IBD

Crohn's Disease

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Crohn's Disease, Terminal Ileitis, Regional Enteritis, Crohn's Colitis, Crohns Disease, Crohn Disease

  • See Also
  1. Inflammatory Bowel Disease
  2. Gynecologic Manifestations of Crohn's Disease
  3. Ulcerative Colitis
  • Epidemiology
  1. Worldwide Prevalence: 3-20 per 100,000
  2. U.S. Prevalence
    1. Child: 58 per 100,000
    2. Adult: 119-241 per 100,000
  3. Peak onset: 15-30 years
    1. Bimodal peak in age 20s and age 50s
    2. However most have onset before age 40 years
  4. Women more often affected than men
  5. More common in caucasian patients and northern latitudes
  6. Familial aggregation
    1. First degree relative confers 2-4 fold risk
    2. Identical twins have greater concordance
    3. Second degree relative confers less increased risk
  • Pathophysiology
  1. Etiology unknown
  2. Related genetic mutation: NOD2 (Chromosome 16 in IBD1)
    1. Associated with increased Crohn's Relative Risk
      1. One NOD 2 mutation: 2 fold Relative Risk
      2. Two NOD 2 mutations: 15-35 fold Relative Risk
    2. Proposed mechanism
      1. Related to defective Bacterial sensing by Monocytes
      2. Results in hyper-immune response to Bacterial LPS
    3. References
      1. Ahmad (2002) Gastroenterology 122:854 [PubMed]
  3. Chronic Granulomatous inflammation
    1. Ulcers form over lymphoid aggregates; ulcers may then coalesce into larger ulcerations
    2. Transmural extension may extend through entire bowel wall
      1. Contrast with Ulcerative Colitis which only affects mucosa
      2. Full, transmural extension through the bowel wall may result in fistulas, sinuses, abscesses or bowel perforation
    3. Secondary fibrosis may result in strictures
  4. May affect entire Gastrointestinal Tract, mouth, Esophagus, Stomach, small and Large Bowel to anus
    1. Distal ileum (33% of cases) and proximal colon most often involved
    2. Isolated colonic involvement in 25% of cases
  5. Irregular involvement ("Skip lesions")
    1. Discontinuous transmural lesions are a hallmark of Crohn Disease
    2. Resulting cobblestoning on endoscopy is of patches of ulceration scattered among normal mucosa
  • Risk Factors
  1. Tobacco Abuse
    1. Associated with greater risk of flares
  2. Oral Contraceptives
  3. Antibiotics
  4. Frequent NSAIDs
  5. Urban environment
  6. NOT associated with Vaccination
  7. Possible Protective Factors (anti-Risk Factors)
    1. Pet or farm animal exposure
    2. Bedroom sharing
    3. More than 2 siblings
    4. High fiber intake
    5. Fruit intake
    6. Physical Activity
  • History
  1. Gastrointestinal and constitutional symptoms (see below)
  2. Nocturnal symptoms
  3. Stool urgency
  4. Food intolerance (e.g. gluten intolerance)
  5. Travel history
  6. Medications (e.g. Antibiotics)
  7. Family history Inflammatory Bowel Disease
  8. Extra-intestinal symptoms (eye, joint, skin)
  • Exam
  1. Vital Signs (identify Unstable Patients)
    1. Heart Rate
    2. Blood Pressure
    3. Temperature
    4. Respiratory Rate
    5. Body weight
  2. Abdominal examination
    1. Abdominal tenderness
    2. Abdominal Distention
    3. Abdominal mass
  3. Anorectal Exam
    1. Anal Fissure
    2. Perirectal fistula
    3. Perirectal Abscess
  • Symptoms
  • General (insidious in most cases)
  1. Fever
  2. Anorexia
  3. Weight loss
  4. Fatigue
  5. Nausea
  6. Abdominal Pain (Low abdominal ache or cramp)
  7. Diarrhea (85%)
  8. Rectal Bleeding
    1. Much less prominent than in Ulcerative Colitis
    2. Non-bloody Diarrhea is typical for Crohn's Disease
  1. Adult (strongest association first)
    1. Perianal lesions other than Hemorrhoids
    2. First degree relative with Inflammatory Bowel Disease
    3. Weight loss (5% of usual body weight) in the past 3 months
    4. Abdominal Pain >3 months
    5. Nocturnal Diarrhea
    6. Fever
    7. Abdominal Pain subsides for 30-45 minutes after meals
    8. No rectal urgency
    9. Danese (2015) J Crohns Colitis 9(8): 601-6 [PubMed]
  2. Child (strongest association first)
    1. Anemia
    2. Hematochezia
    3. Weight loss
    4. El-Chammas (2013) J Pediatr 162(4): 783-7 [PubMed]
  • Symptoms
  • Based on Location
  1. Ileum and colon (35%)
    1. Diarrhea
    2. Abdominal cramping or Abdominal Pain
    3. Weight loss
  2. Colon only (32%)
    1. Diarrhea
    2. Rectal Bleeding
    3. Perirectal Abscess
    4. Fistula
    5. Perirectal ulcer
    6. Associated with skin lesions and Arthralgias
  3. Small Bowel only (28%)
    1. Diarrhea
    2. Abdominal cramping or Abdominal Pain
    3. Weight loss
    4. Associated with fistulas and abscesses
  4. Gastroduodenal region (5%)
    1. Anorexia
    2. Weight loss
    3. Nausea and Vomiting
    4. Associated with Bowel Obstruction
  • Signs
  • Gastrointestinal
  1. Stool Occult Blood positive
  2. Anal Disease(20%)
    1. Perirectal fistula
    2. Anal Skin Tag
    3. Anal Ulceration or Anal Fissure
    4. Perirectal Abscess
  3. Right Lower Quadrant abdominal palpable mass (common)
  4. Minimal increased Colon Cancer risk (contrast with Ulcerative Colitis)
  • Signs
  • Extra-abdominal manifestations (10% Incidence)
  1. See Gynecologic Manifestations of Crohn's Disease
  2. Similar findings in Ulcerative Colitis
    1. However extraintestinal findings are more common with Crohn's Disease
    2. See Ulcerative Colitis extraintestinal manifestations
  3. Anemia (>9%)
  4. Anterior Uveitis (17%)
  5. Episcleritis (29%)
  6. Aphthous Stomatitis (>4%)
  7. Cholelithiasis (>13%)
  8. Erythema Nodosum (>2%)
  9. Inflammatory Arthropathy (>10%)
  10. Nephrolithiasis (>8%)
  11. Osteoporosis (>2%)
  12. Pyogenic gangrenosum (>0.5%)
  13. Scleritis (18%)
  14. Venous Thromboembolism (>10%)
  • Labs
  1. Complete Blood Count with Platelet
    1. Mild Anemia: Chronic blood loss
      1. Anemia is more common in Ulcerative Colitis
    2. Mild Leukocytosis: Crohn's Disease exacerbation
    3. Marked Leukocytosis
      1. Severe colitis
      2. Toxic Megacolon
      3. Intra-abdominal abscess
  2. Comprehensive metabolic panel (Liver Function Tests, Renal Function tests)
    1. Serum Alkaline Phosphatase increased in Primary Sclerosing Cholangitis (in addition to more common causes)
  3. Acute phase reactants
    1. C-Reactive Protein (C-RP)
    2. Erythrocyte Sedimentation Rate (ESR)
  4. Stool studies
    1. Stool Culture or Enteric Nucleic Acid Test
    2. Ova and Parasites
    3. Clostridium difficile Toxin
  5. Markers of nutritional status
    1. Serum Ferritin
    2. Serum Iron
    3. Total Iron Binding Capacity
    4. Serum Vitamin B12
    5. Serum Folate
    6. Serum Albumin
    7. Serum Prealbumin
    8. Vitamin D
    9. Serum Calcium
  6. First-line Diagnostic labs
    1. Fecal Calprotectin
      1. Test Sensitivity: 83-100% in adults (95-100% in children)
      2. Test Specificity: 60-100% in adults (44-93% in children)
      3. Kallel (2010) Eur J Gastroenterol Hepatol 22(3): 340-5 [PubMed]
      4. Waugh (2013) Health Technol Assess 17(55):1-211 [PubMed]
  7. Other diagnostic labs
    1. Fecal lactoferrin
      1. Marker of Crohns Disease activity
      2. Sidhu (2010) Aliment Pharmacol Ther 31(12): 1365-70 [PubMed]
    2. Escherichia coli outer membrane porin Antibody
    3. Saccharomyces cerevisiae Antibody
    4. Perinuclear Antineutrophil Cytoplasmic Antibody (pANCA)
  • Differential Diagnosis
  1. See Inflammatory Bowel Disease
  2. Ulcerative Colitis
    1. Continuous lesions that start in the Rectum, and are typically limited to the colon
    2. Typically involves only the mucosal and submucosal layers
    3. Rectal Bleeding and Anemia are more common and Abdominal Pain is less prominent than in Crohns Disease
  3. Celiac Sprue
  4. Chronic Pancreatitis
  5. Colorectal Cancer
  6. Diverticulitis
  7. Yersinia infection
  8. Mycobacterium infection
  9. Irritable Bowel Syndrome
  10. Ischemic Colitis
  11. Small Bowel Lymphoma
  12. Sarcoidosis
  13. Cummings (2008) BMJ 336(7652): 1062-6 [PubMed]
  • Diagnostics
  1. Colonoscopy with Ileoscopy (first-line study in most patients)
    1. Focal ulcerations: aphthous, stellate, or linear
    2. Skip areas
    3. Rectal sparing
    4. Cobblestone appearance
    5. Strictures
  2. Upper endoscopy
    1. Consider in children (more common to have isolated upper gastrointestinal involvement)
  3. Other studies
    1. Capsule Endoscopy
    2. Enteroscopy
  • Imaging
  1. First Line imaging studies
    1. CT Abdomen (with enterography is preferred)
    2. MRI Abdomen (with enterography is preferred)
  2. Older studies with lower Test Sensitivity and Test Specificity
    1. Small Bowel follow-through
    2. Barium Enema with retrograde terminal ileum filling
      1. May show classic thumbprinting
      2. Defect protrudes into lumen
  • Diagnosis
  1. Crohn Disease often has a delayed diagnosis (mean 7 years of symptoms prior to correct diagnosis)
  2. Step 1: History, physical and labs are inconclusive for Crohn's Disease
    1. Obtain Fecal Calprotectin and unlikely to be Crohn's Disease if negative
  3. Step 2: Fecal Calprotectin positive OR Crohn's Diseases diagnosis thought likely
    1. Toxic presentation
      1. Obtain CT Abdomen with contrast
    2. Non-toxic presentation
      1. Ileocolonoscopy with biopsy
      2. CT or MRI with enterography (defines disease extent and adjunct to inconclusive endoscopy)
  • Grading
  • Severity
  1. Crohn Disease Activity Index (CDAI)
    1. https://www.mdcalc.com/calc/3318/crohns-disease-activity-index-cdai
    2. The CDAI is not typically used in clinical practice (instead used for Research Study patient classification)
  2. Disease in Remission (CDAI <150)
    1. Asymptomatic without Corticosteroid use
  3. Mild to Moderate Disease (CDAI 150 to 220)
    1. Ambulatory, eating and maintaining hydration
    2. No systemic toxicity, abdominal tenderness, painful mass, Intestinal Obstruction
    3. Weight loss <10%
  4. Moderate to Severe Disease (CDAI 220-450)
    1. Refractory to mild to moderate disease management
    2. Prominent symptoms (fever, weight loss, Abdominal Pain or tenderness, Nausea or Vomiting, significant Anemia)
  5. Severe to Fulminant Disease (CDAI>450)
    1. Symptoms persist despite Corticosteroids and Biologic Agents
    2. High fever, persistent Vomiting, Intestinal Obstruction, peritoneal signs, Cachexia or abscess
  • Evaluation
  • Moderate to High Risk patient criteria
  1. Age at initial diagnosis >30 years old
  2. Extensive involvement
  3. Ileal or ileocolonic involvement
  4. Perianal or severe rectal disease
  5. Deep ulcers
  6. Prior surgical resection
  7. Strictures or penetrating involvement
  8. Sandborn (2014) Gastroenterology 147(3): 702-5 [PubMed]
  • Management
  • General Measures
  1. No Immunosuppressants if Infectious Colitis possible
  2. Tobacco Cessation
  3. Update Vaccinations
    1. Hepatitis B Vaccine
    2. Influenza Vaccine
    3. Pneumococal Vaccine
  4. Avoid exacerbating factors
    1. Pregnancy
    2. NSAIDs
    3. Oral Contraceptives
  5. Consider baseline DEXA Scan and Vitamin D level
  6. Consider concurrent Vitamin Supplementation
    1. Folic Acid
    2. Vitamin B12
    3. Vitamin D Supplementation
    4. Fat soluble Vitamins
    5. Calcium Supplementation
  7. Prior to starting an Anti-TNF Agent
    1. Chest XRay
    2. Tuberculosis Screening with Purified Protein Derivative (PPD) or Quantiferon
  • Management
  • Acute Crohns Flare
  1. Evaluate for Crohns Flare versus other gastrointestinal disorder or new complication
    1. Ask the patient if the Abdominal Pain, Diarrhea or other acute symptom is consistent with prior flares
    2. Perform a complete exam including Vital Signs
    3. Obtain labs (e.g. CBC, Chem18, Lipase, C-RP, C Diff, enteric Bacteria)
    4. Obtain CT Abdomen imaging if concerned for Small Bowel Obstruction, infection or peritonitis
  2. Supportive care
    1. Fluid Resuscitation
    2. Analgesics
    3. Avoid antidiarrheal agents (e.g. Imodium) in acute flares
    4. VTE Prophylaxis for admitted patients (Crohns is associated with VTE Risk)
  3. Endoscopy is preferred evaluation if available
    1. Discuss with gastroenterology if Corticosteroids (e.g. Prednisone, budesonide) are considered
  4. Antibiotics may be indicated in ill, febrile or toxic appearing patients
    1. Obtain Clostridium difficile stool Antigen
    2. Obtain Enteric Pathogens Nucleic Acid Test Panels (PCR)
    3. Consider Ciprofloxacin with Metronidazole or with Amoxicillin-clavulanate
  5. Abdominal Pain often requires CT Imaging in Crohns Disease
    1. Contrast with Ulcerative Colitis in which perforation and abscess are uncommon
    2. Griffey (2017) Ann Emerg Med 69(5): 587-99 [PubMed]
  6. Avoid starting maintenance medications during a Crohns flare
    1. Do not initiate Salicylate preparations (e.g. Mesalamine) during a flare
  7. Management of new fistula
    1. Refer to gastroenterology or colorectal surgery
    2. Initiate Antibiotics (e.g. Amoxicillin-clavulanate or Ciprofloxacin with Metronidazole)
  8. References
    1. Stannard, Rogers and Kernen (2023) Crit Dec Emerg Med 37(7): 24-9
    2. Swaminathan and Shoenberger in Herbert (2020) EM:Rap 20(6): 18-9
  • Management
  • Longterm Protocol Based on Severity
  1. Approach
    1. Trend in 2018 is to start Biologic Agents (e.g. TNF Inhibitor) as first-line management
    2. Best efficacy of TNF agents is when started within first 2 years of onset
  2. Mild to Moderate (Weight loss <10%, tolerating P.O.)
    1. Step 1: Start Salicylate (5-ASA preparations)
      1. Mesalamine (Rowasa, Pentasa, Asacol) or
      2. Sulfasalazine (Azulfidine)
    2. Step 2: Treat as moderate to severe if refractory
      1. See below
      2. Previously Metronidazole or Ciprofloxacin was used for refractory cases
        1. These Antibiotics have limited role in treating abscesses and fistulas
    3. Step 3: Maintenance therapy for remission
      1. Mesalamine (Rowasa) 3.2 to 4 grams per day
  3. Moderate to Severe (Significant systemic symptoms)
    1. Step 1: Systemic Corticosteroids
      1. Prednisone tapered over 8-12 weeks
        1. Indicated for diffuse of left colon disease
        2. Start at 40-60 mg orally daily
        3. Taper by 5 mg/week initially, then at 2.5-5 mg/week once dose <20 mg
        4. Consider Budesonide instead of Prednisone for
      2. Budesonide (Entocort EC)
        1. Indicated for ileal and proximal colon disease
        2. Minimal absorption and may be preferred over Prednisone as first line agent
        3. Dose: 9 mg PO qAM for up to 8 weeks
      3. Methylprednisolone IV for severe fulminant disease
      4. Taper once control is achieved
        1. Initial: Taper by 5-10 mg weekly
        2. Below 20 mg: Taper by 2.5 to 5 mg weekly
    2. Step 2: Consider immunosuppresant for maintenance (in combination with TNF agent)
      1. Start while tapering Corticosteroid off
      2. Not typically used as monotherapy (TNF agent usually added)
      3. Azathioprine 50 mg orally daily (maximum 2-2.5 mg/kg/day) or
      4. 6-Mercaptopurine 60 mg orally daily (maximum 1.5 mg/kg/day)
      5. Other immunomodulators to consider
        1. Methotrexate 25 mg weekly
        2. Tacrilimus and Cyclosporine have also been used
    3. Step 3: Anti-Tumor Necrosis Factors (TNF-alpha blockers)
      1. Indicated if refractory to Steps 1 and 2
        1. However, in 2018 these agents are used as first line agents
      2. Precautions
        1. See Tumor Necrosis Factor Inhibitor
        2. Risk of infection, Skin Cancer and require monitoring and frequent labs
        3. Update Vaccines and screen for Tuberculosis before starting therapy
      3. Agents
        1. Adalimumab (Humira, $36,000/year in 2023)
          1. Start 160 mg SQ once initially
          2. Then 80 mg SQ once at week 2
          3. Then 40 mg every 2 weeks
        2. Infliximab (Remicade, $10,400/year plus infusion cost in 2023)
          1. Start 5 mg/kg IV once at weeks 0, 2, and 6
          2. Then 5 mg/kg every 8 weeks
        3. Certrolizumab pegol (Cimzia, $121,000/year in 2018)
          1. Less evidence of benefit than other TNF-alpha blockers
          2. Start 400 mg SQ once at weeks 0, 2, and 4
          3. Then 400 mg every 4 weeks
    4. Step 4: Anti-Integrin agents (target Leukocyte trafficking)
      1. Vedolizumab (Entyvio)
        1. Preferred agent of class (no risk of Progressive Multifocal Leukoencephalopathy)
        2. High efficacy, Specificity for gut Leukocyte trafficking
      2. Natalizumab (Tysabri)
        1. Risk of Progressive Multifocal Leukoencephalopathy
        2. Do not use in patients seropositive for anti-John Cunningham Virus
    5. Step 5: Anti-Interleukin
      1. Consider these agents in disease refractory to other agents (esp. TNF-alpha blockers and Immunosuppressants)
      2. Risankizumab (Skyrizi)
        1. Targets IL-23, p19 subunit
        2. Costs $98,700/year in 2023
      3. Ustekinumab (Stelera)
        1. Antibody targets 12/23p40
        2. Costs $159,000/year in 2023
    6. Step 6: Janus Kinase Inhibitors (JAK Inhibitor)
      1. Upadacitinib (Rinvoq)
        1. Once daily oral medication for moderate to severe Crohns Disease refractory to other measures
        2. Costs $73,500/year in 2023
    7. Step 7: Enteral Nutrition
      1. First-line option in children with Crohns Disease (and may be effective in adults)
  4. References
    1. (2023) Presc Lett 30(8): 47
    2. (2018) Presc Lett 25(7): 40
    3. Knutson (2003) Am Fam Physician 68(4):707-14 [PubMed]
    4. Wall (1999) Pharmacotherapy 19:1138-52 [PubMed]
    5. Hanauer (2003) Gastroenterology 125:906-10 [PubMed]
  • Management
  • Available Preparations
  1. Similar to Ulcerative Colitis Management
  2. Antiinflammatory agents
    1. Corticosteroids
      1. Prednisone
      2. Budesonide
    2. Oral 5 ASA preparations
      1. Not effective for small bowel Crohn's Disease
      2. Sulfasalazine (Azulfidine)
        1. Inexpensive but significant side effects
      3. Olsalazine (Dipentum)
        1. Diarrhea commonly occurs
      4. Mesalamine (Asacol, Pentasa, Canasa, Rowasa)
      5. Balsalazide (Colazal)
    3. Immunosuppressive Agents
      1. 6-Mercaptopurine
      2. Azathioprine
      3. Methotrexate
  3. Fish Oil (Enteric Coated)
    1. Dose: 2.7 g qd
    2. Marked reduction in relapse in 1 year (28% vs 69%)
    3. Serum markers of inflammation also reduced
    4. Reference
      1. Belluzzi (1996) N Engl J Med 334:1557-60 [PubMed]
  4. Anti-Tumor Necrosis Factor agents
    1. Adalimumab (Humira)
    2. Certrolizumab pegol (Cimzia)
    3. Infliximab (Remicade)
  5. Anti-Integrin agents (target Leukocyte trafficking)
    1. Vedolizumab (Entyvio)
    2. Natalizumab (Tysabri, PML risk!)
  6. Anti-Interleukin-12/23p40 Antibody
    1. Ustekinumab (Stelera)
  7. Antibiotics for perianal fistula or abscess
    1. Previously used for refractory disease, but now limited to infection
    2. Metronidazole (Flagyl) 10-20 mg/kg/day up to 500 mg orally four times daily
    3. Ciprofloxacin 500 mg orally twice daily
  8. Other agents currently being researched
    1. Thalidomide (not used in women who can conceive)
    2. Mycophenalate (Cellcept)
    3. Tacrolimus
    4. IL-10, 11 and 18
    5. Probiotics
  • Management
  • Intestinal resection (57% of patients)
  1. Indications
    1. Fistula
    2. Abscess
    3. Perianal disease
    4. Perforation
    5. Stricture
      1. Consider Strictureplasty or endoscopic dilation instead of resection
    6. Dysplasia or cancer
    7. Persistent bleeding
    8. Colon obstruction
    9. Refractory disease
      1. Intractable pain or other symptoms
  2. Efficacy
    1. Not Curative (unlike for Ulcerative Colitis)
    2. Symptoms nearly always recur after surgery
      1. Five years: 30% symptoms recur
      2. Ten years: 50% symptoms recur
      3. Fifteen years: 70% symptoms recur
    3. Surgery associated with improved quality of life
      1. Delaney (2003) J Am Coll Surg 196:714-21 [PubMed]
  3. Approach
    1. Segmental resection is preferred over total resection
    2. Prevent recurrence by starting Anti-TNF Agent with other agents as above (e.g. immunomodulators)
  • Complications
  • Gastrointestinal
  1. Colon Cancer
    1. Much lower risk than with Ulcerative Colitis, but increased risk if more than one third colon involved
  2. Rectal disease (50% of Crohn's Disease patients)
    1. Treatment with Antibiotics (Ciprofloxacin, Metronidazole) and surgery
    2. Rectal Fissure
    3. Rectocutaneous fistula
    4. Perirectal Abscess
  • Prognosis
  • Risk for intestinal resection
  1. Poor prognostic indicators (relapse)
    1. Crohn's involving Small Intestine
    2. Perianal fistulas
  2. Favorable prognostic indicators
    1. Ileocecal disease
    2. Colorectal disease
    3. Relapse-free period of 10 years
  3. References
    1. Bernell (2000) Ann Surg 231:38-45 [PubMed]
  • Prevention
  1. Colon Cancer screening
    1. Periodic Colonoscopy after 15 years of disease (annual in some cases)
    2. Lower Colon Cancer risk than Ulcerative Colitis (but still increased, esp. if more than a third colon involved)
  2. Cervical Cancer Screening
    1. Annual Pap Smear and consider HPV screening if on Immunosuppression
  3. Skin Cancer screening
    1. Increased risk of Melanoma (TNF agents) and non-Melanoma (thioprines) Skin Cancer
  4. Anemia Screening
    1. Screen every 3-12 months
    2. See labs as above
  5. Other cancer risks (if on Immunosuppressants)
    1. Lymphoma of the gastrointestinal and genitourinary tract
    2. Cholangiocarcinoma
    3. Lung Cancer
  6. Immunizations (if on Immunosuppressants)
    1. Annual Influenza Vaccine
    2. Prevnar 13
    3. Pneumovax 23
    4. Avoid Live Vaccines
  7. Other prevention
    1. Major Depression screening (higher risk)
    2. Nutritional deficiency
    3. Osteoporosis
      1. See Corticosteroid Associated Osteoporosis
      2. Also increased risk with Vitamin D Deficiency and chronic inflammation
    4. Tobacco Cessation
    5. Venous Thromboembolism Risk
    6. Immunizations
  • References
  1. Kleinmann (2023) Crit Dis Emerg Med 37(2): 22-9
  2. Botoman (1998) Am Fam Physician 57(1):57-72 [PubMed]
  3. Cummings (2008) BMJ 336(7652): 1062-6 [PubMed]
  4. Lichtenstein (2009) Am J Gastroenterol 104(2): 465-83 [PubMed]
  5. Moses (1998) Postgrad Med 103(5):77-84 [PubMed]
  6. Sands (2000) Gastroenterology 118(2 Suppl 1):S68-82 [PubMed]
  7. Stein (2001) Surg Clin North Am 81(1):71-101 [PubMed]
  8. Veauthier (2018) Am Fam Physician 98(11): 661-9 [PubMed]
  9. Wilkins (2011) Am Fam Physician 84(12):1365-75 [PubMed]