难治性溃疡性结肠炎与CMV、TNF-α关系研究
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摘要
近年来,国内外炎症性肠病的发病率逐渐增高,随着发病率的增高,对于常规治疗反应差或者无反应的病人亦随之增加。对标准剂量的激素反应差,或减药过程中出现症状反跳,或长期依赖激素且出现不良反应的患者称为难治性炎症性肠病。据文献报道,有30%-60%炎症性肠病患者存在激素抵抗或者激素依赖性,目前如何处理难治性炎症性肠病成为临床医师面临的一大难题。目前许多学者认为巨细胞病毒感染是难治性炎症性肠病的原因之一。炎症性肠病的病因和发病机制尚不清楚,与遗传、环境、微生物、免疫等多个因素密切相关,肿瘤坏死因子α(TNF-α)在炎症性肠病的发病机制中占有重要的地位。
目的：炎症性肠病包括克罗恩病(CD)和溃疡性结肠炎(UC)。流行病学资料显示国内外炎症性肠病的发病率均呈逐年增高的趋势。对常规治疗反应差甚至无反应的患者亦逐渐增加,如何处理难治性炎症性肠病已成为临床医师亟需解决的一大难题。因此设计此实验,以探讨难治性炎症性肠病与巨细胞病毒(CMV)感染、肿瘤坏死因子α(TNF-α)表达之间的关系,以及CMV、TNF-α之间的相关性,从而提高对该病的认识和治疗水平。方法：收集2000／7至2009／2期间在天津医科大学总医院诊治的76例IBD患者,所有患者均在临床症状,影像学,结肠镜和病理结果的基础上进行诊断,符合中华医学会消化分会的IBD诊断标准,并且通过Truelove-Witts指标分级,均为中～重度溃疡性结肠炎。根据是否使用激素及其治疗效果,将患者分为有效组、难治组及非激素治疗组,对三组患者的相关临床资料进行比较,同时对其内镜活检组织进行免疫组化染色,观察CMV及TNF-a的阳性感染、表达情况,以及两者之间的相关性。
结果：(1)CMV-negative患者共65例,CMV-positive患者中,难治组为9例,有效组为2例,非激素治疗组0例,三组之间的差异有统计学意义,且出现高热,颈淋巴结肿大,脾肿大等症状和体征的IBD患者与CMV-positive组有关。中度溃疡性结肠炎患者的CMV感染率低于重度患者,两者之间差别有统计学意义。难治组、有效组、非激素治疗组的内镜表现均相似,三组直乙状结肠、左半结肠、全结肠病变分布差异有统计学意义。在此研究病例中,临床表现比较多样,仍以腹泻腹痛为主,其中2人因出现并发症而行结肠切除术,均在CMV-positive组。(2)TNF-a阴性患者共34例,TNF-a阳性患者共42例,其中难治组21例,有效组17例,非激素治疗组5例,三组之间的差异有统计学意义(P<0.05); TNF-a阳性组患者激素抵抗8例,TNF-a阴性患者激素抵抗6例,两组之间差异有统计学意义(P<0.05)。中度溃疡性结肠炎患者的TNF-a阳性表达率低于重度患者,两者之间差别有统计学意义。CMV感染阳性与TNF-a阳性表达之间存在正相关性(rs=0.3866,P<0.05)。
结论：
(1)溃疡性结肠炎病例中,TNF-a的阳性表达率随着疾病严重程度的增加而增高,以难治组为最高。
(2)难治性溃疡性结肠炎与CMV感染相关,随着疾病严重程度增加,CMV感染率增高。CMV感染与TNF-a的阳性表达呈正相关。推测CMV感染后可使炎症性肠病的病程变复杂,出现激素抵抗或依赖。
In recent years, incidences of inflammatory bowel disease(IBD) are gradually growing. As it grows, more and more patients are badly responsible to or non-responsible to traditional therapy. It is named refractory inflammatory bowel disease, when patients are badly responsible to standardized steroid or rebounding during dilution of charge or steroid-dependent and occurring adverse effect. It is reported that patients of inflammatory bowel disease with refractory or steroid-dependent are percent 30 to 60, much of whom are non-responsible to remedial measure such as azathioprine、6-mercaptopurine、cyclosporin A and tumor necrosis factor monoclonal antibody. How to deal with refractory inflammatory bowel disease becomes a difficult problem which clinician confront. The pathogen and nosogenesis of inflammatory bowel disease are still quite unclear, which closely relate to hereditary、circumstance、microorganism、immunity. Tumor necrosis factor plays an important role in nosogenesis of inflammatory bowel disease. In clinical, the serious gastrointestinal tract CMV disease commonly occurs in patients with immunosuppressive, however, it is hardly reported in persons with immunity-competent. At present, much more researchers believe that CMV infection is one of the reasons of refractory bowel disease.
Objective:Inflammatory bowel disease include Crohn's disease and ulcerative colitis. Epidemiology's data show that incidence of inflammatory bowel disease in at home and abroad is gradually increasing. More and more patients are badly responsible to or non-responsible to traditional therapy. How to deal with refractory bowel disease becomes a significant problem that clinician confronts. Based on this reason, we design this experiment to discuss the relationship between refractory inflammatory bowel disease and CMV to improve the cognition and level of therapy.
Method:we collect seventy six patients with inflammatory bowel disease who are diagnosed in Tianjin general hospital from July 2000 to February 2009. All patients are diagnosed by clinical symptom、imaging examinations、colonoscopy and pathologic finding, which agree with diagnostic standard of inflammatory bowel disease. These patients are moderate to serious ulcerative colitis diagnosed by Truelove-Witts index. According to whether you use corticosteroid and the result of treatment, we divide these patients into effective group、refractory group and non-steroid group, which are compared with related clinical data of these group persons. We conduct immunohistochemical staining to colonic biopsy to observe incidence of CMV infection and expression of TNF-a.
Result:(1)Patients with CMV-negative are totally sixty-five. In CMV-positive group, there are nine cases in refractory group、two cases in effective group and zero group in non-steroid group and differences between the three groups were significant. Patients with IBD who suffer from hot fever, cervical lymphadenopathy, splenomegaly are both in CMV-positive group. There is no difference between endoscope and pathological manifestations in refractory group、effective group and non-steroid group. Differences between pancolitis、left-sided、proctitis are significant. In this research, clinical manifestations are more various. Diarrhea and stomach ache are usual and two of these patients perform colectomy because of complication, which are both in CMV-positive group.(2)Patients with TNF-a negative are thirty-four. Patients with TNF-a are forty-two, which include twenty-one in refractory group, seventeen in effective group, five in non-steroid group. Difference between these three groups are significant(P<0.05). Patients with the steroid-refractory are eight in TNF-a positive group and Patients with the steroid-refractory are six in TNF-a negative group. Difference between two groups are significant (P<0.05).
Conclusion:(1)Refractory bowel disease has a certain relationship with CMV. As the higher incidence of CMV is, the more serious the disease is. CMV infection can complicate the course of disease, occurring steroid-refractory. Whether antivirus therapy can improve the sensibility to steroid, it needs to further research. (2)The positive rate of TNF-a expression has a certain relationship with refractory bowel disease. It is higher in refractory bowel disease group.
目的：炎症性肠病包括克罗恩病(CD)和溃疡性结肠炎(UC)。流行病学资料显示国内外炎症性肠病的发病率均呈逐年增高的趋势。对常规治疗反应差甚至无反应的患者亦逐渐增加,如何处理难治性炎症性肠病已成为临床医师亟需解决的一大难题。因此设计此实验,以探讨难治性炎症性肠病与巨细胞病毒(CMV)感染、肿瘤坏死因子α(TNF-α)表达之间的关系,以及CMV、TNF-α之间的相关性,从而提高对该病的认识和治疗水平。方法：收集2000／7至2009／2期间在天津医科大学总医院诊治的76例IBD患者,所有患者均在临床症状,影像学,结肠镜和病理结果的基础上进行诊断,符合中华医学会消化分会的IBD诊断标准,并且通过Truelove-Witts指标分级,均为中～重度溃疡性结肠炎。根据是否使用激素及其治疗效果,将患者分为有效组、难治组及非激素治疗组,对三组患者的相关临床资料进行比较,同时对其内镜活检组织进行免疫组化染色,观察CMV及TNF-a的阳性感染、表达情况,以及两者之间的相关性。
结果：(1)CMV-negative患者共65例,CMV-positive患者中,难治组为9例,有效组为2例,非激素治疗组0例,三组之间的差异有统计学意义,且出现高热,颈淋巴结肿大,脾肿大等症状和体征的IBD患者与CMV-positive组有关。中度溃疡性结肠炎患者的CMV感染率低于重度患者,两者之间差别有统计学意义。难治组、有效组、非激素治疗组的内镜表现均相似,三组直乙状结肠、左半结肠、全结肠病变分布差异有统计学意义。在此研究病例中,临床表现比较多样,仍以腹泻腹痛为主,其中2人因出现并发症而行结肠切除术,均在CMV-positive组。(2)TNF-a阴性患者共34例,TNF-a阳性患者共42例,其中难治组21例,有效组17例,非激素治疗组5例,三组之间的差异有统计学意义(P<0.05); TNF-a阳性组患者激素抵抗8例,TNF-a阴性患者激素抵抗6例,两组之间差异有统计学意义(P<0.05)。中度溃疡性结肠炎患者的TNF-a阳性表达率低于重度患者,两者之间差别有统计学意义。CMV感染阳性与TNF-a阳性表达之间存在正相关性(rs=0.3866,P<0.05)。
结论：
(1)溃疡性结肠炎病例中,TNF-a的阳性表达率随着疾病严重程度的增加而增高,以难治组为最高。
(2)难治性溃疡性结肠炎与CMV感染相关,随着疾病严重程度增加,CMV感染率增高。CMV感染与TNF-a的阳性表达呈正相关。推测CMV感染后可使炎症性肠病的病程变复杂,出现激素抵抗或依赖。
In recent years, incidences of inflammatory bowel disease(IBD) are gradually growing. As it grows, more and more patients are badly responsible to or non-responsible to traditional therapy. It is named refractory inflammatory bowel disease, when patients are badly responsible to standardized steroid or rebounding during dilution of charge or steroid-dependent and occurring adverse effect. It is reported that patients of inflammatory bowel disease with refractory or steroid-dependent are percent 30 to 60, much of whom are non-responsible to remedial measure such as azathioprine、6-mercaptopurine、cyclosporin A and tumor necrosis factor monoclonal antibody. How to deal with refractory inflammatory bowel disease becomes a difficult problem which clinician confront. The pathogen and nosogenesis of inflammatory bowel disease are still quite unclear, which closely relate to hereditary、circumstance、microorganism、immunity. Tumor necrosis factor plays an important role in nosogenesis of inflammatory bowel disease. In clinical, the serious gastrointestinal tract CMV disease commonly occurs in patients with immunosuppressive, however, it is hardly reported in persons with immunity-competent. At present, much more researchers believe that CMV infection is one of the reasons of refractory bowel disease.
Objective:Inflammatory bowel disease include Crohn's disease and ulcerative colitis. Epidemiology's data show that incidence of inflammatory bowel disease in at home and abroad is gradually increasing. More and more patients are badly responsible to or non-responsible to traditional therapy. How to deal with refractory bowel disease becomes a significant problem that clinician confronts. Based on this reason, we design this experiment to discuss the relationship between refractory inflammatory bowel disease and CMV to improve the cognition and level of therapy.
Method:we collect seventy six patients with inflammatory bowel disease who are diagnosed in Tianjin general hospital from July 2000 to February 2009. All patients are diagnosed by clinical symptom、imaging examinations、colonoscopy and pathologic finding, which agree with diagnostic standard of inflammatory bowel disease. These patients are moderate to serious ulcerative colitis diagnosed by Truelove-Witts index. According to whether you use corticosteroid and the result of treatment, we divide these patients into effective group、refractory group and non-steroid group, which are compared with related clinical data of these group persons. We conduct immunohistochemical staining to colonic biopsy to observe incidence of CMV infection and expression of TNF-a.
Result:(1)Patients with CMV-negative are totally sixty-five. In CMV-positive group, there are nine cases in refractory group、two cases in effective group and zero group in non-steroid group and differences between the three groups were significant. Patients with IBD who suffer from hot fever, cervical lymphadenopathy, splenomegaly are both in CMV-positive group. There is no difference between endoscope and pathological manifestations in refractory group、effective group and non-steroid group. Differences between pancolitis、left-sided、proctitis are significant. In this research, clinical manifestations are more various. Diarrhea and stomach ache are usual and two of these patients perform colectomy because of complication, which are both in CMV-positive group.(2)Patients with TNF-a negative are thirty-four. Patients with TNF-a are forty-two, which include twenty-one in refractory group, seventeen in effective group, five in non-steroid group. Difference between these three groups are significant(P<0.05). Patients with the steroid-refractory are eight in TNF-a positive group and Patients with the steroid-refractory are six in TNF-a negative group. Difference between two groups are significant (P<0.05).
Conclusion:(1)Refractory bowel disease has a certain relationship with CMV. As the higher incidence of CMV is, the more serious the disease is. CMV infection can complicate the course of disease, occurring steroid-refractory. Whether antivirus therapy can improve the sensibility to steroid, it needs to further research. (2)The positive rate of TNF-a expression has a certain relationship with refractory bowel disease. It is higher in refractory bowel disease group.
引文
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2.陈隆典.难治性炎症性肠病的治疗对策.胃肠病学,2005,10(1)：53-56.
3.叶任高,陆再英.内科学[M].北京：人民卫生出版社,2005：407.
4. Papadakis KA, Tung JK, Binder SW, et al. Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. Am J Gastroenterol.2001; 96: 2137-2142. doi:10. llll/j.1572-0241.2001.03949.x.
5. Cooper HS, Raffensperger EC,Jonas L,Fitts WT Jr. Cytomegalovirus inclusions in patients with ulcerative colitis and toxic dilation requiring colonic resection. Gastroenterologyl 977;72:1253-6.
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