GI Exam 2 Part 7: Pathophysiology of Bowel Diseases

what are inflammatory bowel diseases (IBD)

a group of related disorders that are characterized by chronic inflammation of the intestine that results in marked dysfunction of the digestive tract

what are the 3 IBDs

Crohn's disease

Ulcerative Colitis

microscopic colitis

what is indeterminate colitis

features of both UC and CD

Crohn's disease

more in the upper regions of the large and small intestine

-involving all layers of the bowel wall in any part of the GIT

-distal colon is NOT involved

-discrete regions can be affected

ulcerative colitis

more in the lower regions of the large intestine and the colon

confined to the large intestine

what population is UC more common in

males

what population is CD more common in

women

what area of the world are IBDs more common in

more prevalent in the western world

peak of IBD diagnosis

16-25 years old is the peak

CD may peak again at 76-85

CD declines more with age while UC is more constant

what symptoms are shared between IBS and IBD

pain and discomfort, urgency and bloating, alteration of bowel habits

how is IBS (irritable bowel syndrome) different than IBD

IBS is usually characterized as functional disease with diagnosis based on a cluster of symptoms but NO structural abnormalities

·      IBD is characterized by inflammation/ulceration, i.e. “organic” changes in the small and/or large intestines, which are not associated with IBS

what are other terms for IBS (irritable bowel syndrome)

spastic colon, spastic colitis, mucous colitis, nervous stomach and nervous diarrhea

symptoms of IBS

· Abdominal discomfort and pain

· Bloating, mucous in stools, diarrhea, constipation, or alternating diarrhea and constipation

· Depression, anxiety, or stress

what are the 3 subtypes of IBS

o   Diarrhea-predominant (IBS-D)

o   Constipation-predominant (IBS-C)

o   Alternating diarrhea and constipation

symptoms of IBD

·      Abdominal pain or discomfort along with diarrhea, vomiting, and rectal bleeding

·      Bloating, mucus in the stools, or a sense that you have not completely emptied your bowels

·      Reduced appetite and unintended weight loss

·      Most people’s symptoms are so mild that they never see a doctor for treatment

which symptoms are more common in Crohn's disease

·      Diarrhea

·      Abdominal pain and tenderness

·      Loss of appetite and weight

·      Fever

·      Fatigue

·      Rectal bleeding

·      Perianal lesions

·      Stunted growth in children

·      Complications

o    Fistula, perforation, abscess

·      Upper gastrointestinal symptoms

·      Extra-intestinal manifestations

Pathophysiology of IBD

·      TLA1 immunological staining shows immune cell invasion in the intestinal tissues

o   Not see in IBS, only IBD

CD vs UC presentation

· CD usually presents as "cobblestoning"

· UC usually presents as pseudopolyps that are more segregated

IBD muscle movement

spasms contract the bowel

movement of GI muscles is thought to be uncoordinated

Instead of contracting and relaxing in waves, they contract irregularly and tend to spasm

extraintestinal manifestations of IBD

o Arthritis

o Osteoporosis

o Erythema nodosum

o Pyoderma gangrenosum

o Episcleritis

o Nutritional deficiency

o Hepatobiliary disease

incidence of IBD

·      Third decade of life is the period of highest incidence of development

·      Relapsing-remitting course of disease can occur

2 environmental risk factors for IBD

intestinal flora and smoking

2 hereditary risk factors for IBD

affected relatives (1st degree relative 10x risk)

genetic polymorphisms (NOD2/CARD15)

immune dysregulation risk factors for IBD

o Failure to down-regulate excess cytokine production

o Apoptosis-resistant immune cells

concordance of IBD

·      Concordance for disease in monozygotic/ indentical twins (~50%)

o   Much higher than in fraternal twins

genome-wide association study (GWAS) of IBD

o   Method that searches the genome for single nucleotide polymorphisms that occur more frequently in people with a particular disease than in those without the disease

§  Compare patient DNA and non-affected people DNA to look for differences in SNPs that then may be associated with the disease

§  Then plotted as a Manhattan plot to look at which SNPs could be associated with the disease

what is the most important genetic loci associated with IBD

IBD1 on chromosome 3

NOD2/CARD15 impact on IBD

the susceptibility gene responsible for linkage of IBD1 locus with Crohn's disease

what are 3 common genetic mutations of CARD15

· Arg702Trp, Gly908Arg, and Leu1007Cis

o Having 2 mutated alleles vastly increases your risk of CD compared to 1 mutation

what are CARD15 mutations associated with?

not associated with UC, only CD

CARD15/NOD2 MOA in IBD

·      gene encodes a protein that acts as an intracellular pattern recognition receptor

·      CARD domains in protein are important for the activation of pro-inflammatory transcription factor NF-KB

o   Mutation dysfunction inflammation

SAR of CARD15/NOD2

·      The centrally located nucleotide-binding domain is important for oligomerization of the protein

·      The C-terminal leucine-rich repeat region (LRR) provides recognition site for bacterial cell wall products

·      NOD2 is a receptor for muramyl dipeptide, a component of the outer wall of certain bacteria

LRR domain of CARD15/NOD2

provides recognition site for bacterial cell wall products

The LRR domain sense of muramyl dipeptide (MDP) motif on a fragment of peptidoglycan (PG), which is a major component of the cell wall of gram-positive bacteria

what regulates CARD15/NOD2

inflammatory cytokines like TNF-a, IFN-y

what does a mutated CARD15/NOD2 do?

·      The mutated NOD2/CARD15 protein is incapable of sensing lipopolysaccharides or peptidoglycans, and of initiating NF-kB signaling ad impairs its ability to eliminate invasive bacteria in intestinal epithelial cells

NOD2/CARD15 function

·      plays a role in the immune response by recognizing the bacteria molecules which possess the muramyl dipeptide (MDP) and by activating the NF-kB system (c-rel/p50)

immune dysregulation in Crohn's disease

Th1 polarization

o   Excessive production of IFN-y, TNF-a, and Il-12

§  Pro-inflammatory cytokines

o   Stimulate extravasation of leukocytes at the site of disease

immune dysregulation in Ulcerative colitis

Th2 polarization

o   IL-4 and IL-5

o   Also have elevated IFN-y and TNF-a (not solely Th2-polarized disease)

Th1 functions

more inflammatory

o   Cell-mediated immunity and inflammation

o   Intracellular pathogens

§  Viruses, bacteria

o   Autoimmunity

o   Inflammation

Th2 functions

more allergenic

o   Antibody-mediated immunity

o   Extracellular parasites

o   Asthma, allergy

how does serotonin related to GI disorders

o An imbalance of serotonin in the gut

o An improper reaction of the digestive system to serotonin

o A faulty communication network between serotonin in the gut and the brain and spinal cord

serotonin 2 major roles

modulating intestinal movement and perception of pain

mycobacterium paratuberculosis and IBD

·      Mycobacterium paratuberculosis has been identified in CD tissues

o   Experts don’t regard it as a biologically plausible factor/cause of IBD

Measles + measles vaccine and IBD

Available evidence doesn’t support an association between IBD and measles infection OR vaccinations

smoking and IBD

is positively correlated with CD

is negatively correlated with UC

may be due to vascular effect of cigarette smoke with CD

bacteria and IBD

o Some bacteria initiate uncontrolled inflammation

o Probiotics can inhibit inflammation