BIOCHEMICAL EVALUATION OF GASTROINTESTINAL DYSFUNCTIONS Prof Dr Arzu

BIOCHEMICAL EVALUATION OF GASTROINTESTINAL DYSFUNCTIONS Prof. Dr. Arzu SEVEN 1

• GI tract is both a major endocrine organ and a major target for many hormones. • GI hormones influence motility, secretion, digestion and absorption in the gut. 2

• GASTRIN • Originates from the cleavage of the precursor, preprogastrin • Clinical Significance: • Zollinger Ellison Syndrome(Z-E): • Fulminant peptic ulcer+massive gastric hypersecretion +non-B-islet cell tumors of pancreas. 3

• 12 hr. overnight HCI>100 mmol/L, basal HCI>20 mmol/L • Hypergastrinemia + diarrhea +steatorrhea + endocrinopathies • diagnosed by secretin challenge provocative test : 4

• 2 µg/kg body weight secretin is infused IV , gastrin is measured 10 min and 1 min before the infusion and at 2, 5, 10, 15, 20 and 30 min. following the infusion. • A positive test, consistent with the diagnosis of gastrinoma, is indicated by an increas in gastrin concentration of 200 ng/L or more over the basal level →A standard test meal (Lundh meal ) has been found to produce a postprandial rise in serum gastrin of >%50. 5

• • • Hypergastrinemi: Gastric ulcer disease Infections with Helicobacter pylori Pernicious anemia Parietal cell antibody (+) chronic atrophic gastritis • Pyloric obstruction • Chronic renal failure 6

• Surgical resection or diseases of kidney/small intestine • Stomach carcinoma 7

• Cholecytokinin(CCK)_Pancreozymin (PZ) • Circulating levels of CCK are increased after a mixed meal. • CCK is rapidly cleared from plasma by the kidney. 8

• CCK secretion is completely inhibited after somatostatin infusion. • Clinical Significance: • Pancreatic exocrine insufficiency and celiac disease ( up to 8500 ng/L) • Fatty food intolerance, gastric ulcer, postgastrectomy state , irritable bowel syndrome 9

Secretin Structural similarities to glucagon, VIP, GHRH Secretin is not released until p. H is lowered to at least 4. 5 • It is released primarily on contact of S cells with gastric HCI. • • 10

• Alcohol appears to increase secretin release by stimulation of gastric acid secretion with subsequent lowering of duodenal p. H. • Kidney is the major site of degradation. • The only known physiological inhibitor of secretin release is somatostatin. 11

• Clinical Significance: • Transient decreases of secretin along with prolonged rises after meals, with highest levels occurring during night, make the normal diurnal patterns of secretion. • Fasting and severe physical stress cause increased secretion levels that can be reversed by glucose ingestion. 12

• Increased secretin secretion is seen in gastric acid hypersecretion (gastrinoma) • prolonged starvation • DM • Decreased secretin secretion in celiac disease. 13

• Vasoactive Intestinal Polypeptide (VIP) • Structural similarity to secretin, GIP and glucagon • Unlike other GI hormones, VIP is not found in the mucosal endocrine cells of GI tract. • Neurotransmitter limited to peripheral and central nervous tissue. 14

• Clinical Significance • Verner-Morrison Syndrome (Pancreatic cholera) • Increased VIP concentration • Watery diarrhea • Hypokalemia • Achlorhydria • hypotension 15

• Cutaneous flashing (vasodilation) (usually associated with a pancreatic tumor) • Overproduction of VIP by tumor is responsible for these symptoms =VIP omas • Medullary thyroid carcinoma • ganglioneuroblastoma 16

• A very useful screaning test for the diagnosis of VIP-secreting tms • An effective tm. marker for detecting occult metastases • hepatic cirrhosis • Crohn’s disease VIP 17

• Gastric Inhibitory Polypeptide (GIP) • Insulinotropic action of GIP glucosedependent insulinotropic peptide 18

• • • Clinical Significance: Starvation prolonged fasting type IV hyperlipoproteinemia renal failure untreated ketotic juvenile DM GIP 19

• Patients with cystic fibrosis or pancreatitis show an increased response of GIP to glucose and a lower response to TG (duo to lipase deficiency) • In duodenal ulcer disease, GIP shows an increased response to glucose (rapid gastric emptying) 20

• • Somatostatin Tissue: antrum of stomach upper small intestine pancreas Hypothalamus Most potent inhibitor of endocrine secretion Somatostatin inhibits GH, TSH, insulin, glucagon, gastrin, CCK, secretin, VIP, GIP, motilin, pancreatic polypeptide, neurotensin, substance P secretion 21

• Function: Inhibitor of pepsin secretion, gastric emptying, inhibition of gallbladder contraction, secretion of bile and pancreatic enzymes. • Long -acting somatostatin analogues inhibit hormone secretion and reduce clinical symptoms in gastrinoma, glucagonoma, VIP oma. 22

• Motilin • Widely distributed in GI tract, from the esophagus to colon, including the gall bladder and biliary tract • Function • A strong stimulant for contraction of smooth muscles of upper GI tract, it increases the motility of the fundus, antrum and duodenum and contractions of lower esophageal sphincter. 23

• Motilin is unique in that its actions are generally restricted to fasting state. • Motilin increases in : • Crohn’s disease • acute intestinal infection • Irritable bowel syndrome • tropical sprue • ulcerative colitis 24

• Pancreatic polypeptide(PP) • Tissue: pancreas • Biphasic effect: it initially increases and then inhibits secretion of pancreatic enzymes , water and electrolytes thus opposing the stimulatory effectors of secretin and CCK , increases gut motility and gastric emptying , relaxation of pyloric and ileocecal sphincters, colon and gallbladder. 25

• • • VIP oma glucagonoma gastrinoma insulinoma duodenal ulcer Juvenile onset DM of long duration PP (biochemical marker for pancreatic endocrine tm) PP 26

• • Enzymes of GI tract Pepsin and Pepsinogen 7 different fractions of pepsinogen 5 fractions that migrate toward the anode most rapidly are identical immunologically (pepsinogen I=pepsinogen A) 27

• 2 other fractions migrate behind group I pepsinogens (pepsinogen II) • Pepsinogen I is the major proteinase in normal tissue. • Both group pepsinogens are detected in blood, only group I is present in urine, group II is present in semen. 28

• Pepsinogen secretion, like gastric lipase , is stimulated by vagus nerve and GI hormones (gastrin, secretin, CCK, VIP) • Pepsinogen I increased gastric output and increased parietal mass Z-E syndrome, gastrinoma, duodenal ulcer (%30 -50) acute and chronic superficial gastritis 29

• H. pylori sero(+) patients have higher serum pepsinogen I levels screening test for H. pylori infection ( + ), marker of H. pylori eradication • Pepsinogen I is decreased in decreased cell mass , atrophic gastritis, gastric carcinoma, myxedema, Addison’s disease and hypopituitarism. 30

• In pernicious anemia pepsinogen II levels are normal but pepsinogen I is low/undetectable. • PGI/PGII Ulcer in gastric body • PGI/PGII Duodenal ulcer 31

• The most sensitive test for fundic atrophic gastritis is PGI/PGII • PGI/PGII<3. 3 moderate/ severe atrophic gastritis and aftere total gastrectomy • Normal ratio: • (PGI/PGII = 5 -6) 32

• • Enzymes Derived From Pancreas : Amylase Lipase Proteolytic Enzymes 33

• Amylase • After an acute pancreatitis attack, amylase activity is increased after 2 -12 hr , reaches a peak at 12 -72 hr • Relatively nonspecific 34

• Lipase • For the diagnosis of acute pancreatitis • Elevations are more pronounced, more prolonged and more specific. • Lipase and amylase (P-type izoenzyme) elevations complement pancreatitis diagnosis. 35

• Trypsinogen • Trypsin α 1 -proteinase inhibitor (α 1 -antitrypsin) Collectively Measured by İmmunological assays 36

• Very high trypsin levels in acute pancreatitis contrast sharply with low/normal levels in chronic pancreatitis • Normal in hepatic jaundice • High in renal disease 37

• Elastase 1 anionic, free or in complex with α-1 proteinase inhibitor in serum • Elastase 2 catonic, exists in serum mainly in bound form • Elastase I is increased in acute and relapsing chronic pancreatitis greater than serum amylase activity. • Elevations persist for a longer time and reflect a better clinical course than amylase. • Increase in carcinoma of pancreas head. 38

• • GASTRİC FUNCTION is evaluated by : Helicobacter pylori test Analysis of gastric residue Secretion rate in basal state and after stimulation Intrinsic factor analysis Pepsinojens analysis 39

• • • Gastric residue: Content of the stomach after 12 hr fast is 20 -100 ml Colorless Odor is sharply sour Total acidity includes hydrogen ions accurring as (1) free HCI (2) mucoprotein (3) acid salts (4) organic acids(Lactic and butyric acid) 40

• The concentration free acid in gastric residue is 0 -40 mmol/L • Absence of free HCI is abnormal only if the condition persists after maximal stimulation with pentagastrin • Before the diagnosis of achlorhydria, gastric stimulation should be made. 41

• Stimulators of gastric secretion: 1. Test meals (Ewald meal ) 2. Caffeine sodium benzoate 3. Alcohol 4. Gastrin 5. Pentagastrin 6. İnsulin 7. Sham feeding 42

• Gastrin is the naturel and most powerful stimulus for gastric HCI secretion • (2 µg gastrin for key of body weight subcutaneously or 1 µg gastrin/kg (IM) • Pentagastrin: synthetic product, 6 µg subcutaneously/kg body weight for maximal stimulation. 43

• Insulin • Hypoglycemia (0. 1 -0. 2 u insulin/kg body weight IV) stimulates acid secretion by vagal and nonvagal mech. 44

• PANCREAS • Production and secretion of pancreatic juice 1. Colorless 2. ph 8. 0 -8. 3 3. As high as 3000 ml/24 hr. 45

• Invasive tests • Nonsive tests Invasive tests: 1. those that stimulate intraluminally pancreatic secretion (by Lundhtmeal : %5 protein %6 fat %15 CH %74 non-nutrient fibers or by duodenal infusion of essential AA) 2. those that stimulate pancreatic secretion by IV hormonal injection (secretin, CCK, secretin +CCK) 46

• Noninvasive tests: • 1 -Measurement of unabsorbed food or fecal pancreatic enzymes: trypsin chymotrypsin elastase in stool (fecal lipids, steatorrhea by microscopic stool examinaton/fat absorption test • 2 -measurement of products of food digestion or synthetic compounds hydrolysed by intraluminal pancreatic enzymes, absorbed by the gut , detected in breath (CO 2 Test ) in blood or urine) Serum carotene, vitamin A , schilling test 47

• 3 -measurements of plasma concentration of hormones, AA or enzymes. • These tests measure pancreatic function, do not diagnose a specific disorder • Pancreatic insufficiency can’t be demonstrated until at least %50 of acinar cells are destroyed. • Clinical symptoms don’t appear until %90 of acinar tissue is lost. 48

• No reference intervals for enzymes after stimulation with either secretin or CCK standardized techniques. • The chronic pancreatitis, the earliest change in secretin test is a decrease of bicarbonate <90 mmol/L • Sweat Test: • Chloride concentration of sweat is considered the most reliable single test in the diagnosis of cystic fibrosis 49

• Test becomes (+) between 3 -5 wk. of age • Symptoms: • Unexplained chronic pulmonary disease + chronic hepatobiliary disease + hypoproteinemia + edema + failure to thrive 50

Tests of intestinal Function D-Xylose Absorption test values celiac disease tropical sprue crohn’s disease Ig deficiency enteropathy pellegra surgical bowel resection after vomiting delayed gastric emptying malabsorption (%80) 51

• Excretory values decrease with age as a reflection of decreased kidney function. • Malabsorption due to pancreatic insufficiency absorption of xylose will be normal if intestinal motility is not increased. 52

• D_xylose test + PABA test for chymotrypsin combine the functional assessment of both exocrine pancreas and small intestinal absorption using serum levels determined by GC/MS • INTESTINAL PERMEABILITY (IP) • IP usually refers to the permeation of molecules with a molecular mass> 150 Da 53

• Permeability is measured as the % excretion of the oral dose in 5 hr. period • IP increases in untreated celiac disease, Crohn’s disease and assessment of therapy • Breath H 2 test for 1. Carbohydrate malabsorption 2. Noninvasive test of intestinal bacterial overgrowth 54

• Fecal occult hidden blood(FOB) • Colorectal cancers have fecal Hb concentration>2 mg/g of stool • Normal < 2 mg/g/d • Either heme or heme-derived porphyrins should be detected 55

• Peroxidase activity of heme=guaiac test (leuko dye ) • Decreased sensitivity(%40) + interferences(dietary +medication) • Alternative test is measurement of fecal α 1 - antitrypsin and haptoglobulin 56