Hypothyroidism

Etiology

Hypothyroidism is primarily categorized as primary and secondary (ie, central) hypothyroidism. In primary hypothyroidism, the thyroid gland cannot produce adequate amounts of thyroid hormone. The less commonly seen secondary or central hypothyroidism occurs when the thyroid gland functions normally; however, hypothyroidism results from the abnormal pituitary gland or hypothalamus function.

The most prevalent etiology of primary hypothyroidism is an iodine deficiency in iodine-deficient geographic areas worldwide. Autoimmune thyroid diseases are the leading causes of hypothyroidism in the iodine-sufficient regions. Hashimoto thyroiditis is the most commonly seen etiology in the US and has a strong association with lymphoma. Hypothyroid etiology can be influenced locally by iodine fortification and the emergence of new iodine-deficient areas.[1] 

Other conditions may also lead to primary hypothyroidism. Postpartum thyroiditis affects nearly 10% of women and often presents 8 to 20 weeks after the delivery of the infant. Only a few women require treatment with thyroid hormone. However, some women are at high risk for permanent hypothyroidism or recurrent postpartum thyroiditis in future pregnancies.[4] The use of radioactive iodine to manage Graves disease usually results in permanent hypothyroidism in about 80% to 90% of the patients within 8 to 20 weeks after treatment.[5][6] A relatively uncommon cause of primary hypothyroidism is subacute granulomatous thyroiditis, also known as de Quervain disease. Subacute granulomatous thyroiditis usually occurs in middle-aged women and is typically self-limited. Hypothyroidism can also be a part of the autoimmune polyendocrinopathy type-1 condition that results from a mutation in the AIRE gene. This condition is a constellation of Addison disease, hypoparathyroidism, and mucocutaneous candidiasis. Polyendocrinopathy type-2 includes hypothyroidism, Addison disease, and type 1 diabetes mellitus.[7][8] Other common causes of hypothyroidism include:

• Medications including amiodarone, thalidomide, oral tyrosine kinase inhibitors (eg, sunitinib, imatinib), stavudine, interferon, bexarotene, perchlorate, rifampin, ethionamide, phenobarbital, phenytoin, carbamazepine, interleukin-2, and lithium.[1][9]
• Thyroid surgery
• Radiotherapy of the head or neck area 
• The use of immune checkpoint inhibitors (eg, anti-CTLA-4 and anti-PD-L1/PD-1 therapy) has been associated with both primary and secondary hypothyroidism.[10][11]

Secondary and tertiary hypothyroidism, also known as central hypothyroidism, is caused by a defect in the hypothalamic-pituitary axis secondary to any of the following (see Image. Pituitary Hyperplasia):

• Neoplastic, infiltrative, inflammatory, genetic, or iatrogenic disorders of the pituitary or hypothalamus.[2] 
• Pituitary tumors
• Tumors compressing hypothalamus
• Sheehan syndrome
• Thyroid-releasing hormone (TRH) resistance [12]
• TRH deficiency
• Lymphocytic hypophysitis [13]
• Radiation therapy to the brain
• Medications (eg, dopamine, prednisone, or opioids) [14]

Epidemiology

The National Health and Nutrition Examination Survey (NHANESIII) study found the prevalence of overt hypothyroidism among individuals aged 12 years and older in the US to be 0.3% and subclinical hypothyroidism 4.3%. Female gender and increasing age are associated with a higher risk for thyroid-stimulating hormone (TSH) and an increased prevalence of antithyroid antibodies.[15] Hypothyroidism is more prevalent in women with small stature at birth and low body mass index in childhood.

Pathophysiology

The most common cause of hypothyroidism is the inability of the thyroid gland to produce a sufficient amount of thyroid hormone; however, less commonly, pituitary and hypothalamus impairment may also result in thyroid dysfunction. The hypothalamus secretes thyrotropin-releasing hormone (TRH) that stimulates the pituitary gland to produce thyroid-stimulating hormone (TSH). Thyroid-stimulating hormones stimulate the thyroid gland to produce and secrete mainly T4, approximately 100 to 125 nmol daily, and smaller quantities of T3. The half-life of T4 is 7 to 10 days, and eventually, T4 is converted to T3 peripherally by 5'-deiodination. Negative feedback on the production of TRH and TSH is exerted primarily by T3 and, to some extent, T4. Alteration in the structure and function of any of these organs or pathways can result in hypothyroidism.[16] Additionally, the decline in the production of T4 results in an increase in the secretion of TSH by the pituitary gland, causing hypertrophy and hyperplasia of the thyroid parenchyma, thereby leading to increased T3 production.

Histopathology

Autoimmune thyroiditis causes an increase in the turnover of iodine and impaired organification. Chronic inflammation of the parenchyma leads to predominant T-cell lymphocytic infiltration.[2] If this persists, the initial lymphocytic hyperplasia and vacuoles are replaced by dense fibrosis and atrophic thyroid follicles. Coexisting or associated malignancies, such as papillary thyroid cancer, can also be seen.[17]

History and Physical

Clinical History

A high index of suspicion for hypothyroidism should be maintained since the signs and symptoms can be mild and nonspecific. Furthermore, symptoms may vary widely in different patients. Classic clinical features, including cold intolerance, puffiness, decreased sweating, and skin changes, may not always be present. Therefore, a thorough inquiry into a patient's symptoms should be performed, including dry skin, voice changes, hair loss, constipation, fatigue, muscle cramps, cold intolerance, sleep disturbances, menstrual cycle abnormalities, weight gain, and galactorrhea.[2] Also, a complete medical, surgical, medication, and family history should be obtained. History of adverse pregnancy and neonatal outcomes should also be sought.[18]

Occasionally, patients with less common symptoms may be encountered. Symptoms of depression, anxiety, psychosis, and cognitive impairments (eg, memory loss) can be present.[19] In rare cases, patients may present with ascites, rhabdomyolysis, and pericardial effusion.[20][21] Patients can also present with carpal tunnel syndrome, sleep apnea, hyponatremia, hypercholesterolemia, congestive heart failure, and prolonged QT interval.[2] Hashimoto disease is difficult to differentiate clinically; however, some features specific to this condition include:

• Throat fullness
• Painless thyroid enlargement
• Episodic neck pains or sore throat

Physical Examination Findings

Most of the patients have normal thyroid examination findings. However, a careful physical examination may reveal some clues since the signs of hypothyroidism are very subtle. Physical examination may be significant for the following:

• Enlarged thyroid gland
• Weight gain
• Slowness of speech and movement
• Dry skin
• Coarse and brittle hair
• Pallor or jaundice
• Dull facial expressions
• Macroglossia
• Bradycardia
• Pericardial effusion
• Prolonged ankle reflex relaxation time [2]

Evaluation

Hyperthyroid Diagnostic Studies

A serum TSH level is typically used to assess for primary hypothyroidism in most patients initially. Characteristic laboratory findings of hypothyroidism include elevated TSH levels and low free T4 levels. In subclinical hypothyroidism, TSH levels are elevated, and free T4 levels are within normal limits.[2] Antithyroid antibodies (eg, thyroid peroxidase antibodies) should also be performed to evaluate for autoimmune thyroid diseases.[2] Patients with subclinical hypothyroidism and thyroid peroxidase antibody positivity have a greater risk of developing overt hypothyroidism.[2] Studies have shown that 50% of these patients will develop primary hypothyroidism within 20 years. The decision to follow up periodically with clinical evaluation and laboratory studies is based on clinical judgment, as there are no guidelines. Laboratory studies in patients with hypothyroidism may also reveal hyperlipidemia, elevated serum creatine kinase, elevated hepatic enzymes, and anemia.[2] Bun, creatinine, and uric acid levels can also be elevated in severe cases.[22]

Central hypothyroidism may be either of pituitary or of hypothalamic origin. In these cases, the TSH produced can be biologically inactive and affect the levels of bioactive TSH; therefore, the diagnosis of central hypothyroidism should be based on free T4 rather than TSH.[2] Imaging studies (eg, ultrasound) of the neck are not routinely recommended for hypothyroidism.

Hospitalized patients should undergo TSH testing only when thyroid dysfunction is suspected.[2] Slight abnormalities of TSH in sick patients during their hospital stay are suggestive of euthyroid sick syndrome. However, if the values of TSH are very high, hypothyroidism is likely. Reverse T3 is elevated when the patient has euthyroid sickness, though this is not routinely checked in clinical practice. 

Hypothyroid Screening Recommendations

While there are no universal guidelines on screening the public for thyroid disease, the American Thyroid Association recommends that screening be performed every 5 years, beginning at the age of 35 years. Individuals at high risk for hypothyroidism include the following:

• Women older than 60 years
• Pregnant women
• Patients with a prior history of head and neck irradiation
• Patients with autoimmune disorders or type 1 diabetes
• Positive thyroid peroxidase antibodies
• Family history of thyroid disorders

Treatment / Management

Hypothyroidism is primarily treated with levothyroxine monotherapy.[3] The replacement levothyroxine dosage should be between 1.6 to 1.8 mcg/kg by mouth daily.[23] However, in patients who are older or with atrial fibrillation, reduction of the dose or starting at a low dosage and titrating up slowly as needed is important.[3] To help the absorption, levothyroxine should be taken 30 to 45 minutes before breakfast or at least 3 hours postprandially, whichever is most convenient for each patient. Moreover, elemental supplements or vitamins (eg, calcium and magnesium) can affect the absorption of levothyroxine; therefore, an interval of at least 4 hours should be placed between these agents and thyroid hormone administration. Furthermore, commonly used medications such as proton pump inhibitors also negatively impact levothyroxine absorption. Maintaining a consistent formulation or brand of levothyroxine might be essential for some patients as there might be slight variations in the dose of the generic formulations, which can have a clinical impact on a small subset of very sensitive hypothyroid patients.[3]

Switching to the intravenous (IV) form of thyroid hormone in the hospital is indicated when a patient is unable to take thyroid replacement orally or when myxedema coma is suspected. The levothyroxine dose is generally reduced to 50% to 75% of the oral dose.[24] The conversion is somewhat controversial regarding the exact dose, as different experts use different conversion percentages. The extreme difference in the cost between both formulations makes the intravenous use of levothyroxine the last resort in the rare cases of myxedema coma and patients with a strict NPO state.[24]

Liquid and gel capsule formulations of thyroid hormone replacements are used in malabsorption syndromes, as they do not require an acidic pH in the stomach.[25][26] The liquid formulation has been shown to achieve better control of hypothyroidism versus the tablet form, in general, as well as for special populations, like pregnancy and older patients.[27][28][29][30] Medications (eg, sucralfate, calcium preparations, and bile acid sequestrants) can interfere with the absorption of levothyroxine.[2] However, the levothyroxine absorption test can be done to prove if a patient can not absorb levothyroxine.[31][32][33](A1)

Based on the 2012 Clinical Practice Guidelines for Hypothyroidism in Adults by the American Association of Clinical Endocrinologists and the American Thyroid Association, therapy should be monitored and titrated based on serum TSH or free T4 measurements. Laboratory studies should be drawn every 4 to 8 weeks until target levels are achieved. Laboratory measurements should also be performed after starting treatment, after any dose change, after any change in the formulation or brand of levothyroxine, and after starting or stopping any medications that may affect the thyroid hormone levels.[2] If thyroid hormone levels are stable, then the monitoring interval can be extended to 6 months; if levels remain stable, then monitoring can be further extended to 12 months or done at shorter intervals on an individualized basis along with clinical evaluation.[2] Central hypothyroidism should be monitored based on free T4 rather than TSH.[2] Patients with cardiac disease should be monitored for the development of any symptoms of angina and atrial fibrillation.[2] If a patient is overly treated with thyroid replacement for an extended period, screening for osteoporosis is warranted.[3](A1)

A comprehensive workup for other differential diagnoses is recommended for unresolved symptoms in the presence of biochemical euthyroidism. Although there is a lack of strong evidence supporting the routine inclusion of triiodothyronine (T3) preparations with levothyroxine in the treatment of hypothyroidism, there might be a need to consider alternative combination T4 and T3 therapy in cases that do not respond to conventional T4 replacement.[34][35] The FDA has approved treatment options, including armor or nature thyroid; however, clinicians should understand that these formulations may increase cardiac arrhythmia risk. Moreover, these formulations are not approved for pregnant patients due to their T3 component or for patients with thyroid cancer, where strict TSH goals are required. 

Effective treatment helps to improve hypothyroid signs and symptoms, improves patient well-being, and normalizes TSH and free T4 levels.[36] However, since the symptoms of hypothyroidism are nonspecific, a symptomatic patient with normalized labs while on thyroid replacement treatment may be indicative of another etiology. This is a difficult situation where the clinician must reevaluate a patient. Strong counseling skills are also of great help. Furthermore, thyroid replacement treatment can exacerbate coexisting adrenal insufficiency. Patients with known or suspected adrenal insufficiency should be tested and treated for adrenal insufficiency while awaiting the final test results.[2] Adrenal insufficiency can also be associated with subclinical hypothyroidism that is reversible with the treatment of adrenal insufficiency.[37] In patients who have confirmed adrenal insufficiency, physicians should consider a reassessment of thyroid tests following an adequate treatment of adrenal insufficiency. Ruling out or treating adrenal insufficiency when a patient has severe hypothyroidism (eg, myxedema coma) is essential. (A1)

Differential Diagnosis

Owing to the subtle signs and symptoms of hypothyroidism, the list of differential diagnoses is extensive. Differential diagnosis is based on signs and symptoms; for instance, fatigue can point to iron deficiency anemia, sleep apnea, depression, and rheumatological diseases.[35] The following disorders may have to be considered in the differential process.

• Euthyroid sick syndrome
• Goiter
• Myxedema coma
• Anemia
• Riedel thyroiditis
• Subacute thyroiditis
• Thyroid lymphoma
• Iodine deficiency
• Addison disease
• Chronic fatigue syndrome
• Depression
• Dysmenorrhea
• Erectile dysfunction
• Familial hypercholesterolemia
• Infertility

Prognosis

Without treatment, hypothyroidism may have a risk of high morbidity and mortality and can eventually lead to coma or even death. In children, failure to treat hypothyroidism can result in severe mental retardation. A leading cause of death in adults is heart failure. Most patients have a good prognosis with treatment, and the symptoms usually reverse in a few weeks or months.

Complications

Severe hypothyroidism may present as myxedema coma, and it is an endocrine emergency. Prompt recognition and early treatment in the intensive care unit (ICU) are essential, and even then, mortality may reach 25% to 60% of the affected cases.[38] Myxedema crisis should be suspected in cases where there is encephalopathy, hypothermia, seizures, hyponatremia, hypoglycemia, arrhythmias, cardiogenic shock, respiratory failure, and fluid retention.[38] Factors leading to an increased risk of myxedema crisis include inadequate doses of thyroid hormone, interruption in treatment, undiagnosed hypothyroidism, or the presence of acute illness such as sepsis [38], perhaps due to increased metabolic demands. Supportive therapy should be provided in the intensive care unit with fluid and electrolyte management, ventilator support, and vasopressors, as well as treatment of hypothermia and any underlying coexisting acute illnesses.[38]

Thyroid replacement treatment is initially provided by intravenous hydrocortisone at stress doses, followed by intravenous levothyroxine, then switched to oral levothyroxine when clinical improvement is achieved. The reason to give steroids is that these patients may have adrenal insufficiency, which can lead to an Addisonian crisis if the thyroid deficiency is replaced without addressing adrenal insufficiency due to creating a hypermetabolic state. It is recommended to check for adrenal insufficiency, but while waiting for the results of the tests, treatment should be started with steroids.

If the treatment is effective, cardiopulmonary and cognitive improvement should be observed.[3] An associated improvement in laboratory derangements should also be noted, including an up-trending of free T4, which should be measured every 1 to 2 days during the initial treatment period. Low-dose intravenous liothyronine (T3) can be considered until initial improvement.[3] TSH may not reflect changes in such cases as it can take up to 4 weeks to normalize; therefore, TSH may not be helpful. Endocrinology consultation should be considered at any time.