How to evaluate and treat hypothyroidism?

Evaluation and Treatment of Hypothyroidism

Initial Diagnostic Evaluation

Measure serum TSH as the primary screening test for suspected hypothyroidism, followed by free T4 if TSH is abnormal. 1, 2

Laboratory Testing Algorithm

• TSH is the most sensitive initial test with sensitivity above 98% and specificity greater than 92% for detecting primary hypothyroidism 1
• If TSH is elevated, measure free T4 to distinguish between:
  • Overt hypothyroidism: elevated TSH with low free T4 1, 3
  • Subclinical hypothyroidism: elevated TSH with normal free T4 1, 4
• Confirm elevated TSH with repeat testing after 3-6 weeks, as 30-60% of elevated values normalize spontaneously 1
• Consider measuring anti-thyroid peroxidase (anti-TPO) antibodies to identify autoimmune etiology (Hashimoto's thyroiditis), which predicts higher progression risk: 4.3% per year versus 2.6% in antibody-negative individuals 1, 5

Clinical Presentation to Assess

• Fatigue (68-83% of patients), weight gain (24-59%), cognitive issues (45-48%) including memory loss and difficulty concentrating 3
• Cold intolerance, constipation, dry skin due to decreased metabolic rate 6
• Menstrual irregularities (approximately 23%) including oligomenorrhea and menorrhagia 3
• Physical examination findings have poor diagnostic accuracy (positive likelihood ratio 1.0-3.88) and cannot reliably confirm or exclude hypothyroidism without laboratory testing 7

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Treatment Initiation Based on TSH Levels

TSH >10 mIU/L (Regardless of Symptoms)

Initiate levothyroxine therapy immediately for all patients with TSH >10 mIU/L, as this threshold carries approximately 5% annual risk of progression to overt hypothyroidism. 1, 5, 4

• This recommendation applies regardless of symptoms or free T4 level 1
• 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 (Individualized Approach)

For TSH 4.5-10 mIU/L with normal free T4, routine levothyroxine treatment is NOT recommended; instead monitor thyroid function tests every 6-12 months. 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 1
• Positive anti-TPO antibodies indicating autoimmune etiology with higher progression risk 1, 5
• Women planning pregnancy or pregnant, as subclinical hypothyroidism is associated with preeclampsia, low birth weight, and potential neurodevelopmental effects 1, 2
• Patients with goiter or infertility 4

Avoid treatment in patients >85 years with TSH ≤10 mIU/L, as limited evidence suggests potential harm in this age group 4

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Levothyroxine Dosing Guidelines

Standard Adult Dosing

For patients <70 years without cardiac disease, start with full replacement dose of approximately 1.6 mcg/kg/day. 1, 5, 2

For patients >70 years or with cardiac disease/multiple comorbidities, start with 25-50 mcg/day and titrate gradually. 1, 5, 2

• Elderly patients with coronary disease are at increased risk of cardiac decompensation, angina, or arrhythmias even with therapeutic doses 1
• Lower starting doses minimize risk of exacerbating cardiac symptoms 1

Pregnancy-Specific Dosing

For pregnant patients with pre-existing hypothyroidism, increase levothyroxine by 12.5-25 mcg/day as soon as pregnancy is confirmed. 2

• Levothyroxine requirements typically increase 25-50% during pregnancy 1
• Monitor TSH every 4 weeks during pregnancy until stable, then each trimester 2
• Maintain TSH in trimester-specific reference range 2
• Reduce to pre-pregnancy dose immediately after delivery and monitor TSH 4-8 weeks postpartum 2

For new-onset hypothyroidism during pregnancy:

• TSH ≥10 mIU/L: start 1.6 mcg/kg/day 2
• TSH <10 mIU/L: start 1.0 mcg/kg/day 2

Critical Safety Consideration

In patients with suspected central hypothyroidism or concurrent adrenal insufficiency, start corticosteroids BEFORE initiating levothyroxine to prevent precipitating adrenal crisis. 1, 4

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Monitoring and Dose Adjustment

Initial Monitoring During Titration

Monitor TSH every 6-8 weeks after initiating treatment or changing dose. 1, 2

• Free T4 can help interpret ongoing abnormal TSH levels, as TSH may take longer to normalize 1
• Target TSH: 0.5-4.5 mIU/L for most patients 1, 4
• For central hypothyroidism, monitor free T4 and maintain in upper half of normal range 2

Dose Adjustment Protocol

Adjust levothyroxine in increments of 12.5-25 mcg based on current dose and patient factors. 1

• Use 25 mcg increments for patients <70 years without cardiac disease 1
• Use 12.5 mcg increments for patients >70 years or with cardiac disease 1
• Wait 6-8 weeks between dose adjustments to reach steady state 1

Long-Term Monitoring

Once TSH is stable at goal, monitor every 6-12 months or when clinical status changes. 1, 2

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Common Pitfalls and Critical Warnings

Risks of Overtreatment

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

Overtreatment (TSH <0.1 mIU/L) increases risk for:

• Atrial fibrillation and cardiac arrhythmias, especially in elderly patients 1, 3, 4
• Osteoporosis and fractures, particularly in postmenopausal women 1, 4
• Increased cardiovascular mortality 1
• Left ventricular hypertrophy and abnormal cardiac output 1

Risks of Undertreatment

Untreated or inadequately treated hypothyroidism can cause:

• Heart failure and increased cardiovascular events 3
• Myxedema coma (mortality rate up to 30%) with hypothermia, hypotension, and altered mental status requiring ICU care 3
• Infertility, disrupted ovulation, and increased miscarriage risk 3
• Insulin resistance and hyperglycemia in patients with diabetes 3
• Cognitive impairment and poor quality of life 1

Critical Diagnostic Pitfalls

• Never treat based on single elevated TSH value without confirmation, as 30-60% normalize spontaneously 1
• Do not rely on physical examination alone to diagnose hypothyroidism—laboratory testing is mandatory 7
• Rule out transient causes before initiating lifelong therapy: recent iodine exposure (CT contrast), acute illness, medications, or recovery from thyroiditis 1
• Check for adrenal insufficiency before starting levothyroxine in suspected central hypothyroidism 1, 4

Special Populations Requiring Modified Approach

Patients on immune checkpoint inhibitors:

• Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 therapy and 20% with combination immunotherapy 8
• Monitor TSH every cycle for first 3 months, then every second cycle 8
• Consider treatment even for subclinical hypothyroidism if fatigue or other complaints present 8
• Continue immunotherapy in most cases; rarely requires treatment interruption 8

Thyroid cancer patients requiring TSH suppression:

• Target TSH varies by risk stratification 1
• Low-risk with excellent response: TSH 0.5-2 mIU/L 1
• Intermediate-to-high risk with biochemical incomplete response: TSH 0.1-0.5 mIU/L 1
• Structural incomplete response: TSH <0.1 mIU/L 1