Flashcards in IBD Deck (39):
What is the most common age for the diagnosis of IBD?
20-30's but can occur at any age
may be a second peak in 70's - 80's
What are the key features of Crohn's disease?
Idiopathic, chronic inflammatory condition
Involves anywhere from mouth - anus
Relapses and remissions
What is the characteristic presentation of Crohn's disease?
Abdominal pain and diarrhoea
often indolent onset
other symptoms include rectal bleeding, fever, weight loss, malnutrition, bone loss, and vitamin deficiencies
What is the pathophysiologiy of Crohn's?
Defective regulation of Th1 cells causes chronic inflammation
Th1 cells release cytokines - IL12 and TNF alpha, interferon gamma which stimulate an inflammatory response
Inflammatory cells release inflammatory mediators
- arachidonic acid metabolites, proteases, platelet activating factor, and free radicals, which result in direct injury to the intestine
Increased production of TNF-α by macrophages in patients with Crohn disease results in increased concentrations of TNF-α in the stool, blood, and mucosa
What are the macroscopic findings of Crohn's?
Initial findings of hyperaemia and oedema of mucosa
Superficial ulcers which can be serpiginous giving a cobblestone appearance
Thickening of bowel and narrowing of lumen due to transmural inflammation - strictures can form
Advance disease: deep ulceration can lead to fistulas, micro perforation, abscess formation, adhesions
What are the histological findings of Crohn's?
Inflammatory infiltrate around crypts
Ulceration of superficial mucosa
- inflammatory cells invade deeper mucosal layers forming non-caveating granulomas*
- due to neutrophil invasion of crypts
* Although granuloma formation is pathognomonic of Crohn disease, its absence does not exclude the diagnosis
Name the genetic abnormalities associated with Crohn's?
More than 70 genes have been found to be involved
- a polymorphic gene involved in the innate immune system.
- 3 single nucleotide polymorphisms (SNPs) play a role in 27% of patients with Crohns, primarily ill disease
- encodes 1 subunit of IL-23 receptor protein
- 2 SNPs identified
TG16L1 gene, which encodes the autophagy-related 16-like protein involved in the autophagosome pathway that processes intracellular bacteria
IRGM gene SNP
mounting evidence that the autophagosome pathway is very important in the pathogenesis of the disease.
XBP1 gene, which is involved in the unfolded protein response pathway of the endoplasmatic reticulum. Other well documented genes which increase the risk of developing Crohn disease are ATG16L1, IL23R, IRGM, and SLC11A1
What are the non-genetic risk factors for Chron's?
Infectious agents such as Mycobacterium paratuberculosis, Pseudomonas species, and Listeria species have all been implicated in the pathogenesis of Crohn disease, suggesting that the inflammation seen with the disease is the result of a dysfunctional, but appropriate, response to an infectious source
Smoking - doubles risk
What is the typical rates of involvement of parts of the large bowel in UC
Left sided colon 20-30%
What is the pathogenesis of UC?
Possible abnormal induction of T2 cells to secrete various cytokines causing superficial mucosal inflammation
Possible abnormal immune response to gut flora
What are some genetic associations with UC (syndromes + specific gene mutations)
What is the risk of a patient with UC having a first degree relative affected?
Clinical manifestations of UC
Freq, small volume diarrhoea
Blood/mucus/pus in BM
Colicky abdo pain
Fever, fatigue, weight loss
Symptoms of anaemia
What is the severity classification for UC?
Mild - less then 4 BM per day, small Blood, normal ESR, no fever, normal haemodynamics
Moderate - 4-6 BM per day with moderate blood, low grade fever, mild anaemia, low grade fever
Severe - greater then 6 BM per day, large blood, febrile, tacy, ESR greater then 30
Fulminant - greater then 10 BM per day with large blood and haemodynamic instability
Extra-intestinal manifestations of UC
Increased risk of arterial and venous clots
Autoimmune haemolytic anaemia
- all except PSC, uveitis, ank spon correlate and flare with disease flares
Biopsy findings in UC
Macro - granular, erythematous mucosa, friable, oedematous mucosa, no skip lesions, back-wash ileitis seen in severe cases
Micro - limited to mucosa, crypt abscesses, atrophy, lymphoid infiltrates
Complications of UC
Acute - massive haemorrhage, toxic mega colon, perforation
Chronic - stricture (malignant until proven otherwise), dysphasia and malignancy
Typical disease course of UC
Relapsing and remitting disease
Proctitis - generally benign course, responds to topical therapy
Those with younger age of diagnosis, fever, weight loss, flare within 2 years of diagnosis have a high risk of relapse
20-30% require colectomy at some stage
Recommendations for colorectal ca screening in UC
No increased risk for those with proctitis or proctosigmoiditis - no screening required over normal population
Every 1-2 years after presence of pancolitis for 8-10 years
Every 1-2 years after presence of left sided colitis 12-15 years prior
Action of 5-amigos alicyclics acid medications
Induce PPAR-gamma gene expression leading to the suppression of cytokine activation
What are the indications for antibiotics in UC
Used in pouchitis (post surg complication) and toxic megacolon
Treatment of c.diff infection - higher rates of metronidazole resistance, used oral vanc first line
What is TPMT and why is it important?
Enzyme that metabolises 6-MP to a toxic metabolite (6-MMP)
1 in 300 individuals lack significant TPMT activity leading to increased production of 6-TGN (active metabolite) leading to myelotoxicity and marrow suppression
How does allopurinol effect thiopurine metabolism
Inhibits xanthene oxidase which increases the amount of 6-MP that is metabolised to active metabolite (6-TGN) and decreases shunting to other inactive metabolites
Can be used in shunters (low levels of 6-TGN but high levels of 6-MMP) in combination with reducing dose
What is the action of thiopurine medications
6-TGN inhibits purine and ribonucleotide synthesis and T + B cell proliferation
How long do thiopurines take to work?
What is the action of Cyclosporin?
Calcineurin inhibitor - blocks production of IL2
What is infliximab?
Anti-TNF alpha therapy
Chimeric (human/mouse) IgG1 antibody against TNF alpha
What are some problems with infliximab?
Development of antibodies to Infliximab - reduced response
Increased risk of lymphoma especially hepatosplenic T-cell lymphoma (fatal, common in young men)
Screening prior to starting infliximab?
Hep B, HIV, varicella
Tb - quantiferon or mantoux
Any evidence of old Tb requires treatment for latent T
Indications for surgery in UC
Failed medical therapy
Toxic mega colon not responding to 72 hours of medical therapy
Preferred surgical treatment of UC?
Illegal pouch anal anastamosis
- preserves continence, stool freq 6-8 per day
- affects fertility
- complicated by pouchitis
Treatment for mild to mod Proctitis/proctosigmoiditis
Remission - topical ASA
Maintaince - ongoing ASA
Steroid foams can be used second line but are less effective
Treatment for mild/mod colitis
Combination oral and topical 5-ASA
Oral steroid if fails to respond to above
Maintain with ongoing ASA and reduce steroids after effect seen (usually 2 weeks)
What is steroid dependant UC
Inability to taper steroids to less than 10mg per day within 3 months of starting steroids or relapse within 3 months of stopping steroids
Exclude other diagnosis - CMV, CDiff etc.
Consider bridge to thiopurine with Cyclosporin or infliximab
What is steroid refractory UC
No reponse to high dose oral steroids over 30 days or IV 7-10'days
Treatment of severe colitis
If well enough trial high dose oral steroids and oral and topical ASA
If too unwell or not responding - IV steroids
If not responding in 7-10'days consider infliximab or Cyclosporin bridging
Treatment of fulminant colitis
Review at 3 days
If no response Cyclosporin or infliximab
What is better Cyclosporin vs infliximab in UC
RCTs have shown same outcomes = equivalent
Ideal with infliximab is use with thiopurine as this reduces risk of antibody development