Gastric Anatomy and Pathology

Question 1

The following biopsy is taken from a patient’s gatric corpus. What is the pathologic diagnosis?

Answer 1

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.

Question 2

Pyloric gland architecture

Answer 2

Question 3

Vagus nerve efferents exert their effects on the stomach via . . .

Answer 3

. . . synapsing on myenteric and submucosal interneurons

Question 4

Extent of acid production in the cephalic phase

Answer 4

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.

Question 5

Antagonism of gastric HCl secretion

Answer 5

Endogenous inhibitors of acid secretion are somatostatin (produced by nearby D-cells, a paracrine mechanism), prostaglandins, and epidermal growth factor.

Question 6

Risk factors for peptic complications (bleeding, perforation) in patients taking NSAIDs

Answer 6

• 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

Question 7

The gastric mucosal barrier

Answer 7

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.

Question 8

Coating agents

Answer 8

• 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.

Question 9

Intestinal phase of gastric secretion

Answer 9

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.

Question 10

Why give PPIs during antibiotic therapy for H. pylori?

Answer 10

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.

Question 11

The gastric antrum and pylorus

Answer 11

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.

Question 12

Surgery in peptic ulcer disease

Answer 12

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.

Question 13

How can you be sure that you biopsied the correct region of the stomach if you aren’t certain of your histologic results?

Answer 13

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.

Question 14

Antacids

Answer 14

• 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

Question 15

What is going on in this endoscopy of the duodenum?

Answer 15

A duodenal ulcer

Question 16

Features of H. pylori that allow it to live in the stomach

Answer 16

• 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.

Question 17

Transcobalamin I

Answer 17

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.

Question 18

Why do patients with atrophic gastritis have ECL cell hyperplasia?

Answer 18

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.

Question 19

Iron digestion

Answer 19

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.

Question 20

H2 blockers

Answer 20

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.

Question 21

Autoimmune gastritis

Answer 21

Note that the risk of neuroendocrine tumors comes form hypergatrinemia and ECL hyperplasia.

Question 22

Phases of gastric secretion

Answer 22

Question 23

Dual output of gastric stretch receptors

Answer 23

Question 24

When the stomach is empty, HCl secretion . . .

Answer 24

When the stomach is empty, HCl secretion is at basal rate (10% maximal),

which is to say, stomach acid is always being made

Question 25

Activating multiple acid-agonistic pathways has a ___ effect.

Answer 25

Activating multiple acid-agonistic pathways has a **multiplicative syngergistic** effect. Thus, inhibition of one of these pathways has a pronounced effect.

Question 26

Performing a proper urea breath test

Answer 26

Instruct the patient to a**void antibiotics, PPIs, and H2 blockers** for a **couple days prior** to the test, and n**o 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.

Question 27

What is wrong with the attached gastric corpus biopsy?

Answer 27

The lamina propria is expanded and full of inflammatory cells Very likely *H. pylori*, possibly Crohn's Disease.

Question 28

Meena's model for the enteric nervous system

Answer 28

Question 29

Rough structure of the gastric nevous system

Answer 29

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**

Question 30

Oxyntic gland architecture

Answer 30

Question 31

For vagal input in digestion, ___ stimulates digestion while ___ inhibits it.

Answer 31

For vagal input in digestion, **Ach** stimulates digestion while **VIP** inhibits it.

Question 32

Erosion vs ulcer

Answer 32

Question 33

Pan-gastritis chronic infection with *H. pylori*

Answer 33

When the chronic infection results in an intense chronic inflammatory state in the corpus and antrum, some patients go on to develop **atrophy of the corpus glands** (termed **_atrophic gastritis_**), resulting in **loss of parietal cells and chief cells**. **_Acid, enzyme, and intrinsic factor production can be low or absent_** in this case. **Gastric ulcers** may develop in this group, and atrophic gastritis is a **risk factor for gastric adenocarcinoma.**

Question 34

Stimuli for HCl secretion from parietal cells

Answer 34

**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.

Question 35

The gastric fundus and body

Answer 35

Largest part of the stomach (80% SA). Acts as a reservoir and mixes foodstuffs. This region of the stomach contains **oxyntic** glands that have a high density of parietal and chief cells. * **Parietal** (or oxyntic) **cells** secrete **acid and intrinsic factor.** * **Chief cells** produce **pepsinogen** * **Enterochromaffin-like (ECL) cells** produce **histamine**, and * **D-cells** produce the inhibitory peptide **somatostatin.** * A subset of distinct D-cells called **P/D1 cells** produce **ghrelin**

Question 36

Early Gastric phase of gastric secretion

Answer 36

During this phase, **stretch of the stomach** from food before much digestion happens. **Afferent stretch receptors** mediate increased **parasympathetic outflow** via vagovagal ‘reflex’ arcs. Intrinsic gastric pathways independent of the vagus nerve also contribute to secretory control.

Question 37

PPIs

Answer 37

**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

Question 38

"Alkaline tide"

Answer 38

**Carbonic anhydrase** enables catalysis of water and CO2 to **bicarbonate and protons.** **Chloride** is **exchanged for bicarbonate** at the basolateral surface of parietal cells when stimulated to secrete. This removal of bicarbonate is necessary to provide directionality to the reaction. **The movement of bicarbonate into the blood stream** during gastric secretion is termed the **‘alkaline tide’**.

Question 39

Summary of neuronal gastric acid regulation

Answer 39

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.

Question 40

Antral-predominant chronic H. pylori

Answer 40

Multiple observations in this population may explain its **association with duodenal ulcers:** 1. **Increased** basal and meal-stimulated **gastrin secretion** 2. **Excess acid secretion** related to an **increased parietal cell mass** 3. **Diminished bicarbonate secretion** from proximal duodenal 4. These differences may all be linked to **D-cell loss or D-cell dysfunction** in the antrum, on account of the chronic infection

Question 41

Indications for PPIs

Answer 41

PPIs are used to **heal and prevent peptic ulcers**. Specifically, in high risk groups, concurrent use of PPIs can decrease the chances of developing or re-developing peptic ulcers. PPIs are also used to **treat esophagitis** and to **prevent stress-related erosive syndrome** (acute ulceration of the stomach) in critically ill patients. The most common use for PPIs is treat of **heartburn (GERD)**

Question 42

Long-term side effects of PPIs

Answer 42

Until the last several years, PPIs long-term safety was thought to be similar to H2 blockers. However, several epidemiological risk associations have been observed: **hip fractures, chronic kidney disease, dementia, iron deficiency, hypomagnesemia, *C. difficile* colitis, and pneumonia.** The strongest evidence for a causal link exists for the latter two.

Question 43

Prostaglandin analogues

Answer 43

**Misoprostol** is a **prostaglandin analogue**, and is able to **prevent both gastric and duodenal ulcers associated with NSAID use**. However, misoprostol is uncommonly used because it **causes diarrhea and abdominal cramping**

Question 44

Potassium competitive acid blockers

Answer 44

‘New kid on the block’ for gastric acid suppression. Block the proton pumps via a different mechanism than conventional PPIs as they compete with the **binding of K+ on the luminal side of the Na⁺/K⁺ ATPase.** **Vonoprazan** is the first in class. Unlike PPIs, **not inactivated by stomach acid**, has **limited inter-individual variability** in CYP metabolism, and can be **dosed without regard to food intake**. At least as effective as conventional PPIs, but long-term studies are not in yet.

Question 45

PPI choice and CYP genetics

Answer 45

**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

Question 46

The two major drivers of peptic ulcers

Answer 46

* NSAIDs * H. pylori

Question 47

Highly selective vagotomy

Answer 47

Cutting of **only the vagal branches that innervate the body** of the stomache. Vagal input in this region is the primary driver of **fasting** **stomach acid production**, so severing these branches increases the fasting pH. There is **no need to cut the branches innervating the antrum** since this area does not produce acid anyway.

Question 48

Functional nerve circuits in the stomach

Answer 48

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.

Question 49

What protein is responsible for the acidification of the gatric lumen?

Answer 49

The partietal cell's **H⁺/K⁺ ATPase** They reside in **tubulovesicles** within the **parietal cell** cytosol and are fused with the membrane upon parietal cell syimulation, forming **apical canaliculi** to increase secretory surface area

Question 50

Hypergastrinemia can induce both . . .

Answer 50

. . . ECL cell and parietal cell hyperplasia

Question 51

Gastrin

Answer 51

A GI hormone that circulates through the blood to influence secretion in gastric body.

Question 52

Stomach pH at different times

Answer 52

The **resting stomach pH is ~3**. When the stomach is actively digesting, its acid secretion goes up. However, the **buffering effect of food** actually results in a more alkaline pH in this period, closer to **pH 4-5.**

Question 53

On endoscopy, the antrum should be. . .

Answer 53

. . . **smooth**. If it is not, there is some pathological process, probably inflammation.

Question 54

Zollinger-Ellison syndrome

Answer 54

**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.**

Question 55

How a parietal cell generates HCl

Answer 55

Question 56

How *H. pylori* causes cancers

Answer 56

Question 57

Gastric phase of gastric secretion

Answer 57

The real digestion phase. . **Antrum D cell SST production** is **dampened** when **luminal pH is \> 3** because of the buffering capacity of food, thus…**G cells are ‘released’ from D cell control,** permitting maximal **gastrin release. Acid secretion is highest** during this phase. **Aromatic amino acids** released from early digestion also help **stimulate G cells** via chemoreception

Question 58

Anatomy of the stomach

Answer 58

Question 59

Type of inflammation induced by H. pylori

Answer 59

Chronic lymphoplasmacytic inflammation (largely plasma cells and Th1) with accompanying acute neutrophilic inflammation.

Question 60

Treating *H. pylori*

Answer 60

Treatment for H. pylori needs multi-drug regimens because the bacteria reside in a **layer of mucus that acts as a barrier to antibiotic penetration.** Eradication rates are generally only 74- 76% with standard approaches, which generally include **two oral antibiotics, bismuth, and/or proton pump inhibitor taken twice per day for two weeks.** Admittedly, **poor adherence is a major reason cure rates are not stellar.** Eradication decreases risk of ulcer recurrence and lowers risk of GI cancer and MALT lymphoma.

Question 61

Triturating

Answer 61

Grinding function of the body/antrum

Question 62

Categories of stomach-protecting drugs

Answer 62

* decrease acid secretion * neutralize acid * enhance normal mucosal defense

Question 63

Fat Digestion

Answer 63

**Mixing and grinding** converts the **oil phase to an emulsion (micelles).** **Gastric lipase** (maximally operative at an acidic pH) converts **triglycerides to diglycerides** and **fatty acids.** **Chief cells** release this enzyme under **same control pathways as pepsinogen.** Gastric fat digestion augments its digestion downstream, because **partially digested triglycerides act on duodenal enteroendocrine cells to produce cholecystokinin,** a primary hormone that influences pancreatic and biliary fluid flow

Question 64

Why is *H. pylori* so damn persistent?

Answer 64

***H. pylori* tricks the immune system by intentionally provoking a Th1 response** in the gastric mucosa, while a Th2 response would have been predicted given the extracellular location of the microbes. The Th1 repertoire of responses are **not adequate to eradicate the infection,** resulting in a vicious cycle of Th1-predominant chronic inflammation in the gastric mucosa. In other words, it **uses Th1 polarization to antagonize Th2 effector cells**.

Question 65

Cephalic phase of gastric secretion

Answer 65

**Vagal afferents** release **Ach** to the **muscarinics** on **G cells (+), parietal cells (+), and D cells (-).** This phase explains why a delicious smell could induce acid secretion when you are hungry

Question 66

PPIs should be taken ____ before a meal.

Answer 66

PPIs should be taken **~30 minutes** before a meal. It needs to go through the stomach (in its protective capsule, it is acid labile), into the duodenum where the capsule dissolves, be absorbed, travel through circulation to the stomach's supplying vessels, and make it into the basolateral side of parietal cells.

Question 67

What to think about GI pain

Answer 67

Pain before vs after eating is not super helpful, and don't let it be the be-all end-all. But, if you have post-prandial pain, the time after eating that it is experienced can give you an idea of where in the process it may be. There is an old myth that gastric pain is relieved by eating and duodenal pain is made worse by eating, but there is really not sufficient evidence to support this for clinical use.

Question 68

Diagnosing *H. pylori*

Answer 68

* **¹³C Urea breath test** * **Mucosal biopsy** (gold standard)

Question 69

Gatric fat digestion in adults vs neonates

Answer 69

Gastric fat digestion may account for 10-30% of intraluminal fat breakdown in adults. In **neonates** with **immature pancreas** and in states of pancreatic insufficiency, this **pathway may assume greater importance.**

Question 70

Functional regions of the stomach

Answer 70

Question 71

"Active" duodenitis

Answer 71

W/ neutrophilic inflammation

Question 72

Pepsinogens

Answer 72

**Pro-enzymes** released from **chief cells** in the gastric glands. Secretion of pepsinogen is stimulated by **increased vagal tone,** the hormones **cholecystokinin**, **secretin**, **gastrin**, and possibly **histamine**. Pepsinogen is activated to pepsin in an **acidic milieu**. Pepsin begins the process of protein digestion. Pepsinogens/Pepsins, however, are **not essential for protein digestion** as the proteolytic enzymes secreted by the pancreas are sufficient. Pepsins are **irreversibly inactivated by the alkaline pH of the duodenum.**

Question 73

The attached is a picture of normal gastric corpus histology. Where are the parietal and chief cells in this picture?

Answer 73

The parietal cells are the pinkish cells in the mid field and the chief cells are the bluish cells towards the bottom.

Question 74

When H. pylori populates the antrum, \_\_\_. When H. pylori populates the entire stomach, \_\_\_.

Answer 74

When H. pylori populates the antrum, **it destroys the negative feedback that the antrum provides to the body, thus there is overactive acid secretion via hypergastrinemia.** When H. pylori populates the entire stomach, **it destroys the ability of the body to secrete acid.**

Question 75

Ultrastructure of resting and acid-secreting parietal cells

Answer 75

Question 76

Systemic vs gastric effects of NSAIDs

Answer 76

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.**

Question 77

Cobalamin metabolism

Answer 77

**Parietal cells** in the stomach body secrete **intrinsic factor (IF)** required for the absorption of Vitamin B12 (cobalamin). This B12/IF complex is **absorbed in the distal ileum**.

Question 78

Caffeine

Answer 78

**May increase the production of stomach acid** via increased **gastrin-release** (although **_decaffeinated coffee stimulates acid secretion to greater degree than caffeine alone_** when administered in an amount equal what would have been in a similar serving of regular coffee).