Management of patients with dyspepsia.

1,2. Physiology of Gastric secretion. Determination of the gastric acid-secretion function. Determination of the gastric pepsin-secretion function.

The gastric epithelial lining consists of rugae that contain microscopic gastric pits, each branching into four or five gastric glands made up of highly specialized epithelial cells. The makeup of gastric glands varies with their anatomic location. Glands within the gastric cardia comprise <5% of the gastric gland area and contain mucous and endocrine cells. The majority of gastric glands (75%) are found within the oxyntic mucosa and contain mucous neck, parietal, chief, endocrine, and enterochromaffin cells. Pyloric glands contain mucous and endocrine cells (including gastrin cells) and are found in the antrum.

The parietal cell, also known as the oxyntic cell, is usually found in the neck, or isthmus, or the oxyntic gland. The resting, or unstimulated, parietal cell has prominent cytoplasmic tubulovesicles and intracellular canaliculi containing short microvilli along its apical surface. H+, K+-ATPase is expressed in the tubulovesicle membrane; upon cell stimulation, this membrane, along with apical membranes, transforms into a dense network of apical intracellular canaliculi containing long microvilli. Acid secretion, a process requiring high energy, occurs at the apical canalicular surface. Numerous mitochondria (30 to 40% of total cell volume) generate the energy required for secretion.

Gastroduodenal Mucosal Defense. The gastric epithelium is under a constant assault by a series of endogenous noxious factors including HCl, pepsinogen/pepsin, and bile salts. In addition, a steady flow of exogenous substances such as medications, alcohol, and bacteria encounter the gastric mucosa. A highly intricate biologic system is in place to provide defense from mucosal injury and to repair any injury that may occur.

The mucosal defense system can be envisioned as a three-level barrier, composed of preepithelial, epithelial, and subepithelial elements. The first line of defense is a mucus-bicarbonate layer, which serves as a physicochemical barrier to multiple molecules including hydrogen ions. Mucus is secreted in a regulated fashion by gastroduodenal surface epithelial cells. It consists primarily of water (95%) and a mixture of lipids and glycoproteins. Mucin is the constituent glycoprotein that, in combination with phospholipids (also secreted by gastric mucous cells), forms a hydrophobic surface with fatty acids that extend into the lumen from the cell membrane. The mucous gel functions as a nonstirred water layer impeding diffusion of ions and molecules such as pepsin. Bicarbonate, secreted by surface epithelial cells of the gastroduodenal mucosa into the mucous gel, forms a pH gradient ranging from 1 to 2 at the gastric luminal surface and reaching 6 to 7 along the epithelial cell surface. Bicarbonate secretion is stimulated by calcium, prostaglandins, cholinergic input, and luminal acidification.

Surface epithelial cells provide the next line of defense through several factors, including mucus production, epithelial cell ionic transporters that maintain intracellular pH and bicarbonate production, and intracellular tight junctions. If the preepithelial barrier were breached, gastric epithelial cells bordering a site of injury can migrate to restore a damaged region (restitution). This process occurs independent of cell division and requires uninterrupted blood flow and an alkaline pH in the surrounding environment. Several growth factors including epidermal growth factor (EGF), transforming growth factor (TGF) a, and basic fibroblast growth factor (FGF) modulate the process of restitution. Larger defects that are not effectively repaired by restitution require cell proliferation. Epithelial cell regeneration is regulated by prostaglandins and growth factors such as EGF and TGF-a. In tandem with epithelial cell renewal, formation of new vessels (angiogenesis) within the injured microvascular bed occurs. Both FGF and vascular endothelial growth factor (VEGF) are important in regulating angiogenesis in the gastric mucosa.

An elaborate microvascular system within the gastric submucosal layer is the key component of the subepithelial defense/repair system. A rich submucosal circulatory bed provides HCO3-, which neutralizes the acid generated by parietal cell secretion of HCl. Moreover, this microcirculatory bed provides an adequate supply of micronutrients and oxygen while removing toxic metabolic by-products.

Prostaglandins play a central role in gastric epithelial defense/repair. The gastric mucosa contains abundant levels of prostaglandins. These metabolites of arachidonic acid regulate the release of mucosal bicarbonate and mucus, inhibit parietal cell secretion, and are important in maintaining mucosal blood flow and epithelial cell restitution. Prostaglandins are derived from esterified arachidonic acid, which is formed from phospholipids (cell membrane) by the action of phospholipase A2. A key enzyme that controls the rate-limiting step in prostaglandin synthesis is cyclooxygenase (COX), which is present in two isoforms (COX-1, COX-2), each having distinct characteristics regarding structure, tissue distribution, and expression. COX-1 is expressed in a host of tissues including the stomach, platelets, kidneys, and endothelial cells. This isoform is expressed in a constitutive manner and plays an important role in maintaining the integrity of renal function, platelet aggregation, and gastrointestinal mucosal integrity. In contrast, the expression of COX-2 is inducible by inflammatory stimuli, and it is expressed in macrophages, leukocytes, fibroblasts, and synovial cells. The beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on tissue inflammation are due to inhibition of COX-2; the toxicity of these drugs (e.g., gastrointestinal mucosal ulceration and renal dysfunction) is related to inhibition of the COX-1 isoform. The highly COX-2-selective NSAIDs have the potential to provide the beneficial effect of decreasing tissue inflammation while minimizing toxicity in the gastrointestinal tract.

Hydrochloric acid and pepsinogen are the two principal gastric secretory products capable of inducing mucosal injury. Acid secretion should be viewed as occurring under basal and stimulated conditions. Basal acid production occurs in a circadian pattern, with highest levels occurring during the night and lowest levels during the morning hours. Cholinergic input via the vagus nerve and histaminergic input from local gastric sources are the principal contributors to basal acid secretion. Stimulated gastric acid secretion occurs primarily in three phases based on the site where the signal originates (cephalic, gastric, and intestinal). Sight, smell, and taste of food are the components of the cephalic phase, which stimulates gastric secretion via the vagus nerve. The gastric phase is activated once food enters the stomach. This component of secretion is driven by nutrients (amino acids and amines) that directly stimulate the G cell to release gastrin, which in turn activates the parietal cell via direct and indirect mechanisms. Distention of the stomach wall also leads to gastrin release and acid production. The last phase of gastric acid secretion is initiated as food enters the intestine and is mediated by luminal distention and nutrient assimilation. A series of pathways that inhibit gastric acid production are also set into motion during these phases. The gastrointestinal hormone somatostatin is released from endocrine cells found in the gastric mucosa (D cells) in response to HCl. Somatostatin can inhibit acid production by both direct (parietal cell) and indirect mechanisms [decreased histamine release from enterochromaffin-like (ECL) cells and gastrin release from G cells]. Additional neural (central and peripheral) and hormonal (secretin, cholecystokinin) factors play a role in counterbalancing acid secretion. Under physiologic circumstances, these phases are occurring simultaneously.

The acid-secreting parietal cell is located in the oxyntic gland, adjacent to other cellular elements (ECL cell, D cell) important in the gastric secretory process. This unique cell also secretes intrinsic factor. The parietal cell expresses receptors for several stimulants of acid secretion including histamine (H2), gastrin (cholecystokinin B/gastrin receptor) and acetylcholine (muscarinic, M3). Each of these are G protein-linked, seven transmembrane-spanning receptors. Binding of histamine to the H2 receptor leads to activation of adenylate cyclase and an increase in cyclic AMP. Activation of the gastrin and muscarinic receptors results in activation of the protein kinase C/phosphoinositide signaling pathway. Each of these signaling pathways in turn regulates a series of downstream kinase cascades, which control the acid-secreting pump, H+, K+-ATPase. The discovery that different ligands and their corresponding receptors lead to activation of different signaling pathways explains the potentiation of acid secretion that occurs when histamine and gastrin or acetylcholine are combined. More importantly, this observation explains why blocking one receptor type (H2) decreases acid secretion stimulated by agents that activate a different pathway (gastrin, acetylcholine). Parietal cells also express receptors for ligands that inhibit acid production (prostaglandins, somatostatin, and EGF).

The enzyme H+, K+-ATPase is responsible for generating the large concentration of H+. It is a membrane-bound protein that consists of two subunits, a and b. The active catalytic site is found within the a subunit; the function of the b subunit is unclear. This enzyme uses the chemical energy of ATP to transfer H+ ions from parietal cell cytoplasm to the secretory canaliculi in exchange for K+. The H+,K+-ATPase is located within the secretory canaliculus and in nonsecretory cytoplasmic tubulovesicles. The tubulovesicles are impermeable to K+, which leads to an inactive pump in this location. The distribution of pumps between the nonsecretory vesicles and the secretory canaliculus varies according to parietal cell. Under resting conditions, only 5% of pumps are within the secretory canaliculus, whereas upon parietal cell stimulation, tubulovesicles are immediately transferred to the secretory canalicular membrane, where 60 to 70% of the pumps are activated. Proton pumps are recycled back to the inactive state in cytoplasmic vesicles once parietal cell activation ceases.

The chief cell, found primarily in the gastric fundus, synthesizes and secretes pepsinogen, the inactive precursor of the proteolytic enzyme pepsin. The acid environment within the stomach leads to cleavage of the inactive precursor to pepsin and provides the low pH (<2.0) required for pepsin activity. Pepsin activity is significantly diminished at a pH of 4 and irreversibly inactivated and denatured at a pH of >7. Many of the secretagogues that stimulate acid secretion also stimulate pepsinogen release. The precise role of pepsin in the pathogenesis of PUD remains to be established.

SECRETORY STUDIES

There are many methods of secretory studies of stomach function by gastric intubation: the acid output is measured in response to pentagastrin, to broth, histamine, insuline.

The acid output is measured in response to pentagastrin, a syntheric pentapeptide which exerts the biological effects of gastrin. Preparation consists of an overnight fast. H₂-receptor antagonist drugs must be stopped for at least 48 hours before the test and omeprasole seven days before. The fasting contents of the stomach are aspirated and their volume measured; then the secretions are collected continuously for one hour. This is termed the ‘basal acid output’. Pentagastrin is then injected subcutaneously and the gastric secretions are collected for a further hour. The acid output in this hour is termed the ‘maximal acid output’.

Table 1

USE OF THE PENTAGASTRINE TEST

- a large volume of fasting juice indicates obstruction of the gastric outlet

- a very high basal acid output suggests that the patient has the Zollinger-Ellison syndrome

- in patients with peptic ulcer it provides a preoperative base line

- achlorhydria can be demonstrated

The insuline test is used after gastric surgery to indicate the completeness of vagotomy.

Stomach contents:

Volume 2-3 l per 24 hours

Specific gravity – 1005

pH – 1,6 – 1,8

The fasting stomach contents:

Volume – 5-40 ml mmol/l

Free hydrochloric acid < 15 mmol/l

Pepsin 0-21 mg %

Basal acid secretion

Total volume of 4 portions collecting for 60 minutes, after aspiration of fasting contents 50 – 100 ml

Total acidity – 40 – 60 mmol/l

Free hydrochloric acid 20 – 40 mmol/l

Fixed hydrochloric acid 10 – 15 mmol/l

Debit-hour of the free hydrochloric acid 1.5 – 5,5 mmol/hour

Debit-hour of the free hydrochloric acid 1.5 – 5,5 mmol/hour

3. Bacteriological and immunological investigation in the diseases of alimentary tract.

DIAGNOSIS FOR H.PYLORI.

Tests for H. pylori can be divided into two groups: invasive tests, which require upper gastrointestinal endoscopy and are based on the analysis of gastric biopsy specimens, and noninvasive tests (Table 2).

Table 2. Tests for Detection of H. pylori
Test	Sensitivity/ Specificity, %	Comments
INVASIVE (ENDOSCOPY/BIOPSY REQUIRED)
Rapid urease	80-95/95-100	Simple; false negative with recent use of PPIs, antibiotics, or bismuth compounds
Histology	80-90/>95	Requires pathology processing and staining; provides histologic information
Culture	-	Time-consuming, expensive, dependent on experience; allows determination of antibiotic susceptibility
NON-INVASIVE
Serology	>80/>90	Inexpensive, convenient; not useful for early follow-up
Urea breath test	>90/>90	Simple, rapid; useful for early follow-up; false negative with recent therapy (see rapid urease test)
NOTE: PPI, proton pump inhibitor.

Invasive tests are preferred for (1) the initial management of dyspeptic patients, because the decision of whether or not to eradicate H. pylori depends on ulcer disease status, and (2) follow-up after

Gastric juice total acidity < 20-30 treatment of patients with gastric ulceration to be certain that the ulcer was not malignant. Follow-up endoscopy should be performed at least 4 weeks after cessation of all anti-Helicobacter drugs, since at earlier points the H. pylori load may be low and tests may be falsely negative. The most convenient endoscopy-based test is the biopsy urease test, in which two antral biopsy specimens are put into a gel containing urea and an indicator. The presence of H. pylori urease elicits a color change, which often takes place within minutes but can require up to 24 h. Histologic examination of biopsy specimens is accurate, provided that a special stain (e.g., a modified Giemsa or silver stain) permitting optimal visualization of H. pylori is used. Histologic study yields additional information, including the degree and pattern of inflammation, atrophy, metaplasia, and dysplasia, although these details are rarely of clinical use. Microbiologic culture is most specific but may be insensitive due to difficulty with H. pylori isolation. Once cultured, the identity of H. pylori can be confirmed by its typical appearance on Gram's stain and its positive reactions in oxidase, catalase, and urease tests. Antibiotic sensitivities also can be determined. Specimens containing H. heilmanii are only weakly positive in the biopsy urease test. The diagnosis is based on visualization of the characteristic long, tight spiral bacteria in histologic sections.

The simplest tests for H. pylori infection are serologic, involving the assessment of specific IgG levels in serum. The best of these tests are as accurate as other diagnostic methods, but many commercial tests, especially rapid office tests, perform poorly. In quantitative tests, a defined drop in antibody titer between matched serum samples taken before and 6 months after treatment (no sooner because of the slow decline in antibody titer) accurately indicates that H. pylori infection has been eradicated. The other major noninvasive tests are the 13C and 14C urea breath tests. In these simple tests, the patient drinks a labeled urea solution and then blows into a tube. The urea is labeled with either the nonradioactive isotope 13C or a minute dose of the radioactive isotope 14C (which exposes the patient to less radiation than a standard chest x-ray). If H. pylori urease is present, the urea is hydrolyzed and labeled carbon dioxide is detected in breath samples. Unlike serologic tests, urea breath tests can be used to assess the outcome of treatment 1 month after its completion and thus may replace endoscopy for this purpose in the follow-up of duodenal ulcer patients. As for endoscopic tests, all anti-Helicobacter drugs should be avoided in this period or the test may be falsely negative.

Chronic diarrhea in a tropical environment is most often caused by infectious agents including G. lamblia, Yersinia enterocolitica, C. difficile, Cryptosporidium parvum, and Cyclospora cayetanensis, among other organisms. Tropical sprue should not be entertained as a possible diagnosis until the presence of cysts and trophozoites has been excluded in three stool samples.

4. Test that measure biosynthetic function of the liver

LABORATORY TESTING

Diagnosis in liver disease is greatly aided by the availability of reliable and sensitive tests of liver injury and function. A typical battery of blood tests used for initial assessment of liver disease includes measuring levels of serum alanine and aspartate aminotransferases (ALT and AST), alkaline phosphatase, direct and total serum bilirubin, and albumin and assessing prothrombin time. The pattern of abnormalities generally points to hepatocellular versus cholestatic liver disease and will help to decide whether the disease is acute or chronic and whether cirrhosis and hepatic failure are present. Based on these results, further testing over time may be necessary. Other laboratory tests may be helpful, such as g-glutamyl transpeptidase (GGT) to define whether alkaline phosphatase elevations are due to liver disease; hepatitis serology to define the type of viral hepatitis; and autoimmune markers to diagnose primary biliary cirrhosis (antimitochondrial antibody; AMA), sclerosing cholangitis (peripheral antineutrophil cytoplasmic antibody; pANCA), autoimmune hepatitis (antinuclear, smooth-muscle, and liver-kidney microsomal antibody). Laboratory Tests. When the physician encounters a patient with unexplained jaundice, there are a battery of tests that are helpful in the initial evaluation. These include total and direct serum bilirubin with fractionation, aminotransferases, alkaline phosphatase, albumin, and prothrombin time tests. Enzyme tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase] are helpful in differentiating between a hepatocellular process and a cholestatic process, a critical step in determining what additional workup is indicated. Patients with a hepatocellular process generally have a disproportionate rise in the aminotransferases compared to the alkaline phosphatase. Patients with a cholestatic process have a disproportionate rise in the alkaline phosphatase compared to the aminotransferases. The bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two.

In addition to the enzyme tests, all jaundiced patients should have additional blood tests, specifically an albumin and a prothrombin time, to assess liver function. A low albumin suggests a chronic process such as cirrhosis or cancer. A normal albumin is suggestive of a more acute process such as viral hepatitis or choledocholithiasis. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.

The results of the bilirubin, enzyme, albumin, and prothrombin time tests will usually indicate whether a jaundiced patient has a hepatocellular or a cholestatic disease. The causes and evaluation of each of these is quite different.

Hepatocellular Conditions Hepatocellular diseases that can cause jaundice include viral hepatitis, drug or environmental toxicity, alcohol, and end-stage cirrhosis from any cause (Table 3).

Table 3. Hepatocellular Conditions That May Produce Jaundice

Viral hepatitis

Hepatitis A, B, C, D, and E

Epstein-Barr virus

Cytomegalovirus

Herpes simplex

Alcohol

Drug toxicity

Predictable, dose-dependent, e.g., acetaminophen

Unpredictable, idosyncratic, e.g., isoniazid

Environmental toxins

Vinyl chloride

Jamaica bush teaæpyrrolizidine alkaloids

Wild mushroomsæAmanita phalloides or verna

Wilson's disease

Autoimmune hepatitis

Cholestatic Conditions When the pattern of the liver tests suggests a cholestatic disorder, the next step is to determine whether it is intra- or extrahepatic cholestasis. Distinguishing intrahepatic from extrahepatic cholestasis may be difficult. History, physical examination, and laboratory tests are often not helpful. The next appropriate test is an ultrasound. The ultrasound is inexpensive, does not expose the patient to ionizing radiation, and can detect dilation of the intra- and extrahepatic biliary tree with a high degree of sensitivity and specificity. The absence of biliary dilatation suggests intrahepatic cholestasis, while the presence of biliary dilatation indicates extrahepatic cholestasis. False-negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing cholangitis (PSC) where scarring prevents the intrahepatic ducts from dilating.

In patients with apparent intrahepatic cholestasis, the diagnosis is often made by serologic testing in combination with percutaneous liver biopsy. The list of possible causes of intrahepatic cholestasis is long and varied (Table 4). A number of conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. Both hepatitis B and C can cause a cholestatic hepatitis (fibrosing cholestatic hepatitis) that has histologic features that mimic large duct obstruction. This disease variant has been reported in patients who have undergone solid organ transplantation. Hepatitis A, alcoholic hepatitis, EBV, and CMV may also present as cholestatic liver disease.

Table 4. Cholestatic Conditions That May Produce Jaundice

I. Intrahepatic

A. Viral hepatitis

1. Fibrosing cholestatic hepatitisæhepatitis B and C

2. Hepatitis A, Epstein-Barr virus, cytomegalovirus

B. Alcoholic hepatitis

C. Drug toxicity

1. Pure cholestasisæanabolic and contraceptive steroids

2. Cholestatic hepatitisæchlorpromazine, erythromycin estolate

3. Chronic cholestasisæchlorpromazine and prochlorperazine

D. Primary biliary cirrhosis

E. Primary sclerosing cholangitis

F. Vanishing bile duct syndrome

1. Chronic rejection of liver tranplants

2. Sarcoidosis

3. Drugs

G. Inherited

1. Benign recurrent cholestasis

H. Cholestasis of pregnancy

I. Total parenteral nutrition

J. Nonhepatobiliary sepsis

K. Benign postoperative cholestasis

L. Paraneoplastic syndrome

M. Venoocclusive disease

N. Graft-versus-host disease

II. Extrahepatic

A. Malignant

1. Cholangiocarcinoma

2. Pancreatic cancer

3. Gallbladder cancer

4. Ampullary cancer

5. Malignant involvement of the porta hepatis lymph nodes

B. Benign

1. Choledocholithiasis

2. Primary sclerosing cholangitis

3. Chronic pancreatitis

4. AIDS cholangiopathy

TESTS THAT MEASURE BIOSYNTHETIC FUNCTION OF THE LIVER

Serum Albumin Serum albumin is synthesized exclusively by hepatocytes. Serum albumin has a long half-life: 15 to 20 days, with approximately 4% degraded per day. Because of this slow turnover, the serum albumin is not a good indicator of acute or mild hepatic dysfunction; only minimal changes in the serum albumin are seen in acute liver conditions such as viral hepatitis, drug-related hepatoxicity, and obstructive jaundice. In hepatitis, albumin levels below 3 g/dL should raise the possibility of chronic liver disease. Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis and usually reflects severe liver damage and decreased albumin synthesis. One exception is the patient with ascites in whom synthesis may be normal or even increased, but levels are low because of the increased volume of distribution. However, hypoalbuminemia is not specific for liver disease and may occur in protein malnutrition of any cause, as well as protein-losing enteropathies, nephrotic syndrome, and chronic infections that are associated with prolonged increases in serum interleukin-1 and/or tumor necrosis factor levels that inhibit albumin synthesis. Serum albumin should not be measured for screening in patients in whom there is no suspicion of liver disease. A general medical clinic study of consecutive patients in whom no indications were present for albumin measurement showed that while 12% of patients had abnormal test results, the finding was of clinical importance in only 0.4%.

Serum Globulins Serum globulins are a group of proteins made up of gamma globulins (immunoglobulins) produced by B lymphocytes and alpha and beta globulins produced primarily in hepatocytes. Gamma globulins are increased in chronic liver disease, such as chronic hepatitis and cirrhosis. In cirrhosis, the increased serum gamma globulin concentration is due to the increased synthesis of antibodies, some of which are directed against intestinal bacteria. This occurs because the cirrhotic liver fails to clear bacterial antigens that normally reach the liver through the hepatic circulation.

Increases in the concentration of specific isotypes of gamma globulins are often helpful in the recognition of certain chronic liver diseases. Diffuse polyclonal increases in IgG levels are common in autoimmune hepatitis; increases greater than 100% should alert the clinician to this possibility. Increases in the IgM levels are common in primary biliary cirrhosis, while increases in the IgA levels occur in alcoholic liver disease.

Coagulation Factors With the exception of factor VIII, the blood clotting factors are made exclusively in hepatocytes. Their serum half-lives are much shorter than albumin, ranging from 6 hours for factor VII to 5 days for fibrinogen. Because of their rapid turnover, measurement of the clotting factors is the single best acute measure of hepatic synthetic function and helpful in both the diagnosis and assessing the prognosis of acute parenchymal liver disease. Useful for this purpose is the serum prothrombin time, which collectively measures factors II, V, VII, and X. Biosynthesis of factors II, VII, IX, and X depends on vitamin K. The prothrombin time may be elevated in hepatitis and cirrhosis as well as in disorders that lead to vitamin K deficiency such as obstructive jaundice or fat malabsorption of any kind. Marked prolongation of the prothrombin time, >5 s above control and not corrected by parenteral vitamin K administration, is a poor prognostic sign in acute viral hepatitis and other acute and chronic liver diseases.

5. Microscopic examination of a stool.

Microscopic examination of a stool specimen stained with Sudan is a simple screening test for steatorrhea. Chemical analysis of 3-day stool collection for fat, with the patient on a standard diet, is used to establish the diagnosis of steatorrhea. The D-xylose absorption test is about 90% accurate in distinguishing mucosal disease from pancreatic insufficiency. Leakage of protein into the intestinal lumen may cause hypoproteinemia and can be demonstrated by the recovery in stools of the serum protein a1-antitrypsin or intravenously administrated markers such as iodine- or chromium-labeled isotopes.

Diarrhea as a symptom may be either a decrease in stool consistency, an increase in stool volume, an increase in number of bowel movements, or any combination of these three changes. In contrast, diarrhea as a sign is a quantitative increase in stool water or weight of >200 to 225 mL, or g per 24 h, when a western-type diet is consumed. Individuals consuming a diet with a higher fiber content may normally have a stool weight of up to 400 g/24 h. Thus, it is essential that the clinician clarify what an individual patient means by diarrhea, especially since 10% of patients referred to gastroenterologists for further evaluation of unexplained diarrhea do not have an increase in stool water when it is determined quantitatively. Such patients may have small, frequent, somewhat loose bowel movements with stool urgency that is indicative of proctitis but do not have an increase in stool weight or volume.

Measurement of stool electrolytes and osmolality requires the comparison of stool Na+ and K+ concentrations determined in liquid stool to the stool osmolality to determine the presence or absence of a so-called stool osmotic gap.

The cation concentrations are doubled to estimate stool anion concentrations. The presence of a significant osmotic gap suggests the presence in stool water of a substance(s) other than Na/K/anions that presumably is responsible for the patient's diarrhea. Originally, stool osmolality was measured, but it is almost invariably greater than the required 290 to 300 mosmol/kg H2O, reflecting bacterial degradation of nonabsorbed carbohydrate either immediately before defecation or in the stool jar while awaiting chemical analysis, even when the stool is refrigerated. As a result, the stool osmolality should be assumed to be 300 mosmol/kg H2O. When the calculated difference is >50, an osmotic gap is present, suggesting that the diarrhea is due to a nonabsorbed dietary nutrient, e.g., a fatty acid and/or carbohydrate. When this difference is <25 to 50, it is presumed that a dietary nutrient is not responsible for the diarrhea. Since elements of both osmotic (i.e., malabsorption of a dietary nutrient) and secretory diarrhea may be present simultaneously, this separation at times is less clear-cut at the bedside than when used as a teaching example. Ideally, the presence of an osmotic gap will be associated with a marked decrease in stool output during a prolonged fast, while the absence of an osmotic gap will likely be present in an individual whose stool output had not been reduced substantially during a period of fasting.

At times, however, a timed (72-h) quantitative stool collection, preferably on a defined diet, must be obtained to determine stool fat content and establish the presence of steatorrhea. The presence of steatorrhea then requires further assessment to establish the pathophysiologic process(es) responsible for the defect in dietary lipid digestion-absorption.

6. Diagnostic and management possibilities of endoscopy with biopsy in gastroenterology.

Gastrointestinal endoscopy has been attempted for over 200 years, but the introduction of semi-rigid gastroscopes in the middle of the twentieth century marked the dawn of the modern endoscopic era. Since then, rapid advances in endoscopic technology have led to dramatic changes in the diagnosis and treatment of many digestive diseases. Innovative endoscopic devices and new endoscopic treatment modalities continue to expand the use of endoscopy in patient care.

Flexible endoscopes provide either an optical image (transmitted over fiberoptic bundles) or an electronic video image. Operator controls permit deflection of the endoscope tip; fiberoptic bundles bring light to the tip of the endoscope; and working channels allow washing, suctioning, and the passage of instruments. Progressive changes in the diameter and stiffness of endoscopes have improved the ease and patient tolerance of endoscopy.

Upper endoscopy

Upper endoscopy, also referred to as esophagogastroduodenoscopy (EGD), is performed by passing a flexible endoscope through the mouth into the esophagus, stomach, bulb, and second duodenum. The procedure is the best method of examining the upper gastrointestinal mucosa. While the upper gastrointestinal radiographic series has similar accuracy for diagnosis of duodenal ulcer, EGD is superior for detection of gastric ulcers and permits directed biopsy and endoscopic therapy, if needed. Topical pharyngeal anesthesia is used, and intravenous conscious sedation is given to most patients in the United States to ease the anxiety and discomfort of the procedure, although in many countries EGD is routinely performed without sedation. The recent development of ultrathin, 5-mm diameter endoscopes for transnasal, unsedated EGD may decrease the use of sedation for EGD in the United States, also decreasing the costs and risks of the procedure.

Colonoscopy Colonoscopy is performed by passing a flexible colonoscope through the anal canal into the rectum and colon. The cecum is reached in over 95% of cases, and the terminal ileum can often be examined. Colonoscopy is the "gold standard" for diagnosis of colonic mucosal disease. Barium enema is more accurate for evaluation of diverticula and for accurate measurement of colonic strictures, but colonoscopy has greater sensitivity for polyps and cancers. Colonoscopy is more uncomfortable than EGD for most patients, and conscious sedation is usually given before colonoscopy in the United States, although a willing patient and a skilled examiner can complete the procedure without sedation in many cases.

Flexible Sigmoidoscopy Flexible sigmoidoscopy is similar to colonoscopy but visualizes only the rectum and a variable portion of the left colon, typically to 60 cm from the anal verge. This procedure causes abdominal cramping, but it is brief and is almost always performed without sedation. Flexible sigmoidoscopy is primarily used to screen asymptomatic, average-risk patients for colonic polyps and may also be used for evaluation of diarrhea and hematochezia.

Enteroscopy Enteroscopy is the relatively new field of small-bowel endoscopy. Two techniques are currently used. "Push" enteroscopy is performed with a long endoscope similar in design to an upper endoscope. The enteroscope is pushed down the small bowel with the help of a stiffening overtube that extends from the mouth to the duodenum. The mid-jejunum can often be reached; an instrument channel is present for biopsies or endoscopic therapy. "Sonde" enteroscopy uses a very thin, long, flexible endoscope with a weighted tip and no biopsy capability. The sonde enteroscope is passed through the nose, dragged to the duodenum by a standard endoscope, then slowly propelled forward by intestinal peristalsis for several hours. The cecum or distal ileum is reached in most cases. The small-bowel mucosa is examined during sonde enteroscope withdrawal, although parts of the mucosa may be missed when the endoscope is pulled back around turns. The major indication for these procedures is unexplained small-bowel bleeding.

Endoscopic Retrograde Cholangiopancreatography (ERCP) During ERCP, a side-viewing endoscope is passed through the mouth to the duodenum, the ampulla of Vater is identified and cannulated with a thin plastic catheter, and radiographic contrast material is injected into the bile duct and pancreatic duct under fluoroscopic guidance. When indicated, the sphincter of Oddi can be opened using the technique of endoscopic sphincterotomy. Stones can be retrieved from the ducts, and strictures of the ducts can be biopsied, dilated, and stented. ERCP is often performed for therapy but remains an important diagnostic tool, especially for bile duct stones.

Endoscopic Ultrasound (EUS) EUS utilizes high-frequency ultrasound transducers incorporated into the tip of a flexible endoscope. Ultrasound images are obtained of the gut wall and adjacent organs, vessels, and lymph nodes. By sacrificing depth of ultrasound penetration and bringing the ultrasound transducer close to the area of interest via endoscopy, very high resolution images are obtained. EUS provides the most accurate preoperative local staging of esophageal, pancreatic, and rectal malignancies, although it does not detect most distant metastases. EUS is also highly sensitive for diagnosis of bile duct stones, gallbladder disease, submucosal gastrointestinal lesions, and chronic pancreatitis. Fine-needle aspiration of masses and lymph nodes in the posterior mediastinum, abdomen, and pelvis can be performed under EUS guidance.

Video: abdominal sonography

7. Oral, intravenous and percutaneous transhepatic cholecystocholangiography.

Oral cholecystography (OCG) is a useful procedure for the diagnosis of gallstones but has been largely replaced by ultrasound. However, OCG is still useful for the selection of patients for nonsurgical therapy of gallstone disease such as lithotripsy or bile acid dissolution therapy. In both these settings, OCG is used to assess the patency of the cystic duct and gallbladder emptying function. Further, OCG can also delineate the size and number of gallstones and determine whether they are calcified. Factors that may produce nonvisualization of the OCG are summarized in Table 1

Table 1. Diagnostic Evaluation of the Gallbladder
Diagnostic Advantages	Diagnostic Limitations	Comment
PLAIN ABDOMINAL X-RAY
Low cost Readily available	Relatively low yield Contraindicated in pregnancy	Pathognomonic findings in: Calcified gallstones Limey bile, porcelain GB Emphysematous cholecystitis Gallstone ileus
ORAL CHOLECYSTOGRAM
Low cost Readily available Accurate identification of gallstones (90-95%) Identification of GB anomalies, hyperplastic cholecystoses Identification of chronic GB disease after nonvisualization on double dose	Contraindicated in pregnancy Contraindicated with his-tory of reaction to iodinated contrast Nonvisualization with: Serum bilirubin >34-68 mmol/L (2-4 mg/dL) Failure to ingest or absorb tablets Impaired hepatic excretion Very small stones may be undetected More time-consuming than GBUS	Largely replaced by GBUS A useful procedure in identification of gallstones if diagnostic limitations prevent GBUS Patency of cystic duct can be evaluated prior to nonsurgical therapy
NOTE: GB, gallbladder; CCK, cholecystokinin; GBUS, gallbladder ultrasound.

Radiopharmaceuticals such as 99mTc-labeled N-substituted iminodiacetic acids (HIDA, DIDA, DISIDA, etc.) are rapidly extracted from the blood and are excreted into the biliary tree in high concentration even in the presence of mild to moderate serum bilirubin elevations. Failure to image the gallbladder in the presence of biliary ductal visualization may indicate cystic duct obstruction, acute or chronic cholecystitis, or surgical absence of the organ. Such scans have their greatest application in the diagnosis of acute cholecystitis.

8. Comparing characteristic of ultrasonography, computed tomography, magnetic resonance imaging in the diagnosis of the diseases of the alimentary tract, liver, biliary system and pancres.

Ultrasonography of the gallbladder is very accurate in the identification of cholelithiasis and has several advantages over oral cholecystography. The gallbladder is easily visualized with the technique, and in fact, failure to image the gallbladder successfully in a fasting patient correlates well with the presence of underlying gallbladder disease. Stones as small as 2 mm in diameter may be confidently identified provided that firm criteria are used [e.g., acoustic "shadowing" of opacities that are within the gallbladder lumen and that change with the patient's position (by gravity)]. In major medical centers, the false-negative and false-positive rates for ultrasound in gallstone patients are about 2 to 4%. Biliary sludge is material of low echogenic activity that typically forms a layer in the most dependent position of the gallbladder. This layer shifts with postural changes but fails to produce acoustic shadowing; these two characteristics distinguish sludges from gallstones. Ultrasound can also be used to assess the emptying function of the gallbladder.

Video: gall bladder ultrasound

Ultrasonography can provide important information in patients with acute pancreatitis, chronic pancreatitis, pancreatic calcification, pseudocyst, and pancreatic carcinoma. Echographic appearances can indicate the presence of edema, inflammation, and calcification (not obvious on plain films of the abdomen), as well as pseudocysts, mass lesions, and gallstones. In acute pancreatitis, the pancreas is characteristically enlarged. In pancreatic pseudocyst, the usual appearance is that of an echo-free, smooth, round fluid collection. Pancreatic carcinoma distorts the usual landmarks, and mass lesions greater than 3.0 cm are usually detected as localized, echo-free solid lesions. Ultrasound is often the initial investigation for most patients with suspected pancreatic disease. However, obesity, excess small- and large-bowel gas, and recently performed barium contrast examinations can interfere with ultrasound studies.

CT is the best imaging study for initial evaluation of a suspected chronic pancreatic disorder and for the complications of acute and chronic pancreatitis. It is especially useful in the detection of pancreatic tumors, fluid-containing lesions such as pseudocysts and abscesses, and calcium deposits. Most lesions are characterized by (1) enlargement of the pancreatic outline, (2) distortion of the pancreatic contour, and/or (3) a fluid filling that has a different attenuation coefficient than normal pancreas. However, it is occasionally difficult to distinguish between inflammatory and neoplastic lesions. Oral water-soluble contrast agents may be used to opacify the stomach and duodenum during CT scans; this strategy permits more precise delineation of various organs as well as mass lesions. Dynamic CT (using rapid intravenous administration of contrast) is useful in estimating the degree of pancreatic necrosis and in predicting morbidity and mortality. Spiral (helical) CT provides clear images much more rapidly and essentially negates artifact caused by patient movement.

Endoscopic ultrasonography (EUS) produces high-resolution images of the pancreatic parenchyma and pancreatic duct with a transducer fixed to an endoscope that can be directed onto the surface of the pancreas through the stomach or duodenum. Although criteria for abnormalities on EUS in severe pancreatic disease have been developed, the true sensitivity and specificity of this procedure has yet to be determined. In particular, it is not clear whether EUS can detect early pancreatic disease before abnormalities appear on more conventional radiograph tests such as ultrasonography or CT. The exact role of EUS versus ERCP and CT has yet to be defined.

Magnetic resonance cholangiopancreatography (MRCP) is now being used to view both the bile duct and the pancreatic duct. Nonbreath-hold and 3D turbo spin-echo techniques are being utilized to produce superb MRCP images. The main pancreatic duct and common bile duct can be seen well, but there is still a question as to whether changes can be detected consistently in the secondary ducts. MRCP may be particularly useful to evaluate the pancreatic duct in high-risk patients such as the elderly because this is a noninvasive procedure.

Both EUS and MRCP may replace ERCP in some patients. As these techniques become more refined, they may well be the diagnostic tests of choice to evaluate the pancreatic duct. ERCP is still needed to perform therapy of bile duct and pancreatic duct lesions.

Selective catheterization of the celiac and superior mesenteric arteries combined with superselective catheterization of others arteries, such as the hepatic, splenic, and gastroduodenal arteries permits visualization of the pancreas and detection of pancreatic neoplasms and pseudocysts. Pancreatic neoplasms can be identified by the sheathing of blood vessels by a mass lesion. Hormone-producing pancreatic tumors are especially likely to exhibit increased vascularity and tumor staining. Angiographic abnormalities are noted in many patients with pancreatic carcinoma but are uncommon in patients without pancreatic disease. Angiography complements ultrasonography and ERCP in the study of patients with a suspected pancreatic lesion and may be carried out if ERCP is either unsuccessful or nondiagnostic.

ERCP may provide useful information on the status of the pancreatic ductal system and thus aid in the differential diagnosis of pancreatic disease. Pancreatic carcinoma is characterized by stenosis or obstruction of either the pancreatic duct or the common bile duct; both ductal systems are often abnormal. In chronic pancreatitis, ERCP abnormalities include (1) luminal narrowing, (2) irregularities in the ductal system with stenosis, dilation, sacculation, and ectasia, and (3) blockage of the pancreatic duct by calcium deposits. The presence of ductal stenosis and irregularity can make it difficult to distinguish chronic pancreatitis from carcinoma. It is important to be aware that ERCP changes interpreted as indicating chronic pancreatitis actually may be due to the effects of aging on the pancreatic duct or to the fact that the procedure was performed within several weeks of an attack of acute pancreatitis. Although aging may cause impressive ductal alterations, it does not affect the results of pancreatic function tests (i.e., the secretin test). Elevated serum and/or urine amylase levels after ERCP have been reported in 25 to 75% of patients, but clinical pancreatitis is uncommon. In a series of 300 patients, pancreatitis occurred in only 5 patients after ERCP. If no lesion is found in the biliary and/or pancreatic ducts in a patient with repeated attacks of acute pancreatitis, manometric studies of the sphincter of Oddi may be indicated. Such studies, however, do increase the risk of post-ERCP/manometry acute pancreatitis. Such pancreatitis appears to be more common in patients with a nondilated pancreatic duct.

Although one or more radiologic abnormalities are found in over 50% of patients, the findings are inconstant and nonspecific. The chief value of conventional x-rays [chest films; kidney, ureter, and bladder (KUB) studies] in acute pancreatitis is to help exclude other diagnoses, especially a perforated viscus. Upper gastrointestinal tract x-rays have been superseded by ultrasonography and computed tomography (CT). A CT scan may confirm the clinical impression of acute pancreatitis even in the face of normal serum amylase levels. Importantly, CT is quite helpful in indicating the severity of acute pancreatitis and the risk of morbidity and mortality. Sonography and radionuclide scanning [N-p-isopropylacetanilide-iminodiacetic acid (PIPIDA) scan; hepatic 2,6-dimethyliminodiacetic acid (HIDA) scan] are useful in acute pancreatitis to evaluate the gallbladder and biliary tree.

Achalasia

Achalasia is a condition which affects approximately 1 in 50,000 people. In this condition the ability of the oesophagus to propel food from the mouth to the stomach is lost and the valve mechanism (sphincter) at the lower end of the oesophagus fails to relax to allow the food bolus into the stomach.

Symptoms

Patients suffering from achalasia may notice progressive difficulty in the ability to swallow food, the time taken to eat a meal increases, the patient may need to drink a lot of liquid in order to "help the food down" and sometimes on swallowing there may be quite severe pain in the central chest and back. After a time weight loss is noted.

Diagnosis

This is made by use of an x-ray (barium swallow), oesophageal manometry (a test to measure the pressure in the sphincter muscle) and endoscopy, the latter to exclude other causes of food blockage.

Treatment

1. Pharmacological therapy
Calcium channel blockers and nitrates may decrease the high pressure in the lower oesophageal sphincter. These medicines are effective in less than 10% of patients and are used principally in elderly patients in whom other forms of treatment may be risky.

2. Injection of Botulinum toxin into the lower oesophageal sphincter.
This drug blocks the release of a nerve transmitter, acetylcholine, promoting the sphincter to relax. Long term results of this have been disappointing and patients may develop antibodies to botulinum.

3. Pneumatic balloon dilatation.
A balloon is placed into the low oesophagus and inflated to a defined pressure. This can "split" the fibres of the low oesophageal sphincter. This treatment is successful in approximately 70% of patients but at least 50% require a further balloon dilatation.

The risk of this treatment is inadvertent perforation of the oesophagus (approximately 5-7%). This complication requires urgent surgery to repair the perforation.

4. Surgical operation - Heller's cardiomyotomy

This can now be done by keyhole surgery with usually a 1-2 night stay in hospital. In this operation the muscle of the lower oesophageal sphincter is divided under direct surgical vision. The operation is successful in approximately 85-90% of patients. A few patients have "resistant" achalasia which may require a further cardiomyotomy or, in very severe cases, removal of the oesophagus (oesophagectomy).

9, 14, 15. Criteria for diagnosis of esophagitis, esophageal diverticula and stricture. Management of the esophagitis the functional diseases of esophagus. Management of the esophageal diverticula and the tumours of the esophagus.

INFLAMMATORY DISORDERS: INFECTIOUS ESOPHAGITIS

Infectious esophagitis can be due to viral, bacterial, fungal, or parasitic organisms. In severely immunocompromised patients, multiple organisms may coexist.

Viral Esophagitis Herpes simplex virus (HSV) type 1 occasionally causes esophagitis in immunocompetent individuals, but either HSV type 1 or HSV type 2 may afflict patients who are immunosuppressed. Patients complain of an acute onset of chest pain, odynophagia, and dysphagia. Bleeding may occur in severe cases; and systemic manifestations such as nausea, vomiting, fever, chills, and mild leukocytosis may be present. Herpetic vesicles on the nose and lips may provide a clue to the diagnosis. Barium swallow is inadequate to detect early lesions and cannot reliably distinguish HSV infection from other types of infections. Endoscopy shows vesicles and small, discrete, punched-out superficial ulcerations with or without a fibrinous exudate. In later stages, a diffuse erosive esophagitis develops from enlargement and coalescence of the ulcers. Mucosal cells from a biopsy sample taken at the edge of an ulcer or from a cytologic smear show ballooning degeneration, ground-glass changes in the nuclei with eosinophilic intranuclear inclusions (Cowdry type A), and giant cell formation on routine stains. Culture for HSV becomes positive within days and is helpful in diagnosis. In patients with severe odynophagia, intravenous acyclovir, 400 mg five times a day, is usually initiated. Symptoms usually resolve in 1 week, but large ulcerations may take longer to heal. Foscarnet (90 mg/kg intravenously every 8 h) is used if resistance to acyclovir occurs.

Varicella-zoster virus (VZV) sometimes produces esophagitis in children with chickenpox and adults with herpes zoster. Esophageal VZV also can be the source of disseminated VZV infection without skin involvement. In an immunocompromised host, VZV esophagitis causes vesicles and confluent ulcers and usually resolves spontaneously, but it may cause necrotizing esophagitis in a severely compromised host. On routine histologic examination of mucosal biopsy samples or cytology specimens, VZV is difficult to distinguish from HSV, but the distinction can be made immunohistologically or by culture. Acyclovir reduces the duration of symptoms in VZV esophagitis.

Patients present with odynophagia, chest pain, hematemesis, nausea, and vomiting. Diagnosis requires endoscopy and biopsies of the ulcer. Mucosal brushings are not useful. Routine histologic examination shows intranuclear and small intracytoplasmic inclusions in large fibroblasts and endothelial cells. Immunohistology with monoclonal antibodies to CMV and in situ hybridization of CMV DNA on centrifugation culture and are useful for early diagnosis. Ganciclovir, 5 mg/kg every 12 h intravenously, is the treatment of choice. Foscarnet (90 mg/kg every 12 h intravenously) is used in resistant cases. Therapy is continued until healing occurs, which may take 2 to 4 weeks.

Gastro-oesophageal reflux disease (GORD) is the most common cause of indigestion, affecting up to 30% of the general population. GORD develops when gastric or duodenal contents flow back into the oesophagus. Oesophageal reflux is only considered a pathological condition when it causes undesirable symptoms.

Gastroesophageal reflux is a normal physiologic phenomenon experienced intermittently by most people, particularly after a meal. Gastroesophageal reflux disease (GERD) occurs when the amount of gastric juice that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without associated esophageal mucosal injury

A study by Richter and a Gallup Organization National Survey estimated that 25-40% of healthy adult Americans experience symptomatic GERD, most commonly manifested clinically by pyrosis (heartburn), at least once a month. Furthermore, approximately 7-10% of the adult population in the United States experiences such symptoms on a daily basis

In most persons with GERD, endogenous defense mechanisms either limit the amount of noxious material that is introduced into the esophagus or rapidly clear the material from the esophagus so that symptoms and esophageal mucosal irritation are minimized. Examples of the defense mechanisms include actions of the lower esophageal sphincter (LES) and normal esophageal motility. When the defense mechanisms are defective or become overwhelmed so that the esophagus is bathed in acid or bile and acid-containing fluid for prolonged periods, GERD can be said to exist.

Patients with GERD can exhibit various symptoms, both typical and atypical. Typical symptoms include heartburn, regurgitation, and dysphagia. Atypical symptoms include noncardiac chest pain, asthma, pneumonia, hoarseness, and aspiration. Patients typically have numerous daily episodes of symptomatic reflux, including pyrosis, water brash or sour taste in the mouth, nighttime coughing or aspiration, pneumonia or pneumonitis, bronchospasm, and laryngitis and voice changes, including hoarseness. In addition, objective evidence of esophageal damage can be seen on esophagogastroduodenoscopy as manifested by the incremental grades of esophagitis discussed below.

The anatomy of the esophagus, stomach, and esophagogastric junction is critical in the understanding of the pathogenesis of reflux.

The esophagus is divided into 3 parts: cervical, thoracic, and abdominal. The body of the esophagus is made up of inner circular and outer longitudinal muscular layers. The proximal third of the esophagus is striated muscle, which transitions to smooth muscle in the distal two thirds. The proximal esophagus contains the upper esophageal sphincter (UES), which comprises the cricopharyngeus and thyropharyngeus muscles.

The distal thoracic esophagus is located to the left side of midline. As the thoracic esophagus enters the abdomen through the esophageal hiatus in the diaphragm, it becomes the abdominal esophagus. The hiatus is formed by the right crus of the diaphragm, which forms a sling around the esophagus with the right and left pillars, so that the esophagus narrows when the diaphragm contracts. The actual contribution the diaphragm provides in maintaining an adequate length of intra-abdominal esophagus is not clearly understood; however, careful identification and approximation of the pillars during surgical treatment is crucial for preventing recurrence of reflux disease.

At this level, the phrenoesophageal ligament or membrane (see the image below), which is the reflection of the subdiaphragmatic fascia onto the transversalis fascia of the anterior abdominal wall, also encircles the esophagus. A prominent fat pad located on the anterior surface of the esophagus marks the lower limit of the phrenoesophageal ligament, which corresponds to the esophagogastric junction. This junction lies in the abdomen and forms the angle of His. The acute angle and the length of abdominal esophagus both contribute to the normal closure of the esophagus when intragastric and intra-abdominal pressures are high.

Relationship of the phrenoesophageal ligament to the diaphragm and esophagus.

The lower esophageal sphincter—or, more accurately, the distal esophageal high-pressure zone (HPZ)—is the distal most segment of the esophagus (3-5 cm in adults) and can be anywhere from 2-5 cm in length. Maintenance of an adequate intra-abdominal HPZ is crucial in preventing GERD. This HPZ does not correspond to any visible anatomic structure. It is a zone created by a complex architecture of smooth muscle fibers, and it is typically identified during manometry.

Usually, GERD is caused by a malfunction of one or more of these anatomic features. Proper surgical treatment requires complete preoperative and intraoperative evaluation and correction of all defective features.

Bllod supply of esophagus and stomach

The blood supply of the esophagus is segmental. The inferior thyroid artery supplies the cervical esophagus. Branches of the bronchial arteries and branches directly off of the aorta supply the proximal and distal thoracic esophagus, respectively. Finally, branches of the left gastric and inferior phrenic artery supply the abdominal esophagus. A relatively constant branch connects the left gastric and inferior phrenic arteries, called the Belsey artery.

Arterial blood supply and lymphatic drainage of the esophagus.

The blood supply of the stomach is rich, with overlap among the vessels. The lesser curve is supplied by the left and right gastric arteries, branches of the celiac trunk and proper hepatic artery, respectively. The greater curve is supplied by the right gastroepiploic artery arising from the gastroduodenal artery and the left gastroepiploic artery and the short gastric arteries originating from the splenic artery. This excellent collateral blood supply of the stomach allows the surgeon to ligate much of the arterial supply (ie, the short gastric arteries during fundoplication) without risk of ischemia

Pathophysiology

Schematically, the esophagus, lower esophageal sphincter (LES), and stomach can be envisioned as a simple plumbing circuit as described by Stein and coworkers. The esophagus functions as an antegrade pump, the LES as a valve, and the stomach as a reservoir. The abnormalities that contribute to GERD can stem from any component of the system. Poor esophageal motility decreases clearance of acidic material. A dysfunctional LES allows reflux of large amounts of gastric juice. Delayed gastric emptying can increase volume and pressure in the reservoir until the valve mechanism is defeated, leading to GERD. From a medical or surgical standpoint, it is extremely important to identify which of these components is defective so that effective therapy can be applied.

Esophageal defense mechanism

Esophageal defense mechanisms can be broken down into 2 categories (ie, esophageal clearance and mucosal resistance). Proper esophageal clearance is an extremely important factor in preventing mucosal injury. Esophageal clearance must be able to neutralize the acid refluxed through the lower esophageal sphincter. (Mechanical clearance is achieved with esophageal peristalsis; chemical clearance is achieved with saliva.) Normal clearance limits the amount of time the esophagus is exposed to refluxed acid or bile and gastric acid mixtures. Abnormal peristalsis can cause inefficient and delayed acid clearance.

Whether peristaltic dysfunction is secondary to esophageal exposure to acids or a primary defect is not understood clearly. In a review by Kahrilas et al, peristaltic dysfunction was progressively more common in patients with greater degrees of esophagitis. Abnormal peristalsis was identified in 25% of patients with mild esophagitis and 48% of patients with severe esophagitis.

Buttar and associates described the importance of esophageal mucosal resistance as a protective mechanism. They classified the factors into pre-epithelial, epithelial, and postepithelial defenses. When the defenses fail, esophagitis and other complications of reflux disease arise.

Dysfunction of the lower esophageal sphincter

The lower esophageal sphincter (LES) is defined by manometry as a zone of elevated intraluminal pressure at the esophagogastric junction. For proper LES function, this junction must be located in the abdomen so that the diaphragmatic crura can assist the action of the LES, thus functioning as an extrinsic sphincter. In addition, the LES must have a normal length and pressure and a normal number of episodes of transient relaxation (relaxation in the absence of swallowing).

LES dysfunction occurs via one of several mechanisms: transient relaxation of the LES (most common mechanism), permanent LES relaxation, and transient increase of intra-abdominal pressure that overcomes the LES pressure.

Delayed gastric emptying

The postulated mechanism by which delayed gastric emptying may cause GERD is an increase in gastric contents resulting in increased intragastric pressure and, ultimately, increased pressure against the lower esophageal sphincter. This pressure eventually defeats the LES and leads to reflux. However, objective studies have produced conflicting data regarding the role of delayed gastric emptying in the pathogenesis of GERD.

Hiatus hernia

When discussing mechanisms for GERD, the issue of hiatal hernia must be addressed. Hiatal hernias can be encountered frequently in patients with reflux disease; however, it has been well proven that not all patients with hiatal hernias have symptomatic reflux.

Buttar and coworkers state that a hiatal hernia may contribute to reflux via a variety of mechanisms.The lower esophageal sphincter may migrate proximally into the chest and lose its abdominal high-pressure zone (HPZ), or the length of the HPZ may decrease. The diaphragmatic hiatus may be widened by a large hernia, which impairs the ability of the crura to function as an external sphincter. Finally, gastric contents may be trapped in the hernial sac and reflux proximally into the esophagus during relaxation of the LES. Reduction of the hernias and crural closure is key to restoring an adequate intra-abdominal length of esophagus and recreating the HPZ.

Epidemiology

Western dietary habits have made GERD a common disease. Richter and associates reported that 25-40% of Americans experience symptomatic GERD at some point. Approximately 7-10% of Americans experience symptoms of GERD on a daily basis. Because many individuals control symptoms with over-the-counter (OTC) medications and without consulting a medical professional, the actual number of individuals with GERD is probably higher.

No sexual predilection exists: GERD is as common in men as in women. However, the male-to-female incidence ratio for esophagitis is 2:1-3:1. The male-to-female incidence ratio for Barrett esophagus is 10:1. White males are at a greater risk for Barrett esophagus and adenocarcinoma than other populations.

GERD occurs in all age groups. The prevalence of GERD increases in people older than 40 years.

The risk factors for reflux include:

· Alcohol (possibly)

· Hiatal hernia (a condition in which part of the stomach moves above the diaphragm, which is the muscle that separates the chest and abdominal cavities)

· Obesity

· Pregnancy

· Smoking

Heartburn and gastroesophageal reflux can be brought on or made worse by pregnancy and many different medications. Such drugs include:

· Anticholinergics (e.g., for seasickness)

· Beta-blockers for high blood pressure or heart disease

· Bronchodilators for asthma

· Calcium channel blockers for high blood pressure

· Progestin for abnormal menstrual bleeding or birth control

· Sedatives for insomnia or anxiety

· Tricyclic antidepressants

If you suspect that one of your medications may be causing heartburn, talk to your doctor. Never change or stop a medication you take regularly without talking to your doctor.

Classification of GERD

(According to unified clinical and statistical classification of diseases of the digestive system (HCD of Ukraine, 2004)

-Endoscopic "-" GERD (without esophagitis)

-Endoscopic "+" GERD (with esophagitis)

Clinical forms of GERD

Nonerosive GERD (is defined as those who have typical reflux symptoms without evidence of erosive changes in their lower esophageal mucosa; observed in approximately 60% of patients with GERD);

Erosive GERD (erosive changes of esophageal epithelium in varying degree, found in 37% of patients);

Grade A - one or more mucosal breaks < 5 mm in maximal length

Grade B - one or more mucosal breaks > 5mm, but without continuity across mucosal folds

Grade C - mucosal breaks continuous between > 2 mucosal folds, but involving less than 75% of the esophageal circumference

Grade D - mucosal breaks involving more than 75% of esophageal circumference

Complications of GERD (Barrett's esophagus, peptic esophageal ulcer, stricture, bleeding) (defined in 3% of patients).

Clinical features of GORD

Gastroesophageal reflux disease (GERD) is associated with a set of typical (esophageal) symptoms, including heartburn, regurgitation, and dysphagia. (However, a diagnosis of GERD based on the presence of typical symptoms is correct in only 70% of patients.) In addition to these typical symptoms, abnormal reflux can cause atypical (extraesophageal) symptoms, such as coughing, chest pain, and wheezing.

The American College of Gastroenterology (ACG) published updated guidelines for the diagnosis and treatment of GERD in 2005. According to the guidelines, for patients with symptoms and history consistent with uncomplicated GERD, the diagnosis of GERD may be assumed and empirical therapy begun. Patients who show signs of GERD complications or other illness or who do not respond to therapy should be considered for further diagnostic testing.

A history of nausea, vomiting, or regurgitation should alert the physician to evaluate for delayed gastric emptying.

Patients with GERD may also experience significant complications associated with the disease, such as esophagitis, stricture, and Barrett esophagus. Approximately 50% of patients with gastric reflux develop esophagitis.

The most common symptoms of oesophageal reflux are dyspepsia, heartburn

and regurgitation, which can be provoked by bending, straining or lying down. Waterbrash, which is salivation due to reflex salivary gland stimulation as acid enters the gullet, is often present. A history of weight gain is common.

Other less common symptoms include dysphagia (difficulty swallowing), odynophagia (pain on swallowing), and symptoms of anaemia. A small number of patients present with atypical chest pain, which may be severe, can mimic angina and is probably due to reflux-induced oesophageal spasm.

Belching air, food, sour, bitter, regurgitation occurs because of retrograde reflux of gastric content into the esophagus and mouth (more than 50% of patients);

Chest pain. Less frequently observed arises from spasm of the esophagus in response to acid-peptic aggression. Localization and irradiation are similar to symptoms in angina. In these patients, excluding cardiac etiology is important prior to labeling the pain as noncardiac chest pain secondary to GERD.

Pathophysiology of GORD

Mandatory studies include upper GI endoscopy and manometry. Endoscopy can help confirm the diagnosis of reflux by demonstrating complications of reflux (esophagitis, strictures, Barrett esophagus) and can help in evaluating the anatomy (eg, hiatal hernia, masses, strictures). Manometry helps surgical planning by determining the lower esophageal sphincter (LES) pressure and identifying any esophageal motility disorders. Esophageal amplitudes and propagation of esophageal swallows are also evaluated.

Optional studies include 24-hour pH probe test and upper GI series. Use of 24-hour pH testing helps confirm the diagnosis in patients in whom the history is not clear, atypical symptoms dominate the clinical picture, or endoscopy shows no complications of reflux disease. Upper GI series can be ordered to further delineate the anatomy. Hiatal hernias can be evaluated (size) and reflux can be demonstrated. In addition, gastric emptying can be evaluated to a limited. If a question exists regarding inadequate gastric emptying or if the patient has a history of nausea and vomiting, a nuclear medicine gastric emptying study can be obtained.

At the authors' institution, endoscopy, manometry, and 24-hour pH studies are obtained routinely. Upper GI series and nuclear medicine gastric emptying studies are ordered only if clinically indicated. Currently, no role exists for CT, MRI, or ultrasonography in the routine evaluation of patients with reflux disease.

Occasional episodes of GORD are common in health, particularly after eating. Gastro-oesophageal reflux disease develops when the oesophageal mucosa is exposed to gastric contents for prolonged periods of time, resulting in symptoms and, in a small proportion of cases, this leads to oesophagitis.

Normally, prevention of acid damage is achieved by a combination of physiological barriers. The LOS is a 3-4 cm long collection of smooth muscle fibres which maintains a resting tone of 10-30mmHg pressure.

Oesophageal manometry studies.

There is also extrinsic pressure exerted from the crura of the diaphragm at the same point and the angle of His (the angle of entry of the oesophagus into the stomach) which both help retain acid within the stomach. Periods of LOS relaxation occur in all individuals and allow transient reflux of acid into the oesophagus. This initiates a distal oesophageal peristaltic wave which progressively clears the acid. Swallowed saliva is alkaline and also helps neutralise oesophageal acid.

Mechanism of protection of oesophagus from acid reflux

Abnormalities of the lower oesophageal sphincter related to GORD

In health the lower oesophageal sphincter is tonically contracted, relaxing only during swallowing. Some patients with GORD have reduced lower oesophageal sphincter tone, permitting reflux when intra-abdominal pressure rises. In others basal sphincter tone is normal but reflux occurs in response to frequent episodes of inappropriate sphincter relaxation.

Hiatus hernia

A hiatal hernia occurs when part of the stomach protrudes through the diaphragm and into the thoracic cavity. Such hernias are extremely common in older people and more common in women than in men. A hiatus hernia causes reflux because the pressure gradient between the abdominal and thoracic cavities, which normally pinches the hiatus, is lost. In addition the oblique angle between the cardia and oesophagus disappears. Many patients who have large hiatus hernias develop reflux symptoms, but the relationship between the presence of a hernia and symptoms is poor. Hiatus hernias are very common in individuals who have no symptoms, and some symptomatic patients have only a very small or no hernia.

Important features of a hiatus hernia include:

• Occur in 30% of the population over the age of 50 years.

• Often asymptomatic.

• Heartburn and regurgitation can occur.

• Gastric volumes may complicate large hernias.

The role of gastric contents in GORD

Gastric acid is the most important oesophageal irritant and there is a close relationship between acid exposure time and symptoms. Alkaline reflux, due to bile reflux following gastric surgery, is of uncertain importance.

Increased intra-abdominal pressure

Pregnancy and obesity are established predisposing causes. Weight loss commonly improves symptoms and patients should be encouraged to avoid tight-fitting garments.

Dietary and environmental factors

Dietary fat, chocolate, alcohol and beverages such as tea and coffee relax the lower oesophageal sphincter and may provoke symptoms.

There is little evidence to incriminate smoking or non-steroidal anti-inflammatory drugs (NSAIDs) as causes of gastro-oesophageal reflux disease.

Delayed oesophageal clearance

Defective oesophageal peristaltic activity can be seen in patients who have GORD. Poor oesophageal clearance leads to increased exposure to acid from the stomach.

Complications of GORD

Oesophagitis

Reflux oesophagitis is a chronic inflammatory process mediated by gastric acid and pepsin from the stomach as well as bile from the duodenum, which can result in ulceration of the mucosa and secondary fibrosis in the muscular wall. A range of endoscopic findings, from mild redness to severe bleeding ulceration with stricture formation, is recognised. There is a poor correlation between symptoms and histological and endoscopic findings. A normal endoscopy and normal oesophageal histology are perfectly compatible with significant gastro-oesophageal reflux disease.

An endoscopic view of a normal oesophagus

Other causes of oesophagitis: infectious diseases. Viruses, bacteria, fungi and mycobacterium can all cause oesophageal infection. The most common of these are candida. Oesophageal candidiasis occurs in debilitated patients and those taking broad-spectrum antibiotics or cytotoxic drugs. It is a particular problem in AIDS patients, who are also susceptible to a spectrum of oesophageal infections. Oesophageal candidiasis rarely develops in patients who do not have an underlying disease such as diabetes, immune deficiency or malignancy. The main symptoms of oesophageal candidiasis are dysphagia and odynophagia. Severe infection of the gullet can destroy oesophageal innervation, causing abnormal motility.

Endoscopic view of mild oesophagitis.

Reflux oesophagitis.

Peptic esophagitis. A rapid urease test (RUT) is performed on the esophageal biopsy sample. The result is positive for esophagitis.

Esophagitis may be diagnosed using endoscopy, although it cannot always be appreciated on endoscopy. As many as 50% of symptomatic patients with GERD demonstrate no evidence of esophagitis on endoscopy. Still, documentation of this complication is important in diagnosing GERD. Degrees of esophagitis are described by the Savary-Miller classification as follows.

• Grade I – Erythema
• Grade II – Linear nonconfluent erosions
• Grade III – Circular confluent erosions
• Grade IV – Stricture or Barrett esophagus.

Reflux esophagitis is demonstrated on barium esophagram.

Reflux oesophagitis.

Reflux oesophagitis.

Corrosives

Accidental or suicidal ingestion of highly alkaline or acidic substances may result in injury to the oesophagus. The most common symptom is odynophagia, but patients may also complain of dysphagia and chest pain. Ingestion of caustic compounds is followed by painful burns of the mouth and pharynx and by extensive erosive oesophagitis. At the time of presentation, management is conservative, based upon analgesia and nutritional support. Vomiting should be avoided and endoscopy should not be done at this stage because of the high risk of oesophageal perforation. Following the acute phase, a barium swallow and X-ray examination is performed to demonstrate the extent of stricture formation. Endoscopic dilation is usually necessary, although it is difficult and hazardous because strictures are often long, tortuous and easily perforated.

Strictures are advanced forms of esophagitis and are caused by circumferential fibrosis due to chronic deep injury. Strictures can result in dysphagia and a short esophagus. Gastroesophageal reflux strictures typically occur in the mid-to-distal esophagus and can be visualized on upper GI tract studies and endoscopy. Presence of a stricture with a history of reflux can also help diagnose GERD. Patients present with dysphagia to solid meals and vomiting of nondigested foods.

As a rule, the presence of any esophageal stricture is an indication that the patient needs surgical consultation and treatment (usually surgical fundoplication). When patients present with dysphagia, barium esophagography is indicated to evaluate for possible stricture formation. In these cases, especially when associated with food impaction, eosinophilic esophagitis must be ruled out prior to attempting any mechanical dilatation of the narrowed esophageal region.

Esophageal stricture

Barrett’s oesophagus

Barrett’s oesophagus is defined as epithelial metaplasia in which the normal squamous epithelium of the oesophagus is replaced by one or more of the following types of columnar epithelium: a specialised columnar epithelium, a junctional type of epithelium; and/or a gastric type of epithelium. Barrett’s oesophagus is thought to be a consequence of chronic gastro-oesophageal reflux.

Diagnosis of Barrett’s oesophagus is made by endoscopic visualisation of the oesophageal mucosa, supported by examination of tissue biopsies. Barrett’s oesophagus is recognised endoscopically as confluent areas or fingers of pink, gastric-like mucosa extending from the cardia of the stomach into the oesophagus. The prevalence of adenocarcinoma in patients with Barrett’s oesophagus is reported to be in the region of 30 to 50 times that of the general population (Clark et al. 2000). Consequently patients discovered to have Barrett’s changes during endoscopy are considered for endoscopic surveillance programmes. Patients with moderate dysplasia should undergo repeated biopsies at 6 to 12-monthly intervals. Patients found to have severe dysplasia usually have associated cancer and are usually referred for oesophageal surgery.

In Barrett esophagus, columnar epithelium extends proximal to the gastroesophageal junction (the imaginary line at which the esophagus ends and the stomach begins, which corresponds to the most proximal extent of the gastric folds).

Histology. Barrett’s oesophagus

Endoscopy. Barrett’s oesophagus

Management of patients with Barrett esophagus.

Anaemia

Iron deficiency anaemia occurs as a consequence of chronic, insiduous blood loss and can result from longstanding oesophagitis.

Benign oesophageal stricture

Strictures are advanced forms of esophagitis and are caused by circumferential fibrosis due to chronic deep injury. Strictures can result in dysphagia and a short esophagus. Gastroesophageal reflux strictures typically occur in the mid-to-distal esophagus and can be visualized on upper GI tract studies and endoscopy. Presence of a stricture with a history of reflux can also help diagnose GERD. Patients present with dysphagia to solid meals and vomiting of nondigested foods.

As a rule, the presence of any esophageal stricture is an indication that the patient needs surgical consultation and treatment (usually surgical fundoplication). When patients present with dysphagia, barium esophagography is indicated to evaluate for possible stricture formation. In these cases, especially when associated with food impaction, eosinophilic esophagitis must be ruled out prior to attempting any mechanical dilatation of the narrowed esophageal region.

Esophageal stricture

Treatment of strictures may involve the use of weighted bougies, pneumatic balloon dilators or graduated plastic Savary-Gillard dilators. Subsequent treatment usually involves long-term therapy with a proton pump inhibitor drug (i.e. omeprazole or lansoprazole) which should be prescribed to reduce the risk of recurrent oesophagitis and stricture formation. The patient should be advised to chew food thoroughly and it is also important to ensure that dentition is adequate.

Balloon dilation of a benign oesophageal stricture.

Investigations for GORD

Investigation is advisable if patients present in middle or late age, if symptoms are atypical or if a complication is suspected. Endoscopy is the investigation of choice. This is done to exclude other upper gastrointestinal diseases that can mimic gastro-oesophageal reflux, and to identify complications. A normal endoscopy in a patient with compatible symptoms should not preclude treatment for gastro-oesophageal reflux disease. When, despite endoscopy, the diagnosis is unclear or if surgical intervention is under consideration, 24-hour pH monitoring is indicated. This involves tethering a slim catheter with a terminal radiotelemetry pHsensitive probe above the gastro-oesophageal junction. The intraluminal pH is recorded whilst the patient undergoes normal activities, and episodes of pain are noted and related to pH. A pH of less than 4 for more than 4% of the study time is diagnostic of reflux disease.

Gastroesophageal reflux may be classified into 3 categories as follows:

• Physiologic (or functional) gastroesophageal reflux: These patients have no underlying predisposing factors or conditions; growth and development are normal; and pharmacologic treatment is typically not necessary, though it may be needed to relieve symptoms if lifestyle changes are unsuccessful.
• Pathologic gastroesophageal reflux or GERD: Patients frequently experience complications noted above, requiring careful evaluation and treatment
• Secondary gastroesophageal reflux: This refers to a case in which an underlying condition may predispose to gastroesophageal reflux, with examples including asthma (a condition that may also be, in part, caused by or exacerbated by reflux) and gastric outlet obstruction

The diagnosis of GERD in patients with atypical symptoms can be difficult. When patients present with atypical complaints, the diagnosis of GERD must be kept in mind. Patients with recurrent aspiration can have asthma, history of pneumonias, and progressive pulmonary fibrosis. Additionally, hoarseness can be present due to chronic laryngeal irritation. Chest pain is another presenting symptom that can be difficult to evaluate. In these patients, excluding cardiac etiology is important prior to labeling the pain as noncardiac chest pain secondary to GERD.

The clinical presentation of GERD in pregnant women is similar to that for the general population. Heartburn and regurgitation are the cardinal symptoms. The diagnostic evaluation consists of a thorough history and physical examination.

Management of GORD

The first-line nursing of patients with GORD should relate to behaviour modification and nurses should encourage the following recommendations:

• weight loss

• avoidance of tight-fitting garments

• avoidance of dietary items which the patient finds worsens symptoms

• elevation of the bed-head in those who experience nocturnal symptoms

• avoidance of late meals

• cessation of smoking

Antacids, which are said to produce a protective mucosal ‘raft’ over the oesophageal mucosa, are taken with considerable symptomatic benefit by most patients. H2 receptor antagonist drugs, which reduce gastric acid secretion, help symptoms without healing oesophagitis. They are well tolerated and the timing of medication and dosage should be tailored to individual need. Proton pump inhibitors are the treatment of choice for severe symptoms and for complicated reflux disease. These drugs irreversibly inhibit the proton pump, reducing the transport of hydrogen (H) ions out of parietal cells. Symptoms almost invariably resolve and oesophagitis heals in the majority of patients. Recurrence of symptoms is almost inevitable when therapy is stopped, and some patients require lifelong treatment. Patients who fail to respond to medical therapy, those who are unwilling to take long-term proton pump inhibitors and those whose major symptom is severe regurgitation are considered for anti-reflux surgery.

Nissen fundoplication.

Evidence-based guidelines for the management of GORD have been published by the Scottish Intercollegiate Guidelines Network (SIGN) (2003) and the British Society of Gastroenterology (BSG) (2002).

Gastric dyspepsia (etiology, diagnosis, differential diagnosis, complications, treatment)

NON-ULCER DYSPEPSIA

It is not unusual for there to be confusion when a diagnosis is based on symptoms alone. This is undoubtedly the case with non-ulcer dyspepsia (NUD), but it is an essential diagnostic group because it represents up to 40% of patients who present with 'persistent or recurrent pain or discomfort that is centred in the upper abdomen or epigastrium' (dyspepsia), and in whom upper GI endoscopy and radiology are normal. Symptoms can be subdivided into:

• Ulcer-like dyspepsia

Epigastric pain relieved by food, often occurring at night

• Dysmotility-like dyspepsia

Upper abdominal discomfort, worse after meals, accompanied with bloating, early satiety and nausea

• Reflux-like dyspepsia

Upper abdominal pain with associated reflux symptoms. This classification has not proved helpful in tailoring therapy, except for reflux-like symptoms which might be better treated as for GORD. The pathology responsible for causing the symptoms of NUD has focused on two main areas:

1. gastric dysmotility

2. Helicobacter pylori-related gastritis.

During fasting, the stomach exhibits migrating motor complexes (MMCs) along with the rest of the GI tract and post-prandially shows relaxation of the gastric fundus to accommodate the food bolus. The antrum has high amplitude contractions to reduce particle size and the pylorus has phasic contractions to allow slow emptying of the stomach. There may be decreased compliance of the gastric fundus in NUD patients but this does not correlate well with symptoms, particularly nausea and early satiety, nor does it predict a good outcome with treatment using promotility agents.

H. pylori-related gastritis has come under close scrutiny in patients with NUD. There appears to be no benefit accrued by eradicating H. pylori in patients with NUD. Gastric acid hypersecretion does not cause NUD as basal and peak acid output is similar in both patients and controls.

Proposed mechanism by which H. pylori can result in gastric ulcer/cancer or duodenal ulcer

Diagnostic tests for H. pylori and their estimated costs.

MANAGEMENT

After the diagnosis of NUD, subsequent further investigation should be avoided as it implies diagnostic uncertainty and may worsen therapeutic outcome. Minimum treatment required should be adopted with simple antacids. More intractable cases may be treated with H2 receptor antagonists or PPIs for 4-6 weeks and then discontinued and reserved for symptom recurrence. Promotility agents may be beneficial and are best taken shortly before meals. Evidence supporting the usefulness of H. pylori eradication in NUD patients is lacking but as peptic ulcer disease is periodic, it is possible that patients were in remission at the time of endoscopy. Consequently, it may be appropriate to offer H. pylori eradication therapy in patients showing relevant symptoms.

Approach to a patient with new and undiagnosed ulcerlike symptoms refractory to a trial of antisecretory therapy with an H2 receptor blocker or a proton pump inhibitor at customary doses or a patient with recurrent ulcerlike symptoms when the antisecretory therapy is stopped.

Main syndromes and symptoms of the diseases of the stomach and duodenum.

CLINICAL FEATURES History Abdominal pain is common to many gastrointestinal disorders, including DU and GU, but has a poor predictive value for the presence of either DU or GU. Up to 10% of patients with NSAID-induced mucosal disease can present with a complication (bleeding, perforation, and obstruction) without antecedent symptoms. Despite this poor correlation, a careful history and physical examination are essential components of the approach to a patient suspected of having peptic ulcers.

Epigastric pain described as a burning or gnawing discomfort can be present in both DU and GU. The discomfort is also described as an ill-defined, aching sensation or as hunger pain. The typical pain pattern in DU occurs 90 min to 3 h after a meal and is frequently relieved by antacids or food. Pain that awakes the patient from sleep (between midnight and 3 A.M.) is the most discriminating symptom, with two-thirds of DU patients describing this complaint. Unfortunately, this symptom is also present in one-third of patients with NUD. The pain pattern in GU patients may be different from that in DU patients, where discomfort may actually be precipitated by food. Nausea and weight loss occur more commonly in GU patients. In the United States, endoscopy detects ulcers in <30% of patients who have dyspepsia. Despite this, 40% of these individuals with typical ulcer symptoms had an ulcer crater, and 40% had gastroduodenitis on endoscopic examination.

The mechanism for development of abdominal pain in ulcer patients is unknown. Several possible explanations include acid-induced activation of chemical receptors in the duodenum, enhanced duodenal sensitivity to bile acids and pepsin, or altered gastroduodenal motility.

Variation in the intensity or distribution of the abdominal pain, as well as the onset of associated symptoms such as nausea and/or vomiting, may be indicative of an ulcer complication. Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset of severe, generalized abdominal pain may indicate perforation. Pain worsening with meals, nausea, and vomiting of undigested food suggest gastric outlet obstruction. Tarry stools or coffee ground emesis indicate bleeding.

Criteria for diagnosis of the gastritis.

A-gastritis.

B-gastritis.

C-gastritis.

The term gastritis should be reserved for histologically documented inflammation of the gastric mucosa. Gastritis is not the mucosal erythema seen during endoscopy and is not interchangeable with "dyspepsia." The etiologic factors leading to gastritis are broad and heterogeneous. Gastritis has been classified based on time course (acute vs. chronic), histologic features, and anatomic distribution or proposed pathogenic mechanism .

The correlation between the histologic findings of gastritis, the clinical picture of abdominal pain or dyspepsia, and endoscopic findings noted on gross inspection of the gastric mucosa is poor. Therefore, there is no typical clinical manifestation of gastritis.

Acute Gastritis. The most common causes of acute gastritis are infectious. Acute infection with H. pylori induces gastritis. However, H. pylori acute gastritis has not been extensively studied. Reported as presenting with sudden onset of epigastric pain, nausea, and vomiting, limited mucosal histologic studies demonstrate a marked infiltrate of neutrophils with edema and hyperemia. If not treated, this picture will evolve into one of chronic gastritis. Hypochlorhydria lasting for up to 1 year may follow acute H. pylori infection.

The highly acidic gastric environment may be one reason why infectious processes of the stomach are rare. Bacterial infection of the stomach or phlegmonous gastritis is a rare potentially life-threatening disorder, characterized by marked and diffuse acute inflammatory infiltrates of the entire gastric wall, at times accompanied by necrosis. Elderly individuals, alcoholics, and AIDS patients may be affected. Potential iatrogenic causes include polypectomy and mucosal injection with India ink. Organisms associated with this entity include streptococci, staphylococci, Escherichia coli, Proteus, and Haemophilus. Failure of supportive measures and antibiotics may result in gastrectomy.

Chronic Gastritis. Chronic gastritis is identified histologically by an inflammatory cell infiltrate consisting primarily of lymphocytes and plasma cells, with very scant neutrophil involvement. Distribution of the inflammation may be patchy, initially involving superficial and glandular portions of the gastric mucosa. This picture may progress to more severe glandular destruction, with atrophy and metaplasia. Chronic gastritis has been classified according to histologic characteristics. These include superficial atrophic changes and gastric atrophy.

The early phase of chronic gastritis is superficial gastritis. The inflammatory changes are limited to the lamina propria of the surface mucosa, with edema and cellular infiltrates separating intact gastric glands. Additional findings may include decreased mucus in the mucous cells and decreased mitotic figures in the glandular cells. The next stage is atrophic gastritis. The inflammatory infiltrate extends deeper into the mucosa, with progressive distortion and destruction of the glands. The final stage of chronic gastritis is gastric atrophy. Glandular structures are lost; there is a paucity of inflammatory infiltrates. Endoscopically the mucosa may be substantially thin, permitting clear visualization of the underlying blood vessels.

Video: chronic gastritis

Gastric glands may undergo morphologic transformation in chronic gastritis. Intestinal metaplasia denotes the conversion of gastric glands to a small intestinal phenotype with small-bowel mucosal glands containing goblet cells. The metaplastic changes may vary in distribution from patchy to fairly extensive gastric involvement. Intestinal metaplasia is an important predisposing factor for gastric cancer.

Chronic gastritis is also classified according to the predominant site of involvement. Type A refers to the body-predominant form (autoimmune) and type B is the central-predominant form (H. pylori-related). This classification is artificial in view of the difficulty in distinguishing these two entities. The term AB gastritis has been used to refer to a mixed antral/body picture.

Type A Gastritis. The less common of the two forms involves primarily the fundus and body, with antral sparing. Traditionally, this form of gastritis has been associated with pernicious anemia in the presence of circulating antibodies against parietal cells and intrinsic factor; thus it is also called autoimmune gastritis. H. pylori infection can lead to a similar distribution of gastritis. The characteristics of an autoimmune picture are not always present.

Antibodies to parietal cells have been detected in >90% of patients with pernicious anemia and in up to 50% of patients with type A gastritis. Anti-parietal cell antibodies are cytotoxic for gastric mucous cells. The parietal cell antibody is directed against H+,K+-ATPase. T cells are also implicated in the injury pattern of this form of gastritis.

Parietal cell antibodies and atrophic gastritis are observed in family members of patients with pernicious anemia. These antibodies are observed in up to 20% of individuals over age 60 and in ~20% of patients with vitiligo and Addison's disease. About half of patients with pernicious anemia have antibodies to thyroid antigens, and about 30% of patients with thyroid disease have circulating anti-parietal cell antibodies. Anti-intrinsic factor antibodies are more specific than parietal cell antibodies for type A gastritis, being present in ~40% of patients with pernicious anemia. Another parameter consistent with this form of gastritis being autoimmune in origin is the higher incidence of specific familial histocompatibility haplotypes such as HLA-B8 and -DR3.

The parietal cell-containing gastric gland is preferentially targeted in this form of gastritis, and achlorhydria results. Parietal cells are the source of intrinsic factor, lack of which will lead to vitamin B12 deficiency and its sequelae (megaloblastic anemia, neurologic dysfunction).

Gastric acid plays an important role in feedback inhibition of gastrin release from G cells. Achlorhydria, coupled with relative sparing of the antral mucosa (site of G cells), leads to hypergastrinemia. Gastrin levels can be markedly elevated (>500 pg/mL) in patients with pernicious anemia. ECL cell hyperplasia with frank development of gastric carcinoid tumors may result from gastrin trophic effects. The role of gastrin in carcinoid development is confirmed by the observation that antrectomy leads to regression of these lesions. Hypergastrinemia and achlorhydria may also be seen in non-pernicious anemia-associated type A gastritis.

Type B gastritis. Type B, or antral-predominant, gastritis is the more common form of chronic gastritis. H. pylori infection is the cause of this entity. Although described as "antral-predominant," this is likely a misnomer in view of studies documenting the progression of the inflammatory process towards the body and fundus of infected individuals. The conversion to a pan-gastritis is time-dependent-estimated to require 15 to 20 years. This form of gastritis increases with age, being present in up to 100% of people over age 70. Histology improves after H. pylori eradication. The number of H. pylori organisms decreases dramatically with progression to gastric atrophy, and the degree of inflammation correlates with the level of these organisms. Early on, with antral-predominant findings, the quantity of H. pylori is highest and a dense chronic inflammatory infiltrate of the lamina propria is noted accompanied by epithelial cell infiltration with polymorphonuclear leukocytes.

Multifocal atrophic gastritis, gastric atrophy with subsequent metaplasia, has been observed in chronic H. pylori-induced gastritis. This may ultimately lead to development of gastric adenocarcinoma. H. pylori infection is now considered an independent risk factor for gastric cancer. Worldwide epidemiologic studies have documented a higher incidence of H. pylori infection in patients with adenocarcinoma of the stomach as compared to control subjects. Seropositivity for H. pylori is associated with a three- to sixfold increased risk of gastric cancer. This risk may be as high as ninefold after adjusting for the inaccuracy of serologic testing in the elderly. The mechanism by which H. pylori infection leads to cancer is unknown. However, eradication of H. pylori as a general preventative measure for gastric cancer is not recommended.

Infection with H. pylori is also associated with development of a low grade B cell lymphoma, gastric MALT lymphoma. The chronic T cell stimulation caused by the infection leads to production of cytokines that promote the B cell tumor. Tumor growth remains dependent upon the presence of H. pylori in that its eradication is often associated with complete regression of the tumor. The tumor may take more than a year to regress after treating the infection. Such patients should be followed by EUS every 2 to 3 months. If the tumor is stable or decreasing in size, no other therapy is necessary. If the tumor grows, it may have become a high-grade B cell lymphoma. When the tumor becomes a high-grade aggressive lymphoma histologically, it loses responsiveness to H. pylori eradication.

Criteria for diagnosis of the ulcer disease.

History. Abdominal pain is common to many gastrointestinal disorders, including DU and GU, but has a poor predictive value for the presence of either DU or GU. Up to 10% of patients with NSAID-induced mucosal disease can present with a complication (bleeding, perforation, and obstruction) without antecedent symptoms. Despite this poor correlation, a careful history and physical examination are essential components of the approach to a patient suspected of having peptic ulcers.

Epigastric pain described as a burning or gnawing discomfort can be present in both DU and GU. The discomfort is also described as an ill-defined, aching sensation or as hunger pain. The typical pain pattern in DU occurs 90 min to 3 h after a meal and is frequently relieved by antacids or food. Pain that awakes the patient from sleep (between midnight and 3 A.M.) is the most discriminating symptom, with two-thirds of DU patients describing this complaint. Unfortunately, this symptom is also present in one-third of patients with NUD. The pain pattern in GU patients may be different from that in DU patients, where discomfort may actually be precipitated by food. Nausea and weight loss occur more commonly in GU patients. In the United States, endoscopy detects ulcers in <30% of patients who have dyspepsia. Despite this, 40% of these individuals with typical ulcer symptoms had an ulcer crater, and 40% had gastroduodenitis on endoscopic examination.

The mechanism for development of abdominal pain in ulcer patients is unknown. Several possible explanations include acid-induced activation of chemical receptors in the duodenum, enhanced duodenal sensitivity to bile acids and pepsin, or altered gastroduodenal motility.

Variation in the intensity or distribution of the abdominal pain, as well as the onset of associated symptoms such as nausea and/or vomiting, may be indicative of an ulcer complication. Dyspepsia that becomes constant, is no longer relieved by food or antacids, or radiates to the back may indicate a penetrating ulcer (pancreas). Sudden onset of severe, generalized abdominal pain may indicate perforation. Pain worsening with meals, nausea, and vomiting of undigested food suggest gastric outlet obstruction. Tarry stools or coffee ground emesis indicate bleeding. .

Physical Examination Epigastric tenderness is the most frequent finding in patients with GU or DU. Pain may be found to the right of the midline in 20% of patients. Unfortunately, the predictive value of this finding is rather low. Physical examination is critically important for discovering evidence of ulcer complication. Tachycardia and orthostasis suggest dehydration secondary to vomiting or active gastrointestinal blood loss. A severely tender, boardlike abdomen suggests a perforation. Presence of a succussion splash indicates retained fluid in the stomach, suggesting gastric outlet obstruction.

Differential Diagnosis. The list of gastrointestinal and nongastrointestinal disorders that can mimic ulceration of the stomach or duodenum is quite extensive. The most commonly encountered diagnosis among patients seen for upper abdominal discomfort is NUD. NUD, also known as functional dyspepsia or essential dyspepsia, refers to a group of heterogeneous disorders typified by upper abdominal pain without the presence of an ulcer. Dyspepsia has been reported to occur in up to 30% of the U.S. population. Up to 60% of patients seeking medical care for dyspepsia have a negative diagnostic evaluation. The etiology of NUD is not established, and the potential role of H. pylori in NUD remains controversial.

Several additional disease processes that may present with "ulcer-like" symptoms include proximal gastrointestinal tumors, gastroesophageal reflux, vascular disease, pancreaticobiliary disease (biliary colic, chronic pancreatitis), and gastroduodenal Crohn's disease.

Diagnostic Evaluation. In view of the poor predictive value of abdominal pain for the presence of a gastroduodenal ulcer and the multiple disease processes that can mimic this disease, the clinician is often confronted with having to establish the presence of an ulcer. Documentation of an ulcer requires either a radiographic (barium study) or an endoscopic procedure.

Barium examination of the stomach and duodenum reveals an ulcer, 1 cm in diameter (arrow), in the duodenal bulb with radiating folds.

Peptic ulcer disease, duodenal, Fig.1	Peptic ulcer disease, duodenal, Fig.2

Barium studies of the proximal gastrointestinal tract are still commonly used as a first test for documenting an ulcer. The sensitivity of older single-contrast barium meals for detecting a DU is as high as 80%, with a double-contrast study providing detection rates as high as 90%. Sensitivity for detection is decreased in small ulcers (<0.5 cm), presence of previous scarring, or in postoperative patients. A DU appears as a well-demarcated crater, most often seen in the bulb. A GU may represent benign or malignant disease. Typically, a benign GU also appears as a discrete crater with radiating mucosal folds originating from the ulcer margin. Ulcers >3 cm in size or those associated with a mass are more often malignant. Unfortunately, up to 8% of GUs that appear to be benign by radiographic appearance are malignant by endoscopy or surgery. Radiographic studies that show a GU must be followed by endoscopy and biopsy.

Endoscopy provides the most sensitive and specific approach for examining the upper gastrointestinal tract. In addition to permitting direct visualization of the mucosa, endoscopy facilitates photographic documentation of a mucosal defect and tissue biopsy to rule out malignancy (GU) or H. pylori. Endoscopic examination is particularly helpful in identifying lesions too small to detect by radiographic examination, for evaluation of atypical radiographic abnormalities, or to determine if an ulcer is a source of blood loss.

Video: peptic ulcer

Video: secondary ulcer

PyloriTek, a biopsy urease test, has a sensitivity and specificity of >90 to 95%. In the interest of making a diagnosis of H. pylori without the need for performing endoscopy, several noninvasive methods for detecting this organism have been developed. Three types of studies routinely used include serologic testing, the 13C- or 14C-urea breath test, and the fecal H. pylori antigen test.

Occasionally, specialized testing such as serum gastrin and gastric acid analysis or sham feeding may be needed in individuals with complicated or refractory PUD. Screening for aspirin or NSAIDS (blood or urine) may also be .

Treatment of the gastritis

Treatment in chronic gastritis is aimed at the sequelae and not the underlying inflammation. Patients with pernicious anemia will require parenteral vitamin B12 supplementation on a long-term basis. Eradication of H. pylori is not routinely recommended unless PUD or a low-grade MALT lymphoma is present.

Miscellaneous Forms of Gastritis. Lymphocytic gastritis is characterized histologically by intense infiltration of the surface epithelium with lymphocytes. The infiltrative process is primarily in the body of the stomach and consists of mature T cells and plasmacytes. The etiology of this form of chronic gastritis is unknown. It has been described in patients with celiac sprue, but whether there is a common factor associating these two entities is unknown. No specific symptoms suggest lymphocytic gastritis. A subgroup of patients has thickened folds noted on endoscopy. These folds are often capped by small nodules that contain a central depression or erosion; this form of the disease is called varioliform gastritis. H. pylori probably plays no significant role in lymphocytic gastritis. Therapy with glucocorticoids or sodium cromoglycate has obtained unclear results.

Marked eosinophilic infiltration involving any layer of the stomach (mucosa, muscularis propria, and serosa) is characteristic of eosinophilic gastritis. Affected individuals will often have circulating eosinophilia with clinical manifestation of systemic allergy. Involvement may range from isolated gastric disease to diffuse eosinophilic gastroenteritis. Antral involvement predominates, with prominent edematous folds being observed on endoscopy. These prominent antral folds can lead to outlet obstruction. Patients can present with epigastric discomfort, nausea, and vomiting. Treatment with glucocorticoids has been successful.

Several systemic disorders may be associated with granulomatous gastritis. Gastric involvement has been observed in Crohn's disease. Involvement may range from granulomatous infiltrates noted only on gastric biopsies to frank ulceration and stricture formation. Gastric Crohn's disease usually occurs in the presence of small-intestinal disease. Several rare infectious processes can lead to granulomatous gastritis, including histoplasmosis, candidiasis, syphilis, and tuberculosis. Other unusual causes of this form of gastritis include sarcoidosis, idiopathic granulomatous gastritis, and eosinophilic granulomas involving the stomach. Establishing the specific etiologic agent in this form of gastritis can be difficult, at times requiring repeat endoscopy with biopsy and cytology. Occasionally, a surgically obtained full-thickness biopsy of the stomach may be required to exclude malignancy.

Treatment of the ulcer diseases.

Before the discovery of H. pylori, the therapy of PUD disease was centered on the old dictum by Schwartz of "no acid, no ulcer." Although acid secretion is still important in the pathogenesis of PUD, eradication of H. pylori and therapy/prevention of NSAID-induced disease is the mainstay. A summary ommonly used drugs for treatment of acid peptic disorders is shown in of c Table 1.

Table 1. Drugs Used in the Treatment of Peptic Ulcer Disease

Drug Type/Mechanism	Examples	Dose
Acid-suppressing drugs
Antacids	Mylanta, Maalox, Tums, Gaviscon	100-140 meq/L 1 and 3 h after meals and hs
H2 receptor antagonists	Cimetidine Ranitidine Famotidine Nizatidine	800 mg hs 300 mg hs 40 mg hs 300 mg hs
Proton pump inhibitors	Omeprazole Lansoprazole Rabeprazole Pantoprazole	20 mg/d 30 mg/d 20 mg/d 40 mg/d
Mucosal protective agents
Sucralfate	Sucralfate	1 g qid
Prostaglandin analogue	Misoprostol	200 mg qid
Bismuth-containing compounds	Bismuth subsalicylate (BSS)	anti-H. Pylori regimens

Acid Neutralizing/Inhibitory Drugs

Antacids Before we understood the important role of histamine in stimulating parietal cell activity, neutralization of secreted acid with antacids constituted the main form of therapy for peptic ulcers. They are now rarely, if ever, used as the primary therapeutic agent but instead are often used by patients for symptomatic relief of dyspepsia. The most commonly used agents are mixtures of aluminum hydroxide and magnesium hydroxide. Aluminum hydroxide can produce constipation and phosphate depletion; magnesium hydroxide may cause loose stools. Many of the commonly used antacids (e.g., Maalox, Mylanta) have a combination of both aluminum and magnesium hydroxide in order to avoid these side effects. The magnesium-containing preparation should not be used in chronic renal failure patients because of possible hypermagnesemia, and aluminum may cause chronic neurotoxicity in these patients.

Calcium carbonate and sodium bicarbonate are potent antacids with varying levels of potential problems. The long-term use of calcium carbonate (converts to calcium chloride in the stomach) can lead to milk-alkali syndrome (hypercalcemia, hyperphosphatemia with possible renal calcinosis and progression to renal insufficiency). Sodium bicarbonate may induce systemic alkalosis.

H2 Receptor antagonists Four of these agents are presently available (cimetidine, ranitidine, famotidine, and nizatidine), and their structures share homology with histamine. Although each has different potency, all will significantly inhibit basal and stimulated acid secretion to comparable levels when used at therapeutic doses. Moreover, similar ulcer-healing rates are achieved with each drug when used at the correct dosage. Presently, this class of drug is often used for treatment of active ulcers (4 to 6 weeks) in combination with antibiotics directed at eradicating H. pylori.

Cimetidine was the first H2 receptor antagonist used for the treatment of acid peptic disorders. The initial recommended dosing profile for cimetidine was 300 mg four times per day. Subsequent studies have documented the efficacy of using 800 mg at bedtime for treatment of active ulcer, with healing rates approaching 80% at 4 weeks. Cimetidine may have weak antiandrogenic side effects resulting in reversible gynecomastia and impotence, primarily in patients receiving high doses for prolonged periods of time (months to years, as in ZES). In view of cimetidine's ability to inhibit cytochrome P450, careful monitoring of drugs such as warfarin, phenytoin, and theophylline is indicated with long-term usage. Other rare reversible adverse effects reported with cimetidine include confusion and elevated levels of serum aminotransferases, creatinine, and serum prolactin. Ranitidine, famotidine, and nizatidine are more potent H2 receptor antagonists than cimetidine. Each can be used once a day at bedtime. Comparable nighttime dosing regimens are ranitidine, 300 mg, famotidine, 40 mg, and nizatidine, 300 mg.

Additional rare, reversible systemic toxicities reported with H2 receptor antagonists include pancytopenia, neutropenia, anemia, and thrombocytopenia, with a prevalence rate varying from 0.01 to 0.2%. Cimetidine and rantidine (to a lesser extent) can bind to hepatic cytochrome P450, whereas the newer agents, famotidine and nizatidine, do not.

Proton pump (H+,K+-ATPase) inhibitors Omeprazole, lansoprazole, and the newest additions, rabeprazole and pantoprazole, are substituted benzimidazole derivatives that covalently bind and irreversibly inhibit H+,K+-ATPase. These are the most potent acid inhibitory agents available. Omeprazole and lansoprazole are the proton pump inhibitors (PPIs) that have been used for the longest time. Both are acid labile and are administered as enteric-coated granules in a sustained-release capsule that dissolves within the small intestine at a pH of 6. These agents are lipophilic compounds; upon entering the parietal cell, they are protonated and trapped within the acid environment of the tubulovesicular and canalicular system. These agents potently inhibit all phases of gastric acid secretion. Onset of action is rapid, with a maximum acid inhibitory effect between 2 and 6 h after administration and duration of inhibition lasting up to 72 to 96 h. With repeated daily dosing, progressive acid inhibitory effects are observed, with basal and secretagogue-stimulated acid production being inhibited by >95% after 1 week of therapy. The half-life of PPIs is approximately 18 h, thus it can take between 2 and 5 days for gastric acid secretion to return to normal levels once these drugs have been discontinued. Because the pumps need to be activated for these agents to be effective, their efficacy is maximized if they are administered before a meal (e.g., in the morning before breakfast). Standard dosing for omeprazole and lansoprazole is 20 mg and 30 mg once per day, respectively. Mild to moderate hypergastrinemia has been observed in patients taking these drugs. Carcinoid tumors developed in some animals given the drugs preclinically; however, extensive experience has failed to demonstrate gastric carcinoid tumor development in humans. Serum gastrin levels return to normal levels within 1 to 2 weeks after drug cessation. As with any agent that leads to significant hypochlorhydria, PPIs may interfere with absorption of drugs such as ketoconazole, ampicillin, iron, and digoxin. Hepatic cytochrome P450 can be inhibited by these agents, but the overall clinical significance of this observation is not definitely established. Caution should be taken when using warfarin, diazepam, and phenytoin concomitantly with PPIs.

Cytoprotective Agents: Sucralfate Sucralfate is a complex sucrose salt in which the hydroxyl groups have been substituted by aluminum hydroxide and sulfate. This compound is insoluble in water and becomes a viscous paste within the stomach and duodenum, binding primarily to sites of active ulceration. Sucralfate may act by several mechanisms. In the gastric environment, aluminum hydroxide dissociates, leaving the polar sulfate anion, which can bind to positively charged tissue proteins found within the ulcer bed, and providing a physicochemical barrier impeding further tissue injury by acid and pepsin. Sucralfate may also induce a trophic effect by binding growth factors such as EGF, enhance prostaglandin synthesis, stimulate mucous and bicarbonate secretion, and enhance mucosal defense and repair. Toxicity from this drug is rare, with constipation being the most common one reported (2 to 3%). It should be avoided in patients with chronic renal insufficiency to prevent aluminum-induced neurotoxicity. Hypophosphatemia and gastric bezoar formation have also been rarely reported. Standard dosing of sucralfate is 1 g four times per day.

Bismuth-containing preparations Sir William Osler considered bismuth-containing compounds the drug of choice for treating PUD. The resurgence in the use of these agents is due to their effect against H. pylori. Colloidal bismuth subcitrate (CBS) and bismuth subsalicylate (BSS, Pepto-Bismol) are the most widely used preparations. The mechanism by which these agents induce ulcer healing is unclear. Potential mechanisms include ulcer coating; prevention of further pepsin/HCl-induced damage; binding of pepsin; and stimulation of prostaglandins, bicarbonate, and mucous secretion. Adverse effects with short-term usage are rare with bismuth compounds. Long-term usage with high doses, especially with the avidly absorbed CBS, may lead to neurotoxicity. These compounds are commonly used as one of the agents in an anti-H. pylori regimen.

Prostaglandin analogues In view of their central role in maintaining mucosal integrity and repair, stable prostaglandin analogues were developed for the treatment of PUD. The prostaglandin E1 derivative misoprostal is the only agent of this class approved by the U.S. Food and Drug Administration for clinical use in the prevention of NSAID-induced gastroduodenal mucosal injury.

The mechanism by which this rapidly absorbed drug provides its therapeutic effect is through enhancement of mucosal defense and repair. Prostaglandin analogues enhance mucous bicarbonate secretion, stimulate mucosal blood flow, and decrease mucosal cell turnover. The most common toxicity noted with this drug is diarrhea (10 to 30% incidence). Other major toxicities include uterine bleeding and contractions; misoprostal is contraindicated in women who may be pregnant, and women of childbearing age must be made clearly aware of this potential drug toxicity. The standard therapeutic dose is 200 ug four times per day.

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