Ischemic colitis during interferon-alpha treatment for chronic active hepatitis C

Tada, Hisashi; Saitoh, Shoichi; Nakagawa, Yoshihiro; Hirana, Hirofumi; Morimoto, Michio; Shima, Toshihide; Shimamoto, Kazuhiko; Okanoue, Takeshi; Kashima, Kei

doi:10.1007/bf02355061

Cited by 69 publications

(19 citation statements)

References 14 publications

(1 reference statement)

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“…In spite of the clinical improvement achieved by a high proportion of patients with HCV-associated mixed cryoglobulinemia treated with IFN␣, most reported series include a minority of patients in whom vasculitic manifestations worsen in association with IFN␣ treatment (4). Moreover, the development of ischemic lesions during IFN␣ therapy for other conditions has also been reported (5,6). Careful followup of our patients revealed that cryoglobulinemic ulcers became progressively devoid of vascularization and granulation tissue, with subsequent appearance of necrosis and bacterial colonization.…”

Section: Discussionsupporting

confidence: 75%

Interferon-? may exacerbate cryoglobulinemia-related ischemic manifestations: An adverse effect potentially related to its anti-angiogenic activity

Cid

Hernández‐Rodríguez

Robert

et al. 1999

Arthritis & Rheumatism

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The discovery of the strong association between hepatitis C virus (HCV) infection and the development of mixed cryoglobulinemia has motivated active testing of antiviral-directed alternative therapies. Several trials have demonstrated that classic cryoglobulinemia-associated manifestations improve with interferon-alpha (IFNalpha) treatment. Herein we report on 3 HCV-infected patients with severe cryoglobulinemia-related ischemic manifestations who were closely followed up during IFNalpha therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryocrit determinations were serially performed. In addition to prednisone and immunosuppressive agents, the patients received IFNalpha at 3 x 10(6) units, 3 times per week for 2 months, 3 months, and 4 months, respectively. In all 3 patients, systemic features improved, liver function results returned to normal, and cryocrit values decreased. However, ischemic lesions became less vascularized and ischemia progressed, leading to transmetatarsal and subcondylar amputation, respectively, in 2 of the patients and fingertip necrosis and ulcer enlargement in the third. Skin biopsies performed before IFNalpha therapy and after 2 months of IFNalpha therapy in the third patient showed a significant decrease in subepidermal microvessels. When IFNalpha was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemic lesions may worsen during IFNalpha treatment, presumably through a decrease in inflammation-induced angiogenesis. The anti-angiogenic activity of IFNalpha may delay the appropriate healing of ischemic lesions.

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Section: Discussionsupporting

confidence: 75%

Interferon-? may exacerbate cryoglobulinemia-related ischemic manifestations: An adverse effect potentially related to its anti-angiogenic activity

Cid

Hernández‐Rodríguez

Robert

et al. 1999

Arthritis & Rheumatism

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“…It has been reported that approximately 60% of patients with chronic hepatitis or cancer treated with Roferon have intestinal disorders, especially diarrhea. Case reports also note rare cases of pseudoinflammatory bowel disease subsequent to IFN alpha/ribavirin treatment for chronic hepatitis 27, 28…”

Section: Discussionmentioning

confidence: 99%

Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa

Jarry

Malard

Bou-Hanna

et al. 2017

Cellular and Molecular Gastroenterology and Hepatology

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Backgound & AimsSeveral lines of investigation suggest that interferon (IFN) alpha can alter human intestinal mucosa homeostasis. These include the endogenous production of IFN alpha in celiac disease or inflammatory bowel diseases, as well as the occurrence of intestinal side effects of exogenous IFN alpha used as a therapeutic tool. Here, we present an ex vivo translational approach to investigate the effects of IFN alpha on the human normal intestinal mucosa, as well as its underlying mechanisms.MethodsHuman normal colonic mucosa explants were cultured in the presence or absence of IFN alpha 2a. Epithelial homeostasis was assessed using the immunohistochemical marker of apoptosis M30. The Wnt inhibitor Dickkopf-Homolog-1 (DKK1) was assayed in the supernatants by enzyme-linked immunosorbent assay. Activation of the inflammasome (caspase-1/interleukin [IL]18) and of a Th1 response was determined by in situ detection of active caspase-1, as well as by measurement of mature IL18 production and the prototype Th1 cytokine IFN gamma by enzyme-linked immunosorbent assay. In addition, mechanistic studies were performed using the specific caspase-1 inhibitor Tyr-Val-Ala-Asp(OMe)-fluoromethylketone (YVAD-FMK), IL18-binding protein, neutralizing anti–IFN gamma, and anti-DKK1 antibodies.ResultsIFN alpha 2a elicited a rapid (24 hours) disruption of surface and crypt colonic epithelial cells via apoptosis that was variable in intensity among the 20 individuals studied. This apoptotic effect was dependent on the initiation of an IFN gamma response elicited by resident T box expressed in T cells–positive lamina propria cells. Both apoptosis and Th1 response were subordinated to active caspase-1 and IL18 production. Finally, neutralization of IFN gamma–induced DKK1 partially protected against IFN alpha–induced epithelial apoptosis.ConclusionsBy using an ex vivo model, we show an interindividual heterogeneity of IFN alpha effects. We show that IFN alpha is able to disrupt both epithelial and immune homeostasis in the human intestine, by activation of an innate immunity platform, the inflammasome, which drives a Th1 response and leads to epithelial barrier disruption.

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“…Multiple anecdotal case reports and case series have described associations of ischaemic colitis with vascular surgery and vascular thromboembolism, 4-7 co-morbid medical conditions [8][9][10][11][12][13][14][15][16][17][18] and medications including vasoconstrictors, psycho-tropics, oral contraceptives, interferon-a and 5-hydroxytryptamine-1 (5-HT 1 ) agonists (triptans). [19][20][21][22][23][24][25] Transient ischaemic colitis was first reported as a clinical finding in the 1960s by Boley et al 26 and Marston et al 27 It has since become a well-recognized clinical entity, with well-characterized endoscopic 28 and pathological 29 findings. Ischaemic colitis has recently become the subject of great controversy, as a new class of medications (5-HT 3 antagonists) has been associated with this condition, 30 leading to the initial withdrawal by the Food and Drug Administration, and later restoration, of alosetron to the market in the USA.…”

Section: Introductionmentioning

confidence: 99%

The epidemiology of ischaemic colitis

Higgins

Davis

Laine

2004

Aliment Pharmacol Ther

230

169

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SUMMARYBackground: Ischaemic colitis has been associated with co-morbid conditions, medications, vascular surgery and advanced age in case reports and case series. Few data exist on the baseline incidence in the general population or on the increased risk imposed by these risk factors. Aim: To systematically review the literature regarding the incidence, prevalence and risk factors for ischaemic colitis. Methods: Searches of bibliographic databases were performed independently by two investigators. Studies were included if they used population-based samples, disease-specific population samples or case-control population-based samples of adults with ischaemic colitis, and reported the incidence, prevalence or

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Ischemic colitis during interferon-alpha treatment for chronic active hepatitis C

Cited by 69 publications

References 14 publications

Interferon-? may exacerbate cryoglobulinemia-related ischemic manifestations: An adverse effect potentially related to its anti-angiogenic activity

Interferon-? may exacerbate cryoglobulinemia-related ischemic manifestations: An adverse effect potentially related to its anti-angiogenic activity

Interferon-Alpha Promotes Th1 Response and Epithelial Apoptosis via Inflammasome Activation in Human Intestinal Mucosa

The epidemiology of ischaemic colitis

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