AACE/ACE Position Statement
James V. Hennessey, MD, FACP, ECNU 1; Jeffrey R. Garber, MD, FACP, FACE 2; Kenneth A. Woeber, MD, FRCPE 3; Rhoda Cobin, MD, MACE, ECNU 4; Irwin Klein, MD5 Written on behalf of the AACE Thyroid Scientific Committee This document represents the official position of the American Association of Clinical Endocrinologists and American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician. ABSTRACT Hypothyroidism and hyperthyroidism can be readily diagnosed and can be treated in a safe, cost-effective manner. Professional organizations have given guidance on how and when to employ thyroid-stimulating hormone testing for the detection of thyroid dysfunction. Most recently, the United States Preventive Services Task Force did not endorse screening for thyroid dysfunction based on a lack of proven benefit and potential harm of treating those with thyroid dysfunction, which is mostly subclinical disease. The American Association of Clinical Endocrinologists (AACE) is concerned that this may discourage physicians
From the 1Division of Endocrinology, Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, 2Division of Endocrinology, Department of Medicine, Harvard Medical School and Harvard Vanguard Medical Associates, Boston, Massachusetts, 3Division of Endocrinology, Department of Medicine, University of California San Francisco Medical School, San Francisco, California, 4Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, and 5Division of Endocrinology, Department of Medicine, NYU School of Medicine, New York, New York. Address correspondence to American Association of Clinical Endocrinologists, 245 Riverside Ave., Suite 200, Jacksonville, FL 32202. E-mail: [email protected]. DOI: 10.4158/EP151038.PS To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2016 AACE. An abridged version of this work has appeared as an opinion piece in the Ann Intern Med. 2015 Aug 18;163(4):311-2. PMID: 26280417.
262
from testing for thyroid dysfunction when clinically appropriate. Given the lack of specificity of thyroid-associated symptoms, the appropriate diagnosis of thyroid disease requires biochemical confirmation. The Thyroid Scientific Committee of the AACE has produced this White Paper to highlight the important difference between screening and case-based testing in the practice of clinical medicine. We recommend that thyroid dysfunction should be frequently considered as a potential etiology for many of the nonspecific complaints that physicians face daily. The application and success of safe and effective interventions are dependent on an accurate diagnosis. We, therefore, advocate for an aggressive case-finding approach, based on identifying those persons most likely to have thyroid disease that will benefit from its treatment. (Endocr Pract. 2016;22:262-270) Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; FT4 = free thyroxine; IHD = ischemic heart disease; TSH = thyroid-stimulating hormone; USPSTF = United States Preventive Services Task Force INTRODUCTION Hypothyroidism and hyperthyroidism can be readily diagnosed and can be treated in a safe, cost-effective manner. During the last 2 decades, professional organizations, including The Endocrine Society, the American
263
Thyroid Association (ATA), and the American Association of Clinical Endocrinologists (AACE), have all given guidance on how and when to employ thyroid-stimulating hormone (TSH) testing for the millions of Americans with undiagnosed thyroid dysfunction (Table 1). The Issue Most recently, the United States Preventive Services Task Force (USPSTF) statement, which did not address pregnancy or the neonatal period, did not endorse screening for thyroid dysfunction (1,2); the AACE is concerned that this may discourage physicians from testing for thyroid dysfunction when clinically appropriate. Although the benefits of identifying and treating overt thyroid dysfunction are clear to all clinicians, and randomized controlled studies do not appear in the current literature, the task force’s recommendations are based on a lack of proven benefit and potential harm of treating those with thyroid dysfunction, which is said to be mostly subclinical disease (1-3). Given the lack of specificity of thyroid-associated symptoms (4), appropriate diagnosis is not possible without thyroid function testing of those who potentially are suffering from a thyroid disorder. The Thyroid Scientific Committee of the AACE has produced this Position Paper to further address this important public health issue. The major thrust of this report is to highlight the important difference between testing as a screening procedure versus case-based testing or aggressive case finding in the practice of clinical medicine. The USPSTF report finds that the current published evidence is insufficient to document a direct effect of screening versus no screening on clinical outcomes. As
such, the USPSTF concludes that although screening can identify patients with subclinical or undiagnosed overt thyroid dysfunction, direct high-quality evidence of the benefits and harms of screening versus no screening remains to be established in nonpregnant adults (1,2). Further, the clinician is admonished to ensure that patients clearly understand the uncertainties surrounding potential clinical benefits of screening, as well as the possibility of harm that this choice may engender (1). This statement would seem to lead us away from the basic surveillance role provided by primary care physicians, who, after a careful history, physical exam (including the thyroid gland), and review of available laboratory data, make a decision to utilize a serum TSH in an individual patient. Which patients to evaluate for the possibility of hypothyroidism are well delineated in the AACE/ATA hypothyroidism Clinical Practice Guidelines for Adults 2012 publication (5) and the Latin American Thyroid Society Clinical Practice Guidelines 2013 publication (6) (Table 1). From a clinician’s perspective, the narrowly focused USPSTF process and the rigid definition of the term ‘screening’ is not used in daily interactions with patients. A definition of the terms is important. Screening is the application of a test to detect a potential thyroid-related disease or condition in a person who has no known signs or symptoms of that condition at the time the test is done (6). From a population perspective, the criteria for screening should include the goal of identifying a condition that is prevalent and an important health problem where early diagnosis is not usually made, the process of making the diagnosis is simple and accurate, and finally, a safe and cost-effective
Table 1 Recommendations of 8 Organizations Regarding Screening of Asymptomatic Adults for Thyroid Dysfunction Organization
Screening recommendations
College of American Pathologists (13)
Women ≥50 year of age should be screened “if they seek medical care;” all geriatric patients should be screened on admission to the hospital and at least every 5 years
American Academy of Family Physicians (9)
Patients ≥60 years of age should be screened
American College of Obstetrics and Gynecology (14)
Women in “high-risk groups” (those with autoimmune disease or a strong family history of thyroid disease) should be screened starting at 19 years of age
American College of Physicians (12)
Women ≥50 years of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluated
U.S. Preventive Services Task Force (10)
Insufficient evidence for or against screening
Royal College of Physicians (11)
Screening of the healthy adult population unjustified
American Association of Clinical Endocrinologists/ American Thyroid Association (5)
Aggressive case finding
Latin American Thyroid Society (6)
Aggressive case finding
264
treatment is available to remedy the situation (5). Despite this seemingly straightforward guidance, expert panels have disagreed about TSH screening of the general population (Table 1 and references 7-13). More recently, the AACE/ATA recommended aggressive case finding rather than general population screening for those with specific clinical features making it more likely to have thyroid dysfunction and to benefit from diagnosis and treatment (5). Reports prior to and following the AACE/ATA recommendations dealing with special issues related to fertility, recurrent miscarriages, and fetal outcomes support this practice (14-21). In contrast, a consensus panel considering only subclinical thyroid disease (22), the Royal College of Physicians of London (11), and also the previous USPSTF (10) do not recommend routine screening for thyroid disease in adults. Aggressive Case Finding The USPSTF process clearly recognizes that clinical decisions involve more considerations than evidence alone. However, when rigorous existing evidence is not available, guidance is still required to facilitate appropriate and consistent clinical care of patients. It is into this recommendation void that we offer our evidence-based approach to the clinically more relevant “case-finding” process that reflects the actual practice of medicine. Clinical case finding is a reflection of the one-on-one process of physicians listening to their patients, considering the historical circumstances, and estimating the potential likelihood that thyroid disease may be playing a role in the patient’s presentation. Case finding may be defined as targeted testing for thyroid dysfunction among patients who visit their clinician without a known diagnosis of thyroid dysfunction (6). While there is no consensus about population screening for hypothyroidism as outlined in Table 1, there is compelling evidence to support case finding for hypothyroidism in the following settings: 1. Diseases and conditions that may be associated with thyroid dysfunction. These include family history of thyroid disease, certain autoimmune disorders, anemias, and chromosomal disorders, history of neck radiation, history of thyroid surgery, and hyperprolactinemia (Table 2). 2. Various medications may induce thyroid dysfunction. These include amiodarone, lithium, and tyrosine kinase inhibitors such as sunitinib and sorafenib used in the treatment of renal cell carcinoma. Moreover, other medications such as interferon-α and interleukin-2 may induce thyroid autoimmunity with resulting dysfunction (Table 2). Improved Outcomes Most importantly, subclinical thyroid dysfunction (elevation or suppression of TSH with normal circulating free thyroxine [FT4] and triiodothyronine levels) may have
adverse consequences on the cardiovascular system and on risk factors for cardiovascular disease that merit case finding. While overt hypothyroidism has long been recognized to have adverse effects on cardiovascular health (23-25), recent evidence indicates that subclinical hypothyroidism (elevated TSH and normal circulating FT4) also affects cardiovascular morbidity and mortality (23,24,26-32). A well-conducted meta-analysis of 12 observational studies in unselected community-dwelling subjects (euthyroid, n = 24,868; subclinical hypothyroidism, n = 2,399) examined the effects of subclinical hypothyroidism on the prevalence and incidence of ischemic heart disease (IHD) and cardiovascular mortality (33). A modest association was noted with subclinical hypothyroidism in the overall population; however, grouping subjects by age (160 mg/dL) be tested for hypothyroidism (35). More recent data substantiates a prevalence of hypothyroidism of 4.3% in patients with hypercholesterolemia (36). Even though this is similar to the general population, the possibility of correcting a portion of the dyslipidemia with a safe and effective medication like L-thyroxine is warranted in lieu of a less physiologic intervention such as statins, which put patients with overt hypothyroidism at risk for myositis (37,38). An additional cardiovascular consideration is the presence of heart failure. A meta-analysis, noted that the risk of heart failure events became elevated with increasing TSH level (39). In patients with pre-existing congestive heart failure, the presence of subclinical hypothyroidism was associated with an increased risk of all-cause mortality versus euthyroidism (27). In addition, a large retrospective cohort study recently found lower risk of all-cause mortality versus euthyroid subjects, despite having an elevated risk of myocardial infarction (40). Several small, randomized studies have evaluated whether levothyroxine therapy reverses markers of cardiovascular morbidity in individuals with even mild thyroid disease. Monzani and coworkers (41) randomized 20 patients with subclinical hypothyroidism to receive levothyroxine for 6 months. Only treated patients achieved
265 Table 2 Overview Table of Aggressive Case-Finding Indications Autoimmune diseases such as: Type 1 diabetes (51-55) Polyglandular autoimmune syndrome (56) Celiac (6,57,58) Vitiligo (59-61) Sjögren syndrome (55,62-65) Pediatric arthritis and rheumatic fever (66) Rheumatoid arthritis (67-71) Systemic lupus erythematosus (68,69) Pernicious anemia (72-74) First-degree relatives with autoimmune thyroid disease (14,75-77) Anemia Common forms of anemia Beta-thalassemia major (78) Anemic elderly patients (79-82) Fanconi anemia (83) Following allogenic hematopoietic stem cell transplantation (84) Non-autoimmune primary and central hypothyroidism (83) Other genetic abnormalities: Down syndrome (85-87) Turner syndrome (6,88-92) History of neck irradiation or 131I treatment (93-95) History of thyroid surgery or dysfunction (96) Abnormal thyroid examination Hyperprolactinemia (97,98) Psychiatric disorders (99-103) Cardiovascular health (23,25-31,33-36,39,40,44,46-49) Pulmonary hypertension (104-107) Medications: Amiodarone (108-110) Ketoconazolea (111-114) Lithium (115-120) Interferon-α (121) Interleukin-2 (122) Tyrosine kinase inhibitors (121) Osteoporosis (45) a Controversial
association.
normal TSH levels and significant improvements in left ventricular function and myocardium textural parameters (41). A similar study found that levothyroxine improved endothelium-dependent vasodilation in individuals with SCH (42). In another study, left ventricular function and mechanics, evaluated using 2- and 3-dimensional echocardiography and speckle tracking imaging, were significantly worse in women with untreated subclinical hypothyroidism compared with normal matched controls, and most importantly, improved in those treated with levothyroxine, within the 1-year follow-up (43). Finally, hyperthyroidism should be identified in those with a family history of thyroid disease, those with new onset of atrial fibrillation or tachycardia, unexplained weight loss, muscle weakness, or exertional dyspnea (44).
Subclinical hyperthyroidism (suppressed TSH, normal circulating FT4 and triiodothyronine levels) is also a risk factor for bone loss and increased fracture risk (45), as well as adverse cardiovascular events. Sawin (46) demonstrated a nearly 3-fold increased risk of new-onset atrial fibrillation after 10 years of follow-up among participants in the Framingham Heart Study with subclinical hyperthyroidism. Cappola et al (47) demonstrated in 3,233 communitydwelling individuals who were more than 65 years old that the risk of atrial fibrillation was nearly doubled after 12 years of follow-up in those with subclinical hyperthyroidism. A nearly 2.5-fold increase in cardiac mortality was demonstrated among subjects with persistent subclinical hyperthyroidism by Iervasi et al (48). Others have reported doubling of congestive heart failure hospitalizations in
266
those with persistent subclinical hyperthyroidism (29). Meta-analysis of cardiovascular risk demonstrate modest elevation for coronary heart disease events and total mortality (30), coronary heart disease mortality, heart failure, and atrial fibrillation (49) among those with subclinical hyperthyroidism. Most recently, a meta-analysis of 70,298 participants in 13 prospective cohorts with a reported follow-up of 762,401 person-years demonstrated an overall increased hazard of hip and any fracture which was even higher and included spinal fractures when endogenous subclinical hyperthyroidism was considered alone (45). This analysis further observed that treatment with levothyroxine was not in and of itself associated with increased fracture risk, and the degree of TSH suppression predicted risk of fracture, with values of TSH
James V. Hennessey, MD, FACP, ECNU 1; Jeffrey R. Garber, MD, FACP, FACE 2; Kenneth A. Woeber, MD, FRCPE 3; Rhoda Cobin, MD, MACE, ECNU 4; Irwin Klein, MD5 Written on behalf of the AACE Thyroid Scientific Committee This document represents the official position of the American Association of Clinical Endocrinologists and American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician. ABSTRACT Hypothyroidism and hyperthyroidism can be readily diagnosed and can be treated in a safe, cost-effective manner. Professional organizations have given guidance on how and when to employ thyroid-stimulating hormone testing for the detection of thyroid dysfunction. Most recently, the United States Preventive Services Task Force did not endorse screening for thyroid dysfunction based on a lack of proven benefit and potential harm of treating those with thyroid dysfunction, which is mostly subclinical disease. The American Association of Clinical Endocrinologists (AACE) is concerned that this may discourage physicians
From the 1Division of Endocrinology, Department of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts, 2Division of Endocrinology, Department of Medicine, Harvard Medical School and Harvard Vanguard Medical Associates, Boston, Massachusetts, 3Division of Endocrinology, Department of Medicine, University of California San Francisco Medical School, San Francisco, California, 4Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, and 5Division of Endocrinology, Department of Medicine, NYU School of Medicine, New York, New York. Address correspondence to American Association of Clinical Endocrinologists, 245 Riverside Ave., Suite 200, Jacksonville, FL 32202. E-mail: [email protected]. DOI: 10.4158/EP151038.PS To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2016 AACE. An abridged version of this work has appeared as an opinion piece in the Ann Intern Med. 2015 Aug 18;163(4):311-2. PMID: 26280417.
262
from testing for thyroid dysfunction when clinically appropriate. Given the lack of specificity of thyroid-associated symptoms, the appropriate diagnosis of thyroid disease requires biochemical confirmation. The Thyroid Scientific Committee of the AACE has produced this White Paper to highlight the important difference between screening and case-based testing in the practice of clinical medicine. We recommend that thyroid dysfunction should be frequently considered as a potential etiology for many of the nonspecific complaints that physicians face daily. The application and success of safe and effective interventions are dependent on an accurate diagnosis. We, therefore, advocate for an aggressive case-finding approach, based on identifying those persons most likely to have thyroid disease that will benefit from its treatment. (Endocr Pract. 2016;22:262-270) Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; FT4 = free thyroxine; IHD = ischemic heart disease; TSH = thyroid-stimulating hormone; USPSTF = United States Preventive Services Task Force INTRODUCTION Hypothyroidism and hyperthyroidism can be readily diagnosed and can be treated in a safe, cost-effective manner. During the last 2 decades, professional organizations, including The Endocrine Society, the American
263
Thyroid Association (ATA), and the American Association of Clinical Endocrinologists (AACE), have all given guidance on how and when to employ thyroid-stimulating hormone (TSH) testing for the millions of Americans with undiagnosed thyroid dysfunction (Table 1). The Issue Most recently, the United States Preventive Services Task Force (USPSTF) statement, which did not address pregnancy or the neonatal period, did not endorse screening for thyroid dysfunction (1,2); the AACE is concerned that this may discourage physicians from testing for thyroid dysfunction when clinically appropriate. Although the benefits of identifying and treating overt thyroid dysfunction are clear to all clinicians, and randomized controlled studies do not appear in the current literature, the task force’s recommendations are based on a lack of proven benefit and potential harm of treating those with thyroid dysfunction, which is said to be mostly subclinical disease (1-3). Given the lack of specificity of thyroid-associated symptoms (4), appropriate diagnosis is not possible without thyroid function testing of those who potentially are suffering from a thyroid disorder. The Thyroid Scientific Committee of the AACE has produced this Position Paper to further address this important public health issue. The major thrust of this report is to highlight the important difference between testing as a screening procedure versus case-based testing or aggressive case finding in the practice of clinical medicine. The USPSTF report finds that the current published evidence is insufficient to document a direct effect of screening versus no screening on clinical outcomes. As
such, the USPSTF concludes that although screening can identify patients with subclinical or undiagnosed overt thyroid dysfunction, direct high-quality evidence of the benefits and harms of screening versus no screening remains to be established in nonpregnant adults (1,2). Further, the clinician is admonished to ensure that patients clearly understand the uncertainties surrounding potential clinical benefits of screening, as well as the possibility of harm that this choice may engender (1). This statement would seem to lead us away from the basic surveillance role provided by primary care physicians, who, after a careful history, physical exam (including the thyroid gland), and review of available laboratory data, make a decision to utilize a serum TSH in an individual patient. Which patients to evaluate for the possibility of hypothyroidism are well delineated in the AACE/ATA hypothyroidism Clinical Practice Guidelines for Adults 2012 publication (5) and the Latin American Thyroid Society Clinical Practice Guidelines 2013 publication (6) (Table 1). From a clinician’s perspective, the narrowly focused USPSTF process and the rigid definition of the term ‘screening’ is not used in daily interactions with patients. A definition of the terms is important. Screening is the application of a test to detect a potential thyroid-related disease or condition in a person who has no known signs or symptoms of that condition at the time the test is done (6). From a population perspective, the criteria for screening should include the goal of identifying a condition that is prevalent and an important health problem where early diagnosis is not usually made, the process of making the diagnosis is simple and accurate, and finally, a safe and cost-effective
Table 1 Recommendations of 8 Organizations Regarding Screening of Asymptomatic Adults for Thyroid Dysfunction Organization
Screening recommendations
College of American Pathologists (13)
Women ≥50 year of age should be screened “if they seek medical care;” all geriatric patients should be screened on admission to the hospital and at least every 5 years
American Academy of Family Physicians (9)
Patients ≥60 years of age should be screened
American College of Obstetrics and Gynecology (14)
Women in “high-risk groups” (those with autoimmune disease or a strong family history of thyroid disease) should be screened starting at 19 years of age
American College of Physicians (12)
Women ≥50 years of age with an incidental finding suggestive of symptomatic thyroid disease should be evaluated
U.S. Preventive Services Task Force (10)
Insufficient evidence for or against screening
Royal College of Physicians (11)
Screening of the healthy adult population unjustified
American Association of Clinical Endocrinologists/ American Thyroid Association (5)
Aggressive case finding
Latin American Thyroid Society (6)
Aggressive case finding
264
treatment is available to remedy the situation (5). Despite this seemingly straightforward guidance, expert panels have disagreed about TSH screening of the general population (Table 1 and references 7-13). More recently, the AACE/ATA recommended aggressive case finding rather than general population screening for those with specific clinical features making it more likely to have thyroid dysfunction and to benefit from diagnosis and treatment (5). Reports prior to and following the AACE/ATA recommendations dealing with special issues related to fertility, recurrent miscarriages, and fetal outcomes support this practice (14-21). In contrast, a consensus panel considering only subclinical thyroid disease (22), the Royal College of Physicians of London (11), and also the previous USPSTF (10) do not recommend routine screening for thyroid disease in adults. Aggressive Case Finding The USPSTF process clearly recognizes that clinical decisions involve more considerations than evidence alone. However, when rigorous existing evidence is not available, guidance is still required to facilitate appropriate and consistent clinical care of patients. It is into this recommendation void that we offer our evidence-based approach to the clinically more relevant “case-finding” process that reflects the actual practice of medicine. Clinical case finding is a reflection of the one-on-one process of physicians listening to their patients, considering the historical circumstances, and estimating the potential likelihood that thyroid disease may be playing a role in the patient’s presentation. Case finding may be defined as targeted testing for thyroid dysfunction among patients who visit their clinician without a known diagnosis of thyroid dysfunction (6). While there is no consensus about population screening for hypothyroidism as outlined in Table 1, there is compelling evidence to support case finding for hypothyroidism in the following settings: 1. Diseases and conditions that may be associated with thyroid dysfunction. These include family history of thyroid disease, certain autoimmune disorders, anemias, and chromosomal disorders, history of neck radiation, history of thyroid surgery, and hyperprolactinemia (Table 2). 2. Various medications may induce thyroid dysfunction. These include amiodarone, lithium, and tyrosine kinase inhibitors such as sunitinib and sorafenib used in the treatment of renal cell carcinoma. Moreover, other medications such as interferon-α and interleukin-2 may induce thyroid autoimmunity with resulting dysfunction (Table 2). Improved Outcomes Most importantly, subclinical thyroid dysfunction (elevation or suppression of TSH with normal circulating free thyroxine [FT4] and triiodothyronine levels) may have
adverse consequences on the cardiovascular system and on risk factors for cardiovascular disease that merit case finding. While overt hypothyroidism has long been recognized to have adverse effects on cardiovascular health (23-25), recent evidence indicates that subclinical hypothyroidism (elevated TSH and normal circulating FT4) also affects cardiovascular morbidity and mortality (23,24,26-32). A well-conducted meta-analysis of 12 observational studies in unselected community-dwelling subjects (euthyroid, n = 24,868; subclinical hypothyroidism, n = 2,399) examined the effects of subclinical hypothyroidism on the prevalence and incidence of ischemic heart disease (IHD) and cardiovascular mortality (33). A modest association was noted with subclinical hypothyroidism in the overall population; however, grouping subjects by age (160 mg/dL) be tested for hypothyroidism (35). More recent data substantiates a prevalence of hypothyroidism of 4.3% in patients with hypercholesterolemia (36). Even though this is similar to the general population, the possibility of correcting a portion of the dyslipidemia with a safe and effective medication like L-thyroxine is warranted in lieu of a less physiologic intervention such as statins, which put patients with overt hypothyroidism at risk for myositis (37,38). An additional cardiovascular consideration is the presence of heart failure. A meta-analysis, noted that the risk of heart failure events became elevated with increasing TSH level (39). In patients with pre-existing congestive heart failure, the presence of subclinical hypothyroidism was associated with an increased risk of all-cause mortality versus euthyroidism (27). In addition, a large retrospective cohort study recently found lower risk of all-cause mortality versus euthyroid subjects, despite having an elevated risk of myocardial infarction (40). Several small, randomized studies have evaluated whether levothyroxine therapy reverses markers of cardiovascular morbidity in individuals with even mild thyroid disease. Monzani and coworkers (41) randomized 20 patients with subclinical hypothyroidism to receive levothyroxine for 6 months. Only treated patients achieved
265 Table 2 Overview Table of Aggressive Case-Finding Indications Autoimmune diseases such as: Type 1 diabetes (51-55) Polyglandular autoimmune syndrome (56) Celiac (6,57,58) Vitiligo (59-61) Sjögren syndrome (55,62-65) Pediatric arthritis and rheumatic fever (66) Rheumatoid arthritis (67-71) Systemic lupus erythematosus (68,69) Pernicious anemia (72-74) First-degree relatives with autoimmune thyroid disease (14,75-77) Anemia Common forms of anemia Beta-thalassemia major (78) Anemic elderly patients (79-82) Fanconi anemia (83) Following allogenic hematopoietic stem cell transplantation (84) Non-autoimmune primary and central hypothyroidism (83) Other genetic abnormalities: Down syndrome (85-87) Turner syndrome (6,88-92) History of neck irradiation or 131I treatment (93-95) History of thyroid surgery or dysfunction (96) Abnormal thyroid examination Hyperprolactinemia (97,98) Psychiatric disorders (99-103) Cardiovascular health (23,25-31,33-36,39,40,44,46-49) Pulmonary hypertension (104-107) Medications: Amiodarone (108-110) Ketoconazolea (111-114) Lithium (115-120) Interferon-α (121) Interleukin-2 (122) Tyrosine kinase inhibitors (121) Osteoporosis (45) a Controversial
association.
normal TSH levels and significant improvements in left ventricular function and myocardium textural parameters (41). A similar study found that levothyroxine improved endothelium-dependent vasodilation in individuals with SCH (42). In another study, left ventricular function and mechanics, evaluated using 2- and 3-dimensional echocardiography and speckle tracking imaging, were significantly worse in women with untreated subclinical hypothyroidism compared with normal matched controls, and most importantly, improved in those treated with levothyroxine, within the 1-year follow-up (43). Finally, hyperthyroidism should be identified in those with a family history of thyroid disease, those with new onset of atrial fibrillation or tachycardia, unexplained weight loss, muscle weakness, or exertional dyspnea (44).
Subclinical hyperthyroidism (suppressed TSH, normal circulating FT4 and triiodothyronine levels) is also a risk factor for bone loss and increased fracture risk (45), as well as adverse cardiovascular events. Sawin (46) demonstrated a nearly 3-fold increased risk of new-onset atrial fibrillation after 10 years of follow-up among participants in the Framingham Heart Study with subclinical hyperthyroidism. Cappola et al (47) demonstrated in 3,233 communitydwelling individuals who were more than 65 years old that the risk of atrial fibrillation was nearly doubled after 12 years of follow-up in those with subclinical hyperthyroidism. A nearly 2.5-fold increase in cardiac mortality was demonstrated among subjects with persistent subclinical hyperthyroidism by Iervasi et al (48). Others have reported doubling of congestive heart failure hospitalizations in
266
those with persistent subclinical hyperthyroidism (29). Meta-analysis of cardiovascular risk demonstrate modest elevation for coronary heart disease events and total mortality (30), coronary heart disease mortality, heart failure, and atrial fibrillation (49) among those with subclinical hyperthyroidism. Most recently, a meta-analysis of 70,298 participants in 13 prospective cohorts with a reported follow-up of 762,401 person-years demonstrated an overall increased hazard of hip and any fracture which was even higher and included spinal fractures when endogenous subclinical hyperthyroidism was considered alone (45). This analysis further observed that treatment with levothyroxine was not in and of itself associated with increased fracture risk, and the degree of TSH suppression predicted risk of fracture, with values of TSH
