What is the next step in management for a patient with normal thyroid function tests and liver enzymes, but symptoms of fatigue, hypotension, and bradycardia, while taking Propylthiouracil (PTU)?

Differential Diagnosis for Fatigue, Hypotension, and Bradycardia on PTU with Normal Laboratory Values

The most critical next step is to immediately evaluate for PTU-induced hepatotoxicity with a comprehensive hepatic panel including ALT, AST, alkaline phosphatase, bilirubin, INR, and albumin, even though initial liver enzymes were normal, as PTU hepatotoxicity can develop rapidly and progress to fulminant hepatic failure. 1, 2

Immediate Reassessment of Hepatic Function

Despite your report of "normal liver enzymes," PTU-induced hepatotoxicity remains the most dangerous possibility that must be urgently excluded:

• PTU hepatotoxicity can develop suddenly after weeks of therapy, with liver injury appearing even when initial monitoring was normal 1, 2
• Obtain a complete hepatic panel including ALT, AST, alkaline phosphatase, total and direct bilirubin, INR, and albumin immediately 1, 2
• PTU-induced hepatitis typically presents with fatigue as the predominant symptom, often before jaundice or other overt signs develop 1, 2
• The timeline matters: symptoms developing after 2-6 weeks of PTU therapy are particularly concerning for drug-induced hepatotoxicity 2

Critical Endocrine Evaluation Beyond Standard Tests

Adrenal Insufficiency Workup

Even with a "normal cortisol level," you must determine the context and adequacy of adrenal testing:

• A single random cortisol is insufficient to exclude adrenal insufficiency - you need an 8 AM cortisol level with simultaneous ACTH 3
• If morning cortisol is <10 mcg/dL or in an indeterminate range (10-18 mcg/dL), perform an ACTH stimulation test 3
• Check basic metabolic panel specifically for hyponatremia and hyperkalemia, which suggest primary adrenal insufficiency 3
• Evaluate for orthostatic hypotension (>20 mmHg systolic drop or >10 mmHg diastolic drop on standing) 3

Hypophysitis and Central Hypothyroidism

Your patient has normal peripheral thyroid hormones (FT4, FT3) with normal TSH, but this pattern can mask central hypothyroidism:

• In hypophysitis, TSH may be inappropriately "normal" despite low thyroid hormones, or both may appear deceptively normal in early/partial pituitary dysfunction 3, 4
• Measure 8 AM ACTH and cortisol simultaneously to evaluate for central adrenal insufficiency 3
• Check FSH, LH, testosterone (men) or estradiol (women) to assess for additional pituitary hormone deficiencies 3
• Obtain MRI of the sella with pituitary cuts to evaluate for pituitary enlargement, stalk thickening, or suprasellar convexity 3
• Hypophysitis presents with headache (85%) and fatigue (66%) - ask specifically about headache and visual changes 3

Cardiovascular Evaluation

The combination of hypotension and bradycardia requires cardiac assessment:

• Obtain 12-lead ECG to evaluate for conduction abnormalities, low voltage (suggesting pericardial effusion or infiltrative disease), or ischemic changes 3
• Check BNP or NT-proBNP to exclude heart failure as a cause of fatigue and hypotension 3
• Perform echocardiography if BNP is elevated or if clinical suspicion for cardiac dysfunction exists 3
• Hypothyroidism causes cardiac dysfunction including delayed relaxation and abnormal cardiac output, even when thyroid tests appear normal in central disease 4

Additional Laboratory Evaluation

Hematologic Assessment

• Recheck complete blood count with differential, as you mentioned "normal white blood cell count" but did not specify hemoglobin 3
• Anemia commonly causes fatigue and can coexist with thyroid or endocrine disorders 3
• Check iron studies (serum iron, ferritin, transferrin saturation) as iron deficiency is a common cause of fatigue 3

Metabolic and Nutritional Evaluation

• Measure vitamin B12 and folate levels, as deficiencies cause fatigue and can coexist with autoimmune thyroid disease 3
• Check 25-hydroxyvitamin D level, as deficiency is associated with fatigue 3
• Verify fasting glucose and HbA1c to exclude diabetes as a cause of fatigue 3

Autoimmune and Inflammatory Markers

• Measure anti-TPO antibodies if not already done, as positive antibodies indicate autoimmune thyroid disease and predict progression 4
• Check ESR and CRP to screen for inflammatory or rheumatologic conditions 3
• Consider ANA and rheumatoid factor if clinical features suggest connective tissue disease 3

Medication Review and Drug-Induced Causes

PTU-Specific Toxicity Beyond Hepatotoxicity

• PTU can cause agranulocytosis - verify that the "normal white blood cell count" includes an absolute neutrophil count >1500/μL 2
• PTU-induced vasculitis can present with fatigue and hypotension - examine for rash, arthralgias, or hematuria 2
• Review for recent paracetamol (acetaminophen) use, as regular paracetamol combined with PTU increases hepatotoxicity risk 1

Other Medication Effects

• Review all medications for drugs that cause bradycardia (beta-blockers, calcium channel blockers, digoxin, amiodarone) 3
• Check for medications causing hypotension (antihypertensives, diuretics, alpha-blockers) 3
• Evaluate for drugs that can suppress TSH or alter thyroid function tests (glucocorticoids, dopamine, NSAIDs) 5

Thyroid Storm Recovery Phase

Consider whether this patient recently had thyroid storm or severe thyrotoxicosis:

• Thyroid storm can be followed by a recovery phase with transient hypothyroidism requiring temporary thyroid hormone replacement 3, 4
• In the recovery phase from thyroiditis, TSH can be transiently elevated or normal while the patient remains symptomatic 4
• If the patient had recent radioactive iodine therapy, thyroid storm can occur 2-3 weeks post-treatment 1

Nonthyroidal Illness Syndrome

Severe systemic illness can suppress thyroid function tests:

• In critically ill patients, TSH and thyroid hormones may appear normal or low despite underlying thyroid dysfunction 4
• Evaluate for occult infection, malignancy, or severe systemic disease 3
• Consider chest X-ray to exclude pneumonia or other pulmonary pathology 3

Algorithmic Approach to This Patient

Immediate (within 24 hours):

1. Comprehensive hepatic panel (ALT, AST, ALP, bilirubin, INR, albumin) 1, 2
2. 8 AM cortisol and ACTH 3
3. Basic metabolic panel for sodium, potassium 3
4. 12-lead ECG 3
5. Complete blood count with differential and absolute neutrophil count 2

If hepatic panel is abnormal:

• Immediately discontinue PTU 1, 2
• Initiate supportive care with IV fluids 1
• Consider prednisone 50-60 mg daily for severe hepatitis 1, 2
• Monitor INR and consider vitamin K if coagulopathy develops 1
• Switch to alternative therapy (methimazole if no allergy, or definitive therapy with radioactive iodine or surgery) 2

If adrenal insufficiency is confirmed:

• Start hydrocortisone 20-30 mg in morning and 10-20 mg in early afternoon immediately 3
• Add fludrocortisone 0.1 mg daily if primary adrenal insufficiency (high ACTH, low cortisol) 3
• Provide stress-dose steroids (2-3 times maintenance) if symptomatic 3
• Never start or increase thyroid hormone before initiating corticosteroids, as this can precipitate adrenal crisis 3, 4

If hypophysitis is suspected:

• Obtain MRI sella with pituitary cuts 3
• Measure FSH, LH, and sex hormones 3
• Initiate physiologic glucocorticoid replacement before any thyroid hormone 3
• Endocrinology consultation is mandatory 3

If cardiac dysfunction is identified:

• Treat underlying heart failure per guidelines 3
• Optimize volume status 3
• Consider cardiac MRI if infiltrative cardiomyopathy suspected 3

Common Pitfalls to Avoid

• Never assume "normal" liver enzymes exclude PTU hepatotoxicity - hepatitis can develop rapidly after initial normal monitoring 1, 2, 6
• Do not rely on a single random cortisol to exclude adrenal insufficiency - timing and ACTH are critical 3
• Never dismiss normal peripheral thyroid hormones as excluding central hypothyroidism - TSH may be inappropriately normal in hypophysitis 3, 4
• Do not overlook the recovery phase of thyroiditis, where transient hypothyroidism can occur despite normal initial tests 4
• Never start thyroid hormone replacement before ruling out and treating adrenal insufficiency - this can precipitate life-threatening adrenal crisis 3, 4
• Do not forget that PTU causes agranulocytosis - verify absolute neutrophil count, not just total WBC 2