GIT- PUD Flashcards
Burning epigastric pain exacerbated by fasting and improved with meals is a symptom complex associated with ______________-
peptic ulcer disease (PUD).
An ____________is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation. Ulcers occur within the stomach and/or duodenum and are often chronic in nature.
ulcer
The gastric epithelial lining consists of rugae that contain microscopic gastric pits, each branching into four or five gastric glands made up of highly specialized epithelial cells.
The makeup of gastric glands varies with their anatomic location. Glands within the gastric cardia comprise <5% of the gastric gland area and contain _______________
The 75% of gastric glands are found within the ____________________. Pyloric glands contain mucous and endocrine cells (including gastrin cells) and are found in the antrum.
- mucous and endocrine cells.
- ** ** oxyntic mucosa and contain mucous neck, parietal, chief, endocrine, enterochromaffin, and enterochromaffin-like (ECL) cells ( Fig. 293-1 ).
The __________- also known as the _________, is usually found in the neck, or isthmus, or in the oxyntic gland. The resting, or unstimulated, parietal cell has prominent cytoplasmic tubulovesicles and intracellular canaliculi containing short microvilli along its apical surface ( Fig. 293-2 ).
H + ,K + -adenosine triphosphatase (ATPase) is expressed in the tubulovesicle membrane; upon cell stimulation, this membrane, along with apical membranes, transforms into a dense network of apical intracellular canaliculi containing long microvilli. Acid secretion, a process requiring high energy, occurs at the apical canalicular surface. Numerous mitochondria (30–40% of total cell volume) generate the energy required for secretion.
parietal cell, oxyntic cell
The mucosal defense system can be envisioned as a three-level
barrier, composed of ___________-,________,________
( Fig. 293-3 ).
preepithelial, epithelial, and subepithelial elements
The first line of defense is a __________-r, which serves as a physicochemical barrier
to multiple molecules, including hydrogen ions. Mucus is secreted
in a regulated fashion by gastroduodenal surface epithelial cells.
mucus-bicarbonate-
phospholipid laye
Mucus is secreted
in a regulated fashion by gastroduodenal surface epithelial cells. It
consists primarily of__________ The mucous gel functions as a nonstirred
water layer impeding diffusion of ions and molecules such
as pepsin.
water (95%) and a mixture of phospholipids and glycoproteins (mucin).
___________is secreted
in a regulated fashion by gastroduodenal surface epithelial cells. It
consists primarily of water (95%) and a mixture of phospholipids
and glycoproteins (mucin). The mucous gel functions as a nonstirred
water layer impeding diffusion of ions and molecules such
as pepsin.
Mucus
_____________ secreted in a regulated manner by surface epithelial cells of the gastroduodenal mucosa into the mucous gel,
forms a pH gradient ranging from 1 to 2 at the gastric luminal surface
and reaching 6 to 7 along the epithelial cell surface.
Bicarbonate,
____________- provide the next line of defense through several factors, including mucus production, epithelial cell ionic transporters that maintain intracellular pH and bicarbonate production, and intracellular tight junctions. These generate heat shock proteins that prevent protein denaturation and protect cells from certain factors such as increased temperature, cytotoxic agents, or oxidative stress.
Surface epithelial cells
Epithelial cells also generate _______________ family peptides and ___________, which also play a role in surface cell protection and regeneration
trefoil factor
cathelicidins
If the preepithelial barrier were breached, gastric epithelial cells bordering a site of injury can migrate to restore a damaged region___________-. This process occurs independent of cell division and requires uninterrupted blood flow and an alkaline pH in the surrounding environment.
( restitution )
Several growth factors, including _________________ modulate the process of restitution.
- epidermal growth factor (EGF),
- transforming growth factor (TGF) α,
- and basic fibroblast growth factor (FGF),
Larger defects that are not effectively repaired by restitution require_____________-.
cell proliferation
Epithelial cell regeneration is regulated by _________________
prostaglandins and growth factors such as EGF and TGF-α.
In tandem with epithelia cell renewal ,formation of ______________
within the injured microvascular bed occurs.
new vessels ( angiogenesis )
Both_____________are important in regulating
angiogenesis in the gastric mucosa.
FGF and vascular
endothelial growth factor (VEGF)
An_________________ within the gastric submucosal layer is the key component of the subepithelial defense/repair system, providing HCO 3 – , which neutralizes the acid generated by the parietal cell. Moreover, this microcirculatory bed provides an adequate supply of micronutrients and oxygen while removing toxic metabolic by-products.
elaborate microvascular system
_______________- play a central role in gastric epithelial defense/ repair ( Fig. 293-4 ). The gastric mucosa contains abundant levels of prostaglandins that regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution.
Prostaglandins
____________ . A key enzyme that controls the rate-limiting step in prostaglandin synthesis is cyclooxygenase (COX), which is present in two isoforms (COX-1, COX-2),
phospholipase A 2
each having distinct characteristics regarding structure, tissue distribution, and expression.
______________is expressed in a host of tissues, including the stomach, platelets, kidneys, and endothelial cells. This isoform is expressed in a constitutive manner and plays an important role in maintaining the integrity of renal function, platelet aggregation, and gastrointestinal (GI) mucosal integrity.
COX-1
In contrast, the
expression of ____________ is inducible by inflammatory stimuli, and it
is expressed in macrophages, leukocytes, fibroblasts, and synovial
cells.
COX-2
The beneficial effects of nonsteroidal anti-inflammatory
drugs (NSAIDs) on tissue inflammation are due to inhibition of
COX-2; the toxicity of these drugs (e.g., GI mucosal ulceration and
renal dysfunction) is ________2 ________-
related to inhibition of the COX-1 isoform.
Nmemonics:
Cox 1 is for maintenance of cells
Cox is promotes inflammation
Dial 1 for house keeping!!!!
Dial 2 for inflamation
The highly _____________ have the potential to provide the beneficial effect of decreasing tissue inflammation while minimizing toxicity in the GI tract. Selective COX-2 inhibitors have had adverse effects on the cardiovascular system, leading to increased risk of myocardial infarction. Therefore, the FDA has removed two of these agents (valdecoxib and rofecoxib) from the market (see below)
COX-2–selective NSAIDs
_________ is important in the maintenance of gastric mucosal integrity. The key enzyme NO synthase is constitutively expressed in the mucosa and contributes to cytoprotection by stimulating gastric mucus, increasing mucosal blood flow and
maintaining epithelial cell barrier function.
Nitric oxide (NO)
_______________are the two principal gastric secretory products capable of inducing mucosal injury.
Hydrochloric acid and pepsinogen
Gastric acid and pepsinogen play a physiologic role in ____________________Acid secretion should be viewed as occurring under basal and stimulated conditions.
- protein digestion,
- absorption of iron and vitamin B 12 as
- well as killing ingested bacteria.
__________________occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours.
Basal acid production
__________________ are the principal contributors to basal acid secretion.
Cholinergic input via the vagus nerve and histaminergic input from local gastric sources
Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates __________________________________
(cephalic, gastric, and intestinal).
Sight, smell, and taste of food are the components of the_____________, which stimulates gastric secretion via the vagus nerve.
cephalic phase
The _____________is activated once food enters the stomach. This component of secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn activates the parietal cell via direct and indirect mechanisms. Distention of the stomach wall also leads to gastrin release and acid production.
gastric phase
The last phase of gastric acid secretion is initiated as food enters the__________________ A series of pathways that inhibit gastric acid production are also set into motion during these phases. The GI hormone somatostatin is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl.
ntestine and is mediated by luminal distention and nutrient assimilation
_____________can inhibit acid production by both direct (parietal cell) and indirect mechanisms (decreased histamine release from ECL cells and gastrin release from G cells
Somatostatin
Additional neural (central and peripheral) and humoral ___________________-, _______________ factors play a role in counterbalancing acid secretion. Under physiologic circumstances, these phases occur simultaneously.
amylin, atrial natriuretic peptide (ANP)** **
cholecystokinin, ghrelin, obestatin, secretin, and serotonin
The_________________is located in the oxyntic gland, adjacent to other cellular elements (ECL cell, D cell) important in the gastric secretory process ( Fig. 293-5 ). This unique cell also secretes intrinsic factor (IF). This expresses receptors for several stimulants of acid secretion, including histamine (H 2 ), gastrin (cholecystokinin B/gastrin receptor), and acetylcholine (muscarinic, M 3 ).
acid-secreting parietal cell
Binding of histamine to the H 2 receptor leads to ____________________ and ___________.
activation of adenylate cyclase and an increase in cyclic adenosine monophosphate (AMP).
Activation of the gastrin and
muscarinic receptors results inactivation of the protein kinase
C/phosphoinositide signaling pathway. Each of these signaling
pathways in turn regulates a series of downstream kinase cascades
that control the acid-secreting pump, _______________
pump, H + ,K + -ATPase
The discovery that different ligands and their corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid secretion that occurs when_______________ are combined. More importantly, this observation explains why blocking one receptor type (H 2 ) decreases acid secretion stimulated by agents that activate a different pathway (gastrin, acetylcholine).
histamine and gastrin or acetylcholine
_____________also express receptors for ligands that inhibit acid production (prostaglandins, somatostatin, and EGF).
**Parietal cells **
___________________also stimulates gastric acid secretion indirectly by activating the histamine H 3 receptor on D-cells, which inhibits somatostatin release.
Histamine
Regulation of gastric acid secretion at the cellular level. ACh, acetylcholine; ANP, atrial natriuretic peptide; CGRP, calcitonin gene-related peptide; EC, enterochromaffin; ECL, enterochromaffin-like; GRP, gastrin-releasing peptide; PACAP, pituitary adenylate-cyclase activating peptide; SST, somatostatin; VIP, vasoactive intestinal peptide.
The enzyme ________________s responsible for generating the large concentration of H +. It is a membrane-bound protein that consists of two subunits, α and β. The active catalytic site is found within the α subunit; the function of the β subunit is unclear.
This enzyme uses the chemical energy of adenosine triphosphate (ATP) to transfer H + ions from parietal cell cytoplasm to the secretory canaliculi in exchange for K +.
This is located within the secretory canaliculus and in nonsecretory cytoplasmic tubulovesicles.
The tubulovesicles are impermeable to K + , which leads to an inactive pump in this location. The distribution of pumps between the nonsecretory vesicles and the secretory canaliculus varies according to parietal cell activity ( Fig. 293-2 ). Proton pumps are recycled back to the inactive state in cytoplasmic vesicles once parietal cell activation ceases.
H + ,K + -ATPase i
The_________-, found primarily in the gastric fundus, synthesizes and secretes pepsinogen, the inactive precursor of the proteolytic enzyme pepsin. The acid environment within the stomach leads to cleavage of the inactive precursor to pepsin and provides the low pH (<2) required for pepsin activity.
chief cell
Pepsin activity is significantly diminished at a ________________and** irreversibly inactivated** and denatured at a__________ Many of the secretagogues that stimulate acid secretion also stimulate pepsinogen release. The precise role of pepsin in the pathogenesis of PUD remains to be established.
pH of 4
pH of ≥7.
PUD encompasses both _____and _________.
gastric and duodenal ulcers
___________ are defined as breaks in the mucosal surface >5 mm in size, with depth to the submucosa. Duodenal ulcers (DUs) and gastric ulcers (GUs); share many common features in terms of pathogenesis, diagnosis, and treatment, but several factors distinguish them from one another.
Ulcers
________ are estimated to occur in 6–15% of the Western population. The incidence of DUs declined steadily from 1960 to 1980 and has remained stable since then. The death rates, need for surgery, and physician visits have decreased by >50% over the past 30 years. The reason for the reduction in the frequency ofthis is likely related to the decreasing frequency of Helicobacter pylori. Before the discovery of H. pylori,
the natural history of this was typified by
frequent recurrences after initial therapy.
Eradication of H. pylori has greatly reduced
these recurrence rates.
Duodenal ulcers DUs
__________ tend to occur later in life than duodenal lesions, with a peak incidence reported in the sixth decade. More than onehalf of GUs occur in males and are less common than DUs, perhaps due to the higher likelihood of this being silent and presenting only after a complication develops. Autopsy studies suggest a similar incidence of DUs and GUs.
Gastric ulcers GUs
Duodenal ulcers DUs occur most often in the________, with _________________-. They are usually ≤1 cm in diameter but can occasionally reach 3–6 cm (giant ulcer). Ulcers are sharply demarcated, with depth at times reaching the muscularis propria. The base of the ulcer often consists of a zone of eosinophilic necrosis with surrounding fibrosis. Malignant DUs are extremely rare.
first portion of the duodenum (>95%)
~90% located within 3 cm of the pylorus
In contrast to DUs,_______can represent a malignancy and should be biopsied upon discovery.
GUs
____________ are most often found distal to the junction between the antrum and the acid secretory mucosa.
Benign GUs
__________ are quite rare in the gastric fundus and are histologically similar to DUs. This is associated with H. pylori are also associated with antral gastritis.
Benign GUs
In contrast, ___________ are not accompanied by chronic active gastritis but may instead have evidence of a chemical gastropathy, typified by foveolar hyperplasia, edema of the lamina propria, and epithelial regeneration in the absence of H. pylori. Extension of smoothmuscle fibers into the upper portions of the mucosa, where they are not typically found, may also occur.
NSAID-related GUs
As in DUs, the majority of _____________ can be attributed to either H. pylori or NSAID-induced mucosal damage.
This that occur in the prepyloric area or those in the body associated with a DU or a duodenal scar are similar in pathogenesis to DUs.
Gastric acid output (basal and stimulated) tends to be normal or decreased in GU patients. When GUs develop in the presence of minimal acid levels, impairment of mucosal defense factors may be present.
Gastric ulcers
Gastric ulcers have been classified based on their location:______________ occur in the gastric body and tend to be associated with low gastric acid production; _________________-occur in the antrum and gastric acid can vary from low to normal;
_________________occur within 3 cm of the pylorus
and are commonly accompanied by duodenal ulcers and normal or
high gastric acid production; and
__________ are found in the cardia
and are associated with low gastric acid production
Type I
type II
type III
type IV
