Crohn's disease (CD) is a chronic inflammatory granulomatous disorder that can affect the entire gastrointestinal tract, with the terminal ileum and adjacent colon being the most commonly involved sites. It typically exhibits a segmental distribution. The main clinical manifestations include abdominal pain, diarrhea, and weight loss, often accompanied by systemic symptoms such as fever and fatigue, local manifestations like perianal abscesses or fistulas, and extraintestinal manifestations involving joints, skin, eyes, and oral mucosa.
This disease is more common in adolescents, with a peak onset age of 18–35 years, and occurs equally in males and females.
Pathology
Macroscopic features include:
- Segmental distribution of lesions.
- Mucosa presenting with longitudinal ulcers and a cobblestone appearance, with early lesions resembling aphthous ulcers.
- Involvement of the entire intestinal wall, leading to thickened and hardened bowel walls with intestinal strictures. Ulcer perforation may cause localized abscesses or penetration into adjacent intestinal segments, organs, or the abdominal wall, forming internal or external fistulas. Fibrinous necrosis of the serosa and chronic perforation may result in intestinal adhesions.
Histological features include:
- Non-caseating granulomas composed of epithelioid cells and multinucleated giant cells, which can occur in all layers of the intestinal wall and regional lymph nodes.
- Fissure ulcers, which are slit-like and may extend into the submucosa, muscularis, or even the serosa.
- Inflammation involving all layers of the intestinal wall, accompanied by lymphocyte aggregation in the basal lamina propria and submucosa, submucosal thickening, lymphatic dilation, and ganglionitis.
Clinical Manifestations
The onset is often insidious and slow, with symptoms sometimes taking months or years from the initial presentation to diagnosis. The disease course alternates between chronic periods of activity and remission of varying durations, often persisting without resolution. A small number of cases present acutely, resembling an acute abdomen, and some patients may be misdiagnosed with acute appendicitis. The primary symptoms include abdominal pain, diarrhea, and weight loss. However, clinical manifestations are highly variable and depend on the clinical type, lesion location, disease phase, and complications.
Gastrointestinal Manifestations
Abdominal Pain
This is the most common symptom, typically located in the right lower quadrant or periumbilical region, and occurs intermittently. Abdominal tenderness, often in the right lower quadrant, is common on physical examination. Persistent abdominal pain and significant tenderness suggest peritoneal involvement or the formation of intra-abdominal abscesses.
Diarrhea
Stools are typically pasty and may contain blood, although the frequency of stools and presence of mucus or bloody stools are usually less pronounced than in UC. Lesions involving the distal colon or anorectal region may result in mucus, pus, and bloody stools, along with tenesmus.
Abdominal Mass
Observed in 10–20% of patients, these masses are often caused by intestinal adhesions, bowel wall thickening, mesenteric lymph node enlargement, internal fistulas, or localized abscesses. They are typically located in the right lower quadrant or periumbilical region.
Fistula Formation
Fistulas are a relatively common and characteristic clinical feature of CD, resulting from transmural inflammatory lesions penetrating the entire intestinal wall into extraintestinal tissues or organs. Fistulas can be classified as internal or external. Internal fistulas may connect to other intestinal segments, the mesentery, bladder, ureter, vagina, or retroperitoneum, while external fistulas open to the abdominal wall or perianal skin. Internal fistulas between intestinal segments may lead to increased diarrhea and malnutrition. Fistulas connecting to other tissues or organs may result in secondary infections due to fecal contamination. External fistulas or those connecting to the bladder or vagina may cause the passage of feces or gas.
Perianal Lesions
These include perianal fistulas, abscesses, and anal fissures. In some cases, perianal lesions may be the initial presentation of the disease.
Systemic Manifestations
Systemic symptoms are common.
Fever
Fever is associated with intestinal inflammation and secondary infections. Intermittent low-grade or moderate fever is common, though in some cases, fever may be the primary symptom. Some patients present with prolonged unexplained fever before the onset of gastrointestinal symptoms. High fever may indicate secondary infections or abscess formation.
Nutritional Disorders
Nutritional deficiencies result from chronic diarrhea, reduced food intake, and chronic infections. The primary manifestations include weight loss, anemia, hypoalbuminemia, and vitamin deficiencies. Patients with onset before puberty often experience growth retardation.
Extraintestinal Manifestations
Extraintestinal manifestations are similar to those seen in UC but occur more frequently in CD. Common manifestations include oral ulcers, erythema nodosum, arthritis, and ocular diseases.
Clinical Classification
Clinical classification aids in assessing disease severity, prognosis, and treatment planning.
Disease Behavior (B)
It can be classified as non-stricturing, non-penetrating (B1), stricturing (B2), or penetrating (B3), with an additional category for perianal disease (P). Overlap and transitions between types may occur.
Lesion Location (L)
It can be classified as terminal ileum involvement (L1), colonic involvement (L2), ileocolonic involvement (L3), or upper gastrointestinal involvement (L4). L1, L2, and L3 may coexist with L4.
Severity
Disease severity is determined using the Crohn's Disease Activity Index (CDAI), which evaluates the severity of primary clinical symptoms and complications. This index is used to distinguish between active and remission phases, assess disease severity (mild, moderate, or severe), and evaluate treatment efficacy.
Complications
The most common complication is intestinal obstruction caused by bowel strictures, followed by intra-abdominal abscesses resulting from bowel wall penetration. Occasionally, acute bowel perforation or massive gastrointestinal hemorrhage may occur. Patients with prolonged unresolved inflammation have an increased risk of malignancy.
Laboratory and Other Examinations
Laboratory Tests
Laboratory findings are similar to those in ulcerative colitis (UC).
Endoscopic Examination
Colonoscopy is recommended as the first-line examination for Crohn's disease (CD), with the scope reaching the terminal ileum. Endoscopic findings typically include segmental, asymmetrical mucosal inflammation. Characteristic features include discontinuous lesions, longitudinal ulcers, and a cobblestone appearance. Capsule endoscopy is suitable for suspected small bowel CD, but intestinal strictures should be excluded beforehand to prevent capsule retention. Double-balloon enteroscopy is indicated for cases where lesions are confined to the small intestine and other diagnostic methods are inconclusive, especially when histological biopsy is required.
Imaging Studies
CT or MRI enterography (CTE/MRE) can reveal inflammatory changes in the bowel wall, the location and extent of lesions, the presence of strictures, and extraintestinal complications such as fistulas, abscesses, or phlegmon. These modalities are considered standard for evaluating small bowel CD.
Typical findings in active CD on CTE/MRE include marked bowel wall thickening, enhanced mucosal contrast with bowel wall stratification, and the "target sign" or "double halo sign." Increased, dilated, and tortuous mesenteric vessels (the "comb sign") are also commonly observed, along with increased mesenteric fat density, mesenteric lymphadenopathy, and blurred surrounding structures. Pelvic MRI is useful for assessing the location and extent of perianal disease, identifying fistula types, and understanding their anatomical relationships with surrounding tissues.
Gastrointestinal barium studies and barium enema have lower diagnostic sensitivity and have largely been replaced by endoscopy and CTE/MRE. However, in facilities with limited resources, these techniques can still be used for CD evaluation. Findings may include irregular mucosal folds, longitudinal ulcers or fissures, cobblestone patterns, pseudopolyps, multiple strictures, rigid bowel walls, fistula formation, and pseudo-diverticular dilatation, with segmental lesion distribution being a characteristic feature.
Abdominal ultrasound is a convenient and cost-effective method for assessing the degree of inflammation in affected bowel segments and identifying fistulas, abscesses, or inflammatory masses. It can be used for disease monitoring during follow-up and for guiding percutaneous drainage of intra-abdominal abscesses.
Diagnosis and Differential Diagnosis
Chronic onset with recurrent abdominal pain, diarrhea, and weight loss—especially when accompanied by intestinal obstruction, abdominal tenderness, abdominal masses, intestinal fistulas, perianal disease, or fever—should raise clinical suspicion of CD. Endoscopy and imaging studies are necessary for evaluation. A provisional diagnosis of CD can be made if endoscopic or imaging findings are consistent with the disease's characteristic features. A definitive diagnosis may be considered if histopathological findings support CD and other causes have been excluded.
As there is no "gold standard" for diagnosing CD, the likelihood of CD increases with the presence of the following features:
- Discontinuous or segmental lesions.
- Cobblestone appearance or longitudinal ulcers.
- Transmural inflammatory response in the bowel wall.
- Non-caseating granulomas.
- Fissures or fistulas.
- Perianal disease.
For newly diagnosed patients, a follow-up period of 3–6 months is recommended to confirm the diagnosis.
CD must be differentiated from various infectious and non-infectious inflammatory bowel diseases and intestinal tumors. During acute episodes, appendicitis should be excluded. In chronic cases, intestinal tuberculosis and intestinal lymphoma are common differential diagnoses. When lesions are confined to the colon, differentiation from UC is necessary.
Intestinal Tuberculosis
Key points for differentiation can be found in the section on intestinal tuberculosis.
Intestinal Lymphoma
Clinical manifestations often include non-specific gastrointestinal symptoms such as abdominal pain, abdominal masses, weight loss, intestinal obstruction, and gastrointestinal hemorrhage, which can make differentiation from CD challenging. Radiographic findings of extensive erosion within a bowel segment, larger indentation or filling defects, and ultrasound or CT evidence of significant bowel wall thickening and enlarged abdominal lymph nodes favor a diagnosis of lymphoma. Lymphoma typically progresses more rapidly. Histopathological confirmation can be obtained through small bowel biopsy during endoscopy or surgical exploration if necessary.
Ulcerative Colitis (UC)
Key points for differentiation can be found in the section on ulcerative colitis.
Acute Appendicitis
Diarrhea is less common, and patients often present with migratory right lower quadrant pain. Tenderness is localized to McBurney's point, with a more pronounced leukocytosis on blood tests.
Other Conditions
Differentiation is required for schistosomiasis, amebic colitis, other infectious colitis (e.g., Yersinia, Campylobacter jejuni, Clostridioides difficile), Behçet's disease, drug-induced enteropathy (e.g., NSAID-induced), eosinophilic enteritis, ischemic enteritis, radiation enteritis, collagenous colitis, various intestinal malignancies, and other causes of intestinal obstruction. Diagnosis should be based on the clinical characteristics of each condition.
Treatment
The treatment goals for Crohn's disease (CD) include inducing and maintaining remission, preventing complications, and improving quality of life. A key objective is achieving mucosal healing. Maintenance therapy is often required to prevent relapse.
Control of Inflammatory Response
Active Phase
Glucocorticoids
These are effective in controlling disease activity and are suitable for symptom relief in patients with active CD. Prednisone is administered at a dose of 0.75–1 mg/(kg·d). For mild to moderate cases with lesions confined to the terminal ileum, ileocecal region, or ascending colon, locally acting budesonide may be used at an oral dose of 3 mg per dose, three times daily.
Immunosuppressants
Azathioprine or 6-mercaptopurine is indicated for patients who are steroid-refractory or steroid-dependent. The dose is 1.5–2.5 mg/(kg·d) for azathioprine or 0.75–1.5 mg/(kg·d) for 6-mercaptopurine. These drugs have a slow onset of action, requiring approximately 3–4 months to achieve maximum therapeutic effect. The main adverse effect is bone marrow suppression, such as leukopenia, necessitating close monitoring during use. Methotrexate may be used as an alternative in patients intolerant to azathioprine or 6-mercaptopurine.
Biological Agents and Oral Small Molecule Drugs
In recent years, various biologics and oral small molecule drugs targeting inflammatory pathways in inflammatory bowel disease (IBD) have shown good efficacy. Biologics include anti-TNF-α monoclonal antibodies such as infliximab and adalimumab, vedolizumab (which blocks lymphocyte migration to intestinal inflammatory sites), and ustekinumab (which inhibits IL-12/IL-23 receptor binding). Oral small molecule drugs, such as the JAK inhibitor upadacitinib, have also been shown to be effective in active CD refractory to conventional treatments. These agents can be used for both induction and maintenance therapy.
Exclusive Enteral Nutrition
For patients who do not respond well to conventional drug therapy or cannot tolerate it, especially adolescents, exclusive elemental diets can help control symptoms and reduce inflammation.
Antibiotics
Antibiotics are mainly used to treat secondary infections, such as intra-abdominal abscesses or perianal abscesses. Antibiotic therapy is administered after adequate drainage. Commonly used antibiotics include nitroimidazoles and fluoroquinolones, although antibiotic selection can also be guided by sensitivity testing.
Remission Phase
Azathioprine or 6-mercaptopurine is commonly used for maintenance therapy, particularly after glucocorticoid-induced remission. Patients achieving remission with biologics or JAK inhibitors typically continue the same agents for maintenance therapy.
Symptomatic Treatment
Attention should be given to correcting water and electrolyte imbalances. Blood transfusions may be administered for anemia, while human albumin infusions are used for hypoalbuminemia. Patients with nutritional risks or malnutrition should receive nutritional support therapy. Exclusive enteral nutrition not only provides nutritional support but also helps induce remission. For significant abdominal pain or diarrhea, anticholinergic or antidiarrheal agents may be used as appropriate. Broad-spectrum antibiotics are recommended for patients with concurrent infections.
Surgical Treatment
Due to the high recurrence rate after surgery, surgical indications are primarily limited to complications, including intestinal obstruction, intra-abdominal abscesses, acute perforation, uncontrolled massive hemorrhage, and malignancy.
Treatment of fistulas is complex and requires close collaboration between medical and surgical teams. Individualized treatment plans, including medical and surgical approaches, are determined based on the specific situation.
For patients with localized disease that has been surgically resected, regular postoperative follow-up is advised. Most patients require medication to prevent recurrence. Immunosuppressants, biologics, and JAK inhibitors can all be used for postoperative recurrence prevention.
Patient Education
Smoking is a risk factor for disease activity and recurrence. Patients should be advised to quit smoking. Other precautions are similar to those for ulcerative colitis.
Prognosis
Although a small number of patients may achieve spontaneous remission, the majority experience recurrent episodes and chronic disease progression. Standardized treatment is crucial for symptom relief, improving mucosal healing rates, and enabling patients to return to normal life. Some patients may require surgical intervention during the course of the disease due to complications.