2008-Issue1.indd ABSTRACT We describe the first case of Graves’ disease occurring at Sultan Qaboos University Hospital, Oman, in a patient who was under treatment with interferon alfa for HCV infection. INF-α is now being widely used to treat patients with a variety of disorders including infection with hepatitis C virus. Clinical thyroid disease, hypo and hyperthyroidism can occur in up to 5% of patients. We emphasize the need for thyroid function screening before and during therapy to identify patients early in the course of their disease.. Key words: Interferon; Thyroid function test; Thyrotoxicosis; Antibodies, thyroid; Case Report, Oman. Graves’ Disease following Interferon Therapy for Chronic Hepatitis C Infection *Omayma El Shafie,1 Samir Hussein,2 Waheed El Awady,3 Nicholas Woodhouse1 SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL MARCH 2008, VOLUME 8, ISSUE 1, P. 75-77 SULTAN QABOOS UNIVERSITY© SUBMITTED - 20TH JUNE 2007 ACCEPTED - 14TH JANUARY 2007 INTERFERON α IFN-α IS A MAJOR THERAPEUTIC modality for patients with severe malignant and non-malignant disease including hepatitis C, the latter being fairly common in Oman.1-4 Prospective studies have shown that up to 15% of those treated with interferon for hepatitis C virus (HCV) will develop clin- ical thyroid disease and 40% thyroid antibodies. IFN-α induced thyroiditis is of 2 types, autoimmune or non- autoimmune. The former is characterised by the devel- opment of thyroid antibodies, with or without clinical disease. These can either block the thyroid stimulating hormone receptor (TSH-R) causing hypothyroidism or stimulate it causing Graves’ disease. Non-autoim- mune disease can present as destructive thyroiditis and sometimes transient thyrotoxicosis followed by hypothyroidism with negative thyroid antibodies.1 In this paper, we report the first case of IFN-α induced Graves’ disease in Oman. With increasing use of INFα in patients with HCV infections we should screen every patient for thyroid disease before and during therapy. C A S E R E P O R T A 60-year old Indian female was diagnosed as hav- ing had chronic hepatitis C infection for many years. She had undergone a hysterectomy for carcinoma of the uterus 17 years previously and received a blood transfusion. The patient had no history of thyroid dis- ease and no relevant family history. The genotype of the virus being Type IV, the patient was treated with peginterferon alfa-2a (IFN-α) (180 µg once weekly by subcutaneous administration) from September 2006 through February 2007. Before treatment was started her thyroid function tests: free thyroxine, triiodothy- ronine and thyroid stimulating hormone (FT4, FT3 and 1Department of Medicine, College of Medicine & Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman; Departments of 2Radiology and Molecular Imaging, and 3Medicine, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman *To whom correspondence should be addressed. Email: omayma0@hotmail.com باالنترفيرون (ج) نوع الكبد املزمن التهاب عالج عن الناجت جريفيز مرض وودهاوز العوضي، نيكوالس وحيد حسني، سامر اميمة الشافعي، االنترفيرون بعقار عالجها نتيجة عمان) (سلطنة قابوس ــلطان الس جامعة ــفى مستش في جريفز اصيبت مبرض ملريضة حالة عن أول تقرير امللخص: قد . (ج) نوع ــي الفيروس الكبد التهاب منها عديدة اضطرابات في عالج ــتخدم يس هذا العقار .) (ج الكبد نوع من التهاب ــت تعاني ــا كان ألنه ، ــا ألف ننصح ولذا . املرضى %15 من ــبة الدرقية بنس الغدة هرمون افراز انخفاض ارتفاع أو ــبب في يتس مما الدرقية الغدة عمل اضطراب إلى العقار هذا يؤدي . املذكور االضطراب حصول املبكر على للتعرف العقار هذا استعمال وأثناء قبل الدرقية الغدة هرمون بفحص . عمان ، حالة تقرير ، الدرقية ، املضادة األجسام ، الدرقي التسمم ، الدرقية الغدة فحص ، انترفيرون الكلمات: مفتاح C A S E R E P O R T O M AY M A E L S H A F I E , S A M I R H U S S E I N , WA H E E D E L AWA D Y, N I C H O L A S WO O D H O U S E 76 TSH) and thyroid antibody studies (antimicrosomal and antithyroglobulin negative) were normal. Twelve weeks after initiation of IFN-α therapy, she complained of palpitations and fatigue and was ad- mitted to the hospital. Physical examination revealed tachycardia, finger tremor, eyelid oedema and a soft thyroid gland with diffuse enlargement: FT4 was 30 (7.9-14.4 pmol/L), TSH <0.005 - (0.34-5.6 mIu/L). IFN-α therapy was discontinued and the patient was started on carbimazole (CB) 45 mg and propanolol 40 mg twice daily. After three months treatment she was euthyroid and was referred to Sultan Qaboos Univer- sity Hospital for radio-active iodine therapy [Table 1]. Her Tc99m thyroid scan showed a diffuse uptake con- sistent with Graves’ Disease [Figure 1], having been on carbimazole for 3 months, with FT4: 8.3 (7.9-14), TSH: 0.34 (0.34-5.6). The TSH receptor antibodies were raised 4.5 (-ve < 1 u/L) as were her thyroid anti- bodies at 420 iu/ml (n 0 - 100). She received I-131 therapy 653 MBq on 22 April 2007 and it was planned to have a repeat thyroid func- tion tests after 2 months. D I S C U S S I O N This patient developed thyrotoxicosis while taking IFN-α therapy. A diagnosis of Graves’ disease was made as the patient showed: 1) clinical signs of thyro- toxicosis with a diffuse goiter and periorbital oedema; 2) elevated levels of thyroid hormones and undetect- able levels of TSH; 3) diffuse high uptake on Tc99m Scan and 4) a raised TSH receptor antibody titer. It has been well documented that treatment of chronic hepatitis B and C infections with IFN-α can lead to induction of thyroid antibodies with hypothy- roidism or thyrotoxicosis.1 - 8 The mechanism by which IFN-α induces thyroid dysfunction remains unclear, but the autoimmune mechanism is thought to play an important role. IFN- α enhances the surface expression of major histocom- patibility complex (MHC) Class I antigens, which ac- tivate cytotoxic T cell function. IFN-α also induces MHC Class II antigens on thyroid cells in patients with autoimmune thyroid diseases. The aberrant expression of MHC antigens on the cell surface, in association with cellular antigens, may be sufficient to interrupt the tolerance and induce autoantibody production. Cytokines (TNFα, IL-1β) that are induced by IFN-α may directly or indirectly disturb the thyroid function by their immunomodulatory effects.2 Interferon-associated thyroid disease was first re- ported in 1985 when three cases of hypothyroidism were seen following IFN-α treatment of breast cancer.2 Since then, many more cases of thyroid disease induced by IFN-α have been published.1–8 IFN-α may provoke two different forms of thyrotoxicosis: a Graves’ disease picture or thyroiditis. The two forms of thyrotoxico- sis should be differentiated as they have different im- plications for therapy.3 The two forms can readily be distinguished by TSH serology and thyroid scintigra- phy. The bi-phasic thyroiditis would not require spe- cific anti-thyroid medications, and the thyrotoxicosis would resolve spontaneously. If the clinical picture is severe, the use of corticosteroids may be appropriate for an anti- inflammatory effect. More important, the risk of subsequent hypothyroidism is high and this re- quires close monitoring. By contrast, Graves’ disease requires standard and prolonged anti-thyroid drugs. Long term follow up of this group of patients will be interesting as their risk of recurrent thyrotoxicosis or subsequent hypothyroidism is unknown. Radioactive iodine therapy may be necessary for some patients. Early detection and therapy of these conditions is Table1: Thyroid hormones and thyroid antibodies before, during, after discontinuation of IFN Treatment FT4 TSH Thyroid Antibodies Before IFN 12 2.4 - ve On IFN (3/12) 30 <0.005 + ve On CB (1/12) 18 0.005 + ve On CB (3/12) 12 0.005 + ve After I-131 (1/12) 8.3 0.34 + ve Normal values: FT4 (7.9-14.4) pmol/L, TSH (0.34 – 5.6) mlu/L IFN: Interferon; CB: Carbimazole; FT4: free thyroxine; TSH: thyroid stimulating hormone G R AV E S ’ D I S E A S E F O L L O W I N G I N T E R F E R O N TH E R A P Y F O R C H R O N I C H E PAT I T I S C I N F E C T I O N 77 important in order to avoid the complications of thy- roid disease such as life threatening cardiac arrhyth- mias. While it is not clear which factors contribute to susceptibility to interferon induced thyroiditis (IIT), recent evidence suggests that genetic factors, gender and hepatitis C infection may play a role. Viral geno- type and therapeutic regimen do not influence suscep- tibility to IIT. The etiology of IIT is unknown and may be secondary to immune modulation by IFN-α and/or direct effects of interferon on the thyroid.1 Our patient, in view of old age, was treated with I- 131 therapy, and our plan is to repeat thyroid function tests after two months. If she becomes hypothyroid, she will require lifelong thyroxine. C O N C L U S I O N Clinical thyroid disease occurs in up to 15% of patients with interferon-α therapy. We therefore recommend measuring the thyroid function tests and thyroid anti- bodies before, during, and after interferon therapy to avoid any associated complications such as life threat- ening cardiac arrhythmias. R E F E R E N C E S 1. Mandac JC, Chaudhry S, Sherman KE, Tomer Y. The clinical and physiological spectrum of interferon-alpha induced thyroiditis: toward a new classification. Hepa- tology, 2006; 43:661-672. 2. Koizumi S, Mashio Y, Mizuo H, Matsuda A, Matsuay K, Mizumoto H, et al. Grave’s Hyperthyroidism Following Transient Thyrotoxicosis during Interferon Therapy for Chronic Hepatitis Type C. Intern Med 1995; 34:58-60. 3. Wong V, Xi-Li Fu A, George J, Wah Cheung N. Thyro- toxicosis induced by alpha-interferon therapy in chron- ic viral hepatitis. Clin Endocrinol 2002; 56:793-798. 4. Tran HA, Jones TL, Batey RG. The spectrum of thy- roid dysfunction in an Australian hepatitis C population treated with combination Interferon-alpha2beta and Ribavirin. BMC Endocr Disord 2005; 5:8. 5. Wong V, Fu AX, George J, Cheung NW. Thyrotoxicosis induced by alpha-interferon in chronic viral hepatitis. Clin Endocrinol 2002; 56:793-798. 6. Bohbot NL, Young J, Orgiazzi J, Buffet C, Francois M, Bernard-Chabert BG, et al. Interferon-alpha-induced hyperthyroidism: a three-stage evolution from silent thyroiditis toward Grave’s diseases. Eur J Endocrinol 2006; 154:367-372. 7. Labbadia G, Martocchia A, Mammarella A, Paoletti V, Rocco A, Benvenuto R, et al. Association between hu- man leukocyte antigen (HLA) and interferon-induced thyroid diseases in four patients with HCV-related chronic hepatitis. Neuro Endocinol Lett 2005; 26:109- 112. 8. Lin YQ, Want X, Murthy MS, Agarwala S. Life-threat- ening thyrotoxicosis induced combination therapy with PEG-interferon and ribavirin in chronic hepatitis C. Endocr Pract 2005; 11:135-139. Figure 1: Tc-99m thyroid scan with diffuse uptake 3.5% (n 1.0 – 4.0)