Graves' disease

An auto-immune condition characterised by thyrotoxicosis and ophthalmopathy, associated with auto-antibodies stimulating the TSH receptor. Diagnosis is often clinical, but the presence of antibodies may help confirm the cause of thyrotoxicosis.

Suspicious characteristics

Any patient with a solitary nodule, a dominant nodule within the gland, with palpable lymph nodes or with any other suspicious features, requires urgent ultrasound guided aspiration.

All patients should be advised to stop smoking

Smoking increases the risk of developing new ophthalmopathy, increases the severity of existing ophthalmopathy, reduces the efficacy of treatment for ophthalmopathy, and increases the risk of ophthalmopathy deteriorating or developing de novo following radioactive iodine treatment.

General advice must be given and referral to a formal smoking cessation clinic discussed.

Suspected eye disease

Patients with suspected eye disease require evaluation by an endocrinologist or ophthalmologist experienced in Graves' ophthalmopathy - see below. Patients should be reassured that treatment is available and is highly effective, and a detailed patient information sheet is available. Simple lubricants, avoidance of smoky environments, and avoidance of bright sunlight and strong winds by wearing sunglasses should be advised in all patients.

Graves' ophthalmopathy

No symptoms or signs present

Patients with a history of Graves’ disease, but with no symptoms nor signs of GO do not require referral. There is now excellent international guidance on best practise for all other categories of patients as below.

Unilateral eye involvement and euthyroid ophthalmopathy

Patients with unusual presentations eg unilateral eye involvement or euthyroid GO should be referred to an ophthalmologist or combined thyroid-eye clinic, however mild their symptoms or signs, in order to make an accurate diagnosis.

Mild Graves' ophthalmopathy

Patients with very mild symptoms of Graves' ophthalmopathy with confirmed hyperthyroidism and with no unusual feautres do not necessarily require ophthalmological assessment. These patients should recieve smoking cessation advice, advice on occular lubricants. Supplements of selenium 100mcg bd have also been shown to reduce severity in one series.

Routine referral to an ophthalmologist or combined thyroid-eye clinic

All patients with suspected eye involvement should be given smoking cessation advice. Patients should also be advised to use occular lubricants liberally, to avoid smokey environments, and to wear sunglasses in very bright sunshine or wind.Patients with very mild involvement eg grittiness only may not require any further assessment or treatment.

The presence of any more severe occular involvement including any of the symptoms or signs listed below should prompt referral to a specialist clinic:

Eyes abnormally sensitive to light: troublesome or deteriorating over the past 1–2 months

Eyes excessively gritty and not improving after 1 week of topical lubricants

Pain in or behind the eyes: troublesome or deteriorating over the past 1–2 months

Progressive change in appearance of the eyes and=or eyelids over the past 1–2 months

Appearance of the eyes has changed causing concern to the patient

Seeing two separate images when there should only be one

Troublesome eyelid retraction

Abnormal swelling or redness of eyelid(s) or conjunctiva

Restriction of eye movements or manifest strabismus

Tilting of the head to avoid double vision

Cases requiring urgent referral to an ophthalmologist or combined thyroid-eye clinic

The presence of any of these symptoms or signs mandates urgent referral according to latest guidelines:

Unexplained deterioration in vision

Awareness of change in intensity or quality of colour vision in one or both eyes

History of eye(s) suddenly ‘popping out’ (Globe subluxation)

Obvious corneal opacity

Cornea still visible when the eyelids are closed

Optic disc swelling on fundoscopy

Classification of disease severity

This should be assessed by an ophthalmologist. EUGOGO recommends the following categories of disease severity:

Sight-threatening GO: patients with dysthyroid optic neuropathy (DON) and=or corneal breakdown. This category warrants immediate intervention.

Moderate to severe GO: patients without sight-threatening GO whose eye disease has sufficient impact on daily life to justify the risks of immunosuppression (if active) or surgical intervention (if inactive). Patients with moderate to severe GO usually have any one or more of the following: lid retraction $ 2 mm, moderate or severe soft tissue involvement, exophthalmos $ 3 mm above normal for race and gender, inconstant or constant diplopia.

Mild GO: patients whose features of GO have only a minor impact on daily life insufficient to justify immunosuppressive or surgical treatment. They usually only have one or more of the following: minor lid retraction (<2mm), mild soft tissue involvement, exophthalmos < 3 mm above normal for race and gender, transient or no diplopia, corneal exposure responsive to lubricants.



Assessment of disease activity

The clinical activity score (CAS) is based on the clinical indicators of inflammation and is calculated as the sum of all items present scoring 1 for each symptom or sign. A CAS above 3/7 indicates active Graves' orbitopathy. MRI scanning may also be helpful to assess disease activity.

Spontaneous retrobulbar pain

Pain on attempted up- or down gaze

Redness of the eyelids

Redness of the conjunctiva

Swelling of the eyelids

Inflammation of the caruncle and=or plica

Conjunctival oedema

Incomplete lid closure and lid retraction

These may be helped in the inactive phase by botulinum toxin or by corrective lid surgery.

Persisting diplopia

Prisms may alleviate this distressing symptom.

Pulsed methyl prednisolone should be considered in patients with active severe disease

If the CAS is above 3 and the disease is moderate to severe or sight threatening, iv glucocorticoids are indicated though must only be prescribed by an experienced thyroid eye specialist. Pulsed iv treatment has been shown to be more effective and cause less side effects than oral therapy.

Orbital decompression

This radical treatment should be considered in sight threatening ophthalmopathy which has not responded within 2 weeks of iv glucocorticoids. 

Orbital radiotherapy

This should be considered for moderate to severe disease not responding to iv glucocorticoids.

Rehabilitative surgery

This is generally only used in stable disease which is inactive, and should only be performed by highly experienced surgeons.

Pregnancy and fertility plans should be discussed with all patients

Offspring of women with high TSH receptor antibodies (TRABs) are at risk of foetal and neonatal thyroid dysfunction. It is therefore useful to test TRABs prior to pregnancy or before the end of the second trimester. Women with negative antibodies require no special monitoring. Women with positive antibodies should be considered at risk of complications. Obstetricians should therefore consider ultrasound monitoring to seek evidence of foetal thyroid dysfunction eg for foetal growth retardation,hydrops, goitre or cardiac failure. TSH testing of cord blood may also be performed and neonatalogists warned at the time of delivery. 

It is standard practise to use propylthiouracil rather than carbimazole in patients who may be or are planning pregnancy, due to small but real concerns regarding teratogenicity from carbimazole. Treatment may frequently be stopped by the second trimester as the disease often spontaneously improves until the post partum period. Monitoring should continue throughout pregnancy and breastfeeding, and carbimazole substituted for propylthiouracil if required during the second trimester (since organogenesis is complete, and the risk of liver failure from propyl thiouracil outweighs the risks of carbimazole during this stage of the pregnancy). 

Patients with uncontrolled thyrotoxicosis should be advised to avoid pregnancy until biochemical control is achieved due to the risk of miscarriage. Treatment during pregnancy requires close monitoring typically every six weeks.

Radioactive iodine is contraindicated in pregnant or breast feeding individuals. Women should be advised to avoid conception for six months and men should avoid fathering children for four months following radioactive iodine treatment.

Medical treatment for thyrotoxicosis

Any patient with severe clinical or biochemical thyrotoxicosis requires immediate medical treatment, before long term decisions are taken, in line with national guidelines. However, the options of medical treatment, radioactive iodine and surgery should all be introduced at this stage.

All patients must receive verbal and written safety warnings regarding drug therapy.

Usual treatment starts with high dose carbimazole, for example 40-60mg daily, though lower doses may be appropriate in those with milder disease. Propyl thiouracil may be substituted in patients intolerant of carbimazole, using an approximate dose equivalence of 50mg propyl thiouracil for 5mg carbimazole.

Patients with tachycardia or other severe symptoms are also usually treated with beta blockade, for example propranolol 120-240mg daily in divided doses.

Dose reduction and treatment monitoring

All patients should receive instructions as to the timing of dose reduction and firm arrangements made for serial monitoring. Typical monitoring intervals are every six weeks initially. There should be rapid dose reduction through 20mg, 15mg, 10mg to a maintenance therapy of 5mg, according to the early fall in T4 levels.

Once on maintenance doses, monitoring of TSH only is necessary, aiming for a detectable, normal TSH with complete resolution of symptoms. This is typically repeated every three months until the end of the treatment course.

Treatment duration and likelihood of relapse should be discussed with all patients

Typical treatment course for Graves' thyrotoxicosis is 18 months. Monitoring is typically required every six weeks initially, and three monthly once patients are on a stable maintenance dose. 

All patients with auto-immune hyperthyroidism should be warned of a 50% chance of disease recurrence after their initial treatment course. Male patients, older patients, those with high antibody titres, those with previous episodes and those with severe biochemical disease are at the highest risk of future recurrence.

A block and replace regimen may be appropriate in exceptional cases

Dose titration may be inappropriate in certain circumstances, in which case high dose carbimazole is continued, with thyroxine added once the serum thyroxine falls to within the normal range.

Thyroxine dose should then be adjusted according to symptoms and aiming for a normal serum TSH level.

Common side effects of anti-thyroid drugs

Agranulocytosis is an uncommon but important side effect of all anti-thyroid drugs. Patients should receive written and verbal warnings to discontinue the drug until they have had a blood count checked if they develop a severe sore throat or mouth ulcers.

Mild neutropaenia <1.5x10*9 is commonly observed in people with Graves disease, some racial groups and with anti-thyroid drugs.

Neutrophil count 1-1.5 - continue drug but institute close monitoring of blood count. 

Neutrophil count <1 - stop antithyroid drug and monitor blood count daily.

Neutrophil count <1 with suspected sepsis or in the unwell patient - stop antithyroid drug and arrange urgent admission. Treat as for neutropaenic sepsis, remembering that pseudomonas is a common infective organism in this group. Monitor blood count every 12 hours initially and take haematological advice. Bone marrow biopsy may be helpful to determine response. Granulocyte-colony stimulating factor (GCSF) should be considered after haematology review of the patient's response to drug cessation. DO NOT RECHALLENGE THE PATIENT WITH AN ALTERNATIVE ANTI-THYROID DRUG.

Rash is common and usually controlled by antihistamines. Alternatively switch to alternative anti-thyroid drug.

Arthralgia and arthritis are uncommon with carbimazole but more common with PTU. Stop the drug. Check antibody screen including ANCA for drug induced lupus and discuss wtih rheumatologist. 

Mild abnormalities of liver function are common with thyrotoxicosis and do not require treatment. Mild transaminitis (<1.6x upper limit of normal) is also common after 3 months therapy with PTU and does not require treatment or monitoring unless baseline liver function was abnormal.

Allergic hepatitis with submassive necrosis occurs in 0.1-0.2% of patients receiving PTU. Stop PTU and involve a hepatologist immediately if this is suspected.

Carbimazole is not associated with this condition, but may cause a cholestatic picture of abnormal liver function. Stop the drug and inform hepatology if this is suspected, though complete resolution is normal on drug withdrawal. 

Discuss radioactive iodine treatment

It is usual to start medical treatment at presentation particularly in those with severe biochemical disease in order to allow them to make an informed decision regarding long term management. Written information about radioactive iodine and other treatments should also be given to the patient to consider before making a decision.

Radioactive iodine is highly effective at rendering patients euthyroid, usually after one treatment of 370-600MBq, and offers the advantage of preventing future recurrence. It is therefore particularly suitable for patients with relapsed Graves' disease, or those at high risk of recurrence for example male patients, those with severe biochemical disease, or those with high antibody titres. The dose should be determined by the responsible ARSAC licence holder in line with local results and policies

Patients must be warned about standard radioactive iodine precautions. Patients should also be warned that transient thyroid swelling may occur, that repeat applications may be necessary, that long term monitoring is required, and that hypothyroidism requiring thyroxine replacement therapy is likely to ensue. Long term studies confirm that weight gain follows all treatments of thyrotoxicosis though this may be more frequently observed wtih radioactive iodine. However, radioactive iodine treatment is associated with the lowest all cause mortality compared to other treatments of thyrotoxicosis. 

Radioactive iodine is absolutely contraindicated in pregnancy. Women should also be advised to avoid conception for six months, and men should avoid fathering children for four months following radioactive iodine treatment.

Graves' ophthalmopathy may be exacerbated by radioactive iodine therapy

Radioactive iodine should be discussed with an experienced ophthalmologist in the case of suspected eye disease, as 15% patients may experience new or worsened ophthalmopathy within 6 months of treatment, though it is usually mild. Mild to moderate eye disease does not preclude the use of radioactive iodine, but it is standard practise to render the patient euthyroid medically, ensure the patient has given up smoking if relevant, and confirm that their eye disease is inactive before treatment.  The ophthalmologist will also advise whether an individual patient will require prophylactic treatment to reduce this risk. If so, a course of ,3 months prednisolone is usually given. In our institution, we have adopted a low dose regimen: 1 day before radioactive iodine is administered, patients start on 0.3mg/kg prednisolone for one week, with the dose reduced gradually over a six week course (eg 25mg then 20mg, 15mg, 10mg, 5mg, 2,5mg for one week each). Bisphosphonate cover is only given if the course is anticipated to last for more than three months. Proton pump inhibitors are considered in patients at high risk of gastrointestingal bleeding (previous ulcer, or taking concomitant aspirin, clopidogrel, warfarin, bisphosphonate or selective serotonin reuptake inhibitor) but are not given routinely.

Post radioactive iodine monitoring and treatment

Thyroid function should be assessed at 6 and 12 weeks, and then at least every three months for the first year after radioactive iodine, and then annually thereafter for emerging hypothyroidism or for recurrent thyrotoxicosis. Hypothyroidism must be avoided in patients with ophthalmopathy.

Subsequent hypothyroidism should be treated conventionally.

Subsequent recurrence, more than 6 months following radioactive iodine should be treated with a repeat application of radioactive iodine.

Long term follow up

Annual monitoring of serum TSH levels is usually all that is required after treatment for Graves' disease. Patients should also be warned to report any symptoms suggestive of thyroid dysfuntion before this routine monitoring. Patients are also at increased risk of developing auto-immune conditions, however, routine surveillance is not usually required if all other baseline investigations were normal.

Discuss thyroid surgery

Surgery is no longer considered a first line treatment for Graves' disease as most patients prefer either a course of medical treatment or a one off treatment with radioactive iodine. However, in patients intolerant or unresponsive to medical treatments, and who decline or are unsuitable for radioactive iodine, surgery can provide an alternative highly effective treatment.

Generally, it is a straight forward and effective procedure, with a very low risk of complications such as hypoparathyroidism or recurrent laryngeal nerve damage. However, all patients must be warned that surgery does not offer a guaranteed cure of their thyrotoxicosis, that relapse is possible, and that they will usually require life long thyroxine replacement therapy which is unfortunately associated with long term weight gain in a large proportion of patients.