eMedicine Specialties > Gastroenterology > Systemic Disease

Crohn Disease

Author: George Y Wu, MD, PhD, Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine
Coauthor(s): Marcy L Coash, DO, Staff Physician, Department of Internal Medicine, University of Connecticut; Senthil Nachimuthu, MD, Fellow, Section of Cardiology, Department of Medicine, Tulane University School of Medicine
Contributor Information and Disclosures

Updated: Jan 20, 2009

Introduction

Background

Crohn disease is an idiopathic, chronic, transmural inflammatory process of the bowel that often leads to fibrosis and obstructive symptoms, which can affect any part of the gastrointestinal (GI) tract from the mouth to the anus. This condition is believed to be the result of an imbalance between proinflammatory and anti-inflammatory mediators. Most Crohn disease cases involve the small bowel, particularly the terminal ileum. The characteristic presentation of Crohn disease is abdominal pain and diarrhea, which may be complicated by intestinal fistulization, obstruction, or both. Unpredictable flares and remissions characterize the long-term course of this illness.^1,2,3

In 1932, Crohn, Ginzberg, and Oppenheimer described this disease and noted its localization to segments of the ileum. It was later noted that Crohn disease may involve any part of the GI tract.⁴

For excellent patient education resources, visit eMedicine's Crohn Disease Center and Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles Crohn Disease, Crohn Disease FAQs, Crohn Disease Medications, and Inflammatory Bowel Disease.

Related eMedicine topics:
Crohn Disease [in the Radiology section]
Crohn Disease: Surgical Perspective [in the Pediatric Surgery section]
Inflammatory Bowel Disease

Pathophysiology

The exact cause of Crohn disease remains unknown. Current theories implicate the role of genetic, microbial, immunologic, environmental, dietary, vascular, and even psychosocial factors as potential causative agents. It has been suggested that patients have an inherited susceptibility for an aberrant immunologic response to one or more of these provoking factors.⁴

Microscopically, the initial lesion starts as a focal inflammatory infiltrate around the crypts, followed by ulceration of superficial mucosa. Later, inflammatory cells invade the deep mucosal layers and, in that process, begin to organize into noncaseating granulomas. The granulomas extend through all layers of the intestinal wall and into the mesentery and the regional lymph nodes. Neutrophil infiltration into the crypts forms crypt abscesses, leading to destruction of the crypt and atrophy of the colon. Chronic damage may be seen in the form of villous blunting in the small intestine as well. Ulcerations are common and are often seen on a background of normal mucosa. Although granuloma formation is pathognomonic of Crohn disease, its absence does not exclude the diagnosis.⁴

Macroscopically, the initial abnormality is hyperemia and edema of the involved mucosa. Later, discrete superficial ulcers form over lymphoid aggregates and are seen as red spots or mucosal depressions. These can become deep, serpiginous ulcers located transversely and longitudinally over an inflamed mucosa, giving the mucosa a cobblestone appearance. The lesions are often segmental, being separated by healthy areas, and are often referred to as skip lesions.⁴

Transmural inflammation results in thickening of the bowel wall and narrowing of the lumen. As Crohn disease progresses, it is complicated by obstruction or deep ulceration leading to fistulization by way of the sinus tracts penetrating the serosa, microperforation, abscess formation, adhesions, and malabsorption.¹

Obstruction is initially caused by significant edema of the mucosa and associated spasm of the bowel. Obstruction is intermittent and is often reversible with conservative measures and anti-inflammatory agents. With further disease progression, the obstruction becomes chronic because of scarring, luminal narrowing, and stricture formation.¹

Fistulae may be enteroenteral, enterovesical, enterovaginal, or enterocutaneous. The inflammation extending through the bowel wall may also involve the mesentery and surrounding lymph nodes. Creeping fat may be seen when the mesentery wraps around the bowel surface.¹

Serosal inflammation causes adhesions; thus, free perforations are less common in Crohn disease as in other inflammatory bowel conditions.¹

Malabsorption occurs as a result of loss of functional mucosal absorptive surface. This phenomenon can lead to protein-calorie malnutrition, dehydration, and multiple nutrient deficiencies. Involvement of the terminal ileum may result in malabsorption of bile acids, which leads to steatorrhea, fat-soluble vitamin deficiency, and gallstone formation. Fat malabsorption, by trapping calcium, may result in increased oxalate excretion (normally complexed by calcium), causing kidney stone formation.¹

Nearly 30% of patients with either large- or small bowel disease develop perianal complications. Perianal complications may precede the development of intestinal symptoms and manifest as anal fissures, perianal fistulae, or abscesses.¹

Although any area of the GI system may be affected, the most common site of Crohn disease is the ileocecal region, followed by the colon, the small intestine alone, the stomach (rarely), and the mouth. The esophagus is very rarely involved.¹

In addition to local complications, a variety of extraintestinal manifestations may be associated with Crohn disease. The usual sites are the skin, joints, mouth, eyes, liver, and bile ducts.⁵

Skin manifestations (eg, erythema nodosum, pyoderma gangrenosum, Sweet syndrome) and peripheral arthritis (eg, asymmetric involvement of larger joints) are probably more common with colitis than with enteritis. Aphthous ulcers are the most common mouth lesions. The more frequent nutritional-deficient–cutaneous manifestation is acrodermatitis enteropathica due to zinc deficiency manifesting as psoriatic erythema.⁵
 
Ocular manifestations (eg, episcleritis, recurrent iritis, uveitis) are other manifestations of Crohn disease. These manifestations often parallel the course of bowel disease and usually subside when the disease is brought under control.⁵

Inflammatory arthropathies are the most common extraintestinal manifestations in patients with inflammatory bowel disease (IBD), with a prevalence between 7% and 25%. These are seronegative autoimmune-related disorders, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and sacroiliitis, which cause hip and back pain, may antedate the bowel disease by several years, and may persist after surgical or medical remission of the disease.⁵

Amyloidosis and thromboembolic manifestations may also occur. Compared with controls, patients with IBD have a 3-fold higher risk of thromboembolism, which is an important cause of morbidity and mortality. These patients have frequent exposure to classic thrombosis risk factors, including immobility, surgery, steroid therapy, and the presence of central venous catheters. Other factors that may play a role include smoking, antiphospholipid antibody syndrome, and hyperhomocysteinemia, which seem to occur more often in patients with IBD than in the general population.⁵
 
Urinary system involvement includes nephrolithiasis due to calcium oxalate stones. These are caused by hyperoxaluria due to increased intestinal absorption of oxalate. Reports of renal amyloidosis have also been shown likely to be due to acute phase reaction proteins.⁵

Involvement of the liver varies from simple elevation of enzyme levels to benign pericholangitis, sclerosing cholangitis, autoimmune chronic active hepatitis, and cirrhosis. Cholelithiasis is more frequent in patients with IBD than in the general population—probably due to bile salt pool alteration for malabsorption. Cholangiocarcinoma is a rare late complication of primary sclerosing cholangitis. Sometimes, a hepatic abscess manifests as fever of unexplained origin. Portal vein thrombosis and suppurative pylephlebitis have also been described.⁵

Frequency

United States

The prevalence of Crohn disease is approximately 7 cases per 100,000 population.¹ The incidence and the prevalence of Crohn disease (especially the colonic subset) seem to have steadily increased over the last 5 decades, mainly in northern climates.

International

Incidence rates in Europe range from 0.7 to 9.8 cases per 100,000 persons. Rates in Asia range from 0.5 to 4.2 per 100,000. The lowest recorded rates of new cases appear to be in South Africa (0.3-2.6 per 100,000) and Latin America (0-0.03 per 100,000) respectively.^1,2
 
The incidence and the prevalence of Crohn disease (especially colonic Crohn disease) seem to have steadily increased over the last 5 decades, mainly in northern climates. Distinct and reproducible geographic and temporal trends in incidence are observed. In both Europe and North America, higher incidence rates have been characterized in more northern latitudes.^1,2
 
Urban areas may have a higher prevalence of inflammatory bowel disease (IBD) than rural areas.^1,2  

Upper socioeconomic classes are thought to have a higher prevalence than lower socioeconomic classes, a fact likely influenced by increased access to health care, although genetic and environmental factors play a role.^1,6

Mortality/Morbidity

Crohn disease usually has a chronic, indolent course regardless of the site of involvement. Studies have estimated ranges from no increased risk to up to a 5-fold increased risk of death. Mortality appears to be the highest in the first 4-5 years after the diagnosis, and the 15-year survival rate is 93.7% of the general population. Over time, 10% of patients will be disabled by their disease.¹
 

• The chance of death and complications in Crohn disease increases with the duration of the illness. Patients with proximal small bowel disease have a higher risk of mortality compared with those who have ileal or ileocecal disease. The excess mortality may be ascribed to complications of Crohn disease.¹
• As the disease progresses, medical therapy becomes less effective. In the first year after diagnosis, the relapse rate approaches 50%, with 10% of patients having a chronic relapsing course.¹
• Most patients develop complications that require surgery (approximately 80%). Crohn disease frequently recurs after surgery.¹

Race

Data on the racial incidence of Crohn disease seem to show that the condition is uncommon in nonwhites in underdeveloped regions; however, this is not applicable to nonwhites in urban settings, where the rate may even exceed that of whites.¹

• Crohn disease is seemingly more common in whites than in blacks or Asians.¹
• A 2- to 4-fold increase in the prevalence of Crohn disease has been found among the Jewish population in the United States, Europe, and South Africa, as compared with other ethnic groups.¹

Sex

Studies throughout the world have shown a small excess risk of Crohn disease among women. Most reports show a female-to-male ratio between unity and 1.2:1.¹

Age

The age of onset of Crohn disease has a bimodal distribution. The first peak occurs between the ages of 15 and 30 years, and the second peak occurs between the ages of 60 and 80 years. However, most cases begin before age 30 years. A greater proportion of colonic and distal Crohn disease has been diagnosed in older patients, whereas younger patients have predominantly ileal disease.¹

Clinical

History

• Patients with Crohn disease most commonly present with symptoms related to a chronic inflammatory process involving the ileocolic region.
  • Low-grade fever, prolonged diarrhea with abdominal pain, weight loss, and generalized fatigability are usually reported.
  • The patients may develop crampy or steady right lower quadrant or periumbilical pain. The pain precedes and may be partially relieved by defecation. Diarrhea is usually nonbloody and often intermittent.
  • If the colon is involved, patients may report diffuse abdominal pain accompanied by mucus, blood, and pus in the stool.^1,2,4,7,8
• Patients with Crohn disease may also present with complaints that are suggestive of intestinal obstruction.
  • Initially, the obstruction is secondary to inflammatory edema and spasm of the bowel and manifests as postprandial bloating, cramping pains, and loud borborygmi. Once the bowel lumen becomes chronically narrowed, patients may complain of constipation and obstipation. Complete obstruction may sometimes be caused by impaction of undigested foods.
  • Perianal fissures or fistulae are common.
  • Cologastric fistulae may manifest as feculent vomiting, enterovesical fistulae as recurrent urinary tract infections and pneumaturia, enterovaginal fistulae as feculent vaginal discharge, and enterocutaneous fistulae as feculent soiling of the skin.
  • Development of fistulae into the mesentery may result in intra-abdominal or retroperitoneal abscess formation.
  • Patients may also have perianal disease, including perianal fissures, abscesses, and fistulae.^1,2,4,7,8
• Patients may have problems related to extraintestinal manifestations of Crohn disease, which may involve the skin, joints, mouth, eyes, liver, and bile ducts.
• Young people with Crohn disease commonly experience unexplained growth failure and delayed puberty.¹

Physical

Physical examination should focus on the patient's temperature, weight, nutritional status, presence of abdominal tenderness or a mass, perianal and rectal examination findings, and extraintestinal manifestations.
 

• Tachycardia and pale mucosa can indicate acute anemia.
• Physical findings on abdominal examination may typically reveal abnormal bowel sounds, right lower quadrant tenderness (which is typical for ileal involvement), or a mass can sometimes be felt secondary to thickened or matted loops of inflamed bowel.
• Inspection of the perianal region can reveal skin tags, fistulae, abscesses, and scarring.  A rectal examination can help determine sphincter tone and help detect gross abnormalities of the rectal mucosa or the presence of hematochezia.
• Examination of the skin and oral mucosa can be useful to reveal extraintestinal manifestations of the skin, including mucocutaneous ulcers, erythema nodosum, and pyoderma gangrenosum.
• Eye involvement is usually manifested as uveitis or episcleritis.
• A peripheral arthritis involving the large joints may also be present.⁶

Causes

Genetic, environmental, microbial, immunologic, dietary, vascular, and psychosocial factors, including smoking, oral contraceptive, and nonsteroidal anti-inflammatory agents (NSAID) use, have been implicated in the pathogenesis of Crohn disease.
 

• Studies have shown compelling evidence for an inheritable risk for the development of Crohn disease. However, classic Mendelian inheritance is not seen. Most of the genes thought to be involved in the development of the disease play a role in mucosal immunity and are found on the mucosal barrier epithelium.⁴ Several genes are thought to contribute to the complex phenotype; however, mutations within the NOD2 gene (or the IBD1 gene or CARD-15-caspase activating recruitment domain) have been shown to confer susceptibility to Crohn disease. Another region studied is the IBD-3 gene on chromosome 6 which is an area that includes the human leukocyte antigen (HLA) complex and has been linked with IBD. In addition, an area linked specifically to Crohn disease is on chromosome 5q, known as IBD-5, which contains a cytokine gene cluster.⁴
• Environmental influences such as tobacco use seem to have an effect on Crohn disease. Smoking has been shown to double the risk, whereas in people who smoke, the risk of developing ulcerative colitis is less than in those who have never smoked.⁴
• Infectious possibilities such as Mycobacterium paratuberculosis, Pseudomonas species, and Listeria species have all been implicated in the pathogenesis of Crohn disease, suggesting that the inflammation seen with the disease is the result of a dysfunctional but appropriate response to an infectious source.⁴
• Interleukins and tumor necrosis factor-alpha (TNF-alpha) have also been implicated in the disease process. Crohn disease is characterized by a T-helper type-1 cellular immune response pattern that leads to production of interleukin 12 (IL-12), TNF, and interferon gamma (IFN-gamma). TNF has been shown to play a critical role in the inflammation in this disease. Increased production of TNF by macrophages in patients with Crohn disease results in increased concentrations of TNF in the stool, blood, and mucosa.⁹

• Search for CME/CE on This Topic »

• Crohn Disease (Pediatrics: Surgery)
• Crohn Disease (Pediatrics: General Medicine)
• Crohn Disease (Radiology)
• Inflammatory Bowel Disease (Ophthalmology)

• Crohn Disease Center
• Crohn Disease Symptoms
• Crohn Disease FAQs
• Understanding Crohn Disease Medications
• Crohn Disease Overview
• Crohn Disease Causes
• Crohn Disease Treatment
• Inflammatory Bowel Disease Overview

• Susceptibility to Induced Colitis Increased by Gene Mutation
• Growth Hormone Safe, Effective for Children With Crohn's Disease on Long-Term Corticosteroids
• Inflammatory Bowel Disease Not Linked to Cervical Abnormalities

• Review and Expert Opinion on Prevention and Treatment of Infliximab-related Infusion Reactions
• The Expanding Universe of Inflammatory Bowel Disease Genetics
• A Case of Infliximab-Induced Psoriasis