Questions and Guideline Recommendations

QUESTIONS AND GUIDELINE RECOMMENDATIONS*

When should anti-thyroid antibodies be measured?

■ RECOMMENDATION 1

Anti-thyroid peroxidase antibody (TPOAb) measurements should be considered when evaluating patients with subclinical hypothyroidism.  Grade B, BEL 1

See: Epidemiology; Primary and secondary etiologies of hypothyroidism

Recommendation 1 was downgraded to B because the best evidence is only predictive in nature. If anti-thyroid antibodies are positive, hypothyroidism occurs at a rate of 4.3% per year versus 2.6% per year when anti-thyroid antibodies are negative. Therefore, the presence of positive TPOAb may or may not influence the decision to treat.

■ RECOMMENDATION 2

TPOAb measurement should be considered in order to identify autoimmune thyroiditis when nodular thyroid disease is suspected to be due to autoimmune thyroid disease.  Grade D, BEL 4

See: Primary and secondary etiologies of hypothyroidism

■ RECOMMENDATION 3

TPOAb measurement should be considered when evaluating patients with recurrent miscarriage, with or without infertility.  Grade A, BEL 2

See: Concurrent conditions of special significanceInfertility

Recommendation 3 was upgraded to A because of favorable risk–benefit potential.

■ RECOMMENDATION 4

Measurement of TSHRAbs using a sensitive assay should be considered in hypothyroid pregnant patients with a history of Graves' disease who were treated with radioactive iodine or thyroidectomy prior to pregnancy. This should be initially done either at 20–26 weeks of gestation or during the first trimester and if they are elevated again at 20–26 weeks of gestation.  Grade A, BEL 2

See: Primary and secondary etiologies of hypothyroidism

Recommendation 4 was upgraded to A because the correlation between a high titer of TSHRAb and the development of fetal or neonatal Graves' disease is strong.

What is the role of clinical scoring systems in the diagnosis of patients with hypothyroidism?

■ RECOMMENDATION 5

Clinical scoring systems should not be used to diagnose hypothyroidism.  Grade A, BEL 1

See: Signs and symptoms of hypothyroidism; Other diagnostic tests for hypothyroidism

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What is the role of diagnostic tests apart from serum thyroid hormone levels and TSH in the evaluation of patients with hypothyroidism?

■ RECOMMENDATION 6

Tests such as clinical assessment of reflex relaxation time, cholesterol, and muscle enzymes should not be used to diagnose hypothyroidism.  Grade B, BEL 2

See: Signs and symptoms of hypothyroidism; Other diagnostic tests for hypothyroidism

What are the preferred thyroid hormone measurements in addition to TSH in the assessment of patients with hypothyroidism?

■ RECOMMENDATION 7

Apart from pregnancy, assessment of serum free T4 should be done instead of total T4 in the evaluation of hypothyroidism. An assessment of serum free T4 includes a free T4 index or free T4 estimate and direct immunoassay of free T4 without physical separation using anti-T4 antibody.  Grade A, BEL 1

See: Measurement of T4 and T3; Table 6

■ RECOMMENDATION 8

Assessment of serum free T4, in addition to TSH, should be considered when monitoring L-thyroxine therapy.  Grade B, BEL 1

See: Measurement of T4 and T3

Recommendation 8 was downgraded to B since it should only be used selectively.

■ RECOMMENDATION 9

In pregnancy, the measurement of total T4 or a free T4 index, in addition to TSH, should be done to assess thyroid status. Because of the wide variation in the results of different free T4 assays, direct immunoassay measurement of free T4 should only be employed when method-specific and trimester-specific reference ranges for serum free T4 are available.  Grade B, BEL 2

See: Measurement of T4 and T3

■ RECOMMENDATION 10

Serum total T3 or assessment of serum free T3 should not be done to diagnose hypothyroidism.  Grade A, BEL 2

See: Measurement of T4 and T3

Recommendation 10 was upgraded to A because of many independent lines of evidence and expert opinion.

■ RECOMMENDATION 11

TSH measurements in hospitalized patients should be done only if there is an index of suspicion for thyroid dysfunction.  Grade A, BEL 2

See: Measurement of T4 and T3; Pitfalls encountered when interpreting serum TSH levels; Concurrent conditions of special significance in hypothyroid patients—Nonthyroidal illness

Recommendation 11 was upgraded to A because of cost considerations and potential for inappropriate intervention.

■ RECOMMENDATION 12

In patients with central hypothyroidism, assessment of free T4 or free T4 index, not TSH, should be done to diagnose and guide treatment of hypothyroidism.  Grade A, BEL 1

See: Measurement of T4 and T3; L-thyroxine treatment of hypothyroidism

When should TSH levels be measured in patients being treated for hypothyroidism?

■ RECOMMENDATION 13

Patients being treated for established hypothyroidism should have serum TSH measurements done at 4–8 weeks after initiating treatment or after a change in dose. Once an adequate replacement dose has been determined, periodic TSH measurements should be done after 6 months and then at 12-month intervals, or more frequently if the clinical situation dictates otherwise.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism

What should be considered the upper limit of the normal range of TSH values?

■ RECOMMENDATION 14.1

The reference range of a given laboratory should determine the upper limit of normal for a third generation TSH assay. The normal TSH reference range changes with age. If an age-based upper limit of normal for a third generation TSH assay is not available in an iodine sufficient area, an upper limit of normal of 4.12 should be considered.  Grade A, BEL 1

See: Pitfalls encountered when interpreting serum TSH levels; Therapeutic endpoints in the treatment of hypothyroidism; Table 7

■ RECOMMENDATION 14.2

In pregnancy, the upper limit of the normal range should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges for TSH are not available in the laboratory, the following upper normal reference ranges are recommended: first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; third trimester, 3.5 mIU/L.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients—Hypothyroidism during pregnancy; Table 7

Which patients with TSH levels above a given laboratory's reference range should be considered for treatment with L-thyroxine?

■ RECOMMENDATION 15

Patients whose serum TSH levels exceed 10 mIU/L are at increased risk for heart failure and cardiovascular mortality, and should be considered for treatment with L-thyroxine.  Grade B, BEL 1

See: Areas for Future Research; When to treat hypothyroidism—Cardiac benefit from treating subclinical hypothyroidism

Recommendation 15 was downgraded to B because it is not generalizable and meta-analysis does not include prospective interventional studies.

■ RECOMMENDATION 16

Treatment based on individual factors for patients with TSH levels between the upper limit of a given laboratory's reference range and 10 mIU/L should be considered particularly if patients have symptoms suggestive of hypothyroidism, positive TPOAb or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases.  Grade B, BEL 1

See: Epidemiology; Primary and secondary etiologies of hypothyroidism; Screening and aggressive case finding for hypothyroidism; When to treat hypothyroidism; Areas for Future ResearchCardiac benefit from treating subclinical hypothyroidism; Table 9

Recommendation 16 was downgraded to B because the evidence is not fully generalizable to the stated recommendation and there are no prospective, interventional studies.

In patients with hypothyroidism being treated with L-thyroxine, what should the target TSH ranges be?

■ RECOMMENDATION 17

In patients with hypothyroidism who are not pregnant, the target range should be the normal range of a third generation TSH assay. If an upper limit of normal for a third generation TSH assay is not available, in iodine-sufficient areas an upper limit of normal of 4.12 mIU/L should be considered and if a lower limit of normal is not available, 0.45 mIU/L should be considered.  Grade B, BEL 2

See: Pitfalls encountered when interpreting serum TSH levels; When to treat hypothyroidism; Therapeutic endpoints in the treatment of hypothyroidism; Table 7

In patients with hypothyroidism being treated with L-thyroxine who are pregnant, what should the target TSH ranges be?

■ RECOMMENDATION 18

In patients with hypothyroidism who are pregnant, the target range for TSH should be based on trimester-specific ranges for that laboratory. If trimester-specific reference ranges are not available in the laboratory, the following upper-normal reference ranges are recommended: first trimester, 2.5 mIU/L; second trimester, 3.0 mIU/L; and third trimester, 3.5 mIU/L.  Grade C, BEL 2

See: Pitfalls encountered when interpreting serum TSH levels; When to treat hypothyroidism; Therapeutic endpoints in the treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patientsHypothyroidism during pregnancy; Table 7

Recommendation 18 was downgraded to C due to lack of prospective studies establishing benefit.

Which patients with normal serum TSH levels should be considered for treatment with L-thyroxine?

■ RECOMMENDATION 19.1

Treatment with L-thyroxine should be considered in women of childbearing age with serum TSH levels between 2.5 mIU/L and the upper limit of normal for a given laboratory's reference range if they are in the first trimester of pregnancy or planning a pregnancy including assisted reproduction in the immediate future. Treatment with L-thyroxine should be considered in women in the second trimester of pregnancy with serum TSH levels between 3.0 mIU/L and the upper limit of normal for a given laboratory's reference range, and in women in the third trimester of pregnancy with serum TSH levels between 3.5 mIU/L and the upper limit of normal for a given laboratory's reference range.  Grade B, BEL 2

See: When to treat hypothyroidism; Concurrent conditions of special significance in hypothyroid patientsHypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 19.2

Treatment with L-thyroxine should be considered in women of childbearing age with normal serum TSH levels when they are pregnant or planning a pregnancy, including assisted reproduction in the immediate future, if they have or have had positive levels of serum TPOAb, particularly when there is a history of miscarriage or past history of hypothyroidism.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patientsHypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 19.3

Women of childbearing age who are pregnant or planning a pregnancy, including assisted reproduction in the immediate future, should be treated with L-thyroxine if they have or have had positive levels of serum TPOAb and their TSH is greater than 2.5 mIU/L.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patientsHypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 19.4

Women with positive levels of serum TPOAb or with a TSH greater than 2.5 mIU/L who are not being treated with L-thyroxine should be monitored every 4 weeks in the first 20 weeks of pregnancy for the development of hypothyroidism.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patientsHypothyroidism during pregnancy; Table 7

Who, among patients who are pregnant, or planning pregnancy, or with other characteristics, should be screened for hypothyroidism?

■ RECOMMENDATION 20.1.1

Universal screening is not recommended for patients who are pregnant or are planning pregnancy, including assisted reproduction.  Grade B, BEL 1

See: Areas for Future Research—Screening for hypothyroidism in pregnancy

Recommendation 20.1.1 was downgraded to B because there are limitations to the evidence and therefore insufficient evidence for lack of benefit.

■ RECOMMENDATION 20.1.2

“Aggressive case finding,” rather than universal screening, should be considered for patients who are planning pregnancy.  Grade C, BEL 2

See: Areas for Future Research—Screening for hypothyroidism in pregnancy

Recommendation 20.1.2 was downgraded to C because even when a diagnosis of hypothyroidism is made, impact on outcomes has not been demonstrated.

■ RECOMMENDATION 20.2

Screening for hypothyroidism should be considered in patients over the age of 60.  Grade B, BEL 1

See: Epidemiology; Primary and secondary etiologies of hypothyroidism; Screening and aggressive case finding for hypothyroidism; Table 8

Recommendation 20.2 was downgraded to B because there is strong evidence that hypothyroidism is common in this group but insufficient evidence of benefit or cost effectiveness.

■ RECOMMENDATION 21

“Aggressive case finding” should be considered in those at increased risk for hypothyroidism.  Grade B, BEL 2

See: Epidemiology; Primary and secondary etiologies of hypothyroidism; Screening and aggressive case finding for hypothyroidism; Table 8

How should patients with hypothyroidism be treated and monitored?

■ RECOMMENDATION 22.1

Patients with hypothyroidism should be treated with L-thyroxine monotherapy.  Grade A, BEL 1

See: L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 22.2

The evidence does not support using L-thyroxine and L-triiodothyronine combinations to treat hypothyroidism.  Grade B, BEL 1

See: L-thyroxine treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patients; Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Desiccated thyroid; Areas for Future Research—L-thyroxine/L-triiodothyronine combination therapy

Recommendation 22.2 was downgraded to Grade B because of still-unresolved issues raised by studies that report that some patients prefer and some patient subgroups may benefit from a combination of L-thyroxine and L-triiodothyronine.

■ RECOMMENDATION 22.3

L-thyroxine and L-triiodothyronine combinations should not be administered to pregnant women or those planning pregnancy.  Grade B, BEL 3

See: Concurrent conditions of special significance in hypothyroid patientsHypothyroidism during pregnancy

Recommendation 22.3 was upgraded to B because of potential for harm.

■ RECOMMENDATION 22.4

There is no evidence to support using desiccated thyroid hormone in preference to L-thyroxine monotherapy in the treatment of hypothyroidism and therefore desiccated thyroid hormone should not be used for the treatment of hypothyroidism.  Grade D, BEL 4

See: L-thyroxine treatment of hypothyroidism; Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Desiccated thyroid

Recommendation 22.4 was a unanimous expert opinion.

■ RECOMMENDATION 22.5

3,5,3′-triiodothyroacetic acid (TRIAC; tiratricol) should not be used to treat primary and central hypothyroidism due to suggestions of harm in the literature.  Grade C, BEL 3

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; 3,5,3′-Triiodothyroacetic acid

■ RECOMMENDATION 22.6

Patients resuming L-thyroxine therapy after interruption (less than 6 weeks) and without an intercurrent cardiac event or marked weight loss may resume their previously employed full replacement doses.  Grade D, BEL 4

See: L-thyroxine treatment of hypothyroidism

Recommendation 22.6 was a unanimous expert opinion.

■ RECOMMENDATION 22.7.1

When initiating therapy in young healthy adults with overt hypothyroidism, beginning treatment with full replacement doses should be considered.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 22.7.2

When initiating therapy in patients older than 50–60 years with overt hypothyroidism, without evidence of coronary heart disease, an L-thyroxine dose of 50 μg daily should be considered.  Grade D, BEL 4

See: L-thyroxine treatment of hypothyroidism

Recommendation 22.7.2 was a unanimous expert opinion.

■ RECOMMENDATION 22.8

In patients with subclinical hypothyroidism, initial L-thyroxine dosing is generally lower than what is required in the treatment of overt hypothyroidism. A daily dose of 25–75 μg should be considered, depending on the degree of TSH elevation. Further adjustments should be guided by clinical response and follow-up laboratory determinations including TSH values.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 22.9

Treatment with glucocorticoids in patients with combined adrenal insufficiency and hypothyroidism should precede treatment with L-thyroxine.  Grade B, BEL 2

See: Disorders associated with hypothyroidism; Pitfalls encountered when trying to interpret serum TSH levels; L-thyroxine treatment of hypothyroidism

■ RECOMMENDATION 23

L-thyroxine should be taken with water consistently 30–60 minutes before breakfast or at bedtime 4 hours after the last meal. It should be stored properly per product insert and not taken with substances or medications that interfere with its absorption.  Grade B, BEL 2

See: L-thyroxine treatment of hypothyroidism; Table 10

■ RECOMMENDATION 24

In patients with central hypothyroidism, assessments of serum free T4 should guide therapy and targeted to exceed the midnormal range value for the assay being used.  Grade B, BEL 3

See: Primary and secondary etiologies of hypothyroidism; Measurement of T4 and T3; Pitfalls encountered when interpreting serum TSH levels; L-thyroxine treatment of hypothyroidism

Recommendation 24 was upgraded to B because more than 50% of patients with central hypothyroidism adequately treated with L-thyroxine have values in this range.

■ RECOMMENDATION 25.1

In patients with hypothyroidism being treated with L-thyroxine who are pregnant, serum TSH should be promptly measured after conception and L-thyroxine dosage adjusted, with a goal TSH of less than 2.5 mIU/L during the first trimester.  Grade B, BEL 2

See: Therapeutic endpoints in the treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patients—Hypothyroidism during pregnancy; Table 7

■ RECOMMENDATION 25.2

In patients with hypothyroidism being treated with L-thyroxine who are pregnant, the goal TSH during the second trimester should be less than 3 mIU/L and during the third trimester should be less than 3.5 mIU/L.  Grade C, BEL 2

See: Therapeutic endpoints in the treatment of hypothyroidism; Concurrent conditions of special significance in hypothyroid patients—Hypothyroidism during pregnancy; Table 7.

Recommendation 25.2 was downgraded to C due to lack of prospective studies establishing benefit.

■ RECOMMENDATION 25.3

Maternal serum TSH (and total T4) should be monitored every 4 weeks during the first half of pregnancy and at least once between 26 and 32 weeks gestation and L-thyroxine dosages adjusted as indicated.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patients—Hypothyroidism during pregnancy

■ RECOMMENDATION 26

In patients receiving L-thyroxine treatment for hypothyroidism, serum TSH should be remeasured within 4–8 weeks of initiation of treatment with drugs that decrease the bioavailability or alter the metabolic disposition of the L-thyroxine dose.  Grade A, BEL 1

See: L-thyroxine treatment of hypothyroidism; Areas for Future Research—Agents and conditions having an impact on L-thyroxine therapy and interpretation of thyroid tests; Tables 5 and 10.

■ RECOMMENDATION 27

Apart from pregnant patients being treated with L-thyroxine for hypothyroidism, the evidence does not support targeting specific TSH values within the normal reference range.  Grade B, BEL 2

See: Therapeutic endpoints in the treatment of hypothyroidism

When should endocrinologists be involved in the care of patients with hypothyroidism?

Physicians who are not endocrinologists, but who are familiar with the diagnosis and treatment of hypothyroidism should be able to care for most patients with primary hypothyroidism. However, patients with hypothyroidism who fall into the following categories should be seen in consultation with an endocrinologist. These categories are (i) children and infants, (ii) patients in whom it is difficult to render and maintain a euthyroid state, (iii) pregnancy, (iv) women planning conception, (v) cardiac disease, (vi) presence of goiter, nodule, or other structural changes in the thyroid gland, (vii) presence of other endocrine disease such as adrenal and pituitary disorders, (viii) unusual constellation of thyroid function test results, and (ix) unusual causes of hypothyroidism such as those induced by agents that interfere with absorption of L-thyroxine, impact thyroid gland hormone production or secretion, affect the hypothalamic–pituitary–thyroid axis (directly or indirectly), increase clearance, or peripherally impact metabolism.  Grade C, BEL 3

See: When to consult an endocrinologist; Table 10

Which patients should not be treated with thyroid hormone?

■ RECOMMENDATION 29

Thyroid hormones should not be used to treat symptoms suggestive of hypothyroidism without biochemical confirmation of the diagnosis.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patientsPatients with normal thyroid tests

■ RECOMMENDATION 30

Thyroid hormones should not be used to treat obesity in euthyroid patients.  Grade A, BEL 2

See: Concurrent conditions of special significance in hypothyroid patientsObesity

Recommendation 30 was upgraded to Grade A because of potential harm.

■ RECOMMENDATION 31

There is insufficient evidence to support using thyroid hormones to treat depression in euthyroid patients.  Grade B, BEL 2

See: Concurrent conditions of special significance in hypothyroid patientsDepression

What is the role of iodine supplementation, dietary supplements, and nutraceuticals in the treatment of hypothyroidism?

■ RECOMMENDATION 32.1

Iodine supplementation, including kelp or other iodine-containing functional foods, should not be used in the management of hypothyroidism in iodine-sufficient areas.  Grade C, BEL 3

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Excess iodine intake and hypothyroidism

■ RECOMMENDATION 32.2

Iodine supplementation in the form of kelp or other seaweed-based products should not be used to treat iodine deficiency in pregnant women.  Grade D, BEL 4

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Excess iodine intake and hypothyroidism

Recommendation 32.2 was a unanimous expert opinion

■ RECOMMENDATION 33

Selenium should not be used to prevent or treat hypothyroidism.  Grade B, BEL 2

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Selenium.

■ RECOMMENDATION 34

Patients taking dietary supplements and nutraceuticals for hypothyroidism should be advised that commercially available thyroid-enhancing products are not a remedy for hypothyroidism and should be counseled about the potential side effects of various preparations particularly those containing iodine or sympathomimetic amines as well as those marked as “thyroid support” since they could be adulterated with L-thyroxine or L-triiodothyronine.  Grade D, BEL 4

See: Dietary supplements and nutraceuticals in the treatment of hypothyroidism; Thyroid enhancing preparations; Thyromimetic preparations

Recommendation 34 was a unanimous expert opinion.

 

*Note: When referring to therapy and therapeutic preparations in the recommendations and elsewhere, L-thyroxine and L-triiodothyronine are generally used instead of their respective hormonal equivalents, T4 and T3