What is the appropriate workup and treatment for a patient with a low Thyroid-Stimulating Hormone (TSH) level indicating hyperthyroidism?

Low TSH Workup

Initial Confirmation and Assessment

Repeat TSH measurement along with free T4 and free T3 after 3-6 weeks to confirm the finding, as TSH can be transiently suppressed by acute illness, medications, or physiological factors 1, 2. A single borderline TSH value should never trigger treatment decisions, as 30-60% of mildly abnormal TSH levels normalize spontaneously on repeat testing 1.

Distinguish Between Subclinical and Overt Hyperthyroidism

• Grade I Subclinical Hyperthyroidism: TSH 0.1-0.4 mIU/L with normal free T4 and T3 3
• Grade II Subclinical Hyperthyroidism: TSH <0.1 mIU/L with normal free T4 and T3 3
• Overt Hyperthyroidism: Suppressed TSH with elevated free T4 and/or T3 2

Determine the Etiology

First-Line Testing

Measure TSH-receptor antibodies (TRAb) to identify Graves' disease, which accounts for 70% of hyperthyroidism cases 4, 2. Positive TRAb confirms Graves' disease as the etiology 4.

Additional Diagnostic Tools

• Thyroid peroxidase antibodies (TPO): Helps identify autoimmune thyroid disease 4
• Thyroid ultrasonography: Evaluates for nodules, goiter size, and thyroid architecture 4
• Thyroid scintigraphy with radioactive iodine uptake: Recommended if thyroid nodules are present or the etiology is unclear 2
  • Diffusely increased uptake: Graves' disease 5, 4
  • Focal increased uptake: Toxic adenoma or toxic multinodular goiter (16% of cases) 4, 6
  • Low or absent uptake: Thyroiditis (3% of cases) or exogenous thyroid hormone 4

Drug-Induced Hyperthyroidism

Evaluate medication history for amiodarone, tyrosine kinase inhibitors, and immune checkpoint inhibitors, which account for 9% of hyperthyroidism cases 4.

Risk Stratification and Treatment Indications

When to Treat Subclinical Hyperthyroidism

Treatment is recommended for patients at highest risk of osteoporosis and cardiovascular disease, particularly those older than 65 years or with persistent serum TSH <0.1 mIU/L 2. Grade II subclinical hyperthyroidism (TSH <0.1 mIU/L) carries significantly higher risk than Grade I 3.

Cardiovascular Risks

• Atrial fibrillation risk increases 3-5 fold with TSH 0.1-0.4 mIU/L, especially in patients over 60 years 1
• All-cause and cardiovascular mortality increase up to 2.2-fold and 3-fold respectively in individuals older than 60 years with TSH below 0.5 mIU/L 1
• Obtain ECG to screen for atrial fibrillation, especially if patient is >60 years or has cardiac disease 1

Bone Health Risks

• Meta-analyses demonstrate significant bone mineral density loss in postmenopausal women with TSH suppression 1
• Women over 65 with TSH ≤0.1 mIU/L have increased risk of hip and spine fractures 1
• Consider bone density assessment in postmenopausal women with persistent TSH suppression 1

Treatment Options Based on Etiology

Graves' Disease

In the United States, radioactive iodine is the treatment of choice in patients without contraindications 5. However, three treatment modalities are effective:

Antithyroid Drugs (Methimazole or Propylthiouracil)

• Methimazole is preferred except in first trimester of pregnancy 7
• Standard course is 12-18 months, but recurrence occurs in approximately 50% of patients 4
• Long-term treatment (5-10 years) is associated with fewer recurrences (15%) compared to short-term treatment 4
• Risk factors for recurrence: Age <40 years, FT4 ≥40 pmol/L, TSH-binding inhibitory immunoglobulins >6 U/L, goiter size ≥WHO grade 2 4

Critical Monitoring for Methimazole 7:

• Patients should report immediately any evidence of illness, particularly sore throat, skin eruptions, fever, headache, or general malaise
• White blood cell and differential counts should be obtained if agranulocytosis is suspected
• Monitor prothrombin time, especially before surgical procedures
• Monitor thyroid function tests periodically during therapy

Radioactive Iodine (131I)

• Well tolerated with only long-term sequela being risk of radioiodine-induced hypothyroidism 6
• Can be used in all age groups except children, pregnancy, and lactation 6
• Pregnancy should be avoided for 4 months following administration 6
• May cause deterioration in Graves' ophthalmopathy; corticosteroid cover may reduce this risk 6

Surgery (Subtotal or Near-Total Thyroidectomy)

• Reserved for patients who refuse radioiodine or have large goiter causing compressive symptoms 6
• Goal is to cure underlying pathology while leaving residual thyroid tissue to maintain euthyroidism 6

Toxic Nodular Goiter (Toxic Adenoma or Toxic Multinodular Goiter)

The treatment of choice is radioiodine 6. Antithyroid drugs will not cure hyperthyroidism associated with toxic nodular goiter 6. Surgery is an alternative option 6, and radiofrequency ablation is rarely used 4.

Thyroiditis (Subacute Granulomatous Thyroiditis)

Symptomatic treatment usually is sufficient because the associated hyperthyroidism is transient 5. Destructive thyrotoxicosis is usually mild and transient, requiring steroids only in severe cases 4.

Special Populations

Pregnant or Breastfeeding Patients

• Methimazole crosses placental membranes and can induce goiter and cretinism in the developing fetus 7
• Due to rare occurrence of congenital malformations with methimazole, it may be appropriate to use propylthiouracil in first trimester during organogenesis 7
• Consider switching from propylthiouracil to methimazole for second and third trimesters given potential maternal hepatotoxicity of propylthiouracil 7
• Methimazole is present in breast milk, but studies found no effect on clinical status in nursing infants 7
• Monitor infant thyroid function at frequent (weekly or biweekly) intervals 7

Patients with Graves' Ophthalmopathy

Radioiodine may cause deterioration in Graves' ophthalmopathy; corticosteroid cover may reduce the risk of this complication 6.

Patients on Levothyroxine with Iatrogenic Hyperthyroidism

• For TSH <0.1 mIU/L: Decrease levothyroxine dose by 25-50 mcg immediately 1
• For TSH 0.1-0.45 mIU/L: Decrease levothyroxine dose by 12.5-25 mcg, particularly in elderly or cardiac patients 1
• Recheck TSH and free T4 in 6-8 weeks after dose adjustment 1

Common Pitfalls to Avoid

• Never treat based on single TSH value without confirmation testing 1, 2
• Do not overlook non-thyroidal causes of TSH suppression, particularly acute illness, medications, or recent iodine exposure 1
• Failing to distinguish between patients who require TSH suppression (thyroid cancer) and those who don't (primary hyperthyroidism) 1
• For patients with known nodular thyroid disease, be cautious with iodine exposure (e.g., radiographic contrast agents) as this may exacerbate hyperthyroidism 1