What is the recommended clinical assessment, diagnostic workup, and management for patients with suspected thyroid disorders?

Thyroid Disorders: Clinical Assessment, Diagnostic Workup, and Management

Initial Clinical Assessment

Begin by measuring serum TSH as the first-line screening test, which has >98% sensitivity and >92% specificity for detecting thyroid dysfunction. 1, 2

Key Clinical Features to Assess

For suspected hypothyroidism, look for:

• Severe fatigue interfering with daily activities (68-83% of patients) 3
• Unexplained weight gain (24-59% of patients) 3
• Cognitive impairment including memory loss and difficulty concentrating (45-48%) 3
• Cold intolerance 3
• Menstrual irregularities (approximately 23%), including oligomenorrhea and menorrhagia 3
• Delayed ankle reflexes 2
• Bradycardia and diastolic dysfunction 2

For suspected hyperthyroidism, assess for:

• Anxiety, insomnia, and palpitations 4
• Unintentional weight loss 4
• Heat intolerance and diarrhea 4
• Tremor 5
• Diffusely enlarged thyroid gland, stare, or exophthalmos (in Graves disease) 4
• Dysphagia, orthopnea, or voice changes (with toxic nodules causing compression) 4

High-Risk Populations Requiring Aggressive Case Finding

Target TSH testing in these specific groups 1:

• Women older than 60 years 1
• Patients with previous thyroid radiation (radioactive iodine or external beam) 1
• Those with prior thyroid surgery or dysfunction 1
• Type 1 diabetes mellitus 1
• Personal history of autoimmune disease 1
• Family history of thyroid disease 1
• Atrial fibrillation 1

Diagnostic Algorithm

Step 1: Measure TSH

If TSH is abnormal, proceed to free T4 measurement to distinguish subclinical from overt disease. 2

Step 2: Interpret Results

For elevated TSH:

• TSH >10 mIU/L with normal free T4 = Subclinical hypothyroidism requiring treatment 2
• TSH >10 mIU/L with low free T4 = Overt hypothyroidism requiring immediate treatment 3
• TSH 4.5-10 mIU/L with normal free T4 = Mild subclinical hypothyroidism; treatment individualized based on symptoms, pregnancy status, or positive anti-TPO antibodies 2

For suppressed TSH:

• TSH <0.1 mIU/L with elevated free T4/T3 = Overt hyperthyroidism 4
• TSH <0.1 mIU/L with normal free T4/T3 = Subclinical hyperthyroidism 4

Step 3: Confirm Persistent Abnormality

Repeat TSH and free T4 after 3-6 weeks before initiating treatment, as 30-60% of elevated TSH values normalize spontaneously. 2 This step is critical to avoid treating transient thyroid dysfunction from acute illness, medications, or recovery from thyroiditis 2.

Step 4: Determine Etiology

For hypothyroidism:

• Measure anti-TPO antibodies to identify Hashimoto thyroiditis (the cause in up to 85% of cases in iodine-sufficient areas) 3
• Positive anti-TPO antibodies predict 4.3% annual progression to overt hypothyroidism versus 2.6% in antibody-negative patients 2

For hyperthyroidism:

• Measure TSH-receptor antibodies to diagnose Graves disease 4
• If thyroid nodules are present or etiology is unclear, obtain thyroid scintigraphy 4
• Radionuclide uptake helps distinguish Graves disease (diffusely increased uptake) from thyroiditis (decreased uptake) or toxic nodular goiter (focal uptake) 6

For thyroid nodules:

• Perform fine needle aspiration cytology (FNAC) for any nodule >1 cm 1
• For nodules <1 cm, perform FNAC only if clinical suspicion exists (history of head/neck irradiation, family history of thyroid cancer, suspicious palpation features, cervical adenopathy) or ultrasonographic features suggest malignancy (hypoechogenicity, microcalcifications, absence of peripheral halo, irregular borders, regional lymphadenopathy) 1
• Measure serum calcitonin as part of the diagnostic evaluation to detect medullary thyroid cancer, which has higher sensitivity than FNAC for this cancer type 1

Management of Hypothyroidism

Treatment Initiation

Levothyroxine is the first-line treatment for hypothyroidism. 3

Initiate treatment immediately for:

• TSH >10 mIU/L regardless of symptoms (carries ~5% annual risk of progression to overt hypothyroidism) 2
• Any TSH elevation with low free T4 (overt hypothyroidism) 3
• Pregnant women or those planning pregnancy with any TSH elevation 2

Critical Safety Consideration

Before starting levothyroxine, rule out concurrent adrenal insufficiency by measuring morning cortisol and ACTH, especially in patients with suspected central hypothyroidism or autoimmune disease. Starting thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis 2. If adrenal insufficiency is present, initiate hydrocortisone (20 mg morning, 10 mg afternoon) for at least one week before levothyroxine 2.

Dosing Strategy

For patients <70 years without cardiac disease:

• Start with full replacement dose of approximately 1.6 mcg/kg/day 2

For patients >70 years or with cardiac disease/multiple comorbidities:

• Start with 25-50 mcg/day and titrate gradually by 12.5-25 mcg every 6-8 weeks 2
• This conservative approach prevents unmasking cardiac ischemia or precipitating arrhythmias 2

Monitoring Protocol

Recheck TSH and free T4 every 6-8 weeks during dose titration until target TSH of 0.5-4.5 mIU/L is achieved. 2 Once stable, monitor TSH every 6-12 months or sooner if symptoms change 2.

Common Pitfalls to Avoid

Overtreatment occurs in 14-21% of treated patients and approximately 25% are unintentionally maintained on doses sufficient to fully suppress TSH. 2 This increases risk for:

• Atrial fibrillation (3-5 fold increase, especially in patients >60 years) 2
• Osteoporosis and fractures (particularly in postmenopausal women) 2
• Cardiovascular mortality 2

If TSH falls <0.1 mIU/L, reduce levothyroxine by 25-50 mcg immediately. 2 For TSH 0.1-0.45 mIU/L, reduce by 12.5-25 mcg, particularly in elderly or cardiac patients 2.

Management of Hyperthyroidism

Treatment Options

In the United States, radioactive iodine is the treatment of choice for Graves disease, toxic multinodular goiter, and toxic adenoma in patients without contraindications. 6

For Graves disease specifically:

• First-line treatment is a 12-18 month course of antithyroid drugs 7
• Alternative options include radioactive iodine or thyroidectomy 7
• Long-term antithyroid drug therapy is also an acceptable option 7

For toxic nodular goiter:

• Radioactive iodine or surgery are preferred 7

For thyroiditis:

• Symptomatic treatment is usually sufficient because the hyperthyroidism is transient 6
• Glucocorticoid therapy may be used in specific cases 7

Treatment for Subclinical Hyperthyroidism

Treatment is recommended for patients at highest risk:

• Those older than 65 years 4
• Persistent serum TSH <0.1 mIU/L 4
• Patients at risk for osteoporosis or cardiovascular disease 4

Management of Thyroid Cancer

Initial Treatment for Differentiated Thyroid Carcinoma (DTC)

Perform careful neck ultrasound before surgery to assess lymph node status. 1

Total or near-total thyroidectomy is indicated when:

• Diagnosis is made before surgery and nodule is ≥1 cm 1
• Any size if metastatic, multifocal, or familial DTC 1

Less extensive surgery may be acceptable for:

• Unifocal DTC diagnosed at final histology after surgery for benign disease 1
• Tumor is small, intrathyroidal, and favorable histology (classical papillary, follicular variant of papillary, or minimally invasive follicular) 1

Post-Surgical Management

Radioiodine ablation (131-I) is indicated:

• In high-risk patients 1
• NOT indicated in very low-risk patients (unifocal T1 tumors <1 cm with favorable histology, no extrathyroidal extension, no lymph node metastases) 1
• Decision must be individualized for intermediate-risk patients 1

TSH suppressive therapy with levothyroxine should be initiated immediately after surgery. 1 Target TSH levels vary by risk stratification:

• Low-risk patients with excellent response: TSH 0.5-2 mIU/L 2
• Intermediate-to-high risk patients with biochemical incomplete response: TSH 0.1-0.5 mIU/L 2
• Structural incomplete response: TSH <0.1 mIU/L 2

Follow-Up Protocol

At 2-3 months post-treatment:

• Check thyroid function tests (FT3, FT4, TSH) to verify adequacy of LT4 suppressive therapy 1

At 6-12 months:

• Physical examination 1
• Neck ultrasound 1
• Basal and rhTSH-stimulated serum thyroglobulin measurement with or without diagnostic whole body scan 1

Subsequent follow-up for disease-free patients:

• Physical examination, basal serum Tg measurement on LT4 therapy, and neck ultrasound once per year 1

Medullary Thyroid Cancer (MTC)

Before surgery, obtain:

• Basal serum calcitonin and CEA 1
• Serum calcium 1
• Plasma or 24-hour urine metanephrines and normetanephrines (to screen for pheochromocytoma in MEN 2) 1

Surgical treatment:

• Total thyroidectomy with bilateral prophylactic central lymph-node dissection for patients without evidence of lymph node metastases 1
• Lateral neck dissection reserved for patients with positive preoperative imaging 1

Post-operative management:

• Replacement thyroxine to maintain TSH within normal range (NOT suppressive therapy) 1
• Monitor serum calcitonin (and CEA in specific cases) 1
• Calcitonin doubling time is paramount for follow-up 1

Special Populations

Pregnancy

For women planning pregnancy:

• Treat any TSH elevation, targeting TSH <2.5 mIU/L in first trimester 2
• Subclinical hypothyroidism during pregnancy is associated with preeclampsia, low birth weight, and potential neurodevelopmental effects in offspring 2

Levothyroxine requirements increase by 25-50% during pregnancy in women with pre-existing hypothyroidism. 2 Monitor TSH every 4 weeks during pregnancy until stable, then at minimum once per trimester 2.

Elderly Patients

For patients >70 years:

• Start levothyroxine at 25-50 mcg/day 2
• Use smaller dose increments (12.5 mcg) to avoid cardiac complications 2
• Consider slightly higher TSH targets (up to 5-6 mIU/L may be acceptable in very elderly patients) 2
• Approximately 12% of persons aged ≥80 years have TSH >4.5 mIU/L without underlying thyroid disease 2

Patients on Immune Checkpoint Inhibitors

Thyroid dysfunction occurs in 6-9% with anti-PD-1/PD-L1 therapy and 16-20% with combination immunotherapy. 2

Management approach:

• Monitor TSH every 4-6 weeks for first 3 months, then every second cycle 2
• Consider treatment even for subclinical hypothyroidism if fatigue or other symptoms present 2
• Continue immunotherapy in most cases; thyroid dysfunction rarely requires treatment interruption 2

Key Caveats

Do not screen asymptomatic populations. The USPSTF found insufficient evidence that screening or treating thyroid dysfunction in asymptomatic adults improves quality of life, cardiovascular outcomes, or mortality 1, 2.

Recognize transient causes of abnormal thyroid function tests:

• Acute illness or hospitalization 2
• Recent iodine exposure (e.g., CT contrast) 2
• Recovery phase from thyroiditis 2
• Certain medications (lithium, amiodarone, interferon) 2

Never treat based on a single abnormal TSH value. Confirm with repeat testing because 30-60% of elevated TSH values normalize spontaneously 2.

TSH secretion is highly variable, with day-to-day fluctuations up to 50% of mean values and intra-day variation up to 40% 2. Serial measurements are required for reliable interpretation 2.