interferon - alpha ( ifn- ) , which is the main therapeutic agent used for chronic hepatitis c virus ( hcv ) infection , is associated with side effects such as flu - like symptoms , hematologic abnormalities and thyroid disease .
prospective studies have shown that up to 40% of patients with hcv infection develop thyroid antibodies during ifn- therapy ( 1 ) , and around 15% develop thyroid disease ( 2 ) . according to tomer et al .
( 3 ) , interferon - induced thyroiditis ( iit ) can be classified as either autoimmune or non - autoimmune .
autoimmune iit includes the de novo production of thyroid autoantibody without clinical disease , hashimoto 's thyroiditis , and graves ' disease , while non - autoimmune iit presents as destructive thyroiditis or non - autoimmune hypothyroidism ( 3 ) .
the development of thyrotoxicosis during ifn- treatment may be due to silent destructive thyroiditis or graves ' disease .
the development of graves ' disease is a less common side effect of ifn- therapy than is destructive thyroiditis .
moreover , destructive thyroiditis followed by graves ' disease associated with ifn- therapy occurs very rarely .
only four cases of destructive thyroiditis followed by graves ' disease asso ciated with ifn- treatment have been reported in the literature ( 4 , 5 ) .
herein , we report a recent case of pegylated ifn- ( pegifn-)-induced destructive thyroiditis followed by transient graves ' disease in a patient with hcv infection .
a 31-yr - old woman with hepatitis c - associated chronic active hepatitis proven on liver biopsy received pegifn- ( schering - plough , korea ) 2b 100 g weekly and ribavirin 800 mg daily from june 2009 to may 2010 .
prior to pegifn- therapy , laboratory testing revealed normal concentrations of total t3 at 2.25 nm / l ( normal range : 1.1 to 2.9 nm / l ) , tsh at 1.011 mu / l ( normal range : 0.35 to 5.50 mu / l ) , and free t4 at 15.18 pm / l ( normal : 9 to 26 pm / l ) , in addition to negative titers of antimicrosomal antibody ( msab ) at 18 u / ml ( negative < 60 u / ml ) and antithyroglobulin antibody ( tgab ) at 26.7 u / ml ( negative < 60 u / ml ) . within two months of pegifn- therapy initiation
seven months into therapy ( january 2010 ) , the patient developed mild tremors and palpitation however she had no fever or pain .
she has no personal and family history of thyroid dysfunction and no specific medication history .
she also had not received any test that could interfere with the thyroid scan uptake .
results of repeated laboratory tests indicated elevated total t3 at 4.26 nm / l , suppressed tsh at 0.009 mu / l , normal total t4 at 148.005 nm / l ( normal : 64 to 154 nm / l ) , and negative titers of msab at 27.1 u / ml and tgab at 31.1 u / ml .
thyrotropin - binding inhibitory immunoglobulin ( tbii ) was also negative at 2.6 u / l ( normal range : 0 to 10 u / l ) .
based on these findings , we diagnosed the patient with interferon - induced destructive thyroiditis and prescribed propranolol 20 mg / d for one month .
two months later ( march 2010 ) , a follow - up thyroid function test demonstrated further decline in total t3 at 3.353 nm / l , tsh at 0.013 mu / l and total t4 at 128.7 nm / l .
she continued pegifn- therapy for an additional four months , for a total treatment duration of 12 months .
two months after the end of therapy ( july 2010 ) , she complained of hand tremors , fatigability , and 3 kg of weight loss .
laboratory tests revealed a total t3 of 12.288 nm / l , tsh of 0.004 mu / l , free t4 of 79.92 pm / l , and a tbii titer of 13.0 u / l .
both thyroid glands were diffusely enlarged with increased vascularities and had heterogeneous echogenicities ( fig .
2 ) . the diagnosis of graves ' disease was made , and the patient started treatment with methimazole and propranolol .
after nine months of antithyroid drug therapy ( april 2011 ) , her thyroid function tests showed normalized total t3 at 2.095 nm / l , tsh at 0.009 mu / l , free t4 at 21.36 pm / l , msab at 40.9 u / ml and tbii at 3.4 u / l .
ifn- is an immunoregulatory cytokine that is currently used as a therapeutic agent for chronic hcv infection .
the most common adverse effects of ifn- are muscle aches and fatigue , but more difficult to manage are the psychological side effects such as depression , anxiety , irritability , sleep disturbance , and difficulty concentrating ( 6 ) .
the association between interferon and thyroid disease was reported as early as 1985 ( 7 ) . since then , numerous studies have reported a high incidence of thyroid abnormalities in patients treated with interferon ( 8 , 9 ) . for many years
it was assumed that side effects associated with ifn- therapy were due to immune dysregulation .
however , while immune mechanisms must play a role in the development of iit , the predilection to the thyroid and the non - autoimmune manifestations of iit suggest that direct effects of ifn- on the thyroid play a major role in the etiology of iit ( 10 ) . the most common clinical manifestation of iit is hashimoto 's thyroiditis .
hashimoto 's thyroiditis is most likely to occur during the course of treatment and has been reported in 45%-60% of patients with pre - existing thyroid autoantibodies ( tabs ) compared to 3%-5% of those with no circulating thyroid antibodies prior to interferon treatment ( 11 ) .
tabs can develop de novo during ifn therapy or their levels can increase during ifn therapy .
the majority of individuals who develop de novo tabs due to ifn- therapy remain tabs - positive after treatment is completed .
the incidence of de novo tabs in interferon - treated hcv patients ranges from 10% to 40% ( 1 , 2 , 12 ) , and tabs develop more frequently in women treated with ifn- than in men .
her tgab titer progressively increased from 26.7 u / ml to 31.1 u / ml during ifn- therapy and remained weakly positive at 63.9 u / ml after the treatment period .
classical destructive thyroiditis initially presents as transient thyrotoxicosis with decreased radionuclide uptake , which develops in three phases , followed inconsistently by a hypothyroid phase that eventually resolves spontaneously within several weeks to months .
graves ' disease is characterized by overt hyperthyroidism with the presence of thyroid stimulating hormone receptor antibody ( tshrab ) and/or diffusely increased radioactive iodine uptake . ifn--induced graves ' disease is less common than is destructive thyroiditis , affecting 1%-2% of patients during ifn- therapy and can manifest following inf- therapy completion ( 13 , 14 ) . typically , ifn--induced graves ' disease patients present with symptomatic thyrotoxicosis and do not go into remission upon completion or cessation of ifn- therapy . in our patient ,
her free t4 concentration was normalized after one month of antithyroid drug treatment ; however , her tsh level remained suppressed after nine months of antithyroid drug therapy .
destructive thyroiditis developed in our case after seven months of ifn- therapy , and graves ' disease was diagnosed after treatment completion .
our case is similar to only one previously reported case . in 1995 , koizemi et al .
( 4 ) described a woman who , after three months of ifn- therapy , successively developed transitory thyrotoxicosis , followed three months later by recurrent hyperthyroidism and the development of high tshrab titers . in this case ,
thyroid peroxidase antibody ( tpoab ) , tgab , and tshrab titers were elevated at the time of ifn- therapy cessation , and symptoms of graves ' disease developed four months later .
however , bohbot et al . ( 5 ) reported three patients with classical destructive thyroiditis followed by graves ' disease manifesting during ifn- therapy . in those cases ,
the time to the appearance of the destructive hyperthyroidism phase was 4 - 6 months , with the graves ' disease phase arising at 8 - 11 months .
it is unclear how ifn- induces graves ' disease , but the underlying mechanism is thought to be causally related to autoimmunity .
some cases of transient thyrotoxicosis followed by graves ' hyperthyroidism not associated with ifn- therapy have been reported ( 15 - 17 ) . in those cases ,
destruction of thyroid tissues and release of autoantigens could have resulted in altered immunotolerance , and the subsequent production of thyroid stimulating antibody may have caused hyperthyroidism .
however , we observed a rare side effect of ifn- therapy as ifn--induced destructive thyroiditis followed by transient graves ' disease in a patient with hcv infection .
 interferon - induced thyroiditis ( iit ) is a major clinical problem for patients receiving interferon - alpha ( ifn- ) therapy . 
 but , destructive thyroiditis followed by graves ' disease associated with ifn- therapy is very rarely reported . 
 herein , we report a rare case of pegylated ifn- ( pegifn- ) induced destructive thyroiditis followed by graves ' disease in a patient with hcv infection . 
 a 31-yr - old woman suffered from chronic active hepatitis c and was treated with pegifn- and ribavirin for 12 months . 
 results of a thyroid function test and autoantibody levels were normal before ifn- therapy was initiated . 
 destructive thyrotoxicosis appeared seven months after the initiation of ifn- therapy , followed by graves ' thyrotoxicosis two months after the cessation of therapy . 
 the diagnoses of destructive thyroiditis and graves ' disease were confirmed by the presence of tsh receptor antibodies in addition to tc-99 m scintigraphy findings . 
 the patient 's antithyroglobulin antibody titer increased gradually during ifn- therapy and remained weakly positive after ifn- therapy was discontinued . 
INTRODUCTION
CASE DESCRIPTION
DISCUSSION