MEDICAL

PROGRESS

Inflammatory disease of the colon: Ulcerative colitis and Crohn's colitis Marvin E. Ament, M.D., Los Angeles, Calif.

SINCE THE last review article on ulcerative colitis appeared in Tins JOURNAL in 1965,1 no major advance has occurred in determining its etiology. Appreciation of the manifestations and prognosis of the illness, however, has increased greatly and another form of colitis, Crohn's disease of the colon (granulomatous colitis, transmural colitis, ileocolitis) has been recognized. In addition, it is recognized that one fifth of patients with colitis cannot be classified as having either ulcerative or Crohn's colitis.2 The purposes of this article are to present the clinical and pathologic similarities and differences between the two conditions, and to discuss current therapy and the outTook for each disorder. ULCERATIVE COLITIS Ulcerative colitis is an inflammatory disease of the colon confined to the mucosa and, to a lesser extent, to the adjacent submucosa. The etiology is unknown. The m u s c u l a r i s i n t e r n a a n d e x t e r n a and the serosa are a l m o s t n e v e r i n v o l v e d e x c e p t in s o - c a l l e d toxic megacolon. Epidemlology. Three recent epidemiologic studies have provided evidence on the prevalence and incidence of ulcerative colitis.3-5Incidence rates in the three studies were comparable and ranged from 3.9 to 7.3 cases per 100,000 general population. Below age 20 the incidence rates are low; patients in this age range account for less than one fifth of all newly diagnosed cases. 6 The highest incidence rates are in the third to sixth decades of life. The prevalence rate ranges from 44.1 to 79.9 cases per 100,000 population. These studies support the earlier impression of a higher incidence From the Departments o f Pediatrics and Medicine, UCLA Center.for the Health Sciences. Reprint address:Department ~2fPediatrics, Room 22-442 MDCC, UCLA Centerfor the Health Sciences, Los Angeles, Cal~l: 90024.

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among Jews and Caucasians. 4 The incidence rate in Jews is two to four times that in non-Jews, and is four times as great in whites as in nonwhites. From 5 to 10 percent of patients have a family history of ulcerative colitis or Crohn's disease, 10 times the n u m b e r which would be expected by chance. 7The frequent association of ulcerative colitis with ankylosing spondylitis is additional evidence of a genetic influence in the pathogenesis of this illness. Abbreviations used SASP: salicylazosulfapyridine SP: sulfapyridine Etiology. T h e cause of ulcerative colitis r e m a i n s u n k n o w n ; the several theories proposed include: infectious, psychosomatic, immunologic, and genetic origins. The infectious theory of ulcerative colitis is based on the tissue reaction in the bowel wall, which resembles that caused by shigella, salmonella, and invasive E. coli. The disease is not, however, regarded as infectious, though bacteria in some way may be related to the coIon's immunologic response) Most gastroenterologists now believe that abnormal psychologic patterns in patients with ulcerative colitis are secondary and the result of the debilitation. Careful studies have not shown any difference in psychologic constitution between patients with ulcerative colitis and control subjects. 9, 10 Some psychiatrists, however, are critical of the m a n n e r in which these studies have been done) 1 Immunologic abnormalities are present in ulcerative colitis, but their precise role remains unclear. Anticolon a n t i b o d i e s are p r e s e n t in the sera of patients with ulcerative colitis; it is not known how they develop, nor is there a correlation of severity of the illness with the titer of antibodies. 12Peripheral blood lymphocytes from

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Fig. 1A. Rectal biopsy taken from 4 cm above dentate line in a patient with ulcerative colitis. Surface epithelium is squamoid or cuboid instead of tall columnar. Rectal glands are decreased in number and depleted of mucus; their lumens are filled with polymorphonuclear leukocytes. Frank crypt abscesses are also seen. The lamina propria contains increased numbers of mononuclear cells and polymorphonuclear leukocytes. (Hematoxylin and eosin; X120.)

Fig. lB. A high-power view of Fig. 1A. (Hematoxylin and eosin; X440.) patients with ulcerative colitis and Crohn's colitis are cytotoxic in tissue culture to autologous colon cells. The cytotoxic effect may require complement and can be demonstrated with cell-free extracts. Circulating imm u n e complexes are also present in the sera of patients with ulcerative or Crohn's colitis, but their relationship to the diseases is not understood. I3 The role of genetic factors in ulcerative colitis is not understood, although, as indicated above, it is recognized that certain families

and ethnic groups have increased susceptibility to the illness.4, 7 Pathophysiology. The diagnosis of idiopathic ulcerative colitis depends on a combination of clinical and pathologic manifestations. The histologic features are not specific 2and many of them may be seen in Crohn's disease of the colon, shigellosis, postradiation colitis, and amebic colitis. The lesions usually develop first in the rectum and spread proximally and diffusely. The

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evolution of the lesions in ulcerative colitis is not completely k n o w n ; s o m e i n v e s t i g a t o r s b e l i e v e t h a t the earliest lesions are microabscesses in the base of crypts. Concurrent with the development of microabscesses, there is vascular engorgement of the mucosa and submucosa, with marked increase in the number of monoand polymorphonuctear leukocytes in the mucosa and, at times, in the submucosa (Fig. 1). The microabscesses in the crypts may coalesce by lateral enlargement to produce shallow ulceration of the mucosa, extending down to the muscularis mucosa. Lateral extension and coalescence of crypt abscesses may undermine the mucosa, leaving an area of ulceration adjacent to a hanging fragment of the mucosa; this is how pseudopolyps are formed. During remissions the mucosa may heal, resulting in atrophic mucosa'with decreased numbers of crypts and distortion o f their a r c h i t e c t u r e . U l c e r a t i o n , v a s c u l a r engorgement, and the development of granulation tissue result in bleeding and loss of tissue fluids. As the mucosa is damaged it is likely that it becomes tess effective in reabsorbing water and electrolytes. Because the inflammatory process is usually confined to the mucosa and submucosa, peritoneal signs, colonic perforation, fistula formation, and signs of obstruction are rare. 2 In severe ulcerative colitis the disease may not remain confined to the mucosa and submucosa but extend through the muscular and serosal layers of the bowel wall, leading to toxic megacolon. 14Loss Of motor tone is due to extension of the disease process. Proetosigmoidoscopy, rectal biopsy, barium enema. Three methods are available to assess the integrity of the colonic mucosa: proctosigmoidoscopy, rectal biopsy, and barium enema. Proctosigmoidoscopy. In 95 percent of individuals with ulcerative colitis the mucosa of the rectosigmoid colon is involved. 2 Therefore, proctosigmoidoscopy is the logical first step in evaluating a patient with suspected colitis, and will establish the diagnosis of ulcerative colitis in mild to moderately severe disease when barium enemas do not disclose any abnormality. Proctosigmoidoscopy is easy tO perform in children p r o v i d e d that they are c o o p e r a t i v e or well sedated. Sedation should be used in children less than 5 yr of age and selectively in older children to prevent them from moving and causing traumatic artifacts and perforation. For sedation we administer 2 mg/kg of meperidine, 1 m g / k g of p r o m e t h a z i n e , and 0.5 m g / k g o f chlorpromazine in children more than 6 mo of age; and 1 mg/kg of meperidine, 0.5 mg/kg of promethazine, and 0.5 mg/kg of chlorpromazine in those less than 6 mo. The maximal doses are: 50 mg of meperidine, 25 mg of promethazine, a n d 25 mg of chlorpromazine.

The Journal of Pediatrics March 1975

The mixture is given 1 hr before the procedure. If the child is not cooperative or relaxed following this sedation, diazepam is administered intravenously, Slowly, and intermittently until the patient is at ease; the dose needed varies but may be as much as 1 mg/kg. W e prefer not to administer enemas or cathartics prior to sigmoidoscopy. E n e m a s may cause mucosal hyperemia, petechiae, increased colonic production of mucus, and hi~tologic changes in the rectal mucosa. Cathartics can worsen diarrhea and cause severe crampy abdominal pain. Patients who do not have diarrhea as their major complaint should be fed a clear liquid diet for 48 hr before the procedure. They should be asked to defecate in the hour preceding the examination. If, after examination of the distal rectum, stool in the upper part of the rectum prevents visualization, an enema may be administered. Six features of the mucosa should be looked for: (1) ramifying blood vessels, (2) friability of the mucosa as evidenced by rubbing with a cotton swab, (3) spontaneous friability, (4) whether the mucosal involvement is diffuse Or patchy, (5) whether mucosal involvement begins in the distal rectum, and (6) the presence of pseudopolyps or ulcers. I n t e r o b s e r v e r a g r e e m e n t is 70-90% for t h e s e features. 15Ulcerative colitis is characterized by diffuse mucosal i n v o l v e m e n t b e g i n n i n g in the distal r e c t u m : friability may be observed or it may be readily induced by swabbing. Ramifying blood vessels may be seen in mild cases prior to wiping the m u c o s a with c o t t o n swabs. Ulcers are almost never seen; pseudopolyps are occasionally present. Diffuse involvement may also be seen in shigellosis and in amebic colitis; in the latter disease characteristic ulcers may be seen. During early i n f a n c y e n t e r o c o l i t i s of H i r s c h s p r u n g ' s d i s e a s e and m i l k - p r o t e i n - i n d u c e d colitis have proctosigmoidoscopic features indistinguishable from those of ulcerative colitis. The anal canal is examined for fissures, fistulas, and ulcers. They are rarely found in ulcerative colitis and, if present, the diagnosis of Crohn's colitis should be suspected. Rectal biopsy. In mild cases of ulcerative colitis the s i g m o i d o s c o p i c findings are o f t e n equivocal. R e c t a l biopsies may be useful in such cases to clarify the diagnosis. 16 Barium enema. There are three major reasons for performing a barium enema: (1) to diagnose disease proximal to the area visible with the sigmoidoscope, (2) to distinguish ulcerative from Crohn's colitis, and (3) to detect cancer in the proximal colon of patients with long-standing ulcerative colitis. Barium enemas may be hazardous to patients with severe ulcerative colitis, because they may cause diia-

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tion or perforation of the Colon. This study should-be done only when the Patient's symptoms are under control or when the disease is mild to moderate in severity. Early roentgenographic changes are usually manifest in the rectum; later changes are evident in the contiguous portions of the co!on. The severity of symptoms, however, does not always correlate with roentgenographic changes, and many patients with ulcerative colitis have n o r m a l colonic p a t t e r n s with b a r i u m e n e m a s . T h e earliest roentgenographic changes are m i n u t e ulcerations along the edge of the bowel. 17Sometimes these are lacking but the p0stevacuation film demonstrates disappearance of the reticulated mucosal pattern. Such findings are not specific and may be seen in bacterial colitis. D i s a p p e a r a n c e or irregular size a n d d i s t r i b u t i o n of haustra in the transverse colon and r!ght colon are indicative of advanced disease. Other signs of advanced disease Is are: evidence of frank ulceration of t h e mucosa in the filled film, decreased length of the colon, decreased distensibility of the bowel wall, and decreased caliber (Fig. 2), polyps evident on the postevacuation film, and widened retrorectal space. 19Ideally, the barium e n e m a should extend to the terminal ileum to determine if there is involvement in this area. The terminal 4-20 cm of the ileum may be involved in 10% of all patients with total colonic involvement. 17 Clinical course. Ulcerative colitis is a severe disease in the pediatric age group; over 90% o f i n v o l v e d children have moderate to severe activity, 6, 2o whereas less than 50 percent of adults have this degree Of activity. The severity and debilitating nature of moderate to severe disease require colectomy within 2 yr of onset in most pediatric patients. Mild disease. Mild disease is characterized by fewer than four bowel movements a day and the absence of a n e m i a , f e v e r , t a c h y c a r d i a , h y p o a l b u m i n e m i a and weight loss. It is u n c o m m o n in the pediatric age range. Some patients may not have diarrhea but have rectal bleeding; others may have diarrhea without blood loss. Toxic megacolo n does not develop unless the disease progresses. In less than 15% of patients with mild disease the lesions progress to involve the entire length of the colon. Rarely extracolonic complications of ulcerative colitis are the initial manifestations. 2~ 21 The longterm prognosis is not much different from that of a control population, 22though there is some increased r i s k o f developing carcinoma of the colon even in those with disease confined to the left colon. Moderate disease. Dim, rhea, abdominal cramps, and fever are Characteristic of patients with moderate disease and progression to severe disease usually occurs. Patients in this category respond dramatically to treatm e n t with adrenocorticosteroids. 2~

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Fig. 2. Roentgenographic study of a patient with severe ulcerative colitis. The entire colon is involved. Pseudopolyps are present diffusely and haustra are absent in the transverse colon. The caliber of,lhe transverse and left colon is decreased.

Severe disease. Severe disease is characterized by more than six bowel movements a day, considerable colonic bleeding, anemia, h y p o a l b u m i n e m i a , fever, tachycardia, and weight loss. W e have seen severely ill p a t i e n t s who were n o t f e b r i l e or a n e m i c ; this is especially true in infants and toddlers. Patients with severe disease may be weak, dehydrated, and pale in aPpearance. Abdominal examination demonstrates tenderness but no evidence of peritonitis. Individuals with severe disease may respond dramatically to treatment with adrenocorticosteroids; they may also be refractory to medical management. Only patients with severe disease develop toxic megacolon; about 2.4% of them develop this complication123 The long-term prognosis is poor. 22 Arthritis in ulcerative colitis. Arthritis is the commonest extracolonic manifestation of ulcerative and of Crohn's colitis. In the former condition it occurs in one fifth and in the latter one tenth of patients throughout t h e pediatric age range. Two different t y p e s occur, singly or in combination: arthritis of the peripheral joints and that affecting primarily the spine. The periph-

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eral arthritis is characterized by: (1) involvement of one or more of the large joints, usually with sparing of the small joints of the hands and feet, (2) synovitis with effusion (the joint is erythematous, tender, and limited in motion), and (3) absence o f degenerative changes in joints, cartilages, and bony appositions with no residual functional limitation or permanent damage. 21, 24 Rarely granulomas may be found in the arthritic joints. 25 Arthritis may precede development of diarrhea, but it usually develops concurrently; it does not necessarily coincide with an exacerbation of bowel symptoms, nor is there correlation with the severity of the bowel disease.24 Joint disease in children is more frequently associated with mucocutaneous lesions than with iritis.21 Back s y m p t o m s are p e r s i s t e n t and progressive and result in permanent disability. Patients with spondylitis often ha.ve accompanying hip disease and are less likely to have associated mucocutaneous lesions. Spondylitis may r e s p o n d to c o r t i c o s t e r o i d s , i n d o m e t h a c i n , or Butazolidin. 21 Successful t r e a t m e n t of bowel disease with systemic adrenocorticosteroids results in amelioration of arthriti~. Following colectomy, arthritis usually disappears permanently. S k i n lesions. Four types of skin lesions may occur in ulcerative and Crohn's colitis26: (1) erythema nodosum, (2) pyoderma gangrenosum, (3) papulonecrotic lesions, and (4) ulcerative erythematous plaques on the shins. These develop in less than 20% of adult 26,27 and 10% of pediatric 21 patients, and may precede the development of gastrointestinal symptoms by months. 26,27 Erythema nodosum is the commonest lesion and almost always develops over the extensor surfaces of the arms and legs. These nodules may occur at any time in the course of the illness. Their presence does not correlate with the extent of disease but does correlate with arthritis. Rarely, both arthritis and erythema nodosum occur prior to the onset of bloody diarrhea. 26 Pyoderma gangrenosum is the second commonest skin lesion. It may be described as a chronic ulcer with undermined edges. These lesions usually occur with the most severe cases and are found most commonly on the cheeks, thighs, feet, hands, legs, and 9 regions. T h e lesions c o n t a i n few p o l y m o r p h o n u c l e a r leukocytes; cultures are sterile. Papulonecrotic nodules are small erythematous papules which separate and necrose to form small ulcers. Ulcerative erythematous plaques are the rarest lesions. All four of these lesions may appear during a bout of active colitis; control o f the colitis with corticosteroids or total colectomy usually results in disappearance oflesions. Stomal ulcerations. Aphthous ulcers frequently oc-

The Journal of Pediatrics March 1975

cur during severe attacks of colitis but may occur during remission. Although 10% of adults with ulcerative colitis develop this symptom, 28 it has been reported in less than 2% of pediatric patients. 6,20,2t Eye lesions. Conjunctivitis, iritis, and episcleritis are the commonest ocular lesions in ulcerative colitis and occur in 4-10% of adult patients. 283~ In two series of nearly 200 pediatric age patients only one case was reported.20, 21 The systemic adrenocorticosteroid therapy used for colitis almost always ameliorates the ocular lesion. Topical steroids and cycloplegic and m y d r i a t i c agents m u s t be used if iritis occurs when colonic disease is inactive. Attacks of iritis do not recur if the entire diseased colon is resected. Clubbing of fingers. This lesion is less c o m m o n in c h i l d r e n than in adults. 31 The frequency of clubbing is related to the duration, extent of involvement, and severity of colitis. It disappears following colectomy or w h e n the disease remits. Thrombophlebitis. This complication is rare in pediatric patients; in only one series is a subject reported with this condition. 2~In adults it occurs in 5-10% of patients at any stage of the disease. 28 Liver disease. Active hepatitis occurs in 1-3% of all patients with ulcerative colitis,6, 20,32although 25-30% of patients with ulcerative colitis have elevated alkaline phosphatase values and sulfobromophthalein retention. Rarely, the initial manifestation of ulcerative colitis is hepatitis; 32 patients may present with anorexia, fever, jaundice and an enlarged 9tender liver, followed by diarrhea days or weeks later. The m o s t c o m m o n pathologic c h a n g e s in a s y m p tomatic p a t i e n t s are fatty infiltration and c h r o n i c pericholangitis. 32 Symptomatic patients with liver disease may have the changes of chronic active hepatitis and cirrhosis. Liver disease may respond to administration of c o r t i c o s t e r o i d s ; in n o n r e s p o n d e r s the lesion progresses to cirrhosis. There is some evidence that colectomy may ameliorate or stop the progression of liver involvement. 33Sclerosing cholangitis is a rare complication of ulcerative colitis but has not been described in children. Ulcerative colitis during infancy. Ulcerative colitis in children under age 2 is relatively rare and accounts for less than 1% of reported cases. 6 It is a far more serious disease in this age group and usually has a severe, rapid c o u r s e 34 o r results in s e v e r e growth r e t a r d a t i o n and debility. 3s During infancy the extracolonic manifestations of ulcerative colitis are rare. The results of medical therapy during infancy are difficult to evaluate because of the limited n u m b e r of reported cases. Because most infants are quite ill, suppor-

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tive intravenous therapy with fluids is almost always necessary. Plasma or blood may be administered if the p a t i e n t s are h y p o p r o t e i n e m i c and anemic. A l t h o u g h both rectal and parenteraladrenocorticosteroid therapy has b e e n used, n e i t h e r has p r o v e d beneficial e v e n though administered for a prolonged time. 34, 35 Failure of a patient to respond dramatically within 72 hours is a sign of poor prognosis and indicates that colectomy should be considered. In debilitated patients surgery should be done without a trial of medical therapy. The usual operation in this age group is an ileostomy and subtotal colectomy. Later, when the child has grown, consideration must be given to removal of the rectal stump, if active disease persists. Because of the debilitated nature of these infants at the time of surgery, deaths from sepsis have been frequent in the postoperative period. 34 Treatment. Dietary management. There is no evidence that any specific diet prevents relapses in patients with ulcerative colitis. One small clinical trial indicated that restriction of milk protein from the diet prevented relapses in t h e initial year of d i s e a s e b u t not s u b s e q u e n t l y . 36 Although hemagglutinating antibodies to tanned red cells coated with cow's milk proteins are present in the serum of patients with ulcerative colitis, the titer of such antibodies bears no relation to the state of activity o f the d i s e a s e nor to the p r e s e n c e or a b s e n c e o f gastrointestinal symptoms. Lactase deficiency is present in some patients with ulcerative colitis; the more severe and prolonged the duration of colitis the greater the likelihood of lactase deficiency. 37The correlation between lactase deficiency and lactose intolerance, however, is not direct. 38 Patients with ulcerative colitis who have diarrhea despite optimal medical management should .be tested for lactose intolerance to determine whether lactose containing foods should be excluded from the diet. Opiates. In general, opiates should be avoided in patients with severe colitis because they may c o n t r i b u t e to the development of toxic megacolon. Anticholinergic drugs are not recommended for the same reason. In less severely ill patients, however, both types of drugs may be used to ameliorate cramps and nocturnal diarrhe a . SASP (Azullidine). SASP is an agent which is composed of salicylate and sulfapyridine; t h e m e c h a n i s m of action is unknown. Approximately one third of a given dose of SASP is absorbed from the small intestine; the remainder passes to the colon where SASP is split into its components by bacteria. Most of the SP liberated is absorbed, but only about one third of the 5-aminosalicylic acid. In the liver, SP undergoes N 4 acetylation

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a n d 5 ' - h y d r o x y l a t i o n followed by c o n j u g a t i o n with glucuronic acid. 39 The metabolism of SASP depends on the rate of acetylation. In this respect patients may be divided into two groups: slow and fast acetylators. The latter group m a y need larger doses of SASP to obtain therapeutic effect. Nausea, vomiting anorexia, indigestion, and abdominal discomfort are the most frequent side effects and are dose related. They occur in one fifth to one half of patients who take 4 gm/day of SASP. Fever, rash, headache, and dermatitis are other frequeot complications of therapy. Severe leukopenia occurs in less than 1% of patients; deaths due to agranulocytosis have been reported. 39 SASP may be used for initiating remission in mild l e f t - s i d e d colitis, but is not as effective 9 as steroid enemas or systemic administration of corticosteroids in inducing remission4~ only 30-40% of patients with mild disease go into remission as compared to 70-90% with adrenocorticosteroid therapy. If SASP is used to induce remission, a dose of 50 mg/kg/day should be given initially. Should the symptoms not improve within 10 days the dose may be increased. The m a x i m u m dose is 4 gin/ day of SASP. This agent should be the first choice in mild ulcerative colitis during childhood, because it does not affect growth. Patients with mild disease who fail to r e s p o n d tO this m e d i c a t i o n s h o u l d be t r e a t e d with adrenocor ticosteroids. Once remission is achieved with rectal or systemic administration of steroids in moderate to severe disease, SASP is most useful in maintaining remission. Steroids in low dosage are not effective in maintaining remission. 42 In well-controlled clinical trials in adults, a dose of 2 gin/day of SASP was found to be three times more effective than placebo in maintaining remission. 43 Two recent studies in adults differ in their conclusions about continuing SASP after remission is maintained for t yr. In one study there was no difference in the exacerbation rate between those individuals who received SASP for a second year and those who did not. 44 In another study, patients who received d u m m y tablets had more than four times as many relapses as those receiving SASP.45 The latter study may be more accurate because it included repeated sigmoidoscopic examinations as a criterion for evaluation. Adrenocorticosteroids. For the mild to moderately ill patient with colitis, steroids may be given either rectally or orally.46,47 Since both methods have been shown to be equally effective and steroids are far less expensive a n d easier to a d m i n i s t e r orally t h a n as e n e m a s , we prefer oral administration. Some physicians prefer to use steroids rectally because systemic side effects are

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less frequent. The oral dose of prednisone or prednisolone is 1.5-2 rag/K/day with a maxiihum of 40 mg, given in four divided doses. Rarely a patient may require 60 mg of prednisone to induce remission. In our experience such individuals are difficult to maintain in remission when the dose of adrenocorticosteroids is reduced. Symptoms usually improve dramatically within 72 hr if complete remission is to be attained. Steroids should be continued at the maximum dose for 2 wk before tapering is begun; the dose is then reduced by 2.5-5 mg/day/wk. When a dose of !5 rag/day is reached, SASP is started and tapering of the dose of steroids is continued. Alternate day, single-dose steroid therapy has been recommended; however, individuals treated in this manner experience growth retardation. 48Patients wit h severe disease should receive steroids intravenously, given as methylprednisolone semiacetate and continued until the patient is no longer toxic. An oral form should then be started and the dose tapered in the same way as for mild to moderate disease, Failure of the patient to respond promptly within 72 hr to intravenous administration of steroids may indicate that colectomy .should be done. Although some physicians use ACTH intravenously or intramuscularly in patients w i t h severe disease, it has not been ,shown to be superior to administration of corticosteroids intravenously, Early studies comparing the effectiveness of oral cortisone to intramuscular ACTH showed the latter to be twice as successful in initiating remission in relapse of established disease. 49Complicationsl however, were substantially more frequent in those who received ACTH. Azathioprine. The long-term risks of using azathioprine for maintenance therapy are far greater than the possible benefits. 5~ In one double-blind study azathioprine was not more effective than placebo in obtaining remission. 5~ Surgery. There are six indications for surgical treatment in ulcerative colitis: profuse hemorrhage, toxic megacolon, perforation, obstruction, malignancy, and c h r o n i c d i s a b l e m e n t w i t h g r o w t h failure.53~55 Ehrenpreis 56 reported that 45 of 225 pediatric patients required surgery over a 12 yr period. Approximately one third of them required emergency operations. All had a rapidly progressive course with high fever, marked anemia, and gross weight loss. None of the group had bowel perforations, obstructive strictures, or malignancies. Indications for elective surgery include one or more years of total and continuous disability after initiation of medical management. Growth retardation is a valid reason for advising colectomy. Total colectomy reverses growth failure if performed before epiphyses fuse.54 , 55 Operation of choice is radical excision, panproctocolectomy combined with

The Journal of Pediatrics March 1975

permanent ileostomy. However, total colectomy is often omitted in severely toxic and debilitated patients because of the increased operative time; subsequent proctectomy is usually required. If the rectum is left in place and anastomosed to the ileum, residual symptoms from proctitis usually require Secondary removal of the rectum with ileostomy. Furthermore, in patients with ileorectal anastomosis, malignant degeneration in the rectum may develop. Surgical mortality rates are approximately 2% in those treated electively, 10% in those requiring urgent surgery, and 15-20% for emergency operations. 57 The influence of treatment with adrenocorticosteroids on the mortality and morbidity rates of patients undergoing surgical treatment for ulcerative colitis was examined in a retrospective study. 58 No difference in operative results, complications, duration of postoperative hospital stay, healing of the perineal wound, and status o f health could be f o u n d between patients treated and those not treated with steroids. Poor results correlated directly with severity of colitis. Cancer, Four factors are associated with a high risk of subsequent development of cancer: (1) extreme severity of the first attack of ulcerative colitis, (2) universal involvement of the entire colon as judged radiologically, (3) continuous rather than intermittent symptoms, and (4) onset of the disease in childhood. 22 Without surgery the long-term prognosis is poor for children with ulcerative colitis. In Devroede's study, 20% of subjects died during each decade of the followup period. The risk of developing cancer was 20% per decade for those at risk after the first 10 yr of ulcerative colitis. During the first 10 years the risk was about 3%. The risk of developing cancer was less in those who had only rectal involvement but it was still considerably greater than in the general population. After the first 10 yr of illness a physician has to consider advising an elective panproctocolectomy to prevent development of cancer.

CROHN'S DISEASE OF THE COLON (TRANSMURAL AND GRANULOMATOUS COLITIS, SEGMENTAL AND RIGHT-SIDED

COLITIS)

Crohn's disease of the colon is an idiopathic, chronic, inflammatory bowel disease characterized pathologically by discontinuous and transmural involvement of all layers of the bowel wall and noncaseating granulomas. 2 Pathologically the lesion is the same as Crohn's disease of the small intestine. Approximately half of the patients with Crohn's disease of the small intestine also have colonic involvement. EpidemiologY. Specific incidence and prevalence

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Fig. 3A. Rectal biopsy from a patient with Crohn's ileocolitis.Proctosigmoidoscopic examination was normal. A giant cell and granuloma are seen in the lamina propria. Rectal glands are parallel and surface epithelium is intact. (Hematoxylin and eosin; X120.)

Fig, 3B. A high-power view of the giant cell and granuloma seen in Fig. 3A. (Hematoxylin and eosin; X440.) figures for Crohn's disease of the colon in the pediatric age range are not available. The incidence of the disease ranges from 1.4 to 3.4 per 100,000 in the caucasian poptllation.5 Certain groups, particularly Jews, are more apt to develop the illness.4 In one series of Pediatric patients with colitis, two thirds were categorized as having ulcerative colitis and one third as Crohn's disease. 21 Although the disease may occur in children as young as 1 yr and in the elderly, it most commonly develops bet w e e n the second and fourth decades. 59 In the younger

patients the involvement of colon and small intestine may be more extensive. 6~ Etiology. There is some recent controversy concerning the relationship of sarcoidosis to Crohn's disease based on different results obtained with the Kveim test, 61-63but the relationship between the two diseases remains unanswered. Mitchell and Rees 64 reproduced epithelioid and giant-cell g r a n u l o m a s in footpads of mice with homogenates of gut and lymph nodes from patients with C r o h n ' s disease. Positive K v e i m tests

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Fig. 4. Roentgenographic study of a patient with Crohn's colitis, showing segmental involvement of the left and transverse colon. were s e e n only in mice w h i c h had epithelioid and giant-cell granulomas in their footpads. No mycobacteria were cultured from any of the Crohn's homogenates. It was speculated that a transmissible agent for mice had been demonstrated in human Crohn's disease tissue. Patients with Crohn's colitis do have impairment of cell-mediated immunity, 65, 66 e.g., variable degrees of anergy to t u b e r c u l i n a n t i g e n s , a high f r e q u e n c y of failure to respond to dinitrochlorobenzene, and a frequently diminished r e a c t i v i t y of cultured circulating lymphocytes to phytohemagglutinin. How impairment of cell-mediated immunity contributes to the development of Crohn's disease remains unknown. Furthermore, it is unclear whether Crohn's disease is directly related to ulcerative colitis. Pathology. The pathognomonic histologic features of Crohn's colitis are: transmural inflammation, lymphangiectasia, deep long linear ulcerations or fissures with normal mucosa between involved areas, enteric fistulas, and noncaseating granulomas. 2, 67, 68 These pathologic characteristics distinguish Crohn's disease from ulcerative colitis.

The Journal of Pediatrics March 1975

F i b r o s i s from the c h r o n i c i n f l a m m a t o r y r e a c t i o n results in stenosis. Noncaseating granulomas are seen in 50-90% of the cases in which resection has been performed 67 and may be found in all layers of the bowel wall. Fistulas develop between loops of adjacent intestine a n d b e t w e e n t h e bladder, vagina, ovaries, F a l l o p i a n tubes, and abdominal wall. Disease is frequently segmental in distribution. If the right colon and cecum are involved, ileal involvement is present in more than 90% of cases .60,69 Presenting gastrointestinal manifestations. Diarrhea and crampy abdominal pain are the commonest gastrointestinal symptoms and occur in more than 80% of patients. 6~ 70,71 Diagnosis is often delayed for months to years 6~ 71 because diarrhea is mild and occurs interm i t t e n t l y . Severe d i a r r h e a a s s o c i a t e d with l o w - g r a d e fever, weight loss, anorexia, and hematochezia occur in a third of patients. 54,60,70 Crampy abdomin~il pain develops because the propulsive waves of motility must pass through the inflamed colonic wall, and is most frequently experienced in the right lower quadrant. At times pain from the ileocolic region is referred to the midepigastric area or right upper quadrant, but differs from the typical pain of peptic ulcer in that eating accentuates it. C r o h n ' s colitis may be difficult to d i a g n o s e 6~ 70 because symptoms are nonspecific. Delayed puberty and menarche 71 or failure to gain weight and grow 72, 73 may be initial manifestations. Illness may present as anemia due to enteric blood loss or as hypoproteinemia due to protein loss. Protein-losing enteropathy is the most frequently recognized abnormality in intestinal function. 74 Patients may develop steatorrhea secondary to malabsorption of bile salts 75 and to decrease in the circulating bile salt pool if there is significant ileal disease. Perianal disease. Perianal disease is three times as common in Crohn's disease of the colon as in ulcerative colitis. Nearly one fourth of patients have anal lesions before the onset of intestinal symptoms. 76These lesions frequently develop months to years before intestinal symptoms. Ulceration of the anal canal is the commonest lesion and leads to the formation of one or more anal fissures. 76, 77 T h e y differ from o r d i n a r y fissures because they may occur in any part of the anal canal and not just in the dorsal part. Rarely the ulcers enlarge and extend onto the perianal skin and destroy the anal sphincters. Infrequently ulcers involve the groin and vulva. Other c o m m o n anal disease includes abscesses, fistulas, and skin tags. Sigmoidoseopy, rectal biopsy, and barium enema. A

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careful anal and p r o c t o s i g m o i d o s c o p i c e x a m i n a t i o n should always be the first study in patients suspected of having Crohn's colitis. Because 50% of patients with Crohn's colitis do not have involvement of the rectum 77 the examination may be normal. If the rectosigmoid mucosa is affected the involvement is patchy; normallooking mucosa is interspersed between diseased areas. Loss of vascular pattern, granular appearance of the mucosa, and spontaneous or induced friability with cotton swabs are the most commonly observed findings in abnormal areas. Discrete ulcers may be seen in both normal- and abnormal-appearing mucosa. Rectal biopsy should always be obtained; even when the mucosa appears to be normal, microscopic mucosal changes are frequently found. 16, 78, 79 Granulomas with or without giant cells and patchy inflammatory changes may be seen (Fig. 3). At times diffuse inflammatory changes are observed which cannot be differentiated from those of ulcerative colitis. Biopsy should be done b e f o r e b a r i u m e n e m a b e c a u s e mild i n f l a m m a t o r y response may occur in tlae tissue after the latter procedure. Radiologic changes. Barium enema may be a more useful study in the diagnosis of Crohn's colitis than of ulcerative colitis because in the former the rectum may appear normal on proctosigmoidoscopic examination (Fig. 4). Certain roentgen findings are typical of Crohn's colitis but virtually none are diagnostic except for ident i f i c a t i o n o f a b s c e s s e s . 79The m o s t c h a r a c t e r i s t i c changes are: Segmental or focal involvement, eccentric i n v o l v e m e n t , ulcers g r e a t e r than 2 m m in d e p t h , fissures perpendicular to the bowel lumen and, frequently, fistulas. Involvement of the terminal ileum may be seen on barium enema; changes include a contracted irregular lumen w i t h l o s s of mucosal pattern, fissures, a thickened ileocecal valve, and cecoileal fistula. An upper gastrointestinal and small bowel series should always be done to determine if there is evidence of small intestinal disease. Extraintestinal manifestations. Occasionally the ext r a i n t e s t i n a l m a n i f e s t a t i o n s may be the p r e s e n t i n g s y m p t o m s . 2 1 . V~ arthritis, ankylosing spondylitis,2~,24 uveitis, skin lesions, aphthous ulcers, 8~finger clubbing, 81 and liver disease occur in Crohn's colitis, but do not occur as frequently a s - - a n d are not different f r o m - - t h o s e in ulcerative colitis. Amyloidosis, another rare complication of Crohn's colitis, 82 has not b e e n r e p o r t e d in the pediatric age group. It is believed to be reversible by resection of the diseased bowel. Hydronephrosis. Obstruction of the ureters by the

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t r a n s m u r a l i n f l a m m a t o r y process may r e s u l t in hydronephrosis and pyelonephritis. 83 Patients with transmural colitis, who have small bowel involvement, pain in a hip or the anterior aspect of thigh or flank, and fever, Should be suspected of this complication and have an intravenous pyelogram. Renal and vesical calculi. The incidence of renal and vesical calculi in adult p a t i e n t s with u l c e r a t i v e and Crohn's colitis is approximately 6 per 100. 84 In pediatric patients incidence figures are unavailable. Stones may form secondary to fluid and electrolyte loss which resuits in a concentrated acid urine that predisposes to uric acid precipitation. In addition, patients with severe involvement of the terminal ileum absorb excessive a m o u n t s of oxalate in the colon and e x c r e t e large amounts in the urine 8s and thus are susceptible to calciu m oxalate stone formation. C h o l e l i t h i a s i s . T h e i n c i d e n c e o f gall s t o n e s in Crohn's disease involving the ileum and right colon in the pediatric age range is unknown. Up to 30% of adult patients with ileal involvement have cholelithiasis 86as a r e s u l t of their diminished bile salt pool. Laboratory data. Patients with Crohn's colitis may have h y p o c h r o m i c microcytic anemia as a result of chronic blood loss or a macrocytic anemia secondary to lack of dietary folate and malabsorption of vitamin B12. The erythrocyte sedimentation rate is usually elevated 6~ but may be normal. Hypoproteinemia is the commonest ab normality of blood chemistry. 6~ 74 Medical management. There have been few controlled clinical trials of drug therapy for Crohn's colitis. The medical treatment is similar to that of ulcerative colitis. One must be certain that no complications are present which require surgery before instituting drug therapy. Dosages of corticosteroids and SASP are the same as for ulcerative colitis, and indications for their use are similar. Often remissions may not be maintained with SASP, and corticosteroids must be used. The lowest steroid dose possible to maintain remission must b e used to minimize the side effects of the drug and to prevent masking of perforation, abscess, and fistula formation. 7~ W e do not recommend the use of azathioprine, 87-9~ b e c a u s e it is unlikely that the drug is b e t t e r than placebo, and its toxicity is considerable. Diet should not be limited; only those foods which the patient believes worsen his symptoms should be eliminated. Iron, folic acid, and parenteral vitamin B12 may be necessary in certain cases. Abdominal pain, anorexia, and toxicity from the disease often inhibit the patient's appetite. Surgical indications--emergency. The three indica-

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tions for emergency surgery 6~ 69are: perforation of the colon, massive uncontrolled ileocolic hemmorrhage, and toxic megacolon. Perforation is an u n c o m m o n occurrence. 91The optimum treatment is primary excis!on of the perforated segment and of all the distal diseased bowel. Massive bleeding as the prime indication for surgical t r e a t m e n t of C r o h n ' s colitis is quite rare because the bleeding often stops spontaneously; less than 5% of patients with Crohn's disease have this complication.60, 70 Acute toxic dilation of the colon is a rare complication of the disease and is managed by total colectomy with ileostomy. 92 Surgical i n d i c a t i o n s , e l e c t i v e . A t t e m p t s to cure Crohn's colitis or ileocolitiS by surgical resection 6~ 92 have not proved successful, 7~but there are indications for elective surgery; these include intractability, colonic obstruction secondary to stenosis, abscess, fistula formation, and severe perianal disease. Patients with i n t r a c t a b l e disease characterized by persistent diarrhea, abdominal pain, fever, and failure to respond to medical management should have surgical excision. Total or subtotal colectomy with ileostomy and reanastomosis are the s t a n d a r d operations for diffuse disease of the colon.93 For segmental colitis in the right colon and ileocolic disease, right hemicolectomy with ileotransverse c010stomy is the operation most frequently done. The recurrence rate is 18-50% after 5 yr in almost all series. 67,94,95 There is no evidence that resection of long segments of normal intestine or colon on each side of the affected area reduces the rate of recurrence; even after such radical resections rec~urrence rates of 40% have been re, ported. 6~ Surgical excision is often done for severe chronic perianal disease but frequently does not result in reversal of the lesions and does not prevent their recurrence. 92 Patients with Crohn's colitis or ileocolitis require surgery one to two times during their lives.96The prognosis for survival is better than for patients with Crohn's disease confined to the small intestine. Risk of cancer. A follow-up s t u d y of 449 patients from the Mayo Clinic s9 with C r o h n ' s enteritis, enterocolitis, or colitis showed the incidence of cotonorec{al cancer to be 20 times greater than in a control population, and a greater than expected risk of adenocarcinoma of the small i n t e s t i n e s At the time of cancer diagnosis all patients had severe involvement of the colon and rectum. The ascending colon was the most common site of cancer; the majority of these patients died from the m a l i g n a n t disease. The d u r a t i o n of o n s e t varied from 7-45 yr; the risk was small when compared to that in ulcerative colitis. Most of the patients who de-

The Journal of Pediatrics March 1975

veloped cancer were in the third and fourth decades of life. SUMMARY Ulcerative colitis differs from C r o h n ' s colitis in several ways. In ulcerative colitis the disease is limited to the m u c o s a and, occasionally, the s u b m u c 0 s a ; Crohn,s colitis may involve all layers of the large intestine. Ulcerative colitis almost always begins in the rectum, is diffuse, and spreads proximally. Crohn's colit i s may spare the rectum and has a patchy distribution. Perianal fistulas and ulcers are rare in ulcerative colitis but are c o m m o n in Crohn's colitis. G r a n u l o m a s and giant cells are not found in ulcerative colitis but are seen in the majority of patients with Crohn's colitis. Colonic and extraintestinal symptoms in the two illnesses may be indistinguishable but growth failure is far more severe in Crohn's colitis and may precede intestinal symptoms by months to years. Cancer of the colon is a risk in patients with either ulcerative or Crohn's colitis but is far more common in the former. It is important to distinguish between ulcerative colitis and Crohn's colitis because response to treatment and prognosis are different. Although neither condition can be Cured by medical management, patients with ulcerative colitis may respond more frequently. Unfortunately, in the pediatric age range most cases of ulcerative and Crohn's colitis may be classified as moderate to severe. Fortunately for patients with ulcerative colitis, total colectomy with ileostomy will result in cure of illness. Patients with Crohn's colitis who require surgery may obtain remission of symptoms, but the disease is likely to recur in the small intestine.

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