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In hyperthyroidism the thyroid gland produces inappropriately large amounts of thyroid hormones, usually due to stimulation by auto-antibodies. It is characterized by hyperkinesis, hyper-metabolic state, goitre and eye signs. Biochemically serum levels of T3 and T4 are elevated, and TSH reduced. Antithyroid medicines reduce the amount of thyroid hormones produced, released or conversion of T4 to T3 in the peripheral tissues.
Excess function of the thyroid gland was recognized even in the 19th century (1,2).
Hyperthyroidism is a specific form of thyrotoxicosis where excessive thyroid hormones are produced by the thyroid in contrast to exogenous administration of inappropriately large thyroid hormones, or a leak of thyroid hormones in thyroiditis (3). Thyrotoxicosis comprised 13% of all individuals referred for evaluation of thyroid status in our Centre (4).
Common causes of thyroid hormone excess (5).
A rare form of autosomal dominant hereditary nonautoimmune hyperthyroidism was reported that is caused by constitutively activating germ-line mutations in the TSH-receptor gene (6). It is characterized by familial occurrence of hyperthyroidism in more than two generations, with onset in the neonatal or childhood period, relapsing after surgery or antithyroid drugs. Mutation analysis of genomic DNA shows germ-line mutations in TSH-receptor gene. Near total thyroidectomy and genetic counselling are advised.
Graves' disease: In Graves' disease, antibodies against TSH receptor (TSAb) of the thyroid follicular cells bind and stimulate thyroid hormone production, similar to thyrotropin, but without normal feedback inhibition (7). Lack of antibody positivity can be a manifestation of mild Graves' disease, although routine testing is neither feasible nor warranted (8).
Nodular goitre: In nodular goitre some of the follicles assume autonomy, resulting in hyper-secretion of thyroid hormones, uncoupled from physiological restraint. Some autonomously functioning thyroid nodules have a mutation of the gene for the TSH receptor that results in constitutive activation of the receptor (9).
The symptoms and signs can be grouped as follows (7)
Clinical features of hyperthyroidism
Symptoms
Signs
*The American Thyroid Association classified eye signs of Graves' disease as follows:
A rare clinical manifestation in Grave's ophthalmopathy is the 'flashing lights in thyroid eye disease': patients with restrictive thyroid ophthalmopathy complained of flashing lights in the superior visual field when looking upward (13). This was seen in people with tight inferior recti muscles and burnt out phase of thyroid eye disease.
The clinical features of 255 individuals with thyroid hormone excess from India are given in Tables 1 and 2.
Table 1
Symptoms in persons with excess thyroid hormone (n: 255): EDC data
| Symptom Number | (%) |
|---|---|
| Anxiety 185 | (72.55) |
| Weight loss 173 | (67.8) |
| Tremor 169 | (66.27) |
| Palpitation 168 | (65.88) |
| Shortness of temper, crying 161 | (63.14) |
| Hair loss 156 | (61.18) |
| Sleep disturbances 113 | (44.31) |
| Increased appetite 96 | (37.65) |
| Frequency of bowel movement 89 | (34.9) |
| Heat intolerance 72 | (28.23) |
| Skin changes 48 | (18.82) |
Table 2
Signs in persons with excess thyroid hormone (n: 255): EDC data
| Sign Number | (%) |
|---|---|
| Goitre+ 235 | (92.16) |
| Hand tremor, hyperkinesis 175 | (68.63) |
| Skin changes 147 | (57.65) |
| Eye signs 96 | (37.65) |
The common symptoms and signs were related to anxiety and hyperkinesis, with loss of weight and hair closely following. Similarly goitre was present in the majority of patients.
The three cardinal manifestations can be summarized as
Hyperthyroidism may be misdiagnosed due to (5)
Sub-clinical hyperthyroidism.
With the widespread use of sensitive TSH assays, sub-clinical hyperthyroidism is commonly identified. It is characterized by normal levels of peripheral thyroid hormones with low serum TSH (14). It is reported between 0.2-11.8% in different series, particularly in women (15). A recent study from India suggests sub-clinical hyperthyroidism could be an etiological factor in hyper-kinetic behaviour in children (16).
The health implications of sub-clinical hyperthyroidism hinge on
Sweeping guidelines cannot be made about its management, but depend on a comprehensive clinical assessment, risk profile and risk-benefit ratio in each individual.
Cardiac risks in the elderly
Cardiac risks are especially important in those above 50 years. Anticoagulation is recommended for thyrotoxic patients with atrial fibrillation, with past history of embolization, with hyper-tension or echocardiographic evidence of left atrial enlargement (17).
Apathetic thyrotoxicosis
In apathetic thyrotoxicosis, rather than typical hyperkinesis and eye signs, there may merely be anorexia, cool dry skin and constipation. Cardiac disorders such as arrhythmia, congestive heart failure and myopathy may be prominent (5). It often occurs in the elderly, and needs a high index of suspicion
Thyroid storm
There is an abrupt severe exacerbation of thyrotoxicosis in thyroid storm (18,19). It is characterized by fever, marked tachycardia and an abnormal mental state. Thyroid storm could be precipitated by sudden discontinuation of antithyroid drugs or an increase in metabolic stress (such as infection, surgery, and trauma). Prevention is best; the next best is emergency treatment, initiated at the earliest suspicion. Careful assessment, follow up and consultation with cardiologist, chest physician, anesthesiologist is required. The crucial steps in management are given here (for the sake of continuity):
Pregnancy and thyrotoxicosis
Two main forms of hyperthyroidism are described in pregnancy (20)
Thyrotoxic periodic paralysis
Non-familial hypokalemic thyrotoxic periodic paralysis is described in Asians (22) more than in Caucasians. It often presents as sudden paralysis occurring while at rest after a large carbohydrate meal or strenuous exercise in an undiagnosed mild thyrotoxic patient (23). Intra-cellular shifts of potassium triggered or facilitated by hyperthyroidism and hyperinsulinemia are the biochemical features. Treatment consists of correcting thyrotoxicosis; judicious potassium supplementation may be necessary to prevent life-threatening arrhythmia in the hypokalemic phase. Non hypokalemic periodic paralysis can also occur in thyrotoxicosis (24).
Thyroid nodules in Graves' disease
The presence of thyroid nodules in Graves' disease raises the possibility of malignancy (see next section). In an outpatient study of 468 patients with Graves's disease, thyroid nodules were seen in 60 patients (12.8%) (25). They could be classed as
Ten percent of those with nodules had malignancy, the maximum (five) being in the first group. Fine needle aspiration biopsy can distinguish malignant from benign nodules. Any single cold nodule that remains or develops after treatment carries a high risk of malignancy.
Thyroid carcinoma in Graves' disease
Although it is accepted wisdom that the diagnosis of hyperthyroidism virtually rules out the possibility of thyroid carcinoma, the two may coexist, though rarely. In a large series of patients with thyroid cancer from Tata Memorial Centre, Mumbai, five out of 488 (1%) had hyperthyroidism (26). Cancer coexisting with Graves' disease is reported to be more aggressive than in matched euthyroid controls (27), although the view is not unanimous. In a recent study it was shown that the majority of patients with thyroid cancer and concurrent hyperthyroidism had small carcinomas (28). There was no predictive relation between distant metastases and any of these factors: age, sex, duration of thyrotoxic symptoms, tumour size, histopathological findings, extent of surgery, post surgery ablation and post operative serum levels of thyroglobulin or thyrotropin.
Thyroid hormone resistance
Thyroid hormone resistance is a rare form of thyrotoxicosis, in which there is a pituitary resistance to thyroid hormones (29). It is caused by mutations in the exon for the thyroid hormone receptor, and responds to 3,4,3'-triiodothyroacetic acid (TRIAC). Prenatal diagnosis of the condition is possible by chorionic villi sampling, and polymerase chain reaction analysis.
Whereas clinical features are signposts, documenting that thyroid hormone levels are raised confirms the clinical impression. In primary hyperthyroidism, the serum levels of T4 and T3 are elevated, whereas serum TSH is depressed. When reliable ultrasensitive TSH assays are available, levels of TSH below the normal range suggest thyrotoxicosis (30). Inappropriately increased thyroid hormone levels suppress the TSH secreted from the pituitary. In rare conditions such as a TSH secreting pituitary tumour, there could be an elevation of TSH along with T3 and T4 (31).
A low radioiodine uptake of the thyroid can identify transient thyrotoxicosis due to thyroid hormone leak in thyroiditis, in contrast to hyperthyroidism. Similarly gray scale ultrasonography can offer additional clues to Graves disease (32).
The principal methods of treating hyperthyroidism is by
In addition, treatment with beta-blockers, inorganic iodine and lithium may be employed.
Forty-five practicing thyroidologists who were members of the Endocrine Society of India were mailed a proforma containing one index case with Graves' disease and five variations. They were asked to indicate the investigations of choice and therapy (33). Response from 32 (72%) showed that antithyroid drugs were the first choice in most except in those with relapse, or a hypothetical 65 year old woman, where radioiodine therapy was the choice of the majority. The results were comparable to those from Europe, but differed from the United States of America, where radioactive iodine ablation is used more liberally.
Antithyroid drugs
A variety of antithyroid agents are available, and can be grouped based on which process in thyroid hormone formation is affected (34):
Thionamides
Propylthiouracil and carbimazole ('Neomercazole') are commonly used; the latter is freely available in our country. Both inhibit hormone synthesis; only when the preformed hormone is depleted and the concentrations of circulating thyroid hormones begin to decline do clinical effects become noticeable. This happens earlier in areas of iodine deficiency such as India (35). Additionally propylthiouracil inhibits peripheral deiodination of T4 to T3. The pharmacokinetic features can be summarized as follows
| Feature | Propylthiouracil | Carbimazole |
|---|---|---|
| Plasma half life | 75 min | #4-6 hours |
| Metabolism of drug during Illness: | liver disease | Normal Decreased |
| Renal disease | Normal | Normal |
| Transplacental passage | Low | Not low |
| Levels in breast milk | Low | Not low |
In addition, propylthiouracil appears to be an anti-oxidant as well (36), unlike carbimazole (37). Methimazole has been shown to reduce thyroid auto-antibodies, suggesting an effect on the immune system (38).
A study from India has shown that carbimazole can be given in a single daily dose. It was as effective as divided dose therapy to treat hyperthyroidism in an area of mild iodine deficiency (39). There was no increase in remission with a higher dose of antithyroid drug (methimazole 10 or 40 mg/day). The overall relapse rate was 58% in a large series of 313 patients with Graves' disease followed for a mean period of 4.3 years (40). In India, antithyroid drugs were able to induce long remission in 43% of patients with Graves' disease (41). Besides, abnormal T4 suppression test was a reliable parameter for predicting relapse, comparable to other markers such as TRH stimulation test and thyroid receptor antibodies (41). Long term treatment with carbimazole therapy resulted in the tendency of patients to become positive for insulin auto-antibodies (42).
Combination of antithyroid drugs with thyroxine to suppress TSH
A combination of high dose carbimazole with add-back thyroxine treatment (6 months of 100 mg carbimazole per day plus thyroxine) versus low dose carbimazole (starting at 25 mg and titrating the dose to maintain normal thyroid hormone levels) was compared in Graves' disease. High dose carbimazole treatment delayed but did not prevent relapse from Graves' disease, in those who were able to tolerate the treatment. However high dose led to more frequent adverse reactions (43). Similar results were seen in another study from France (44).
Outcome of treatment with antithyroid drugs
Younger patients with Graves' disease might benefit from a higher initial dose of carbimazole (45). In a study of 159 patients of Graves' disease from Ireland followed up for a mean of 10.5 years, 28% of patients treated with antithyroid drug were in remission, 68% relapsed and 4% became hypothyroid (46). Among the elderly, long term use of antithyroid medicines is not safe, especially with toxic nodule goitre, due to poor compliance (47).
Stress, quality of life and Graves' disease
There are intriguing early results suggesting that chronic psychological stress adversely affects the course of Graves' disease in women, at least in the short-term (48). Similarly, the degree of disability as a result of Graves' ophthalmopathy can be quantified by a specific quality of life questionnaire, which measures the result of treatment in terms of what the patient perceives (49). It can serve as an additional measure of treatment outcome, supplementing the traditional physiological or biological measures of health status (50).
Combination therapy with colestipol
The enterohepatic circulation of T3 and T4 is higher in thyrotoxicosis. Bile-salt sequestrants bind thyroid hormones and thereby increase their fecal excretion. The effect of colestipol-hydrochloride, a bile-acid sequestrant was studied to increase fecal excretion of thyroid hormones (51). It was effective and well tolerated as an adjunct to methimazole. It is mainly useful in severe cases of thyrotoxicosis in the first phase of treatment. As an adjunct, it reduces the dose of methimazole required.
Adverse drug reactions with antithyroid drugs
Adverse reactions with antithyroid drugs are varied and rare. The most serious and less common reaction is agranulocytosis, which may be seen, with both carbimazole in a dose dependent manner, and with propylthiouracil independent of the dose. It can develop swiftly; periodic monitoring of WBC counts is usually of little help. Patients should immediately report the development of sore throat or fever, which heralds the onset of agranulocytosis. It is reversible on stopping the drug. Recombinant human granulocyte colony-stimulating factor given in a dose of 5 ug/kg/day can correct it. (52).
Other common but less serious side effects include urticarial papular rash, which often subsides spontaneously. Less common ones are auto-immune disorders (vasculitis, lupus erythematosis, polyarthritis (53), paresthesia, nausea, drug fever, hepatitis (54), nephritis and Wegner's granulomatosis (55).
Percutaneous ethanol injection in thyroid nodules
Percutaneous ethanol injection (PEI) is an alternative to surgery in the management of thyroid nodules. In a series of 108 patients, including 47 with hyper-functional solid nodules, PEI resulted in 91.5% cure among hyperthyroid patients (56). It is a cheap, easy to perform outpatient procedure, especially useful in some patients with small toxic benign thyroid nodules. It can be made more objective by ultrasound-guidance (57).
It is necessary that patients with thyrotoxicosis be followed up regularly to
Hyperthyroidism is best managed with clinical skill, with knowledge of biology pharmacology and an understanding of the patients' desires risks and benefits. It demands of a combination of anticipation and restraint. So managed, it is one of the most gratifying of endocrine diseases to treat.
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