HYPOTHYROIDISM

HYPOTHYROIDISM

Current Diagnosis

• Hypothyroidism is more common in women as they age.

• The signs and symptoms of hypothyroidism are nonspecific and can mimic other diseases found in the elderly, so clinicians need to have a high index of suspicion.

• The key diagnostic test is to find a low free T4. The presence of an elevated TSH indicates primary hypothyroidism, and a low TSH indicates secondary hypothyroidism.

• There is insufficient evidence for screening for hypothyroidism in asymptomatic adults.

Current Therapy

• Thyroxine replacement with l-thyroxine (Synthroid, Levoxyl) is the treatment for hypothyroidism. Medication should be titrated to normalize the thyroid-stimulating hormone (TSH) level, which is usually achieved at an overall dose of 100 to 150 µg.

• Initial dosing for those with potential cardiac disease should be started low (25–50 µg/day) and advanced slowly every 6 to 8 weeks.

• Partial substitution of triiodothyronine (Cytomel) for thyroxine should be reserved for elderly patients with persistent neurocognitive dysfunction despite normalization of their TSH.

• Patients who have subclinical hypothyroidism with a TSH greater than 10.0 should be considered for treatment. Patients with a TSH lower than this do not require therapy.

Epidemiology

Hypothyroidism is second only to diabetes in the prevalence of endocrine disorders in adults in the United States. Hypothyroidism occurs in up to 18/1000 population, with women outnumbering men by approximately 10:1. Rates of hypothyroidism increase dramatically with age, so that about 2% to 3% of all older women have hypothyroidism, and the prevalence is up to 5% in nursing home populations.

Risk Factors

Thyroid conditions are more common in patients who have a family history of thyroid disorders. In addition, hypothyroidism as well as thyroid cancers are more common in patients who had neck irradiation in childhood. However, most cases of hypothyroidism occur in people who have no risk factors.

Pathophysiology

Several conditions can lead to hypothyroidism (Box 1). Two categories, hypothyroidism following thyroiditis and iatrogenic hypothyroidism secondary to treatment of Graves’ disease, account for the overwhelming majority of cases of hypothyroidism in the United States.

Box 1  
Conditions Causing Hypothyroidism
Thyroiditis

Hashimoto’s thyroiditis

Subacute granulomatous thyroiditis (de Quervain’s thyroiditis)

Subacute lymphocytic thyroiditis (silent or painless thyroiditis)

Iatrogenic Hypothyroidism

Radioactive iodine treatment of Graves’ disease

Thyroidectomy

Secondary Hypothyroidism (Pituitary Dysfunction)

Pituitary surgery

Intercranial radiation

Congenital panhypopituitarism

Other Causes

Infiltratative diseases (sarcoidosis, amyloidosis, hemochromatosis)

Drugs (lithium, interferon, amiodarone [Cordarone])

Iodine deficiency

The most common non-iatrogenic condition causing hypothyroidism in the United States is Hashimoto’s thyroiditis. Most idiopathic hypothyroidism also represents Hashimoto’s thyroiditis that has followed an indolent course. Hashimoto’s thyroiditis, also called chronic lymphocytic thyroiditis, is the most common of the inflammatory thyroid disorders and the most common cause of goiter in the United States. The prevalence of Hashimoto’s thyroiditis has been increasing dramatically since the 1960s in the United States, but the cause for this rise is unknown. In patients with acute thyroiditis, either subacute granulomatous (also known as de Quervain’s) and subacute lymphocytic (also known as silent or painless), transient hypothyroidism is common following an acute attack, and 10% of these patients also develop long-term hypothyroidism.

Another common cause of hypothyroidism is a medical intervention to treat Graves’ disease or thyroidectomy for chronic fibrocytic thyroiditis (Riedel’s struma). Radioactive iodine ablation of the thyroid for Graves’ disease often results in underproduction of thyroxine in the remaining tissue, necessitating thyroid replacement.

A third uncommon cause of hypothyroidism that should not be overlooked is secondary hypothyroidism due to hypothalamic or pituitary dysfunction. These conditions are seen primarily in patients who have received intracranial irradiation or surgical removal of a pituitary adenoma.

Finally, a variety of other conditions including infiltration of the thyroid (amyloidosis, sarcoidosis), iodine deficiency, or medications (such as amiodarone [Cordarone] or interferon) can cause hypothyroidism.

Prevention

There are no known interventions to prevent hypothyroidism. According to their 2015 analysis, the U.S. Preventive Services Task Force found insufficient evidence to support early detection through routine screening of asymptomatic persons.

Clinical Manifestations

Individual who have hypothyroidism can present with a variety of symptoms, many of which are not specific. Consequently, clinicians must have a high index of suspicion for hypothyroidism when patients come in with any one or combination of the symptoms that could signal hypothyroidism.

Symptoms of hypothyroidism include lethargy, weight gain, hair loss, dry skin, constipation, poor concentration, trouble thinking or forgetfulness, and depression (Box 2). In older patients, hypothyroidism easily can be confused with Alzheimer’s disease or other conditions that cause dementia. Patients who present with depression also should have their thyroid function assessed.

Box 2  
Symptoms and Signs of  Hypothyroidism
Common Symptoms

Lethargy

Weight gain

Constipation

Slowed mentation, forgetfulness

Depression

Hair loss

Dry skin

Neck enlargement or goiter

Physical Examination Findings

Goiter

Low blood pressure and slow pulse

Hair thinning or loss

Dry skin

 

Confusion

Depressed affect

Non-pitting edema

The thyroid examination in most patients with hypothyroidism is completely normal. Patients might have a painless goiter; tenderness in the thyroid is generally a sign of active inflammation consistent with acute thyroiditis. Once the thyroid inflammation has subsided, thyroid function might return to normal. Other physical findings that can occur with hypothyroidism include low blood pressure, bradycardia, nonpitting edema, generalized hair loss especially along the outer third of the eyebrows, dry skin, and a lag in the relaxation phase of reflexes that can be assessed most easily in the ankle jerk reflexes.

Diagnosis

The diagnosis of hypothyroidism is based on finding a low free thyroxine (T4) level, usually with an elevation in the thyroid stimulating hormone (TSH) levels. For patients with hypothyroidism due to pituitary dysfunction, also called secondary hypothyroidism, both the free T4  and the TSH levels are low.

One situation where clinicians need to be wary is evaluating thyroid status in patients who are severely ill. During times of acute physiologic stress, patients may have mildly elevated TSH levels that suggest hypothyroidism but are, in fact, euthyroid. This condition, called euthyroid sick syndrome, does not require treatment with thyroid replacement and resolves within a few weeks of recovery, but it may be difficult to distinguish from preexisting or new-onset hypothyroidism. Clinicians need to use other clinical symptoms to try to differentiate euthyroid sick syndrome from hypothyroidism. Even though it does not require treatment, the presence of euthyroid sick syndrome in a critically ill patient is a poor prognostic sign.

In contrast to hyperthyroidism, there is no role for thyroid scans or iodine uptake testing in patients with hypothyroidism. The only exception to this is when the clinician identifies a mass on physical examination. In that situation, scanning or other imaging is essential to determine the malignancy potential of the mass.

Differential Diagnosis

The differential diagnosis for hypothyroidism is broad and depends on the primary complaints given by patients. For patients with slowed mentation, depressed affect, or confusion, clinicians should suspect depression. Patients with lethargy and a slow pulse and low blood pressure might have adrenal insufficiency. Patients with constipation need to have colonic obstruction from a mass considered as well. In the elderly, common drugs that can cause depression (such as centrally acting antihypertensive agents), bradycardia (such as β- blockers or calcium channel blockers), constipation (calcium channel blockers), hair loss, or confusion also should be considered.

In patients with pituitary failure, other pituitary hormones are likely to be deficient as well, so clinicians should look for evidence of adrenal and gonadotropic failure.

Treatment

The treatment for hypothyroidism is thyroxine replacement (Synthroid, Levoxyl). The usual dose required to achieve full replacement is between 100 µg and 150 µg, although patients who are treated with radioactive iodine and have some remaining thyroid activity might require lower doses. For patients with known heart disease or at risk for heart problems, doses should be initiated at 25 to 50  µg with increases of 25 µg every 4 to 6 weeks guided by TSH levels. Young patients who are at low risk for cardiac problems can be started at doses of 100 µg.

In choosing an agent to use for thyroid replacement, there is good evidence that generic substitutes are just as effective as brand-name drugs. A detailed study examining the metabolic effectiveness of a variety of generic drugs compared to a brand-name medication demonstrated no clinical or subclinical differences among preparations. So even though clinicians often hear that they should use a brand-name drug to maintain the stability of the replacement dose, this is not supported by the evidence.

One area of uncertainty is whether the addition of triiodothyronine (T3, Cytomel) adds additional benefit to thyroid replacement with thyroxine. In some studies with elderly patients, subjects with continued neurocognitive dysfunction benefited from the addition of T3 at a dose of 125 µg, with a concomitant decrease in the T4 dose of 50 µg. However, subsequent studies of younger patients (aged 29–44 years) failed to find any benefits of partial T3 substitution.

Furthermore, studies of patients on doses of T4 adequate to restore TSH levels to normal have been found to have normal T3  levels. At this time, routine use of T3 cannot be recommended; however, for selected elderly patients who have lingering confusion, depression, or slow mentation on adequate doses of T4, a trial of T3 partial substitution might be tried.

Another situation where there is controversy is the use of thyroid replacement in patients with a mildly elevated TSH and a normal free T4. This condition, called subacute hypothyroidism or mild hypothyroidism, is more common in white elderly women. Some studies have shown clinical improvement in symptoms when low doses of T4 are given to these patients, although the patient populations tend to be those with preexisting thyroid disease (such as Graves’ disease), and studies have had only a small number of patients. An expert panel has suggested using the TSH level as an indication for therapy. Patients with a TSH less than 10 do not require any therapy. Treatment is reasonable in those with a TSH level of 10.0 because these patients may be most symptomatic and have a progression to overt hypothyroidism of 5%.

Monitoring

In general, once a patient receives a full replacement dose of T4 (usually between 100 and 150 µg) and has a TSH consistently in the normal range, there is little likelihood that their thyroid requirement will change over time. Although many advocate annual retesting of TSH to ensure patients are euthyroid, there is no evidence to show this is necessary.

Some conditions do warrant closer monitoring of the TSH level.

Because T4 and T3 are highly protein bound, any conditions where a patient’s serum protein status changes should prompt additional testing. This includes conditions that lower serum protein levels, such as liver disease, nephrotic syndrome, or malnutrition, as well as those where serum proteins are increased, such as pregnancy or initiation of estrogen therapy. Because patients’ dietary protein usually decreases with advancing age, older patients whose diet declines can also require monitoring and a lowering of their T4 dose over time.

Patients with subclinical hypothyroidism also might benefit from annual retesting of their free T4 levels. Approximately 10% of patients with subacute hypothyroidism progress to hypothyroidism within 3 years of diagnosis. Because of this, yearly testing is recommended.

Also, 50% of patients with subacute hypothyroidism have positive anti-thyroid antibodies; however, routine testing for these is not recommended.

Complications

Most of the complications of hypothyroidism are associated with undertreatment or overtreatment. Patients with inadequately treated hypothyroidism are at higher risk for cardiac disease. On the other hand, over-replacement of thyroxine increases the risk of both atrial fibrillation and osteoporosis.

In addition, Hashimoto’s thyroiditis is associated with other endocrine autoimmune diseases such as Addison’s disease and pernicious anemia. Clinicians should be aware of these associations and not overlook new endocrine disorders that might have clinical features similar to hypothyroidism.

Finally, patients with Hashimoto’s hypothyroidism also are at higher risk for the future development of lymphoma. Clinicians should educate patients about the need to have newly enlarged lymph nodes evaluated and be aggressive about evaluating symptoms or signs consistent with the development of a lymphoma.

References

1.     Bunevicius R., Kazanavicius G., Zalinkevicius R., Prange A.J. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340:424–429.

2.    Dong B.J., Hauck W.W., Gambertoglio J.G., et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA. 1997;277:1205–1213.

3.     Helfand M., Crapo L.M. Screening for thyroid disease. Ann Intern Med. 1990;112:840–849.

4.    Sawin C.T., Chopra D., Azizi F., et al. The aging thyroid. Increased prevalence of elevated serum thyrotropin levels in the elderly. JAMA. 1979;242:1386–1388.

5.     Surks M.I., Ortiz E., Daniels G.H., et al. Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2):228–238.

6.      U.S. Preventive Services Task Force: Screening for thyroid disease. Available at http://www.ahrq.gov/clinic/uspstf/uspsthyr.htm [accessed July 11, 2015].

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