BIOCHEMICAL EVALUATION OF GASTROINTESTINAL DYSFUNCTIONS

Prof.Dr.Arzu SEVEN

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• 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.

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• 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.

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• 12 hr. overnight HCI>100 mmol/L, basal HCI>20 mmol/L

• Hypergastrinemia + diarrhea +steatorrhea + endocrinopathies

• diagnosed by secretin challenge provocative test :

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• 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.

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• Hypergastrinemi:• Gastric ulcer disease• Infections with Helicobacter pylori• Pernicious anemia• Parietal cell antibody (+) chronic atrophic

gastritis • Pyloric obstruction• Chronic renal failure

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• Surgical resection or diseases of kidney/small intestine

• Stomach carcinoma

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• Cholecytokinin(CCK)_Pancreozymin (PZ)• Circulating levels of CCK are increased after a

mixed meal.• CCK is rapidly cleared from plasma by the

kidney.

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• 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

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• 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.

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• 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.

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• 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.

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• Increased secretin secretion is seen in gastric acid hypersecretion (gastrinoma)

• prolonged starvation• DM• Decreased secretin secretion in celiac disease.

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• 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.

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

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• 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

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• 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

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• Gastric Inhibitory Polypeptide (GIP)• Insulinotropic action of GIP glucose-

dependent insulinotropic peptide

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

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• 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)

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• 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

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• 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.

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• 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.

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• 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 colitis24

• 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.

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

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• 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)

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• 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.

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• 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

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• 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 .

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• In pernicious anemia pepsinogen II levels are normal but pepsinogen I is low/undetectable.

• PGI/PGII Ulcer in gastric body• PGI/PGII Duodenal ulcer

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• 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)

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

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• Amylase• After an acute pancreatitis attack, amylase

activity is increased after 2-12 hr ,reaches a peak at 12-72 hr

• Relatively nonspecific

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• 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.

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• Trypsinogen• Trypsin • Trypsin α1-proteinase inhibitor (α1-antitrypsin)

Collectively Measured byİmmunologicalassays

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• Very high trypsin levels in acute pancreatitis contrast sharply with low/normal levels in chronic pancreatitis

• Normal in hepatic jaundice • High in renal disease

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• 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 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.

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• 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

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• 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)

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• 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.

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• Stimulators of gastric secretion:1.Test meals (Ewald meal )2.Caffeine sodium benzoate3.Alcohol4.Gastrin5.Pentagastrin6.İnsulin7.Sham feeding

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• 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.

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• Insulin• Hypoglycemia (0.1-0.2 u insulin/kg body

weight IV) stimulates acid secretion by vagal and nonvagal mech.

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• PANCREAS • Production and secretion of pancreatic juice1.Colorless2.ph 8.0-8.3 3.As high as 3000 ml/24 hr.

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• 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)

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• 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 (CO2 Test ) in blood or urine)

Serum carotene, vitamin A ,schilling test

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• 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.

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• 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

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• Test becomes (+) between 3-5 wk. of age• Symptoms:• Unexplained chronic pulmonary disease +

chronic hepatobiliary disease + hypoproteinemia + edema + failure to thrive

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Tests of intestinal FunctionD-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)

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• 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.

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• 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

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• 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 H2 test for1.Carbohydrate malabsorption2.Noninvasive test of intestinal bacterial

overgrowth

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• 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

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• Peroxidase activity of heme=guaiac test (leuko dye )

• Decreased sensitivity(%40) + interferences(dietary +medication)• Alternative test is measurement of fecal

α1- antitrypsin and haptoglobulin

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