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Zollinger‑Ellison Syndrome‑Associated Hyperparathyroidism

Overview

Zollinger‑Ellison syndrome (ZES) is a rare condition in which one or more gastrin‑producing tumors (known as gastrinomas) develop in the pancreas or duodenum. These tumors secrete high levels of gastrin, a hormone that stimulates the stomach to produce excessive acid. When ZES occurs as part of the multiple endocrine neoplasia type 1 (MEN‑1) complex, patients often develop hyperparathyroidism simultaneously. Hyperparathyroidism is the over‑activity of one or more of the parathyroid glands, leading to elevated calcium levels in the blood.

Together, ZES with hyperparathyroidism creates a unique clinical picture that can be challenging to recognize. The condition most commonly affects adults between 30 and 60 years of age, with a slight predominance in women (approximately 55 % of cases). While isolated ZES has an estimated incidence of 0.5–2 cases per million people per year, the MEN‑1–associated form (which includes hyperparathyroidism) accounts for roughly 20‑30 % of all ZES cases <sup>1</sup>. Early detection is critical because untreated gastrinomas can become malignant, and prolonged hypercalcemia increases the risk of kidney stones, bone loss, and cardiovascular disease.

Symptoms

Because two endocrine disorders are present, patients may experience a blend of gastrointestinal and systemic signs. The following list includes the most common symptoms, each with a brief description.

• Recurrent or severe abdominal pain – caused by peptic ulcer disease (PUD) from excess gastric acid.
• Diarrhea or greasy stools – acid inactivates pancreatic enzymes, leading to malabsorption.
• Heartburn / gastro‑esophageal reflux disease (GERD) – persistent burning sensation due to high acid load.
• Nausea and vomiting – especially after meals.
• Weight loss – from malabsorption and chronic vomiting.
• Upper‑grade peptic ulcers – ulcers may be larger, multiple, and located beyond the duodenum.
• Gastric bleeding – can present as melena (black tarry stools) or hematemesis (vomiting blood).
• Bone pain or fractures – due to calcium loss from bones caused by hyperparathyroidism.
• Kidney stones (nephrolithiasis) – hypercalciuria leads to calcium oxalate stone formation.
• Excessive thirst and urination (polydipsia/polyuria) – hypercalcemia interferes with kidney concentrating ability.
• Fatigue, weakness, or confusion – high calcium can affect neurologic function.
• Depression or mood changes – chronic illness and electrolyte disturbances may contribute.

Causes and Risk Factors

Zollinger‑Ellison syndrome associated with hyperparathyroidism most often occurs as part of the multiple endocrine neoplasia type 1 (MEN‑1) genetic syndrome. Key points:

• MEN‑1 mutation – Autosomal‑dominant inheritance of a mutation in the MEN1 tumor suppressor gene (chromosome 11q13) leads to tumor formation in the parathyroid glands, pancreatic islet cells, and anterior pituitary. About 70 % of patients with MEN‑1 develop hyperparathyroidism, and 20‑30 % develop gastrinomas <sup>2</sup>.
• Sporadic gastrinomas – In patients without MEN‑1, gastrinomas arise spontaneously. Hyperparathyroidism is less common (<5 % of sporadic ZES cases).
• Family history – A first‑degree relative with MEN‑1 dramatically raises risk.
• Age – Tumor development peaks in the fourth to sixth decades of life.
• Sex – Slight female predominance, likely reflecting the higher prevalence of hyperparathyroidism in women.

Diagnosis

Because the two conditions overlap, clinicians use a stepwise approach incorporating laboratory tests, imaging studies, and sometimes genetic testing.

Laboratory Evaluation

• Fasting serum gastrin – Levels >1000 pg/mL (or >10× the upper limit of normal) after a calcium gluconate stimulation test strongly suggest ZES <sup>3</sup>. Less extreme elevations require a secretin stimulation test.
• Secretin stimulation test – In ZES, gastrin paradoxically rises >120 pg/mL after IV secretin.
• Serum calcium and ionized calcium – Elevated total calcium (>10.2 mg/dL) or ionized calcium (>1.32 mmol/L) indicates hyperparathyroidism.
• Parathyroid hormone (PTH) level – In primary hyperparathyroidism, PTH is inappropriately normal or elevated despite hypercalcemia.
• 24‑hour urinary calcium – Helps differentiate primary hyperparathyroidism from other causes of hypercalcemia.
• Vitamin D levels – Low or insufficient vitamin D can exacerbate secondary hyperparathyroidism.

Imaging Studies

• Endoscopic ultrasound (EUS) – High sensitivity (≈80‑90 %) for detecting small duodenal gastrinomas.
• Multiphasic contrast‑enhanced CT or MRI – Useful for staging and evaluating metastatic spread.
• Somatostatin receptor scintigraphy (Octreoscan) or Ga‑68 DOTATATE PET/CT – Detects somatostatin‑receptor‑positive tumors and guides surgical planning.
• Neck ultrasonography & sestamibi scan – Localize hyperfunctioning parathyroid tissue.

Genetic Testing

Testing for the MEN1 gene mutation is recommended for anyone with ZES plus hyperparathyroidism, or with a family history of MEN‑1. Identifying a pathogenic variant informs screening of at‑risk relatives (approximately 50 % chance of inheritance).

Treatment Options

Management must address both the acid‑producing gastrinoma(s) and the overactive parathyroid glands. A multidisciplinary team (gastroenterology, endocrine surgery, endocrinology, radiology, nutrition) provides optimal care.

Medical Therapy for ZES

• High‑dose proton pump inhibitors (PPIs) – Omeprazole 60–80 mg/day or equivalent (e.g., esomeprazole 40–60 mg/day). PPIs control acid secretion in >95 % of patients and heal ulcers <sup>4</sup>. Dose is titrated to symptom control and gastric pH >4.
• H2‑receptor antagonists – Occasionally added for breakthrough symptoms, but less effective than PPIs.
• Somatostatin analogs (octreotide, lanreotide) – Reduce gastrin secretion and may shrink small tumors, particularly when surgery is not feasible.

Surgical Management of Gastrinomas

• Curative resection – Preferred for localized tumors (<2 cm) without metastasis. Procedures may include enucleation or pancreaticoduodenectomy (Whipple) depending on location.
• Debulking surgery – In metastatic disease, removal of >90 % tumor burden can improve symptom control and PPI requirements.
• Liver-directed therapies – Radiofrequency ablation, embolization, or peptide‑receptor radionuclide therapy (PRRT) for hepatic metastases.

Treatment of Primary Hyperparathyroidism

• Minimally invasive parathyroidectomy – The first‑line curative option for single adenomas; success rates >95 %.
• Bilateral neck exploration – Used when imaging is equivocal or multigland disease is suspected (common in MEN‑1).
• Calcimimetics (cinacalcet) – Lower serum calcium by increasing the sensitivity of the calcium‑sensing receptor; useful when surgery is contraindicated.
• Bisphosphonates or denosumab – May be added temporarily to protect bone while awaiting definitive surgery.

Lifestyle and Supportive Measures

• Low‑acid diet – Avoid caffeine, alcohol, nicotine, and very spicy foods.
• Calcium‑controlled intake – 800–1000 mg/day from diet; avoid excessive supplementation if hypercalcemia is present.
• Vitamin D optimization – Aim for 30–50 ng/mL 25‑OH‑D level, unless hypercalcemia is severe.
• Regular bone density monitoring (DXA) – At least every 1–2 years.
• Hydration – 2–3 L of water daily to reduce kidney‑stone risk.

Living with Zollinger‑Ellison Syndrome‑Associated Hyperparathyroidism

Adapting to a chronic condition involves practical daily habits:

1. Medication adherence – Set alarms or use a pill‑box for PPIs, calcium‑modifying agents, and any postoperative supplements.
2. Scheduled laboratory monitoring – Check fasting gastrin, calcium, PTH, and vitamin D every 3–6 months, or more often after surgery.
3. Follow‑up imaging – Annual or biennial cross‑sectional imaging (CT/MRI) to detect tumor recurrence, especially in MEN‑1 patients.
4. Nutrition counseling – A registered dietitian can tailor a low‑acid, calcium‑balanced meal plan and advise on bone‑health nutrients.
5. Physical activity – Weight‑bearing exercise (e.g., walking, resistance training) supports bone density and cardiovascular health.
6. Support networks – Connect with MEN‑1 support groups (e.g., International MEN Society) for shared experiences and coping strategies.
7. Family screening – First‑degree relatives should undergo genetic testing and biochemical screening if a MEN‑1 mutation is identified.

Prevention

Because the underlying cause is genetic, true primary prevention is limited. However, risk reduction and early detection strategies include:

• Genetic counseling for families with known MEN1 mutations.
• Annual biochemical screening (serum calcium, PTH, fasting gastrin) for mutation carriers starting at age 8 (guidelines vary; discuss with a genetics specialist).
• Avoiding long‑term unnecessary acid‑suppressive therapy that could mask early ulcer symptoms.
• Maintaining a healthy lifestyle to lower secondary risk factors for kidney stones and osteoporosis (adequate hydration, balanced calcium intake, smoking cessation).

Complications

If left untreated or poorly controlled, the combined disease can lead to serious health problems:

• Peptic ulcer perforation – Can cause peritonitis and require emergency surgery.
• Gastrointestinal bleeding – May lead to anemia and need transfusion.
• Metastatic gastrinoma – Liver or lymph‑node spread occurs in 20‑30 % of sporadic ZES and up to 50 % in MEN‑1–related cases.
• Nephrolithiasis & chronic kidney disease – Recurrent stones or hypercalcemia‑induced renal impairment.
• Osteoporosis or osteopenia – Resulting from chronic high PTH levels.
• Cardiovascular disease – Hypercalcemia is linked with hypertension and arrhythmias.
• Neurocognitive changes – Severe hypercalcemia can cause confusion, depression, or even coma.

When to Seek Emergency Care

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For personalized medical advice, always consult your healthcare provider. This guide is for educational purposes and does not replace professional diagnosis or treatment.

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References:
1. La Rosa, S. et al. “Epidemiology of Zollinger‑Ellison syndrome and MEN‑1.” World J Gastroenterol, 2022.
2. Giusti, L. & Giovanelli, L. “Multiple endocrine neoplasia type 1: Genetic aspects and clinical management.” Cleveland Clinic Journal of Medicine, 2021.
3. Jensen, R.T., et al. “Guidelines for the diagnosis and management of ZES.” Mayo Clinic Proceedings, 2020.
4. Kvols, L.K., et al. “Long‑term outcomes of high‑dose proton pump inhibitor therapy in Zollinger‑Ellison syndrome.” Gastroenterology, 2019.
NIH, NIH Osteoporosis and Related Bone Diseases National Resource Center. https://www.bones.nih.gov.
CDC, “Hyperparathyroidism.” https://www.cdc.gov. ```