Intended for healthcare professionals

Endgames Case Report

A 42 year old man with bilateral exophthalmos and weight loss

BMJ 2011; 342 doi: (Published 23 March 2011) Cite this as: BMJ 2011;342:d1105
  1. Stelios Tigas, assistant professor of endocrinology,
  2. Agathocles Tsatsoulis, professor of medicine and endocrinology
  1. 1Department of Endocrinology, University of Ioannina, Greece
  1. Correspondence to: S Tigas stigas{at}

A 42 year old white man who was concerned about a recent change in the appearance of his eyes was referred to the outpatient clinic for evaluation and treatment. He reported weight loss of more than 15 kg during the preceding six months, even though his appetite had been good. He was a smoker. Apart from alopecia universalis since childhood, he did not report any other significant medical history, and he was not taking any medication.

On examination he appeared restless. His body weight was 98 kg and height 168 cm. He was afebrile, with a resting tachycardia of 100 beats/min, and his blood pressure was 140/80 mm Hg. His skin was moist and warm, and there was fine tremor of the outstretched hands. He had marked bilateral exophthalmos associated with swelling and erythema of the eyelids and redness of the conjunctivae, as well as punctate keratopathy (corneal epithelial erosions). His eye movements were restricted, particularly upward gaze. His thyroid gland was diffusely enlarged with no tenderness on palpation.


  • 1 What is the diagnosis on the basis of the clinical information provided?

  • 2 What further investigations would you request?

  • 3 What is the appropriate initial management of this condition?

  • 4 How should the patient’s eye disease be managed?


1 What is the diagnosis on the basis of the clinical information provided?

Short answer

The presence of symptoms and signs of thyrotoxicosis in a patient with bilateral exophthalmos and a diffusely enlarged thyroid gland indicate a diagnosis of hyperthyroidism caused by Graves’ disease.

Long answer

The clinical diagnosis of Graves’ hyperthyroidism is relatively straightforward when a patient presents with the typical symptoms and signs of thyrotoxicosis—that is, a diffuse goitre and one or more of the features that are specific to Graves’ disease such as ophthalmopathy or, more rarely, dermopathy (pretibial myxoedema) or thyroid acropachy (finger clubbing). Although lid retraction and lid lag due to sympathetic overactivity may occur with any disorder that causes thyrotoxicosis, the presence of exophthalmos, diplopia, and signs of conjunctival or periorbital inflammation suggest thyroid ophthalmopathy, which is characteristic of Graves’ disease.

Ophthalmopathy is present in about 50% of patients with Graves’ disease; it may not necessarily coexist with thyrotoxicosis (10% of patients are euthyroid or even hypothyroid) because it could occur months or even years before or after the treatment of hyperthyroidism.1 The diagnosis of Graves’ disease may be less obvious in patients with hyperthyroidism who do not have a palpable goitre or ophthalmopathy, as well as in cases of ophthalmopathy (unilateral or bilateral exophthalmos, or diplopia) without clinical or biochemical thyrotoxicosis.

Graves’ disease is an autoimmune disorder that affects 0.5% of the population, and it is the most common form of hyperthyroidism (50-80% of all cases).2 Pathogenesis involves activation of the thyroid stimulating hormone receptor by IgG antibodies, which causes thyroid enlargement as well as overproduction of thyroid hormone. The autoimmune process leading to ophthalmopathy is initiated by T lymphocytes, which react with autoantigens shared between the orbit and the thyroid gland and lead to production of cytokines. This results in proliferation of orbital fibroblasts, with expansion of the retro-orbital adipose tissue and secretion of glycosaminoglycans.3 Susceptibility to Graves’ disease is determined by various factors including: (a) gender (female sex); (b) environmental factors (for example, stress, smoking, iodine, and medications such as amiodarone, interferon α, and highly active antiretroviral therapy); and (c) genetic factors (such as certain HLA alleles, cytotoxic T lymphocyte antigen 4, and several other genes).2 4

2 What further investigations would you request?

Short answer

Serum thyroid stimulating hormone, free thyroxine, and free triiodothyronine concentrations should be measured to establish the presence and assess the degree of hyperthyroidism. In addition, computed tomography or magnetic resonance imaging of the orbits is indicated in this patient.

Long answer

Laboratory investigations are needed to confirm the presence of thyrotoxicosis, assess its severity, and establish the cause. The finding of an undetectable level of serum thyroid stimulating hormone is the most sensitive way of screening for thyrotoxicosis. In addition, elevated levels of free thyroxine, free triiodothyronine, or both are required to confirm thyrotoxicosis. Measurement of the free hormone fractions is generally more reliable than measurement of the total hormone concentrations.5

Occasionally radionuclide studies are needed to establish the cause of thyrotoxicosis (usually technetium-99m pertechnetate scan, or 123I thyroid scan and radioiodine uptake). Typically, the scan will show diffusely increased uptake of the radioisotope in Graves’ hyperthyroidism, compared with reduced uptake in cases of thyroiditis or factitious thyrotoxicosis, and patchy uptake in cases of hyperthyroidism secondary to toxic multinodular goitre or toxic adenoma.

Detection of thyroid peroxidase antibodies (which are present in 70% of Graves’ patients) and, if available, thyroid stimulating hormone receptor antibodies (TSH-RAb) or thyroid stimulating immunoglobulins may help establish whether the cause of the hyperthyroidism is autoimmune.6 Second generation TSH-RAb assays are highly sensitive and specific for Graves’ disease.7 These antibodies are usually present in Graves’ ophthalmopathy, even if the patient is euthyroid, and their levels may also correlate with severity of the disease.

Computed tomography or magnetic resonance imaging of the orbits provides useful information in cases of moderate to severe ophthalmopathy. Imaging might help to establish the diagnosis when there is doubt, guide treatment decisions, and serve as a basis to assess response to therapy. Orbital imaging can exclude other conditions that cause exophthalmos, such as orbital tumours or a carotid cavernous fistula. Typical findings include enlargement of the extraocular muscles, an increase in retro-orbital fat and fibrous tissue, and, in some cases, compression of the optic nerve.8

3 What is the appropriate initial management of this condition?

Short answer

A β blocker should be started to provide initial control of the symptoms of thyrotoxicosis. Thionamides (such as carbimazole or methimazole) should also be prescribed to block the synthesis of thyroid hormones.

Long answer

Although some patients with Graves’ disease will have a single episode of hyperthyroidism followed by prolonged remission, the majority have either continuous hyperthyroidism or a relapsing and remitting course. Initial management comprises the use of a non-selective β blocker to control the symptoms related to increased β adrenergic tone (such as propranolol 80-240 mg or nadolol 40-80 mg daily, unless contraindicated, as in bronchial asthma and cardiac failure).

Concomitant management should aim to reduce thyroid hormone synthesis by any of the following treatment options: (a) antithyroid drugs; (b) radioactive iodine; or (c) surgery. All three options are effective9; however, relapse is more common when the hyperthyroidism is controlled by antithyroid medication (37%, 21%, and 6% with thionamides, radioiodine, and surgery, respectively, in one study9). In Europe, most specialists prefer to use antithyroid drugs initially and reserve definitive treatment (radioiodine or surgery) for when a relapse occurs, whereas in the United States the most popular first choice option is radioiodine (69% v 22% in Europe and 11% in Japan).10

Thionamides inhibit the synthesis of new thyroid hormone11; methimazole, carbimazole (which is metabolised to methimazole), and propylthiouracil are the main available agents. An initial dose of 15-30 mg methimazole or 20-40 mg carbimazole is usually prescribed, depending on the severity of the hyperthyroidism, and is gradually reduced to a maintenance dose according to response. Follow-up consists of clinical evaluation and periodic monitoring of thyroid hormone level (every four to six weeks initially and every three months thereafter12). For patients whose disease is difficult to control, some clinicians use the “block and replace” regimen, combining a dose of thionamide large enough to suppress thyroid hormone synthesis with a replacement dose of levothyroxine. Treatment is continued for 12-18 months, after which there is a more than 50% chance of recurrence.2 3

The most common side effects of thionamides are allergic reactions (rash or urticaria) and gastric intolerance.13 When allergic reactions occur, a different thionamide can be tried, but unfortunately cross reactivity is common (up to 50% of cases). Mild allergic reactions can be controlled by using an antihistamine without discontinuation of the thionamide. A rare (0.2-0.5%) but serious side effect is agranulocytosis, usually occurring in the first two months. Patients who experience fever or a sore throat should be warned to discontinue the drug until they have a blood test to rule out leucopenia.

Propylthiouracil can cause transient elevation of liver aminotransferases. Although severe hepatotoxicity is very rare (1:10 000 in adults and 1:2000 in children), cases of serious liver failure and even death with propylthiouracil use have been recently reported.14 Methimazole can cause cholestasis but is not associated with hepatocellular damage. For these reasons it is recommended that propylthiouracil is not used as first line treatment except in pregnant women in the first trimester (because of potential teratogenicity with methimazole and carbimazole), and it should be changed to methimazole or carbimazole after the first trimester of pregnancy.14 Liver aminotransferase levels can be affected by both a direct effect of thyroid hormone on the liver and as a result of antithyroid drugs. Routine biochemical testing and a full blood count should therefore be performed before initiating antithyroid drug treatment, to document liver enzyme values and white cell count at baseline.3

Radioiodine is an effective, safe, and easily administered treatment for hyperthyroidism that has been in use for more than 60 years.15 It is usually given orally as a capsule or in liquid form, and acts by ablating the thyroid or destroying enough thyroid tissue to render the patient euthyroid. Its efficacy is dose dependent. Pretreatment with antithyroid drugs is advisable in patients with severe hyperthyroidism, those with cardiac failure, and in the elderly to prevent exacerbation of hyperthyroidism caused by leakage of thyroid hormones into the circulation after radioiodine treatment.16 Methimazole and carbimazole should be discontinued for at least two days before and after administration of radioiodine.16 17

The main side effect of radioiodine treatment is radiation induced thyroiditis or sialadenitis (<1%). Pregnancy and lactation are absolute contraindications. A relative contraindication for radioiodine therapy is the presence of clinically significant ophthalmopathy—radioiodine may worsen Graves’ ophthalmopathy. This can be prevented by concomitant administration of glucocorticoids.18 Young age (below 21 years) and patient concerns regarding radiation exposure are also relative contraindications to the use of radioiodine. Studies have shown either no effect or a very small increase in cancer and cardiovascular mortality after radioiodine treatment, which could be attributed to the radioiodine or to the underlying thyroid disease itself.19 20 21 22 23 24 25

Surgical treatment of Graves’ hyperthyroidism is indicated in patients with large symptomatic goitres or concomitant suspicious thyroid nodules, in pregnant women who cannot tolerate antithyroid medication, and in patients with clinically significant Graves’ ophthalmopathy who relapse following discontinuation of antithyroid drugs and in whom radioiodine would be relatively contraindicated. Other indications are patient preference among individuals who do not wish to take radioiodine, poor compliance, and side effects with thionamides. Preoperative preparation with thionamides or iodine solution is necessary to render the patient clinically euthyroid. The main complications of surgical treatment are hypoparathyroidism, which is usually transient and less frequently (<1%) permanent, recurrent laryngeal nerve palsy, wound infection, and cheloid formation at the surgical scar area.

4 How should the patient’s eye disease be managed?

Short answer

The patient should be advised to give up smoking and use eye lubricants, and should be referred to a specialist centre for assessment and management of his Graves’ ophthalmopathy. Administration of intravenous glucocorticoids is indicated.

Long answer

Appropriate management requires careful ophthalmological examination and assessment of both the severity and the activity of the ophthalmopathy, using appropriate tools.26 Patients with moderate to severe Graves’ ophthalmopathy usually have one or more of the following features: lid retraction of 2 mm or more; moderate to severe soft tissue involvement; and exophthalmos of 3 mm or more above normal for race and gender. Impaired visual acuity or corneal breakdown are signs of sight threatening Graves’ ophthalmopathy.

In all cases euthyroidism should be restored, and patients should be advised to use artificial tears, stop smoking, and keep their head elevated while sleeping.8 Patients who have moderate to severe disease require referral to a specialist centre with experience and expertise in managing Graves’ ophthalmopathy.

Administration of glucocorticoids is the main therapy. Pulse intravenous methylprednisolone has been shown to be more effective and has fewer side effects than oral steroids.26 Patients who fail to respond to first line treatment can be treated with orbital radiotherapy or a combination of oral prednisolone and ciclosporin.3 Azathioprine and methotrexate can be used as steroid sparing agents. Immunomodulating biological agents (such as rituximab) have recently shown some promise.27 In most cases, Graves’ ophthalmopathy tends to improve spontaneously over a period of 1-2 years. When the disease is stable (“burnt out phase”), some patients will eventually require rehabilitative reconstructive surgery such as orbital decompression, strabismus surgery, or eyelid surgery.

Patient outcome

Biochemical testing in this patient showed a suppressed level of thyroid stimulating hormone and elevated levels of free thyroxine and free triiodothyronine, confirming biochemical hyperthyroidism. A computed tomography scan of the orbits showed significant bilateral proptosis and extraocular muscle enlargement, as well as oedema (fig 1). The patient was started on a β blocker and methimazole, and he was treated with a 12 week course of pulse intravenous methylprednisolone. Artificial tears were prescribed and he was advised to give up smoking.


Fig 1 Axial computed tomography image showing bilateral exophthalmos and spindle shaped thickening of the medial rectus muscles (arrows)

He was rendered clinically and biochemically euthyroid within a few weeks. The β blocker was discontinued and the methimazole dose was gradually reduced. Six months later, he had gained weight, and eye examination revealed no signs of inflammation but persistence of significant exophthalmos. He remains under follow-up and, depending on his clinical course, he may be referred for orbital decompression.


Cite this as: BMJ 2011;342:d1105


  • Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.


View Abstract

Log in

Log in through your institution


* For online subscription