Immunity

Current opinion appears to favor a defect in immune regulation as the primary cause of UC. As opposed to the predominantly cell-mediated response seen in Crohn’s disease, the immunologic profile of patients with UC is characterized by a predominantly humoral response. In UC, there is marked overproduction of immunoglobulin G ₁ (IgG ₁ ) by both intestinal lymphocytes and those in the peripheral circulation. Autoantibodies have been identified that are directed against colonic epithelial proteins such as the cytoskeletal protein tropomyosin. In addition, these autoantibodies cross-react with antigens in tissues commonly affected by the extraintestinal manifestations of UC, including the biliary epithelium, skin, chondrocyte, and ciliary body of the eye. Which factor or factors initiate this autoimmune process remains to be elucidated.

The genetic discoveries of the last few years, however, appear to confirm the hypothesis that UC is caused by a defect in immune regulation. The genes that have been shown to be associated with UC potentially play important roles in preventing enteric organisms from accessing the lamina propria (e.g., decreased production of P-glycoprotein due to defective MDR1 gene expression) or in immune response (e.g., HLA genes, IL-11, TNF α, IL-10R). These functions suggest that the driving force for the unremitting inflammation characterizing UC appears to be the normal enteric flora rather than an enteric pathogen. How these genes promote the chronic inflammation of UC, and whether they predispose to the development of autoantibodies, remains to be determined.

Infectious Agents

Although there is great clinical similarity between UC and infectious colitides, no solid evidence supports the theory that an infectious agent is the primary cause of colonic inflammation in UC. Children can initially present with documented enteric infection, only to be found after clearance of the pathogen to have persistent, chronic inflammation. In fact, compared to controls that never had a documented infection with either Salmonella or Campylobacter , a population-based study from Denmark identified a nearly threefold increase in IBD (both UC and Crohn’s disease) in subjects in the 15-year period following one of these infections. Despite this, the majority of patients lack such a history. Although cytomegalovirus is probably not an etiologic agent in the development of UC, it does appear to be associated with up to 25% of cases of steroid-resistant fulminant disease.

Dysbiosis of the Gut Microbiome

The interplay between the gut microbiome and the enteric immune system has been the focus of important research over the last decade. Intestinal dysbiosis characterized by an overall decrease in microbial biodiversity with a decrease of Firmicutes and increase in Enterobacteriaceae has been described. In children hospitalized with a severe UC exacerbation, the richness, evenness, and biodiversity of the gut microbiome was notably reduced compared to controls. Further study of the factors associated with these microbial changes holds the promise of a better pathogenic, prognostic, and therapeutic understanding of this illness.

Food Allergy

Allergic reactions, especially to dietary antigens such as milk, have been investigated extensively, but data supporting an allergic etiology for UC are lacking. High titers of antibodies to dietary antigens such as milk are not specific to UC. Patients with UC at times respond to elemental or elimination diets, but when the particular food that appeared to induce symptoms is reintroduced, symptoms are only rarely reproduced consistently.

Psychological Factors

In the past, UC has been considered to be a psychosomatic disorder. However, although children with UC often demonstrate psychologic profiles that distinguish them from healthy children and other chronic disease controls, these traits do not appear to be the cause of the illness. An analysis of the literature on the psychosomatic etiology of UC demonstrates many methodologic deficiencies, including lack of controls, lack of diagnostic criteria, and nonblinded collection of data. None of the well-designed studies in the literature shows an association between UC and psychiatric disturbance.

Metabolic Deficiencies—Short-Chain Fatty Acids

Short-chain fatty acids extracted from the luminal contents are a major source of energy for the colonocyte. The observation that fecal butyrate is increased in UC has suggested the possibility that UC might represent a form of colonic mucosal “malnutrition.” It is not clear, however, that the observed increase in fecal butyrate in UC is due to the colonocyte’s inability to utilize short-chain fatty acids, as changes in butyrate production due to intestinal dysbiosis could instead explain these findings.

Diet

Little is known about the effect of diet on the development of UC in children. A prospective study in adults has demonstrated that subjects with the highest intake of n-6 polyunsaturated fatty acids (PUFAs) (as linoleic acid) were more than twice as likely (odds ratio [OR] 2.49, 95% CI 1.23 to 5.07; p = 0.01) as those with the lowest intake to develop UC. By contrast, those with the highest intake of the n-3 PUFA, docosahexaenoic acid, had a significantly reduced OR (0.23, 95% CI 0.06 to 0.97) for the development of UC. Because n-6 PUFAs are converted into proinflammatory molecules including arachidonic acid, prostaglandin E2, leukotriene B4, and thromboxane A2, there is biologic plausibility for the hypothesis that high consumption of linoleic acid (found in red meats and cooking oils) might contribute to the development of UC. Similarly, n-3 PUFAs promote the production of anti-inflammatory molecules, such that a diet high in these fatty acids might plausibly protect against the development of UC.

Fiber and vitamin D intake may have less effect on the development of UC. In a prospective study of almost 240,000 registered nurses, a high cumulative average intake of dietary fiber was associated with a lower incidence of Crohn’s disease but no similar protective effect was observed for those who developed UC. Similarly, higher plasma 25(OH) vitamin D levels were significantly associated with a lower risk of developing CD, but not UC.

Anatomic Distribution

The extent of UC at the time of diagnosis appears to have varied over the years, possibly as a function of the area of the world being described. Before the mid-1970s, the extent of disease in UC determined by barium enema and sigmoidoscopy estimated that 60% of children had pancolitis, 22% left-sided colitis, and 17% proctitis or proctosigmoiditis. A study from the northeastern United States in the 1980s and early 1990s, however, found that at diagnosis only 41% of children have pancolitis, whereas 34% had left-sided disease and 26% proctitis or proctosigmoiditis. There has been a suggestion that pancolitis is more common in younger children, with one report from the United States identifying pancolitis in 71% of children younger than 10 years of age presenting with UC. However, a Danish study identified pancolitis in only 13% of children younger than 10 years, and a U.S. study of children younger than the age of 5 years at diagnosis identified pancolitis in only 40%. It is estimated that there is proximal extension of disease within 3 years of initial UC diagnosis in up to 25% of children initially presenting with proctosigmoiditis and 29% to 70% over the course of follow-up.

Although UC has classically been described as a diffuse inflammation confined to the rectum and colon, careful endoscopic and pathologic studies demonstrate that this is not entirely true. Upper gastrointestinal involvement has been found, with esophageal disease in 15% to 50% of cases and gastroduodenal inflammation in 25% to 69%. Gastric biopsies examined by immunostaining reveal lymphocytes expressing markers characteristic of a T helper cell type 2 (Th2) immune response, similar to that found in the rectum of children with UC. Descriptions of distal colonic UC associated with periappendiceal or appendiceal inflammation have also been published. Therefore, in a patient with colitis, inflammation in the proximal gastrointestinal tract or partial colonic involvement with associated “skip” lesions is not necessarily evidence of Crohn’s disease.

Macroscopic Findings

The inflammatory changes characteristic of UC are confined to the mucosal surface. Therefore, to the surgeon or pathologist, the external surface of the colon appears normal. On the other hand, macroscopic changes are immediately apparent to the endoscopist. Classically, mucosal abnormalities begin at the anal verge and extend proximally to a variable extent. In the untreated patient, rectal sparing should suggest Crohn’s disease, although a few children with well-documented UC have been described to have macroscopic rectal sparing at initial presentation. Because treatment (both systemic and rectal) can significantly change the appearance of the mucosa, particular care must be taken in interpreting the finding of rectal sparing in the child undergoing endoscopy once therapy has been initiated.

The gross appearance of the mucosa in UC depends on the severity of inflammation ( Figure 43-1 ). Mild disease is characterized by diffuse erythema and loss of the normal mucosal vascular pattern. A fine granularity can also be present. Moderate inflammation results in numerous small surface ulcerations, scattered flecks of exudate, and spontaneous or contact bleeding from the mucosal surface. With more active disease, larger, deep ulcerations covered with shaggy exudate become widespread. Because these ulcers surround less involved areas of mucosa, single or multiple pseudopolyps form ( Figure 43-2 ). All of these changes are present diffusely in involved areas of the large bowel, but the severity of the inflammatory process can vary from location to location.

Endoscopic appearance of the colon in ulcerative colitis. (A) Mild inflammation. (B) Moderate inflammation. (C) Severe inflammation. (See plate section for color.)

Macroscopic appearance of the colon of a 16-year-old patient with ulcerative colitis at the time of subtotal colectomy. Note the mucosa characterized by diffuse ulceration and multiple pseudopolyps.

(Courtesy Ellen Kahn, MD.)

Microscopic Findings

Neutrophilic infiltration of crypts (cryptitis) often accompanied by crypt abscesses, depletion of goblet cell mucin, and chronic inflammatory cells in the lamina propria constitute the primary histologic findings in UC ( Figure 43-3 ). In addition, signs of chronicity include evidence of crypt damage such as crypt distortion, a papillary configuration to the surface epithelium, and Paneth cell metaplasia. None of these findings is pathognomonic for UC, as similar changes can be seen in severe Crohn’s colitis. Infectious colitis may also have a similar appearance, although histologic differentiation of UC from acute self-limiting colitis is generally possible. Although diffuse histologic involvement of the affected bowel is typical in the untreated patient, a few children have manifested patchy inflammation and rectal sparing. In surgical specimens obtained from patients with severe or fulminant disease, ulceration can, at times, extend into the submucosa or rarely the deeper layers of the bowel wall.

Colonic biopsy. Active ulcerative colitis, characterized by neutrophilic infiltration of the crypts, crypt abscesses, and crypt distortion. Hematoxylin & eosin stain, ×125.

(Courtesy Ellen Kahn, MD.)

Symptoms and Signs

Children with UC most commonly present with diarrhea, rectal bleeding, and abdominal pain ( Table 43-1 ). Frequent watery stools can contain either streaks of blood or clots, and are most common on arising in the morning, after eating, and during the night. Children often describe both tenesmus and urgency, although the former symptom is at times misinterpreted as constipation by the child or parent. Acute weight loss is common, but abnormalities of linear growth are unusual (see later discussion).

The severity of symptoms at presentation is variable. Some 40% to 50% of children and adolescents present with mild symptoms, characterized by fewer than four stools per day, only intermittent hematochezia, and minimal (if any) systemic symptoms or weight loss. These children generally have normal findings on physical examination, or only minimal tenderness on palpation of the lower abdomen. Stools may have streaks of blood or may be positive only for occult blood. Laboratory studies can reveal mild anemia and raised acute-phase reactants such as the erythrocyte sedimentation rate. However, some children have entirely normal laboratory findings.

Another third of children are moderately ill, often displaying weight loss, more frequent diarrhea, and systemic symptoms. Physical examination demonstrates abdominal tenderness, whereas laboratory studies often are characterized by moderate leukocytosis, mild anemia, and raised acute-phase reactants.

The final 10% to 15% of the pediatric UC population has an acute fulminant disease presentation. These patients appear moderately to severely toxic and have severe crampy abdominal pain, fever, more than six diarrheal stools per day, and, at times, copious rectal bleeding. They frequently manifest tachycardia, orthostatic hypotension, diffuse abdominal tenderness without peritoneal signs, and distension. Laboratory studies reveal leukocytosis, often with numerous band forms, anemia, thrombocytosis, and hypoproteinemia. Toxic megacolon represents the most dangerous extreme of acute fulminant colitis and is quite rare in the pediatric age group.

Extraintestinal Manifestations

Extraintestinal manifestations are common in children with UC and can affect almost every organ system. The more common sites of involvement are the skin, eye, biliary tree, and joints. Although the etiology of these extraintestinal manifestations remains unknown, it has been shown that an anti-colonocyte antibody detectable in the serum of patients with UC cross-reacts with antigens present in the skin, ciliary body of the eye, bile duct, and joints. Many of the extraintestinal manifestations tend to occur at times of increased colitis activity. It is therefore tempting to speculate that extraintestinal symptoms develop when autoantibodies capable of recognizing these nonintestinal tissues are produced as part of the humoral response characteristic of UC.

Hepatobiliary

The most serious hepatobiliary diseases associated with UC are primary sclerosing cholangitis (PSC) and autoimmune hepatitis. The presentation and severity of these manifestations are generally independent of the activity of colitis and often do not appear to be affected by medical management of UC or by colectomy. PSC occurs in 3.5% of children and adolescents with UC, although with long-term follow-up into adulthood rates as high as 9.8% have been described. Autoimmune hepatitis is seen in less than 1%. Either may be present at the time of, or even precede, the initial diagnosis of UC, or may develop during the course of the illness.

Both illnesses cause variable degrees of chronic liver disease, ranging from mild to end-stage liver disease requiring transplantation, or death. PSC also is a risk factor for the development of cholangiocarcinoma.

Compared to patients with UC alone, adults with PSC and UC tend to present at a younger age and have a greater likelihood of having more extensive, but less severe, colitis. It has also been shown that the presence of PSC enhances the risk of colorectal aneuploidy, dysplasia, and cancer in patients with UC. The absolute cumulative risk for colorectal cancer in patients with UC and PSC is 9%, 31%, and 50% after 10, 20, and 25 years of disease, respectively, compared with 2%, 5%, and 10% in patients with UC without PSC. In patients with UC and PSC who have a colectomy and ileal pouch, the risk of severe mucosal atrophy, aneuploidy, and dysplasia in the pouch also appears to be increased. In addition, those with PSC and UC complicated by colorectal cancer are at increased risk of cholangiocarcinoma, compared with patients with PSC and UC but no colorectal malignancy. Although treatment with ursodeoxycholic acid has shown some potential benefit in decreasing the risk of colonic cancer in adult patients with UC and PSC, earlier initiation and increased frequency of colonic surveillance is indicated.

In addition, liver function abnormalities can be seen in a variety of other clinical circumstances, for instance during periods of increased colitis activity, as well as in association with specific therapies used for colitis including corticosteroids, sulfasalazine, parenteral hyperalimentation, azathioprine, and 6-mercaptopurine (6-MP), or with fatty changes associated with massive acute weight gain.

Joints

Arthralgia has been described in up to 32% of children with UC at some time during their course. Arthritis, either a peripheral migratory type affecting the large joints or a monoarticular nondeforming arthritis primarily affecting the knees or ankles, has been reported in 10% to 20% of children. The presence and activity of arthritis and arthralgia generally, but not invariably, correlate with the activity of the bowel disease. Ankylosing spondylitis occurs in up to 6% of adults with UC, but is rare during childhood.

Skin

Cutaneous manifestations occur during periods of enhanced colitis activity, with erythema nodosum occurring more commonly than pyoderma gangrenosum. Erythema nodosum lesions appear as raised, erythematous, painful circular nodules that usually occur over the tibia, but may also be present on the lower leg, ankle, or extensor surface of the arm. Lesions persist for several days to a few weeks and generally remit with treatments directed at the enhanced colitis activity. Pyoderma gangrenosum usually appears as small, painful, sterile pustules that coalesce into a larger sterile abscess ( Figure 43-4 ). This ultimately drains, forming a deep, necrotic ulcer. Lesions usually occur on the lower extremities, although the upper extremities, trunk, and head are not spared. A variety of possibly beneficial therapies have been reported, although at present systemic or local ciclosporin, tacrolimus, and intravenous infliximab appear to be the treatments of choice.

(A) Pustular phase of pyoderma gangrenosum in a 15-year-old boy with ulcerative colitis. Cutaneous lesions began to appear 2 weeks after initial gastrointestinal symptoms. (B) Typical chronic ulcer of pyoderma gangrenosum from the same patient located on the dorsal surface of the forearm.

Thromboembolic Disorders

Case reports document the occurrence of thromboembolic complications in children with UC. Sites of venous or arterial thrombosis include the extremities, portal or hepatic vein, lung, and central nervous system. Although thrombophilia, hyperhomocysteinemia possibly due to folate deficiency or vitamin B ₆ deficiency, and specific mutations of coagulation factors such as factor V Leiden have been described in individual patients with UC and a history of thrombosis, no consistent abnormality has been identified to explain why only a subset of patients develops thrombotic complications.

A recent discussion has introduced a novel pathologic mechanism that may explain the increased risk of thrombosis in IBD. Studies in adults have shown an increase in endogenous thrombin potential (ETP). Unlike coagulation intermediates or fragments, which are markers of thrombin produced, the ETP measures thrombin activity that can be generated in plasma. A study using pediatric IBD subjects has also shown increased ETP compared to controls. Furthermore, this study was able to demonstrate significantly increased amounts of microparticles in those children with active UC. Microparticles are microvesicles released from the plasma membrane that catalyze the formation of clotting factors and have been implicated in the coagulation process. Therefore, their increased amounts at times of inflammation may indicate a hypercoagulable state, and in future studies may prove useful as a prognostic marker for thrombosis.

Ocular Disorders

Eye involvement in UC is rare in children, although episcleritis and asymptomatic uveitis have been described. Other ocular disorders such as posterior subcapsular cataracts or increased ocular pressure may be the result of corticosteroid therapy.

Measurements of Disease Activity

A variety of disease activity indices ( Table 43-2 ) have been proposed as a means of standardizing definitions of UC severity and serving as an outcome variable for clinical trials. The pediatric ulcerative colitis activity index (PUCAI) has been extensively validated, with cut-offs for remission at less than 10 points, mild disease 10 to 34 points, moderate disease 35 to 64 points, and severe disease greater than 64 points. It has been demonstrated to be useful in predicting the response of children hospitalized with moderate-to-severe UC to intravenous corticosteroid therapy, and in indicating when second-line therapy is warranted. Additional clinical indices assessing endoscopic clinical appearance have also been proposed ( Table 43-2 ). Although no index has been used or accepted universally, several have been used in pediatric clinical trials. Newer indices are being developed to improve validity and reliability of endoscopic mucosal assessment.

Bleeding

Hematochezia is nearly universal in UC, but severe hemorrhage requiring urgent or multiple transfusions occurs in less than 5% of cases. When present, severe hemorrhage is usually the result of diffuse, active, mucosal ulceration. Children who continue to require blood transfusions after 7 to 14 days of intensive medical therapy have been shown to be at risk for significant complications and colectomy.

Perforation

Free perforation of the colon is an emergent complication of UC that occurs rarely. Circumstances that predispose to perforation include acute fulminant colitis, toxic megacolon, and diagnostic interventions such as barium enema or colonoscopy. In these settings, gaseous distension or direct pressure from an endoscope can generate sufficient force to perforate the inflamed colon. Peritonitis and septic shock can result. These potentially life-threatening complications require appropriate fluid resuscitation, broad-spectrum antibiotics, and emergent surgery. Plain radiographs of the abdomen may be required to identify a possible free perforation in children with UC who develop worsening symptoms or shoulder pain, as concomitant corticosteroid therapy may mask physical findings such as boardlike rigidity or diffuse rebound tenderness.

Toxic Megacolon

This complication represents a medical and potentially surgical emergency. It has been described in up to 5% of children and adolescents with UC, although data gathered in the 1980s and 1990s described only one patient with toxic megacolon in 171 children followed for a total of 823 patient-years. At the time of diagnosis of toxic megacolon, altered levels of consciousness and hypotension appear to be rare in children, whereas fever, tachycardia, electrolyte disturbance, and dehydration are more common. Radiographic signs suggestive of toxic megacolon include intestinal thickening, abnormal colonic haustra, and a transverse colon diameter of 56 mm or greater. Improper diagnosis or treatment can lead to a rapidly progressive deterioration complicated by severe electrolyte disturbances, hypoalbuminemia, hemorrhage, perforation, sepsis, and/or shock. Precipitating factors include the use of antidiarrheal agents such as anticholinergics or opiates, and excessive colonic distension during barium enema or colonoscopy.

Carcinoma

The colorectal tumors that develop in the setting of chronic UC are adenocarcinomas. In contrast to sporadic adenocarcinomas, tumors that arise in UC do not begin as adenomatous polyps, but rather as flat lesions characterized by the presence of dysplasia. The genetic alterations that precede the development of dysplasia occur multifocally in the colon, so that the resulting adenocarcinomas are evenly distributed about the colon. Multifocal or synchronous tumors are present in 10% to 20% of patients.

Individuals who develop UC during childhood have a particularly high lifetime risk of colorectal cancer because duration (greater than 10 years) and extent (pancolitis > left-sided colitis > proctitis) of colitis are the two most critical risk factors for cancer in this condition. Other less well-characterized risk factors include concomitant sclerosing cholangitis; an excluded, defunctionalized, or bypassed segment; depressed red-blood-cell folate levels; and having a family history of non–colitis-associated colon cancer. Patients as young as 16 years of age have been demonstrated to have colonic aneuploidy, dysplasia, or cancer, although, as in adults, the risk for these changes does not appear to be significant in the first decade of illness.

Population-based studies support the observation that children with UC have an increased lifetime risk of colorectal cancer. A large Swedish study revealed that children with onset of UC before the age of 15 years have a standardized incidence ratio (SIR, the ratio of observed to expected cases) of colorectal cancer of 118 (162 for those with pancolitis), compared with an SIR ranging from 2.2 to 16.5 in individuals older than 15 years at diagnosis. These values translate into cumulative colorectal cancer incidence rates of 5% at 20 years and 40% at 35 years for patients with colitis onset at ages 0 to 14 years, and 5% and 30%, respectively, for those whose colitis began between the ages of 15 and 39 years.

Given the high risk of colorectal cancer, surveillance colonoscopy has been advocated as an approach that might lessen the need for prophylactic proctocolectomy. Surveillance programs as currently practiced have a lack of objective premalignant markers and problems associated with invasive testing. A standardized definition of dysplasia (negative, indefinite, low grade, high grade) is in widespread use, but interobserver variability using these definitions results in major discrepancy rates of 4% to 7.5% between expert pathologists reviewing the same slides. In addition, evaluations must be made, but have not always been reported, based on an “intent to treat” model, because noncompliance with the surveillance protocol (refusal to enroll or maintain a regular examination schedule) and inability to evaluate the entire colon adequately because of stricture, poor bowel preparation, or active disease constitute realities of surveillance that have a direct bearing on the efficacy of the surveillance strategy.

The literature generally reflects the practice of performing colectomy only when high-grade dysplasia or cancer is detected. With this approach, a review of prospective cohort studies has revealed that surveillance detects cancer at an early and potentially curable stage 65% of the time, thereby reducing the frequency of detecting advanced lesions from 60% to 35%. However, the data suggest that 33 patients would have to be under regular surveillance for 15 years to prevent one incurable cancer. With biannual examinations resulting in seven to eight colonoscopies per patient, a total of about 250 procedures would be performed to prevent one incurable cancer. Analyses such as these have led to a vigorous discussion regarding the cost-effectiveness of surveillance as currently practiced.

These data have led to a search for better markers to enhance the predictive accuracy of surveillance. Meta-analysis supports the inclusion of low-grade dysplasia as an indication for colectomy, as identification of low-grade dysplasia during surveillance colonoscopy is associated with a 9-fold increased risk of developing colorectal cancer and a 12-fold risk of any advanced lesion. Other markers, including aneuploidy, loss of tumor suppressor gene (e.g., p53 ) function, expression of proto-oncogenes (e.g., K- ras ), and expression of abnormal mucin-associated antigens (e.g., sialosyl-Tn), have also been investigated as adjuncts to surveillance for dysplasia.

No prospective studies have assessed the optimal schedule of surveillance, although a cost–benefit analysis has suggested colonoscopies every 3 years for the first 10 years of surveillance, with more frequent investigations as the duration of colitis increases. Current practice generally begins with biannual colonoscopies 7 to 10 years after diagnosis. Although many advocate initiating surveillance only after 15 to 20 years of disease in adults with left-sided colitis or proctosigmoiditis, the frequent proximal extension of these disease distributions in patients with onset of disease during childhood suggests that all patients with childhood-onset UC of any extent be enrolled in a surveillance program within 10 years of initial diagnosis.

The optimal approach to performing surveillance is also in flux as new equipment and techniques become available. The previous gold standard, panendoscopy to the cecum with two to four biopsies every 10 cm from the cecum to the rectum, has been shown to be insensitive for detecting dysplasia. Newer modalities including high definition and magnification white light endoscopes, chromoendoscopy, narrow band imaging, and confocal endomicroscopy have all been shown to enhance dysplasia rates by allowing more directed mucosal biopsies. Current recommendations for colectomy include any identification of dysplasia (low or high grade) confirmed by two independent experienced pathologists. Repeat colonoscopy for confirmation of dysplasia on new biopsies is not recommended, because there is no way to guarantee that the identical site can be biopsied on a subsequent procedure. If indefinite dysplasia is identified, aggressive medical management to reduce active inflammation followed by repeat surveillance colonoscopy within 3 to 6 months is indicated.

Growth and Development

It is common for children to demonstrate acute weight loss at the time of diagnosis or during periods of increased disease activity. However, children who develop UC are not immune to obesity, and studies from two independent North American populations have identified that 20% to 30% of children with UC have elevated body mass index (BMI) at diagnosis consistent with overweight or risk for overweight. However, as opposed to Crohn’s disease, only about 10% of children with UC demonstrate significantly impaired linear growth.

History

Many children present with obvious symptoms of diarrhea and rectal bleeding. However, in others, symptoms are less obvious and more difficult to elicit, especially in children or adolescents who are unwilling or too embarrassed to discuss the frequency and consistency of their bowel movements. Awakening with pain or the need to defecate is an especially important symptom, as it often helps to differentiate the child with organic illness from one with a functional condition. The history should seek to identify evidence of recent weight loss, poor growth, arrested sexual development, or, in the postmenarchal adolescent, secondary amenorrhea. When family history reveals other relatives with IBD, the possibility that UC is present is increased.

Physical Examination

A careful physical examination may demonstrate a number of findings that help suggest the appropriate diagnosis. Children with active colitis often have mild-to-moderate abdominal tenderness, especially in the left lower quadrant or midepigastric area. Tender bowel loops may be palpable, although inflammatory masses are lacking. With fulminant disease, marked tenderness can be present. Perianal inspection is generally normal, and the presence of perianal tags or fistulas suggests Crohn’s disease. The presence of skin lesions, such as erythema nodosum, pyoderma gangrenosum, or cutaneous vasculitis, or of arthritis is an important clue to the autoimmune nature of the child’s illness.

Laboratory Studies

Once UC is suspected, the laboratory studies outlined in Box 43-2 help to exclude other illnesses and provide evidence to support proceeding to more invasive radiologic and endoscopic diagnostic procedures. Microcytic anemia, mild-to-moderate thrombocytosis, elevated erythrocyte sedimentation rate, C-reactive protein, and hypoalbuminemia are present in 40% to 80% of patients. Total white blood cell count is normal to only mildly increased, unless the illness is complicated by acute fulminant colitis. Abnormal liver function is found in 3% of children at the time of initial diagnosis and reflects signs of potentially serious concomitant liver disease (chronic active hepatitis or sclerosing cholangitis) in about half of them. In a number of children, however, all laboratory studies can be normal. Fecal levels of calprotectin, a neutrophil-associated protein present in the stools in conditions associated with intestinal inflammation, are higher in patients with active UC than in healthy controls and correlate well with the severity of endoscopically determined mucosal inflammation. Although calprotectin levels can also be elevated in patients with enteric infection or Crohn’s disease, an increased fecal calprotectin assay can help determine which children with abdominal pain or diarrhea should undergo more invasive testing for UC or Crohn’s disease. Screening of children using fecal calprotectin is effective and cost-effective to identify those with IBD. An elevated fecal calprotectin level has also been shown to predict relapse in patients with apparent quiescent UC. Rapid decreases in fecal calprotectin levels at week 2 and week 10 of infliximab induction were shown to predict endoscopic and clinical remission in infliximab-naive adult patients with UC. Consequently, absence of a rapid decrease in fecal calprotectin may identify a group of infliximab nonresponders. When used to monitor pediatric UC disease, fecal calprotectin levels may lag behind improvements in clinical activity as measured by the PUCAI, which may reflect delayed mucosal healing or ongoing subclinical activity.

Enteric pathogens must be excluded in all patients, both at the time of diagnosis and during acute flares of active disease after diagnosis. Particular attention should be given to the possibility of Clostridium difficile –mediated colitis. If a pathogen is identified, it must be treated and the patient followed, as it is not unusual for children with UC to present initially with superimposed infection. If symptoms persist despite eradication of the identified pathogen, workup should continue.

Serologic tests for the detection of circulating perinuclear antineutrophil cytoplasmic antibody (pANCA) can be useful in differentiating UC from other colitides, including Crohn’s disease. pANCA can be detected in about 70% of patients with UC, but is present in only 6% of Crohn’s patients, and 3% of controls. However, pANCA-positive Crohn’s patients tend to have “UC-like” disease, making reliance on this serologic marker as a means of differentiating UC from Crohn’s disease problematic. Although the other serologic markers commonly identified in patients with IBD (anti- Saccharomyces cerevisiae antibody [ASCA] and anti-outer membrane porin of Escherichia coli [anti-ompC]) are found only rarely, the anti-flagellin antibody (anti-CBir1) can be found in up to 30% of children with UC. The use of these antibodies for differentiating IBD from functional disorders has also been made more problematic by the recognition that anti-flagellin antibodies can also be identified in adults with irritable bowel syndrome. Despite this, a positive pANCA coupled with a negative ASCA titer has a sensitivity of 69.2%, specificity of 95.1%, positive predictive value of 90.0%, and negative predictive value of 87.1% for the diagnosis of UC in children. Although children with indeterminate colitis may be negative for all serologic markers, at times the markers can be helpful in determining whether the child actually has Crohn’s disease or UC. In adults with indeterminate colitis, a finding of pANCA+/ASCA− predicts UC in 64%, whereas pANCA−/ASCA+ findings predict Crohn’s disease in 80%.

Radiography

Endoscopy has replaced radiography as the modality of choice for diagnosing UC. Barium enema, computed tomographic (CT) and magnetic resonance (MR) colonography are rarely indicated. In most circumstances, however, the child with suspected UC should undergo an evaluation of the small bowel to help exclude the possibility of Crohn’s disease. This can be done by upper gastrointestinal series with small bowel follow-through, CT or MR enterography, or capsule endoscopy depending on local availability and expertise with each of the modalities.

Abdominal ultrasonography and various scintigraphic techniques including technetium-99m-hexamethylpropyleneamine oxime (HMPAO)–labeled white cell scan can be used to assess the presence and extent of intestinal inflammation, although these studies are not used widely to establish the initial diagnosis. Overall, these modalities, along with CT or MR studies, are more useful in identifying complications associated with Crohn’s disease than for UC.

Endoscopy

Colonoscopy allows accurate determination of the extent and distribution of colitis through direct visualization and biopsy of the affected segments. UC is characterized by diffuse inflammation, which begins at the anal verge and progresses proximally to a variable degree. Although rectal sparing is generally associated with Crohn’s disease, untreated children can have rectal sparing at initial col­onoscopy yet subsequently evidence typical UC. In mild UC, the rectal and colonic mucosa appears erythematous, the normal vascular markings are lost, and there is increased friability evidenced by petechiae or contact hemorrhage (see Figure 43-1A ). With more active disease, exudate, ulcerations, and marked hemorrhage are evident (see Figure 43-1B,C ). Skip lesions, aphthous ulcerations, and significant ileal inflammation are indicative of Crohn’s disease. All children who undergo endoscopy should be biopsied, because the histologic appearance can often help differentiate among acute self-limiting colitis, Crohn’s disease, and UC.

Although UC is described as an inflammatory disease confined to the colon, endoscopic studies can reveal inflammation of the proximal gastrointestinal tract. A pattern of focally enhanced gastritis is seen in 21% of children with UC, and 50% can have features of chronic gastritis. UC-associated gastroduodenitis has been described in adults with UC who have significant upper gastrointestinal hemorrhage following colectomy. These observations require that clinicians do not automatically exclude the possible diagnosis of UC in a child with colitis who is shown to have endoscopic or histologic gastritis. Similarly, children with UC can also have discontinuous disease, with concomitant diffuse distal colitis and cecal or periappendiceal inflammation.

Capsule endoscopy has been shown to be of benefit when there is some doubt in the diagnosis of UC versus Crohn’s disease. Although a negative capsule study does not confirm a diagnosis of UC, detection of clear-cut ulceration in the small bowel disease can be helpful in confirming a diagnosis of Crohn’s disease. In a study assessing the impact of capsule endoscopy on decision making in pediatric IBD, half of the children with presumed UC/IBD-unclassified had their diagnosis changed to Crohn’s disease.

Nutritional Therapy

Although nutritional therapies have a role as primary treatment in Crohn’s disease, UC is less amenable to nutritional interventions. Elimination diets rarely result in significant improvement in symptoms and can promote inadequate nutritional intake in the child who finds the elimination diet prescribed unpalatable or too restrictive. Similarly, although “bowel rest” can ameliorate symptoms in Crohn’s disease of the small bowel, it is often ineffective in UC, possibly because the colonocyte derives energy from the fecal stream in the form of short-chain fatty acids. In addition, because growth failure is a much more frequent and dramatic problem in Crohn’s disease than in UC, the nutritional therapy of growth failure becomes more central to the treatment of the former illness.

One possible nutritional approach is the oral supplementation of n-3 fatty acids derived from fish oil. Initial studies suggested that early relapse of UC could be delayed by supplementing the diet with 5.1 g/day of n-3 fatty acids, although relapse rates after 3 months were comparable to those in placebo-treated controls. Similarly, n-3 fatty acids provided no, or only modest, steroid-sparing effect compared with placebo in the treatment of acute UC. Only a single small pediatric trial has been reported. Compared with pretreatment values, children with UC in remission who were supplemented orally with purified eicosapentaenoic acid for 2 months had decreased leukocyte and rectal production of leukotriene B ₄ .

Corticosteroids

Corticosteroids appear to downregulate multiple steps in the inflammatory cascade that results in UC. The initial use of corticosteroids as treatment for children with UC was largely extrapolated from studies in adults. Pediatric treatment regimens have evolved through empiric use and clinical experience, rather than controlled clinical trial. Prednisone, methylprednisolone, and hydrocortisone are the agents most frequently used. Commonly prescribed dosages are comparable to those prescribed for children with Crohn’s disease. Oral doses greater than 40 mg of prednisone are rarely necessary for efficacy and can be associated with significant toxicity. Oral corticosteroids are well absorbed, although occasionally children with poor absorption or corticosteroid resistance may benefit from intravenous bolus or continuous infusion dosing. When fulminant disease requires hospitalization for intravenous corticosteroid therapy, prospective pediatric data demonstrate that clinical features can predict the success or failure of therapy. A PUCAI greater than 45 on day 3 of intravenous corticosteroids serves as a screen for those failing corticosteroid therapy, and a PUCAI greater than 70 on day 5 indicates the likely need for salvage therapy. Because there are now reasonable medical alternatives to an extended course of intravenous corticosteroid (see later discussion), such observations strongly argue for limiting the use of intravenous corticosteroid to no more than 5 to 7 days when significant symptom improvement is not seen during that period of time. Rectal corticosteroids are particularly beneficial in children with severe tenesmus and urgency, but many children have difficulty retaining enema formulations, so that foam-based treatments or suppositories may be preferable in selected individuals.

The decision to use corticosteroids must be balanced by their potential adverse effects. A wide spectrum of complications occasionally occurs ( Box 43-5 ). More important, systemically active corticosteroids can interfere with linear bone growth, even in the face of adequate dietary intake. Alternate-day dosing minimizes these effects while maintaining reduced disease activity and appears to have no deleterious effect on bone mineralization in children. However, in patients who have not completed their linear growth and whose disease activity cannot be controlled by alternate-day dosing regimens, the anti-inflammatory effects of daily corticosteroids must be weighed against the coincident suppression of linear growth.

Topically active corticosteroids such as budesonide have the potential to provide anti-inflammatory activity to the gut without systemic toxicity because of their high first-pass metabolism. These agents may offer particular advantages for the treatment of children if they prove to be minimally growth suppressive, but adequate pediatric studies in UC have yet to be reported. In adults, the enema formulation of budesonide is as effective as rectal mesalamine and rectal prednisolone or hydrocortisone in the treatment of left-sided and distal colitis. A budesonide rectal foam is also as effective as a hydrocortisone foam in adults with proctosigmoiditis, and 52% of previous rectal mesalamine failures responded to the budesonide foam.

Due to fewer systemic side effects, oral second-generation corticosteroids with high first-pass metabolism represent an attractive therapeutic option. Data on their effect in UC, and especially pediatric UC, are limited, however. One formulation of oral budesonide, Entocort EC, often is of limited usefulness in UC because it uses a pH-dependent coating to release the locally acting corticosteroid predominantly in the distal ileum and proximal colon. Uceris, a newer formulation of budesonide with a colonic release system (MMX, Multi-Matrix System), has been developed that can target drug delivery to the entire colon. In a randomized multicenter study of adult UC patients, budesonide MMX was shown to induce clinical and endoscopic remission significantly more than Entocort EC and placebo. Additional studies are required to determine whether the oral formulation of budesonide with MMX technology will be effective therapy in children with UC.

Corticosteroid resistance remains a difficult problem for many patients. Although only 21% of a small pediatric UC cohort demonstrated no response to an acute course of corticosteroid, a complete response was seen in only 57% at 1 year, whereas 14% were steroid dependent and 29% required colectomy. A large North American multicenter registry reported that 50% of children were responsive to an initial course of corticosteroid, but 45% were steroid dependent at 1 year. A number of different mechanisms appear to result in corticosteroid resistance, including IL-2-induced inhibition of glucocorticoid receptor activity and decreased intracellular glucocorticoid levels due to overexpression of the multidrug resistance gene 1. Therapeutic strategies designed to overcome these factors are under investigation.

5-Aminosalicylates

It is postulated that the 5-ASA drugs (sulfasalazine, mesalamine, olsalazine, and balsalazide) exert local anti-inflammatory effects through a number of different mechanisms. These include inhibition of 5-lipoxygenase with resulting decreased production of leukotriene B ₄ , scavenging of reactive oxygen metabolites, prevention of the upregulation of leukocyte adhesion molecules, and inhibition of IL-1 synthesis. Because 5-ASA is rapidly absorbed from the upper intestinal tract on oral ingestion, different delivery systems have been used to prevent absorption until the active drug can be delivered to the distal small bowel and colon. Sulfasalazine (Azulfidine) links 5-ASA via an azo bond to sulfapyridine. Bacterial enzymes in the colon break the azo linkage, releasing 5-ASA to exert its anti-inflammatory effect in the colon. Because the sulfapyridine moiety causes most of the untoward reactions to sulfasalazine and is thought to have no therapeutic activity, newer agents have been designed to deliver 5-ASA without sulfapyridine. Olsalazine (Dipentum) links two molecules of 5-ASA via an azo bond, and balsalazide (Colazal and Colazide) links 5-ASA via an azo bond to an inert, nonabsorbed carrier. A number of other delayed release preparations (Delzicol, Asacol-HD, Claversal, Mesasal, Salofalk, and Apriso) prevent rapid absorption of 5-ASA (also known generically as mesalamine) by coating it with pH-sensitive resins. Another preparation (Pentasa) coats microgranules of mesalamine with ethylcellulose, releasing it in a time-dependent fashion. Still another preparation (Lialda) utilizes a novel matrix system to deliver high concentrations of 5-ASA to the colonic mucosa. Uncoated mesalamine is also available as a rectal suppository (Canasa and Salofalk) or enema formulation (Rowasa). Unfortunately, no liquid formulation of oral 5-ASA is commercially available in the United States, and only the azo-bond formulations can be extemporaneously compounded into a suspension. Similarly, the coated formulations cannot be crushed or broken, thereby limiting their use to children who are able to swallow pills intact.

Overall, the 5-ASA drugs have been shown to be effective in controlling mild-to-moderate UC in adults in 50% to 90% of cases, and effective in maintaining remission in 70% to 90%. In addition, chronic treatment with a 5-ASA medication has been shown to be a chemopreventative therapy, decreasing the risk for the development of UC-associated colon cancer. In a large prospective, multicenter study of children with newly diagnosed UC, 40% of children taking 5-ASA drugs were corticosteroid free at 1 year, and did not require rescue therapy. Those with mild-to-moderate disease were more likely to respond. Dosing regimens in children have largely been extrapolated from studies in adults, such that many physicians prescribe between two and four divided doses throughout the day. A National Institutes of Health (NIH)–funded (ClinicalTrials.gov Identifier: NCT01536535 ) multicenter prospective cohort study (25 sites) is currently enrolling newly diagnosed pediatric patients with UC to examine the effectiveness of standardized medical therapy (mesalamine or corticosteroids) in pediatric UC while collecting biospecimens (blood, stool, and colonic biopsy tissue) to assess the effect of genetics, mechanisms of inflammation, vitamin D, and the stool microbiome on clinical outcomes. The high pill burden of some of the 5-ASA formulations as well as the frequent dosing regimens can result in poor adherence to a prescribed treatment regimen, a problem that occurs frequently and can be associated with poor clinical outcomes. Higher potency oral formulations have been developed for adult use, and although these preparations have not been evaluated in children, studies in adults suggest that high-dose, once-daily dosing may be comparable, or even superior, to more traditional split-dose regimens. When rectal preparations of mesalazine were added to the first 4 weeks of oral mesalazine in adults with UC, there was significant improvement in time to cessation of rectal bleeding and in clinical improvement at 2 weeks of treatment over those who only used oral mesalazine. At week 4 of the study, those who received combination therapy showed significantly better mucosal healing.

Adverse reactions to all of the 5-ASA preparations have been described, requiring discontinuation of treatment in 5% to 15% of cases. The more serious complications reported in children have included pancreatitis, nephritis, exacerbation of disease, and sulfa- or salicylate-induced allergic reactions. Although some toxicities (e.g., headache) to sulfasalazine have been attributed to slow acetylation of the drug, a study has demonstrated no association between N -acetyltransferase 1 or 2 genotype and efficacy or toxicity from either mesalamine or sulfasalazine.

Antibiotics

There may be some role for antibiotics in the primary therapy of active UC. Based on experience in adults, metronidazole is occasionally used for the treatment of mild-to-moderate UC or the maintenance of remission in 5-ASA-intolerant or 5-ASA-allergic patients. A controlled trial of ciprofloxacin as an adjunct to corticosteroids in adults with active UC demonstrated no benefit compared with placebo. In a recent meta-analysis, adult patients with UC who were undergoing antibacterial therapy were twofold more likely to experience clinical remission than patients who did not receive antibacterial therapy. Because of the increasing recognition that the microbiome has a role in disease pathogenesis, there has been interest in using antibiotics to eradicate possibly pathogenic species. Compared to placebo, a 2-week course of amoxicillin, tetracycline, and metronidazole was associated with improved clinical response, remission, and steroid withdrawal in active UC. No pediatric studies exist with the more commonly used antibiotics. However, in a retrospective study looking at the use of rifaximin in children with Crohn’s disease or UC, more than 60% experienced relief of their symptoms when rifaximin was identified as the only meaningful change.

Immunomodulators

Fecal Microbial Transplantation

The recognition of intestinal dysbiosis in UC has led to interest in the use of fecal microbial transplantation (FMT) as a treatment for UC. In theory, infusion of healthy donor feces can “normalize” the recipient’s fecal microbial composition and restore microbial metabolic functions to induce and maintain intestinal homeostasis. FMT has become a valid option to treat refractory Clostridium difficile infection and early reports documented complete clinical, colonoscopic, and histologic reversal of UC in six adult patients. In a single-center pilot study, 10 children (7 to 21 years) with mild-to-moderate UC received FMT from healthy family members or close friends by fecal retention enema daily for five consecutive days. Of the nine patients that were included in the clinical response analysis, seven showed clinical response by PUCAI score within 1 week, which was maintained at 1 month in 6 of 9 subjects. Concerns remain about the safety of this therapeutic approach, especially in children receiving concomitant immunosuppressive medications. Until larger studies with standardized treatment regimens are completed in children with UC, FMT should be reserved for treatment within established research protocols.

Leukocyte Apheresis

Leukocyte apheresis involves passing blood from a patient over an extracorporeal filter that acts as a selective adsorptive column. Two different columns have been investigated as treatments for UC, the Adacolumn and the Cellsorba column. Each column has somewhat different filtration properties, such that it appears that results from the two systems may ultimately prove to be somewhat different. The treated blood is reinfused, and depleted of granulocytes, monocytes, and activated platelets. Studies on the effects of apheresis suggest a number of potential mechanisms of action, including reduction in reactive oxygen species–producing granulocytes, reduction of activated platelets, changes in lymphocyte populations, and decreases in circulating proinflammatory cytokines.

Apheresis has been shown to effectively reduce corticosteroid requirements in adults with steroid-dependent UC, resulting in both clinical and endoscopic improvement. It has also been beneficial in the treatment of adults with toxic megacolon. Small studies in children with UC from Japan, Scandinavia, and Spain describe similar beneficial results. This approach appears to be quite safe. A review of 11,428 apheresis sessions performed for a wide variety of non-UC indications reported few adverse effects, with difficulty obtaining venous access (3.1%) and hypotension (1.6%) being the most common.

Colon Cancer Prophylaxis

Because the goals of treatment for UC include prevention of complications in addition to control of inflammation, the potential of medical therapy to prevent colitis-associated cancer has become the focus of intense interest. Epidemiologic and case-control studies have suggested that treatment with an aminosalicylate is associated with a decreased rate of dysplasia and colon cancer. Although the mechanism of action for this benefit is not entirely clear, one recent study has documented that these agents can suppress expression of a colorectal cancer–associated protein, thereby inducing gene-level changes in several critical carcinogenic pathways. Preliminary studies have also suggested that chronic folate supplementation might provide a degree of chemoprevention through suppression of DNA hypermethylation. The effect of other medications used for the treatment of UC, including 6-MP and infliximab, on prevention of colon carcinogenesis are less clear. Increased histologic degree of inflammation was associated with a greater risk for colorectal neoplasia in a large case-controlled retrospective review of adult UC patients. The same study demonstrated that male sex is an important risk factor for neoplasia and that thiopurine exposure may be protective.