Complications of Inflammatory Bowel Disease

The complications of inflammatory bowel disease (IBD) are generally classified according to the areas involved: the intestinal tract itself (local) or the rest of the organ systems (systemic). Many complications associated with IBD can occur with either ulcerative colitis or Crohn disease, but others are specific for each condition.

The presence of liver test abnormalities (ie, alkaline phosphatase [AP], gamma-glutamyl transpeptidase [GGT], aspartate aminotransferase [AST], or alanine aminotransferase [ALT] levels) appears to be an independent prognostic factor for the development of complicated disease behavior in patients with newly diagnosed Crohn disease. ^[1] In a retrospective study of 383 patients newly diagnosed with Crohn disease, 34.1% showed liver test abnormalities, of whom 33.2% developed complicated disease during a 5-year follow-up period compared to 14.6% of patients without such abnormalities (P <  0.001).

Radiologic findings may also be prognostic of future complications. For example, a retrospective, case control study of 108 patients with Crohn disease found that those with a fixed small bowel stricture on cross-sectional imaging were more likely to have complications. ^[2] Moreover, the presence of a stricture and upstream dilatation conferred a 3.4-fold increased likelihood of a complication developing within 2 years; the risk increased to 15-fold in the setting of hypervascularity and/or evidence of active inflammation. ^[2]

For more information, see Inflammatory Bowel Disease (main article).

Strictures

Intestinal strictures are usually benign in patients with inflammatory bowel disease (IBD), but they can lead to obstruction; both findings are not uncommon in persons with Crohn disease (see the images below). ^{[3, 4]} The strictures are often inflamed and frequently resolve with medical treatment. Fixed (scarred or fibrotic [cicatrix]) strictures may require endoscopic or surgical intervention to relieve obstructions. ^[5] However, in persons with ulcerative colitis, colonic strictures are of significant concern and should be presumed to be malignant unless proven otherwise (usually by resection).

Fistulae and Abscesses

Fistulae and abscesses are much more common in Crohn disease, but they are observed in about 20% of patients with ulcerative colitis. Fistula types include enterovesical (leading to recurrent urinary tract infections and pneumaturia), enteroenteric, enteromesenteric, enterocutaneous, rectovaginal, and perianal. ^[3] Additional problems include stenosis and obstruction. Perianal complications occur in 90% of patients with Crohn disease. An obstructive hydronephrosis may result from a right lower quadrant inflammatory mass, leading to an external compression of the right ureter.

Fistulae and perianal disease may be refractory to vigorous medical treatment, including antibiotic therapy (see the following image). Surgical intervention is often required for the treatment of these conditions, but both are associated with a high risk of recurrence.

Perforation and Toxic Megacolon

Perforation and toxic megacolon are the most frightening complications of ulcerative colitis. Intestinal perforation can occur in the presence of fulminant disease, even in the absence of toxic megacolon. The mortality rate is 50% if perforation occurs. Toxic megacolon is a life-threatening complication of ulcerative colitis that can be precipitated by antidiarrheal agents, hypokalemia, narcotics, cathartics, and enemas, including barium enemas, and requires urgent surgical intervention if medical therapy is unsuccessful.

Suspect toxic megacolon in a patient with fulminant ulcerative colitis, especially if the number of daily stools has declined sharply without a corresponding improvement in symptoms. The abdomen is typically distended, tender, and tympanitic. The best method of diagnosing toxic megacolon is through the use of plain radiography.

Infectious Colitis

Infectious colitis is in the differential diagnosis of ulcerative colitis and must be excluded before the diagnosis of ulcerative colitis can be made. However, in patients with well-established ulcerative colitis, superimposed infection can occur. Infection with Clostridium difficile is by far the most common; therefore, the stools of patients hospitalized for a flare of ulcerative colitis should be tested for C difficile toxin. Treatment of C difficile infection (if present) generally helps put the flare into remission.

Malignancy

Malignancy is the most feared long-term intestinal complication of ulcerative colitis. Ulcerative colitis carries a 10- to 30-fold increased risk in the development of colon cancer, with an increasing risk related to the extent and duration of the disease. In fact, the risk begins to rise significantly above that of the general population, approximately 8-10 years after diagnosis. The cumulative risk of cancer after 15, 20, and 25 years is 8%, 12%, and 25%, respectively. For cancer prevention, surveillance colonoscopy with biopsies, especially in patients with pancolitis, every 2 years after 8 years of disease is recommended -- more frequently if areas of pathologic concern are evident. Most authors recommend beginning surveillance approximately 10 years after onset of disease and repeating surveillance at 1- to 2-year intervals.

Evidence currently does not support the need for cancer surveillance in Crohn disease. The risk of cancer in Crohn disease may be equal to that of ulcerative colitis if the entire colon is involved. Hence, screening may be beneficial for patients with Crohn disease who have pancolitis. The risk of small intestinal malignancy in Crohn disease is increased, but the malignancy is as likely to arise in a previously normal area as in an inflamed area. Unfortunately, no screening protocol has ever been demonstrated to be effective for small bowel Crohn disease.

Extraintestinal complications occur in approximately 20% of patients with inflammatory bowel disease (IBD). In some cases, they may be more problematic than the bowel disease itself. In addition, many of the medications used to treat IBD may cause significant adverse systemic effects. Mucocutaneous manifestations, arthritis type 1, and uveitis appear to be significantly more frequent in patients with Crohn disease than in those with ulcerative colitis. ^[6]

Arthritides

In addition to medication-induced arthropathies, two varieties of arthritides are associated with IBD: axial (or central) arthritis and peripheral arthritis. ^[7] The axial arthritis consists of ankylosing spondylitis and sacroiliitis and occurs in approximately 5% of patients with IBD (often Crohn disease). Axial arthritis is typically independent of disease activity and is often associated with human leukocyte antigen (HLA)-B27.

The peripheral arthritides are usually migratory and monoarticular and tend to parallel the underlying disease activity but may antedate IBD. Peripheral arthritis occurs in approximately 10% of patients with IBD; it is a nondestructive arthritis, and patients have seronegative findings for rheumatoid factor (RF). The peripheral arthritis is typically asymmetric, and although it is typically monoarticular, different joints on both sides of the body may be involved. The classic peripheral arthritis affects large weight-bearing joints, although any joint may be involved.

Ophthalmologic Complications

Episcleritis, shown in the image below, manifests with burning eyes and scleral injection and is observed in 3-4% of IBD cases. Episcleritis parallels the course of the disease and resolves with treatment of the IBD. Topical steroids may be administered.

Iritis, which manifests as an acute painful red eye with photophobia and conjunctival injection, often runs a course independent of the intestinal disease. It can progress to blindness. Treatment is with topical or systemic steroids. Cataracts are associated with long-term steroid use. Patients taking long-term steroids should have an annual slit-lamp examination.

Both episcleritis and iritis (uveitis) often require high-dose systemic steroids or infliximab, and either condition can cause significant vision loss if left untreated. ^[8]

Dermatologic Complications

The major skin diseases associated with IBD are erythema nodosum and pyoderma gangrenosum. ^[9] Erythema nodosum is characterized by painful, tender, raised red or violaceous subcutaneous nodules, usually found over the extensor aspects of the arms and the legs, especially over the tibia. Activity usually follows that of the underlying intestinal disease and often heralds onset of increased bowel activity. Treating the bowel disease usually dissipates the erythema nodosum.

However, pyoderma gangrenosum, shown in the images below, is characterized by ulcerating, relatively painless lesions that correlate with bowel activity in about 50% of patients. This skin lesion starts as an inflamed patch of skin ranging from one to several centimeters in diameter that progresses until it ulcerates. Upon ulceration, the lesion may persist for many months before healing.

Urinary Complications

The urinary complications of IBD are more common in Crohn disease. Calcium oxalate stones are the most common type of renal calculi associated with Crohn disease; the treatment is to increase hydration and to use oral calcium citrate supplements, which bind the oxalate within the intestinal tract and prevent its excretion in the urinary tract. Because of its proximity to the ureters, inflammation of the small bowel may involve the ureters, causing obstruction and hydronephrosis. Fistulae occasionally occur between the bowel and the bladder or ureters.

Other Complications

Zivkovic et al investigated catestatin concentrations in 80 IBD patients compared to 75 control subjects and the association of catestatin levels with arterial stiffness parameters. The investigators found that catestatin levels were significantly higher in the IBD group. They concluded that catestatin could have a role in cardiovascular complications of IBD. ^[10]

Additional extraintestinal manifestations of IBD include aphthous ulcers, pericholangitis, primary sclerosing cholangitis, cholelithiasis, anemia, hypercoagulable state, and osteoporosis, which are briefly discussed below, as well as chronic active hepatitis, cirrhosis, and bile duct carcinoma, which are beyond the scope of this article.

Aphthous ulcers

Aphthous ulcers are painful oral lesions that occur more commonly in patients with IBD than in the general population. These lesions are usually diagnosed on the basis of the history and clinical presentation; there are no available laboratory procedures for a definitive diagnosis.

Pericholangitis and primary sclerosing cholangitis

Pericholangitis is the most common hepatic complication of IBD and is usually asymptomatic. Look for elevations of the alkaline phosphatase, less often bilirubin. ^[11]

Primary sclerosing cholangitis is a disease of the biliary tree, and it is most commonly associated with ulcerative colitis, which may be clinically evident within 2 years of the diagnosis of sclerosing cholangitis if the colitis is present and has not been diagnosed first. Although this condition may be indolent for many years, sclerosing cholangitis typically manifests as fatigue, itching and, perhaps, jaundice, and is far more commonly sought when abnormal liver function test (LFT) results in a cholestatic pattern that is found in a patient with ulcerative colitis. Although ursodeoxycholic acid may help improve serum LFT results, this has not translated into improved survival. The most concerning complication of sclerosing cholangitis is the development of cholangiocarcinoma.

If sclerosing cholangitis is diagnosed in the absence of a known history of ulcerative colitis, colonoscopy is indicated. Sclerosing cholangitis can progress to cirrhosis, in which case liver transplantation is the treatment of choice; however, sclerosing cholangitis can recur in the transplanted liver.

Cholelithiasis

Gallstones occur in about one third of patients with Crohn disease, resulting from increased lithogenicity of the bile due to impaired ileal absorption of bile acids. ^[12] Affected individuals are usually asymptomatic; occasionally, cholecystectomy is necessary if the patient becomes symptomatic.

Anemia

The anemia associated with IBD may be of 2 types: iron deficiency anemia secondary to chronic blood loss, and anemia of chronic disease. ^{[13, 14]} Because iron is absorbed in the duodenum, patients with Crohn disease involving the proximal small intestine may have difficulty absorbing oral iron; occasionally, parenteral iron replacement is necessary.

Hypercoagulable state

A hypercoagulable state can occur in IBD, with an estimated occurrence in as many as one third of patients with IBD; however, this condition may go unrecognized until a thrombotic event occurs. The incidence of thrombotic complications may be as high as 39%; however, massive hemorrhage occurs in less than 1% of patients. Strokes, deep venous thromboses, pulmonary embolism, and arterial thromboses are not uncommon. Additionally, portal or hepatic vein thrombosis, retinal venous thrombosis, gonadal vein thrombosis, and mesenteric venous thrombosis have been reported. ^[15]

The hypercoagulable state correlates with the activity of the disease. ^[16] Its cause is unclear but may be related to increased levels of plasminogen activator inhibitor, factors V and VIII, and fibrinogen or to decreased levels of factor V Leiden, antithrombin III, and proteins C and S. The common laboratory tests include prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time, and treatment generally consists of anticoagulant therapy.

Osteoporosis

Crippling osteoporosis can be a very serious complication for patients with IBD. The condition arises either from decreased calcium absorption (because of the underlying disease process) or because of corticosteroid use. ^[17] The threshold for obtaining bone density studies should be low, and treatment (with bisphosphonates and calcium supplements) can be initiated in patients with significantly low bone density.

Hidalgo et al conducted a meta-analysis to evaluate the risk of developing osteoporotic fractures among IBD patients. Seven studies with a total population of 242,524 patients were included in the statistical analysis. The investigators found that patients with IBD had a32% increased risk of developing osteoporotic fractures as compared to individuals without IBD. ^[18]