Zollinger-Ellison Syndrome

Genetic and Molecular Basis

• Sporadic ZES accounts for approximately 75–80% of cases, with no identified genetic mutation.
• MEN1-associated ZES occurs in 20–25% of cases due to mutations in the MEN1 gene on chromosome 11q13.
• The MEN1 gene encodes menin, a tumour suppressor that regulates cell proliferation. Mutations in this gene result in uncontrolled cell growth and tumour formation.

Tumour Origin and Distribution

• Duodenal gastrinomas (70–80%) are the most common, typically small, multiple, and less aggressive.
• Pancreatic gastrinomas (20–30%) tend to be larger, solitary, and more prone to metastasis.
• Ectopic gastrinomas are rare but can occur in the stomach, liver, bile duct, ovary, heart, and lung.

Mechanisms of Hypergastrinaemia and Acid Hypersecretion

• Gastrinomas overproduce gastrin, which stimulates parietal cells to significantly increase basal and maximal acid output.
• Gastric mucosal hypertrophy occurs due to prolonged stimulation, increasing the number of parietal cells and further amplifying acid secretion.
• Reduced somatostatin secretion, a key inhibitor of gastrin, enhances acid hypersecretion.

Malignancy and Metastatic Potential

• 55–90% of gastrinomas are malignant, frequently metastasising to the liver (40–60%) and lymph nodes.
• Bone metastases commonly affect the axial skeleton, leading to significant morbidity.

Gastrin Secretion and Acid Hypersecretion

• Gastrinomas, typically found in the duodenum (70–80%) or pancreas (20–30%), secrete large amounts of gastrin, directly stimulating parietal cells to increase gastric acid production.
• Gastrin also acts on enterochromaffin-like (ECL) cells, promoting histamine release, which further enhances acid secretion.
• Gastric acid output in ZES is typically four- to sixfold higher than normal and, in severe cases, can exceed tenfold.

Mucosal Hypertrophy and Peptic Ulceration

• Hypertrophy of the gastric mucosa occurs due to chronic stimulation by gastrin, leading to an increased number of parietal cells, further amplifying acid production.
• The resultant severe peptic ulceration occurs in the duodenum, jejunum, and occasionally beyond the ligament of Treitz.
• More than 90% of patients with ZES develop ulcers, which are often refractory to standard acid-suppressive therapy.

Malabsorption and Diarrhoea

• Diarrhoea in ZES is multifactorial, caused by:
  • Excessive acid secretion overwhelming the neutralising effect of pancreatic bicarbonate, leading to a low intestinal pH that inactivates digestive enzymes.
  • Bile acid precipitation, which impairs fat emulsification and leads to steatorrhoea.
  • Direct epithelial damage, resulting in further malabsorption.
  • High gastrin levels interfering with sodium and water absorption in the small intestine, contributing to a secretory component in diarrhoea.

Association with Multiple Endocrine Neoplasia Type 1 (MEN1)

• Around 20–25% of ZES cases occur in the context of MEN1, an autosomal dominant syndrome that involves parathyroid, pancreatic, and pituitary tumours.
• MEN1-associated ZES often presents with multifocal gastrinomas and elevated serum calcium levels.
• The presence of multiple tumours increases the risk of metastatic spread, particularly to the liver (40–60%) and bone.

Incidence and Prevalence

• Zollinger-Ellison syndrome (ZES) is a rare condition, with an estimated incidence of 0.5 to 2 cases per million people per year.
• It accounts for approximately 0.1–1% of all duodenal ulcer cases.
• Reported incidence varies by region:
  • 1–3 cases per million per year in Sweden.
  • 0.5 per million per year in Ireland.
  • 0.1–0.2 per million per year in Denmark.

Age and Sex Distribution

• The mean age of onset is 43 years, with MEN1-associated ZES presenting about a decade earlier.
• There is a slight male predominance, with a male-to-female ratio of 1.3:1.
• Diagnosis is often delayed by 5–7 years.
• Fewer than 3% of cases occur in individuals under 20 years old.
• 7% of cases occur in those over 60 years of age.

Sporadic vs. MEN1-Associated Cases

• 80% of cases are sporadic, while 20–30% occur in association with MEN1.
• Sporadic gastrinomas are more likely to be solitary.
• MEN1-associated ZES typically presents with multifocal tumours.

Tumour Location and Distribution

• 50–88% of sporadic cases and 70–100% of MEN1-associated cases involve duodenal gastrinomas.
• Duodenal gastrinomas are usually small (<1 cm), multiple, and less aggressive.
• Pancreatic gastrinomas tend to be larger and more likely to metastasise.
• In 5–15% of cases, gastrinomas arise in non-duodenal, non-pancreatic sites including:
  • Stomach
  • Liver
  • Bile duct
  • Peripancreatic lymph nodes
  • Ovary
  • Heart

Key Diagnostic Features

 Refractory or recurrent peptic ulcer disease

• Persistent ulcers, often multiple and extending beyond the duodenal bulb, are common.
• Ulcers that fail to respond to standard therapy should raise suspicion.

Diarrhoea

• Present in 37–73% of patients.
• Often due to acid-induced inactivation of pancreatic enzymes, leading to malabsorption and steatorrhoea.

Epigastric abdominal pain

• Reported in 70–100% of cases.
• Typically relieved by food or antacids, resembling peptic ulcer disease.

Gastro-oesophageal reflux disease (GORD)

• Occurs in 44% of patients.
• Chronic acid reflux may lead to oesophagitis and complications such as Barrett’s oesophagus.

Gastrointestinal bleeding

• May present as haematemesis or melaena.
• Often due to severe ulceration.

Weight loss

• Can result from chronic diarrhoea and malabsorption.

Risk Factors and Associated Conditions

 Multiple endocrine neoplasia type 1 (MEN1)

• 20–30% of ZES cases are associated with MEN1.
• MEN1 is an autosomal dominant disorder characterised by parathyroid hyperplasia, pancreatic endocrine tumours, and pituitary adenomas.
• Suspicion should be raised in individuals with a family history of MEN1-related tumours.
• Features such as nephrolithiasis and hypercalcaemia may suggest MEN1 involvement.

Metastatic Disease

• Bone metastases may cause low back pain or bone pain.
• Liver metastases can present with hepatomegaly or nonspecific gastrointestinal symptoms.

Family and Personal Medical History

• A family history of peptic ulcers, nephrolithiasis, hyperparathyroidism, or pituitary tumours should prompt consideration of MEN1-associated ZES.
• A personal history of chronic unexplained diarrhoea, refractory ulcers, or multiple ulcer recurrences despite therapy should warrant further investigation.

Common Examination Findings

 Pallor

• May indicate chronic gastrointestinal bleeding from severe ulceration.

Epigastric tenderness

• Often localised to the upper abdomen, suggesting peptic ulcer disease.

Dental erosions

• Seen in chronic gastro-oesophageal reflux disease (GORD) due to persistent acid reflux.

Hepatomegaly

• Suggests liver metastases, which occur in 40–60% of cases with malignant gastrinomas.

Less Common Findings

 Jaundice

• Rare but may develop due to common bile duct compression by a tumour.

Bone tenderness

• May indicate bone metastases, particularly in the axial skeleton.

Signs of MEN1

• If associated with multiple endocrine neoplasia type 1 (MEN1), additional findings may include:
  • Nephrolithiasis (suggestive of parathyroid hyperplasia).
  • Acromegaly or Cushing’s syndrome (linked to pituitary adenomas).
  • Hypoglycaemia or hyperglycaemia (due to pancreatic tumours).

Initial Diagnostic Tests

 Fasting Serum Gastrin (FSG)

• First-line test for suspected Zollinger-Ellison syndrome (ZES).
• Elevated in >99% of patients with ZES.
• A level >481 picomols/L (>1000 pg/mL) strongly suggests ZES, especially in the absence of renal failure.
• Alone is insufficient due to other causes of hypergastrinaemia (e.g., H. pylori, atrophic gastritis, PPI use).
• Requires concurrent gastric pH measurement for diagnostic accuracy.

Gastric pH Measurement

• Distinguishes between appropriate and inappropriate hypergastrinaemia.
• A pH <2 with elevated FSG supports ZES diagnosis.
• Measured via nasogastric aspiration or endoscopy (preferred for reproducibility and comfort).

Confirmatory Tests

 Secretin Stimulation Test

• Used when FSG is elevated but not >10-fold normal and pH <2.
• ZES gastrinomas paradoxically respond to secretin with increased gastrin secretion.
• A rise of ≥58 picomols/L (≥120 pg/mL) within 15 minutes is diagnostic.
• PPIs should be withheld for at least one week beforehand.

Calcium Infusion Test

• Based on calcium-sensing receptor expression in gastrinomas.
• Positive if gastrin rises >192 picomols/L (>400 pg/mL) within 60 minutes.
• Less sensitive and specific than the secretin test.

Glucagon Stimulation Test

• An alternative where secretin is unavailable.
• Less commonly used in practice.

Imaging Studies for Tumour Localisation

 Abdominal CT and MRI

• First-line imaging with contrast-enhanced multiphasic protocols.
• Less sensitive for detecting gastrinomas <1 cm.
• MRI preferred for liver metastasis detection.

Somatostatin Receptor Scintigraphy (SRS)

• Uses radiolabelled octreotide to target somatostatin receptor-expressing tumours.
• Sensitivity: 77–78%; Specificity: 93–94%.
• Accuracy improves with single-photon emission CT (SPECT).

Gallium-68 DOTATATE PET/CT

• Superior sensitivity and specificity for neuroendocrine tumours.
• Sensitivity: 72–100%; Specificity: 83–100%.
• Useful for both localisation and staging.

Endoscopic Ultrasound (EUS)

• Best modality for identifying duodenal gastrinomas <1 cm.
• Allows fine-needle aspiration biopsy for histology.
• Especially useful in MEN1 patients.

Oesophagogastroduodenoscopy (OGD)

• Assesses gastric and duodenal mucosa.
• Findings suggestive of ZES: postbulbar ulcers, prominent gastric folds.
• Supportive but not diagnostic alone.

Genetic Testing for MEN1

• Indicated in patients with features such as:
  • Hyperparathyroidism
  • Pituitary adenomas
  • Family history of MEN1

Conditions Associated with Hypergastrinaemia

Atrophic Gastritis

• Clinical Features: Often asymptomatic or associated with nausea, bloating, and weight loss.
• Pathophysiology: Chronic inflammation leads to parietal cell loss, causing hypochlorhydria and reflex hypergastrinaemia.
• Investigations:
  • Fasting serum gastrin: Elevated.
  • Gastric pH: >2 (hypochlorhydria present).
  • Secretin stimulation test: Negative.
  • Endoscopy: Thinned gastric mucosa; biopsy may reveal atrophy and intestinal metaplasia.

Pernicious Anaemia

• Clinical Features: Fatigue, paraesthesia, glossitis, mild jaundice, and neurological symptoms.
• Pathophysiology: Autoimmune destruction of parietal cells leads to achlorhydria, causing reflex hypergastrinaemia.
• Investigations:
  • Fasting serum gastrin: Elevated.
  • Gastric pH: >2 (achlorhydria).
  • Secretin stimulation test: Negative.
  • Intrinsic factor antibodies: Positive.
  • Vitamin B12 levels: Low.

Chronic Kidney Disease

• Clinical Features: Fatigue, pruritus, nausea, restless legs, and anaemia.
• Pathophysiology: Reduced renal clearance leads to hypergastrinaemia, independent of gastric acid output.
• Investigations:
  • Fasting serum gastrin: Elevated.
  • Gastric pH: Variable.
  • Secretin stimulation test: Negative.
  • Serum creatinine & GFR: Abnormal, consistent with kidney disease.

Proton Pump Inhibitor (PPI) Use

• Clinical Features: Often asymptomatic; may have mild GORD symptoms.
• Pathophysiology: Long-term PPI use causes hypochlorhydria, leading to reactive hypergastrinaemia.
• Investigations:
  • Fasting serum gastrin: Elevated.
  • Gastric pH: >2 (hypochlorhydria).
  • Secretin stimulation test: Negative.
  • Resolution of hypergastrinaemia 1-2 weeks after PPI withdrawal supports the diagnosis.

Conditions Associated with Gastric Acid Hypersecretion

Peptic Ulcer Disease due to Helicobacter pylori

• Clinical Features: Epigastric pain, nausea, bloating, and dyspepsia.
• Pathophysiology: H. pylori infection impairs somatostatin secretion, increasing gastrin release and acid secretion.
• Investigations:
  • Fasting serum gastrin: Elevated in some cases.
  • Gastric pH: Normal to low (<2).
  • Secretin stimulation test: Negative.
  • Urea breath test, stool antigen test, or biopsy: Positive for H. pylori.

Idiopathic Gastric Hypersecretion

• Clinical Features: Similar to peptic ulcer disease, but without H. pylori infection.
• Pathophysiology: Postprandial acid hypersecretion without a gastrinoma.
• Investigations:
  • Fasting serum gastrin: Normal.
  • Gastric pH: <2.
  • Secretin stimulation test: Negative.

Antral G-cell Hyperplasia

• Clinical Features: May cause recurrent peptic ulcers.
• Pathophysiology: Hyperplasia of gastrin-secreting G-cells in the gastric antrum leads to mild hypergastrinaemia and increased acid secretion.
• Investigations:
  • Fasting serum gastrin: Elevated.
  • Gastric pH: <2.
  • Secretin stimulation test: Negative.

Post-Surgical Conditions Mimicking ZES

Retained Antrum Syndrome

• Clinical Features: Recurrent ulcers after Billroth I or II surgery.
• Pathophysiology: Incomplete antral resection results in continued gastrin secretion.
• Investigations:
  • Fasting serum gastrin: Mildly elevated.
  • Gastric pH: <2.
  • Secretin stimulation test: Negative.
  • Surgical history helps differentiate from ZES.

Gastric Outlet Obstruction

• Clinical Features: Nausea, vomiting, weight loss, and postprandial fullness.
• Pathophysiology: Chronic obstruction leads to gastric distension, stimulating gastrin release.
• Investigations:
  • Fasting serum gastrin: Mildly elevated.
  • Gastric pH: Variable.
  • Imaging: May reveal gastric dilation and obstruction.

Acid Suppression Therapy

• Proton pump inhibitors (PPIs) are the first-line treatment to control gastric acid hypersecretion, preventing complications such as peptic ulcer disease and gastrointestinal bleeding.
• No preference exists between PPI agents, and treatment is usually initiated at high doses.
• Acid output targets:
  • <10 mEq/hour in sporadic ZES.
  • <5 mEq/hour in ZES associated with MEN1.
• Intravenous PPIs are used in patients unable to tolerate oral therapy or in the perioperative period.

Alternative Medical Therapies

• Somatostatin analogues (octreotide, lanreotide) can be used in refractory cases but are not first-line due to variable response and the need for parenteral administration.
• H2-receptor antagonists are largely obsolete due to lower efficacy and the development of tolerance.

Long-Term Risks of PPI Therapy

• Increased fracture risk
• Higher incidence of enteric infections
• Possible association with dementia and magnesium deficiency
• Hypergastrinaemia
• Subacute cutaneous lupus erythematosus
• Potential drug interactions
• Despite these concerns, PPIs should not be discontinued in ZES patients, as acid suppression is critical.

Surgical Management

Localised Sporadic Disease

• Curative resection is recommended in patients with sporadic ZES, even when preoperative imaging fails to identify a tumour.
• Duodenal gastrinomas: Managed with duodenotomy, local excision, and periduodenal node dissection.
• Pancreatic gastrinomas:
  • Enucleation is performed for superficial or exophytic lesions.
  • Pancreatoduodenectomy is needed for deeper lesions or those near the pancreatic duct.
• Lymphadenectomy is essential, as 30–70% of patients with duodenal or pancreatic gastrinomas have lymph node metastases.

Surgical Management in MEN1

• Surgery is controversial due to the multifocal nature of tumours.
• Traditionally, patients with MEN1 and ZES are managed with lifelong PPI therapy.
• Surgical resection is considered if:
  • Tumour size >2 cm.
  • Tumour shows rapid growth over 6–12 months.
  • Symptoms are refractory to medical therapy.

Management of Metastatic Disease

Patients with Liver Metastases

• Somatostatin analogues (octreotide, lanreotide) control symptoms of excess gastrin secretion.
• Liver-directed therapies:
  • Cytoreductive surgery (>90% tumour burden removal) for patients with indolent disease.
  • Thermal ablation (radiofrequency or microwave) for limited hepatic lesions.
  • Hepatic arterial embolisation for symptomatic, unresectable liver metastases.
  • Liver transplantation in highly selected patients with unresectable disease, meeting strict inclusion criteria.

Patients with Progressive or Extrahepatic Metastases

• Everolimus (mTOR inhibitor) and sunitinib (tyrosine kinase inhibitor) are effective in slowing tumour progression.
• Peptide receptor radionuclide therapy (PRRT) with lutetium-177-dotatate targets somatostatin receptor-expressing tumour cells.
• Systemic chemotherapy (e.g., temozolomide, fluorouracil, capecitabine) is used for rapidly progressing disease but has limited efficacy.
• Palliative radiotherapy is considered for bone metastases or oligometastatic disease.

Impact of Metastases

• The most significant determinant of mortality in Zollinger-Ellison syndrome is metastatic spread, particularly to the liver, bones, and distant sites.
• In multiple endocrine neoplasia type 1 (MEN1), malignant gastrinoma accounts for 31% to 57% of deaths.
• A long-term study of 185 patients followed for 12.5 years found:
  • 22% of patients without MEN1 had liver metastases at diagnosis, compared with 6% of MEN1 patients.
  • Liver metastases were more common in pancreatic gastrinomas than duodenal tumours.
  • 10-year survival for patients with liver metastases was 30%.

Prognosis Without Metastases

• In sporadic ZES without metastases, 15-year survival exceeds 80%.
• In MEN1 patients without liver metastases, 20-year survival is 100%.
• A separate study of MEN1-ZES found 30-year survival at 82%, with a mean age at death of 55 years.
• Deaths from uncontrolled gastric acid hypersecretion are rare due to effective acid suppression.

Morbidity and Complications

• Fewer than 5% of patients develop severe complications, which include:
  • Peptic ulcer perforation, particularly in the duodenum and jejunum.
  • Oesophageal strictures due to chronic acid reflux.
  • Gastrointestinal bleeding from extensive ulceration.
  • Gastric outlet obstruction from tumour-related narrowing.
  • Gastric carcinoids, particularly in MEN1 patients.

Long-Term Outlook and Survival

• Early diagnosis and intervention improve outcomes.
• In localised disease, surgical resection improves survival and reduces complications.
• In non-surgical cases, lifelong proton-pump inhibitor (PPI) therapy remains the primary treatment.
• MEN1-ZES patients require lifelong monitoring due to the risk of multiple tumour recurrences.

Peptic Ulcer-Related Complications

• Patients with Zollinger-Ellison syndrome (ZES) have an increased risk of peptic ulcer disease due to excessive gastric acid secretion.
• Complications include perforation, gastric outlet obstruction, and gastrointestinal bleeding.
• The duodenum and jejunum are the most common sites of ulceration.
• Proton pump inhibitor (PPI) therapy has significantly reduced the incidence of severe ulcer-related complications.

Anaemia

• Chronic gastrointestinal bleeding from peptic ulcers may lead to iron deficiency anaemia.
• Symptoms include fatigue, pallor, and exertional dyspnoea.
• Haemoglobin and ferritin levels should be monitored regularly in patients with chronic peptic ulcer disease.
• Iron supplementation may be required in addition to acid suppression therapy.

Nephrolithiasis

• Nephrolithiasis has been observed in patients with multiple endocrine neoplasia type 1 (MEN1).
• Hypercalcaemia due to associated primary hyperparathyroidism in MEN1 can contribute to calcium stone formation.
• Preventative measures include adequate hydration and monitoring of serum calcium levels.

Gastrointestinal Bleeding

• Ulcer-related bleeding remains a serious complication, particularly in undiagnosed or inadequately treated patients.
• Endoscopic haemostasis is required for active bleeding ulcers.
• Patients on long-term PPI therapy should be monitored for evidence of occult bleeding.

Oesophageal Stricture

• Chronic exposure to gastric acid may lead to oesophageal mucosal damage and stricture formation.
• Symptoms include progressive dysphagia and reflux symptoms.
• Management includes acid suppression therapy and, in severe cases, endoscopic dilation.

Gastric Carcinoids

• Gastric carcinoids are more prevalent in patients with ZES associated with MEN1.
• Hypergastrinaemia may contribute to the development of these lesions.
• Small carcinoids (<2 cm) may be managed with surveillance, while larger lesions or those with atypical features require endoscopic or surgical resection.

Bowel Obstruction

• Peptic ulcer-related fibrosis or gastric outlet obstruction may develop over time.
• Symptoms include nausea, vomiting, postprandial fullness, and weight loss.
• Endoscopic evaluation and imaging studies are required for diagnosis.
• Severe cases may require surgical intervention.

Recurrent Peptic Ulcers

• Despite PPI therapy, some patients may experience recurrent ulceration.
• Causes include inadequate acid suppression, non-adherence to treatment, or the presence of residual gastrinomas.
• Dosage adjustments or the addition of somatostatin analogues may be required in refractory cases.

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