Sections

Hypothyroidism

Treatment

Approach Considerations

The treatment goals for hypothyroidism are to reverse clinical progression and correct metabolic derangements, as evidenced by normal blood levels of thyroid-stimulating hormone (TSH) and free thyroxine (T4). Thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4).

Thyroid hormone can be started at anticipated full replacement doses in individuals who are young and otherwise healthy (1.6 μg/kg/day). Pregnant women will require doses about 25% higher. In elderly patients and those with known ischemic heart disease, treatment should begin with one fourth to one half the expected dosage, and the dosage should be adjusted in small increments after no less than 4-6 weeks. For most cases of mild to moderate hypothyroidism, a starting levothyroxine dosage of 50-75 µg/day will suffice.

Clinical benefits begin in 3-5 days and level off after 4-6 weeks. Achieving a TSH level within the reference range may take several months because of delayed readaptation of the hypothalamic-pituitary axis. In patients receiving treatment with LT4, dosing changes should be made every 4-6 weeks until the patient’s TSH is in target range.

In patients with central (ie, pituitary or hypothalamic) hypothyroidism, T4 levels rather than TSH levels are used to guide treatment. In most cases, the free T4 level should be kept in the upper third of the reference range.

After dosage stabilization, patients can be monitored with annual or semiannual clinical evaluations and TSH monitoring. Patients should be monitored for symptoms and signs of overtreatment, which include the following:

Tachycardia
Palpitations
Atrial fibrillation
Nervousness
Tiredness
Headache
Increased excitability
Sleeplessness
Tremors
Possible angina

The updated guidelines on hypothyroidism issued by the American Thyroid Association in 2014 maintain the recommendation of levothyroxine as the preparation of choice for hypothyroidism, with the following considerations^{[85, 86]}:

If levothyroxine dose requirements are much higher than expected, consider evaluating for gastrointestinal disorders such as H pylori –related gastritis, atrophic gastritis, or celiac disease; if such disorders are detected and effectively treated, re-evaluation of thyroid function and levothyroxine dosage is recommended
Initiation or discontinuation of estrogen (or menopause) and androgens should be followed by reassessment of serum TSH at steady state, since such medications may alter levothyroxine requirement
Serum TSH should be reassessed upon initiation of agents such as tyrosine kinase inhibitors that affect thyroxine metabolism and thyroxine or triiodothyronine deiodination
Serum TSH monitoring is advisable when medications such as phenobarbital, phenytoin, carbamazepine, rifampin, and sertraline are started
When deciding on a starting dose of levothyroxine, the patient’s weight, lean body mass, pregnancy status, etiology of hypothyroidism, degree of TSH elevation, age, and general clinical context, including the presence of cardiac disease, should be considered; the serum TSH goal appropriate for the clinical situation should also be considered
Thyroid hormone therapy should be initiated as an initial full replacement or as partial replacement with gradual increments in the dose titrated upward using serum TSH as the goal
Dose adjustments should be made upon significant changes in body weight, with aging, and with pregnancy; TSH assessment should be performed 4-6 weeks after any dosage change
Reference ranges of serum TSH levels are higher in older populations (eg, >65 years), so higher serum TSH targets may be appropriate; per the American Thyroid Association (ATA), target serum TSH may be raised to 4-6 mIU/L in patients aged 70-80 years

A meta-analysis of randomized, controlled trials of T4-triiodothyronine (T3) combination therapy versus T4 monotherapy for treatment of clinical hypothyroidism found no difference in effectiveness between combination therapy and monotherapy with respect to side effects such as bodily pain, depression, fatigue, body weight, anxiety, quality of life, and total low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels.^[87]

A study of athyreotic patients found a high heterogeneity in these patients’ ability to produce T3 when treated with levothyroxine. Approximately 20% of these athyreotic patients did not maintain normal free T4 or free T3 values despite a normal TSH.^[88]However, it is unclear whether more physiologic treatments offer any benefit, even in subgroups of hypothyroid patients.

In patients who continue to have symptoms (eg, weight gain and fatigue) despite normalization of the TSH level, one should consider causes other than hypothyroidism, rather than simply increasing the thyroid hormone dose on the basis of symptoms alone (see DDx). In rare cases, however, symptom persistence is the result of a polymorphism of the deiodinase 2 enzyme, which converts T4 to T3 in the brain; these patients may benefit from combined LT4-liothyronine (LT3) therapy, using a physiologic LT4-to-LT3 ratio in the range of 10-14:1.^[89]

Most patients with hypothyroidism can be treated in an ambulatory care setting. Patients who require long-term continuous tube feeding may need intravenous (IV) LT4 replacement because the absorption of oral agents is impaired by the contents of tube feeds. Alternatively, tube feeds can be withheld for 1 hour while the patient receives an oral preparation of LT4. It should be noted that oral and IV preparations of LT4 are not equivalent; consequently, great care must be taken in switching between these formulations.

Patients with severe hypothyroidism requiring hospitalization (eg, myxedema) may require aggressive management. Overreplacement or aggressive replacement with any thyroid hormone may precipitate tachyarrhythmias or, very rarely, thyroid storm and should be balanced against the need for urgent replacement. Risk is higher with T3 therapy.

Surgery is rarely needed in patients with hypothyroidism; it is more commonly required in the treatment of hyperthyroidism. However, surgery is indicated for large goiters that compromise tracheoesophageal function.

Hypothyroidism in Pregnancy

The updated guidelines on hypothyroidism issued by the ATA in 2014 concerning hypothyroidism treatment in pregnant women are as follows^{[85, 86]}:

Pregnant women with overt hypothyroidism should receive levothyroxine replacement therapy with the dose titrated to achieve a TSH concentration within the trimester-specific reference range
Serial serum TSH levels should be assessed every 4 weeks during the first half of pregnancy to adjust levothyroxine dosing to maintain TSH within the trimester-specific range
Serum TSH should be reassessed during the second half of pregnancy
In women already taking levothyroxine, two additional doses per week of the current levothyroxine dose, given as one extra dose twice weekly with several days’ separation, may be started as soon as pregnancy is confirmed

Hypothyroidism in pregnancy can produce an array of obstetric complications. Even mild disease may have adverse effects on the offspring. Adverse effects of hypothyroidism in pregnancy include the following:

Preeclampsia
Anemia
Postpartum hemorrhage
Cardiac ventricular dysfunction
Increased risk of spontaneous abortion
Low birth weight
Impaired cognitive development in offspring ^[90]
Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder ^[91]
Fetal mortality

Despite the possibility of poor fetal outcomes, routine screening for thyroid dysfunction is not recommended by ACOG (2020) in the United States and remains a controversial topic. A study reviewing the records of pregnant women screened between June 2005 and May 2008 found that only 23% of these women were tested for hypothyroidism.^[92] A literature review by Dong and Stagnaro-Green found that the pooled prevalence rate for overt hypothyroidism in pregnancy was 0.50% (with the 97.5th percentile used as an upper limit for TSH).^[93]

Increased thyroid hormone dosage requirements should be anticipated during pregnancy, especially in the first and second trimesters. Studies have suggested that in pregnant women with hypothyroidism, the LT4 dose should be increased by 25% at the confirmation of pregnancy and subsequently adjusted in accordance with TSH levels.

In addition, iodine demands are higher with pregnancy and lactation. Iodine needs rise from approximately 150 µg/day in the nonpregnant woman to 240-290 µg/day with pregnancy and lactation. Guidelines from the American Thyroid Association recommend that all pregnant and lactating women ingest a minimum of 250 mg iodine daily—optimally, in the form of potassium iodide, to ensure consistent delivery.^[94]

For pregnant women with previously diagnosed hypothyroidism, serum TSH levels should be measured every 3-4 weeks during the first half of pregnancy and every 6-10 weeks thereafter. The LT4 dose should be adjusted so as to keep the serum TSH below 2.5 mIU/L. TSH and free T4 levels should be measured 3-4 weeks after every dosage adjustment.^[95]

Autoimmune thyroid disease without overt hypothyroidism has been associated with adverse pregnancy outcomes, as has subclinical hypothyroidism. In a meta-analysis of 19 prospective cohort studies (47,045 women), the risk of preterm birth was higher in association with subclinical hypothyroidism, isolated hypothyroxinemia (decreased free T4 concentration with normal TSH concentration), and thyroid peroxidase antibody positivity.^[96]Additionally, Negro et al showed that euthyroid Caucasian women with positive anti−thyroid peroxidase (anti-TPO) antibodies who were treated with LT4 during the first trimester had lower miscarriage rates than those who were not treated. These women also had lower rates of premature delivery, comparable to rates in women without thyroid antibodies.^[97]Interestingly, treatment with LT4 prior to conception did not significantly alter the rates of live births, pregnancy loss, preterm birth, or neonatal outcomes in a study of 952 euthyroid women with positive anti-TPO antibodies.^[77]

In a meta-analysis of three studies involving 220 women with subclinical hypothyroidism or thyroid autoimmunity who were undergoing procedures with assisted reproduction technologies, Velkeniers et al concluded that treatment with LT4 should be recommended to improve pregnancy outcomes.^[98]In pooled analyses, LT4 treatment resulted in a significantly higher delivery rate and a significantly lower miscarriage rate.

Such findings, if confirmed by sufficient data, would provide an indication for treating euthyroid pregnant women who have thyroid antibodies or subclinical hypothyroidism. At this time, treatment recommendations for the periconception period in women with subclinical hypothyroidism, hypothyroxinemia, or thyroid autoimmunity remain inconclusive.

LT4 should not be taken with prenatal vitamin preparations containing iron and calcium. After delivery, the LT4 dose can be reduced to the prepregnancy level, and TSH should be checked in 6 weeks.

In a study of 77 pregnant women with newly diagnosed subclinical (64 women) or overt (13 women) hypothyroidism, Abalovich et al determined the specific levothyroxine (LT4) dosages required to return these patients to a euthyroid state. The investigators found that the most successful dosages, as follow, varied according to baseline levels of thyroid stimulating hormone (TSH)^{[99, 100]}:

· Subclinical hypothyroidism (TSH 4.2 mIU/L or less): 1.2 µg/kg/day

· Subclinical hypothyroidism (TSH > 4.2-10 mIU/L): 1.42 µg/kg/day

· Overt hypothyroidism: 2.33 µg/kg/day

These dosages proved appropriate in 89% and 77% of patients with subclinical or overt hypothyroidism, respectively, and were recommended by the study's authors for pregnant patients with hypothyroidism that has been newly diagnosed during pregnancy.

Due to the decreased thyroid hormone demand following delivery, prepregnancy doses of LT4 should be resumed in women with subclinical hypothyroidism. A serum TSH level should be obtained at week 6 post delivery.^[101]

Subclinical Hypothyroidism

Significant controversy persists regarding the treatment of patients with mild hypothyroidism.^[9]Reviews by the US Preventive Services Task Force^[10]and an independent expert panel^[11]found inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L.

Some have argued that treatment of these patients improves symptoms, prevents progression to overt hypothyroidism, and may have cardioprotective benefits. However a randomized, controlled trial with 95 participants found that treatment with LT4 did not lead to significant improvement of the left ventricular ejection fraction after 52 weeks in patients with subclinical hypothyroidism and acute myocardial infarction.^[102]

In pregnant women with subclinical hypothyroidism (using a TSH cutoff of ≥4.0 mIU/L) and negative anti-TPO antibodies, LT4 therapy may reduce the risk for preterm delivery.^[103]The Endocrine Society recommends T4 replacement in pregnant women with subclinical hypothyroidism,^[104] but ACOG does not recommend it as a routine measure.^[105]

Ultrasonography may have prognostic value in subclinical hypothyroidism. In an Italian study, progression to overt hypothyroidism occurred more often in patients whose ultrasonographic thyroid scan showed diffuse hypoechogenicity (an indication of chronic thyroiditis).^[106]

In nonpregnant patients, following subclinical hypothyroidism and treating on a case-by-case basis is reasonable. Treatment of subclinical hypothyroidism has been shown to reduce total cholesterol, non-HDL cholesterol, and apolipoprotein B levels^[107]and to decrease arterial stiffness and systolic blood pressure.^[108]In patients with concomitant subclinical hypothyroidism and iron deficiency anemia, iron supplementation may be ineffective if LT4 is not given.^[109]

Guidelines from the American Association of Clinical Endocrinologists (AACE) recommend treatment in patients with TSH levels higher than 10 mIU/L and in patients with TSH levels of 5-10 mIU/L in conjunction with goiter or positive anti-TPO antibodies; these patients have the highest rates of progression to overt hypothyroidism. An initial LT4 dosage of 50-75 µg/day can be used, which can be titrated every 6-8 weeks to achieve a target TSH of between 0.3 and 3 mIU/L.^[83]

A literature review by Abreu et al suggested that LT4 therapy can hinder the development of coronary artery disease in subclinical hypothyroidism. Evaluating randomized, placebo-controlled trials, the investigators reported that patients receiving LT4 experienced significant reductions in serum TSH and in total and low-density lipoprotein cholesterol compared with patients receiving placebo.^[110]

In older adults (≥65 years) with subclinical hypothyroidism, treatment guidelines remain inconclusive. Generally, treatment is not recommended if TSH is between 4.5-6.9 mIU/L, given the low risk for progression to overt hypothyroidism and the more relaxed TSH targets in the elderly favored by some guidelines.^[111]

The TRUST trial, a randomized, controlled study of LT4 therapy for subclinical hypothyroidism in older adults, randomized 737 men and women aged 65 years or older to treatment with LT4 versus placebo. Results showed no benefit in primary outcomes of hypothyroid symptoms and fatigue score after 12 months of therapy. There were also no significant benefits noted with regard to the secondary outcomes of quality of life, handgrip strength, cognitive function, blood pressure, weight, body mass index (BMI), waist circumference, carotid intima medial thickness (CIMT), and carotid plaque thickness.^[112]In a substudy of the TRUST trial, participants treated with LT4 for 18 months did not have any significant differences in carotid atherosclerosis and CIMT compared with the placebo group.^[113]In a nested study within the TRUST trial, no significant difference was seen in systolic or diastolic heart function in LT4-treated participants compared with placebo.^[114]

In general, for patients older than 70 years with TSH of 10 mIU/L or greater, treatment should be based on individual patient factors, including hypothyroid symptoms, presence of anti-TPO antibodies, and cardiac risk factors.

Myxedema Coma

In patients with myxedema coma, an effective approach consists of the following:

Give 4 µg of LT4 per kilogram of lean body weight (approximately 200-250 µg) as an IV bolus in a single or divided dose, depending on the patient’s risk of cardiac disease and age
24 hours later, give 100 µg IV
Subsequently, give 50 µg/day IV, along with stress doses of IV glucocorticoids
Adjust the dosage on the basis of clinical and laboratory findings
Provide antibiotic coverage for sepsis
Avoid volume contraction

If adrenal insufficiency is suspected (eg, in a patient with hypothyroidism secondary to panhypopituitarism), that diagnosis should be investigated. If adrenal insufficiency is confirmed, stress doses of IV glucocorticoids should be given before hypothyroidism is treated. If the patient’s condition is critical and there is no time to complete the workup for adrenal insufficiency before the necessary use of IV LT4, the patient must be given stress-dose glucocorticoids to prevent the catastrophic complication of adrenal crisis.

Use of IV LT3 is controversial and based on expert opinion. It is associated with a higher frequency of adverse cardiac events and is generally reserved for patients who are not improving clinically on LT4. LT3 can be given initially as a 10 µg IV bolus, which is repeated every 8-12 hours until the patient can take maintenance oral doses of T4.

Advanced age, high-dose T4 therapy, and cardiac complications have the highest associations with mortality in myxedema coma (see Hypothyroidism and Myxedema Coma in Emergency Medicine).^[115]

Complications of Treatment

Thyroid hormone replacement can precipitate adrenal crises in patients with untreated adrenal insufficiency by enhancing hepatic corticosteroid metabolism. If adrenal insufficiency is suspected, it should be confirmed or ruled out; if confirmed, it should be treated before treatment of hypothyroidism.

Aggressive replacement of thyroid hormone may compromise cardiac function in patients with existing cardiac disease. In these patients, administer smaller initial doses of LT4, and titrate the dosage upward in small increments.

Subclinical hyperthyroidism is a more common complication of treatment with LT4, and caution should be used in initiating full replacement doses of LT4 in the elderly. In a study by Sawin et al, 2007 elderly patients (aged ≥60 years) without a prior history of atrial fibrillation were followed over a 10-year period to assess the frequency of this arrhythmia according to TSH levels. The investigators found that the risk of atrial fibrillation was three times higher in the cohort with low TSH levels (≤0.1 mIU/L), with a 10-year cumulative incidence of 28% for atrial fibrillation, compared with 11% in those with normal TSH levels (>0.4-5.0 mIU/L).^[116]

The relationship of overtreatment to osteoporosis and fracture is best studied in the elderly and in postmenopausal women. A large population-based, nested case-control study demonstrated a two- to three-fold increase in fractures in LT4 users older than 70 years; the increase was dose-related.^[117]An observational cohort study that evaluated the association between serum TSH level and risk for cardiovascular disease, dysrhythmias, and fractures in patients on T4-replacement therapy showed an increased risk for all three outcomes with an elevated (>4.0 mIU/L) or suppressed (≤0.03 mIU/L) TSH level. Interestingly, patients with a low (0.04-0.4 mIU/L), but not suppressed, TSH level did not have an increased risk for these outcomes.^[118]Nonetheless, these studies support careful dose titration and avoidance of TSH oversuppression, especially in elderly patients.

Overall, patients at risk for osteoporosis (eg, women who are estrogen-deficient and the elderly) and individuals receiving a long-term suppressive dose of LT4 (eg, patients with differentiated thyroid cancer) should be closely monitored. A meta-analysis of 385 premenopausal women and 409 postmenopausal women, all on suppressive LT4 therapy, revealed that the treatment was associated with a significant detrimental effect on bone mass of the hip and spine in the postmenopausal group.^[119]

It should be noted that patients with thyroid cancer are usually on a higher dose of LT4. The desired TSH depends on the staging of the cancer and on the evidence of active disease. In patients with stage IV thyroid cancer, it is desirable to keep the TSH below 0.1 mIU/L in the long term.

Patients should be advised that in rare cases, vision may temporarily worsen when hormone therapy is initiated. Pseudotumor cerebri may occur, albeit uncommonly. Patients with depression may develop mania, and psychosis may be exacerbated in patients with severe psychological illness.

Because most brain growth occurs in the first 2 years of life, untreated hypothyroidism in infants can cause irreversible mental retardation. Older infants are spared nervous system damage but continue to have slowed physical and linear bone growth. They also have delayed dental development.

Diet and Activity

No specific diets are required for hypothyroidism. Subclinical hypothyroidism has been seen in increased frequency in patients with greater iodine intake. The World Health Organization (WHO) recommends a daily dietary iodine intake of 150 µg for adults, 200 µg for pregnant and lactating women, and 50-120 µg for children.

Although there is no evidence that avoiding certain foods will aid thyroid function, some foods can discourage the absorption of thyroid hormone replacement medication and so should not be consumed at the same time as the medication. These include the following^[120]:

Walnuts
Soybean flour
Cottonseed meal
Iron supplements or iron-containing multivitamins
Calcium supplements

Patients who have hypothyroidism have generalized hypotonia and may be at risk for ligamentous injury, particularly from excessive force across joints. Thus, patients should exercise caution with certain activities, such as contact sports and heavy physical labor.

Patients with uncontrolled hypothyroidism may have difficulty maintaining concentration in low-stimulus activities and may have slowed reaction times. Patients should use caution when engaging in an activity that poses a risk of injury (eg, operating presses or heavy equipment and driving).

Consultations

Indications for referral to an endocrinologist include any of the following^[3]:

· A nodular thyroid, suspicious thyroid nodules, or compressive symptoms (eg, dysphagia)

· Pregnancy (or planned pregnancy)

· Underlying cardiac disorders or other endocrine disorders

· Age younger than 18 years

· Secondary or tertiary hypothyroidism

· Unusual constellation of thyroid function test results

· Inability to maintain TSH in the target range

· Unresponsiveness to treatment

Some patients with subacute or postpartum thyroiditis can develop thyrotoxicosis (or symptoms consistent with hyperthyroidism) before developing hypothyroidism. These patients also may benefit from consultation with an endocrinologist.

Suspected myxedema coma is a medical emergency with a high risk of mortality, and it necessitates requires initiation of IV LT4 and glucocorticoid therapy before laboratory confirmation. An urgent endocrinology consultation should be obtained.

Rarely, an increase in size of a goiter in a patient with autoimmune thyroid disease could indicate a lymphoma. These patients should be evaluated by an endocrinologist.

Long-Term Monitoring

Once an appropriate therapeutic dosage is arrived at, patients can be monitored annually or semiannually with laboratory evaluation and physical examination. In addition, monitor patients for signs of excess dosing (eg, nervousness, palpitations, diarrhea, excessive sweating, heat intolerance, chest pain, or insomnia). Monitor pulse rate, blood pressure, and vital signs. In children, sleeping pulse rate and basal temperature can be used as guides to the adequacy of the clinical response to treatment.

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The hypothalamic-pituitary-thyroid axis. Levels of circulating thyroid hormones are regulated by a complex feedback system involving the hypothalamus and pituitary gland.

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Author

Philip R Orlander, MD, FACP Professor, Department of Internal Medicine, Director, Division of Endocrinology, Diabetes and Metabolism, Associate Dean for Educational Programs, Vice-Chair of Medicine for Education, Edward Randall III Chair in Internal Medicine, Program Director, Endocrinology, Diabetes and Metabolism Fellowship Program, University of Texas Health Science Center at Houston, McGovern Medical School

Philip R Orlander, MD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, Endocrine Society, Harris County Medical Society, Texas Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Jeena M Varghese, MD Assistant Professor, Department of Internal Medicine, Division of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center

Jeena M Varghese, MD is a member of the following medical societies: Endocrine Society, Harris County Medical Society, Texas Medical Association

Disclosure: Nothing to disclose.

Sapna Naik, MD Assistant Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, UTHealth, University of Texas Health Science Center at Houston, McGovern Medical School; Attending Physician, Department of Gastroenterology, Memorial Hermann Hospital – Texas Medical Center, and Lyndon B Johnson General Hospital

Sapna Naik, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Texas Medical Association

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for Physician Leadership, American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society, International Society for Clinical Densitometry, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

Lance M Freeman, MD Fellow, Division of Endocrinology, University of Texas Health Science Center at Houston

Disclosure: Nothing to disclose.

Acknowledgements

Anu Bhalla Davis, MD Assistant Professor, Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Texas Medical School at Houston