top of page

Scientific Review by Alun Stevens MSc FIAA

During 2002 the US National Academy of Clinical Biochemists published a comprehensive set of guidelines for the Laboratory Support for the Diagnosis and Monitoring of Thyroid Disease. This is a comprehensive overview of the various tests used to diagnose and manage thyroid disease. The guidelines also provide a set of consensus recommendations from an international panel of experts regarding the use and interpretation of the tests.


These consensus recommendations provide patients with a firm and clear statement on what they can expect from their doctors. The guidelines are highly technical and as a result may not be useful to everyone, but the specific recommendations are mostly written in language which can be understood by anyone with a basic understanding of thyroid function and who knows the terminology. Even if you find the language daunting, you can still take a copy to your doctor.


There are 79 specific guidelines for doctors, laboratories and manufacturers. The document extends to 125 pages. I will summarise the guidelines which are relevant to the majority of our members.

Guideline 2: Thyroid Testing of Ambulatory Patients
  • Patients with stable thyroid status: With stable thyroid status and intact hypothalamus-pituitary feedback, TSH is the more sensitive test to detect mild thyroid excess or deficiency.

  • Patients with unstable thyroid status: Free T4 is more reliable than TSH as an indicator of thyroid status when that status is unstable. This means that Free T4 is more reliable during the early stages of treatment for both hypo and hyperthyroidism. The hypothalamus-pituitary feedback mechanism can take 6 – 12 weeks to stabilize.

Guideline 4: Thyroid Testing of Pregnant Patients
  • Hypothyroidism during early pregnancy has detrimental outcomes – foetal wastage and lower infant IQ.

  • Pre-pregnancy or first trimester screening using serum TSH and Thyroid Peroxidase Antibodies (TPOAb) is important for detecting mild thyroid failure and assessing the risk of post-partum thyroiditis.

  • Thyroxine replacement therapy should be considered if TSH>4.0 during the first trimester.

  • A high serum TPOAb reading during the first trimester is a risk factor for post-partum thyroiditis.

  • TSH should be tested each trimester for those taking replacement thyroxine.

  • Trimester specific reference ranges should be used. Not the standard reference ranges.

Guideline 22: TSH Reference Intervals


Serum TSH in healthy people varies during the day from a high in the middle of the night to a low around the middle of the day which is approximately half the overnight maximum.

Population reference intervals are probably too wide because of the inclusion of people who have thyroid dysfunction which is not obvious. It is likely that the upper limit of the reference interval will be reduced to 2.5 mIU/L because more than 95% of rigorously screened individuals have TSH levels between 0.4 and 2.5 mIU/L.

TSH reference intervals should be established from the 95% confidence limits of at least 120 rigorously screened individuals who have:

  • No detectable thyroid autoantibodies – TPOAb or Thyroglobulin Antibodies (TgAb)

  • No personal or family history of thyroid dysfunction.

  • No visible or palpable goitre.

  • No medications (except oestrogen).

Guideline 23: Thyroxine Replacement Therapy for Hypothyroidism
  • Levothyroxine (L-T4) is the preferred medication for long term replacement therapy.

  • A euthyroid state is usually achieved with an average daily L-T4 dose of 1.6 µg/Kg body weight. The initial dose and time to full replacement should be individualised according to age, weight and cardiac status. An initial L-T4 dose is normally 50-100 µg daily. Serum TSH measurement after six weeks will indicate the need for dose adjustment by 25-50 µg increments.

  • Children require higher doses of L-T4, up to 4.0 µg/kg body weight per day, due to rapid metabolism. Serum TSH and FT4 values should be assessed using age-specific reference ranges.

  • A serum TSH level between 0.5 and 2.0 mIU/L is generally considered the optimal therapeutic target for the L-T4 replacement dose for primary hypothyroidism.

  • TSH is slow to re-equilibrate to a new thyroxine status (Guideline 2). Six to 8 weeks is needed before retesting TSH after changing the L-T4 dose or brand of thyroid medication.

  • Intermittent or non-compliance with L-T4 replacement therapy will result in serum TSH and FT4 values which are not consistent (high TSH/high FT4) because of a persistently unstable thyroid state (Guideline 2). Both TSH and FT4 should be used for monitoring such patients.

  • Thyroxine requirements decline with age. Older individuals may require less than 1.0 µg/kg per day and may need to be titrated [dose adjusted] slowly. Some physicians prefer to gradually titrate such patients. An initial dose of 25 µg is recommended for patients with evidence of ischaemic heart disease followed by dose increments of 25 µg every 3-4 weeks until the full replacement dose is achieved. Some believe that a higher target TSH (0.5-3.0 mIU/L) value may be appropriate for the elderly patient.

  • In severe hypothyroidism an initial L-T4 loading dose is the most rapid means for restoring a therapeutic FT4 level because the excess of unoccupied binding sites may blunt the FT4 response to treatment.

  • Thyroxine requirements increase during pregnancy. Thyroid status should be checked with TSH plus FT4 during each trimester of pregnancy. The L-T4 dose should be increased (usually by 50 µg/day) to maintain a serum TSH between 0.5 and 2.0 mIU/L and a serum FT4 in the upper third of the normal reference interval.

  • Post-menopausal women starting hormone replacement therapy may need an increase in their L–T4 dose to keep the serum TSH within the therapeutic target.

  • TSH testing of patients receiving a stable L-T4 dose is recommended on an annual basis. The best time for TSH testing is not influenced by the time of day the L-T4 dose is ingested.

  • Ideally L-T4 should be taken before eating, at the same time of day, and at least 4 hours apart from any other medications or vitamins. Bedtime dosing should be 2 hours after the last meal.

  • Patients beginning chronic therapy with cholestyramine, ferrous sulfate, calcium carbonate, soy protein, sucralfate and antacids containing aluminum hydroxide that influence L-T4 absorption may require a larger L-T4 dose to maintain TSH within the therapeutic target range.

  • Patients taking Rifampin and anticonvulsants that influence the metabolism of L-T4 may also need an increased L-T4 dose to maintain the TSH within the therapeutic target range.


TSH tests are not influenced by thyroxine that is taken a few hours before the test, but Free T4 tests are affected. Free T4 levels are significantly increased (~13%) for up to 9 hours after the last dose. On the day of a blood test, that day’s thyroxine dose should not be taken until after the blood sample is drawn.


It is well documented that hypothyroid patients will have serum Free T4 values in the upper third of the reference range when the L-T4 dose is adjusted to bring the serum TSH value into the target range of 0.5 to 2.0 mIU/L.

Guideline 27: Clinical Utility of TSH Assays
  • Serum TSH measurement is the most diagnostically sensitive test for detecting mild (subclinical), as well as overt, primary hypo- or hyperthyroidism in ambulatory patients.

  • The majority (>95%) of healthy euthyroid subjects have a serum TSH concentration below 2.5 mIU/L. Ambulatory patients with a serum TSH above 2.5 mIU/L when confirmed by a repeat TSH measurement made after 3-4 weeks, may be in the early stages of thyroid failure, especially if TPOAb is detected.

  • Serum TSH measurements are more reliable than FT4 in hospitalized patients with non-thyroidal illness not receiving dopamine. Serum TSH should be used in conjunction with T4 testing for hospitalized patients.

  • TSH cannot be used to diagnose central hypothyroidism because current TSH assays measure biologically inactive forms of TSH.

  • When the serum FT4 is low and yet the serum TSH is only minimally elevated (<10 mIU/L), a diagnosis of central hypothyroidism should be considered.

  • Serum TSH measurements are an important pre-natal and first trimester screening test to detect mild (subclinical) hypothyroidism in the mother (see Guideline 4).

  • A low TSH in the setting of a multinodular goiter suggests the presence of mild (subclinical) hyperthyroidism due to thyroid autonomy.

  • A serum TSH measurement is required for confirming that an elevated thyroid hormone level is due to hyperthyroidism and not a thyroid hormone binding protein abnormality.

The full NACB Guidelines can be found at

Please discuss these guidelines with your doctor in the context of your situation.

(c) Copyright 2002, Natiional Academy of Clinical Biochemists

bottom of page