confidentiality of individual patients’ and individual general practices’ data was maintained, and all statistical analysis was performed on anonymized data sets (15). The study was approved by the Tayside Research and Ethics Committee, and permission to access patient data was obtained from Tayside Caldicott Guardians.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The follow-up for the general population was 3,116,719 patient-years from 524,152 persons. From 1994 to 2001, there were 79,345 patient-years of follow-up among the 15,889 patients that were being treated for primary hypothyroidism. For the incident cases, there were 28,616 patient-years of follow-up for 7,904 patients. For the treated hyperthyroid cohort, there were 21,190 patient-years of follow-up for the 3,888 patients, and for the incident cases, there were 2,417 patient-years of follow-up among 772 patients.

By June 30, 2001, the prevalence of treated hypothyroidism was 3.4%, and the prevalence of diabetes was 2.9%. Of the subjects with treated hypothyroidism, 8.4% had diabetes, which represents an approximately three times increased risk of treated hypothyroid patients also having diabetes. The prevalence of patients with treated hyperthyroidism was 0.7%. Of the subjects with hyperthyroidism, 6.9% had diabetes, which represents an approximately 2.5 times increased risk of treated hyperthyroid patients also having diabetes.

Over the 8 yr of the study period, there were 37,095 deaths among the resident population of Tayside. For patients with treated primary hypothyroid, there were 2681 observed deaths. When adjusted for age, sex, and diabetes, the expected number of deaths was 2608.3 [SMR 1.03, 95% confidence interval (CI) 0.99–1.07]. This represents a nonsignificant excess of 73 deaths. Among the patients treated for hyperthyroidism, there were 565 observed deaths. When adjusted for age, sex, and diabetes, the expected number of deaths was 539.2 (SMR 1.05, 95% CI 0.96–1.14). This represents a nonsignificant excess of 26 deaths.

There were 25,863 serious vascular events in the population of Tayside. Within the treated primary hypothyroid population, there were 1926 observed events. The expected number of events adjusted for age, sex, and diabetes was 1745.0 (SIR 1.10, 95% CI 1.06–1.15). This represents an excess of 181 serious vascular events in Tayside over the 8 yr of the study, and this was statistically significant. Within the treated hyperthyroid population, there were 386 observed events. The expected number of events adjusted for age, sex, and diabetes was 367.6 (SIR 1.05, 95% CI 0.95–1.16). This represents an excess of 18 events and was not statistically significant.

These findings were explored by examining data for the incident cases of thyroid disease only and breaking down the mortality and morbidity findings for both cohorts. Table 1 shows mortality broken down by cause of death, and Table 2 shows different causes of morbidity. Both these are adjusted for age, sex, and diabetes. Table 3 also shows causes of morbidity but is adjusted for age, sex, diabetes, and preexisting vascular disease. Figure 1 shows the SIR for serious vascular events in the initial years after treatment adjusted for age, sex, and diabetes.

View larger version (12K): [in this window] [in a new window]   FIG. 1. The relative level of serious cardiovascular events in patients in the initial years after first treatment for hyperthyroidism and hypothyroidism.

Table 2 shows that for patients with treated hyperthyroidism, there was no increased morbidity observed for circulatory diseases, ischemic heart diseases, or cerebrovascular disease; however, there was for dysrhythmias. Table 3 shows that this persisted after adjustment for preexisting vascular disease. For the incident primary hypothyroid cohort, circulatory disease and all subcategories of circulatory disease (including ischemic heart disease, dysrhythmias, and cerebrovascular disease) showed significantly increased levels of morbidity as measured by hospital admissions. Table 3 shows that this was partly accounted for by adjusting for preexisting vascular disease but that there was still increased morbidity after allowing for this: only the morbidities associated with heart failure and cerebrovascular disease were reduced to a nonsignificant level.

Figure 1 shows that there was no trend in the relative number of serious vascular events observed in the years immediately after initial treatment for either hyperthyroidism or hypothyroidism.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
This study has established relative mortalities and morbidities in a cohort of patients who have been treated for thyroid dysfunction. We found that there was no significant difference between all-cause mortality in the general population and the thyroid population. However, there was a higher level of serious vascular events in those suffering from primary hypothyroidism. These findings have been explored by examining cause-specific mortality and morbidity in those with hyperthyroidism and those with primary hypothyroidism. To allow adjustment for preexisting vascular disease, we conducted analyses using incident cases only. We have shown that patients with thyroid dysfunction are at increased risk of having diabetes and that any increases in mortality and morbidity are not confounded by this relationship. Furthermore, although increases in morbidity are partly confounded by preexisting vascular disease, there is still a measurable effect after adjustment.

These findings have been shown in cases of thyroid dysfunction arising from the general population of Tayside. The data were checked using a fixed population, and the results achieved were found to be very similar. Recent census findings show that the Tayside population is broadly representative of the Scotland population in terms of its age-sex distribution and proportion of nonwhite ethnic groups (16). The area has a low subject migration of 2.7% per year (17).

Hyperthyroidism

In those who have been treated for hyperthyroidism, there was increased risk of nonfatal dysrhythmias but not of other circulatory diseases, death, or serious vascular disease. Despite the risk of dysrhythmias, the patients were not at increased risk of cerebrovascular disease. Intriguingly, the increased prevalence of dysrhythmias in treated hyperthyroidism was not associated with ischemic heart disease or diabetes and therefore probably has a different etiology from that seen in patients with treated hypothyroidism. It may be due to direct cardiotoxicity of hyperthroxinemia during the pretreatment/prediagnostic phase of hyperthyroidism, which has also been noted in untreated hyperthyroidism (18). Our results suggest that whatever the cause, it is not fully reversed by curing the hyperthyroidism.

Previous population studies have studied hyperthyroid subjects after treatment for their disorder. Franklyn et al. (6) studied 3611 radioactive iodine-treated patients after treatment with radioactive iodine and found a small but statistically significant increase in all-cause mortality, a large part of which was attributed to an increase in circulatory mortality. Much of this was due to increased mortality in the first year after treatment. We found no evidence of this. Two studies investigated relative levels of cancer in subjects also after treatment for radioactive iodine: Ron et al. (7) found no excess cancer mortality except thyroid cancer, and Franklyn et al. (8) found no excess incidence of cancer except for that of the thyroid and small bowel. Both of these increases represented a small attributable number of cases, and overall cancer rates were not increased. Our results are from all patients treated for hyperthyroidism and are consistent with these previous findings.

Hypothyroidism

We have demonstrated for the first time that despite treatment for primary hypothyroidism with T₄, patients are at increased risk of morbidity associated with circulatory diseases, ischemic heart disease, dysrhythmias, and cerebrovascular disease. There was no increased risk of all-cause mortality or cancer mortality. We have shown that even after adjusting for diagnosis of diabetes, there was still an increase in circulatory diseases in treated hypothyroid patients. Adjustment for preexisting vascular disease reduced the risks, but they remained significant except for heart failure and cerebrovascular disease. We also showed ongoing risk beyond the initial years of treatment. There is a plausible biological explanation for our findings. Primary hypothyroidism is frequently undiagnosed for some time before treatment and during this time can be associated with adverse dyslipidemia (19). Treatment with T₄ may not fully reverse the atherosclerotic process, even if it does reverse the dyslipidemia (20). Another possibility is that hypothyroidism is not being treated optimally, either as a failure to reach target, i.e. normalization of TSH concentrations, or possibly because those targets may be inappropriate. Further research is required to address these possibilities.

Only one small study has investigated patients with treated hypothyroidism taking T₄ (21): no excess mortality or morbidity of any type was found; however, the numbers were small (n = 29, 12-yr follow-up) and would be underpowered to detected differences such as those presented here.

The reason for the consistently higher level of nonfatal events than fatal events is not known. The most likely explanation is that these patients are subject to a higher level of care due to their frequent interaction with health care services and that this higher level of care may protect them from the most serious effects of vascular events.

If, despite apparently adequate treatment of thyroid disease, there remains an increased risk of circulatory disease, perhaps clinicians need to be more aggressive about investigating cardiovascular risk factors and disease in such patients. Further research is required, but there may be a possible role for more widespread use of cardioprotective drugs such as aspirin, statins, and angiotensin-converting enzyme inhibitors in these patients.

There are limitations to this study. There is a reliance on SMR1 data; however, these data are validated and have been widely used in record-linkage studies. Also, no adjustment has been made for concurrent medications, i.e. statin use. Residual confounding could also explain the findings; this may arise from other unknown and unadjusted for confounders that exhibit an independent association with both treated thyroid dysfunction and cardiovascular morbidity and that affect the risk of developing these diseases. An example would be smoking, which is often found to have a confounding effect in epidemiological studies but that we have been unable to adjust for in our study. There is also the possibility of surveillance bias, with an increased likelihood of circulatory diseases being detected in persons who are also being treated for hypothyroidism; however, this would be unlikely to result in our outcome measure of disease-specific hospital admission.

In conclusion, we have found that patients who have treated and stabilized thyroid disease are not at increased risk of mortality or serious vascular events; however, they may be at increased risk of specific nonfatal vascular events. In the case of primary hypothyroidism, there is increased ischemic heart disease and dysrhythmias, whereas for hyperthyroidism there is increased risk of dysrhythmias.

	Footnotes

 
This work was supported by Chest Heart and Stroke Scotland, Anonymous Trust, University of Dundee, Social Dimensions of Health Institute, and the Universities of Dundee and St. Andrews.

First Published Online March 14, 2006

Abbreviations: CHNo, Community health number; CI, confidence interval; ISD, Information and Statistics Division; MEMO, Medicines Monitoring Unit; SIR, standardized incidence ratio; SMR, standardized mortality ratio; SMR1, Scottish Morbidity Records; TEARS, Thyroid Epidemiology, Audit, and Research Study.

Received August 12, 2005.

Accepted March 7, 2006.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Flynn, R. W. V. Articles by Leese, G. P. Search for Related Content PubMed PubMed Citation Articles by Flynn, R. W. V. Articles by Leese, G. P. Related Collections Thyroid Cardiovascular Endocrinology