gastrointestinal physiology valerie parker, dvm, dacvim february 16, 2012
TRANSCRIPT
Gastrointestinal Physiology
Valerie Parker, DVM, DACVIM
February 16, 2012
Objectives
We will cover GI hormones/secretions/glands
Pertinent veterinary literature We will not cover
Anatomy GI motility Digestion
GI hormones
Gastrin Cholecystokinin (CCK) Secretin Motilin Incretins
Hormone
Origin
Stimulus
Effect
Gastrin
G-cell Antrum of stomach
Stimulated by Gastric distension Protein digestion Gastrin releasing peptide Acetylcholine (ACh)
Gastrin
Effects Stimulates gastric acid secretion Stimulates growth of gastric
mucosa
Gastrin
Measured in 125 fasted (healthy) dogs 78 males and 47 females
Differences in sex/age As age increased – [gastrin] higher in
malesNo difference between sexes when
younger
[Gastrin] = 46.7 +/- 22.9 pg/mlTorres JA, et al. Medicina Veterinaria. 2000;17:54-62
Gastrinoma
Non-β-cell islet (delta?) cell tumors Autonomously secrete excessive
gastrin Leads to gastric acid hypersecretion GI erosions/ulceration
Gastrinomas may secrete other hormones Eg, insulin, ACTH
Gastrinoma
Gastrinoma = APUDoma Peptide-secreting cell tumor APUD = amine precursor uptake &
decarboxylation
Zollinger-Ellison syndrome
Triad of Hypergastrinemia Neuroendocrine neoplasm Gastrointestinal ulceration
Diagnosis
Typically have clinical evidence
Gastric concentration 72-2780 pg/ml in dogs w/ gastrinoma 350, 1000 pg/ml in cats
Most animals have [gastrin] > 3x normal Not pathognomonic
Normal gastrin does not rule-out gastrinoma
Additional testing
Provocative stimulation tests Secretin stimulation test Calcium stimulation test Combined secretin-calcium
stimulation
Gastrinoma
Treatment Surgical procedure (if possible)
Partial gastrectomy Acid reduction
H2-receptor antagonistsProton-pump inhibitors*Somatostatin analogue (octreotide)
Cholecystokinin (CCK)
I-cell Mucosa of duodenum & jejujum
Stimulated by Fat digestion
CCK
Effects Gall bladder contraction Inhibits gastric contraction
Allows time for fat digestion
Secretin
S-cell Mucosa of duodenum
Stimulated by Acidic gastric fluid in duodenum
Effects Pancreatic secretion of bicarbonate Mild effect on GI motility
Motilin
Upper duodenum
Fasted state Released cyclically
Effects Increases GI motility
Incretins
Hormones secreted in response to nutrients in intestinal lumen
Glucose-dependent insulinotropic polypeptide (GIP) Aka gastric inhibitory peptide
Glucagon-like polypeptide-1 (GLP-1)
Gastric inhibitory peptide (GIP)
K cell (intestine)
Stimulated by Fat & protein digestion Lesser extent CHO digestion
Effects Decreases gastric emptying
Glucagon-like peptide-1 (GLP-1)
L-cell (intestine)
Actions Glucose-dependent stimulation of
insulin Suppresses glucagon secretion
Incretins
Actions Stimulate insulin release Reduce gastric emptying
Slow rate of nutrient absorption Inhibit glucagon release
Inactivated by dipeptidyl peptidase-4 (DDP-4)
Exenatide = GLP-1 mimetic Increases insulin secretion Delays gastric emptying Increases satiety Improves β-cell function
9 healthy cats Isoglycemic glucose clamps
To mimic [BG] of oral glucose tolerance test 1 ug/kg exenatide SQ
Measured BG, insulin, exenatide concentrations
Insulin increased within 15 minutes Quickly returned to baseline Increased again w/ dextrose infusion
Exenatide peaked at 45 minutes Detectable in some cats up to 8 hrs Vs. GLP-1 – t-½ = 1-2 min
No adverse effects noted 1 cat developed hypoglycemia
54 mg/dl @ 1 hr post-injection
Conclusions Exenatide affects insulin secretion in
cats in a glucose-dependent manner May benefit survival of pancreatic β-
cells in cats with NIDDM
Somatostatin
D-cell
Stimulated by Gastric pH < 3
Somatostatin
Decreases Gastrin Histamine Acid secretion
Inhibits Insulin Glucagon Growth hormone
Alimentary glands
Mucous glands Crypts of Lieberkühn Tubular glands
Oxyntic (gastric) Pyloric
Extra-GI Salivary glands Pancreaatic Hepatic
Tubular glands
Oxyntic (gastric) glands Pyloric glands
Pyloric glands
Antrum Distal 20% stomach
Secrete Mucus Gastrin
Pyloric gland cellularity
Mostly mucous cells Lubrication food movement Protection of stomach wall from
acid
G-cells Gastrin
Oxyntic (aka gastric) glands
Oxyntic = acid-forming
Body & fundus Proximal 80% stomach
Oxyntic gland cellularity
Mucous neck cell
Peptic (chief) cell Pepsinogen
Parietal (oxyntic) cell Hydrochloric acid Intrinsic factor (dog)*
Cobalamin absorption
1. Binds to R protein2. Then gastric/pancreatic intrinsic
factor3. Finally to receptors in ileum
Hypocobalaminemia in LSA
58 dogs w/ multicentric LSA
Hypocobalaminemia (< 252 ng/L) Present in 16% Associated with poor outcome May be prognostic
Cook AC, et al. J Am Vet Med Assoc 2009;235:1437–1441
Hypocobalaminemia in LSA
Hypocobalaminemia in LSA
Pepsinogen
From peptic (chief) cell
Activated by contact with HCl Forms pepsin
Proteolytic actions in acidic pH (1.8-3.5) Inactivated by pH > 5
Pepsinogen
Secreted by peptic cells
Stimulated by ACh Also indirectly in response to acid
Pepsinogen pepsin (active)
Acid Secretion
Many stimuli Gastrin (G-cell) = most potent Histamine
Enterochromaffin-like cell (ECL)Mast cell
Acetylcholine
Inhibited by somatostatin
Hydrochloric acid
Secreted by parietal cell (oxyntic gland)
Rate of secretion directly related to histamine release (ECL-cell) Affected by gastrin
Histamine & gastrin in MCT
17 dogs with mast cell tumor [Histamine] higher in MCT vs. normal
dogs [Gastrin] lower in MCT vs. normal
dogs Inversely related to histamine
Indirect evidence for hyperacidity from hyperhistaminemia
Fox LE, et al. J Vet Intern Med 1990;4:242-246
Protection from acid
Gastric mucosal barrier (GMB) Epithelial cells Bicarbonate-rich mucus layer Mucosal blood supply
BicarbonateOxygenNutrientsProstaglandins
PGE2
Pancreatic digestive enzymes
Protein digestion Trypsin Chymotrypsin
Split proteins peptides (not amino acids)
CarboxypolypeptidaseCan break peptides into amino acids
Pancreatic digestive enzymes
Enzymes secreted as inactive zymogens
Activated after secreted into intestine Eg. Trypsinogen activated by
enterokinase
Activation is self-perpetuated Trypsinogen activated by trypsin Inhibited by trypsin inhibitor
Pancreatic digestive enzymes
Carbohydrate digestion Pancreatic amylase
Hydrolysis of starch, glycogen, etc.Not cellulose
Pancreatic digestive enzymes
Fat digestion Pancreatic lipase
Fat hydrolysis fatty acids & monoglycerides
Cholesterol esteraseHydrolysis of cholesterol esters
PhospholipaseSplits fatty acids from phospholipase
Spec cPL in 11 healthy dogs
Measured daily, weekly, monthly 14 times over 12 weeks
Goals Determine biological variability Validity of applying reference range Difference needed for sequential results
Carney PC, et al. J Vet Intern Med 2011;25:825–830
Spec cPL
Spec cPL
Mean serum concentration = 62.3 mg/L Range = 29.0–516.2 mg/L
Interindividual variability = 49% Intraindividual variability = 194%
~ 5-fold difference must be seen to reflect a change in the animal rather than biological variation (healthy dogs)
Pancreatic juice
In addition to enzymes Bicarbonate Water
Bicarb secretion can exceed 5x [plasma] Neutralizes HCl in duodenum
Pancreatic stimuli
Acetylcholine CCK
Stimulates acinar cellsLarge quantities enzymesLess water, electrolytes
Secretin Stimulates secretion of
water/bicarbonate
Bile secretion
Bile stimulated by CCK Response to fat digestion Also stimulated by ACh
Bile
Bile composition Mostly bile salts Bilirubin Cholesterol Lecithin Electrolytes
Bile acids
BAs synthesized in liver (cholesterol)
Conjugated to taurine (cat) or glycine Stored in gall bladderCCK stimulates release (fat digestion) Transported from ileum to portal
circulation
Bile acids
Primary BAs = cholic & chenodeoxycholic acids Formed in liver
90-95% absorbed from ileum (Na-K ATPase pump)
5-10% primary BAs reach colon Secondary BAs = deoxycholic & lithocholic
acids
Enterohepatic circulation
Small intestinal secretions
Brunner’s glands (mucus glands) Located in proximal duodenum
Secrete alkaline mucus in response to: Irritating stimuli ACh (vagal stimuli) Secretin
Inhibited by sympathetic stimulation
Small intestinal secretions
Crypts of Lieberkuhn Located between villi
2 cell types Goblet cell mucus Enterocytes
Crypts secrete water & electrolytesVilli reabsorb
Small intestinal enzymes
Protein digestion Peptidases
CHO digestion Sucrase Maltase/isomaltase Lactase
Fat digestion Intestinal lipase
Summary
There’s a lot going on in the GI tract!
Good references: Guyton/Ganong physiology Feldman/Nelson
Endocrinology/ReproductionGI hormones (page 646)
Ettinger
Questions?