Hypothyroidism results from low levels of thyroid hormone with varied etiology and manifestations. Untreated hypothyroidism increases morbidity and mortality. In the US, autoimmune thyroid disease (Hashimoto thyroiditis) is the most common cause of hypothyroidism but globally lack of iodine in the diet is the most common cause. The patient presentation can vary from asymptomatic disease to myxedema coma. Today, the diagnosis of hypothyroidism is easily made with simple blood tests and can be treated with exogenous thyroid hormone.
This activity reviews the etiology, clinical presentation, diagnosis, and management of hypothyroidism.
Hyperthyroidism is majorly divided into two categories i.e., primary vs central (secondary) hypothyroidism. Primary hypothyroidism is when the thyroid gland itself is involved. The less common, secondary or central hypothyroidism when the pathology is related to the pituitary gland or hypothalamic origin.
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. Hashimoto's thyroiditis is the most common in the US. It is also associated with lymphoma. Etiology can be influenced locally by iodine fortification and the emergence of new iodine-deficient areas.
Other common causes of hypothyroidism are drugs such as amiodarone, thalidomide, stavudine, interferon, rifampin, phenobarbital, interleukin-2 and lithium, thyroid radioactive iodine therapy or thyroid surgery, radiotherapy to head or neck area, and central hypothyroidism from neoplastic, infiltrative, inflammatory, genetic or iatrogenic disorders of the pituitary or hypothalamus. A new class of cancer medications such as anti-CTLA-4 and anti-PD-L1/PD-1 therapy has been associated with both primary and/or secondary hypothyroidism.
Postpartum thyroiditis affects nearly 10% of women and often presents 8-20 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.
Use of radioactive iodine to manage Graves disease usually results in permanent hypothyroidism in about 80-90% of the patients within 8-20 weeks after treatment. Radiation treatment to the head and neck area can also result in hypothyroidism.
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 the prevalence of antithyroid antibodies.
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 and while smaller quantities of T3. However, T3 is produced mainly by the conversion of T4 to T3. Levels of T3 majorly and T4 to some extent, in turn, exert negative feedback on the production of TRH and TSH. Alteration in the structure and function of any of these organs or pathways can result in hypothyroidism.
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. Also obtain a complete medical, surgical, medication and family history.
History of adverse pregnancy and neonatal outcomes should also be sought.
Patients can also present with carpal tunnel syndrome, sleep apnea, hyponatremia, Hypercholesterolemia, congestive heart failure, and prolonged QT interval.
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. However, most of the patients have normal thyroid examination.
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.
Central hypothyroidism is of pituitary or hypothalamic origin. TSH produced can be biologically inactive and can affect the levels of bioactive TSH, hence the diagnosis of central hypothyroidism should be based on free T4 rather than TSH.
Labs should include evaluation for autoimmune thyroid diseases with levels of anti-thyroid antibodies such as the thyroid peroxidase antibodies. 
Patients with subclinical hypothyroidism and thyroid peroxidase antibody positivity have a greater risk of developing overt hypothyroidism. The studies have shown that 50% of the patients will develop primary hypothyroidism at the end of 20 years. The decision to follow up periodically with clinical evaluation as well as lab tests is based on clinical judgment as there is no clear cut guidelines in this regard.
"Total T3" is a reliable test and is majorly used in hyperthyroidism evaluation especially if T3 thyrotoxicosis is suspected. However, "Free T3" levels are not a reliable or recommended test due to lab assay issues. Hospitalized patients should undergo TSH testing only when thyroid dysfunction is suspected. Slightly abnormalities of TSH during sick patients in the hospitals should hint towards euthyroid sickness. However, if the values of TSH are very high, it does suggest hypothyroidism. "Reverse T3" will be elevated when the patient has euthyroid sickness, however, it is not routinely checked in clinical practice.
Imaging studies (ultrasound) of the neck are not routinely recommended for hypothyroidism.
Screening for Hypothyroidism
While there are no universal guidelines on screening the public for thyroid disease, the America Thyroid Association recommends that screening should start at age 35 and continue every 5 years. Individuals at high risk for hypothyroidism include the following:
Hypothyroidism is mainly treated with levothyroxine monotherapy.
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. Adrenal insufficiency can also be associated with subclinical hypothyroidism that is reversible with treatment of adrenal insufficiency. In patients who have confirmed adrenal insufficiency consider a reassessment of thyroid tests following an adequate treatment of adrenal insufficiency. It is important to rule out or treat adrenal insufficiency when a patient has severe hypothyroidism as in myxedema coma.
Replacement levothyroxine dose is 1.6 mcg/kg per day, however in elderly and atrial fibrillation patients, it is important to reduce the dose. In order to help the absorption, Levothyroxine should be taken 30-45 minutes before breakfast and at least 3 hours post-meal at bedtime the practical times for most patients. Moreover, elemental supplements such as Calcium, Magnesium to name a few, do affect the absorption of levothyroxine. Commonly used medications such as proton pump inhibitors also have a negative impact on levothyroxine absorption. Maintaining a consistent formulation or brand of levothyroxine is important. There can slight variation in the dose of the generic formulations, which can have clinical impact in a small sub-set of very sensitive hypothyroid patients.
When switching to the intravenous (IV) form in the hospitals when a patient is unable to take thyroid replacement orally, or there is suspected myxedema coma. The dose of levothyroxine is reduced to generally 50% of the oral dose. The conversion is somewhat controversial in terms of the exact dose as different experts use different conversion percentages.
Gel formulations of thyroid hormone replacements, such as Triocent, is being used in Malabsorption syndromes, medications such as sucralfate, calcium preparations, and bile acid sequestrants can interfere with the absorption of levothyroxine. However, the Levothyroxine absorption test is done to prove that a patient can not absorb levothyroxine.
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, after starting or stopping of any medications that may affect levels. If stable, then the 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. Central hypothyroidism should be monitored based on free T4 rather than TSH.
Patients with cardiac disease should be monitored for the development of any symptoms of angina and atrial fibrillation. If a patient is overly treated with thyroid replacement for an extended period of time, screening for osteoporosis is warranted.
Effective treatment helps to 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). However, since the symptoms of hypothyroidism are non-specific, in a patient is normalized thyroid labs while on thyroid replacement treatment, it signifies that symptoms are not from hypothyroidism. This is a difficult situation that clinicians deal and strong counseling skills will be helpful.
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. FDA has approved treatment options such as armor or nature thyroid, however, it's important to understand that these formulations increase risks for cardiac arrhythmias. Moreover, these formulations are not approved for pregnant patients due to the T3 component as well as in thyroid cancer patients where strict TSH goals are required.
If symptoms persist despite normalization of TSH/free T4 levels, then non-endocrine related etiologies should be considered.
Differential diagnosis is based on signs and symptoms; for example, fatigue can point to iron deficiency anemia, sleep apnea, depression, and rheumatological diseases. Given that symptoms are very non-specific, it will be important to keep an open mind and evaluate based on clinical judgment.
Without treatment, hypothyroidism may have a risk of high morbidity and mortality. It 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. With treatment, most patients have a good prognosis and the symptoms usually reverse in a few weeks or months.
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%.
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. 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  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.
Thyroid replacement treatment is with intravenous hydrocortisone at stress doses followed by intravenous levothyroxine then switched to oral levothyroxine after clinical improvement. The reasons to give steroids is that these patients may have adrenal insufficiency which can lead to Addisonian crisis if the thyroid deficiency is replaced without addressing adrenal insufficiency. It is recommended to check for Adrenal insufficiency but do not wait for the results and start treatment with steroids.
If the treatment is effective, this should result in cardiopulmonary and cognitive improvement. There should also be an associated improvement in laboratory derangements 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. TSH may not reflect changes in such case as it can take up to 4 weeks to normalize, hence it may not be helpful.
Endocrinology consultation should be considered.
Hypothyroidism affects multiple organ systems across all age groups and affects patient well-being and ability to function on a daily basis. This disorder is best managed by the primary care physician or endocrinologist. Treatment is with levothyroxine monotherapy (Grade A, Best Evidence Level 1).
Effective treatment calls for a team-based and patient-centered approach. When patient symptoms are not adequately controlled despite normalization of thyroid labs, its important to rule out nonendocrine pathologies for the nonspecific symptoms.
Endocrinology consultation is also recommended in complex scenarios such as preconception, pregnancy, congenital and pediatric hypothyroidism, failure of treatment, thyroid replacement absorption issues, co-existing cardiac or other endocrine disorders, difficulty in interpretation of thyroid test results, drug-induced hypothyroidism. Other specialists that may be needed are psychiatrists, obstetrician-gynecologist, pediatricians, cardiologists, and intensivists.
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 severe long-term hypothyroidism causes hemodynamic instability from myxedema coma. Close interprofessional communication with all the involved teams, is essential to improve patient outcomes. [Level 5]
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