Consensus # 9 The treatment of clinically hypothyroid, but biochemically euthyroid patientsApril 12, 2007After an extensive literature review and discussions with physicians from all over the world who are well versed in treating patients with endocrine abnormalities, we, the Consensus Group of Experts of the International Hormone Society (IHS), think there is enough clinical and theoretical evidence to expand the application of thyroid treatment beyond the current conventional parameters. Is the diagnosis of hypothyroidism based on biochemical evaluation or clinical evidence? There is a controversy between groups of physicians. One group essentially diagnoses hypothyroidism solely with laboratory tests, while the other relies more on clinical factors. Solid scientific evidence does not support the idea that the diagnosis of hypothyroidism can or should only be based on laboratory tests. This would imply that hypothyroidism only exists in patients with a serum TSH beyond the actual upper reference range, and serum thyroxine (T4) and triiodothyronine (T3) levels below the lower reference range, and neglects the clinical signs and symptoms. The IHS's position is intermediate. The decision to initiate (thyroid) therapy should be based on both clinical and laboratory findings, and not solely on the results of a single test, exactly as expressed in the medical journals JAMA and Thyroid presenting the American Thyroid Association's guidelines for use of laboratory tests in thyroid disorders (1). The diagnosis of hypothyroidism is further substantiated when treatment results in the relief of clinical signs and symptoms and the laboratory tests are improved. Clinical information is essential in diagnosing a hormone deficiency. The clinical data needed to make a diagnosis of hypothyroidism include the physical and emotional complaints of patients, physical signs, personal and familial medical histories suggestive of a thyroid deficiency and the existence of a thyroid gland abnormality (nodule or goiter) and/or autoimmune thyroiditis. The following evidence supports the existence of patients who are clinically hypothyroid, but mistakenly considered biochemically euthyroid, and who may benefit from thyroid treatment: 1) The normal reference ranges for thyroid tests are too broad and ignore specific individual reference ranges.
- Excessively broad reference ranges: Large reference intervals may include serum levels of T3, T4 and TSH that are compatible with thyroid dysfunction, in particular, with various degrees of mild thyroid failure. The experts on the consensus panel did not find any studies proving that the normal thyroid test reference ranges discriminate adequately between hypo-, eu- and hyperthyroidism. On the contrary, we found studies whose data questioned the usefulness of these reference ranges, in particular, for serum TSH, T3 and T4. The data from these studies support the use of narrower ranges for these serum tests. The broader reference ranges include levels that may be consistent with thyroid dysfunction, especially in its milder forms. This is not surprising, as the reference ranges of a test are not values indicative of health, but merely values found in 95% of a population, generally the population of patients going to the laboratory. Levels compatible with both health and (thyroid) disease may be included.
- The TSH reference range: The difference between the upper and lower ends of the reference range is more than 20-fold (0.2-4.1 mIU per liter).
- In several studies, a serum TSH above 1.5 or 2 mIU per liter has been linked with increased hypothyroid-associated lipid and inflammatory pathologies (such as higher serum levels of homocysteine, cholesterol and highly sensitive CRP). These higher TSH levels have also been linked with coronary and vascular abnormalities (such as higher coronary artery diseases scores, increased risk of multi-vessel disease, increased arterial stiffness), lower birth weight, premature birth of children from mothers with TSH above 2, and an increased risk of progression from mild to overt hypothyroidism. Depending on the study, at TSH levels above 0.4 or 0.9 mIU per liter there is an increased risk of thyroid malignancy in patients with morphological abnormalities of the thyroid. The increased risk may be reversed by treatment with thyroid medication. Other disorders have been observed in patients with a serum TSH within the reference range but above the 25th percentile such as a higher risk of severe depression, a poorer response to antidepressants, an increased incidence of somatic disease, a higher body mass index, an increased waist circumference, higher systolic and diastolic blood pressures, and higher serum glucose and triglycerides. Medicating these patients who are apparently in mild thyroid failure and have a high risk of becoming overtly hypothyroid may prevent the important sequellae associated with the progression of hypothyroidism.
- Other data support the need for improved serum TSH reference ranges. If the serum TSH reference range is based upon a cohort of truly normal individuals, for example, with no personal or family history of thyroid dysfunction, no visible or palpable goiter, no medication use, no thyroid peroxidase antibodies and with fasting blood samples taken in the morning (610 AM) then the TSH reference range would be 0.42.5 mIU per liter. The data support the acceptance of a value below 3 as an upper limit for the TSH reference range. When data for subjects with positive thyroid peroxidase antibodies or a family history of autoimmune thyroid disease are excluded, the normal reference interval becomes much tighter, i.e. 0.42.0 mIU per liter.
- Moreover, the results of several investigations indicate a mean serum TSH of 1.5 mIU per liter for an iodine-sufficient population, demonstrating that the reference range of 0.1 5.1 mIU per liter is far too broad.
- Ethnic differences should also be taken into account: A study has shown the mean TSH level in African-Americans to be 1.18 mU/liter, in contrast to a mean of 1.40 mU/liter in Caucasians, due to the greater frequency of autoimmune thyroid disease in whites. This may have skewed the upper end of the TSH curve (NHANES data). For African-Americans, the TSH reference range is possibly lower than in whites.
- The American Association of Clinical Endocrinologists in 2002 therefore narrowed the serum TSH reference range to 0.3-3.0 mIU/L, lowering the upper reference end to 3. The National Academy of Clinical Biochemistry reduced the upper end of the reference range from 5.5 to 4.1 mIU per liter in 2003. The latter group also stated that more than 95% of healthy, euthyroid subjects have a serum TSH between 0.4 - 2.5 mIU per liter" and that patients with a serum TSH above 2.5 mIU per liter, when confirmed by repeat TSH measurement made after three to four weeks, may be in the early stages of thyroid failure, especially if thyroid peroxidase antibodies are detected. In 2003, the consensus panel (Endocrine Society, American Association of Clinical Endocrinologists, and American Thyroid Association) recommended a target TSH range of 1.0 to 1.5 mIU per liter in patients already receiving thyroxine therapy.
- Erroneously low TSH: Some patients may suffer from centralized hypothyroidism and will have a low TSH even with a low T4 and a low T3. TSH is currently the primary thyroid screening test recommended. In this population of patients, a hypothyroid disorder will be missed if the low TSH is not followed up by testing free T3 and free T4.
- Serum free T3 and T4 reference ranges: The difference between the upper and lower reference ends is more than two-fold (1.8-3.7 ng per liter for free T3 and 0.8-1.8 ng per deciliter for free T4). Although the size of the reference range of free, unbound thyroid hormones is less impressive than that of serum TSH, a patient whose thyroid hormones are borderline high (while still within the normal reference range) may have twice the amount of thyroid hormones in his/her blood than a patient who is borderline low (but also in the reference range of euthyroid patients). If one of these patients is clinically well, then the other probably has a thyroid dysfunction. Patients with a serum T3 in the lower third of the reference range have been documented to undergo more inflammatory processes, to have an increased risk of breast cancer and increased severity of coronary heart disease. Cardiac function has been observed to be decreased in patients with serum T3 in the lower quintile (20%) of the reference range. Studies can be found where lower serum free or total T3 levels within the reference range are correlated with increased severity of illness and/or worse prognosis of a disease, including an increased mortality rate. This is particularly true in cases of myocardial infarction, chronic heart failure and stroke. For serum T4 values within the lower half of the normal reference range in children, there are reports that maximal intellectual development has been impaired, while in the same lower half of the serum T4 range, the rate of depression in patients with Alzheimers disease appears to be significantly higher. Moreover, a serum T4 in the lower third of the reference range has been associated with increased insulin resistance, premature atherosclerosis (with significantly higher levels of CRP), increased memory loss, and increased mortality. There is enough data to support the need for a profound revision of thyroid hormone reference ranges, where narrower reference ranges with higher lower ends would provide more useful, truly healthy, reference ranges.
- Need for narrower reference ranges for thyroid tests: In light of the above data and considerations, the IHS consensus panel of experts stresses the importance of undertaking studies to establish more accurate and narrower reference ranges that reflect true euthyroidism. Narrower reference ranges allow more patients with mild thyroid failure or excess to be detected and treated. Mild thyroid failure is reflected by borderline low serum T3 and T4 and/or borderline high serum TSH. The panel is aware of at least one study in which the treatment of clinically hypothyroid, but biochemically euthyroid, patients was done using thyroxine with no beneficial result. Possibly, the dose or the type of thyroid treatment, namely thyroxine alone, was insufficient to obtain beneficial clinical results. A higher dose or a combined thyroxine-triiodothyronine medication might have been more appropriate. In one study of patients with coronary heart disease, for example, the progression of coronary atherosclerosis over one year was apparent in all patients taking 100 micrograms or less of thyroxine per day, while only one sixth of patients taking 150 micrograms or more had disease progression. Earlier studies have shown significantly better efficacy of combined thyroxin-triiodothyronine medications, compared to thyroxine alone. Improvement was found in such divergent parameters as serum cholesterol, mental and physical symptoms, and, in animals, goiter formation and intracellular triiodothyronine (T3) euthyroidism, to name a few of the possible increased benefits.
- Specific individual reference ranges: The optimal reference ranges for an individual can be different from the population reference ranges used by laboratories. Individual reference ranges are usually narrower (for example, 0.5 to 1.5 mIU per liter of serum TSH, rather than 0.2-4.1). Moreover, specific cut-off points between eu- and hypothyroidism may differ from one individual to another. One person may be euthyroid at a serum TSH of 0.5 and hypothyroid at 0.6, while another may be euthyroid at a TSH of 2 and hypothyroid at 2.1. Because of such inter-subject variations, when the results of thyroid tests dont match the clinical picture of thyroid dysfunction, the clinical impression of the experienced physician who has examined the patient should prevail and, if the patient is clinically hypothyroid, a therapeutic trial of thyroid hormones administered, starting at low doses.
- Tertiles, quartiles or quintiles of insufficiency may have to be considered to diagnosis hypothyroidism, rather than values below or above the reference range. Serum levels of thyroid hormones in the lower tertile, quartile or quintile, and serum levels of TSH in the upper half of the reference range, have been associated with increased disease and mortality rates, as mentioned above.
2) Excessive fluctuations of serum levels of T3, T4 and TSH: Differences up to three-fold in serum TSH and serum T4 have been found within the same individual during a single day. Such dramatic variations put the reliability of thyroid tests in question. At the time of the blood draw a person may be at his/her lowest TSH level, which is well under the upper reference range and looks reassuringly normal, while at other times s/he may be clearly above the upper reference range with a value consistent with subclinical or even overt hypothyroidism.
3) Thyroid dysfunction at the cellular level, undetectable by classical laboratory tests. A lack of thyroid activity may also be caused by a decline in the number, availability or affinity of thyroid nuclear cell receptors, in particular of T3. It is known from animal experiments that thyroid (T3) nuclear cell receptors decrease with age. This has also been observed in some human hormone deficiencies such as Addisons disease. A decline in cell receptors cannot be confirmed by classical thyroid tests, as tests for T3 nuclear cell receptors are not currently available in conventional laboratories. The only way to detect insufficient thyroid cell receptors is to evaluate the psychological and somatic effects of thyroid hormones on the body. This must be done through physical examination and interview, checking for hypothyroid signs and symptoms. Useful information might be deduced by testing the peripheral effects of thyroid hormones on serum parameters that increase in proportion to thyroid activity, such as serum SHBG (sex hormone binding globulin), alcalin phosphatase or osteocalcin, and/or that decrease with increasing thyroid function, such as serum total cholesterol. Alternatively, we could test for direct metabolites of T3, namely the T2s (diiodothyronines), but these tests are not yet available. Furthermore, even if thyroid hormone serum levels and receptors are optimal, vitamins, trace elements, minerals or amino acids necessary for enzyme production or function could be deficient, thereby reducing the efficacy of metabolic reactions under control of thyroid hormones.
Thyroid treatment of clinically hypothyroid, though biochemical euthyroid, patients: If a patient is clinically hypothyroid, presenting with several signs and symptoms of hypothyroidism, but is considered biochemically euthyroid, with low normal laboratory levels of serum T3 and/or T4, and/or high normal serum TSH according to the actual reference range, a trial of thyroid therapy may be started to see if the patients signs and symptoms regress under therapy. Thyroid hormone levels may be considered low normal when in the lower third or half of the reference range, while the serum TSH may be considered high normal when in the upper third or half of the actual TSH reference range (0.2-4.1 mU per liter). In these zones, the patient may be hypothyroid, as demonstrated by several studies in which hypothyroidism is reflected by upcoming disorders such as lipid, vascular, cardiac, insulin and mental disturbances, and cancer and mortality risks, and sharp increases in risk of progression to overt hypothyroidism, as discussed above. These pathologies suggest mild thyroid failure that may regress under therapy. We recommend that physicians be careful to exclude, before thyroid intervention, other pathologies that may explain the symptoms. A trial of thyroid hormones should be started at low doses that are progressively increased, and progress should be carefully evaluated, taking care that the patient is not overdosed. Is there any danger in treating thyroid dysfunction? The most common adverse effect is iatrogenic hyperthyroidism. This is caused either by overdose or intolerance. Intolerance with peaks of T3-hyperthyroidism can be caused by excess conversion of thyroxine (T4) into triiodothyronine (T3), thus accelerating thyroid activity, and is more likely to occur with other hormone deficiencies, such as an adrenal insufficiency (cortisol), a lack of estrogens, and other hormone inadequacies that stimulate the conversion of T4 to T3. Safety can be increased by starting at low doses.
Follow-up on thyroid treatment of clinically hypothyroid, though biochemical euthyroid, patients:Under treatment, most initially clinically hypothyroid (though mistakenly considered biochemically euthyroid) patients, should have normal lab values (with levels of T3, T4 and TSH inside the reference range when the tests are done more than 9 hours after taking thyroid medication). They should become clinically euthyroid. However, peak serum levels of T4 and T3 may be found that are not representative of the patients real thyroid activity during the first 9 hours after intake of thyroid medication, and some studies suggest that between 36 and 47 % of patients clinically euthyroid under thyroid therapy have an undetectable serum TSH. Conclusion: Clinically hypothyroid, though biochemically euthyroid, patients may have a mild degree of thyroid failure. Such patients may benefit from a trial with thyroid hormones starting at low doses that are progressively increased. Before commencing the trial, other pathologies that may be causing the clinical signs and symptoms should be excluded. Careful monitoring is recommended. (1).JAMA 1993, 269:2736, Thyroid, 1993; 3 (4): 353-54 Please sign here158 signatures for this petition 1 to 10 07/07/2010 Angela McGuigan United Kingdom (no comment) 07/06/2010 Lynne Maguire United Kingdom (no comment) 06/26/2010 Sue Morgan United Kingdom (no comment) 06/26/2010 Isobel Wilson Sweden (no comment) 04/22/2010 Merilyn Skorza Australia (no comment) 04/21/2010 Ul.A.Garuna, 16-6 Nadya Melyanets Belarus (no comment) 02/26/2010 Elin Hallendorff Sweden Keep up the good work! It`s really inportant what you do! 02/19/2010 Marie Ekdahl Sweden (no comment) 02/17/2010 SeK Cheong Toh Malaysia Good article. helpful to those with thyroid problems.
pls continue the good work.
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