Incidence of Thyroid Dysfunction During Interferon Alfa-2B and Ribavirin Therapy in Men with Chronic Hepatitis C a Prospective Cohort Study

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ORIGINAL INVESTIGATION Incidence of Thyroid Dysfunction During Interferon Alfa-2b and Ribavirin Therapy in Men With Chronic Hepatitis C A Prospective Cohort Study

Edmund J. Bini, MD, MPH; Saurabh Mehandru, MD

Background: Thyroid dysfunction is a known compli- in 4.0% (95% confidence interval, 1.8%-7.4%). In the 12 cation of interferon monotherapy in women with hepa- patients with overt hypothyroidism, antithyroglobulin titis C virus (HCV) infection. The aims of this study were antibodies were present in 11 and antithyroid peroxi- to determine the incidence and long-term outcome of thy- dase antibodies were present in 10, whereas thyroid- roid dysfunction in HCV-infected men receiving inter- stimulating immunoglobulins were present in 2 of the 3 feron and ribavirin combination therapy. individuals with overt hyperthyroidism. Most of the patients with thyroid dysfunction completed HCV therapy, Methods: We prospectively studied 225 HCV-infected and thyroid disease resolved in 10 of the 12 patients with men with baseline levels of thyrotropin (TSH) within the overt hypothyroidism, 2 of the 3 with overt hyperthy- reference range who were treated with subcutaneous in- roidism, and all 9 with subclinical thyroid disease. terferon alfa-2b (3 million units 3 times per week) and oral ribavirin (1000-1200 mg/d) for 24 to 48 weeks. Pa- Conclusions: Men with HCV infection treated with in- tients underwent screening of TSH levels every 12 weeks terferon and ribavirin should undergo routine screen- during HCV therapy and at weeks 12 and 24 after comple- ing for thyroid disease. Treatment of HCV can be safely tion of treatment. Patients with abnormal TSH levels underwent a comprehensive thyroid evaluation. continued in these patients because thyroid disease responds well to treatment and is reversible in most indi- Results: Among the 225 patients, overt thyroid disease viduals. developed in 6.7% (95% confidence interval, 3.8%- 10.8%), and subclinical thyroid disease was diagnosed Arch Intern Med. 2004;164:2371-2376

HE WORLD HEALTH ORGA- der can be precipitated or exacerbated by nization estimates that 3% interferon alfa, especially in women.10-13 Al- of the world population is though several published studies have re- infected with the hepatitis ported the development of hypothyroid- C virus (HCV) and that ism and hyperthyroidism in patients moreT than 170 million individuals with treated with interferon monotherapy, there chronic infection are at risk of develop- is a paucity of literature describing the in- ing liver cirrhosis and hepatocellular car- cidence of thyroid dysfunction during in- cinoma.1 Treatment of HCV infection with terferon alfa and ribavirin combination interferon alfa monotherapy leads to a sus- therapy in men. Therefore, we con- tained virological response in only 10% to ducted a prospective cohort study to determine the incidence, clinical presenta- 15% of HCV-infected patients.2-4 How- tion, and long-term outcome of thyroid ever, the combination of interferon alfa and dysfunction in men with chronic HCV in- ribavirin leads to significantly higher sus- fection who were treated with a combina- tained virological response rates (36%- tion of interferon alfa-2b and ribavirin. 43%),5-7 and recent clinical trials showed Author Affiliations: that pegylated interferon alfa in combina- METHODS Department of Medicine and tion with ribavirin can achieve sustained Division of Gastroenterology, virological response rates of greater than Veterans Affairs New York 8,9 STUDY POPULATION Harbor Healthcare System and 50%. New York University School of Thyroid dysfunction has been de- Men who had not been treated previously with Medicine, New York. scribed as an extrahepatic manifestation interferon or ribavirin were eligible for the study Financial Disclosure: None. of chronic HCV infection, and this disor- if they had a test finding positive for anti-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 14 HCV antibody (Ortho HCV enzyme-linked immunosorbent as- T3,FT3,T4, and FT4. Patients who developed overt hypothy- say, version 3.0; Ortho-Clinical Diagnostics, Inc, Raritan, NJ), roidism and who had not yet completed therapy for HCV were a polymerase chain reaction (COBAS Amplicor HCV Monitor treated with levothyroxine sodium, 50 µg/d, and the dosage was Test version 2.0; Roche Diagnostics, Branchburg, NJ) finding increased as needed.15 Patients with overt hypothyroidism who positive for HCV RNA, findings consistent with a diagnosis of completed their HCV therapy at the time thyroid disease was chronic HCV on results of a liver biopsy, and baseline levels of diagnosed and those with subclinical hypothyroidism were not thyrotropin (TSH) within the reference range. treated with levothyroxine. Patients were excluded from this study if they were co- Levothyroxine therapy was continued for 4 weeks after HCV infected with the hepatitis B virus or human immunodefi- therapy was completed and then tapered during the next 8 ciency virus; had known thyroid disease or decompensated cir- weeks. Levels of TSH, FT3, and FT4 were obtained every 4 weeks rhosis; had undergone an organ transplantation; were taking during levothyroxine therapy and until resolution of hypothy- immunosuppressive medications; had neoplastic, autoim- roidism. mune, or severe cardiac, pulmonary, or other comorbid diseases; had severe depression or other psychiatric disorders; or DIAGNOSIS AND MANAGEMENT were currently using alcohol or other drugs. OF HYPERTHYROIDISM

STUDY DESIGN Patients with low TSH levels (Ͻ0.4 mIU/L) underwent testing for levels of total T3,FT3, total T4,FT4, and thyroid-stimu- This prospective cohort study was conducted at the Veterans lating immunoglobulin. A luciferase in vitro bioassay was used Affairs New York Harbor Healthcare System in New York from to determine thyroid-stimulating immunoglobulin levels (ref- January 1, 1999, through December 31, 2001. The protocol was erence range, Ͻ130.0% of basal activity; Nichols Institute Di- approved by our local institutional review board, and all pa- agnostics). Overt hyperthyroidism was defined as a low TSH Ͻ Ͼ tients provided written informed consent. level ( 0.4 mIU/L) along with elevated levels of T3 ( 194 ng/dL Ͼ Ͼ Ͼ Ͼ Patients were treated with US Food and Drug Administra- [ 3.0 nmol/L]), FT3 ( 420 pg/dL [ 6.5 pmol/L]), T4 ( 12.8 Ͼ Ͼ Ͼ tion–approved doses of Rebetron (Schering-Plough, Kenil- µg/dL [ 164.7 nmol/L]), and FT4 ( 2.7 ng/dL [ 34.7 pmol/ worth, NJ), which included subcutaneous interferon alfa-2b, L]), whereas subclinical hyperthyroidism was defined as a low Ͻ 3 million units 3 times per week, and oral ribavirin, 1000 mg/d TSH level ( 0.4 mIU/L) with reference-range levels of T3,FT3, 14 (weight, Ͻ75 kg) or 1200 mg/d (weight, Ն75 kg). Patients with T4, and FT4. In those with overt hyperthyroidism, an iodine I genotypes 2 or 3 were treated for 24 weeks, whereas those with 123–labeled thyroid scan (reference range, 15.0%-40.0% at 24 genotype 1 were treated for up to 48 weeks. In patients with hours) was performed to differentiate thyroiditis from Graves genotype 1, therapy was stopped after 24 weeks if HCV RNA disease.16 was still detectable by means of polymerase chain reaction Patients with overt hyperthyroidism were treated with (COBAS Amplicor HCV Monitor Test version 2.0; sensitivity, ␤-blockers (atenolol, 50 mg/d) during HCV therapy, and the 100 copies/mL). Genotyping of HCV was performed using the dosage was increased as needed.15 In addition, patients with Inno-LiPA HCV II assay (Innogenetics, Gent, Belgium). Graves hyperthyroidism were treated with propylthiouracil at Patients were followed up at weeks 2 and 4 and every 4 weeks a dosage of 100 mg 3 times daily. Patients with subclinical hy- thereafter during treatment and at 4, 8, 12, and 24 weeks after perthyroidism were not treated with ␤-blockers or propylthio- therapy. At each visit, the presence and severity of adverse events uracil. were assessed and routine laboratory testing was performed. Therapy for hyperthyroidism was continued for 4 weeks af- Patients underwent screening for thyroid disease by means of ter HCV therapy was completed and then tapered during the TSH levels every 12 weeks during therapy and at weeks 12 and next 8 weeks. Levels of TSH, FT3, and FT4 were obtained ev- 24 after treatment. ery 4 weeks during ␤-blocker therapy alone or in combination with propylthiouracil until resolution of hyperthyroidism. DIAGNOSIS AND MANAGEMENT OF HYPOTHYROIDISM STUDY OUTCOMES

Patients with elevated TSH levels underwent testing for levels The primary outcome of this study was the development of overt of total triiodothyronine (T ), free T (FT ), total thyroxine thyroid dysfunction during interferon alfa-2b and ribavirin 3 3 3 therapy. Secondary outcomes included development of sub- (T4), and free T4 (FT4); antithyroglobulin antibody titers; and antithyroid peroxidase antibody titers. Diagnostic testing of clinical thyroid dysfunction, symptoms at the time thyroid dis- TSH (ultrasensitive TSH assay with a reference range of 0.4- ease was diagnosed, prevalence of thyroid autoantibodies, re- 5.5 mIU/L), T (reference range, 58-194 ng/dL [0.9-3.0 nmol/ sponse to treatment of thyroid disease, and reversibility of thyroid 3 dysfunction after completion of HCV therapy. Follow-up was L]), FT3 (reference range, 230-420 pg/dL [3.5-6.5 pmol/L]), T (reference range, 4.8-12.8 µg/dL [61.8-164.7 nmol/L]), and performed until June 30, 2003, and the duration of follow-up 4 was calculated as the time since the completion of HCV therapy FT4 (reference range, 0.8-2.7 ng/dL [10.3-34.7 pmol/L]) was performed using commercially available chemiluminescence until the last time that the patient was seen in the outpatient immunoassays (Bayer Diagnostics, Tarrytown, NY). Antithy- clinic. roid peroxidase antibody (reference range, Ͻ2.1 IU/mL) and antithyroglobulin antibody (reference range, Ͻ2.0 IU/mL) STATISTICAL ANALYSIS was detected using chemiluminescence assays (Nichols Insti- tute Diagnostics, San Clemente, Calif). Continuous variables were compared using the unpaired, 2-tailed Overt hypothyroidism was defined as an elevated TSH level t test or the Mann-Whitney test. Data are expressed as mean±SD Ͼ Ͻ Ͻ ( 5.5 mIU/L) along with low levels of T3 ( 58 ng/dL [ 0.9 for those variables that were normally distributed, and medi- Ͻ Ͻ Ͻ nmol/L]), FT3 ( 230 pg/dL [ 3.5 pmol/L]), T4 ( 4.8 µg/dL ans and interquartile range (IQR; 25th to 75th percentiles) for Ͻ Ͻ Ͻ [ 61.8 nmol/L]), and FT4 ( 0.8 ng/dL [ 10.3 pmol/L]), those with a nongaussian distribution. Categorical variables were whereas subclinical hypothyroidism was defined as an el- compared using the ␹2 test with Yates correction or the Fisher evated TSH level (Ͼ5.5 mIU/L) with reference-range levels of exact test. A comparison of patients with and without overt thy-

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 roid dysfunction was performed, and we calculated odds ra- tios (ORs) and 95% confidence intervals (CIs) for those vari- Table 1. Baseline Characteristics of the 225 Male Patients* ables that were significantly associated with the development of overt thyroid dysfunction. We performed statistical analy- Characteristic Value sis using SPSS software, version 11.5 for Windows (SPSS Inc, Age, mean ± SD, y 49.7 ± 6.4 Chicago, Ill), and a 2-tailed P value of less than .05 was con- Race sidered statistically significant. White 97 (43.1) African American 77 (34.2) RESULTS Hispanic 46 (20.4) Other 5 (2.2) Source of HCV infection† PATIENT CHARACTERISTICS Injected drug use 138 (61.3) Transfusion 41 (18.2) A total of 225 men with baseline TSH levels within the Other or unknown 57 (25.3) reference range were enrolled in this study. The popu- Duration of HCV infection, median (IQR), y‡ 26.0 (20.0-30.0) Serum HCV RNA lation was racially diverse, and nearly two thirds had HCV Median (IQR) No. of copies/mL ϫ 106 1.4 (0.6-4.3) infection from use of injected drugs (Table 1). Most pa- Ͼ2 Copies/mL ϫ 106 98 (43.6) tients were infected with genotype 1, and the frequency HCV genotype was similar to the proportion reported among HCV- 1 181 (80.4) infected patients in the United States.17 2 29 (12.9) 3 15 (6.7) Serum alanine aminotransferase level, 77.0 (59.0-121.0) INCIDENCE OF THYROID DYSFUNCTION median (IQR), IU/L Cirrhosis on liver biopsy results 25 (11.1) Among the 225 patients who were treated with inter- Family history of thyroid disease 8 (3.6) feron alfa-2b and ribavirin, 188 (83.6%) completed a full course of therapy. During treatment, overt thyroid dis- Abbreviations: HCV, hepatitis C virus; IQR, interquartile range. ease was diagnosed in 15 (6.7%; 95% CI, 3.8%-10.8%) *Unless otherwise indicated, data are expressed as number (percentage) of patients. Percentages have been rounded and might not sum to 100. of the 225 patients, including hypothyroidism in 12 (5.3%; †The total exceeds 100% because some patients had more than 1 risk 95% CI, 2.8%-9.1%) and hyperthyroidism in 3 (1.3%; 95% factor identified. CI, 0.3%-3.8%). In addition, 9 patients (4.0%; 95% CI, ‡Estimated from the date the patient first used injected drugs or the date of blood transfusion and could not be calculated for patients with other or 1.8%-7.4%) received a diagnosis of subclinical thyroid unknown risk factors. disease, including subclinical hypothyroidism in 6 (2.7%; 95% CI, 1.0%-5.7%) and subclinical hyperthyroidism in 3 (1.3%; 95% CI, 0.3%-3.8%). Therefore, the overall incidence of thyroid dysfunction (overt and subclinical) in had thyromegaly, thyroid nodules, bradycardia, cold in- our male patient population was 10.7% (95% CI, 7.0%- tolerance, or edema. Deep tendon reflexes were not as- 15.4%). New-onset diabetes also developed in 2 pa- sessed. tients (both with overt hypothyroidism) during HCV treat- Nine (75.0%) of the 12 patients with overt hypothy- ment. Thyroid dysfunction did not develop in any patient roidism were treated with levothyroxine, with 100.0% during the 6-month follow-up after HCV therapy was having resolution or improvement of clinical symptoms completed. and 8 (66.7%) having normalization of TSH levels dur- Patients who developed overt thyroid disease were ing HCV therapy. All 9 patients treated with levothyrox- significantly more likely to self-report a family history ine were able to complete a full course of HCV therapy. of thyroid disease in a first-degree relative than those Three patients were not treated with levothyroxine be- without thyroid dysfunction (20.0% vs 2.4%; P=.01; cause hypothyroidism was diagnosed at the end of HCV OR, 10.3; 95% CI, 2.2-48.1). The remaining patient treatment. characteristics shown in Table 1 did not differ signifi- During a median follow-up of 24.4 months (IQR, cantly between patients with and without overt thyroid 19.0-32.8 months) after the completion of HCV therapy, dysfunction. overt hypothyroidism resolved in 10 of the 12 patients (83.3%), and 2 individuals required long-term levothy- DIAGNOSIS, MANAGEMENT, AND OUTCOME roxine therapy. Subclinical hypothyroidism resolved OF HYPOTHYROIDISM spontaneously in all 6 patients after completion of HCV therapy. The characteristics of the 12 patients with overt hypothyroidism are shown in Table 2. In addition, FT3 and DIAGNOSIS, MANAGEMENT, AND OUTCOME FT4 levels were low in all 12 individuals at the time of OF HYPERTHYROIDISM diagnosis. At least 1 thyroid autoantibody was present in all 12 patients, including antithyroglobulin antibod- The characteristics of the 3 patients with overt hyper- ies in 11 and antithyroid peroxidase antibodies in 10. Fa- thyroidism are shown in Table 3. In addition, FT3 and tigue (12/12 [100%]), decreased appetite (11/12 [91.7%]), FT4 levels were obtained at the time of diagnosis in all 3 depression (9/12 [75.0%]), and myalgias (9/12 [75.0%]) patients, and the levels were elevated in all 3 individu- were common symptoms at the time of the diagnosis of als. Thyroid-stimulating immunoglobulins were pres- hypothyroidism. In contrast, none of these individuals ent in 2 of the 3 patients, and both of these individuals

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table 2. Patient Characteristics and Laboratory Data of the Patients With Overt Hypothyroidism*

Patient No./ Week of TSH Total T3 Total T4 Anti-TPO Anti-Tg Age, y Race Diagnosis† Level, mIU/L Level, ng/dL Level, µg/dL Titers, IU/mL Titers, IU/mL 1/60 White 24 74.5 21.6 1.6 104.0 77.8 2/39 African American 24 68.3 15.7 0.9 91.3 83.5 3/40 African American 12 59.2 11.3 0.7 ND 112.0 4/62 White 24 55.1 22.6 2.3 65.9 55.8 5/60 Hispanic 36 84.2 14.7 1.8 77.2 84.2 6/40 Hispanic 36 46.8 18.3 3.3 76.6 ND 7/40 Hispanic 36 51.3 26.5 0.8 148.1 40.4 8/41 African American 24 88.9 13.2 0.4 72.9 65.5 9/41 African American 36 63.5 21.5 2.1 ND 59.8 10/42 Other 48 47.3 19.6 0.3 88.1 86.7 11/42 African American 36 39.5 27.8 2.2 65.3 60.3 12/42 African American 36 31.1 31.4 2.5 68.4 49.7

Abbreviations: anti-Tg, antithyroglobulin antibody; anti-TPO, antithyroid peroxidase antibody; ND, not detected; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.

SI conversion factors: To convert T3 to nanomoles per liter, multiply by 0.0154; T4 to nanomoles per liter, multiply by 12.87. *Reference ranges are as follows: TSH, 0.4-5.5 mIU/L; total T3, 58.0-194.0 ng/dL; total T4, 4.8-12.8 µg/dL; anti-TPO titers, Ͻ2.1 IU/mL; and anti-Tg titers, Ͻ2.0 IU/mL. †Indicates duration of interferon alfa-2b and ribavirin treatment before diagnosis of hypothyroidism.

Table 3. Patient Characteristics and Laboratory Data of the Patients With Overt Hyperthyroidism*

Patient No./ Week of TSH Level, Total T3 Total T4 Uptake on Age, y Race Diagnosis† mIU/L Level, ng/dL Level, µg/dL TSI, % 123I Scan, % 1/60 White 8 Ͻ0.01 651.8 18.2 465.0 79.6 2/59 Hispanic 12 0.04 439.6 14.9 310.0 63.2 3/51 Hispanic 12 0.09 277.8 23.1 ND 5.2

123 Abbreviations: I, iodine I 123–labeled; ND, not detected; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin; TSI, thyroid-stimulating immunoglobulins. SI conversion factors: To convert T3 to nanomoles per liter, multiply by 0.0154; T4 to nanomoles per liter, multiply by 12.87. 123 *Reference ranges are as follows: TSH,0.4-5.5 mIU/L; total T3,58.0-194.0 ng/dL; total T4, 4.8-12.8 µg/dL; TSI, Ͻ130.0% of basal activity; and uptake on I scan, 15.0%-40.0% at 24 hours. †Indicates duration of interferon alfa-2b and ribavirin treatment before diagnosis of hyperthyroidism.

had increased uptake on results of the 123I thyroid scan, term therapy for thyroid disease. Subclinical hyperthy- findings that are compatible with a diagnosis of Graves roidism resolved spontaneously in all 3 patients after disease. Patient 3 did not have thyroid-stimulating im- completion of HCV therapy. munoglobulin detected and had 123I thyroid scan findings compatible with a diagnosis of thyroiditis. All 3 individuals reported nervousness, irritability, fatigue, COMMENT insomnia, and weight loss, and 1 patient had a resting tremor and palpitations at the time of diagnosis. In con- The development of thyroid dysfunction during inter- trast, none of these individuals had thyromegaly, thy- feron alfa monotherapy in patients with HCV has been roid nodules, or heat intolerance. Deep tendon reflexes well described, and the incidence ranges from 2.5% to were not assessed. 34.3%,18-41 with a mean incidence of 6.6%.42 These stud- All 3 patients with overt hyperthyroidism were treated ies have shown that hypothyroidism was more common with ␤-blockers, and the 2 individuals with Graves dis- than hyperthyroidism (3.8% vs 2.8%), and thyroid dys- ease were also prescribed propylthiouracil. Although all function occurred more often in female than in male pa- of them had resolution or improvement of clinical symp- tients (13.0% vs 3.0%).42 The strongest risk factors that toms, none had normalization of TSH levels during HCV were associated with an increased risk of development therapy. Two of the 3 patients were able to complete a of thyroid disease during interferon alfa therapy were fe- full course of HCV therapy, whereas 1 individual with male sex and the presence of thyroid autoantibodies (par- Graves disease discontinued antiviral therapy after 16 ticularly antithyroid peroxidase antibodies) before the ini- weeks because of worsening hyperthyroidism, tachycar- tiation of therapy.21,28,31,35,42 Thyroid disease is less likely dia, and palpitations. to develop in patients with chronic hepatitis B infection During a median follow-up of 22.7 months (IQR, 21.4- who are treated with interferon alfa than in those with 31.0 months) after the completion of HCV therapy, overt chronic HCV infection, despite the use of higher doses hyperthyroidism resolved in 2 (66.7%) of the 3 pa- of interferon alfa for the treatment of hepatitis B virus.35 tients, and 1 patient with Graves disease required long- This finding suggests that HCV and interferon alfa may

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Downloaded From: https://jamanetwork.com/ on 09/27/2021 have a synergistic role in inducing thyroid disease dur- hyperthyroidism had resolution of their thyroid dysfunc- ing antiviral therapy. tion and did not require long-term therapy. In addition, To date, only a few studies have evaluated the inci- thyroid disease resolved spontaneously after comple- dence of thyroid dysfunction in HCV-infected patients tion of HCV therapy in all 9 patients with subclinical thy- treated with interferon alfa and ribavirin combination roid disease. These findings have been noted by other in- therapy. Ribavirin is a nucleoside analogue with a broad vestigators and suggest that combination therapy for HCV spectrum of activity against several RNA and DNA vi- can be continued, even in those who develop overt thy- ruses.43 This drug is known to have immunomodula- roid disease.19,24,28,29,34,35,40 However, thyroid disease may tory effects,43 and it is possible that ribavirin may stimu- persist in some patients, thus necessitating long-term treat- late the immune system alone or synergistically with ment.18,31,46 In a review of the literature, Koh et al42 re- interferon alfa to cause thyroid disease via an autoim- ported that interferon alfa–induced thyroid dysfunction mune mechanism. was reversible in 61.2% of patients, including 55.8% of The development of thyroid dysfunction during in- patients with hypothyroidism and 69.7% of those with terferon alfa and ribavirin combination therapy has been thyrotoxicosis. Although the median follow-up was longer reported to occur in 4.7% to 27.8% of patients, with a than 20 months in our patients with thyroid dysfunc- mean incidence of 12.1%.44-48 Therefore, the mean inci- tion, it is possible that longer follow-up may be needed dence of thyroid dysfunction in patients treated with in- to confidently establish resolution of thyroid disease. Pa- terferon alfa and ribavirin combination therapy (12.1%) tients who are treated with interferon alfa and ribavirin is higher than in those treated with interferon alone therapy should be informed about the risks of develop- (6.6%).42 Similar to the published data on thyroid dys- ment of thyroid dysfunction and the possibility of the need function in patients treated with interferon alone, these for long-term treatment of their thyroid disease. combination therapy studies have shown that hypothyroidism was more common than hyperthyroidism (8.1% CONCLUSIONS vs 3.8%) and that thyroid dysfunction occurred more of- 44-48 ten in female than in male patients (17.7% vs 8.3%). Our study demonstrates that overt thyroid dysfunction Our study found that the incidence of overt thyroid dys- occurs in 6.7% of HCV-infected men treated with com- function during combination antiviral therapy in 225 male bined interferon alfa-2b and ribavirin. Based on our find- patients was 6.7% and was even higher (10.7%) if pa- ings, we recommend that HCV-infected men undergo tients with subclinical disease were included. The inci- screening for thyroid disease before and during inter- dence of thyroid dysfunction in our patients was higher feron alfa and ribavirin treatment, especially those with than the 3.0% incidence reported in male patients treated a family history of thyroid disease. Treatment of HCV can with interferon monotherapy,42 but was similar to the be safely continued in men who develop thyroid dys- mean incidence of 8.3% in male patients treated with in- function, because thyroid disease responds well to treat- terferon and ribavirin combination therapy.44-48 ment and is reversible in most individuals. Future stud- Fatigue, decreased appetite, depression, and myal- ies to determine the optimal method and frequency of gias were common in our patients with overt hypothy- screening for thyroid dysfunction during HCV therapy roidism, whereas nervousness, irritability, fatigue, in- and to evaluate the incidence and outcome of thyroid dis- somnia, and weight loss were prevalent in those with overt ease in HCV-infected patients treated with pegylated in- hyperthyroidism. Although these symptoms are com- terferon in combination with ribavirin are needed. mon in patients with thyroid disease,14,49 they could eas- ily be mistaken for adverse effects of HCV therapy, and Accepted for Publication: April 12, 2004. thyroid dysfunction could have remained undiagnosed Correspondence: Edmund J. Bini, MD, MPH, Division if the patients did not undergo routine periodic screen- of Gastroenterology (111D), Veterans Affairs New York ing of TSH levels.45,46 Therefore, it is recommended that Harbor Healthcare System, 423 E 23rd St, New York, NY screening for thyroid disease be routinely performed in 10010 ([email protected]). all patients with HCV infection who are treated with interferon alone or in combination with ribavirin.13,50 How- ever, the optimal diagnostic strategy and frequency of test- REFERENCES ing are not known. Despite the development of thyroid disease, all 12 of our 1. World Health Organization. Hepatitis C: global prevalence. Wkly Epidemiol Rec. 1997;72:341-344. patients with overt hypothyroidism and 2 of the 3 with overt 2. Carithers RL Jr, Emerson SS. Therapy of hepatitis C: meta-analysis of interferon hyperthyroidism were able to complete a full course of HCV alfa-2b trials. Hepatology. 1997;26:83S-88S. treatment. 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