What are the guidelines for thyroid function testing and differential diagnosis?

From the Guidelines

Thyroid testing should begin with measuring thyroid-stimulating hormone (TSH) as the primary screening test, followed by free T4 if TSH is abnormal, as recommended by the American Thyroid Association 1. When evaluating thyroid disorders, it is essential to consider the patient's medical history, physical examination, and serum thyroid function tests. The TSH test has a high sensitivity (98%) and specificity (92%) for detecting thyroid disease in patients referred to an endocrine specialty clinic 1. However, in primary care populations, the positive predictive value of TSH in detecting thyroid disease is low, and the interpretation of a positive test result can be complicated by underlying illness or frailty 1.

Key Considerations

• The normal TSH range is typically 0.4-4.0 mIU/L, with values above suggesting hypothyroidism and below indicating hyperthyroidism 1.
• For suspected hyperthyroidism, add free T3 testing to the initial TSH and free T4 tests.
• When evaluating thyroid disorders, consider testing for thyroid antibodies: thyroid peroxidase (TPO) and thyroglobulin antibodies for autoimmune thyroiditis, and TSH receptor antibodies for Graves' disease.
• The differential diagnosis for thyroid disorders includes Hashimoto's thyroiditis and iodine deficiency for hypothyroidism; Graves' disease, toxic multinodular goiter, and thyroiditis for hyperthyroidism; and medication effects, pregnancy, and non-thyroidal illness that can affect thyroid function tests.

Treatment and Management

• For hypothyroidism, start levothyroxine at 1.6 mcg/kg/day (typically 75-100 mcg daily), with lower doses (25-50 mcg) for elderly patients or those with cardiac disease.
• For hyperthyroidism, options include methimazole (starting at 10-30 mg daily based on severity), propranolol for symptom control (20-40 mg three times daily), and consideration of radioactive iodine or surgery for definitive treatment.
• Recheck TSH and free T4 6-8 weeks after initiating treatment to assess response and adjust medication accordingly, as recommended by the American Family Physician 1.

From the FDA Drug Label

Assess the adequacy of therapy by periodic assessment of laboratory tests and clinical evaluation. In adult patients with primary hypothyroidism, monitor serum TSH levels after an interval of 6 to 8 weeks after any change in dosage. In patients on a stable and appropriate replacement dosage, evaluate clinical and biochemical response every 6 to 12 months and whenever there is a change in the patient’s clinical status In patients with hypothyroidism, assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4. Monitor TSH and total or free-T4 in pediatric patients as follows: 2 and 4 weeks after the initiation of treatment, 2 weeks after any change in dosage, and then every 3 to 12 months thereafter following dosage stabilization until growth is completed The general aim of therapy is to normalize the serum TSH level For pregnant patients with pre-existing hypothyroidism, measure serum TSH and free-T4 as soon as pregnancy is confirmed and, at minimum, during each trimester of pregnancy. In pregnant patients with primary hypothyroidism, maintain serum TSH in the trimester-specific reference range

The guidelines for thyroid function testing are to:

• Monitor serum TSH levels in adult patients with primary hypothyroidism after an interval of 6 to 8 weeks after any change in dosage
• Evaluate clinical and biochemical response every 6 to 12 months in patients on a stable and appropriate replacement dosage
• Assess the adequacy of replacement therapy by measuring both serum TSH and total or free-T4 in pediatric patients
• Monitor TSH and total or free-T4 in pediatric patients at specific intervals
• Maintain serum TSH in the trimester-specific reference range in pregnant patients with primary hypothyroidism
• Measure serum TSH and free-T4 as soon as pregnancy is confirmed and during each trimester of pregnancy in patients with pre-existing hypothyroidism

The guidelines for differential diagnosis are to:

• Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of levothyroxine sodium
• Evaluate clinical and biochemical response to therapy
• Monitor for signs of inadequate absorption, poor compliance, drug interactions, or a combination of these factors
• Perform routine clinical examination, including assessment of development, mental and physical growth, and bone maturation, at regular intervals 2

From the Research

Guidelines for Thyroid Function Testing

• The initial evaluation of suspected primary hypothyroidism should start with a thyroid-stimulating hormone (TSH) level test 3
• If TSH is abnormal, a free thyroxine (T4) level will further narrow the diagnosis 3
• A two-step approach, where TSH is tested first and fT4 is assessed only if TSH is out of the reference range, may be sufficient for initial evaluation 4
• Simultaneous initial measurement of both TSH and fT4 may not be necessary, as the two-step approach would have missed only 3.8% of participants with a normal TSH but a fT4 outside the reference range 4

Differential Diagnosis

• Overt hypothyroidism is characterized by an elevated TSH level and a low free T4 level with symptoms of hypothyroidism 5, 6
• Subclinical hypothyroidism is characterized by an elevated TSH level with a normal T4 value, and the decision to treat should be based on patient characteristics and shared decision-making discussions 5, 7, 6
• The natural history of hypothyroidism depends on its cause, and chronic autoimmune thyroiditis generally worsens over time 5
• Transient hypothyroidism may last several weeks or months, and watchful waiting is an alternative to routine levothyroxine prescription in case of TSH elevation 5

Treatment and Management

• Levothyroxine therapy is recommended for patients with overt hypothyroidism and a blood TSH concentration above 10 mIU/L 5, 7
• For subclinical hypothyroidism, treatment guidelines recommend levothyroxine therapy for younger patients (<65-70 years) with serum TSH >10 mU/l, and a trial of L-thyroxine replacement therapy should be considered for younger patients with symptoms suggestive of hypothyroidism 7
• The aim for most adults should be to reach a stable serum TSH in the lower half of the reference range (0.4-2.5 mU/l) 7
• Thyroid hormone should be titrated based on goal TSH values, symptoms, and potential treatment adverse effects 6