How do I diagnose hypothyroidism using thyroid‑stimulating hormone and free thyroxine levels, and what considerations apply for subclinical, central, pregnant, or elderly patients?

Diagnosis of Hypothyroidism

Primary Diagnostic Approach

Measure serum TSH as the first-line screening test, followed by free T4 if TSH is abnormal, to distinguish between subclinical and overt hypothyroidism. TSH demonstrates approximately 98% sensitivity and greater than 92% specificity for detecting thyroid dysfunction, making it the most reliable initial test 1, 2. When TSH is elevated, measure free T4 to differentiate subclinical hypothyroidism (normal free T4) from overt hypothyroidism (low free T4) 1.

Initial Testing Algorithm

• Step 1: Obtain serum TSH in any patient with suspected hypothyroidism 1, 2
• Step 2: If TSH is elevated (>4.5 mIU/L), measure free T4 to determine disease severity 1, 3
• Step 3: Confirm persistent elevation by repeating TSH and free T4 after 3–6 weeks, as 30–60% of initially elevated TSH values normalize spontaneously 1

Diagnostic Categories

Overt hypothyroidism is defined by elevated TSH with low free T4, representing clear thyroid hormone deficiency requiring treatment 4, 5. Subclinical hypothyroidism is characterized by elevated TSH (typically 4.5–10 mIU/L) with normal free T4 and T3, often without overt symptoms 5, 3.

Subclinical Hypothyroidism: Severity Stratification

The TSH level determines both prognosis and treatment urgency 1, 3:

• TSH >10 mIU/L: Carries approximately 5% annual risk of progression to overt hypothyroidism and warrants treatment regardless of symptoms 1, 5
• TSH 4.5–10 mIU/L: Lower progression risk; treatment decisions should be individualized based on symptoms, antibody status, and patient characteristics 1, 3

Confirmatory Testing

Before initiating treatment, repeat TSH and free T4 after 2–3 months because transient TSH elevations are common during recovery from acute illness, after iodine exposure, or in the recovery phase of thyroiditis 1, 3. Measure anti-thyroid peroxidase (anti-TPO) antibodies to identify autoimmune thyroiditis, which predicts higher progression risk (4.3% vs 2.6% annually in antibody-negative individuals) 1, 3.

Central (Secondary) Hypothyroidism

In central hypothyroidism, TSH is low or inappropriately normal despite low free T4, reflecting pituitary or hypothalamic dysfunction 4, 5. This pattern requires different diagnostic and treatment approaches:

• Measure free T4 alongside TSH in patients with pituitary disease or symptoms despite normal TSH 1
• Before starting levothyroxine, assess morning cortisol and ACTH to exclude adrenal insufficiency, as thyroid hormone replacement can precipitate adrenal crisis 1, 4
• Evaluate other pituitary hormones, particularly the hypothalamic-pituitary-adrenal axis 5

Special Population Considerations

Pregnant Women

• Any TSH elevation in pregnancy warrants treatment, targeting TSH <2.5 mIU/L in the first trimester 1, 5
• Untreated maternal hypothyroidism increases risk of preeclampsia, low birth weight, and neurodevelopmental impairment in offspring 1
• Levothyroxine requirements typically increase 25–50% during pregnancy 1

Elderly Patients (>70–80 Years)

• Age-adjusted reference ranges should be considered, as approximately 12% of persons aged ≥80 years have TSH >4.5 mIU/L without thyroid disease 1, 3
• For TSH 4.5–10 mIU/L in asymptomatic elderly patients, a "wait-and-see" strategy is often appropriate 3
• When treatment is indicated, start levothyroxine at low doses (25–50 mcg daily) to avoid cardiac complications 1, 5

Patients on Immune Checkpoint Inhibitors

• Thyroid dysfunction occurs in 6–9% with anti-PD-1/PD-L1 therapy and 16–20% with combination immunotherapy 1
• Monitor TSH every 4–6 weeks for the first 3 months, then every second cycle 1
• Consider treatment even for subclinical hypothyroidism if fatigue or other symptoms are present 1

Critical Diagnostic Pitfalls

• Never treat based on a single elevated TSH value without confirmation, as transient elevations normalize in 30–60% of cases 1, 3
• Exclude transient causes before diagnosing chronic hypothyroidism: acute illness, recent iodine exposure (CT contrast), recovery from thyroiditis, or medications (lithium, amiodarone, interferon) 1
• In suspected central hypothyroidism, always rule out adrenal insufficiency before starting levothyroxine to prevent life-threatening adrenal crisis 1, 4, 5
• Do not rely on imaging (ultrasound, CT, MRI) to diagnose hypothyroidism, as thyroid size and appearance cannot differentiate etiologies 1

Monitoring After Diagnosis

• Recheck TSH and free T4 every 6–8 weeks during dose titration until target TSH (0.5–4.5 mIU/L) is achieved 1
• Once stable, monitor TSH every 6–12 months or sooner if symptoms change 1, 3
• Free T4 helps interpret ongoing abnormal TSH during therapy, as TSH may take longer to normalize 1