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Am Fam Physician. 2021;103(10):605-613

Related letter: Weight-Based Levothyroxine Dosage Adjustment for Hypothyroidism

Related letter: Family Physicians Should Treat Pregnant Patients With Hypothyroidism

Patient information: A handout on this topic is available at https://familydoctor.org/condition/hypothyroidism/.

This clinical content conforms to AAFP criteria for CME.

Clinical hypothyroidism affects one in 300 people in the United States, with a higher prevalence among female and older patients. Symptoms range from minimal to life-threatening (myxedema coma); more common symptoms include cold intolerance, fatigue, weight gain, dry skin, constipation, and voice changes. The signs and symptoms that suggest thyroid dysfunction are nonspecific and nondiagnostic, especially early in disease presentation; therefore, a diagnosis is based on blood levels of thyroid-stimulating hormone and free thyroxine. There is no evidence that population screening is beneficial. Symptom relief and normalized thyroid-stimulating hormone levels are achieved with levothyroxine replacement therapy, started at 1.5 to 1.8 mcg per kg per day. Adding triiodothyronine is not recommended, even in patients with persistent symptoms and normal levels of thyroid-stimulating hormone. Patients older than 60 years or with known or suspected ischemic heart disease should start at a lower dosage of levothyroxine (12.5 to 50 mcg per day). Women with hypothyroidism who become pregnant should increase their weekly dosage by 30% up to nine doses per week (i.e., take one extra dose twice per week), followed by monthly evaluation and management. Patients with persistent symptoms after adequate levothyroxine dosing should be reassessed for other causes or the need for referral. Early recognition of myxedema coma and appropriate treatment is essential. Most patients with subclinical hypothyroidism do not benefit from treatment unless the thyroid-stimulating hormone level is greater than 10 mIU per L or the thyroid peroxidase antibody is elevated.

Hypothyroidism occurs when there is inadequate thyroid hormone production by the thyroid gland or insufficient stimulation by the hypothalamus or pituitary gland. Causes may include primary gland failure or can be iatrogenic, transient, or central (Table 1).14 Central causes, such as low levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4), are rare.

RecommendationSponsoring organization
Do not screen asymptomatic pregnant patients for subclinical hypothyroidism.Society for Maternal-Fetal Medicine
Do not order multiple tests for the initial evaluation of a patient with suspected thyroid disease. Order thyroid-stimulating hormone level and, if abnormal, follow up with additional evaluation or treatment depending on the findings.American Society for Clinical Pathology
Do not routinely order thyroid ultrasonography in patients with abnormal thyroid function tests if there is no palpable abnormality of the thyroid gland.Endocrine Society/American Association of Clinical Endocrinologists
Do not obtain a total or free triiodothyronine level when assessing levothyroxine dose in patients with hypothyroidism.Endocrine Society/American Association of Clinical Endocrinologists
Central (hypothalamic or pituitary)
Inappropriately normal or low levels of thyroid-stimulating hormone despite low thyroid hormone
Medications (amiodarone, immune checkpoint inhibitors, interleukin-2, interferon-alfa, lithium, tyrosine kinase inhibitors)*
Pituitary tumor or disorder
Iatrogenic
Hyperthyroid treatment (radioactive iodine or antithyroid medications)*
Radiation therapy to treat head and neck cancers*
Thyroid surgery*
Primary gland failure
Autoimmune thyroiditis
(Hashimoto thyroiditis)
Congenital abnormalities
Infiltrative diseases
Severe iodine deficiency or relative excess
Transient
Postpartum thyroiditis
Pregnancy
Silent thyroiditis
Subacute thyroiditis
Thyroiditis associated with thyroid-stimulating hormone receptor–blocking antibodies

Clinical hypothyroidism occurs in 0.3% of the U.S. general population, with a higher prevalence in people older than 65 years.57 It is seven times more common in females than in males (40 out of 10,000 vs. six out of 10,000).8 Other risk factors include autoimmune disease (e.g., type 1 diabetes mellitus, celiac disease, autoimmune gastric atrophy, multiple autoimmune endocrinopathies), Down syndrome, and Turner syndrome.2 Cigarette smoking and moderate alcohol intake decrease the risk of thyroid cancer and hypothyroidism.2,9 Untreated hypothyroidism can contribute to numerous physiologic and metabolic derangements.

Signs and symptoms are nonspecific and can vary in individual presentations (Table 2 and Table 31,3,10 ). Diagnosis is based on blood levels of decreased FT4, with a corresponding elevated thyrotropin (i.e., TSH) level in primary causes (thyroid source); the TSH level may be normal to low in secondary (pituitary source) or tertiary (hypothalamic source) causes.5 Subclinical hypothyroidism describes the state of normal FT4 levels when the TSH level is elevated. This article focuses on primary hypothyroidism in adults.

Bradycardia
Coarse facies
Cognitive impairment
Delayed relaxation phase of deep tendon reflexes
Diastolic hypertension
Edema
Goiter
Hoarseness
Hypothermia
Laboratory abnormalities
Anemia (normocytic)
Elevated C-reactive protein
Hyperprolactinemia
Hyponatremia
Increased creatine kinase
Increased low-density lipoprotein
Increased triglycerides
Proteinuria
Lateral eyebrow thinning
Low-voltage electrocardiography
Macroglossia
Pericardial effusion
Periorbital edema
Pleural effusion
Arthralgias
Cognitive impairment
Cold intolerance*
Constipation*
Depression
Difficulty focusing/concentrating
Dry skin*
Edema
Fatigue*
Hair changes (i.e., dryness, thinning, or loss)
Infertility
Lethargy*
Memory impairment
Menorrhagia
Muscle cramps
Myalgia
Voice changes*
Weakness
Weight gain*

Pathophysiology

A sensitive negative feedback loop regulates the thyroid hormone. The hypothalamus produces thyrotropin-releasing hormone that controls anterior pituitary gland secretion of TSH, regulating the secretion of thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) by the thyroid gland.11,12 Thyroid hormone affects the metabolism and function of many cells and organs. This central role is reflected by the signs and symptoms of thyroid dysregulation. Thyroid hormone also regulates thyroid metabolism by providing negative feedback to the hypothalamus and pituitary gland. The hypothalamus adjusts the release of thyrotropin-releasing hormone based on circulating levels of thyroid hormone. Together, these hormones regulate the secretion of TSH from the anterior lobe of the pituitary gland. This functioning feedback loop keeps the blood level of the thyroid hormone normal.

Screening

The U.S. Preventive Services Task Force concludes that there is insufficient evidence to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant, asymptomatic adults.13 Consider targeted screening at initial diagnosis or medication initiation in patients with Down syndrome, Turner syndrome, subtotal thyroidectomy, type 1 diabetes, autoimmune adrenal insufficiency (Addison disease), radioiodine treatment, radiation therapy of the neck, and use of medications such as amiodarone, lithium, interferons, and rifampin.2,3 Other medications that may prompt screening include tyrosine kinase inhibitors, phenobarbital, interleukin-2, and immune checkpoint inhibitors.3,14

Diagnosis

TSH elevation indicates hypothyroidism. Low-end normal TSH is 0.4 mIU per L.2,57 The upper-end normal range is from 4.0 to 4.5 mIU per L.2,57 FT4 level is used to distinguish clinical (low FT4) from subclinical (normal FT4) hypothyroidism. Routinely evaluating total T3, total T4, or FT3 levels is not indicated.2 Testing for the thyroid peroxidase (TPO) antibody does not help diagnose hypothyroidism; however, a positive test result suggests an autoimmune etiology.2 Thyroid ultrasonography is used to evaluate palpable thyroid nodules and is not part of routine evaluation.4

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