2450 PART 10 Disorders of the Gastrointestinal System

present, independent of the NSAID status, triple therapy is recommended for 14 days, followed by continued acid-suppressing

drugs (H2

 receptor antagonist or PPIs) for a total of 4–6 weeks. H.

pylori eradication should be documented 4 weeks after completing

antibiotics. The test of choice for documenting eradication is the

laboratory-based validated monoclonal stool antigen test or a urea

breath test (UBT). The patient must be off antisecretory agents for

at least 7 days when being tested for eradication of H. pylori with

UBT or stool antigen. Serologic testing is not useful for the purpose

of documenting eradication because antibody titers fall slowly and

often do not become undetectable. Some recommend that patients

with complicated ulcer disease or who are frail should be treated

with long-term acid suppression, thus making documentation of

H. pylori eradication a moot point. In view of this discrepancy in

practice, it would be best to discuss with the patient the different

options available.

Several issues differentiate the approach to a GU versus a DU.

GUs, especially of the body and fundus, have the potential of being

malignant. Multiple biopsies of a GU should be taken initially; even

if these are negative for neoplasm, repeat endoscopy to document

healing at 8–12 weeks should be performed, with biopsy if the ulcer

is still present. About 70% of GUs eventually found to be malignant

undergo significant (usually incomplete) healing. Repeat endoscopy is warranted in patients with DU if symptoms persist despite

medical therapy or a complication is suspected.

The majority (>90%) of GUs and DUs heal with the conventional

therapy outlined above. A GU that fails to heal after 12 weeks and a

DU that does not heal after 8 weeks of therapy should be considered

refractory. Once poor compliance and persistent H. pylori infection

have been excluded, NSAID use, either inadvertent or surreptitious, must be excluded. In addition, cigarette smoking must be

eliminated. For a GU, malignancy must be meticulously excluded.

Next, consideration should be given to a gastric acid hypersecretory

state such as ZES (see “Zollinger-Ellison Syndrome,” below) or the

idiopathic form, which can be excluded with gastric acid analysis.

Although a subset of patients has gastric acid hypersecretion of

unclear etiology as a contributing factor to refractory ulcers, ZES

should be excluded with a fasting gastrin or secretin stimulation

test (see below). More than 90% of refractory ulcers (either DUs

or GUs) heal after 8 weeks of treatment with higher doses of PPI

(omeprazole 40 mg/d; lansoprazole 30–60 mg/d). This higher dose

is also effective in maintaining remission. Surgical intervention

may be a consideration at this point; however, other rare causes of

refractory ulcers must be excluded before recommending surgery.

Rare etiologies of refractory ulcers that may be diagnosed by gastric

or duodenal biopsies include ischemia, Crohn’s disease, amyloidosis, sarcoidosis, lymphoma, eosinophilic gastroenteritis, smoking

crack cocaine, or infection (cytomegalovirus [CMV], tuberculosis,

or syphilis).

SURGICAL THERAPY

Surgical intervention in PUD can be viewed as being either elective, for treatment of medically refractory disease, or as urgent/

emergent, for the treatment of an ulcer-related complication. The

development of pharmacologic and endoscopic approaches for

the treatment of peptic disease and its complications has led to a

substantial decrease in the number of operations needed for this

disorder with a drop of >90% for elective ulcer surgery over the past

four decades. Refractory ulcers are an exceedingly rare occurrence.

Surgery is more often required for treatment of an ulcer-related

complication.

Hemorrhage is the most common ulcer-related complication,

occurring in ~15–25% of patients. Bleeding may occur in any age

group but is most often seen in older patients (sixth decade or

beyond). The majority of patients stop bleeding spontaneously, but

endoscopic therapy (Chap. 322) is necessary in some. Parenterally

and orally administered PPIs also decrease ulcer rebleeding in patients

who have undergone endoscopic therapy. Patients unresponsive or

refractory to endoscopic intervention will require angiographic intervention or surgery (~5% of transfusion-requiring patients).

Free peritoneal perforation occurs in ~2–3% of DU patients,

with NSAID-induced GU perforations occurring more commonly.

Sudden onset of severe abdominal pain with peritoneal signs and

evidence of pneumoperitoneum on abdominal imaging is the classic presentation of a perforated viscous, but this presentation occurs

in only two-thirds of patients. The latter is especially true in elderly

patients (>70 years old), obese individuals, and immunocompromised patients. It is important to keep in mind that, as in the case

of bleeding, up to 10% of these patients will not have antecedent

ulcer symptoms. Delay in diagnosis clearly leads to higher mortality; thus, early suspicion and intervention with nasogastric suction,

intravenous PPI, antibiotics and surgical consultation are essential.

Concomitant bleeding may occur in up to 10% of patients with

perforation, with mortality being increased substantially. Peptic

ulcer can also penetrate into adjacent organs, especially with a

posterior DU, which can penetrate into the pancreas, colon, liver,

or biliary tree.

Pyloric channel ulcers or DUs can lead to gastric outlet obstruction in ~2–3% of patients. This can result from chronic scarring

or from impaired motility due to inflammation and/or edema

with pylorospasm. Patients may present with early satiety, nausea,

vomiting of undigested food, and weight loss. Conservative management with nasogastric suction, intravenous hydration/nutrition,

and antisecretory agents is indicated for 7–10 days with the hope

that a functional obstruction will reverse. If a mechanical obstruction persists, endoscopic intervention with balloon dilation may be

effective. Surgery should be considered if all else fails.

Specific Operations for Duodenal Ulcers Surgical treatment was

originally designed to decrease gastric acid secretion. Operations

most commonly performed include (1) vagotomy and drainage

(by pyloroplasty, gastroduodenostomy, or gastrojejunostomy), (2)

highly selective vagotomy (which does not require a drainage procedure), and (3) vagotomy with antrectomy. The specific procedure

performed is dictated by the underlying circumstances: elective

versus emergency, the degree and extent of duodenal ulceration,

the etiology of the ulcer (H. pylori, NSAIDs, malignancy), and the

expertise of the surgeon. Moreover, the trend has been toward a

>40 years old

Alarm symptoms

New-Onset Dyspepsia

–

Noninvasive Hp testing

Confirm eradication UBT

+

Anti-Hp

therapy

Empiric trial

H2 blocker

4 weeks

after therapy

or

–

Refer to

gastroenterologist

+

Symptoms remain or recur

Exclude by history GERD, biliary

 pain, IBS, aerophagia,

 medication-related

FIGURE 324-14 Overview of new-onset dyspepsia. GERD, gastroesophageal reflux

disease; Hp, Helicobacter pylori; IBS, irritable bowel syndrome; UBT, urea breath

test. (Reproduced with permission from BS Anand, DY Graham: State-of-the-Art:

Ulcer and Gastritis, Endoscopy 31:215, 1999. © Georg Thieme Verlag KG.)

2451Peptic Ulcer Disease and Related Disorders CHAPTER 324

dramatic decrease in the need for surgery for treatment of refractory PUD, and when needed, minimally invasive and anatomypreserving operations are preferred.

Vagotomy is a component of each of these procedures and is

aimed at decreasing acid secretion through ablating cholinergic

input to the stomach. Unfortunately, both truncal and selective

vagotomy (preserves the celiac and hepatic branches) result in

gastric atony despite successful reduction of both basal acid output (BAO; decreased by 85%) and maximal acid output (MAO;

decreased by 50%). Drainage through pyloroplasty or gastroduodenostomy is required in an effort to compensate for the vagotomyinduced gastric motility disorder. This procedure has an intermediate complication rate and a 10% ulcer recurrence rate. To minimize gastric dysmotility, highly selective vagotomy (also known as

parietal cell, super-selective, or proximal vagotomy) was developed.

Only the vagal fibers innervating the portion of the stomach that

contains parietal cells are transected, thus leaving fibers important

for regulating gastric motility intact. Although this procedure

leads to an immediate decrease in both BAO and stimulated acid

output, acid secretion recovers over time. By the end of the first

postoperative year, basal and stimulated acid output are ~30 and

50%, respectively, of preoperative levels. Ulcer recurrence rates are

higher with highly selective vagotomy (≥10%), although the overall

complication rates are the lowest of the three procedures.

The procedure that provides the lowest rates of ulcer recurrence

(1%) 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. Two principal types of reanastomoses are used after antrectomy: gastroduodenostomy (Billroth I) or gastrojejunostomy

(Billroth II) (Fig. 324-15). Although Billroth I is often preferred

over II, severe duodenal inflammation or scarring may preclude its

performance. Prospective, randomized studies confirm that partial

gastrectomy followed by Roux-en-Y reconstruction leads to a significantly better clinical, endoscopic, and histologic outcome than

Billroth II reconstruction.

Of these procedures, highly selective vagotomy may be the procedure of choice in the elective setting, except in situations where

ulcer recurrence rates are high (prepyloric ulcers and those refractory to medical 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 has occurred. Laparoscopic repair

of perforated peptic ulcers is safe, feasible for the experienced surgeon, and associated with decreased postoperative pain, although it

does take longer than an open approach. Moreover, no difference

between the two approaches is noted in postoperative complications or length of hospital stay.

Specific Operations for GUs The location and 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 (Csendes’ 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 anatomic

modification performed. Minimal alteration (highly selective vagotomy) is associated with higher rates of ulcer recurrence and less

GI disturbance. More aggressive surgical procedures have a lower

rate of ulcer recurrence but a greater incidence of GI 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.

Recurrent Ulceration The risk of ulcer recurrence is directly

related to the procedure performed. Ulcers that recur after partial

gastric resection tend to develop at the anastomosis (stomal or

marginal ulcer). Epigastric abdominal pain is the most frequent

presenting complaint (>90%). Severity and duration of pain tend to

be more progressive than observed with DUs before surgery.

Ulcers may recur for several reasons, including incomplete vagotomy, inadequate drainage, retained antrum, and, less likely, persistent or recurrent H. pylori infection. ZES should have been excluded

preoperatively. Surreptitious use of NSAIDs is an important reason

for recurrent ulcers after surgery, especially if the initial procedure

was done for an NSAID-induced ulcer. Once H. pylori and NSAIDs

have been excluded as etiologic factors, the question of incomplete

vagotomy or retained gastric antrum should be explored. For the

latter, fasting plasma gastrin levels should be determined. If elevated, retained antrum or ZES (see below) should be considered.

Incomplete vagotomy can be ruled out by gastric acid analysis coupled with sham feeding. In this test, gastric acid output is measured

while the patient sees, smells, and chews a meal (without swallowing). The cephalic phase of gastric secretion, which is mediated by

the vagus, is being assessed with this study. An increase in gastric

acid output in response to sham feeding is evidence that the vagus

nerve is intact. A rise in serum pancreatic polypeptide >50% within

30 min of sham feeding is also suggestive of an intact vagus nerve.

Antrum

Fundus

Billroth I Billroth II

Duodenum

FIGURE 324-15 Schematic representation of Billroth I and II procedures.

2452 PART 10 Disorders of the Gastrointestinal System

Medical therapy with H2

 blockers will heal postoperative ulceration in 70–90% of patients. The efficacy of PPIs has not been fully

assessed in this group, but one may anticipate greater rates of ulcer

healing compared to those obtained with H2

 blockers. Repeat operation (complete vagotomy, partial gastrectomy) may be required in

a small subgroup of patients who have not responded to aggressive

medical management.

Afferent Loop Syndromes Although rarely seen today as a result

of the decrease in the performance of Billroth II anastomosis, two

types of afferent loop syndrome can occur in patients who have

undergone this type of partial gastric resection. The more common

of the two is bacterial overgrowth in the afferent limb secondary

to stasis. Patients may experience postprandial abdominal pain,

bloating, and diarrhea with concomitant malabsorption of fats and

vitamin B12. Cases refractory to antibiotics may require surgical

revision of the loop. The less common afferent loop syndrome

can present with severe abdominal pain and bloating that occur

20–60 min after meals. Pain is often followed by nausea and

vomiting of bile-containing material. The pain and bloating may

improve after emesis. The cause of this clinical picture is theorized

to be incomplete drainage of bile and pancreatic secretions from an

afferent loop that is partially obstructed. Cases refractory to dietary

measures may need surgical revision or conversion of the Billroth

II anastomosis to a Roux-en-Y gastrojejunostomy.

Dumping Syndrome Dumping syndrome consists of a series of vasomotor and GI signs and symptoms and occurs in patients who have

undergone vagotomy and drainage (especially Billroth procedures).

Two phases of dumping, early and late, can occur. Early dumping

takes place 15–30 min after meals and consists of crampy abdominal discomfort, nausea, diarrhea, belching, tachycardia, palpitations,

diaphoresis, light-headedness, and, rarely, syncope. These signs and

symptoms arise from the rapid emptying of hyperosmolar gastric

contents into the small intestine, resulting in a fluid shift into the gut

lumen with plasma volume contraction and acute intestinal distention.

Release of vasoactive GI hormones (vasoactive intestinal polypeptide,

neurotensin, motilin) is also theorized to play a role in early dumping.

The late phase of dumping typically occurs 90 min to 3 h after

meals. Vasomotor symptoms (light-headedness, diaphoresis, palpitations, tachycardia, and syncope) predominate during this phase.

This component of dumping is thought to be secondary to hypoglycemia from excessive insulin release.

Dumping syndrome is most noticeable after meals rich in simple

carbohydrates (especially sucrose) and high osmolarity. Ingestion

of large amounts of fluids may also contribute. After vagotomy and

drainage, up to 50% of patients will experience dumping syndrome

to some degree early on. Signs and symptoms often improve with

time, but a severe protracted picture can occur in up to 1% of

patients.

Dietary modification is the cornerstone of therapy for patients

with dumping syndrome. Small, multiple (six) meals devoid of

simple carbohydrates coupled with elimination of liquids during

meals is important. Antidiarrheals and anticholinergic agents are

complementary to diet. Guar and pectin, which increase the viscosity of intraluminal contents, may be beneficial in more symptomatic

individuals. Acarbose, an α-glucosidase inhibitor that delays digestion of ingested carbohydrates, has also been shown to be beneficial

in the treatment of the late phases of dumping. The somatostatin

analogue octreotide has been successful in diet-refractory cases.

This drug is administered subcutaneously (50 μg tid), titrated

according to clinical response. A long-acting depot formulation of

octreotide can be administered once every 28 days and provides

symptom relief comparable to the short-acting agent. In addition,

patient weight gain and quality of life appear to be superior with the

long-acting form.

Postvagotomy Diarrhea Up to 10% of patients may seek medical

attention for the treatment of postvagotomy diarrhea. This complication is most commonly observed after truncal vagotomy, which

is rarely performed today. Patients may complain of intermittent

diarrhea that occurs typically 1–2 h after meals. Occasionally, the

symptoms may be severe and relentless. This is due to a motility

disorder from interruption of the vagal fibers supplying the luminal

gut. Other contributing factors may include decreased absorption

of nutrients (see below), increased excretion of bile acids, and

release of luminal factors that promote secretion. Diphenoxylate or

loperamide is often useful in symptom control. The bile salt–binding

agent cholestyramine may be helpful in severe cases. Surgical reversal of a 10-cm segment of jejunum may yield a substantial improvement in bowel frequency in a subset of patients.

Bile Reflux Gastropathy A subset of post–partial gastrectomy

patients who present with abdominal pain, early satiety, nausea,

and vomiting will have mucosal erythema of the gastric remnant

as the only finding. Histologic examination of the gastric mucosa

reveals minimal inflammation but the presence of epithelial cell

injury. This clinical picture is categorized as bile or alkaline reflux

gastropathy/gastritis. Although reflux of bile is implicated as the

reason for this disorder, the mechanism is unknown. Prokinetic

agents, cholestyramine, and sucralfate have been somewhat effective treatments. Severe refractory symptoms may require using

either nuclear scanning with 99mTc-HIDA to document reflux.

Surgical diversion of pancreaticobiliary secretions away from the

gastric remnant with a Roux-en-Y gastrojejunostomy consisting of

a long (50–60 cm) Roux limb has been used in severe cases. Bilious

vomiting improves, but early satiety and bloating may persist in up

to 50% of patients.

Maldigestion and Malabsorption Weight loss can be observed

in up to 60% of patients after partial gastric resection. Patients

can experience a 10% loss of body weight, which stabilizes

3 months postoperatively. A significant component of this weight

reduction is due to decreased oral intake. However, mild steatorrhea can also develop. Reasons for maldigestion/malabsorption

include decreased gastric acid production, rapid gastric emptying,

decreased food dispersion in the stomach, reduced luminal bile

concentration, reduced pancreatic secretory response to feeding,

and rapid intestinal transit.

Decreased serum vitamin B12 levels can be observed after partial

gastrectomy. This is usually not due to deficiency of IF, since a

minimal amount of parietal cells (source of IF) is removed during

antrectomy. Reduced vitamin B12 may be due to competition for

the vitamin by bacterial overgrowth or inability to split the vitamin

from its protein-bound source due to hypochlorhydria.

Iron-deficiency anemia may be a consequence of impaired

absorption of dietary iron in patients with a Billroth II gastrojejunostomy. Absorption of iron salts is normal in these individuals;

thus, a favorable response to oral iron supplementation can be

anticipated. Folate deficiency with concomitant anemia can also

develop in these patients. This deficiency may be secondary to

decreased absorption or diminished oral intake.

Malabsorption of vitamin D and calcium resulting in osteoporosis and osteomalacia is common after partial gastrectomy and

gastrojejunostomy (Billroth II). Osteomalacia can occur as a late

complication in up to 25% of post–partial gastrectomy patients.

Bone fractures occur twice as commonly in men after gastric

surgery as in a control population. It may take years before x-ray

findings demonstrate diminished bone density. Elevated alkaline

phosphatase, reduced serum calcium, bone pain, and pathologic

fractures may be seen in patients with osteomalacia. The high incidence of these abnormalities in this subgroup of patients justifies

treating them with vitamin D and calcium supplementation indefinitely. Therapy is especially important in females. Copper deficiency has also been reported in patients undergoing surgeries that

bypass the duodenum, where copper is primarily absorbed. Patients

may present with a rare syndrome that includes ataxia, myelopathy,

and peripheral neuropathy.

Gastric Adenocarcinoma The incidence of adenocarcinoma in

the gastric stump is increased 15 years after resection. Some have

reported a four- to fivefold increase in gastric cancer 20–25 years

2453Peptic Ulcer Disease and Related Disorders CHAPTER 324

after resection. The pathogenesis is unclear but may involve alkaline reflux, bacterial proliferation, or hypochlorhydria. The role

of endoscopic screening is not clear, and most guidelines do not

support its use.

Additional Complications Reflux esophagitis and a higher incidence of gallstones and cholecystitis have been reported in patients

undergoing subtotal gastrectomy. The latter is thought to be due to

decreased gallbladder contractility associated with vagotomy and

bypass of the duodenum, leading to decreased postprandial release

of cholecystokinin.

RELATED CONDITIONS

■ ZOLLINGER-ELLISON SYNDROME

Severe peptic ulcer diathesis secondary to gastric acid hypersecretion due to unregulated gastrin release from a non–β-cell, often

well-differentiated neuroendocrine tumor (NET; gastrinoma) defines

the components of ZES. Initially, ZES was typified by aggressive and

refractory ulceration in which total gastrectomy provided the only chance

for enhancing survival. Today, it can be cured by surgical resection in up

to 40% of patients with the sporadic form of the disease (see below).

Epidemiology The true incidence of ZES is unknown, but estimates suggest that it varies from 0.1 to 1% of individuals presenting

with PUD, with 0.1–3 individuals per year having this rare diagnosis.

Others have estimated an incidence of 0.5–3 per million population.

Females are slightly more commonly affected than males, and the

majority of patients are diagnosed between ages 30 and 50. Gastrinomas are classified into sporadic tumors (80%) and those associated

with multiple endocrine neoplasia (MEN) type 1 (see below). The

widespread availability and use of PPIs have led to a decreased patient

referral for gastrinoma evaluation, delay in diagnosis, and an increase

in false-positive diagnoses of ZES. In fact, diagnosis may be delayed for

≥6 years after symptoms consistent with ZES are displayed.

Pathophysiology Hypergastrinemia originating from an autonomous neoplasm is the driving force responsible for the clinical manifestations in ZES. Gastrin stimulates acid secretion through gastrin

receptors on parietal cells and by inducing histamine release from ECL

cells. Gastrin also has a trophic action on gastric epithelial cells. Longstanding hypergastrinemia leads to markedly increased gastric acid

secretion through both parietal cell stimulation and increased parietal

cell mass. The increased gastric acid output leads to peptic ulcer diathesis, erosive esophagitis, and diarrhea.

Tumor Distribution Although early studies suggested that the

vast majority of gastrinomas occurred within the pancreas, a significant number of these lesions are extrapancreatic. Between 60 and 90%

of these tumors are found within the hypothetical gastrinoma triangle

(confluence of the cystic and common bile ducts superiorly, junction

of the second and third portions of the duodenum inferiorly, and

junction of the neck and body of the pancreas medially). Duodenal

tumors constitute the most common nonpancreatic lesion; between 60

and 100% of gastrinomas are found here. Duodenal tumors are smaller,

slower growing, and less likely to metastasize than pancreatic lesions.

Less common extrapancreatic sites include stomach, bones, ovaries,

heart, liver, and lymph nodes. More than 60% of tumors are considered

malignant, with up to 30–50% of patients having multiple lesions or

metastatic disease at presentation. Histologically, gastrin-producing

cells appear well-differentiated (grade 1 or 2 histologically), expressing

markers typically found in endocrine neoplasms (chromogranin, neuron-specific enolase). Although not clearly established in gastrinomas,

histologic grade in pancreatic NETs generally is an important predictor

of survival in these rare neoplasms (Chap. 84).

Clinical Manifestations Gastric acid hypersecretion is responsible for the signs and symptoms observed in patients with ZES. The

most common clinical presentation for gastrinoma patients is abdominal pain in the presence of acid peptic disorders. Peptic ulcer is the

most common clinical manifestation, occurring in >90% of gastrinoma

patients. Initial presentation and ulcer location (duodenal bulb) may be

indistinguishable from common PUD. Clinical situations that should

create suspicion of gastrinoma are ulcers in unusual locations (second

part of the duodenum and beyond), ulcers refractory to standard

medical therapy, ulcer recurrence after acid-reducing surgery, ulcers

presenting with frank complications (bleeding, obstruction, and perforation), or ulcers in the absence of H. pylori or NSAID ingestion.

Symptoms of esophageal origin are present in up to two-thirds of

patients with ZES, with a spectrum ranging from mild esophagitis to

frank ulceration with stricture and Barrett’s mucosa.

Diarrhea, the next most common clinical manifestation, is found in

up to 70% of patients. Although diarrhea often occurs concomitantly

with acid peptic disease, it may also occur independent of an ulcer and

classically will abate with PPI therapy. Etiology of the diarrhea is multifactorial, resulting from marked volume overload to the small bowel,

pancreatic enzyme inactivation by acid, and damage of the intestinal

epithelial surface by acid. The epithelial damage can lead to a mild

degree of maldigestion and malabsorption of nutrients. The diarrhea

may also have a secretory component due to the direct stimulatory

effect of gastrin on enterocytes or the co-secretion of additional hormones from the tumor such as vasoactive intestinal peptide.

Gastrinomas can develop in the presence of MEN 1 syndrome

(Chaps. 84 and 388) in ~25% of patients. This autosomal dominant

disorder involves primarily three organ sites: the parathyroid glands

(80–90%), pancreas (40–80%), and pituitary gland (30–60%). The

syndrome is caused by inactivating mutations of the MEN1 tumorsuppressor gene found on the long arm of chromosome 11q13. The

gene encodes for menin, which has an important role in DNA replication and transcriptional regulation. A genetic diagnosis is obtained by

sequencing of the MEN1 gene, which can reveal mutations in 70–90%

of typical MEN 1 cases. A family may have an unknown mutation,

making a genetic diagnosis impossible, and therefore, certain individuals will require a clinical diagnosis, which is determined by whether a

patient has tumors in two of the three endocrine organs (parathyroid,

pancreas/duodenum, or pituitary) or has a family history of MEN 1

and one of the endocrine organ tumors. In view of the stimulatory

effect of calcium on gastric secretion, the hyperparathyroidism and

hypercalcemia seen in MEN 1 patients may have a direct effect on ulcer

disease. Resolution of hypercalcemia by parathyroidectomy reduces

gastrin and gastric acid output in gastrinoma patients. An additional

distinguishing feature in ZES patients with MEN 1 is the higher incidence of gastric carcinoid tumor development (as compared to patients

with sporadic gastrinomas). ZES presents and is diagnosed earlier in

MEN 1 patients, and they have a more indolent course as compared

to patients with sporadic gastrinoma. Gastrinomas tend to be smaller,

multiple, and located in the duodenal wall more often than is seen in

patients with sporadic ZES. Establishing the diagnosis of MEN 1 is

critical in order to provide genetic counseling to the patient and his or

her family and also to determine the recommended surgical approach.

Therefore, gastrinoma patients should be screened for MEN 1 by performing a detailed family history and obtaining several serum markers

including calcium, parathyroid, prolactin, and pancreatic polypeptide

levels.

Diagnosis Establishing an early diagnosis is important in order to

minimize the long-term sequelae of gastric acid hypersecretion, prevent metastatic disease, and counsel family members if a diagnosis of

MEN 1 is established. Biochemical measurements of gastrin and acid

secretion in patients suspected of having ZES play an important role

is establishing this rare diagnosis. Often, patients suspected of having

ZES will be treated with a PPI in an effort to ameliorate symptoms and

decrease the likelihood of possible acid-related complications. The

presence of the PPI, which will lower acid secretion and potentially

elevate fasting gastrin levels in normal individuals, will make the

diagnostic approach in these individuals somewhat difficult. Significant morbidity related to peptic diathesis has been described when

stopping PPIs in gastrinoma patients; therefore, a systematic approach

in stopping these agents is warranted (see below). The first step in the