Article Author:
Nikita Patil
Article Editor:
Ishwarlal Jialal
1/7/2019 11:39:26 AM
PubMed Link:


The thyroid gland located in the anterior neck secretes thyroid hormones. It is essential for multiple metabolic functions spanning almost every organ system. Hypothyroidism results from low levels of thyroid hormone. It has varied etiology and manifestations. Clinicians treat hypothyroidism with levothyroxine. Untreated hypothyroidism increases morbidity and mortality. This article reviews etiology, clinical presentation, diagnosis, and management of hypothyroidism.


The most common etiology is iodine deficiency in iodine-deficient geographic areas worldwide. Autoimmune thyroid diseases are the leading cause of hypothyroidism in the United States and the iodine-sufficient regions. Etiology can be influenced locally by iodine fortification and emergence of new iodine-deficient areas.[1]

Other common causes of hypothyroidism are drugs such as amiodarone and lithium,[1] thyroid radioactive iodine therapy or thyroid surgery, radiotherapy to head or neck area, and central hypothyroidism from neoplastic, infiltrative, inflammatory, or iatrogenic disorders of the pituitary or hypothalamus.[2]


The NHANESIII (National Health and Nutrition Examination Survey) study found the prevalence of overt hypothyroidism among US adults (12 years of age and older) to be 0.3% and subclinical hypothyroidism 4.3%. Female gender and increasing age were associated with higher thyroid-stimulating hormone (TSH) and prevalence of antithyroid antibodies.[3]


The hypothalamus secretes thyrotropin-releasing hormone (TRH) that stimulates the pituitary gland to produce thyroid-stimulating hormone (TSH). Thyroid-stimulating hormone stimulates the thyroid gland to produce and secrete mainly T4 while T3 is produced mainly by conversion of T4 to T3. Levels of T3 and T4, in turn, exert a negative feedback on the production of TRH and TSH. Alteration in structure and function of any of these organs or pathways can result in hypothyroidism.


Predominant T-cell lymphocytic infiltration is seen in autoimmune thyroid disease.[2] Co-existing or associated malignancy such as papillary thyroid cancer can also be seen.[4]

History and Physical

It is important to maintain a high index of suspicion for hypothyroidism since the signs and symptoms can be mild and nonspecific and different symptoms may be present in different patients.

Inquire about dry skin, voice changes, hair loss, constipation, fatigue, muscle cramps, cold intolerance, sleep disturbances, menstrual cycle abnormalities, weight gain, galactorrhea.[2] Also obtain a complete medical, surgical, medication and family history.

History of adverse pregnancy and neonatal outcomes should also be sought.[5]

Symptoms of depression, anxiety, psychosis, cognitive impairments such as memory loss can be present.[6] Rarely patients can present with ascites,[7] rhabdomyolysis, and pericardial effusion.[8]

Patients can also present with carpal tunnel syndrome, sleep apnea, hyponatremia, Hypercholesterolemia, congestive heart failure, and prolonged QT interval.[2]

A physical examination may reveal an enlarged thyroid gland, the presence of nodules, prolonged ankle reflex relaxation time, hoarse voice, and skin and hair changes.[2]


Serum TSH level is used to screen for primary hypothyroidism in most patients. In overt hypothyroidism, TSH levels are elevated, and free T4 levels are low. In subclinical hypothyroidism, TSH levels are elevated, and free T4 levels are normal.[2]

Central hypothyroidism is of pituitary or hypothalamic origin. TSH produced can be biologically inactive and can affect the levels of bioactive TSH, hence diagnosis of central hypothyroidism should be based on free T4 rather than TSH.[2]

Labs should include evaluation for autoimmune thyroid diseases with levels of anti-thyroid antibodies: the thyroid peroxidase antibodies and anti-thyroglobulin antibodies. Particularly in patients with thyroid nodules, fine-needle aspiration biopsy should be considered.[2]

Patients with subclinical hypothyroidism and thyroid peroxidase antibody positivity have a greater risk of developing overt hypothyroidism[2] and should be followed up periodically with clinical evaluation and lab tests for the same.

T3 levels are not a reliable or recommended test. Hospitalized patients should undergo TSH testing only when thyroid dysfunction is suspected.[2]

On labs, hyperlipidemia, elevated serum CK, elevated hepatic enzymes, anemia can be present.[2]

BUN, creatinine, and uric acid levels can also be elevated.[9]

Treatment / Management

Hypothyroidism is mainly treated with levothyroxine monotherapy.[10]

Thyroid replacement treatment can exacerbate co-existing adrenal insufficiency. Patients with known or suspected adrenal insufficiency should be tested and treated for the adrenal insufficiency while awaiting results.[2] Adrenal insufficiency can also be associated with subclinical hypothyroidism that is reversible with treatment of adrenal insufficiency.[11] In patients who have confirmed adrenal insufficiency consider a reassessment of thyroid tests following adequate treatment of adrenal insufficiency.

Replacement levothyroxine dose is 1.6 mcg/kg per day, should be taken 60 minutes before a meal and at least 3 hours post-meal which makes before breakfast or at bedtime the practical times for most patients. Maintaining a consistent formulation or brand of levothyroxine is important.[10]

When switching to the intravenous (IV) form, reduce the dose to 70% of the oral dose. Malabsorption syndromes, medications such as sucralfate, calcium preparations, and bile acid sequestrants can interfere with the absorption of levothyroxine.[2]

Based on the 2012 Clinical Practice Guidelines for Hypothyroidism in Adults by American Association of Clinical Endocrinologists and the American Thyroid Association, therapy should be monitored and titrated based on TSH measurements. Serum free T4 can also be used. Labs should be drawn every 4 to 8 weeks until target levels are achieved after starting the treatment, after any dose changes, changes in formulation or brand of levothyroxine,[2] after starting or stopping of any medications that may affect levels. If stable, then monitoring interval can be extended to 6 months, and if stable then, further monitoring can be extended to 12 months or can be done at shorter intervals on a case-to-case basis along with clinical evaluation.[2] Central hypothyroidism should be monitored based on free T4 rather than TSH.[2]

For elderly patients and patients with cardiac diseases, starting at a lower dose and titrating slowly is recommended.[10] Patients with cardiac disease should be monitored for the development of any symptoms of angina.[2] Monitor for side effects of treatment such as atrial fibrillation and osteoporosis.[10]

Effective treatment should achieve a clinical improvement of signs and symptoms, along with an improved sense of patient well-being and normal TSH (or free T4 levels as applicable).[12]

A comprehensive differential diagnosis workup is recommended for unresolved symptoms in the presence of biochemical euthyroidism. There is a lack of strong evidence supporting the routine inclusion of triiodothyronine (T3) preparations with levothyroxine in the treatment of hypothyroidism.[13]

If symptoms persist despite normalization of TSH/free T4 levels, then consultation with an endocrinologist should also be considered.

Differential Diagnosis

Differential diagnosis is based on signs and symptoms; for example, fatigue can point to iron deficiency anemia, sleep apnea, depression, and rheumatological diseases.[13]


Myxedema coma is a presentation of severe hypothyroidism and is an endocrine emergency. Early recognition and prompt treatment in the intensive care unit (ICU) is essential, and even then, mortality reaches 25% to 60%.[14]

Myxedema crisis should be suspected in patients that have encephalopathy, hypothermia, seizures, severe hyponatremia, hypoglycemia, cardiogenic shock and arrhythmias, respiratory failure, and manifestations of fluid retention.[14] A combination of a few or all of these manifestations and other symptoms of mild to severe hypothyroidism as stated above can be present.

Factors leading to an increased risk of myxedema crisis include inadequate doses of thyroid hormone, interruption in treatment, undiagnosed hypothyroidism, or presence of acute illness such as sepsis [14] perhaps due to increased metabolic demands.

Supportive treatment should be provided in the intensive care unit with fluid and electrolyte management, ventilator support, vasopressors, treatment of coexisting acute illness, and hypothermia.[14]

Thyroid replacement treatment is with intravenous hydrocortisone at stress doses followed by intravenous levothyroxine then switched to oral levothyroxine after clinical improvement. If effective, this should result in cardiopulmonary and cognitive improvement.[10] There should also be an associated improvement in laboratory derangements including a down trending of TSH which should be measured every 1 to 2 days during the initial treatment period. Intravenous liothyronine (T3) can be considered until initial improvement.[10]

Endocrinology consultation should be considered.

Enhancing Healthcare Team Outcomes

Hypothyroidism affects multiple organ systems across all age groups and affects patient well-being and ability to function on a daily basis. Treatment is with levothyroxine monotherapy (Grade A, Best Evidence Level 1).[2]

Effective treatment calls for a team-based and patient-centered approach. When patient symptoms are not adequately controlled an endocrinology consult should be obtained.

Endocrinology consultation is also recommended in complex scenarios such as preconception, pregnancy, congenital and pediatric hypothyroidism, failure of treatment, co-existing cardiac or other endocrine disorders, difficulty in interpretation of thyroid test results, drug-induced hypothyroidism.[2] Other specialists that may be needed are a psychiatrist, obstetrician-gynecologist, pediatrician, cardiologist, and intensivist.

It is helpful to work closely with a pharmacist to determine medication and food interactions, the effect of changes in levothyroxine formulations, to investigate the causes for the requirement of unusually high doses of levothyroxine or fluctuating TSH levels. Prompt notification of unusually high levels of TSH by laboratory personnel, close monitoring of vital signs and mental status by nurses can facilitate early treatment and better outcomes, especially in the inpatient setting such as in myxedema coma. Rapid response teams can be effectively utilized when hypothyroidism causes hemodynamic instability.