Wk 3 - Symposium 4 (Clinical): Irritable Bowel Disease (UC and CD) Flashcards
What is irritable bowel syndrome?
- Group of disorders of the gut possibly due to inflammation and immune response
- UC -Limited to colon and Crohn’s from mouth to anus
- Relapsing-remitting diseases
- Unknown cause –idiopathic
- Triggers immune system damaging gut to lead to diarrhoea and abdominal cramps
- Genetic, infections, immunologic, psychologic factors all investigated
- Possible inability to limit “turn off” immune response
IBD is usually a…
relapsing-remitting disease
What are the types of IBD?
- Ulcerative colitis
- Crohn’s disease
- Indeterminate colitis
IBD is more common in _____ (Asia and Africa/North America and Europe).
IBD is more common in North America and Europe.
What part of the GI is usually affected by ulcerative colitis?
-
Limited to colon
- Backwash ileitis
- More severe in distal colon
- May only involve rectum
- Caecal patch lesion
Describe the macroscopic features of ulcerative colitis.
- Superficial mucosal ulceration
- Pseudopolyp formation
- Normal serosal surface
- Confluent involvement
- Featureless mucosa in chronic disease
Describe the microscopic features of ulcerative colitis?
- Inflammation limited to mucosa
- Acute & chronic inflammation
- Cryptitis
- Crypt abscesses
- Inflammation evenly distributed
- Mucosal granulomas
- Distortion of glands
Describe the distribution of Crohn’s disease
- May involve entire gastrointestinal tract
- Oral ulceration
- Perianal fistulas, abscesses
- Classically involves terminal ileum
Crohn’s disease usually involves the ____ ileum.
Crohn’s disease usually involves the terminal ileum.
Describe the macroscopic features of Crohn’s disease.
-
Deep ulceration
- Cobblestone mucosa
- Bowel wall thickening & strictures
- Abnormal serosa
- Fat wrapping (not specific to Crohn’s but characteristic)
- Patchy involvement
- Skip lesions
Describe the microscopic features of Crohn’s disease.
- Transmural inflammation – in all of bowel
- Acute & chronic inflammation
- Lymphoid aggregates
- Fissuring ulceration (vs superficial in ulcerative colitis)
- Inflammation patchy
- Transmural granulomas
- Neuronal hyperplasia – thickened nerves (less useful sign though)
What other diseases should be eliminated before making an IBD diagnosis - i.e. differential diagnosis?
- Infective colitis
- Diverticular disease
- Sigmoid colon
- Ischaemic colitis
- Diversion colitis
- Defunctioned rectum
- Pouchitis
- Ileal pouch post colectomy
- Tuberculosis (vs Crohn’s disease)
- TB mimics Crohn’s in terminal ileum (+ histo granulomas also v common in TB)
List some of the complications of ulcerative colitis.
- Toxic megacolon (acute)
- Dysplasia (pre-cancerous – only happens in minority but v important to monitor)
- Longstanding disease
- Total colonic involvement
- Malignancy
- Adenocarcinoma
- 10% risk @ 20 years (total colitis)
What are the complications of Crohn’s disease?
- Fistula formation
- Enteroenteric
- Enterovesical
- Enterovaginal
- Enterocutaneous
- Abscess & sinus formation (in the peri-anal region)
- Bowel obstruction (due to bowel narrowing)
- Inflammatory stricture formation
- Malignancy
List some extraintestinal complications associated with IBD.
-
Liver
- sclerosing cholangitis (esp. UC)
-
Skin
- erythema nodosum, pyoderma gangrenosum
-
Joints
- arthritis, ankylosing spondylitis
-
Eye
- episcleritis, uveitis, conjunctivitis
- Systemic amyloidosis
What causes IBD?
- UNCERTAIN
- Genetic factors
- Gut microbial factors
- Environmental factors
- Immunological abnormalities
List some infective agents associated with IBD?
- Mycobacteria
- Rotavirus, chlamydia, measles virus
- Microbial DNA identified in tissues
- Some evidence anecdotal
- No clear evidence for a single infective cause
- An abnormal inflammatory reaction to normal gut flora
- Increased mucosal permeability
Ulcerative colitis inflammation is usually limited to the ____ while Crohn’s is _____ inflammation.
Ulcerative colitis inflammation is usually limited to the mucosa while Crohn’s is transmural (ie all layers of bowel) inflammation.
What gene mutations are found to be involved in Crohn’s disease?
In Crohn’s disease particularly, there appears to be a genetic association with phenotypes. Specifically, NOD2/CARD15 mutations were found to be associated with a phenotype of Crohn’s disease which was associated in those diagnosed at a younger age, with ileal involvement, increased severity of ileal disease requiring surgical intervention/reoperation.
Crohn’s disease is primarily regulated by ___ and ___ mediated processes.
Crohn’s disease is primarily regulated by TH1 and TH17 mediated processes.
List some examples of cytokines associated with colonic Crohn’s.
Crohn’s lesions were found to have high levels of cytokines like IFN-gamma, IL-2, IL-12, and IL-18.
Describe the symptoms associated with intestinal inflammation (colitis vs ileitis\jejunitis).
- Colitis:
- bloody and pus-filled stools
- tenesmus
- urgency
- Ileitis/Jejunitis:
- diarrhoea
- abdo pain
- weight loss (or failure to growth in paeds)
- systemic malaise
Malnutrition (due to malabsorption) is often more associated with ____ (Crohn’s disease/UC).
Malnutrition (due to malabsorption) is often more associated with Crohn’s disease.
What is calprotectin?
Calprotectin is a protein biomarker that is present in the faeces when intestinal inflammation occurs –> used in diagnosis of IBD (+ colonoscopy).
How is Crohn’s treated/managed?
- Mild to moderate disease can be treated by oral mesalamine, immunomodulators such as thiopurines (mercaptopurines, azathioprine), methotrexate, and steroids.
- Moderate to severe disease (including fistulizing disease) will be best treated using a combination of immunomodulators and biologics (infliximab, adalimumab, golimumab, vedolizumab) or biologics alone.
- Generally, now avoid immunomodulators (as toxic) and give biologics.
How is IBD treated?
- Nutritional changes/adjunct therapy
- Drug therapy
- Surgery
- Other
Describe adjunctive therapy* of IBD.
*Adjunctive Therapy is therapy given in addition to the main treatment to maximize its effectiveness
- Attention to diet – High fibre, “healthy diet”
- IBS whilst in remission from UC, low fibre, use of antispasmodics –propantheline, mebeverine (antimuscarinic)
- Avoid antimotility drugs–codeine, loperamide – precipitate paralytic ileus in active UC
- Bile salt diarrhoea – colestyramine – binds bile salts (bile salts are irritants)
- Antibiotics – metronidazole, ciprofloxacin
- C. difficile colitis – metronidazole, vancomycin
List the different drugs ‘groups’ used in IBD.
Can be divided into immunosuppressants and anti-inflammatory treatment.
- Immunosuppressant
- Antibody therapy (strongest)
- Immunosuppressants
- Anti-inflammatory
- Steroids
- Aminosalicylates
In addition to that, antibiotics, pain killers, vitamin minerals and other adjunct therapies can be used.
What are aminosalicylates?
Aminosalicylates are a group of medicines used to treat inflammation of the gut that are used to treat and prevent flare-ups of ulcerative colitis.
List some aminosalicylates.
Sulfasalazine, mesalazine, olsalazine, balsalazine
How do aminosalicylates work?
- Mechanism unknown
- Possible block of inflammation, Prostaglandins, Leukotrienes, Platelet Activating Factor (PAF)
Aminosalicylates are usually used as first-line treatment for ____ to ____ UC reducing relapse rate.
Aminosalicylates are usually used as first-line treatment for mild to moderate UC reducing relapse rate.
Aminosalicylates are usually good in…
Maintaining remission NOT treating disease
List some possible S/Es of aminosalicylates.
- Nausea, controlled through reduced dosing
- Ulcers of the mouth, sore mouth, loose bowel movements
- Reduced white cell, reduced platelets
- Rash
- Orange urine and sweat
- Depression in young men (effect on testosterone?)
- Oligospermia
What are steroids?
Also called corticosteroids, are anti-inflammatory medicines used to treat a range of conditions.
List some corticosteroids.
Prednisolone, hydrocortisone, budesonide
Steroids are used in UC and Crohn’s to…
Induce and maintain remission
Steroids are unsuitable for ____ because of their ____.
Steroids are unsuitable for maintenance because of their adverse reactions.
How do steroids work?
Anti-inflammatory effects are complex, but via binding to cellular glucocorticoid receptors, steroids act to inhibit inflammatory cells and suppress the expression of inflammatory mediators.
Steroids are used in ____ IBD and unresponsive cases.
Steroids are used in diffuse IBD and unresponsive cases.
What steroids are usually used in diffuse IBD?
Oral prednisolone and budesonide (modified release)
Steroids can also be used in ___ and ___ disease alongside 5-ASA (aminosalicylate).
Steroids can also be used in refractory and moderate disease alongside 5-ASA (aminosalicylate).
List some S/Es of corticosteroids.
- Osteoporosis
- Diabetes
- Muscle Wasting
- Cushing’s syndrome
- Growth suppression
- Infection
- Adrenal atrophy long term (reduced with slow release budesonide)
What immunosuppressants are used in treating IBD?
- Azathioprine - in steroid dependent Crohn’s and in refractoy UC
- Methotrexate - useful in Crohn’s
- Calcineurin inhibitors (cyclosporin and tacrolimus) - may induce remission in steroid-resistant UC
How does Azathioprine work?
- Inhibits purine synthesis
- Can prevent relapse
- Mercaptopurine is the active metabolite of Aza
- Can take weeks to months to reach peak effectiveness
List some S/Es of Azathioprine.
Side effects: Nausea, vomiting, pneumonia, Herpes and diabetes, pancreatitis (1.2%)
What is the active metabolite of azathioprine?
Mercaptopurine
How does methotrexate work?
Methotrexate is a folate derivative that inhibits several enzymes responsible for nucleotide synthesis including dihydrofolate reductase. This inhibition leads to suppression of inflammation as well as prevention of cell division.
How do cyclosporin and tacrolimus work (calcineurin inhibitor)?
- Both are calcineurin inhibitors that inhibit T cell activation.
- Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin.
- This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions.
- NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process.
What does antibody therapy do?
In general, antibody therapy works by inhibiting pro-inflammatory cytokines e.g. IL-13, IL-12 and TNFα.
Antibody therapy in IBD is only indicated for…
resistant Crohn’s
What monoclonal antibody is approved for Crohn’s disease treatment?
Infliximab
How does Infliximab work?
Blocks pro-inflammatory cytokine TNFα
Infliximab is a IgG1κ monoclonal antibody that binds to soluble and transmembrane forms of TNF-α with high affinity to disrupt the pro-inflammatory cascade signalling. Binding of the antibody to TNF-α prevents TNF-α from interacting with its receptors.
List some S/Es of infliximab.
Fever, chills, urticaria ie hives (15%), serious infection -TB (due to weakened immune system)
Currently, only ____ is effective in decreasing the need for surgery in Crohn’s.
Currently, only infliximab is effective in decreasing the need for surgery in Crohn’s.
State the main difference between the location of Crohn’s and UC.
- Crohn’s - from mouth to anus ie anywhere in the GI tract
- UC - usually in the colon and rectum (maybe caecum)
Give an example of an important cytokine in Crohn’s disease.
The immune-mediated response in Crohn’s disease involves both innate and acquired mechanisms by macrophages, neutrophils, and T-cells in the intestine which promote pro-inflammatory mediators like TNF-alpha*.
*TNF is a molecule secreted by white blood cells that increases inflammation. High levels of TNF-alpha have been associated with the development of intestinal inflammation in Crohn’s disease.
List some investigations carried out in IBD.
- Blood - check anaemia, low albumin, inflammation (CRP, ESR, high platelets)
- Stool - Calprotectin in faeces?, infection?
- Colonoscopy - macroscopic appearance + histo
Discuss initial anti-inflammatory treatment in IBD.
- Aminoscyclates
- 5ASA (sulfasalazine) for UC maintenance
- Corticosteroids - prednisolone and budesonide
- To induce remission in UC and Crohn’s
- NOT USEFUL for maintenance due to long-term S/Es of steroids
Describe immunosuppressant therapy for IBD.
- Immunosupressants (AZA) in refractory cases (UC + Crohn’s)
- Antibody therapy (infliximab) in resistant Crohn’s
