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   Table of Contents     
CASE REPORT  
Year : 2012  |  Volume : 4  |  Issue : 2  |  Page : 128-131
Multisystem sarcoidosis in a patient on interferon-α therapy for chronic hepatitis C


1 Department of Hepatogastroenterology, University Hospital of Fez, Morocco
2 Clinical Neurosciences Laboratory, Faculty of Medicine and Pharmacy of Fez; Department of Neurosurgery, University Hospital of Fez, Morocco
3 Clinical Neurosciences Laboratory, Department of Biophysics and Clinical MRI Methods, Faculty of Medicine and Pharmacy of Fez, Morocco
4 Department of Neurosurgery and Neurology, University Hospital of Fez, Morocco

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Date of Web Publication30-May-2012
 

   Abstract 

Sarcoidosis is a chronic multisystemic granulomatous disease that is triggered by an autoimmune process. Nowadays, this pathology represents a well-recognized but uncommon complication for antiviral treatment in hepatitis C virus (HCV) infection. Herein, we report a remarkable case of 47-year-old woman treated for chronic HCV infection; the patient has developed interferon alfa-induced sarcoidosis involving the central nervous system. The evolution was fatal despite disrupting the antiviral therapy and initiating a high-dose corticotherapy. This complication of interferon alfa treatment was reported in the literature in only one case. Through this case and a review of the literature, we aim to underline the importance of screening for sarcoidosis before and during the follow-up of HCV patients undergoing antiviral therapy.

Keywords: Chronic hepatitis C, Complication, Interferon alfa, Neurosarcoidosis, Treatment

How to cite this article:
Oudghiri B, Benzagmout M, Boujraf S, Belahcen F, Ibrahimi A. Multisystem sarcoidosis in a patient on interferon-α therapy for chronic hepatitis C. J Global Infect Dis 2012;4:128-31

How to cite this URL:
Oudghiri B, Benzagmout M, Boujraf S, Belahcen F, Ibrahimi A. Multisystem sarcoidosis in a patient on interferon-α therapy for chronic hepatitis C. J Global Infect Dis [serial online] 2012 [cited 2019 Aug 21];4:128-31. Available from: http://www.jgid.org/text.asp?2012/4/2/128/96779



   Introduction Top


Sarcoidosis is a chronic multisystemic disease of unknown origin; it is characterized by an accumulation of noncaseating epithelioid granulomas. This pathology affects most commonly the lung, skin, lymph nodes, eyes, and rarely the nervous system. [1] The relationship between the occurrence of sarcoidosis and interferon alfa (IFN-α) therapy in viral hepatitis C was suggested in earlier reports. [1],[2],[3],[4] This was also supported by the spontaneous resolution of sarcoidosis after cessation of IFN-α treatment for hepatitis C. Reported clinical manifestations include cutaneous sarcoidotic lesions, pulmonary nodules, and peripheral neuropathy. [1],[4]

In this paper, we report the second case in the literature of fatal central nervous system sarcoidosis secondary to IFN-α and ribavirin treatment.[5] We aim to underline the importance of screening for sarcoidosis before and during the follow-up of hepatitis C virus (HCV) patients undergoing antiviral therapy.


   Case Report Top


Since March 2002, a 47-year-old woman without any history of sarcoidosis was regularly monitored in consultation for chronic viral hepatitis C (genotype 1). In April 2007, the alanine and aspartate aminotransferase serum levels have increased to 116 and 98 IU/l compared to normal values of 40 IU/l; the serum HCV RNA was 6.2×10 6 copies/ml. However, the physical and abdominal ultrasound examinations did not show any abnormalities. Because of the presence of biological cytolysis, a percutaneous liver biopsy was performed and revealed severe hepatic fibrosis (Metavir score A2/F3). Then, the antiviral treatment was started, and the patient received once a week the pegylated INF-2a at the rate of 180 μg that injected subcutaneously, and ribavirin 400 mg was administrated orally twice a day. The biological response was good, and the transaminases were standardized after 2 weeks of treatment.

Six weeks after the beginning of the treatment, the patient noticed weight loss of 5 kg associated with dyspnea and progressive appearance of skin small firm nodules on both her upper and lower extremities. Chest X-ray was normal. However, thoracic computed tomography (CT) scan revealed pulmonary nodules associated with bilateral mediastinal lymphadenopathies, suggesting tuberculosis, lymphoma, and/or sarcoidosis. Abdominal CT scan was normal. The tuberculin skin test was negative. Afterward, bronchoalveolar lavage fluid was performed and showed an increased number of lymphocytes with a normal amount of eosinophils and neutrophils. The histological study of transbronchial lung biopsy revealed a patchy distribution of mild interstitial and perivascular fibrosis, without distinctive granulomas or significant inflammatory cell infiltrations. In addition, cultures for fungi, mycoses, and tuberculosis were all normal. Finally, a biopsy of the skin nodules was performed and found a noncaseating epithelioid granuloma formation strongly suggestive of sarcoidosis [Figure 1]. The serum angiotensin-converting enzyme was significantly elevated (130 U/l for the normal value <40 U/l); the diagnosis of sarcoidosis was retained and oral corticotherapy was started at the dose of 60 mg daily.
Figure 1: No caseating epithelioid granuloma formation composed of macrophages, lymphocytes, and fibroblasts

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Four days later, the patient suddenly presented a heaviness of the right upper limb predominant distally, associated with a right central facial paralysis and aphasia; however, she was lethargic and her ophthalmologic examination was normal. The cerebral magnetic resonance imaging (MRI) showed a gyriform and nodular left frontal and parietal subcortical enhancement associated with an important perilesional edema [Figure 2]a-b. INF-α and ribavirin therapies were discontinued, and intravenous bolus methyl prednisolone was then started at the rate of 10 mg/kg/day for consecutive 3 days; this was followed by prednisone (1 mg/kg/day). Nevertheless, no clinical improvement was noticed. On the contrary, the neurological state of the patient worsened rapidly and the patient died a week later.
Figure 2: Cerebral MRI in postgadolinium axial T1-weighted image (a) and FLAIR image (b), showing a gyriform and nodular left frontal and parietal subcortical enhancement associated with an important perilesional edema

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   Discussion Top


More than 170 million people worldwide are infected with chronic viral hepatitis C. [6] Current antiviral treatments are effective in eradicating the virus in up to 60% of patients. Several treatment regimens have been used. Pegylated IFN-α plus ribavirin was found to be superior to all other protocols for sustained eradication of the HCV, especially in individuals with more resistant viral genotypes 1, 4, 5, and 6. [7]

Although several reports have suggested an association between IFN therapy and sarcoidosis, this association was rarely described in the literature. In 1987, Abdi et al. [3] had described the first case of pulmonary sarcoidosis in a patient who received IFN-β treatment for renal cell cancer. Since then, various cases have been published suggesting a relationship between sarcoidosis and IFN treatment in patients with a variety of diseases, including renal cell carcinoma, hematological malignancies, and viral hepatitis. So far, more than 30 cases of sarcoidosis occurring in the context of chronic hepatitis C treated by IFN-α have been reported in the literature.[2],[3],[4] Reported clinical manifestations include cutaneous sarcoidotic lesions, pulmonary nodules, and peripheral neuropathy. In this paper, we report the second case in the literature of severe central nervous system sarcoidosis secondary to IFN-α treatment. To the best of our knowledge, only one case of neurosarcoidosis associated with IFN therapy has been reported in the literature. [5]

Most of the cases described in the literature occurred in patients who have received a treatment combining IFN-α or pegylated IFN-α and ribavirin.[4] Indeed, it is well recognized that IFN-α is an immunomodulator that has not only direct antiviral activity but also powerful stimulation of the immune activities, especially on T-helper (Th1) immune response,[8],[9],[10] which is strongly involved in the pathogenesis of sarcoidosis. [11],[12] Furthermore, granulomas in sarcoidosis are associated with an abundance of CD4 + T lymphocytes and mononuclear phagocytes, which are being considered a result of cytokine stimulation and immunologic dysregulation. [13]

Importantly, in cases of chronic hepatitis C, INF could induce [2] and reactivate sarcoidosis, [14] and INF-based combination antiviral regimens cannot eliminate the occurrence of sarcoidosis. [15] In contrast, ribavirin, an antiviral agent that increases the anti-HCV effect of INF in chronic hepatitis C, would also enhance Th1 cytokine response while inhibiting Th2 cytokine response. [11],[12]

All patients previously solely treated with INF-α did show any manifestation of sarcoidosis. Furthermore, there was no case report of sarcoidosis in patients treated using ribavirin only. This suggests that the combination of INF-α and ribavirin enhances the immune response, consequently predisposing the patient to sarcoidosis.

The mean time to the onset of the disease after starting INF-α therapy is 4 months.[1] In our case, manifestations of sarcoidosis occurred earlier, associating rapid deterioration of clinical symptoms, which lead to death in 10 weeks.

Most patients with INF-α associated sarcoidosis had spontaneous resolution of the disease without immunosuppressive treatment. Indeed, INF-α treatment was discontinued in several cases and subsequent resolution of sarcoidosis within months has followed. In contrast, the treatment protocol was not modified in other cases, and the sarcoidosis resolved several months later, either during or after the achievement of treatment. However, some patients were treated with oral corticosteroids with rapid resolution of sarcoidosis. Indeed, steroids that are the main treatment for systemic sarcoidosis increase the HCV load in both in vitro and in vivo. [16] Thus, physicians should exert caution while treating INF-α associated sarcoidosis with systemic corticosteroids.

The prognosis of peripheral neurosarcoidosis is better as compared to the central nervous system involvement, which leads to higher disability and mortality. [16],[17] In addition, neurosarcoidosis of the CNS usually occur in the early stages of the disease, while peripheral nervous system and skeletal muscle sarcoidosis are typically seen in the chronic stages of the disease. [17] This would suggest that our patient has recent neurosarcoidosis after introducing INF-α and ribavirin therapy.


   Conclusion Top


Based on this case report, INF-α associated sarcoidosis might also include CNS involvement and might lead to death. Considering earlier reports of heterogeneous spectra of sarcoidosis manifestations, clinicians should be aware of associated potential complication while evaluating the benefit/risk ratio of the treatment in patients with chronic hepatitis C infection. Therefore, patients suggested such treatments are recommended to be monitored for sarcoidosis before and during IFN therapy.

 
   References Top

1.Delaney P. Neurologic manifestations in sarcoidosis: Review of literature, with a report of 23 cases. Ann Intern Med 1977;87:336-45.  Back to cited text no. 1
    
2.Celik G, Sen E, Ulger AF, Kumbasar OO, Bozkaya H, Alper D, et al. Sarcoidosis caused by interferon therapy. Respirology 2005;10:535-40.  Back to cited text no. 2
    
3.Abdi EA, Nguyen GK, Ludwig RN, Dickout WJ. Pulmonary sarcoidosis following interferon therapy for advanced renal cell carcinoma. Cancer 1987;59:896-900.  Back to cited text no. 3
    
4.Hurst EA, Mauro T. Sarcoidosis associated with pegylated interferon alfa and ribavirin treatment for chronic hepatitis C: A case report and review of the literature. Arch Dermatol 2005;141:865-8.  Back to cited text no. 4
    
5.Miwa H, Furuya T, Tanaka S, Mizuno Y. Neurosarcoidosis associated with interferon therapy. Eur Neurol 2001;45:288-9.  Back to cited text no. 5
    
6.World Health Organization. Global distribution of hepatitis A, B, and C, 2001. Wkly Epidemiol Record 2002;77:6.  Back to cited text no. 6
    
7.Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet 2003;362:2095-100.  Back to cited text no. 7
    
8.Schattner A. Interferons and autoimmunity. Am J Med Sci 1988;295:532-44.  Back to cited text no. 8
    
9.Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the frequency of interferon gamma-producing human CD4 + T cells. J Exp Med 1993;178:1655-63.  Back to cited text no. 9
    
10.Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: A disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med 1981;305:429-34.  Back to cited text no. 10
    
11.Fireman EM, Topilsky MR. Sarcoidosis: An organized pattern of reaction from immunology to therapy. Immunol Today 1994;15:199-201.  Back to cited text no. 11
    
12.Tam RC, Pai B, Bard J, Lim C, Averett DR, Phan UT, et al. Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile. J Hepatol 1999;30:376-82.  Back to cited text no. 12
    
13.Hultgren C, Milich DR, Weiland O, Sallberg M. The antiviral compound ribavirin modulates the T helper (Th) 1/Th2 subset balance in hepatitis B and C virus-specific immune responses. J Gen Virol 1998;79:2381-91.  Back to cited text no. 13
    
14.Li SD, Yong S, Srinivas D, van Thiel DH. Reactivation of sarcoidosis during interferon therapy. J Gastroenterol 2002;37:50-4.  Back to cited text no. 14
    
15.Nakajima M, Kubota Y, Miyashita N, Niki Y, Matsushima T, Manabe T. Recurrence of sarcoidosis following interferon alpha therapy for chronic hepatitis C. Intern Med 1996;35:376-9.  Back to cited text no. 15
    
16.Ferriby D, De Seze J, Stojkovic T, Hachulla E, Wallaert B, Destée A, et al. Long-term follow-up of neurosarcoidosis. Neurology 2001;57:927-9.  Back to cited text no. 16
    
17.Chapelon-Abric C. Neurosarcoidosis. Ann Med Intern 2001;152:113-24.  Back to cited text no. 17
    

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Correspondence Address:
Sad Boujraf
Clinical Neurosciences Laboratory, Department of Biophysics and Clinical MRI Methods, Faculty of Medicine and Pharmacy of Fez
Morocco
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-777X.96779

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    Figures

  [Figure 1], [Figure 2]

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