Inflammatory bowel disorders (Block 5)

Question 1

Major intestinal structures

Answer 1

Duodenum
Jejunum
Ileum
Colon

Question 2

Duodenum

Answer 2

20-25cm
Receives gastric chyme from stomach, digestive juices & enzymes from pancreas & gall bladder added, breaks down proteins and emulsifies fats, alkaline mucus neutralises stomach acid

Question 3

Jejunum

Answer 3

2.5m
Midsection of small intestine, extensive villi and microvilli, products of digestion (sugars, amino acids, and fatty acids) absorbed into the bloodstream

Question 4

Ileum

Answer 4

3m
Final section of small intestine, also many villi, absorbs vitamin B12, bile acids, and other remaining nutrients

Question 5

Colon size and function

Answer 5

1.5m, principal function is absorption of water

Question 6

Total length of intestines together

Answer 6

> 8m

Question 7

Basic structure of the intestines (walls)

Answer 7

Concentric rings of Mucosa, Submucosa, Muscularis externa and Adventitia layers
Epithelium forms part of the mucosa layer, alongside the lamina propria and muscularis mucosa
Folds, villi and microvilli greatly increase the surface area

Question 8

Gut microbiota

Answer 8

100s of trillions of bacterial cells
Total weight: 1-2kg
More than 95% of human bacteria
Up to 50x smaller than human cells
Outnumber human cells 10:1

Question 9

Number of bacteria in stomach

Answer 9

10^1-10^3 CFU/ml

Question 10

Number of bacteria in duodenum

Answer 10

10^1-10^2 CFU/ml

Question 11

Number of bacteria in Jejunum and ileum

Answer 11

10^4-10^7 CFU/ml

Question 12

Number of bacteria in the colon

Answer 12

10^10-10^11 CFU/ml

Question 13

Challenges of bacterial exposure

Answer 13

GI tract had to be prepared to fight bacteria WHEN APPROPRIATE
Protective mechanism -> epithelial layer protects against harmful bacteria, but can tolerate healthy bacteria (gut flora) because it keeps everything compartmentalised. IF something ends up where it shouldn’t then it is recognised and targeted by the immune system

Question 14

Intestinal homeostasis

Answer 14

Exists in a state of “controlled physiological inflammation”
Normal state, resulting from delicate equilibrium between:
Gut microbes
Gastrointestinal barriers (mucus, epithelial)
Innate immune system that processes and presents antigens
Adaptive immune system that possesses “memory”

Question 15

Disorders of the intestinal tract

Answer 15

Irritable bowel syndrome
Coeliac disease
Inflammatory bowel disease (IBD)

Question 16

Coeliac disease

Answer 16

Autoimmune disorder
Allergy to gliadin
Inflammation
Villus atrophy

Question 17

2 types of IBD

Answer 17

Ulcerative colitis (UC)
Chron’s disease (CD)

Question 18

How common are UC and CD?

Answer 18

1 in every 123 people in the UK suffer from one or the other

Question 19

Age at onset of UC and CD

Answer 19

15-40 years for both

Question 20

Sites of CD and UC

Answer 20

UC -> colon only
CD -> most of GI tract

Question 21

Pathology of UC and CD

Answer 21

UC -> continuous inflammation
CD -> patches of inflammation

Question 22

Histology of UC and CD

Answer 22

UC -> superficial, mucosa and submucosa
CD -> Transmural, all layers of gut wall

Question 23

Symptoms of UC and CD

Answer 23

UC -> pain, diarrhoea, bleeding, weight loss, fatigue
CD -> fever, pain, diarrhoea, bleeding, weight loss, fatigue

Question 24

Complications of UC and CD

Answer 24

UC -> haemorrhage, bowel rupture, colon cancer
CD -> abscesses, fistulas, colon cancer

Question 25

Incidence of UC and CD

Answer 25

UC -> 2.2-19.2 cases per 100,000 pa CD -> 3.1-20.2 cases per 100,000 pa

Question 26

Potential risk factors for CD and UC

Answer 26

Genetics - CD appears to have greater inheritability than UC Smoking - elevates risk of CD, protects against UC Diet - consumption of polyunsaturated fatty acids elevates risk

Question 27

Basic cellular mechanisms in IBD

Answer 27

Controlled physiological inflammation is temporarily overcome Loss of barrier function Microbes invade gut wall leading to local immune response Failure of regulation; loss of protective effects or enhanced pro-inflammatory response If not resolved, then chronic cytokine involvement and tissue destruction

Question 28

Theory of what underpins IBD

Answer 28

Controlled physiological inflammation becomes uncontrolled pathological inflammation The processing and recognition of enteric antigens typically results in immunological tolerance An inappropriate response to the presence of enteric antigens results in IBD

Question 29

Principal cell types involved in IBD

Answer 29

Epithelial cells T cells Dendritic cells Neutrophils Macrophages

Question 30

Epithelial cells

Answer 30

Physiological barrier; compromised allowing microbial invasion of gut wall

Question 31

T cell

Answer 31

Recognition cells of the immune system; determine self from non-self

Question 32

Dendritic cell

Answer 32

Phagocytose microbes & microbial particles; act as antigen presenting cells

Question 33

Neutrophils

Answer 33

First responder in inflammation arising from bacterial infection; destroy bacteria

Question 34

Macrophages

Answer 34

Phagocytose ‘spent’ neutrophils after they have initially tackled the invading pathogen

Question 35

4 key classes of IBD therapy

Answer 35

Anti-inflammatories Immuno-suppressants Antibiotics/Probiotics Biologicals

Question 36

Corticosteroids

Answer 36

Steroid drugs used to treat acute inflammatory effects in IBD

Question 37

Mechanisms of corticosteroids include:

Answer 37

Reduced expression of COX enzymes Reduced prostaglandin synthesis Reduced cytokine production Reduced T cell activation and proliferation Reduced neutrophil chemotaxis

Question 38

Potential adverse effects from long-term use of corticosteroids

Answer 38

Redistribution of body fat Poor wound healing Moon face Thinning of skin Osteoporosis

Question 39

Aminosalicylates

Answer 39

First-line for chronic treatment of IBDs Used to maintain remission from symptoms Marginally more effective in ulcerative colitis than in Crohn’s disease

Question 40

How do aminosalicylates reduce inflammation?

Answer 40

Scavenging free radicals Inhibiting prostaglandin and leukotriene production Decreasing neutrophil chemotaxis Blocking superoxide generation

Question 41

Aminosalicylates - main compounds

Answer 41

Sulfasalazine Mesalazine Olsalazine Balsalazine

Question 42

Potential adverse effects of aminosalicylates

Answer 42

Diarrhoea Salicylate sensitivity Intestinal nephritis

Question 43

Immunosuppressants

Answer 43

Used in severe cases of IBD, after failure of aminosalicylates Drugs more commonly used in rheumatoid arthritis, some leukaemias and organ transplantation

Question 44

Immunosuppressants - examples

Answer 44

Azathioprine: active metabolite is 6-thioguanine, purine antagonist, interferes with DNA and RNA synthesis, inhibits proliferation of T cells and B cells Methotrexate: inhibits purine metabolism, inhibits T cell activation, down-regulates B cells, reduces production of multiple cytokines Cyclosporin A: used in ulcerative colitis unresponsive to steroids, reduces T cell activation and reduces release of interleukins

Question 45

Antibiotics and probiotics

Answer 45

Antibiotics used to treat septic complications (i.e. abscesses) in IBD Many also be useful in primary disease process in Crohn’s disease but not effective in ulcerative colitis

Question 46

Benefits of antibiotics and probiotics assume what?

Answer 46

Bacterial involvement in pathogenesis of the disease

Question 47

Benefits of antibiotics and probiotics include:

Answer 47

Decreased concentrations of bacteria in the gut lumen Altered composition of microbiota to favour beneficial bacteria Decreased bacterial tissue invasion Treatment of micro-abscesses Probiotic drinks (i.e. yogurts) suggested to be beneficial

Question 48

Main antibiotics used in Crohn's disease

Answer 48

Metronidazole Ciprofloxacin Clarithromycin

Question 49

Biologicals - examples

Answer 49

Infliximab: chimera of mouse and human antibodies, human backbone with mouse recognition sites – anti-TNFa Adalimumab: fully human mAb, less effective than infliximab - anti-TNFa Certolizumab: human Fab (fragment antigen binding) – anti-TNFa All such monoclonals are associated with potential for severe adverse effects related to immunosuppression and risk of infection

Question 50

Biologicals

Answer 50

Treatment of many immune and inflammatory disorders has been revolutionised by use of monoclonal antibodies (mAbs) Infliximab, adalimumab and certolizumab licensed for treatment of Crohn’s disease and ulcerative colitis Monoclonal antibodies against TNF-; bind with high affinity to soluble & transmembrane forms of TNF- and prevent interaction with its receptor Expensive, often restricted to severe IBD that is unresponsive to other medications

Question 51

Newer therapies

Answer 51

Vedolizumab Acts T helper cell-specific integrins to inhibit their localisation through the epithelial layer Thereby stopping excessive inflammation Ustekinumab Binds IL-12 and IL-23 Inhibits cytokine binding to receptor on immune cells Decreases activation of immune system Risankizumab Binds IL-23 only Inhibits cytokine binding to receptor on immune cells (IL23R) Decreases inflammatory signalling