A 2013 survey of clinical practice patterns in the management of primary hypothyroidism.

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A 2013 Survey of Clinical Practice Patterns in the Management of Primary Hypothyroidism Henry B. Burch, Kenneth D. Burman, David S. Cooper, and James V. Hennessey Endocrinology Division (H.B.B.), Walter Reed National Military Medical Center, Bethesda, Maryland 20889, and Uniformed Services University of Health Sciences, Bethesda, Maryland 20814; Endocrinology Section (K.D.B.), Washington Hospital Center, Washington, DC 20010; Georgetown University Medical Center (K.D.B.), Washington, DC 20007; Division of Endocrinology (D.S.C.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; Division of Endocrinology (J.V.H.), Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215; and Harvard Medical School (J.V.H.), Boston, Massachusetts 02115 Context: In 2012, comprehensive clinical practice guidelines (CPGs) were published regarding the management of hypothyroidism. Objective: We sought to document current practices in the management of primary hypothyroidism and compare these results with recommendations made in the 2012 American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) hypothyroidism CPGs. In addition, we sought to examine differences in management among international members of U.S.-based endocrine societies and to compare survey results with those obtained from a survey of ATA members performed 12 years earlier. Methods: Clinical members of The Endocrine Society (TES), the ATA, and the AACE were asked to take a web-based survey consisting of 30 questions dealing with testing, treatment, and modulating factors in the management of primary hypothyroidism. Results: In total, 880 respondents completed the survey, including 618 members of TES, 582 AACE members, and 208 ATA members. North American respondents accounted for 67.6%, Latin American 9.7%, European 9.2%, Asia and Oceania 8.1%, and Africa and Middle East 5.5%. Overt hypothyroidism would be treated using L-T4 alone by 99.2% of respondents; 0.8% would use combination L-T4 and liothyronine (L-T3) therapy. Generic L-T4 would be used by 49.3% and a brand name by 49.9%. The rate of replacement would be gradual (38.5%); an empiric dose, adjusted to achieve target (33.6%); or a calculated full replacement dose (27.8%). A target TSH of 1.0 to 1.9 mU/L was favored in the index case, but 3.0 to 3.9 mU/L was the most commonly selected TSH target for an octogenarian. Persistent hypothyroid symptoms despite achieving a target TSH would prompt testing for other causes by 84.3% of respondents, a referral to primary care by 11.3%, and a change to L-T4 plus L-T3 therapy by 3.6%. Evaluation of persistent symptoms would include measurement of T3 levels by 21.9% of respondents. Subclinical disease with a TSH 5.0 to 10.0 mU/L would be treated without further justification by 21.3% of respondents, or in the presence of positive thyroid peroxidase antibodies (62.3%), hypothyroid symptoms (60.9%), high low-density lipoprotein (52.9%), or goiter (46.6%). The TSH target for a newly pregnant patient was ⬍2.5 mU/L for 96.1% of respondents, with 63.5% preferring a TSH target ⬍1.5 mU/L. Thyroid hormone levels would be checked every 4 weeks during pregnancy by 67.7% and every 8 weeks by an additional 21.4%. A hypothyroid patient with TSH of 0.5 mU/L who becomes pregnant would receive an immediate L-T4 dose increase by only 36.9% of respondents.

Conclusion: The current survey of clinical endocrinologists catalogs current practice patterns in the management of hypothyroidism and demonstrates 1) a nearly exclusive preference for L-T4 alone as initial therapy, 2) the widespread use of age-specific TSH targets for replacement therapy, 3) a low threshold for treating mild thyroid failure, 4) meticulous attention to TSH targets in the pregnant and prepregnant woman, and 5) a highly variable approach to both the rate and means of restoring euthyroidism for overt disease. Both alignment and focal divergence from recent CPGs are demonstrated. (J Clin Endocrinol Metab 99: 2077–2085, 2014)

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received January 7, 2014. Accepted February 6, 2014. First Published Online February 14, 2014

doi: 10.1210/jc.2014-1046

Abbreviations: Ab, antibody; CPG, clinical practice guideline; TPO, thyroid peroxidase.

J Clin Endocrinol Metab, June 2014, 99(6):2077–2085

jcem.endojournals.org

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Hypothyroidism Management Survey

evothyroxine therapy (L-T4) results in a resolution of signs and symptoms in most patients with overt hypothyroidism. Still, a number of controversies remain, including 1) the treatment threshold in patients with mild or subclinical disease (1, 2), 2) the need for age-specific targets for serum TSH levels (3–5), 3) whether administration of L-T4 alone provides adequate tissue-level triiodothyronine (T3) levels (6, 7); 4) optimal control of thyroid function during pregnancy (8, 9); and 5) screening indications for the detection of hypothyroidism in the general population and in women planning pregnancy (10, 11). In 2012, a joint task force of the American Association of Clinical Endocrinologists (AACE) and American Thyroid Association(ATA) published clinical practice guidelines (CPGs) dealing with diagnostic evaluation and treatment strategies for adults with hypothyroidism (1). Clinicians were encouraged to use the 52 recommendations contained in those guidelines in conjunction with their own clinical judgment and within the context of individual patient circumstances. It is not clear to what extent current practices differ from recommendations made in the 2012 AACE/ATA hypothyroidism CPG, because the only existing survey of clinical management practices for patients with hypothyroidism was published more than a decade ago (12). The objectives of the current study were 1) to document current practices in the management of primary hypothyroidism; 2) to evaluate management modifications in unique

L

Table 1.

R22.1 R22.2 R22.4 R22.7.2 R25.1 R25.3 R27 R28 R29

clinical circumstances such as subclinical hypothyroidism, pregnancy, and old age; 3) to compare current practice with that recommended in the 2012 AACE/ATA hypothyroidism guidelines; and 4) to assess for any international differences in the management of hypothyroidism.

Materials and Methods Survey design The survey was designed in a manner similar to our recently published Graves’ disease management survey (13). A commercial web-based, survey management service (Survey Monkey, Palo Alto, CA) was used to administer the survey. The survey included questions pertaining to diagnostic evaluation, choice of therapy, and follow-up for an index case (see below) of primary overt hypothyroidism followed by 3 clinical variants including a patient with persistent symptoms of hypothyroidism despite having achieved target thyroid hormone levels, a patient anticipating pregnancy, and a patient with subclinical hypothyroidism (Table 1).

Index case A 52-year old woman presents with a 9 month history of fatigue, cold intolerance, poor concentration, and constipation. She is otherwise healthy, takes no medications, and does not smoke cigarettes. She has a blood pressure of 135/90, a pulse rate of 55 beats per minute, and weighs 132 pounds (60 kilograms). She has a firm goiter, approximately twice normal size. Serum TSH is 20 mU/L (normal 0.4 – 4.5 mU/L), and free T4 is 0.7 ng/dL (normal 0.8 –1.8 ng/dL).

Comparison of CPG Recommendations With Survey Response

Recommendation No. R1 R8 R10 R13 R14.1 R 14.2 R15 R16 R17 R19.3


CPG Recommendation (Abbreviated) Measure TPO Ab in subclinical hypothyroidism Use both free T4 and TSH to monitor L-T4 treatment Do not use T3 to diagnose hypothyroidism Measure TSH 4 – 8 wk after starting or adjusting L-T4 Use age-specific normal ranges for TSH when available Use pregnancy-specific normal ranges for TSH when available Treat patients with TSH above 10 mIU/L Consider other factors before treating patients with TSH 5–10 mU/L Target TSH should be within the normal range when treating hypothyroidism Treat pregnant women or those planning pregnancy when TPO Ab positive and serum TSH is ⬎2.5 mIU/L Use L-T4 alone to treat hypothyroidism Do not use L-T4 and L-T3 combinations to treat hypothyroidism Do not use desiccated thyroid hormone to treat hypothyroidism Gradually restore euthyroidism in patients older than 50 – 60 y of age Adjust L-T4 to give TSH ⬍2.5 mU/L when pregnancy is diagnosed Check thyroid laboratory studies every 4 wk for the first half of pregnancy Do not adjust L-T4 therapy to give low-normal TSH values in hypothyroid patients who are not pregnanta Endocrinologists should be consulted for a subset of hypothyroid patientsb Do not treat symptoms suggestive of hypothyroidism if thyroid laboratory studies are normal

Survey Concordance (%) 91.9 59.9 86.3 74.9 84.2 96.1 98.9 78.7 99.5 95.1 99.2 99.2 100 38.3 95.1 70.6 43.6 34.9 99.4

a

Assessed by calculating the percentage of respondents accepting a TSH value ⬎2 to 4.9 mU/L.

b

Expressed as the percentage of respondents who would return an uncomplicated hypothyroidism case to the primary care physician.


doi: 10.1210/jc.2014-1046

Strategy for question design Most questions required a single best response to be selected from multiple choices. Diagnostic preference questions allowed multiple items to be simultaneously selected. To limit bias, questions were constructed to omit phrasing that could influence respondents’ answers, and a broad range of answers were included, arranged alphabetically, numerically, or in an order randomized by the survey tool (14). The survey was designed and tested to allow a completion time of approximately 10 to 15 minutes. Before general release, the survey was vetted through council members of the 3 societies and the research committee of the ATA.

Contact of potential respondents The target groups for the survey were clinically active international members of The Endocrine Society (TES), the ATA, and the AACE. Clinically active members of these 3 societies received an e-mail invitation for participation in the survey from society administrators, which described the survey and contained an electronic link to the survey website. The authors did not contact potential respondents directly, and no reminders were sent to nonrespondents; a second general e-mail was sent to the ATA membership 1 month after the initial invitation.

Collection and summary of responses Survey responses were anonymously collected and stored electronically by the survey service, accessible in a passwordprotected manner. Repeat submissions from the same IP address were automatically blocked by the survey service. The survey website was open for the 2-month period from August 1, 2013, through September 30, 2013.

Geographical region of respondents The geographical location was localized to country of the respondents’ clinical practices. To preserve anonymity, the city or town of origin of individual respondents was not requested. Respondents were grouped according to the United Nations country grouping of the following geographical regions: Africa, Asia, Europe and Eastern Europe, Central America, South America, Caribbean, the Middle East, North America (United States and Canada), and Oceania (principally Australia and New Zealand). Responses from Central America, South America, and the Caribbean were pooled as were responses from Asia and Oceania and responses from Africa and the Middle East.

Statistical analysis Summary statistics were prepared for responses to each question. Because not every participant answered all questions, the percentage of respondents providing a given answer was calculated individually for each question, using the number of respondents to that question as the denominator. Statistical analysis explored the relationship between respondent demographics and key diagnostic or treatment preferences for the index case. Fisher’s exact test (two-tailed) was used to compare gender and the geographical region of respondents to preferred treatment strategy. ANOVA was used to compare year of medical school graduation between groups with a Bonferroni correction to adjust for multiple comparisons. Data were analyzed using IBM SPSS Statistics version 19 software.


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Results Professional society membership Of 880 respondents participating in the survey, 815 (92.6%) completed all sections. The 809 respondents providing society membership consisted of 618 TES members, 582 AACE members, and 208 ATA members. Multiple society membership was commonly reported. One hundred fifty-seven (19.4%) belonged only to TES, 151 (18.7%) belonged only to AACE, and 27 (3.3%) belonged solely to the ATA. Dual membership in TES and AACE was noted by 293 respondents (36.2%), TES and ATA in 43 respondents (5.3%), and ATA and AACE in 13 (1.6%) respondents. Membership in all 3 societies was noted by 125 respondents (15.5%). Response rate Among TES members, 5650 physicians were sent the e-mail, of which 5398 were successfully delivered and 1762 (32.6%) opened. For ATA members, an initial email was sent to 1478 members, 407 (27.5%) of whom opened the e-mail. A second mailing to ATA members 1 month later resulted in an additional 162 unique e-mail openings (among 1533 recipients), for a final ATA member opening rate of 37.1% (569 of 1533). Among AACE members, 6444 were sent an e-mail invitation; opening rates were not available. The approximate response rates for society members opening the e-mail was 35.1% (618 of 1762) for TES, and 51.1% (208 of 407) for ATA members. The percentage of clinically active society members represented by survey respondents was 208 of 1533 (13.6%) for the ATA, 618 of 5650 (10.9%) for TES, and 582 of 6444 (9.0%) for AACE. Respondent demographics The type of medical practice reported by respondents was adult endocrinology (90.7%), either alone (83.8%) or combined with another specialty such as internal medicine (6.9%), pediatric endocrinology alone (3.0%), general internal medicine (1.5%), general surgery (1.5%), nuclear medicine (1.0%), and other (2.1%). The geographical regions of the respondents’ practices were diverse, including North America (67.5%: United States, 65.0%; Canada, 2.5%), Latin America (9.7%), Europe (9.2%), Asia and Oceania (8.1%), and the Middle East and Africa (5.5%). Gender was reported by 801 respondents, among whom 62.9% (504 of 801) were men, and 37.1% (297 of 801) were women. The median year of graduation from medical school was 1987 (mean, 1986 ⫾13 years). The number of new hypothyroidism cases seen on a monthly basis was 1 to 5 for 40.9% of respondents, 6 to 10 for 28.3% of respondents, and ⬎10 for 29.1% of respondents.


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An-TPO


4 weeks (23.0%), 2 weeks (20.5%), 8 weeks (18.0%), and 12 weeks (2.8%). Gender had no significant impact on choice of correction technique. An earlier year of graduation from medical school was positively associated with a gradual approach (P ⬍ .001).

79.6%

Repeat TSH

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Thyroid US

44.4%

An-Tg

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33.6%

Lipid panel

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Free T3

9.3%

Total T3

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300 400 500 600 Number of Respondents

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Figure 1. Percentage of participants who would request the listed testing in a patient with overt hypothyroidism.

Diagnostic evaluation of the index case Figure 1 shows the percentage of respondents ordering the listed laboratory tests for the index case. Regional differences were noted, with a higher use of ultrasound examination in hypothyroid patients undergoing initial evaluation in regions outside of North America. Specifically, whereas 37.9% of North American endocrinologists would obtain a thyroid ultrasound in this setting, the rate was 58.0% in Latin America (P ⫽ .001 vs North America), 58.8% in Europe (P ⫽ .001), 58.2% in Asia-Oceania (P ⫽ .001), and 56.3% in Middle East-Africa (P ⫽ .014). Thyroid peroxidase (TPO) antibody (Ab) testing was similar across regions. Therapy for overt hypothyroidism Decision to treat Among 870 respondents, 860 (98.9%) would initiate thyroid hormone therapy in the index case of overt hypothyroidism. Rate of correction We queried respondents about their usual technique for correcting overt hypothyroidism. Among 851 respondents to this question, 328 (38.5%) would gradually restore euthyroidism, 286 (33.6%) would select an empiric dose adjusted to achieve target levels, and 237 (27.8%) would start with a calculated full-replacement dose. There were regional differences, with a greater use of a gradual approach outside of North America. Whereas 30.5% of North American respondents would use a gradual approach, the latter was favored in all other regions, including Latin America (60.5%, P ⬍ .001 vs North America), Europe (55.8%, P ⬍ .001), Asia-Oceania (55.1%, P ⬍ .001), and Middle East-Africa (46.8%, P ⫽ .081). For respondents preferring a gradual restoration of euthyroidism, most (61.1%) would increase in increments of 25 ␮g, followed by 50 ␮g (26.9%), and 12.5 ␮g (12.0%). The frequency of incremental increases was 6 weeks (35.7%),

Preferred initial thyroid hormone preparation Among 743 respondents, 371 (49.9%) would use a brand name of L-T4, and 366 (49.3%) would use a generic formulation for the initial therapy of overt hypothyroidism. There was a significantly lower use of brand-name formulations in North America (37.9%) compared with Latin America (58.0%, P ⬍ .001) and Europe (58.8%, P ⬍ .001). The percentage of respondents using a brand-name formulation in Asia-Oceania (58.2%) and in the Middle East-Africa (56.3%) was similar to that of Europe and Latin America, but did not achieve significance vs North America. Combined L-T4/L-T3 or thyroid extract as initial therapy Only 13 respondents (0.8%) selected combined L-T4/ L-T3 as initial therapy in the index case. Among these respondents, 4 would add 10 ␮g daily of L-T3, and 2 each would add 5 ␮g of L-T3 once, twice, or 3 times daily. No respondents selected thyroid extract as initial therapy. Follow-up testing and dose adjustment Among 859 respondents, 423 (49.2%) would recheck thyroid hormone levels 6 weeks after starting thyroid hormone therapy, followed by 8 weeks (25.7%), 4 weeks (16.0%), 12 weeks (8.0%), and 2 weeks (1.1%). Specific testing at the time of follow-up included TSH for 845 of 856 (98.7%) respondents, free T4 in 513 respondents (59.9%), free T3 (7.8%), or total T3 (3.4%). TSH targets in primary hypothyroidism Among 856 respondents, the target TSH in the 52-yearold index case was 1.0 to 1.9 mU/L for 408 respondents (47.7%), 2.0 to 2.9 mU/L in 284 respondents (33.2%), 0.5 to 0.9 mU/L in 66 respondents (7.7%), and 3.0 to 3.9 mU/L in 66 respondents (7.7%). When asked what the TSH target would be in a 25-year-old patient, there was a shift toward lower TSH values, with 61.6% now selecting 1.0 to 1.9 mU/L, followed by 2.0 to 2.9 mU/L (18.1%) and 0.5 to 0.9 mU/L (14.4%). Conversely, in an 85-year-old patient, 29.5% would select a TSH from 3.0 to 3.9 mU/L, followed by 2.0 to 2.9 mU/L (25.8%), 4.0 to 4.9 mU/L (22.5%), and 5.0 to 9.9 mU/L (10.4%). A comparison of TSH targets for the 3 age variants is shown in Figure 2.


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25-year-old 52-year-old

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85-year-old

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is planning pregnancy and has a serum TSH of 3.5 mU/L on L-T4 therapy (for full case description, see Supplemental Table 1, published on the Endocrine Society’s Journals Online web site at http://press.endocrine.org/journal/jcem). For the prepregnant patient, the preferred TSH target for 824 respondents was 1.0 to 1.4 mU/L (36.3%), followed by 0.5 to 0.9 mU/L (23.9%), 1.5 to 1.9 mU/L (19.8%), 2.0 to 2.4 mU/L (14.1%), and ⱖ2.5 mU/L (4.9%).

100 L-T4

0 0.1-0.4 0.5-0.9 1.0-1.9 2.0-2.9 3.0-3.9 4.0-4.9 5.0-9.9 Target TSH (mU/L)

Figure 2. Age-specific TSH targets among survey participants.

Long-term follow-up After achieving stable target TSH values, respondents were asked how often they would repeat thyroid laboratory testing. Among 847 respondents, 55.5% would obtain laboratory studies at 6-month intervals, followed by 12 months (34.0%), 3 months (9.3%), and ⬍3 months (1.2%). The manner in which asymptomatic patients at target TSH values would be followed was by laboratory studies plus office visits by 56.2% of 849 respondents, return to the primary care physician by 34.9%, or laboratory studies plus a phone call by 9.0% of respondents. There was a lower rate of return to primary care in Latin America (23.8%, P ⫽ .020 vs North America) and a higher rate of return to primary care physicians in Europe (54.5%) vs North America (34.9%, P ⬍ .001). Variation 1: Persistent hypothyroid symptoms We queried respondents about their response to a patient who despite achieving target TSH values on L-T4 therapy still has persistent hypothyroid symptoms. Among 843 respondents, 84.3% would perform testing for other sources of the patient’s symptoms, 11.3% would refer the patient back to their primary care physician for further evaluation, 3.6% would add L-T3 therapy to L-T4, and fewer than 1% would either refer the patient to behavioral health or increase the dose of the patient’s L-T4. Additional testing requested in patients with persistent unexplained hypothyroid symptoms would include a complete cell count by 90.3% of 723 respondents, a complete metabolic panel (82.4%), morning cortisol level (58.5%), B-12 levels (57.4%), or T3 levels (21.9%). Free text responses included measurement of 25-hydroxyvitamin D levels (4.7%), and evaluation for a sleep disorder (2.2%). Variation 2: hypothyroidism management in a patient planning pregnancy Prepregnancy TSH target Respondents were queried regarding their approach to a 25-year-old woman with Hashimoto’s thyroiditis, who

changes with confirmed pregnancy Respondents were next asked about immediate changes in L-T4 dose after a confirmed pregnancy in a woman with a recent TSH value of 0.5 mU/L. Among 821 respondents, 57.1% would continue the current dose of L-T4, 34.6% would increase the dose by one-third, 5.1% would decrease the dose by one-third, and 2.3% would increase the dose by 50%. Target TSH value during pregnancy The preferred TSH range during pregnancy was similar to the prepregnant patient, with a TSH target of 1.0 to 1.4 mU/L among 33.5% of 822 respondents, 0.5 to 0.9 mU/L (25.5%), 1.5 to 1.9 mU/L (19.1%), 2.0 to 2.4 mU/L (13.5%), 0.1 to 0.4 mU/L (4.5%), and ⱖ2.5 mU/L (3.9%) (Figure 3). Frequency of monitoring during pregnancy Among 821 respondents, 67.7% would check thyroid laboratory studies every 4 weeks during pregnancy, 21.4% every 8 weeks, 7.9% every 12 weeks, and 2.9% every 2 weeks. Variation 3: subclinical hypothyroidism management Survey participants were next presented with a case of subclinical hypothyroidism in an asymptomatic 52-year-

350 300 Number of Respondents

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Prepregnancy Pregnancy

250 200 150 100 50 0

0.1-0.4 0.5-0.9 1.0-1.4 1.5-1.9 2.0-2.4 2.5-2.9 3.0-3.4 Target TSH (mU/L) Figure 3. TSH targets in the pregnant and prepregnant patient.


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old woman with a serum TSH of 7.7 mU/L (for full case description, see Supplemental Table 2). Testing in subclinical hypothyroidism Among 795 respondents, 91.9% would perform TPO Ab testing, 50.6% would obtain a lipid panel, 50.4% would request a thyroid ultrasound, 41.5% would obtain antithyroglobulin Ab, and 19.7% would order either a free T3 or total T3 level. For respondents selecting more than one laboratory test, TPO Ab testing and a lipid panel were requested most frequently (46.7%). Factors influencing the decision to treat subclinical hypothyroidism Among 802 respondents, the percentage that would start L-T4 therapy for subclinical hypothyroidism in the presence of the listed clinical factors is shown in Figure 4. Most respondents (73.8%) indicated more than one potential indication for treatment. Treatment without additional justification was selected more frequently in North America (24.7%) compared with Latin America (10.8%, P ⫽ .008), Europe (14.3%, P ⫽ .045), or Asia-Oceania (9.3%, P ⫽ .005), but at a similar frequency to Middle East-Africa (20.0%, P ⫽ .589). Free text responses indicated a desire to wait 3 to 6 months and repeat testing before treating (5 respondents), treating only if TSH increased further (5 respondents), or defer the treatment decision to the patient (3 respondents).

Discussion The current report provides results from a large modern survey of clinical practices in the management of primary hypothyroidism. It includes a demographically diverse collection of endocrinologists, representing members from 3 major endocrine societies and 76 different coun-

Posive TPO anbodies

62.3%

Hypothyroidism symptoms

60.9%

LDL-cholesterol elevaon

52.9%

Goiter

46.6%

Known CAD

26.3%

Treat without jusﬁcaon

21.3%

Risk factors for CAD

20.7% 0

100

200

300

400

500

600

Number of Respondents

Figure 4. Percentage of participants who would initiate treatment of subclinical hypothyroidism in the presence of the listed circumstance.

tries. Key findings include 1) a nearly exclusive preference for L-T4 alone as initial therapy, 2) the widespread use of age-specific TSH targets for replacement therapy, 3) a low threshold for treating mild thyroid failure, 4) meticulous attention to TSH targets in the pregnant and prepregnant woman, and 5) a highly variable approach to both the rate and means of restoring euthyroidism for overt disease. International differences in management techniques and changes in management trends over the past 12 years were also identified. The rate of overt hypothyroidism correction preferred by respondents was highly variable, with a slightly higher percentage using a start low and go slow approach, compared with an empiric dose adjusted to achieve target TSH values or a calculated full replacement dose. This diversity demonstrates that the optimal rate of correction of overt hypothyroidism remains controversial (15), although a recent randomized controlled trial showed that full replacement therapy was safe in otherwise healthy individuals who were free of cardiovascular disease (16). Repeat laboratory studies would generally be obtained at 6 or 8 weeks, and L-T4 adjustments made using 25 ␮g increments, to achieve a target TSH value of 1 to 2 mU/L in younger patients and 2 to 5 mU/L in an octogenarian. The approach to a patient with persistent hypothyroid symptoms despite having target TSH values has received considerable attention in the past decade (17). Only 1 in 5 respondents would also assess T3 levels in this circumstance, and fewer than 4% would switch to combination L-T4/L-T3 therapy. The low level of interest in combination L-T4/L-T3 therapy among survey respondents, either as initial therapy or in the management of patients with poor symptomatic relief on L-T4, likely reflects several factors, including the absence of long-acting preparations of L-T3, which would therefore presently require 3 times daily dosing (18), concerns over potential adverse effects associated with unregulated T3 availability at the tissue level, and most importantly, the lack of evidence showing beneficial effects of combination therapy (1, 6). Although the use of combination L-T4/L-T3 therapy was low among our respondents, it is possible that this underestimates the prevalent use of combination therapy among primary care physicians. Patients with subclinical hypothyroidism and TSH values in the 5- to 10-mU/L range represent a subset in which treatment with thyroid hormone is of unproven benefit, yet more than 20% of respondents would treat such a patient with thyroid hormone without further justification. The poor selectivity of current criteria for treatment of subclinical hypothyroidism has been noted recently in a retrospective review in which 92% of such patients would meet at least one of the criteria for treatment ac-


doi: 10.1210/jc.2014-1046

cording to the ATA/AACE hypothyroidism guidelines (19). Because overtreatment with thyroid hormone is a frequent finding in patients intended for replacement therapy (20, 21), and the resultant subclinical thyrotoxicosis is linked to adverse consequences such as atrial fibrillation (22, 23) and osteoporosis (22), the tendency among survey respondents to treat mild subclinical hypothyroidism likely reflects confidence in their ability to achieve and maintain proper TSH targets in this patient subset. Management of established hypothyroidism in the pregnant or prepregnant woman has been addressed in recent CPGs (24, 25). Although some variation exists in recommendations among CPGs in this area (26), there is general agreement that L-T4 requirements increase in most pregnant women, often by up to 50% above baseline requirements (27, 28). Furthermore, due to concerns regarding adverse neurodevelopmental consequences associated with maternal hypothyroidism during early pregnancy (29, 30), lower TSH targets are recommended in this setting. Respondents to the current survey preferred to keep TSH values well beneath the recommended first-trimester upper limit of 2.5 mU/L in both pregnant and prepregnant patients, with most respondents selecting TSH values of 0.5 to 1.4 mU/L. Despite the current recommendation to increase the dose of L-T4 by 2 pills per week at pregnancy confirmation in the hypothyroid patient (9, 27), our patient with a TSH value of 0.5 mU/L at pregnancy diagnosis would be maintained on the same dose by more than half of respondents. The management practices for hypothyroidism identified in the current study mirror the 2012 AACE/ATA Hypothyroidism CPG in many areas although diverging significantly in others (Table 1). Because the survey was conducted shortly after the release of the CPGs, it is unlikely that recommendations contained in the CPGs would already have been incorporated into clinical practice. Regarding diagnostic evaluation, a reliance on TPO Ab testing was recommended in the CPG for the purpose of predicting progression of subclinical hypothyroidism. More than 90% of respondents would obtain TPO Ab testing in this circumstance, as would 80% in patients presenting with overt hypothyroidism. Similarly, the CPG recommended against the use of T3 measurement in making the diagnosis of hypothyroidism, and nearly 90% of respondents agreed. Thyroid ultrasound was not recommended routinely in the hypothyroid patient in the ATA/AACE guidelines, but more than 40% of respondents would obtain this study in patients with overt hypothyroidism and 50% in patients with subclinical disease. This may represent the prevalent use of thyroid ultrasound in the endocrine clinic to augment the physical examination, assess for diffuse heterogeneity typical of Hashimoto’s thyroid-


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itis, and exclude concurrent thyroid nodules in these patients. The use of T4 monotherapy was recommended in the CPG, and nearly 100% of respondents agreed. Our survey showed an equivalent use of generic and brandname preparations of L-T4 among respondents. The CPG did not compare generic and brand names of L-T4 but emphasized the need for a consistent preparation. Several areas of current clinical practice appear to deviate from that recommended in the guidelines. First, although a gradual correction of hypothyroidism was suggested for all patients over 50 to 60 years of age, only 39% of respondents selected this approach, the remaining selecting more rapid correction. Second, the guidelines discourage the use of specific TSH targets within the normal range in nonpregnant patients, yet most respondents preferred TSH values below 2 mU/L in the index case. Third, the measurement of both free T4 and TSH was recommended to monitor thyroid hormone replacement therapy, but 40% of respondents use TSH alone. Finally, the guidelines provide specific referral criteria, implying that many hypothyroid patients do not require subspecialty care. However, only 35% of respondents would return the index case to the primary care physician after attaining target TSH values. The current survey uncovered some interesting differences among international endocrinologists in the management of primary hypothyroidism. North American endocrinologists (largely U.S.-based) performed less auxiliary testing, were more likely to use a generic preparation of L-T4, were more likely to correct overt hypothyroidism rapidly, and were more likely to treat mild thyroid failure than in other geographical regions. It is not clear to what extent differences in healthcare systems contribute to these dissimilarities. In comparison with an earlier survey of hypothyroidism management practices published in 2001 (12), several differences were noted. First, in 2001, 73% of ATA respondents indicated a preference for a gradual replacement approach to a 73-year-old patient with overt hypothyroidism, whereas only 39% of current respondents would select a gradual approach in our 52-year-old patient. However, it is likely that at least some of this difference is attributable to the different ages of the 2 index cases in these surveys. Second, in the earlier survey, 65% of ATA members would have treated a patient with mild fatigue and negative TPO Ab, and 92% would have treated in the presence of TPO Ab. In contrast, only 21% of our survey respondents would treat an asymptomatic patient with subclinical hypothyroidism without further justification, and 62% would treat in the presence of TPO Ab, suggesting a lower tendency to treat mild thyroid failure in 2013 compared with 2001. This is contrary to a


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report from the United Kingdom in which a trend toward a lower threshold for treating subclinical hypothyroidism occurred from 2001 to 2009, with the median TSH of patients selected for therapy dropping from 8.7 mU/L in 2001 to 7.9 mU/L in 2009 (31). Third, an increase in the use of generic L-T4 has occurred, with 17% of ATA members using generic brands in the 2001 survey, compared with 62% of North American endocrinologists in 2013. This likely reflects the wider availability of approved generic brands and perhaps a greater attention to cost containment at the time of the current survey. Our study has both strengths and limitations. The number of respondents was large and represented a diverse international group of endocrinologists. The electronic mail invitation to participate provided an opportunity for more than 10 000 potential respondents to learn about the survey. A limitation of the current study is the relatively low percentage of active society membership participating, accounting for 9% to 14% of clinically active members. Another limitation is an underrepresentation of non– U.S.-based endocrinologists and potential selection bias when including international members of U.S.-based endocrine societies. Therefore, the international differences noted in management practices may underestimate those obtained using independent surveys in those regions. In addition, it is possible that respondents to management surveys are more likely to be aware of CPGs and potentially adhere to their recommendations, although we are not aware of evidence to support that possibility. In summary, our survey of clinical endocrinologists on the management of primary hypothyroidism catalogs current practice patterns and demonstrates both alignment and focal deviation from recent CPGs. Both international differences and a change in practice patterns over the past decade are demonstrated.

Acknowledgments We thank Ms Robin Howard for assistance with the statistical analysis, and AACE (Dr Jeffrey I. Mechanick, President; Mr Donald C. Jones, CEO; and Ms Xiomara Villanueva, Executive Assistant), ATA (Dr John C. Morris, Secretary; and Ms Barbara R. Smith, Executive Director), and TES (Ms Meredith Dyer, Associate Director, Health Policy; and Ms. Stephanie Kutler, Director, Government Affairs) for their expert assistance in reviewing and vetting the survey and forwarding it to society membership. We also thank the many national and international colleagues who took the time to participate in this survey. Address all correspondence and requests for reprints to: Henry B. Burch, MD, COL MC U.S. Army, Endocrinology Division, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Building 19, Room 5053, Bethesda, MD


20889 –5600. E-mail [email protected] or [email protected]. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of the Army, Navy, the Department of Defense or the U.S. Government. One or more authors are military service members (or employees of the U.S. Government). This work was prepared as part of our official duties. Title 17 U.S.C. 105 provides that the “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. We certify that all individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the analysis of data (when applicable), the writing of the document, and/or the approval of the submission of this version; that the document represents valid work; that if we used information derived from another source, we obtained all necessary approvals to use it and made appropriate acknowledgments in the document; and that each takes public responsibility for it. Disclosure Summary: The authors have nothing to disclose.

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