Approach to the patient with primary hyperglucagonemia.

Glucagonomas are a rare hormone-producing pancreatic neuroendocrine tumor (panNET), with an estimated incidence of 1 to 2 cases per million persons. They typically present at diagnosis as large, metastatic panNET and are characterized clinically by diabetes mellitus, weight loss, thromboembolic complications and necrolytic migratory erythema. The diagnosis of glucagonoma syndrome requires the presence of both elevated fasting plasma glucagon levels and glucagonoma symptoms. Staging relies on cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI), complemented by somatostatin receptor positron emission tomography (PET) imaging. Initial management of glucagonoma includes supportive therapy with supplementation of amino acids, essential fatty acids, zinc, and other micronutrients as well as glycemic control and anticoagulation. Surgical resection is the only curative treatment. For unresectable or metastatic disease, palliative management parallels that of nonfunctioning panNET and includes somatostatin analogues, targeted therapies, peptide receptor radionuclide therapy with radiolabeled somatostatin analogues, and cytotoxic chemotherapy. Prognosis depends on tumor stage and grade, with reported 10-year survival rates approaching 100% for localized disease and approximately 50% for metastatic glucagonoma. A rare hereditary cause of hyperglucagonemia due to glucagon receptor mutations is glucagon cell hyperplasia and neoplasia, also termed Mahvash disease. These patients develop alpha cell hyperplasia and panNET but lack the classical glucagonoma symptoms. In conclusion, fasting glucagon levels should be measured in patients with typical features such as necrolytic migratory erythema, an advanced panNET associated with cachexia and new-onset or worsening diabetes mellitus or diffuse alpha cell hyperplasia.