08 - Gastrointestinal and Exocrine Pancreatic Function

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8 - Gastrointestinal and Exocrine Pancreatic Function

Pancreatic Endocrine Functions

• To synthesize hormones such as glycogen, insulin and gastrin

• Originate from a group of cells called islets located in an area islets of Langerhans

• Islet cells contain beta, alpha and delta cells which is responsible for the production of hormones (glycogen, insulin and gastrin)

• Islet cells are surrounded by acinar cells which are responsible for the production of exocrine digestive enzymes such amylase and lipase

Pancreatic exocrine function tests

• Diagnosis of diseases such malabsorption and cystic fibrosis

• Tests useful in the diagnosis – B-carotine test of pancreatic malabsorption

process

– Vitamin B12 test – Sweat chloride test

Endocrine Functions from the Islets of Langerhans Cell Production Action Outcome Alpha Cells

Glucagon Glycogenolysis Gluconeogenesis

Glucose

Glucose

Beta Cells

Preinsulin Insulin

Glucose uptake Glucose

Delta Cells

Gastrin Digestion Gastric acid

Exocrine Functions from the Acinar Cells Cell Production Enzymes Digestive

Stimulation Acinar Cells

Enzymes and proteolytic enzymes precursors

Trypsin α-Amylase Cholesterol esterase

Phospholipase A Lipase

Protein Starch Cholesterol esters Phospholipids

Triglycerides

Common Gastrointestinal disorders

• Gastric disorders

– Peptic Acid disease

• Pancreatic disorders

– Macro amylassemia – Acute pancreatitis

– Chronic pancreatitis

– Cystic fibrosis

• Intestinal disorders

– Chronic diarrhea

– HIV-related diarrhea

– Nosocomial diarrhea

Gastric Disorders

Peptic Acid Disorders

• Main cause of duodenitits and duodenal ulcers: Helicobacter pylori

• Associated conditions: – Type B chronic antral gastritis

– Gastric ulcers

– Non ulcer dyspepsia

– Gastric carcinoma

Tests utilized for Peptic Acid disorders

• H. pylori test

– Ability of organism to produce urease • Radioactive and nonradioactive breath hydrogen ion

tests

• Enzyme-linked immunosorbent

Urease-based chemical tests

• Specimen: Fresh biopsy specimens

• Principle:

– Bacterial urease splits the urea producing ammonia

• End results: – Change of pH affect the color indicator

Other causes of extensive peptic acid disease

• Hypersecretory states

– (in the absence of H. pylori and the use NSAIDS)

– Failure to respond to the usual dose of histamine 2 (H2) receptor blocking agents

– Proton pump inhibitor • Gastric levels with and without secretion stimulation

– Zollinger-Ellison syndrome

* Serum gastrin levels greater than 150 ng/L (normal <100 ng/L) especially with simultaneous gastric pH value of <3 are highly suggestive of gastrinoma

Pancreatic Disorders

Macroamylasemia

• A condition of persistently elevated serum amylase activity with no apparent clinical symptoms of pancreatic disorder

• Attibuted to the presence of an amylase macromolecule complex whose larger size precludes its excretion in urine

• Is a circulatory complex of normal amylase linked to an immunoglobulin (IgA and IgG)

Differential Diagnosis of Hyperamylasemia and Macroamylasemia CONDITION

SERU

M

AMYL

ASE

SE

RUM

LI

PASE

U

RIN

ARY

AMYL

ASE

C am

:Ccr

SERU

M

AMAC

RO-

AMYL

ASE

Pancreatic hyperamylasemia

↑ ↑ ↑ ↑ -

Salivary hyperamylasemia

↑ N ↓ / N ↓ / N -

Macroamylasemia type 1

↑ N ↓ Very ↓

↑

Macroamylasemia type 2

↑ N ↓ / N ↓ M

Macroamylasemia N N N ↓ / N T

N - Normal M - Moderate

T - Trace

Cam:Ccr = amylase clearance:creatinine clearance ratio = (urinary amylase/serum amylase) X (serum creatinine/urinary creatinine)


Acute Pancreatitis

• Serum Amylase

– Universal laboratory test

– Derived from pancreatic acinar cells

– Disease pattern

• Serum amylase level appear first 2-12 hours after the onset of acute pancreatitis reaches its peaks at 48 hours and return to normal within 3-5 days

• Serum Lipase

– Derived from pancreatic acinar cells

– Disease pattern

• Rises 4-8 hours after the onset of acute panceatitis (earlier than serum amylase), reaches its peak at 24 hours and last longer in the serum 8-14 days

– More sensitive and more specific than serum amylase

For Etiologic usefulness

• SGPT/SGOT

• Lipase/amylase

• Carbohydrate deficient transferin (CDT)

For severity of disease

• Trypsinogen Activation peptide (TAP)

• Hematocrit • C-reactive protein (CRP)

Chronic Pancreatitis

• Marked by progressive destruction of islet cells and acinar tissue (Acinar tissue is responsible for maldigestion associated with chronic pancreatitis due to loss of enzyme secretion responsible for digestion of food stuff)

• Routine laboratory testing is of little value although amylase and lipase maybe elevated however the absence of these enzyme in the serum does not rule out chronic pancreatitis

Clinical diagnosis of chronic pancreatitis depends on

• Finding of structural abnormalities in the ductal anatomy found on imaging

• The simplest method of functional testing of the pancreas

– Assessment of the presence of fat in the stool

– Serum trypsinogen assays can be done but can be useful only when the values are below 20 ng/mL but the values are only to be low in patients with advanced disease typically when steatorrhea is already present)

– Fecal elestase can be used in the diagnosis because of inadequate delivery of fecal elastase in the duodenum


Cystic Fibrosis

• Autosomal rescessive disease • Characterized by abnormal secretion from the various

exocrine glands of the body including the: • Pancreas

• Salivary glands

• Peritracheal glands

• Peribronchial glands

• Peribronciolar glands

• Sweat glands

• Mucosal glands of the small bowel • Bileducts

• Complications (major clinical problems)

• Laboratory diagnosis

• Sweat testing

• Demonstration of increased sodium and chloride in the sweat

• Testing should be done on two occassions with chloride concentration of over 60 mmoL/L of sweat are diagnostic

Intestinal disorders

• Chronic diarrhea

• HIV related diarrhea

• Nosocomial diarrhea

Testing for Malabsorption and Cystic Fibrosis Testing for Malabsorption Tripeptide Hydrolysis Test

Decreased para-aminobenzoic acid results suggest pancreatic insufficiency

Fecal Fat Values 5-10g% suggest malabsorption Values > 10 g% suggest maldigestion

14C-Triolein Breath

Decreased 14CO2 in expired air suggsts fat malabsorption

D-Xylose Absorption

Values below reference ranges suggest little to no absorption capacity of the proximal small bowel mucosa

Vitamin B12 Malabsorption

Patients who excrete < 7% are suspected to have pernicious anemia

Β-Carotine Decreased levels are seen in patients with malabsorption and/or malnutrition

Testing for Cystic Fibrosis Sweat Chloride Increased levels are diagnostic of cystic

fibrosis

FECALYSIS

• Analysis of stool contents

– Collection of Feces

– Examination of feces

• Macroscopic examination

• Microscopic examination

Collection of Feces

Adult Collection

• 24-hour stool collection

• Method: A. Ingestion of dye (0.3 g) at the beginning and

charcoal at the end of collecting period

B. Use of inert, non absorbable stool markers • Collected over a period of 3 days

• Weight / no. of days of collection

• Begin : Carmine dye(0.3g)

• End: charcoal (1 g)

• Start collecting stool at the appearance of the dye and end at the appearance of the charcoal

Pediatric collection

• Method: – Use of a thick-walled glass tube, which is

lubricated by clipping into water and then inserted into the young child rectum

• Thick-walled glass tube lubricated with water

• Core of feces can be obtained

• Poked out with applicator stick

Examination of Feces

Inspection

• Parasitic infestation

• Obstructive jaundice

• Diarrhea

• Malabsorption • Rectosigmoidal obstruction

• Dysentery

• Ulcerative colitis

• GIT bleeding

Macroscopic characteristics

Quantity

• 100 to 200 gms/day

Form

• Abnormal Forms – Diarrheal (watery)

– Steatorrhea (large amount, foul-smelling gray stool floats on water)

– Constipation (scybala)

Diarrhea

• If the amount of fluid entering or secreted into the large intestine exceeds the capacity for absorption, diarrhea results

• Normally: Ileum large intestine (500 -1500 ml of fluid) stool (150 ml)

Classification of Diarrhea

• Inflammatory/Exudative – Immune-mediated injury of GI mucosa

– Inflammatory bowel disease

– Crohn’s disease

– Ulcerative colitis

– Infectious

– Salmonella

– Shigella – Campylobacter

– Eteroinvasive E. coli – Yersinia enterocolitica – HIV enteropathy

• Secretory – Increased secretion of water and

electrolytes into the GI tract lumen

• Enteric infection

• Salmonella

• Shigella • Enterotoxigenic E. coli • V. cholera

• Staphylococci • Clostridia

• Protozoan

• Rotavirus

• Hormone mediated


• Osmotic

– Non-absorbed substances retain water in the GI tract lumen

– Maldigestion- Incomplete breakdown of protein, lipid,and/or carbohydrates

– Pancreatic insufficiency: • Chronic pancreatitis, cystic fibrosis,

obstruction at ampulla of Vater, pancreatic adenocarcinoma, somatostatinoma

– Carbohydrate intolerance: deficiency on

• Lactase, isomaltase-sucrase,and trehalase enzymes

– Others: Biliary obstruction, resection of ileum, chronic intestinal ischemia

• Malabsorption – Short bowel syndrome, Whipple’s disease,

celiac disease, tropical sprue, bacterial overgrowth, abetalipoproteinemia, GI lymphoma, glucose-galactose malabsorption, congenital chloridorrhea, hypogammaglobulinemia, parasitic infections

– Osmotically active dietary products: Psyllium fiber, magnesium citrate, sorbitol

• Altered motility

– increased peristalsis reduces transit time down GI tract

– Irritable bowel syndrome, hyperthyroidism, fecal impaction, neurologic diseases, diabetes, hypocalcemia, systemic sclerosis, GI bleeding, post-vagotomy

• Increased filtration

– GI capillary hydrostatic/oncotic pressure imbalance

– Portal hypertension, severe hypoalbuminemia, partial small bowel obstruction

• Iatrogenic – Medical treatment side effect

– GI surgery, Abdominal radiation therapy, medications (magnesium citrate, laxatives, antibiotics, cardiac medications, chemotherapeutic drugs, metoclopramide, cisapride, lactulose,theophyllin, etc.

• Factitious

– Self- induced

– Surreptitious laxative abuse associated with psychiatric disorders

Consistency • Formed

• Watery stool • Mucoidal

Constipation:

• Scybala: passage of small firm, spherical masses of stool

• Irritable colon syndrome secondary to anxiety or overuse of laxatives

• Carcinoma

• Repeated occult blood determination Narrow, ribbon-like stool:

• Spastic bowel or rectal narrowing or stricture

Color

• Clay colored stool:

– Diminution or absence of bile – Presence of barium sulfate

• Bloody stool:

– Red color stool Lower GIT Bleeding

Red Beets in the diet (false positive)

– Black tarry stool (melena)

Upper GIT Bleeding

Bismuth Iron and Charcoal intake (false positive)

• Green stool: – Biliverdin – Ingestion of spinach or green vegetables or

caramel (false positive) – Oral antibiotics (false positive)

Mucus

Recognizable mucus in stool is abnormal

• Transluscent gelatinous mucus on the surface of formed stool

– spastic constipation – mucous colitis

• Bloody mucus on stool – rectal neoplasm – inflammatory process in the rectal canal

• Mucus with pus and blood

– ulcerative colitis

– bacillary dysentery

– ulcerating diverticulitis

– intestinal TB

• Copius mucus (3 to 4 L/24hr)

– villous adenoma of the colon

Microscopic Examination

Pus

• Chronic ulcerative colitis

• Chronic bacillary dysentery

• Localized abcesses or fistulas communicating with

sigmoid colon, rectum, or anus

Fat

Method

• Sudan III • Sudan IV

• Oil Red O stains

Procedure

Neutral fat + soaps Fatty acids (stains strongly with Sudan III)

Indication

• Steatorrhea (Pancreatic origin)

Normal • 60-100/hpf of stained neutral fats)

Mineral oil or castor oil may mimic neutral fats

36% acetic acid


Meat Fiber

Method

Stool + 10% alcohol sol’n of eosin Rectangular fibers with striations

Leukocytes

• Small fleck of mucus/ a drop of liquid stool • 2 gtts Loeffler methylene blue

• Average number of WBC and RBC/ hpf

Fleck of mucus/ + 2 gtt of Loeffler Nuclear staining 1 gtt of liquid stool Methylene blue (Leucocytes)

• Only cells (mononuclear or polymorphonuclear leukocytes are included)

• Average number of WBC and RBC/ hpf

Fecal Blood

Causes

• Hemorrhoids or anal fissures

• Drugs: – Salicylates, steroids, rauwolfia derivatives,

phenylbutazone, indomethacin • Tarry stool for 2-3 days: blood loss of at least 1000 ml

and occult blood may persist for 5 to 12 days

Occult Blood Tests: • Principle:

determination of peroxidase and pseudoperoxidase activity of RBCs including Hgb

indicator used

- Quaiac rgt, orthotoluidine, orthodinisidine, benzidine

• Procedure: (guaiac test)

Blood + H2O2 + (guaiac rgt) blue quinone (stool) cpd

• Normally: 2.0 to 2.5 mL blood loss in GIT

(+) occult blood test - blood loss of > 5-10 ml per day (5-10 mg of

hgb/gm stool)

• Food giving false positive results: myoglobin and hemoglobin from meat and

fish

aspirin-containing preparations and iron cpds.

bacteria in the intestines, veggies and fruits: horseradish, turnips, bananas, black grapes, pears, plums

• Drugs giving false positive results: Vit. C and other antioxidants

• HemoQuant Converts heme to fluorescent porphyrin Not affected by: dietary peroxidase, Vit. C,

specimen storage, or hydration

• Immunologic tests using antisera or human hgb: RID, ELISA, Latex agglutination, and

hemagglutination

Latex agglutination assays (rotavirus, adenovirus)

• High sensitivity

• High specificity

• High PPV

• High NPV

• A good alternative to electron microscopy

• Requirements for occult blood test: Diet free of exogenous sources of

peroxidase activity for at least 3 days before the test

High residue foods in the diet: prunes, bran, raw veggies, corn, and peanuts

• Should be done at LEAST 3X and preferably 6X

Carcinoid Tumors and the Carcinoid Syndrome

Carcinoid tumors

• Neuroendocrine neoplasms of entrerochromaffin cells belonging to the amine precursor uptake and decarboxylation(APUCD) system.

• Organs involved with argentaffin cells: appendix, terminal ileum, rectum, bronchus, jejenum, duodenum, stomach, liver, pancreas, and gonads

• Sxs: mechanical bowel obstruction or paraneoplastic manifestations with peak incidence in the 6th decade of life

Carcinoid syndrome

• Symptoms: • Skin flushing

• Abdominal cramps

• Nausea

• Vomiting

• Diarrhea

• Hypotension

• Bronchoconstriction • Cyanosis

• Cardiac lesions with endocardial and valvular thickening and fibrosis, predominantly involving the right ventricle

• Carcinoid tumors sythesize and release serotonin • Other hormones secreted:

gastrin ACTH

insulin glucagon

somatostatin hCG subunits

motilin calcitonin

Enterochromaffin cell (carcinoid tumors) ↓

Serotonin ↓

Tryptophan 5-HTP

Dopa decarboxylase Monoamine oxidase

5-HTP (5-hydroxytryptophan)

5-HT (5-hydroxytryptamine [serotonin])

5-HIAA (5-hydroxyindoleacetic acid) metabolite from 24-hour urine

3 mins

1-2 mins

tryptophan hydroxylase

5-HT

5-HIAA

Aldehyde dehydrogenase


Diagnostic Tests for Carcinoid Syndrome

5-HIAA in 24 hr urine:

(acidified with 10 ml 6N HCl to prevent oxidation)

• Method: Colorimetry Fluorometry Gas chromatography Radioimmunoassay

Fluorescence polarization immunoassay

High-pressure liquid chromatography(HPLC)

• NV: 2-8 mg/24 hr • False positive increase:

A. Food

bananas

plantains

tomatoes

eggplant

B. Drugs

Acetaminophen

Guanifenesin

• False positive decrease: A. Drugs

Reserpine Salicylates Monoamine oxidase inhibitors

Phenothiazines L-dopa

Serotonin (5-HT) in blood

• Blood in EDTA tube with ascorbic acid as preservative

• Whole blood or platelet-rich plasma

• Method: HPLC

• Ref. interval: WB serotonin: 50 to 200 ng/ml Platelet rich plasma: 125 to 500 ng/109 platelets

Malabsorption Syndromes

• Definition: – Result from impaired digestion or

assimilation of foodstuffs by the small bowel

• Common causes: (pancreatic diseases )

Chronic pancreatitis

Carcinoma of the pancreas

Cystic fibrosis of the pancreas

• Manifestations: Creatorrhea

- Undigested meat fibers in the feces

Steatorrhea

- An increase in fat - largely triglyceride (>5 grams of lipids (FA) in feces/24hrs)

Hepatic Maldigestion

• Interference with bile flow

– Loss of bile salts interference

• Fat emulsificaton • Diminishes surface area available

for lipolytic action

• Loss of bile salt activation by lipase • Cause

– Neoplasma obstructing the ampulla of Vater

• Results

– Hepatic steatorrhea – Pancreatic steatorrhea

Enteric Malabsorption

• Normal digestion but inadequate net assimilation of food stuffs resulting from:

– Competition by bacteria

– Altered bacterial flora • Causes

– Blind loop syndrome

– Diverticulosis – Obstruction of the lymph flow

• Whipple disease

• Lymphoma – Diseases affecting the bowel mucosa

• Amyloidosis • Inflammation following radiation

– Atrophy of small bowel due to wheat protein, gluten or gliadin-sensitivity in coeliac disease

– Vitamin B6 or B12 deficiency • Deficiencies of fat-soluble vitamins: A,D,E,& K

• Weight loss due to large caloric loss & nutritional deficiencies :

– Hypoprothrombinemia

– Glossitis

– Anemia

– Edema

– Ascites

– Osteomalacia

• Single foodstuff or vitamin or small group of substances deficiency:

– Lactose intolerance - lactase deficiency – Pernicious anemia - Vit. B12 deficiency

due to intrinsic factor deficiency

• Major Sign

– Steatorrhea

Excretion or presence of more than 5 gms of lipid

Differentiating Causes

Pancreatic vs. enteric malabsorption

• Cystic fibrosis of the pancreas

o Sweat electrolyte determination

Result: increase sweat chloride

o Trypsin activity Result: absence of trypsin in stool

Enteric malabsorption • D-xylose absorption test (25 g pentose sugar in water

taken orally)

• Result: < 3g excretion in urine over a 5- hr period

Celiac disease:

• Cellobiose-mannitol permeability test • Lactulose-mannitol test

• Patients with celiac disease underabsorb small molecules such as mannitol and absorb larger molecules such cellulose and lactalose

Intestinal Disaccharidase Deficiency

• Primary Disaccharide Deficiencies

– Sucrase-isomaltase deficiency

– Lactase deficiency

– Primary alactasia – Primary trehalase deficiency

pineapple kiwi fruit walnuts

hickory nuts pecans avocados


• Secondary Disaccharide Deficiencies

(transient; involve more than one enzyme)

– Celiac disease – Tropical sprue – Acute viral gastroenteritis

– Drugs (neomycin,kanamycin, methotrexate)

Intestinal Disaccharidase Deficiency in these disorders:

• Unhydrolyzed and unabsorbed carbohydates are fermented by intestinal bacteria, producing gas, lactic acid. Normally, absorption of digested carbohydrates is rapid and fairly complete in the proximal small intestine

• Unhydrolyzed dissacharides or unabsorbed monosaccharides due to deficiencies in transport are osmotically active which causes secretion of water and electrolytes into the small intestines

o Protracted diarrhea, bloating and flatulence

Screening tests for disaccharidase deficiencies:

• Oral challenge of suspected disaccharides stool analysis - watery, acidic (<pH5.5)

• Clinitest tablet (reducing substances) ≥0.5 g/dL or more than 250 mg/dl (abnormal)

Normal: 250 mg/dL of feces

• Definitive Dx: mucosa of small intestinal biopsy showing low enzymatic activity

Glucose – Galactose Malabsorption • Hereditary (autosomal recessive traits) disorder of

active absorption of glucose and galactose from the small intestine

• Problem: Diarrhea

• Laboratory tests

– Glucose oxidase – Galactose oxidase – Chromatography

– OGTT (flat curve)

Protein-Losing Enteropathy

Causes: • Ménétrier’s disease

• Gastric cancer

• Chronic gastritis

• Benign or malignant tumors

• Crohn’s disease

• Celiac disease

• Tropical sprue

• Ulcerative colitis

• Intestinal lymphatic obstruction

• Graft-vs.-host disease of the intestine

• Whipple’s disease (bacterial overgrowth)

• Infectious enteritis

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08 - Gastrointestinal and Exocrine Pancreatic Function