Graves disease

A 38-year-old female presents with a 3-month history of weight loss despite a good appetite, palpitations, insomnia, anxiety, and a fine hand tremor. Heart rate is 110 beats per minute and blood pressure is 140/80 mm Hg. Examination reveals exophthalmos, a diffusely enlarged non-tender thyroid, and a fine tremor. Thyroid function tests show suppressed TSH with elevated free T3 and free T4. Thyroid-stimulating immunoglobulin is positive. Radioactive iodine uptake demonstrates diffuse increased uptake. Diagnosis?

Diagnosis is Graves Disease.

1. Definition

Graves disease is an autoimmune cause of hyperthyroidism caused by stimulating autoantibodies against the TSH receptor, resulting in excessive thyroid hormone synthesis and secretion.

It is the most common cause of hyperthyroidism in many iodine-sufficient populations.

2. Pathophysiology

1.      TSH receptor antibodies stimulate thyroid hormone synthesis and secretion

2.      Cause diffuse thyroid follicular hyperplasia and goiter

3.      Lead to suppression of pituitary TSH

4.      In thyroid eye disease, immune activation of orbital fibroblasts causes:

o    Glycosaminoglycan accumulation

o    Edema

o    Adipose tissue expansion

o    Extraocular muscle enlargement

5.      Smoking is an important modifiable risk factor for development and progression of thyroid eye disease

3. Clinical Features

3.1 Hyperthyroid Features

1.      Weight loss despite normal or increased appetite

2.      Heat intolerance and sweating

3.      Palpitations and tachycardia

4.      Fine tremor

5.      Anxiety and insomnia

6.      Hyperdefecation

7.      Proximal muscle weakness

8.      Atrial fibrillation, particularly in older patients

3.2 Thyroid Findings

1.      Diffuse, non-tender goiter

2.      Thyroid bruit may occur because of increased vascularity

3.3 Extrathyroidal Features

1.      Thyroid eye disease, including:

o    Proptosis

o    Eyelid retraction

o    Periorbital edema

o    Diplopia

o    Exposure keratopathy in severe disease

o    Compressive optic neuropathy in sight-threatening disease

2.      Pretibial myxedema, uncommon

3.      Thyroid acropachy, rare

4. Diagnostic Evaluation

4.1 Thyroid Function Tests

1.      Suppressed TSH

2.      Elevated free T4 and/or T3

3.      Predominant elevation of T3 may occur as T3 thyrotoxicosis

4.2 TSH Receptor Antibodies

1.      Positive TSH receptor antibodies (TRAb) or thyroid-stimulating immunoglobulin (TSI) strongly support Graves disease

2.      In the appropriate clinical setting, positive TRAb or TSI can establish the autoimmune etiology

4.3 Radioactive Iodine Uptake

1.      Graves disease typically shows diffuse, homogeneous increased radioactive iodine uptake

2.      This helps distinguish it from destructive thyroiditis, which typically shows low radioactive iodine uptake

3.      Radioactive iodine uptake testing is often unnecessary when the diagnosis is already established by typical clinical findings and positive TRAb or TSI

4.      Radioactive iodine should not be administered during pregnancy

5.      Diagnostic radionuclide testing during lactation requires isotope-specific precautions regarding interruption or cessation of breastfeeding

5. Management

5.1 Symptomatic Treatment

1.      Beta blockers, such as propranolol, atenolol, or metoprolol, help control:

o    Tachycardia

o    Palpitations

o    Tremor

o    Adrenergic symptoms

2.      At higher doses, propranolol also decreases peripheral conversion of T4 to T3

5.2 Antithyroid Drugs

1.      Methimazole is generally the preferred antithyroid drug for most nonpregnant adults

2.      It has a longer duration of action and a lower risk of severe hepatotoxicity compared with propylthiouracil

3.      Propylthiouracil (PTU) is preferred when antithyroid treatment is required during early pregnancy, generally through week 16

4.      Methimazole may be considered thereafter

5.      PTU is also commonly used in thyroid storm because it inhibits peripheral conversion of T4 to T3, although methimazole is also an effective thionamide option

6.      Important adverse effects include:

o    Agranulocytosis

o    Rash

o    Hepatotoxicity

7.      Patients taking antithyroid drugs should seek urgent medical evaluation for fever or sore throat because of the possibility of agranulocytosis

5.3 Radioactive Iodine Therapy

1.      Radioactive iodine is a definitive treatment that destroys thyroid tissue

2.      It commonly results in hypothyroidism requiring levothyroxine replacement

3.      It is contraindicated during pregnancy

4.      Therapeutic I-131 is contraindicated during breastfeeding

5.      It may worsen thyroid eye disease, particularly in patients with active disease or risk factors such as smoking

6.      It is generally avoided in active moderate-to-severe or sight-threatening thyroid eye disease

7.      Glucocorticoid prophylaxis may be considered in selected patients with thyroid eye disease who undergo radioactive iodine therapy

5.4 Thyroidectomy

Thyroidectomy may be preferred in patients with:

1.      Large or compressive goiter

2.      Suspicious thyroid nodules or coexisting thyroid cancer

3.      Need for rapid definitive control

4.      Significant thyroid eye disease when definitive treatment is required

5.      Contraindication to or preference against other therapies

6. Thyroid Eye Disease

Management includes:

1.      Achieving and maintaining euthyroidism

2.      Smoking cessation

3.      Ophthalmology assessment for clinically significant disease

4.      Urgent specialist evaluation for sight-threatening disease, particularly:

o    Compressive optic neuropathy

o    Severe corneal exposure

7. Complications

1.      Thyroid storm

2.      Atrial fibrillation

3.      Heart failure

4.      Osteoporosis and increased fracture risk

5.      Severe thyroid eye disease, including optic neuropathy and visual loss

8. Key Clinical Insight

Suppressed TSH + elevated T3/T4 + diffuse goiter + positive TSH receptor antibodies strongly indicate Graves disease.

Diffuse increased radioactive iodine uptake supports Graves disease and helps distinguish it from destructive thyroiditis.

Proptosis or other features of thyroid eye disease strongly support Graves disease as the cause of hyperthyroidism.

Methimazole is generally the preferred antithyroid drug for most nonpregnant adults. PTU is preferred when treatment is required during early pregnancy, generally through week 16, and is commonly used in thyroid storm.

References

1.      Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. doi:10.1089/thy.2016.0229.

2.      Burch HB, Perros P, Bednarczuk T, et al. Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association. Thyroid. 2022;32(12):1439-1470. doi:10.1089/thy.2022.0251.

3.      Korevaar TIM, Leung AM, Alexander EK, et al. American Thyroid Association 2026 Guidelines for Thyroid Disease in Preconception, Pregnancy, and Postpartum. Thyroid. 2026;36(5):481-544. doi:10.1177/10507256261445624.