Zollinger-Ellison Syndrome

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1- Introduction, Definition & Anatomical Location

2- Pathophysiology

3- Risk Factors & Precipitating Events

4- Clinical Presentation (Signs & Symptoms)

5- Endoscopic Findings

6- Initial Resuscitation

7- Pharmacological & Supportive Treatment

8- Prognosis & Recurrence Risk

Introduction

Zollinger–Ellison syndrome (ZES) is a rare condition characterized by gastrin-secreting tumors (gastrinomas), usually found in the pancreas or duodenum, leading to excess gastric acid secretion. This hyperacidity causes recurrent and severe peptic ulcers, often in atypical locations, and may also lead to diarrhoea and malabsorption.

ZES should be suspected in patients with refractory ulcers, multiple ulcers, or ulcers located beyond the duodenal bulb.

Pathophysiology

1. Gastrinoma Formation

Gastrinomas are neuroendocrine tumors, most often located in the duodenum (60%) or pancreas (30%).
Around 25% of cases are associated with Multiple Endocrine Neoplasia type 1 (MEN-1).

2. Excess Gastrin Secretion

Tumor cells secrete large quantities of gastrin, independent of normal regulatory feedback.

3. Stimulation of Parietal Cells

Gastrin stimulates:
- Parietal cells in the gastric body to secrete hydrochloric acid (HCl).
- Enterochromaffin-like (ECL) cells to release histamine, further promoting acid secretion.

4. Hyperacidity Effects

The excessive acid causes:
- Multiple and recurrent peptic ulcers, often in the duodenum and even beyond (e.g. jejunum).
- Gastric mucosal damage, leading to pain and bleeding.
- Inactivation of pancreatic enzymes, which impairs digestion and contributes to malabsorption.

5. Gastrointestinal Sequelae

High acid load may:
- Cause diarrhoea due to fluid secretion and impaired fat digestion.
- Lead to steatorrhoea (fatty stools) and weight loss in advanced cases.

Risk Factors & Precipitating Events

1. Established Risk Factors

a. Genetic Syndromes

Multiple Endocrine Neoplasia type 1 (MEN-1)
- Accounts for ~25% of ZES cases.
- Inherited in an autosomal dominant pattern.
- Associated with parathyroid adenomas, pituitary tumors, and pancreatic neuroendocrine tumors, including gastrinomas.

b. Male Sex

ZES is slightly more common in men, particularly in MEN-1–associated cases.

c. Age

Most cases present between 30 and 50 years, but MEN-1–related cases may present earlier.

2. Tumor-Associated Risk Factors

Neuroendocrine tumors of the pancreas or duodenum are the source of gastrin production.
Metastatic disease, especially to the liver or lymph nodes, increases severity and complicates management.

3. Precipitating Events

There are no identified environmental or lifestyle triggers that directly cause or precipitate ZES. However, certain features might lead to its diagnosis:

Refractory or recurrent peptic ulcers, despite standard therapy.
Ulcers in atypical locations, e.g. jejunum.
Chronic diarrhoea or malabsorption unexplained by other causes.

Clinical Presentation

1. Gastrointestinal Symptoms

a. Peptic Ulceration

Most common presentation
Features:
- Epigastric pain, often burning or gnawing.
- Worsens with fasting and may be relieved by food or antacids.
- Refractory to standard ulcer treatments.
- May present with:
  - Upper GI bleeding (haematemesis or melaena)
  - Perforation
  - Ulcers in unusual sites (e.g. distal duodenum or jejunum)

b. Gastro-oesophageal Reflux Disease (GORD)

Due to excessive acid load.
Heartburn, regurgitation, or oesophagitis.

c. Diarrhoea

Present in ~50–70% of patients.
Caused by:
- Acid-induced inactivation of pancreatic enzymes, impairing digestion.
- Increased intestinal secretion and motility.
Often watery and voluminous.

d. Steatorrhoea

Fat malabsorption leads to pale, bulky, foul-smelling stools.
May be accompanied by weight loss and nutritional deficiencies.

2. Systemic or Constitutional Symptoms

Weight loss: due to malabsorption or chronic ulcer pain.
Anemia: from chronic bleeding ulcers.
Fatigue: secondary to anemia or nutrient loss.

3. MEN-1–Associated Features (if applicable)

In patients with Multiple Endocrine Neoplasia type 1, ZES may co-exist with:

Hyperparathyroidism → hypercalcaemia symptoms (polyuria, nephrolithiasis)
Pituitary tumors → prolactinoma or growth hormone excess
Other pancreatic neuroendocrine tumors

Endoscopic Findings

Finding	Description
Multiple peptic ulcers	Found in the stomach, duodenum, and often the jejunum.
Ulcers beyond the duodenal bulb	Ulcers in the second or third part of the duodenum or proximal jejunum, which is highly suggestive of ZES.
Refractory or recurrent ulcers	Ulcers that fail to heal despite high-dose proton pump inhibitors.
Hypertrophic gastric rugae	Thickened folds in the stomach due to parietal cell hyperplasia from chronic gastrin stimulation.
Severe erosive oesophagitis	May range from mild inflammation to deep erosions and strictures due to chronic acid reflux.
Gastric mucosal erythema	Nonspecific but may reflect gastric acid-related inflammation.

Initial Resuscitation

1. Airway, Breathing, Circulation (ABC)

Assess airway and breathing, especially if the patient is vomiting or bleeding.
Secure IV access with large-bore cannulas.
Administer IV fluids (e.g. normal saline or Ringer’s lactate) to correct dehydration or shock.

2. Control Acid Secretion

Start high-dose intravenous proton pump inhibitor (PPI) therapy:
- e.g. Pantoprazole 80 mg IV bolus, then 8 mg/hour infusion.
This helps reduce acid damage and stabilize ulcers.

3. Manage GI Bleeding (if present)

Monitor haemoglobin, haematocrit.
Cross-match blood and transfuse as needed.
Insert a nasogastric tube if large upper GI bleeding is suspected.

4. Correct Electrolytes and Nutrition

Monitor and correct potassium, magnesium, and calcium levels.
Begin nutritional support if malabsorption is significant.

5. Investigate and Monitor

Check serum gastrin levels once the patient is stable (note: stop PPIs for accurate measurement if feasible).
Monitor vital signs, urine output, and ongoing symptoms.

Pharmacological & Supportive Treatment

1. Pharmacological Therapy

a. Proton Pump Inhibitors (PPIs) — First-line

High-dose PPI therapy is essential to block acid secretion.
Examples:
- Omeprazole 60–120 mg/day (oral, divided doses)
- Pantoprazole or Esomeprazole may be used IV in acute cases
Titrated to control symptoms and maintain gastric pH > 4.
Most patients require lifelong PPI therapy if surgery is not curative.

b. Somatostatin Analogues (for metastatic or functional control)

Used if gastrinomas are metastatic or PPI control is inadequate.
Octreotide or Lanreotide may reduce both:
- Gastrin secretion
- Tumor growth in some patients

2. Supportive Treatment

a. Fluid and Electrolyte Management

IV fluid replacement in patients with significant diarrhoea or dehydration.
Correct:
- Hypokalaemia
- Hypomagnesaemia
- Metabolic alkalosis

b. Nutritional Support

Patients with chronic diarrhoea or steatorrhoea may require:
- Pancreatic enzyme supplements
- Fat-soluble vitamin replacement (A, D, E, K)
- High-calorie oral or enteral nutrition

c. Antidiarrhoeal Agents (if needed)

Loperamide may provide symptomatic relief, but should not be used without acid suppression, as diarrhoea is acid-driven.

3. Monitoring

Regular monitoring of:
- Serum gastrin levels
- Gastric pH (if needed)
- Nutritional status and weight
- Liver function (in case of metastases)

Prognosis & Recurrence Risk

Prognosis

Scenario	Prognosis
Localized, resectable gastrinoma	Excellent prognosis with potential surgical cure and long-term survival.
Metastatic disease (e.g. to liver)	Variable prognosis; median survival may exceed 10 years with effective acid suppression and supportive care.
MEN-1–associated ZES	Lower cure rate due to multiple tumors and frequent recurrence, but overall survival is still favorable with control of acid secretion.

5-year survival: >80% overall with treatment.
Death is rarely due to acid complications; more commonly due to tumor burden or metastatic progression.

Recurrence Risk

Factor	Effect on Recurrence Risk
MEN-1 syndrome	High risk due to multifocal and recurrent tumors.
Incomplete surgical resection	Recurrence likely within years.
No tumor localization	Long-term recurrence risk unclear; surveillance needed.
Metastatic disease	Not truly “recurrent”—represents ongoing tumor activity.

Monitoring for Recurrence

Serum gastrin levels: Rising levels suggest recurrence or progression.
Imaging: Regular scans (CT, MRI, or somatostatin receptor imaging) to assess for new lesions or metastasis.
Symptom recurrence: Return of ulcers, diarrhoea, or weight loss may indicate uncontrolled disease.