What is the diagnosis and treatment for a patient with suppressed Thyroid-Stimulating Hormone (TSH) levels, elevated Free Thyroxine (FT4) levels, and elevated Triiodothyronine (FT3) levels?

Overt Hyperthyroidism (Thyrotoxicosis)

Diagnosis

Your patient has overt hyperthyroidism (thyrotoxicosis), defined by suppressed TSH (<0.005 mIU/L) with elevated free T4 (2.60 ng/dL) and elevated T3 (35 pg/mL), indicating excess thyroid hormone that has suppressed pituitary TSH production through negative feedback. 1, 2, 3

• This biochemical pattern confirms thyrotoxicosis and requires immediate diagnostic workup to determine the underlying cause before initiating appropriate treatment 1, 4
• The combination of suppressed TSH with elevated thyroid hormones represents a serious medical disorder that can compromise life if left untreated 2, 5

Immediate Management

Start a non-selective beta-blocker immediately to control symptoms while determining the underlying cause. 1

• Carvedilol is preferred due to its alpha-receptor blocking capacity, which provides superior control of heart rate, tremor, anxiety, and palpitations 1
• Propranolol or atenolol are acceptable alternatives for symptomatic relief 1, 6
• Evaluate urgently for thyroid storm if the patient has fever, tachycardia out of proportion to fever, altered mental status, or cardiac arrhythmia—this is a medical emergency requiring immediate hospitalization 1

Determine the Underlying Cause

The next critical step is identifying the etiology, as this determines definitive treatment. 1, 3, 4

Diagnostic workup required:

• Measure TSH-receptor antibodies (TRAb) to diagnose or exclude Graves' disease, which is the most common cause (70% of cases) 3, 4, 5
• Thyroid ultrasound to assess gland size, vascularity, and presence of nodules 3, 7
• Thyroid scintigraphy with radioiodine or 99mTc-pertechnetate if nodules are present or etiology is unclear 1, 7
• Consider measuring thyroid peroxidase antibodies (anti-TPO) 4

Most likely etiologies based on prevalence:

• Graves' disease (70%): Diffusely enlarged thyroid, positive TRAb, diffuse uptake on scintigraphy, may have exophthalmos or stare 2, 3, 5
• Toxic nodular goiter (16%): Single or multiple nodules, focal uptake on scintigraphy, may have compressive symptoms (dysphagia, orthopnea, voice changes) 2, 3
• Thyroiditis (3%): Transient, low uptake on scintigraphy, negative TRAb 3, 7
• Drug-induced (9%): Recent exposure to amiodarone, tyrosine kinase inhibitors, or immune checkpoint inhibitors 8, 3

Definitive Treatment Based on Etiology

For Graves' Disease:

First-line treatment is methimazole (MMI) 10-30 mg daily for 12-18 months. 1

• Propylthiouracil (PTU) is reserved for specific situations: first trimester of pregnancy, methimazole allergy, or thyroid storm 1, 6
• PTU carries significant hepatotoxicity risk, including hepatic failure requiring transplantation or resulting in death, particularly in pediatric patients 6
• Initial PTU dosing for adults is 300 mg daily in divided doses; severe cases may require 400-900 mg daily 6
• Recheck thyroid function tests (TSH, free T4, free T3) every 4-6 weeks while titrating antithyroid drugs 1
• Target euthyroid state with TSH 0.5-4.5 mIU/L and normal free T4/T3 levels 1
• Recurrence after 12-18 months of antithyroid drugs occurs in approximately 50% of patients 3

For Toxic Nodular Goiter:

Radioactive iodine (131I) or thyroidectomy are the preferred treatments. 7

• Antithyroid drugs provide only temporary control and are not curative 7
• Radiofrequency ablation is rarely used 3
• The goal is to achieve euthyroid status 7

For Thyroiditis:

Conservative management during the thyrotoxic phase with beta-blockers for symptom control. 1, 7

• Do not use antithyroid drugs as this is destructive thyrotoxicosis, not increased hormone synthesis 1, 7
• Steroids are reserved only for severe cases 3
• Anticipate hypothyroidism developing approximately 1 month after the thyrotoxic phase, requiring levothyroxine replacement 1

Special Populations

Pregnancy:

• Switch from methimazole to propylthiouracil immediately, especially during the first trimester, to avoid methimazole teratogenicity 1, 6
• Radioactive iodine is absolutely contraindicated in pregnancy 1
• Thyroidectomy can be performed in the second trimester if necessary 1
• Untreated hyperthyroidism increases risk of maternal heart failure, spontaneous abortion, preterm birth, stillbirth, and fetal/neonatal hyperthyroidism 6

Patients on Immune Checkpoint Inhibitors:

• Thyroiditis is the most common cause, occurring in 6-9% with anti-PD-1/PD-L1 therapy and 10% with combination immunotherapy 8, 1
• Continue immunotherapy in most cases—high-dose corticosteroids are rarely required for thyroid dysfunction 8, 1
• Monitor TSH every cycle for the first 3 months, then every second cycle thereafter 8

Critical Monitoring and Safety

Patients on propylthiouracil require close surveillance for hepatotoxicity and agranulocytosis. 6

• Report immediately: sore throat, skin eruptions, fever, headache, general malaise (agranulocytosis warning signs) 6
• Report immediately: anorexia, pruritus, jaundice, light-colored stools, dark urine, right upper quadrant pain (hepatotoxicity warning signs) 6
• Obtain white blood cell and differential counts if illness symptoms develop 6
• Monitor liver function tests (bilirubin, alkaline phosphatase, ALT/AST) particularly in the first 6 months 6
• Monitor prothrombin time, especially before surgical procedures, as PTU may cause hypoprothrombinemia 6

Complications of Untreated Hyperthyroidism

Untreated hyperthyroidism causes cardiac arrhythmias, heart failure, osteoporosis, adverse pregnancy outcomes, unintentional weight loss, and increased mortality. 2, 3

• Atrial fibrillation is more common in severe hyperthyroidism (15.8% vs 0-5.4% in milder forms) 5
• Severe hyperthyroidism patients show higher heart rate, larger goiter, and more pronounced clinical signs than milder forms 5
• Younger age, presence of asthenia, and higher heart rate are independent clinical variables associated with severe hyperthyroidism 5

Common Pitfalls

• Never delay beta-blocker therapy while awaiting diagnostic workup—symptom control is essential and safe regardless of etiology 1
• Do not use antithyroid drugs for thyroiditis—this will not work and delays appropriate management 1, 7
• Do not miss thyroid storm—fever, extreme tachycardia, altered mental status, or arrhythmia require immediate hospitalization 1
• In pregnancy, never use radioactive iodine and switch from methimazole to PTU in the first trimester 1, 6
• Monitor closely for PTU hepatotoxicity, especially in the first 6 months—this can be fatal 6