Aetiology

The cause of sporadic Zollinger-Ellison syndrome (ZES) is unknown. About one third of patients with multiple endocrine neoplasia type 1 (MEN1) develop ZES. A gene mutation on the short arm of chromosome 11 encoding the protein menin is thought to result in the development of pancreatic endocrine tumours in these patients.

Pathophysiology

The syndrome is caused by excessive gastrin secretion by duodenal or pancreatic neuroendocrine tumours (gastrinomas). The majority of these gastrinomas arise from enteroendocrine cells in the small intestine; 70% to 80% are duodenal in location.[7] The remainder arise from delta cells in the pancreas, and a minority from other intra-abdominal areas (e.g., stomach, peripancreatic lymph nodes, liver, bile duct, ovary) and extra-abdominal (heart, small cell lung cancer) locations.[8]

Gastrinomas located in the duodenum are usually multiple and small in size and are less likely to become malignant than pancreatic gastrinomas, which tend to be larger, solitary, and sporadic. About 55% to 90% of gastrinomas are malignant and commonly metastasise to the lymph nodes and liver.[9] About 20% of patients with ZES have MEN1.[3] These patients may have elevated levels of serum calcium and a family history of ZES. The presence of multifocal gastrinomas increases the probability of MEN1.[10][11]

Gastrin not only directly stimulates parietal cell secretion but also causes hypertrophy of the gastric mucosa, leading to increased numbers of parietal cells. This results in an increase in basal acid output and maximal acid output, leading to gastro-oesophageal reflux disease symptoms and damage to the mucosal lining of the gastrointestinal tract, causing peptic ulcers. In addition, the acid inactivates pancreatic enzymes, resulting in diarrhoea, steatorrhoea, and malabsorption of lipid-soluble nutrients.[12]

Classification

Clinical classification

There is no formal classification system; however, the following categories are commonly used:

  • Sporadic form: more common

  • Genetic form: related to patients with MEN1; about 20% of patients with ZES have MEN1.[3]

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