What is the recommended management for hypothyroidism (underactive thyroid)?

Hypothyroidism Management

Initial Diagnosis and Treatment Initiation

Levothyroxine monotherapy is the first-line treatment for hypothyroidism, with dosing tailored to age and cardiac status. 1, 2

Diagnostic Confirmation Before Treatment

• Measure both TSH and free T4 to distinguish overt hypothyroidism (elevated TSH with low free T4) from subclinical hypothyroidism (elevated TSH with normal free T4). 1, 2
• TSH is the most sensitive screening test with sensitivity above 98% and specificity greater than 92%. 1, 2
• Consider anti-TPO antibody testing to identify autoimmune etiology (Hashimoto's thyroiditis), which predicts higher progression risk to overt hypothyroidism (4.3% vs 2.6% per year in antibody-negative individuals). 1, 2
• Confirm elevated TSH with repeat testing after 3-6 weeks, as 30-60% of elevated TSH levels normalize spontaneously. 1

Critical Pre-Treatment Safety Check

In patients with suspected central hypothyroidism or hypophysitis, always initiate corticosteroids BEFORE starting levothyroxine to prevent adrenal crisis. 1, 2

• Evaluate morning cortisol and ACTH if central hypothyroidism is suspected (low or inappropriately normal TSH with low free T4). 2
• Starting thyroid hormone before addressing adrenal insufficiency can precipitate life-threatening adrenal crisis. 1, 3

Levothyroxine Dosing Strategy

Initial Dosing Based on Patient Characteristics

For patients <70 years without cardiac disease:

• Start levothyroxine at full replacement dose of approximately 1.6 mcg/kg/day. 1, 2, 4
• This approach rapidly normalizes thyroid function and prevents complications. 1

For patients >70 years OR with cardiac disease/atrial fibrillation:

• Start at low dose of 25-50 mcg/day and titrate gradually. 1, 2, 5
• Increase by no more than 12.5-25 mcg increments every 6-8 weeks. 1, 2
• Elderly patients and those with coronary artery disease are at increased risk of cardiac decompensation, angina, or arrhythmias even with therapeutic doses. 1, 5, 6

Dose Adjustment Protocol

• Adjust levothyroxine dose in 12.5-25 mcg increments based on current dose and patient characteristics. 1, 2
• Use smaller increments (12.5 mcg) for elderly patients or those with cardiac disease to avoid cardiac complications. 1
• Larger adjustments may lead to overtreatment and should be avoided. 1

Monitoring and Target TSH Levels

Initial Monitoring During Dose Titration

• Recheck TSH and free T4 every 6-8 weeks after initiating therapy or changing dose until TSH normalizes. 1, 2, 6
• This 6-8 week interval represents the time needed to reach steady state. 1
• Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize. 1

Target TSH Range

For primary hypothyroidism, target TSH within the reference range of 0.5-4.5 mIU/L with normal free T4 levels. 1, 7

• More specifically, aim for TSH 0.5-2.0 mIU/L for optimal replacement. 7
• For patients with thyroid cancer, TSH targets vary by risk stratification and require endocrinologist consultation. 1

Long-Term Monitoring After Stabilization

• Once adequately treated with stable dose, repeat TSH testing every 6-12 months. 1, 2
• Recheck sooner if symptoms change or clinical status changes. 1

Treatment Based on TSH Levels

TSH >10 mIU/L (Regardless of Free T4)

Initiate levothyroxine therapy regardless of symptoms, as this level carries approximately 5% annual risk of progression to overt hypothyroidism. 1, 6

• Treatment may improve symptoms and lower LDL cholesterol. 1
• Evidence quality is rated as "fair" by expert panels. 1

TSH 4.5-10 mIU/L with Normal Free T4 (Subclinical Hypothyroidism)

Routine levothyroxine treatment is NOT recommended for all patients in this range. 1

• Monitor thyroid function tests at 6-12 month intervals. 1
• Consider treatment in specific situations:
  • Symptomatic patients with fatigue, weight gain, cold intolerance, or constipation may benefit from a 3-4 month trial of levothyroxine with clear evaluation of benefit. 1, 6
  • Pregnant women or those planning pregnancy should be treated at any TSH elevation due to risk of adverse pregnancy outcomes (preeclampsia, low birth weight, neurodevelopmental effects). 1, 5
  • Patients with positive anti-TPO antibodies have higher progression risk (4.3% vs 2.6% per year) and may benefit from treatment. 1, 7

Special Populations

Pregnancy

• Levothyroxine requirements increase by 25-50% during pregnancy. 1, 5
• Monitor TSH and adjust dose during pregnancy to prevent adverse outcomes. 5
• Return to pre-pregnancy dose immediately after delivery. 5
• Untreated maternal hypothyroidism is associated with spontaneous abortion, gestational hypertension, pre-eclampsia, stillbirth, premature delivery, and adverse fetal neurocognitive development. 5

Patients on Immune Checkpoint Inhibitors

• Thyroid dysfunction occurs in 5-10% with anti-PD-1/PD-L1 therapy and 20% with combination immunotherapy. 1
• Continue checkpoint inhibitors while treating hypothyroidism with standard levothyroxine replacement. 2
• Most patients develop permanent hypothyroidism requiring lifelong treatment. 2
• Consider treatment even for subclinical hypothyroidism if fatigue or other complaints are present. 1

Risks of Inadequate Treatment vs. Overtreatment

Undertreatment Risks

• Persistent hypothyroid symptoms (fatigue, weight gain, cognitive impairment, menstrual irregularities). 1, 6
• Cardiovascular dysfunction including delayed relaxation and abnormal cardiac output. 1, 6
• Adverse lipid profiles. 1
• Increased cardiovascular mortality. 2, 6
• In pregnancy: increased risk of miscarriage, preeclampsia, and impaired fetal neurodevelopment. 1, 5

Overtreatment Risks (TSH <0.1 mIU/L)

Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, significantly increasing morbidity risks. 1

• Atrial fibrillation and cardiac arrhythmias, especially in elderly patients (5-fold increased risk with TSH <0.4 mIU/L in those ≥45 years). 1, 2, 6
• Osteoporosis and increased fracture risk, particularly in postmenopausal women (hip and spine fractures in women >65 years with TSH ≤0.1 mIU/L). 1, 2
• Left ventricular hypertrophy and abnormal cardiac output. 1
• Increased cardiovascular mortality. 1, 2

Managing Overtreatment

If TSH is suppressed (<0.1 mIU/L), reduce levothyroxine dose by 25-50 mcg immediately. 1

• For TSH 0.1-0.45 mIU/L, reduce dose by 12.5-25 mcg, particularly if in the lower part of this range or in patients with atrial fibrillation or cardiac disease. 1
• Recheck TSH and free T4 in 6-8 weeks after dose adjustment. 1
• For patients with atrial fibrillation, cardiac disease, or serious medical conditions, consider repeating testing within 2 weeks. 1

Common Pitfalls to Avoid

• Do not treat based on a single elevated TSH value without confirmation, as 30-60% normalize spontaneously. 1
• Never start thyroid hormone before ruling out adrenal insufficiency in patients with suspected central hypothyroidism, as this can precipitate adrenal crisis. 1, 2, 3
• Avoid adjusting doses too frequently before reaching steady state—wait 6-8 weeks between adjustments. 1
• Do not assume hypothyroidism is permanent without reassessment—consider transient thyroiditis, especially in recovery phase. 1
• Failing to distinguish between patients requiring TSH suppression (thyroid cancer) versus those who don't (primary hypothyroidism) leads to inappropriate management. 1
• Underestimating fracture risk from even slight overdose, especially in elderly and postmenopausal women. 1

Medication Considerations

Levothyroxine Administration

• Take levothyroxine on an empty stomach, typically 30-60 minutes before breakfast, for optimal absorption. 8
• Many factors can impair absorption: malabsorption syndromes, autoimmune gastritis, pancreatic and liver disorders, drug interactions (calcium, iron, proton pump inhibitors), and high fiber diet. 8
• Non-compliance is the most common cause of persistent hypothyroidism despite adequate prescribed dose. 8

Alternative Thyroid Preparations

Levothyroxine monotherapy remains the standard of care. 7, 4, 9

• Levothyroxine is preferred because of consistent potency, restoration of normal constant serum levels of T4 and T3, ease of interpretation of thyroid hormone levels, long serum half-life, and low cost. 4, 9
• Combination therapy with levothyroxine plus liothyronine is not routinely recommended, though patients with DIO2 gene polymorphism may benefit. 1, 4
• Other preparations containing T3 (liothyronine, liotrix, desiccated thyroid) result in postabsorptive elevated T3 levels that may cause thyrotoxic symptoms and misleading estimates of thyroid dosage. 9