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Clinical manifestations and complications of inflammatory bowel disease in children and adolescents

Clinical manifestations and complications of inflammatory bowel disease in children and adolescents
Literature review current through: Jan 2024.
This topic last updated: Jul 19, 2022.

INTRODUCTION — Inflammatory bowel disease (IBD) is comprised of two major disorders: Crohn disease (CD) and ulcerative colitis (UC). CD can involve any component of the gastrointestinal tract from the oral cavity to the anus and is characterized by transmural inflammation. It typically involves the ileum, ileum and cecum, or ileum and portions of or the entire colon. UC affects the colon and is characterized by inflammation of the mucosal layer. Mild ileal inflammation (usually histologic, with mild ileal erythema and granularity, or "backwash ileitis") can be seen in UC. The diagnosis and differentiation between UC and CD are based on a critical assessment of clinical features, biochemical studies, endoscopic findings, histology, and luminal imaging. These disorders have distinct pathologic and clinical characteristics but may sometimes be difficult to distinguish in cases without small bowel involvement.

The peak incidence of IBD occurs in patients between the ages of 15 and 30 years and appears to be rising in the pediatric age group [1-4]. Approximately 20 percent of patients with CD and 12 percent of patients with UC develop their IBD before the age of 20 years [5]. Adults and children with IBD may present with similar clinical features; however, children are at risk for growth failure and delayed puberty due primarily to persistent chronic inflammation. Therefore, in addition to treating the intestinal manifestations of IBD, the treating clinician must monitor and treat the extraintestinal manifestations of IBD, which can be subtle. These include malnutrition, impairment of linear growth, liver inflammation, osteopenia, and mental health issues.

The clinical manifestations of IBD in children and adolescents are reviewed here. The diagnosis of IBD, including the differentiation between CD and UC, is discussed separately. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

PRESENTING SYMPTOMS

Typical presentation – Patients with IBD typically present in late childhood or adolescence with one or several of the following features:

Gastrointestinal symptoms – Patients with ulcerative colitis (UC) usually present with bloody diarrhea, abdominal pain often around bowel movements, and tenesmus. The gastrointestinal manifestations of Crohn disease (CD) can be more subtle, with low-grade abdominal pain, weight loss, lack of appetite, and diarrhea with or without blood. However, the clinical presentations are quite variable, so these features are not sufficient to distinguish between these disorders.

Systemic symptoms – Fever, fatigue, and anorexia are common at presentation and during flares of disease.

Physical findings

-Gastrointestinal – In UC, the abdominal examination is often normal, though some tenderness may be seen. In CD, the abdominal examination may be normal or abdominal tenderness and/or mass (classically in the right lower quadrant) and perianal disease (fistulae, anal skin tags, or fissures) may be seen. Either CD or UC may have gross or occult blood in stool. Some patients, especially those with CD, may have pubertal delay (Tanner stage less than expected for chronologic age).

-Extraintestinal manifestations – Extraintestinal manifestations of IBD include oral ulcerations (aphthous stomatitis), digital clubbing, rash (erythema nodosum or pyoderma gangrenosum), eye inflammation (uveitis), jaundice or hepatomegaly (due to sclerosing cholangitis or hepatitis), or arthritis. (See 'Extraintestinal manifestations' below.)

-Growth – Growth failure (subnormal gains in height or weight, or weight loss) and/or delayed puberty is a common feature, especially in children with CD. Many children are of normal weight, however, and some may even be overweight at presentation [6]. Thus, obesity or lack of growth failure should not preclude a diagnosis of IBD.

Although growth failure is frequently present at the time of diagnosis [7,8], it may not be recognized by the child or family. The earliest and most subtle form of growth failure is a decrease in height velocity, which may be present for months or years before other symptoms are present. This may progress to short stature for age, delayed bone age, and/or pubertal delay. (See 'Growth failure' below.)

Very early-onset IBD – Occasionally, IBD presents during early childhood (<6 years) or even in infancy. These children are somewhat less likely to present with abdominal pain and weight loss and are more likely to present with rectal bleeding (33 percent) compared with those with onset later in childhood [9]. A subset of patients with very early-onset IBD have an underlying genetic defect that affects immune function or disturbs epithelial barrier function, sometimes known as "monogenic IBD." A focused evaluation for such disorders is warranted. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Very early-onset inflammatory bowel disease'.)

GASTROINTESTINAL MANIFESTATIONS

Ulcerative colitis — Ulcerative colitis (UC) is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon. It commonly involves the rectum and may extend proximally in a continuous fashion to involve other parts of the colon. In some patients, the disease pattern persists throughout the clinical course. For other patients, the disease extends proximally as disease activity increases.

For clinical care, it is useful to categorize UC into the following categories (table 1):

Ulcerative proctitis – Disease limited to the rectum

Left-sided disease – Disease that extends from the rectum into the left colon but not proximal to the splenic flexure

Extensive colitis – Disease that extends from the rectum into the transverse colon but not proximal to the hepatic flexure

Pancolitis – Disease that extends throughout the colon, including some or all of the cecum

UC extends proximally in a continuous pattern, in contrast with the discontinuous pattern sometimes seen in Crohn disease (CD). Mild histologic inflammation in the terminal ileum occasionally occurs in UC (sometimes called "backwash" ileitis), but more severe ileal inflammation, or involvement of other segments of the small bowel, suggests that the patient has CD instead of UC. Occasionally, a patient with UC has focal inflammation around the appendiceal orifice that is not contiguous with disease elsewhere in the colon (a "cecal patch"). (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Differentiation between Crohn disease and ulcerative colitis'.)

Crohn disease

Intestinal disease localization — CD can affect the entire gastrointestinal tract and is a progressive condition causing transmural inflammation. In children and adolescents, it can present with involvement of both small bowel and colon (59 percent), colon only (28 percent), or primarily the small bowel (16 percent, usually in the terminal ileum) [4]. CD may be limited to the colon and, in such cases, may be difficult to distinguish from UC. CD that involves the colon is more likely to have a discontinuous pattern ("skip" lesions), involving the rectum and other parts of the gastrointestinal tract, separated by normal segments, whereas UC typically has a continuous pattern throughout the involved segments. The most important clinical features that classify a patient as having CD rather than UC are significant small bowel disease, perianal disease, or presence of granulomas in the gastrointestinal tract on biopsy. While the finding of granulomas on intestinal biopsy has been considered virtually pathognomonic (strongly predictive) for CD, some investigators have suggested that gastric granulomas may also rarely be seen in UC [10].

A small number of children at presentation have more diffuse small bowel disease, isolated perianal disease, esophageal or gastric disease, or severe orofacial disease. Patients may be classified by age, disease location (ileum only, colon only, ileocolon, or upper gastrointestinal tract), and disease behavior (inflammatory, stricturing, or penetrating). Documenting and monitoring these characteristics and their evolution over time is an important part of clinical care. It is important to note that although disease location and severity may wax and wane during the disease course, the extent and severity of IBD is defined by worst extent and severity experienced by the patient.

Research studies and registries sometimes use the Paris classification to categorize the location and other clinical features of CD in children (figure 1 and table 2) [4]. The Paris classification is a modification of the Montreal classification system that is used in adults and includes a clearer definition of earlier-onset IBD and growth delay [11,12]. The Paris classification can also be utilized in clinical practice. (See "Overview of the management of Crohn disease in children and adolescents", section on 'Clinical assessment'.)

Intestinal disease complications — A substantial proportion of children and adolescents with CD present with or progress to developing intestinal complications, which are an important cause of morbidity. Patients who tend to develop these complications are often categorized as having a stricturing and/or penetrating phenotype, present in approximately 30 percent of pediatric patients and up to 45 percent of adult patients [13,14]. The main risk factors for these complications are a stricturing and/or penetrating phenotype, extensive small bowel disease involvement (over and above small bowel disease only involving the terminal ileum), and longer disease duration [15]. Children diagnosed during adolescence appear to have a higher risk for these complications compared with those diagnosed at a younger age [16]. They are most likely to develop over time in patients with severe or refractory disease but occasionally are a presenting feature. These complications include:

Fistulae – Fistulae may develop between the diseased bowel and a variety of adjacent tissues. Fistulae between different segments of the bowel (enteroenteric) may be asymptomatic or may cause symptoms because of malabsorption or small intestinal bacterial overgrowth.

Fistulae from the bowel to the bladder (enterovesicular) tend to present with recurrent urinary tract infection or a sensation of air in the urine stream (pneumaturia)

Fistulae from the bowel to the genitalia (enterogenital) tend to present with pain or fecal leakage

Fistulae from the bowel to the skin (enterocutaneous) are most common in the perianal area and may form subcutaneous abscesses

Treatment may include immunomodulators, biologic agents, antibiotics (eg, metronidazole), or total parenteral nutrition with bowel rest. Surgery (intestinal diversion) is used for fistulizing disease that is refractory to treatment. Anti-tumor necrosis factor (anti-TNF) agents (infliximab and adalimumab) are the best-established agents for treating fistulizing disease. (See "Medical management of moderate to severe Crohn disease in adults", section on 'Fistulizing disease'.)

Localized peritonitis – Localized peritonitis tends to present with fever, chills, leukocytosis, nausea or vomiting, and focal abdominal pain, often in the right lower quadrant. It is caused by a microperforation of the bowel with containment of the resultant infection by surrounding bowel loops. The initial treatment usually consists of broad-spectrum antibiotics and bowel rest. (See "Medical management of moderate to severe Crohn disease in adults", section on 'Localized peritonitis'.)

Abdominal abscess – An abscess tends to develop adjacent to actively inflamed bowel loops and may develop further into a fistula. Similar to patients with localized peritonitis, patients with an abdominal abscess tend to present with fever, leukocytosis, and focal abdominal pain, often in the right lower quadrant or pelvis [15]. A high index of suspicion is warranted for patients who are on immunosuppressive therapy, who may present with more subtle symptoms and without fever or leukocytosis. The onset of symptoms may be gradual or sudden.

The evaluation includes imaging (ultrasonography, computed tomography [CT], or magnetic resonance imaging [MRI]). Initial treatment consists of antibiotics, typically with percutaneous drainage for abscesses that are >2 cm in diameter, and optimization of CD therapy. Because abdominal abscesses result from bowel perforations (typically in the ileum), surgical resection of the diseased bowel is often needed. In some cases, small abscesses can be managed by optimizing medical management rather than proceeding to surgery. However, we advise caution about extending the use of biologics or other immunosuppressive medications in the presence of an active abscess because of the risk of ongoing leak and infection, in addition to the potential increased risk of surgery in patients after prolonged immunosuppression. (See "Surgical management of Crohn disease", section on 'Abscess' and "Medical management of moderate to severe Crohn disease in adults", section on 'Abscess'.)

Small bowel obstruction – Severe disease of the small intestinal lumen, with ulceration and transmural inflammation, tends to lead to stricture formation. Depending on the location and severity, this can cause partial or complete intestinal obstruction, presenting with symptoms of nausea, vomiting, and abdominal pain. A stricture often becomes symptomatic because of superimposed inflammation and spasm, so the obstruction may improve with conservative management, including bowel rest and parenteral glucocorticoids or biologic agents such as infliximab, which help to decrease any inflammatory component of the obstruction. Acute deterioration (eg, worsening obstruction or bowel ischemia) may require urgent surgery. Elective surgery is frequently required in patients who develop recurrent obstructive episodes from a fibrotic stricture. (See "Medical management of moderate to severe Crohn disease in adults", section on 'Partial small bowel obstruction'.)

Oral and perianal disease

Perianal disease – Perianal abnormalities are common. They are sometimes present at diagnosis and eventually develop in approximately one-third of children with CD [17]. Perianal involvement may be mild (consisting of small skin tags or anal fissures (picture 1)) or more severe (abscesses and fistulae). In a series of pediatric patients with CD, 10 percent had perianal fistulas and/or abscesses at the time of diagnosis and one-third of these had persistent perianal disease for more than one year despite treatment [18]. As many as 5 percent of children develop a highly destructive form of perianal disease that is characterized by recurrent perianal abscesses, fistulae involving the genitalia, and development of rectal strictures (picture 2).

Severe perianal disease may be refractory to medical treatment (including antibiotics, biologic agents such as infliximab, immunomodulators such as azathioprine, and exclusive enteral nutrition [19]). Ustekinumab has also been reported to have efficacy in treating perianal fistulae [20]. Surgical options for perianal fistulas include Seton placement or fistulotomy; a minority of patients may require colonic diversion [17,21]. (See "Perianal Crohn disease" and "Overview of the management of Crohn disease in children and adolescents", section on 'Exclusive enteral nutrition'.)

Oral lesions – Orofacial lesions are reported in 10 to 40 percent of children with CD (picture 3) [22,23]. (See 'Mouth' below.)

Isolated orofacial and perianal findings – Isolated orofacial and perianal inflammation can occur in the absence of bowel disease or may precede the development of bowel disease by several years [24]. In these patients, a biopsy of the inflamed lips, buccal mucosa, or perianal skin tags may demonstrate granulomas.

Esophageal and gastric disease — Esophageal and gastric disease are present in approximately 30 percent of patients with CD and are more common among those with perianal disease or more severe ileocolonic disease [4,25]. In case series of children and adolescents with CD, approximately 10 percent had visible lesions on endoscopy (ulcers, erosions, and edematous nodules), 20 percent had microscopic evidence of CD, and 40 percent had nonspecific microscopic signs of inflammation [25,26]. Approximately one-third of patients with esophageal CD report esophageal symptoms [25,26]. Isolated esophageal CD is rare, and concurrent gastric and duodenal involvement is common. As a result, performing upper endoscopy is an essential part of the evaluation of CD and especially for patients with upper gastrointestinal symptoms, severe CD, or perianal disease. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

Symptomatic esophageal and gastric CD is treated with acid-suppressing medications, in addition to vigorous treatment for the underlying CD using immunosuppressive medications and/or enteral nutrition. Optimal treatment and natural history of esophageal CD have not been well studied. We generally do not use acid-suppressing medications for asymptomatic patients, due to concerns that these medications may increase the risk for Clostridioides difficile infection. (See "Proton pump inhibitors: Overview of use and adverse effects in the treatment of acid related disorders", section on 'Clostridioides difficile and other enteric infections'.)

Mild nonspecific abnormalities of the upper gastrointestinal tract are common in both UC and CD, but significant ulceration of the esophagus, stomach, or duodenum is inconsistent with UC. Mild gastritis with histologic inflammation can be seen in either CD or UC. However, severe gastric disease or granulomas in a patient with colitis suggests the diagnosis of CD. Esophagitis with aphthae also may be seen in CD. Eosinophilic esophagitis has been reported in a subset of patients with either UC or CD [27,28], but this may be the result of case finding in a referral population [29]. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Differentiation between Crohn disease and ulcerative colitis'.)

GROWTH AND NUTRITION

Growth failure — Growth failure is seen in 10 to 30 percent of children with Crohn disease (CD) [7,8,15,30-33] and 5 to 10 percent of children with ulcerative colitis (UC) [7]. Growth failure can be defined dynamically as a fall in the height percentile of more than 0.3 standard deviations/year, a height velocity of less than 5 cm/year, or a decrease in the height velocity of more than or equal to 2 cm compared with the previous year, during early to mid-puberty. To assess most accurately for growth failure, a child's growth rate should be compared with expected growth rates for age (figure 2). (See "Diagnostic approach to children and adolescents with short stature".)

One study using these definitions found that approximately 30 percent of children with CD had growth failure [7]. In another report, approximately 50 percent of children with untreated CD had short stature or evidence of diminished height velocity [8]. The diminished height velocity may occur before the onset of symptoms and may be unrecognized by the child's caregivers, but it can be detected by plotting a patient's height and weight on the appropriate growth chart. Delays in IBD diagnosis are associated with growth delays that can persist well beyond one year after diagnosis [34]. Delayed sexual maturation (pubertal delay) commonly accompanies growth failure in adolescents.

The causes, assessment, and management of growth failure and poor weight gain in children with IBD are discussed in a separate topic review. Timely and effective therapy that reduces inflammation may help reverse growth failure in children. Treatment of the IBD with exclusive enteral nutrition may be particularly helpful for this group of patients. (See "Growth failure and pubertal delay in children with inflammatory bowel disease" and "Overview of the management of Crohn disease in children and adolescents", section on 'Nutritional therapy'.)

Vitamin and mineral deficiencies — The risk for vitamin and mineral deficiencies in IBD depends upon the type of IBD (CD versus UC), disease location, and disease activity. Causes of vitamin deficiencies in this population include malabsorption and limited intake (perhaps driven by altered dietary habits due to IBD symptoms).

CD – A number of vitamin and mineral deficiencies have been associated with CD. These include deficiencies in vitamins A, D, and E; zinc; and vitamin B12 (the latter is most common in patients with ileal CD). Vitamin D deficiency appears to be the most common deficiency and may contribute to osteopenia and increased fracture risk, which are also exacerbated by disease-related inflammatory activity. In general, patients with active disease have a higher prevalence of deficiencies of vitamin D and other micronutrients.

UC – Vitamin and mineral deficiencies are less common in children with UC, except for those with uncontrolled acute severe colitis. An exception is that patients who have had colectomy with ileal pouch anal anastomosis may be at risk for vitamin B12 deficiency because of changes in intestinal morphology in the terminal ileum.

Details about the risks, monitoring, and management are discussed separately. (See "Vitamin and mineral deficiencies in inflammatory bowel disease" and "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Bone mineral density'.)

EXTRAINTESTINAL MANIFESTATIONS — Extraintestinal conditions associated with IBD may be present at diagnosis or develop later in the disease course [35]. These may involve the skin, joints, hepatobiliary tract, eye, kidney (ie, stones), and (rarely) pancreas and respiratory systems, as well as risks for venous thrombosis (table 3A-B). These disorders appear idiosyncratically in some patients and not others but are more often associated with colonic disease; they do not consistently correlate with the degree of intestinal inflammation.

Skin — IBD is associated with several different dermatologic disorders:

Erythema nodosum is characterized by painful, raised, red lesions 1 to 3 cm in diameter and seen most commonly on the shins (picture 4A-B). It is a presenting feature in approximately 5 percent of children with IBD and typically resolves rapidly when IBD therapy is instituted; it is seen more often in patients with Crohn disease (CD) than ulcerative colitis (UC) [36-38]. Erythema nodosum also may be caused by disorders other than IBD, including infections (eg, group A Streptococcus, tuberculosis), medications (eg, penicillin, phenytoin), autoimmune disease (eg, rheumatoid arthritis, lupus), and malignancy. (See "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Erythema nodosum'.)

Pyoderma gangrenosum, a severe ulcerating rash that responds to immunosuppression, is rare in children and is seen more often in patients with longstanding UC than in patients with CD. However, it has been described in an infant with CD [39]. (See "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Pyoderma gangrenosum'.)

Metastatic CD is a rare dermatologic manifestation characterized by erythema, edema, ulcerating nodules, and violaceous plaques, sometimes in a linear or "knifelike" pattern (picture 5 and picture 6). Most cases in children are in the genital area [40,41]. Such patients may present to the urologist with swelling of the penis and scrotum and be given the diagnosis of "granulomatous lymphangitis" [42]. The lesions may appear before, during, or after the gastrointestinal manifestations of CD. (See "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Metastatic Crohn disease'.)

Hidradenitis suppurativa is a chronic inflammatory skin condition characterized by painful, deep-seated, inflamed nodules that occur primarily in the axillae and inguinal areas. Multiple studies suggest an association with IBD and, particularly, CD [43]. There is a strong female predominance. Most data on hidradenitis suppurativa and IBD are in adults, but case series have also described this combination in adolescents [44]. (See "Hidradenitis suppurativa: Pathogenesis, clinical features, and diagnosis" and "Hidradenitis suppurativa: Management".)

Psoriasis, an immune-mediated inflammatory condition of the skin, is significantly associated with IBD. A meta-analysis notes 3.6 percent prevalence of psoriasis among CD and 2.8 percent in UC [45]. One study suggests that patients with psoriasis have a fourfold increased risk for the development of CD, suggesting that the psoriasis often precedes development of CD [46]. (See "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Psoriasis'.)

Certain psoriatic medications may induce or worsen IBD. Conversely, psoriasiform eruption is a known adverse effect of anti-tumor necrosis factor-alpha (anti-TNF-alpha) therapy, occurring in over 10 percent of children with IBD who are treated with these drugs [47,48]. Withdrawal of systemic corticosteroids used in IBD can sometimes cause a rebound in psoriasiform lesions [49]. (See "Medical therapies for Crohn disease in children and adolescents" and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Psoriatic skin lesions'.)

Mouth — A variety of oral lesions are associated with IBD (picture 3) [50,51]. The most common is aphthous stomatitis (superficial ulcerations), which occurs in approximately 10 percent of children with IBD [24,35,36,38] and is approximately three times more common among those with CD compared with UC [38]. As an example, among 48 children who were rigorously evaluated by a dentist, the following oral lesions were identified [22,51]:

Mucogingivitis (12 patients) (picture 7)

Mucosal tags (4 patients) (picture 8)

Deep ulceration (4 patients) (picture 9)

Cobblestoning (3 patients) (picture 10)

Lip swelling (3 patients) (picture 11)

Pyostomatitis vegetans (1 patient)

Pyostomatitis vegetans is an uncommon oral manifestation of IBD (primarily in UC); it is characterized by multiple small pustules and erosions on the oral mucosa [50].

These oral manifestations tend to correlate with intestinal disease activity and respond to treatments for the intestinal disease [50]. Adjunctive therapy in acute or unresponsive cases may include topical glucocorticoids. (See 'Oral and perianal disease' above.)

Medications used for IBD occasionally cause oral lesions, including nonspecific erythema (methotrexate, thiopurines) and oral lichenoid reactions (sulfasalazine and biologic agents) [50]. Other more severe reactions that require drug cessation are erythema multiforme (many drugs) and Stevens-Johnson syndrome.

Eyes — Episcleritis/scleritis occurs in 2 to 5 percent of patients with IBD [35,36,52]. Affected patients may be asymptomatic or complain of burning and itching. Injection of the ciliary vessels and inflammation of the episcleral tissues are the prominent features on physical examination (picture 12).

Uveitis is less common than episcleritis, occurring in 0.5 to 3.0 percent of patients with IBD [53]. However, its consequences are often more severe. The uveitis is frequently bilateral, posterior to the lens, insidious in onset, chronic in duration, and more common in females than males [54]. "Iritis" is an alternate term for anterior uveitis. (See "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Ocular disease'.)

Cataracts may develop in patients with IBD who are chronically treated with glucocorticoids. (See "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Rare ocular diseases'.)

Aminotransferase elevations — Nonspecific mild elevations of serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are common and often caused by medications or hepatic steatosis [55,56]. IBD medications that may contribute to liver injury include sulfasalazine, thiopurines (mercaptopurine or azathioprine), methotrexate, and infliximab [57].

Aminotransferase elevations also may be caused by specific disorders associated with IBD: Individuals with CD have an increased risk for cholelithiasis, but this is uncommon in UC [57-59]. Patients with IBD also have an increased risk for autoimmune hepatitis [57,60-62]. (See "Overview of hepatobiliary disorders in patients with inflammatory bowel disease".)

Sclerosing cholangitis — The most significant immunologic liver disease associated with IBD is sclerosing cholangitis (SC), a condition that causes inflammation and scarring of the bile ducts and progresses to complicated hepatobiliary disease, including cholangitis, hepatic cirrhosis, and liver failure [61].

Incidence and clinical presentation – SC occurs in 2 to 10 percent of patients with UC and a smaller proportion of patients with Crohn colitis [35,38,57,61,63]. Patients with SC may present with fatigue, pruritus, and intermittent jaundice; the severity of the SC is not correlated with the colitis disease activity. Between 30 and 70 percent of IBD patients with SC have concurrent clinical, biochemical, and histologic findings of autoimmune hepatitis, in addition to cholangiographic findings consistent with SC; this combination of features is known as autoimmune SC (ASC) or SC-autoimmune hepatitis overlap syndrome [57,64,65].

Screening and evaluation – Patients with IBD should undergo laboratory screening for hepatobiliary disease at diagnosis and periodically thereafter. SC is characterized by an elevation of gamma-glutamyl transpeptidase (GGTP) and alkaline phosphatase and a less pronounced elevation of ALT and AST. Patients with marked and persistent liver enzyme elevations (especially of GGTP) should be further evaluated for SC using radiographic imaging (ultrasound, magnetic resonance cholangiopancreatography [MRCP]), and liver biopsy. The liver biopsy evaluates for small-duct SC and autoimmune hepatitis, while the MRCP identifies large duct (hepatic duct, common bile duct disease). Improvements in MRCP quality have resulted in a reduction in use of diagnostic endoscopic retrograde cholangiopancreatography (ERCP), though ERCP may be needed if MRCP is equivocal of if therapeutic intervention is needed for bile duct stricture.

Autoimmune markers (antinuclear antibodies [ANA], anti-smooth muscle antibodies [ASMA], antimitochondrial antibodies, and anti-liver-kidney microsomal antibodies) and total immunoglobulin G (IgG) should be measured to evaluate for the possibility of associated autoimmune hepatitis (table 4) [66]. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis" and "Overview of autoimmune hepatitis", section on 'Diagnosis'.)

Diagnosis – SC is diagnosed based on evidence of cholestasis (elevated GGTP) with characteristic findings on MRCP or ERCP (multifocal stricturing and segmental dilations of the biliary tree, indicating large-duct SC) and/or liver biopsy (periductal concentric fibrosis, fibro-obliterative cholangitis, or primary ductular involvement, without large duct involvement, indicating small-duct SC) [64].

The ASC subtype is diagnosed based on the presence of autoimmune markers (primarily ANA and ASMA and, sometimes, perinuclear antineutrophil cytoplasmic autoantibodies), in combination with the above evidence of bile duct damage and hepatitis. The histology of autoimmune hepatitis includes features such as interface hepatitis (with lymphocytes, eosinophils, or plasma cells), periportal hepatocyte necrosis, and varying degrees of fibrosis [67]. Scoring criteria for diagnosing ASC and autoimmune hepatitis in children have been proposed [66].

Management – Treatment of SC is mainly supportive and palliative; no therapy has been shown to alter the natural history of the disease [57,68,69].

Patients with ASC (ie, with SC associated autoimmune liver disease) should be treated for that disorder, which typically includes glucocorticoid induction followed by maintenance thiopurine [66]. This may be identical to or overlap with the treatment selected for the underlying IBD. (See "Management of autoimmune hepatitis", section on 'Pediatric patients' and "Autoimmune hepatitis variants: Definitions and treatment", section on 'Autoimmune hepatitis-PSC overlap'.)

Treatment with ursodeoxycholic acid (UCDA) has been associated with improvement of laboratory markers of hepatic inflammation and cholestasis [65,70]. In our practice, we routinely utilize UDCA in a dose of approximately 15 mg/kg/day, in two divided doses. However, it should be noted that a causal effect has not been established and spontaneous improvement in laboratory parameters is common [68,71]. Moreover, higher-dose treatment with UCDA (28 to 30 mg/kg/day) may be detrimental [72]. Immunosuppressive medications may improve the underlying IBD but do not alter the course of SC.

Vancomycin has also been utilized to treat pediatric SC, with some positive outcomes in small observational studies [73-75], but was not effective in another observational study with propensity-score matching [68].

Management of SC in adults is discussed separately. (See "Primary sclerosing cholangitis in adults: Management".)

Outcomes – In a multinational study that included more than 500 children with IBD-associated SC with five-year follow-up, 21 percent developed portal hypertensive complications (eg, esophageal varices or ascites), 12 percent developed biliary complications (cholangitis with stricture requiring dilatation), and 11 percent progressed to liver transplantation or death [64]. These outcomes were somewhat better than for children with SC that was not associated with IBD. In a smaller single-center study with five-year follow-up (n = 55), 22 percent developed splenomegaly but none had portal hypertension complications, only 4 percent developed biliary complications, and none progressed to liver transplantation or death [65]. By 10 years (n = 16), 12 percent had progressed to transplantation or death. The relatively low rate of complications in this series may have been related to earlier identification of affected patients and/or management strategies, which included routine use of UCDA and treatment for associated autoimmune liver disease, when present.

SC is associated with a substantial risk for hepatobiliary cancer (cholangiocarcinoma). In the multinational study cited above, cholangiocarcinoma developed in eight patients (1 percent of pediatric patients with SC with or without IBD); these cases presented at a median of six years after the SC diagnosis, and all were between ages 15 and 18 years and had a biliary stricture that required dilation [64]. Surveillance for cholangiocarcinoma has not been established for pediatric patients. (See "Primary sclerosing cholangitis in adults: Management", section on 'Gallbladder carcinoma and cholangiocarcinoma'.)

In addition, individuals with UC and SC also appear to be at higher risk for developing colorectal cancer compared with patients with UC alone. Therefore, early initiation and frequent surveillance ileocolonoscopy is recommended for patients with SC [76]. (See "Primary sclerosing cholangitis: Inflammatory bowel disease and colorectal cancer" and "Primary sclerosing cholangitis in adults: Management", section on 'Colon cancer'.)

Joints — Approximately 4 percent of patients with IBD have arthritis within the first few years after diagnosis, and up to 20 percent have arthralgias, which may present before the gastrointestinal symptoms [36,38,77]. Arthritis is approximately twice as common in CD compared with UC but is more common in patients with Crohn colitis compared with those with gastroduodenal CD [38,78,79]. The arthritis typically is nonerosive and asymmetric, affects large joints (including the hips, knees, and wrists), and parallels the activity of the intestinal involvement [35,78,80]. In contrast, axial skeletal involvement, in the form of ankylosing spondylitis and sacroiliac joint arthritis, is less common and may follow an independent course [79]. (See "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)

Chronic recurrent multifocal osteomyelitis is a rare complication of both CD and UC [81-83]. (See "Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO)".)

Venous thromboembolism

Prevalence and risk factors – Active IBD is associated with an increased risk for venous thromboembolism (VTE), which occurs in 1 to 2 percent of hospitalized patients and occasionally includes pulmonary embolism and cerebrovascular events [84-89]. Factors that further increase the risk for VTE include the presence of a central venous catheter, severe disease activity, older age, parenteral nutrition, oral contraceptives, and underlying inherited thrombophilia; the risk is generally higher for patients with active UC compared with active CD [90]. In an observational study, 1 percent of hospitalized patients developed VTE, with increased risks for those who were undergoing major surgery (odds ratio [OR] 1.98, 95% CI 1.54-2.55) or having an underlying hypercoagulable diagnosis (OR 7.39, 95% CI 5.34-10.20) [88].

In one case series, the most common locations for VTEs were in the cerebral sinuses or lower extremities [89]. Portal vein thrombosis is a rare but potentially life-threatening thrombotic complication, which may present with an acute abdomen or abdominal distension due to ileus [57]. Hepatic vein thrombosis (Budd-Chiari syndrome) also has been reported.

Management of VTE – For patients who develop VTE, anticoagulation (eg, low molecular weight heparin) is feasible and appropriate, even in the context of gastrointestinal bleeding [85]. (See "Pulmonary complications of inflammatory bowel disease", section on 'Prophylaxis for venous thromboembolism' and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

Prevention of VTE – All hospitalized children with IBD should be treated with nonpharmacologic measures to minimize the risk for VTE, including adequate hydration, mobilization, and use of compression stockings or pneumatic devices if appropriate.

In addition to nonpharmacologic measures, we suggest prophylactic anticoagulation for any hospitalized child with severe IBD activity and a prior history of thrombosis, consistent with Canadian and European guidelines [91,92]. Prophylactic anticoagulation therapy should be seriously considered for older children (>12 years) with severe IBD activity and other risk factors, including the presence of a central venous line, a family history of VTE, plans to undergo major surgery, or immobility [84,86,92,93]. For patients who have moderate or severe gastrointestinal bleeding, mechanical methods of thromboprophylaxis are preferred, based on recommendations for adults with IBD [93,94]. Drug selection and dosing are discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

Primary prophylaxis is generally recommended for adult IBD patients with severe disease activity and additional risk factors for VTE, such as a central venous catheter and/or a strong family history of VTE [95]. For pediatric patients, the risk of primary VTE is probably somewhat lower than in adults, but the consequences can be serious. In a retrospective study in hospitalized children with IBD and central venous catheters, the rate of thromboembolic complications was lower in patients who received anticoagulant prophylaxis (0 of 24 hospitalizations) compared with patients who were not treated with prophylaxis (5 of 23 hospitalizations; 22 percent) [86]. (See "Pulmonary complications of inflammatory bowel disease", section on 'Prophylaxis for venous thromboembolism'.)

Other — Other complications of IBD include:

Osteopenia – May be caused by malnutrition, inflammation, pubertal delays, vitamin D deficiency, or treatment with glucocorticoids [96]. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Bone mineral density' and "Metabolic bone disease in inflammatory bowel disease".)

Kidney stones – Due to malabsorption of calcium and increased absorption of oxalate. (See "Kidney stones in adults: Epidemiology and risk factors".)

Gallstones – Due to bile acid malabsorption. (See "Overview of hepatobiliary disorders in patients with inflammatory bowel disease", section on 'Gallstones'.)

Pancreatitis – Caused by disease-related inflammation near the pancreatic duct or medication-related (eg, aminosalicylates or thiopurines). (See "Causes and contributing risk factors for chronic pancreatitis in children and adolescents", section on 'Obstructive' and "Medical therapies for Crohn disease in children and adolescents".)

Genital inflammation – In CD, granulomatous inflammation occasionally affects the vulva [97] or penis and scrotum [98,99] and is independent of fistulizing disease. (See "Vulvar lesions: Differential diagnosis of red lesions", section on 'Crohn disease'.)

Granulomatous inflammation of other areas, including the lymph nodes and lungs (image 1), also may be seen in individuals with CD [100]. (See "Pulmonary complications of inflammatory bowel disease".)

PSYCHOSOCIAL — Children and adolescents with any chronic disease, including Crohn disease (CD), are at risk for the development of a variety of psychosocial problems, including depression and anxiety. These problems can interfere with their ability to participate in their normal activities and can also interfere with the medical management of their disease [101-103]. Patients with CD who are suffering from untreated and/or unrecognized depression and anxiety are at increased risk for higher health cost, hospitalization, and disease flares. (See "Important health maintenance issues for children and adolescents with inflammatory bowel disease", section on 'Psychological screening and support'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inflammatory bowel disease in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Crohn disease in children (The Basics)")

Beyond the Basics topic (see "Patient education: Crohn disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Types of inflammatory bowel disease (IBD) – IBD is comprised of two major categories: Crohn disease (CD) and ulcerative colitis (UC). CD can involve any component of the gastrointestinal tract from the oral cavity to the anus. In contrast, UC is generally limited to the colon, although mild inflammation of the terminal ileum and upper gastrointestinal tract can be also seen in UC. (See 'Gastrointestinal manifestations' above.)

Presenting symptoms – Patients with IBD typically present in late childhood or adolescence with abdominal pain, weight loss, diarrhea, and hematochezia. Some patients have systemic symptoms including weight loss, fever, and fatigue. Growth failure is often present but may be subtle and not recognized by the patient or family. (See 'Presenting symptoms' above.)

Oral and perianal disease – Oral and perianal disease occurs in approximately one-third of patients with CD; it is not a feature of UC:

Significant perianal disease, including perianal fistulae or abscesses, occurs in approximately 30 percent of children and adolescents with CD. A highly destructive form of perianal disease occurs in approximately 5 percent of patients. More minor manifestations of perianal disease include anal fissures and skin tags (picture 1). (See 'Oral and perianal disease' above and "Perianal Crohn disease".)

Oral lesions occur in up to 40 percent of children with CD and may include mucogingivitis, aphthous ulcers, or swelling. Occasionally, oral and perianal disease occurs in the absence of significant intestinal disease. (See 'Oral and perianal disease' above.)

Growth failure – Growth failure is present in approximately 30 percent of children and adolescents with CD and is less common in children with UC. It is caused by a combination of anorexia and increased energy needs, related to inflammation. It is often heralded by diminishing height velocity and is best assessed by serial measurements of height, compared with previous height velocity and expected height velocity for age (figure 2). (See 'Growth failure' above and "Growth failure and pubertal delay in children with inflammatory bowel disease".)

Extraintestinal manifestations – Extraintestinal manifestations are sometimes seen in either CD or UC. They may involve the skin, joints, hepatobiliary, eye, and respiratory systems (table 3A-B). These disorders appear idiosyncratically in some patients and not others but are more often associated with colonic disease. The presence or severity of extraintestinal manifestations do not consistently correlate with the degree of intestinal inflammation. This is particularly true for liver disease. (See 'Extraintestinal manifestations' above.)

Sclerosing cholangitis (SC) – The most serious liver disease associated with IBD is SC, a condition causing inflammation and scarring of the bile ducts, which may lead to complicated hepatobiliary disease, including cholangitis, hepatic cirrhosis, and liver failure, as well as risk for hepatobiliary cancer. SC occurs in up to 10 percent of patients with UC and a smaller proportion of patients with Crohn colitis and is often associated with concomitant autoimmune hepatitis. Patients with IBD should undergo laboratory screening for hepatobiliary disease at diagnosis and periodically thereafter. Those with abnormal results should undergo a full evaluation for SC and the possibility of associated autoimmune hepatitis. (See 'Sclerosing cholangitis' above.)

Venous thromboembolism (VTE) – Active IBD is associated with an increased risk for VTE, which occurs in up to 2 percent of hospitalized patients and can have life-threatening consequences. Nonpharmacologic interventions to minimize the risk of thromboembolism should be used for all hospitalized children with IBD, including adequate hydration, mobilization, and use of compression stockings or pneumatic devices if appropriate.

For any hospitalized child with severe IBD activity and a prior history of thromboembolism, we suggest prophylactic anticoagulation therapy, provided that gastrointestinal bleeding is not moderate or severe (Grade 2C). We also suggest prophylactic anticoagulation therapy for older children (>12 years) with the combination of severe IBD activity and other risk factors, including the presence of a central venous line, family history of thromboembolism, or immobility (Grade 2C). (See 'Venous thromboembolism' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Tyler Burpee, MD, Alan Leichtner, MD, George H Russell, MD, MS, and Mala Setty, MD, who contributed to earlier versions of this topic review.

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Topic 5865 Version 30.0

References

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