Thyroid dysfunction and goitre: therapeutic dilemmas

Summary
Thyroxine can be used to suppress or replace thyroid hormone secretion. Suppressive treatment is considered for euthyroid patients with a smooth goitre, but it is contraindicated if the concentration of thyroid stimulating hormone is below normal. Patients with hypothyroidism require replacement therapy, but this should be introduced cautiously if the patient has ischaemic heart disease. The treatment of hyperthyroidism with antithyroid drugs should be monitored by measurement of tri-iodothyronine as well as thyroxine. A history of iodine exposure should be sought if the hyperthyroidism develops suddenly or the antithyroid drugs are ineffective. Specialist advice may be needed for patients with thyroid dysfunction taking drugs such as amiodarone, lithium or phenytoin and those with intercurrent conditions such as heart failure or pregnancy.

Introduction
Hyperthyroidism, hypothyroidism and goitre commonly present challenges in deciding optimal management. Sensitive specific tests of thyroid function allow early diagnosis of hyper- or hypothyroidism, but the results rarely provide a clear basis for therapy.

When treatment with thyroid hormone, usually thyroxine (T₄), is given, a distinction should be made between replacement and suppressive therapy. Replacement for hypothyroidism is usually given with the aim of normalising the level of thyroid stimulating hormone (TSH). In contrast, suppressive therapy to minimise the chance of thyroid cancer recurrence or, in some circumstances, to reduce goitre size aims to reduce TSH to levels well below the normal range. This important distinction depends on the use of recently available, highly sensitive TSH assays.

Goitre and thyroid masses
Clinical, biochemical, imaging and histological assessments must be closely co-ordinated in patients with goitre or thyroid dysfunction. A history of recent goitre enlargement, local pain or pressure symptoms, or the presence of a solitary or predominant nodule suggests the possibilities of malignancy, thyroiditis or haemorrhage within the gland.

Fine needle biopsy followed by expert cytological examination is now regarded as a first-line investigation of any suspicious thyroid lesion (Fig. 1).

Even if there is no strong clinical suspicion of thyroid dysfunction, the level of TSH can provide valuable information in planning optimal management for a patient with a benign goitre (Fig. 1). An elevated level of TSH suggests either diminished thyroid reserve¹, or primary hypothyroidism, depending on whether T₄ is normal or subnormal. TSH may be transiently elevated during the recovery phase of thyroiditis, so that a further sample 4-8 weeks later is appropriate before commencing lifelong treatment with T₄.

If the level of TSH is normal in the presence of a substantial smooth goitre, especially in a young patient, it is important to consider suppressive T₄ treatment with the aim of inducing goitre regression and preventing long term development of an autonomous nodular goitre or thoracic inlet obstruction from progressive enlargement of a retrosternal goitre. After careful assessment of thyroid size, T₄ can be given for at least 6 months in doses that suppress TSH to <0.1 mU/L (i.e. 0.2-0.3 mg daily). The measurement of thyroid size by volumetric ultrasound is well established in Europe, but is still infrequently done in Australia. If the goitre regresses, T₄ can be continued long term at a reduced dose that achieves low normal TSH levels. If there is no regression of goitre, T₄ should be discontinued.

In using TSH values to assess optimal replacement (normal TSH) or suppressive therapy (subnormal TSH), it is important to establish whether each particular TSH method has adequate precision at subnormal levels. Inadequate assays with little discrimination in the 0.1-0.3 mU/L range should now be discarded.

Autonomous goitre
If a euthyroid goitrous patient has TSH levels that are subnormal or suppressed (i.e. <0.3 mU/L), it is likely that all or part of the gland is already autonomous, i.e. that function is independent of TSH stimulation. The use of T₄ in an attempt to shrink the gland is then contraindicated the ingested hormone may merely add to endogenous production and cause thyrotoxicosis.

In patients with autonomous goitres, it is important to avoid exposure to iodine excess because of the risk of inducing hyperthyroidism which often responds poorly to antithyroid drugs. (This effect of iodine is in sharp contrast to its key role in goitre prevention in iodine deficient regions of the world.) Iodine contamination often occurs from radiological contrast media, iodine-containing cough mixtures, topical preparations or various herbal preparations. If a patient with an autonomous goitre is inadvertently exposed to iodine, thyroid status should be assessed after 4-6 weeks and again at 3 months. While CT scanning is useful in the assessment of thyroid masses, contrast media should never be given routinely, if a goitre is present.

Elective surgery has a definite place in the management of autonomous multinodular goitres because of their potential for later hyperthyroidism or progressive enlargement with obstruction of the thoracic inlet. The alternative of using high dose ¹³¹I therapy is also gaining acceptance.

Hypothyroidism

Assessment of thyroid replacement
In otherwise healthy patients, optimal T₄ replacement usually requires a dosage of 0.1-0.2 mg/day (i.e. 1.5-3.0 micrograms/kg/day). Biochemical monitoring of dosage is appropriate 3-6 months after commencing therapy and every 1-2 years thereafter. The optimal dose can usually be established by achieving normal TSH concentrations, often associated with a somewhat elevated level of free T₄. Marked suppression of TSH should be avoided in long term replacement therapy because of potential adverse effects of thyroid hormone excess on bone density and the cardiovascular system. In patients with established ischaemic heart disease, the T₄ dose should be based on clinical rather than biochemical assessment (see below). If the measured level is unexpectedly low, compliance should be checked. T₄ absorption is usually reliable, but cholestyramine and soy bean formulations can impair its absorption.

Should sub clinical hypothyroidism be treated?
Serum free T₄ and TSH are normally in an inverse feedback relationship, even within their normal reference ranges. Therefore, an increase in serum TSH usually occurs at an early stage of thyroid failure while the circulating levels of T₄ and triiodothyronine (T₃) are still within the normal reference range. However, the isolated finding of marginal elevations of TSH, in the range 5-10 mU/L, does not justify the diagnosis of primary hypothyroidism. The common entity of `sub clinical hypothyroidism' or `diminished thyroid reserve' exists when slightly elevated levels of TSH coexist with normal circulating T₄.¹

Progression of sub clinical to frank hypothyroidism occurs at a rate of less than 5% per year and is more likely at higher levels of TSH or in the presence of antithyroid peroxidase (antimicrosomal) antibodies. In general, biochemical testing should be repeated at 6 months and annually thereafter. If there is a clear rising trend in TSH, T₄ replacement is commenced. In making the decision to treat, it is important to remember that TSH is secreted episodically with substantial fluctuations in serum level. In the range 5-10 mU/L, a doubling of TSH in successive follow up samples indicates a definite trend.

Hypothyroidism and ischaemic heart disease
Abruptly starting thyroid replacement can worsen ischaemic symptoms or precipitate myocardial infarction in hypothyroid patients. Thyroid hormone replacement is usually begun at low doses in any patient perceived to be at risk, e.g. 0.025-0.05 mg T₄ daily, often with a beta blocker. The half life of T₄ is about a week, so the dose should not be increased in less than 3 weeks, until a new steady state is approached after about 3 half lives. Attempts to normalise TSH may be quite inappropriate; the optimal dose of T₄ in this situation is a clinical compromise. Coronary artery bypass grafting can be carried out before hypothyroidism is corrected, provided that anaesthetic doses and postoperative care are appropriately modified.²

When ischaemic heart disease coexists with sleep apnoea, T₄ treatment may aggravate arrhythmias during nocturnal hypoxic episodes. Continuous positive airways pressure with low dose T₄ replacement has been advocated in this situation.

Hyperthyroidism

Monitoring antithyroid drug treatment
In severe hyperthyroidism, antithyroid drugs are generally used as first-line treatment in fairly high doses, e.g. carbimazole (CBZ) 15 mg 3 times daily, often as a prelude to definitive treatment with radioiodine or surgery after the patient has been made euthyroid. The dose should be lowered by at least 50% as soon as a biochemical response is apparent, usually after 2-4 weeks. Biochemical monitoring in the early phase should be based on measurement of T₃ as well as T₄, because T₃ elevation may persist after normalisation of T₄. TSH may remain suppressed for several months after correction of hyperthyroidism and therefore should not be the sole guide to therapy.

Some patients are very sensitive to low doses, so that as little as 2.5-5 mg CBZ/day may be required to maintain control. If the response to antithyroid drugs is poor, compliance may be inadequate. A history of previous iodide excess should be sought if there is apparent resistance or delayed response to antithyroid drugs. Iodide induced hyperthyroidism may ultimately be self-limiting.

In some situations, a `block-replace' regimen with concurrent antithyroid drug and T₄ can be used. A combination such as T₄ 0.1 mg daily and CBZ 10 mg twice daily has the advantage that it requires minimal follow up. Combined treatment has also been claimed to induce a high remission rate in Graves' disease, but this effect is so far unproven.

Agranulocytosis can occur with CBZ, methimazole and propylthiouracil (PTU). This complication may be dose-related and, although it is more frequent in the elderly, it can occur in any age group. Patients must be warned to report fever, malaise or severe sore throat so that the neutrophil count can immediately be assessed. Other adverse effects include rashes, gastrointestinal intolerance and myalgia.

Hyperthyroidism and pregnancy
If a woman treated for Graves' disease with an antithyroid drug wishes to become pregnant, there are two options. Medical treatment can be continued, with a preference for PTU rather than CBZ.⁵ Based on monthly monitoring of free T₄, free T₃ and TSH during pregnancy, dosage must be minimised to avoid fetal goitre due to over treatment. If pregnancy can be deferred for at least 6 months, definitive treatment by surgery or ¹³¹I may be preferable; monitoring will still be required to ensure normal thyroid status.

Hyperthyroidism and cardiac failure
Higher than normal doses of digoxin may be required to control the ventricular rate in patients with a trial fibrillation and hyperthyroidism.³ Beta blockers, which alleviate some symptoms of hyperthyroidism, can be very effective, but should be used with caution because their negative inotropic effect may sometimes cause a marked deterioration in some patients. During diuretic therapy, depletion of intravascular volume and negative fluid balances of more than 0.5 L/day should be avoided. As a trial fibrillation is associated with a danger of arterial emboli, especially in patients with heart failure⁴, there is a case for anticoagulation. Paradoxically, if warfarin is used, a lower than normal dose may be required in hyperthyroid patients.³

Therapeutic options
Antithyroid drugs, radioiodine and surgery each have a definite place in the management of patients with hyperthyroidism. These modalities should be regarded as complementary rather than in competition with each other.⁵

Difficult associated drugs

Amiodarone
Amiodarone induced hyperthyroidism is often atypical in its clinical presentation, with weight loss and myopathy as the dominant features. This condition may be life threatening, with an unpredictable response to antithyroid drugs, but it can resolve spontaneously. In severe cases, glucocorticoids may be beneficial. High levels of T₄ are common during amiodarone therapy and, even if T₄ is markedly elevated, this finding alone does not indicate hyperthyroidism unless accompanied by T₃ excess and TSH suppression.⁶ Amiodarone can also cause hypothyroidism, especially in the presence of antimicrosomal (antiperoxidase) antibodies. Treatment with T₄ may be complicated by the associated heart disease.

Phenytoin
Phenytoin has multiple complex interactions with the pituitary thyroid axis so that the normal criteria for diagnosis of hypothyroidism become unreliable. Phenytoin treated patients often show low T₄ levels without the anticipated rise in TSH, suggesting central hypothyroidism. Benefit from T₄ treatment has not been clearly established.

Lithium
Lithium treatment will accentuate any underlying predisposition to goitre or hypothyroidism, especially in patients with a background of autoimmune thyroid disease. Hypothyroidism may be misdiagnosed as a depressive relapse or lithium induced weight gain. Annual monitoring of TSH and assessment of thyroid size is appropriate so that T₄ treatment can be initiated promptly, either to correct hypothyroidism or to prevent progressive goitre enlargement. The presence of antiperoxidase antibodies indicates an increased likelihood of hypothyroidism with both lithium and amiodarone.