潰瘍性大腸炎に関する2，3の一般的観察

SOME GENERAL OBSERVATIONS ON ULCERATIVE COLITIS

　潰瘍性大腸炎は直腸出血，下痢，腹痛，発熱，食欲不振と体重減少を特徴とする直腸と結腸の急性ならびに慢性の炎症性潰瘍性疾患である．直腸S状結腸鏡所見では，浮腫，充血，うっ血およびビマン性斑点状潰瘍と血膿性分泌物を伴う粘膜の易出血がみられる．組織学的には多型核細胞にリンパ球，単核球およびプラズマ細胞が加わった組織反応が認められる．陰窩膿瘍（Crypt Abscesses）もしばしばみられるが．この疾患に特有なものではない．病変は粘膜層と粘膜一ド層に始まり，最も著明であるが，全腸壁を侵すこともある．レ線的特徴は直腸と結腸の膨張性の減少，微小ulcerationsを示す辺縁の”のこぎり歯状の切れ込み”，結腸の正常なHaustra形成の喪失，腸の狭窄と短縮ならびに粘膜パタンの偽ポリープ様変化である．X線でみると，少なくとも50％の患者では全大腸がおかされ，45％に結腸のいろいろの部分の変化がみられ，ほぼ5％には病変は認められない．これはおそらく経過の軽いためであろう．

　発病は軽くて直腸出血が唯一の症状である場合もあるが，ときには急激で，発熱，毒血症，激しい下痢，血液，電解質および液体の著明な喪失を伴うこともある．潰瘍性大腸炎の経過はいろいろで，長期の症状緩解もあリ，度々の一時的悪化もみられ，あるいは持続的な進行性疾患になることもある．再発は最初の病変，の解剖的な広さの範囲以内にしばしば現われ（例えば下行結腸，S状結腸および直腸），臨床的に病状が再び活動的になっても解剖学的にそれ以上進行しないという事実は興味のあることである．再発はしばしば感情的緊張，上気管道感染および他のいろいろな疾患，肉体的疲労，食餌の下摂生，抗生物質や下剤の使用，手術，女性の場合はまた月経などに伴っておきる．このように“triggering”（誘発因子となる）事情は多種多様であり，すべての困難な黙生活状況”を含んでいる．潰瘍性大腸炎は局部と全身の合併症をもつ疾患である．結腸の合併症は出血，結腸周囲炎，穿孔，腹膜炎，狭窄，閉塞，中毒性拡張および結腸癌の頻度の増加などである．全身的には貧血，低蛋白血症，関節炎，強直性背椎炎，仙腸骨炎，結節性紅斑，壊疸性濃皮症，虹彩炎，血管血栓症，血小板増加症，脂肪肝，肝炎，胆管周囲炎および胆汁性肝硬変，腎孟腎炎，腎石症，膵と副腎の炎症性変化および軽度の性格異常，精神分裂症，急性精神異常，麻薬常習および自殺の企てなど感情的な問題も合併症に含まれている．

　Ulcerative colitis is an acute and chronic inflammatory and ulcerative disease of the rectum and colon, characterized by rectal bleeding, diarrhea, abdominal pain, fever, anorexia and weight loss. The proctosigmoidoscopic findings include edema, hyperemia, congestion and easy bleeding of the mucosa, with diffuse punctate ulcerations and sanguinopurulent discharge. Histologically, the tissue reaction includes lymphocytes, mononuclear cells and plasma cells, in addition to polymorphonuclear cells. Crypt abscesses are observed frequently but are not specific for this disease. The changes begin and are most pronounced in the mucosa and submucosa but may involve the entire bowel wall. The roentgenologic features include decreased distensability of the rectum and colon, marginal serration reflecting minute ulcerations, loss of the normal haustrations of the colon, narrowing and shortening of the bowel and pseudopolypoid alteration of the mucosal pattern. The entire large bowel, as viewed by x-ray, is involved in at least 50% of patients; varying portions of the colon are affected in 45%; and in approximately 5 % there are no discernable changes, presumably because of the mildness of the process.

　The onset may be mild with slight rectal bleeding as the sole manifestation; or it may be abrupt and severe, with fever, toxemia, intense diarrhea, pronounced loss of blood, electrolytes and fluid. The course of ulcerative colitis varies, with long periods of remission, frequent bouts of activity, or continuously active disease. Of interest is the fact that the recurrences often develop within the initial anatomic extent of the disease (e.g. descending colon, sigmoid and rectum) without further anatomic progression of the disease despite renewed clinical activity. The recurrences often are associated with emotional tension, upper respiratory infections and other illnesses, physical fatigue, dietary indiscretions, the use of antibiotics and cathartics, operations and, in women, with the menses; the “triggering” circumstances are numerous and varied, encompassing all difficult “life situations”. Ulcerative colitis is a disease of complications, local and general. In the colon, they include hemorrhage, pericolitis, perforation, peritonitis, stricture, obsrtuction, toxic dilatation, and an increased incidence of colon carcinoma. Systemically, they include anemia, hypoproteinemia, arthritis, ankylosing spondylitis, sacro-iliitis, erythema nodosum, pyoderma gangrenosum, iritis, vascular thromboses, thrombocytosis, fatty liver, hepatitis, pericholagitis, and biliary-type cirrhosis of the liver, pyelonephritis, nephrolithiasis, inflanma tory changes in the pancreas and adrenal glands, and emotional problems including personality disorders, schizophrenia, acute psychosis, narcotic addiction and suicidal attempts.

　The cause of ulcerative colitis remains obscure despite continuing interest in the problem. The many theories include infection (bacteria, viruses, fungi), a Shwartzman-like phenomenon involving gram-negative bacterial endotoxins present within the bowel; the cytolytic action of proteolytic and mucolytic enzymes; vascular insufficiency of the rnicrocirculation of the colon; alteration in colonic ground substance; psychogenic and neurogenically-mediated mechanisms perhaps involving the motor activity or vasculature of the colon and intracellular enzyme systems; allergy to foods and inhalants; and abnormalities of the colonic epithelium and colonic mucus leading to primary or secondary immunological phenomena. However, the formulation of these concepts remains vague and decisive supporting evidence is lacking. The frequency of ulcerative colitis among children and young people suggests mechanisms involving tissue hyper-reactivity. We have been intrigued for many years with the multiple family occurrences of ulcerative colitis and also with the unique vulnerability of some individuals to the disease. The onset of the disease not infrequently is in one member of a family or a group of individuals all exposed to acute food poisoning or other enteric infection; or after the use of antibiotics prescribed for a respiratory illness and other non-gastrointestinal disorders. On the basis of this experience, we have emphasized a concept of individual vulnerability to ulcerative colitis, probably genetically influenced though not excluding other determinants; expressed in a tissue hyper-responsive; ness to various “trigger circumstances”, such as those enumerated for the recurrences of the disease. The genetic pattern probably reflects a polygenic inheritance with the interaction of several genes. Perhaps it is in this latent state of individual vulnerability or “disease-readiness” that emotional stress plays its most significant role. Possibly in this setting also “auto-immune” factors are most important. Of added interest is that while family members tend to develop the same inflammatory bowel disease as the propositus (e.g. ulcerative colitis or regional enteritis), these two types of bowel disease and so-called.ileocolit-is are intermingled among family members sufiiciently often as to suggest an etiological interrelationship. The higher incidence of ulcerative colitis among Jewish patients and among individuals of comparatively higher socioeconomic groups also is noteworthy, although the disease is found among all ethnic groups and among people of varying occupational, economic and social status.

　The possible involvement of allergy e.g., sensitivity to milk, was suggested by Andresen in 1924. Whereas occasional patients benefit clinically from the elimination of milk or other suspected allergenic foods from the diet, many patients are uninfluenced by this maneuver. The possible role of immunologic or auto-immune phenomena in ulcerative colitis was suggested by Kirsner and Palmer in 1954. Subsequent studies in our laboratory demonstrated that the colon is fully capable of generating and participating in immunologic reactions. However, attempts to produce an “immune colitis” in animals as a model for further study failed. Later, circulating antibodies or reactants against extracts of colonic tissue or epithelial cells were reported by various investigators. However, this finding does not necessarily establish their etiologic importance in the pathogenesis of ulcerative colitis; they may represent secondary rather than primary manifestations of the disease. Serum containing anti-colon antibodies is not cytotoxic for human fetal colon ells in tissue culture; the “specific” antibodies have not been demonstrated in colonic tissue involved by ulcerative colitis; and no correlation has beene stablished between such antibodies and the duration, severity, and course of the disease, the presence or absence of extra-colonic manifestations, or treatment with corticosteroids. Many other circulating anti-tissue reactants have been detected in the serum of patients with ulcerative colitis, including antinuclear factors, anti-erythrocyte antibodies, to gastric and small intestinal mucus cells, gastric parietal cell antibodies, antibodies to thyroglobulin, bile ductular cells, and to phenol-water extracts of liver and kidney.

　The nature of the possible colonic antigen or antigens also has not been determined. In particular, the role of bacteria and of bacterial antigens requires much more consideration, especially because of the immunologic relationship between colonic antigens obtained from germ-free gastrointestinal mucins and a lipopolysaccharide extractable from Escherichia coli 014. This lipopolysaccharide contains large amounts of an heterogenetic antigen present in most strains of enterobacteriaceae. Recently; cellular immune mechanisms have attracted interest, especially the possible cytotoxic effects of circulating small lymphocytes from patients with ulcerative colitis; the reaction to autologous leukocytes intradermally; and the apparent inhibition of in vitro migration of circulating leukocytes by homogenates of sterile fetal colonic and jejunoileal mucosa; but the importance of these observations remains unclear. The significance of the IgA system including “secretory piece” and the gastrointestinal tract has attracted special attention in recent years and this problem, including the possible immunologic role of the “intestinal lymphocyte”, is a very important area for further investigation. Serum 1gA concentrationstend to be elevated in patients with ulcerative colitis continuing for longer than 10 years and particularly in patients who have undergone total colectomy and ileostomy but, in general, serum immunoglobulin levels vary widely, without consistent relation to the extent or severity of the disease. Although IgA containing lymphoid cells predominated over IgM, IgG and IgD…containing cells, the population density of IgA cells in the lamina propria of the rectal mucosa in ulcerative colitis was lower than in normal rectal tissue. IgA commonly was present in extra cellular intestinal mucosal sites. The significance of these observations also awaits further study. At present, the evidence implicating immune mechanisms in ulcerative colitis must be regarded as inconclusive; although the many interesting immunologic potentialities of the ulcerative colitis problem merit further investigation.

　In recent years, careful clinical observations have identified two apparently separate forms of colitis, heretofore grouped with ulcerative colitis. These are “regional enteritis of the colon” (“Crohn's colitis”, “granulomatous colitis”) and “ischemic colitis”. The latter condition is noted especially in people above the age of 50; and also in association with reconstructive operations upon the aorta, and in certain systemic diseases (e.g., scleroderma, rheumatoid arthritis) including a vascular component. More recently, we have encountered a colitis not unlike ischemic colitis, in several female patients taking contraceptive medication for long periods; the nature of this form of “colitis” awaits further study. This disorder tends to begin abruptly, within days after the initiation of oral contraceptive medication; and seems to resemble the appearance of “ischemic colitis”, proctoscopically and radiologically. Ulcerative colitis thus probably continues to comprise an heterogeneous group of diseases of varying etiology, whose separate classification, as with amebic and bacillary dysentery or the colitis associated with lymphopathia venereum, awaits recognition of the specific cause. The newer observations re-emphasize the importance of the careful description of inflammatory bowel disease and its unique clinical variations, in the hope of more complete clarification of “idiopathic”, “non-specific” ulcerative colitis.

　The treatment of ulcerative colitis remains limited to generally non-specific but nevertheless useful measures, including rest, sedation, restoration of nutrition with food, iron orally or intra-muscularly, transfusions of blood, plasma or albumin, and vitamins, restoration of electrolyte and fluid balance, antispasmoclic and antidiarrheal drugs, antibacterial medication, in some cases the avoidance of milk and ‘milk products. from the diet, adrenocorticotrophic hormone, and adrenal corticosteroids. Supportive psychotherapy and, in selected instances, formal psychotherapy may be helpful. Therapy must be comprehensive, prolonged and continuous. Because of individual differences in the severity-and course of the disease and in the response to drugs, treatment must be adapted to each patient. While these principles of treatment are straight-forward, the colitis patient often requires not only a diet and a collection of drugs, but also a special interest or “feel” for the disease on the part of the physician.

　ACTH and the adrenal steroids may initiate dramatic control of severe disease, decreasing the fever and toxemia and reducing the diarrhea, bleedig and rectal urgency. Their greatest usefulness is as adjuncts, potentiating the medical approach already described. These compounds do not cure ulcerative colitis and their use requires experience and careful supervision. Among the steroids, hydrocortisone and prednisone have been preferred, in our experience, although other preparations also may be effective. Steroids, in the form of retention enemas given at bedtime, especially hydrocortisone, are helpful in controlling relatively mild disease of the rectum and sigmoid colon. Antibacterial agents, especially sulfonamides, are helpful also as adjuncts but the long-term effects upon the bacterial flora of the colon are not known. Azulficline, sulfathalitline, sulfaguanidine and sulfadiazine, among others, appear to be especially helpfu‘ Broad spectrum antibiotics usually are not recommended because of the occasional recurrences associated with their use. However, tetracycline and Ampicillin and other antibiotics appear useful in occasional patients.

　The possible role of immune mechanisms in the development or persistence of ulcerative colitis has suggested the use of immunosuppressive drugs such as azathioprine (Imuran) and 6-mercaptopurine. While “promising” results have been reported in isolated cases (personal communications) their value in ulcerative colitis has not been established. Furthermore, their administration is hazardous and, test therapy, if undertaken, should be only by the most experienced physicians, under carefully supervised conditions. The development of lymphoma in several patients given Imuran in connection with renal homotransplants is of interest. Anti-lymphocyte serum also has been employed in a small group of patients, with unimpressive results thus far.

　The chief indications for surgery in ulcerative colitis are perforation of the colon, uncontrollable hemorrhage, obstruction, the presence or strong suspicion of carcinoma of the colon, and, most often, the failure of the disease to respond consistently to maximal medical treatment. Retardation of growth in children with ulcerative colitis is another indication for operation. The operation of choice is total colectomy and ileostomy performed usually in one stage. This procedure now is being accomplished in approximately 15 to 20% of our patients. However, in very sick patients, e.g. with perforation of the colon and peritonitis, subtotal colectomy and ileostomy may be preferred; deferring removal of the rectum and distal sigmoid for a later date.

　The potential reversibility of ulcerative colitis, even in occasional instances, is not appreciated fully. Striking and long-sustained improvement may occur despite the presence of initially severe disease. The factors involved in the apparent recovery are as obscure as the cause of the colitis, but such occurrences continue to sustain the hope that both the etiology and the cure of ulcerative colitis some day will become known.