Crohn's Disease

Inflammatory bowel disease can be split into two categories – Crohn’s disease which affects any part of the gastrointestinal (GI) tract from the mouth to the anus, and Ulcerative Colitis which exclusively affects the colon. These notes will focus on Crohn’s disease.

Epidemiology

Crohn’s disease is estimated to have a prevalence of 157 per 100,000 in the United Kingdom.^[i] The condition is more commonly seen in individuals from northern climates, and people of Ashkenazi Jewish ancestry (often geographically from Eastern Europe and Russia).^[ii]

Risk Factors

• Family History
• Smoking
• Living in urban/industralised countries
• High fat diet
• Use of NSAIDs

Pathophysiology

The pathophysiology of Crohn’s disease is complex, and it is thought a combination of the following factors can lead to the development of Crohn’s disease:

1.    Genetic susceptibility

2.    Dysregulated immune response

3.    Environmental exposures and triggers

4.    Disruption in the gut microbiome

Genetic Susceptibility and Dysregulation of Immune Responses

Many gene mutations are associated with the development of Crohn’s disease, a major one being NOD2. The NOD2 gene is involved in regulating immune responses in the gut for example, by suppressing Th17 immune responses. NOD2 also protects the host by detecting components of bacterial cell walls e.g. muranyl dipeptide (MDP). Detection of this promotes killing of intracellular bacteria. Mutations in NOD2 can lead to exaggerated immune responses, inflammation and insufficient clearing of invasive bacteria.

Environmental Exposures

People living in developed regions may benefit from a more sanitary environment and thus less exposure to microbes, which would otherwise have helped develop the gut microbiome and immunity (hygiene hypothesis). Thus, living in areas of higher sanitation which is actually a risk factor for Crohn's disease.^[iii] Environmental factors such as smoking and poor diet can affect the gut microbiome.

Disruption in the Gut Microbiome

The diversity of the gut microbiome has been shown to be reduced in patients with inflammatory bowel diseases. Precise reasons as to why this is the case is still being researched though some theories exist, such as genetic factors leading to reduced variability in the gut microbiome. The gut microbiome is crucial for immune regulation in the bowel e.g. it forms an epithelial barrier and regulates immune responses.

Adherent invasive E.coli bacteria have been isolated in many individuals suffering from Crohn’s disease. These bacteria induce inflammation by releasing the inflammatory cytokine TNF-alpha and are resistant to xenophagy (process by which intracellular bacteria are degraded using phagosomes and lysosomes).^[iv] This further adds to the inflammation in the bowel.

Clinical Features

Gastrointestinal Manifestations

• Abdominal Pain (described as crampy)
• Diarrhoea +/- Blood/Mucus
• Peri-anal symptoms
  • Perianal itching
  • Perianal abscesses/fistulae

Extra-Intestinal Manifestations

• Mouth: Oral aphthous ulcers
• Eyes:
  • Episcleritis: Red eye which is usually painless
  • Anterior uveitis: Blurred vision with a painful red eye
• Skin:
  • Pyoderma gangrenosum: Large ulcerations of the skin which may have pus. Usually on the legs though they can be elsewhere. Sometimes look a bit purple.
  • Erythema nodosum: Inflammation of subcutaneous tissue manifesting as tender, red nodules, usually on the shins.
• Hepatobiliary: Associated with primary sclerosing cholangitis (PSC) and gallstones
• Renal: Kidney stones (calcium oxalate)
• Musculoskeletal: Spondyloarthropathy associated with Crohn’s disease

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Pyoderma Gangrenosum

Systemic Manifesations

• Fatigue
• Weight loss secondary to malabsorption
• Anaemia:
  • Iron deficiency: Blood loss
  • Megaloblastic anaemia: Vitamin B12 deficiency due to involvement of the terminal ileum (vitamin B12 is absorbed by the body at that level)
  • Anaemia of chronic disease
• Failure to thrive in children

Histopathology

• Most commonly, terminal ileum, colon, and anus are involved although any part of the GI tract can bei nvolved.
• Skip Lesions: Usually affects the GIT in ‘patches’ known as skip lesions whereby there is a clear difference between the part of the bowel which is affected and the part which is not.
• Transumral Inflammation: affects the entire width of the bowel from mucosa to serosa^[v]
• Thickened Bowel Wall: Secondary to inflammation and oedema. This can result in intestinal obstruction.
• Fissuring ulcers also occur – if they break through the muscularis propria, they can create abnormal communications between adjacent organs forming a fistula e.g. between the bowel and bladder or bowel and vagina. If the fissure breaks through the bowel wall and causes leaking of intestinal contents into the peritoneum, it may lead to an abscess or peritonitis.
• Cobblestone Appearance: The combination of convex swelling of the bowel wall, criss-crossed by deep fissuring ulcers results in this type of appearance which can be seen on endoscopy.^[vi]
• Granulomas: Seen on histology, comprise of giant cells. These are non-caseating granulomas (different to those seen in tuberculosis)

Nephron, CC BY-SA 3.0 , via Wikimedia Commons

Histology of Crohn's Disease

Investigations

 Bloods

• FBC: Raised white cells or anaemia
• ESR and CRP: May be raised
• Vitamin B12: Megaloblastic anaemia
• Albumin: Hypoalbuminaemia due to malabsorption^[vii]
• Ferritin and Total Iron Binding Capacity: To investigate anaemia
• Liver function test: May be deranged if there is co-existing PSC

Stool

• Faecal calprotectin: This is a marker of inflammation in the intestines - it's produced by neutrophils and is raised in IBD.
• Microscopy, culture and sensitivity (MC&S): Exclude infective cause of diarrhoea
• C.difficile toxin assay: Exclude C.difficile as cause of diarrhoea

Colonoscopy

Colonoscopy with biopsy is extremely important for diagnosis as the bowel can directly be visualised and a pathologist can look for characteristic features of Crohn’s disease as described above. The British Society of Gastroenterologists recommends that biopsies be taken from the ileum, rectum and a minimum of four colonic sites.^[viii]

Perianal disease can develop due to inflammation of the anus. Perianal fistulas are investigated with examination under anaesthesia which involves a normal examination (inspection, palpation) but under general anaesthesia.^[ix]. [x]

Management

Management focuses on two main things; either you're trying to induce remission, or you're trying to maintain remission. We'll go through each scenario in turn.

Inducing Remission – In the case of one exacerbation in a 12-month period

1. Steroid: Most often a corticosteroid e.g. prednisolone, methylprednisolone or IV hydrocortisone is given
    
2. Budesonide: If a corticosteroid is contraindicated and the patient has a specific pattern of disease (disease of the distal ileum, ileocaecum or right-sided colon).
    
3. Aminosalicylates: If corticosteroids are contraindicated or not tolerated, these can be used though they may not be as effective as steroids or budesonide.

Inducing Remission – In the case of 2 or more exacerbations in a 12-month period

1. Corticosteroid/Budesonide + Consider adding one of the following agents:
   • Azathioprine
   • Mercaptopurine
     • Thiopurine methyltransferase (TPMT) is an enzyme which metabolises the two drugs mentioned above.^[xi] Some individuals have TPMT deficiencies which can lead to life-threatening bone marrow toxicity following doses of azathioprine and mercaptopurine. Therefore, it is vital to check TPMT levels prior to offering these drugs.
        
2. If a patient has low levels of TPMT or they cannot tolerate azathioprine/mercaptopurine, you can add methotrexate. Regardless of which drug is added, it is crucial to monitor for side effects.^[xii]

Maintaining Remission

Remission is typically maintained with azathioprine, although mercaptopurine can be used as well. If these are contraindicated, methotrexate can be offered. Steroids are not used to maintain remission.

Biologics

Biologic treatments are monoclonal antibodies. TNF-alpha has been shown to play a role in the pathogenesis of Crohn’s, so this is a common target for biologics e.g. infliximab and adalimumab. Biologics can be used in severe disease which has not responded to steroid/immunosuppressive treatment. It is important to monitor side effects and assess the patient to look for improvement. These drugs are started by specialists.

Surgery

Surgery should be avoided where possible, particularly since disease could recur elsewhere in the GIT. Indications include failure to respond to drug treatment, fistulae or intestinal obstruction. Several types exist:

• Resection and Anastamosis: Cutting out affected bowel (resection) and then joining it up (anastomasosis). This is done depending on the part of the bowel affected e.g. if the terminal ileum is involved, an ileocaecal resection may be done. This involves removal (resection) of the terminal ileum and caecum, and then joining the remaining small bowel to the colon.
   
• Right Hemicolectomy: If only the right hemicolon is affected, it can be removed, and the remaining bowel will be anastamosed to the caecum.
   
• Colectomy: This is removing the entire colon. A colectomy can be combined with either:
   
• Ileostomy: The colon is removed and the remaining ileum is brought out onto the skin to create a stoma.
   
• Ileo-Rectal Anastamosis: The ileum is anastamosed to the rectum. Patients may have watery stools and need to open their bowels frequently.
   
• Strictureplasty: Used to open up a stricture
   
• Proctocolectomy and Ileostomy: This is removal of the rectum and the entire colon and is usually combined with an ileostomy.^[xiii]

Complications

• Fistulae
• Bowel perforation
• Bowel obstruction
• Abscess
• Toxic megacolon
• Colorectal carcinoma

References

^[i] GP Online. Crohn’s disease – Clinical review. [internet]. 2017. [cited 18^th August 2019]. Available from: https://www.gponline.com/crohns-disease-clinical-review/gi-inflammatory-bowel-disease/crohns-disease/article/1213250#1

^[ii] Feuerstein JD and Cheifetz AS. Crohn Disease: Epidemiology, Diagnosis and Management. [internet]. 2017. [cited 18^th August 2019]. Available from: https://www.mayoclinicproceedings.org/article/S0025-6196(17)30313-0/fulltext#sec2

^[iii] Dutta AK and Chacko A. Influence of environmental factors on the onset and course of inflammatory bowel disease. [internet]. 2016. [cited 20^th August 2019]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4716022/

^[iv] Boyapati R, Satsangi J and Ho G. Pathogenesis of Crohn’s disease. [internet]. 2015. [cited 20^th August 2019]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447044/

^[v] Choi D, Jin Lee S, Ah Cho Y, Lim HK, Hoon Kim S, Jae Lee W et al. Bowel wall thickening in patients with Crohn's disease: CT patterns and correlation with inflammatory activity. [internet]. 2003. [cited 20^th August 2019]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/12565208

^[vi] O’Dowd G, Bell S and Wright S. Wheater’s Pathology: A text, Atlas and Review of Histopathology. 6e. Elsevier. 2020.

^[vii] Medscape. What is the role of chronic inflammation in the etiology of hypoalbuminemia. [internet]. 2018. [cited 20^th August 2019]. Available from: https://www.medscape.com/answers/166724-41459/what-is-the-role-of-chronic-inflammation-in-the-etiology-of-hypoalbuminemia

^[viii] Feakins RM. Inflammatory bowel disease biopsies: updated British Society of Gastroenterology reporting guidelines. [internet]. 2013. [cited 20^th August 2019]. Available from: file:///Users/HR/Downloads/BSG%20guidelines%20on%20inflammatory%20bowel%20disease%20biopsies.pdf

^[ix] Medscape. Evaluation of perianal fistulas in patients with Crohn’s disease. [internet]. 2005. [cited 20^th August 2019]. Available from: https://www.medscape.com/viewarticle/503224_4

^[x] Kumar and Clark’s

^[xi] Drug and Therapeutics Bulletin 2009;47:9-12.

^[xii] NICE. Crohn’s disease: management. [internet]. 2019. [cited 20^th August 2019]. Available from: https://www.nice.org.uk/guidance/ng129/chapter/Recommendations#providing-information-and-support

^[xiii] Crohn’s & Colitis UK. Surgery for Crohn’s disease. [internet]. 2019. [cited 20^th August 2019]. Available from: http://s3-eu-west-1.amazonaws.com/files.crohnsandcolitis.org.uk/Publications/surgery-for-crohns-disease.pdf