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235 Cards in this Set
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GI Pharmacology
From UpToDate: The physiologic stimulation of acid secretion has classically been divided into three interrelated phases: ___________________. The cephalic phase is activated by the thought, taste, smell and site of food, and swallowing. It is mediated mostly by __________ mechanisms. The gastric phase is due to the __________ effects of food and distension of the stomach. _________ appears to be the major mediator since the response to food is largely inhibited by immunoneutralizing or blocking gastrin. The intestinal phase accounts for only a small proportion of the acid secretory response to a meal; its mediators remain controversial. The observation that ___________ antagonists block the cephalic and gastric phases underscores the importance of __________ mediation of the stimulatory response, and illustrates the interdependence of the different phases. |
cephalic, gastric, and intestinal
cholinergic/vagal chemical, Gastrin H2 receptor, histamine |
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GI Pharmacology
UpToDate: The parietal cell — Upon stimulation (increase in intracellular ___ or ___) secretory vesicles coalesce to canaliculi that drain to the apical lumen. The secretory membrane lining these structures contains the ____________ pump. This pump is always active, but exists in a short-circuited state in resting vesicles, lacking a pathway for ___________, which allows ____________ to occur. |
Ca2+, cAMP
hydrogen-potassium-ATPase acid-secreting potassium-chloride cotransport hydrogen-potassium exchange |
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GI Pharmacology
UpToDate: _______ is the major endocrine regulator of the secretory response to a protein meal. It is released from ________ cells localized to the ______. It enhances ________ secretion from __________ cells in normal subjects by two mechanisms: it has a trophic action on _______ cells and on ____________ cells; and it stimulates parietal cells largely via the release of __________. This process is tightly controlled by a second hormone, ___________, which is a potent inhibitor of both gastrin and histamine synthesis and release, and gastric acid secretion. Gastrin is the best identified trophic regulator of parietal cell mass in humans. This relationship is evidenced by the presence of _________ in gastrinoma patients who have chronic exposure to elevated gastrin levels, and ________ of the parietal cell mass with antrectomy, which decreases gastrin levels. |
Gastrin
Gastrin-expressing cells (G cells) antrum gastric acid, parietal parietal, histamine-secreting enterochromaffin-like (ECL) histamine somatostatin gastric hypertrophy atrophy |
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GI Pharmacology
UpToDate: Complex mechanisms control gastrin release from ________ cells. Two meal-related factors stimulate gastrin secretion: |
antral G cells
gastric distention, and amino acids |
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GI Pharmacology
UpToDate: __________ is the major paracrine stimulator of acid secretion. It can be found in ___________ cells, localized to the acid-secreting oxyntic or body mucosa, in direct proximity to the parietal cell. __________ is the primary stimulus to histamine release from ECL cells. The effects of histamine are largely mediated by the __ receptors, which explain the efficacy of __ receptor blockers in the treatment of acid-peptic disease. |
Histamine
enterochromaffin-like (ECL) cells Gastrin H2 |
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GI Pharmacology
UpToDate: ___________ is a potent inhibitor of acid secretion. It is released from ______ cells, which are present ____________. Although somatostatin has some effects on parietal cells, its major effects are exerted on the inhibition of _________ release and to a lesser extent on ____________ release. The secretion of somatostatin is increased by gastric acid and by gastrin itself, suggesting that a major function is to modulate the acid secretory response to gastrin. |
Somatostatin
D cells throughout the gastric mucosa histamine (ECL cells) gastrin (antral G cells) |
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GI Pharmacology
UpToDate: Neural input may serve as an important integrator of secretory function. ___________ is the major stimulatory mediator. The major effects of __________ receptor activation are to ________ gastrin release, __________ parietal cells, and _________ somatostatin secretion. |
Acetylcholine
muscarinic increase gastrin stimulate parietal cells inhibit somatostatin secretion |
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GI Pharmacology
Peptic ulcer treatment: Tolerance to _____ develops after as few as seven days of therapy, with diminished effectiveness against nocturnal and pentagastrin-stimulated acid secretion. Tolerance does not occur with ___________, probably because they block the final stage of acid secretion, the __________. Rebound acid hypersecretion occurs after the cessation of one to nine months of _________ therapy. Increases have been noted in nocturnal acid secretion and in the acid secretory response to a meal. |
H2RA
proton pump inhibitors (the hydrogen-potassium-ATPase pump) H2RA |
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GI Pharmacology
UpToDate: ___________ agents, such as _________, dramatically reduce acid secretion in some patients in whom nocturnal acid secretion was refractory to H2 blockade. |
Antimuscarinic
atropine This observation is consistent the hypothesis that muscarinic pathways play a role in H2 RA-refractory secretion. |
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GI Pharmacology
Acid secretion: ___________ is the chief neurocrine transmitter, which is released by vagal postganglionic neurons and appears to stimulate hydrogen ion generation directly via a parietal cell muscarinic M3 receptor. __________ is the primary paracrine transmitter that binds to H2-specific receptors on the parietal cell basolateral membrane, while ________, secreted from antral G-cells, comprises the primary endocrine pathway. _________ stimulates the generation of hydrogen ions both directly and indirectly, the latter by stimulating _________ secretion from enterochromaffin-like (ECL) cells in the proximate vicinity of parietal cells. Release of hydrochloric acid: Is ___ if only one ligand binds to parietal cells Is ___ if all three ligands bind to parietal cells |
Acetylcholine
Histamine gastrin Gastrin histamine Low High |
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GI Pharmacology
For each cell: what does it secrete? what stimulates secretion? what is the function? Mucous neck cell Parietal cell Enterochromaffin-like cell Chief cell D cell G cell |
Mucous neck cell - Mucous and Bicarb. Tonic Secretion. Barrier/Buffer.
Parietal cell - Gastric acid, Intrinsic factor. ACh/Gastrin/histamine. Activates pepsin; kills bacteria. Permits B12 absorption. Enterochromaffin-like cell - Histamine. Stim's HCl secretion. Chief cell - Pepsin(ogen), Gastric lipase. ACh, secretin. Digests proteins/fats. D cell- Somatostatin. Stim'd by acid in the stomach. Inhibit acid secretion. G cell - Gastrin. ACh, peptides, amino acids. Stim's HCl secretion. |
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Gastric Contractile Activity
Peristaltic waves move toward the pylorus at the rate of _ per minute This basic electrical rhythm (BER) is initiated by ______. Most vigorous peristalsis and mixing occurs near the ______ Chyme is either: (2) |
3
pacemaker cells (cells of Cajal) pylorus Delivered in small amounts to the duodenum or Forced backward into the stomach for further mixing |
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GI Pharmacology (lecture)
General effects of drugs – Antacids H2 antagonists PPIs NSAIDs |
General effects of drugs –
Antacids neutralize the acid released from parietal cells H2 antagonists interfere in acid production PPIs block the pump NSAIDs block production of Prostaglandin E2 (PGE2=>parietal cell cAMP decrease => inhibition) and Prostacyclin PGI2 (PGI2=>Stimulation of glycoprotein (mucin) and bicarbonate secretion by epithelial cells; other protective mechs: vasodilatory and proliferative). Gastric and duodenal injury by acid and pepsin occurs when these protective functions are compromised as a consequence of PG deficiency induced by a COX-1 inhibiting NSAID or by antibodies to PGs. |
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GI Pharmacology (lecture)
Peptic Ulcer Disease Acid neutralizing therapies? (2) + Mech. |
(1) Eating food –
Increases gastric pH to 5 for one hour Food provides buffering Increase in blood flow increases the mucosal bicarbonate production (2) Antacids - Neutralize HCl Increase luminal pH Inactivate pepsin and bind bile salts |
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GI Pharmacology (lecture)
Antacids - Pharmacokinetics – NaHCO3, CaCO3, Mg2+/Al3+ Solids v. liquids? |
NaHCO3 – very water soluble and rapidly cleared, increases alkali and sodium load
CaCO3 – rapidly neutralized, causes belching Combination Mg2+/Al3+ - slower absorption but longer activity Aluminium relaxes smooth muscle of the gut decreasing motility, whereas Magnesium increases gut motility. The hydroxides of both last longer in the gut. Liquids work better because it doesn’t need to be broken down and is quickly accessible to the system. |
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GI Pharmacology (lecture)
What is one characteristic of each: Tums-Ex – CaCO3 Milk of Magnesia – Mg(OH)2 – Aluminium + Magensium (MaaloxTC) – |
Tums-Ex – CaCO3 – causes belching
Milk of Magnesia – Mg(OH)2 – causes diarrhea Aluminium + Magensium – better because they last longer |
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GI Pharmacology (lecture)
Antacids: Clinical Indications – Toxicities – |
Indications: Duodenal Ulcers, GERD, Stress ulcer prophylaxis
Toxicities – Reduce absorption of other drugs Alter gut motility Aluminium can be toxic in renal patients |
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-prazoles ?
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PPIs
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GI Pharmacology (lecture)
Acid Reduction – Histamine 2 Receptor Antagonists: Name? Mechanism of Action? PK? Indications? Toxicities? |
Ranitidine
Mechanism of Action – Competitive inhibition of histamine Dose-dependent response Inhibits basal acid secretion (fasting, night) Less inhibition of physiologic acid secretion (feeding) Pharmacokinetics – Reach peak concentration in 1-2 hours Renal elimination Taken multiple times Clinical Indications Duodenal ulcers, gastric ulcers, GERD Toxicities Inhibits CYP450 Confusion, somnolence, gynecomastia |
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GI Pharmacology (lecture)
Which is reversible and which is irreversible - PPIs and H2 receptor blockers? |
PPIs = Irreversible Covalent Binding!
H2 receptor blockers are competitive antagonists |
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GI Pharmacology (lecture)
PPIs (-prazoles) Mechanism of Action? PK? Indications? Toxicities? |
Mechanism of Action – Irreversible Covalent Binding!
Pro drug has to be protonated in the parietal cell before becoming activated and interacts covalently causing inhibition of the pump so the effect is present after disappearance of drug from plasma, so saturation can block pumps until the stomach can make new pumps. Acid production is decreased by 95%. Pharmacokinetics – Degraded by stomach if unprotected, so they are coated or delivered with a base. Half-life – 2 hours but duration of action is 1+ days. Some pumps may be dormant at the time of administration of the medication and so may not have an effect on all the pumps. Need to adjust dosing? Metabolized by the liver Omeprazole(am) + Ranitidine(pm) have best effect! Omeprazole Clinical Indications – PUD, GERD, Zollinger-Ellison syndrome (ulcer from acid hypersecretion) Toxicities – False alarm regarding hypergastrinemia-hyperplasia and ECL carcinoid tumours – only found in rats… Potential bacterial overgrowth in bowel Inhibits CYP450 Increased risk of community acquired pneumonia Osteoporosis (one-study phenomenon) |
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GI Pharmacology (lecture)
Ranitidine |
histamine H2-receptor antagonist
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GI Pharmacology (lecture)
Omeprazole |
PPI
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GI Pharmacology (lecture)
____________ controls nocturnal acid breakthrough on omeprazole. |
Ranitidine -- better than another dose of omeprazole
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GI Pharmacology (lecture)
Sucralfate |
Sulfated Polysaccharides (Protective Mucosal Barrier)
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GI Pharmacology (lecture)
Sulfated Polysaccharides: Name? Mechanism of Action? PK? Indications? Toxicities? |
Sucralfate
Mechanism of Action – Activated by acid, forms a gel that binds electrostatically to positively charges protein molecules in ulcer craters. Inhibits pepsin and adsorbs bile salts Pharmacokinetics – Excreted unchanged Constipation and renal failure (Aluminium) Should be taken on an empty stomach to prevent binding to protein in food. Clinical Indication – Stress ulcers, PUD, Bile-reflux disease Toxicites – Constipation Reduces bioavailability of phenytoin, digoxin, theophylline since it is a resin. |
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GI Pharmacology (lecture)
Protective Mucosal Barrier categories? (2) |
Sulfated Polysaccharides (sucralfate)
Prostaglandin Analogue |
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GI Pharmacology (lecture)
Prostaglandin Analogue Name? Mechanism of Action? PK? Indications? Toxicities? |
Misoprostol
Mechanism of Action – Anti-secretory – Inhibits basal acid secretion Cytoprotective – Increases mucous and bicarbonate production Pharmacokinetics – Well-absorbed orally Clinical Indication – Gastric ulcers in patients on chronic NSAIDs Toxicites – Uterine contractions – abortions Diarrhea, Abdominal cramping |
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GI Pharmacology (lecture)
Misoprostol |
Prostaglandin Analogue
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GI Pharmacology (lecture)
H Pylori: Associated disease Mechanism of disease Treatment |
H. pylori
Gram Negative Rod associated with gastritis, most gastric and duodenal ulcers, adenocarcinoma, gastric B cell lymphoma Mechanism of Action – Decrease in antral D cells – decrease in somatostatin – increase in serum gastrin – increase in acid production Treatment – [C+A/M] Clarithromycin + Amoxicillin (or Metronidazole) + PPI for 10-14 days (resistance is increasing) |
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GI pharmacology (lecture)
Diagram shows a number of neurotransmitter systems acting on the myenteric plexus. Which one do we have to know? |
Prokinetic:
Serotonin (5-HT) - specifically 5HT-4 receptor (& "motilin-like agents' - macrolides - activate motilin receptors) Also prokinetic: --ACh muscarinic receptor agonists --Dopamine antagonists |
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GI pharmacology (lecture)
Metoclopramide |
5HT-4 receptor agonist
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GI pharmacology (lecture)
Tegaserod |
Partial agonist of 5HT-4
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GI pharmacology (lecture)
Metoclopromide Name of drug? Mechanism of Action – Pharmacokinetics – Clinical Indication – Toxicities – |
Metoclopromide –
Mechanism of Action – 5-HT4 receptor activation (primary), (dopamine antagonist and cholinergic agonist (secondary)) Enhances smooth muscle contraction of upper gut and accelerates gastric emptying Increases LES tone Anti-emetic effect (dopamine antagonism) Pharmacokinetics – Half-life increases in patients with renal failure Clinical Indication – Gastroparesis, GERD, Nausea/vomiting Toxicities – Somnolence, nervousness Reversible extrapyramidal motor effects (Parkinson-like) Irreversible tardive dyskinesia |
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GI pharmacology (lecture)
Tegaserod Mechanism of Action – Pharmacokinetics – Clinical Indication – Toxicities – |
Mechanism of Action –
High affinity binding to serotonin 4 receptors, partial agonist Stimulates peristalsis and secretion in whole gut Decreases visceral sensitivity (imp for patients with IBD) Affects the whole gut! Unlike Metoclopromide Pharmacokinetics – Metabolized by liver and eliminated by kidneys ~1/3 absorbed, less when taken with food Clinical Indication – IBS (with constipation) in women, Chronic constipation, Gastroparesis/GERD Toxicities – Diarrhea |
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GI pharmacology (lecture)
Emetic stimuli? Drugs that have other primary mechanisms that have anti-emetic effects: (4) |
Emetic stimuli –
The Chemoreceptor Trigger Zone can sense local irritants, emetics, etc and induce vomiting. Motion sickness occurs via the inner ear and the cerebellum. Gagging occurs via the pharynx and solitary tract nucleus. Fear, dread, and anticipation can cause vomiting via higher brain centers. Important receptors involved are Serotonin, Dopamine, Muscarinic, Histamine receptors. Drugs that have other primary mechanisms that have anti-emetic effects: Serotonin antagonists (Ondanestron) Dopamine antagonists Benzodiazepines Antihistamine – Anticholinergic agents |
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GI pharmacology (lecture)
Ondanestron Drug class? Mechanism of Action – Pharmacokinetics – Clinical Indication – Toxicities – |
Antiemitic
Mechanism of Action – Blocks serotonin receptors in the CNS (chemoreceptor trigger zone) Blocks vagal afferent fibers in the GI tract Pharmacokinetics – Well absorbed Metabolized by CYP450 Effects lasts longer than drug plasma level Clinical Indications – Chemo-induced, upper gut obstruction, pregnancy, post-op nausea Not for motion sickness Toxicities – Well tolerated Diarrhea, constipation, headache, lightheadedness Financial! |
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GI pharmacology (lecture)
Prochlorperazine |
Phenothiazine antiemitic
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GI pharmacology (lecture)
Other antiemitics (besides Ondanestron) -Most commonly used? |
Phenothiazines –
Blocks dopamine at CTZ Better than ondansetron for motion sickness Prochlorperazine |
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GI pharmacology (lecture)
Ondanestron blocks _________. Prochlorperazine blocks __________. |
SerotoniN
DopaminE |
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GI pharmacology (lecture)
Motion sickness drug? Mech? |
Anticholinergics –
Motion sickness Anti-muscarinic Scopolamine |
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GI pharmacology (lecture)
3 exta anti-emitic drug classes: |
Prokinetic drugs –
Anti-dopamine activtity in CTZ as well Metoclopramide and Domperidone Antihistamines – Useful for motion sickness and post-op emesis Promethazine, Diphenhydramine Cannabinoids – Stimulation of cannabinoid receptors Dronabinol |
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GI pharmacology (lecture)
Promethazine, Diphenhydramine |
Antihistamines
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GI pharmacology (lecture)
Dronabinol |
Cannabinoid
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GI pharmacology (lecture)
Normal stool has _______% of its weight = water Faster transit time => Slower transit time => The absorptive capacity of the colon is ___ liters per day. |
70-85%
Faster transit time = less fluid absorption = diarrhea Slower transit time = more fluid absorption = constipation 4-5L/day |
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GI pharmacology (lecture)
Psyllium |
Intraluminal hydroscopic agent (metamucil) - absorb excess water
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GI pharmacology (lecture)
Cholestyramine |
Intraluminal Bile salt binder
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GI pharmacology (lecture)
Bismuth subsalicylate Mech? Effects? |
Intraluminal bismuth
Antisecretory, anti-inflammatory, antimicrobial effects Mech unknown |
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GI pharmacology (lecture)
Hydroscopic agents |
Absorbs excess water
Examples – Psyllium (Metamucil), |
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GI pharmacology (lecture)
Bile salt binders |
Mechanism – Bind excess bile salts to avoid colon secretion
Examples – Cholestyramine |
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GI pharmacology (lecture)
Loperamide |
Opioid Antimotility and Antisecretory agent
(Imodium A-D) |
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GI pharmacology (lecture)
Opioid Antimotility and Antisecretory agents Mech Example PK Indication Toxicity |
Mechanism of Action –
Increase fluid absorption, decrease fluid secretion, Decrease motility (increase transit time) by decreasing longitudinal muscle action and increasing segmentation Examples – Loperamide (Imodium A-D) Pharmacokinetics – Limited CNS penetration 40-50 times more potent than morphine with a quick onset, reaches plasma level quickly, and is metabolized in the liver Clinical Indication = Diarrhea Toxicities – Sedation and paralytic ileus |
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GI pharmacology (lecture)
Laxatives and Cathartics General approaches to Constipation (3) |
Retention of intraluminal fluid by hydrophilic or osmotic mechanisms
Decreased net absorption of fluid Inhibit segmenting/nonpropulsive contractions AND/OR stimulate propulsive contractions |
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GI pharmacology (lecture)
Dioctyl sodium sulfosuccinate |
Emollients - stool softener
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GI pharmacology (lecture)
Emollients – Mech? Example? Use? |
Mechanism of Action –
Active in the lumen Decreases the surface tension of stool permitting penetration of water and fats Examples – Dioctyl sodium sulfosuccinate (docusate sodium – colace) Used more for hard stools than for constipation |
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GI pharmacology (lecture)
Bulk-forming laxatives – Mech? Use? |
Hydrophilic compounds which hold water in the stool and inhibit absorption of bile acids stimulating water secretion by the colon
Used for IBD more than constipation |
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GI pharmacology (lecture)
Most commonly used laxatives? |
Mg salts
i.e. The saline laxatives such as milk of magnesia are poorly absorbed agents that act as hyperosmolar solutions. |
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GI pharmacology (lecture)
Mg salts Mech? (2) |
Laxatives:
Increases the intraluminal osmolarity which increases water retention May stimulate CCK secretion which increases gut motility |
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GI pharmacology (lecture)
Bisacodyl? anthraquinone? Drug class? Mech? risks? |
They directly affect enterocytes, enteric neurons, and muscle
Mechanism - Induce low inflammation in the small bowel and colon, thereby increasing intraluminal sections and electrolyte concentrations, thereby stimulating motility anthraquinone laxatives risk: cathartic colon with years of abuse, which causes neuron loss and atrophy of muscularis propria (Not for long term use) |
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GI pharmacology (lecture)
Stimulant cathartics – |
They directly affect enterocytes, enteric neurons, and muscle
Mechanism - Induce low inflammation in the small bowel and colon, thereby increasing intraluminal sections and electrolyte concentrations, thereby stimulating motility Examples are Bisacodyl (Dulcolax, correctal) and anthraquinone laxatives (aloe, senna), which causes a cathartic colon with years of abuse, which causes neuron loss and atrophy of muscularis propria (Not for long term use). Ricinoleic acid (castor oil) works by increasing the small intestinal stimulation of fluid and electrolye secretion which results in speedier intestinal transit times but can have potentially toxic side effects on intestinal epithelium and enteric neurons. |
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GI pharmacology (lecture)
Non-absorbable sugars – lactose, glycerin, sorbitol, mannitol What about them? eh? |
Not absorbed by the small intestine and reaches the colon where it is metabolized to organic fatty acids that are osmotically active and increase fluid accumulation increasing motility in the colon.
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UpToDate (Dysphagia):
The term "odynophagia" refers to |
pain with swallowing.
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UpToDate (Dysphagia):
Dysphagia to both solids and liquids from the onset of symptoms is probably due to ______________. In contrast, dysphagia for solids that later progresses to involve liquids is more likely to reflect ____________. |
a motility disorder of the esophagus
mechanical obstruction |
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UpToDate (Dysphagia):
Progressive mechanical dysphagia is usually caused by _______ or _________, while intermittent dysphagia is most often related to ___________. However, patients with motility disorders may also have progressive (usually _________ or _________) or intermittent (usually ____________, or nonspecific motility disorders) dysphagia. |
cancer OR a peptic stricture (GERD changes to lower esophagus)
a lower esophageal ring achalasia (regurg+respiratory+weightloss) OR scleroderma (chronic heartburn seen) diffuse esophageal spasm |
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UpToDate (Dysphagia):
Is heartburn specific in a dysphagia patient? |
No. -- may be a clue to the presence of complications of gastroesophageal reflux disease, such as erosive esophagitis, peptic stricture, and adenocarcinoma of the esophagus.
BUT, patients with achalasia may complain or heartburn. Scleroderma too. |
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UpToDate (Dysphagia):
Categories of esophageal dysphagia: (3) |
(1) Mechanical lesions
--a. Intrinsic (Benign tumors, Caustic esophagitis/stricture, Diverticula, Malignancy, Peptic esophagitis/stricture, Eosinophilic esophagitis, Pill esophagitis, Post surgery (laryngeal, esophageal, gastric), Radiation esophagitis/stricture, Rings and webs --b. Extrinsic (Aberrant subclavian artery, Cervical osteophytes, Enlarged aorta, Enlarged left atrium, mediastinal mass (lymphadenopathy, lung cancer, etc.), Post surgery (laryngeal, spinal) (2) Motility disorders (Achalasia, Chagas' disease, Diffuse esophageal spasm, Hypertensive lower esophageal sphincter, Nonspecific esophageal motility disorder, Nutcracker esophagus, Scleroderma) (3) Functional - Functional dysphagia |
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UpToDate (Dysphagia):
What is a Schatzki ring? |
A ring found in the lower part of the esophagus that can cause difficulty swallowing. The ring is made up of mucosal tissue (less common: muscular tissue). Patients with Schatzki rings can develop intermittent dysphagia (difficulty swallowing), or, more seriously, a completely blocked esophagus.
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Swallowing Disorders and Reflux Disease
Normal Swallowing: Airway protection? Upper Esophageal Sphincter action? LES action? Flow= ? Deglutition? |
Airway protection from consumed food
Epiglottis tilts backwards Larynx elevates Vocal cords come together Coughing Inhibition of respiration Upper Esophageal Sphincter – Separates the pharynx from the esophagus Blocks the esophagus tonically Prevents inhaled air from filling the esophagus and prevents regurgitation of food into larynx. Lower esophageal sphincter, or LES, is also tonically contracted. It separates esophagus from stomach, preventing reflux of irritating gastric contents into the esophagus. Flow = Pressure/ Resistance Weak pressure and increased resistance prevent flow of material Deglutition – It is the act of initiating the swallowing sequence |
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Swallowing Disorders and Reflux Disease
Weaker deglutition muscles - striated or smooth? Neural control? |
Transition from striated to smooth muscle has a weakening of contractions because of different anatomy.
Vagal stimulation makes striated muscle contract as long as stimulation is present. This part of the muscle is under direct CNS control. Once the stimulation ends the smooth muscle begins to contract. Smooth muscle contractions are intrinsic to the muscle and are not under CNS control, and begin at the end of vagal stimulation. |
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Swallowing Disorders and Reflux Disease
progressive peristalsis |
A coordinated contractile wave begins in the pharynx and continues through the esophagus pushing the swallowed bolus before it.
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Swallowing Disorders and Reflux Disease
Duration Response |
– Longitudinal muscle (outer layer) shortens the esophagus during the stimulus.
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Swallowing Disorders and Reflux Disease
On response – Off response – Latency gradient? Deglutitive inhibition? |
With swallowing/neural signal (which causes longitudinal muscle to contract), there is a weak, transient, simultaneous contraction of the circular smooth muscle throughout the esophagus (the on response).
The main contraction is initiated only with the termination of neural stimulation (the off response). There is an intrinsic delay between the end of the stimulation and the actual muscular contraction (the latency period). Upper: CNS coordination of the striated muscles Lower: intrinsic coordination of the esophageal smooth muscle -- The latency period of the esophageal smooth muscle increases with distance from the pharynx, producing a latency gradient which is responsible for the coordinated propagation of the peristaltic wave. During a sequence of rapid swallows, the initiation of esophageal peristalsis is delayed, and LES relaxation is sustained, until the last swallow (deglutitive inhibition). |
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Swallowing Disorders and Reflux Disease
Primary and secondary peristalsis? |
Primary = normal, coordinated peristaltic wave initiated by a swallow
Secondary = 'clean up' - Distention produces a coordinated contractile wave that begins just above the level of distention. (also normal) Tertiary peristalsis (or more accurately tertiary contractions) on the other hand refers to abnormal, uncoordinated contractions. |
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Swallowing Disorders and Reflux Disease
Penetration v. Aspiration |
penetration is a term used when, during objective studies (either laryngoscopy or barium studies), a portion of the swallowed bolus enters the larynx but remains above the vocal cords. Aspiration is used when this material passes beyond the cords into the trachea.
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Swallowing Disorders and Reflux Disease
Mechanisms of Dysphagia Structural: Luminal Stenosis (Strictures) Types? Type of dysphagia? When do people get symptoms? Dx? Tx? |
Narrowing of the esophageal lumen – webs and Schatzki’s rings
Dysphagia of solid foods only Can occur as a result of GERD Less than 10mm – everyone is symptomatic Greater than 20mm – no-one is symptomatic Diagnosis – Barium study followed by endoscopy to treat/biopsy Treatment – Surgery or dilation |
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Swallowing Disorders and Reflux Disease
Mechanisms of Dysphagia Structural: Diverticulum What is it? Types? When do people get symptoms? Dx? Tx? |
Diverticulum formation
A diverticulum is a pouch extending out from the lumen. They may occur in the hypopharynx just above the UES (Zenker’s diverticulum), or esophagus (esophageal diverticulum), most often located in the distal esophagus. They become symptomatic when they become large. Need to find out the cause of the diverticulum to stop it from recurring since they can occur as a results of luminal stenosis. Diagnosis – Barium Studies Treatment – treat the underlying problem or surgery (diverticulectomy) |
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Swallowing Disorders and Reflux Disease
Mechanisms of Dysphagia Motor Paresis What can cause this? How does it present? |
Usually a neurological disorder (CVAs, ALS, head and neck trauma, or brain surgery) can affect swallowing. Rarer - It often accompanies connective tissue disorders, especially scleroderma.
Dysphagia is usually for liquids and solids. Coughing during swallowing is common in patients with pharyngeal weakness, both because of the weakness of the pharyngeal constrictor muscles and because of impaired laryngeal closure. Bolus transit is generally by gravity, assisted by tongue thrust when tongue function is not also affected. LES is involved and becomes weak, so there is reflux from the stomach Diagnosis – Barium study or Video recordings (needed for pharyngeal barium study) Treatment – None available, can try to increase contractility |
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Swallowing Disorders and Reflux Disease
Zenker’s diverticulum |
Diverticula in the hypopharynx just above the UES
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Swallowing Disorders and Reflux Disease
Mechanisms of Dysphagia Motor Sphincteric Dysfunction Describe. Dx? Tx? |
Isolated sphincteric dysfunction of both the UES (cricopharyngeal dysfunction) and LES (isolated LES dysfunction or the hypertensive LES) may cause dysphagia.
best described disorder - Achalasia – Irreversible damage to the ganglion of the myenteric plexus results in severe esophageal paresis combined with failure of the LES to relax. It can be Classical (no motility) or Vigorous (spastic contractions that are not progressive). Regurgitation can occur hours after eating. Diagnosis – Barium studies Endoscopy is required to rule out a stricture Treatment – Weaken or tear the sphincter! Smooth muscle relaxant – Calcium channel blockers, nitrates Botulinum toxin Large – diameter balloon dilatation Surgery |
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Swallowing Disorders and Reflux Disease
Mechanisms of Dysphagia Motor Uncoordinated Motor Function Describe. (2) Symptom? Tx? |
dysmotility noted by barium or manometric studies
Tertiary Contraction – It is an individual abnormally coordinated contraction. Diffuse Esophageal Spasm – It is a diffuse condition resulting in uncoordinated contractions. It is often idiopathic. Symptoms include dysphagia for liquids and solids, regurgitation immediately after swallowing, and/or chest pain. Chest pain is a common symptom, which is a result of spasms in the esophagus. Chest pain is also seen in patients suffering from nutcracker esophagus (high or prolonged peristaltic contractions) and in visceral hyperalgesia (an abnormality of sensory perception, which can cause esophageal spasms in the absence of esophageal motility). Treatment – (Aimed at decreasing the amplitude of spasms) Nitroglycerin, Reflux is the most common secondary cause of DES so in this case, treat reflux more than spasm |
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Swallowing Disorders and Reflux Disease
GERD Common symptoms? Why does it occur? Normal factors preventing reflux? (3) Dx? Best test? Tx? |
Common symptoms include a burning sensation behind the sternum as well as regurgitation of sour or bitter tasting contents.
It occurs when there is a problem with the anti-reflux barrier Multiple factors prevent reflux Normal anatomic configuration of gastro-esophageal junction (barium studies/endoscopy) Normal strength and function of LES (manometry) Higher LES resting pressure Presence of an axial hiatal hernia and low resting pressure increases the likelihood of GERD Diagnosis – Acid perfusion test Barium swallow (used mostly for strictures) Endoscopy (best test for esophagitis) Continous pH monitoring – best test!! PPI test (used to rule out extra-esophageal symptoms causing chest pain) Treatment – Diet modification Lifestyle modification Drugs – Antacids, H-2 blockers, PPI, prokinetic agents Fundoplication (Anti-reflux surgery) |
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Swallowing Disorders and Reflux Disease
Patients who have a fixed axial hiatal hernia (also called a sliding hiatal hernia), in which the EG junction has been displaced above the diaphragm, and those with a low LES resting pressure, are much more likely to have .... |
reflux
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Swallowing Disorders and Reflux Disease
the PPI test |
trend towards using a brief course of high-dose proton pump inhibitors as an alternative to objective testing by CpHM for the diagnosis of reflux as a cause of chest pain or extraesophageal symptoms
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Gastric Secretion and Peptic Ulcer Disease
The epithelial lining of the stomach has folds called ______, which invaginate into microscopic gastric pits. Each pit opens into ____ glands. Cell types: Cardiac region – 2 Fundus region – (5) Body – (5) Pyloric Antrum – 3 Pylorus – 3 |
rugae
4-5 Cardiac region – Mucous cells Endocrine cells Fundus region – Parietal cells Chief cells Mucous neck cells Endocrine cells ECL cells (histamine) Body – Parietal cells Chief cells Mucous neck cells Endocrine cells ECL cells Pyloric Antrum – G cells Mucous cells Endocrine cells Pylorus – G cells Mucous cells Endocrine cells Endocrine cells may contain: gastrin, histamine, endorphins, serotonin, cholecystokinin (CCK), and somatostatin |
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Gastric Secretion and Peptic Ulcer Disease
The vagal nerve promotes acid secretion via Acetylcholine in three ways: |
1. Simulates muscarinic receptors on parietal cells to increase HCl
2. Stimulates ECL cells to release histamine (which stim’s parietal cells) 3. Interacts with D cells to suppress the release of Somatostatin |
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Gastric Secretion and Peptic Ulcer Disease
Cells of the stomach: Mucous neck cells ? Parietal cells Enterochromaffin cells Chief Cells D cells G cells |
Mucous neck cells
Produce mucous (barrier between lumen and epithelium) Produce bicarbonate (buffers gastric acid) Prostaglandins are important from mucosal protection and use of NSAIDs can result in damage to the gastric mucosa. Parietal cells Produce HCl In the resting state, parietal cells have many tubulovesicles that are impermeable to K+. When stimulated, these tubulovesicles fuse with each other and with the apical membrane forming canaliculi, which contain proton pumps. The proton pumps exhcnage K+ back into the cell for H+ out of the cell and Cl- follows in equimolar concentrations. When stimulated, the parietal cells become permeable to K+ allowing the pumps to function. The resultant secretion has a pH ~1. Production is stimulated by ACh, Histamine, and Gastrin Produce Intrisic Factor (complexes with B12 to permit absorption) Enterochromaffin cells Produce Histamine 1. H2 receptors on parietal cells to increase HCl 2. H3 receptors on D cells to decrease Somatostatin Chief Cells – Produce Pepsinogen and Gastric Lipase Pepsin has a positive feedback mechanism D cells – Produce Somatostatin in response to a decreased pH and blocks HCl production by parietal cells G cells – Produce gastrin stimulated by Gastrin Releasing Peptide (GRP) and amino acids |
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Gastric Secretion and Peptic Ulcer Disease
Stomach Contains a low pH but doesn’t auto-digest because of: (4) |
Thick bicarbonate rich mucus on stomach wall
Epithelial cells joined by tight junctions Gastric glands have cells that are impermeable to HCl Damaged cells are quickly replaced |
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Gastric Secretion and Peptic Ulcer Disease
Regulation of Gastric Secretions Highest secretions occur when? Stimulatory and inhibitory events occur in three phases: |
in the evening and lowest in the early morning
[High vagal tone=>basal hypersecretion or temp. stress hypersecretion. M>F.] Cephalic (reflex) phase: Prior to food entry Mediated by the vagus nerve Excitatory – sight or thought of food, stimulation of taste and smell receptors Inhibitory – loss of appetite, depression, decrease in parasympathetic stimulation Gastric phase: once food enters the stomach Mediated by neural reflex pathways and G cell stimulation Excitatory – distenstion, stretch and chemoreceptors, release of gastrin into blood Inhibitory – low pH, emotional distress that overrides parasympathetic drive Intestinal phase: as partially digested food enters the duodenum Mediated by gastrin and direct stimulation of parietal cells Excitatory – low pH, entry of partially digested food Inhibition – distension, presence of irritants or fatty, acidic, hypertonic chyme, it results in closure of the pyloric sphincter and release of enterogastrones that inhibit gastric secretions |
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Gastric Secretion and Peptic Ulcer Disease
_________ cells are the major driver of gastric acid production and are stimulated by production of Ach, histamine, and gastrin |
Parietal
Gastric Acid production is highest if all three ligands bind to parietal cells. |
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Gastric Secretion and Peptic Ulcer Disease
H. pylori colonizes where? It produces what? This affects what cells? ... with what effect? |
H. pylori is not an invasive organism and lives adjacent to gastric epithelial cells. It colonizes gastric mucin cells but does not invade. It produces urease, which lets it buffer the environment. It is a selective H3 agonist which is probably why it leads to a decrease in the number of antral D cells resulting in a decreased level of Somatostatin and increased basal acid level.
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Gastric Secretion and Peptic Ulcer Disease
H. pylori is associated with: (5) |
Gastritis
Gastric and Duodenal ulcers Diffuse type adenocarcinoma Intestinal type adenocarcinoma Gastric lymphoma |
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Gastric Secretion and Peptic Ulcer Disease
Association with H. pylori: Duodenal Ulcers Who gets 'em? What causes it? What's it look like (histology)? Symptoms? Tx? |
Duodenal Ulcers – It is a chronic disease, predominantly affecting young males, and has a high recurrence rate. It occurs because the stomach supplies the duodenum with more acid than it can handle, due to H. pylori infection, and the cells in the duodenum undergo metaplasia to gastric mucin cells which become damaged and have a decreased resistance to acid. Symptoms include indigestion and epigastric pain that occurs 2-3 hours after eating and is relieved with eating (food increases luminal pH). H. pylori gastritis is observed in all patients with DU. Treating the infection can stop recurrence of duodenal ulcers.
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Gastric Secretion and Peptic Ulcer Disease
Association with H. pylori Gastric Ulcers Where are these ulcers? How do they present? RFs? Tx? |
– It is usually located in the antrum and presents as pain following ingestion of food (15-20 minutes). Fasting and nocturnal pain is rare unlike in DU. Patients usually have H. pylori gastritis (70-80%) or have increased NSAID use. Suppression of gastric acid is a good treatment but unless the organism is eradicated, GU will recur. Patients that continue to take NSAIDs have a slower healing rate.
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Gastric Secretion and Peptic Ulcer Disease
Zollinger-Ellison Syndrome What is it? Dx? Tx? |
Triad of: Basal gastric acid hypersecretion (>15mmol per hour), Pancreatic Islet cell tumour, post bulbar DU.
Diagnosis is via serum gastrin levels (which should be elevated) and via a secretin test (where secretin is infused via I.V. and results in an increase in serum gastrin levels by more than 200pg/dl in ZE patients whereas normal patients have no change or a decrease in serum gastrin levels). Diarrhea is common due to intestinal fluid overload, and some paitents may also have MEN1 (Multiple Endocrine Neoplasia type 1 syndrome) and die of malignancies (50% in 10 years). Therapy is with PPIs but is not curative. |
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Gastric Secretion and Peptic Ulcer Disease
Stress Ulcers What are they? Where are they? Why are they? |
These are solitary or multiple ulcers or erosions presenting with upper GI bleeding (tarry black stool) and are located in the fundus or body of the stomach. They occur in states where mucosal flow is decreased (due to shock, hypovolemia, severe burns, etc) and result in low mucus and HCO3- production causing a compromise in gastric mucosal protection. If pH is maintained about 4, the ulcers are prevented.
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Gastric Secretion and Peptic Ulcer Disease
Diagnosis of H. pylori infection (5) Tx? |
Culture
Histology Rapid urease test 13C or 14C – Urea breath test Serology – ELISA PPI based triple therapy PPI AND Clarithromycin AND Amoxycillin or Metronidazole |
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Gastric Secretion and Peptic Ulcer Disease
H. pylori negative ulcers are caused by (meds) |
NSAIDs and Aspirin. NSAIDs inhibit either COX-2 only (anti-inflammatory only) or COX-1 and COX-2. The latter induces damage of gastric mucosa. NSAIDs block the mucus and bicarbonate production allowing gastric acid to damage the epithelial layer.
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Fat Absorption and Malabsorption
Passage of food into the body and failure of this process results in malabsorption It can be generalized (eg. _______) or specific (__________) |
Generalized - Celiac disease
Specific - pernicious anemia |
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Fat Absorption and Malabsorption
________ is a symptom of fat malabsorption. It results in _________ stool. |
Steatorrhea
foul, oily |
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Fat Absorption and Malabsorption
____________ is the major chemical constituent in animal fat or vegetable oil and is a concentrated source of fat (9 kcal/g). |
Triglyceride
[Cholesterol is of no nutritional significance] |
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Fat Absorption and Malabsorption
Fat Absorption (8 steps) |
1. Emulsification of dietary fat
2. Release of cholecystokinin-pancreozymin (CCK-PZ) 3. Pancreatic Lipolysis 4. Solubilization by micelles 5. Mucosal Uptake 6. Triglyceride Re-synthesis 7. Chylomicron formation 8. Lymphatic Transport |
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Fat Absorption and Malabsorption
Fat Absorption 1. Emulsification of dietary fat a. ______ due to motility of stomach which results in breakdown of components b. The purpose of emulsification is to increase the _____________ between water and lipid where ________ takes place. 2. Release of cholecystokinin-pancreozymin (CCK-PZ) a. _____ and ______ evoke the release of CCK-PZ from the _____________. b. CCK-PZ induces ________ contraction and relaxation of the _____________. As a result, the gallbladder’s contents are discharged into the duodenum. c. CCK-PZ induces the discharge of zymogen granules into the ________ and possibly synthesis of new enzymes. The final result is the discharge of ____________ into the ____________. Enzymes are secreted as proenzymes and are activated as enterokinase. 3. Pancreatic Lipolysis a. ___________ is responsible for hydrolysis of dietary triglyceride. The enzyme is secreted in the _____ form and absorbs to the oil water interface, where is partially hydrolyses triglyceride molecules. This is position specific. b. The enzyme works extremely rapidly and in the presence of bile acids has an optimal pH ___ during fat digestion. There is ten-fold excess, therefore, lipase concentrations must be reduced by __% before steatorrhea is observed. c. Two additional enzymes involved in lipid digestion are present in pancreatic juice: a nonspecific esterase, which hydrolyses ______________; and a phospholipase, which hydrolyses _________. The 1-lysolecithin, which is formed, is water-soluble. |
Mixing
surface interface, lipolysis Fatty acids and certain essential amino acids, the proximal small intestine gallbladder, sphincter of Oddi pancreatic acini, pancreatic enzymes and proenzymes, duodenum Pancreatic lipase, active form (not as a proenzyme) pH 6-7 identical to that present in the duodenum and jejunum during fat digestion 90% cholesterol esters and other ester lipids, lecithin |
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Fat Absorption and Malabsorption
4. Solubilization by micelles a. ________ are synthesized in the liver, stored in the gall bladder, secreted into the small intestine, and returned to the liver from the ______ via portal circulation. This cycle is called the _____________. They solubilize the otherwise droplet-forming TG breakdown products (and cholesterol and fat-sol. vitamins; not TGs). 5. Mucosal Uptake a. Via a __________ protein 6. Triglyceride Re-synthesis a. The primary pathway is monoglyceride acylation in which one molecule of 2-monoglyceride is jointed to _____________. 7. Chylomicron formation a. The lipid droplets are provided a ________ coat to become aqueous and extruded through lateral and basal cell membrane of the absorbing enterocyte. 8. Lymphatic Transport a. The chylomicrons are too large to enter the intestinal capillaries but enter the ___________ and then to thoracic duct and general circulation. |
Bile acids, ileum, enterohepatic circulation of bile acids
fatty acid binding protein two molecules of fatty acid CoA lipoprotein coat lymphatics (lacteals) |
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Fat Absorption and Malabsorption
Defects in Fat Absorption 1. Emulsification of dietary fat 2. Release of cholecystokinin-pancreozymin (CCK-PZ) 3. Pancreatic Lipolysis 4. Solubilization by micelles 5. Mucosal Uptake (6. Triglyceride Synthesis - none mentioned) 7. Chylomicron formation 8. Lymphatic Transport |
1. Emulsification
Loss of gastric churning caused by vagotomy, gastric resection, gastric motility dysfunction, or gastro-jejunostomy 2. CCK-PZ Release a. Due to surgery (post gastrectomy) when the duodenum is bypassed. 3. Pancreatic Lipolysis a. Seen in patients with history of chronic pancreatitis due to excessive alcohol intake, cystic fibrosis etc. They cannot secrete enzymes including lipase. You need to reduce lipase output by 90% to see a defect in fat absorption. Low pH in the duodenum (caused by Zollinger-Ellison syndrome) can inactivate pancreatic lipase. 4. Micelle Formation a. Decreased bile acid secretion (liver dz, eg.) b. Precipitation of the bile salts in the intestinal lumen by low pH or drugs, and deconjugation by an overgrowth of bacteria 5. Mucosal Uptake a. Diseases associated with epithelial cell damage such as celiac disease, tropical sprue, intestinal infections and extensive surgical resection of the small intestine. 6. Chylomicron Formation a. Failure to synthesize the protein coat results in failure to export the absorped lipid. b. Abetalipproteinemia – Autosomal Recessive – Cannot make chylomicrons, see fat in the enterocyte that cannot leave 7. Lymphatic Transportation a. Tumours, infections, or trauma, which involve the lymphatics, interfere with transport of lipids (e.g. Whipple's Disease) |
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Fat Absorption and Malabsorption
Clinical Evaluation of Malabsorption Symptoms (8) Findings (5) Tests (3) |
Clinical Evaluation of Malabsorption
Symptoms Weight loss – Calories Steatorrhea – Fat Diarrhea – OH-Fatty acids Anemai – Fe, B12, Folate Edema – protein Osteoporosis – Ca, Protein Milk Intolerance – Lactose Bleeding/Bruising – Vitamin K Findings Hypoalbuminemia Hypcalcemia Increased prothrombin time Reduced carotene level Abnormal small bowel series Tests C14 Triolein breath test Stool Sudan staining (fat turns orange) 72-hour fecal fat collection (positive when more than 6g of fat per day) |
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Fat Absorption and Malabsorption
What is the problem? Stomach (1) Intestine – Intraluminal – (3) Mucosal – (2) Removal – (2) |
Stomach – Emulsification
Intestine – Intraluminal – CCK-PZ Release, Lipolysis, Micelle Formation Mucosal – Mucosal Uptake, Chylomicron Formation Removal – Lymphatic System, Thoracic Duct |
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Fat Absorption and Malabsorption
Evaluations: Lundh test Bentiromide test |
Intraluminal – Pancreatic exocrine tests
Lundh test –no longer used – was 300cc liquid test meal with duodenal fluid collection Bentiromide test (procedure done to test for pancreatic sufficiency where they drink Bentiramide, which would normally be cleaved by chymotrypsin to form PABA and would be secreted in the urine, so lack of PABA implies pancreatic insufficiency) |
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Fat Absorption and Malabsorption
Evaluations: D-xylose absorption test: Describe this test. What does it test? What are two complementary to test this (... mucosa)? |
Mucosal –
D-xylose absorption test (uses D-xylose which is a simple sugar (no digestion req'd) taken up by SI and is excreted in the urine under normal circumstances, and when negative implies that patients is not taking up substance from the small intestine so it is a mucosal problem) Small bowel series (x-rays utilize barium contrast to outline the mucosa of the small intestine and evaluate for mucosal abnormality) Mucosal biopsy (can be diagnostic, characteristic, or non-specific) |
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Fat Absorption and Malabsorption
Glucose hydrogen breath test |
(feed glucose ... patients that have excess amounts of bacteria which metabolizes the glucose and liberates a hydrogen ion that is detected in their breath)
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Fat Absorption and Malabsorption
Schilling test |
(Part 1: administer a big IM dose of B12 and then give them radioactive B12 so they urinate out the all the radioactive B12; if there is a lot in the urine, it implies the patient absorbed the vitamin (so their diet is low!), but if there is none in the urine, the patient didn’t absorb any which means you have to do Part 2; Part 2: administer radioactive B12 and IF and if they absorb it now, they have pernicious anemia, but if they still don’t absorb it, they had surgical removal of their bowel and they now lack receptors; Part 3: give antibiotics and test them again; Part 4: R factor is added to B12 which is later cleaved by pancreatic enzymes and this is tested in Part 4)
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Fat Absorption and Malabsorption
Removal – |
Mucosal biopsy (can be diagnostic, characteristic, or non-specific)
Mesenteric lymphangiography |
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FUNCTIONAL GASTROINTESTINAL DISORDERS
Gastroparesis, Constipation, IBS, etc. Based on a ___________ of symptoms (6) Need a comprehensive approach and not just rely on pharmacology All affect _________ predominantly |
constellation
(nausea, vomiting, bloating, pain, diarrhea, constipation) women |
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FUNCTIONAL GASTROINTESTINAL DISORDERS
Gastroparesis, Constipation, IBS Gastroparesis It is the __________ emptying of the stomach in the absence of ______________. Gastropathy is ____________. Most incidences of gastroparesis are ____________. |
delayed, absence of mechanical obstruction
the constellation of symptoms suggestive of delayed gastric emptying idiopathic (followed by diabetes, post-surgical) |
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FUNCTIONAL GASTROINTESTINAL DISORDERS
Gastroparesis, Constipation, IBS Gastroparesis Dx (early vs. late)? Tests? (2) Are symptoms diagnostic? |
Diagnosis –
Early – Normal physical exam Late – Succussion splash, weight loss, dehydration Tests – Endoscopy – Need to exclude gastric outlet obstruction Solid phase gastric emptying scan (use labeled food) [Also manometry, electrical studies, pressure studies, satiety study] No. People can have symptoms of gastroparesis in the absence of delayed gastric emptying. [Blood tests too! CBC, metabolic profile, amylase, pregnancy test, TSH] |
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FUNCTIONAL GASTROINTESTINAL DISORDERS
Gastroparesis, Constipation, IBS Pathophysiology of Gastroparesis • Loss of fundal accommodation → _ • Prolonged pylorospasm possibly due to deficiency in _ • Visceral hypersensitivity → _ • Gastric dysrhythmias (tachygastria, bradygastria) → _ • Loss of interstitial cells of Cajal – experimental models suggest hyperglycemia, insulin deficiency, or IGF-1 deficiency may be the cause. • Hyperglycemia – reduces antral contractility in healthy volunteers as well as diabetics. • Autoimmune antibodies – purified IgG from type I DM patients injected into mice caused colonic dysmotility. |
bloating, early satiety
nitric oxide or nitric oxide synthase abdominal pain, early satiety disrupted peristalsis |
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FUNCTIONAL GASTROINTESTINAL DISORDERS
Normal gastric function • The ______ expands to ACCOMMODATE the ingested food and maintain a constant intragastric pressure as stomach fills. • Solids are broken down into 1-2 mm sized particles occurs as a result of gastric contractions against ______________. • Gastric emptying typically occurs in ___________. |
fundus
a closed pylorus 2 to 4 hours. 50% of solid food is emptied into the duodenum in 2 hours; 90% is empted in 4 hours. |
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Gastroparesis, Constipation, IBS
Treatments for gastroparesis? |
1. Diet – frequent small meals, liquids may be better tolerated than solids, limit intake of fat and fiber
2. Glycemic control – serum glucose > 288 mg/dl delays gastric emptying 3. Pharmacotherapy i. Prokinetics – metaclopramide, domperidone, tegaserod, erythromycin ii. Anti-emetics – 5HT3 inhibitors, NK-1 receptor antagonists, scopolamine, marinol iii. Analgesics 4. Botulinum toxin – injected directly into the pylorus during upper endoscopy; restores relative imbalance between excitatory acetylcholine and inhibitory nitric oxide 5. Gastric Electrostimulation – neurostimulation improves symptoms of nausea and vomiting, but therapeutic gain beyond placebo has not yet been demonstrated. Symptomatic improvement does not improve rate of gastric emptying, but is attributed to modulation of visceral afferent activity 6. Percutaneous gastrostomy and jejunostomy – tubes placed for gastric decompression and jejunal tube feeding 7. Total gastrectomy – last resort |
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Gastroparesis, Constipation, IBS
Constipation: Symptoms may be intermittent and mild or chronic and debilitating Symptoms? |
– hard, infrequent stools, excessive straining, sense of incomplete evacuation, excessive time spent in the bathroom
(but does not meet Rome III criteria for IBS - changes in frequency/form and pain or discomfort) |
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Gastroparesis, Constipation, IBS
2 types of contractile activities in the colon Average transit time? |
A) Segmental-mixing for the absorption of water and electrolytes, and B) Infrequent high-amplitude propagating contractions (HAPCs) responsible for moving stool toward the rectum, often precede defecation; 5 HAPCs occur on average each day
36 hours |
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Gastroparesis, Constipation, IBS
Causes of secondary constipation? |
Medication side effect, loss of physical activity, metabolic (calcium) disorders, neurologic-muscle disorders, congenital disorders, structural obstruction can all cause constipation...
Possible contributing factors to constipation: 1. Reduced fiber intake 2. Reduced fluid intake 3. Reduced physical activity |
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Gastroparesis, Constipation, IBS
Constipation Physiologic tests |
a. Colonic scintigraphy - a radiologic method to measure colonic transit time after patients eat a radiolabeled meal
b. Radiopaque marker test i. Distinguishes slow transit from normal transit constipation ii. Pt swallows radiopaque markers and abdominal X-ray is obtained 120 hours iii. Retention of more than 20% of markers indicates prolonged transit, either due to slow-transit or defecatory disorder b. Anorectal manometry – research purposes |
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Gastroparesis, Constipation, IBS
Clinical types of constipation: 3 types |
1. Normal-transit constipation (59%):
Individuals perceive difficult evacuation, hard stools. May report bloating and abdominal discomfort. Colonic transit is normal. Treatment is high-fiber diet (25-30 gms/day), adequate fluid intake, exercise 2. Slow Transit Patients who have fewer than one bowel movement per week Fewer high-amplitude peristaltic contractions after meals Colonic inertia, lack of increased motor activity (myenteric problem - substance P, VIP, NO disturbances) Treatment – Osmotic or stimulant laxatives Severe/nonresponsive: Total colectomy Defecatory Disorder a. Colonic obstruction Tx: surgery b. Dysfunction of the pelvic floor or anal sphincter (Called anismus, pelvic floor dyssynergia) A failure of the puborectalis muscle and external anal sphincter to relax [and in multiparous women associated findings are: weakening of the rectal muscles, abnormal perineal descent, rectal prolapse, development of a rectocoele.] Dx: low anal sphincter tone, nonresponsive. Manometry. Balloon expulsion test. Barium proctogram= fluoroscopy while defecating. Treatment – Laxative, biofeedback, surgical correction of rectocele, rectal prolapse |
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Gastroparesis, Constipation, IBS
What is IBS? |
•Abdominal discomfort associated with altered bowel function
•Constipation, diarrhea, or alternating constipation and diarrhea may be present •Structural or biochemical abnormalities are absent |
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Gastroparesis, Constipation, IBS
IBS What are the red flags that make something not IBS? (5) |
• Gastrointestinal bleeding
• Weight loss • Fever • Anemia • Abdominal mass |
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Gastroparesis, Constipation, IBS
IBS - Epidemiology |
• Up to 20% of the North American population
• Equal division among IBS w/constipation, IBS w/diarrhea, and IBS w/alternating constipation and diarrhea • 2:1 female predominance • Twin studies and familial studies suggest that there is a genetic contribution to IBS |
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Gastroparesis, Constipation, IBS
IBS - Pathophysiology |
No longer thought to arise solely from gut dysmotility.
Other causes now considered: 1. Brain-gut dysregulation • Abnormalities in visceral sensitivity and intestinal motility • Enhanced perception of visceral events occurs throughout the gut, not just intestine • Mediated by alterations in the central nervous system and or enteric nervous system • Recent studies indicate that, while normal subjects activate the prefrontal areas and descending inhibitory pathways for pain, with IBS there is increased activity of the anterior mid-cingulate (aMCC), leading to increased fear and central hypervigilance to pain 2. Dysfunctional CNS pain regulation • Measurements of regional cerebral blood flow during rectal distention have shown that IBS patients have greater activation of the anterior cingulate cortex, amygdala and dorsomedial frontal cortex • Brains of people without IBS may be better able to activate endogenous pain inhibition areas • Studies using both functional MRI and PET show increases in activity of unspecified areas of the anterior cingulated cortex (ACC) compared with controls 3. Bacterial overgrowth • 10 - 80% of IBS patients have bacterial overgrowth of the small bowel • Dysregulated gastrointestinal motor function may produce stasis • Rifamaxin recently reported to reduce IBS symptoms in those with bacterial overgrowth 4. Post-infectious IBS • 25% of IBS pts • A Spanish study reported that the relative risk of developing IBS after Salmonella gastroenteritis was increased eightfold in the subsequent year • Risk for IBS is highest when there is concurrent psychological stress w/infection • Infection may alter gut immune function 5. Psychological stress does not CAUSE IBS, but may EXACERBATE IBS symptoms. |
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IBS
Imaging or scoping needed for dx? |
Abdominal imaging or endoscopy are not required to make a diagnosis in the setting of positive symptoms and no alarm features
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IBS
May not be IBS if: |
• Short symptom duration
• Onset in an older patient • Family history of colon cancer or inflammatory bowel disease • No concurrent psychosocial difficulties or symptom behaviors • Nocturnal diarrhea |
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IBS
Disorders that often accompany IBS: |
• Functional dyspepsia
• Fibromyalgia • Headache • Backache • Genitourinary symptoms |
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IBS
Therapy |
• Education and reassurance
• Diet • Address psychosocial factors • Pharmacotherapy • Behavior therapy Symptoms: Constipation 1) Bulking agents (fiber supplements) 2) Serotonin re-uptake inhibitor (tegaserod) • Increases intestinal and colonic transit • Reduces the firing of rectal afferent nerves • Reduces visceral sensitivity Diarrhea 1) Antidiarrheal agents (e.g. loperamide) • Decreases stool frequency by slowing intestinal transit • Does not relieve global IBS symptoms 2) Serotonin receptor antagonist (alosetron) • Slows colonic transit • Decreases discomfort associated with colonic distention Abdominal discomfort 1) Tricyclic antidepressants • May decrease abdominal pain when used at doses lower than that used for depression 2) Serotonin re-uptake inhibitors (SSRIs) • Currently being studied 3) Probiotics (e.g. bifidobacterium) may be an alternative approach for the treatment of bloating 4) Antibiotics – for bacterial overgrowth 5) Behavioral therapy |
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Mechanisms of Diarrhea
In developing countries: |
The major target is children younger than 5 years of age. 3.2 epidoses/year and the total burden is not decreasing. It causes 20% of death of children younger than 5 years of age. There are 1.9 million deaths per year (down from 2.9 million in 1990). The decrease in mortality rate is due to use of ORS.
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Mechanisms of Diarrhea
In United States: |
There are 135,000,000 due to non-foodborne outbreaks and 3,100,000 due to food-borne outbreaks. The mortality rates in the US are in the low hundreds/year. Most of this mortality is in the older population (85% of deaths in people over the age of 60) versus the predominant mortality in younger children in the developing world.
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Mechanisms of Diarrhea
Define diarrhea. Normal? What is the amount of GI water flow and uptake /day? |
Increased loss of water in the stool
Normal = 130ml/24 hours Diarrhea = >200ml/24 hours (3 standard deviations above normal) The GI system doesn’t have many compensatory mechanisms unlike the kidney GI is presented with 9 liters of water (1 liter of which is secreted by the gut itself), it absorbs 8.8 liters of water (most of which comes from the salivary glands, stomach, pancreas, biliary tract, small intestine, etc), receives 1.5 liters from the small intestine, and secretes up to 200 ml per day. |
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Mechanisms of Diarrhea
Water movement follows what? What is absorbed in the GI tract? Where? What is secreted? Where? |
Solutes.
Absorption – Sodium absorptive process in villi in colon and small intestine Secretion – Chloride secretion via crypts in colon and small intestine |
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Mechanisms of Diarrhea
Nature of GI epithelium enabling secretion/absorption? |
Epithelial cells are polar cells with a basolateral membrane and apical membrane.
They line up in the same orientation They are joined at apical surfaces by tight junctions Transport proteins are asymmetrically localized |
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Mechanisms of Diarrhea
Intestinal Sodium Absorption: How does it work? What are the different types? Is it different in different GI segments? |
Sodium transport is active and occurs via the Na+/K+ ATPase, which is only present on the basolateral membrane.
Types: Electrogenic – Sodium only, Sodium + Glucose (movement of charge) Neutral – Sodium and Chloride, Sodium/H+ exchanger linked to Cl-/HCO3- exchanger, which are physically associated and chemically linked by carbonic anhydrase (no movement of charge). --- It explains most basal absorption of Na+, the increase in Na+ absorption, is the only process inhibited in most diarrheal diseases, and is increased in CF. Colonic Sodium Absorption involves Short Chain Fatty Acids which exchange with OH- and is linked to the Na+/H+ exchanger. Jejunum couples sodium to glucose and amino acids. Ileum=NaCl. Colon (L) = NaCl. Colon (R) = ENac (Na channel). |
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Mechanisms of Diarrhea
Which part of the gut absorbs the most water? The most efficiently? |
The proximal part of the GI tract absorbs most of the water but has low efficiency, whereas the distal part of the GI tract absorbs a lower amount but with a higher efficiency. This is because the small intestine has leakier tight junctions, which allow for a tremendous movement of water, whereas the lower gut has tight junctions that regulate the movement of water more.
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Mechanisms of Diarrhea
Intestinal Chloride Secretion |
This has a Na+/K+ ATPase that is linked to a Na+/K+/2Cl, which results in a net movement of Cl into the cell and through a chloride transporter through the apical membrane (for example, CFTR).
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Mechanisms of Diarrhea
Mechanism of Diarrhea Which dominates - secretion or absorption? Is this more like fasting or fed state? |
Diarrheal diseases are similar to the post-feeding state where the secretions are predominant versus absorption. Local nerves, endocrine, paracrine, inflammatory cells regulate the shifting from a predominantly absorptive to a predominantly secretory state.
In the fasting state – more water enters than leaves (net absorption) In the diarrheal state – more water leaves than enters (net secretion) |
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Mechanisms of Diarrhea
Intestinal Secretogogues (cause secretion) (4) |
Major secretogogues are bacterial enterotoxins, humoral agents, and endogenous and exogenous laxatives.
They are present in lumen, lamina propria, or blood and can affect the apical or basolateral membranes. In order to cause diarrhea, they need to overwhelm the maximal absorptive capacity of the GI tract. |
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Mechanisms of Diarrhea
Mechanisms of net secretion: (4) |
Inhibition of active electrolyte absorption (most common) (Cholera)
Stimulation of active electrolyte secretion (most common) (Cholera) Increased luminal osmolarity (Lactose Intolerance) Increased tissue hydrostatic pressure (Paradoxical Diarrhea) |
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Mechanisms of Diarrhea
Inhibition of active electrolyte absorption Name a bacteria and a neoplasm. |
1. Pancreatic, which is caused by a tumour producing a secretory hormone (can be seen in US)
2. Bacterial, which is caused by Vibrio cholera that releases a toxin (seen worldwide) |
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Mechanisms of Diarrhea
Molecular mech of cholera toxin... |
The toxin is an AB toxin (active + binding subunits)
There are 5 binding subunits and 2 active subunits (A1 is more active than A2). The B subunit binds to GM1. The toxin is taken up and goes from the early endosome to the Golgi and back to the membrane instead of forming a late endosome and becoming a lysosome or recycling back through the RE (recycling endosome?) to the apical membrane. The A1 subunit then enters the cytosol and interacts with the adenylate cyclase complex on the basolateral membrane. The adenylate cyclase complex has three subunits, one of which is the catalytic subunit that is kept inactivated by the G subunit. A1 undergoes a ribosylation reaction with Gα, which activates the catalytic unit of the adenylate cyclase, and results in increased cAMP. In the sodium absorptive cell, the Na+/H+ exchanger (NHE3) is blocked. NHE3 is present as a complex with a regulatory protein (NHERF) and to an anchoring protein (ezrin), which feeds back on to itself and inhibits itself via PKA II. So net Na+ absorption is reduced. In the chloride secretory cell, the increase in cAMP results in an increase in the opening of chloride channels resulting in a large loss of chloride through the apical membrane. So net chloride secretion is increased. |
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Mechanisms of Diarrhea
Cholera: Net Na+ absorption is ________. Net chloride secretion is __________. |
reduced
increased |
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Mechanisms of Diarrhea
Cholera: Presentation |
Patients present with low K+ and low HCO3- but do not present with changes in Na+ and Cl-. You get a low levels of HCO3- because the Cl-/HCO3- exchanger is functional but is just getting more substrate in the lumen, due to upstream dumping, which results in a loss of HCO3-.
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Mechanisms of Diarrhea
Extra cholera gems: |
Cholera also affects enteric nerves, affects enteric serotonin cells, and increases prostaglandins. Serotonin is important.
Other toxins in V. cholerae – ZOT – Zonula Occludens Toxin – makes the tight junctions leaky which allows for the loss of water following chloride secretion. |
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Mechanisms of Diarrhea
ORT advances |
• Hypo-osmolar solutions increase the absorption and effectives in rehydration in acute diarrheal illnesses
• Ceralyte is rice-based and has an anti-secretory component • ORS containing resistant starch which is broken down into short chain fatty acids by bacteria that will be exchanged for OH- and stimulate the Na+/H+ exhcnager (NHE2 not NHE3 which is inhibited) |
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Mechanisms of Diarrhea
cGMP in Diarrheal diseases |
Heat Stable E. coli enterotoxin
Yersinia enterocolitica enterotoxin Guanylin *Often cAMP and cGMP have opposing activities but in intestinal cells they have the same effect. |
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Mechanisms of Diarrhea
Calcium in Diarrheal diseases |
C. difficile
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Mechanisms of Diarrhea
Small intestine has a _____ reserve capacity for absorption. ___________ colonizes small intestine. Colon has a _____ reserve capacity for absorption, so diarrhea more often arises in the colon. Some non-Beta cell pancreatic tumors can secrete tons of ___, which inhibits gastric acid secretion and relaxes the intestines/sphincters. Causes __________. |
Small intestine has a large reserve capacity for absorption. Vibrio cholera colonizes small intestine.
Colon has a small reserve capacity for absorption, so diarrhea more often arises in the colon. Some non-Beta cell pancreatic tumors can secrete tons of VIP, which inhibits gastric acid secretion and relaxes the intestines/sphincters. Causes severe chronic watery diarrhea. |
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Mechanisms of Diarrhea
Ileum resection and diarrhea? |
**If <100 cm of ileum are resected, bile acids arrive in high concentration in the colon, inducing colonic diarrhea. This will be improved with cholestyramine.
**If >100 cm of ileum are resected, the liver can’t keep up with bile loss in the stool. Bile levels decrease, and diarrhea now results from excess fat instead of excess bile. This will be made worse with cholestyramine. |
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Mechanisms of Diarrhea
Vibrio Cholera V. cholera doesn’t invade, but colonizes. _____________ is an intestinal cell surface glycoprotein that confers susceptibility to cholera. The active subunit of the toxin is A1/A2. This enters cells and travels back to the basolateral surface via “retrograde transport.” A1 turns on what system? With what five effects?: Another cholera toxin called ZOT decreases the number of epithelial tight junctions, allowing water to flood down its concentration gradient into the lumen. Much of the chloride is reabsorbed in exchange for HCO3, so cholera diarrhea is very high in Na+, K+, and HCO3-. The resulting hypokalemia may cause transient muscle paralysis. |
GM1 Ganglioside
A1 constitutively activates the G-protein on adenylate cyclase, which begins to churn out cAMP. Effects of cAMP 1. Blocks neutral, but not electrogenic, NaCl absorption. 2. Increases passive diffusion of chloride out of cells into the lumen. 3. Activates the Na:K:2Cl transporter. 4. Activates K+ secretion into the lumen. 5. Stimulates serotonin and prostaglandin secretion, activating the enteric nervous system. |
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Mechanisms of Diarrhea
Other causes for diarrhea: Decreased water absorption (4 conditions) |
- Due to decreased Na absorption: eg in carcinoid syndrome
- Due to absorptive cell damage: eg in celiac sprue, viral gastroenteritis - Due to increased motility: eg in hyperthyroidism - Due to decreased villous blood flow: eg in ischemic bowel - Cannot treat such by oral rehydration, since it’s a all cells have a decreased absorption problem |
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Mechanisms of Diarrhea
Other causes for diarrhea: Due to increased lumen osmolarity |
Osmotic Diarrheas
1. Trehalase deficiency causes mushroom intolerance. 2. Lactase deficiency causes lactose intolerance. This is a colonic, not small intestinal, diarrhea. Lactose gets to the colon and osmotically draws water into the lumen, causing diarrhea. Lactose is also fermented by bacteria. This releases acid (causes erosion and pain) and H2 gas (causes cramping and gives a positive hydrogen breath test) Sucrase – Isomaltase deficiency Lactulose |
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Mechanisms of Diarrhea
Paradoxical diarrhea |
Increase in tissue hydrostatic pressure
Paradoxical diarrhea is when patients complain of diarrhea but have partial bowel obstruction from colon cancer, etc. This increases the pressure on the basolateral surface causing increased secretion and decreased absorption from the apical surface. |
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Mechanisms of Diarrhea
Syndromes associated with problems in the GI tract -- locations? Celiac Disease Ulcerative Colitis Crohn’s Disease ZE syndrome |
Stomach – ZE syndrome
Jejunum – Celiac Disease Ileum – Crohn’s Disease Colon – Ulcerative Colitis |
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IBD
General IBD: Duration Onset Platelets Hct Bx |
Duration is greater than 4 weeks
Insidious onset Platelets > 450K Low Hct Abnormal biopsy with chronic inflammation |
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IBD - Potential test question
UC Risk of colon cancer - proctitis (i.e. rectum) vs. entire colon? What else affects risk? (3) What is protective? (4) |
Risk of colorectal cancer is the same as the general population if there is just proctitis but if the entire colon is affected the risk increases to 20 fold!
(Duration, anatomical extent, family history of CRC affect risk) (Protection – 5ASA (5ASA is considered a first-line therapy for mild and moderately active UC), folate, tight medical control, surveillance colonoscopy) |
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IBD
pANCA associated with |
UC
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IBD
Does Crohn's always bleed? |
No. 20-30% w/o bleeding
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IBD
Crohn's |
Is most commonly ileo-colic
Can be inflammatory, obstructive, appendicitis-like (micro-perforations), or with fistulas • Inflammatory – Right lower quadrant pain, weight loss, pain, diarrhea • Obstruction – Post-prandial cramps, distention, vomiting, weight loss (avoidance of food), borborygmi • Fistulization – back pain, UTI, air on urination, feces from the vagina, etc • Micro-perforations – Appendicitis-like pain Formation of aphthous ulcers, which are tiny, punched out ulcers with a white exudate Granulomas can also be present in the mucosa Creeping fat occurs secondary to the transmural inflammation Complications – Strictures, fistulae, hydronephrosis (obstruction of the ureter), mucosal bridging (unique to Crohn’s disease) where the disease travels from one wall to another wall, increased risk for colorectal cancer (must begin surveillance colonoscopy at 7-8 years) No cure for Crohn’s disease unlike Ulcerative Colitis Post-operative recurrence in Crohn’s does occur if patients stop medicaitons Patients that are ASCA positive are more likely to have CD. |
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IBD
ASCA+ |
Crohn's association
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IBD - Potential test question
Colon cancer and Crohn's |
increased risk for colorectal cancer (must begin surveillance colonoscopy at 7-8 years)
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IBS vs IBD
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Don’t have anemia, weight loss, fever, bloody stool, perianal disease, fecal WBC, occult blood, etc. IBS patients suffer from abdominal disturbance and bowel discomfort.
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IBD
Extra-intestinal manifestations |
Both patients can get osteoporosis, arthritis, gallstones, renal problems, etc. Oral aphthous ulcers are associated with Crohn’s Disease.
UC – Two extraintestinal manifestations after removal of colon that remain = central arthritis, liver disease (PSC- Primary Sclerosing Cholangitis) that predisposes you to cholangiocarcinoma |
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IBD
UC – Two extraintestinal manifestations after removal of colon that remain |
= central arthritis (spondylitis), liver disease (PSC- Primary Sclerosing Cholangitis) that predisposes you to cholangiocarcinoma
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IBD
FYI |
Children often present by falling off their growth curve.
Most people are diagnosed between 15 and 25 years and then at 40 to 50 years but not very much after the 60’s. FYI!!! Nicotine and smoking makes the disease better in UC! But worse in CD! |
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IBD
Four etiologic hypotheses: |
1. Recurrent infection
2. Defective mucosal integrity 3. Dysregulated immune response 4. Dysbiosis |
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IBD
Genetics? |
There is a familial occurrence with polygenic susceptibility but monozygotic twins have less than 50% concordance.
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IBD
Therapy? |
Goals of therapy:
• Induce remission • Maintain remission • Enhance quality of life • Reduce toxicity of medications Use step up therapy (for mild disease) [see slide] or top down therapy (when faced with aggressive diseases) Sulfasalazine Sulfapyridine + 5-ASA Some patients have sulfa toxicity so the drugs replace the saulfapyridine carrier Toxicities – Male infertility, rash, fever, headache, nausea, hepatitis Other therapies include: (Abx) Metronidazole, Corticosteroids, Azathioprine (converted to 6-Mercaptopurine), Antibodies to TNF (Infliximab – chimerized or CDP 571 - humanized), |
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IBD - potential test question:
Use for antibodies in IBD tx? |
Antibodies to TNF (Infliximab – chimerized or CDP 571 - humanized)
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Gallbladder Disease
Anatomy review |
The location of the gallbladder is inferior to the liver.
It consists of the fundus, the body, the infundibulum, and the neck that drains into the cystic duct. The Cystic duct merges with the common bile duct and enters the duodenum at the major papilla. The circle of smooth muscle cells surrounding the ducts at the major papilla is called the Sphincter of Oddi and serves to prevent reflux of intestinal contents into the gallbladder and assist in the filling and emptying of the gallbladder. |
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Gallbladder Disease
Histology The gallbladder has four layers. |
Mucosa: Single layer of cuboidal epithelium.
Fibromuscular layer: Consisting of connective tissue with elastic fibers, vessels and lymphatics as well as a mixed layer of circular, longitudinal and oblique muscle fibers. This is technically not a true muscularis mucosa. Subserosal connective tissue: Loosely arranged collagen and elastic fibers with larger vessels, lymphatics and nerves. Peritoneum: Consists of a peritoneal covering over the gallbladder except where it is in embedded in the liver bed. |
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Gallbladder Disease
Visceral pain sensation from gallbladder distention or inflammation is conducted via afferent |
sympathetic fibers
[gallbladder is innervated by both the parasympathetic and sympathetic nervous systems. The parasympathetic nerves arise from branches of the vagus nerve. Preganglionic sympathetic nerves arise from the T8 and T9 levels. Postganglionic sympathetic nerves originate from the celiac plexus. ] |
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Gallbladder Disease
blood supply to the gallbladder |
variations but is most often supplied by the cystic artery, which arises from the right hepatic artery (hepatic artery also supplies the bile ducts)
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Gallbladder Disease
What structure prevents excessive distention or collapse of the gallbladder with ductal pressure and to block passage of gallstones into the common bile duct? |
spiral valves of Heister (folds in the cystic duct)
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Gallbladder Disease
In the gallbladder itself, small tubular ducts that do not connect with the gallbladder lumen as well as minute diverticulae are occasionally seen. |
These ducts of Luschka and Rokitansky-Aschoff sinuses can be a location of gallstone nucleation and inflammation.
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Gallbladder Disease
Bile Secreted by ? Functions of Bile? Composition - electrolytes? Organic solutes? |
The liver produces about 600 to 1200 mL of bile each day. Bile is essential for normal intestinal lipid digestion and absorption, excretion of lipid-soluble xenobiotics and toxins, cholesterol homeostasis.
Iso-osmotic with plasma Contains water, electrolytes (not responsible for any osmotic activity because they are sequestered), and organic solutes such as bile salts, lecithins, cholesterol (unesterified), proteins, bilirubin *Gallstones are combinations of all the organic solutes |
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Gallbladder Disease
Bile acids: Derived from ? primary, secondary and tertiary bile acids? |
Cholesterol
Primary -Cholic acid and Chenodeoxycholic acid - made in liver from cholesterol. Secondary - Deoxycholic acid and Lithocholic acid - made from primary by intestinal bacteria. Tertiary - Ursodeoxycholic acid and Sulfolithocholic acid - made in liver from secondary. |
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Gallbladder Disease
Organic solutes in bile? (4) |
- Bile salts (2/3): conjugated cholesterols that are amphophilic (hence a detergent) and are impermeable to GI tract (requires active transport out of lumen), must be above critical micellar concentration to solubilize fats (CMC can be lowered by obstruction, deconjugation by bacterial overgrowth, bile salt wasting, etc)
- Lecithin (aka phosphatidylcholine): ↑ cholesterol solubilization by bile salts - Cholesterol: free unesterified cholesterol is excreted with bile - Proteins: regulates cholesterol-rich crystal formation (see gallstone formation) |
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Gallbladder Disease
Bile Salt Conjugation: Bile salts are both hydrophobic (_________ nucleus) and hydrophilic (__________ side chain) The 3’ and 7’ –OH substituents and conjugation with taurine or glycine increases their __________, which: --___________ their impermeability keeping them in the biliary tract or lumen. --__________ their absorption by enterocytes, so they need to be ________ transported across the membrane via a transporter --Prevents digestion by ________ enzymes. __________ are macromolecular aggregates and are created when the concentration reaches a critical micellar concentration (CMC) normally ranging from 0.5-5 mmol/L. They allow _________ molecules to be transported. Absence of bile salts result in low absorption of (3) Occurs with: Bile Salt wasting (CD, Ileal resection) Bacterial overgrowth (scleroderma) Abnormal Small Intestine acidity (ZES) Cholestatic Disorders |
steroid nucleus
aliphatic side chain hydrophilicity Increases Prevents their absorption, actively pancreatic Micelles, hydrophobic cholesterol, lecithin, vitamins A, D, E, K |
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Gallbladder Disease
Components of Bile It is the major phospholipid in bile and originates from hepatocytes. It is also an amphipathic molecule and increases the ability of bile salts to solubilize cholesterol |
Phospholipids – Lecitihin (Phosphatidylcholine)
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Gallbladder Disease
Components of Bile It is the major sterol in bile and is converted to bile salts via 7α-hydroxylase It can be generated from three sources: |
Cholesterol
Made endogenously from HMG CoA Reductsase Made from a cholesterol ester pool (CEH converts it to free cholesterol) Made from lipoproteins that bind to their receptor and deposit cholesterol Cholesterol can be: Converted to cholesterol esters via ACAT Secreted into bile Converted into bile via 7α-hydroxylase |
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Gallbladder Disease
Components of Bile Proteins |
Contain factors that are important for either promoting or inhibiting the nucleation of cholesterol-rich crystals
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Gallbladder Disease
Hepatocyte configuration |
Hepatocytes are arranged in plates with canalicular spaces in between neighboring hepatocytes that are connected via tight junctions.
Bile salts are conjugated and secreted into the canaliculi. Sinusoids (blood) exist between plates of hepatocytes and are lined by sinusoidal epithelial cells The space of Disse is the space between the sinusoidal epithelial cell and the hepatocyte. |
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Gallbladder Disease
Enterohepatic circulation |
Bile conjugation in hepatocytes → active secretion in canaliculi → storage and concentration in gallbladder → CCK-mediated bile excretion into duodenum → some bile loss in stool but most actively absorbed in ileum → blood → bile reuptake by by passive diffusion and carrier mediated mechanisms into hepatocytes
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Gallbladder Disease
Gallbladder Function Storage of bile - when? Processing? Secretion? Evacuation triggered by ___________? |
Storage of bile during the interdigestive period – concentration of bile and isotonic reabsorption of electrolytes (not including Calcium)
Secretion of mucus Evacuation of bile – triggered by CCK (released from enterochromaffin cells in the duodenal mucosa), which contracts the gallbladder and relaxes the Sphincter of Oddi |
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Gallbladder Disease
Enterohepatic circulation What organs? Efficiency? |
Limited to the liver, gallbladder, SI, enterocytes, and portal circulation
It is 90% effieicent and includes both passive and active processes Bile salts are passively absorbed in the proximal small intestine with increased acidity. Absorbed via active transport in the distal ileum. In the colon, bacteria deconjugate the bile salts and make them more hydrophobic increasing their reabsorption passively In the first pass through the liver, only 70% of bile salts are reabsorbed. The rest enter systemic circulation, and then when they are presented to the liver again, and the amount reabsorbed increases |
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Gallbladder Disease
Gallstones There are two types of gallstones – |
– cholesterol and pigment (brown and black)
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Gallbladder Disease
Gallstones Most common? Major component? |
Cholesterol stones (85%)
Major component – cholesterol monohydrate crystals + mucin glycoprotein matrix |
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Gallbladder Disease
Cholesterol stones (85%) Major component? RFs? Mech? |
Major component – cholesterol monohydrate crystals + mucin glycoprotein matrix
Bile salts, bilirubin, protein, calcium Risk factors include: older age (due to decreased activity of 7α-hydroxylase activity), female gender (due to estrogen), genetics, drugs (estrogens), diet (high calories and high cholesterol), GI disorders (CD, resections, DM), decreased gallbladder motility (obesity, rapid weight loss, pregnancy – all due to increased HMG CoA Reductase increasing cholesterol synthesis) [- Risk factors: 4Fs (fat, female, fertile, 40), genetics, drugs (eg clofibrate), high fat or high cholesterol diet, GI disorders or diabetes] **Cholesterol supersaturation leads to stone formation – increased cholesterol, decreased concentration of bile salts, increased conversion to secondary bile salts |
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Gallbladder Disease
Pigment stones (15%) Major component? RFs? Mech? |
Major component – bilirubin
Bile salts, fatty acids, calcium Bilirubin precipitation with calcium Risk factors include: Asians, rural areas, chronic hemolysis, alcohol cirrhosis, biliary infection, and old age Black stones – Stasis conditions & increased biliary deconjugation Brown stones – Infected bile & increased bacterial metabolism |
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Gallbladder Disease
Pigment stones - Which asssociated with infection in biliary tree? Stasis or chronic hemolysis? |
- Black stones: made of unconjugated bilirubin (eg due to stasis or chronic hemolysis)
- Brown stones: associated with infections of biliary tree |
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Gallbladder Disease
Gallstone Clinical Presentations (4) Biliary colic Acute cholecystitis Choledocholithiasis Gallstone Ileus |
Biliary colic – Biliary pain in the RUQ brought on by fatty meals
Acute cholecystitis – inflammation of the gallbladder Presents with prolonged and intense pain with fever, leukocytosis 90% of these patients have a gallstone obstructing the cystic duct 10% lack gallstones – Acalculous cholecystitis Choledocholithiasis – stone in the common bile duct Presents with cholangitis, sepsis, obstructive jaundice, gallstone pancreatitis Gallstone Ileus – bowel obstruction due to erosion into duodenum |
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Gallbladder Disease
Treatment of stones |
Surgery (cholecystectomy)
Laparoscopic approach Extra-corporeal shock-wave lithotripsy Oral dissolution therapy (only works for cholesterol stones) Endoscopy to visualize the stone and remove it |
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Gallbladder Disease
Gallbladder carcinoma Who gets it - M or F? Association? At-risk groups? Good or Bad? |
Disease of the elderly, females > male
Strong association with gallstones (especially if > 40 year history) Also associated with biliary cysts, S. typhi High prevalence in *Native Americans, Latin Americas, Japanese, Northern Europeans Most are diagnosed late because of lack of symptoms and non-specific symptoms Most patients are diagnosed at Stage IV and median survival is 5 months No role for chemotherapy or radiation therapy |
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Pancreatic Cancer
Pancreatic adenocarcinoma Symptoms (3) Epidemiology? |
Symptoms
-Extrahepatic biliary obstruction (jaundice, pruritis) -Abdominal and/or back pain (compression of celiac plexus) -Protean sx (weight loss, weakness, malaise, poor appetite, GI sx, etc.) Epidemiology - Affects elderly (50-80 yrs) & is 4th largest cause of CA death (almost uniformly fatal) - Risk factors: smoking (2-3x) but NOT coffee ?pancreatitis, ?DM, ?gender, ?ethnicity, ?genetics |
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Pancreatic Cancer
Pancreatic adenocarcinoma Complications Treatment |
Complications
Obstructive jaundice Abdominal and back pain (compression of celiac plexus) GI bleeding Gastroduodenal obstruction Pancreatitis and pancreatic exocrine insufficiency - Pancreas is located near the stomach, duodenum, and celiac plexus, and its blood drains to the portal vein; these are all possible places of expansion/invasion - Extremely high mortality rate (2% 5yr survival) despite low tumor burden, suggesting prominent role of mass effect and systemic effects Treatment Pancreaticoduodenectomy (aka Whippel operation; 26% 5yr survival at JHH) Palliative surgery and medical therapy to treat complications Early detection, eg by ultrasound screening |
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Pancreatic Cancer
Pancreatic adenocarcinoma Pathology Genetic abnormalities |
Pathology
Precursor lesion is called PanIN (pancreas intraepithelial neoplasia) Pancreatic adenocarcinoma Moderately differentiated ductal adenocarcinoma Exuberant desmoplastic (scarring) reaction Nerve invasion Usually located in pancreatic head, with metastases to nodes and liver common Genetic abnormalities Telomere shortening: early and ubiquitous, possibly a broken checkpoint Commonly, loss of G1 checkpoints: K-ras, p53, p16, DPC4 Other mutations: TGFβ, activin receptors, BRCA2, MKK4, LKB1/STK11, etc |
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Pancreatic Cancer
Other pancreatic tumors (not adeno) |
Exocrine tumors
Benign: true cysts, cystadenoma Malignant: acinar cell carcinoma, cystadnocarcinoma Neuroendocrine tumors Nearby nonpancreatic tumors: duodenal, ampullary, and distal bile duct cancers |
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Pancreatic Cancer
Pancreatic cancer is highly _________ and lethal. Only affects ______ adults. Incidence and mortality rates are __________, because it’s so lethal. Risk factors include being (gender) or (ethnicity). _________ is a huge risk factor. **Coffee? |
aggressive
older almost equivalent male or black. Smoking is a huge risk factor. **Coffee is not a risk factor, although it is widely believed to be by patients. |
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Pancreatic Cancer
Clinical features of pancreatic cancer Presents with _____________ obstruction (__________ and pruritis) because the common bile duct runs through the pancreas. Labs will show very elevated __________. There will be severe abdominal pains, weight loss, and poor appetite. Treatment is by “Pancreaticoduodenectomy” (_________ procedure), but prognosis is still poor. **Paradox of Tumor Burden? |
extrahepatic biliary
jaundice bilirubin Whipple The tumor burden at time of death is often very low! |
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Pancreatic Cancer
Histopathology ____________ is exuberant and universally seen. _______ invasion by glands is common, and is what causes the horrible pain. Most tumors arise in the ____________, and metastasize to ___________. |
Desmoplasia - The vast majority of tumor bulk is formed from this non-neoplastic scarring desmoplastic reaction!
Nerve head of the pancreas local nodes, liver, or lungs. |
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Pancreatic Cancer
Genetic Factors in Pancreas Cancer |
--K-Ras mutations are seen in almost all pancreatic cancers.
--p53 and p16 mutations are common. --BRCA2 mutations confer heritable risk. --PRSS1 mutation in trypsinogen (see pancreatitis lecture) may be a risk factor. --LKB1/STK11 mutations cause the inherited Peutz-Jeghers Syndrome of inflammatory intestinal polyps, mucocutanous pigmented spots, and predisposition for pancreatic cancer. If three or more relatives have pancreatic cancer, relative risk inreases 57-fold. |
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Pancreatic Cancer
Are any serologic markers diagnostic? |
Serologic markers not diagnostic
(Increased Bilirubin, Alkaline phospatase, Liver transaminase) |
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Pancreatic Cancer
Clinical Course |
High mortality with a 2% five-year survival
80% of patients are unresectable, mostly due to metastatic disease Tumours that are at the head of the pancreas can often present early (resectable but not curable) |
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Pancreatic Cancer
Histopathology |
Moderately differentiated ductal adenocarcinoma with a strong desmoplastic reaction
Ductal cells are less than 5% of normal pancreatic cells but give rise to >90% of cancers May occur as a result of digestion of ductal cells by enzymes causing multiple cycles of degeneration and repair resulting in a cancer Only 25% of the nuclei are neoplastic nuclei Biopsy diagnosis can fool people due to high desmoplastic reaction Nerve invasion Mostly occurs in the head of the pancreas Metasases to nodes and liver are common Precursor lesion is Pancreatic Intraepithelial Neoplasia (PanIN) |
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Acute Pancreatitis
Presentation |
- Sx: upper abdominal pain w/ possible radiation to back, N/V, fever, Grey-Turner’s or Cullen’s sign (bluish discoloration of left flank or umbilicus), etc
- Resembles sepsis - Danger signs: encephalopathy, hypoxemia, tachycardia, hypotension, ↑ Hct (fluid loss into abdominal cavity), oliguria, azotemia - Severity rating 3 or more (of 11) Ranson’s signs is considered severe; CT scan graded on A-E scale (look for pancreatic and peripancreatic changes) |
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Acute Pancreatitis
Etiology Main 2? Other? |
- Alcoholic pancreatitis
- Gallstone pancreatitis: due to gall stone obstruction of common channel of bile and pancreatic ducts → retrograde flow of bile to pancreas → pancreatitis - Other: idiopathic, drugs, infections, hyperlipidemia, hypercalcemia, ductal obstruction, trauma, hypotension, post-op, etc |
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Acute Pancreatitis
- Genetic predispositions? (2) |
- Hereditary pancreatitis: caused by AD mutation in PRSS1 and made worse by SPINK1 mutation; PRSS1 and SPINK1 inhibit intracellular trypsin activation, so mutation results in autodigestion leading to pancreatitis
- Cystic fibrosis: CFTR mutation leading to chronic pancreatitis |
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Acute Pancreatitis
Pathophysiology How can it start (3) Local effect? Systemic? |
local damage to ducts and acini as well as systemic effects
1. Bile reflux, alcohol, hypercalcemia → ↑ pancreatic duct permeability 2. Obstruction → damage to acini 3. Exocytosis blockage → intracellular enzyme activation → autodigestion >>>> - Local effects of enzymes: inflammation, fluid loss into peritoneal cavity*, necrosis of pancreas, fat, or peripancreatic structures - Systemic effects of enzymes: vessel leakage, inflammation, fat necrosis, ARDS (surfactant affected), etc |
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Acute Pancreatitis
Pathology |
Pancreas not usually biopsied but will show edema, PMN inflam., necrosis
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Acute Pancreatitis
Treatment |
primarily supportive:
- IV fluid and electrolyte repletion, NPO and nutritional support, analgesia, treat complications (eg Abx, respiratory support) - No specific therapies have been demonstrated to be effective - Surgery if 1. uncertain diagnosis 2. treatment of pancreatic sepsis/abscess 3. cholecystectomy or Sphincter of Oddi dilation (remove gallstone obstruction) 4. deterioration of clinical status |
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Acute Pancreatitis
Prognosis: Acute – gallstones Chronic – alcohol Chronic Obstructive |
Acute -- Usually complete recovery. Sometimes death.
Chronic -- Slow deterioration (treated), Progressive deterioration (untreated), sometimes death Chronic obstructive -- Improvement (treated), Progressive deterioration (untreated) |
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Acute Pancreatitis
1. Alcohol |
– dose-related linear relationship, women require less alcohol
Abnormal blood flow, toxic metabolites, stimulation of CCK and secretin, sensitization of acinar cells due to CCK with premature zymogen activation, spasms of Sphincter of Oddi are all possible effects of alcohol |
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Acute Pancreatitis
2. Gallstones |
– causes a temporary obstruction of the common duct
Wide duct, many stones, smaller size of stones increase the risk of pancreatitis (get out of gallbladder) |
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Acute Pancreatitis
3. Microlithiasis |
– small crystals of bile, no stone formation
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Acute Pancreatitis
Treatment for gallstones? Most effective? |
Endoscopic Retrograde Cholangio-Pancreatography (ERCP)
Cholecystectomies are 95% effective in preventing pancreatitis because gallstones can still be formed since the liver makes bile |
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Acute Pancreatitis
Acute pancreatitis is characterized by symptoms of _________ pain, and __________. Findings include fever, tachycardia, elevated WBC, and elevated serum _________. The main two etiologies are _______ and __________! Less common etiologies include infections, hyperlipidemia, or hypercalcemia. Some drugs may also cause pancreatitis. These include: |
upper abdominal (onset in minutes, lasts for days)
nausea - hours amylase - most frequently ordered test to diagnose acute pancreatitis. It rises within 6 to 12 hours of onset, and remains elevated for three to five days. alcohol, gallstones AIDS therapy — didanosine, pentamidine Antimicrobial agents — metronidazole, stibogluconate, sulfonamides, tetracycline Diuretics — furosemide, thiazides Drugs used for inflammatory bowel disease — sulphasalazine, 5-ASA Immunosuppressive agents — L-asparaginase, azathioprine Neuropsychiatric agents — valproic acid Antiinflammatory drugs — sulindac, salicylates Others — calcium, estrogen, tamoxifen (as noted above, estrogen and tamoxifen may act via the induction of hypertriglyceridemia |
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Acute Pancreatitis
Acute gallstone pancreatitis occurs more often in ______, while alcoholic pancreatitis occurs more often in ______. |
women
men |
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Acute Pancreatitis
Pathophysiology of Inflammation Alcohol or hypercalcemia? Gallstones? |
Alcohol and hypercalcemia cause increased permeability of pancreatic enzymes within the pancreas.
Gallstones cause bile reflux and obstructive damage to pancreatic ducts. |
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Acute Pancreatitis
Dose-related 'poison' effect on pancreatitis |
Ethanol, IV lipid infusions, organophosphorous insecticides
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Acute Pancreatitis
Infections causing? |
Mumps
Coxsackie Hepatitis A & B Mycoplasma sp. Salmonella sp. Mycobacterium tuberculosis Ascaris Clonorchis Immunocompromised CMV Cryptococcus neoformans M. tuberculosis HSV Mycobacterium avium complex Toxoplasma gondii Pneumocystis carinii Leishmania sp. Candida sp. |
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Acute Pancreatitis
Hypertriglycerides – |
Often have levels > 1000 and associated with familial dyslipidemia
Can cause chronic pancreatitis |
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Acute Pancreatitis
Genetic Suscpetibility – |
PRSS1 (Protease, Serine) – Cationic Trypsinogen Gene
When mutated it causes a premature and excessive action of trypsinogen and prolonged survival of trypsin, shifting the balance of inactive trypsinogen to active trypsin Associated with pancreatic adenocarcinoma SPINK1 (Serine Protease Inhibitor, Kasal Type 1) Mutations results in early activation of trypsinogen Carrier status is associated with pancreatitis but patients with the gene mutation may never get pancreatitis CFTR (Cystic Fibrosis Transmembrane Regulator) Homozygous mutation – Classic CF Heterozygous – decreased pancreatic function, absence of vas deferens, clinical pancreatitis |
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Acute Pancreatitis
**Spillage of lipase leads to |
to fat necrosis.
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Acute Pancreatitis
**Spillage of trypsin leads to |
elevated WBC, vasodilation, increased capillary permeability, destruction of cell membranes and blood vessels. Complications of this destruction include ARDS, DIC, and third-space fluid accumulation (leads to hypotension, tachycardia).
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Acute Pancreatitis
Sensitivity with: Ultrasound? CT? CT w/ contrast? |
Ultrasound – Poor sensitivity – best for gallstones
CT scan – Good sensitivity – Detects edema CT IV contrast – Excellent Sensitivity and High Specificity – Detects necrosis Balthazar’s CT Severity Index – worse prognosis with higher scores |
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Acute Pancreatitis
Interstitial Pancreatitis Necrotizing Pancreatitis |
Interstitial Pancreatitis – 80% of cases, good prognosis
Necrotizing Pancreatitis – 20% of cases, bad prognosis, possibility of superinfection |
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Acute Pancreatitis
Causes of Mortality – |
Early – Systemic Inflammatory Response Syndrome with multi-organ failure
(One week) Late – Multi-organ failure, pancreatic infections and sepsis (Greater than one week) |
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Acute Pancreatitis
Guidelines for Complicated Acute Pancreatitis |
Supportive care, reduce inflammation
CT scan IV Antibiotics (Prophylactic and Therapeutic) Don’t drain acute fluid collections TPN vs Jejunal tube feeds (cannot feed into stomach, rest the pancreas) |
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Chronic Pancreatitis
What is it? What causes it? (4) |
Gradual fibrotic destruction of pancreatic tissue with impaired endocrine and exocrine functions with many psychological sequelae
Can be caused by recurrent bouts of acute pancreatitis Alcohol-Related Chronic Pancreatitis Females are affected less than males, with mean age of onset of 35 years Recurrent attacks are common and pain is very severe Tropical Chronic Pancreatitis Present in India, Africa, South America Mostly due to malnourishment Autoimmune Pancreatitis (AIP) Due to lymphplasmocytic infiltration of the pancreas is associated with other autoimmune conditions Pain is milder than other forms Test for serum IgG4 and treat with corticosteroids Idiopathic CP Early onset in 1st or 2nd decades of life with severe abdominal pain and without structural or functional changes Late onset is in 4th or 5th decades of life with many structural and functional changes but minimal pain |
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Chronic Pancreatitis
Clinical features? Dx tests? |
Clinical Features
Abdominal pain, steatorrhea, diabetes, calicification Diagnostic Tests Imaging if presenting with pain Pancreatic Enzyme trial, insufficiency tests, x-ray, ultrasound, CT, ERCP, PET |
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Chronic Pancreatitis
Pain relief in Chronic Pancreatitis: Glandular damage due to ischemia and fibrosis – Pancreatic Duct Blockage – Pancreatic Pseudocysts – Celiac plexus mediates pain – |
Glandular damage due to ischemia and fibrosis – Medication
Pancreatic Duct Blockage – ERCP Pancreatic Pseudocysts – Drainage Celiac plexus mediates pain – Block |
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Chronic Pancreatitis
Tx? |
pain relief +
Medical Treatment Stop Alcohol and smoking Analgesics, enzyme therapy, treat malnutrition ERCP Stone removal and stent placement Surgery Pain and dilated duct, non-dilated duct, pseudocyst repair, chronic stricture |
