A 55 year old man with chronic hepatitis C presented with diarrhoea and bloody stools in July 2003. Colonoscopic examination showed redness and oedematous mucosa in the rectum and ulcerative colitis was suspected. Biopsy of the lesion confirmed the diagnosis and treatment was initiated with mesalazine (5‐ASA 2250 mg/day). However, he showed short term improvement and mesalazine was discontinued. He was treated with percutaneous radiofrequency ablation therapy (RFA)(Cool‐tip) for adenomatous hyperplasia in S5 of the liver in December 2004. After providing consent to treatment with interferon (IFN), the patient underwent combination therapy with PEG‐IFNα‐2b (100 mg/week) and ribavirin (800 mg/day) for chronic hepatitis C. Liver biopsy and blood biochemistry revealed chronic active hepatitis C virus (HCV) F3/A2, genotype 1b, liver injury associated with HCV, aspartate aminotransferase (AST) 109 IU/l, alanine aminotransferase (ALT) 126 IU/l, and HCV RNA 3400.0 KIU/ml (by reverse transcription nested polymerase chain reaction, high range method).
One month after initiation of combination therapy, AST was 20 IU/l, ALT 24 IU/l, and transaminase levels were normal. However, 2.5 months after initiation of combination therapy, bloody diarrhoea was first observed and the incidence of bloody diarrhoea continually increased. Colonoscopic findings and biopsy specimens were compatible with active ulcerative colitis (fig 1A, B) and we confirmed the diagnosis of exacerbation of ulcerative colitis. We discontinued PEG‐IFN and ribavirin in April 2005, and continued treatment for ulcerative colitis with continuous oral mesalazine and prednisolone. Despite discontinuation of PEG‐IFN and ribavirin, the patient's symptoms did not change and he was hospitalised in May 2005. The patient improved following treatment for ulcerative colitis with mesalazine and steroid therapy. He was discharged on 3 June 2005 and was followed and observed as an outpatient.
Figure 1 (A) Colonoscopic findings. Colonoscopic examination revealed the absence of vessel pattern, easy bleeding on contact, and oedema in the mucosa from the rectum to the descending colon in a continuous fashion. (B) Histological findings. Biopsy specimens from the colonic mucosa showed crypt abscess, decreased number of goblet cells, and marked infiltration of inflammatory cells. Haematoxylin‐eosin, ×100.
We encountered a case of ulcerative colitis apparently caused by combination therapy of PEG‐IFN and ribavirin for hepatitis C. A literature search using Japana Centra Revuo Medicina (keywords: interferon, ulcerative colitis; retrieval period: 1983–2006) found seven cases1,2,3,4,5,6,7 of onset and exacerbation of ulcerative colitis caused by IFN therapy in Japan (table 1). Conversely, a literature search using MEDLINE (keywords: interferon, ulcerative colitis) found only three reports in English worldwide (Mitoro and colleagues,1 Mavrogiannis and colleagues,8 and Sprenger and colleagues) (table 1).9 Moreover, only one of these cases described exacerbation of ulcerative colitis due to combination therapy with PEG‐IFN and ribavirin.9 Thus our patient is the second reported case to date.
Table 1 Reported cases of exacerbation of ulcerative colitis induced by interferon (IFN) therapy in Japana Centra Revuo Medicina (in Japan) and in MEDLINE.
| Author, year, country | Age/ sex | Background | IFN | Period to exacerbation | Region of colitis | Therapy | Result |
|---|---|---|---|---|---|---|---|
| Mitoro 1993 Japan1 | 34M | Hepatitis C | IFN‐α | 23 days | R‐A | Conservative | Reinjection of IFN under administration of SASP |
| Honda 1993 Japan2 | 50M | Hepatitis C | IFN‐α | 14 months | R‐D | SASP | Exacerbation after readministration of IFN |
| Yasumori 1995 Japan3 | 42M | Hepatitis B | IFN‐α | 1 day | Total colon | Total colectomy | Death |
| Yamamoto 1995 Japan4 | 40M | Hepatitis C | IFN‐α | 5 months | R‐S | SASP | Discontinuation of IFN |
| Usami 1999 Japan5 | 47M | Renal cancer | IFN‐α,γ | 12 months | R‐A | Conservative | Discontinuation of IFN |
| Mavrogianni 2001 Greece8 | 29F | Hepatitis C | IFN‐α | 14 days | R | Mesalazine+steroid | Continuation of IFN under administration of mesalazine and steroid resulted in exacerbation of UC |
| Niki T 2001 Japan6 | 49M | Hepatitis C | IFN‐α | 2 months | Total colon | Mesalazine, steroid | Discontinuation of IFN |
| Awakawa 2002 Japan7 | 48M | Hepatitis C | IFN‐β | 7 days | R‐A | Mesalazine | Discontinuation of IFN |
| Sprenger 2005 Austria9 | 54M | Hepatitis C | PEG‐IFN‐α + ribavirin | 3.5 months | Total colon | Mesalazine+steroid | Discontinuation of PEG‐IFN‐α and ribavirin |
| Watanabe (2006) Japan (present study) | 55M | Hepatitis C | PEG‐IFN‐α + ribavirin | 2.5 months | R‐D | Mesalazine+steroid | Discontinuation of PEG‐IFN‐α and ribavirin |
R, rectum; S, sigmoid colon; D, descending colon; A, ascending colon; SASP, salazosulfapyridine; UC, ulcerative colitis.
As PEG‐IFN can maintain higher blood levels than classical IFN, IFN may have a larger effect on the immune system. Furthermore, it has been reported that ribavirin alters the balance of Th1/Th2 and causes resistance to HCV by cellular immune processes.10 Combination therapy with PEG‐IFN and ribavirin may thus have more significant effects on immunomodulation than classical IFN treatment.
This is a case of chronic hepatitis C with adenomatous hyperplasia of the liver at the age of 55 years. Antiviral therapy for chronic hepatitis C after RFA for adenomatous hyperplasia might prevent future carcinogenesis in the liver. We conclude that the benefits of prevention of carcinogenesis in the liver by combination therapy with PEG‐IFN and ribavirin supersede the risk of relapse and exacerbation of ulcerative colitis. Furthermore, we selected the combination therapy of PEG‐IFN and ribavirin for antiviral therapy because the patient had HCV genotype 1 infection and high pretreatment viral burdens.
We expect the use of IFN, as an antiviral therapy for hepatitis C, to continue to increase. Changes to immune system regulation and specific adverse reactions such as ulcerative colitis associated with combination therapy may be expected to occur at a significantly higher frequency than with monotherapy IFN. Further discussion in needed on how to prevent adverse reactions with combination therapy.
Footnotes
Conflict of interest: None declared.
This article is based on a case report first reported in the Japanese Society of Gastroenterology, “Nippon Shokakibyo Gakkai Zasshi” (in Japanese). Watanabe T, Inoue M, Harada K, et al. A case of the exacerbation of ulcerative colitis induced by the combination therapy with PEG‐interferon α‐2b and ribavirin. Nippon Shokakibyo Gakkai Zasshi 2006 (in press).
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