Hyperglucagonemia (Glucagonoma Syndrome) Clinical Presentation

Updated: Feb 18, 2019
  • Author: George T Griffing, MD; Chief Editor: George T Griffing, MD  more...
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Hyperglucagonemia is rare. It is caused by a tumor of the alpha cells of the pancreatic islets, most commonly located at the body or tail of the pancreas or, in rare cases, at the head of the pancreas. [10, 11] It can occur as part of the multiple endocrine neoplasia (MEN) type 1 syndrome. [12, 13]

The tumor usually grows slowly and has an indolent course. An estimated 50-60% of these tumors are malignant. At diagnosis, the average size of the tumor is 5 cm or more, and 50% of the tumors are metastatic, usually to the liver. Less common sites of metastases include the lymph nodes, bone, kidney, adrenal gland, and lung. The median age at presentation is 55 years, with equal incidence in men and women. The benign glucagonomas usually are small and asymptomatic.

The most common clinical features of glucagonoma syndrome are weight loss, necrolytic migratory erythema (NME), and diabetes. [15, 16, 17, 18, 19, 20, 1] The presence of diabetes and NME usually heightens the index of suspicion for the syndrome and leads to an early diagnosis. It is likely that glucagon causes these symptoms, because a prolonged infusion of glucagon in patients without glucagonoma can reproduce these clinical features. Glucagonomas can be diagnosed with reasonable accuracy on clinical criteria alone. [2]

Weight loss is one of the most prominent and common features of the glucagonoma syndrome. Weight loss results from accelerated rates of protein and fat turnover caused by the catabolic effects of glucagon. The nonspecific symptoms of nausea, anorexia, and general ill health could very well lead to poor food intake and contribute to weight loss. Although diarrhea may occur in some patients, malabsorption is rare.

NME [15, 16, 18, 19, 20, 1]  occurs in up to 50% of cases. It typically is described as a superficial erythema with a moving edge associated with the formation of bullae, which sequentially rupture, form a crust, and then heal in areas with hyperpigmentation. This sequence recurs over 7-14 days, with a waxing and waning pattern, and tends to involve the buttocks, perineum, groin, and lower extremities. Extensive skin involvement can occur and may be complicated by secondary bacterial or fungal infection. All mucous membranes are involved, causing cheilosis, angular stomatitis, glossitis, and inflammation of the buccal mucosa. On histologic examination, NME tends to resemble toxic epidermal necrolysis.

Diagnosis is aided by the typical skin appearance of patients with NME and by the evaluation of a skin biopsy. However, several biopsies may be needed to visualize the characteristic histologic changes that help lead to a diagnosis. NME usually follows diabetes in manifestation. The cause of NME is not clear, but postulated causes include the direct effect of glucagon, as well as the effects of amino acid, fatty acid, and zinc deficiency. Indeed, the cause may be multifactorial.

Improvements have been noted with tumor resection and normalization of the glucagon levels, as well as with amino acid therapy and zinc supplementation. [21, 22]

The diabetes mellitus associated with glucagonoma syndrome tends to be mild and usually can be controlled with diet and/or oral hypoglycemic agents. Some patients may require insulin for optimal glycemic control. Hyperglycemia is due to the glycogenolytic and gluconeogenic actions of glucagon occurring in the context of an altered insulin-to-glucagon ratio and tends to correlate poorly with the plasma glucagon levels. Insulin resistance is not a feature of diabetes in glucagonoma syndrome. Unless a preexisting state of insulin resistance exists, the diabetes resolves with surgical removal of the tumor or with treatment with octreotide. No evidence exists of an increased tendency to develop diabetic ketoacidosis or any of the long-term complications of diabetes.

The anemia in glucagonoma syndrome usually is mild. However, a correlation exists between the severity of the hyperglucagonemia and the extent of the anemia. Typically, the anemia is normochromic normocytic, although macrocytic anemia has been described in some patients. The cause is not certain but is thought to be due to the catabolic action of glucagon on the bone marrow, perhaps coupled with the chronic disease state. Bone marrow biopsy results are normal, with normal iron stores.

Venous thrombosis is thought to occur in as many as 30% of patients with glucagonoma syndrome. It most commonly affects deep veins, such as the iliac veins and the splenic vein, and may affect the pulmonary artery. Venous thrombosis has a high mortality rate. Test results of coagulation function usually are normal, and the cause is not clear. Venous thrombosis also tends to be a common problem with other types of pancreatic islet cell tumors.

Depression, dementia, insomnia, ataxia, proximal muscle weakness, and optic atrophy all have been described in patients with glucagonoma syndrome. Neuropsychiatric manifestations tend to respond to improvement in glucagon level

Nonspecific symptoms can include weakness, constipation, diarrhea, abdominal pain, and peptic ulcer disease. Diarrhea may be due in part to other hormones, including gastrin, vasoactive intestinal peptide (VIP), 5-hydroxytryptamine (5-HT), and calcitonin, secreted from mixed cell populations within the tumor. Peptic ulcer disease may result from the effects of gastrin.

Features of hypercalcemia and/or anterior pituitary dysfunction may be present when glucagonoma syndrome is part of the MEN type 1 syndrome. [12, 13]

Dystrophic nails are another dermatologic manifestation of glucagonoma syndrome.

A reversible dilated cardiomyopathy has been reported in at least 1 patient. [39]



Most patients are middle-aged and may appear wasted and ill.

The characteristic necrolytic migratory erythematous rash affecting the groin, perineum, and lower extremities could be generalized and associated with inflammation of the mucous membranes. However, since the most common skin feature evident in most nearly all reported cases is the presence of mucosal lesions and annular, eroded, eczematous patches and plaques of intertriginous areas and not NME, it has been proposed to rename the eruption associated with glucagonoma mucosal and intertriginous erosive dermatitis. [40]

The liver may be enlarged in cases of hepatic metastatic disease.

When present, features of deep venous thrombosis or pulmonary embolism may be evident.



Glucagonoma syndrome occurs as a result of either a benign or malignant tumor of the alpha cells of the pancreatic islets. The glucagon levels usually are in excess of 500 pg/mL (normal levels are < 60 pg/mL). Glucagonoma is seen in about 1-2% patients with MEN type 1 syndrome and is usually associated with an aggressive tumor and a poor prognosis. [12, 13]

Other causes of hyperglucagonemia include pathophysiologic states in which a loss of the normal restraining influence of insulin on alpha-cell function occurs. Such influence is lost in circumstances of relative or absolute insulin deficiency. The glucagon levels in these situations usually are less than 500 pg/mL. Additional causes of hyperglucagonemia include diabetes mellitus and acute diabetic complications, pancreatitis, trauma, burns, infection and sepsis, myocardial infarction, increased cortisol levels, increased catecholamine or growth hormone levels, renal failure, and hepatic cirrhosis. [41, 14]

Diabetic complications can include diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic state. In type 2 diabetes with relative hyperinsulinemia, the cause of hyperglucagonemia is not clear, but the suppression of glucagon secretion is impaired despite high insulin levels. Persons who are obese and have type 2 diabetes are reported to have an exaggerated glucagon response to a protein meal and to increased arginine levels. This exaggerated response is not corrected by restoration of normoglycemia or even by insulin infusion.

The mechanism of hyperglucagonemia in burns, as in any other stressful situation, is secondary to an increased production of catecholamines. [41]

Increased cortisol, as in Cushing syndrome, leads to hyperglucagonemia by increasing glucagon production. It also potentiates the actions of glucagon on the liver.

In renal failure, glucagon is metabolized and excreted in the liver and kidney.

Hepatic cirrhosis is due to impaired metabolism and excretion of glucagon.