I. Problem/Condition.

Hypothyroidism is frequently encountered by the hospitalist, whether as the primary abnormality or one of a patient’s multiple medical problems. Decreased levels of thyroid hormones, either thyroxine (T4) or triiodothyronine (T3), may occur as a result of glandular failure, systemic illnesses, and assorted medications.

Symptoms are initially mild, or even absent, and are non-specific manifestations of decreased metabolism including fatigue, weight gain, weakness, depression, and cold intolerance. Dry skin, constipation, headaches, arthralgia, myalgia, paresthesia, and menorrhagia may also occur.

Myxedema crisis, the extreme of symptomatic hypothyroidism, is life-threatening and includes vital sign abnormalities such as bradycardia, diastolic hypertension, hypothermia and symptoms such as edema, dyspnea, and altered mental status including psychosis and coma.

Increasingly recognized as a factor in cardiovascular health, subclinical hypothyroidism may affect up to 20% of the general population and is often asymptomatic or associated with very minimal symptoms.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The presenting symptoms for hypothyroidism are varied and diverse, and each of those symptoms has its own differential. It is the constellation of the above symptoms that brings to mind hypothyroidism though other possibilities could include other thyroid diseases, pituitary adenoma, adrenal disease, and infectious mononucleosis.

Once a diagnosis of hypothyroidism has been established there are several considerations for its underlying etiology. Primary hypothyroidism from thyroid gland disease is by far the most common etiology. Globally, iodine-deficiency is the leading cause of hypothyroidism though in iodine-sufficient regions, Hashimoto’s thyroiditis is the most frequent etiology. Primary hypothyroidism may also arise after the “burnout” of an initial hyperthyroid phase in other viral and autoimmune thyroiditides (e.g., painless post-partum thyroiditis).

Central hypothyroidism results from pituitary insufficiency. Euthyroid sick syndrome is a transient abnormality in thyroid function tests due to a non-thyroidal illness. This occurs for varying reasons. In acute, mild diseases there is decreased conversion of T4 to the biologically active T3. In severe illness and sepsis, degradation of T4 and transient central hypothyroidism occur in addition to drastic decreases in T3 from various mechanisms. Rarely, a true secondary hypothyroidism from central suppression due to prolonged dopamine therapy may occur.

Thyroid disease may also occur secondary to medication. Both lithium and amiodarone are two iodine-containing agents commonly implicated in causing true thyroid dysfunction due to changes in iodine metabolism. In most cases, medication interactions cause a false hypothyroidism (changes in thyroid function tests without thyroid disease). This occurs secondary to changes in thyroid hormone metabolism such as the anti-epileptics phenytoin, carbamazepine, and phenobarbital increasing the clearance of T4.

Lastly, structural diseases included in the differential include thyroid damage from radiation therapy or post-surgical absence of thyroid tissue.

B. Describe a diagnostic approach/method to the patient with this problem

History and physical exam are used both to identify possible cases of hypothyroidism and differentiate straight-forward disease from the emergency of myxedema crisis. Once suspicion of hypothyroidism arises, laboratory tests and imaging can diagnose both the disease and its underlying etiology.

1. Historical information important in the diagnosis of this problem.

Beyond a comprehensive review of symptoms, important items from the patient’s medical history include any recent or concurrent illnesses, changes in medications, or other recent treatments. An active medication list (both home and inpatient, as appropriate) also lends important information toward potential etiologies. Personal history of thyroid surgery or chest/neck radiation would suggest structural disease. Personal or family history of thyroid or other autoimmune diseases point toward Hashimoto’s disease or another autoimmune thyroiditis, while growing up in and/or recently moving from an iodine-deficient region makes iodine-deficiency a more plausible explanation.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

In early hypothyroidism, physical exam findings may include dry skin, brittle hair and nails, and pallor or yellowing of the skin. Diastolic hypertension and delayed deep tendon reflexes may also be noted. Beyond depression of vital signs, physical exam findings concerning for advanced hypothyroidism include thickening of the skin and edema (myxedema), especially of the eyelids and face, peripheral edema, and decreased breath and/or heart sounds as in pleural or pericardial effusion. Altered mental status may include psychosis, stupor or coma.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Thyroid stimulating hormone (TSH) is the initial laboratory screening test to assess for thyroid dysfunction and is elevated in most cases of hypothyroidism. Checking the level of free T4 (fT4) and testing for anti-thyroperoxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies are part of the further work-up to diagnose etiology of the hypothyroidism. Though not generally part of the necessary evaluation for hypothyroidism, total T4 and T3 are occasionally used in monitoring and are required tests to differentiate euthyroid sick syndrome from true thyroid disease in critically ill patients.

Other potential laboratory abnormalities include positive antinuclear antibody (ANA), hyponatremia, hypoglycemia, anemia, elevated low-density lipoprotein (LDL) and creatine kinase (CK). Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be noted in DeQuervain’s thyroiditis. A thyroid ultrasound is useful in evaluating an enlarged thyroid gland to distinguish discrete nodules or multinodular goiter. Heterogeneous enlargement and hypoechogenicity are ultrasound findings consistent with Hashimoto’s disease.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Primary and central hypothyroidism are differentiated by TSH, which is elevated in primary hypothyroidism while central or pituitary causes yield an inappropriately normal or decreased TSH. FT4 is low or low-normal in both cases. In the majority of cases of Hashimoto’s thyroiditis, anti-TPO is positive and anti-Tg may also be elevated.

Euthyroid sick syndrome may manifest with a variety of laboratory values. TSH is often initially elevated, with levels up to 20 mIU/L; in the acute setting, elevations beyond that level are usually accompanied by underlying permanent thyroid disease. In euthyroid sick syndrome, T4 is often normal though T3 is decreased; TSH decreases to normal or low values with prolonged non-thyroidal illness.

Events or circumstances such as pregnancy or medications/medical treatments rather than specific laboratory tests are the main means of diagnosing less frequent causes of hypothyroidism or abnormal thyroid function tests. Further confirmation is provided when symptoms/abnormalities resolve with discontinuation of the implicated agent.

Myxedema coma can occur with hypothyroidism of any etiology though is most frequently seen in elderly women and is often associated with cessation of thyroid supplementation or precipitants such as infection, ischemia/infarction, cold exposure, and medications such as high-dose opioids or occasionally amiodarone- or lithium-associated thyroid disease.

Subclinical hypothyroidism is characterized by an elevation in TSH with normal levels of thyroid hormones.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

In the hospital setting there are only a few occasions when thyroid function testing is necessary beyond TSH, fT4, and perhaps thyroid antibodies. Given the changes in thyroid function tests during acute illness, further evaluation is indicated only in critically ill patients in whom true thyroid disease needs to be differentiated from euthyroid sick syndrome. In that situation, checking levels of T3 and total T4 are an appropriate addition to TSH and fT4 values. As an elevation of TSH up to 20 mIU/L can be associated with acute illness such as sepsis, further evaluation to look for underlying thyroid disease is indicated when the TSH is greater than 20 mIU/L.

III. Management while the Diagnostic Process is Proceeding

A. Management of hypothyroidism.

Emergencies in hypothyroidism are uncommon with the main exception being myxedema crisis which is treated with thyroid hormone replacement as well as hydrocortisone intravenously until adrenal insufficiency can be ruled out. Intravenous loading of T4 with 400 mcg bolus is followed by continued intravenous T4 therapy daily until oral therapy can safely be initiated (50-100 mcg, depending on underlying cardiovascular risk factors and age). Though somewhat controversial, recommendations are also generally for intravenous therapy with T3 (as it is the biologically active form) for approximately 48 hours (5-10 mcg every 8 hours).

Concurrent supportive therapy addresses precipitants such as infection, medications, and cerebrovascular disease as well as symptoms such as hypothermia and hypotension. Aggressive antibiotics, gradual passive re-warming (to avoid cardiac complications of vasodilation), and blood pressure support are all appropriate. Hypotension not responsive to fluids should be treated with pressors until thyroid hormone levels rise. Hyponatremia is often present so care when administering fluids is needed to avoid worsening that state. Caution needs to be used in administering opioids as the underlying myxedema crisis makes patients exquisitely sensitive such that normal dosages may be fatal.

Whether in the hospital or outpatient setting, standard long-term treatment of hypothyroidism is with levothyroxine to replace the decreased fT4. Like in the acute cases, addressing possible adrenal insufficiency is important and should be ruled out before initiation of therapy. Starting doses of levothyroxine are weight-based and lower for elderly patients or those with underlying coronary artery disease (1.7 mcg/kg in young and middle-aged adults; 1 mcg/kg in elderly and cardiac disease). Dosages are titrated up every 2-3 weeks until the patient is asymptomatic with goal TSH between 0.4 and 2 mIU/L. Level of T4 should peak by 3-4 weeks of appropriate therapy.

What's the evidence?

Truter, I. “Clinical review: hyper- and hypothyroidism”. S Afr Pharm J. vol. 78. 2011. pp. 10-14.

Economidou, F,, Douka, E,, Tzanela, M,, Nanas, S. “Thyroid function during critical illness.”. Hormones. vol. 10. 2011. pp. 117-124.

Mitchell, JE,, Hellkamp, AS,, Mark, DB,, Anderson, J. “Thyroid Function in Heart Failure and Impact on Mortality.”. JACC Heart Fail. vol. 1. 2013. pp. 48-55.

Selmer, C,, Olesen, JB,, Hansen, ML,, von Kappelgaard, LM. “Subclinical and Overt Thyroid Dysfunction and Risk of All-Cause Mortality and Cardiovascular Events: A Large Population Study.”. J Clin Endocrinol Metab. vol. 99. 2014. pp. 2372-82.

Pearce, EN,, Farwell, AP,, Braverman, LE. “Thyroiditis”. N Engl J Med. vol. 348. 2003. pp. 2646-2655.

Stathatos, N,, Daniels, GH. “Autoimmune thyroid disease”. Curr Opin Rheumatol. vol. 24. 2012. pp. 70-75.

Barbesino, G. “Drugs Affecting Thyroid Function”. Thyroid. vol. 20. 2010. pp. 763-770.

Fitzgerald, PA, McPhee, SJ,, Papadakis, MA. “Endocrine Disorders”. Current Medical Diagnosis & Treatment. 2010.

Jameson, JL,, Weetman, AP, Fauci, AS,, Braunwald, E,, Kasper, DL,, Hauser, SL,, Longo, DL,, Jameson, JL,, Loscalzo, J. “Disorders of the Thyroid Gland”. Harrison’s Principles of Internal Medicine. 2008.

Vivek, M,, Misgar,, RA,, Ghosh, S,, Mukhopadhyay, P,, Roychowdhury, P,, Pandit, K,, Mukhopadhyay, S,, Chowdhury, S., Myxedema, Coma. “A New Look into an Old Crisis”. J Thyroid Res. 2011. pp. 1-7.