Sandbox cerebral palsy

## Pathophysiology

### Mucosal barrier
- 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.
- 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.
- 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.

# 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

## 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
- 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

## 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.
- 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 Crohns 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.
- 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 Crohns 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.
- 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
- Increased platelet count is a common feature of active Crohns 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.
- TNF alpha enhances mitochondrial NF-kappa B expression, down-regulating mitochondrial RNA expression.
- Resulting in impaired oxidative phosphorylation,with abnormalities in complexes III and IV.
- Vitamin B12 is essential for the metabolism of homo-cysteine to cysteine, taurine, sulfate, and glutathione.
- Conditions that result in vit-B6 deficiency can lead to an increased levels of homo-cysteine levels.
- Higher levels of homo-cysteine levels are associated with hypocoagulation states and subsequent thrombosis.
- Therefore Crohn's patients are at risk for thrombo-embolism due to high homo-cysteine levels.

# The Lactulose-Mannitol Test for Small Intestinal Hyperpermeability
- Patient is made to swallows a solution of 5 g mannitol and 5 g lactulose.
- Urine sample is collected for six hours.
- Assay for total lactulose and mannitol
< 14% mannitol = carbohydrate malabsorption
1% lactulose = disaccharide hyperpermeability
- < 14% mannitol = carbohydrate malabsorption
- >1% lactulose = disaccharide hyperpermeability