消化道病理(二)

1、炎症性肠病的临床病理 THE CLINICO-PATHOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD)王军臣2015-11-24溃疡性结肠炎（Ulcerative colitis）克罗思病（Crohns disease）未定型结肠炎（Indeterminate colitis）IBM一词主要是指两种肠病：克罗思病和溃疡性结肠炎。两者临床病程与病史不同，病变有别，但某些特点相同，而治疗原则不同。 Inflammatory bowel disease is a term that describes two diseases: Crohn disease and

2、ulcerative colitis. Although these two disorders have different clinical courses as well as natural histories and are usually clearly distinguishable, they have certain common features.IBD的类型无特异性实验室检测指标（No specific laboratory tests）抗中性粒细胞胞质抗体 pANCA (anti-neutrophil cytoplasmic antibody) 60-75%的溃疡性结肠

3、炎病例（Ulcerative colitis: 60-75%） 10-40%的克罗思病病例（Crohns disease: 10-40%）抗酿酒酵母菌抗体 ASCA (anti-Saccharomyces cerevisiae antibody) 40-80%的溃疡性结肠炎病例（Crohns disease: 40-80%） 10%的克罗思病病例（Ulcerative colitis: 10%）基因检测： NOD2 和其他的IBD 基因 （Genetic testing for NOD2 and other IBD genes） IBD的实验室检测克罗恩病（Crohn Disease） 克罗恩

4、病（Crohn Disease） 肠炎特点（Features of Inflammation of the Intestine） 慢性，节段性，透壁性（Chronic, Segmental, Transmural）病变以小肠远端为主，右半结肠可受累，可有消化道甚至肠外组织受累 （Crohn disease occurs principally in the distal small intestine but may involve any part of the digestive tract and even extraintestinal tissues. The colon, part

5、icularly the right colon, may be affected.）2022/10/8克罗恩病的流行病学（Epidemiology）全球发生克罗思病，每年发病率为0.5 - 5 人/ 每10万人群。过去30年来，来自各国的报道表明，全球的克罗思发病率急剧增加。 （Crohn disease occurs worldwide, with an annual incidence of 0.5 to 5 per 100,000. Reports from various countries indicate that the incidence has increased dram

6、atically over the past 30 years. ）欧洲的该病病例最常见于青少年或年轻成人,犹太人群呈高发病率，女性较男性稍微多见(1.6:1). The disease usually appears in adolescents or young adults and is most common among persons of European origin, with a considerably higher frequency in the Jewish population. There is a slight female predominance (1.6:

7、1).2022/10/8发病机制（Pathogenesis）家族性遗传性体质 Concordance rates in twin pairs and siblings strongly implicate a genetic predisposition to Crohn disease. A family history of inflammatory bowel disease is more common for Crohn disease than for ulcerative colitis. A putative susceptibility locus for Crohn dis

8、ease has been assigned to the centromeric region of chromosome 16 where it is associated with the NOD2/CARD15 locus, which codes for an intracellular receptor for bacterial products involved in innate immunity. 自身免疫机制 The possibility that Crohn disease reflects immunologically mediated damage to the

9、 intestine is suggested by (1) the chronic and recurrent nature（慢性反复发作） of the inflammation and (2) its association with systemic manifestations（全身损害） that are suggestive of autoimmune disease. Most recent immunologic studies focus on the possible role of cell-mediated cytotoxicity.2022/10/8肠道粪便流的作用

10、 The fecal stream appears to be of prime importance in the pathogenesis of Crohn disease, as evidenced by：(1) the beneficial effects of surgical bypass（肠旁路吻合的好处）(2) the pattern of preanastomotic recurrence in patients with side-to-end anastomotic sites（侧-端吻合处前段复发）, and (3) the frequency of early inf

11、lammatory lesions (aphthoid erosions) in the epithelium in association with mucosal lymphoid tissue（淋巴组织增生之上皮处早期炎症-口疮样糜烂）.2022/10/8病理变化（Pathology） 克罗思病有两大病变特征，以此与其他的炎症性肠病相鉴别： Two major characteristics of Crohn disease differentiate it from other GI inflammatory diseases. 第一，严重通常累及肠壁全层，故称之为透壁性炎症。 Fir

12、st, the inflammation usually involves all layers of the bowel wall and is, therefore, referred to as transmural inflammatory disease. 第二，肠壁病变是间断性的，即节段性肠炎病变，间有未受累及的正常肠组织 Second, the involvement of the intestine is discontinuous; that is, segments of inflamed tissue are separated by apparently normal

13、intestine.2022/10/8克罗恩病病变分布的四大部位特征回盲部病变为主，占50% mainly the ileum and cecum in about 50% of cases仅有小肠病变，占15% only the small intestine in 15%仅有大肠病变，占20% only the colon in 20%肛门直肠区病变为主，占15% 女性肛门直肠区克罗恩病可蔓延到外阴部 mainly the anorectal region in 15%. In women with anorectal Crohn disease, the inflammation may

14、 spread to involve the external genitalia.2022/10/8大体观(Grossly )肠壁与邻近肠系膜增厚，水肿，肠系膜脂肪环绕肠周（爬行脂肪） The bowel and adjacent mesentery are thickened as well as edematous, and mesenteric fat often wraps around the bowel (Creeping fat). 肠系膜淋巴结常常肿大，变硬，相互融合 Mesenteric lymph nodes are frequently enlarged, firm,

15、and matted together. 肠腔狭窄（水肿与纤维化共同作用所致），可见鹅卵石状外观（因结节状肿胀、肠壁纤维化和粘膜溃疡所致） The intestinal lumen is narrowed by a combination of edema and fibrosis. Nodular swelling, fibrosis, and mucosal ulceration lead to a cobblestone appearance . 溃疡特点：早期的溃疡呈口疮状或葡行状；晚期的溃疡变深呈线状裂缝或裂纹状 In early cases, ulcers have either

16、an aphthous or a serpiginous appearance; later, they become deeper and appear as linear clefts or fissures (see Fig. 13-23B).2022/10/8图片A.末端回肠远端肠壁明显增厚，伴有回盲瓣变形。可见一纵向溃疡 (箭头所示)图片B. 该回肠节段另一纵向溃疡。受损粘膜水肿，形成圆形/卵圆形结节状隆起，使病变肠段粘膜呈鹅卵石样外观。右下侧局部粘膜部分未受累2022/10/8 克罗恩病肠切除标本大体观大体切面观The cut surface of the bowel wall s

17、hows the transmural （透壁性）nature of the disease, with thickening（增厚）, edema（水肿）, and fibrosis（纤维化） of all layers. Involved loops of bowel are often adherent（粘连）, and fistulas（瘘管） between such segments are frequent. These fistulas may also penetrate from the bowel into other organs（肠壁瘘管穿入其它器官）, includ

18、ing the bladder, uterus, vagina, and skin. Lesions in the distal rectum and anus may create perianal fistulas（肛旁瘘）, a well-known presenting feature.2022/10/8Microscopically, Crohn disease appears as a chronic inflammatory process. During early phases of the disease, the inflammation may be confined

19、to（局限于） the mucosa and submucosa. Small, superficial mucosal ulcerations (aphthous ulcers口疮样溃疡) are seen. Later, long, deep, fissure-like（裂隙状） ulcers are seen, and vascular hyalinization and fibrosis become apparent.The microscopic hallmark of Crohn disease is transmural, nodular, lymphoid aggregate

20、s (Fig. 13-24). Discrete（散在的）, noncaseating（非干酪样） granulomas（肉芽肿）, mostly in the submucosa, may be present. Although the presence of granulomas is strong evidence in favor of Crohn disease, less than half of the cases show these lesions. The pathologic features of Crohn disease are summarized in Fig

21、ure 13-25.2022/10/8正常的结肠粘膜组织结构Figure 13-24. 克罗恩病. 图片A显示溃疡至粘膜下层；淋巴组织聚集在粘膜下、邻近肌层和浆膜下。图片B显示粘膜活检，可见小灶上皮样肉芽肿位于两个无损的腺隐窝之间。 A. The colon involved with Crohn disease shows an area of mucosal ulceration, an expanded submucosa with lymphoid aggregates, and numerous lymphoid aggregates in the subserosal tissue

22、s immediately adjacent to the muscularis externa. B. This mucosal biopsy in Crohn disease shows a small epithelioid granuloma (arrows) between two intact crypts.2022/10/8克罗恩病的肉芽肿病变克罗恩病肉芽肿的高倍镜下观大肠腺上皮隐窝结构变形克罗恩病回肠炎下图见裂缝状溃疡逆流性回肠炎克罗恩病肠道活检H-E染色切片组织学观察箭头所示克罗恩病的透壁性炎症临床特点(Clinical Features)克罗恩病的临床表现与病史各自不同，与

23、发病部位相关 The clinical manifestations and natural history of Crohn disease are highly variable and relate to the anatomical sites involved by the disease. 最常见症状：75%病人腹痛腹泻；50%病人回归热The most frequent symptoms are abdominal pain and diarrhea, which are seen in more than 75% of patients, and recurrent fever

24、, evident in 50%. 吸收不良和营养不良；腹泻和肠出血；以直肠肛门病变为主的可反复发生肛瘘 When the small intestine is diffusely involved, malabsorption and malnutrition may be major features. Crohn disease of the colon leads to diarrhea and sometimes colonic bleeding. In a few patients, the major site of involvement is the anorectal re

25、gion, and recurrent anorectal fistulas may be the presenting sign.2022/10/8克罗恩病的继发病变肠道阻塞、瘘管和肠穿孔Intestinal obstruction and fistulas are the most common intestinal complications of Crohn disease. Occasionally, free perforation of the bowel occurs. 发生肠癌 Small bowel cancer is at least threefold more com

26、mon in patients with Crohn disease, and the disease also predisposes to colorectal cancer.No cure for Crohn disease is available. Several medications suppress the inflammatory reaction, including corticosteroids, sulfasalazine, metronidazole, 6-mercaptopurine, cyclosporine, and anti-TNF antibodies.

27、Surgical resection of obstructed areas or of severely involved portions of intestine and drainage of abscesses caused by fistulas are often required.2022/10/8克罗恩病小肠节段性病变特征模式图2022/10/8溃疡性结肠炎（ Ulcerative Colitis ） 溃疡性结肠炎（Ulcerative Colitis）是结直肠发生的慢性浅表性炎症 Ulcerative Colitis is a Chronic Superficial Inf

28、lammation of the Colon and Rectum临床表现慢性腹泻，直肠出血。是有加重和缓解，可伴有局部和全身并发症 Ulcerative colitis is characterized by chronic diarrhea and rectal bleeding, with a pattern of exacerbations and remissions and with the possibility of serious local and systemic complications.2022/10/8流行病学（Epidemiology）In Europe and

29、 North America, the incidence of ulcerative colitis is 4 to 7 per 100,000 population, and its prevalence is 40 to 80 per 100,000. It usually begins in early adult life, with a peak incidence in the third decade. However, it also occurs in childhood and old age. In the United States, whites are affec

30、ted more commonly than blacks.2022/10/8发病机制（Pathogenesis）原因不清，可能与遗传相关 The cause of ulcerative colitis is unknown. In some families as many as six patients with this disease have been described, and concordance has been reported in monozygotic twins. However, available family studies do not suggest a

31、ny distinct mode of genetic transmission.自身免疫病机制 The possibility that an abnormal immune response may be involved has been studied extensively. There is abundant lymphoid tissue throughout the colon, and ulcerative colitis may occur with autoimmune-like conditions, such as uveitis, erythema nodosum,

32、 and vasculitis. Increased circulating antibodies against antigens in colonic epithelial cells and against cross-reacting antigens in enterobacteria may occur. Antineutrophil cytoplasmic antibodies are found in 80% of patients with ulcerative colitis. However, these abnormalities are neither unique

33、for ulcerative colitis, nor are they a prerequisite for the development of the disease.2022/10/8病理变化（Pathology）Ulcerative colitis is a diffuse disease. It usually extends from the most distal part of the rectum（远端直肠） for a variable distance proximally (Fig. 13-26). Sparing of the rectum or involveme

34、nt of the right side of the colon alone is rare and suggests the possibility of another disorder, such as Crohn disease.Inflammation in ulcerative colitis is generally limited to the colon and rectum. It rarely involves the small intestine, stomach, or esophagus.Ulcerative colitis is essentially a m

35、ucosal disease. Deeper layers are uncommonly involved, mainly in fulminant cases and usually in association with toxic megacolon.2022/10/8三大主要病变Three major pathologic features characterize ulcerative colitis and help to differentiate it from other inflammatory conditions:Figure 13-26. Ulcerative col

36、itis. Prominent erythema and ulceration of the colon begin in the ascending colon and are most severe in the rectosigmoid area.2022/10/8The following morphologic sequence may develop rapidly or over a course of years.EARLY COLITIS: Early in the evolution of the disease, the mucosal surface is raw, r

37、ed, and granular. It is frequently covered with a yellowish exudate and bleeds easily. Later small, superficial erosions or ulcers may appear. These occasionally coalesce to form irregular, shallow, ulcerated areas that appear to surround islands of intact mucosa.The microscopic features of early ul

38、cerative colitis include (1) mucosal congestion, edema, and microscopic hemorrhages; (2) a diffuse chronic inflammatory infiltrate in the lamina propria; and (3) damage and distortion of the colorectal crypts, which are often surrounded and infiltrated by neutrophils. Suppurative necrosis of the cry

39、pt epithelium gives rise to the characteristic crypt abscess, which appears as a dilated crypt filled with neutrophils (Fig. 13-27).2022/10/8Figure 13-27. Ulcerative colitis. A. A full-thickness section of colon resected for ulcerative colitis shows inflammation affecting the mucosa with sparing of

40、the submucosa and muscularis propria. B. Sections of a mucosal biopsy from a patient with active ulcerative colitis show expansion of the lamina propria and several crypt abscesses (arrows). C. Chronic ulcerative colitis shows significant crypt distortion and atrophy.2022/10/8PROGRESSIVE COLITIS: As

41、 the disease continues, mucosal folds are lost. Lateral extension and coalescence of crypt abscesses can undermine the mucosa, leaving areas of ulceration adjacent to hanging fragments of mucosa. Such mucosal excrescences are termed inflammatory polyps. Granulation tissue develops in denuded areas.

42、Importantly, the strictures characteristic of Crohn disease are absent. Microscopically, colorectal crypts may appear tortuous, branched, and shortened in the late stages, and the mucosa may be diffusely atrophic.2022/10/8ADVANCED COLITIS: In long-standing cases, the large bowel is often shortened,

43、especially in the left side. Mucosal folds are indistinct and are replaced by a granular or smooth mucosal pattern. Microscopically, advanced ulcerative colitis is characterized by mucosal atrophy and a chronic inflammatory infiltrate in the mucosa and superficial submucosa. Paneth metaplasia is com

44、mon.2022/10/8Clinical FeaturesThe clinical course and manifestations are very variable. Most patients (70%) have intermittent attacks, with partial or complete remission between attacks. A small number (10%) have a very long remission (several years) after their first attack. The remaining 20% have

45、continuous symptoms without remission.2022/10/8MILD COLITIS: Half of patients with ulcerative colitis have mild disease. Their major symptom is rectal bleeding, sometimes accompanied by tenesmus (rectal pressure and discomfort). The disease in these patients is usually limited to the rectum but may

46、extend to the distal sigmoid colon. Extraintestinal complications are uncommon, and in most patients in this category, disease remains mild throughout their lives.2022/10/8MODERATE COLITIS: About 40% of patients have moderate ulcerative colitis. They usually have recurrent episodes of loose bloody s

47、tools, crampy abdominal pain, and frequently low-grade fever, lasting days or weeks. Moderate anemia is a common result of chronic fecal blood loss.2022/10/8SEVERE COLITIS: About 10% of patients have severe or fulminant ulcerative colitis, often during a flare of activity. They may have more than 6

48、and sometimes more than 20 bloody bowel movements daily, often with fever and other systemic manifestations. Blood and fluid loss rapidly leads to anemia, dehydration, and electrolyte depletion. Massive hemorrhage may be life-threatening. A particularly dangerous complication is toxic megacolon, whi

49、ch is characterized by extreme dilation of the colon and an associated high risk for perforation. Fulminant ulcerative colitis is a medical emergency requiring immediate, intensive medical therapy, and, in some cases, prompt colectomy. About 15% of patients with fulminant ulcerative colitis die of t

50、he disease.2022/10/8The distinction between ulcerative colitis and Crohn colitis is based on different anatomical localization and histopathology (Table 13-1). The medical treatment of ulcerative colitis depends on the sites involved and the severity of the inflammation. The 5-aminosalicylate鈥揵ased

51、compounds are the mainstays of treatment for patients with mild-to-moderate ulcerative colitis. Corticosteroids and immunosuppressive and immunoregulatory agents (azathioprine or mercaptopurine) are used in patients who have severe and refractory disease.2022/10/8Extraintestinal ManifestationsArthri

52、tis is seen in 25% of patients with ulcerative colitis. Eye inflammation (mostly uveitis) and skin lesions develop in about 10%. The most common cutaneous lesions are erythema nodosum and pyoderma gangrenosum; the latter is a serious, noninfective disorder characterized by deep, purulent, necrotic u

53、lcers in the skin. Liver disease occurs in about 4% of patients, most commonly primary sclerosing cholangitis. Thromboembolic phenomena, usually deep vein thromboses of the lower extremities, occur in 6% of ulcerative colitis patients.2022/10/8Ulcerative Colitis and Colorectal CancerPeople with long

54、-standing ulcerative colitis have a higher risk of colorectal cancer than the general population. Colorectal epithelial dysplasia is a neoplastic epithelial proliferation and precursor to colorectal carcinoma in patients with long-term ulcerative colitis. High-grade epithelial dysplasia reflects a s

55、ignificant risk for the development of colorectal cancer, and when identified in a biopsy, it is a strong indication for colectomy.2022/10/8TABLE 13-1 Comparison of the Pathologic Features in the Colon of Crohn Disease and Ulcerative Colitis2022/10/8LesionCrohn DiseaseUlcerative ColitisMacroscopIcTh

56、ickened bowel wallTypicalUncommonLuminal narrowingTypicalUncommon透壁性 lesionsCommonAbsentRight colon predominanceTypicalAbsentFissures and fistulasCommonAbsentCircumscribed ulcersCommonAbsentConfluent linear ulcersCommonAbsentPseudopolypsAbsentCommonMICROSCOPIcTransmural inflammationTypicalUncommonSu

57、bmucosal fibrosisTypicalAbsentFissuresTypicalRareGranulomasCommonAbsentCrypt abscessesUncommonTypicalSUMMARYCrohn disease and ulcerative colitis are idiopathic inflammatory bowel diseases believed to result from abnormal local immune responses against unknown microbes and/or self antigens in the Crohn disease Associated with HLA-DR7 and -DQ4 alleles, and wi