More than a gut reaction: Extraintestinal complications of IBD

More than a gut reaction: Extraintestinal complications of IBD

By Maria Oliva-Hemker, MD

Crohn disease and ulcerative colitis are not confined to the gastrointestinal tract. Growth failure, painful joints, and oral or skin lesions are just a few of the nonintestinal signs and symptoms of inflammatory bowel disease that can help you make a diagnosis-- sometimes even before GI problems appear.

Inflammatory bowel disease (IBD) is a disease of children: More than 25% of people with IBD have been diagnosed before they are 20. The pediatrician may suspect IBD, which includes Crohn disease and ulcerative colitis, in the child with abdominal pain, chronic diarrhea, or blood in the stools. Yet IBD affects many systems, and symptoms related to the gastrointestinal tract may not be prominent either at diagnosis or through the course of the disease. Instead, the child's illness may become evident through growth failure or skin lesions, or in a host of other ways. To make the correct diagnosis and avoid delays in treatment, pediatricians need to be familiar with the extraintestinal signs and symptoms of IBD and maintain a high index of suspicion when they are confronted with them.

The cause of IBD has not been clearly established, though we know that genetic, immunologic, and environmental factors contribute to its development. An initiating event, such as an infection or luminal antigen, may lead to an inflammation in the intestinal tract that an individual who is genetically suspectible to IBD cannot down-regulate ("cool down") appropriately. Likewise, the pathogenesis of many extraintestinal manifestations of IBD, including common ones, remains a puzzle. Some investigators believe that the inflammatory response destroys the intestine's ability to act as a selective barrier. The resulting uptake of bacterial products or dietary antigens can lead to circulating immune complexes or induce a systemic inflammatory response, according to this theory.¹ Autoimmunity directed against an antigen shared among the intestine, skin, synovium, eye, and biliary tree, which cross-reacts with a bacterial epitope, has also been proposed.²

About one third of patients with IBD have at least one extraintestinal manifestation of their condition. These manifestations have been classified by their relationship either to colonic or small intestine inflammation or to the degree of inflammatory activity of the underlying bowel disease (see Table 1).³ Few other illnesses are associated with as extensive a variety of systemic manifestations as IBD. A recent review listed more than 130 extraintestinal manifestations of Crohn disease or ulcerative colitis; fortunately, most of them are rare, affecting fewer than 1% of patients.⁴ I will emphasize the nongastrointestinal manifestations of IBD that pediatricians are most likely to see.

Growth failure

Growth failure is associated with almost all categories of extraintestinal manifestations of IBD. About 30% of children with Crohn disease and 5% to 10% of those with ulcerative colitis exhibit growth failure. The changes in weight and height velocities can be very subtle, however, and they may precede clinical evidence of bowel disease and progress despite few symptoms of the disease.⁵ The growth chart in Figure 1 illustrates this important point. All of the heights and weights in this boy's chart were within normal percentiles. After his parents noted that their son was shorter than a younger sibling, however, the pediatrician plotted the values to make the trend of the boy's growth more apparent. It then was obvious that beginning at the age of 9, his height and weight dropped into successively lower percentiles. Although the child had few gastrointestinal symptoms, his growth curve triggered further evaluation and the diagnosis of Crohn disease.

IBD­associated growth failure is affected by many factors, including nutrient intake, digestion, absorption, and metabolic demands. The major cause, however, is chronic caloric insufficiency.⁶ Growth failure might also have an endocrine basis; this has not been clearly established, though in some children with IBD­associated growth failure, bone maturation and pubertal development are delayed. Once IBD is diagnosed, the detrimental effects of the inflammatory process on growth need to be weighed against those of corticosteroid therapy, which is routinely used to treat IBD. Pediatricians should use corticosteroids judiciously and consider alternative medications such as aminosalicylate preparations or 6-mercaptopurine--which increasingly is being used for its steroid-sparing effect.

The patient whose growth is stunted can be nutritionally rehabilitated with oral, enteral, or parenteral supplementation in conjunction with medications. The oral route is usually the first and most acceptable option, but even the most highly motivated and compliant child may find it difficult to consume the necessary amounts of supplemental formula. A nasogastric tube sometimes is an option. A wide variety of formulas is available; they can be infused overnight to avoid interfering with school or daily routines. Placement of a gastrostomy tube is a useful option in patients who expect to have infusions over a long period. Surgery--a colectomy or other intestinal resection--occasionally may be required if growth failure continues in spite of aggressive medical management.

Joint manifestations

Of the extraintestinal manifestations of IBD shared by adults and children, joint inflammation is the most common. Up to one quarter of children with IBD have arthritis, and even more complain of arthralgias (joint pain without clinically obvious signs).⁷ Like many other extraintestinal manifestations, arthritis or arthralgia may precede symptoms suggesting bowel disease and often leads to an initial referral to a rheumatologist. In the peripheral form of arthritis and arthralgia, the affected joints are the larger peripheral joints such as the knees, ankles, hips, wrists, and elbows; in the axial form, pain is in the axial spine and sacroiliac joints (Figure 2).

Peripheral form. Peripheral arthritis and arthralgias are most common in patients with colonic inflammation, but they can also be associated with small bowel disease. Often, the condition affects only a few joints (pauciarticularity) and not symmetrically; it is characterized by erythema, swelling, and decreased range of motion. Joint complications do not routinely lead to chronic joint deformity, however. Arthritis tends to parallel the intestinal inflammation, becoming worse during times of increasing disease. Treatment is initially directed toward decreasing the inflammation in the bowel with aminosalicylate medications, corticosteroids, or other immunomodulating agents. The attacks usually last less than eight weeks and resolve either spontaneously or with treatment of the underlying bowel disease.⁷ If joint symptoms continue, nonsteroidal anti-inflammatory agents can be considered, though the potential for gastrointestinal mucosal injury needs to be addressed. Intra-articular corticosteroid injections and methotrexate are reserved for severe cases.

Axial form. Joint manifestations in this category include ankylosing spondylitis (inflammation of the vertebrae) and sacroileitis (inflammation in the sacroiliac joint). Ankylosing spondylitis develops in fewer than 2% of patients and is most commonly associated with ulcerative colitis. As in the general population, ankylosing spondylitis in patients with IBD is associated with the B27 human leukocyte antigen. Patients may complain of back stiffness and pain or, with time, become stooped. The sacroiliac joints almost always are affected, and sometimes the peripheral joints as well. Sacroileitis can develop in the absence of ankylosing spondylitis, however. Most patients with sacroileitis remain asymptomatic and the condition often is undiagnosed, especially in its early stages, unless it is aggressively sought with bone scans. Unlike the peripheral form of joint complications, the axial form progresses without any apparent relationship to inflammation in the bowel. Physical therapy and exercise programs to retard disability and limit deformity are the primary management strategies.

Other bone complications that are associated with IBD include osteonecrosis of the femoral head, especially in patients who have received steroids over a long period and complain of hip or knee pain. Clubbing (hypertrophic osteoarthropathy) can also be tied to IBD. Its cause is unknown, but some investigators speculate that production of circulating cytokines, whose levels are elevated in IBD, may increase blood flow to the fingers and increase connective tissue growth. The condition is most likely to be seen in patients with Crohn disease that is located in the small intestine. (Crohn disease may affect one or more segments of gut, but is most likely to be in the distal ileum or colon.)

Oral lesions

The oral lesions most often associated with IBD are recurrent aphthous ulcers; they develop in about 20% of patients with Crohn disease and in far fewer of those with ulcerative colitis (Figure 3).⁴ The aphthous ulcers often predate intestinal symptoms, but then tend to parallel disease activity. Other reported lesions include lip swelling, fissures, gingivitis, and major ulcers. A biopsy of the lesions may reveal granulomas.⁸ Pyostomatitis vegetans, an unusual disorder associated with ulcerative colitis, has both oral and cutaneous findings--on the axillae, genital areas, and scalp. The oral lesions are multiple neutrophil and eosinophil-filled pustules on erythematous bases, which erode and fuse to form shallow ulcers in a "snail track" configuration.⁹

Oral lesions that cause significant discomfort may be treated with topical, intralesional, or systemic corticosteroids, or with aminosalicylate preparations directed at the bowel disease.

Skin lesions

Even though trace mineral and vitamin deficiencies are common in children with IBD, especially those with Crohn disease, skin rashes such as acrodermatitis enteropathica, pellagra, and scurvy are unusual. Erythema nodosum and pyoderma gangrenosum (Figure 4) are the most common skin manifestations of IBD.

Erythema nodosum, the most common skin manifestation of IBD in children, is more often associated with Crohn disease than with ulcerative colitis. This condition also is common in children who don't have IBD and, like all extraintestinal manifestations of IBD, can appear before onset of obvious gastrointestinal disease. So pediatricians should keep IBD in their differential diagnosis when they see a child with erythema nodosum.

Erythema nodosum is characterized by subcutaneous, erythematous nodules; they are painful and usually develop symmetrically on the extremities, especially the lower legs. Histopathically, the lesion is primarily a panniculitis made of a lymphohistiocytic infiltrate. The child may appear ill with fever and joint pain; most patients with erythema nodosum develop arthritis. As the nodules flatten and turn brown or gray, they can be mistaken for bruises. Since exacerbations of erythema nodosum often parallel increased intestinal inflammation, treating the bowel inflammation is the primary form of management.

Pyoderma gangrenosum is an ulcerating lesion that most often appears on the legs. It usually is associated with extensive and active disease in the colon. Histopathology reveals endothelial injury with fibrinoid necrosis of blood vessels and marked neutrophilic and lymphocytic infiltrates. The lesion can be difficult to treat and may require large doses of systemic steroids or steroid-sparing agents as well as topical ulcer care. In some extreme cases, skin grafting becomes necessary. Fortunately, pyoderma gangrenosum is rare.

Eye lesions

The eye manifestations of IBD are often associated with other extraintestinal manifestations such as arthritis and erythema nodosum. Episcleritis, which tends to parallel bowel activity, and uveitis, whose course may be independent of bowel activity, are the most common ophthalmologic lesions.

Episcleritis. Inflammation of the blood vessel­rich episclera can easily be confused with conjunctivitis (Figure 5). Eyes are red and burn, but vision is unimpaired. Topical corticosteroids are usually effective. Protracted intestinal disease may give rise to significant scleritis.

Anterior uveitis. An inflamed iris and ciliary body characterize this condition. A slit-lamp examination makes the diagnosis. Early signs of uveitis include a cellular or proteinaceous exudate of inflammatory cells in the anterior chamber of the eye. The patient with uveitis may have acute or subacute eye pain, headache, photophobia, and blurred vision. Occasionally, visual acuity is impaired. Acute anterior uveitis is an ophthalmologic emergency requiring prompt intervention. If the uveitis progresses and becomes severe, iris atrophy, synechiae, pigment deposits, glaucoma, cataracts, and permanent visual deficits may result. Management includes covering the eye to reduce pain and photophobia, pupillary dilatation, and the use of topical or systemic corticosteroids.

When uveitis first develops it often has no symptoms. A 1993 study of 147 children with IBD but no symptoms of uveitis, half of whom had active bowel disease when they underwent an ophthalmologic screening, addressed the value of screening.¹⁰ Of the patients with Crohn disease, 6.1% had uveitis; none of those with ulcerative colitis had the condition. The natural history of uveitis in children with IBD is unknown.

Liver disease

Fewer than 5% of patients with IBD have liver pathology, which may include hepatitis, fatty liver, cholelithiasis, amyloidosis, and primary sclerosing cholangitis. Since many children may have few symptoms when their liver disease begins, a regular check of at least serum aminotransferases, alkaline phosphatase, gamma glutamyltransferase, and bilirubin is warranted.

Primary sclerosing cholangitis (PSC) is probably the most worrisome and threatening of the IBD­associated liver diseases that children may acquire. PSC is diagnosed more frequently than it used to be now that endoscopic retrograde cholangiopancreatography can be readily performed in children. The disease is a chronic, fibrosing inflammation that affects both intra- and extrahepatic bile ducts (Figure 6); its cause is unknown. The bile duct lumen eventually is obliterated, and cirrhosis usually develops. PSC is generally associated with ulcerative colitis, though it also can be seen with Crohn disease in the colon. The presenting symptoms can be nonspecific fatigue, anorexia, jaundice, and pruritus, for example. Hepatomegaly may be present. Persistent elevations in alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase should raise one's suspicion that the child has PSC.

In the largest published series of childhood PSC in North America, poor outcome was associated with jaundice, prolonged prothrombin time, abnormal bilirubin, older age at presentation, and splenomegaly.¹¹ Half of the children in this series were diagnosed with IBD after PSC was diagnosed. Thus, pediatricians should strongly consider evaluating children diagnosed with PSC for IBD. In adults, 70% of patients with PSC have ulcerative colitis.

Complications of the end-stage liver disease that may arise from PSC are managed as they are in other forms of liver disease. In addition, dominant biliary strictures can be treated with balloon dilatation and stent placement. In severe cases, surgical biliary reconstruction may be attempted. Unfortunately, PSC marches to its own drummer, unaffected by the state of the patient's inflammatory bowel disease, and proctocolectomy is not beneficial. Although many therapeutic agents have been tried, such as D-penicillamine, corticosteroids, azathioprine, and cyclosporine, results have been disappointing. The choleretic agent ursodeoxycholic acid has improved symptoms and biochemical markers in small studies and is being used in children, but larger controlled clinical trials are needed to evaluate its effectiveness.

For patients who develop end-stage liver disease from PSC, the treatment of choice is liver transplantation. Of 32 children reported in a study in Toronto, one died and 10 received transplants or were awaiting them because of rapid progression to cirrhosis or a high-grade extrahepatic biliary stricture.¹¹ Less severe liver disease may remain stable for many years, however.

Osteoporosis

Since IBD is most often diagnosed during adolescence and young adulthood, when bone mass is increasing rapidly, it is not surprising that osteopenia (mild bone loss) can affect up to two thirds of patients with IBD; one cross-sectional study documents it in at least one third.¹² Children with IBD, particularly Crohn disease, are thus at higher risk than other children for developing osteoporosis (significant bone loss), which can lead to bone fracture, deformity, and chronic pain. The many causes of low bone-mineral density in IBD include inadequate intake or malabsorption of calcium and vitamin D, corticosteroid use, low estrogen in females, and circulating pro-inflammatory cytokines.¹³ The relative importance of these factors is controversial. Osteopenia and osteoporosis can be diagnosed rapidly and with very low radiation using dual-energy X-ray absorptiometry, which measures bone-mineral density in the spine, femoral neck, or other bones.

How to prevent bone loss in patients with IBD remains unclear; the literature contains few relevant studies. Once bone is lost, nutritional supplements such as calcium and vitamin D may not undo the damage but can prevent further deterioration.

To help a child achieve appropriate peak bone mass, encourage consumption of at least the recommended daily requirements for age (RDA) of calcium and vitamin D, encourage exercise, and minimize exposure to corticosteroids. Determining whether children with IBD need more than the RDA of calcium and vitamin D requires more study.

Hematologic abnormalities

Anemia and thrombocytosis are common complications of IBD; as many as half of patients with active disease may have these conditions. Usually the anemia is caused by iron deficiency, but vitamin B₁₂ and folic acid deficiencies can also contribute, as can the anemia of chronic disease. The thrombocytosis may result from higher-than-normal levels of circulating inflammatory cytokines, which can stimulate platelet production. Although inflammatory exacerbations do not increase the erythrocyte sedimentation rate or C-reactive protein of every patient with IBD, these markers are often useful in diagnosing disease flares.

Other extraintestinal manifestations

Some rare complications--occurring in fewer than 1% to 2% of children with IBD--are worth mentioning to emphasize the wide spectrum of manifestations that fall under the IBD umbrella.

Renal complications include glomerulonephritis with immune complex deposition, which can progress to severe disease. Amyloidosis has been described in children with Crohn disease and can lead to renal failure. Patients with extensive ileal disease or ileal resection may have significant fat malabsorption or fluid losses and are at risk for developing calcium oxalate and uric acid stones. Extension of abscesses or the inflammatory process surrounding the terminal ileum can lead to ureteral compression with subsequent hydronephrosis or perinephric abscesses.

Pulmonary manifestations joined the list of extraintestinal IBD manifestations during the last three decades.¹⁴ Most studies are small and include few children. Pulmonary manifestations include bronchitis, bronchiectasis, tracheal obstruction, interstitial pneumonitis, pleuritis, and granulomatous lung disease. In general, these conditions respond to inhaled, oral, or intravenous corticosteroids. Pulmonary disease can predate bowel disease by months or years though it usually follows the IBD by weeks to months. Sulfasalazine and mesalamine, both used to treat IBD, have been associated with hypersensitivity pneumonitis.

Vascular complications range from peripheral venous thrombosis, primarily in the lower extremities, to central strokes. In a few instances, children have developed seizures or encephalopathic changes due to thromboembolic disease of the central nervous system. Arteritis of small or large vessels has also been described in children with IBD.

Neurologic manifestations include peripheral nerve disorders, myopathy, and epilepsy.¹⁵

Pancreatitis has been associated with IBD, though it usually results from medications such as 5-aminosalicylate preparations or 6-mercaptopurine, which generally must be discontinued.

Cardiac manifestations, such as myopericarditis and pleuropericarditis, are not necessarily associated with active bowel disease. They can present with chest pain and dyspnea. Treatment includes use of corticosteroids and nonsteroidal anti-inflammatory agents.

A clinical challenge

Crohn disease and ulcerative colitis should be viewed as challenging multisystemic diseases, not as illnesses confined to the gastrointestinal tract. The extraintestinal manifestations of these chronic conditions can be the presenting symptoms of IBD as well as predominant sources of illness. Familiarity with these extraintestinal signs and symptoms enables pediatricians to avoid delays in diagnosing IBD and more readily recognize subsequent complications.

THE AUTHOR is Director, Johns Hopkins Pediatric Inflammatory Disease Center, Baltimore, MD, and Assistant Professor of Pediatrics, Johns Hopkins School of Medicine, Baltimore.

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Maria Olive-Hemker. More than a gut reaction: Extraintestinal complications of IBD. Contemporary Pediatrics 1999;10:45.