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, which interfere 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, with 1–3 cases per million per year in Sweden, 0.5 per million per year in Ireland, and 0.1–0.2 per million per year in Denmark.
  
  

Age and Sex Distribution

• The mean age of onset is 43 years, though individuals with multiple endocrine neoplasia type 1 (MEN1)-associated ZES tend to present 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, with fewer than 3% of cases occurring in individuals under 20 years old, and 7% in those over 60 years.
  
  

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, whereas MEN1-associated ZES presents with multifocal tumours.
  
  

Tumour Location and Distribution

• Duodenal gastrinomas are often small (<1 cm), multiple, and less aggressive, whereas 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 the stomach, liver, bile duct, peripancreatic lymph nodes, ovary, and 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, with chronic acid reflux leading to oesophagitis and potential 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, 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
  • Patients with bone metastases may experience 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

• The first-line test for suspected Zollinger-Ellison syndrome.
• Elevated in >99% of patients with ZES.
• A level >481 picomols/L (>1000 picograms/mL) is strongly indicative of ZES, particularly in the absence of renal failure.
• FSG alone is insufficient for diagnosis due to other potential causes of hypergastrinaemia, such as atrophic gastritis, Helicobacter pylori infection, pernicious anaemia, and proton pump inhibitor (PPI) use.
• Gastric pH measurement is required alongside FSG to confirm inappropriate acid hypersecretion.
  
  

• Helps distinguish appropriate hypergastrinaemia (gastric pH >2) from inappropriate hypergastrinaemia (gastric pH <2, suggesting ZES).
• A gastric pH <2 with an elevated FSG supports the diagnosis.
• Can be assessed via nasogastric aspiration or endoscopic sampling, with endoscopy providing more patient tolerance and reproducibility.
  
  

Confirmatory Tests

• Performed when FSG is elevated but <10-fold above normal, with a gastric pH <2.
• Secretin paradoxically stimulates gastrin release in ZES, whereas normal gastric G cells are inhibited.
• A rise of ≥58 picomols/L (≥120 picograms/mL) within 15 minutes is diagnostic.
• PPIs should ideally be discontinued one week prior to reduce the risk of false positives.
  
  

• Based on the principle that gastrinomas express calcium-sensing receptors, leading to increased gastrin secretion upon calcium infusion.
• A rise of >192 picomols/L (>400 picograms/mL) within 60 minutes is considered positive.
• Less commonly used than the secretin test due to lower sensitivity and specificity.
  
  

• An alternative to the secretin test, though less widely used.
• May be considered in cases where secretin is unavailable.
  
  

Imaging Studies for Tumour Localisation

• Multiphasic CT or MRI with contrast is the first-line imaging modality for tumour localisation.
• Limited sensitivity for detecting small gastrinomas (<1 cm).
• MRI is superior to CT for detecting liver metastases.
  
  

• Uses radiolabelled octreotide, which binds to somatostatin receptors on gastrinomas.
• Sensitivity: 77–78%; Specificity: 93–94% for detecting primary tumours and metastases.
• Combining SRS with single-photon emission CT (SPECT) improves accuracy.
  
  

• Highly sensitive and specific for neuroendocrine tumours, including gastrinomas.
• Sensitivity: 72–100%; Specificity: 83–100%.
• Recommended for both primary tumour localisation and staging.
  
  

• Preferred for detecting small duodenal gastrinomas (<1 cm) that may not be visible on CT or MRI.
• Allows for fine-needle aspiration biopsy to confirm tumour histology.
• Particularly useful in screening for multiple endocrine neoplasia type 1 (MEN1).
  
  

• Used to assess gastric and duodenal ulcers.
• Prominent gastric folds (90% of ZES cases) and postbulbar ulcers suggest the diagnosis.
• Not diagnostic on its own but supportive if other findings align.
  
  

Genetic Testing for MEN1

• Indicated in patients with suspected MEN1, particularly those with:
  • Hyperparathyroidism
  • Pituitary tumours
  • A family history of MEN1
    
    

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