Gastric Anatomy and Pathology Flashcards
The following biopsy is taken from a patient’s gatric corpus. What is the pathologic diagnosis?
Atrophic gastritis
There is a complete loss of oxyntic glands and replacement with intestinal-type epithelium with goblet cells. There is also extensive lymphoplasmacytic inflammation all the way down the lamina propria.
Pyloric gland architecture
Vagus nerve efferents exert their effects on the stomach via . . .
. . . synapsing on myenteric and submucosal interneurons
Extent of acid production in the cephalic phase
The cephalic phase results in as much acid secretion as the gastric phase through vagal stimulation, however this secretion is not sustained if food never actually enters the stomache. It will result in a quick up and down in H+ pumping.
Antagonism of gastric HCl secretion
Endogenous inhibitors of acid secretion are somatostatin (produced by nearby D-cells, a paracrine mechanism), prostaglandins, and epidermal growth factor.
Risk factors for peptic complications (bleeding, perforation) in patients taking NSAIDs
- Older age
- History of prior peptic ulcer
- Concurrent use of corticosteroids, anti-coagulants, and/or low dose aspirin
- Poor heart function
- chronic kidney disease
- Concurrent H. pylori infection
The gastric mucosal barrier
Gastric epithelium is coated in a layer of mucous gel containing bicarbonate. This provides a diffusion barrier against H+ and protects the gastric surface from pepsin.
The barrier must be actively maintained, and thus depends on sufficient blood and nutrient flow to the stomach.
Coating agents
- Sucralfate is used to improve symptoms associated with peptic ulcer disease. Coats the surface of the stomach without affecting luminal pH. Not systemically absorbed and has few side effects, but can bind other oral medications and interfere with their absorption
- Bismuth salts (pepto-bismol) also work as coating agents. May also stimulate mucosal bicarbonate and prostaglandin synthesis. Pepto-Bismol contains salicylate, which is somewhat counterintuitive, and its mechanism of effectiveness is not well understood.
Intestinal phase of gastric secretion
Acid secretion is down-regulated, as food moves into the duodenum. With buffering capacity of food diminishing, the pH falls in the stomach as the parietal cell mass continues to secrete HCL. SST is released from D cells in the antrum when luminal pH is 3 or less.
Other conditions which lead to down-regulation of secretion include less neurocrine mediated stretch stimulation and endocrine factors released in the small intestine in response to calorie exposure, a negative feedback step that moderates acid secretion in stomach when foodstuffs have moved distally.
Paracrine SST markedly down-regulates G, ECL cells, and parietal cells. Paracrine SST is by far the dominant control mechanism.
Why give PPIs during antibiotic therapy for H. pylori?
Despite being able to live at a low pH, H. pylori replicates best at neutral pH. So, neutralizing the stomach acid via PPI increases H. pylori proliferation, which makes them a better target for bactericidal antibiotics.
The gastric antrum and pylorus
Vigorously mix and grind food to small particles. The pylorus acts as a valve and a sieve to allow only small particles in small boluses to exit the stomach at a rate that comports with the digestive capacity of the small bowel. The pylorus also acts as a valve to prevent the passage of material backwards from duodenum to stomach.
These areas contain pyloric glands, which contain mucous cells and enteroendocrine cells. The enteroendocrine cells of pyloric glands include G-cells which produce gastrin and D cells which produce somatostatin.
Surgery in peptic ulcer disease
Does not have the central role that it once did. Now, surgery for peptic ulcer disease is largely about repairing acute perforations. Surgical approaches to decreasing acid/pepsin secretion have included ligating the Vagus nerve, antrectomy, sub-total gastrectomy, or a combination thereof.
How can you be sure that you biopsied the correct region of the stomach if you aren’t certain of your histologic results?
Stain for G cells!
If you have G cells, you are for sure in the antrum.
If you don’t, you are for sure in the corpus.
Antacids
- Common antacids include mixtures of aluminum hydroxide and magnesium hydroxide. Common side effects include diarrhea if using magnesium-containing compounds or constipation and hypophosphatemia (weakness, malaise and anorexia) if using aluminum-containing compounds.
- Sodium bicarbonate is also common, but contains lots of sodium and so should be avoided in patients with hypertension or fluid overload.
- Calcium bicarbonate is sometimes used, and is a good antacid for patients who need supplemental calcium
What is going on in this endoscopy of the duodenum?
A duodenal ulcer
Features of H. pylori that allow it to live in the stomach
- Microaerophilic, spiral shape, flagella ⇒ traverse mucus layer, live in oxygen poor environment
- Tissue specific adhesion ⇒ H. pylori has tissue tropism for gastric surface mucosa. The bacterial protein BabA binds to specific surface proteins on gastric epithelial cells
- Urease ⇒ Hydrolyzes urea to ammonia and carbon dioxide. Ammonia acts as a buffer.
- Evade immune system ⇒ H. pylori produce catalase that detoxifies free radicals. The lipopolysaccharide produced is less immunogenic than that of other gram-negative pathogens.
Transcobalamin I
Transcobalamin I rapidly binds to cobalamin in the stomache. It protects cobalamin from the stomache’s acidic pH.
Once the complex enters the alkaline environment of the duodenum, transcobalamin is digested by pancreatic enzymes, releasing cobalamin and freeing it up to bind intrinsic factor.
Why do patients with atrophic gastritis have ECL cell hyperplasia?
The lack of acid production leads to chronic inhibition of D cells and stimulation of G cells via chemoreception. High levels of gastrin are produced, and gastrin is a trophic factor for ECL cells. Thus, ECL cells will hypertrophy and proliferate.
Iron digestion
Inorganic iron (as compared to heme iron found in meat) largely exists as insoluble salts (complexed with hydroxide, phosphate, bicarbonate) or is bound to compounds in food such as phytates and fiber.
In an acidic milieu, however, more of this inorganic iron is made soluble for subsequent absorption in the upper small bowel.
H2 blockers
Block histamine H2 receptors on the basolateral surface of parietal cells. Main treatment for peptic ulcer disease, but sadly lose efficacy over time.
Four FDA approved are cimetidine, famotidine, ranitidine, and nizatidine.
Peak effect are achieved in 1-3 hours. Elimination occurs by a combination of hepatic metabolism, renal filtration, and renal tubular secretion. Nizatidine is unique in that it undergoes very little first-pass metabolism in the liver. Cimetidine is rarely used because it can produce gynecomastia and impotence in men. It also crosses the placenta and is secreted in breast milk so is not recommended for pregnant or nursing women.
Autoimmune gastritis
Note that the risk of neuroendocrine tumors comes form hypergatrinemia and ECL hyperplasia.
Phases of gastric secretion
Dual output of gastric stretch receptors
When the stomach is empty, HCl secretion . . .
When the stomach is empty, HCl secretion is at basal rate (10% maximal),
which is to say, stomach acid is always being made
Activating multiple acid-agonistic pathways has a ___ effect.
Activating multiple acid-agonistic pathways has a multiplicative syngergistic effect.
Thus, inhibition of one of these pathways has a pronounced effect.
Performing a proper urea breath test
Instruct the patient to avoid antibiotics, PPIs, and H2 blockers for a couple days prior to the test, and no eating or drinking 1 hour prior to the test.
Patient swallows 13C urea and 15 minutes later takes a deep breath and exhales into a balloon. The balloon contents and mass are measured.
What is wrong with the attached gastric corpus biopsy?
The lamina propria is expanded and full of inflammatory cells
Very likely H. pylori, possibly Crohn’s Disease.
Meena’s model for the enteric nervous system
Rough structure of the gastric nevous system
Note that: 1) The pre-ganglionic input comes from the vagus nerve, 2) Ach is used by pre-ganglionic nerves as well as post-ganglionic neurons, and 3) that post-ganglionic nerves use a variety of signaling molecules
Oxyntic gland architecture
For vagal input in digestion, ___ stimulates digestion while ___ inhibits it.
For vagal input in digestion, Ach stimulates digestion while VIP inhibits it.
Erosion vs ulcer
Stimuli for HCl secretion from parietal cells
Acetylcholine (neurocrine, CNS stimulated, M3 receptor), histamine (paracrine, ECL-cell stimulated, H2 receptor), and gastrin (endocrine, G-cell stimulated, CCK-B or CCK2 receptor) are the three physiological agonists of HCl secretion. Both Ca++ and cAMP-dependent second messenger systems are involved in intracellular signaling.
Note that while gastrin itself has some acid agonistic effect, its primary effect is through stimulating ECL cells to release histamine.
PPIs
Permanently inhibit the H+/K+ ATPases in the parietal cell apical membranes responsible for secreting protons (acid) into the stomach lumen. Proton pump inhibitors are acid labile; they must be released in the small intestine. Peak concentration in serum occurs 1-3 hours after ingestion.
Omeprazole is the main one. Preferentially concentrated in the acidic cellular compartments containing the H+/K+ ATPases. In the presence of acid, omeprazole is activated to a reactive intermediate. This intermediate covalently binds to an apical moiety on the H+/K+ ATPase, permanently disabling the pump. Extensively metabolized in the liver via the cytochrome P450 system
Summary of neuronal gastric acid regulation
Red asterisks indicate Vagus outflow in the context of the cephalic phase of acid secretion.
Gastrin circulates through blood from antrum to parietal cells in body, denoted by ‘blood stream’ and schematic blood vessel just above it. Acid in lumen stimulates SST release from antral D-cells. As it happens, this action is mediated by CGRP (calcitonin gene-releasing peptide) producing sensory neurons in antrum. Vagal influence on ECL cells is likely via PACAP-containing secretomotor neurons.
Antral-predominant chronic H. pylori
Multiple observations in this population may explain its association with duodenal ulcers:
- Increased basal and meal-stimulated gastrin secretion
- Excess acid secretion related to an increased parietal cell mass
- Diminished bicarbonate secretion from proximal duodenal
- These differences may all be linked to D-cell loss or D-cell dysfunction in the antrum, on account of the chronic infection
PPI choice and CYP genetics
CYP2C19 is the principle enzyme that metabolizes omeprazole to inactive metabolites. Approximately 3% of Caucasians and 20% of Asians have reduced or absent CYP2C19 activity
Studies have found improved eradication of H. pylori in patients who are poor metabolizers.
In the near future, it may be routine to screen for the presence of CYP2C19 polymorphisms to help guide drug choice, dosing, and anticipate drug-drug interactions
Functional nerve circuits in the stomach
Note that distension and pH change are sensed by sensory neurons, this signal is relayed to an interneuron, and then the interneuron synapses on a muscular or secretory effector neuron.
Zollinger-Ellison syndrome
Gastrin-secreting tumor or hyperplasia of G cells causes inappropriate hypergastrinemia, then leading to ECL cell and parietal cell hyperplasia and macroscopic increase in ruggal folds. This may then lead to peptic ulcer disease.
How a parietal cell generates HCl
How H. pylori causes cancers
Anatomy of the stomach
Triturating
Grinding function of the body/antrum
Functional regions of the stomach
The attached is a picture of normal gastric corpus histology. Where are the parietal and chief cells in this picture?
The parietal cells are the pinkish cells in the mid field and the chief cells are the bluish cells towards the bottom.
Ultrastructure of resting and acid-secreting parietal cells
Systemic vs gastric effects of NSAIDs
Note that NSAIDs may also be damaging to the gastric mucosa because of their presence in the gastric lumen. This is called the topical effect. This is hypothesized to be due to the drug’s chemical action as a weak acid, allowing it to migrate through the different barriers with different pHs and eventually become stuck in the cell cytoplasm as an ion.
Not listed below, but the main gastric action contributing to peptic ulcers is decreasing mucous production.
