Graves’ Disease Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: This is the most common cause of hyperthyroidism in our population. You need to be able to recognise and manage it, especially its life-threatening complication, thyroid storm.
High-Yield Definition: Graves' disease is an autoimmune disorder characterised by the production of autoantibodies that bind to and stimulate the thyrotropin (TSH) receptor, resulting in unregulated thyroid hormone production and secretion. (Source: UpToDate).
Clinical One-Liner: The body's immune system is stuck on the accelerator pedal of the thyroid gland.
II. Etiology & Risk Factors
Etiology: Autoimmune production of TSH receptor antibodies (TRAb). The specific trigger is often unknown.
Risk Factors:
Female sex (8:1 ratio)
Age 20-50 years
Family history of autoimmune disease (thyroid or otherwise)
Smoking (strongest modifiable risk factor, especially for developing ophthalmopathy)
Significant life stress, recent infection
Postpartum period
III. Quick Pathophysiology
Stimulating TSH receptor antibodies (TRAb) mimic TSH. They bind to the TSH receptors on thyroid follicular cells, leading to two main consequences:
Hyperplasia: The gland grows, causing a diffuse goitre.
Hyperfunction: Uncontrolled synthesis and release of T4 and T3, leading to thyrotoxicosis.
The extrathyroidal signs (orbitopathy, dermopathy) are due to these same antibodies targeting TSH receptors on orbital fibroblasts and dermal fibroblasts, causing inflammation and glycosaminoglycan deposition.
IV. Classification
Classification is based on clinical presentation rather than a formal staging system. We think of it in terms of the three main clinical manifestations:
Hyperthyroidism (biochemically and clinically)
Graves' Orbitopathy (GO) or Thyroid Eye Disease (TED)
Dermopathy (typically pretibial myxedema)
V. Clinical Assessment
Red Flags & Immediate Actions
Thyroid Storm: Hyperpyrexia (>39.4°C), tachycardia out of proportion to fever (e.g., HR >140), marked agitation or delirium, cardiac failure, GI-hepatic dysfunction (jaundice).
Action: This is a medical emergency. Escalate to your senior/specialist immediately. Secure ABCs, send urgent labs, and initiate treatment (beta-blockers, antithyroid drugs, steroids). Do not wait for confirmation.
History
Key Diagnostic Clues: The classic triad is diffuse goitre, hyperthyroidism, and extrathyroidal manifestations (orbitopathy, pretibial myxedema).
Symptom Breakdown:
Common (>50%): Palpitations, heat intolerance, diaphoresis (sweating), fatigue, tremor, anxiety/irritability, weight loss despite normal or increased appetite, menstrual irregularity (oligomenorrhoea).
Less Common (10-50%): Diarrhoea, proximal muscle weakness, insomnia, signs of mild orbitopathy (grittiness, staring appearance).
Rare (<10%): Severe orbitopathy, pretibial myxedema, thyroid acropachy (clubbing).
Pertinent Negatives:
No neck pain or fever (makes subacute thyroiditis less likely).
No recent iodine contrast load or amiodarone use.
No consumption of traditional/herbal weight loss supplements.
Physical Examination (OSCE Approach)
General Inspection: Anxious, restless, sweaty. May have a visible goitre. Look for a "stare" from the end of the bed. Weight loss may be apparent.
Vitals: Sinus tachycardia or atrial fibrillation. Hypertension with a wide pulse pressure (e.g., 150/60 mmHg).
Disease-Specific Examination:
Neck:
Look: Symmetrical, diffuse enlargement of the thyroid gland.
Feel: Smooth, firm, non-tender goitre. No discrete nodules.
Auscultate: Listen for a thyroid bruit over the lateral lobes—this indicates high vascularity and is highly suggestive of Graves'.
Eyes (Graves' Orbitopathy):
Lid retraction (Dalrymple's sign - sclera visible above the iris).
Lid lag (von Graefe's sign - upper eyelid lags behind globe on downward gaze).
Proptosis/Exophthalmos: Eyeball protrusion (best viewed from above the patient).
Ophthalmoplegia: Check extraocular movements; may have diplopia on upward or lateral gaze.
Hands & Legs:
Fine tremor (place a paper on outstretched hands).
Warm, moist palms.
Pretibial myxedema: "Peau d'orange" (orange peel) appearance—thickened, indurated skin over the shins.
Thyroid acropachy: Clubbing (rare).
Clinical Pearl: If you feel a diffuse goitre in a young, thyrotoxic patient, you must specifically look for the eye signs and listen for a bruit. Finding any of these makes Graves' the top diagnosis.
VI. Diagnostic Workflow
Differential Diagnosis
Toxic Multinodular Goitre (TMNG):
Points For: Thyrotoxicosis.
Points Against: Palpably nodular goitre, usually in older patients, no orbitopathy or bruit.
How to Differentiate: Thyroid ultrasound.
Subacute Thyroiditis (de Quervain's):
Points For: Thyrotoxicosis, sometimes a goitre.
Points Against: Prodromal viral illness, tender/painful neck, high ESR/CRP.
How to Differentiate: Clinical history and a thyroid uptake scan (uptake is low/absent in thyroiditis, high in Graves').
Anxiety Disorder:
Points For: Palpitations, tremor, anxiety.
Points Against: Normal appetite, no weight loss, no goitre, no eye signs.
How to Differentiate: Thyroid Function Test (TFT).
Investigations Plan
Bedside:
ECG: Sinus tachycardia is common. Look for Atrial Fibrillation.
First-Line Labs & Imaging:
Thyroid Function Test (TFT): The key test. Expect suppressed TSH (<0.01 mIU/L) with elevated Free T4 and/or Free T3. "T3 toxicosis" (normal T4, high T3) can occur.
FBC, RP, LFT: Baseline before starting antithyroid drugs (risk of agranulocytosis and hepatotoxicity).
Confirmatory / Gold Standard:
TSH Receptor Antibody (TRAb): A positive result confirms the diagnosis of Graves' disease. This is the definitive test.
Thyroid Radionuclide Uptake & Scan: Only necessary if TRAb is negative or the diagnosis is uncertain. Graves' shows diffuse, high uptake.
VII. Staging & Severity Assessment
Hyperthyroidism Severity: Assessed biochemically (how high are T3/T4) and clinically (degree of symptoms, presence of complications like AF or heart failure).
Graves' Orbitopathy (GO) Severity: We use the EUGOGO classification.
Mild: Minor impact on daily life (e.g., minor lid retraction, mild soft tissue involvement).
Moderate-to-Severe: Significant impact on daily life without sight loss (e.g., significant proptosis, troublesome diplopia).
Sight-Threatening: Optic neuropathy or corneal breakdown. Requires immediate ophthalmology referral and high-dose steroids.
VIII. Management Plan
A. Principle of Management
Control symptoms rapidly.
Restore and maintain a euthyroid state.
Induce long-term remission.
B. Immediate Stabilisation (The ABCDE Plan)
This is for Thyroid Storm only. For routine thyrotoxicosis, go to C.
A/B: High-flow oxygen.
C: IV access, aggressive fluid resuscitation.
D: IV Propranolol, high-dose Carbimazole or PTU via NG tube, IV Hydrocortisone, Lugol's iodine (1 hour after ATD).
E: Active cooling measures.
C. Definitive Treatment (The Ward Round Plan)
There are three main options. The choice depends on patient factors and preference.
Antithyroid Drugs (ATDs):
Symptomatic Control: Start Propranolol 20-40mg TDS immediately to control palpitations, tremor and anxiety.
First-Line ATD: Carbimazole 20-40mg OD. Counsel patient on side effects: minor (rash) and major (agranulocytosis - warn them to stop drug and seek immediate medical attention if they develop fever or sore throat).
Monitoring: Repeat TFT in 4-6 weeks and titrate dose accordingly. Treatment course is typically 12-18 months.
Radioactive Iodine (RAI) Therapy (I-131):
Mechanism: Destroys thyroid tissue, leading to permanent hypothyroidism.
Indications: Relapsed disease after ATDs, patient preference.
Contraindications: Pregnancy, breastfeeding, severe active orbitopathy (can worsen it).
Surgery (Total Thyroidectomy):
Indications: Large goitre with compressive symptoms, suspected malignancy, patient preference, or when ATD/RAI are contraindicated.
Pre-requisite: Patient must be made euthyroid with ATDs before surgery to prevent precipitating a thyroid storm.
D. Long-Term & Discharge Plan
Educate on medication compliance and side effects.
Advise on smoking cessation.
Regular follow-up with TFT monitoring.
Patients treated with RAI or surgery will require lifelong levothyroxine replacement.
IX. Complications
Immediate: Thyroid Storm (high mortality if missed).
Short-Term / Cardiac: Atrial fibrillation (requires anticoagulation based on CHA₂DS₂-VASc score), high-output cardiac failure.
Long-Term:
Graves' Orbitopathy: Can progress even after the patient becomes euthyroid. Requires ophthalmology co-management.
Osteoporosis: Due to increased bone turnover from excess thyroid hormone.
X. Prognosis
With treatment, prognosis is excellent.
Remission rate after an 18-month course of ATDs is around 50%.
Poor prognostic factors for remission (i.e., higher chance of relapse):
High TRAb levels at diagnosis/end of treatment
Large goitre size
Male sex
Smoker
XI. How to Present to Your Senior
Use the SBAR format. Be concise.
"Dr. [Senior's Name], referring a patient for your review.
S: This is [Patient Name], a 32-year-old lady in Bed 5, admitted for palpitations and weight loss.
B: She is clinically thyrotoxic with a heart rate of 110, has a diffuse non-tender goitre with a bruit, and bilateral exophthalmos.
A: My impression is new-onset Graves' disease.
R: I've sent off a TFT and TRAb. Her ECG shows sinus tachycardia. I would like to start her on Propranolol 20mg TDS and Carbimazole 30mg OD pending your review."
XII. Summary & Further Reading
Top 3 Takeaways:
Graves' is the top cause of hyperthyroidism; suspect it in any thyrotoxic patient with a diffuse goitre or eye signs.
Diagnosis is clinical, confirmed with TFT and a positive TRAb.
Management involves immediate symptom control with beta-blockers and definitive treatment with ATDs, RAI, or surgery. Always warn about agranulocytosis.
Key Resources:
Malaysian CPG for the Management of Type 2 Diabetes Mellitus (6th Edition, 2020) - Note: While there is no dedicated Malaysian CPG for thyrotoxicosis, this CPG has relevant sections and follows similar principles of endocrine management.
UpToDate: Search for "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment".
Amboss: Search for "Graves Disease".
