Which mechanism of action explains how propylthiouracil PTU manages hyperthyroidism?

Iodine

Since thionamides block the organification of iodine and incorporation of iodine into iodotyrosines, they inhibit the uptake of 131I used therapeutically in hyperthyroidism. For this reason, thionamides are generally withdrawn for a period of up to a week before 131I therapy is planned, and re-introduction is similarly delayed until several days after 131I therapy. The effect of treatment with either thiamazole or propylthiouracil before 131I has been studied retrospectively [183], the thionamide being withdrawn 5–55 days before 131I administration. The findings confirmed the view that propylthiouracil, but not thiamazole, significantly reduced the cure rate after 131I compared with that found in subjects not pretreated with propylthiouracil, and that discontinuation for 4 months was required for the cure rates to be similar. These findings highlight the fact that thionamides cause a relative “radio-resistance,” and prolonged drug withdrawal or an increased dose of 131I may be required to produce an acceptable cure rate.

Treatment Strategies

The purpose of treatment of Graves’ disease hyperthyroidism with antithyroid drugs is to achieve stable euthyroidism. Antithyroid drugs can be used either as preparatory treatment before surgery or radioiodine or as a primary management tool of the disease in an attempt to induce long-term remission of thyrotoxicosis. A direct effect of methimazole and propylthiouracil on the immune system has been proposed to explain the observation that a minority of patients experience long-lasting remissions of Graves’ disease thyrotoxicosis after withdrawal of these drugs.148 This view is suggested by the following lines of evidence. In some follow-up studies, patients treated with antithyroid drugs had a higher remission rate than did those to whom β-blockers alone were administered,148 but randomized studies have never been performed. Treatment of Graves’ disease with antithyroid drugs is followed by a fall in the levels of circulating TRAb, AbTg, and AbTPO,146,301-303 although this effect is not dose dependent.284 In vitro experiments have suggested a down-regulating effect of methimazole on antigen presentation,304 and in vivo studies have shown that the drug is able to reduce the severity of experimental thyroiditis.305,306 Despite these observations, the immunosuppressive effect of thionamides remains controversial. A decrease in circulating thyroid antibody titer has also been observed in hyperthyroid patients treated with perchlorate, a drug with different pharmacologic properties.307 Restoration of euthyroidism per se might be responsible for the decrease in thyroid autoantibodies, through a direct effect of thyroid hormone on the immune system.308 The natural history of the disease, which like that of many other autoimmune disorders is characterized by cycles of spontaneous relapse and remission, could also explain the reduction in thyroid autoantibody titers. In other words, a course of 12 to 24 months of thionamides would merely be a way of keeping the patient euthyroid while waiting for the autoimmune process to subside or even vanish.

Thionamide treatment is usually started with high doses (20 to 40 mg/day of methimazole or 200 to 400 mg/day of propylthiouracil). Doses of methimazole above 40 mg/day are rarely necessary. When long-term thionamide treatment is planned, one of two treatment strategies is currently used:

Maintenance of euthyroidism with the minimum effective dose throughout the trial period, with thyroid function tests performed every 1 to 3 months. The minimum dose capable of maintaining euthyroidism is derived by “back-titration” every 4 to 6 weeks.

Administration of fixed, relatively high doses of thionamide in combination with levothyroxine to prevent iatrogenic hypothyroidism, the so-called block-and-replace regimen.

With both schemes, patients should be kept completely euthyroid, with serum TSH levels within the normal range.

The second protocol was proposed because of the supposed immunosuppressive effect of higher doses of thionamides and because of studies suggesting a greater remission rate of hyperthyroidism in Graves’ patients treated with high doses of thionamides (60 versus 15 mg of methimazole per day).309 The addition of levothyroxine supposedly provides an extra advantage, and very high remission rates were reported in Japanese patients treated with methimazole for 6 months and then given a combination of methimazole and levothyroxine for an additional year, followed by levothyroxine alone for 3 years.309,310 However, the latter results have not been reproduced by a number of subsequent studies.301-315 In a prospective randomized trial of low (10 mg/day) versus moderately high (40 mg/day) doses of methimazole, no advantages were observed in terms of a decrease in TRAb titer or the rate of relapse of hyperthyroidism.284 The rate of adverse reactions was greater in the group of patients receiving methimazole at 40 mg/day. Thus at present, the block-and-replace regimen has no proven advantage, although one point in favor of it is that it probably requires less testing. The block-and-replacement strategy can also be useful in rare patients who experience changes from hyperthyroidism to hypothyroidism and vice versa after minimal changes in the dosage of antithyroid drugs (“brittle hyperthyroidism”). In these unusual patients, maintenance of euthyroidism is difficult with antithyroid drugs alone.

Regardless of the chosen regimen, treatment is maintained for 12 to 24 months, after which thionamide therapy is usually discontinued. Indefinite treatment even with low doses of thionamides is not a common practice.

In summary, thionamide treatment of Graves’ disease thyrotoxicosis has the major advantages of not causing permanent hypothyroidism and of limiting exposure to radiation. It is, however, associated with a very high failure rate, and in many cases it is only a way to delay thyroid ablation by radioiodine or surgery.

Medical Management—Antithyroid Drugs

The thionamide drugs (carbimazole, its metabolite methimazole, and propylthiouracil) compete with Tg to act as substrates for iodination by TPO. Once iodinated, they are metabolized peripherally, depleting thyroid iodine stores. When the thyroid iodine stores are depleted and the intrathyroidal thionamide concentration is high enough, thyroid hormone synthesis is abrogated. Most individuals become euthyroid following 4–8 weeks of treatment; however, euthyroidism may take longer to achieve in those with poor medication compliance or with a history of recent iodide exposure. Following initial treatment, thionamides may either be administered as a fixed high dose, with levothyroxine supplementation to prevent hypothyroidism (known as a “block and replace” regimen), or at progressively lower doses, titrated to allow adequate thyroid hormone generation. Following 6–18 months of thionamide treatment, about 50% of patients will remain in remission following cessation of therapy. There is no improvement in remission rate in individuals with GD who are treated for longer than 18 months. The mechanism of the thionamide-induced remission in GD remains obscure; however, the lymphocytic infiltrate in the GD thyroid is rapidly abolished by thionamide treatment, and serum TSH-R and TPO autoantibodies also decrease during treatment, suggesting an immunomodulatory effect. It is telling that several induced murine models of thyroiditis can be ameliorated by thionamide treatment, suggesting an immunomodulatory role that is distinct from the antithyroid hormone synthesis action. If the patient's disease relapses following medical treatment, definitive treatment should be considered, as a second course of thionamide treatment rarely induces prolonged remission.

Immunosuppressive Action of Thionamides

Thionamide drugs may also directly influence the immune response in patients with autoimmune thyroid disease.56 This action occurs within the thyroid gland, where the drugs are concentrated. The action on the thyroid cells themselves decreases thyroid antigen expression and decreases prostaglandin and cytokine release from thyroid cells. Thionamides also inhibit the generation of oxygen radicals in T cells, B cells, and particularly antigen-presenting cells and hence may cause a further decline in antigen presentation. It has also been shown that methimazole induces the expression of Fas ligand on thyroid epithelial cell, thereby inducing apoptosis of infiltrating lymphocytes such as T cells that express FasL and decreasing the lymphocytic infiltration.165,166 The clinical importance of immunosuppression and induction of apoptosis compared with inhibition of thyroid hormone formation is unclear. However, the decrease in immune infiltration seen in patients taking such drugs and the fall in autoantibody levels after initiation of such therapy is powerful evidence of their effect.

Action of Thionamides on the Immune System.

Thionamide drugs may directly influence the immune response in patients with AITD.185 This action may occur within the thyroid gland, where the drugs are concentrated. The action on the thyroid cells themselves decreases thyroid antigen expression and decreases prostaglandin and cytokine release from thyroid cells. Thionamides also inhibit the generation of oxygen radicals in T cells, B cells, and particularly antigen-presenting cells and hence may cause a further decline in antigen presentation. It has also been shown that methimazole induces the expression of Fas ligand on the thyroid epithelial cell, thus inducing apoptosis of infiltrating lymphocytes such as T cells that express Fas ligand and decreasing the lymphocytic infiltration.186 The clinical importance of immunosuppression and induction of apoptosis compared with inhibition of thyroid hormone formation is unclear. Some investigators find that a more likely cause for the decrease in autoimmunity in patients treated with antithyroid drugs is that the patients become euthyroid. Thyroid hormones have multiple effects on the immune system, some of which appear to be nongenomic,187 and the thyrotoxic state my worsen autoimmunity. The circle is broken when patients become euthyroid by drug therapy.

ANTITHYROID DRUGS

The thionamide antithyroid drugs—methimazole and propylthiouracil in the United States and carbimazole in Europe and Asia—have limited roles in the management of patients with nontoxic nodular goiter. Unlike hyperthyroid Graves’ disease, thyroid autonomy in toxic nodular goiter rarely remits unless it has been provoked by an iodine load. Furthermore, because of the substantial store of previously synthesized thyroid hormone that can be present in the large gland of a patient with toxic nodular goiter, thionamide therapy alone may not control hyperthyroidism completely for weeks or months.

Nonetheless, there remain certain indications for short-term antithyroid drug therapy. First, thionamides can be useful for the initial control of hyperthyroidism that is severe or complicates cardiac or other conditions in a fragile patient. By restoring euthyroidism, such thionamide pretreatment can then make subsequent surgery or radioiodine therapy safer. Second, PTU is the immediate treatment of choice for pregnant patients with hyperthyroidism, although toxic nodular goiter is rare in this population. Third, a time-limited course of antithyroid drugs can sometimes be useful to evaluate the clinical status of patients with subclinical hyperthyroidism who have nonspecific symptoms, such as nervousness or insomnia, that may or may not improve with definitive treatment of mild hyperthyroidism. If a patient experiences an improvement in symptoms or sense of well-being when thyroid function has been restored to normal on thionamide therapy, then the case for radioiodine therapy or surgery is stronger.

The specific mechanisms of action, doses, and side effects of the thionamide antithyroid drugs have been extensively reviewed.148

Clinical Pharmacology

Thionamides (methimazole, carbimazole, and propylthiouracil) were described and introduced into clinical practice in the early 1940s.9 Their major action is to inhibit the organification of iodine and coupling of iodotyrosines, thus blocking the synthesis of hormones.242 Carbimazole is not active as it is, but it is almost completely converted to methimazole in the body, and their effects are comparable. Propylthiouracil has the additional effect of partially inhibiting the conversion of T4 to T3 in peripheral tissues, but this effect is of limited clinical value. Methimazole is at least 10 times more potent than propylthiouracil. The pharmacologic properties of the two major thionamides are compared in Table 82-3. Both methimazole and propylthiouracil are very effective in controlling hyperthyroidism.242 They do not block the release of preformed thyroid hormones, so euthyroidism is not obtained until intrathyroidal hormone and iodine stores are depleted. This process requires 1 to 6 weeks, depending on factors such as disease activity, initial levels of circulating hormones, and intrathyroidal hormone and iodine stores. Large goiters with abundant deposits of thyroid hormone, especially when iodine excess is present, often show a delayed response.

Surveys from the early 1990s indicated that propylthiouracil was favored over methimazole by North American endocrinologists, whereas the majority of their European colleagues preferred methimazole.281 However, in recent years methimazole has been chosen as the first-line agent also in North America, mostly because of its superior side effect profile,282 with propylthiouracil relegated to specific clinical circumstances, such as allergy to methimazole or pregnancy. The recommendation against the use of propylthiouracil has recently been strengthened by an increasing numbers of reports of severe liver toxicity, in some cases leading to transplantation and in a few to death from fulminant hepatic failure.282-284

The main problem with thionamide treatment is the high relapse rate of thyrotoxicosis after discontinuation of even long-term treatment. Although remission rates of 50% to 70% within 1 year after withdrawal of thionamides have been reported in a few series,285,286 in most studies hyperthyroidism recurred in 50% to 80% of patients, depending on the duration of the follow-up period.287,288 Remission rates have been decreasing over time, possibly as a result of increased iodine supply in the diet.289,290 A practical problem is that no single test or combination of tests will accurately separate patients who will relapse from those who will not. Size of the goiter before or during antithyroid drug treatment, HLA-DR3 typing, TRAb or TPOAb levels, serum Tg concentrations, thyroid echogenicity, circulating activated T cells, T cell subset ratios, and presence of ophthalmopathy have all been indicated as significant pretreatment risk factors for relapse, but none has the required sensitivity or specificity to predict the outcome in individual patients. The presence of a large goiter seems to be the most significant predictor (Fig. 82-8).287 Similar considerations apply during treatment to parameters such as T3 suppression of 99mTc uptake, the thyrotropin-releasing hormone test, and the T3/T4 ratio at the time of discontinuation of thionamide therapy. In children, a longer initial duration of euthyroid state with antithyroid drugs seems to be the only variable related to the risk for relapse.288 Regardless of age, a good predictor of relapse of hyperthyroidism is a positive TSAb test before discontinuation of medical treatment. However, even when TSAbs disappear, the chances of relapse are still high, ranging from 20% to 50%.291

Most relapses of hyperthyroidism occur within 3 to 6 months after therapy is discontinued, and more than two-thirds of patients who relapse will do so within 2 years. However, hyperthyroidism can also recur much later. Late evolution to primary hypothyroidism can be observed as well, mainly in patients who remain euthyroid after discontinuation of therapy.292,293 Relapse of hyperthyroidism after a full cycle of thionamides is a strong indication for alternative treatments such as radioiodine or thyroidectomy, but a second course of the drug can be given, for example, to adolescents, while bearing in mind that people who have relapsed once are more likely to do so after a second cycle.

Minor side effects of thionamides have been reported in 1% to 15% of patients, but the average appears to be 6%. Pruritus, skin rash, and much less commonly, urticaria are the most prominent manifestations.242 Arthralgias have also been reported. These side effects frequently resolve spontaneously despite continued therapy. However, when any of them occur, it is generally advisable to replace one thionamide with the other, although cross-sensitivity to these drugs may occur. Antihistamine drugs can be used to control mild side effects. Slight elevations in liver enzyme levels have often been reported, and sometimes it is difficult to distinguish this effect of thionamides from that of thyrotoxicosis itself. When detected, serious alterations in liver function test results must be monitored closely because toxic hepatitis may develop suddenly.

Serious side effects are uncommon and are observed in approximately 3 of every 1000 patients.242 Agranulocytosis (granulocyte count <500/mm3) may be observed with both methimazole and propylthiouracil. It has been reported more frequently in older adult patients, but it can occur at any age. It is most often detected within the first 3 to 4 months after starting therapy. Agranulocytosis may develop so suddenly that even weekly white blood cell counts may not detect it. Typically, agranulocytosis is initially manifested by fever and evidence of infections, most often in the upper respiratory tract. Instructing all patients taking antithyroid drugs to report these symptoms immediately is probably the safest measure for immediate detection of this complication. Routine white blood cell counts should be performed in all patients before initiation of treatment because mild leukopenia is common in Graves’ disease and needs to be distinguished from a drug reaction. In addition to prompt discontinuation of the antithyroid drug, treatment includes the administration of broad-spectrum antibiotics and growth factors to stimulate bone marrow. Patients usually recover within 2 to 3 weeks, but some deaths have been reported.

Cholestatic (mostly observed with methimazole) or necrotic (mostly observed with propylthiouracil) hepatitis is another relatively rare, but severe complication of thionamide treatment, being associated with significant mortality and sometimes requiring liver transplantation.242 As mentioned earlier, there have been several, recent reports of propylthiouracil-induced severe liver toxicity.282-284

Vasculitis and lupus-like syndromes are rare; so is aplastic anemia.242 In the presence of a major adverse reaction to thionamides such as agranulocytosis, hepatitis, or vasculitis, prompt withdrawal of the drug is mandatory. The risk for cross-reactivity is such that switching from methimazole to propylthiouracil or vice versa is not recommended when side effects are severe, so alternative treatments must be sought.

ADJUNCTIVE TREATMENTS

Decreasing hormone production and secretion

Thionamides, such as propylthiouracil and methimazole, effectively block new thyroid hormone synthesis, but they do not prevent the release of stored hormone. Thionamides have immunosuppressive properties that decrease the expression of antithyroptropin-receptor antibodies. Propylthiouracil inhibits the peripheral conversion of T4 to T3 but must be given two to three times per day and has been associated with severe liver toxicity. Methimazole can be given once daily.27,36

High-dose iodine, such as saturated potassium iodide solutions or potassium iodide-iodine (Lugol’s solution), can acutely block the release of T4 and T3.37 Iodine products, however, should only be given after thyroid synthesis has been blocked for several hours. If synthetic function is not adequately inhibited, the iodine will enhance thyroid hormone synthesis and can exacerbate the thyrotoxicosis.33

Iopanoic acid and other iodinated oral radiographic contrast agents have extremely high iodine concentrations and have been used off-label in lieu of iodine solutions. In addition to decreasing thyroid hormone release, these agents attenuate the effects of thyroid hormone by decreasing hepatic uptake of T4, inhibiting peripheral conversion of T4 to T3, and blocking cellular binding of T4 and T3.38,39 Thyroid synthesis should be blocked before use to prevent enriched thyroid hormone production.

Lithium carbonate can also block the formation and release of thyroid hormone33; however, lithium is not considered a first-line therapy because of a narrow therapeutic window and is reserved for patients with an iodine allergy. l-carnitine blocks nuclear uptake of thyroid hormone and has been suggested as a treatment of thyrotoxicosis in combination with methimazole.40

Drugs for Treatment of Hyperthyroidism