Inflammatory Bowel Disease Flashcards
What is IBD?
A chronic inflammatory disease if the GI tract of unknown aetiology
What conditions does IBD include?
Crohn’s disease
Ulcerative colitis
How is IBD characterised?
As a multi focal infarction
Pathogenic infection
Relapsing and remitting course that may lead to surgical intervention
What are the risk factors of IBD?
Thought to be a genetic predisposition
Infection
Local ischaemia
Altered immune state
Maybe Cigarette smoking
What aspects of the GI system does ulcerative colitis affect?
Confined to the mucosal and sub mucosal layers
Restricted to the large intestine
(Especially the rectum)
How is UC characterised?
Crypt abscesses and ulceration
Continuous inflammation rather than patchy
What are the symptoms of UC
Bloody diarrhoea
Abdominal tenderness
Abdominal distension
Are there any extra colonic symptoms of UC?
Reactive arthritis
(Possibly due to the proliferation and migration of activated T lymphocytes)
Anaemia
Fever
Weight loss
What is Crohn’s disease?
A transmural granulomatous condition characterised by macrophages lesions
Where does Crohn’s disease normally affect?
Can involve any section of the gut
Usually spares the rectum
How is inflammation caused by Crohn’s normally categorised?
Discontinuous and segmental inflammation
There will be inflamed portions next to healthy region of tissues
(Skipper areas)
What abnormalities can help diagnose Crohn’s?
Fistulas
(Abnormal connections between sections of the bowel)
Small bowel strictures
(Narrowing of the intestine making it hard for things to pass through)
Abscesses
Anal fissures
What are the symptoms of Crohn’s?
Diarrhoea
Abdominal pain
Fatigue
What is the molecular pathophysiology of IBD?
Poorly understood
Thought to be linked to a dysfunction in the intestinal epithelial barrier
(NOD2 gene mutation)
Or to dysregulation of innate immunity
Abnormal chemokine production
Impaired barrier repair and maintenance function
T lymphocyte migration
How does the innate immune system affect the chances of Crohn’s?
Defects in the innate immune system are associated with a predisposition to infections and autoimmune diseases
Describe how immune cell imbalances may influence IBD
T cells
Imbalances between pro inflammatory T helper 1 and T helper 2 cells and anti inflammatory T helper 3 and T regulatory cells
Disruption to this system may contribute to the pathophysiology of IBD
Molecular pathophysiology 2
Aggressive activation of adaptive immunity (cytokines)
Dysfunctional neuro immune regulation
Excessive production of nitric oxide and other radicals
Enhanced expression of matrix metalloproteinases
What is the point of therapeutic management
To induce and maintain remission
High failure rate usually results in surgery
What drugs are used in the treatment of IBD?
Corticosteroids
Aminosalicylates
Immunomodulators
TNF alpha antibodies
What are two immunomodulators used for IBD?
Thiopurines
Methotrexate
Give two examples of TNF alpha antibodies
Ciclosporin
Anti microbial agents
What do corticosteroids do?
Dampen the general inflammatory response
Reduce expression of cytokines, COX and adhesion molecules
Induce remission of active disease (particularly Crohn’s
What are some of the formulation of corticosteroids?
Oral prednisolone
Foam/ enemas for left sided distal UC
Novel drug delivery (extended controlled release)
Budesonide topically active (extensive first pass metabolism - few side effects)
IV hydrocortisone (sever disease not responding to oral therapy)
What are the side effects of using corticosteroids?
Cushing like syndrome
Metabolic disturbance
Diabetes
Fat redistribution
Bone / muscle breakdown
Growth suppression
Peptic ulcer
Hypertension
Acne
Behavioural changes
What is associated with prolonged use of corticosteroids?
Dependence
Resistance
Increased susceptibility to infections
Are there risk factors associated with stopping corticosteroid treatments?
Withdrawal symptoms
Acute adrenal insufficiency
Advised to taper off the treatment
1 year treatment = 2 months tapering roughly
What are aminosalicylates?
Prodrugs metabolised by enteric bacteria to 5-aminosalicylate
How can aminosalicylates be administered?
Sulfasalazine
Mesalazine
Rectal foams
Suppositories of 5-ASA
Slow oral release preparations of pro drugs
What are the three types of aminosalicylates?
Azo-bonded prodrugs
oh-dependent drugs
Time-dependent drugs
What sites do specific types of 5-ASAs treat?
Azo - colon
pH - ileum and colon
Time - duodenum, small bowel, colon
What is the mechanism of action for aminosalicylates?
Mechanism is unclear
Suppression of inflammation
Induces remission of mild active disease (UC > Crohns)
Maintenance of UC remission
What pathways can 5-ASAs target?
PPAR gamma agonist
Increase TGF-beta
Decreases NF-kB
MAPK
COX-2
Pro inflammatory cytokines
Scavenges ROS and RNS
What are the side effects of taking aminosalicylates?
Diarrhoea
Nausea
Abdominal pain
Headache
Rash
Allergic reactions
Lupus like syndrome
Nephritis
Reversible oligospermia
Give two examples of thiopurines
6-mercaptipurine
Azathioprine (pro drug)
How do thiopurines work?
Metabolised to active 6-thioguanine phosphates
Randomly incorporated into nucleic acid as false purine analogs
Inhibit gene transcription
Inhibits activation and proliferation
Promotes apoptosis of T lymphocytes
What are the side effects of thiopurines?
Nausea
Diarrhoea
Abdominal pain
long term use:
Hepatotoxicity
Allergic reactions
Pancreatitis
Bone marrow suppression
Lymphoma
Infection
What is the treatment plan for thiopurines?
Slow onset (>3 months)
Given for over five years
Mainstay for remission (steroid dependent Crohns)
What sort of things must be monitored when using thiopurines?
6-mercaptopurine metabolite levels
(Guides dosing regime and monitors compliance)
Serum amylase (predictor for pancreatitis)
Regular FBC and liver function tests
What is methotrexate?
Folic acid analogue that interferes with nucleic acid synthesis
How does methotrexate work?
Inhibits dihydrofolate reductase (purine and pyrimidine synthesis)
Reduces cytokine expression
Increases T cell apoptosis
When and how often is methotrexate used?
Controls inflammation and allows withdrawal from steroids while maintaining remission
Given weekly by mouth or injection
What are the minor side effects of methotrexate?
Mild headache
Nausea
Abdominal pain
Diarrhoea
Rarely opportunistic infections
What are the more severe side effects of methotrexate?
Bone marrow suppression
Blood disorders
Hepatotoxicity
Sperm toxicity?
Teratogenic?
Spontaneous abortions?
How is methotrexate use monitored?
Regular FBC, renal and live function tests (initially every 1-2 weeks)
Methylene tetrahydrofolate reductase mutations used as a predictor for toxic effects
When should methotrexate be avoided?
Avoids in hepatic and renal impairment
Avoid in pregnancy for 3 months following cessation
What is ciclosporin?
An immunosuppressant
How does ciclosporin work?
Inhibits calcineurin to attenuate transcription of pro inflammatory cytokines and lymphocyte proliferation
Effective in severe steroid refractory or dependent UC
What are the side effects of ciclosporin?
Renal toxicity
Tremor
Increased infection
Hypertension
Nausea
Headache
Gingival hyperplasia
Diarrhoea
Fatigue
How is ciclosporin wise monitored?
Liver and renal function tests
Blood pressure
Lipid profile
Give three examples of anti bacterials used for IBD
Metronidazole
Ciprofloxacin
Ornidazole
Why are antibacterial used to treat IBD?
They promote remission and reduce post operative relapse
Combine with steroids in active Crohns to reduce the overgrowth of bacteria in the small bowel
Are there any risks when using anti bacterials?
Potential risk of nerve damage
Describe how changes to the adaptive immune system might affect IBD
The adaptive immune system is defined by the presence of T or B lymphocytes including CD 8+ cytotoxic T cells, CD 4+ helper T cells and B cells that present antigens and produce antibodies
Disruption to this system may contribute to the pathophysiology of IBD
