Endocrinology Metabolism

Subclinical hypothyroidism

Are you sure the patient has subclinical hypothyroidism?

Subclinical hypothyroidism is usually detected in patients who have had thyroid function testing performed due to symptoms of hypothyroidism. Despite a name that suggests a requirement for an absence of symptoms, subclinical hypothyroidism is purely a biochemical diagnosis. It is defined by finding an elevated thyroid stimulating hormone (TSH) level with normal free thyroxine (free T4) levels.

Patients may have any of the myriad of signs and symptoms of hypothyroidism or none at all.

The causes of subclinical hypothyroidism are the same as those of (overt) hypothyroidism and include chronic lymphocytic (Hashimoto's) thyroiditis, partial thyroidectomy, radioactive iodine therapy, and damage to the thyroid from radiation treatment. Overtreatment with anti-thyroid medications, undertreatment with thyroid hormone replacement, and iodine-containing medications such as amiodarone may also lead to subclinical hypothyroidism.

What else could the patient have?

It is important to consider the clinical context in which the thyroid testing was performed. Thyroid function testing suggesting subclinical hypothyroidism may be transient in two types of clinical conditions:

Acute inflammation of the thyroid can cause the release of preformed thyroid hormones from the gland in one of several types of thyroiditis (subacute, silent, or postpartum). After these thyroid hormones are cleared from the body, there is a recovery period during which new thyroid hormone is synthesized. Patients may have testing consistent with subclinical hypothyroidism during this recovery period. Not all patients present for clinical attention during the initial hyperthyroid phase, and their first presentation may only be during this recovery period.

Patients with recent severe illness, particularly those in the intensive care unit, may have low thyroid hormone levels due to nonthyroidal illness. During recovery from the primary illness, thyroid function tests also recover. TSH may appropriately be elevated to stimulate the normalization of thyroid hormone levels, and subclinical hypothyroidism may be detected during this window of time.

Key laboratory and imaging tests

Because subclinical hypothyroidism due to thyroiditis or nonthyroidal illness usually spontaneously resolves, repeat thyroid function testing 1-3 months after initial testing, consistent with subclinical hypothyroidism, will confirm this. This testing should include serum TSH and free T4 levels. Serum total or free triiodothyronine (T3) levels are not indicated, nor are thyroid ultrasound or thyroid nuclear uptake and scan.

Other tests that may prove helpful diagnostically

Testing for serum anti-thyroid peroxidase (anti-TPO) antibodies may be helpful in suggesting the underlying etiology of subclinical hypothyroidism and the likelihood of progression to overt hypothyroidism. Positive anti-TPO antibodies are more likely to be found in chronic lymphocytic, silent, and postpartum thyroiditis. Observational studies of the natural history of subclinical hypothyroidism show a higher rate progression to overt hypothyroidism in those with positive anti-TPO antibodies than in those with negative anti-TPO antibodies.

Management and treatment of the disease

All women with subclinical hypothyroidism who are pregnant or who are trying to conceive should be treated with levothyroxine therapy without the 1-3 month delay indicated for other patient populations, regardless of their degree of TSH elevation. Untreated subclinical hypothyroidism may be associated with adverse obstetric and/or neonatal outcomes, including fetal and neonatal death.

Patients who are taking anti-thyroid drugs or thyroid hormone should have their medications adjusted to normalize TSH levels.

In all other patient populations, if repeat testing confirms subclinical hypothyroidism, either treatment or ongoing monitoring can be considered.

The degree of TSH elevation is helpful in determining which patients should be treated. Those with higher TSH levels more closely resemble patients with overt hypothyroidism and those with lower TSH levels more closely resemble euthyroid individuals. All patients with TSH levels of 10 mU/L or higher should be treated, regardless of symptoms, because of a higher risk of progression to overt hypothyroidism and development of cardiovascular disease if left untreated, and an improvement in symptoms with treatment.

There is some evidence to suggest that these risks and benefits are present to a milder degree in those whose TSH levels range from 7.0 to 9.9 mU/L, and, unless the patient strongly prefers continued monitoring, treatment should be initiated in this TSH range as well.

Most patients with subclinical hypothyroidism have TSH levels that are below 7.0 mU/L, a range in which treatment is controversial. In addition, TSH levels of 5 and 6 mU/L are very common in patients aged 70 years and older; these patients were not included in therapeutic clinical trials and they may also be more susceptible to risks from over-replacement.

There are no data from large randomized trials with clinical endpoints. Evidence from smaller trials and observational data do not suggest clinical benefit to initiating thyroid replacement therapy in those with TSH levels below 7.0 mU/L. However, a therapeutic trial may be considered in symptomatic patients, with a target TSH in the lower half of the reference range. If symptoms do not resolve within several months of TSH levels in the euthyroid range, levothyroxine therapy should be discontinued and other etiologies of individual symptoms should be explored.

For patients in whom treatment is indicated, levothyroxine (LT4) is the treatment of choice. The usual starting dose is 25 to 50 mcg daily, with upward dose titration at 6-8 week intervals, until TSH levels are in the lower half of the reference range. The average levothyroxine dose requirement in subclinical hypothyroidism is 0.5 mcg/kg/day. There is no role for T3-containing preparations in the management of subclinical hypothyroidism.

For patients who are being monitored with sequential testing, TSH levels should be obtained at 6-12 month intervals (sooner if new symptoms develop).

What’s the Evidence?/References

Biondi, B, Cooper, DS. "The clinical significance of subclinical thyroid dysfunction". Endocr Rev. vol. 29. 2008. pp. 76-131.

(This comprehensive review presents all of the studies of subclinical hypothyroidism through the time of publication.)

Surks, MI, Ortiz, E, Daniels, GH, Sawin, CT, Col, NF. "Subclinical thyroid disease: scientific review and guidelines for diagnosis and management". JAMA. vol. 291. 2004. pp. 228-38.

(These are the most recent management guidelines from an expert panel.)

Gharib, H, Tuttle, RM, Baskin, HJ, Fish, LH, Singer, PA. "Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society". J Clin Endocrinol Metab. vol. 90. 2005. pp. 581-5.

(This is a response to the guidelines from the expert panel.)

Diez, JJ, Iglesias, P. "Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure". J Clin Endocrinol Metab. vol. 89. 2004. pp. 4890-7.

(Observational study of patients with subclinical hypothyroidism showing increased risk of progression to overt hypothyroidism at higher levels of TSH and increased risk of reversion to euthyroidism at lower levels of TSH.)

Vanderpump, MP, Tunbridge, WM, French, JM, Appleton, D, Bates, D. "The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey". Clin Endocrinol (Oxf). vol. 43. 1995. pp. 55-68.

(Observational study of the natural history of subclinical hypothyroidism, with 20 years of follow-up. Annual incidence of overt hypothyroidism was 2.6% in those with elevated TSH and 4.3% in those with both elevated TSH and positive anti-TPO antibodies.)

Rodondi, N, den Elzen, WP, Bauer, DC, Cappola, AR, Razvi, S. "Subclinical hypothyroidism and the risk of coronary heart disease and mortality". JAMA. vol. 304. 2010. pp. 1365-74.

(Meta-analysis of eleven observational studies demonstrating increased risk of coronary heart disease and cardiovascular death in those with subclinical hypothyroidism with TSH levels greater than 10 mU/L, increased risk of cardiovascular death in those with TSH levels of 7.0-9.9 mU/L, and no cardiovascular risk in the 4.5-6.9 mU/L range.)

Surks, MI, Hollowell, JG. "Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism". J Clin Endocrinol Metab. vol. 92. 2007. pp. 4575-82.

(Data from the National Health and Nutrition Examination Survey (NHANES) in people without underlying thyroid disease showing a shift in the TSH distribution to higher levels with increasing age.)

Gussekloo, J, van, EE, de Craen, AJ, Meinders, AE, Frolich, M. "Thyroid status, disability and cognitive function, and survival in old age". JAMA. vol. 292. 2004. pp. 2591-9.

(Study of men and women aged 85 years showing no difference in disability or cognitive function between those with subclinical hypothyroidism and euthyroid individuals, and decreased mortality in those with higher TSH levels.)

Abalovich, M, Amino, N, Barbour, LA, Cobin, RH, De Groot, LJ. "Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. vol. 92. 2007. pp. S1-47.

(These guidelines include management of subclinical hypothyroidism during pregnancy.)
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