Residency · Residency · Family Medicine

Thyroid Disorders: Hypo- and Hyperthyroidism in Primary Care

Overview

Thyroid disorders are among the most common endocrine conditions encountered in primary care, affecting approximately 5% of the adult population. Hypothyroidism is far more prevalent than hyperthyroidism. Family physicians must be skilled at TSH-based screening, levothyroxine management, thyroid nodule evaluation, and the nuanced decision-making around subclinical disease.

Thyroid Physiology

The hypothalamic-pituitary-thyroid axis operates through a classic negative feedback loop. The hypothalamus releases TRH, which stimulates the anterior pituitary to secrete TSH. TSH drives the thyroid gland to produce predominantly T4 and a smaller amount of T3. Peripheral deiodinase enzymes convert T4 into the biologically active T3. As T3 and T4 levels rise, they suppress both TRH and TSH release. TSH is the most sensitive marker of thyroid function because it changes logarithmically in response to even small changes in free T4, making it the ideal first-line screening test.

Hypothyroidism

Etiology

Hashimoto thyroiditis is the most common cause of hypothyroidism in iodine-sufficient regions. It is an autoimmune process that gradually destroys thyroid tissue, with anti-TPO antibodies positive in 90 to 95% of cases. Iatrogenic causes include post-thyroidectomy, post-radioactive iodine ablation, and external radiation to the neck. Several medications can induce hypothyroidism, including amiodarone (which can cause both hypo- and hyperthyroidism), lithium, tyrosine kinase inhibitors, and immune checkpoint inhibitors. Iodine deficiency remains the most common cause worldwide. Central hypothyroidism, caused by pituitary or hypothalamic disease, presents with a low or inappropriately normal TSH alongside a low free T4. Transient hypothyroidism can follow subacute thyroiditis or postpartum thyroiditis.

Clinical Presentation

Classic symptoms include fatigue, cold intolerance, weight gain, constipation, and dry skin. Examination may reveal bradycardia, diastolic hypertension, and delayed relaxation of deep tendon reflexes. Menstrual irregularities, particularly menorrhagia, and infertility are common in women. Depression, cognitive slowing, and myalgias frequently accompany the condition. Myxedema, the most severe presentation, is a medical emergency characterized by hypothermia, altered mental status, and hypoventilation.

Diagnosis

Primary hypothyroidism is diagnosed by an elevated TSH with a low free T4. Subclinical hypothyroidism shows an elevated TSH with a normal free T4. Anti-TPO antibodies confirm an autoimmune etiology and predict the likelihood of progression from subclinical to overt disease.

Treatment: Levothyroxine (T4)

Levothyroxine is the standard treatment, with a full replacement dose of approximately 1.6 mcg/kg/day. In elderly patients and those with cardiac disease, therapy should start at 25 to 50 mcg/day with gradual titration every six to eight weeks. The medication should be taken on an empty stomach, 30 to 60 minutes before breakfast (or at bedtime, three hours after the last meal). Calcium, iron, proton pump inhibitors, and antacids must be separated from levothyroxine by at least four hours to avoid impaired absorption. TSH should be rechecked six to eight weeks after any dose change and, once stable, every 6 to 12 months. The target TSH for most adults is 0.5 to 2.5 mU/L, though higher targets of 4 to 6 mU/L are acceptable in the elderly. Formulation consistency matters, as some patients are sensitive to changes between brands or generic manufacturers.

T3 Supplementation Controversy

Liothyronine (T3) or combination T4/T3 therapy is not recommended by ATA guidelines. Some patients report persistent symptoms despite a normalized TSH on T4 alone, but no randomized controlled trials have demonstrated sustained benefit of combination therapy. Desiccated thyroid extract (Armour Thyroid) contains both T4 and T3 but in a non-physiologic ratio, with inconsistent dosing between lots.

Subclinical Hypothyroidism

Subclinical hypothyroidism, defined as TSH 4.5 to 10 mU/L with a normal free T4, has a prevalence of 4 to 10% and is more common in women and the elderly. Treatment is recommended when TSH exceeds 10, when anti-TPO antibodies are positive, when symptoms are present, during pregnancy or planning for pregnancy, or when a goiter is present. In elderly patients over 65 to 70, observation is often preferable, as the TRUST trial demonstrated no benefit from treatment of subclinical hypothyroidism in older adults and potential for harm. TSH should be repeated in two to three months before committing to treatment, as levels may normalize spontaneously.

Hyperthyroidism

Etiology

Graves disease is the most common cause in young adults. It is autoimmune in origin, driven by TSH receptor antibodies (TRAb/TSI), and has unique features including ophthalmopathy, pretibial myxedema, and thyroid acropachy. Toxic multinodular goiter is most common in the elderly and involves autonomous nodules functioning independently of TSH. Toxic adenoma is a single hyperfunctioning nodule. Thyroiditis (subacute or de Quervain, painless, or postpartum) causes transient thyrotoxicosis from release of preformed hormone, followed by a hypothyroid phase. Amiodarone causes two patterns: type 1 (iodine-induced synthesis of excess hormone) and type 2 (destructive thyroiditis). Rare causes include TSH-secreting pituitary adenoma, struma ovarii, and HCG-mediated thyrotoxicosis from molar pregnancy.

Clinical Presentation

Patients present with anxiety, tremor, heat intolerance, and weight loss despite increased appetite. Cardiovascular findings include tachycardia, atrial fibrillation, and widened pulse pressure. Hyperdefecation and menstrual irregularities (oligomenorrhea) are common. Lid lag and stare occur with all causes of hyperthyroidism, while proptosis and periorbital edema are specific to Graves disease. Thyroid storm is a life-threatening emergency presenting with fever, severe tachycardia, altered mental status, and multiorgan dysfunction.

Diagnosis

Overt hyperthyroidism shows a suppressed TSH (below 0.1 mU/L) with an elevated free T4. T3 thyrotoxicosis presents with a suppressed TSH, normal free T4, but elevated free T3. Subclinical hyperthyroidism shows a suppressed TSH with normal free T4 and T3. A radioactive iodine uptake scan differentiates Graves disease (diffuse uptake) from toxic nodular disease (focal uptake) and thyroiditis (low uptake). TSH receptor antibodies can confirm Graves disease and may obviate the need for a scan.

Treatment

Antithyroid Drugs

Methimazole is the preferred agent, starting at 10 to 30 mg daily depending on severity. It is titrated to the lowest effective dose with free T4 monitoring every four to six weeks initially. Side effects include rash, arthralgias, cholestatic hepatotoxicity, and agranulocytosis (occurring in 0.2 to 0.5% of patients). All patients must be warned to seek immediate care for fever or sore throat, as these may signal agranulocytosis requiring urgent CBC. A typical course for Graves disease is 12 to 18 months, with a 30 to 50% remission rate. Propylthiouracil (PTU) is reserved for the first trimester of pregnancy (methimazole is teratogenic, causing aplasia cutis and choanal atresia) and for thyroid storm, as it also blocks peripheral T4-to-T3 conversion. PTU carries a higher risk of hepatocellular toxicity that can be fatal.

Beta-Blockers

Propranolol (which also inhibits T4-to-T3 conversion) or atenolol should be started for symptomatic control of tachycardia, tremor, and anxiety, regardless of which definitive treatment is planned.

Radioactive Iodine (RAI)

RAI provides definitive treatment for Graves disease and toxic nodular disease. It usually results in permanent hypothyroidism, which is the expected outcome requiring lifelong levothyroxine replacement. It is contraindicated in pregnancy and breastfeeding. RAI may worsen Graves ophthalmopathy, and steroid prophylaxis should be considered for patients with active eye disease.

Surgery (Thyroidectomy)

Thyroidectomy is indicated for large goiters with compressive symptoms, when a suspicious coexisting nodule requires excision, for moderate-to-severe Graves ophthalmopathy, or based on patient preference. Risks include recurrent laryngeal nerve injury, hypoparathyroidism, and hypothyroidism.

Subclinical Hyperthyroidism

Subclinical hyperthyroidism, defined as a persistently suppressed TSH below 0.1 mU/L with normal free T4 and T3, increases the risk of atrial fibrillation, osteoporosis, and cardiovascular mortality. Treatment is recommended for grade II disease (TSH below 0.1) in patients over 65, postmenopausal women, those with cardiac risk factors, or those with osteoporosis. Observation with repeat testing in three to six months is appropriate for grade I disease (TSH 0.1 to 0.4) without risk factors.

Thyroid Nodule Evaluation

Prevalence and Risk

Thyroid nodules are found incidentally in 50 to 65% of adults on ultrasound, and the vast majority are benign. The cancer risk is approximately 5 to 15% of nodules. Features that increase malignancy suspicion include rapid growth, a fixed or hard nodule, cervical lymphadenopathy, voice hoarseness, family history of MEN2 or medullary thyroid cancer, and prior radiation exposure.

Evaluation Algorithm

The evaluation begins with TSH. If TSH is low, a radioactive iodine uptake scan should be obtained, as hyperfunctioning (hot) nodules are almost never malignant. Thyroid ultrasound characterizes the nodule, and the TI-RADS scoring system guides biopsy decisions. Fine-needle aspiration biopsy is recommended based on size and ultrasound features: nodules 1 cm or larger with suspicious features, 1.5 cm or larger with intermediate features, and 2 cm or larger with low-suspicion features. Spongiform or purely cystic nodules usually do not require biopsy.

The Bethesda classification of cytology results guides management. Category I (non-diagnostic) requires repeat FNA. Category II (benign) warrants surveillance. Category III (AUS/FLUS) may require repeat FNA or molecular testing. Category IV (follicular neoplasm) typically leads to lobectomy or molecular testing. Category V (suspicious for malignancy) usually leads to lobectomy or thyroidectomy. Category VI (malignant) requires thyroidectomy.

Molecular Testing

Molecular tests such as the Afirma Gene Sequencing Classifier and ThyroSeq v3 help reclassify indeterminate (Bethesda III/IV) nodules. Their high negative predictive value can prevent unnecessary surgery for patients with benign molecular profiles.

Thyroid Disease in Pregnancy

TSH reference ranges differ by trimester: approximately 0.1 to 2.5 in the first trimester, 0.2 to 3.0 in the second, and 0.3 to 3.5 in the third, though laboratory-specific ranges are preferred. Overt hypothyroidism requires aggressive treatment, with levothyroxine dose typically increased by 25 to 30% as soon as pregnancy is confirmed. Subclinical hypothyroidism in pregnancy should be treated if TPO antibodies are positive or TSH exceeds 4.0. For hyperthyroidism, PTU is used in the first trimester and methimazole in the second and third trimesters. Clinicians should distinguish Graves disease from gestational thyrotoxicosis, which is HCG-mediated, self-limited, and does not require antithyroid drugs.

<image>A diagnostic flowchart for thyroid function test interpretation starting with TSH as the initial test, branching into high TSH (check free T4 to differentiate overt from subclinical hypothyroidism) and low TSH (check free T4 and T3 to differentiate overt hyperthyroidism from subclinical), with further branches showing the appropriate next steps including antibody testing, RAIU scan, and treatment options for each diagnosis.</image>

<image>An ultrasound pattern recognition guide for thyroid nodules showing examples of benign features (purely cystic, spongiform, isoechoic with smooth margins) versus suspicious features (solid hypoechoic, microcalcifications, irregular margins, taller-than-wide, extrathyroidal extension) with corresponding TI-RADS scores and biopsy thresholds.</image>

<image>A comparison table infographic of the three definitive treatment options for Graves disease (antithyroid drugs, radioactive iodine, surgery) showing mechanism, success rate, timeline to euthyroidism, major risks, contraindications, and impact on Graves ophthalmopathy. Use a three-column layout with icons for each treatment modality.</image>

Clinical Pearls

TSH is the single best screening test for thyroid dysfunction; free T4 is only necessary when TSH is abnormal. In elderly patients over 70, subclinical hypothyroidism with TSH below 10 often does not require treatment and may represent an adaptive, protective response. Levothyroxine absorption is impaired by calcium, iron, PPIs, and coffee, making patient education on proper timing essential. Methimazole is teratogenic and must be switched to PTU during the first trimester. All patients starting methimazole must be warned about agranulocytosis and instructed to present urgently if they develop fever and sore throat. A suppressed TSH in the setting of a thyroid nodule should prompt a radioactive iodine uptake scan before FNA, as hot nodules rarely require biopsy. Amiodarone causes both hypothyroidism and hyperthyroidism, and TSH should be monitored every six months during and after its use. Thyroid storm has high mortality and should be suspected in any severely thyrotoxic patient presenting with fever, tachycardia, and altered mental status.

References

• Jonklaas J et al. ATA Guidelines for Treatment of Hypothyroidism. Thyroid. 2014
• Ross DS et al. ATA Guidelines for Diagnosis and Management of Hyperthyroidism. Thyroid. 2016
• Haugen BR et al. ATA Management Guidelines for Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016
• Stott DJ et al. TRUST Trial: Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. NEJM. 2017
• Tessler FN et al. ACR TI-RADS: Thyroid Imaging Reporting and Data System. J Am Coll Radiol. 2017
• Alexander EK et al. 2017 ATA Guidelines for Thyroid Disease During Pregnancy. Thyroid. 2017

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