Dyspepsia pathophysiology

Functional dyspepsia is now classified as a disorder of gut-brain interaction, affecting approximately 7% of the community, and is diagnosed by the presence of bothersome epigastric pain or burning, early satiation, and/or postprandial fullness for longer than 8 weeks in the absence of an identifiable organic cause.^[1] The symptoms of functional dyspepsia are directly caused by two major pathophysiological abnormalities in gastric motility and visceral sensitivity, with recent evidence adding impaired gastric accommodation and low-grade duodenal mucosal inflammation, including duodenal eosinophilia and increased mast cell density, as key contributory mechanisms.^[2] These mechanisms occur in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes. The process may be modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, impaired duodenal mucosal barrier integrity, diet, and lifestyle.

The pathophysiology of dyspepsia is as follows:^{[3][4][5][6][7][8][9][1][2]}

• In humans, digestion begins in the mouth where food is chewed.
• Salivary amylase aids in the chemical breakdown of polysaccharides such as starch into disaccharides such as maltose.
• The chewed food is pushed down the esophagus into the stomach through peristaltic contraction of these muscles.
• Food enters the stomach where it is further broken down and thoroughly mixed with gastric acid, pepsin, and other digestive enzymes to break down proteins, fats and carbohydrates.
• After consumption of food, digestive “tonic” and peristaltic contractions begin, which helps break down the food and move it through the gastrointestinal tract. Gastric emptying is the release of food from the stomach into the duodenum.
• Gastric emptying has attracted medical interest as rapid gastric emptying is related to obesity and delayed gastric emptying syndrome is associated with diabetes mellitus, aging, gastroparesis and gastroesophageal reflux.
• After being processed in the stomach, food is passed to the small intestine. The majority of digestion and absorption occurs here after the milky chyme enters the duodenum. Here it is further mixed with three different digestive juices:
  • Bile which is produced by the liver and stored in the gallbladder emulsifies fats and neutralizes the chyme.
  • Pancreatic juice made by the pancreas. It secrete enzymes such as pancreatic amylase, pancreatic lipase, and trypsinogen.
  • Intestinal juice secreted by the intestinal glands in the small intestine. It contains enzymes such as enteropeptidase, erepsin, trypsin, chymotrypsin, maltase, lactase, and sucrase.

• The symptoms of functional dyspepsia (FD) are directly caused by multiple, overlapping physiological abnormalities, now understood to include:
  • Abnormal gastric motility, including delayed gastric emptying. Gastroparesis and functional dyspepsia may be the same entity, as tertiary-care cohorts show overlapping clinical and pathological features between the two syndromes.^[10]
  • Impaired gastric accommodation. Failure of the proximal stomach to relax normally in response to a meal results in uneven food distribution, antral pooling of chyme, and premature antral distension; impaired accommodation is present in up to one-third of patients and correlates most closely with early satiation and weight loss.^[2][3]
  • Visceral hypersensitivity, characterized by heightened perception of normal gastric distension and duodenal chemosensitivity (particularly to lipids and acid), which correlates with meal-related symptom severity.^[9][2]
  • Low-grade duodenal mucosal inflammation and impaired barrier integrity. Duodenal biopsies in FD show increased intraepithelial and lamina propria eosinophil and mast cell infiltration, with associated downregulation of the tight-junction proteins occludin and claudin, increased paracellular permeability, and abnormal β-catenin and desmosomal protein expression. This “leaky gut” phenotype is thought to allow luminal antigens to activate submucosal immune and neural pathways, driving symptom generation.^[11][12]
  • Altered gut-brain axis signaling. FD is now classified as a disorder of gut-brain interaction; peripheral duodenal signals (immune activation, chemosensitivity) are relayed via vagal and spinal afferent pathways to central pain-processing and emotional regulation centers, which are further modulated by psychological comorbidity, anxiety, and depression.^[1][2]
  • Helicobacter pylori infection and post-infectious states (following acute gastroenteritis) can trigger or perpetuate the above mechanisms through sustained low-grade mucosal inflammation.^[7]
• These mechanisms occur in patients who have acquired excessive responsiveness to stress as a result of the environment during early life, genetic abnormalities, residual inflammation after gastrointestinal infections, or other causes, with the process modified by factors including psychophysiological abnormalities, abnormal secretion of gastric acid, Helicobacter pylori infection, diet, and lifestyle.
• If the basis of this model of FD pathogenesis is excessive responsiveness of gastrointestinal function to stress and external stimuli, psychosomatic approaches to alter stress perception could be important treatment options.^[13]

• Gastric ulcers are most often localized on the lesser curvature of the stomach
• Duodenal ulcers are more located at bulb of duodenum
• Characteristic findings of a peptic ulcer on gross pathology include:
  • Round to oval
  • Two to four cm diameter
  • Smooth base with perpendicular borders.
  • Parietal scarring with radial folds may be evident in the surrounding mucosa

• 
  A benign gastric ulcer (from the antrum) of a gastrectomy Source:https://commons.wikimedia.org/wiki/File:Benign_gastric_ulcer_1.jpg#/media/File:Benign_gastric_ulcer_1.jpg
• 
  Duodenal ulcer specimen. Source: https://commons.wikimedia.org/wiki/File:Duodenal_ulcer01.jpg#/media/File:Duodenal_ulcer01.jpg
• 
  Gastric ulcer specimen Source:https://commons.wikimedia.org/wiki/File:Gastric_ulcer_3.jpg#/media/File:Gastric_ulcer_3.jpg

• A peptic ulcer is a mucosal defect produced by acid-pepsin aggression which penetrates the muscularis mucosae and muscularis propria
• There is increased plasma cells, neutrophilic infiltrate, villous blunting
• The surface epithelium usually shows mucous cell (pseudopyloric) metaplasia
• During the active phase, the base of the ulcer shows 4 zones:
  • Inflammatory exudate: polymorphonuclear infiltration which along with bacterial products stimulate the production of IL-8 and tumor necrosis factor alpha (TNF-α) and IL-1 released by macrophages in response to bacterial lipopolysaccharide
  • Fibrinoid necrosis
  • Granulation tissue
  • Fibrous tissue. The fibrous base of the ulcer may contain vessels with thickened wall or with thrombosis^[14]
• In functional dyspepsia specifically, routine histology is typically unremarkable on standard staining, but quantitative studies using specialized immunohistochemistry demonstrate increased duodenal eosinophil and mast cell counts per high-power field compared with controls, supporting a distinct microscopic correlate of the “leaky gut” model described above.^[11][15]

• 
  Erosive gastric ulcer source: https://commons.wikimedia.org/wiki/File:Erosive_gastric_ulcer.jpg#/media/File:Erosive_gastric_ulcer.jpg

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