Interferon alfa thyroid dysfunction

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). 

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. 

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... 

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. 

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