Approach

Evaluate patients for thyroid disorders when they have unexplained weight loss, palpitations, atrial fibrillation or other supraventricular tachycardias, tremor, generalised proximal muscle weakness, or unexplained protrusion of the eyes.[2][4]​​​[45]​ Investigate diffuse enlargement of the thyroid, particularly if there is a bruit. Moist and velvety skin, hair loss, onycholysis, menstrual irregularities in women, and sexual dysfunction might also be associated with hyperthyroidism.[2]​​[46][47]

Symptoms such as unexplained weight loss and generalised weakness may cause a patient to be concerned about an underlying malignant cause. Order appropriate investigations and follow patient safety-netting procedures where any symptoms of malignancy are present that cannot be explained by another cause.

Diagnosis is mostly clinical. The combination of elevated thyroid-stimulating hormone (TSH) receptor antibodies (or elevated radioactive iodine/technetium-99 uptake by the thyroid if TSH receptor antibody testing is unavailable or diagnosis is uncertain); suppressed TSH; and elevated levels of circulating thyroid hormones (free T4 and total or free T3) is the standard for diagnosis of Graves' hyperthyroidism.

Subclinical hyperthyroidism

A number of otherwise asymptomatic individuals may be diagnosed with subclinical hyperthyroidism due to Graves’ disease on routine tests for other indications. Take a detailed clinical history (including family history of autoimmune diseases), carry out a physical examination, and repeat the thyroid function tests along with TSH receptor antibody after 8-12 weeks to determine if the biochemical abnormality is transient (such as due to non-thyroidal illness) or due to an autoimmune process.

Laboratory tests

Request a serum TSH assay as the initial laboratory screening test.[48]

Serum TSH and circulating thyroid hormones

Most symptomatic hyperthyroid Graves' disease patients have a serum TSH less than the detection limit of third-generation assays (e.g., <0.01 mIU/L).[49] The diagnosis of hyperthyroidism is confirmed by high serum levels of free T4 and total or free T3 in the presence of a low TSH.[2][45]​ Total T4 and T3 measurements may give misleading results because they are affected by protein binding; measurement of the free fraction of T4 is preferred. Total T3 is commonly used because of limitations with free T3 assays.[45][49]​​

In mild Graves' disease, free T4 levels may be normal, but T3 may be elevated ('T3 toxicosis').[45]

A high T3/T4 ratio is suggestive of Graves’ disease rather than thyroiditis.[50][51]

It may be helpful to calculate total T3/T4 or FT3/FT4 ratio to distinguish thyroiditis from Graves' disease, and from toxic nodular goitre (when radioiodine uptake is contraindicated e.g., in pregnancy or lactation).[52]

Patients with subclinical disease have low serum TSH levels with peripheral thyroid hormone levels within the reference range.[7][8][9]​

TSH receptor antibodies

Measured by either immunoassay or bioassay, TSH receptor antibodies are typically elevated in >90% of patients with Graves’ disease. Reference range may differ between laboratories.

Older patients with Graves’ disease tend to have lower thyroid hormone elevation for the same level of circulating TSH receptor antibodies compared with younger patients.[53]​ 

Bioassays allow differentiation of TSH receptor-stimulating antibodies and TSH receptor-blocking antibodies, facilitating prediction of: extrathyroidal manifestations; and, fetal or neonatal hyperthyroidism among pregnant and postnatal women with Graves' disease.[48]​​[49]​ Immunoassays measure inhibition of TSH receptor binding and are unable to distinguish between thyroid-stimulating and thyroid-blocking antibodies.

Thyroid peroxidase antibodies

Testing for thyroid peroxidase antibodies may be helpful if TSH receptor antibody testing is unavailable and/or isotope scans are contraindicated (e.g., in pregnant women). 70% of people with Graves’ disease will be positive.

Radiological tests

Do not request radiological tests in patients with thyrotoxic biochemistry and elevated TSH receptor antibodies.

If TSH receptor antibody testing is negative and the cause of thyrotoxicosis is unknown, thyroid uptake of radioactive iodine-123 (I-123) or technetium-99 (Tc-99) may be considered.[54]​ I-123 or Tc-99 uptake provides a quantitative measure of the accumulation and retention of radioactive tracer by the thyroid. Radioactive tracer uptake can inform the diagnosis, and is useful in excluding low-uptake hyperthyroid syndromes such as painless thyroiditis. Additionally, results from the radioactive iodine uptake test can be used in treatment planning.

Thyroid scan (scintigraphy) using I-123 or Tc-99 allows the evaluation of thyroid tissue by showing the distribution pattern of the radioactive tracer (via two-dimensional images). Thyroid scan can differentiate Graves’ disease (diffuse uptake) from toxic multinodular goitre (patchy with focal areas of increased uptake).[2][45]

Thyroid uptake and scan is used less since TSH receptor antibody measurement became more widely available.

Thyroid ultrasound

Order a thyroid ultrasound when nodules are suspected on examination or present on thyroid scan. Colour-flow Doppler may help to distinguish Graves' disease (increased flow) from painless thyroiditis and amiodarone-induced hyperthyroidism (reduced flow).[2][45]​​​[55]​​

Thyroid ultrasound should not routinely be ordered if there is no palpable abnormality of the thyroid gland.[56][57]

[Figure caption and citation for the preceding image starts]: Iodine uptake scans. Typical appearances of absent uptake in thyroiditis (top panel). Diffuse increased uptake in Graves' disease (lower left panel). Areas of increased and decreased uptake in toxic multinodular goitre (lower middle panel). Single area of increased uptake in a toxic adenoma (lower right panel)Courtesy of Dr Petros Perros [Citation ends].com.bmj.content.model.Caption@458fae31

Orbitopathy/dermopathy

Examine patients carefully for bilateral proptosis and lid retraction. In the presence of hyperthyroidism, these clinical features are sufficient for the diagnosis of Graves' orbitopathy.

Request cross-sectional imaging of the orbit (i.e., CT or MRI scan) in patients with euthyroid unilateral orbitopathy, or other atypical presentations (e.g., no previous or present evidence of thyroid dysfunction, absence of upper eyelid retraction, divergent strabismus, diplopia sole manifestation, history of diplopia worsening towards the end of the day); demonstration of typical muscle thickening is needed in order to rule out other diagnoses.[34] Elevated TSH receptor antibodies increase the probability of the diagnosis being Graves' orbitopathy, but this measure is no substitute for orbital imaging if there is suspicion of an alternative diagnosis.[3][34][58]

Examine the patient for thyroid dermopathy (pretibial myxoedema), which may present as non-pitting oedema, plaque, nodule(s), or elephantiasis.[19] In the presence of Graves' orbitopathy, this is diagnostic of Graves' disease. Dermopathy and/or acropachy without orbitopathy are exceptionally rare and should raise suspicion of alternative causes for the skin and nail changes. In questionable cases, request a skin biopsy.[59][60]​ 

Be aware that Graves' orbitopathy is often diagnosed late or misdiagnosed as allergy or conjunctivitis, especially when the eye symptoms precede the diagnosis of Graves' disease.

It is currently unclear whether mild Graves' orbitopathy is a chronic relapsing and remitting process or whether it is a transient event in the course of illness.[61]

The DiaGO (diagnosis of Graves' orbitopathy) test is a 20-point assessment tool that can be used by clinicians (including non-ophthalmic specialists) to help identify patients with Graves' orbitopathy; however, confirmatory studies are required before this can be used in clinical practice.[62] Guidelines on early detection and management of Graves' orbitopathy have been published.[58][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@55a8dfe5[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@5fe69e40[Figure caption and citation for the preceding image starts]: Orbitopathy and elephantiasisCourtesy of Dr Vahab Fatourechi [Citation ends].com.bmj.content.model.Caption@489cfb9f​​[Figure caption and citation for the preceding image starts]: Axial CT scan through the orbits of a patient with Graves' orbitopathy showing increased thickness of medial rectiCourtesy of Dr Petros Perros [Citation ends].com.bmj.content.model.Caption@1732a19​​

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