Management of Hypothyroidism
Primary Treatment: Levothyroxine Monotherapy
Levothyroxine (T4) is the first-line and standard treatment for all forms of hypothyroidism, whether overt or subclinical, primary or central. 1, 2, 3, 4
The superiority of levothyroxine stems from its consistent potency, ability to restore normal constant serum levels of both T4 and T3 through peripheral conversion, ease of laboratory interpretation, long serum half-life allowing once-daily dosing, excellent safety profile, and low cost. 3, 4, 5
Diagnosis and Confirmation
Initial Testing
- Measure serum TSH as the primary screening test for suspected thyroid dysfunction, with sensitivity above 98% and specificity greater than 92%. 1, 2
- Confirm any abnormal TSH with repeat testing after 3-6 weeks, as 30-60% of elevated TSH values normalize spontaneously. 1, 2
- Measure both TSH and free T4 to distinguish between subclinical hypothyroidism (elevated TSH with normal free T4) and overt hypothyroidism (elevated TSH with low free T4). 1, 2
Additional Diagnostic Testing
- Check anti-thyroid peroxidase (anti-TPO) antibodies to confirm autoimmune etiology (Hashimoto's thyroiditis), which predicts higher progression risk to overt hypothyroidism (4.3% per year vs 2.6% in antibody-negative individuals). 1, 6
- Review lipid profiles, as hypothyroidism affects cholesterol metabolism. 1
Critical pitfall: Never treat based on a single elevated TSH value without confirmation testing, as transient elevations from nonthyroidal illness, medications, or recovery-phase thyroiditis are common. 1
Treatment Algorithm Based on TSH Levels
TSH >10 mIU/L (Regardless of Symptoms)
Initiate levothyroxine therapy immediately for all patients with confirmed TSH >10 mIU/L, regardless of age or symptoms. 1, 2, 3
This threshold carries approximately 5% annual risk of progression to overt hypothyroidism and is associated with increased cardiovascular risk, including heart failure. 1, 6 Treatment may improve symptoms, lower LDL cholesterol, and prevent progression to overt disease. 1, 3
TSH 4.5-10 mIU/L (Subclinical Hypothyroidism)
Routine levothyroxine treatment is NOT recommended for asymptomatic patients with TSH 4.5-10 mIU/L. 1, 2, 3
Instead, monitor thyroid function tests every 6-12 months. 1 However, consider treatment in these specific situations:
- Pregnant women or those planning pregnancy (any TSH elevation warrants treatment to prevent adverse pregnancy outcomes including preeclampsia, low birth weight, premature delivery, and impaired fetal neurocognitive development). 1, 2, 7, 3
- Symptomatic patients with fatigue, weight gain, cold intolerance, or constipation may benefit from a 3-4 month trial of levothyroxine. 1, 3
- Patients with positive anti-TPO antibodies, who have 4.3% annual progression risk versus 2.6% in antibody-negative patients. 1, 3
- Patients with infertility or goiter. 3
Important caveat: Treatment should probably be avoided in patients aged >85 years with TSH ≤10 mIU/L, as limited evidence suggests potential harm in this population. 3
Initial Levothyroxine Dosing
Young, Healthy Adults (<70 years, No Cardiac Disease)
Start with full replacement dose of approximately 1.6 mcg/kg/day. 1, 3
This approach rapidly normalizes thyroid function in patients without cardiac risk factors. 1
Elderly Patients (>70 years) or Those with Cardiac Disease
Start with a lower dose of 25-50 mcg/day and titrate gradually. 1, 7, 3
Elderly patients and those with coronary artery disease are at increased risk of cardiac decompensation, angina, or arrhythmias even with therapeutic levothyroxine doses. 1 Atrial fibrillation is the most common arrhythmia observed with levothyroxine overtreatment in the elderly. 7
Patients with Long-Standing Severe Hypothyroidism
Start with lower doses (25-50 mcg/day) regardless of age to avoid unmasking or worsening cardiac ischemia. 3
Pediatric Patients
Initiate levothyroxine therapy immediately upon diagnosis to prevent adverse effects on cognitive development and physical growth. 7
For pediatric patients at risk for hyperactivity, start at one-fourth the recommended full replacement dosage and increase weekly by one-fourth until full dose is reached. 7
Dose Titration and Monitoring
During Initial Titration
- Monitor TSH and free T4 every 6-8 weeks after initiating therapy or changing dosage. 1, 3
- Adjust levothyroxine dose by 12.5-25 mcg increments based on current dose and patient factors. 1
- Use larger increments (25 mcg) for younger patients without cardiac disease; use smaller increments (12.5 mcg) for elderly or cardiac patients. 1
- Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize. 1
Critical pitfall: Avoid adjusting doses too frequently before reaching steady state—wait 6-8 weeks between adjustments. 1
Target TSH Levels
- For primary hypothyroidism: Target TSH 0.5-4.5 mIU/L with normal free T4. 1, 3
- More specifically, aim for TSH 0.5-2.0 mIU/L for optimal replacement. 3
After Stabilization
- Monitor TSH every 6-12 months once adequately treated on a stable dose. 1, 2, 7
- Recheck sooner if symptoms change or clinical status changes. 1, 7
Special Monitoring for Pediatric Patients
Monitor TSH and total or free T4 at 2 and 4 weeks after initiation, 2 weeks after any dosage change, then every 3-12 months after stabilization until growth is completed. 7 Perform routine clinical examination including assessment of development, mental and physical growth, and bone maturation at regular intervals. 7
Special Populations
Pregnant Patients
For pre-existing hypothyroidism, measure TSH and free T4 as soon as pregnancy is confirmed and at minimum during each trimester. 7
Pregnancy increases levothyroxine requirements by 25-50% above pre-pregnancy doses. 1 Increase levothyroxine by 12.5-25 mcg/day to maintain TSH in trimester-specific reference range. 7 Monitor TSH every 4 weeks until stable. 7
Immediately after delivery, reduce levothyroxine to pre-pregnancy dose and monitor TSH 4-8 weeks postpartum. 7
For new-onset hypothyroidism during pregnancy with TSH ≥10 mIU/L, start 1.6 mcg/kg/day; for TSH <10 mIU/L, start 1.0 mcg/kg/day. 7
Central (Secondary/Tertiary) Hypothyroidism
Before initiating levothyroxine, rule out concurrent adrenal insufficiency, as starting thyroid hormone before corticosteroids can precipitate adrenal crisis. 1, 3, 5
Evaluate other pituitary hormones, especially the hypothalamic-pituitary-adrenal axis. 3 If hypocortisolism is present, start corticosteroids several days before initiating thyroid hormone. 1
Monitor serum free T4 levels (not TSH) and maintain in the upper half of the normal range. 7, 3
Patients on Immune Checkpoint Inhibitors
Thyroid dysfunction occurs in 5-10% with anti-PD-1/PD-L1 therapy and 20% with combination immunotherapy. 1 Consider treatment even for subclinical hypothyroidism if fatigue or other hypothyroid symptoms are present. 1 Continue immunotherapy in most cases, as thyroid dysfunction rarely requires treatment interruption. 1
Risks of Overtreatment
Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH (<0.1 mIU/L), creating iatrogenic hyperthyroidism. 1, 2
Serious Complications of Overtreatment Include:
- 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, 7
- Osteoporosis and fractures, particularly hip and spine fractures in women >65 years with TSH ≤0.1 mIU/L. 1, 2
- Increased cardiovascular mortality. 1
- Ventricular hypertrophy and abnormal cardiac output. 1, 2
Management of 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 by 12.5-25 mcg. 1 Recheck TSH and free T4 in 6-8 weeks. 1
For patients with atrial fibrillation, cardiac disease, or serious medical conditions, consider repeating testing within 2 weeks rather than waiting 6-8 weeks. 1
Common Causes of Inadequate Response to Treatment
If TSH remains elevated despite apparently adequate levothyroxine dosing, evaluate for:
- Poor compliance (most common cause). 3, 5
- Malabsorption syndromes (celiac disease, inflammatory bowel disease, autoimmune gastritis). 5
- Drug interactions (proton pump inhibitors, calcium, iron, bile acid sequestrants, soy products). 1, 5
- High fiber diet interfering with absorption. 5
- Taking levothyroxine with food rather than on an empty stomach. 5
- Pancreatic and liver disorders. 5
Critical pitfall: Failure to recognize transient hypothyroidism (from thyroiditis, medications, or nonthyroidal illness) may lead to unnecessary lifelong treatment. 1
Key Clinical Pearls
- Levothyroxine has a narrow therapeutic index—both overtreatment and undertreatment have serious consequences for cardiovascular function, bone metabolism, cognitive function, and quality of life. 7, 6
- Never discontinue levothyroxine during pregnancy; hypothyroidism diagnosed during pregnancy should be promptly treated. 7
- Levothyroxine is generally continued for life in patients with primary hypothyroidism. 7
- Compliance is compromised by daily fasting schedule—counsel patients to take levothyroxine on an empty stomach, 30-60 minutes before breakfast. 5
- Screening for hypothyroidism is not recommended for asymptomatic individuals; targeted testing is recommended only for high-risk patients (e.g., those with type 1 diabetes, first-degree relatives with hypothyroidism, history of neck radiation). 2, 6