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

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

3. GASTRIN Originate s 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

4. 12 hr. o vernight HCI>100 mmol/L, basal HCI>20 mmol/L Hypergastrinemia + diarrhea +steatorrhea + endocrinopathies diagnosed by secretin challenge prov o cative test : 4

5. 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. f o llowing 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

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

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

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

9. 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

10. Secretin Structural similarities to glucagon, VIP, GIP, GHRH Secretin is not released until pH is lowered to at least 4.5 It is released primarily on contact of S cells with gastric HCI. 10

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

12. Clinical Significance: Transient decreases of secretin along with prolonged rises after meals, with highest levels o ccurring 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

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

14. 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

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

16. 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

17. 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

18. Gastric Inhibitory Polypeptide (GIP) Insulinotropic action of GIP glucose- dependent insulinotropic peptide 18

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

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

21. 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

22. 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

23. 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

24. 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 ulcer a tive colitis 24

25. 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

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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

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

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

35. 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

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

37. 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

38. Elastase 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 relapsin g 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

39. 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

40. 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

41. The concentration free acid in gastric residue is 0-40 mmol/L Abse nce 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

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

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

44. Insulin Hypoglycemia (0.1-0.2 u insulin/kg body weight IV) stimulates acid secretion by vagal and nonvagal mech. 44

45. PANCREAS Production and secretion of pancreatic juice 1.Colorless 2.ph 8.0-8.3 3.As high as 3000 ml/24 hr. 45

46. Invasive tests Nonsive tests Invasive tests: 1.those that stimulate intraluminally pancreatic secretion (by Lundh t meal : %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

47. Noninvasive tests : 1-Measurement of unabsorbed food or fecal pancreatic enzymes : trypsin chymotrypsin elastas e in stool (fecal lipids, steatorrhea by microscopic stool examinaton/fat absorption test 2-measurement of products of food digestion or synthetic compounds hy d rolysed 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

48. 3-measurements of plasma concentration of hormones, AA or e n zymes. 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

49. 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: Chlo ri de concentration of sweat is considered the most reliable single test in the diagnosis of cystic fibrosis 49

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

51. Test s 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

52. 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

53. 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

54. 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

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

56. 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