History and exam

Key diagnostic factors

common

family history of autoimmune thyroid disease

Concordance rate among monozygotic twins is 20%. History of autoimmune thyroid disease in a first-degree relative increases the risk of development of Graves disease.[2]​​

history of tobacco use

Tobacco use is strongly associated with Graves hyperthyroidism, and numerous observational studies show that current and previous tobacco use increases the risk of orbitopathy 4- to 8-fold.[29] Among patients who have orbitopathy, the severe forms are more often in smokers. Tobacco use increases adipogenesis from orbital fibroblasts.[35]

heat intolerance

Relates to increased metabolism leading to higher body temperature.

sweating

Not to be confused with “hot flashes” related to estrogen deficiency.

weight loss

Is caused by accelerated metabolism and higher basal metabolic rate.

palpitations

Including atrial fibrillation or other supraventricular tachycardias, especially in older people.

tremor

Usually fine.​[2]​​

diffuse goiter

Key diagnostic factor, especially in nonendemic areas. Goiter in combination with other symptoms and signs is a strong diagnostic indicator. Goiter may be difficult to identify in older people, especially if kyphosis is present.

orbitopathy

Clinically present in around 25% of patients and is usually mild.[1] Upper eyelid retraction is present in over 90% of cases. The presence of upper eyelid retraction with thyroid dysfunction, exophthalmos/optic neuropathy, and/or extraocular muscle involvement is diagnostic of Graves orbitopathy.[34] Subclinical abnormalities can be demonstrated by CT or MRI scan of the orbit, or by measurement of intraocular pressure in upward gaze.[65][Figure caption and citation for the preceding image starts]: Lid retraction, mild proptosis, and mild chemosisCourtesy of Dr Vahab Fatourechi [Citation ends].com.bmj.content.model.Caption@4f3b3df4

Other diagnostic factors

common

irritability

Nonspecific.

cardiac flow murmur

Is due to the increased flow of blood through the heart valves.

moist, velvety skin

Suggestive of Graves disease, but not diagnostic.[66]

scalp hair loss

Nonspecific.[66]

sexual dysfunction

Hyperthyroidism has been reported to impair libido in men and women and erectile and ejaculatory dysfunction in men.[47]

uncommon

muscle weakness

May be generalized or proximal.

thyroid bruit

Less common than goiter in Graves disease, but has diagnostic value.​​[2]​​

onycholysis

Detachment of nail from nail bed, when present, is a good diagnostic physical finding.​[2]​​

vitiligo

Associated autoimmune process that is not directly related to Graves disease but suggests an autoimmune diathesis.[66]

pretibial myxedema

May present as non-pitting edema, plaque, nodule(s), or elephantiasis.[19] Almost always associated with orbitopathy. The combination of Graves orbitopathy and dermopathy is highly diagnostic.[18][19][Figure caption and citation for the preceding image starts]: Pretibial myxedema (nonpitting edema)Courtesy of Dr Vahab Fatourechi [Citation ends].com.bmj.content.model.Caption@1e731bc8[Figure caption and citation for the preceding image starts]: Orbitopathy and elephantiasisCourtesy of Dr Vahab Fatourechi [Citation ends].com.bmj.content.model.Caption@62950e5f

acropachy

Due to subperiosteal new bone formation. Manifests as clubbing of the fingers and toes with soft-tissue swelling.[62] Almost always associated with orbitopathy.

menstrual irregularity

Menstrual disturbances are common in thyroid dysfunction. Oligomenorrhea may be present in severe hyperthyroidism.[46]

Risk factors

strong

family history autoimmune thyroid disease

The disease concordance rate for monozygotic twins is greater than that reported for dizygotic twins.[24][25]​

History of autoimmune thyroid disease in a first-degree relative increases the risk of development of Graves disease.​[2]​​

female gender

Graves disease is 6 times more common in women than in men.​[2]​​

tobacco use

Tobacco use increases risk for Graves hyperthyroidism and for more severe ophthalmopathy.[29][30]​

Tobacco use increases adipogenesis from orbital fibroblasts.[35]

weak

high iodine intake

Epidemiologic studies indicate increased prevalence of autoimmune thyroid disease, including Graves disease, in areas with high iodine supplementation, presumably through stimulation of the autoimmune process.​[2]​​[13]

lithium therapy

Long-term lithium use has been associated with a possible increased risk of hyperthyroidism due to painless thyroiditis or Graves disease. Lithium increases thyroid autoimmunity if present before therapy.[36]

biologic agent and cytokine therapies

Biologic agent therapy (e.g., alemtuzumab, ipilimumab, nivolumab, pembrolizumab) and cytokine therapy (e.g., interferon) are associated with autoimmune thyroid disease, including painless thyroiditis and Graves hyperthyroidism.[37][38]

radiation

There have been cases of Graves disease following neck radiation for lymphoma.[39]​ However, hypothyroidism is the common outcome.[40][41]

radioiodine therapy for benign nodular goiter

Patients with benign multinodular goiters have been reported to develop Graves hyperthyroidism after radioiodine therapy, presumably because of release of thyroid antigens.[42]

stress

Many thyroidologists have noted an association between severe psychological trauma and development of Graves disease. Case control studies support the view that stress affects the onset and progress of the disease.[43][44] However, there is no proven evidence for a causative relationship.

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