Ulcerative colitis

Japanese: 潰瘍性大腸炎

Concept : A diffuse, nonspecific inflammatory disease of the large intestine of unknown cause, characterized by a chronic, recurrent course. Inflammation occurs primarily in the mucosa, and spreads continuously from the rectum to various areas of the oral side of the large intestine. Together with Crohn's disease, it is referred to as inflammatory bowel disease (IBD) in the narrow sense.
Classification ① Classification by clinical severity (Table 8-5-7) This is important in determining the treatment plan described below. ② Classification by disease type according to the extent of the lesion (Table 8-5-8) ③ Disease stage classification (Table 8-5-9) ④ Classification by endoscopic findings in the active stage (Table 8-5-10)
Etiology The etiology of inflammatory bowel disease has yet to be elucidated, but in recent years it has been suggested that inflammatory bowel disease develops in patients with a genetic predisposition due to an abnormal and excessive immune response to antigens such as enterobacteria. Genome-wide correlation analysis has revealed many susceptibility genes common to both inflammatory bowel disease and Crohn's disease, demonstrating that inflammatory bowel disease is a multifactorial disease. In addition, some of these candidate susceptibility genes have been found to be related to specific functions, such as abnormalities in the gastrointestinal epithelial barrier in ulcerative colitis. Epidemiological studies have identified several environmental factors that trigger the onset of inflammatory bowel disease, and smoking has been shown to have a suppressive effect on the onset of the disease (while in Crohn's disease, it is thought to be a trigger or exacerbating factor for the onset of the disease). In addition, a history of appendectomy before the age of 20 has a suppressive effect on the onset of the disease.
Epidemiology: This disease is designated as one of the specific diseases by the Ministry of Health, Labor and Welfare, and as of the end of fiscal year 2010, the total number of people with medical benefit certificates and registration certificates was 12,600. There is no gender difference, with a male to female ratio of 1:1. The peak age of onset is between 25 and 29 years old, but onset in children and the elderly is not uncommon, and it must always be kept in mind when making a differential diagnosis of diarrhea and bloody stool.
Overseas, the incidence and prevalence of this disease is higher in North America and Europe than in Japan, while it is considered a rare disease in so-called developing countries. Traditionally, it was thought that the incidence rate was higher the further north you went in Europe, but in recent years, this difference seems to be disappearing.
Pathological findings of the colonic mucosa include irregularity, a decrease in number, and distortion of crypts, which suggest their destruction and subsequent regeneration, an increase in the distance between the crypt base and the muscularis mucosae, and Paneth cell metaplasia. In addition, plasma cells and lymphocytic infiltration in the base, which are signs of chronic inflammation, are observed (Figure 8-5-20). These findings are rare in acute infectious enteritis. In cases of active inflammation, neutrophil infiltration and crypt abscesses (an image in which the lumen of the crypt glandular ducts is filled with neutrophils) are observed, but these are not disease-specific findings as they can also be seen in Crohn's disease and infectious enteritis. Ulcers are usually shallow, and deep ulcers that penetrate the muscularis mucosae are usually only observed in severe cases.
In this disease, these findings are observed continuously from the rectum, so when taking biopsy specimens during lower gastrointestinal endoscopy, it is important to take specimens from all areas of the large intestine, including the rectum, even if the endoscopic findings appear normal.
Clinical manifestations
1) Symptoms : The typical symptoms are bloody mucus in the stool and diarrhea, but sometimes the stool is not present, and it is not uncommon for patients with proctitis to complain of constipation. Although the disease may develop acutely, chronic or recurrent symptoms of bloody mucus in the stool and diarrhea should be suspected. Nocturnal diarrhea is rarely seen in irritable bowel syndrome, which is a strong reason to suspect this disease. Even if the patient does not complain of it, it is not uncommon for fecal leakage to significantly impair the patient's quality of life. Patients who also experience abdominal pain will experience pain associated with spasms, especially during defecation, and in severe cases, persistent abdominal pain. When the range of the disease becomes widespread, systemic symptoms such as fever, fatigue, and weight loss will appear. In addition, pain due to oral aphthae, joint pain, and skin rashes may appear, especially during the active stage.
2) Objective symptoms:
Symptoms such as fever, tachycardia, and anemia are seen in severe cases. Attention should also be paid to extraintestinal complications such as oral aphthae, arthritis, and skin rashes (erythema nodosum, pyoderma gangrenosum, etc.). In terms of abdominal findings, in severe cases, tenderness may be observed in the colon. In addition to intestinal dilation, if intestinal peristalsis sounds are absent or weakened, megacolon should be suspected. Furthermore, widespread abdominal tenderness and muscular guarding should be suspected as large intestinal perforation. In particular, caution is required during steroid treatment, as strong abdominal findings may not be observed.
Test results
1) Stool (culture) test:
At the time of initial onset, this test is essential to differentiate from infectious enteritis caused by Campylobacter, Salmonella, etc. However, during the course of ulcerative colitis, Clostridium difficile enteritis may occur, and in the event of an acute exacerbation, anaerobic culture of stool and CD toxin testing are performed.
2) General blood tests:
In severe cases, anemia and elevated erythrocyte sedimentation rate are observed. In mild or moderate cases, blood test results may not show abnormalities, so normal blood test results are not a reason to exclude the diagnosis.
3) Lower gastrointestinal endoscopy:
This is an essential test for diagnosing this disease. In the active stage, the mucosa is diffusely damaged, and the vascular image that is normally observed is weakened or disappears, and appears coarse or fine granular. Mucous and purulent secretions are attached, and bleeding occurs from contact bleeding, and in severe cases, spontaneous bleeding occurs. In severe cases, extensive ulcers are observed, which may run longitudinally, making it important to differentiate this from Crohn's disease (Figures 8-5-21 and 8-5-22). In addition, endoscopic severity and clinical severity may differ, but the treatment plan described below is basically determined by clinical severity. Since the extent of the disease is determined by endoscopic findings, it is necessary to observe the entire colon, but in severe cases, full colonoscopy carries the risk of perforation, and from the perspective of diagnosis and evaluation of the disease, the scope should not be inserted too deeply.
4) Plain abdominal X-ray:
Although its diagnostic value is not necessarily high, it can be useful in diagnosing complications such as megacolon and colonic perforation.
5) Barium enema X-ray examination:
It is being performed less and less for diagnostic purposes.
DiagnosisIn Japan, diagnostic criteria were created by the "Study Study on Refractory Inflammatory Bowel Disorders" group of the Ministry of Health, Labor and Welfare (at the time). Basically, a diagnosis is made comprehensively based on clinical symptoms, imaging tests centered on endoscopic examinations, and pathological tests such as biopsy tissue (Table 8-5-11). Attention should also be paid to the "Diseases to be excluded" in the margin.
Differential diagnosis: Differentiation from Crohn's disease (colon type) can be difficult. Few smokers have this disease, and its onset after smoking cessation suggests this disease. Generally, bloody stools are rare in Crohn's disease, and Crohn's disease is suggested in patients with a normal rectum. Although intractable anal fistulas are characteristic of Crohn's disease, anal lesions are not uncommon in this disease. If non-caseating epithelioid cell granulomas are found pathologically, Crohn's disease is diagnosed. In patients with chronic progression of bloody mucus in the stool, it is important to differentiate from amebic dysentery. In recent years, the number of female patients has been increasing, and this must be kept in mind when diagnosing this disease. In terms of differentiation from irritable bowel syndrome, in patients with chronic diarrhea, nocturnal bowel movements, bloody stools, anemia, and weight loss are indicative of inflammatory bowel disease, and colonoscopy should be actively performed.
complications
1) Intestinal complications:
a) Toxic megacolon: This condition is accompanied by severe systemic symptoms such as fever, tachycardia, and impaired consciousness, as well as colonic dilatation (transverse colon diameter exceeds 6 cm on X-ray). There is a high risk of perforation, and emergency surgery is indicated. In severe cases, the administration of antidiarrheal drugs may precipitate the onset of the disease.
b) Stenosis: Stenosis can occur not only in Crohn's disease, but also in cases of long-term ulcerative colitis, and must be differentiated from malignant stenosis. Since this makes surveillance for colon cancer, which will be described later, difficult, surgery must be considered even if there are no symptoms.
c) Colitic cancer: Patients with ulcerative colitis, except for those with proctitis, are at high risk for developing colorectal cancer. Known risk factors include 1) long duration of disease, 2) widespread extent of disease, 3) family history of colorectal cancer, 4) severe inflammation, and 5) coexistence with primary sclerosing cholangitis. Early diagnosis based on symptoms and fecal occult blood testing is difficult, so in cases of left-sided colitis and pancolitis, surveillance for colorectal cancer (pancolonoscopy) is recommended once the disease has lasted seven years, especially in patients with left-sided colitis and pancolitis. When biopsy is performed, attention should be paid to (flat) elevated lesions, and biopsy should be performed proactively using chromoendoscopy and other techniques. Blind biopsy is recommended in Europe and the United States. Studies in Japan have also shown that the incidence of colorectal cancer exceeds 10% within 20 years of onset of the disease.
2) Extraintestinal complications:
Some complications are related to intestinal lesions, while others are unrelated to intestinal lesions (in some cases, after total colectomy). The main complications are joint complications (peripheral arthritis, sacroiliac joint inflammation, ankylosing spondylitis), skin complications (erythema nodosum, pyoderma gangrenosum, etc.), eye complications (uveitis, etc.), and hepatobiliary complications (primary sclerosing cholangitis, etc.). Not only do these complications occur during the course of the disease, but it is not uncommon for these complications to be the trigger for the diagnosis of this disease.
prognosis
1) Prognosis:
The prognosis for ulcerative colitis is thought to be roughly the same as that of healthy individuals. However, in severe cases involving elderly patients, death is not uncommon, and care must be taken not to delay the timing of surgery.
2) Surgery rate:
The cumulative surgical rate for this disease is determined by the severity of the disease at onset and the affected area. In severe cases at onset, approximately half of patients require surgery within 10 years.
Treatment
1) Treatment principles:
Treatment for this disease is determined by factors such as the clinical severity, the extent of the disease visible on endoscopic examination, and the course of treatment to date. It is also necessary to consider induction therapy during the active phase and maintenance therapy during the remission phase separately. There have been significant advances in the medical treatment of this disease, and in difficult cases in particular, it is advisable to receive treatment at a facility with extensive experience.
2) Internal medicine treatment (Table 8-5-12):
Induction of remission in mild and moderate cases involves the oral or local administration (enema or suppository) of aminosalicylic acid preparations (mesalazine, salazosulfapyridine), or a combination of both. In severe cases or in cases where these treatments do not improve the condition, corticosteroids are administered orally or intravenously. Treatment for steroid-resistant cases that do not respond to steroid therapy includes cytapheresis, anti-TNF-α receptor antagonists (infliximab), or immunosuppressants such as tacrolimus and cyclosporine. On the other hand, in cases of relapse after reducing or ceasing steroids (steroid-dependent cases), immunomodulators such as azathioprine and 6-mercaptopurine are useful for maintaining remission and weaning patients off steroids. Long-term administration of steroids, even in small doses, is not recommended from a safety perspective.
3) Surgical treatment:
Emergency surgery is indicated in cases of perforation, massive bleeding, and severe cases in which medical treatment is ineffective. Surgical operations may also be performed in cases where medical treatment is unresponsive or intolerant, or for complications such as stenosis, colon cancer, or dysplasia. For elective surgery, total colectomy and ileocystoanal (tube) anastomosis are the standard procedures. In emergency cases, subtotal colectomy, "ileostomy/sigmoid mucous fistula creation," or Hartmann's operation may also be performed. [Nagahori Masakazu and Watanabe Mamoru]
■ References <br /> Research Group on Refractory Inflammatory Bowel Disorders (Watanabe Group): IBD at a Glance - For doctors treating inflammatory bowel diseases, created in October 2010. Research Group on Refractory Inflammatory Bowel Diseases (Watanabe Group): Ulcerative colitis and Crohn's disease treatment guidelines for 2010, supplementary volume of 2010 shared research report.

Table 8-5-7
Clinical Severity

Table 8-5-7

Table 8-5-8
Classification by extent of disease

Table 8-5-8

Table 8-5-9
Stage Classification

Table 8-5-9

Table 8-5-10
Classification by endoscopic findings in the active stage ">

Table 8-5-10

Table 8-5-11
Diagnostic Criteria for Ulcerative Colitis ">

Table 8-5-11

Table 8-5-12
Guidelines for the medical treatment of ulcerative colitis ">

Table 8-5-12

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

概念
　原因不明の大腸のびまん性非特異性炎症性疾患であり，慢性・再発性の経過を特徴とする．炎症は主として粘膜に生じ，直腸からさまざまな範囲で連続性に大腸の口側に進展する．Crohn病と合わせて狭義の炎症性腸疾患（inflammatory bowel disease：IBD）とよばれる．
分類
①臨床的重症度による分類（表8-5-7）　後述の治療方針を決める上で重要である．②病変の広がりによる病型分類（表8-5-8）③病期分類（表8-5-9）④活動期内視鏡所見による分類（表8-5-10）
病因
　炎症性腸疾患の病因はいまだ解明されていないが，近年では遺伝的素因をもつ患者に腸内細菌などの抗原に対する異常で過剰な免疫反応が生じて，発症すると考えられている．全ゲノム相関解析の結果から本症，Crohn病および両疾患共通の多くの感受性遺伝子が明らかとなり，炎症性腸疾患が多因子疾患であることが明らかになった．また，これらの感受性候補遺伝子のいくつかは，潰瘍性大腸炎における消化管上皮バリア異常など，ある特定の機能に関連した遺伝子であることが明らかになっている．疫学研究から，発症の誘因となるいくつかの環境因子が同定されているが，喫煙は発病に対して抑制的に働くことがわかっている（一方，Crohn病では発病の誘因または増悪因子と考えられている）．また，20歳未満における虫垂切除の既往は発病に対して抑制的に働く．
疫学
　本症は厚生労働省の指定する特定疾患の1つであるが，平成22年度末の時点で，医療受給者証および登録者証保持者数の合計は12600人に上っている．男女比は1：1で性差はない．発症年齢のピークは25から29歳にあるが，小児や高齢者の発症もまれとはいえず，下痢，下血の鑑別診断では常に念頭におく必要がある．
　海外では，北米・ヨーロッパはわが国以上に罹患率，有病率は高く，一方，いわゆる開発途上国ではまれな疾患とされている．従来，ヨーロッパでは北に行くほど罹患率が高いとされていたが，近年，その差はなくなりつつあるようである．
病理
　大腸粘膜の病理所見としては，陰窩の破壊とその後の再生を示唆する陰窩の不整・数の減少・歪み，陰窩底と粘膜筋板間の距離の増大，Paneth細胞化生が認められる．また，慢性炎症の所見である基底部の形質細胞，リンパ球浸潤が認められる（図8-5-20）．これらの所見は急性の感染性腸炎ではまれである．活動性の炎症がある場合，好中球の浸潤，陰窩膿瘍（crypt abscess：陰窩の腺管内腔に好中球が充満している像）が認められるが，これらはCrohn病や感染性腸炎でも認められることがあるため，疾患特異的な所見ではない．潰瘍は通常は浅く，粘膜筋板を貫通するような深い潰瘍が認められるのは，通常重症例のみである．
　本症ではこれらの所見が直腸から連続性に認められるため，下部消化管内視鏡検査にて生検検体を採取する際には，内視鏡所見が正常にみえる場合でも，直腸を含めた大腸各領域から検体を採取することが重要である．
臨床症状
1）自覚症状
：典型的な症状は粘血便・下痢であるが，血便を認めないこともあり，また，特に直腸炎型の患者では便秘を訴える患者もまれではない．急性発症の経過をとることもあるが，粘血便や下痢を，慢性または再発性に認めた場合に本症が疑われる．夜間の下痢は過敏性腸症候群では認められることは少なく，本症を強く疑う理由となる．また，患者からの訴えがなくとも，漏便が患者のQOLを大きく損ねていることもまれではない．腹痛も認める患者では，特に排便時の攣縮に伴う痛みのほか，重症例では持続的な腹痛を認める．罹患範囲が広範になると，発熱，倦怠感，体重減少などの全身症状が認められるようになる．また，特に活動期では，口腔内アフタによる疼痛，関節痛，皮疹などが出現することがある．
2）他覚症状：
発熱，頻脈，貧血などの所見は重症例での所見である．口腔内アフタ，関節炎，皮疹（結節性紅斑，壊疽性膿皮症など）などの腸管外合併症の所見にも注意を払う必要がある．腹部所見であるが，重症例では，結腸に一致して圧痛を認めることがある．腸管の拡張に加え，腸蠕動音が消失・減弱している場合は巨大結腸症を疑う必要がある．また，広範な腹部の圧痛や筋性防御は大腸穿孔を疑う必要がある．特に，ステロイド治療中では，強い腹部所見が認められないことがあり，注意が必要である．
検査成績
1）便（培養）検査：
初発時にはカンピロバクター菌やサルモネラ菌などによる感染性腸炎との鑑別のため必須の検査である．一方，潰瘍性大腸炎経過中にClostridium difficile腸炎を合併することがあり，急性増悪時には，便の嫌気培養やCDトキシンの検査を行う．
2）一般血液検査：
重症例では貧血や赤沈の亢進を認める．一方，軽症または中等症例では，血液検査の異常は認められないこともあるため，血液検査が正常でも本症を除外する理由とはならない．
3）下部消化管内視鏡検査：
本症の診断に必須の検査である．活動期では，粘膜はびまん性に障害され，正常では認められる血管像は減弱・消失し，粗造または細顆粒状を呈する．粘血膿性の分泌物が付着し，出血は接触出血から，重症例では自然出血を認める．また，重症例では広範な潰瘍を認め，縦走することもあり，Crohn病との鑑別が重要である（図8-5-21，図8-5-22）．また，内視鏡的重症度と臨床的重症度は乖離することがあるが，後述する治療方針は基本的には臨床的重症度にて決定される．罹患範囲は内視鏡所見をもって決定されるため，全大腸の観察が必要となるが，重症例における全大腸内視鏡検査は穿孔などのリスクもあり，診断や病勢の評価という点からも，無理に深部へのスコープの挿入はすべきでない．
4）腹部単純X線写真：
診断における有用性は必ずしも高くないが，巨大結腸症や大腸穿孔などの合併症の診断には有用なことがある．
5）注腸X線検査：
診断のために行われる機会は減ってきている．
診断
　わが国では，厚生省（当時）「難治性炎症性腸管障害に関する調査研究」班により診断基準が作成されている．基本的には臨床症状，内視鏡検査を中心とした画像検査，生検組織などの病理学的検査により総合的に診断する（表8-5-11）．欄外にある「除外すべき疾患」についても注意が必要である．
鑑別診断
　Crohn病（大腸型）との鑑別が困難なことがある．本症に喫煙者は少なく，禁煙後の発症は本症を示唆する．一般的にCrohn病では，血便はまれであり，また，直腸が正常な例ではCrohn病が示唆される．難治性痔瘻はCrohn病に特徴的だが，本症でも肛門病変はまれではない．病理学的に非乾酪性類上皮細胞肉芽腫が認められればCrohn病と診断される．　慢性の経過で粘血便を認める患者ではアメーバ赤痢との鑑別が重要である．近年は女性患者の増加も指摘されており，本症診断時に念頭においておく必要がある．　過敏性腸症候群との鑑別であるが，慢性下痢症の患者で，夜間の排便，血便のほか，貧血，体重減少などは炎症性腸疾患を示唆しており，積極的に大腸内視鏡検査を行う．
合併症
1）腸管合併症：
　a）中毒性巨大結腸症：発熱，頻脈，意識障害などの重篤な全身症状と結腸の拡張（X線写真にて横行結腸径が６ cmをこえる）を伴い，穿孔のリスクが高く，緊急手術の適応である．重症例における止痢薬の投与が発病の誘因となることがある．
　b）狭窄：Crohn病だけでなく，潰瘍性大腸炎の長期経過例では狭窄をきたすことがあり，悪性狭窄との鑑別を要する．後述の大腸癌のサーベイランスが困難となるため，症状がなくとも手術を考えなくてはならない．
　c）colitic cancer：直腸炎型の患者を除く潰瘍性大腸炎患者は大腸癌発病のハイリスク群である．危険因子としては①罹病期間が長い，②罹患範囲が広範，③大腸癌の家族歴，④炎症が強い，⑤原発性硬化性胆管炎合併などが知られている．症状や便潜血反応検査で早期に診断することは困難であるため，左側大腸炎および全大腸炎型の症例では特に罹病期間が7年を経過した時点で，以降，１〜２年に１回の大腸癌のサーベイランス（全大腸内視鏡検査）が望ましい．生検時には（平坦）隆起性病変に注意し，色素内視鏡検査などを併用し，積極的に生検検査を行う．欧米では盲目的生検が勧められている．わが国における検討でも発病20年では大腸癌の合併が10%をこえるとされている．
2）腸管外合併症：
腸管病変に関連して合併するものと，腸管病変とは無関係に（場合によっては，大腸全摘後に）合併するものとがある．おもなものとして，関節合併症（末梢関節炎，仙腸関節炎，強直性脊椎炎），皮膚合併症（結節性紅斑，壊疽性膿皮症など），眼合併症（ブドウ膜炎など），肝胆道系合併症（原発性硬化性胆管炎など）がある．経過中に合併するだけでなく，これらの合併症が本症診断のきっかけとなることもまれではない．
予後
1）生命予後：
潰瘍性大腸炎の生命予後は健常人とほぼ同等と考えられている．しかし，高齢発症の重症例などでは死亡例もまれではなく，手術のタイミングが遅れないよう注意が必要である．
2）手術率：
本症における累積手術率は，発病時の重症度と罹患部位によって決定されるとされている．発症時重症例では，10年の経過で約半分の患者が手術を必要とする．
治療
1）治療原則：
本症の治療は，臨床的重症度，内視鏡検査における肉眼的罹患範囲，これまでの治療経過などによって決定される．また，活動期における寛解導入療法と，寛解期における寛解維持療法も分けて考える必要がある．本症の内科治療の進歩は著しく，特に難治例においては，治療経験豊富な施設での治療が望ましい．
2）内科治療（表8-5-12）：
軽症および中等症の寛解導入療法としては，アミノサリチル酸製剤（メサラジン，サラゾスルファピリジン）の内服または局所投与（注腸剤または坐薬）または両者の併用が行われる．これらの治療で改善しない場合や重症例では，副腎皮質ステロイド薬の内服や静脈投与が行われる．ステロイド治療に反応しないステロイド抵抗例への治療としては，血球成分除去療法，抗TNF-α受容体拮抗薬（インフリキシマブ），あるいは，タクロリムス，シクロスポリンなどの免疫抑制薬の治療が行われる．一方，ステロイド薬減量や中止後の再燃例（ステロイド依存例）にはアザチオプリンや６-メルカプトプリンなどの免疫調節薬が，寛解維持およびステロイド薬からの離脱に有用である．ステロイド薬の長期投与は少量であっても，安全性の面から勧められない．
3）外科治療：
穿孔，大量出血のほか，内科治療が無効な重症例などが緊急手術の適応となる．内科治療不応または不耐例，狭窄や大腸癌または異形成などの合併症に対して外科手術が行われることもある．待期手術では大腸全摘，回腸囊肛門（管）吻合術が標準手術である．また，緊急時には結腸亜全摘，「回腸人工肛門・Ｓ状結腸粘液瘻造設術」，またはHartmann手術が行われることもある．［長堀正和・渡辺　守］
■文献
難治性炎症性腸管障害に関する調査研究班（渡辺班）：一目でわかるIBD 炎症性腸疾患を診察されている先生方へ，2010年10月作成．難治性炎症性腸管病害に関する調査研究班（渡辺班）：潰瘍性大腸炎・クローン病平成22年度治療指針，平成22年度分担研究報告書別冊．

表8-5-7
臨床的重症度">

表8-5-7

表8-5-8
罹患範囲による分類">

表8-5-8

表8-5-9
病期による分類">

表8-5-9

表8-5-10
活動期の内視鏡所見による分類">

表8-5-10

表8-5-11
潰瘍性大腸炎診断基準">

表8-5-11

表8-5-12
潰瘍性大腸炎の内科治療指針">

表8-5-12