The gastric mucosa is protected from the acidic environment by mucus, bicarbonate, prostaglandins, and blood flow.
This mucosal barrier consists of three protective components which include:
Layer of epithelial cells lining.
Layer of mucus, secreted by surface epithelial cells and Foveolar cells.
Bicarbonate ions, secreted by the surface epithelial cells.
Mechanism of Action
The insoluble mucus forms a protective gel-like coating over the entire surface of the gastric mucosa.
The mucus protects the gastric mucosa from autodigestion by e.g. pepsin and from erosion by acids and other caustic materials that are ingested.
The bicarbonate ions act to neutralize harsh acids.
If the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage
Pathogenesis
Regardless of etiology, if the balance of gastric acid secretion and mucosal defenses is disrupted, acid interacts with the epithelium to cause damage.
Helicobacter pylori disrupts the mucosal barrier and causes inflammation of the mucosa of the stomach and duodenum.
As the ulcer progresses beyond the mucosa to the submucosa the inflammation causes weakening and necrosis of arterial walls, leading to pseudoaneurysm formation followed by rupture and hemorrhage.
NSAIDs inhibit cyclooxygenase, leading to impaired mucosal defenses by decreasing mucosal prostaglandin synthesis.
During stress, there is acid hypersecretion; therefore, the breakdown of mucosal defenses leads to injury of the mucosa and subsequent bleeding.
Mucosal defects along with dilated and tortuous vessels in dieulafoy lesion put them at risk for rupture because of necrosis of the arterial wall from exposure to gastric acid.
Inflammatory Bowel Disease
Crohn's Disease
Ulcerative colitis
Based on Region involved
Based on Severity
Ileocolic Crohn's disease
Crohn's ileitis
Crohn's colitis
Stricturing disease
Penetrating disease
Inflammatory disease
Based on Region involved
Based on Severity
Distal UC
Proximal UC
Mild
Moderate
Severe
Flumiant
A01
B01
C01
C02
D01
E01
F01
G01
H01
H02
I01
I02
J01
Pathogenesis of Crohn's disease
Genetic component
Stress and environmental component
Microbial component
Inflammatory component
Genetic Component
Genes involved
NOD2/CARD15 gene
OCTN1 gene
DLG5 gene
TLR4 gene
Genes
Chromosome
Function
Mutation
NOD2/CARD15
16
16q12.1
Encodes a scaffolding protein important for maintaining epithelial integrity
Disrupts normal epithelial integrity
OCTN1
05
5q31
Ecodes an ion channel
Alters the function of cation transporters and cell-to-cell signaling
DLG5
10
10q22.3
Interact additively with the NOD2/CARD15 gene
Iincrease susceptibility to CD along with CARD15
TLR4
09
9q33.1
Lipopolysaccharide signaling, bacterial recognition, and subsequent immune response
Altered immune response to pathogens and a subsequent increase in inflammation.
Stress and Environmental Component
Stress signals are perceived by the central nervous system (CNS), triggering the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis.
Neuroendocrine mediators released in response to stress not only modulate secretory, absorptive, and barrier functions in the gut but also increase the gut permeability.
Stress increases gut permeability along with other factors which inlude
Corticotropin-releasing factor
Autonomic nervous system
Enteric nervous system
Microbial Component
The possible mechanisms for a bacterial etiology in the development of CD include:
Initial immune response to a specific pathogen resulting in intestinal infection
Alterations in normal bacterial flora of the intestinal tract
Defective mucosal barrier and overwhelming exposure to resident bacteria and their antigens and endotoxins
Alterations to the intestinal immune response
Infectious Pathogens Implicated in Crohn’s Disease
Escherichia coli
Listeria monocytogenes
Yersinia enterocolitica
Mycobacterium avium subspecies paratuberculosis
Measles virus
Immune Component
Altered immune response:
An abnormal antibody response to an unspecified bacterial antigen is mainly responsible for inflammation in Crohn's disease.
The inflammatory response is believed to be triggered when elimination of specified microbial antigen was unsuccessful leading to altered immune response
Dysregulation of normal mucosal immune response results in failure of phagocytosis leading to antigen persistence.
Antigen persistance leads to antibodies production against all the normal gut flora.
Activation resulted in secretion of tumor necrosis factor-alpha (TNF-alpha) and subsequent epithelial changes.
Cytokine response:
The primary precipitating event in Crohn's disease is T-cell mediated immune response.
Activated T cells are responsible for the release of cytokines.
The production of inflammatory cytokines results in ulceration and increased intestinal permeability.
The characteristic granulomatous lesion seen in Crohn’s disease is evidence of a cell-mediated immune response.
The early lesions of Crohn's disease are characterized by elevations in interleukin-4 (IL-4) and decrease in IFN-gamma, a pattern more consistent with an overactive Th2 immune response.
Chronic lesions are associated with high levels of interleukin-2 (IL-2), interferon gamma (IFN-gamma), TNF-alpha, and interleukin-12 and -18 (IL-12 and IL-18) consistent with an Th1 immune response.
Tumor necrosis factor appears to play a significant role in the pathogenesis of CD.
TNF-alpha induces expression of adhesion factors that allow for inflammatory cells to infiltrate and activates macrophages to promote release of other pro-inflammatory mediators such as IFN-gamma.
Neutralization of TNF resulted in significant decrease in inflammation.
TNF-alpha concentrations in the stool can be used to monitor disease activity in both CD and UC.
Oxidative stress
Oxidative stress also plays a significant role in the pathogenesis of Crohn's disease.
Endogenous antioxidants such as superoxide dismutase (SOD), glutathione, and catalase normally counteract oxidative stress in the intestinal mucosa.
However, during the times of inflammation the demand for these antioxidants is increased resulting in an imbalance between oxidants and antioxidants, with subsequent mucosal damage.
Oxidative DNA damage can be measured from the amount of 8-hydroxy-deoxy-guanosine (8-OhdG) present in blood.
Levels of 8-OhdG are higher in patients with Crohn's disease.
Oxidative stress can also activate nuclear factor-kappaB (NF-kappaB) gene leading to release of TNF-alpha and interleukins involved in inflammation.
Other factors responsible for Pathogenesis of Crohn's disease
Platelet Abnormalities
Increased platelet count is a common feature of active Crohn’s disease and contributes to the increased incidence of thromboembolism seen in both CD and UC.
In addition to increased platelet count, CD is characterized by increased platelet activation in the mesenteric vessels.
Although platelet function has historically been considered to involve primarily blood clotting, there is considerable evidence for platelet involvement in inflammation.
Platelets from inflammatory bowel-diseased tissues have been found to express a number of inflammatory mediators, including CD40 L, a substance similar to tumor necrosis factor that directs platelets toward inflammation instead of aggregation.
A sequence of events has been postulated in which platelets trigger chemokine-mediated adhesion of white blood cells to the endothelium, causing leukocyte migration and subsequent focal inflammatory lesions.
