Hyperglucagonemia (Glucagonoma Syndrome) Workup

Updated: Feb 18, 2019
  • Author: George T Griffing, MD; Chief Editor: George T Griffing, MD  more...
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Laboratory Studies

The diagnosis of glucagonoma syndrome depends on the presence of the clinical features of disease and elevated plasma glucagon levels. NME, diabetes, and hyperglucagonemia may be present in as many as 70-90% of patients with glucagonoma syndrome. This should be confirmed by the demonstration of a pancreatic islet cell tumor mass and by examination of a tissue biopsy or surgical specimen.

The presence of a pancreatic islet cell tumor is necessary to exclude other nonspecific causes of hyperglucagonemia.

Glucagonomas usually demonstrate immunoreactivity to antiglucagon antibody staining. Large tumors may be inefficient at glucagon production and may therefore produce negative results on glucagon immunostaining.

Glucagon should be tested by RIA of a fasting plasma sample. The normal plasma glucagon level is less than 60 pg/mL. In glucagonoma syndrome, glucagon levels are well in excess of 500 pg/mL and are reported to increase even further with the administration of intravenous tolbutamide. Other causes of hyperglucagonemia usually result in glucagon levels in the range of 120-500 pg/mL.

Hormones that may be elevated in glucagonoma syndrome include insulin, VIP, gastrin, pancreatic polypeptide, 5-HT, calcitonin, adrenocorticotropic hormone, and adrenocorticotropic hormone (ACTH). Fifty percent of the pancreatic islet cell tumors secrete pancreatic polypeptide, and the presence of elevated levels of this compound in association with other endocrine tumor syndromes indicates a pancreatic tumor source. Pancreatic polypeptide on its own has no recognized physiologic activity.

Other nonspecific laboratory studies include complete blood count (CBC), serum or urine amino acid levels, fasting plasma glucose, glycosylated hemoglobin (HbA1c), comprehensive metabolic panel (CMP), and zinc levels. On CBC, the common finding is a normochromic normocytic anemia, but a macrocytic anemia may be present in some patients. Serum or urine amino acid levels demonstrate hypoaminoacidemia. [42] A general decrease in gluconeogenic and nongluconeogenic amino acids, especially alanine and glutamine, occurs. The cause of the hypoaminoacidemia is thought to be the increased hepatic extraction of amino acids for gluconeogenesis and increased ureagenesis combined with decreased protein synthesis.

Fasting plasma glucose are used to diagnose diabetes mellitus.

Glycosylated hemoglobin (HbA1c) assesses the level or degree of hyperglycemia in the preceding 2-3 months.

Hypokalemia may occur in cases of protracted diarrhea. Hypercalcemia indicates the presence of hyperparathyroidism and, therefore, of MEN type 1 syndrome.

Zinc deficiency is postulated to be one of the causes of the NME that occurs in the glucagonoma syndrome.


Imaging Studies


Transabdominal ultrasonography is noninvasive and may be the initial imaging modality of choice for the detection of pancreatic tumors. However, it has obvious limitations in obese patients and after surgery of the upper abdomen (when air may be present in the peritoneal cavity and obscure accurate imaging).

Computed tomography (CT) scanning of the abdomen has a sensitivity and specificity similar to that of transabdominal ultrasonography and can be used in obese persons. CT scanning can reliably detect small tumors and is useful for tumor staging. [43]

Magnetic resonance imaging (MRI) of the abdomen may be superior to transabdominal ultrasonography and CT scanning. MRI is most helpful in pancreatic evaluation after surgery and in pancreatic tumor staging.

Selective angiography can be useful because the characteristic feature of islet cell tumors is their hypervascularity. Primary and metastatic glucagonomas are reported to have a dense, circumscribed, homogeneous capillary blush appearance that persists into the parenchymal phase.

Positron emission tomography (PET) scans of glucagonomas show increased F-18 fluorodeoxyglucose in the primary pancreatic tumor and in hepatic metastases. [44]

Endoscopic retrograde cholangiopancreatography (ERCP) may help to detect distortion of the pancreatic duct in pancreatic tumors, but it is more useful in the diagnosis of ductal carcinomas.

Endoscopic ultrasonography reportedly provides a better-quality assessment of pancreatic configuration and the highest rate of detection of pancreatic tumors. It also can be combined with guided fine-needle aspiration biopsy for tissue diagnosis.

Transhepatic portal venous sampling is another option; however, it is highly invasive.


Histologic Findings

NME is not specific to glucagonoma syndrome. It affects the upper one third of the epidermis, which shows edema, pallor, necrolysis, and mild lymphocytic infiltration around the blood vessels. NME may appear as a nonspecific dermatitis in the early stages. [15, 16, 18, 19, 20, 1]

Glucagonomas are alpha-cell tumors, which demonstrate neurosecretory granules on electron microscopy and have positive immunoreactivity to antiglucagon stains. Benign glucagonomas show more granules than do malignant glucagonomas. Some tumors, however, can have mixed cell types, and large tumors can have negative immunoreactivity to antiglucagon immunostains.