Interferon-α-Related Thyroid Disease: Pathophysiological, Epidemiological, and Clinical Aspects

Thyroid disease is a frequent side effect of interferon (IFN)-α therapy for hepatitis C virus (HCV) and other disorders, and the clinical approach to this complication is often carried out by personal judgment rather than by defined guidelines. Indeed, clinicians often reduce the dose or sometimes discontinue IFNα treatment in those patients who develop thyroid dysfunction, thus possibly compromising the therapeutic response to this agent. The uncertainty in the clinical management of patients developing IFNαa-induced thyroid disease may also be due to the fact that this side effect has variable expressions and different long-term outcomes. In this review, we will discuss relevant studies concerning IFNα-induced thyroid disease to identify the clinical strategies helpful for the appropriate management of patients developing this disorder. Most of the studies are related to patients with HCV in whom IFNα represents the mainstay of treatment (1–3). The importance of this disorder is emphasized by the fact that 1.5–2.2% of Western populations are positive for HCV (4, 5), and HCV infection is a potentially life-threatening disease because 75% of affected patients with acute infection develop chronic disease with a high risk of cirrhosis and hepatocellular carcinoma (6, 7). IFNs are a family of naturally occurring, small protein molecules with molecular weights of approximately 15,000–21,000 Da (8). They are included in three groups, IFNα, IFNβ, and IFNγ, with different biological effects and variable duration of activity (8). They are produced and secreted by cells in response to viral infections or to various synthetic and biological inducers (7). IFN was discovered almost 50 yr ago by Isaacs and Lindenmann (9), who observed that virus-infected cultures produced a protein that reacted with cells, making them resistant to infection by many other viruses. Further studies demonstrated that, in addition to their antiviral actions, IFNs play important roles in reducing tumor growth and modulating immune responses. Because of these effects, IFNs have been widely used in the treatment of neoplastic, viral, and autoimmune diseases. Adverse effects of IFN treatment include systemic and organ-specific pathological changes, many of them being the consequences of immune enhancement or immune dysregulation induced by IFN itself (10–12). The main effect of IFNα on the immune system is the enhancement of cell cytotoxicity, which is important for antineoplastic and antiviral activity (10). The stimulation of cytotoxicity is mainly due to an up-regulation of perforin expression in peripheral natural killer and T cells (13), very likely sustained by suppression of T helper (Th) 2 and an increase in Th1 immune response (14–19). However, the effects of IFNα on immune response are still controversial because the molecule was also shown to suppress the production of Th1 cytokines, which are important for the clearance of HCV virus (20–23). In patients treated with IFN, activation of the immune system is important for the development of thyroid disease. Furthermore, IFN has direct inhibitory effects on thyroid hormone synthesis, release, and metabolism (24–26). The critical point is to understand how a generalized activation of the immune system, induced by the cytokine treatment, may result in an organ-specific involvement of the thyroid gland. A genetic predisposition to thyroid autoimmune disease is probably necessary for the development of thyroid disease in patients treated with IFN (27–29). However, the widespread effects of IFNα on the immune system may be important for inducing thyroid disease because peripheral features of systemic immune involvement have been described in patients with thyroid autoimmunity (30–32). In addition to the systemic effects, IFNs may have direct effects on the thyroid gland by modulating the aberrant expression of major histocompatibility antigens on thyroid cells (33, 34) and favoring a cytokine microenvironment, which may lead to the immune-mediated damage of thyroid tissue (35). After the original description of IFN-related hypothyroidism (36), 153 studies concerning IFNα-related thyroid disease are recorded on Medline as of October 2003. The prevalence of thyroid disease during IFN treatment is extremely variable, ranging between 1 and 35% (37). The low rates are likely an underestimation of the true prevalence because in some studies a careful evaluation of thyroid status was not carried out (38). For example, some authors collected retrospective data using questionnaires, whereas others evaluated thyroid status clinically rather than by obtaining thyroid function tests (39). Nevertheless, the remarkable variation in the prevalence of IFN-related thyroid disease may also reflect variable individual predisposition to the disease. Women are more susceptible than men to develop IFN-related thyroid disease, having a relative risk 3- to 7-fold higher as reported in some (37, 38, 40–42) but not all studies (27, 43–46). It has been argued that virus-related factors, especially HCV infection itself, may predispose to the development of thyroid autoimmune disease (40, 42, 46, 47). Positive thyroid antibodies were found in 20–42% of patients infected with HCV but in only 5–10% with hepatitis B virus infection (40, 47). It has been suggested that HCV might share partial sequences in a few amino acid segments with thyroid tissue antigens (46). In accordance with this hypothesis, some viral features (mixed HCV genotypes infection and lower HCV RNA levels) have been reported to be associated with an increased risk of developing thyroid disease (42). However, population-based studies exclude a specific role of HCV infection in determining the development of thyroid disease (48, 49). Epidemiological and clinical evidence suggests that iodine supplementation in an iodine-deficient population may precipitate the onset of thyroid autoimmunity (50, 51). It is not known whether iodine intake influences the occurrence of thyroid disease during IFN treatment. IFN molecules seem to exert an important role in mediating the effects of iodine inducing experimental autoimmune thyroiditis in mice (52). In humans, the concomitant administration of pharmacological quantities of iodine to euthyroid patients treated with IFNα did not increase the frequency of thyroid dysfunction, especially hypothyroidism, more than that observed with iodine alone (53). Therapeutic regimen-related factors may influence the development of thyroid disease. Patients with cancer treated with lymphoblastoid IFNα1 had a higher frequency of early thyroid dysfunction than those treated with recombinant IFNα. The presence of trace amounts of IFNγ in natural IFNα could explain the different observed rates of thyroid autoimmunity (54). Moreover, differences in the structure of lymphoblastoid IFNα1a and recombinant IFNα may be another possibility. In HCV patients, therapy with IFNαcon-1, a newly developed type-1 recombinant molecule, has been reported to have higher cytotoxic effects on thyroid cells and, therefore, to cause a higher incidence of destructive thyroiditis than therapy with IFNα1 (55). In contrast, the newer long-acting pegylated IFNα molecules have not been reported to cause thyroid side effects at a different rate, compared with IFNα (3, 56). The development of thyroid disease does not seem to be related to the dose of IFNα (57). In contrast, the duration of IFNα treatment has been related to the occurrence of thyroid dysfunction in some studies (43, 58). However, two or more cycles of IFNα therapy did not increase the risk of the development of thyroid disease (59). In fact, it has been pointed out that patients with negative thyroid autoantibody tests during the first treatment with IFNα continue to have negative thyroid antibodies during successive administrations, even with different schedules (29). Ribavirin is a synthetic guanoside nucleoside analog that exerts immunomodulatory effects by inducing Th1 cytokines in the immune response against HCV infection (59–61) and is frequently given with IFNα in the treatment of HCV patients. Patients treated with both drug do not have an increased risk of developing thyroid autoimmunity but do have a 4.3 relative risk to develop thyroid dysfunction, likely as a consequence of enhancement of the Th1 immune response, which induces cell-mediated cytotoxicity (62). It is noteworthy that the immune activation induced by IFNs, as well as ribavirin, does not involve just the virus-specific immune response but a generalized activation of the immune system, predisposing to the development of untoward events in addition to the therapeutic effects (63). An increased risk to develop thyroid disease was also found in patients treated with IFNα and IL-2 for malignancies (58). In addition to constitutional and treatment-related factors, the risk of developing thyroid dysfunction during IFNα therapy is closely correlated with preexisting thyroid antibodies. A metaanalysis of the literature by Koh et al. showed that about 50% of patients with positive thyroperoxidase antibodies (TPOAbs) before IFNα treatment developed thyroid dysfunction in comparison with 5.4% in antibody-negative patients (37). The relative risk to develop thyroid dysfunction, mainly hypothyroidism, is 2- to 14-fold higher in patients with preexisting positive TPOAbs, compared with patients with negative antibodies (25, 64, 65). Positive thyroid antibodies with normal thyroid function tests is the most common finding in patients treated with IFNα, whereas thyroid dysfunction is usually described in no more than 15% of all treated patients (37, 38). Thyroid dysfunction may present as destructive thyrotoxicosis, Graves’ thyrotoxicosis, and hypothyroidism. These pathological conditions may occur in the same patient as the result of different immunological effects of IFNα therapy on the thyroid gland (66–70). The prevalence of thyrotoxicosis in HCV patients treated with IFNα has been reported to occur in 2–3% of the treated patients (37, 69). Perhaps the true prevalence of this disorder is much higher than that reported in the literature because it is often transient and has mild clinical manifestations and, therefore, can be easily missed (55, 69). In many patients who develop positive thyroid antibodies during IFN treatment, an inflammatory process may involve the thyroid gland, a process known as a destructive thyroiditis (55). Destructive thyrotoxicosis usually occurs in the first weeks of IFN treatment in close temporal relationship with the appearance of thyroid autoantibodies, especially thyroglobulin antibodies (TgAbs) (55). The excessive release of thyroid hormones by the damaged thyroid follicles is responsible for the occurrence of thyrotoxicosis similar to that observed in subacute, postpartum, and sporadic silent thyroiditis (71–73). In contrast to patients with subacute thyroiditis, neck pain is rarely present (72, 73). Thyrotoxicosis is frequently mild and transient without overt clinical manifestations and may be diagnosed only by obtaining frequent thyroid function tests, i.e. serum TSH and free T4 (FT4) concentrations. In a minority of patients, the inflammatory destruction of thyroid follicles is more extensive and leads to overt thyrotoxicosis characterized by suppressed serum TSH and markedly elevated FT4 and free T3 (FT3) concentrations. Destructive thyrotoxicosis is definitely established by a low radioiodine uptake (RAIU) and, if measured, by negative anti-TSH receptor antibodies (TSHRAbs) (69). Ultrasound evaluation of the thyroid gland, especially if performed with the auxiliary application of a quantitative computerized analysis (74, 75), shows a diffuse hypoechogenicity accompanied sometimes by reduced vascularity (color flow Doppler) as observed in other types of destructive thyroiditis (76). The duration of destructive thyrotoxicosis is variable, ranging from a few weeks to a few months. Although isolated destructive thyrotoxicosis has been occasionally described, hypothyroidism often develops later as observed during the course of sporadic silent and postpartum and painful subacute thyroiditis. The progression of IFN-induced thyrotoxicosis to hypothyroidism is accompanied by a characteristic change in the pattern of thyroid autoantibodies (55). TgAb appears first during the course of IFNα treatment in patients who were thyroid autoantibody negative before treatment (29, 55, 77). In patients treated with IFNα, the positivity of only TgAbs at low titer is a specific marker of thyroid follicular destruction, whereas in the general population the presence of circulating TgAbs is not considered an important risk factor for the development of thyroid dysfunction (55, 71, 78, 79). IFN treatment may also induce Graves’ hyperthyroidism (69). The prevalence of this disorder is less frequent than other thyroid dysfunction because only 20–25% of all patients with IFN-related thyrotoxicosis is due to Graves’ disease induced by circulating TSHRAbs (38). The low prevalence of Graves’ disease during IFNα treatment may be related to the generalized suppressive effects of this cytokine on the Th2 immune response, which probably plays an important role in the pathogenesis of this disease (80). Graves’ hyperthyroidism may occur even after a transient phase of destructive thyrotoxicosis or even following a period of hypothyroidism (55, 70), likely reflecting fluctuations in serum TSHRAbs with inhibiting and stimulating activity. Suppressed serum TSH concentrations with elevated or normal FT4 and FT3 concentrations accompanied by elevated or normal thyroid radioiodine uptake value and positive TSHRAbs confirm the diagnosis of Graves’ hyperthyroidism. Although sporadic cases of Graves’ ophthalmopathy have been described in patients treated with IFNα (81, 82), it is interesting that most patients developing Graves’ hyperthyroidism do not have signs of autoimmune ophthalmopathy (69). In patients treated with IFNα, hypothyroidism occurs in 2.4–19.0% of the patients, especially in those with preexisting thyroid autoimmunity (37, 44, 65). Hypothyroidism is also more frequent in patients treated with both IFNα and ribavirin (62). Hypothyroidism occurs after an episode of destructive thyroiditis in approximately 66% of those developing hypothyroidism. In patients with IFN-induced hypothyroidism, TPOAbs alone are frequently positive and may occur in association with TgAbs. Although it is uncertain whether TPOAbs have a major pathophysiological role in inducing hypothyroidism (83), it has been suggested that these antibodies reflect a more advanced and aggressive underlying autoimmune destructive process of the thyroid gland (29, 84–86). It should be pointed out that IFN treatment may also induce a subtle defect in the thyroidal organification of iodide, thus further impairing hormone synthesis (25). Severity of IFN-induced hypothyroidism varies from mild, defined by elevated serum TSH and normal FT4 concentrations, to overt hypothyroidism, defined by elevated serum TSH levels and decreased FT4 concentrations. The degree of hypothyroidism is not related to the duration of IFNα treatment, whereas the combined treatment with IFNα and ribavirin seems to be associated with a higher percentage of overt hypothyroidism than monotherapy (62). Overt hypothyroidism is also more frequent in patients with thyroid autoantibodies before IFN treatment (37, 44, 65). Elevated serum TSH concentrations are sufficient to diagnose hypothyroidism in patients treated with IFNα. Data on the evolution of IFN-related thyroid disease after IFN treatment are controversial. Some authors have reported complete recovery of thyroid function within a few months after IFN withdrawal (45, 64). However, others have reported only a partial reversal of thyroid dysfunction (29, 40, 65, 87). These contrasting results may be due to either the variable length of follow-up after IFN withdrawal or the criteria used to define the recovery from thyroid disease. A single case of severe hypothyroidism resolved spontaneously after IFN withdrawal (88). However, the underlying autoimmune process usually persists. Thyroid autoantibodies remain positive indefinitely in about 50% of the patients with IFN-induced thyroid disease, whereas in others circulating antibodies disappear after IFN withdrawal. However, even years later thyroid autoantibodies may reappear (29). As previously discussed, patients developing thyroid autoimmune disease during IFNα appear to be genetically predisposed. For this reason, the relapse of circulating thyroid antibodies has occurred several years after IFN has been discontinued (29). Also, hypothyroidism may occur several years after IFN withdrawal due to the progression of the thyroid autoimmune process (29). The thyroid autoantibody pattern at the end of IFN therapy may be a reliable marker for the subsequent outcome of thyroid function (29). Thus, patients with high titers of thyroid autoantibodies and those with coexistent TgAbs and TPOAbs at the end of IFN treatment have an increased risk to develop hypothyroidism in the following years (29), supporting the hypothesis that the activity of the intrathyroidal autoimmune process may be reflective of peripheral autoantibody patterns (81, 82). Finally, euthyroid patients with a previous episode of IFN-induced thyroid dysfunction are prone to develop altered thyroid function when exposed to excess iodine (89). Management of patients with chronic hepatitis C who develop IFN-α-induced thyroid disorders Management of patients with chronic hepatitis C who develop IFN-α-induced thyroid disorders Before patients undergoing IFNα therapy, we suggest that serum TSH, FT4, TgAb, and TPOAb concentrations and perhaps a thyroid echography be carried out to identify preexisting thyroid dysfunction and autoimmunity. Given the fundamental importance of IFNα therapy in HCV patients (1–3), prior thyroid dysfunction is not a contraindication to the antiviral therapy. IFNα treatment should be started after adequate correction of the existing thyroid dysfunction. During IFNα treatment, measurement of serum TSH concentrations should be carried out every 8–12 wk. This is adequate to identify patients with hypothyroidism in whom clinical symptoms and signs are frequently mild and masked by the underlying liver disease and the concomitant malaise induced by IFNα treatment (56, 90). We do not have sufficient literature and personal experience to suggest the timing for testing thyroid function to identify all patients developing thyrotoxicosis. However, it would seem appropriate to determine serum TSH values at the same frequency and measure serum FT4 and FT3 concentrations if serum TSH is low. Because destructive thyrotoxicosis is usually mild, it is likely that it will not be diagnosed clinically. However, the presence of the symptoms and signs of thyrotoxicosis should alert the physician to evaluate thyroid function. In patients developing hypothyroidism during IFNα treatment, substitutive levothyroxine therapy is indicated without the need to withdraw IFN therapy. At the termination of IFNα therapy, levothyroxine therapy may be discontinued because hypothyroidism may be reversible, even in severe cases (88). However, in patients with positive TgAbs and TPOAbs, permanent hypothyroidism is more likely (29) and therefore levothyroxine withdrawal may not be indicated. When destructive thyrotoxicosis has been established, treatment with β-blocking agents are useful to control the symptoms and signs of thyrotoxicosis. As in other forms of destructive thyrotoxicosis, such as painful subacute thyroiditis and type II amiodarone-induced thyrotoxicosis, corticosteroid therapy might be efficacious (91–93). Very recently IFNα was discontinued in patients with IFN-induced destructive thyrotoxicosis. They were then treated with 4–16 mg/d methylprednisolone or left untreated, and both groups became euthyroid 6 months after the onset of destructive thyrotoxicosis (94). In our view, the treatment of patients with destructive thyrotoxicosis with β-blockers is usually sufficient, and IFN treatment can be continued. However, if the symptoms and signs are not well controlled by β-blocking agents and thyrotoxicosis persists, we would suggest that IFN treatment be discontinued, although the literature and personal experience do not indicate that this approach may influence the natural history of the disease. A reevaluation of thyroid function should be carried out 4–6 wk after IFN has been discontinued, and if normal thyroid function returns or hypothyroidism develops and is treated with l-thyroxine, cytokine treatment could be resumed. The decision to start IFN treatment again after recovering from thyrotoxicosis is supported by the fact that a sustained antiviral response is best when full adherence to the prescribed regimen is maintained, especially when the infection is due to HCV genotype 1, which requires a longer treatment than that needed in the presence of genotypes 2 and 3 (2). The approach to patients with Graves’ hyperthyroidism is different from that in patients with destructive thyrotoxicosis. In patients with mild Graves’ hyperthyroidism, IFN treatment may be continued with the administration of antithyroid drugs at low doses to control the excessive thyroid hormone production. In patients with severe hyperthyroidism, withdrawal of IFNα seems appropriate for many reasons. Remission of Graves’ disease is unlikely (92, 95) and large doses of antithyroid drugs would be necessary to control the hyperthyroidism. The higher doses may adversely affect liver function and possibly decrease the polymorphonuclear white blood cells. Furthermore, the time to achieve remission of Graves’ disease with antithyroid drug treatment is long, and relapse of hyperthyroidism may occur. Because of these problems, definitive treatment of hyperthyroidism with radioiodine or by thyroidectomy followed by levothyroxine substitutive treatment may be an appropriate option (96), especially if the patient requires continued or reinstitution of IFN. Free T3; free T4; hepatitis C virus; interferon; radioiodine uptake; thyroglobulin antibody; T helper; thyroperoxidase antibody; TSH receptor antibody.