Topic : DISEASES OF THE STOMACH

Anatomy of stomach
The stomach is J-shaped, baglike organ that expands to store food . Typical of that of the entire digestive tract,
the wall of the stomach contains four layers. However, the inner layer, the mucosa, is modified for the specialized
functions of the stomach. In particular, the innermost layer of the mucosa (facing the lumen) contains a layer of
simple columnar epithelium consisting of goblet cells. Gastric pits on the surface penetrate deep into the layer,
forming ducts whose walls are lined with various gastric glands. A summary of the glands in the mucosa follows: 
  Mucous surface cells are the goblet cells that make up the surface layer of the simple columnar
epithelium. These cells secrete mucus, which protects the mucosa from the action of acid and digestive
enzymes.
 Mucous neck cells line the upper walls (“necks”) of the ducts. Like the mucous surface cells, they
secrete mucus.
 Parietal (oxyntic) cells are scattered along the neck and lower walls of the ducts. They secrete
hydrochloric acid (HC) and intrinsic factor. Intrinsic factor is necessary for the absorption of Vitamin B12
in the small intestine.
 Chief (zymogenic) cells also line the lower walls of the ducts. They secrete pepsinogen, the inactive
form of pepsin. Pepsin is a protease, an enzyme that breaks down proteins.
 Enteroendocrine cells secrete various hormones that diffuse into nearby blood vessels. One important
hormone, gastrin, stimulates other glands in the stomach to increase their output.
The first four glands listed in the preceding list are exocrine glands, whose secretions, collectively called gastric
juice, enter the stomach and mix with food. The last gland is an endocrine gland, whose hormone secretions
enter the blood supply.

The stomach is divided into 4 sections, each of which has different cells and functions. The sections are:

Cardia Where the contents of the esophagus empty into the stomach.

Fundus Formed by the upper curvature of the organ.

Body or
The main, central region.
Corpus

The lower section of the organ that facilitates emptying the contents into the small
Pylorus
intestine

Blood supply

Chematic image of the blood supply to the stomach: left and right gastric artery, left and right gastro-omental
artery andshort gastric artery.

The lesser curvature of the stomach is supplied by the right gastric artery inferiorly, and the left gastric
artery superiorly, which also supplies the cardiac region. The greater curvature is supplied by the right
gastroepiploic artery inferiorly and the left gastroepiploic artery superiorly. The fundus of the stomach,
and also the upper portion of the greater curvature, are supplied by the short gastric artery.
Like the other parts of the gastrointestinal tract, the stomach walls are made of the following layers,
from inside to outside:

The first main layer. This consists of an epithelium, the lamina propria composed of

mucosa loose connective tissue and which has gastric glands in it underneath, and a thin layer
of smooth muscle called the muscularis mucosae.

This layer lies over the mucosa and consists of fibrous connective tissue, separating
submucosa
the mucosa from the next layer. TheMeissner's plexus is in this layer.

Over the submucosa, the muscularis externa in the stomach differs from that of other
GI organs in that it has three layers ofsmooth muscle instead of two.

 inner oblique layer: This layer is responsible for creating the motion that churns
and physically breaks down the food. It is the only layer of the three which is not
seen in other parts of the digestive system. The antrum has thicker skin cells in its
muscularis
walls and performs more forceful contractions than the fundus.
externa
 middle circular layer: At this layer, the pylorus is surrounded by a thick circular
muscular wall which is normally tonically constricted forming a functional (if not
anatomically discrete) pyloric sphincter, which controls the movement of chyme into
theduodenum. This layer is concentric to the longitudinal axis of the stomach.
 outer longitudinal layer: Auerbach's plexus is found between this layer and the
middle circular layer.
This layer is over the muscularis externa, consisting of layers of connective tissue
serosa
continuous with the peritoneum.

The stomach serves a variety of functions:

 Storage. Because of its accordionlike folds (called rugae), the wall of the stomach can expand to store
two to four liters of material. Temporary storage is important because you eat considerably faster than
you can digest food and absorb its nutrients.
 Mixing. The stomach mixes the food with water and gastric juice to produce a creamy medium called
chyme.
 Physical breakdown. Three layers of smooth muscles (rather than the usual two) in the muscularis
externa churn the contents of the stomach, physically breaking food down into smaller particles. In
addition, HCl denatures (or unfolds) proteins and loosens the cementing substances between cells (of the
food). The HCl also kills most bacteria that may accompany the food.
 Chemical breakdown. Proteins are chemically broken down by the enzyme pepsin. Chief cells, as well
as other stomach cells, are protected from self-digestion because chief cells produce and secrete an
inactive form of pepsin, pepsinogen. Pepsinogen is converted to pepsin by the HCl produced by the
parietal cells. Only after pepsinogen is secreted into the stomach cavity can protein digestion begin. Once
protein digestion begins, the stomach is protected by the layer of mucus secreted by the mucous cells.
 Controlled release. Movement of chyme into the small intestine is regulated by a valve at the end of the
stomach, the pyloric sphincter.
DISEASES OF THE STOMACH.

1.) PEPTIC ULCER

Peptic ulcer disease (PUD) is a common disorder that affects millions of individuals in the United
States each year. PUD has a major impact on our health care system by accounting for roughly 10%
of medical costs for digestive diseases. In the last two decades, major advances have been made in
the understanding of the pathophysiology of PUD, particularly regarding the role ofHelicobacter pylori
infection and nonsteroidal anti-inflammatory drugs (NSAIDs). This has led to important changes in
diagnostic and treatment strategies, with the potential for improving the clinical outcome and for
decreasing health care costs.

Classification

 Stomach (called gastric ulcer)
 Duodenum (called duodenal ulcer)
 Esophagus (called Esophageal ulcer)
 Meckel's Diverticulum (called Meckel's Diverticulum ulcer)

Types of peptic ulcers:

 Type I: Ulcer along the lesser curve of stomach

 Type II: Two ulcers present - one gastric, one duodenal
 Type III: Prepyloric ulcer
 Type IV: Proximal gastroesophageal ulcer
 Type V: Anywhere

Pathophysiology

Peptic ulcers are defects in the gastric or duodenal mucosa that extend through the muscularis
mucosa. H pylori infection and NSAID use are the most common etiologic factors. Other, less
common causes are hypersecretory states, such as Zollinger-Ellison syndrome, G-cell hyperplasia,
mastocytosis, and basophilic leukemias.

Under normal conditions, a physiologic balance exists between peptic acid secretion and
gastroduodenal mucosal defense. Mucosal injury and, thus, peptic ulcer occur when the balance
between the aggressive factors and the defensive mechanisms is disrupted. Aggressive factors, such
as NSAIDs, H pylori, alcohol, bile salts, acid, and pepsin, can alter the mucosal defense by allowing
back diffusion of hydrogen ions and subsequent epithelial cell injury. The defensive mechanisms
include tight intercellular junctions, mucus, mucosal blood flow, cellular restitution, and epithelial
renewal.

Histologic Findings
Gastritis lymphonodular hyperplasia is a characteristic finding of endoscopic biopsies in children
infected with H pylori. Lymphonodular hyperplasia alone has been shown to be highly predictive of H
pylori infection and seems to resolve with eradication of the infection. Antral nodularity, however,
depends more on inflammation than on the presence of lymphoid follicles. Histologically, the antral
mucosa may demonstrate a severe chronic inflammatory infiltrate. The combination of chronic antral
inflammation and lymphonodular hyperplasia provides further evidence of H pylori infection.

Clinical manifestation

History

 Epigastric pain (the most common symptom)

o Gnawing or burning sensation
o Occurs 2-3 hours after meals
o Relieved by food or antacids
o Patient awakens with pain at night.
o May radiate to the back (consider penetration)
 Nausea
 Vomiting, which might be related to partial or complete gastric outlet obstruction
 Dyspepsia, including belching, bloating, distention, and fatty food intolerance
 Heartburn
 Chest discomfort
 Anorexia, weight loss
 Hematemesis or melena resulting from gastrointestinal bleeding
 Dyspeptic symptoms that might suggest PUD are not specific because only 20-25% of
patients with symptoms suggestive of peptic ulceration are found on investigation to have a
peptic ulcer.

Physical

 In uncomplicated PUD, clinical findings are few and nonspecific.

o Epigastric tenderness
o Guaiac-positive stool resulting from occult blood loss
o Melena resulting from acute or subacute gastrointestinal bleeding
o Succussion splash resulting from partial or complete gastric outlet obstruction

 A history of heartburn, gastroesophageal reflux disease (GERD) and use of certain forms of

medication can raise the suspicion for peptic ulcer. Medicines associated with peptic ulcer
include NSAID (non-steroid anti-inflammatory drugs) that inhibit cyclooxygenase, and
most glucocorticoids (e.g. dexamethasone and prednisolone).

 In patients over 45 with more than two weeks of the above symptoms, the odds for peptic
ulceration are high enough to warrant rapid investigation by EGD

 The timing of the symptoms in relation to the meal may differentiate

between gastric and duodenal ulcers: A gastric ulcer would give epigastric pain during the
meal, as gastric acid is secreted, or after the meal, as the alkaline duodenal contents reflux
into the stomach. Symptoms of duodenal ulcers would manifest mostly before the meal—
when acid (production stimulated by hunger) is passed into the duodenum. However, this is
not a reliable sign in clinical practice.
  Also, the symptoms of peptic ulcers may vary with the location of the ulcer and the patient's
age. Furthermore, typical ulcers tend to heal and recur and as a result the pain may occur for
few days and weeks and then wane or disappear.  Usually, children and the elderly do not
develop any symptoms unless complications have arisen.

 Burning or gnawing feeling in the stomach area lasting between 30 minutes and 3 hours
commonly accompanies ulcers. This pain can be misinterpreted as hunger, indigestion or
heartburn. Pain is usually caused by the ulcer but it may be aggravated by the stomach
acid when it comes into contact with the ulcerated area. The pain caused by peptic ulcers can
be felt anywhere from the navel up to the breastbone, it may last from few minutes to several
hours and it may be worse when the stomach is empty. Also, sometimes the pain may flare at
night and it can commonly be temporarily relived by eating foods that buffer stomach acid or
by taking anti-acid medication.  However, peptic ulcer disease symptoms may be different for
every sufferer.

Causes

   H pylori infection
o H pylori infection and NSAID use account for most cases of PUD.
o The rate of H pylori infection for duodenal ulcers in the United States is less than 75%
for patients who do not use NSAIDs. Excluding patients who use NSAIDs, 61% of
duodenal ulcers and 63% ofgastric ulcers are positive for H pylori in one study. This
rate also depends on the demographic, which appears to be less frequent in whites
as compared to nonwhites.
o Prevalence in complicated ulcers (ie, bleeding, perforation) is significantly lower than
that found in uncomplicated ulcer disease.
 Nonsteroidal anti-inflammatory drugs
o Similar to H pylori infection, NSAID use is a common cause for PUD.
o Corticosteroids alone do not increase the risk for PUD; however, they can potentiate
the ulcer risk in patients who use NSAIDs concurrently.
 Severe physiologic stress
o Burns
o CNS trauma
o Surgery
o Severe medical illness
 Hypersecretory states (uncommon)
o Gastrinoma (Zollinger-Ellison syndrome) or multiple endocrine neoplasia (MEN-I)
o Antral G cell hyperplasia
o Systemic mastocytosis
o Basophilic leukemias
 Diseases associated with an increased risk of PUD include cirrhosis, chronic obstructive
pulmonary disease, renal failure, and organ transplantation.
 Additional rare, miscellaneous causes include radiation-induced or chemotherapy-induced
ulcers, vascular insufficiency (crack cocaine), and duodenal obstruction.

Risk Factors:
 Heredity
 Older age
 Chronic pain, from any cause such as arthritis, fibromyalgia, repetitive stress injuries (like
carpal tunnel syndrome), or persistent back pain, causing long-term use of aspirin or NSAIDs
 Alcohol abuse
 Diabetes may increase your risk of having H. pylori
 Lifestyle factors, including chronic stress, coffee drinking (even decaf), and smoking, may
make you more susceptible to damage from NSAIDs or H. pylori if you are a carrier of this
organism. But these factors do not cause an ulcer on their own.

Methods of investigation

Laboratory Studies

 In most patients with uncomplicated PUD, routine laboratory tests usually are not helpful.
Documentation of PUD depends on radiographic and endoscopic confirmation.
 If the diagnosis of PUD is unclear or complicated and PUD is suspected, obtaining CBC, liver
function tests (LFTs), amylase, and lipase might be useful.

Imaging Studies

 Upper gastrointestinal series

o Double-contrast radiography performed by an experienced radiologist might approach

the diagnostic accuracy of upper GI endoscopy. However, it has been replaced
largely by diagnostic endoscopy, when available.
o It is not as sensitive as endoscopy for establishing a diagnosis of small ulcers (<0.5
cm).
o It also does not allow for obtaining a biopsy to rule out malignancy in the setting of a
gastric ulcer or to assess for H pylori infection in the setting of a gastroduodenal
ulcer.

Other Tests

 Detection of H pylori infection is essential in all patients with peptic ulcers.

 Endoscopic or invasive tests include a rapid urease test, histopathology, and culture.
o Rapid urease tests are considered the endoscopic diagnostic test of choice. The
presence of H pyloriin gastric mucosal biopsy specimens is detected by testing for the
bacterial product urease. Three kits (ie, CLO test, Hp-fast, Pyloritek) are commercially
available, each containing a combination of a urea substrate and a pH sensitive
indicator. One or more gastric biopsy specimens are placed in the rapid urease test
kit. If H pylori is present, bacterial urease converts urea to ammonia, which changes
pH and produces a color change.
 o Obtain histopathology, often considered the criterion standard to establish a
diagnosis of H pyloriinfection , if the rapid urease test result is negative and a high
suspicion for H pylori persists (presence of a duodenal ulcer).
o Culture primarily is used in research studies and is not available routinely for clinical
use.
 Non endoscopic or non invasive tests include serum H pylori antibody detection, fecal antigen
tests, and urea breath tests.
o Antibodies (immunoglobulin G [IgG]) to H pylori can be measured in serum, plasma,
or whole blood. Results with whole blood tests obtained from finger sticks are less
reliable.
o Urea breath tests detect active H pylori infection by testing for the enzymatic activity
of bacterial urease. In the presence of urease produced by H pylori, labeled carbon
dioxide (heavy isotope, carbon-13, or radioactive isotope, carbon-14) is produced in
the stomach, absorbed into the bloodstream, diffused into the lungs, and exhaled.
o Fecal antigen testing identifies active H pylori infection by detecting the presence
of H pylori antigens in stools. This test is more accurate than antibody testing and is
less expensive than urea breath tests.
o
 Special studies
o A fasting serum gastrin level should be obtained in certain cases to screen
for Zollinger-Ellison syndrome. Such cases include the following: patients with
multiple ulcers; ulcers occurring distal to the duodenal bulb; strong family history of
PUD; peptic ulcer associated with diarrhea, steatorrhea, or weight loss; peptic ulcer
not associated with H pylori infection or NSAID use; peptic ulcer associated with
hypercalcemia or renal stones; ulcer refractory to medical therapy; and ulcer recurs
after surgery.
o A secretin stimulation test may be used if the diagnosis of Zollinger-Ellison syndrome
cannot be made with the gastrin level alone. This test can distinguish Zollinger-Ellison
syndrome from other conditions with a high serum gastrin level, such as antisecretory
therapy with a proton pump inhibitor, renal failure, or gastric outlet obstruction.
o Measurement of acid secretion is not useful in the routine evaluation of PUD.

Procedures

 Upper GI endoscopy

o Preferred diagnostic test in the evaluation of patients with suspected PUD

o Highly sensitive for the diagnosis of gastric and duodenal ulcers
o Allows for biopsies and cytologic brushings in the setting of a gastric ulcer to
differentiate a benign ulcer from a malignant lesion
o Allows for detection of H pylori infection with antral biopsies for a rapid urease test
and/or histopathology in patients with PUD
Differential diagnosis

Biliary Colic Mesenteric Artery Ischemia

Cholecystitis Pancreatic Cancer
Cholelithiasis Pancreatitis, Acute
Gastritis, Acute Pancreatitis, Chronic
Gastritis, Chronic
Gastroesophageal Reflux Disease

Treatment

Medical Care

 Given the current understanding of the pathogenesis of PUD, most patients with PUD are
treated successfully with cure ofH pylori infection and/or avoidance of NSAIDs, along with the
appropriate use of antisecretory therapy.
 A number of treatment options exist for patients presenting with symptoms suggestive of PUD
or ulcerlike dyspepsia, including empiric antisecretory therapy, empiric triple therapy for H
pylori infection, endoscopy followed by appropriate therapy based on findings, and H
pylori serology followed by triple therapy for patients who are infected. Breath testing for
active H pylori infection may be used.
 Computer models have suggested that obtaining H pylori serology followed by triple therapy
for patients who are infected is the most cost-effective approach; however, no direct evidence
from clinical trials provides confirmation.
 Perform endoscopy early in patients older than 45-50 years and in patients with associated
so-called alarm symptoms, such as dysphagia, recurrent vomiting, weight loss, or bleeding.

Surgical Care
With the success of medical therapy, surgery has a very limited role in the management of PUD.

 Potential indications for surgery include refractory disease. Complications of PUD include the
following:
o Refractory, symptomatic peptic ulcers, though rare with the cure of H pylori infection
and the appropriate use of antisecretory therapy, are a potential complication of PUD.
o Perforation usually is managed emergently with surgical repair. However, this is not
mandatory for all patients.
o Obstruction can complicate PUD, particularly if PUD is refractory to aggressive
antisecretory therapy, H pylori eradication, or avoidance of NSAIDs. Obstruction may
persist or recur despite endoscopic balloon dilation.
o Penetration, particularly if not walled off or if a gastrocolic fistula develops, is a
potential complication of PUD.
o Bleeding can complicate PUD, particularly in patients with massive hemorrhage and
hemodynamic instability, recurrent bleeding on medical therapy, and failure of
therapeutic endoscopy to control bleeding.
 The appropriate surgical procedure depends on the location and nature of the ulcer.
o Many authorities recommend simple over sewing of the ulcer with treatment of the
underlying H pylori infection or cessation of NSAIDs for bleeding PUD.
 o Additional surgical options for refractory or complicated PUD include vagotomy and
pyloroplasty, vagotomy and antrectomy with gastroduodenal reconstruction (Billroth I)
or gastrojejunal reconstruction (Billroth II), or a highly selective vagotomy.

Consultations
Consult a general surgeon if the clinical presentation suggests a complicated peptic ulcer.

Diet
No special diet is required.

Medication

Treat all patients with peptic ulcers and associated H pylori infection with proton pump inhibitor (PPI)-
based triple therapy, which results in a cure rate of infection and healing in approximately 85-90% of
cases. Ulcers can relapse in the absence of successful H pylori eradication.

Dual therapies, which are alternative regimens for treating H pylori infection, are usually not
recommended as first-line therapy because of a variable cure rate that is significantly less than the
cure rate achieved with triple therapy.

Active ulcers associated with NSAID use are treated with an appropriate course of PPI therapy and
the cessation of NSAIDs. For patients with a known history of ulcer, and in whom NSAID use is
unavoidable, the lowest possible dose and duration of the NSAID and co-therapy with a PPI or
misoprostol are recommended.

PPI-based triple therapies for H pylori are considered the first-line therapies for the treatment of H
pylori in the United States with a cure rate of 85-90%. These regimens consist of a PPI, amoxicillin,
and clarithromycin for 7-14 days. A longer duration of treatment (14 d vs 7 d) appears to be more
affective and is currently the recommended duration of treatment. Amoxicillin should only be
substituted by metronidazole in penicillin-allergic patients because of the high rate of metronidazole
resistance.

In the setting of active ulcers caused by H pylori, treatment with a PPI beyond the 14-day course of
antibiotics and until the confirmation for the eradication of H pylori is recommended for complicated
ulcers.

PPI-based triple therapies consist of a 14-day treatment of the following:

Omeprazole (Prilosec): 20 mg PO bid or

Lansoprazole (Prevacid): 30 mg PO bid or

Rabeprazole (Aciphex): 20 mg PO bid or

Esomeprazole (Nexium): 40 mg PO qd

Plus:

Clarithromycin (Biaxin): 500 mg PO bid and

Amoxicillin (Amoxil): 1 g PO bid

The alternative combination therapy consists of the following treatments administered for 14 days:

Omeprazole (Prilosec): 20 mg PO bid or

Lansoprazole (Prevacid): 30 mg PO bid or

Rabeprazole (Aciphex): 20 mg PO bid or

Esomeprazole (Nexium): 40 mg PO qd

Plus:

Clarithromycin (Biaxin): 500 mg PO bid and

Metronidazole (Flagyl): 500 mg PO bid

Quadruple therapies for H pylori infection are generally reserved for patients who have failed a course
of treatment and are administered for 14 days. The treatment includes the following drugs:

PPI PO bid and

Bismuth 525 mg PO qid and

Metronidazole 500 mg PO qid and

Tetracycline 500 mg PO qid

Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the
context of the clinical setting.

Amoxicillin (Amoxil, Biomox, Trimox)

Metronidazole

Tetracycline

Clarithromycin

Tetracycline

Proton pump inhibitors (PPIs)

Lansoprazole

Esomeprazole

Omeprazole

H2-receptor blockers
Cimetidine

Ranitidine

Famotidine
Nizatidine

Further Outpatient Care

 Endoscopy is required to document healing of gastric ulcers and to rule out gastric cancer.
This usually is performed 6-8 weeks after the initial diagnosis of PUD.
 Documentation of H pylori cure with a noninvasive test, such as the urea breath test or fecal
antigen test, is appropriate in patients with complicated ulcers.

Inpatient & Outpatient Medications

 Consider maintenance therapy with half standard doses of H2-receptor antagonists at

bedtime in patients with recurrent, refractory, or complicated ulcers, particularly if cure of H
pylori has not been documented or if an H pylori -negative ulcer is present.

Deterrence/Prevention

 Primary prevention of NSAID-induced ulcers includes the following:

o Avoid unnecessary use of NSAIDs.
o Use acetaminophen or nonacetylated salicylates when possible.
o Use the lowest effective dose of an NSAID and switch to less toxic NSAIDs, such as
the newer NSAIDs or cyclooxygenase-2 (COX-2) inhibitors, in high-risk patients
without cardiovascular disease.
 Consider prophylactic or preventive therapy for the following patients:
o Patients with NSAID-induced ulcers who require chronic, daily NSAID therapy
o Patients older than 60 years
o Patients with a history of PUD or a complication such as gastrointestinal bleeding
o Patients taking concomitant steroids or anticoagulants or patients with significant
comorbid medical illnesses
 Prophylactic regimens that have been shown to dramatically reduce (prevent) the risk of
NSAID-induced gastric and duodenal ulcers include the use of a prostaglandin analogue or a
PPI.
o Misoprostol 100-200 mcg PO 4 times per day
o Omeprazole 20-40 mg PO every day
o Lansoprazole 15-30 mg PO every day

Complications

 Perforation
 Penetration
 Obstruction
 Bleeding

Prognosis

 When the underlying cause is addressed, the prognosis is excellent. Most patients
are treated successfully with the cure of H pylori infection, avoidance of NSAIDs, and
the appropriate use of antisecretory therapy.
  Cure of H pylori infection changes the natural history of the disease, with a decrease
in the ulcer recurrence rate from 60-90% to approximately 10-20%. However, this is a
higher recurrence rate than previously reported, suggesting an increased number of
ulcers not caused by H pylori infection.

Patient Education

 Stop smoking.
 Avoid NSAID and aspirin use.
 Avoid heavy alcohol use.
 Stress reduction counseling might be helpful in individual cases but is not needed routinely

2.) ZOLLINGER-ELLISON SYNDROME (ZES)

Zollinger-Ellison syndrome (ZES) is caused by a non–beta islet cell, gastrin-secreting tumor of the
pancreas that stimulates the acid-secreting cells of the stomach to maximal activity, with consequent
gastrointestinal mucosal ulceration. ZES may occur sporadically or as part of an autosomal dominant
familial syndrome called multiple endocrine neoplasia type 1 (MEN 1). The primary tumor is usually
located in the duodenum, the pancreas, and abdominal lymph nodes, but ectopic locations have also
been described (eg, heart, ovary, gall bladder, liver, kidney).

Pathophysiology
The symptoms of ZES are secondary to hypergastrinemia, which causes hypertrophy of the gastric
mucosa, leading to increased numbers of parietal cells and increased maximal acid output. Gastrin by
itself also stimulates acid secretion, resulting in increased basal acid secretion. The large quantity of
acid produced leads to gastrointestinal mucosal ulceration. It also leads to diarrhea and
malabsorption. Malabsorption in ZES usually is multifactorial, being caused by direct mucosal damage
by acid, inactivation of pancreatic enzymes, and precipitation of bile salts. ZES is sporadic in 75% of
patients, while in the other 25% it is associated with MEN 1, an autosomal dominant condition
characterized by hyperparathyroidism, pancreatic endocrine tumors, and pituitary tumors.

Clinical manifestation

History
A high index of clinical awareness is needed to make a diagnosis of ZES.

 Abdominal pain is the most common symptom, present in 75% of patients. Typically, it is
located in the upper abdomen and mimics that of peptic ulcer disease. This symptom is
reported more frequently by men and patients with the sporadic form of ZES.
 Of patients with ZES, 73% have diarrhea, and this is the most common symptom in patients
who have MEN 1/ZES and in female patients.
 The combination of diarrhea and abdominal pain is present in more than half the patients.
 Heartburn is the third most common symptom, and this symptom mimics gastroesophageal
reflux disease (GERD).
  Other symptoms include nausea, vomiting, gastrointestinal bleeding, and weight loss.
Gastrointestinal bleeding frequently is due to ulceration in the duodenum and is the
presenting symptom in 25% of patients.
 In patients in whom MEN 1/ZES is suspected, a history indicative of nephrolithiasis,
hypercalcemia, and pituitary disorders should be sought. A family history of nephrolithiasis,
hyperparathyroidism, and gastrinoma also may be present.

Physical
The findings of the physical examination may be normal.

 Patients may be pale if presenting with gastrointestinal bleeding.

 Jaundice may occur if the tumor compresses the common bile duct, although this
presentation is very rare.
 Epigastric tenderness may be present.
 Dental erosions may be noted if symptoms consistent with GERD are present.
 The presence of hepatomegaly suggests liver metastasis.

Causes

 ZES is caused by a non–beta islet cell, gastrin-secreting tumor of the pancreas that
stimulates the acid-secreting cells of the stomach to maximal activity, with consequent
gastrointestinal mucosal ulceration.
 ZES may occur sporadically or as part of MEN 1.

Method of investigation

Laboratory Studies

 Fasting serum gastrin

o Fasting serum gastrin is the best single screening test.
o Preferably, patients should not be taking gastric antisecretory medications at the time
of the test, but this is not essential for the initial screen.
o Because fasting gastrin levels can fluctuate from day to day and can appear to be
normal, serial measurements on different days should be performed.
o Normal levels of serum gastrin in untreated ZES are extremely rare (<1%).
 Gastric acid secretory tests
o Basal acid output (BAO) greater than 15 mEq/h or greater than 5 mEq/h in patients
with a prior vagotomy and partial gastrectomy is suggestive of ZES.
o Basal gastric secretory volume greater than 140 mL in patients with no prior gastric
acid–reducing surgery has a high sensitivity and specificity.
o Gastric pH less than 2.0 in the presence of a large gastric volume (>140 mL over 1 h
in patients without prior gastric acid–reducing surgery) is highly suggestive of ZES.
o Currently, maximal acid output measurement rarely is performed.
 Provocative tests
o Various provocative diagnostic tests for ZES have been proposed, including the
secretin stimulation test, calcium stimulation test, secretin-plus-calcium stimulation
tests, bombesin test, and protein meal test.
o The secretin stimulation test is the provocative test of choice because of its higher
sensitivity. In this test, a 2-U/kg bolus of secretin is administered intravenously after
an overnight fast, and serum levels of gastrin are determined at 0, 2, 5, 10, and 15
minutes. An increase in serum gastrin of greater than 200 pg/mL is diagnostic.
  Elevated serum calcium levels should prompt a search for MEN 1 syndrome.
 A suggested algorithm for the evaluation of a patient with suspected gastrinoma is as follows:
o Step 1: Check gastrin level. Measure at least 3 fasting levels of gastrin on different
days.
o Step 2: Perform gastric acid secretory studies. A BAO value of greater than 15 mEq/h
or a gastric volume of greater than 140 mL and pH of less than 2.0 are highly
suggestive of gastrinoma.
o Step 3: Perform a provocative test. The secretin stimulation test is the preferred test.
o Step 4: Perform somatostatin receptor scintigraphy (SRS).
o Step 5: Perform imaging studies to stage and localize the gastrinoma.
o Step 6: Determine if patient is a surgical candidate for tumor resection.

Imaging Studies

 SRS is the most sensitive imaging modality for detection of primary or metastatic lesions in
ZES and, thus, is the imaging modality of choice in ZES.
 CT scan can be performed to localize the tumor and is useful for evaluation for metastatic
disease. However, its sensitivity for primary tumor localization is only 50%, and frequently,
tumors smaller than 1 cm are missed.
 Other imaging studies, such as magnetic resonance imaging and abdominal ultrasound, also
can be performed. However, sensitivity is lower compared to CT scan or SRS.
 Endoscopic ultrasound is one of the newer methods for localizing gastrinomas. Its sensitivity
is higher for pancreatic gastrinoma (40-75%) than for duodenal gastrinoma (50%).

Procedures

 Esophagogastroduodenoscopy should be performed to look for duodenal ulcerations and

hypertrophy of gastric folds. Sensitivity for hypertrophic gastric folds is 94%. Rarely, thickened
duodenal folds also may be present.

Treatment

Medical Care

 The goals of treatment are medical control of gastric acid hypersecretion and surgical
resection of the tumor.
o If the patient is acutely ill, immediate control of gastric acid hypersecretion can be
achieved with intravenous proton pump inhibitors. Previously, this was accomplished
with histamine 2 (H2) receptor blockers. Intravenous pantoprazole was approved
recently by the US Food and Drug Administration. Proton pump inhibitors are superior
to H2 blockers for the control of gastric acid hypersecretion.
o Patients who are candidates for surgical resection should be referred for resection of
the tumor.
o For patients with metastatic disease, chemotherapy, interferon, and octreotide may
be helpful. The response to these agents in most studies has been low. Liver
transplantation for hepatic metastasis also has been reported. For patients with a
single confined liver metastatic lesion, surgical resection may be attempted.
Surgical Care

 All patients with sporadic ZES without hepatic metastases or medical contraindications to
surgery are advised to undergo surgical resection of the tumor because this decreases the
risk of developing liver metastases, which can decrease the survival of these patients.
 The role and timing of surgical resection in patients with MEN 1 is less clear. An attempt at
surgical resection has been recommended if the tumor is larger than 2.5 cm. Cure is rarely
achieved by surgical resection in patients with MEN 1; however, it may reduce the risk of
subsequent metastatic disease.
 In a single-institution retrospective study with a median follow-up of 18 years from a diagnosis
of ZES, Mortellaro et al examined the long-term outcomes in 12 patients with MEN 1 and ZES
from 1970 to the present.1 The pancreas (n = 10), duodenum (n = 4), lymph nodes (n = 3),
and liver (n = 1) were the most commonly identified gastrinoma sites. A total of 15 celiotomies
were performed, and surgeries included 4 each of distal pancreatectomies and acid-reducing
procedures, 3 each of enucleation of pancreatic gastrinoma and duodenal resection, 1
pancreaticoduodenectomy, 7 noted as other.1 There was 1 each of a patient with transient (3
y) biochemical postsurgical cure and liver metastasis of gastrinoma (but no deaths from
metastatic gastrinoma).1 Deaths included causes such as respiratory arrest (n = 1), possibly
due to aspiration or pulmonary embolus, and nondisease related (n = 3). At last follow-up, 7
patients were alive. The investigators observed patients with MEN 1 and ZES rarely achieve
biochemical cures with surgery; however, extended surgical resection was not only not
needed in resection of localized gastrinomas, but it was also associated with excellent long-
term outcomes.1
 Because this is a rare tumor, surgical resection should be attempted only at centers with
personnel experienced in treating patients with ZES.

Consultations

 Gastroenterologist
 Surgeon
 Oncologist
 Possibly, endocrinologist

Medication

 Proton pump-inhibitor

- Omeprazole
- Lansoprazole
- Pantoprazole
- Esomeprazole

Further Inpatient Care

 Inpatient care is aimed at first controlling the gastric acid hypersecretion.

 Once gastric acid hypersecretion is controlled, imaging studies should be obtained to localize
the tumor and determine tumor extent.

Further Outpatient Care

  After surgical resection for gastrinoma, patients should be assessed for evidence of
recurrence with serum fasting gastrin levels, a secretin test, and SRS. The first evaluation
should be performed at 3-6 months postresection and then, optimally, yearly thereafter.
 Proton pump inhibitors can be continued with the goal of maintaining the BAO at less than 10
mEq/h before the next dose of the proton pump inhibitors.

Complications

 Abdominal perforation secondary to ulceration (Duodenum and jejunum are the most
common sites.)
 Esophageal stricture, with reflux
 Obstruction
 Gastrointestinal bleeding
 Gastric carcinoids (especially in patients with MEN 1)

Prognosis

 Prognosis is excellent in patients without metastatic disease

3.) GERD

Gastroesophageal reflux disease (GERD), gastro-oesophageal reflux disease (GORD), gastric reflux

disease, or acid reflux disease is defined as chronic symptoms or mucosal damage produced by the
abnormal reflux of stomach acid to the esophagus.  A typical symptom is heartburn.

This is commonly due to transient or permanent changes in the barrier between the esophagus and
the stomach. This can be due to incompetence of the lower esophageal sphincter, transient lower
esophageal sphincter relaxation, impaired expulsion of gastric reflux from the esophagus, or a hiatal
hernia.

A different type of acid reflux which produces respiratory and laryngeal manifestations

is laryngopharyngeal reflux (LPR), also called extraesophageal reflux disease (EERD). Unlike GERD,
LPR is unlikely to produce heartburn, and is thus sometimes called silent reflux.

Signs and symptoms

Adults

The most-common symptoms of GERD are:

 Heartburn
 Regurgitation
 Trouble swallowing (dysphagia)

Less-common symptoms include:

 Pain with swallowing (odynophagia)
 Excessive salivation (this is common during heartburn, as saliva is generally slightly
alkaline[ and is the body's natural response to heartburn, acting similarly to an antacid)
 Nausea
 Chest pain

GERD sometimes causes injury of the esophagus. These injuries may include:

 Reflux esophagitis—necrosis of esophageal epithelium causing ulcers near the junction of the
stomach and esophagus.
 Esophageal strictures—the persistent narrowing of the esophagus caused by reflux-induced
inflammation.
 Barrett's esophagus—metaplasia (changes of the epithelial cells from squamous to columnar
epithelium) of the distal esophagus.
 Esophageal adenocarcinoma—a rare form of cancer.

Several other atypical symptoms are associated with GERD, but there is good evidence for causation
only when they are accompanied by esophageal injury. These symptoms are:

 Chronic cough
 Laryngitis (hoarseness, throat clearing)
 Asthma
 Erosion of dental enamel
 Dentine hypersensitivity
 Sinusitis and damaged teeth[4]

Some people have proposed that symptoms such as pharyngitis, sinusitis, recurrent ear infections,
and idiopathic pulmonary fibrosis are due to GERD; however, a causative role has not been
established.

Children

GERD may be difficult to detect in infants and children. Symptoms may vary from typical adult
symptoms. GERD in children may cause repeated vomiting, effortless spitting up,coughing, and other
respiratory problems. Inconsolable crying, failure to gain adequate weight, refusing food, bad breath,
and belching or burping are also common. Children may have one symptom or many — no single
symptom is universal in all children with GERD.

Common symptoms of Pediatric Reflux

 Irritability and pain, sometimes screaming suddenly when asleep. Constant or sudden crying
or colic-like symptoms. Babies can be inconsolable especially when laid down flat.
 Poor sleep habits typically with arching their necks and back during or after feeding
 Excessive possetting or vomiting
 Frequent burping or frequent hiccups
 Excessive dribbling or running nose
 Swallowing problems, gagging and choking
 Frequent ear infections or sinus congestion
 Babies are often very gassy and extremely difficult to “burp” after feeds
 Refusing feeds or frequent feeds for comfort
 Night time coughing, extreme cases of acid reflux can cause apnoea and respiratory
problems such as asthma, bronchitis and pneumonia if stomach contents are inhaled.
 Bad breath – smelling acidy
 Rancid/acid smelling diapers with loose stool. Bowel movements can be very frequent or
babies can be constipated.

Vomiting feeds

Possetting after a feed is quite normal with most infants. They gain weight, feed well and have no
other symptoms, but still this can be upsetting for parents. As the child gets older the lower
oesophageal sphincter becomes more competent so the vomiting should begin to show signs of
improvement and eventually stop. Some babies suffer more with reflux and about 60% of these
babies with persistent reflux may have weight gain issues. It is a very popular misconception though
that all babies and children with reflux are underweight. This isn't always the case, some may comfort
eat and feed very frequently and not all are sick. Many doctors advise that babies outgrow reflux once
they can sit up, or once they stand. Many do, but some will not only fail to outgrow it, but will
noticeably worsen with developmental milestones, teething episodes, viral illness and weaning.

Silent Reflux

Some babies with reflux do not vomit at all. This is actually more of a problem because the acidic
stomach contents go up the throat and back down again, causing twice the pain and twice the
damage. There is no clear relationship between symptoms and the severity of reflux.

It is estimated that of the approximately 4 million babies born in the U.S. each year, up to 35% of them
may have difficulties with reflux in the first few months of their life, known as spitting up Most of those
children will outgrow their reflux by their first birthday. However, a small but significant number of them
will not outgrow the condition. This is particularly true where there is a family history of GERD present.

Barrett's esophagus

GERD may lead to Barrett's esophagus, a type of metaplasia which is in turn a precursor condition for
carcinoma. The risk of progression from Barrett's to dysplasia is uncertain but is estimated at about
20% of cases. Due to the risk of chronic heartburn progressing to Barrett's, EGD every 5 years is
recommended for patients with chronic heartburn, or who take drugs for chronic GERD.

Diagnosis

Endoscopic image of peptic stricture, or narrowing of the esophagus near the junction with the stomach. This is a
complication of chronic gastroesophageal reflux disease and can be a cause of dysphagia or difficulty swallowing

A detailed historical knowledge is vital for an accurate diagnosis. Useful investigations may include
ambulatory Esophageal pH Monitoring, barium swallow X-rays, esophageal manometry,
and Esophagogastroduodenoscopy (EGD).

The current gold standard for diagnosis of GERD is esophageal pH monitoring. It is the most objective
test to diagnose the reflux disease and it also allows to monitor GERD patients in regards of their
response to medical or surgical treatment. One practice for diagnosis of GERD is a short-term
treatment with proton pump inhibitors, with improvement in symptoms suggesting a positive diagnosis.
According to a systematic review, short-term treatment with proton pump inhibitors may help predict
abnormal 24-hr pH monitoring results among patients with symptoms suggestive of GERD. In this
study, the positive likelihood ratio of a symptomatic response detecting GERD ranged from 1.63 to
1.87, with sensitivity of 0.78% though specificity was only 0.54%.

In general, an EGD is done when the patient either does not respond well to treatment or has alarm
symptoms including dysphagia, anemia, blood in the stool (detected chemically), wheezing, weight
loss, or voice changes. Some physicians advocate either once-in-a-lifetime or 5/10-yearly endoscopy
for patients with longstanding GERD, to evaluate the possible presence of dysplasia or Barrett's
esophagus, a precursor lesion foresophageal adenocarcinoma.
Esophagogastroduodenoscopy (EGD) (a form of endoscopy) involves insertion of a thin scope
through the mouth and throat into the esophagus and stomach (often while the patient is sedated) in
order to assess the internal surfaces of the esophagus, stomach, and duodenum.

Biopsies can be performed during gastroscopy and these may show:

 Edema and basal hyperplasia (non-specific inflammatory changes)

 Lymphocytic inflammation (non-specific)
 Neutrophilic inflammation (usually due to reflux or Helicobacter gastritis)
 Eosinophilic inflammation (usually due to reflux)
 Goblet cell intestinal metaplasia or Barretts esophagus
 Elongation of the papillae
 Thinning of the squamous cell layer
 Dysplasia or pre-cancer
 Carcinoma

Reflux changes may be non-erosive in nature, leading to the entity "non-erosive reflux disease".

Pathophysiology

GERD is caused by a failure of the cardia. In healthy patients, the "Angle of His"—the angle at which
the esophagus enters the stomach—creates a valve that prevents duodenal bile, enzymes, and
stomach acid from traveling back into the esophagus where they can cause burning and inflammation
of sensitive esophageal tissue.

Factors that can contribute to GERD:

 Hiatal hernia, which increases the likelihood of GERD due to mechanical and motility factors.
 Obesity: increasing body mass index is associated with more severe GERD. . In a large
series of 2000 patients with symptomatic reflux disease, it has been shown that 13 % of changes
in esophageal acid exposure is attributable to changes in body mass index.
 Zollinger-Ellison syndrome, which can be present with increased gastric acidity due
to gastrin production
 Hypercalcemia, which can increase gastrin production, leading to increased acidity
 Scleroderma and systemic sclerosis, which can feature esophageal dysmotility
 The use of medicines such as prednisolone
 Visceroptosis or Glénard syndrome, in which the stomach has sunk in the abdomen upsetting
the motility and acid secretion of the stomach.

GERD has been linked to a variety of respiratory and laryngeal complaints such as laryngitis,
chronic cough, pulmonary fibrosis, earache, and asthma, even when not clinically apparent. These
atypical manifestations of GERD is commonly referred to as laryngopharyngeal reflux or as
extraesophageal reflux disease (EERD).

Factors that have been linked with GERD but not conclusively:

 Obstructive sleep apnea

 Gallstones, which can impede the flow of bile into the Duodenum, which can affect the ability
to neutralize gastric acid

Prevention

Relief is often found by raising the head of the bed, raising the upper body with pillows, or sleeping
sitting up. Avoid pillows that raise the head only, as this does little for heartburn and places
continuous strain on the neck. Eating a big meal causes excess stomach acid production, and attacks
can be minimized by eating small frequent meals instead of large meals, especially for dinner. To
minimize attacks, a sufferer may benefit from avoiding certain foods that stimulate excess acid
secretion and/or relax the opening between the stomach and esophagus. Acidic fruit or juice, fatty
foods, pretzels, coffee, tea, onions, peppermint, chocolate, or highly spiced foods are to be avoided,
especially shortly before bedtime. While there are clearly other health-related benefits associated with
dietary interventions, a zealous recommendation for dietary restrictions is not evidence-based, and
there is stronger support for reducing the symptoms of acid reflux found in behavioral changes such
as eating less and elevating one's head while sleeping. Tight clothing around the abdomen can also
increase the risk of heartburn because it puts pressure on the stomach, which can cause the food and
acids in the stomach to reflux to the lower esophageal sphincter.

Treatment

Three types of treatments exist for GERD. These include lifestyle modifications, medications, and
surgery.

Lifestyle modifications
Diet

Certain foods and lifestyle are considered to promote gastroesophageal reflux, but a 2006 review
suggested that evidence for most dietary interventions is anecdotal; only weight loss and elevating the
head of the bed were supported by evidence.  A subsequent randomized crossover study showed
benefit by avoiding eating two hours before bedtime.
The following may exacerbate the symptoms of GERD:

 Antacids based on calcium carbonate (but not aluminum hydroxide) were found to actually

increase the acidity of the stomach. However, all antacids reduced acidity in the lower esophagus,
so the net effect on GERD symptoms may still be positive.
 Smoking reduces lower esophageal sphincter competence.

Position

Sleeping on the left side has been shown to reduce nighttime reflux episodes in patients. [

A meta-analysis suggested that elevating the head of the bed is an effective therapy, although this
conclusion was only supported by nonrandomized studies. The head of the bed can be elevated by
plastic or wooden bed risers that support bed posts or legs, a therapeutic bed wedge pillow, a wedge
or an inflatable mattress lifter that fits in between mattress and box spring or a hospital bed with an
elevate feature. The height of the elevation is critical and must be at least 6 to 8 inches (15 to 20 cm)
to be at least minimally effective to prevent the backflow of gastric fluids. Some innerspring
mattresses do not work well when inclined and may cause back pain; some prefer foam mattresses.
Some practitioners use higher degrees of incline than provided by the commonly suggested 6 to 8
inches (15 to 20 cm) and claim greater success.

Medications
A number of drugs are approved to treat GERD, and are among the most prescribed medication in
Western countries.

 Proton pump inhibitors (such as omeprazole, esomeprazole, pantoprazole, lansoprazole,

and rabeprazole) are the most effective in reducing gastric acid secretion. These drugs stop acid
secretion at the source of acid production, i.e., the proton pump.
 Gastric H2 receptor blockers (such as ranitidine, famotidine and cimetidine) can reduce gastric
secretion of acid. These drugs are technically antihistamines. They relieve complaints in about
50% of all GERD patients. Compared to placebo (which also is associated with symptom
improvement), they have a number needed to treat (NNT) of eight (8).
 Antacids before meals or symptomatically after symptoms begin can reduce gastric acidity
(increase pH).
 Alginic acid (Gaviscon) may coat the mucosa as well as increase pH and decrease reflux.
A meta-analysis of randomized controlled trials suggests alginic acid may be the most effective of
non-prescription treatments with a NNT of four.
 Prokinetics strengthen the lower esophageal sphincter (LES) and speed up gastric
emptying. Cisapride, a member of this class, was withdrawn from the market for causing long QT
syndrome. Reglan (metoclopramide) is a prokinetic with a better side-effect profile.
 Sucralfate (Carafate) is also useful as an adjunct in helping to heal and prevent esophageal
damage caused by GERD, however it must be taken several times daily and at least two (2)
hours apart from meals and medications.
 Mosapride citrate is a 5-HT4 receptor agonist used outside the United States largely as a
therapy for GERD and dyspepsia.

Clinical trials which compare GERD treatments head-to-head provide physicians with critical
information. Unfortunately most pharmaceutical-company sponsored studies are conducted versus
placebo and not an active control. However, the DIAMOND has shown rough equivalence of efficacy
between a "step-up" approach to therapy (antacids, followed by histamine antagonists, followed by
PPIs) and a "step-down" approach (the reverse). The primary endpoint of the study was treatment
success after 6 months, and was achieved for 70% of patients in "step-down" versus 72% of patients
in "step-up.”

Surgery
The standard surgical treatment is the Nissen fundoplication. In this procedure the upper part of the
stomach is wrapped around the lower esophageal sphincter (LES) to strengthen the sphincter and
prevent acid reflux and to repair a hiatal hernia. The procedure is often done laparoscopically. When
compared to medical management laparoscopic fundoplication had better results at 1 year.  In
addition, laparoscopic fundoplication may reduce SF-36 score (quality of life questionnaire) among
patients with gastro-esophageal reflux disease as compared to medical management according to a
Cochrane systematic review of randomized controlled trials.  There were statistically significant
improvements in quality of life at 3 months and 1 year after surgery compared to medical therapy, with
an SF-36 general health score mean difference of -5.23 in favor of surgery

An obsolete treatment is vagotomy ("highly selective vagotomy"), the surgical removal of vagus

nerve branches that innervate the stomach lining. This treatment has been largely replaced by
medication.

Another treatment is transoral incisionless fundoplication (TIF) with the use of a device called
Esophyx, which allows doctors to rebuild the valve between the stomach and the diaphragm by going
through the esophagus.

Other treatments.
Pregnancy

In pregnancy dietary modifications and lifestyle changes may be attempted but often have little effect.
Calcium-based antacids are recommended if these changes are not effective. Aluminum- and
magnesium antacids are also safe as is ranitidine
Gastric surgery

Ulcer Recurrence
Operation Rates, % Complication Rates
Vagotomy and antrectomy (Billroth I or 1 Highest
II)
Vagotomy and pyloroplasty 10 Intermediate
Highly selective vagotomy 10 Lowest

The procedure that provides the lowest rates of ulcer recurrence but has the highest
complication rate is vagotomy (truncal or selective) in combination with antrectomy.
Antrectomy is aimed at eliminating an additional stimulant of gastric acid secretion, gastrin.
Gastrin originates from G cells found in the antrum. Two principal types of reanastomoses
are used after antrectomy, gastroduodenostomy (Billroth I) or gastrojejunostomy (Billroth II)
(Fig. 285-11). Although Billroth I is often preferred over II, severe duodenal inflammation or
scarring may preclude its performance.

Figure 285-11: Schematic representation of Billroth I and II procedures.

Of these procedures, highly selective vagotomy may be the one of choice in the elective
setting, except in situations where ulcer recurrence rates are high (prepyloric ulcers and those
refractory to H2 therapy). Selection of vagotomy and antrectomy may be more appropriate in
these circumstances.

These procedures have been traditionally performed by standard laparotomy. The advent of
laparoscopic surgery has led several surgical teams to successfully perform highly selective
vagotomy, truncal vagotomy/pyloroplasty, and truncal vagotomy/antrectomy through this
approach. An increase in the number of laparoscopic procedures for treatment of PUD is
expected.

Specific Operations for Gastric Ulcers

The location and the presence of a concomitant DU dictate the operative procedure
performed for a GU. Antrectomy (including the ulcer) with a Billroth I anastomosis is the
treatment of choice for an antral ulcer. Vagotomy is performed only if a DU is present.
Although ulcer excision with vagotomy and drainage procedure has been proposed, the
higher incidence of ulcer recurrence makes this a less desirable approach. Ulcers located near
the esophagogastric junction may require a more radical approach, a subtotal gastrectomy
with a Roux-en-Y esophagogastrojejunostomy (Csende's procedure). A less aggressive
approach including antrectomy, intraoperative ulcer biopsy, and vagotomy (Kelling-Madlener
procedure) may be indicated in fragile patients with a high GU. Ulcer recurrence approaches
30% with this procedure.

Surgery-Related Complications

Complications seen after surgery for PUD are related primarily to the extent of the
anatomical modification performed. Minimal alteration (highly selective vagotomy) is
associated with higher rates of ulcer recurrence and less gastrointestinal disturbance. More
aggressive surgical procedures have a lower rate of ulcer recurrence but a greater incidence of
gastrointestinal dysfunction. Overall, morbidity and mortality related to these procedures are
quite low. Morbidity associated with vagotomy and antrectomy or pyloroplasty is  5%, with
mortality ~1%. Highly selective vagotomy has lower morbidity and mortality rates of 1 and
0.3%, respectively.

In addition to the potential early consequences of any intraabdominal procedure (bleeding,

infection, thromboembolism), gastroparesis, duodenal stump leak, and efferent loop
obstruction can be observed.
 4.) Chron Disease
Crohn disease is an idiopathic, chronic, transmural inflammatory process of the bowel that often leads
to fibrosis and obstructive symptoms, which can affect any part of the gastrointestinal (GI) tract from
the mouth to the anus. This condition is believed to be the result of an imbalance between
proinflammatory and anti-inflammatory mediators. Most Crohn disease cases involve the small bowel,
particularly the terminal ileum. The characteristic presentation of Crohn disease is abdominal pain and
diarrhea, which may be complicated by intestinal fistulization, obstruction, or both. Unpredictable
flares and remissions characterize the long-term course of this illness.

Pathophysiology
The exact cause of Crohn disease remains unknown. Current theories implicate the role of genetic,
microbial, immunologic, environmental, dietary, vascular, and even psychosocial factors as potential
causative agents. It has been suggested that patients have an inherited susceptibility for an aberrant
immunologic response to one or more of these provoking factors.

Microscopically, the initial lesion starts as a focal inflammatory infiltrate around the crypts, followed by
ulceration of superficial mucosa. Later, inflammatory cells invade the deep mucosal layers and, in that
process, begin to organize into noncaseating granulomas. The granulomas extend through all layers
of the intestinal wall and into the mesentery and the regional lymph nodes. Neutrophil infiltration into
the crypts forms crypt abscesses, leading to destruction of the crypt and atrophy of the colon. Chronic
damage may be seen in the form of villous blunting in the small intestine as well. Ulcerations are
common and are often seen on a background of normal mucosa. Although granuloma formation is
pathognomonic of Crohn disease, its absence does not exclude the diagnosis.

Macroscopically, the initial abnormality is hyperemia and edema of the involved mucosa. Later,
discrete superficial ulcers form over lymphoid aggregates and are seen as red spots or mucosal
depressions. These can become deep, serpiginous ulcers located transversely and longitudinally over
an inflamed mucosa, giving the mucosa a cobblestone appearance. The lesions are often segmental,
being separated by healthy areas, and are often referred to as skip lesions.

Transmural inflammation results in thickening of the bowel wall and narrowing of the lumen. As Crohn
disease progresses, it is complicated by obstruction or deep ulceration leading to fistulization by way
of the sinus tracts penetrating the serosa, microperforation, abscess formation, adhesions,
and malabsorption.

Obstruction is initially caused by significant edema of the mucosa and associated spasm of the bowel.
Obstruction is intermittent and is often reversible with conservative measures and anti-inflammatory
agents. With further disease progression, the obstruction becomes chronic because of scarring,
luminal narrowing, and stricture formation.

Fistulae may be enteroenteral, enterovesical, enterovaginal, or enterocutaneous. The inflammation

extending through the bowel wall may also involve the mesentery and surrounding lymph nodes.
Creeping fat may be seen when the mesentery wraps around the bowel surface.

Serosal inflammation causes adhesions; thus, free perforations are less common in Crohn disease as
in other inflammatory bowel conditions.

Malabsorption occurs as a result of loss of functional mucosal absorptive surface. This phenomenon
can lead to protein-calorie malnutrition, dehydration, and multiple nutrient deficiencies. Involvement of
the terminal ileum may result in malabsorption of bile acids, which leads to steatorrhea, fat-soluble
vitamin deficiency, and gallstone formation. Fat malabsorption, by trapping calcium, may result in
increased oxalate excretion (normally complexed by calcium), causing kidney stone formation. 1

Nearly 30% of patients with either large- or small bowel disease develop perianal
complications. Perianal complications may precede the development of intestinal symptoms and
manifest as anal fissures, perianal fistulae, or abscesses.

Although any area of the GI system may be affected, the most common site of Crohn disease is the
ileocecal region, followed by the colon, the small intestine alone, the stomach (rarely), and the mouth.
The esophagus is very rarely involved.

In addition to local complications, a variety of extraintestinal manifestations may be associated with

Crohn disease. The usual sites are the skin, joints, mouth, eyes, liver, and bile ducts.

Skin manifestations (eg, erythema nodosum, pyoderma gangrenosum, Sweet syndrome) and

peripheral arthritis (eg, asymmetric involvement of larger joints) are probably more common with
colitis than with enteritis. Aphthous ulcers are the most common mouth lesions. The more frequent
nutritional-deficient–cutaneous manifestation isacrodermatitis enteropathica due to zinc deficiency
manifesting as psoriatic erythema.
 
Ocular manifestations (eg, episcleritis, recurrent iritis, uveitis) are other manifestations of Crohn
disease. These manifestations often parallel the course of bowel disease and usually subside when
the disease is brought under control.

Inflammatory arthropathies are the most common extraintestinal manifestations in patients

with inflammatory bowel disease (IBD), with a prevalence between 7% and 25%. These are
seronegative autoimmune-related disorders, including ankylosing spondylitis, psoriatic arthritis,
reactive arthritis, and sacroiliitis, which cause hip and back pain, may antedate the bowel disease by
several years, and may persist after surgical or medical remission of the disease.

Amyloidosis and thromboembolic manifestations may also occur. Compared with controls, patients
with IBD have a 3-fold higher risk of thromboembolism, which is an important cause of morbidity and
mortality. These patients have frequent exposure to classic thrombosis risk factors, including
immobility, surgery, steroid therapy, and the presence of central venous catheters. Other factors that
may play a role include smoking, antiphospholipid antibody syndrome, and hyperhomocysteinemia,
which seem to occur more often in patients with IBD than in the general population.
 
Urinary system involvement includes nephrolithiasis due to calcium oxalate stones. These are caused
by hyperoxaluria due to increased intestinal absorption of oxalate. Reports of renal amyloidosis have
also been shown likely to be due to acute phase reaction proteins.

Involvement of the liver varies from simple elevation of enzyme levels to benign pericholangitis,
sclerosing cholangitis, autoimmune chronic active hepatitis, and cirrhosis. Cholelithiasis is more
frequent in patients with IBD than in the general population—probably due to bile salt pool alteration
for malabsorption. Cholangiocarcinoma is a rare late complication of primary sclerosing cholangitis.
Sometimes, a hepatic abscess manifests as fever of unexplained origin. Portal vein thrombosis and
suppurative pylephlebitis have also been described.
History

 Patients with Crohn disease most commonly present with symptoms related to a chronic
inflammatory process involving the ileocolic region.
o Low-grade fever, prolonged diarrhea with abdominal pain, weight loss, and
generalized fatigability are usually reported.
o The patients may develop crampy or steady right lower quadrant or periumbilical
pain. The pain precedes and may be partially relieved by defecation. Diarrhea is
usually nonbloody and often intermittent.
o If the colon is involved, patients may report diffuse abdominal pain accompanied by
mucus, blood, and pus in the stool.
 Patients with Crohn disease may also present with complaints that are suggestive of intestinal
obstruction.
o Initially, the obstruction is secondary to inflammatory edema and spasm of the bowel
and manifests as postprandial bloating, cramping pains, and loud borborygmi. Once
the bowel lumen becomes chronically narrowed, patients may complain of
constipation and obstipation. Complete obstruction may sometimes be caused by
impaction of undigested foods.
o Perianal fissures or fistulae are common.
o Cologastric fistulae may manifest as feculent vomiting, enterovesical fistulae as
recurrent urinary tract infections and pneumaturia, enterovaginal fistulae as feculent
vaginal discharge, and enterocutaneous fistulae as feculent soiling of the skin.
o Development of fistulae into the mesentery may result in intra-abdominal or
retroperitoneal abscess formation.
o Patients may also have perianal disease, including perianal fissures, abscesses, and
fistulae.
 Patients may have problems related to extraintestinal manifestations of Crohn disease, which
may involve the skin, joints, mouth, eyes, liver, and bile ducts.
 Young people with Crohn disease commonly experience unexplained growth failure and
delayed puberty.

Physical
Physical examination should focus on the patient's temperature, weight, nutritional status, presence of
abdominal tenderness or a mass, perianal and rectal examination findings, and extraintestinal
manifestations.
 

 Tachycardia and pale mucosa can indicate acute anemia.

 Physical findings on abdominal examination may typically reveal abnormal bowel sounds,
right lower quadrant tenderness (which is typical for ileal involvement), or a mass can
sometimes be felt secondary to thickened or matted loops of inflamed bowel.
 Inspection of the perianal region can reveal skin tags, fistulae, abscesses, and scarring. A
rectal examination can help determine sphincter tone and help detect gross abnormalities of
the rectal mucosa or the presence of hematochezia.
 Examination of the skin and oral mucosa can be useful to reveal extraintestinal manifestations
of the skin, including mucocutaneous ulcers, erythema nodosum, and pyoderma
gangrenosum.
 Eye involvement is usually manifested as uveitis or episcleritis.
 A peripheral arthritis involving the large joints may also be present.
Causes
Genetic, environmental, microbial, immunologic, dietary, vascular, and psychosocial factors, including
smoking, oral contraceptive, and nonsteroidal anti-inflammatory agents (NSAID) use, have been
implicated in the pathogenesis of Crohn disease.
 

 Studies have shown compelling evidence for an inheritable risk for the development of Crohn
disease. However, classic Mendelian inheritance is not seen. Most of the genes thought to be
involved in the development of the disease play a role in mucosal immunity and are found on
the mucosal barrier epithelium
o Several genes are thought to contribute to the complex phenotype; however,
mutations within theNOD2 gene (or the IBD1 gene or CARD-15-caspase activating
recruitment domain) have been shown to confer susceptibility to Crohn disease.
Another region studied is the IBD-3 gene on chromosome 6 which is an area that
includes the human leukocyte antigen (HLA) complex and has been linked with IBD.
In addition, an area linked specifically to Crohn disease is on chromosome 5q, known
as IBD-5, which contains a cytokine gene cluster.4
 Environmental influences such as tobacco use seem to have an effect on Crohn disease.
Smoking has been shown to double the risk, whereas in people who smoke, the risk of
developing ulcerative colitis is less than in those who have never smoked.
 Infectious possibilities such as Mycobacterium paratuberculosis, Pseudomonas species,
and Listeriaspecies have all been implicated in the pathogenesis of Crohn disease,
suggesting that the inflammation seen with the disease is the result of a dysfunctional but
appropriate response to an infectious source.
 Interleukins and tumor necrosis factor-alpha (TNF-alpha) have also been implicated in the
disease process. Crohn disease is characterized by a T-helper type-1 cellular immune
response pattern that leads to production of interleukin 12 (IL-12), TNF, and interferon
gamma (IFN-gamma). TNF has been shown to play a critical role in the inflammation in this
disease. Increased production of TNF by macrophages in patients with Crohn disease results
in increased concentrations of TNF in the stool, blood, and mucosa.

Differential diagnosis

Amebiasis
Carcinoid Tumor, Intestinal
Diverticulitis

Other Problems to Be Considered

Acute appendicitis
Endometriosis (Yersinia enterocolitica)
Ileocecal tuberculosis
Systemic vasculitis
Tubo-ovarian pathologies
Laboratory Studies

 Laboratory study findings in the evaluation of Crohn disease may indicate the presence of
inflammatory activity or nutritional deficiencies.
o Anemia may be due to multiple causes, including chronic inflammation, iron
malabsorption, chronic blood loss, and malabsorption of vitamin B-12 or folate.
o Leukocytosis may be due to chronic inflammation, abscess, or steroid treatment.
o Hypoalbuminemia, hypocholesterolemia, hypocalcemia, hypomagnesemia,
andhypoprothrombinemia may reflect malabsorption.
o Acute inflammatory markers, such as C-reactive protein (CRP) and orosomucoid,
correlate closely with disease activity. The erythrocyte sedimentation rate (ESR) is
thought to be more helpful in assessing the disease activity of Crohn colitis than
ileitis.
o Stool samples should be tested for routine pathogens, ova, parasites,
and Clostridium difficile toxin. These studies should also be checked to rule out
infectious etiologies during relapses and before initiating immunosuppressive agents
 Two serologic tests are available to attempt to differentiate ulcerative colitis from Crohn
disease.
o Perinuclear antineutrophil cytoplasmic antibody (p-ANCA), a myeloperoxidase
antigen, is more commonly found in ulcerative colitis, whereas antibodies to the
yeast Saccharomyces cerevisiae (ie, anti-S cerevisiae antibodies [ASCA]) are more
commonly found in Crohn disease.
o Therefore, a test result positive for p-ANCA antigen and negative for ASCA suggests
the diagnosis of ulcerative colitis; conversely, a test result positive for ASCA and
negative for p-ANCA antigen suggests the presence of Crohn disease.
o However, these tests are only recommended as an adjunct to clinical diagnosis, as
the test results are not specific and have been found to be positive in other bowel
diseases.
o Additional serologic markers such as Escherichia coli anti-ompC (outer membrane
porin C) can be found in >50% of Crohn disease cases, and only a small percentage
of ulcerative colitis case. Pseudomonas fluorescens (anti-12) may be found in
>50% of Crohn disease cases and only 10% of ulcerative colitis cases. Flagellin-like
antigen (anti-Cbir1) is associated independently with small bowel, intestinal
penetrating, and fibrostenosing disease. These tests further increase sensitivity and
diagnostic value.
o These tests can provide prognostic information as well. Patients with Crohn disease
whose condition is ASCA positive have a higher rate of surgery and require surgery
earlier in the course of the disease, independent of the disease location.

Imaging Studies

 Barium contrast studies

o These studies are very useful in defining the nature, distribution, and severity
of Crohn disease. An experienced radiologist should perform these studies to obtain
the most information.
o An upper GI series, together with a small bowel follow-through (SBFT) and spot films
of the terminal ileum, is the initial diagnostic procedure of choice in most patients who
present with typical symptoms of Crohn disease.
o SBFT can only indirectly detect alteration of the small bowel wall, and its sensitivity to
detect marginal changes is low in comparison with direct inspection of the mucosa by
endoscopy.
 o Once the patient can tolerate the procedure, barium enema may help in the
evaluation of colonic lesions. Barium contrast studies are useful in evaluating features
such as rigidity, pseudodiverticula, fistulization, and submucosal edema. These
studies are noninvasive and usually well tolerated. In patients with ileitis, the terminal
ileum may not be visualized, possibly because of spasming of the ileocecal valve.
o Radiographic findings in both the small and large bowel parallel the clinical pattern.
o Edema and ulceration of the mucosa in the small bowel may appear as thickening
and distortion of valvulae conniventes. Edema of the deep layers of the bowel wall
results in separation of the barium-filled bowel loops.
o Tracking of deep ulcerations, both transversely and longitudinally, results in a
cobblestone appearance.
o Ileitis can also manifest as a string sign on barium study secondary to spasms or,
rarely, because of fibrotic stricturing.
o Fistulae can also be detected by barium studies of the digestive tract or through
injection into the opening of the suspected fistulae.
 Computed tomography (CT) scanning is helpful in the assessment of extramural
complications such as fistulae and abscesses, as well as hepatobiliary and renal
complications. CT enterography can be helpful in the assessment of subtle mucosal damage.
 Magnetic resonance imaging (MRI) can be superior to CT scanning in demonstrating pelvic
lesions. Because of differential water content, MRI can differentiate active inflammation from
fibrosis, and it can distinguish between inflammatory and (fixed) fibrostenotic lesions in Crohn
disease.
 Ultrasonography is helpful in differentiating tubo-ovarian pathology. However, this modality
can also detect enlarged lymph nodes, abscesses, stenoses, and even fistulae, and
ultrasonography is regarded as a quick and inexpensive screening method to aid in the
diagnosis of IBD or to repeatedly evaluate patients for complications.
 Rectal endoscopic ultrasonography has been used as an alternative to MRI in the
assessment of perianal disease. This technique allows the differentiation of simple from
complex fistulae, as well as the assessment of the tracts of the fistulae in relation to the
sphincter muscle
 Radionucleotide scanning may be helpful in assessing the severity and extent of the disease
in patients who are too ill to undergo colonoscopy or barium studies.

Procedures

 Colonoscopy
o Colonoscopy can be helpful when single-contrast barium enema has not
been informative in evaluating a colonic lesion.
o Colonoscopy is useful in obtaining biopsy tissue, which helps in the differentiation of
other diseases, in the evaluation of mass lesions, and in the performance of cancer
surveillance.
o Colonoscopy also enables dilation of fibrotic strictures in patients with long-standing
disease. Colonoscopy may also be used in the postoperative period to evaluate
surgical anastomoses to predict the likelihood of clinical relapse as well as the
response to postoperative therapy.1
 Upper endoscopy
o Upper endoscopy with biopsy is helpful in differentiating Crohn disease from peptic
ulcer disease in patients with upper GI tract symptoms.
o Endoscopic retrograde cholangiopancreatography (ERCP) is helpful both as a
diagnostic procedure and a therapeutic tool in patients with sclerosing cholangitis and
stricture formation.
 o Endoscopic ultrasonography (EUS) and magnetic resonance
cholangiopancreatography (MRCP) may provide equally valuable information without
invasive complications.
o Double balloon endoscopy allows complete evaluation of the small bowel and makes
distal ileal biopsies feasible.
o Wireless capsule endoscopy helps to identify involvement of the upper GI tract which
will occur in 40% of patients with Crohn disease. However, drawbacks include the
inability to take biopsies, the risk of acute obstruction in stricturizing disease, and the
time required for analysis.
o Endoscopy can also be helpful in the detection of complications of Crohn
disease. Magnifying endoscopy allows a more detailed view of the mucosal surface
than conventional endoscopy. In combination with chromoendoscopy (indigo
carmine), it is possible to further analyze the surface staining pattern to help identify
neoplastic changes in situ.

Histologic Findings
Transmural involvement with noncaseating granulomas is seen in about 50% of cases of Crohn
disease. Patchy skip lesions and lymphoid aggregates may also be seen throughout the bowel

Treatment

Medical Care

 Diarrhea
o Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as
loperamide (2-4 mg), diphenoxylate with atropine (1 tab), and tincture of opium (8-15
gtt). Such agents may be administered up to 4 times daily, but they should not be
given to patients with active colitis because of the risk of developing toxic megacolon.
o Patients with terminal ileal disease may not absorb bile acids normally, which can
lead to secretory diarrhea in the colon. These patients may benefit from bile acid
sequestrants (eg, cholestyramine [2-4 g], colestipol [5 g] bid/tid ac). Those who have
extensive ileal disease or resection of more than 100 cm of the ileum have defective
bile salt absorption and develop steatorrhea. These patients benefit from a low-fat
diet and medium-chain triglyceride preparations. Bile sequestrants exacerbate this
type of diarrhea.
o Diarrhea may also develop because of bacterial overgrowth, short-bowel syndrome,
and lactase deficiency.
o Abdominal cramps may be reduced with propantheline (0.125 mg), dicyclomine (10-
20 mg), or hyoscyamine (0.125 mg). These drugs should not be used if there is the
possibility of a bowel obstruction
 For colon and small bowel inflammation, anti-inflammatory drugs or antibiotics are helpful.
o Sulfasalazine is mainly useful in colonic disease, because the active compound, 5-
aminosalicylic acid (5-ASA), is released in the large bowel by bacterial degradation of
the parent compound. Sulfasalazine does not alleviate small bowel disease. Products
such as mesalamine (Asacol) that release 5-ASA in the distal small bowel secondary
to pH changes are more useful in patients with small intestinal Crohn disease. Long-
term maintenance with mesalamine (800 mg tid) may delay clinical relapse.
  Sulfasalazine does not have an additive effect or a steroid-sparing effect
when used in conjunction with corticosteroids. In contrast to its action in
ulcerative colitis, sulfasalazine does not seem to maintain remission in Crohn
disease.
o A short course of steroid therapy is indicated in patients with severe systemic
symptoms (eg, fever, nausea, weight loss) and in those whose condition does not
respond to anti-inflammatory agents. Prednisone (40-60 mg/d) is generally helpful in
acute inflammation. Once remission is achieved, the agent is slowly tapered (5-10 mg
q1-2wk). It should be noted that steroids are not disease modifying and do not induce
sustained mucosal healing.
o In patients who relapse after the withdrawal of steroids, other treatment options are
required. Steroids are not indicated for maintenance therapy because of serious
complications, such as aseptic necrosis of the hip, osteoporosis, cataract, diabetes,
and hypertension.
o In patients with a tender, palpable mass, exclude the possibility of an underlying
abscess before starting steroids. Adding antibiotics is always beneficial if coexisting
infection is considered likely.
o Consider immunosuppressants such as azathioprine (2 mg/kg/d) or its active
metabolite, 6-mercaptopurine (6-MP), if steroid withdrawal proves difficult. Response
is usually observed within 3-6 months. Careful supervision is needed because of the
risk of bone marrow suppression.
o If medical therapy fails, surgical resection of the inflamed bowel, with restoration of
continuity, is indicated. Urgent surgery may be required in rare cases of sustained or
recurrent hemorrhage and toxic megacolon. Partial small bowel obstruction may
sometimes be treated conservatively with intravenous hydration, nasogastric suction,
and parenteral nutrition if there is no evidence of adhesion or strangulation. 2,13
 Fistulae
o Fistulae between bowel loops (eg, ileoileal, ileocecal, ileosigmoid) are usually benign
and may not produce any major problems.
o Enterovesicular, enterocutaneous, cologastric, and coloduodenal fistulae are more
serious. Surgical intervention is rarely required, unless fistulae are complicated by
progressive obstruction or abscess formation or a large segment of bowel is
bypassed, leading to severe diarrhea and malabsorption. Otherwise, medical
management is used to treat underlying infections and symptoms with oral
metronidazole (1 g/d) for at least 1-2 months.
 Ciprofloxacin confers additional benefit if no improvement occurs. One study
demonstrated that the combination of ciprofloxacin and metronidazole in 14
patients with perianal fistulae healed the fistulae in 3 patients and improved
85% of them.
o Antimetabolites are beneficial in reducing drainage and closing fistulae in 30-40% of
patients. Total parenteral nutrition (TPN) and bowel rest may promote fistulae healing
during medical therapy.
 New medical therapies
o Anti–TNF antibody
 TNF, a key inflammatory cytokine and mediator of intestinal inflammation, is
expressed prominently in IBD. Infliximab is a chimeric mouse-human
monoclonal antibody against TNF and shows promise in Crohn disease; it
blocks TNF in the serum and at the cell surface, leading to the lysis of TNF-
producing macrophages and T cells.
 In one study, nearly 65% of refractory cases of Crohn disease responded
well to treatment with infliximab (5 mg/kg), and one third went into complete
 remission. Patients who relapsed after the initial response responded again
to further infusions. Infliximab is also effective in patients who have refractory
perianal and enterocutaneous fistulae. On average, the effect lasts for 12
weeks.
 Important adverse effects include the development of a lupus-like
syndrome and an increased incidence of tuberculosis. Anti–double-
stranded DNA is not always associated with clinical lupus. An added
benefit of infliximab treatment is the ability to possibly taper steroids,
which will decrease further adverse effects.
 Unfortunately, infliximab is immunogenic, and repeated administration may
result in the development of antibodies to infliximab that lead to infusion
reactions, loss of efficacy, and delayed hypersensitivity reactions.
 Two anti-TNF agents, adalimumab and certolizumab, may be less
immunogenic than infliximab and have shown efficacy in the treatment of
Crohn disease that is refractory to the standard medical treatment of
corticosteroids and immunomodulatory agents.
 Adalimumab is a recombinant human immunoglobulin (Ig) G1 monoclonal
antibody that binds with high affinity and specificity to human soluble TNF-
alpha but not to lymphotoxin (TNF-beta). Results have shown that the
immunogenicity of adalimumab is low compared with the chimeric mouse-
human monoclonal antibody infliximab.
 Two placebo-controlled trials, CLASSIC I and CLASSIC II, showed that
adalimumab was effective for both induction and maintenance of remission in
patients who were previously naive to anti-TNF therapy. The CHARM trial
demonstrated the same effect in a mixed population of patients who were
either were naive to infliximab therapy or who had previously been on
infliximab therapy.
 In patients who had lost response or become intolerant of infliximab,
the GAIN trial results showed a benefit from adalimumab therapy
induction with remission at 4 weeks. Furthermore, an open-label
study conducted in France that assessed the long-term efficacy and
safety of adalimumab maintenance therapy in this population showed
that it was well tolerated and effective in maintaining clinical
remission in patients who had Crohn disease with a lost response or
intolerance to infliximab.
 Certolizumab pegol, a humanized Fab' antibody fragment conjugated to
polyethylene glycol, has also demonstrated efficacy in maintaining remission
in patients with moderately to severely active Crohn disease whose condition
previously responded to induction therapy with the same agent (PRECISE
trial). However, the data only covered a 6-month period.
 Immunosuppressive agents
o Tacrolimus may be effective in treating Crohn disease.
o Mycophenolate mofetil acts by inhibiting a de novo pathway of purine synthesis in
lymphocytes, leading to intracellular depletion of guanosine monophosphate. This
results in the suppression of cytotoxic T cells and the formation of antibodies by
activated B cells. A dose of 500 mg twice a day in 2 divided doses is well tolerated by
patients and can be used to reduce the steroid dose.
o Anti-inflammatory cytokines: The use of IL-10 ilodecakin resulted in a trend toward
clinical improvement but not remission in chronic active Crohn disease, and IL-11
oprelvekin was found to be effective in inducing remission in a preliminary study in
patients with mild to moderate Crohn disease. However, more trials are needed.
 o Monoclonal antibody to IL-6 receptor tocilizumab has been suggested to have a
beneficial clinical effect in Crohn disease as well as antibody to IL-12, which has been
found to decrease the T helper-1 mediated inflammatory cytokines at the site of
disease.2
o Natalizumab is a monoclonal antibody against the alpha4 integrin subunit that inhibits
leukocyte adhesion and migration to areas of inflammation. Pooled clinical data
suggest that this drug may be effective for inducing clinical response and remission,
although trials were suspended due to 3 reported cases of progressive
multileukoencephalopathy (PML) in 2 patients with multiple sclerosis receiving this
agent in combination with IFN beta-1A.
o Filgrastim or colony-stimulating factor (CSF) (granulocyte monocyte [GM]-CSF) has
been shown to have a positive response to treatment in patients with fistulae. 2
 Valentine et al examined whether use of sargramostim, a recombinant GM-
CSF and activator of innate immunity, provided steroid-sparing capabilities in
patients with Crohn disease.19Patients were randomized (2:1 ratio) to receive
either sargramostim 6 mcg/kg SC qd (n = 87) or placebo (n = 42) for up to 22
weeks. During weeks 1-4, patients received sargramostim or placebo
adjunctively to their corticosteroid therapy, during weeks 4-14 corticosteroids
were titrated downward, and finally an observation phase of study drug plus
prednisone less than or equal to 7.5 mg/d. Corticosteroid-free remission was
obtained in 18.6% of sargramostim group compared with 4.9% of the placebo
group (P = 0.03).19 However, patients receiving sargramostim experienced
more pain, injection site reactions, and dyspnea than those receiving
placebo. Use of sargramostim may reduce the dose or duration of
corticosteroids in patients with Crohn disease, thereby reducing steroid-
induced adverse effects.
o Fontolizumab is an antibody to IFN-gamma that has provided significantly better
clinical response rates and remission than placebo.

Surgical Care

 Surgery plays an integral role in the treatment of Crohn disease to control symptoms and treat
complications. By the 20th year of onset of symptoms, approximately 75% of patients with
Crohn disease will have had surgery. Due to the high rate of disease recurrence after
segmental bowel resection, the guiding principle of surgery is preservation of intestinal length
and function.
 The recommended guidelines for those requiring surgery include persistent symptoms despite
high-dose corticosteroids, treatment-related complications including intra-abdominal
abscesses, medically intractable fistulae, fibrotic strictures with obstructive symptoms, toxic
megacolon, hemorrhage, and cancer.
 Fibrostenotic obstruction may require surgical correction; in some cases, endoscopic dilation
is effective.1
 Patients with perianal fistulae will usually have a good response to medical treatment (eg,
metronidazole, 6-MP, cyclosporin [in refractory cases]). Surgical treatment is indicated if
medical treatment fails or if an abscess is present.
 The postoperative recurrence rate remains high despite medical management in the
postoperative period. The recurrence rate for patients undergoing total colectomy and
ileostomy appears to be lower than for those undergoing segmental procedures.
Diet
The diet should be balanced in patients with Crohn disease. Fiber supplementation is said to be
beneficial for patients with colonic disease due to the fact that dietary fiber can be converted to short-
chain fatty acids, which provide fuel for colonic mucosal healing, whereas a low-roughage diet is
usually indicated for patients with obstructive symptoms.

 Patients with Crohn disease of the small intestine often have lactose intolerance; therefore,
avoidance of dairy products may be indicated. However supplementation with calcium may be
required. Osteoporosis is a common nutritional complication of Crohn disease due to the
above reason, as well as the release of cytokines from inflammatory cells, which stimulate
osteoclast activity and lead to increased bone breakdown. Corticosteroid use is also another
significant risk factor for the development of osteoporosis.
 Patients who undergo extensive resection of the terminal portion of the ileum may benefit
from a low-fat diet with the addition of medium-chain triglyceride preparations.
 Enteral therapy with an elemental diet has been suggested to induce remission in acute
Crohn disease, consumption of at least 1200 kcal/day was associated with lower rates of
disease relapse, but patients' conditions have frequently relapsed after initiation of a normal
diet.
 Indications for TPN
o Short-term use: Patients with active inflammation and severe malnutrition and those
with fistulae (given preoperatively)
o Long-term use: Patients who have had extensive intestinal resection, resulting in
short bowel syndrome