What are the signs and symptoms of Graves' disease and autoimmune thyroiditis?

Signs and Symptoms of Graves' Disease and Autoimmune Thyroiditis

Graves' Disease: Clinical Presentation

Graves' disease presents with hyperthyroidism caused by thyroid-stimulating hormone receptor (TSHR) autoantibodies that act as agonists, inducing excessive thyroid hormone secretion and releasing the thyroid gland from pituitary control. 1

Thyroid-Related Manifestations

• Hyperthyroidism symptoms include suppressed TSH with elevated free T4 and/or triiodothyronine 2
• Patients develop a hypermetabolic state with increased thyroid hormone production that persists until treated 2
• The thyroid gland undergoes hyperplasia and hyperfunction due to continuous TSHR antibody stimulation 3

Extrathyroidal Manifestations (Pathognomonic Features)

• Graves' ophthalmopathy (GO) occurs in approximately 30% of patients (984 of 3209 in one large series), caused by synergism between insulin-like growth factor 1 receptor (IGF1R) and TSHR autoantibodies, resulting in retro-orbital tissue expansion and inflammation 4, 1
• Physical examination findings of ophthalmopathy or thyroid bruit are diagnostic of Graves' disease and should prompt early endocrine referral 2
• Pretibial myxedema (dermopathy) can develop, involving the same pathophysiologic mechanism as ophthalmopathy with IGF1R-TSHR autoantibody synergism 1

Associated Autoimmune Conditions

• 16.7% of Graves' disease patients have another associated autoimmune disease, with patients having GO showing higher rates (18.9%) compared to those without GO (15.6%) 4
• The most common associations include: vitiligo (2.6%), chronic autoimmune gastritis (2.4%), rheumatoid arthritis (1.9%), polymyalgia rheumatica (1.3%), celiac disease (1.1%), type 1 diabetes (0.9%), and Sjögren disease (0.8%) 4
• Autoimmune thyroid disease (AITD) is the most common concurrent autoimmune condition in patients with other autoimmune disorders, accounting for 10.5% of cases 2

Symptomatic Presentation Requiring Grading

• Grade 1 (asymptomatic or mild symptoms): Patients can continue treatment with close monitoring 2
• Grade 2 (moderate symptoms, able to perform activities of daily living): Requires beta-blocker therapy (atenolol or propranolol) for symptomatic relief, hydration, and supportive care 2
• Grade 3-4 (severe symptoms, medically significant or life-threatening): Includes severe hyperthyroid symptoms or concern for thyroid storm, requiring hospitalization and aggressive treatment with beta-blockers, corticosteroids, and possible thionamides 2

Autoimmune Thyroiditis (Hashimoto's Thyroiditis): Clinical Presentation

Hashimoto's thyroiditis is the most common cause of hypothyroidism in industrialized nations, characterized by chronic autoimmune destruction of the thyroid gland leading to hypothyroidism. 5

Primary Hypothyroid Manifestations

• Elevated TSH with low or normal free T4 defines the hypothyroid state, with TSH >10 mIU/L indicating more severe disease requiring immediate treatment 6, 5
• Classic hypothyroid symptoms include chronic fatigue, weight gain (despite weight loss in some cases), extensive hair loss, cold intolerance, constipation, and menstrual irregularities (including short menstrual periods) 6
• Cardiovascular dysfunction develops, including delayed relaxation, abnormal cardiac output, and reduced cerebral perfusion that can manifest as dizziness 6

Autoantibody Profile

• Positive anti-thyroid peroxidase (anti-TPO) antibodies confirm autoimmune etiology and predict higher risk of permanent hypothyroidism (4.3% annual progression vs 2.6% in antibody-negative individuals) 6, 5
• Thyroglobulin antibodies are also commonly present in Hashimoto's thyroiditis 3
• The presence of TSH stimulation-blocking antibody (TSBAb) blocks TSH hormone action, leading to thyroid damage and atrophy 3

Biphasic Presentation (Hashitoxicosis)

• Initial thyrotoxic phase can occur in Hashimoto's thyroiditis, with transient hyperthyroidism that resolves within weeks to either primary hypothyroidism or normal thyroid function 2
• This represents thyroiditis with destructive release of preformed thyroid hormone, not increased production like in Graves' disease 2
• The history of hyperthyroidism followed by hypothyroidism likely represents past Hashimoto's thyroiditis with an initial thyrotoxic phase that has progressed to the hypothyroid phase, which is the most common pattern 6

Progression from Graves' Disease to Hashimoto's Thyroiditis

• Approximately 15-20% of patients with Graves' disease develop spontaneous hypothyroidism resulting from chronic thyroiditis (Hashimoto's disease) 3
• This transition can occur 7 to 25 years after Graves' disease treatment, though some cases develop within months 3
• The progression involves extended immune response including endogenous thyroid antigens (thyroid peroxidase and thyroglobulin), enhancing lymphocytic infiltration and causing Hashimoto's thyroiditis 3, 7
• Intermolecular spreading of the TSHR antibody response to other self thyroid antigens (murine thyroid peroxidase and thyroglobulin) occurs with lymphocytic infiltration 7

Associated Autoimmune Conditions

• Hashimoto's thyroiditis shows similar patterns of associated autoimmune disorders as Graves' disease, with no significant difference in the spectrum of associated conditions 4
• Thyroid disorders are the most common concurrent autoimmune disease in patients with other autoimmune conditions, particularly in women of reproductive age 2, 5

Physical Examination Findings

• Goiter may be present, though the thyroid can also be atrophic in advanced disease 6
• Lymphocytic infiltration of the thyroid gland is the hallmark pathologic finding, confirmed by fine needle aspiration biopsy or histopathology 3

Critical Diagnostic Distinctions

• Graves' disease is persistent with increased thyroid hormone production requiring antithyroid medical therapy, radioactive iodine, or surgery 2
• Thyroiditis (including Hashimoto's) is often transient in its hyperthyroid phase, resolving to primary hypothyroidism or normal function, and does not respond to thionamides 2
• Physical examination findings of ophthalmopathy or thyroid bruit definitively diagnose Graves' disease and distinguish it from other causes of hyperthyroidism 2
• Persistent hyperthyroidism beyond 6 weeks suggests Graves' disease rather than transient thyroiditis and warrants workup for TSH receptor antibodies (TSI or TRAb) 2