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.

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.

NSAIDS

Inhibits cycloxygenase pathway

COX-1

COX-2

Reduced mucosal blood flow

Reduced mucosal and bicarbonate secreation

Impaired platelet aggregation

Reduced angiogenesis

Increased leucocyte adherence

Impaired defence Impaired healing

Mucosal Injury

A01

A02

A02

B01

B02

C02

D01

E01

E01

B01

B03

C03

D02

B01

B02

C01

B01

A01

A02

A03

B01

B02

C01

C02

D01

E01

D01

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 are normally able to counteract oxidative stress in the intestinal mucosa.
• However, inflammation increases the demand for these antioxidants and results in an imbalance between pro-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.
• Researchers have studied the connection between oxidative stress and immune-regulated inflammatory factors. Reactive oxygen species (ROS) have been found to be involved in activation of nuclear factor-kappaB (NF-kappaB), which is necessary for encoding genes for TNF-alpha and some of the interleukins involved in inflammation.
• Antioxidant levels and inflammatory mediators were examined in 26 CD patients compared to 15 healthy controls.
• Selenium and glutathione peroxidase (GSHPx) activity were both decreased in CD patients, while TNF-alpha levels and ESR were increased and negatively correlated with selenium and GSHPx.
• Selenium levels decreased in accordance with disease activity, with the most severe disease manifestation exhibiting the lowest levels.
• These findings occurred in subjects who did not have evidence of malabsorption, indicating malabsorption is not the sole factor contributing to selenium deficiency.
• The researchers conclude, “Öselenium supplementation in deficient patient groups [should be] regarded as a potential protecting factor against oxidative burst, NFkappaB activation and excessive inflammatory and immune response.”
• A study examining indices of oxidative stress and plasma levels of vitamins A and E in 20 CD patients found higher peroxidative status and lower vitamin A and E levels compared to controls.
• Conservative surgery to remove bowel obstructions resulted in improvements in vitamin A status and oxidative stress measured by thiobarbituric acid reactive substances (TBARS).98
• A similar study found significantly higher levels of breath-pentane and -ethane and F2- isoprostane (measurements of oxidative stress) in 37 non-smoking CD patients compared to matched controls.
• At the same time, plasma levels of vitamin C and the carotenoids alpha- and beta-carotene, lycopene, and beta-cryptoxanthin were significantly lower in CD patients.99
• Pediatric patients also demonstrate signs of increased oxidative stress.
• In a study of 22 pediatric CD patients, malondialdehyde (MDA) levels were 70-percent higher than controls.
• Antioxidant levels were measured and only vitamin A was found significantly low, while alpha- and gammatocopherol and beta-carotene were no different than controls.
• Red blood cell levels of glutathione were higher in CD patients than controls. The researchers speculate these higher levels may be due to an attempt to compensate for increased oxidative stress.100
• Although oxidative stress is a factor in the pathogenesis of both UC and CD, the parameters may vary between the two. Both UC and CD are associated with increased levels of MDA, a sign of lipid peroxidation.
• However, one study found elevated levels of MDA in CD were associated with levels of the antioxidant metallothionein (a hydroxyl radical scavenger) and manganese-dependent SOD (active in the mitochondria); whereas, in UC the MDA levels were associated with catalase, GSHPx, and myeloperoxidase.
• Based on this data, the researchers suggest the likelihood of the ROS hydroxyl radicals and superoxide anions in the pathogenesis of CD, while hydrogen peroxide and hypochlorous acid may be more associated with UC.101 Antioxidants for the treatment of CD are discussed below in the treatment section.

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