Crohns Disease


Crohn’s Disease

  1. Overview
    • chronic, nonspecific granulomatous disease of the alimentary tract of unknown etiology
    • characterized by periods of remission and exacerbation

  2. Incidence
    • highest incidence in North America and Northern Europe
    • men = women
    • whites > blacks, Asians
    • strong familial association, but the disease is not inherited in an autosomal dominant fashion
    • primarily affects young adults, but a bimodal distribution occurs with a second peak occurring in the sixth decade
    • Jews have a greater incidence than other races

  3. Etiology
    • no specific cause has been identified
    • microbiologic, immunologic, genetic, and environmental etiologies have all been proposed

    1. Microbiologic
      • attention has been focused on atypical mycobacteria as a cause but this has yet to be proved
      • other potential agents are viruses and Yersinia enterocolitica
      • empirical therapy with antimicrobial agents has failed to cure the disease

    2. Immunologic
      • an immunologic response plays an important role in the pathogenesis of the disease, buts its role as an etiologic agent is unclear
      • an autoimmune mechanism has been suggested, since humoral and cell-mediated reactions against gut cells have been identified
      • however, there has been no direct correlation between these immunologic abnormalities and the development of Crohn’s disease

    3. Genetic
      • strongest risk factor by far is having a primary relative with the disease
      • susceptibility loci on chromosomes 16q, 5q, 19p, 7q, and 3p have been tentatively identified
      • genetic variants of the NOD2 gene have the greatest association with Crohn’s disease

    4. Environmental
      • smokers have a higher incidence of the disease
      • spouses of patients with Crohn’s disease have a higher incidence of the disease

  4. Pathology
    • can involve the GI tract anywhere from the mouth to the anus
    • disease is discontinuous and segmental
    • small and large intestines are the most frequent sites of involvement (33% have ileitis only, 50% have ileocolitis, 20% have Crohn’s colitis only)
    • 33% have perianal disease
    • other sites are rare

    1. Gross Pathology
      • earliest gross lesion is a superficial aphthous ulcer (small, flat ulcer with a whitish center and a red border)
      • as the disease progresses, the ulcers grow and coalesce and complete transmural inflammation results
      • the bowel wall becomes thickened, edematous, and rigid
      • thickening and hypertrophy of the submucosa and muscularis result in narrowing of the lumen
      • at operation, extensive fat-wrapping is found and involved segments are often adherent to other loops or adjacent viscera

      Crohn's Disease - Gross Specimen
    2. Microscopic Features
      • chronic inflammatory cells are found throughout the bowel wall
      • noncaseating granulomas are found in the bowel wall and regional nodes in 60% to 75% of patients

  5. Clinical Manifestations
    1. Symptoms
      • typical patient is less than 40 years old
      • onset is often insidious, with a slow, protracted course
      • lower abdominal pain, often cramping in nature, is the most common symptom
      • diarrhea, usually non-bloody, is the next most common symptom
      • fever, weight loss, malaise occur in 33% to 50% of patients

      1. Extraintestinal Manifestations
        • present in 30% of patients
        • skin: erythema nodosum, pyoderma gangrenosum
        • eye: iritis, uveitis
        • joints: arthritis, ankylosing spondylitis
        • liver: hepatitis, pericholangitis, sclerosing cholangitis

        Erythema Nodusom and Pyoderma Gangrenosum
    2. Intestinal Complications
      1. Obstruction
        • occurs as a result of chronic disease with fibrosis and narrowing of the bowel lumen
        • may be partial or complete
        • terminal ileum adjacent to the ileocecal valve is the most common site
        • involved segments are often short

      2. Fistulas
        • fistulas and intraabdominal abscesses are the result of contained perforations
        • can develop between the diseased bowel and any adjacent organ (small bowel, colon, rectum, bladder, vagina, skin)

      3. Cancer
        • Crohn’s disease is a premalignant condition
        • incidence of small bowel cancer is 100 times that of the general population
        • patients have a worse overall prognosis
        • usually arises in bowel segments that have had Crohn’s disease for more than 10 years

      4. Malabsorption
        • extensive involvement of the terminal ileum may result in bile salt malabsorption
        • if the liver is unable to increase bile acid synthesis, then fat malabsorption and diarrhea will occur, resulting in protein calorie malnutrition, hypocalcemia, vitamin deficiencies, and metabolic bone disease

    3. Vienna Classification
      • age, location, and disease type are key variables used to predict disease behavior
      • classification helps guide therapy and predict disease recurrence
      • recurrent disease is often of the same type

      Crohn's Disease Vienna Classification
  6. Diagnosis
    1. Endoscopy
      • colonoscopy will delineate the disease in the colon
      • the terminal ileum is often accessible with the colonoscope
      • capsule endoscopy is limited because of concern for capsule retention
      • anoscopy can show perianal disease (fistulas, abscesses)

      Crohn's Disease - Endoscopy
    2. Contrast Radiology
      • barium studies of the small intestine may show scattered ulcers, a cobblestone appearance of the mucosa, luminal narrowing (string sign), and a thickened bowel wall
      • fistulas may be apparent

      Crohn's Disease - UGI String Sign and Cobblestoning
    3. CT Scan
      • shows marked transmural thickening
      • aids in diagnosing extramural complications
      • radiation exposure is a concern since patients need numerous studies over the course of their disease

      Crohn's Disease Abscess - CT Scan
      Crohn's disease with abscess

    4. MRI
      • superior for detecting strictures
      • radiation-free study, making it the preferred test, if available

      Crohn's Disease MRI
    5. Laboratory
      • cultures are necessary to rule out specific causes of inflammation, such as salmonella, shigella, ameba, intestinal tuberculosis
      • serologic markers (ASCA) can be useful in diagnosing Crohn’s Disease
      • stool lactoferrin and fecal calprotectin are inflammatory markers specific to the intestine that have shown promise in the detection and surveillance of Crohn’s disease
      • C-reactive protein and erythrocyte sedimentation rate are nonspecific markers of inflammation

  7. Medical Therapy
    • treatment is nonspecific and aimed at reducing inflammation
    • palliation of symptoms is the goal: relieving abdominal pain, controlling diarrhea, correcting nutritional deficiencies

    1. Aminosalicylates
      • anti-inflammatory agents used orally or rectally – sulfasalazine, mesalamine (Pentasa)
      • used to treat and maintain remission in mild to moderate CD
      • mesalamine is slowly released throughout the small bowel and colon
      • not associated with increased surgical complications

    2. Steroids
      • used to treat acute moderate to severe disease
      • not ideal for maintenance therapy because of side effects
      • Budesonide has a high first-pass hepatic metabolism, which allows targeted intestinal delivery with minimal systemic side effects

    3. Immunosuppressive Agents
      • azathioprine, 6-mercaptopurine, methotrexate work by inhibiting RNA synthesis, which affects rapidly proliferating lymphocytes
      • have a slow onset of action, so they are not used during acute flares
      • used for maintaining steroid-induced remissions
      • most common side effects are pancreatitis, hepatitis, fever, rash
      • bone marrow suppression and malignant transformation are the most serious side effects
      • before starting 6-MP or azathioprine, must check for thiopurine methyltransferase activity (TPMT)
      • decreased activity of TPMT is associated with the most serious side effects

    4. Biologic Agents
      • newest and most effective drugs
      • monoclonal antibodies against TNF-α reduce T-cell proliferation, thereby reducing inflammation
      • 3 agents in clinical use: infliximab (Remicade), adalimumab (Humira), and certolizumab pegol (Cimzia)
      • effective as monotherapy for maintenance
      • may be used during acute flareups
      • side effects include increased risk of opportunistic infections and lymphoma
      • often combined with immunologic agents in moderate to severe disease

    5. Nutritional Therapy
      • elemental diets are not effective in the maintenance and remission of CD
      • bowel rest and TPN as a treatment for CD has not been supported by randomized studies
      • many patients will need nutritional supplementation

    6. Smoking Cessation
      • smoking increases the incidence of relapse and failure of maintenance therapy
      • smoking cessation reduces disease recurrence by 50%

  8. Surgery
    1. Indications
      • at least 50% of Crohn’s patients eventually require surgery
      • surgery is limited to complications: obstruction, abscess, fistulas, free perforation, bleeding, medically refractory disease, suspicion of malignancy, growth retardation in children

    2. Preoperative Preparation
      • nutritional status of the patient must be optimized – this may require hyperalimentation
      • profound anemia should be corrected
      • in nonobstructed patients a standard purgative bowel prep combined with oral antibiotics should be administered
      • stress doses of steroids will be necessary for patients currently receiving steroids and then tapered postoperatively
      • immunosuppressive drugs can be discontinued right before surgery

      1. Biological Agents
        • effect on surgical outcomes is controversial
        • some studies have shown increased postoperative complications, but not others
        • if possible, surgery should be delayed until serum levels of biologic agents have decreased
        • if immediate operation is required, consideration should be given to a stoma over an anastomosis

    3. General Principles of Operation
      • surgery is palliative, not curative, and most patients will ultimately relapse
      • goal is to treat only the complication and preserve as much bowel length as possible
      • resecting bowel with histologically negative margins does not reduce the risk of recurrence and leads to unnecessarily large resections
      • bypass of involved segments of bowel should be avoided: it leaves the diseased bowel in situ where it is prone to further complications and bacterial overgrowth
      • laparoscopic surgery offers specific benefits (fewer adhesions, decreased pain, decreased septic complications and wound complications), but may be technically challenging

    4. Management of Specific Problems
      1. Acute Ileitis
        • usual preoperative diagnosis is appendicitis
        • terminal ileum is inflamed, with a thickened mesentery with enlarged nodes
        • does not progress to Crohn’s disease
        • Yersinia or Campylobacter infections are the cause in some patients
        • no reason to resect the ileum
        • if the appendix and cecum are not involved, then appendectomy should be performed

      2. Acute Ileocolonic Crohn’s Disease
        • mimics acute appendicitis
        • appendectomy may be performed if the cecum is relatively normal, otherwise the appendix should be left alone
        • resection should not be performed

      3. Obstruction
        • most frequent indication for surgery
        • nonoperative management is indicated initially since many obstructions will resolve spontaneously
        • resection of the involved segment with primary anastomosis is the usual operation performed
        • strictureplasty should be considered in patients with short fibrotic strictures (<5 cm) - full thickness biopsy with frozen section is necessary to rule out malignant disease
        • if accessible by endoscopy, then balloon dilatation may be attempted

      4. Fistulas
        • any associated abscesses should be drained, usually percutaneously
        • patients should be ‘cooled down’ with long-term bowel rest and hyperalimentation
        • the segment of bowel with active disease should be resected; the defect in the adjacent normal organ or bowel may simply be closed

    5. Complications
      1. Early Complications
        • anastomotic leak is the most feared complication and may be difficult to recognize early in immunosuppressed patients
        • CT scan with oral contrast or a Gastrografin study should be ordered if there is any suspicion of a leak
        • treatment will require reexploration and diversion

      2. Late Complications
        • extensive ileal resections can result in malabsorption of vitamin B12, bile salts, and fat-soluble vitamins
        • bile salt depletion leads to steatorrhea, oxalate urinary stones, gallstones, and diarrhea
        • extensive small bowel resections can result in short gut syndrome
        • some symptomatic malabsorption can be expected if less than 200 cm of small bowel remains
        • 50% of patients eventually require a second surgery






References

  1. Sabiston, 20th ed., pgs 1254 - 1266
  2. Cameron, 11th ed., pgs 113 – 117
  3. UpToDate. Clinical Manifestations, Diagnosis, and Prognosis of Crohn’s disease in Adults. Peppercorn MD, Mark and Kane MD, Sunanda. Nov 13, 2019
  4. UpToDate. Operative Management of Crohn Disease of the Small bowel, Colon, and Rectum. Fleshner MD, Phillip. Nov 26, 2019. Pgs 1 – 33