Unit 1 Flashcards
mucosa
comprised of epithelial layer plus underlying lamina propria, which is the loose and well vascularized connective tissue. lymphocytes, plasma cells and marcophages are located in the lamina propria. the muscularis mucosae underlies this and is a thin layer of smooth muscle.
submucosa
contains connective tissue that is denser than mucosa, with larger blood vessels, nerve plexus, glands, and lymphatic nodules. there are lymphoid cells of various types scattered throughout.
muscularis externa
composed of inner circularly and outer longitudinally arranged layers of smooth muscle and nerve plexus, for peristalsis and churning of the lumenal contents. In the stomach, there is a third oblique layer of smooth muscle, located lumenally to the circular muscle layer. efferent fibers of the myenteric nerve plexus (of Auerbach) innervate the externa. clusters of ganglion cell bodies are present between the two layers of the externa.
serosa/ adventitia
the serosa is an outer covering of squamous epithelial cells separated from the underlying muscular layers by a relatively thin layer of connective tissue. above the diaphragm, in the esophagus, it is called the adventia, where the outer squamous layer is absent.
esophagus
muscular tube from pharynx to stomach, lined with non-cornified squamous epithelium. upper portion is skeletal muscle (voluntary control), midway is a mix. lower 1/3 is only smooth muscle. muscous glands are present in both mucosa and submucosa, for lubrication. a small incomplete sphincter prevents reflux of stomach contents. esophagus lacks a thick mucous covering, therefore reflux produces burning, which can lead to ulceration if it occurs frequently.
divisions of the stomach
there are three histological zones: cardia is located around the entry to the stomach with mucus-secreting glands; fundus is the main body of the stomach that secretes acid, peptic digestive products, and mucus; and the pyloris located at the exit and secretes mainly mucus and has a high population of endocrine cells that secrete gastrin.
rugae aka plicae mucosae
longitudinal folds in the wall of the stomach, disappear with distention
gastric epithelium
facing the lumen of the stomach, there are surface mucous-secreting cells arranged in many folds. there is also an underlying lamina propria. between these folds, there are spaces called gastric pits. at the bottom of these mucus secreting pits, the epithelium changes and dives deep into the muscosa becoming tubular gastric glands, which contains differentiated epithelia cells that begin to digest food at a low pH.
stem cells of the stomach
gastric epithelium cells are renewed every 3-5 days. differentiated cells deep in the glands turn over about every 6-12 months. undifferentiated cells in the upper neck region of the deep pits either rise up to become mucus secreting cells or downward to become specialized cells within gastric gland.
surface mucous cells
contain large vesicles full of stomach mucins and bicarbonate that are released and act locally to provide a viscous protective layer protecting epithelial cells against stomach acid and abrasion from churning chyme. there is also a structured layer of cell surface glycoproteins, called the glycocalyx, directly covering the microvilli of the surface cells.
chief cells
secret protein with apical granules and elaborate basal RER. secrete pepisnogen, which gets converted into pepsin, a protease, in the presence of acid. chief cells can be divided or derived from stem cells.
parietal cells
specialized to pump H ions using H/K ATPase into the lumen of the gastric glands, against a gradient. this allows the pH of gastric juice to be around 1-1.5, which is energy demanding. they also have extensive set of microvilli bordering canaliculi that extend down into the cell, allowing for a large amount of surface area for pumping protons into the lumen. there is a lot of mitochondria. are stimulated to produce acid by gastrin and histamine. Also secrete glycoprotein, intrinsic factor, required for vitamin b12.
zollinger-ellison syndrome
also known as a gastrinoma is a non-beta cell islet tumor of the pancreas, which secretes high amounts of gastrin, leading to maximal HCl by parietal cells. It cannot be neutralized in small intestine, leading to duodenal ulcers and complications.
enteroendocrine cells
these cells are apart of a widely dispersed population of cells known as amine precursor uptake decarboxylation cells (APUD cells). G-cells, A-cells, EC-cells, D-cells are included in this category. most are oriented toward the vascular side to release into bloodstream.
G-cells
secrete gastrin (stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility) and located in the pylorus, is a type of enteroendocrine cell.
A-cells
a type of enteroendocrine cell that secrete glucagon, which raises the concentration of glucose in the bloodstream
EC cells
a type of enteroendocrine cell that secrete serotonin
D-cells
a type of enteroendocrine cell that secrete somatostin (a hormone secreted in the pancreas and pituitary gland that inhibits gastric secretion and somatotropin release) and are widely distributed except in the middle portion of the stomach.
helicobacter pylori
most common cause of ulceration in the stomach.
small intestine
divided into duodenum, jejunum and ileum. 5 meters in length. enteroendocrine cells secrete different hormones than those in the stomach. villi are most abundant in the duodenum than decrease distally. once chyme is neutralized, enzymes produced by the pancreas and enterocytes digest proteins to amino acids, complex carbs to single monomers like glucose and galactose and lipids to fatty acids and monoglycerides.
plicae circulares
permanent transverse oriented folds in the small intestine and project up to 1cm into the lumen. are covered with villi that increase the surface area by about 8 fold.
enterocytes
absorptive/digestive epithelial cells, have microvilli at the surface that increases surface area by about 30 fold. there is a glycocalyx layer over the microvilli in which digestive enzymes are found.
goblet mucous cells
are scatterred between absorptive/digestive cells and produce muscous for protection and lubrication. they are the least abundant in the duodenum.
crypts of lieberkuhn
simple tubular glands that penetrate from the base of the villi deeper into the mucosa. the epithelium of the crypts are continuous with surface epithelium. stem cells are abundant in the lower third giving rise to mucous cells, enterocytes, or paneth cells.
paneth cells
contain large eosinophilic granules that have defensins, antibacterial peptides, lysozyme and phosophlipase.
brunner’s glands
only found in duodenum and release large quantities of bicarbonate into the crypts in order to neutralize the acid arriving from the pyloric sphincter. they also secrete mucins.
intestinal villi
contain loose lamina propria core containing small blood vessels and capillaries, lymphocytes, and series of small lymphatic spaces that connect to the lacteal, a larger lymphatic vessel in the center, which transports fluid entering from lumen and chylomicrons (lipoprotein droplets) that are exocytosed by enterocytes on the side facing the lamina propria. enterocytes take up fatty acids and monoglycerides from the lumen of the gut and resynthesizes them into di and triglycerides to be released by exocytosis on the opposite side. nutrients taken up of capillaries are transported to the liver via the hepatic portal system; lacteals enter larger lymphatics and proceed to the bloodstream via the thoracic duct.
lymphoid tissue in GI tract
lymphoid tissue is present both as scattered individual cells and as lymphatic nodules and peyer’s patches, groups of nodules, in the mucosa of the intestine.
M-cells
specialized epithelial cells that take up antigen cells and phagocytose luminal contents and present these antigens to underlying lymphocytes and macrophages.
plasma cells of lymphatic nodules
release IgA, which bind to receptors on epithelial cells and then are transcytosed to the lumenal surface where they act as antibacterial agents by discouraging pathogenic bacterial colonization and adherence (mucus production also aids in this)
exocrine pancreas
the gland is organized into acini, which are clusters of pancreatic acinar cells arranged at the end of a common duct (like a cul de sac). the basal portion of these cells have RER that synthesizes proteins for secretion and stored in zymogen granules (secretory granules). most secreted enzymes are initially released as zygomens than partial degraded to become enzymatically active. such enzymes include trypsin, chymotrypsin, elastase, carboxypeptidase, and triacylglycerol lipase. amylase (which degrades starch to glucose and maltose) and ribonuclease (which cleaves RNA) are synthesized by the pancreas in their active forms. zygomens prevent autodigestion. (98% of pancreas is dedicated to exocrine function but the pancreas also houses endocrine islets of langerhans cells).
trypsin
trypsinogen is the zygomen, which is activated by enterokinase, which is not secreted but is a membrane anchored enzyme in the apical plama membrane of duodenal digestive/absorptive cells. trypsin activates other zymogens through proteolysis
sphincter of oddi
where larger ducts join together to join the common bile duct than join the bile duct to form the sphincter of oddi.
centroacinar cells
also found in acini of the pancreas, represent the beginning of the duct system and secrete much of the pancreatic juice, including water and bicarb to help the brunner’s glands to neutralize the chyme arriving from the stomach. secretin and cholycystokinin control secretion.
large intestine
composed of the cecum and appendix, transverse and descending colons and rectum. compared to the small intestine, it is smooth and lacks plicae and villi. it has many straight tubular glands or crypts and the epithelial layer has two cell types, abundant mucous-producing cells and absorptive cells. the main function of the large intestine is recovery of water and salt during concentration of fecal material. the lamina propria and submucosa contain numerous lymphocytes, scattered and in large aggregates and nodules. 2/3 of wall is muscular, with large bands of circular muscles. the longitudinal layer has muscular specializations, mostly consisting ob bands called taeniae. segmented contraction of these bands causes sacculation of the bowel, which compresses and segments fecal material. at the anus, the circular layer is thickened to form the internal anal sphincter and downstream is circular striated muscle, the external anal sphincter.
columns of morgagni
longitudinal structural folds of the mucosa in the distal region of the rectum.
oral cavity glands and secretions
contains three main salivary glands including paired submandibular glands, sublingual and the paired parotid glands, which secrete serous (parotid), mucous (sublingual), or mixed (submandibular). they are all based on the acinar design with circumferential myoepithelial cells. contraction of myoepithelial cells propel salivary secretions from the acini. serous secretions are watery with amylase, DNase, RNase. Mucous secretions are lubricative and protective. serous epithelial cells also transport IgA that, in combination with lysozyme and peroxidase, provide antibacterial action. Ducts modify the ionic contents of saliva as they move towards major ducts.
scleroderma affecting GI
manifests in 80-90% of pts. The principal pathological abnormalities of the GI tract consist of smooth muscle atrophy and gut wall fibrosis. smooth muscle atrophy in esophagus leads to weak peristalsis and dysphagia, also leads to weak LES and GERD. chronic GERD can lead to esophagitits and strictures. esophageal manometry is diagnostic.
Physiology of gastric emptying
Receptive relaxation (vagally mediated inhibition of body tone. Liquid emptying by tonic pressure gradient. Solid emptying by vagally-mediated contractions. Residual solids emptied during non-fed state by MMC every 90-120 minutes
dyspepsia
dyspepsia is discomfort or pain related to eating. organic causes includePUD, atypical GERD, gastric/esophageal caner, pancreaticobiliary disorders, food drug (NSAIDs) intolerance.
functional dyspepsia
no organic etiology. pathophysiology may involve alterations in gastric motility, 40% of pts have impaired gastric accommodation.
Gastroparesis
stomach paralysis leading to impaired transit of food from stomach to duodenum. need to exclude gastric outlet obstruction. clinical manifestations include N/V, early satiety, portprondial abdominal distention and pain. causes include idiopathic (post-infectious?), post sugical (vagal nerve injury due to gastric esophageal, thoracic surgical procedures, ie lung transport), diabetes (neuropathy), medication (opiates), paraneoplastic, rheumatologic, neurologic, myopathic (scleroderma). diagnosed with gastric emptying study. management includes lifestyle and diet measures (small meals, low fat, glucose control), medications (prokinetic and antiemetics), gastric electric stimulation, and surgery.
Chronic Intestinal Psuedo-Obstruction (CIPO)
Signs and symptoms of mechanical obstruction of the small bowel without a lesion obstructing flow of intestinal contents. Characterized by the presence of dilation of the bowel on imaging. Major Manifestation of Small Intestinal Dysmotility. Small Intestinal Bacterial Overgrowth a complication of CIPO, stasis leads to bacterial overgrowth, fermentation, and malabsorpbtion. Symptoms include N/V, abdominal pain, distention, constipation, diarrhea, urinary symptoms. Neuropathic causes include degenerative neuropathies (parkinson’s), paraneoplastic atuoimmune (anti-Hu Ab), changas diases (parasite Trypanosoma cruzi), diabetes. Mixed myopathic and neuropathic causes includes infiltrative conditions such as scleroderma, amyloidosis, eosinophillic gastroenteritis. And idiopathic. In children it is mostly congenital, mostly primary condition (visceral neuropathy with myopathy). Absent MMC predicts need for IV nutrition. One third of infants born die in 1st year of life.
anatomy of the anal canal
The anorectal junction is formed by the longitudinal muscle of the rectum, the sling fibers of the puborectalis muscle, the attachments of the levator ani muscle, and the proximal margins of the internal and external anal sphincters. this is the approximately 90 degree anorectal angle formed by the puborectalis. The puborectalis and levator ani muscles are straited muscles that form part of the pelvic floor. They are in a state of constant tone pulling the rectum anteriorly and elevating the rectum, thereby reducing the anorectal angle. The IAS is a thickened band of circular smooth muscle with high tone that is in continuity with the circular smooth muscle of the rectum. It is innervated thru the pelvic plexus by lumbar sympathetics and sacral parasympathetic nerves. It receives powerful inhibitory innervation from enteric inhibitory motor neurons, the cell bodies of which are in the enteric ganglia. It contributes approximately 75% of the resting sphincter pressure and is primarily responsible for maintaining anal continence at rest. The EAS is a striated muscle that is an expansion of the levator ani muscle and is distal to but partly overlapping the IAS and also has high resting tone. But unlike the IAS, its tone can be influenced by voluntary effort to help maintain continence. The EAS and other pelvic floor muscles are innervated thru the pudendal nerve (S3-S4) by motor neurons within cell bodies in the spinal cord.
Hirschsprung’s Disease
Hirschsprung’s is a congenital absence of myenteric neurons of the distal colon. As a result, there is no reflex inhibition of the IAS following rectal distention. It is more common in Males compared with female and occurs in 1 in 5000 births. There is a characteristic pattern on anal manometry, showing megarectum/megacolon on defecography (no relazation of IAS with pressure), and the diagnosis is confirmed by a deep rectal biopsy which shows no myenteric neurons.
Pelvic Floor Muscles At Rest and With Defecation
Bowel evacuation is facilitated by coordinated activity of the abdominal and the pelvic floor muscles. At rest, the puborectalis and internal and external anal sphincter muscles are tonically contracted. Propagated HAPC motor activity propels undigested residue from the colon into the rectum, resulting in rectal distention and triggering the urge to defecate. When the time is right for defecation, the internal and external anal sphincters and the puborectalis muscle relax during the bear down maneuver (which also involves coordination with abdominal muscle activity) leading to pelvic floor descent, an increase (widening) of the anorectal angle, and thus, an open and straighter canal through which stool can pass. Certain defecation disorders, such as pelvic floor dyssynergia (inadvertent contraction or failure to relax of the pelvic floor muscles with bearing down) can result in a relative obstruction to outflow of contents (not shown) and symptoms of constipation. Significant risk factors for constipation in older women are failure of the anorectal angle to open or excessive perineal descent, which represent disturbances of pelvic floor function and rectal evacuation.
pelvic floor dysfunction
Inability to coordinate the abdominal, rectoanal and pelvic floor muscles during defecation, due to Anismus (high anal resting pressure), Incomplete anal relaxation, Paradoxical contraction of the pelvic floor and external anal sphincters (dyssynergia), Rectal hyposensitivity, Excessive perineal descent, Rectocoele. Causes include Bad toilet habits, Painful defecation, Obstetric or back injury, Brain gut dysfunction
Dyssynergia
Abnormal anorectal manometry, showing paradoxical contraction of the pelvic floor and external anal sphincters. Treatment: Biofeedback therapy is effective
treatment for H. Pylori
Triple Therapy: Clarithromycin-Amoxicillin or Metronidazole-PPI. Quadruple Therapy: Bismuth subsalicylate-Metronidazole-Tetracycline-PPI or H2 Antagonist. Sequential Therapy: Amoxicillin-PPI (5 days) then Clarithromycin-Tinidazole-PPI (5 days)
Proton Pump Inhibitors [PPIs]
[PPIs] (Omeprazole [Prilosec] / Esomeprazole [Nexium], Lansoprazole [Prevacid], Rabeprazole [Aciphex], Pantoprazole (Protonix]). Omeprazole is available OTC.
Proton Pump Inhibitors [PPIs] pharmacodynamics
administered as prodrug, than absorbed into systemic system where it diffuses into parietal cell where the proton catalyzed formation of the active sulfenamide the drug in the acidic secretory canniculi. Covalent linkage of sulfenamide form to sulfhydryl groups of H+-K+-ATPase irreversibly inactivates enzyme. Since 18 hours are required for synthesis of new enzyme this action results in an 80-95% reduction in daily acid production despite a plasma half-life of only 0.5-2 hours. Maximal suppression of acid secretion may require several doses of PPIs (not all pumps are active simultaneously), thus it may take 2-5 days to reach steady state level of 80% inhibition. Efficacy of the 5 available PPIs is equivalent at comparable doses
PPI pharmacokinetics
Rapidly absorbed, highly protein bound. Best to give on empty stomach 1 hour ac (before meals) so peak plasma concentration occurs with maximal proton pump secretion. Rapid first pass metabolism via CYP450 enzymes (2C19 and 3A4); consider dosage reduction in patients with severe hepatic disease (esomeprazole, lansoprazole). No drug accumulation in chronic renal failure with once-daily dosing
clinical uses of PPI
GERD. Most effective agent for nonerosive and erosive reflux disease and complications (85-90% with QD dosing, 15% require BID dosing). Peptic ulcer disease. More rapid symptom relief and faster healing than H2 antagonists [90% for duodenal (4 weeks) and gastric ulcers (6-8 weeks)]. H. pylori associated ulcers also require therapy with antibiotic combination. NSAID-induced ulcers. Effective for treatment (healing impaired if NSAID not stopped) or prevention of ulcers and ulcer-related complications. Prevention of stress gastritis. Increasing use in critically ill patients to reduce mucosal bleeding, despite any clear demonstration of efficacy at present time. Zollinger-Ellison syndrome. Higher doses provide complete symptomatic relief and ulcer healing.
adverse effects of PPI
very safe. Mild side effects (1-5%). Headache, abdominal pain, nausea, constipation, diarrhea Minor reduction in oral cyanocobalamin (B12) absorption and levels. Hypergastrinemia resulting from chronic PPI use (5-10%) does NOT result in tolerance (as with H2 antagonists) but may contribute to rebound increases in gastric acidity upon discontinuation. Drug-drug interactions due to actions on CYP450 enzymes: omeprazole may inhibit conversion of antiplatelet agent clopidogrel to active form
H2 Receptor Antagonists
(Ranitidine [Zantac], Cimetidine [Tagamet], Famotidine [Pepcid], Nizatidine [Axid]). All agents are available OTC for acute gastritis (lower dosage strengths).
H2 Receptor Antagonists Pharmacodynamics
Mechanism of action is reversible, competitive block at parietal cell H2 receptors on basolateral membrane. Less efficacious than PPIs but still suppress 24 hour acid secretion by 70%. Better at blocking nocturnal (basal, H2-mediated) acid secretion (90%) than meal-stimulated (ACh- and gastrin-mediated, 60-80%). Since suppression of nocturnal acidity is key to duodenal ulcer healing, evening dosing of H2 antagonists is usually adequate therapy.
H2 Receptor Antagonists Pharmacokinetics
All are rapidly absorbed from the GI tract; some enhancement with food, small decrease if given with antacids. Less protein binding than PPIs. Some hepatic metabolism (10-35%), but no dosage adjustment for liver disease Major route of elimination is renal excretion; half-lives of 1-4 hours with duration of action dependent on dose given. Dosage reduction required if impaired renal function (especially in elderly patients).
H2 Receptor Antagonists Clinical Uses
GERD. Infrequent heartburn can be managed with OTC antacids (more rapid onset) or intermittent H2 antagonists. Frequent heartburn generally requires BID H2 antagonists. Proton pump inhibitors (PPIs) preferred in severe erosive esophagitis. Peptic ulcer disease. H2 antagonists largely replaced by PPIs. Still useful in suppressing nocturnal acid secretion (given at bedtime) for acute uncomplicated ulcers (6-8 week duration, 80-90% healing rate). Stress-related gastritis. Reduced bleeding when given IV.
H2 Receptor Antagonists Side Effects
Generally well tolerated (side effects in 8 weeks and in high doses): Gynecomastia, galactorrhea, decreased sperm count. Rare: Blood dyscrasias with cimetidine; liver toxicity (reversible), seen with all agents.
H2 Receptor Antagonists Drug Interactions
Cimetidine inhibits cytochrome P450 oxidative metabolism (CYP1A2, 2C9, 2D6, 3A4) that can increase the effects or toxicity of number of drugs (theophylline, warfarin, phenytoin, carbamazepine, ketoconazole, itraconazole, benzodiazepines). All antisecretory agents can decrease ketoconazole absorption by causing an increase in gastric pH.
Sucralfate [Carafate]
Mucosal Protective Agents. When acid-induced damage occurs, pepsin will hydrolyze mucosal proteins causing erosion and ulcerations. This process is inhibited by this sulfated disaccharide aluminum salt that selectively binds to necrotic ulcer tissue to form protective barrier (single dose up to 6 hrs)
Also decreases back diffusion of H+ ions and binds to pepsin and bile acids. Possible action to stimulate prostaglandin and epidermal growth factor production. Activated by acid pH
Misoprostol (Cytotec)
Prostaglandin (PGE1) analog. Prostaglandins have physiological action in gastric parietal cells to inhibit cAMP formation that results in decreased H+ secretion (most important clinical effect); they also stimulate acid neutralizing HCO3− formation and cytoprotective mucus formation. Major indication is alleviation of NSAID-induced GI ulceration. Side effects include diarrhea (promote fluid secretion) and/or uterine stimulation (cramping) in up to 30% of patients. Contraindicated during pregnancy because of increase in uterine motility.
Gastric Antacids
Primary use is pain relief (healing?) due to peptic ulceration and acute gastritis. Should rapidly raise pH of stomach contents to 4-5 (above the pH optimum of pepsin); if raised to pH 7 can cause rebound acid secretion (via increased gastrin release). Should be nonabsorbable. Antacids vary in extent of systemic absorption. NaHCO3 results in the highest levels of systemic actions and its use is generally avoided.
Adverse effects of antacids
Adverse effects include constipation (Ca++ and Al+++ antacids) or diarrhea (Mg++ antacids) is common. Fixed combinations of Mg and Al antacids (e.g., Mylanta® and Maalox®) used to theoretically counteract the adverse effects of each other.
Drug interactions of antacids
General rule is to space drug dosing around antacid dosing to minimize potential for interactions. Decreased absorption due to binding or adsorption interactions in gut (chelation with Al+++ - Ca++ - Mg++): Tetracycline, fluoroquinolones, digoxin, chlorpromazine, indomethacin. Altered absorption due to effect on gastric emptying. Altered excretion due to alkaline urine: Aspirin (increased), quinidine (decreased). Reduced bioavailability of H2 antagonists and ketoconazole via increased gastric pH
Calcium
Tums. Exerts rapid, prolonged neutralization of acid, but can see rebound secretion due to Ca++ effect on gastrin release. Safe, generally non-systemic, not recommended for chronic use (but OK as Ca++ supplementation). Constipation can occur; hypercalcemia / renal calculi possible if prolonged use
Aluminum
(hydroxide [Amphojel], carbonate [Basaljel], phosphate [Phosphojel]). Very widely used, binds phosphate in gut (also used in chronic renal failure to treat hyperphosphatemia). Main side effect is constipation. Chronic intake may lead to CNS toxicity (encephalopathy)
Magnesium
Magnesium (as oxide, hydroxide [Milk of Magnesia], carbonate). Major side effect is osmotic diarrhea; often added to antacid preparations to counteract Al+++ or Ca++-induced constipation. Avoid use if renal disease present (retention of Mg++ ions can occur)
Sodium bicarbonate (Baking Soda)
Potent and effective, evolution of CO2. Contraindicated for prolonged therapy due to systemic effects: Na+ overload and alkalosis. Avoid if: Pregnant, CHF, hypertension, edema, renal failure (i.e., conditions exacerbated by fluid retention)
Erthromycin
agonist at excitatory neuronal and smooth muscle motilin receptors
Cisapride
agonist at excitatory neuronal 5-HT4 receptors on enteric nervous system cholinergic motor neurons. Tegaserod (Zelnorm), Cisapride (Propulsid) act as agonists at postsynaptic 5HT4 receptors to directly increase ACh release. Stimulates motility and increases transit in esophagus, stomach, small intestine and ascending colon. Reduces bloating associated with irritable bowel syndrome. Cisapride may cause life-threatening arrhythmias from prolongation of QT interval (especially if its metabolism by cytochrome P450 is inhibited). This side effect has led to its use being severely restricted.
Metoclopramide
Dopamine antagonist that blocks presynaptic inhibition of ACh release by dopamine at D2 receptors. Will produce coordinated contractions that enhance transit of luminal contents. As a dopamine antagonist, metoclopramide has additional advantageous effect to relieve nausea and vomiting by block of dopamine receptors in chemoreceptor trigger zone. Metoclopramide (as a dopamine receptor antagonist) may cause somnolence, dystonic reactions, and tardive dyskinesia.
Neostigmine
inhibits (-) hydrolysis of acetylcholine by acetylcholinesterase (AChE)
Bethanechol
acts directly as an agonist (+) at excitatory (+) M3 smooth muscle receptors
Prokinetic Agents
Direct activation of M3 muscarinic receptors in the gut (as with older cholinergic agents such as direct receptor agonists [bethanechol] or cholinesterase inhibitors [neostigmine]) will increase GI motility BUT will NOT do so in a coordinated manner that will be NO net increase in propulsive activity and will also tend to increase gastric and pancreatic secretions. The mechanism of action common to most prokinetic agents is an “upstream” effect on the motor neuron itself rather than a postsynaptic action. They act to increase gastric motility by increasing release of acetylcholine from cholinergic neurons in the enteric nervous system. This allows maintenance of the coordinated activity among gut segments that is necessary for propulsion of luminal contents.
Anti-Emetic Agents Pathophysiology and Therapeutic Targets
Vomiting center / solitary tract nucleus coordinate complex actions, contain high concentrations of muscarinic, H1, and serotonin receptors. Afferent input includes chemoreceptor trigger zone / area postrema (dopamine, 5-HT3, muscarinic, and mu opioid receptors), vestibular apparatus (muscarinic and H1 receptors), vagal / enteric afferents (5-HT3), and higher CNS centers.
Ondansetron [Zofran]
Block of serotonin (5-HT3) receptors at chemoreceptor trigger zone (CTZ in CNS), solitary tract nucleus, and on visceral afferents (GI tract). All agents well absorbed from GI tract with metabolism via CYP enzymes. Parenteral formulations available. Biologic half-life exceeds pharmacologic half-life, i.e., anti-emetic effects remain after disappearance of parent drug from plasma. Well tolerated, occasionally headaches, constipation, drowsiness. Associated with QT prolongation so caution if underlying heart condition-hypomagnesemia-hypokalemia. Particularly effective in prevention and treatment of vomiting caused by cytotoxic drugs. Also used for emesis and nausea and vomiting associated with post-operative use of opioid analgesics.
Prochlorperazine [Compazine]
Blockade of dopamine receptors in CTZ (high dose metoclopramide used to treat nausea/vomiting of cancer chemotherapy probably also block 5HT3 receptors). Side effects are largely due to block of dopamine receptors at other sites including extrapyramidal symptoms (movement disorders), restlessness, fatigue, drowsiness, diarrhea. Phenothiazines are generally not effective against emetic stimuli in gut (mediated via 5HT3 receptors); also have some blocking actions at muscarinic and histamine receptors which increases their utility in other forms of nausea such as that associated with motion sickness.
Antihistamines Agents
(meclizine [Bonine], hydroxyzine [Vistaril], diphenhydramine as dimenhydrinate [Dramamine], cyclizine [Marezine], promethazine [Phenergan]). First generation agents with good CNS penetration and additional muscarinic receptor blocking actions. Available orally; promethazine also parenterally and rectally. Primary use for motion sickness and postoperative emesis
Anticholinergic agents
(scopolamine [Transderm-Scop transdermal patch]). Primary use is prevention and treatment of motion sickness; some efficacy in post-operative nausea and vomiting. Most commonly administered transdermally with duration of action of 72 hours
Dronabinol (delta-9-tetrahydrocannabinol [Marinol])
Useful as prophylactic agent against emesis in patients receiving cancer chemotherapy that have not responded to other anti-emetic therapy. Mechanism of action is unknown, probably related to stimulation of CB1 cannabinoid receptors on neurons in and around area postrema. Highly lipid soluble compound that is rapidly absorbed orally with extensive first pass metabolism (bioavailability is 10-20%). Large volume of distribution contributes to persistence of metabolites for several weeks after a single dose.
Dronabinol side effects
central sympathomimetic actions include tachycardia, palpitations, hypotension, vasodilation. Behavioral actions include euphoria, somnolence, detachment, nervousness, panic. Use with caution in patients with history of substance abuse (Controlled Substance - Schedule III). Reports of abstinence syndrome (irritability, insomnia, restlessness) following abrupt withdrawal
Aprepitant (Emend)
Substance P receptor antagonist. Specific indication for the delayed phase emesis (2-5 days later) associated with the highly emetogenic cisplatin. Given for 3 days at start of therapy. Block the actions of the neurotransmitter substance P at the neurokinin 1 (NK1) receptor that are mediated via vagal afferent fibers to the solitary tract nucleus and the area postrema. Administered orally, extensive binding to plasma proteins, primarily eliminated by hepatic metabolism with half-life of 9-13 hours. Metabolism by CYP3A4 has potential for drug-drug interactions with other 3A4 substrates such as methylprednisolone, warfarin, and dexamethasone (may require their dosage to be reduced)
Dexamethasone [Decadron] and Methylprednisolone (Solu-Medrol]
Anti-inflammatory glucocorticoids. Possible anti-emetic action via mechanism to suppress peritumoral inflammation and prostaglandin production
Lorazepam [Ativan]
Benzodiazepines. Sedative, anti-anxiety, and amnestic properties can reduce the anticipatory component of nausea and vomiting
Treatment of Nausea and Vomiting of Pregnancy (Morning Sickness)
Nausea is common in early pregnancy - severe vomiting with dehydration and weight loss (hyperemesis gravidum) has a lower rate of occurrence. Nonpharmacologic treatment approaches include: dietary manipulations, avoidance of triggers, acupuncture and acupressure, and hypnosis. Pharmacologic treatment if nonpharmacologic measures fail. Addition of pharmacotherapy is reasonable with use of drugs reported to be effective and with the best maternal-fetal side effect profile. Trials of 3-4 days can be used to observe for improvement in nausea and vomiting symptoms - if no improvement add a second drug - if side effects occur use another drug. Ginger improves nausea but does not decrease episodes of vomiting. Pyridoxine (vitamin B6) is effective against mild to moderate nausea, but no effect on vomiting. H1 antagonists, Doxylamine is first-line agent-and most commonly used and acts on the vestibular system to decrease stimulation of the vomiting center. Dopamine antagonists are second line agents due to less favorable safety profile. Oral-IV routes Ondansetron most commonly used agent - greater efficacy in reducing both nausea and vomiting than pyridoxine-doxylamine.
Anatomy and histology of the stomach
Stomach acid facilitates absorption of iron, calcium, and vitamin B-12. The four anatomical regions of the stomach are the cardia, fundus, body, and antrum. The mucosa of each of these regions contains gastric pits into which several types of glands empty. Cardiac glands consist of mucous cells, which secrete mucus and small amounts of pepsinogen. Oxyntic glands are in the fundus and body. They contain mucous cells, parietal cells, chief cells, endocrine cells and enterochromaffin cells. The gastric antrum contains pyloric glands with mucous cells and endocrine cells, most importantly G cells that produce gastrin and D cells, which produce somatostatin.
reservoir and pump function of the stomach
food enters the proximal stomach triggering receptive relaxation occurs, which is vagally mediated inhibition of fundic and body tone. Vagally mediated segmental contractions originating in the mid-body of the greater curve mix the food. Non-digestible retained gastric solids (those larger than 1 mm) are emptied in the fasting state by the interdigestive migrating motor complex (MMC). The MMC occurs every 1 ½ to 2 hours in the non-fed state and consists of contractions, which begin in the stomach, moving the residual particulate matter through an open pylorus, and then into and through the small bowel. Gastric contents in the duodenum and upper small intestine stimulate receptors, which respond to low pH, high osmolality (osmoreceptors), fatty acids, and caloric density. Activation of these receptors, in turn, triggers enterogastric reflexes that slow gastric emptying. Hormones such as secretin, CCK, and GIP may play a role in these reflexes. The purpose of these inhibitory mechanisms is to prevent the small intestine from being overwhelmed by rapid entry of nutrients from the stomach.
acid secretion in the stomach
Hydrochloric acid is bactericidal to most microorganisms. Thus, the stomach serves as a gatekeeper to the small intestine, keeping out most potential pathogens. The stomach itself, because of its acidic milieu coupled with gastric motility, is usually sterile. Only micro-aerophilic spiral organisms (i.e., Helicobacter pylori and Helicobacter Heilmannei) are found in the healthy human subject. Gastric juice is a combination of parietal (acid) and non-parietal secretions. Parietal cells secrete intrinsic factor and hydrochloric acid at a concentration of 160 mmol/L (pH~0.8) and a volume determined by the number of actively secreting parietal cells. Non-parietal secretions include electrolytes and mucus. The relative proportions of parietal and non-parietal secretions determine the volume and acidity of gastric juice produced during any given period.
Mucosal defense factors in the stomach
Because of their constant exposure to high concentrations of hydrochloric acid, gastro-duodenal epithelial cells would appear to be at risk of auto-digestion. However, under normal circumstances mucosal protective factors prevent such self-destruction. These factors involve prostaglandin E2 and prostacyclin. The means by which prostaglandins protect gastroduodenal mucosa include the secretion of mucus, stimulation of bicarbonate secretion, and maintenance of mucosal blood flow during periods of potential injury. Bicarbonate secretion is enhanced in the duodenum at pH levels below three.
Gastroparesis
Symptoms of delayed gastric emptying include early satiety (86%), epigastric fullness, pain or bloating (90%), nausea (93%), and/or vomiting (68%). Before attributing symptoms to a motility disorder, it is imperative to exclude mechanical obstruction like gastric outlet obstruction (e.g. from a chronic duodenal ulcer) by upper endoscopy or an oral contrast study radiology study. A radionuclide scan diagnoses gastroparesis using a radio labeled meal, usually an egg salad sandwich; the amount of radionuclide remaining at multiple time points is measured. Greater than 10 percent remaining at 4 hours or greater than 70 percent remaining at 2 hours defines gastroparesis. Causes of delayed emptying include post-surgical states, endocrine disorders (e.g. diabetes, hypothyroidism), muscular disorders, systemic sclerosis, and drugs. Vagal nerve dysfunction or destruction leads to failure of receptive relaxation, causing early satiety and failure of antral grinding, leading to delayed emptying. Gastroparesis secondary to autonomic nerve damage from long standing diabetes is the most common. Post viral (Norwalk, Rotavirus) gastroparesis occurs and usually resolves in 1-12 months. A variety of medications like narcotics, tricyclic antidepressants, and clonidine slow gastric emptying.
Helicobacter pylori
a microaerophilic, gram-negative rod that produces abundant urease which produces ammonia and raises the local pH. The organism is also able to escape the effects of acidic gastric juice, by burrowing through the mucus layer and colonizing the surface epithelium of the gastric mucosa, where the pH is near neutral. H. pylori possess a wide variety of virulence factors, including adhesins, phospholipases, cytotoxins, cytokines and urease, permit the organism to avoid destruction by gastric acid, colonize the gastric epithelium, damage epithelial cells, and incite an inflammatory response. It virtually never penetrates the epithelium but does inject proteins like CagA that causes numerous cellular effects including the activation of NFkB and are linked to the development of gastric cancer. H. pylori elicits a robust inflammatory response (active and chronic gastritis-see below), which persist throughout life unless the organism is eradicated. Whether H. pylori are pathogenic (causes disease) relates to both H. pylori related pathogenic factors (e.g. bacterial strain). H. pylori may increase suppressive regulatory T cells. T regs, in part, may explain how the bacterium elicits inflammation without clearance of infection. Both oral-oral and fecal-oral mechanisms of transmission are believed to occur.
H. pylori diagnostic tests
Mucosal biopsies are used for histological demonstration of the organism or the presence of urease (CLO test). Urease will split urea into ammonia and carbon dioxide. The ammonia will raise the pH of the test medium and change the color of a pH sensitive indicator (i.e. phenol red from yellow to red). Culture is the least sensitive of the direct techniques, perhaps because of the fastidious growth characteristics of the organism. Noninvasive methods include blood antibody tests, urea breath tests, and a stool antigen test. Chronic H. pylori infection produces a circulating antibody response readily detected by ELISA tests. Most antibody tests have 85% sensitivity and 79% specificity (due to prior cleared infection). Antibody tests cannot be used acutely for confirming eradication. Other non-invasive means of detecting H. pylori are the urea breath tests (UBT). A stool antigen test has performance characteristics similar to that of the UBT and is the most commonly used test in the outpatient setting to confirm eradication.
Urase breath test
urea labeled with either 13C or 14C is ingested with a liquid meal. If urease is present, labeled carbon dioxide will be split off and absorbed into the circulation where its presence can be determined by analysis of expired breath. This test has virtually 100% positive predictive value and about 95% negative predictive value. As with the rapid urease test, proton pump inhibitors or high doses of H2 receptor antagonists may result in falsely negative tests.
H. pylori histologic manifestations
H. pylori infection is always accompanied by infiltration of the gastric mucosa with neutrophils (active gastritis) and/or lymphocytes (chronic gastritis). The presence of chronic active gastritis (CAG) is considered by many to be a surrogate marker of H. pylori infection even when the organism is not specifically identified. This inflammatory response is associated with release of cytokines and increased cellular proliferation of the mucosa, which may be an important initiating factor in the minority of H. pylori, infected patients who will develop an ulcer, gastric cancer, or gastric lymphoma.
phenotypic forms of H. pylori gastritis
Most infected subjects have a mild, diffuse chronic active superficial gastritis unassociated with symptoms or disease states. A second group has antral predominant gastritis, with relative sparing of the gastric body. Such individuals tend to have high levels of acid secretion and may develop duodenal ulcer. The third group has multifocal atrophic gastritis. Because the gastric body is atrophic, acid secretion tends to be low. This group of patients is at risk for gastric ulceration or, through the pathway of metaplasia and dysplasia, gastric adenocarcinoma. While all patients infected with H. pylori should be offered treatment, infection should be sought only in selected situations, including peptic ulcer disease, low-grade gastric B – cell lymphoma, and a family history of gastric adenocarcinoma.
H. pylori Treatment
The most often used regimen consists of a proton pump inhibitor (because the antibiotics work better at a more neutral pH), amoxicillin 1 gm, and clarithromycin 500 mg each given twice daily for 7-14 days. Patients who fail first line therapy are often treated with “classsical” quadruple therapy consisting of a PPI, bismuth, tetracycline, and metronidazole. Recently, sequential therapy has been touted as better than triple therapy.
Infectious Gastritis
With the exception of H. pylori gastritis, infectious causes of gastritis are very uncommon. Bacterial causes include syphilis and tuberculosis. Fungal diseases include Candidiasis, Aspergillosis, Histoplasmosis and Mucormycosis. Parasitic diseases include Giardiasis, Cryptosporidiosis, Anisakiasis, and Stongyloidiasis. Viruses (e.g., CMV) are rare causes of gastritis and ulceration and occur in the immuno-compromised host (e.g. AIDS, chemotherapy).
Lymphocytic Gastritis
Endoscopically, lymphocytic gastritis may appear with normal gastric folds, mucosal nodularity with erosions, volcano-like (varioliform gastritis), or with giant gastric folds (hypertrophic lymphocytic gastritis). Biopsies show extensive lymphocytic infiltration. H.pylori infection must be ruled out first. The cause is unknown. Symptoms include vague abdominal pain, anorexia, weight loss, occult bleeding, and hypoalbuminemia. An association with celiac spruce has been noted. The most important aspect of management is to exclude lymphoma or other specific forms of gastritis. There is no proven therapy, although case reports note efficacy with anti-ulcer therapy, sodium cromoglycate, or corticosteroids.
Eosinophilic Gastritis
This entity is associated with infiltration of the gastric wall with eosinophils. Depending upon the layers involved, there may be mucosal ulceration or luminal obstruction, producing symptoms of delayed gastric emptying (i.e., early satiety, nausea, and vomiting). There is associated peripheral eosinophilia. Parasitic infestation should be excluded. Treatment of eosinophilic gastritis is with corticosteroids and, occasionally, surgery. The cause is unknown.
Gastritis Associated with Systemic Disease
Crohn’s disease and sarcoidosis, may be associated with granulomatous inflammation. Patients with AIDS, or immunosuppressed following organ transplantation, are at risk of infection with opportunistic organisms such as CMV.
Hypertrophic Fold Syndromes
includes menetier disease, H. pyolri, Z-E syndrome, gastric lymphoma and gastric adenocarcinoma.
Menetrier Disease
This rare disease has hyptertrophic rugal folds, often sparing the antrum, and histologic features of massive foveolar hyperplasia with cystic dilation, which may penetrate into the submucosa. Symptoms include abdominal pain, weight loss, and bleeding. Hypoalbuminemia occurs frequently. When the process is extensive, there may be replacement of parietal cells and resultant hypochlorhydria. There is relatively little inflammation and H. pylori are usually absent.
H.pylori and hypertrophy of gastric folds
A Menetrier’s-like syndrome with large gastric folds and protein-losing gastropathy may be one manifestation of H. pylori gastritis. Histologically, there is foveolar hyperplasia and chronic active gastritis. Eradication of infection usually leads to resolution of the syndrome.
Z-E Syndrome and hypertrophy of gastric folds
Acid hypersecretory states resulting from a large parietal cell mass can be associated with large gastric folds. Zollinger-Ellison syndrome is when a gastrin secreting neuroendocrine tumor stimulates parietal cells and increases acid secretion.
Gastropathies
non-inflammatory of epithelial cell injury. The entities frequently produce dramatic visual damage to gastroduodenal epithelium. Includes injury due to NSAIDs, ethanol, and stress related.
NSAID-Induced Injury
Ulceration, defined as a lesion greater than 5mm in diameter with depth and breaches the muscularis mucosa, is believed to be the result of prostaglandin depletion, since even NSAIDs administered intravenously, with enteric coatings, or as rectal suppositories, can cause upper gastrointestinal ulcers. Patients with prior ulcer disease and perhaps the elderly are at an increased risk of developing NSAID ulcer complications. Duodenal ulcers also occur because of NSAID use, but less often than gastric ulcers. NSAID-induced ulceration is important only if associated with dyspepsia or, more ominously, bleeding or perforation.
Treatment of NSAID –induced ulcers
is with PPIs, healing usually occurs even if the NSAID is continued. H2-receptor antagonists may heal duodenal ulcers in the NSAID user, but are much less effective with the more commonly seen NSAID gastric ulcers. Misoprostol was used as a treatment for NSAID-induced ulcers but causes diarrhea. H2-receptor antagonists in standard ulcer healing doses will effectively prevent the formation of NSAID-induced duodenal ulcers but not gastric ulcers. More potent H2 receptor antagonists or proton pump inhibitors will prevent gastric ulcers as well. Misoprostol, reduces the development of NSAID-induced gastric ulcers. prophylaxis with misoprostol or PPIs reduces the incidence of ulcer complications, but the absolute benefit is small.
COX-2 specific NSAIDs
Another area of interest was development of NSAIDs which are less damaging to gastro-duodenal mucosa. Approaches include the development of COX-2 specific NSAIDs. Examples include celecoxib, rofecoxib, and valdecoxib. They inhibit only cyclooxygenase-2, they do not inhibit prostaglandin formation in the stomach and duodenum. As a result, fewer gastroduodenal ulcers develop and fewer ulcer complications occur as well. Dyspepsia occurs as often with COX-2 selective agents as with non-selective NSAIDs. However, most COX-2 selective NSAIDs except celecoxib were removed from the marked because they increase the risk of myocardial infarction.
Ethanol-Induced Injury
The ingestion of ethanol will produce lesions that are similar to acute NSAID-induced lesions (i.e., erythema, erosions, and subepithelial hemorrhages). The clinical importance of such lesions has been greatly over-emphasized, as there is poor correlation with symptoms and serious bleeding is rare. There is little to no associated histologic inflammation.
Stress-Related Mucosal Injury
Hemorrhage and erosions of the stomach and duodenum occur in patients who are under “physiologic stress.” These include patients with CNS injury, prolonged mechanical ventilation, coagulopathy, and burns, but not patients admitted to coronary care units. The pathogenesis of these lesions is probably multifactorial but may involve elements of mucosal ischemia in the presence of gastric acid. While most such patients are not acid “hypersecretors,” it appears that acid is an essential permissive factor, since reduction of gastric acidity will prevent the lesions. Exceptions to the rule regarding acid secretion include patients with CNS injuries, burns, or sepsis. Such patients may hypersecrete acid and are at risk for the development of peptic ulcers (e.g., Cushing’s ulcer, Curling’s ulcer) with the attendant complications of bleeding or perforation.
pathophysiology of peptic acid disease
Peptic ulcers (and accompanying symptoms) occur when gastroduodenal mucosal defenses are unable to protect the epithelium from the corrosive effects of acid and proteases, such as pepsin. it is primarily a disease of failed mucosal integrity, not of excess acid/pepsin secretion. While a certain minimal level of gastric acid and pepsin are necessary for the formation of an ulcer, their presence alone (with the exception of Zollinger-Ellison Syndrome) is not sufficient to produce an ulcer. most patients with ulcer disease secrete normal amounts of acid. The most important factors predisposing to failure of mucosal integrity are H. pylori infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs). Duodenal ulcers most often occur in areas of inflamed gastric metaplasia in the duodenal bulb and gastric ulcers in antral mucosa, often near the junction of oxyntic and antral epithelium.
Epidemiology of peptic acid disease
The lifetime prevalence of peptic ulcer is a 5-10% with prevalence in men and women being about equal for gastric ulcer but with men predominating for duodenal ulcer. The incidence increases with age, a phenomenon that may be explained by a higher prevalence of H. pylori and the increased use of NSAIDs in the elderly. The incidence of non-NSAID associated ulcers has declined substantially, likely due to the declining prevalence of H. pylori. Other ulcer risk factors include smoking and certain diseases (chronic lung disease, cirrhosis, chronic renal failure).
Clinical Manifestations of peptic acid disease
While many ulcers may be asymptomatic, they most often present with burning epigastric pain. The pain is typically relieved with food or antacids and may often awaken a patient from sleep. Nocturnal pain relieved with antacids may be the most specific symptom of peptic ulcer. The pain of peptic ulcers, as with the ulcers themselves, comes and goes. With therapy, ulcer pain generally subsides quickly, long before healing of the ulcer.
Bleeding of ulcers
An episode of bleeding occurs in as many as 30% of patients with peptic ulcer disease in their lifetimes. Factors associated with a poor outcome from a bleeding ulcer include hemodynamic instability following the bleed, continuation, or recurrence of bleeding in hospital, and age/concomitant diseases. Large, deep ulcers high on the lesser gastric curve or posterior duodenal bulb are more likely to erode major vessels and result in substantial bleeding. Ulcers which initially cease bleeding but in which endoscopic examination discloses a visible vessel will re-bleed in hospital up to 50% of the time and therefore warrant prophylactic therapy.
obstruction due to ulcers
The least common complication of ulcer disease is obstruction, leading to nausea, vomiting, and early satiety. While the edema surrounding an acute ulcer may produce transient obstruction, which resolves with ulcer healing, chronic obstruction is the result of repeated bouts of acute ulceration, leading to the formation of scar tissue and narrowing.
treatment of ulcers
Ulcer medications speed the rate of healing of an ulcer and relieve ulcer symptoms faster. The most frequently used approach to treat an ulcer is with anti-acid secretory medications. Liquid antacids like Maalox are of historical interest only in terms of ulcer healing. The most important factors determining the speed of ulcer healing with antisecretory agents are the duration of time that gastric pH is above 3.0 (rather than the degree which pH is raised above 3.0) and the number of weeks of therapy. Proton pump inhibitor treatment and H. pylori eradication are the cornerstones of therapy. In severe acute bleeds PPI “drips” are used in the ICU to tightly control pH.
Gastric Adenocarcinoma
Adenocarcinomas are classified histologically as “diffuse” or “intestinal”. This type of cancer has become less common in the United States. Could reflect changes in H. pylori prevalence, diet, sanitation. There is a close association between gastric adenocarcinoma of both types and chronic H. pylori gastritis. Other factors include carcinogenesis, since only a small proportion of patients infected with H. pylori will develop cancer. Early gastric cancer is limited to the mucosa or submucosa (regardless of lymph node involvement) and has a much better 5-year survival than advanced gastric cancer involving disease that has penetrated the muscular layer. Unless there is evidence of distant metastasis or the patient is a poor operative candidate, surgical or endoscopic resection is usually attempted, but only about half of the patients undergoing surgery are potentially curable. the overall 5-year survival is 10%. chemotherapeutic regimens can be used as adjuvant therapy or as primary therapy in patients with unresectable disease; however, survival has not been significantly prolonged.
Diffuse type adenocarcinoma
The diffuse type is less common, is relatively undifferentiated, and may be associated with signet-ring cells and excess mucin production. The diffuse form of cancer is believed to evolve from non-atrophic gastritis.
Intestinal type adenocarcinoma
The intestinal type forms glands, is found in association with atrophic gastritis, intestinal metaplasia, and dysplasia, and is the type that occurs in regions with a high incidence of gastric adenocarcinoma. H. pylori superficial gastritis evolves in some patients through atrophic gastritis to intestinal metaplasia, dysplasia, and the intestinal type of gastric adenocarcinoma.
Gastric Polyps
adenoma, hyperplastic and fundic gland.
Hyperplastic polyps
Hyperplastic polyps are proliferations of gastric foveolar cells (mucus producing) and arise from chronic inflammation and are found in gastric body autoimmune gastritis and in H. Pylori infection with chronic atrophic gastritis. Polyps larger than 1cm have an increased risk of harboring dysplasia or adenocarcinoma.
Gastric adenomas
Gastric adenomas arise from dysplastic epithelial cells and have a risk of progressing to adenocarcinoma. They should be removed endoscopically with subsequent surveillance. There is an especially high incidence of adenomatous polyps, sometimes multiple polyps, in patients with familial adenomatous polyposis (FAP). Additionally, FAP patients have a predilection for adenomas in the region of the duodenal papilla.
Fundic gland polyps
Fundic gland polyps consist of dilated oxyntic glands lined by flattened parietal and mucus cells. They are the most common (74% of gastric polyps, seen at 6% EGDs) type of gastric polyp and usually result from long term PPI therapy. They are unrelated to H. pylori infection and have no malignant potential. Fundic gland polyps also arise in patients with FAP but usually number >20, occur in the antrum, and are found with duodenal adenomas (above) which helps differentiate the cause.
Stromal Tumors
Benign gastric tumors arising from the supporting tissues (stromal tumors) include leiomyomas and lipomas. These tumors may be submucosal, bulging into the gastric lumen; subserosal, extending extraluminally; or both. Small stromal tumors are usually asymptomatic, but larger ones may present with abdominal pain or gastrointestinal bleeding. Malignant counterparts of these tumors are leiomyosarcoma or liposarcoma. The larger the tumor, the more likely it is to be malignant, but the only definitive means of differentiating benign from malignant tumors is by evidence of invasion or metastasis. Treatment is with surgical resection. Stromal tumors can be found in the duodenum but account for only about 5% of duodenal tumors.
Gastrointestinal stromal tumors (GISTs)
Gastrointestinal stromal tumors or GISTs are a specific subtype of stromal tumor that has a different prognosis (based on size and number of mitoses per 50 high power fields) and treatment implications vs. the other stromal tumors. GISTs express c-KIT (CD117), a transmembrane receptor tyrosine kinase (identified with immunostaining) and show a dramatic clinical response to therapy with imatinib, a receptor tyrosine kinase inhibitor. They arise from the interstitial cells of Cajal, the GI pacemaker cells. They are often removed surgically and treated with adjuvant or neoadjuvant imatinib
Neuro-endocrine Tumors
Tumors of neuro-endocrine cell origin have various names depending on their location (i.e., gut-carcinoid tumors; pancreas-islet cell tumors) or, if appropriate, by the peptide secreted. If the peptide is present in high levels in the circulation, there may be an associated clinical syndrome (e.g., gastrinoma, insulinoma, VIPoma) as well. Histologically these tumors are composed of nests of small, rather bland looking cells. Carcinoid tumors are included in this category.
Carcinoid tumors
Carcinoid tumors usually arise from enterochromaffin or enterochromaffin-like cells of the intestinal tract. Most intestinal carcinoids are endocrinologically silent. If hepatic metastasis of intestinal carcinoid occurs, high circulating level of vasoactive amines can produce the carcinoid syndrome. Carcinoid tumors of the stomach are relatively rare, they occur primarily in the fundus and body. There are two types of carcinoid tumor. The first is the sporadic type, usually single or few in numbers. They may metastasize and in general, surgical resection is recommended, especially if they are large. The second type, often smaller and more numerous, is found primarily in patients with achlorhydria secondary to atrophic gastritis of the type in which the antrum is spared (autoimmune atrophic gastritis). Here, achlorhydria results in high levels of gastrin, which is trophic for ECL cells of the proximal stomach. If a carcinoid tumor is found in achlorhydric patients with hypergastrinemia, antrectomy has been reported to lead to regression of the tumor. Carcinoid tumors may be the second most common duodenal tumor after adenocarcinoma. As in the stomach, surgical resection may be possible depending upon the size of the tumor and the operative suitability of the patient.
Gastric Lymphoma
Gastric lymphoma accounts for less than 5% of all gastric neoplasms. Evidence shows a strong association between H. pylori infection and primary gastric B-cell lymphoma. The likely sequence of events is development of a low-grade clonal proliferation of B-cells in H. pylori induced gastric MALT (mucosa associated lymphoid tissue). This lesion (low-grade B cell MALToma), which accounts for about 10% of primary gastric lymphomas, resolves about 70% of the time after successful eradication of H. pylori. If not treated in the low-grade stages, the lesion may progress to high-grade lymphoma, which is no longer amenable to antimicrobial therapy and requires conventional surgical treatment and/or radiation and chemotherapy. It is imperative with suspected MALT tumors that high-grade lymphoma is excluded. Thus, CT scan and EUS staging of the lesion should be performed in all cases of suspected MALT to avoid missing “hidden” high-grade lymphoma. High-grade lymphoma is treated with systemic chemotherapy.
gross anatomy of the pancreas
The pancreas is a lobulated organ situated posterior to the stomach and anterior to the thoracic spine and ribs in the retroperitoneum. It transverses the abdomen from left to right infero-diagonally, with the tail situated immediately medial to the splenic hilum and the head sandwiched within the C-loop of the duodenum. Its blood supply is derived from branches of the superior pancreatoduodenal and splenic arteries (off the celiac axis) and the inferior pancreatoduodenal artery (off the SMA). It lies immediately anterior to the SMV-PV confluence and the SMA, and immediately inferior/anterior to the splenic artery and vein.
normal function of the pancreas
Over 80% of pancreatic cells are epithelial in origin and comprise the acinar glands. These cells form the exocrine component. Acinar cells produce a multitude of digestive pro-enzymes that are secreted across the apical cell membrane into a tiny ductule at the center of each acinus. These ductules coalesce into the larger exocrine duct system of the pancreas that ultimately leads to the main (ventral) duct and the ampulla of Vater. In 5-10% of individuals the dominant route of exocrine flow (main duct) is the dorsal duct which empties into the duodenum via the minor papilla. A small minority of the enzymes produced, specifically amylase and lipase, are metabolically active when secreted, though they typically cause no pathology in humans under physiologic conditions. Most of the enzymes are produced and secreted into pancreas ducts as inactive pro-enzymes or zymogen forms. These pro-enzymes are packaged and secreted into the ducts of the pancreas. They will later require activation within the duodenal lumen in order to provide digestive function.
trypsinogen
the precursor form or zymogen of the pancreatic enzyme trypsin. It is found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is activated by enteropeptidase, which is found in the intestinal mucosa, to form trypsin. Once activated, the trypsin can activate more trypsinogen into trypsin. Trypsin cleaves the peptide bond on the carboxyl side of basic amino acids such as arginine and lysine.
chymotrypsinogen
a proteolytic enzyme and a precursor (zymogen) of the digestive enzyme chymotrypsin. It is synthesized in the acinar cells of the pancreas and stored inside membrane-bounded granules at the apex of the acinar cell. The cell is then stimulated by either a hormonal signal or a nerve impulse and the contents of the granules spill into a duct leading into the duodenum. It is activated into its active form by another enzyme called trypsin. Chymotrypsin preferentially cleaves peptide amide bonds where the carboxyl side of the amide bond (the P1 position) is a large hydrophobic amino acid (tyrosine, tryptophan, and phenylalanine). These amino acids contain an aromatic ring in their sidechain.
pancreatic secretions
the main proteases include proteases such as trypsinogen, chymotrypsinogen, and carboxypeptidases A/B, which get slightly modified when activated in the duodenum. Acinar and ductal epithelial cells also produce large amounts of bicarbonate and water. These ingredients form the bulk of pancreas juice volume. They maintain flow throughout the ducts and keep zymogens inactive with a high pH. Besides providing an aqueous medium for digestive enzymes, the role of bicarbonate and water is to neutralize gastric acid within the duodenum. Without pancreatic HCO3 and water, the duodenum and jejunum would be damaged by low-pH gastric secretions. Also, bile acids and pancreatic enzymes require a neutral pH in order to maintain structure and function. Thus, pancreatic HCO3 and water also help maintain pancreatic and biliary digestive function. Within the pancreas under normal conditions, trypsin inhibitor deactivates any trypsin that is prematurely activated. Also, basal pancreatic juice flow, maintained by water and bicarbonate secretion, continually flushes out any activated enzymes.
Pancreatic islet cells
Pancreatic islet cells make up the endocrine function of the pancreas. They contain specialized cells that produce insulin, somatostatin, VIP, glucagon, and others. Their role in health and disease will be addressed elsewhere.
Acute pancreatitis
Acute pancreatitis is a relatively common condition that varies from mild to severe. In severe cases (5-10%), it can be fatal. Acute pancreatitis occurs when pancreatic enzymes are inappropriately and prematurely activated resulting in autolysis of the gland. This may result in severe inflammation and/or necrosis of pancreatic tissue. It most commonly occurs when the pancreatic duct becomes obstructed, which results in stagnation of pancreas enzymes within the duct lumen and activation of the enzyme activation cascade. Premature activation of enzymes occurs to a small extent in normal individuals, but peristalsis of the duct, sphincter of Oddi relaxation, bicarbonate/water secretion and flow, and trypsin inhibitor function within normal duct keep this process from getting out of control. Alternatively, ethanol may cause pancreatitis via several mechanisms including a direct toxic effect on pancreatic acinar cells and ductal epithelium, which causes both premature release and activation of trypsinogen and stagnant flow of pancreas juice.
causes of acute pancreatitis
The most common cause of pancreatitis in western countries is a gallstone. Gallstone pancreatitis occurs when a stone (even if small or transient) lodges in the distal common bile and/or ampulla. This may result in obstruction of the ventral duct (of Wirsung) and/or bile reflux into the pancreas, which reinforces zymogen activation. The second most common cause of acute pancreatitis is alcohol abuse. Abusers of alcohol typically develop acute pancreatitis within 3-5 days of a binge. Acute pancreatitis has been linked to other causes of duct obstruction including tumors or procedures that cause swelling of the duodenum and/or ampulla, e.g. balloon enteroscopy or endoscopic retrograde cholangiopancreatography (ERCP). Congenital ductal abnormalities (e.g. pancreas divisum, annular pancreas) may occasionally cause a functional duct obstruction and pancreatitis, and such abnormalities increase the risk of acute pancreatitis when other risk factors (e.g. ETOH abuse) are present. Sphincter of Oddi dysfunction types 2 or 3 may result in recurrent acute pancreatitis. Severe hyperlipidemia may precipitate acute pancreatitis. Blunt or penetrating trauma to the abdomen may cause pancreatitis by direct ductal injury and enzyme release. Less common causes of acute pancreatitis include drugs (thiazide diuretics, azathioprine, anti-retroviral drugs), hypercalcemia states, infections (Mumps, Coxsackievirus), and cystic fibrosis.
symptoms of pancreatitis
The typical symptoms of acute pancreatitis are severe pain in the upper abdomen, sometimes radiating to the back, and nausea/vomiting. Low-grade fevers may accompany this. The pain is usually intolerable, prompting an urgent visit to the ER or doctor’s office.
Lipase role in pancreatitis
Lipase released from dying acinar cells breaks down fat, liberating free fatty acids which precipitate with calcium and form insoluble soaps. In severe pancreatitis, there may be frank coagulation necrosis of the gland and/or hemorrhage into the retroperitoneum. Microscopically, necrosis of pancreatic tissue is associated with intense infiltrates of neutrophils and apoptosis of epithelial cells.
diagnosis of pancreatitis
The diagnosis of acute pancreatitis is usually suggested by the history and physical exam, typically a female with risk factors of gallstones or individual with known alcohol abuse. The diagnosis requires confirmation by serum blood tests (lipase and amylase) or imaging. Other diagnostic tests include ultrasound or CT scan of the abdomen. Ultrasound is cheap, noninvasive, and readily available. It is very good (90% accurate) at detecting gallstones but less effective at imaging the pancreas or bile ducts. When severe cases are suspected or the diagnosis remains questionable, a contrast CT scan should be considered. CT will show inflammatory changes within and surrounding the pancreas - gland edema, fat stranding, fluid - and may occasionally reveal a cause such as a tumor. CT may also detect complications such as necrosis, pseudocyst, or hemorrhage.
Lipase and amylase as markers of pancreatitis
A diagnostic blood test is a serum level of amylase and lipase elevated greater than 3 times the upper limit of normal. When the pancreas is inflamed, enzymes leak out into the bloodstream and the elevated levels will be detected in serum. Lipase is more specific for pancreatitis and equally to slightly more sensitive than serum amylase, since it rises within 1-2 hours and decreases over the following week. Serum amylase rises and falls within 24-48 hours but its specificity is imperfect since amylase may be elevated in non-pancreatitis diseases including Mumps, Sjogrens syndrome, penetrating peptic ulcer, intestinal trauma or ischemia, and ectopic pregnancy.
treatment of pancreatitis
Treatment of acute pancreatitis involves admission to the hospital, making the patient NPO (nothing to eat or drink), intravenous pain medications, and time. The vast majority of patients with uncomplicated acute pancreatitis will improve with these supportive measures alone. Avoidance of alcohol is pivotal in preventing disease recurrence or progression to chronic pancreatitis. Patients with gallstones who are otherwise fairly healthy will need cholecystectomy (gallbladder surgery) at a later date to remove the source of the stones. Most offending bile duct stones will pass into the duodenum spontaneously. But in cases where the stone does not pass (based on blood tests or imaging studies), the persistent bile duct stone requires extraction. This is typically done via ERCP but can also be done surgically (a longer, more complicated procedure than gallbladder removal alone).
Chronic pancreatitis
Chronic pancreatitis (CP) is a condition that develops after repeated bouts of acute pancreatitis. It most commonly occurs as a result of chronic alcohol abuse. Macroscopically, it is characterized by replacement of healthy pancreatic tissue by hard fibrous tissue. There may also be atrophy of the gland. Pancreas juice may become viscous, and calcifications (stones) may develop within the duct if these clumps of protein precipitate with into calcium salts. Microscopically, broad bands of scar tissue replace lost lobular tissue. Sometimes, moderate numbers of lymphocytes and/or plasma cells are present. There is relative sparing of the islets cells. Fibrous tissue may result in narrowings (strictures) of the duct. Calcified pancreatic duct stones, sometimes large, may also contribute to obstruction, particularly when lodged above a stricture. Along with gland destruction/loss and atrophy, these factors contribute to the symptoms of malabsorption, pain, and malnutrition.
causes of chronic pancreatitis
The most common cause of CP in western countries is chronic alcohol abuse. Cigarette smoking also contributes significantly to fibrosis, particularly in those who abuse alcohol. In a growing number of patients, familial (inherited) causes are identified. Genetic conditions that predispose to CP include CFTR gene mutations and/or cystic fibrosis, mutations in the trypsinogen (PRSS) or trypsin inhibitor (SPINK) genes, and familial hypertriglyceridemia. In some equatorial countries (e.g. Saharan Africa), over 25% of CP cases have been attributed to an idiopathic variant that occurs at a young age with extensive calcifications, so-called tropical pancreatitis.
pathology of chronic pancreatitis
Several pathologic factors have been proposed in the development of CP, especially the variant caused by alcohol: Intraductal plugs may form as the result of changes in protein secretion or pH conditions of the pancreatic duct. Oxidative and non-oxidative metabolites of ethanol may have a role in injury. Cigarette smoking may promote pancreatic fibrosis through oxidative pathways. It has also been proposed that episodes of necrosis may lead to pancreatic fibrosis. The importance of each mechanism is unclear. Pancreatic stellate cells have a central role in the generation of pancreatic fibrosis, although the stimulating factors are still being determined. When stimulated, stellate cells proliferate and transform into collagen-synthesizing cells.
lipase secretion in chronic pancreatitis
Pancreatic lipase secretion must decrease to a level less than 10% of normal before a person eating a regular diet will develop excess fecal fat excretion (steatorrhea). In healthy individuals, some fat (~ 10g or less daily) is excreted into the stool. Similar reserves are found for the endocrine pancreas. The fact that the pancreas has large reserves means that much of the pancreas can be removed or damaged before endocrine or exocrine insufficiency occurs. In CP, once more than 90% of the gland has been destroyed, fat malabsorption may occur. Protein and carbohydrate malabsorption generally occurs even later (after 95% gland destruction) since salivary amylase and gastric pepsin can provide a digestive function reserve.
symptoms of chronic pancreatitis
symptoms of pain and/or malabsorption in the form of steatorrhea. Abdominal pain is the most frequent presenting symptom. It usually waxes and wanes but never entirely disappears. The pain is typically epigastric and radiates directly to the back, or it may be present with back pain alone. Pain is multifactorial and results from an obstructed duct (stones or strictures), chronic inflammation within the pancreas or surrounding nerves, and/or pseudocysts that impinge on adjacent structures. Patients may eventually develop diarrhea, weight loss, or anemia related to malabsorption of carbohydrates and proteins. A normocytic or macrocytic anemia may also occur because of Vitamin B12 deficiency. Pancreatic proteases are required to cleave the R-protein-cobalamin complex, allowing for intrinsic factor to bond to B12. Thus, pancreatic duct obstruction or atrophy in CP may lead to B12 malabsorption and eventually a macrocytic anemia. Bleeding diathesis may develop as result of fat-soluble vitamin malabsorption, specifically vitamin K.
malabsorption with chronic pancreatitis
The dominant malabsorbed nutrient is lipid, thereby causing the distinct form of diarrhea knows as steatorrhea. Steatorrhea – frequent, oily, foul-smelling, and/or buoyant stools which increase in frequency after meals – flatulence (gas), and weight loss are the cardinal symptoms of pancreatic malabsorption. Another specific feature of steatorrhea is the presence of (oil-like) lipid droplets in the toilet water. Malabsorption does not occur until later stages of chronic pancreatitis since only 10-20% of acinar cells are required for maintaining lipase reserve, as described above. This is illustrated in the graph below.
diagnosis of chronic pancreatitis
A thorough history and physical is paramount in importance and nearly always suggestive. A plain x-ray of the abdomen may showed calcifications scattered over the epigastrium in patients (20-30%) with severe/calcific disease. A rapid fat (Sudan) stool stain (qualitative) is a quick, useful test that may be diagnostic if the appearance of the stool and patient’s history are also compatible. Otherwise, the definitive test for fat malabsorption is a 72-hour quantitative stool collection for fat analysis. While the patient ingests a high-fat diet (e.g.> 100 g fat/day), a 72-hour stool collection should show > 10-20% fecal fat excretion or 50g fat in the stool. Though rarely used nowadays, the gold standard diagnosing pancreatic insufficiency is the secretin stimulation test.
secretin stimulation test
The test is performed using two aspiration tubes. One is placed in the stomach to remove gastric acid and prevent acid-related secretin release. The second tube is placed just distal to the major papilla within the duodenal lumen. After a 1-hr basal collection period, secretin is given intravenously and the collections are continued for 1-2 hrs. A duodenal bicarbonate response to secretin, specifically a [HCO3] less than 80mEq/L after 2 hours is diagnostic of pancreatic exocrine failure. This test is non-specific and abnormal results may also be found in patients with pancreatic duct tumors, previous pancreatic surgery, or cystic fibrosis.
Pseudocyst
Following acute or chronic pancreatitis, focal auto-digestion of the pancreas and/or leakage of pancreas enzymes outside the duct may allow for fluid collections to develop. These are organized collections of liquefied/auto-digested pancreatic parenchyma, containing a mixture of pancreas juice and clumps of semi-solid, necrotic tissue. Since these fluid collections line a true epithelial lining characteristic of a cyst, they are called “pseudocysts.” Over time pseudocysts usually resolve as the pancreatitis improves (provided the cause is addressed), but sometimes (particularly in alcoholics who continue to drink), they may persist, grow, and/or push on adjacent structures and cause various symptoms. In these cases, patients may require surgical or endoscopic drainage.
Adenocarcinoma of the pancreas
Pancreatic adenocarcinoma (PA) is a major (4th-leading) cause of cancer mortality among adult men and women in the US. The vast majority of these tumors (90-95%) arise from ductal epithelial cells and the remaining 5-10% arise from acinar cells. Both cells types carry a similar prognosis. A typical PA develops from ductal epithelial cells along the following histologic sequence: normal, atypia, low-grade dysplasia, high-grade dysplasia, invasive cancer. The cancer cells usually form primitive, mucin-positive, gland-like structures. The tumor cells elicit a strong, fibrotic reaction known as “desmoplasia,” which makes their texture very hard and the cancer cells less permeable to chemotherapy drugs. Additionally, the tumors often grow with microscopic tentacles that are not visible on imaging studies.
Types of pancreatic adenocarcinoma
A typical PA develops from ductal epithelial cells. Other types of pancreatic adenocarcinoma include mucinous cystadenocarcinomas, and intraductal papillary mucinous tumors (IPMTs). These cancers arise from cystic lesions in the pancreas and are much less common than ductal adenocarcinoma. They may cause symptoms or be detected on imaging while still at an early, benign, (adenomatous) cystic stage. Hence they carry a more favorable prognosis.
risk factors of pancreatic adenocarcinoma
The risk of pancreatic adenocarcinoma (PA) is increased by a positive family history, tobacco abuse, chronic pancreatitis, obesity, and occasionally a genetic syndrome (e.g. Peutz-Jeghers, Von Hippel-Lindau). The various mechanisms of carcinogenesis are still poorly understood.
Symptoms of pancreatic adenocarcinoma
The most common presenting symptoms are vague abdominal or back pain and weight loss. Pain typically indicates invasion of the pancreatic capsule or nerve invasion and a later stage of disease. Because most PAs originate in the head of the pancreas, patients may also present with symptoms of bile duct obstruction, including jaundice, choluria (dark color of the urine caused by bilirubinuria), acholic stools, or pruritus (from bile acid retention). Head of pancreas (HOP) cancers that present with jaundice are typically at an earlier stage than body or tail cancers that present with abdominal/back pain, so most patients who undergo surgery have disease confined to the HOP and obstructive jaundice. Occasionally, PA causes acute pancreatitis by obstructing the main pancreatic duct. Patients with PA have an increased risk for developing blood clots because of an associated hyper-coaguable state known as Trousseau’s syndrome and because of physical inactivity.
diagnosis of pancreatic adenocarcinoma
Because of the location of the pancreas deep within the retroperitioneum and the difficulty imaging or palpating the organ, there is no cheap, noninvasive, accurate and readily available, universal screening test for PA. Unfortunately, most patients present with locally advanced or metastatic disease after the onset of symptoms. The diagnosis of PA is usually made by contrast abdominal CT scan (80-90%), which shows the pancreas, bile ducts, and pancreatic duct very well. CT can also demonstrate for liver and other distant metastases. Abdominal ultrasound is less accurate (
prognosis of pancreatic adenocarcinoma
The five-year survival of pancreatic adenocarcinoma is dismal, around 2-4%.
treatment of pancreatic adenocarcinoma
In the unusual cases where the disease appears localized to the pancreas and the patient is healthy enough to tolerate a major surgery, resection (usually a Whipple’s procedure, which involves surgical removal of the pancreas head, gallbladder, bile duct, and duodenum) provides the only chance for cure. Unfortunately, even in patients who undergo surgery, the tumor is usually found to be more advanced in the operating room or recurs shortly thereafter. Neoadjuvant (pre-operative) chemotherapy, sometimes with radiation, may increase the yield of surgery but is still a topic of debate. In patients with metastases, recurrent disease, or high surgical risk, palliative measures may be offered. The most common palliative procedure is ERCP with placement of a stent across the bile duct stricture. This will relieve cholestasis symptoms. EUS-guided injection of the celiac nerve, known as celiac plexus neurolysis, helps relieve pain and reduces narcotic use in many patients. Palliative chemotherapy may also be offered to some patients, but this carries side effects and at best only increases the lifespan by 3-6 months.
Neuroendocrine tumors of the pancreas
Neuroendocrine tumors (NETs) arise from the enterochromaffin cells of the lung, GI tract, or the pancreatic islets. These were previously called carcinoids (carcinoma-like) because of their histologic appearance mimicking carcinoma but relatively benign clinically course compared to gastric or rectal carcinomas. Now it generally only applies to metastatic NETs that produce serotonin by products resulting in the carcinoid syndrome. Most pancreatic NETs are clinically silent and are detected on routine imaging when still small. Others may cause pain (when very large or metastatic) or produce symptoms via hormone secretion such as insulin, glucagon, gastrin, VIP, or somatostatin.
types of productive neuroendocrine tumors of the pancreas
produce symptoms via hormone secretion such as insulin, glucagon, gastrin, VIP, or somatostatin. The type of hormone produced by the tumor differentiates determines the cell type and thus the tumor name – insulinoma, glucagonoma, gastrinoma, VIPoma, or somatistatinoma. Insulinomas cause recurrent hypoglycemia. Glucagonomas cause hyperglycemia/diabetes, weight loss, and diarrhea. Gastrinomas cause GERD or peptic ulcers, diarrhea, and fat malabsorption from deactivation of pancreatic enzymes. VIPomas produce severe, chronic, secretory-type diarrhea with hypokalemia and weight loss. Somatistatinomas are rare but cause weight loss, malabsorption, and acalculous cholecystitis by decreasing GI motility and exocrine secretion.
diagnosis of neuroendocrine tumors of the pancreas
The diagnosis of NET is made by cross-sectional imaging, CT or MRI, and confirmed by fine-needle aspiration (FNA), octreotide scanning (for gastrinoma or VIPoma), or surgical resection.
somatostatin
Somatostatin is secreted at several locations in the digestive system: Delta cells in the pyloric antrum, the duodenum and the pancreatic islets. In the stomach, somatostatin acts directly on the acid-producing parietal cells via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion. Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including gastrin, secretin and histamine which effectively slows down the digestive process.
benign vs. malignant neuroendocrine tumors of the pancreas
All NETs carry a risk of malignant degeneration and metastasis, with the risk increasing directly with size of the lesion and the cell type (glucagonoma and somatistatinoma are almost always malignant whereas insulinomas are almost always benign). The differentiation between benign and malignant cannot be made histologically; it is made based on the presence of metastases, usually by imaging studies. Because all NETs carry some risk, surgical resection is indicated for nearly all NETs in surgically fit patients. Small (
Autoimmune pancreatitis
Autoimmune pancreatitis (AIP) is a chronic, inflammatory condition that results in a particular set of symptoms. The underlying trigger is unknown, but in AIP, IgG-4 + plasma cells and lymphocytes infiltrate the pancreas and its vessels resulting in localized or diffuse enlargement of the pancreatic parenchyma and narrowing of the pancreatic duct and/or bile duct. Glandular atrophy, ductal dilation, calcifications, and steatorrhea are features of chronic pancreatitis but NOT features of AIP.
risk factors of autoimmune pancreatitis
Patients with AIP are typically males aged 45-70 without a history of alcohol or hyperlipidemia or a family history of pancreatitis. Associated autoimmune diseases including rheumatoid arthritis, inflammatory bowel disease, lupus, or sjogren’s syndrome (among others) occur in ~ 25%.
symptoms of autoimmune pancreatitis
AIP produces symptoms more like cancer than chronic pancreatitis or recurrent acute pancreatitis. Most patients present with chronic epigastric or diffuse abdominal pain, and nearly half also develop cholestasis (jaundice, dark urine, and/or itching) from an associated BBS.
diagnosis of autoimmune pancreatitis
Serum IgG-4 is elevated in ~ 80% of patients and is > 70% specific for the disease. IgG-total, ANA, and rheumatoid factor are elevated in a minority. CT, US, or MRI show a focally or diffusely enlarged pancreas with decreased enhancement and loss of the lobular contour. ERCP and EUS show a focally or diffusely narrowed pancreatic duct and, in about half of cases, a bile duct stricture. In cases where malignancy cannot be ruled out, a definitive diagnosis can be made by EUS-guided or percutaneous biopsy of the pancreas with IgG-4 staining or endoscopic biopsy of the ampulla.
treatment of autoimmune pancreatitis
Treatment of AIP with a 6-week course of PO corticosteroids is prompt and effective. Patients with jaundice or pruritus may benefit from ERCP with placement of a temporary biliary stent. Immunomodulators can be used in rare, refractory cases.
Oropharyngeal (transfer) dysphagia
inability to initiate a swallow or transfer food bolus into esophagus.May occur with obstruction or neuromuscular disease (leading to dysfunction of oropharyngeal musculatire causing a propulsive/motility disorder). Nasal regurgitation may occur. Aspiration, food or liquids passing into airway or lungs, may occur.
types of oropharyngeal disease
neurologic propulsive/ motility diseases include stroke, ALS, parkinson’s, MS, and polio. Muscular propulsive/ motility diseases include myasthenia gravis, muscular dystrophy, and muscle injury due to surgery or radiation therapy. Benign structural diseases includes zenker’s diverticulum (outpouching of esophagus leading to food regurgitation or bacterial colonization (halitosis)), crycopharyngeal bar, or other (thyromegaly, fibrosis (e.g. radiation)). Malignant structural diseases include squamous cell carcinoma of tongue, oropharynx, soft palate, or upper larynx (Head and Neck Cancers)
motility disorders of the esophagus
symptoms include dysphagia to both solids and liquids and chest pain. Etiology includes achlasia (abnormal peristalsis, failure of LES relaxation), spastic disorder, peak peristalsis, and scleroderma. Must first excluding structural lesions (with upper endoscopy or barium esophagram) then diagnosis with esophageal manometry.
achalasia
Loss of peristalsis in distal esophagus. Failure of LES to relax with swallowing. Age of incidence is 25-60, equal M:F ration. Most common symptoms include dysphagia to solids and liquids, weight loss, regurgitation. Other symptoms include chest pain, difficulty belching, heartburn, and hiccups. 98% are primary and idiopathic. Secondary (pseudoachalasia) achalasia includes direct mechanical obstruction of LES, infiltrative submucosal invasion (either a primary esophageal or gastric malignancy or infiltrative metastatic malignancy (pancreatic, breast, neurofibromatosis, bladder, prostate, etc)), paraneoplastic syndrome (such as small cell lung cancer, pancreatic, prostate), and chagas disease. With paraneoplastic syndrome, tumors expresses neuronal antigen, which is also expressed in neuron, this leads to T cells attacking neurons of the myenteric plexus.
types of manometry findings and corresponding treatments
Types I (classic) shows no significant change in esophageal pressurization with swallowing. Type II shows simultaneous pressurization spanning entire esophagus length with swallowing. Treatments target the LES and include botox injections, pneumatic dilation, surgical myotomy with good outcomes. Type III (spastic) shows abnormal, lumen obliterating contractions and spasms. Botox injections, pneumatic dilation, surgical myotomy have poor outcomes.
pathophysiology of achalasia
Normally, LES pressure & relaxation is regulated by excitatory and inhibitory neurotransmitters. With achalasia, selective loss of inhibitory neurons in the myenteric plexus results in relatively unopposed excitatory (cholinergic) neurons leading to hypertensive nonrelaxed esophageal sphincter
treatment for achalasia
medical treatments include nitrates (stimulates guanylate cyclase, decreasing intracellular Ca and causing SMC relaxation), calcium channels, slidenafil. Endoscopic therapy is much more effective, which includes GC injections of botulinum toxin (causing inhibition of ACh release from nerve endings), pneumatic ballon dilation (which tears LES muscle fibers), and per-oral endoscopic myotomy (POEM). Surgical (Heller) myotomy is usually laparoscopic, 70-85% remission at 10 years, and complications include reflux (unless combined with fundoplication) and perforation.
Scleroderma/Progressive Systemic Sclerosis (PSS)
Multisystem disorder characterized by obliterative small vessel vasculitis and connective tissue proliferation with fibrosis of multiple organs. GI manifestations in 80-90%. The principal pathological abnormalities of the GI tract consist of smooth muscle atrophy and gut wall fibrosis. Smooth muscle atrophy and gut wall fibrosis is predominantly a myopathic process and leads to weak peristalsis causing dysphagia and weak LES causing GERD. Unrepentant GERD causes esophagitis and stricture.
Spastic Disorders of the Esophagus
Conditions of uncertain etiology. Peristalsis preserved. Symptoms usually chest pain and dysphagia. Postulated pathophysiology related to overactivity of excitatory nerves or overreactivity of the smooth muscle response
esophageal structural disorders
are caused by luminal narrowing and obstruction. symptoms include dysphagia to solids and liquids only much later, weight loss, and sometimes heartburn. Benign causes include strictures (GERD related or due to caustic ingestions), schatzki’s ring, and eosinophilic esophagitis (leading to extrinsic compression). Malignant causes include esophageal cancer (adenocarcinoma or squamous cell cancer), metastsis (rare, includes melanoma, breast cancer, renal cell carcinoma, lung cancer), and direct invasion. Treatment of benign esophageal strictures is endoscopic dilation using balloons or sequential commercial dilators.
Eosinophilic Esophagitis (EoE)
Chronic immune/antigen-mediated esophageal disease. Clinicopathologic diagnosis is based on symptoms of esophageal dysfunction, eosinophilic infiltrate in the esophagus, and absence of other potential causes of esophageal eosinophilia. Increasing incidence and prevalence. 0.2-4/1000 in general population. In adults & adolescents, it causes dysphagia (25-100%) and is about 50% of cases of acute food impaction. Other clinical features include food avoidance and maybe heartburn. In children, it is more non-specific (feeding intolerance, failure to thrive, abdominal pain). It is most common in those over 40 years of age, white males (but being diagnosed more frequently in minority populations), and is commonly associated with other allergic diseases (asthma, atopic dermatitis, seasonal allergies, food allergies). With endoscope, one can see ringed esophagus with linear furrow. Microscopically, there are many eosinophils.
Treatment of Eosinophilic Esophagitis (EoE)
Treatment includes dilation, diet changes, and medical treatments, including topical steroid. Asthma preparations are swallowed. Elemental Diet (allergen-free) is effective in children. More practical is the 6 food elimination diet (SFED), which includes eliminates 6 most common food allergens such as milk, eggs, wheat, soy, seafood, nuts
Gastroesophageal reflux disease (GERD)
Pathologic reflux of gastric juice Acid) into esophagus. Classic symptoms include heartburn and regurgitation with acidic taste (postitional). Heartburn presents as burning sensation, substernal or epigastric, rises in chest and is often post-prandial (after meals) and may be positional (lying down/nocturnal). Less Classic Symptoms include water brash, throat clearing, cough, and rare symptoms, such as wheezing, stridor, hoarseness. Relieved by antacids or anti-secretory medications
Pathophysiology of GERD
Acid in the esophagus or airway causing symptoms and/or esophageal damage. Esophagus lacks defenses (mucous secretion, alkalinity) against acid. Can be caused by inappropriate LES relaxation, hiatal hernia, gastric or esophageal surgery, dysmotility, or obstruction and rarely Zollinger-Ellison, Sjogren’s, Scleroderma
GERD risk factors
Males = females, Obesity, Alcohol? (Minimally if at all) Tobacco, Medications, Pregnancy, and Other medical illnesses (scleroderma, ZE, gastroparesis)
Barrett’s esophagus
an abnormal change (metaplasia) in the cells of the lower portion of the esophagus. It is characterized by the replacement of the normal stratified squamous epithelium lining of the esophagus by simple columnar epithelium with goblet cells (which are usually found lower in the gastrointestinal tract). It is a consequence of GERD. Risk factors include being male, white, having central adiposity, advancing age (plateau in 60s), and chronic GERD. It is a significant in risk of developing esophageal adenocarcinoma. Previously thought to be higher risk, currently estimated at ~ 0.1-0.5% per year. Patients may benefit from endoscopy with biopsies every 3-5 years to assess for dysplasia. Presence of dysplasia is a much greater risk for the development of esophageal cancer. Low-grade dysplasia merits even closer surveillance. High-grade dysplasia is ominous and merits treatment. Endoscopic treatments are used for HGD and early esophageal adenocarcinomas and include ablation of Barrett’s tissue and endoscopic resection of visible lesions
Esophageal cancer
Symptoms include progressive dysphagia from solids to liquids, weight loss, sometimes profound. Rare symptoms include hemoptysis, chest pain, or anemia. Does not cause symptoms until advanced. Preferred treatment is surgical resection, if detected early. Chemotherapy/radiation initially in advanced cases (most). Metal stent placement or feeding tube for palliation. Types include squamous cell carcinoma (risk factors are older age, alcohol/tobacco use, caustic injuries) and adenocarcinoma (risk factors include older age, smoking, obesity, GERD, and Barrett’s esophagus and nearly always in distal esophagus or gastric cardia).
Hypertrophic Pyloric Stenosis
Hyperplasia of pyloric muscularis propria leading to obstruction of gastric outflow. M:F = 4:1. Presents in 2-3rd week of life with regurgitation and persistent projectile non-bilious vomiting. Firm ovoid abdominal mass. Treatment includes surgical splitting of muscularis propria (“myotomy”)
Stress-related Mucosal Disease
Morphologically resembles acute gastritis. Injury is mediated by vasoconstriction/ischemia. Erosion and ulceration may be widespread. Occurs in 75% of critically ill patients. Trauma, shock, or sepsis (stress ulcers). Burns (Curling ulcers). Intracranial disease (Cushing ulcers)
causes of chronic gastritis
Helicobacter pylori infection. Autoimmune gastritis. Eosinophilic gastropathy, an allergic disease [e.g. cow’s milk] and parasitic infection. Lymphocytic gastropathy, which is associated with celiac disease. Granulomatous gastropathy, such as crohn’s disease, sarcoidosis, infection
Autoimmune Gastritis
Corpus restricted chronic atrophic gastritis. Anti-parietal cell and anti-intrinsic factor antibodies, with or without pernicious anemia. Common in scandinavian and northern european descent. Lymphocyte and plasma cell infiltrate in the body of stomach and glandular atrophy. There is also intestinal metaplasia.
Inflammatory/hyperplastic gastric polyp
Rare progression to cancer; associated with Helicobacter and other chronic gastritides. Microscopic findings include mucosal inflammation and edema and cystically dilated foveolae.
Fundic gland gastric polyp
Very rare progression to cancer (in FAP patients); FAP associated and sporadic (usually PPI associated). Microscopic findings show cystically dilated oxyntic gland
Gastric adenoma
Common progression to cancer; increased incidence in FAP, Helicobacter gastritis, and other chronic gastritides. Microscopic findings include dark, atypical cells.
Pathology findings with gastric adenocarcinoma
Types include intertinal type with an ulcerating pattern and diffuse type (signet ring cell) with linitis plastica pattern.
Mutations with gastric adenocarcinoma
Wnt signalling pathway activation is common in intestinal type cancers and can occur with loss of APC (as in FAP). Loss of CDH1 (mutation or methylation) is common in diffuse type cancers. There are germline loss of CDH1 in familial gastric cancer. Amplification of Her2/neu occurs in a minority of tumors (intestinal > diffuse). This is important because of susceptibility to tyrosine kinase inhibitor trastuzumab
Pathology findings with MALT lymphoma
Microscopic findings include diffuse infiltrate of B-cells and disruption of gastric glands (lymphoepithelial lesions).
Pathology findings with neuroendocrine tumors
they are well differentiated. They are associated with gastric atrophy and type 1 multiple endocrine neoplasia (MEN-1), an autosomal dominant disorders. Microscopic findings include nests and trabeculae of monomorphic cells.
Pathology Findings with Gastrointestinal Stromal Tumor (GIST)
Most contain a mutation in the c-kit oncogene, which is used as diagnostic aid on tissue and is targeted with therapy with tyrosine kinase inhibitor imatinib. Microscopic findings include spindle cell proliferation and c-kit staining.
Zenkers diverticula
Located in the uppermost portion of the esophagus. Symptoms include regurgitation, halitosis, and aspiration (clinical: gurgling). It is associated with reduced UES compliance
acid secretions stimulation in the stomach
Acid secretion is stimulated by the parasympathetic neurotransmitter acetylcholine (ACh), the hormone gastrin, and the paracrine substance histamine. ACh binds to muscarinic receptors on the basolateral membrane, which leads to the activation of a G-protein intermediate and a rise in intracellular Ca2+. Gastrin is also thought to act by increasing intracellular Ca2+. Histamine binding to histaminergic H2 receptors leads to the activation of a different G-protein that turns on adenylate cyclase. This enzyme catalyzes the synthesis of cyclic AMP (cAMP). Ca2+ and cAMP activate distinct protein kinases that phosphorylate H+/K+-ATPase. ACh and gastrin potentiate acid secretion as a result of their stimulation of histamine release from enterochromaffin-like (ECL) cells. Thus, in the direct pathway, ACh, gastrin and histamine directly stimulate the parietal cell, triggering the secretion of H+ into the lumen. In the indirect pathway, ACh and gastrin stimulate the ECL cells, resulting in secretion of histamine. This histamine then acts on the parietal cell.
Phases of gastric acid secretion
There are 4 phases of gastric acid secretion, a basal phase and 3 phases associated with eating. The rate of acid secretion between meals is low. The basal (inter-digestive) phase follows a circadian rhythm: the rate of acid secretion is lowest in the morning before awakening and highest in the evening. The resting pH can range from 3 to 7. The rate of acid secretion is enhanced several-fold by eating. The smell, sight, taste and swallowing of food initiate the cephalic phase, which is primarily mediated by the vagus nerve. Stimulation of the vagus nerve results in release of ACh, triggering of the histamine release from ECL cells, release of gastrin-releasing peptide (GRP) from the vagal and enteric neurons (ENS); and inhibition of somatostatin release from the delta cells (D cells) in the stomach. The cephalic phase accounts for 30% of total acid secretion. Entry of food into the stomach initiates the gastric phase of acid secretion. First, the food distends the gastric mucosa, which activates a vagovagal reflex as well as local ENS reflexes. Second, partially digested proteins stimulate antral gastrin (G) cells, which release gastrin. The gastric phase accounts for about 50% to 60% of total acid secretion. In the intestinal phase, the presence of amino acid and partially digested peptides in the proximal portion of the small intestine stimulates acid secretion by stimulating duodenal gastrin (G) cells to secrete gastrin. Approximately 5% to 10% of total acid secretion is a result of the intestinal phase.
Carbohydrate digestion and absorption
Plant starch, amylopectin, is the largest single source of carbohydrates in most human diets. It is a polymer of glucose containing both α-1,4 and α-1,6 linkages. In contrast, cellulose is a β-1,4 linked polymer that cannot be digested by intestinal enzymes. It is the major component of dietary “fiber”. Amylase catalyzes only the hydrolysis of internal α-1,4 linkages to generate maltose, maltotriose (3 glucose monomers) and α-limit dextrin. Because of the enzyme’s specificity, free glucose is never the product of amylase digestion. The other major carbohydrates in the diet are the disaccharides sucrose and lactose.
Mucosal sucrase-isomaltase (SI)
Mucosal sucrase-isomaltase (SI) activity represents the last stage of small-intestinal digestion of branch points of starch to glucose.
Mucosal maltase-glucoamylase activity (MGA)
serves as the final step in small-intestinal digestion of linear forms of starch to glucose
Intestinal sugar transporters
Intestinal sugar transporters are responsible for transporting the monosaccharides (glucose, galactose and fructose) from the intestinal lumen to the blood. The Na+-dependent glucose transporter SGLT1 is located in the brush-border or apical membrane of enterocytes. SGLT1 transports glucose and galactose, along with Na+, from the intestinal lumen into the cytosol. The Na+-independent fructose transporter GLUT5 is also apical, a unique member of the facilitative glucose transporter family, and transports fructose from the lumen into the cytosol. The Na‘-independent fructose transporter GLUT2 is basolateral and transports all three monosaccharides from the cytosol to the blood.
Disorders of sugar digestion or transport
Lactose intolerance is caused by the absence of the brush border enzyme lactase. Unabsorbed lactose draws water into the intestinal lumen, producing an osmotic diarrhea. In addition, the gut bacterial flora metabolize the unabsorbed lactose, forming gases such as hydrogen, methane and carbon dioxide. Genetic absence of Na+/glucose co-transporter SGLT1 in the intestinal brush-border causes glucose-galactose malabsorption in humans. These patients have diarrhea when they ingest dietary sugars. This diarrhea results from reduced small intestinal Na+ and fluid absorption as well as fluid secretion secondary to the osmotic effects of non-absorbed monosaccharide. Diarrhea associated with glucose-galactose malabsorption is rectified by replacing dietary glucose with fructose because fructose is absorbed by a distinct carrier (GLUT5). The genetic mutations of human SGLT1 result in the potentially fatal neonatal condition of glucose-galactose malabsorption.
endopeptidases
The secreted endopeptidases hydrolyze the interior peptide bonds: Pepsin - aromatic amino acids, Trypsin - arginine (R) and lysine (K), Chymotrypsin - aromatic amino acids, Elastase - neutral aliphatic amino acids
exopeptidases
The secreted exopeptidases (carboxypeptidases) hydrolyze one amino acid at a time from the C-(carboxy)-terminus of proteins and peptides: Carboxypeptidases A and Carboxypeptidases B
Aminopeptidase
an exoprotease that removes one amino acid at a time from the N(amino)-terminus. brush border protease
Dipeptidyl aminopeptidase
removes dipeptides from the N-terminus. brush border protease
Dipeptidase
converts dipeptides to amino acids. brush border protease
steps in small intestinal protein digestion
- Activation of trypsinogen to trypsin by the brush border protease enterokinase. 2. Activation of all other precursors by trypsin. 3. Trypsin, chymotrypsin, elastase, carboxypeptidase A & B all hydrolyze protein to amino acids and di-, tri- and oligopeptides. 4. The brush border proteases hydrolyze oligopeptides to amino acids. 5. Pancreatic proteases digest themselves and each other.
Protein absorption
Absorption of the products of protein digestion occurs by Na+-dependent co-transport . Unlike carbohydrate absorption (in which only monomers are absorbed), di- and tripeptides are absorbed intact. In fact, it is estimated that up to 70% of protein is absorbed in this way. Four different amino acid carriers have been identified with the following specificities: neutral, basic, acidic, and a special carrier that efficiently transports proline and glycine across the enterocyte brush border. Within the enterocytes, di- and tripeptides are hydrolyzed to amino acids by cytoplasmic peptidases. Amino acids exit the basolateral membrane of the enterocyte by facilitated diffusion and enter blood capillaries.
Disorders of amino acid transport
Conditions exist in which deficiency of pancreatic enzymes occur, e.g. in chronic pancreatitis. The absence of trypsin alone makes it appear as if all of the pancreatic enzymes are missing. Conditions also exist in which specific transporters are missing, e.g. in cysteinuria, Hartnup disease and cystic fibrosis. Cysteinuriajs a genetic absence/defect of the Na+-amino acid transporters. It is called cysteinuria because in these patients the same Na+-amino acid transporter is also missing from the kidneys. These patients lack the capacity for renal or intestinal absorption of cystine, lysine, arginine and ornithine amino acids. The intestinal defect results in the excretion of amino acids in feces. The renal defect results in excretion of the amino acids in urine (Cysteinuria means excess cystine urinary excretion). Hartnup disease is a genetic absence/defect of the neutral amino acid transporter. Cystic fibrosis is a genetic absence/defect in the Cl- channel called the CFTR or cystic fibrosis transmembrane receptor.
colipase
a protein that helps to anchor lipase to the surface of the droplets.
Triglyceride
a neutral fat. The most abundant storage form of fat in animals and plants, and hence the most important dietary lipid. A molecule of triglyceride is composed of a molecule of glycerol in which each of the three carbons is linked through an ester bond to a fatty acid. Triglycerides cannot be efficiently absorbed, and are enzymatically digested by pancreatic lipase into a 2-monoglyceride and two free fatty acids, all of which can be absorbed.
Steps involved in triglyceride digestion and absorption
Fat droplets are emulsified by bile salts and lecithin to form particles on the order of 1 µm in diameter. This process increases the surface area for subsequent digestion by lipase and colipase, a protein that helps to anchor lipase to the surface of the droplets. The products of lipase digestion are 2’-monoglycerides and fatty acids, which are solubilized in bile-salt micelles. Inside the enterocytes, triglycerides are re-synthesized from monoglycerides and fatty acids. They are then packaged into lipoprotein particles called chylomicrons.
Micelles
are cylindrical structures about 10 nm across, with hydrophilic groups oriented toward the aqueous phase and hydrophobic groups associating in the interior. Micelles are required to transport the products of fat digestion through the unstirred water layer near the surface of enterocytes.
the unstirred water layer near the surface of enterocytes
The abundance of hydrophilic glycoproteins protruding from the brush border membrane, as well as mucus are responsible for the unstirred layer. Lipids move in and out of the micelles, and when they strike the cell surface they are able to diffuse passively through the membrane and into the cells.
Chylomicrons
lipoprotein particles synthesized from triglycerides in the enterocyte. In addition to containing triglycerides, chylomicrons contain phospholipids, cholesterol (also absorbed from micelles), and apolipoproteins. In the Golgi they are incorporated into secretory vesicles. Vesicles migrate to the basolateral membrane, and the chylomicrons are released into the interstitial space by exocytosis. They then enter the lacteals because they are too large for capillaries. Fat-soluble vitamins (A, D, E, K) are absorbed by precisely the same route as fat digestion products and cholesterol.
Fat malabsorption-associated digestive disorders
Inadequate triglyceride digestion results in steatorrhea (excessive loss of fat in the stool). This is a hallmark of a diverse group of digestive disorders that cause fat malabsorption. Along with fat malabsoption comes fat-soluble vitamin malabsorption. Fat malabsorption digestive disorders include: Liver disease with bile salt deficiency: patients with chronic liver disease cannot make micelles. Pancreatic insufficiency: patients with chronic pancreatitis and cystic fibrosis lack enzymes to digest fat. Weight loss medication: new anti-obesity drugs inhibit lipase activity resulting in fat malabsorption and so-called “anal leakage”.
H2O absorption
1) H2O readily moves across the intestinal epithelium. A consequence of this is that chyme entering the duodenum is rapidly brought into isotonic equilibrium with the blood. 2) H2O absorption follows the absorption of solutes and is therefore said to be absorbed isotonically. In the duodenum and jejunum, the absorption of sugars and amino acids in co-transport with Na+ causes Cl- to follow for electrical reasons, and H2O to follow for osmotic reasons. Cl- and H2O move across the epithelium by paracellular pathways. the primary active transport process that drives all subsequent absorption processes is the Na+/K+-ATPase. In addition, Na+ can be absorbed in exchange for H+ via the apical Na+/H+ exchanger. the vast volume of the extracellular fluid does not instantly dilute absorbed solutes. Solutes are deposited in the confined regions between cells, and diffusion is slowed somewhat by a basement membrane that exists between the cells and the capillaries. This sets up a standing osmotic gradient that provides the driving force for H2O absorption.
Absorption in the ileum
In the ileum, the mechanisms of water and electrolyte absorption are very similar to those in the upper small intestine. Under normal circumstances the vast majority of nutrients have already been absorbed by the time digested chyme reaches the ileum. Other than specialized absorption tasks (bile salts and vitamin B12), the main job left to the ileum is to continue to absorb H2O. Most Cl- is absorbed by a transcellular pathway involving Cl-/HCO3- exchange in the apical membrane, and facilitated diffusion across the basolateral membrane.
Absorption in the colon
In the colon, no sugars or amino acids are absorbed. An important mechanism for Na absorption is via the apical Na+ channels (epithelial sodium channel, ENaC). Any stimulus that brings about an increase in plasma aldosterone levels causes very similar changes in colonic epithelia cells of the GI tract to those that occur in epithelial cells of the distal nephron of the kidneys. The colon, along with the kidneys, is instructed to absorb more Na+, and consequently more H2O. Another similarity is that increased Na+ absorption by this pathway leads to increased K+ secretion across the apical membrane. In the colon there is net K+ secretion when the lumenal concentration drops below 25 mM. Normally K+ ions secreted in the colon are of little consequence for electrolyte balance because the volume of fluid flowing through these regions is quite small. In severe diarrhea, however, the fluid loss is substantial, and can lead to hypokalemia. For this reason potassium is included in fluids given to patients with severe diarrhea. Water soluble vitamins (B vitamins, vitamin C, niacin, folic acid, pantothenic acid, and biotin) are absorbed either by co-transport with Na+, or by passive diffusion. As with other solutes, their absorption is virtually complete in the upper small intestine. An important exception is vitamin B12
Absorption of vit B12
is absorbed in the distal ileum in a complex with intrinsic factor. The brush border membrane of ileal enterocytes contains a specific receptor for the B12-IF complex. Impaired absorption of B12 leads to a disease called pernicious anemia.
slow waves or basic electrical rhythm (BER)
Slow waves generally consist of an upstroke depolarization, a partial repolarization, and a plateau potential that can last for several seconds. Slow waves are an intrinsic property of muscle cells in a given region (i.e. no external stimulation is required). Another way of saying this is that the BER is myogenic or muscle-derived. each depolarization does not cause contraction (measured as an increase in tension, T). Contraction only occurs when the depolarization exceeds a specific membrane potential. In many parts of the GI tract a sufficient depolarization is reached during one or more action potentials (or spike potentials) that fire at the peak of a slow wave. The addition of acetylcholine to the preparation causes action potentials to fire at each peak, and the muscle contracts at the frequency set by the BER. The force of each contraction is proportional to the number of action potentials. The entry of Ca2+ ions during the action potentials, due to opening of voltage-dependent Ca2+ channels on the smooth muscle cell membrane, triggers a contraction.
Smooth muscle contraction of the intestine
The contractile apparatus of most of the Gl tract is made up of smooth muscle cells. Actin and myosin are the major contractile proteins. Actin is polymerized into thin filaments, and myosin is arranged in thick filaments, with cross-bridges extending to make contact with the thin filaments. The ratio of thin to thick filaments is about 10:1 (2:1 in skeletal muscle). Contraction of smooth muscle cell occurs when myosin interacts with actin, triggered by the entry of Ca+ ions into the cell. Formation of a complex between Ca2+ and calmodulin activates myosin light chain kinase, which phosphorylates myosin and allows cross-bridge formation (cycling) to occur. Nerve axons run through the bundles of smooth muscle cells and release neurotransmitters, which also induce Ca2+ entry and therefore can initiate contraction.
segmentation in GI motility
is the predominant motor activity in the intestines, helping to ensure proper digestion and absorption. contractions are isolated and not coordinated with movement above and below, it propels contents in both directions. When the contracting area relaxes, the contents flow back into the original segment with the result that mixing has occurred without net propulsion.
Peristalsis
contractions of adjacent segments are coordinated in a proximal to distal manner, resulting in net propulsion of contents. The contractile ring moves towards the bolus, pushing it distally. At the same time, the intestine relaxes distal to the bolus (called receptive relaxation, produced by the pressure of the proximal bolus). This facilitates properly polarized propulsion. This coordination requires nerves of the myenteric plexus. In the stomach, peristalsis occurs when the BERs are coordinated by vagal input in such a way that contraction of a distal segment follows just after contraction of the immediately preceding segment. following a vagotomy, BERs are still observed, but they become disorganized and coordinated peristaltic movements are abolished.
Esophageal peristalsis
The upper third of the esophagus consists of skeletal muscle, and the remainder consists of smooth muscle. A peristaltic wave of contraction pushes the bolus ahead to the lower esophageal sphincter (LES) in about 5 sec (liquids plummet to the LES much faster than the peristaltic wave). Just before the bolus arrives, the LES relaxes, and the bolus is propelled into the stomach. The peristaltic wave is controlled by the vagus nerve, which receives its signals from the swallowing center. However, if the vagus nerve is severed, a local myenteric complex can maintain swallowing. Note that the primary function of LES is to prevent reflux of acid gastric contents into the esophagus, whose epithelium (above distal 2-3 cm) is not adequately protected against this material.
Major functions of the stomach
storage, mixing and slow controlled emptying of the food. In synchrony with relaxation of the LES, the stomach undergoes the process of receptive relaxation. The fundus and the body of the stomach can accommodate volume increases as large as 1.5 L without a marked increase in intra-gastric pressure. This process is also regulated by the vagus nerve.
Gastric motility
(1) After eating, contractions start around mid-stomach at the frequency of slow waves (~3/min). Peristaltic waves push a bolus toward the antrum, (2) The contractions become stronger and faster in the antrum and begin to outrun the bolus. Since pyloric opening small, most content reflected backward toward the body of the stomach. This process is called retropulslon. It serves to break up the food into smaller particles and mix it with digestive juices so that absorption can take place later in the gut. The digestive juice mixture is called chyme. (3) Transient opening of the pylorus allows smaller particles and chyme to leave the stomach and enter the duodenum. No movement of the gastric contents occurs between contractions.
Gastric emptying
is controlled by the pyloric sphincter, which is normally under the high tone. Intense waves force a few mls of chyme through the sphincter into the duodenum. Rate of emptying is increased by distension. Increased stretch leads to increased peristalsis through vagal and myenteric reflexes and decreases pyloric tone. Gastrin is a hormone secreted in response to the presence of food in the stomach. Gastrin also increases peristaltic contraction and decreases pyloric tone. Thus, the combination of distension and gastrin increase the rate of gastric emptying.
Reflexes and secretions of the duodenum
Arrival of food into the duodenum causes distention and irritation by acidity and solutions of high osmolarity. Detection of food in the duodenum leads to the reflex inhibition of gastric peristalsis and an increase in pyloric tone. Thus, the duodenum controls delivery rate so that it is not overwhelmed. Additionally, arrival of fats in the duodenum leads to secretion of cholecystokinin (CCK) by enteric endocrine cells. CCK decreases gastric motility providing a further method whereby the actions in the duodenum decrease the rate of gastric emptying to prevent overwhelming of the intestinal absorptive capacity.
Motility of the small intestine
Contraction of the small intestine during digestion consists of segmentation and peristalsis. The rhythm of the segmentation is the same as that of the BER. During segmentation the chyme is mixed with digestive enzymes and kneaded so that the intestine’s absorptive surfaces are constantly being exposed to new contents. Peristaltic movements occur over short distances to propel the digestive chyme at ~1cm/min in an aboral (distal) direction, so it takes 3-5 hrs to transit the intestine. Between meals a process known as migrating myoelectric motor complexes (MMC) sweep down the gastric antrum and along the small intestines. This process occurs about every 90 min, and performs a housekeeping role to remove bacteria and indigestible material. A long wave of peristalsis begins in the stomach, travels to the ileocecal sphincter and then repeats. At any one time 40cm of intestine is involved. Involvement of a region lasts 10-15 minutes, during which ~50 peristaltic waves occur. The region involved changes slowly, moving towards the ileum. When it arrives (~2 hrs), new activity begins in the stomach. Each wave is preceded by a rise in the plasma concentration of the hormone motilin, which is released from the small intestine and appears to initiate the process. Note that eating terminates the MMC, which only occur during fasting.
Large intestinal motility
Distension in the ileum causes relaxation of the ileocecal sphincter, and contents pass into the cecum of the large intestine. In the colon, segmentation contractions mix and dry the chyme, so that only 100-200 ml of fluid is lost daily in the feces. These contractions are quite prominent in some species, forming sacculatlons in the colon known as hausta (the haustratlons). Most forward propulsion in the colon takes place during a process known as a mass movement. Mass movements constitute a type of motility not seen elsewhere in the digestive tract. Known also as giant migrating contractions, this pattern of motility is like a very intense and prolonged peristaltic contraction that strips an area of large intestine clear of contents. During these movements segmental activity temporarily ceases and there is a loss of haustration. Thus, most prominent patterns of motility observed in the colon are segmentation movements, which are responsible for haustrations of the colon, and forward propulsions, known as mass movements.
Defecation
In periods between meals, the colon is generally quiescent. Following a meal, colonic motility increases significantly, due to signals propagated through the enteric nervous system - the so-called gastrocolic and duodenocolic reflexes, manifestations of enteric nervous system control. Additionally, distension of the colon is a primary stimulator of contractions. Several times each day, mass movements push feces into the rectum, which is usually empty. The gastrocolic reflex is a stimulus for this. Feces enter the rectum, leading to distension of the rectum and stimulation of the defecation reflex. This is largely a spinal reflex mediated via the pelvic nerves, and results in reflex relaxation of the internal anal sphincter followed by voluntary relaxation of the external anal sphincter and defecation. The external anal sphincter consists of striated muscle. The urge to defecate accompanies distension of the rectum. In humans and “house-trained” animals, defecation can be prevented by voluntary constriction of the external sphincter. In order for defecation to proceed, the sphincter must be released voluntarily. If the external sphincter is not released, defecation reflex will ultimately be inhibited. In babies and in people with damaged spinal cords, the defecation reflex is sufficient to empty lower bowel without voluntary input.
components of saliva
Mucins, large glycoproteins that lubricate food and facilitate swallowing; The enzymes Amylase and lingual lipase which begin the digestion of starches and fats; NaHCO3, which helps to maintain an optimal pH for enzyme activity and also to reduce Ca2+ solubility. When the pH > 7.0, teeth do not lose Ca2+ to oral fluids; The antibacterial agents immunoglobulin A (lgA), lysozyme which destroys bacterial cell walls, and Iactoferrln which chelates iron thus preventing the growth of bacteria that require iron.
cells of submaxillary and sublingual glands
The acini of the submaxillary and sublingual glands contain two types of cells, serous and mucous. Serous acinar cells are responsible for the secretion of fluid, electrolytes, and enzymes; mucous acinar cells secrete mucins. Proteins are released from acinar cells by exocytosis of secretory granules, a process triggered by a rise in intracellular Ca2+. From the acinus, saliva passes relatively unchanged through a short intercalated duct and into a striated duct. The striated duct is lined by epithelial cells that function like renal tubule cells to modify the inorganic ion composition.
flow rates effect of salivary concentrations
At high flow rates, saliva is slightly hypotonic and rich in bicarbonate, while at low flow rates it becomes quite hypotonic. At low flow rates there is time for the ducts to modify the secretion. Na+ and Cl- ions are transported out of the lumen of the duct. The HCO3- and K+ ions are secreted into the lumen of the ductd. Because the ductal cells are quite impermeable to water, the modified saliva becomes hypotonic. Salivary secretion is under the control of the autonomic nervous system. Interestingly, both parasympathetic and sympathetic stimulation increase secretion, parasympathetic input being the more profound influence.
Pancreatic secretion
Pancreatic exocrine secretion consists of enzymatic components and aqueous components. Acinar cells produce and secrete digestive enzymes. An important feature is that each cell produces the full complement of pancreatic enzymes. Active enzymes, and in some cases enzyme precursors, are packaged into secretory granules and released by exocytosis. Unlike the enzymes of saliva and gastric juice, the pancreatic enzymes are essential for normal digestion and absorption, 95% of acinar cell protein synthesis is secretory enzymes (zymogens): Trypsinogen, Chymotrypsinogen, RNase/amylase/lipase, etc., Zymogens, so not enzymatically active until activated by proteolytic cleavage, Enterokinase (produced by small intestinal mucosa) activates trypsin, which activates the rest by proteolytic cleavage. In normal circumstances, these enzymes are inactive, however if even a small amount becomes active while still in the pancreas, this sparks a chain reaction - autodigestion (acute pancreatitis).
cholecystokinin (CCK)
When chyme (i.e. fat-containing digestion products) arrives in the small intestine, it stimulates release of cholecystokinin (CCK). CCK is a 33 amino acid peptide (last 4 amino acid residues are the same as those of gastrin). The 8-carboxy terminal amino acid residues are necessary for activity. CCK is most important stimulus for aclnar cell secretion. Inositol triphosphate (IP¬3) and Ca2+ are probably the most important 2nd messengers for CCK. ACh is also stimulatory for secretion, as is gastrin, again through lP¬3/Ca2+ pathways. This shows once again how digestive phases are coordinated, since gastric mediators also impact on pancreatic secretion.
aqueous component of pancreatic secretions
The aqueous component consists mostly of water and bicarbonate, and is produced by duct cells. This component neutralizes acid in the duodenum, preventing injury to the duodenal mucosa and bringing the pH to an optimum level for enzymatic digestion of chyme to proceed. Thus, this HCO3 rich solution serves two purposes: Solvates enzymatic secretions - keeps them moving down duct; Alkalinity necessary to neutralize gastric acid dumped from stomach into small intestine. Presence of acid in small intestine leads to secretion from duodenal endocrine cells of secretin. Secretin is most important stimulus for NaHCO3 ~ thus, the presence of acid in the intestine leads to the secretion of a neutralizing solution; Secretin and CCK both inhibit gastric acid/fluid production and delay gastric emptying until the intestine is ready for more.
