What Human Leukocyte Antigen (HLA) is associated with an increased risk of developing Graves' disease?

HLA Association in Graves' Disease and Management

HLA-DR3 is the primary HLA antigen associated with Graves' disease, conferring a significant increased risk with an odds ratio of approximately 3.9-7.6. 1, 2, 3

HLA Associations in Graves' Disease

Primary HLA Association

• HLA-DR3 is the most strongly associated HLA antigen with Graves' disease
• HLA-B8 is also frequently found in patients with Graves' disease (often in linkage disequilibrium with DR3)
• The HLA-B8-DR3 haplotype confers even greater risk, particularly for persistent disease 2

Other HLA Associations

• DRB3*0101 has been identified as a significant risk factor, particularly in homozygous individuals 4
• Some studies suggest that HLA-DRB3*0101/*0202 heterozygosity is associated with increased risk of Graves' ophthalmopathy 4
• The combination of HLA-DR3 and a thyrotropin receptor codon 52 polymorphism appears to confer synergistic risk 3

Clinical Features of Graves' Disease

Classic Triad

1. Hyperthyroidism - weight loss, heat intolerance, tachycardia, tremor, anxiety
2. Goiter - diffuse, non-tender thyroid enlargement
3. Ophthalmopathy - proptosis, periorbital edema, extraocular muscle dysfunction

Other Clinical Manifestations

• Pretibial myxedema (dermopathy)
• Thyroid acropachy (clubbing)
• Onycholysis
• Vitiligo
• Increased risk of other autoimmune disorders (Hashimoto's thyroiditis, type 1 diabetes, celiac disease, Addison's disease, vitiligo, autoimmune hepatitis, myasthenia gravis, and pernicious anemia) 5

Diagnostic Approach

Laboratory Testing

1. Thyroid Function Tests:

   • Suppressed TSH
   • Elevated free T4 and/or T3

2. Antibody Testing:

   • TSH receptor antibodies (TRAb) - diagnostic for Graves' disease
   • Thyroid peroxidase antibodies (TPOAb) - often positive but not specific
   • Thyroglobulin antibodies (TgAb) - may be positive

3. Imaging (when diagnosis is uncertain):

   • Radioactive iodine uptake scan - diffusely increased uptake
   • Thyroid ultrasound - diffuse hypoechogenicity with increased vascularity

Management of Graves' Disease

First-Line Treatment Options

1. Antithyroid Drugs (ATDs):

   • Methimazole (preferred) or propylthiouracil (PTU)
   • Initial dosing based on severity: methimazole 10-30 mg daily or PTU 100-300 mg divided doses
   • Monitor thyroid function every 4-6 weeks initially
   • Treatment duration: 12-18 months
   • TRAb index at 12 months can predict relapse risk 6

2. Radioactive Iodine (RAI) Therapy:

   • Definitive treatment option
   • Contraindicated in pregnancy, breastfeeding
   • May worsen ophthalmopathy (pre-treatment with steroids may be needed)
   • Often leads to hypothyroidism requiring lifelong levothyroxine

3. Thyroidectomy:

   • Indicated for large goiters, suspected malignancy, pregnancy with ATD intolerance
   • Requires preoperative normalization of thyroid function
   • Risks include hypoparathyroidism, recurrent laryngeal nerve damage
   • Results in permanent hypothyroidism requiring lifelong levothyroxine

Adjunctive Treatments

1. Beta-blockers:

   • For symptomatic control (tachycardia, tremor, anxiety)
   • Propranolol 10-40 mg 3-4 times daily or longer-acting alternatives

2. Management of Ophthalmopathy:

   • Artificial tears, elevation of head during sleep
   • Selenium supplementation for mild cases
   • Glucocorticoids for moderate-severe cases
   • Orbital decompression surgery for severe cases

3. Treatment of Thyroid Storm (severe, life-threatening hyperthyroidism):

   • High-dose ATDs (PTU preferred due to additional T4→T3 conversion inhibition)
   • Beta-blockers, glucocorticoids, cooling measures
   • Supportive care in ICU setting

Prognostic Factors and Long-term Follow-up

• Presence of HLA-B8-DR3 haplotype is associated with persistent disease activity 2
• TRAb levels at 12 months can predict relapse risk for the next 3 years 6
• Regular monitoring of thyroid function is essential, especially after definitive treatment
• Screening for other autoimmune conditions should be considered

Special Considerations

• Pregnancy: ATDs are preferred (PTU in first trimester, methimazole thereafter); lowest effective dose
• Children: ATDs typically used for longer duration before considering definitive therapy
• Elderly: Higher risk of adverse effects from hyperthyroidism; definitive treatment often preferred

The management approach should be based on patient factors including age, disease severity, comorbidities, and patient preference, with the primary goal of reducing morbidity and mortality associated with hyperthyroidism while preserving quality of life.