What is the diagnosis and treatment for a patient with low Thyroid-Stimulating Hormone (TSH) and elevated Thyroxine (T4) levels, indicating hyperthyroidism?

Hyperthyroidism: Low TSH with Elevated T4

Diagnosis

A low TSH with elevated T4 indicates hyperthyroidism, which requires immediate confirmation with free T3 measurement and determination of the underlying cause through TSH-receptor antibodies and thyroid imaging. 1, 2

Biochemical Confirmation

• Measure free T3 alongside TSH and free T4 to confirm overt hyperthyroidism (suppressed TSH with elevated T4 and/or T3) versus subclinical hyperthyroidism (suppressed TSH with normal T4 and T3) 1, 2
• TSH suppression with elevated free hormones definitively establishes the diagnosis of overt hyperthyroidism 2

Determining the Etiology

The most critical step after biochemical confirmation is identifying which disease is causing the hyperthyroidism:

Graves' Disease (70% of cases):

• Measure TSH-receptor antibodies (TRAb) - positive in Graves' disease 1
• Check thyroid peroxidase (TPO) antibodies 1
• Perform thyroid ultrasonography showing diffuse enlargement with increased vascularity 1
• Clinical findings: diffusely enlarged thyroid, stare, exophthalmos 2

Toxic Nodular Goiter (16% of cases):

• Thyroid scintigraphy is mandatory if thyroid nodules are present or etiology is unclear 2
• Shows focal areas of increased uptake (hot nodules) with suppression of surrounding tissue 1, 3
• Ultrasound reveals nodular architecture 1
• Clinical findings: symptoms from local compression (dysphagia, orthopnea, voice changes) 2

Destructive Thyroiditis (3% of cases):

• Subacute granulomatous thyroiditis or silent thyroiditis 1
• Scintigraphy shows low or absent uptake (distinguishes from Graves'/toxic nodules) 1
• Usually transient, self-limited 1

Drug-Induced (9% of cases):

• Amiodarone, tyrosine kinase inhibitors, immune checkpoint inhibitors 1
• History is key to diagnosis 1

Treatment

For Graves' Disease and Toxic Nodular Goiter

Antithyroid drugs (methimazole or propylthiouracil) are first-line treatment for Graves' hyperthyroidism, while toxic nodular goiter is preferably treated with radioiodine or thyroidectomy. 1, 2

Antithyroid Drug Therapy (Graves' Disease)

Methimazole is preferred over propylthiouracil except in specific circumstances:

• Use propylthiouracil in the first trimester of pregnancy due to lower risk of congenital malformations compared to methimazole 4, 5
• Switch to methimazole for second and third trimesters due to propylthiouracil's hepatotoxicity risk 4, 5
• Use propylthiouracil for thyroid storm or severe methimazole allergy 4

Standard Course (12-18 months):

• Recurrence occurs in approximately 50% of patients after standard 12-18 month course 1
• Higher recurrence risk with: age <40 years, FT4 ≥40 pmol/L, TSH-binding inhibitory immunoglobulins >6 U/L, goiter size ≥WHO grade 2 1

Long-Term Treatment (5-10 years):

• Associated with only 15% recurrence rate versus 50% with short-term treatment 1
• Consider for patients at high risk of recurrence 1

Critical Monitoring Requirements

For Methimazole: 4

• Monitor for agranulocytosis - instruct patients to report immediately: sore throat, fever, skin eruptions, general malaise
• Obtain white blood cell and differential counts if illness develops
• Monitor for vasculitis - report new rash, hematuria, decreased urine output, dyspnea, hemoptysis
• Check prothrombin time before surgical procedures (methimazole inhibits vitamin K activity)
• Monitor thyroid function tests periodically; rising TSH indicates need for dose reduction

For Propylthiouracil: 5

• Hepatotoxicity is the major concern - monitor liver function (bilirubin, alkaline phosphatase, ALT/AST) especially in first 6 months
• Report immediately: anorexia, pruritus, jaundice, light-colored stools, dark urine, right upper quadrant pain
• Monitor for agranulocytosis and vasculitis (same as methimazole)
• Check prothrombin time before surgical procedures

Drug Interactions (Both Agents)

Warfarin: Additional PT/INR monitoring required, especially before surgery 4, 5

Beta-blockers: Dose reduction needed when patient becomes euthyroid (hyperthyroidism increases clearance) 4, 5

Digoxin: Reduced dose needed when euthyroid (serum levels increase) 4, 5

Theophylline: Reduced dose needed when euthyroid (clearance decreases) 4, 5

For Toxic Nodular Goiter

Radioiodine (¹³¹I) or thyroidectomy are preferred treatments - antithyroid drugs rarely used 1

• Radiofrequency ablation is an emerging option 1

For Destructive Thyroiditis

Observation with supportive care is usually sufficient 1, 2

• Thyrotoxicosis is typically mild and transient 1
• Steroids reserved only for severe cases 1
• Beta-blockers for symptomatic relief of palpitations, tremor, anxiety 2

For Subclinical Hyperthyroidism

Treatment is recommended for patients at highest risk: 2

• Age >65 years
• Persistent TSH <0.1 mIU/L
• Presence of osteoporosis or cardiovascular disease
• These patients face increased risk of atrial fibrillation, heart failure, and bone loss 2

Critical Complications Requiring Urgent Management

Atrial fibrillation: Common complication requiring rate control and anticoagulation consideration 1, 2

Thyroid storm: Medical emergency requiring immediate intensive care 1

Pregnancy: Untreated hyperthyroidism causes maternal heart failure, spontaneous abortion, preterm birth, stillbirth, fetal/neonatal hyperthyroidism 4, 5

Osteoporosis: Untreated hyperthyroidism accelerates bone loss 2

Prognosis and Mortality

Hyperthyroidism is associated with increased mortality - prognosis improves with rapid and sustained control of hyperthyroidism 1, 2

• Untreated disease leads to cardiac arrhythmias, heart failure, unintentional weight loss 2
• Treatment should not be delayed once diagnosis is confirmed 1, 2