What are the differential diagnoses for a 55‑year‑old East Indian man with hyperthyroidism (suppressed TSH, free T3 greater than free T4), subjective fever, weight loss, mild elevation of liver enzymes (ALT 57 U/L, AST 36 U/L, alkaline phosphatase 148 U/L, GGT 98 U/L, normal bilirubin), normal liver ultrasound, negative HIV and hepatitis B and C serologies, elevated ferritin, elevated erythrocyte sedimentation rate, leukocytosis with left shift, hemoglobin 12 g/dL, normal platelets, and no orbitopathy or dermopathy?

Differential Diagnoses in a 55-Year-Old East Indian Man with Hyperthyroidism and Systemic Inflammation

The most likely diagnosis is subacute thyroiditis (likely viral or granulomatous), given the constellation of hyperthyroidism with subjective fever, elevated inflammatory markers (ESR 36, ferritin 498), leukocytosis with left shift, and the absence of orbitopathy or dermopathy that would suggest Graves' disease. 1, 2

Primary Differential Diagnoses

1. Subacute (Granulomatous) Thyroiditis – Most Likely

• Subacute thyroiditis typically presents with hyperthyroidism, fever, and elevated inflammatory markers following a viral upper respiratory infection, and can present as fever of unknown origin in 3% of hyperthyroid cases. 1, 2, 3
• The pattern of free T3 > free T4 with suppressed TSH is consistent with destructive thyrotoxicosis, where preformed thyroid hormone is released from inflamed thyroid tissue. 3, 4
• Subjective fever with elevated ESR (36) and ferritin (498) strongly supports an inflammatory thyroid process rather than autoimmune hyperthyroidism. 1, 2
• The absence of orbitopathy and dermopathy argues against Graves' disease, making subacute thyroiditis more probable. 3
• Leukocytosis with left shift (WBC 12.2) indicates an acute inflammatory or infectious process, which is characteristic of subacute thyroiditis but not typical of Graves' disease. 1, 2

Next diagnostic step: Obtain thyroid ultrasound looking for heterogeneous, hypoechoic areas with decreased vascularity; measure TSH receptor antibodies (TRAb) and thyroid peroxidase antibodies (TPO-Ab) to exclude Graves' disease; consider thyroid scintigraphy showing low uptake if diagnosis remains unclear. 3, 4

2. Graves' Disease with Concurrent Infection

• Graves' disease accounts for 70% of hyperthyroidism cases and presents with suppressed TSH and elevated free thyroid hormones. 3, 4
• However, the absence of orbitopathy (present in 25-50% of Graves' patients) and dermopathy makes this diagnosis less likely. 3
• The fever, leukocytosis, and elevated inflammatory markers suggest a concurrent infectious process rather than Graves' disease alone. 3
• TSH receptor antibodies (TRAb) would be elevated in Graves' disease (typically >6 U/L predicts recurrence), which should be measured to confirm or exclude this diagnosis. 3

Distinguishing feature: Graves' disease would show increased vascularity on thyroid ultrasound and increased uptake on radioiodine scintigraphy, whereas subacute thyroiditis shows decreased uptake. 3, 4

3. Drug-Induced Thyroiditis

• Drug-induced hyperthyroidism accounts for 9% of cases, with common culprits including amiodarone, tyrosine kinase inhibitors, and immune checkpoint inhibitors. 3, 4
• The patient history should be carefully reviewed for these medications, though none are mentioned in the presentation. 3
• Drug-induced thyroiditis can present with destructive thyrotoxicosis (low radioiodine uptake) similar to subacute thyroiditis. 3, 4

4. Toxic Nodular Goiter

• Toxic nodular goiter accounts for 16% of hyperthyroidism cases and typically occurs in older patients with longstanding goiter. 3
• The absence of information about thyroid examination limits assessment, but this diagnosis would be confirmed by thyroid ultrasound showing nodules and scintigraphy showing focal areas of increased uptake. 3, 4
• This diagnosis is less likely given the acute presentation with fever and systemic inflammation. 3

Hepatic Manifestations of Hyperthyroidism

Liver Enzyme Abnormalities

• Deranged liver enzymes occur in 15-76% of patients with untreated thyrotoxicosis, with the pattern in this patient (ALT 57, AST 36, ALP 148, GGT 98, normal bilirubin) consistent with hyperthyroid hepatopathy. 5, 6
• GGT is the most frequently abnormal liver enzyme in Graves' disease (74% of cases), followed by ALT (57%), ALP (39%), and AST (29%). 6
• The degree of liver enzyme elevation correlates more strongly with free T3 and free T4 levels than with TSH receptor antibody levels, suggesting direct thyrotoxic hepatocyte injury. 6
• Liver enzymes normalize in 77-83% of patients once antithyroid medications are initiated, typically within weeks to months of achieving euthyroidism. 5, 6

Critical pitfall: Do not attribute liver dysfunction solely to intrinsic liver disease without first treating the hyperthyroidism, as 1-2% of patients can develop fulminant hepatitis from thyrotoxicosis alone. 5

Hematologic Findings

• The mild anemia (Hgb 12 g/dL) can occur with hyperthyroidism due to increased plasma volume and accelerated red cell turnover. 3
• Leukocytosis with left shift suggests either subacute thyroiditis with inflammatory response or a concurrent infectious process. 1, 2
• Elevated ferritin (498) reflects acute inflammation rather than iron overload, consistent with subacute thyroiditis. 1, 2

Diagnostic Algorithm

Step 1: Measure TSH receptor antibodies (TRAb) and thyroid peroxidase antibodies (TPO-Ab) immediately. 3, 4

• If TRAb positive (>6 U/L): Graves' disease is confirmed
• If both negative: Subacute thyroiditis or toxic nodular goiter more likely

Step 2: Obtain thyroid ultrasound with Doppler. 3, 4

• Heterogeneous, hypoechoic areas with decreased vascularity → subacute thyroiditis
• Diffuse enlargement with increased vascularity → Graves' disease
• Discrete nodules → toxic nodular goiter

Step 3: If diagnosis remains unclear, obtain radioiodine uptake scan. 3, 4

• Low uptake (<5%) → destructive thyrotoxicosis (subacute thyroiditis, drug-induced)
• High uptake (>25%) → Graves' disease or toxic nodular goiter

Step 4: Monitor liver enzymes closely and initiate treatment based on etiology. 5, 6

Treatment Considerations Based on Etiology

If Subacute Thyroiditis (Most Likely)

• Destructive thyrotoxicosis is usually mild and transient, requiring steroids only in severe cases. 3
• Beta-blockers (e.g., propranolol 20-40 mg three times daily) for symptomatic relief of tachycardia and palpitations. 3
• NSAIDs or corticosteroids (prednisone 40 mg daily, tapered over 4-6 weeks) if severe pain or systemic symptoms. 1, 2
• Antithyroid drugs are NOT indicated because this is destructive thyrotoxicosis, not increased thyroid hormone synthesis. 3, 4
• Monitor for hypothyroid phase (occurs in 20-30% of cases) 4-8 weeks after presentation. 3

If Graves' Disease

• First-line treatment is a 12-18 month course of antithyroid drugs (methimazole preferred over propylthiouracil except in first trimester pregnancy or thyroid storm). 3, 4
• Start methimazole 10-20 mg daily (higher doses for severe hyperthyroidism with free T4 >40 pmol/L above normal). 3
• Monitor liver enzymes closely, as antithyroid drugs can cause hepatotoxicity, though liver dysfunction from hyperthyroidism itself typically improves with treatment. 5, 6
• Recurrence after 12-18 months of antithyroid drugs occurs in approximately 50% of patients; risk factors include age <40 years, free T4 ≥40 pmol/L, TRAb >6 U/L, and goiter ≥WHO grade 2. 3

Critical Pitfalls to Avoid

• Do not assume Graves' disease without measuring TRAb and performing imaging, as the absence of orbitopathy/dermopathy and presence of fever with inflammatory markers suggest subacute thyroiditis. 1, 2, 3
• Do not delay thyroid function testing in patients with fever of unknown origin, as subacute thyroiditis can present primarily with fever and minimal thyroid symptoms. 1, 2
• Do not attribute liver dysfunction to intrinsic liver disease without first treating hyperthyroidism, as liver enzymes normalize in 77-83% of cases with thyroid treatment alone. 5, 6
• Do not start antithyroid drugs empirically before confirming the diagnosis, as destructive thyrotoxicosis (subacute thyroiditis) does not respond to these medications and requires different management. 3, 4
• Maintain high clinical suspicion for thyroid storm if fever worsens or cardiovascular instability develops, as this is a medical emergency requiring immediate intervention. 7, 3