History and exam

Key diagnostic factors

common

presence of risk factors

Key risk factors include family history and female sex.[2]​[24][25]​​ Tobacco use is an important risk factor for orbitopathy.[29][30]​​[35]

heat intolerance

Relates to increased metabolism leading to higher body temperature.

sweating

Not to be confused with 'hot flushes' related to oestrogen 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 goitre

Key diagnostic factor, especially in non-endemic areas. Goitre in combination with other symptoms and signs is a strong diagnostic indicator. Goitre 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 intra-ocular pressure in upward gaze.[63][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@55869157

Other diagnostic factors

common

irritability

Non-specific.

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.[64]

scalp hair loss

Non-specific.[64]

uncommon

muscle weakness

May be generalised or proximal.

thyroid bruit

Less common than goitre 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.[64]

pretibial myxoedema

May present as non-pitting oedema, 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 myxoedema (non-pitting oedema)Courtesy of Dr Vahab Fatourechi [Citation ends].com.bmj.content.model.Caption@579f8fb7[Figure caption and citation for the preceding image starts]: Orbitopathy and elephantiasisCourtesy of Dr Vahab Fatourechi [Citation ends].com.bmj.content.model.Caption@109c5759

acropachy

Due to sub-periosteal new bone formation. Manifests as clubbing of the fingers and toes with soft-tissue swelling.[60] Almost always associated with orbitopathy.

menstrual irregularity

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

sexual dysfunction

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

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 sex

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

Epidemiological 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]

biological agent and cytokine therapies

Biological 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 goitre

Patients with benign multinodular goitres 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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