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Disorders of the Stomach & Peptic Ulcer Disease

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Parietal cells located in the oxyntic glands of the fundus and body of the stomach
Where in the stomach does acid secretion occur and which cells are responsible for this?
Neurocrine, paracrine, & endocrine pathways
What are the 3 different pathways for stimulation of acid secretion in the stomach?
Vagal release of ACh promotes accumulation of intracellular Ca2+
How does the neurocrine pathway stimulate acid secretion in the stomach?
Histamine release from mast cells and enterochromaffin-like cells in the stomach leads to cascade of Gs activation which activates adenylate cyclase, which in turn generates cAMP
How does the paracrine pathway stimulate acid secretion in the stomach?
Release of gastrin from antral G cells promotes accumulation of intracellular Ca2+
How does the endocrine pathway stimulate acid secretion in the stomach?
Prostaglandin & somatostatin
Which factors act to inhibit acid secretion in the stomach?
Gi that inhibits adenylate cyclase; somatostatin also inhibits gastrin release
How do prostaglandin & somatostatin inhibit acid secretion in the stomach?
Activate protein kinases which activate H+/K-ATPase
How do second messengers result in the stimulation of acid secretion?
Mucins, phospholipids, & bicarbonate secretion
What creates the pH gradient in the mucus layer between the acidic gastric lumen and the cell surface, which serves a protective role?
↑ mucus secretion, ↑ bicarbonate production, maintaining mucosal blood flow, and ↑ resistance of epithelial cells to injury
How do prostaglandins play a role in enhancing mucosal protection?
pH gradient (physiochemical barrier); epithelial (surface cells); submucosal microvascular system; prostaglandins
What are the components of the gastroduodenal mucosal barrier against injury?
Provides HCO3 & nutrients; removes toxic metabolic by products
How does the submucosal microvascular system contribute to the gastroduodenal mucosal barrier against injury?
Chronic active gastritis
What is H. pylori infection virtually always associated with?
10 to 15%
What percentage of individuals infected by H. pylori develop frank peptic ulceration?
Gastritis
Histologically documented inflammation of the gastric mucosa.
Lymphocytes and plasma cells infiltrated
When is gastritis considered chronic?
Antrum
Though it will encompass the entire stomach over time, to which part of the stomach does H. pylori orient towards?
Superficial inflammation with edema and cellular infiltrates in lamina propia of surface mucosa over time progress to atrophic gastritis which progresses deeper into mucosa and progressively destroys the glands
What is the natural course of H. pylori infection?
Gastric atrophy with a paucity of inflammatory infiltrates
What is the final stage of H. pylori infection?
Level of H. pylori
What correlates with the degree of inflammation in gastritis?
Gastric atrophy
Why might an advanced case of gastritis show low levels of H. pylori?
Early in life; unknown
When does infection by H. pylori typically occur and what is the mode of transmission?
Flagellae, ability to adhere to the mucus layer, and production of urease
What is colonization of H. pylori in the mucus layer overlying the gastric epithelium facilitated by?
Acute and chronic inflammation consisting of neutrophils, plasma cells, T cells, and macrophages accompanied by varying degrees of epithelial cell injury
What does colonization of H. pylori in the mucus layer overlying the gastric epithelium cause?
Vacuolating toxin (vacA) gene, cytotoxin-associated antigen (cagA) gene, IgA protease, flagella, & urease
What are the virulence factors that promote H. pylori infection?
VacA gene
Virulence factor that directly damages epithelial cells.
Peptic ulcer disease
In which patients is vacA gene more common?
CagA gene
Essential for the expression of vacA gene.
Duodenal & gastric ulcers
What might develop in a minority of patients infected by H. pylori?
Gastric cancer
What does atrophic gastritis increase the risk of?
Monoclonal B cell proliferation in MALT (lymphoma)
What might the mucosal lymphocytic response to H. pylori lead to?
Enhances mucosal permeability by lowering mucosal potential difference and enhancing back-diffusion of H+; weak acids that remain in a nonionized lipophilic form in the stomach migrate across lipid membranes of epithelial cells, leading to cell injury once trapped intracellularly in an ionized form
How do NSAIDs result in direct injury to the gastric mucosa?
Inhibition of prostaglandin synthesis results in ↓ mucus and HCO3 production and mucosal blood flow, which may lead to frank ulceration
How do NSAIDs result in gastric mucosal injury in the long run?
Hyperemia, subepithelial hemorrhage, and superficial erosions
What does direct injury to gastric mucosa by NSAIDs result in?
Reactive pattern of injury with little/no increase in inflammatory cells
How are the results of direct gastric mucosal injury by NSAIDs histologically characterized?
Shock, sepsis, massive burns, severe trauma, or head injury
Which patients are susceptible to developing acute (stress-related) gastric mucosal disease?
Acid-producing portions (fundus & body)
Which portions of the stomach are typically damaged by stress-induced gastric mucosal diseases?
GI bleeding; usually minimal but occasionally life-threatening
What is the most common presentation of acute stress-related gastric mucosal disease? How severe is this?
Respiratory failure requiring mechanical ventilation and underlying coagulopathy
What are the risk factors for GI bleeding caused by stress-induced gastric mucosal disease?
No inflammation or H. pylori
Why is stress-induced gastric mucosal disease not considered gastritis?
Mucosal ischemia & breakdown of normal protective barriers
What processes are responsible for the damage caused by stress-induced gastric mucosal disease?
↓ blood flow (from shock, hypotension, or catecholamine release)
What is mucosal ischemia in stress-induced gastric mucosal disease caused by?
Evolves into erosions and then frank ulceration in the stomach and duodenum
How does hyperemia in stress-induced gastric mucosal disease typically evolve?
Keep pH >3.5 until their stomachs can recover or use sucralfate
What is the general treatment approach for stress-induced gastric mucosal disease?
Pernicious anemia
What is the hematologic disease most commonly associated with chronic autoimmune gastritis, achlorhydria, and vitamin B12 deficiency?
Autoantibodies to the components of gastric gland parietal cells including Abs against the H/K -ATPase, gastrin receptor, and IF; gland destruction and mucosal atrophy lead to the loss of acid production; production of IF is lost in the most severe cases
What are the events that lead to pernicious anemia?
Chronic gastritis, achlorhydria, & vitamin B12 deficiency
What complications result from pernicious anemia?
Ab damage and T cell mediated attacks
How does chronic gastritis occur in pernicious anemia?
Achlorhydria
No HCl in gastric juice.
Parietal cells, the source of IF, are destroyed; vitamin B12 deficiency and its sequelae (megaloblastic anemia, neurologic dysfunction)
How is IF production lost in pernicious anemia? What will this result in?
Immunocompromised (HIV, chemotherapy, or organ transplantation); elderly; alcoholics
What are the typical host characteristics of patients with gastric infections NOT due to H. pylori?
Salmonella
What infection are achlorhydric patients at increased risk of developing?
NSAIDs; H. pylori; acid secretory abnormalities; smoking; some chronic diseases (CRF or chronic pulmonary disease); possible: genetic, psychological stress, & diet
What are the risk factors for duodenal and gastric ulcer?
Dyspepsia
Impaired gastric function or "upset stomach" due to some disorder of the stomach.
Epigastric pain, sometimes burning, nausea, and gaseous eructation
What is dyspepsia characterized by?
Ill-defined epigastric or aching/hunger pain 1.5 to 3 hours that is relieved by antacids or food; pain that wakes patient from sleep (most discriminating)
What type of pain reported on history might indicate peptic ulcers?
Poor
What is the general predictive value of epigastric tenderness upon physical examination of suspected peptic ulcer disease?
Ulcer complications (fluid loss, perforated stomach; boardlike painful abdomen, gastric outlet obstruction)
If the predictive value of epigastric tenderness is poor, why is physical examination important for peptic ulcer disease?
13C & 14C labeled urea breath test to measure urease action or serology; fecal H. pylori antigen test
What non-invasive measures are available to test for H. pylori infection?
EGD biopsy for culture or rapid urease test
What invasive measures are available to test for H. pylori infection?
EGD biopsy
What is the most sensitive & specific approach for evaluating peptic ulcers?
EGD to determine pathogenesis
What is required if treatment of peptic ulcer disease with antisecretory or prokinetic drugs fails?
NEVER
Is empirical therapy of peptic ulcer disease with antibiotics warranted?
Barium study or endoscopy
What does documentation of an ulcer require?
Individuals who are otherwise healthy & < 45
When is empirical therapy BEFORE embarking on a diagnostic evaluation of peptic ulcer disease appropriate?
No
Is hyperacidity a necessary prerequisite for developing peptic ulcers?
First
In which portion of the duodenum do ulcers typically develop?
Usually <1 cm in diameter; sharply demarcated with depth reaching up to muscularis propria; base often consists of a zone of eosinophilic necrosis with surrounding fibrosis
Describe the gross pathology of ulcers.
Distal to junction between antrum and acid secretory mucosa
In which portion of the stomach do ulcers typically develop?
Non-ulcer dyspepsia (NUD or functional/essential dyspepsia)
A group of heterogeneous disorders typified by upper abdominal pain without the presence of an ulcer.
GERD, gastric cancer, & gastroparesis
Aside from ulcers, what can cause dyspepsia?
Eradication of H. pylori
What essentially cures peptic ulcer disease (PUD)?
Triple therapy for 14 days followed by continued acid suppression for 4-6 weeks
What is the general therapeutic approach for managing patients with a documented ulcer caused by H. pylori (independent of NSAID status)?
Treated patients only require non-invasive measures, whereas untreated patients can also have invasive measures
What is the difference in approach to testing treated and untreated patients for H. pylori?
Hematemesis, melena, or hematochezia
What hemorrhagic complications could possibly occur from a peptic ulcer?
3 days
Within what timespan will most bleeding due to a peptic ulcer recur?
15-20%
What percentage of peptic ulcer patients experience hemorrhagic complications?
Hemorrhage
What is the most frequent complication of peptic ulcers?
25%
What percentage of ulcer deaths is due to hemorrhage?
PE demonstrates volume depletion
How can hemorrhagic complications of ulcers be identified?
2%
Approximately what percentage of ulcer patients experience gastric outlet obstruction (from edema or scarring)?
pyloric channel; duodenal
Gastric outlet obstruction is most often due to ____ ulcers, though it may also occur with ____ ulcers.
Incapacitating, crampy abdominal pain; rarely may lead to total obstruction with intractable vomiting
What does gastric outlet obstruction lead to?
New onset of early satiety, nausea, vomiting, increase of postprandial abdominal pain, and weight loss
What findings make gastric outlet obstruction a possible diagnosis?
5%
Approximately what percentage of ulcer patients experience perforation?
66%
What percentage of ulcer deaths is accounted for by perforation?
Rarely
How often is a perforation the first indication of an ulcer?
Duodenal; gastric
____ ulcer can lead to pancreatitis as it tunnels to pancreas and ____ ulcers penetrate into left hepatic lobe.
Antacid
Neutralizes acids, simultaneously inactivating pepsin.
Aluminum hydroxide (diarrhea) & calcium carbonate (metabolic alkalosis)
What are some commonly used antacids and their side effects?
H2 receptor antagonists
Blocks histamine action, preventing release of acid + gastrin.
H2 receptor antagonists
Cimetidine, ranitidine, famotidine, and nizatidine.
Proton pump inhibitor (PPI)
Inhibits H/K ATPase, results in long-lasting inhibition (2-5 days) of gastric acid secretion.
PPI
Which anti-secretory drugs relieve peptic ulcer symptoms more rapidly, H2 antagonists or PPIs?
PPIs
Omeprazole, esomeprazole, lansoprazole, rabeprazole, and pantoprazole.
Sucralfate & prostaglandin E analogues
Which drugs used in the treatment of PUD influence mucosal defense?
Complex salt of sucrose sulfate & aluminum hydroxide
What is sucralfate composed of?
Just as effective
How does sucralfate compare to H2 receptor antagonists?
Sucralfate
In presence of acid, the insoluble salt becomes a gel-like substance that binds to active sites of ulceration primarily and acts as a physical barrier to the diffusion of acid, pepsin, and bile acids.
Prostaglandin E analogues
Which drugs are effective for the prophylaxis of NSAID-induced ulcers?
Diarrhea & abdominal cramps
What are the side effects of prostaglandin E analogues?
Prostaglandin E analogue
Misoprostol.
Combinations of 2 antibiotics (amoxicillin, metronidazole, or clarithromycin + tetracycline) + PPI, H2 antagonist, or bismuth
What does "triple therapy" of H. pylori infection involve?
Side effects & large pill number
Why is compliance with medication for H. pylori difficult?
Negligible
Generally speaking, what role does surgical therapy play in the management of uncomplicated PUD?
Urgent operative intervention (perforation, bleeding, gastric outlet obstruction, peritonitis); intractable disease due to NSAIDs or persistent disease despite total eradication of H. pylori; high cost of prolonged ulcer therapy in economically disadvantaged countries
When is surgery indicated in the management of PUD?
Vagotomy & antrectomy
What type of surgical procedures are performed for the management of PUD?
Zollinger-Ellison syndrome (ZES)
Severe peptic ulcer diathesis secondary to gastric acid hypersecretion due to unregulated gastrin release from a non-β cell endocrine tumor (gastrinoma).
High fasting gastrin concentration of > 1000 pg/mL in the setting of acid hypersecretion caused by gastrin-secreting tumor
How is ZES typically diagnosed?
Pancreas & duodenum
Where is the gastrinoma responsible for ZES usually located?
Peptic ulcer (esp. in unusual locations, refractory to Tx, & no NSAID or H. pylori); esophageal involvement; diarrhea
What are the signs and symptoms of ZES?
Check fasting gastrin. If high, check acid secretion. If low, then high gastrin is due to low acid secretion. If high or normal, more testing needed.
What does the biochemical diagnosis of ZES involve?
Secretin is infused into blood and gastrin levels are measured, if the increase is large and fast enough (>200 pg/ml in 15 minutes) ZES is highly likely
What does the gastrin provocative test involve?
High levels of fasting gastrin (> 150 to 200 pg/mL) + gastric acid hypersecretion (>15 mEq/hr prior to surgery, >5 mEq/hr if post-surgery)
How do serum gastrin & gastric acid analysis play a role in the diagnosis of ZES?
Abdominal CT, MRI, or octreoscan to exclude metastatic disease
Once a biochemical diagnosis of ZES has been confirmed, what should the patient first undergo and why?
Octreoscan; endoscopic USG
What is the best imaging test for gastrinomas? Second best?
Octreoscan
Somatostatin receptor scintigraphy (SRS).
Radioactive octreotide, a drug similar to somatostatin, is injected into a vein and travels through the bloodstream and attaches to tumor cells that have somatostatin receptors. A radiation-measuring device detects the octreotide, and makes pictures showing where the tumor cells are in the body
Briefly explain the SRS (octreoscan) imaging method.
Gastrinoma, gastric outlet obstruction, hypercalcemia, hyperparathyroidism, MEN-1, atrophic gastritis, pernicious anemia, vagotomy, gastric carcinoma, renal disease, rheumatoid arthritis, vitiligo
Other than ZES, what are the most common causes of hypergastrinemia?
Early satiety, bloating, epigastric fullness, nausea, vomiting, belching; anorexia, weight loss, & nutritional deficiency
What are the symptoms of delayed gastric emptying & what do they lead to?
Radionuclide scintigraphy using a mixed solid/liquid meal
What type of diagnostic testing reveals/quantitates delayed gastric emptying?
Endoscopy
What type of diagnostic testing is used to determine the presence of any structural abnormalities?
GI manometry & electrogastrography
What type of diagnostic testing may be used in the most difficult cases of delayed gastric emptying?
Diabetic (most likely related to neural injury)
What is the most important and frequent cause of gastroparesis?
Eat blended foods and liquid supplements; avoid foods high in fat & fiber (because they slow gastric emptying)
What are the dietary treatment recommendations for gastroparesis?
Prokinetic drugs & anti-emetics
What are the pharmacologic treatment recommendations for gastroparesis?
Metoclopramide (D2 receptor antagonist)
Prokinetic drug that facilitates release of ACh, accelerating gastric emptying.
Cisapride
Prokinetic drug that increases gastric motor activity by facilitating release of ACh at the myenteric plexus.
Erythromycin
Prokinetic drug that acts as a motilin agonist.
Implantation of gastric electrical pacemakers and neurostimulators
What option can be considered for refractory cases of gastroparesis?
Menetrier's disease
A rare entity characterized by large, tortuous gastric mucosal folds.
ZES; malignancy; infectious; infiltrative disorders
What is the differential diagnosis of large gastric folds, excluding Menetrier's disease?
Body and fundus
In which portion of the stomach are the mucosal folds of Menetrier's disease most often prominent?
Massive foveolar hyperplasia (hyperplasia of surface and glandular mucous cells) which replaces most of the chief and parietal cells and produces the prominent folds observed. The pits of the gastric glands elongate and may become extremely tortuous.
Briefly describe the histologic appearance of Menetrier's disease.
Unknown; possibly growth factor overexpression in superficial gastric epithelium
What is the etiology of Mentrier's disease?
Epigastric discomfort, diarrhea, weight loss, and sometimes bleeding
What are the signs & symptoms of Menetrier's disease?
Protein losses from excessive gastric secretions, which may cause hypoalbuminemia & peripheral edema
What does increased mucus production from mucous cell hyperplasia in Menetrier's disease result in?
High in less developed countries; lower SES; M:F of 2:1
What are the epidemiological risk factors for gastric carcinoma?
Long-term ingestion of high concentrations of nitrates in dried, smoked, and salted foods; bacteria found in partially decaying food can convert nitrates to carcinogens
What are the dietary risk factors for gastric carcinoma?
Infection by H. pylori; chronic gastritis, partial gastrectomy, gastric adenomas, Barrett esophagus
What are the pre-existing disease states that are risk factors for gastric carcinoma?
85%
What percentage of stomach cancers are adenocarcinomas?
15%
What percentage of stomach cancers are due to lymphomas & GI stromal tumors?
Depth of invasion
What has the greatest impact on clinical outcome of gastric carcinomas?
Early is confined to mucosa & submucosa (regardless of lymph node involvement); advanced extends below submucosa into muscular wall
What is the difference between early and advanced gastric carcinoma?
Exophytic, flat/depressed, & excavated
What are the 3 macroscopic growth patterns of gastric carcinomas?
Exophytic
Protrusion of tumor mass into the lumen.
Flat or depressed
No obvious tumor mass within the mucosa.
Excavated
Shallow/deeply erosive crater is present in the wall of the stomach.
Intestinal & diffuse
What are the 2 histological types of gastric adenocarcinomas?
Intestinal
Gastric adenocarcinoma characterized by cohesive neoplastic cells that form glandlike tubular structures.
Frequently ulcerative & often preceded by extended precancerous process
What complications are associated with intestinal gastric adenocarcinoma?
Antrum and lesser curvature of the stomach
Where in the stomach do intestinal gastric adenocarcinomas most commonly appear?
Diffuse
Gastric adenocarcinoma in which cell cohesion is absent, so that individual cells infiltrate and thicken the stomach wall without forming a discrete mass.
Younger
Which patients are more commonly affected by diffuse gastric adenocarcinoma?
It develops through the stomach causing loss of gastric wall distensibility
What causes the leather bottle appearance of diffuse gastric adenocarcinoma?
Poor
What is the general prognosis of diffuse gastric adenocarcinoma?
Neoplastic intestinal glands & gastric type mucous cells
What type of cells constitute intestinal & diffuse gastric adenocarcinomas, respectively?
Expanding & infiltrative
What is the growth pattern of intestinal & diffuse gastric adenocarcinomas, respectively?
Mucin formation expands the malignant cells and pushes the nucleus to the periphery
What causes the signet-ring conformation observed in diffuse gastric adenocarcinoma?
Penetrate the wall to involve the serosa and spread to regional and more distant lymph nodes
If gastric carcinomas are left untreated, what do they eventually do?
Asymptomatic until late; weight loss, abdominal pain, anorexia, vomiting, altered bowel habits; less frequently, dysphagia, anemic symptoms, and hemorrhage
What are the typical presenting symptoms of gastric carcinomas?
Supraclavicular sentinel (Virchow) node
To where do gastric carcinomas frequently metastasize as the first clinical manifestation of an occult neoplasm?
Sister Mary Joseph nodule
Gastric carcinomas can metastasize to the periumbilical region to form a subcutaneous nodule called ____.
Complete surgical removal of the tumor with resection of adjacent lymph nodes; may include chemo or radiotherapy
What does the treatment of gastric carcinoma involve?
1/3
What fraction of patients are able to receive surgical treatment of gastric carcinomas?
95%
What is the 5-year survival rate for EARLY gastric cancers?
< 15%
What is the 5-year survival rate for ADVANCED gastric cancers?
20%
What is the overall 5-year survival rate for gastric cancer?
Causes chronic gastritis, loss of gastric acidity, and bacterial growth in the stomach
What role does H. pylori play in gastric carcinoma?
B-cell lymphomas of MALT (MALToma)
What type of lymphomas are nearly all gastric lymphomas?
Chronic gastritis & H. pylori infection
What are the majority (>80%) of MALTomas associated with?
Mucosa or superficial submucosa
Where do gastric lymphomas commonly occur?
MALToma
A monomorphic lymphocytic infiltrate of the lamina propria surrounds gastric glands massively infiltrated with atypical lymphocytes and undergoing destruction.
Gastric adenocarcinoma
From what condition is a MALToma difficult to clinically distinguish from?
Epigastric pain, early satiety, and generalized fatigue
What do MALTomas typically present with?
MALToma much more treatable
Which is more treatable, MALToma or gastric adenocarcinoma?
50-75%
What is the regression rate of MALTomas after antibiotic treatment for H. pylori?
40-60%
What is the 5 year survival rate of subtotal gastrectomy with localized high grade lymphomas?
Carcinoid tumor
Well differentiated neuroendocrine tumors that arise from multiple organs and tissues.
GI stromal tumors (GISTs)
What are the most common mesenchymal tumors of the digestive tract?
50%
Approximately what percentage of GISTs originate in the stomach?
About half
What fraction of GIST presents with blood loss anemia?