Thyrotoxicosis or hyperthyroidism

Hyperthyroidism, or thyrotoxicosis, refers to thyroid overactivity of any cause. Diagnosis is often clinical, but antibody testing may help identify the cause.

Any suspicious characteristics

Any patient with a solitary palpable nodule greater than 1cm in diameter, or any nodule with suspicious characteristics arising within a multinodular goitre, or any nodule with associated lymph nodes, will require urgent an ultrasound scan. The radiological characteristics taken with the level of clinical suspicious will then determine whether ultrasound guided aspiration is required according to international guidelines. Clinically guided fine needle aspirations of thyroid nodules are now rarely performed, and only if ultrasound is unavailable to help define whether aspiration is indicated at all, and which area of the lesion to aspirate.

Suspected eye disease

Patients with suspected eye disease require evaluation by an endocrinologist or ophthalmologist experienced in Graves' ophthalmopathy. 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.

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.

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 of thyrotoxicosis

Any patient with severe clinical or biochemical thyrotoxicosis requires immediate medical treatment, before long term decisions are taken. All patients must also receive verbal and written safety warnings regarding drug therapy, and clear instructions on the need for serial blood tests and dose adjustment.

Usual treatment starts with high dose carbimazole, for example 40-60mg daily, though lower doses (5-10mg) may be appropriate in those with milder disease.

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

Dose titration and thyroid function testing

All patients should receive instructions as to the timing of dose reduction and firm arrangements made for serial monitoring. Appropriate dose reduction will depend on symptom control, and on the rapidity of the fall in free thyroxine levels in the early stages, as TSH does not tend to respond as quickly to treatment.

Typical monitoring intervals are every six weeks, with dose reduction from 40mg, to 20mg, 15mg, 10mg and then to maintenance therapy of 5mg. Long term treatment should be monitored with serum TSH, aiming for a level within the normal range with complete resolution of all symptoms.

Treatment duration and likelihood of relapse

Treatment duration and likelihood of relapse should be discussed with all patients at the start of a treatment course, and other options discussed.

Typical treatment courses for Graves' thyrotoxicosis are 18 months. 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.

Patients with hyperthyroidism secondary to thyroid nodules or multinodular goitres will need life long medical treatment if they do not choose to have radioactive iodine.

Block and replace regimes

Dose titration may be difficult or inappropriate in occasional circumstances. In such cases, high dose carbimazole (40-60mg) may be continued, and thyroxine added once the serum thyroxine falls to within the normal range. Thyroxine dose is then adjusted according to symptoms and aiming for a normal serum TSH level.

Common side effects of antithyroid 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. 

Radioactive iodine should be offered to all patients with thyrotoxicosis

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. However, radioactive iodine is the best long term treatment for thyrotoxicosis in most cases.

Detailed guidance on the indications and precautions needed for radioactive iodine are available. Radioactive iodine is highly effective at rendering patients euthyroid, usually after one treatment, and offers the advantage of preventing future recurrence in auto-immune thyroid disease. Patients must be warned about standard radiation precautions, and given written information about this and other available treatments. Patients should also be warned that transient thyroid swelling may occur, repeat applications may be necessary, long term monitoring is required, and hypothyroidism requiring thyroxine replacement therapy may ensue.

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. 

Post radioactive iodine monitoring and treatment

Thyroid function should be assessed at 6 and 12 weeks post radioactive iodine, then at least every three months for the first year after radioactive iodine, and then annually thereafter for emerging hypothyroidism or for recurrent thyrotoxicosis.

Subsequent hypothyroidism should be treated conventionally.

Subsequent recurrence of hyperthyroidism may occur, and should be treated with a repeat application of radioactive iodine.

Graves' ophthalmopathy may be exacerbated by radioactive iodine therapy

Radioactive iodine should be discussed with an experienced ophthalmologist in the case of suspected Graves' 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.

Surgery should be discussed with all patients

Surgery is rarely recommended as a first line treatment for straight forward thyrotoxicosis. However, all options should be discussed with patients to allow an informed choice to be made.

Patients who do not tolerate medical therapy, or who require life long treatment but are unsuitable for radioactive iodine, should strongly consider surgery as a definitive treatment. Surgery may also be used during the second trimester of pregnancy, if severe thyrotoxicosis cannot be controlled medically. Patients with obstructive symptoms from nodular disease are also recommended surgery in most cases. 

Long term follow up

After treatment for thyrotoxicosis, most patients can be followed up by their family physician long term with an annual TSH alone. This is sufficient to monitor thyroxine replacement, or detect early recurrence of thyrotoxicosis. Patients will auto-immune thyroid disease are at increased risk of developing further auto-immune conditions, though routine monitoring is not generally necessary if their initial screening tests were satisfactory.