gastrointestinal physiology valerie parker, dvm, dacvim february 16, 2012

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?