Lecture 7 Introduction The stomach intestinal tract and pancreas are closely related both anatomically and functionally and clinical manifestations such as diarrhea or malabsorption may be associated with disease or disorders of any of these organs ID: 910329
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Slide1
Gastric, Pancreatic, and Intestinal Function
Lecture 7
Slide2Introduction
The stomach, intestinal tract, and pancreas are closely related, both anatomically and functionally, and clinical manifestations, such as diarrhea or malabsorption, may be associated with disease or disorders of any of these organs
Advances in imaging techniques and improvements in endoscopic procedures has led to many traditional laboratory tests of gastrointestinal (GI) and pancreatic function becoming obsolete.
However, in recent years, there has been a resurgence in the role of the laboratory in the investigation of the GI tract, particularly with the development of noninvasive biomarkers of GI tract inflammation and in the detection of pancreatic insufficiency.
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Slide3PHASES OF DIGESTION
The processes of digestion can be divided into neurogenic, gastric, and intestinal phases.
Neurogenic Phase
The neurogenic, or cephalic, phase is initiated by the intake of food into the mouth; the sight, smell, and taste of food stimulates the cerebral cortex and subsequently the vagal nuclei.
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Slide4PHASES OF DIGESTION
Gastric Phase
When food enters the stomach the resulting distention initiates the gastric phase of digestion.
Hydrochloric acid release is caused by direct vagal stimulation of the parietal cells, local distention of the antrum, and vagal stimulation of antral cells to secrete gastrin.
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Gastrin also stimulates antral motility, secretion of pepsinogens and of pancreatic fluid rich in enzymes, and release of hormones such as secretin, insulin, acetylcholine, somatostatin, and pancreatic polypeptide.
Slide5PHASES OF DIGESTION
As a result of the acid environment pepsinogen is rapidly converted to the active proteolytic enzyme pepsin.
Food is mixed by contractions of the stomach and is partially degraded into chyme by the chemical secretions of the stomach.
The pylorus plays a role in emptying chyme into the duodenum by virtue of its strong musculature.
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Slide6PHASES OF DIGESTION
Intestinal Phase
The intestinal phase of digestion begins when the weakly acidic digestive products of proteins enter the duodenum.
Many hormones and other regulatory peptides are released by both neural and local stimulation and act within the GI tract to regulate digestion and absorption.
Digestion, absorption, and storage functions are stimulated or inhibited by different hormones, creating a control system that regulates the action of intestinal hormones and provides for secretion of bile acids, bicarbonate, and numerous enzymes involved in the digestion of food.
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Slide7STOMACH: DISEASES ANDLABORATORY INVESTIGATIONS
Growth in endoscopic procedures, with direct visualization of the interior of the stomach, has largely removed the need for the laboratory to carry out investigation of gastric contents.
Situations remain, however, in which the laboratory continues to play a role in diagnosing gastric diseases and in monitoring the effectiveness of treatment.
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Slide8STOMACH: DISEASES AND LABORATORY INVESTIGATIONSHelicobacter pylori
H. pylori
is the predominant cause of gastric and duodenal ulcers, the remainder being associated with the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDS) and, rarely,
gastrinomas.
H. pylori
is present in the mucus layer of the stomach in half of the world’s population.
In Europe 30% to 50% of adults and in the United States at least 20% of the adult population are infected with the bacterium.
Chronic infection produces an inflammatory response (gastritis) and carries an increased risk for developing a peptic ulcer (3- to 10-fold) and/or adenocarcinoma (2- to 10-fold).
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Slide9STOMACH: DISEASES AND LABORATORY INVESTIGATIONSHelicobacter pylori
Up to 90% of gastric cancer patients are infected with
H. pylori
. In a European study comparing the prevalence of H. pylori versus gastric cancer rates in 13 countries, a significant correlation was found between the infection rate and gastric cancer incidence and mortality.
H. pylori
may cause dyspepsia in the absence of an ulcer, and current recommendations suggest a low threshold for testing for
H. pylori
and some advocate treatment without testing.
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Slide10STOMACH: DISEASES AND LABORATORY INVESTIGATIONSHelicobacter pylori
The mode of transmission of
H. pylori
is unclear.In many cases the infection appears to originate in childhood, presumably by the fecal-oral route, because the prevalence is higher in developing countries and is inversely related to food hygiene.
Almost all individuals infected with
H. pylori
develop chronic gastritis, but only 10% of cases manifest as peptic ulcers.
H. pylori
infection predominantly affects the gastric mucosa, with the antrum usually the most densely colonized area.
At least 95% of patients with duodenal ulcers have
H. pylori
infection, and eradication of the organism results in healing of the ulcer and a reduction in relapse rates.
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Slide1111
Slide12STOMACH: DISEASES AND LABORATORY INVESTIGATIONSHelicobacter pylori
This variation is governed by a number of factors including the site of infection, virulence factors (
eg
, vacuolating cytotoxins [VAC], CagA protein), mucus secretion and extent of pepsinogen secretion.
Infection of the mid-body of the stomach is the commonest form, occurs in people with a strong immune system and involves a type of
H. pylori
with low expression of
CagA and VAC. However, if the infection is in the antrum, the inflammation causes the G cells to become hyperactive with a resulting disproportionate secretion of gastrin in response to food and gastric distention and consequent increases in acid output.
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Slide13STOMACH: DISEASES AND LABORATORY INVESTIGATIONSHelicobacter pylori
Basal acid output has been shown to be higher in
H. pylori
–infected subjects, and this resolves after eradication of the organism.Hypergastrinemia is believed to be only one of the mechanisms leading to increased acid output.
H. pylori
produces urease, and hydrolysis of this endogenously produced urea to bicarbonate and ammonia may create a more hospitable environment for the survival of the organism in the stomach.
This ability of
H. pylori to hydrolyze urea forms the basis of urea breath tests and direct urease tests on gastric biopsy samples.
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Slide14STOMACH: DISEASES AND LABORATORY INVESTIGATIONS
Helicobacter pylori
:
Diagnostic Tests for
H. pylori
Numerous invasive and noninvasive diagnostic tests for
H. pylori
have been described:
Invasive tests: Using gastric mucosal biopsy samples
Histology
: Microscopy after Giemsa, silver staining or IHC staining
Direct urease test
: Biopsy included in urea/ indicator solution—visual end point
Culture
: Incubation in suitable media for 4 to 10 days
Polymerase chain reaction
: Amplification of specific DNA sequences
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Direct urease test
Slide15STOMACH: DISEASES AND LABORATORY INVESTIGATIONS
Helicobacter pylori
:
Diagnostic Tests for
H. pylori
Noninvasive tests: Using breath, blood, saliva, or feces
Breath tests: Rise in
14
CO
2
or
13
CO2 after ingestion of
14
C- or
13
C-labeled urea
The breath test has sensitivity and specificity for
H. pylori
in excess of 95% and can be used both for diagnosis and to assess the success of eradication therapy.
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Slide16STOMACH: DISEASES AND LABORATORY INVESTIGATIONS
Helicobacter pylori
:
Diagnostic Tests for
H. pylori
Serum, saliva, or feces tests
Serologic methods are available to detect
H. pylori
–specific antibodies (IgG or IgA), but have some drawbacks compared to the urea breath test.
The systemic antibody response is variable, with equivocal results often occurring in subjects older than 50 years.
The sensitivity (92%) and specificity (83%) are also lower than those for the breath test.
Serologic tests cannot be used to confirm eradication of the bacterium because of the persistence of the antibodies for variable periods after completion of treatment.
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Slide17STOMACH: DISEASES AND LABORATORY INVESTIGATIONS
Helicobacter pylori
:
Diagnostic Tests for
H. pylori
H. pylori
is shed in feces, and several tests have been described that can detect the organism.
Polyclonal or monoclonal antibodies to
H. pylori
can be configured into various immunoassay formats, although sensitivity and specificity are lower than for breath tests.
Commercial kits are available that use polymerase chain reaction to amplify nuclear sequences specific for
H. pylori
in feces (or saliva) and have a sensitivity and specificity of 95% and 94%, respectively.
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Slide18STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and Gastrinomas
Collection of gastric juice and analysis of acid output was at one time extensively carried out in the investigation of possible
gastrinomas
. This invasive technique has now been replaced by the greater availability of: plasma gastrin measurements,
endoscopy, and
imaging modalities, including:
computed tomography (CT) and magnetic resonance imaging (MRI).
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Slide19STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and Gastrinomas
:
Gastrin
Three molecular forms of gastrin occur in blood and tissues: G-34, G-17, and G-14.
Gastrin is produced and stored mainly by:
endocrine cells (G cells) of the antral mucosa
to a lesser extent by G cells of the proximal duodenum and
Δ cells of the pancreatic islets
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Proximal duodenum
Slide20STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and Gastrinomas
:
Gastrin
After secretion, gastrin is transported by the blood through the liver to the
parietal cells
of the fundus of the stomach, where it stimulates the secretion of
gastric acid
. Gastrin is secreted in response to antral distention from food and by the presence of amino acids, peptides, and polypeptides in the stomach from partially digested proteins.
Other stimuli of gastrin include alcohol, caffeine, insulin induced hypoglycemia, and calcium.
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Slide21STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and Gastrinomas
:
Gastrin
Maximal secretion of gastrin occurs at an antral pH of 5 to 7. At pH 2.5, secretion of gastrin is reduced by approximately 80%, with maximal suppression occurring at pH 1.
Secretion is inhibited by the direct action of acid on the G cells.
This negative feedback prevents excess acid production regardless of the stimulant.
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Slide22STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and Gastrinomas
:
Gastrin
The principal circulating form of gastrin is in healthy individuals and in patients with hypergastrinemia is G-34.
Trypsin cleaves G-34 into two fragments one of which has the amino acid sequence of G-17.
On a molar basis, G-17 is 6 to 8 times more potent than G-34 as a stimulant of gastric acid secretion.
In the fasting state, the ratio of G-34 to G-17 is approximately 2:1.
After meals, the concentration of G-34 doubles but that of G-17 increases fourfold so the ratio approaches 1:1.
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Slide23STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and
Gastrinomas
:
Gastrinoma & the Zollinger-Ellison Syndrome
In 1955, Zollinger and Ellison described a syndrome consisting of:
Multiple peptic ulcers,
Gastric acid hypersecretion, and
Non–β islet cell tumors of the pancreas secreting gastrin.
Gastrinomas
are a rare cause (<0.5%) of gastroduodenal ulcers.
The persistently high circulating gastrin concentrations lead to hypersecretion of gastric acid and increased parietal cell mass.
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Slide24STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and Gastrinomas
:
Gastrinoma & the Zollinger-Ellison Syndrome
Duodenal ulceration and ulcers resistant to standard therapies must be considered suspicious.
Gastrinomas
are most often sporadic, but also may be associated with multiple endocrine neoplasia type 1 (MEN1,
Wermer’s
syndrome), a syndrome characterized by the presence of two or more tumors sited in the pituitary, parathyroid glands, or pancreas. MEN1 is also associated with an increased prevalence of adrenal and thyroid.
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Slide25STOMACH: DISEASES AND LABORATORY INVESTIGATIONS Gastric Acid Secretion and Gastrinomas
:
Gastrinoma & the Zollinger-Ellison Syndrome
Gastrinomas are commonly located in the pancreas, but can arise from the stomach, duodenum, or other tissues.
They are more often (60%) malignant than benign, with metastases frequently present at the time of diagnosis.
Measurement of plasma gastrin in a fasting sample is the initial step in aiding the differential diagnosis (concentration more than 10 times the upper limit of the reference range).
A mildly elevated plasma gastrin concentration may be observed in long-term PPI therapy, hypochlorhydria, pernicious anemia, and G-cell hyperplasia.
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Slide26INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Pathophysiology of Celiac Disease
Celiac disease occurs in genetically predisposed subjects as a consequence of an inappropriate T cell–mediated immune response to ingestion of gluten from wheat and to similar proteins in barley and rye.
The role of genetic factors in celiac disease has been recognized for many years; a 70% concordance for celiac disease has been reported in identical twins
The major genetic component has been localized to the human leukocyte antigen (HLA) region of chromosome 6.
Approximately 95% of subjects with celiac disease express a specific HLA heterodimer (HLA DQ2
α/β).
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Slide27INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Pathophysiology of Celiac Disease
The external trigger to the development of celiac disease in genetically susceptible individuals is found in gluten, which is the complex group of proteins found in wheat and other grains.
The major toxic proteins of
wheat
are the
gliadins
that account for 50% of the wheat protein, with homologous proteins (the hordeins
and
secalins
) occurring in
barley
and rye, respectively.All proteins (and peptides) that are toxic to the small bowel mucosa in subjects with celiac disease contain large amounts of glutamine.
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Slide28INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Pathophysiology of Celiac Disease
The identification in 1997 of small bowel tissue transglutaminase as the autoantigen of celiac disease has led to a greater understanding of the pathogenesis of the condition.
The tissue transglutaminases are a family of calcium-dependent enzymes that are released from cells during wound healing.
They catalyze the cross-linking or deamidation of proteins leading to stabilization of the wound area.
Expression of the enzyme is increased during apoptosis and in active celiac disease.
Deamidation of gliadin peptides enhances their binding to HLA DQ2/DQ8 and increases recognition of these peptides by gut-derived T cells from subjects with celiac disease.
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Slide29INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Pathophysiology of Celiac Disease
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Slide30INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Pathophysiology of Celiac Disease
The characteristic enteropathy is then induced by the release of interferon-γ and other proinflammatory cytokines.
A 33–amino acid peptide of gluten appears to be the primary initiator of the inflammatory response.
It is resistant to breakdown by all gastric, pancreatic, and brush border membrane proteases, thus allowing it to reach the small intestine intact.
Homologs of the peptide are found in food grains that are toxic to patients with celiac disease but are absent from nontoxic food grains.
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Slide31INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Pathophysiology of Celiac Disease
Increased intestinal permeability in untreated celiac disease that is reversible on withdrawal of gluten from the diet has been recognized since the early 1980s.
Evidence suggests that this increase in paracellular permeability may be mediated by increased expression of
zonulin
, modulator of intercellular tight junctions (TJ) (a protein that opens small intestinal
TJ
), or by decreased expression of intercellular epithelial cell adhesion molecules such as catenin, and cadherin.
The
zonulin
pathway is now thought to play a significant role in the entry of allergens into cells and hence in the autoimmune response.
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Slide32INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Pathophysiology of Celiac Disease
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Slide33INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATIONCeliac Disease:
Tests for Celiac Disease
Serologic tests have played a significant role in raising awareness of the high prevalence of this disorder and appropriately standardized tests have high clinical sensitivity and specificity for diagnosis and monitoring of compliance with a gluten free diet.
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Slide34INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bacterial Overgrowth
The proximal small intestine (duodenum and jejunum) normally contains few bacteria.
Most ingested bacteria do not survive the acidic environment of the stomach; therefore few live organisms enter the small bowel.
The motility of the jejunum prevents fecal-type organisms from progressing up into the jejunum from the cecum.
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The ileum normally contains some fecal-type bacteria.
Colonization of the upper small bowel is described as bacterial overgrowth and usually occurs as a consequence of other abnormalities (structural or motility disorders) of the small intestine.
Slide35INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bacterial Overgrowth
Gastric hypochlorhydria (associated with the use of PPIs) may contribute to bacterial overgrowth.
Abnormalities that can result in bacterial overgrowth include:
The systemic immune system, eg, isolated IgA deficiency, hypogammaglobulinemia, combined immunodeficiency, infection with the human immunodeficiency virus [HIV]
Impaired motility, pancreatic insufficiency, intrinsic small bowel disease, or surgically induced blind loops are often associated with bacterial overgrowth.
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Slide36INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bacterial Overgrowth
Small bowel bacterial overgrowth can be asymptomatic or associated with nonspecific symptoms that include abdominal distention and diarrhea resembling IBS.
Bacteria colonizing the small bowel (
eg, Escherichiacoli
and
Bacteroides
species) deconjugate and dehydroxylate bile salts, resulting in conjugated bile salt deficiency and mild fat malabsorption.
Bacterial metabolism of vitamin B12 can occur, leading to deficiency, whereas plasma folate concentration may be increased owing to production by the bacteria.
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Slide37INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bacterial Overgrowth
The gold standard diagnostic procedure is microbiologic examination of small bowel contents, but this is seldom practical.
Noninvasive procedures based on oral administration of substances metabolized by bacteria to yield products that can be detected in breath are now the most common tests for bacterial overgrowth.
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Slide38INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bacterial Overgrowth
Small bowel bacterial breath tests in routine use involve test substances labeled with
13
C and the breath hydrogen tests. Lactulose is not normally absorbed from the small bowel and is therefore available for metabolism by bacteria throughout the gut; alternatively, labeled glucose can be used. In a normal subject, breath hydrogen does not increase until the substrate reaches the large intestine and the time from ingestion to a rise in breath hydrogen is an indicator of small bowel transit time.
In bacterial overgrowth an early rise in breath hydrogen of at least 20 ppm (20
μl
/L) is observed within 30 minutes of ingestion.
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Slide39INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bile Acid Malabsorption
Bile acids are synthesized in the liver and pass into the lumen of the small bowel via the gallbladder.
Bile acids are present in bile as taurine or glycine conjugates; because the pH of bile is slightly alkaline and contains significant amounts of sodium and potassium, most of the bile acids and their conjugates exist as salts (
ie, bile salts). In practice, the terms
bile acids
and
bile salts
are frequently used synonymously. Their major function is to act as surface-active agents, forming micelles and facilitating the digestion of triglycerides and the absorption of cholesterol and fat-soluble vitamins.
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Slide4040
Enterohepatic circulation of bile salts and bile acids.
Slide41INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bile Acid Malabsorption
Little reabsorption of bile acids occurs in the proximal small bowel, but normally more than 90% is reabsorbed in the terminal ileum.
The bile acids return to the liver via the portal circulation and can be
resecreted into bile (enterohepatic circulation).Less than 10% of secreted bile acid is lost in the feces (~0.2 to 0.6 g/24 h).
Bile acid malabsorption leading to chronic diarrhea occurs when ileal disease is present, or after resection of the terminal ileum; it also may occur after cholecystectomy and is present in some patients with IBS.
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Slide42INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bile Acid Malabsorption
Malabsorption of bile salts produces diarrhea by two different mechanisms.
When significant bile salt depletion occurs, the deficiency of intraluminal bile salts leads to fat malabsorption and steatorrhea.
More commonly, malabsorption of bile salts in the ileum leads to increased concentrations of bile salts in the colon, where they alter water and electrolyte absorption.
This leads to net secretion of water into the lumen and diarrhea.
Bile salt malabsorption is probably an underdiagnosed condition and should be suspected in patients with unexplained chronic diarrhea.
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Slide43INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bile Acid Malabsorption
Two blood tests have been proposed: fibroblast growth factor-19 (FGF-19) and 7α-hydroxy-4-cholesten-3-one (C4).
C4 is the intermediary step between cholesterol and taurocholic acid and reflects the activity of hepatic cholesterol 7α-hydroxylase and therefore, because this is the rate-limiting enzyme, the rate of bile acid synthesis.
Bile acid malabsorption is associated with increased plasma concentrations of C4 as hepatic synthesis is up-regulated to maintain the pool of circulating bile acids.
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Slide4444
Slide45INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Bile Acid Malabsorption
The presence of bile acids in the ileum has been shown to stimulate the production of FGF-19.
Good correlation has been demonstrated between both serum C4 and FGF-19.
Several publications have demonstrated good sensitivity for identifying bile acid–induced diarrhea.With growing awareness of the role of bile salt malabsorption in chronic diarrhea in a proportion of patients with IBS or inflammatory bowel disease (IBD), and the therapeutic effectiveness of cholestyramine, measurement of C4 and/or FGF-19 may become routine.
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Slide46INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease and Irritable Bowel Syndrome
Intestinal symptoms including abdominal pain or discomfort with diarrhea or constipation are common to both IBD and IBS.
IBD includes ulcerative colitis (UC) and Crohn disease (CD), as well as a number of microscopic inflammatory bowel conditions.
IBS is a functional bowel disorder for which there is no identifiable pathologic process or known cause. Although IBS may produce symptoms that are sufficient to interfere with daily life, it is seldom associated with serious morbidity.
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Slide47INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)
IBS may affect up to 10% to 20% of the adult population in the developed world, with a typical age at presentation of 20 to 30 years and a female preponderance.
Both UC and CD are chronic conditions that tend to follow a remitting and relapsing course.
The prognosis of patients with CD tends to be worse than that of UC, although in the latter it is estimated that up to 10% of patients will require surgical intervention within 10 years of diagnosis.
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Slide48INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)
The cause of IBD is not fully understood, but both genetic and environmental factors have been implicated.
Genomewide
association studies have identified over 160 susceptibility loci/genes that are significantly associated with IBD.Studies in monozygotic twins, however, have shown a lower than expected concordance rate (15% to 19% for UC, 27% to 50% for CD) if IBD were simply an inherited disorder.
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Slide49INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)
The enteric GI microbiota are now accepted as a central etiologic factor in the pathogenesis of IBD, although the mechanistic details are lacking.
Tissue damage is a consequence of neutrophil activation and the production of proinflammatory cytokines and chemokines.
The success of treatments based on immunosuppressive agents or tumor necrosis factor-alpha (TNF-α) inhibitors appears to support an immune basis for the development of IBD.
Environmental factors implicated in triggering the development of active disease include a protective effect of breastfeeding and an increased risk in patients who have recurrent GI infections or exposure to drug therapy (antibiotics, oral contraceptives, NSAIDs) along with socioeconomic factors, stress, smoking, and diet.
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Slide50INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)
The conventional diagnostic pathway includes a full blood count to detect/exclude anemia, markers of generalized inflammation (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) and serologic testing for celiac disease.
In the past 20 years, there have been significant advances in biomarkers that can aid in differentiating IBD from IBS and in monitoring disease activity or response to treatment.
Most of these are fecal markers.
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Slide51INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)
Calprotectin
Accounts for approximately 60% of cytosolic protein in neutrophils.
It is also present in monocytes and macrophages at lower concentrations than in neutrophils and may have antimicrobial properties.Any disruption to the mucosal architecture of the GI tract allows neutrophils that accumulate at sites of active inflammation to be released into the lumen and subsequently shed in feces.
The fecal concentration of calprotectin is directly related to the extent of inflammation
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Slide52INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)
The sensitivity and specificity for calprotectin for the detection of IBD were 89% and 79%, respectively.
Combining calprotectin with the Rome questionnaire had a predictive value approaching 100%.
Fecal calprotectin is not, however, specific to IBD and has been shown to be increased in patients with colorectal carcinoma, the chronic use of NSAIDs, bacterial infections, and diverticular disease.
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Slide53INTESTINAL DISORDERS & THEIR LABORATORY INVESTIGATION Inflammatory Bowel Disease (IBD) and Irritable Bowel Syndrome (IBS)
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Slide54Other Fecal Markers
M2-PK
The glycolytic enzyme pyruvate kinase is present in normal cells as tissue-specific isoenzymes (in rapidly dividing cells as dimeric)
It is essentially a marker of increased cellular turnover and was shown to be high in patients with IBD
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Slide55PANCREAS: DISEASE AND ASSESSMENTOF EXOCRINE PANCREATIC FUNCTION
The pancreas plays a central role in the absorptive process for carbohydrates, fats, and proteins.
Disorders of the exocrine pancreas therefore are frequently associated with symptoms of malabsorption such as diarrhea or steatorrhea.
Adult exocrine pancreatic disorders will be briefly discussed and tests that can be used to assess exocrine pancreatic function are described.
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Slide56PANCREAS: DISEASE AND ASSESSMENTOF EXOCRINE PANCREATIC FUNCTION
The major exocrine pancreatic disorders manifesting in adult life are acute pancreatitis, chronic pancreatitis, and carcinoma of the pancreas.
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Slide57PANCREAS: DISEASE AND ASSESSMENTOF EXOCRINE PANCREATIC FUNCTION
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Slide5858
Slide59Tests of Exocrine Function of the Pancreas
The predominant exocrine function of the pancreas is the production and secretion of pancreatic juice, which is rich in enzymes and bicarbonate.
Normal pancreatic juice is colorless and odorless; it has a pH of 8.0 to 8.3 and a specific gravity of 1.007 to 1.042.
The total 24-hour volume secreted may be as high as 3000 mL.Laboratory tests used to assess exocrine pancreatic function can be divided into invasive and noninvasive categories
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Slide60Tests of Exocrine Function of the PancreasInvasive Tests of Exocrine Pancreatic Function
The secretin-cholecystokinin test is based on the principle that secretion of pancreatic juice and bicarbonate output are related to the functional mass of the pancreas.
After an overnight fast a tube is sited in the duodenum to permit the collection of pancreatic juices.
Secretin (1 unit/kg body weight) is given intravenously, and the duodenal fluid collected at 15-minute intervals for at least 1 hour.
Secretin stimulates the secretion of pancreatic juice and bicarbonate.
CCK then can be given to stimulate the secretion of pancreatic enzymes, allowing a more complete assessment of pancreatic reserve than can be obtained with secretin alone.
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Slide61Tests of Exocrine Function of the Pancreas Noninvasive Tests of Exocrine Pancreatic Function
A range of tubeless tests have been proposed, but none has adequate sensitivity for reliably detecting early pancreatic disease.
When malabsorption is present, such tests are of value in confirming or excluding pancreatic disease.
It has been estimated that pancreatic insufficiency cannot clearly be demonstrated until at least 50% of the acinar cells have been destroyed. Clinical signs of pancreatic insufficiency often do not appear until 90% of acinar tissue has been destroyed.
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Slide62Tests of Exocrine Function of the Pancreas Noninvasive Tests of Exocrine Pancreatic Function
The noninvasive tests are based on the reduction in secretion of pancreatic enzymes with measurement of the enzymes in feces (chymotrypsin or elastase) or detection of products of their catalytic reactions, after oral administration of synthetic substrates, in urine or in breath.
Measurement of fecal elastase is currently the noninvasive method of choice for assessing pancreatic insufficiency.
Pancreatic elastase-1 is a pancreas-specific protease present in pancreatic juice.
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Slide63Tests of Exocrine Function of the Pancreas Noninvasive Tests of Exocrine Pancreatic Function
It is not degraded during passage through the gut, and concentrations in feces are fivefold to
sixfold
greater than those in pancreatic juice.The enzyme can be measured by ELISA with two monoclonal antibodies specific to the human enzyme. Treatment of patients with pancreatic enzyme supplements therefore does not interfere with the test.
Fecal elastase-1 has been evaluated extensively in both CF and adult pancreatic insufficiency, and its use is recommended in both groups.
Fecal elastase is often undetectable (<15
μg
/g) in children with CF, and values below 200
μg
/g after 4 weeks of age are indicative of pancreatic insufficiency.
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Slide64Tests of Exocrine Function of the Pancreas Noninvasive Tests of Exocrine Pancreatic Function
Measurement of pancreatic elastase-1 in feces has high sensitivity for the detection of severe and moderate chronic pancreatitis in adults.
It has better sensitivity than other tests for detecting mild chronic pancreatitis and high sensitivity and can be used for discriminating between diarrhea of pancreatic and nonpancreatic origin.
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Slide65Case Studies
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Slide66Case 1
A 25‐year‐old woman in the first trimester of pregnancy presented with acute abdominal pain.
Initial biochemistry results revealed a serum amylase result of 2500 U/L (reference range <100 U/L).
What is the differential diagnosis?
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Slide67Comments
With an amylase result elevated to this degree, the most likely diagnosis is acute pancreatitis.
However, other possible differential diagnoses include ruptured ectopic pregnancy and obstruction.
An obstetric referral ruled out ruptured ectopic pregnancy as the cause and further investigations revealed the presence of gallstones. The diagnosis was confirmed as acute pancreatitis secondary to cholelithiasis.
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Slide68Case 2
Since commencing chemotherapy, a 6-year-old female with acute lymphoblastic leukemia had increasing nausea and vomiting. She also developed abdominal pain and jaundice.
Her treatment regimen included the drugs asparaginase and vincristine. A plasma amylase result at this time was within the reference interval. Three days after admission, she developed abdominal wall erythema,
circumumbilical pallor and left flank bruising.The results for both amylase and lipase on multiple plasma samples (both at the beginning and end of the acute pancreatitis) are shown.
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Slide69Case 2
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Slide70Comments
Abdominal wall erythema,
circumumbilical
pallor and left flank bruising, classic signs of acute hemorrhagic pancreatitis.This was confirmed by computer tomography of the abdomen, which showed a swollen pancreas. Her pancreatitis was attributed to asparaginase.After the diagnosis was made, plasma lipase also was measured.
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Slide71Comments
The results show that plasma lipase levels increased both earlier and to a higher level than plasma amylase.
In this case, measurement of plasma lipase would have made the diagnosis of pancreatitis earlier.
Plasma amylase levels were shown to rise and fall but failed to breach the upper limit of normal.This case demonstrates that plasma amylase levels may be “normal” in acute pancreatitis.Measurement of plasma lipase is therefore recommended in the diagnosis of acute pancreatitis.
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Slide72Case 3
A 49‐year‐old man presented with a history of weight loss and chronic abdominal pain which was sometimes exacerbated by eating. He had
experienced episodes of
diarrhoea and had been passing greasy foul‐smelling stools, which were difficult to flush. He consumed up to a bottle of whisky per day. Biochemical testing showed that Urea & Electrolytes were within reference limits. Other results were as follows:
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Slide73Case 3
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Comment on these results. What is the most likely diagnosis?
Slide74Comments
When a patient presents with chronic abdominal pain associated with
steatorrhoea
but without a previous history of acute pancreatitis, the usual diagnostic problem is to distinguish between chronic pancreatitis and carcinoma of the pancreas.The modestly raised serum amylase is not diagnostic of pancreatic disease because similar levels may be found in other abdominal disorders such as perforated peptic ulcer or cholecystitis.
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Slide75Comments
An ultrasound examination and CT scan revealed dilation and calcification of the main pancreatic duct and was consistent with the diagnosis of chronic pancreatitis.
The subsequent demonstration of a low level of
faecal elastase (76 μg/g faeces; reference range >200 μg/g faeces
) confirmed that the exocrine pancreatic secretory function was inadequate.
It is likely that the cause of this patient’s disease was long‐term alcohol abuse and that this was responsible for the elevation of serum GGT through hepatic enzyme induction.
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Slide76Comments
The elevation of ALP was found to be due to the bone isoenzyme, suggesting that fat malabsorption had led to vitamin D deficiency,
osteomalacia
and low serum calcium. The elevated random plasma glucose is consistent with clinical diabetes that tends to occur relatively late in the course of chronic pancreatitis.
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