Interferon alfa thyroid

Contraindications to interferon alfa therapy include hepatic decompensation, autoimmune disease, and history of cardiac arrhythmia. Caution is advised in the setting of psychiatric disease, epilepsy, thyroid disease, ischemic cardiac disease, severe renal insufficiency, and cytopenia. Alfa interferons are abortifacient in primates and should not be administered in pregnancy. Potential drug-drug interactions include increased theophylline levels and increased methadone levels. Co-administration with didanosine is not recommended because of a risk of hepatic failure, and co-administration with zidovudine may exacerbate cytopenias. 

Since the first reports of hypothyroidism, a number of studies have reported the occurrence of thyroid dysfunction in patients receiving aldesleukin alone or in combination with LAK cells, interferon alfa, interferon gamma, or tumor necrosis factor alfa (SED-13, 1104 6). Symptoms were usually observed after 2-4 months of treatment (7-9), and mostly consisted of moderate hypothyroidism, which resolved after immunotherapy withdrawal or thyroxine treatment (9,10). Patients treated with aldesleukin plus interferon alfa more commonly developed biphasic thyroiditis with subsequent hypothyroidism or hyperthyroidism (10-13). 

The possibility of a positive correlation between the development of thyroid dysfunction and the probability of a favorable tumor response has been debated (7,9,14). The incidence of thyroid dysfunction did not correlate with the dose or the underlying disease, but increased with treatment duration (6). In a large survey of 281 cancer patients receiving low-dose (72 000 IU/kg) or high-dose (720 000 IU/kg) aldesleukin, up to 41% of previously euthyroid cancer patients developed thyroid dysfunction (15). Combined immunotherapy was also associated with more frequent thyroid disorders. Aldesleukin plus interferon alfa produced thyroid dysfunction in 20-91% of patients (6), and the incidence of laboratory thyroid dysfunction reached 100% in patients given five or six cycles of both cytokines (11). Aldesleukin plus interferon alfa also tended to be a risk factor for the development of biphasic thyroiditis (9). 

Since the original 1988 report of hypothyroidism in patients with breast cancer receiving leukocyte-derived interferon alfa (498), numerous investigators have provided clear clinical and biological data on thyroid disorders induced by different forms of interferon in patients with various diseases (499,500-503). Two of these reports also mentioned associated adverse effects that developed concomitantly, namely myelosuppression and severe proximal myopathy (Hoffmann s syndrome). 

The spectrum of interferon alfa-induced thyroid disorders ranges from asymptomatic appearance or increase in antithyroid autoantibody titers to moderate or severe clinical features of hypothyroidism, hyperthyroidism, and acute biphasic thyroiditis. Antithyroid hormone antibodies have also been found in one patient, and this could have been the cause of erroneously raised thyroid hormone concentrations (504). 

The clinical, biochemical, and thyroid imaging characteristics of thyrotoxicosis resulting from interferon alfa treatment have been retrospectively analysed from data on 10 of 321 patients with chronic hepatitis (75 with chronic hepatitis B and 246 with chronic hepatitis C) who developed biochemical thyrotoxicosis (505). Seven patients had symptomatic disorders, but none had ocular symptoms or a palpable goiter. Six had features of Graves disease that required interferon alfa withdrawal in four and prolonged treatment with antithyroid drugs in all six. Three presented with transient thyrotoxicosis that... 

Although thyroid disorders in patients treated with interferon alfa generally follows a benign course after interferon alfa withdrawal or specific treatment, severe long-lasting ophthalmopathy resulting from Graves disease has been described in a 49-year-old woman (507). 

A middle-aged woman developed subacute thyroiditis by the sixth month of treatment with interferon alfa (508). She also had the classic symptoms of hyperthyroidism, although it is clear that these could easily have been mistaken for adverse effects of interferon alfa itself, for example weakness, weight loss, and palpitation. 

After 6 months of treatment, 12% of patients with chronic hepatitis C had thyroid disorders, compared with 3% of patients with chronic hepatitis B. This study also suggested a possible relation between low free triiodothyronine serum concentrations before treatment and the subsequent occurrence of thyroid dysfunction. After a follow-up of 6 months after the end of interferon alfa treatment, 60% of affected patients with chronic hepatitis C still had persistent thyroid dysfunction all had been positive for thyroid peroxidase antibodies before treatment. Long-term surveillance is therefore needed in these patients. 

Data on interferon alfa-associated thyroid disease have been comprehensively reviewed (512,513). There was a mean prevalence of 6% for incident thyroid dysfunction, and treatment for malignancies was associated with the highest prevalence (11%). 

Hypothyroidism occurs more often than hyperthyroidism, and spontaneous resolution is expected in almost 60% of patients with or without interferon alfa withdrawal. Finally, female sex and the presence of baseline thyroid autoimmunity were confirmed to be the most significant risk factors. The mechanisms of interferon alfa-induced thyroid dysfunction are not yet fully clarified. Although an autoimmune reaction or immune dys-regulation are the most likely mechanisms, a direct inhibitory effect of interferon alfa on thyrocytes should be considered in patients without thyroid antibodies. 

In addition to the underlying disease, there are many potential susceptibility factors (499,519). There is as yet no definitive evidence that age, sex, dose, and duration of treatment play an important role in the development of thyroid disorders. However, patients with previous thyroid abnormalities are predisposed to develop more severe thyroid disease (SEDA-20, 328). The incidence of thyroid disease was not different between natural and recombinant interferon alfa. Although this should be taken into account, a previous familial or personal history of thyroid disease was generally not considered a major risk factor. Finally, only pre-treatment positivity or the development of thyroid antibodies during treatment seem to be strongly associated with the occurrence of thyroid dysfunction. 

The immunological predisposition to thyroid disorders has been studied in 17 of 439 Japanese patients who had symptomatic autoimmune thyroid disorders during interferon alfa treatment (521). There was a significantly higher incidence of the human leukocyte antigen (HLA)-A2 hap-lotype compared with the general Japanese population (88 versus 41%), suggesting that HLA-A2 is a possible additional risk factor for the development of interferon alfa-induced autoimmune thyroid disease. 

Among other potential predisposing factors, treatment with iodine for 2 months in 21 patients with chronic hepatitis C receiving interferon alfa did not increase the likelihood of thyroid abnormalities compared with eight patients who received iodine alone, but abnormal thyroid tests were more frequent compared with 27 patients who received interferon alfa alone (522). This suggests that excess iodine had no synergistic effects on the occurrence of thyroid dysfunction induced by interferon alfa. 

The occurrence of thyroid dysfunction in 72 patients treated with interferon alfa plus ribavirin (1.0-1.2 g/day) has been compared with that of 75 age- and sex-matched patients treated with interferon alfa alone for chronic hepatitis C (523). Of the former, 42 patients, and of the latter, 40 patients had received previous treatment with interferon alfa alone. There was no difference in the rate of thyroid autoimmunity (antithyroglobulin, antithyroid peroxidase, and thyroid-stimulating hormone receptor... 

Of 62 initially autoantibody-negative patients treated with interferon alfa for chronic hepatitis C for a mean of 8 months, three developed antibodies to 21b-hydroxylase, a sensitive assay of adrenocortical autoimmunity (528). However, there were no cases of Addison s disease or subclinical adrenal insufficiency. This study suggested that the adrenal cortex is another potential target organ of autoimmune effects of interferon alfa, along with thyroid and pancreatic islet cells. 

Autoimmune polyglandular syndrome with progressive thyroid autoimmunity, type 1 diabetes mellitus, amenorrhea, and adrenal insufficiency has been reported in a 51-year-old woman treated with interferon alfa for chronic hepatitis C (545). Pancreas and pituitary gland autoantibodies, which were undetectable before interferon alfa treatment, were present at the time of diagnosis. After withdrawal, she recovered normal thyroid function, but was still insulin dependent with amenorrhea and adrenal insufficiency. 

Prummel MF, Laurberg P. Interferon-alfa and autoimmune thyroid disease. Thyroid 2003 13 547-51. 

In 33 patients with chronic hepatitis C, of whom 10 developed major depressive disorders during interferon alfa treatment, there was no relation between changes in thyroid function and the development of depression... 

In a randomized comparison of recombinant interferon alfa-2b and interferon alfa n-3 (9 MU/week for 1 year) in 168 naive patients with chronic hepatitis C, there was no significant difference in clinical outcomes and the incidence or type of adverse effects between the groups (9). There was a non-significant trend toward more severe leukopenia and a higher incidence of severe thyroid disorders in patients who received recombinant interferon alfa-2b. 

Although the adverse effects profiles of the currently available formulations of interferon alfa are very similar, patients who have adverse effects with one formulation can be successfully re-treated with another type of interferon alfa. This has been shown in 22 patients in whom lymphoblastoid interferon alfa was withdrawn because of severe adverse effects (leukopenia, thrombocytopenia, thyroid disorders, and psychiatric disturbances) and were successfully re-treated with similar dosages of leukocyte interferon alfa (22). Only one of these patients had severe leukopenia again. 

The spectrum of interferon alfa-induced thyroid disorders ranges from asymptomatic appearance or increase in antithyroid autoantibody titers to moderate or severe... 

In a prospective study, the overall incidence of biochemical thyroid disorders was 12% in 254 patients with chronic hepatitis C randomized to receive ribavirin plus high-dose interferon alfa (6 MU/day for 4 weeks then 9 MU/week for 22 weeks) or conventional treatment (9 MU/week for 26 weeks) (165). There was no difference in the incidence or the time to occurrence of thyroid disorders between the groups. Of the 30 affected patients, 11 (37%) had positive thyroid peroxidase autoantibodies (compared with 1% of patients without thjroid dysfunction), nine developed symptomatic thjroid dysfunction, and only three had to discontinue treatment. There was no correlation between the viral response and the occurrence of thyroid disorders, and only female sex and Asian origin were independent predictors of thyroid disorders. 

Possible mechanisms need to be clarified. Since thyroid autoantibodies are detected in most patients who develop thyroid disorders, the induction or exacerbation of preexisting latent thyroid autoimmunity is the most attractive hypothesis. This is in accordance with the relatively frequent occurrence of other autoantibodies or clinical autoimmune disorders in patients who develop thyroid disorders (168). However, 20-30% of patients who develop thyroid diseases have no thyroid antibodies, and it is thus not yet proven that autoimmunity is the universal or primary mechanism. In fact, there were subtle and reversible defects in the intrathjroidal organification of iodine in 22% of antithyroid antibody-negative patients treated with interferon alfa (169). In addition, the acute systemic administration of interferon alfa in volunteers or chronic hepatitis patients reduces TSH concentrations (SED-13,1093) (170), and in vitro studies have suggested that interferon alfa directly inhibits thyrocyte function (SED-13, 1093) (171). Finally, the thyroid autoantibody... 

The possibility of autoimmune disorders during interferon alfa treatment has been addressed by many authors. The spectrum of interferon alfa-induced immune diseases includes organ-specific and systemic autoimmune diseases, such as thyroiditis, diabetes, hematological disorders, systemic lupus erythematosus, rheumatoid arthritis, dermatological disease, and myasthenia gravis (156). Several have been discussed in appropriate sections elsewhere in this monograph. The exact role of interferon alfa is usually difficult to ascertain, because the underlying disease, that is chronic hepatitis C, can also be associated with immune-mediated disease. 

Two studies have provided insights into the incidence and risk factors of the immune-mediated comphcations of interferon alfa in patients with chronic myeloid leukemia. In the first study, 13 of 46 patients had autoimmune manifestations consisting of a combination of autoimmune thyroiditis in four, a direct antiglobulin test without hemolysis in eight, cryoagglutinins in one, Raynaud s phenomenon in two, and chronic autoimmune hepatitis in one (343). Overall, six patients had chnically symptomatic manifestations after a median of 15 months of treatment. In the second study, there were autoimmune diseases in seven of 76 patients after a median of 19 months of treatment, including hypothyroidism in one, immune-mediated hemolysis in two, systemic lupus erythematosus in two, Raynaud s phenomenon in one, and mixed connective tissue disease in one (344). In... 

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