What is the most likely additional diagnosis for a patient with symptoms of thirst, tiredness, and indigestion, elevated gastrin (290 pmol/l) and calcium (2.91 mmol/l) levels, unknown family medical history due to adoption, and normal physical examination findings?

Most Likely Additional Diagnosis: Multiple Endocrine Neoplasia Type 1 (MEN1)

This patient's combination of elevated gastrin (290 pmol/l) and hypercalcemia (2.91 mmol/l) strongly suggests Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome, making insulinoma (Option E) the most likely additional diagnosis, as MEN1 patients frequently harbor multiple pancreatic neuroendocrine tumors including gastrinomas and insulinomas. 1, 2

Clinical Reasoning

The Gastrinoma-MEN1 Connection

• All patients with gastrinoma should be evaluated for MEN1 syndrome, as recommended by guidelines, with mandatory measurement of fasting calcium, parathyroid hormone, and prolactin 1, 2

• This patient presents with both elevated gastrin (290 pmol/l, normal <55) and hypercalcemia (2.91 mmol/l), which is the classic biochemical signature of MEN1-associated gastrinoma with primary hyperparathyroidism 1, 3

• Chronic hypercalcemia itself elevates serum gastrin concentrations in 22-28% of patients with hypercalcemia, but marked elevations (>250 pg/mL) suggest either achlorhydria or MEN1 3

Why Insulinoma is Most Likely Among the Options

• MEN1 patients develop multiple pancreatic neuroendocrine tumors, with gastrinomas being the most common functional tumor (54%) and insulinomas occurring in approximately 10-30% of MEN1 cases 1

• The patient's symptoms of tiredness could represent hypoglycemic episodes from an insulinoma, which may be subtle and not yet recognized as hypoglycemia 1

• Insulinomas in MEN1 are often multiple and small, making them difficult to detect initially, but they should be actively sought once MEN1 is suspected 1

Excluding Other Options

Option A (Hypercortisolaemia/Cushing's): Not associated with MEN1 syndrome or the gastrinoma-hypercalcemia combination presented 1

Option B (Medullary Thyroid Carcinoma): This is a feature of MEN2 syndrome (along with pheochromocytoma and hyperparathyroidism), not MEN1. MEN2 does not cause gastrinomas 1, 2

Option C (VIPoma): While VIPomas can occur in MEN1, they are extremely rare (<1% of MEN1 cases) and would present with profuse watery diarrhea (>1 liter/day), hypokalemia, and achlorhydria—none of which are described in this patient 2, 4

Option D (Pheochromocytoma): This is part of MEN2 syndrome, not MEN1. The patient's normal blood pressure (132/72) and lack of paroxysmal symptoms make this unlikely 1

Diagnostic Workup Required

Confirm Gastrinoma Diagnosis

• Stop any proton pump inhibitors for 10-14 days before repeating fasting gastrin, as PPIs cause false elevation of both gastrin and chromogranin A 1, 2, 4

• Measure gastric pH to distinguish between gastrinoma (pH <2) and atrophic gastritis (pH >4-5), which is the key discriminator 2, 5

• If gastrin remains elevated with pH <2, **perform secretin stimulation test** (increase >120 pg/mL has 94% sensitivity and 100% specificity for gastrinoma) 6

Evaluate for MEN1 Syndrome

• Measure parathyroid hormone (PTH) to confirm primary hyperparathyroidism, which is present in >90% of MEN1 patients and is usually the first manifestation 1, 2

• Measure fasting insulin, C-peptide, and proinsulin to screen for insulinoma 1

• Consider 48-72 hour supervised fast if insulinoma is suspected based on symptoms or biochemistry, as this will trigger hypoglycemia in most cases within 24 hours 1, 4

• Measure prolactin to screen for pituitary adenomas, which occur in 30-40% of MEN1 patients 1, 2

Imaging Studies

• Multiphasic CT or MRI of abdomen and pelvis to localize gastrinoma and evaluate for other pancreatic neuroendocrine tumors 2, 4

• Endoscopic ultrasound (EUS) has 83% sensitivity for pancreatic gastrinomas and should be performed, though sensitivity is lower for duodenal lesions 7

• Somatostatin receptor scintigraphy (Octreoscan) or Gallium-68 DOTATOC PET for comprehensive tumor localization, as these have high sensitivity and specificity 7

Critical Clinical Pitfalls

• Do not interpret elevated gastrin while patient is on PPIs—this is the most common cause of false positives and will lead to misdiagnosis 1, 2, 4

• Do not assume isolated gastrinoma—the presence of hypercalcemia mandates full MEN1 evaluation, as these patients require different surgical management and lifelong surveillance 1, 2

• Do not miss insulinoma in MEN1 patients—symptoms may be subtle (tiredness, confusion) and hypoglycemia may only occur postprandially in 5% of cases 1

• Renal insufficiency (creatinine 103 micromol/l is borderline elevated) can cause spurious gastrin elevation and must be considered in the differential, though the concurrent hypercalcemia makes MEN1 more likely 2, 4