Glucagon

Glucagon is a tumor from pancreatic a-cells secreting glucagon, causing hyperglycemia and a characteristic rash on the skin. The diagnosis is established with an increase in glucagon levels and instrumental studies. The tumor is identified with CT and endoscopic ultrasound. Treatment consists in surgical resection.

[1], [2], [3], [4]

Epidemiology

Glucagons are rare, but like other tumors from islet cells, the primary tumor and metastatic lesions have a slow growth: usually the survival time is about 15 years. Eighty percent of glucagon is cancerous. The average age of patients with symptoms is 50 years; 80% are women. In some patients there is a type I of multiple endocrine neoplasia.

The clinical description of the glucagon secretant tumor was given accidentally by dermatologists as far back as 1942. However, only in 1966 the first strictly proven case of glucagonoma was published. The final idea of this disease was formed by 1974. Then the term "glucagonoma syndrome" appeared. More than 150 similar observations are currently available in the literature. The disease rarely affects people under 30 years old, the age of 85% of patients at the time of diagnosis is 50 years or more.

[5], [6], [7], [8], [9]

Symptoms of the glucagon

Because glucagonomes secrete glucagon, the symptoms are similar to  diabetes mellitus. Often there are weight loss, normochromic anemia, hypoaminoacidemia and  lipid lowering, but the main distinctive clinical feature is a chronic rash that affects the limbs, often associated with a smooth, shiny, bright red color and cheilitis. Skin peeling, hyperpigmentation, erythematous lesions with superficial necrolysis are called necrolytic migratory erythema.

The clinical picture of glucagonoma is dominated by cutaneous manifestations, so the vast majority of patients are detected by dermatologists. Dermatitis was called necrolytic migratory erythema. The process is cyclical, lasting from 7 to 14 days. It starts with a spot or a group of spots that consistently pass through the stage of papules, vesicles, erosion and crusts or flakes, after which a hyperpigmentation site remains. A special feature of dermatitis is polymorphism, that is, the presence of lesions located simultaneously in different stages of development, which gives the skin a mottled appearance. Often the secondary process is joined by a secondary infection.

Most often, dermatitis develops on the lower extremities, in the groin, perineum, perianal area, lower abdomen. On the face the process manifests itself in the form of an angular cheilitis. Necrotic migratory erythema in most patients is resistant to ongoing therapy, both topically and inward, including corticosteroids. This is his second feature. The cause of dermatitis is a pronounced catabolic process in conditions of tumor hyperglucagonemia, which leads to a disruption in the exchange of proteins and amino acids in tissue structures.

The defeat of the mucous membranes with glucagonome is characterized by the presence of stomatitis, gingivitis, glossitis. Language - characteristic - large, fleshy, red, with smoothed papillae. Balanitis and vaginitis are less common. The reason for the changes on the mucous membranes is similar to the process on the skin.

Among the factors influencing the violation of carbohydrate metabolism, the role of glucagon, a recognized hyperglycaemic peptide, causes the greatest disagreement. In most cases, it is difficult to show a direct relationship between the level of glucagon and the magnitude of glycemia. Moreover, even after radical removal of the tumor, signs of a violation of carbohydrate metabolism persist for a long time, despite the normalization of glucagon in the first hours and days. In some cases, diabetes remains after surgery, despite the complete remission of other manifestations of the syndrome.

Diabetes in glucagonoma syndrome in 75% of patients is easy, to compensate for which it is enough to comply with the diet. A quarter of patients need insulin therapy, the daily dose of which in half the cases does not exceed 40 units. Another feature of diabetes is the rarity of ketoacidosis and the absence of traditional complications in the form of nephro-, angio- and neuropathy.

Expressed catabolic changes in glucagon, regardless of the character of the tumor process (malignant or benign), are the cause and weight loss, the distinctive feature of which is loss of body weight in the absence of anorexia. Anemia in the syndrome of glucagonoma is characterized as normochromic and normocytic. The main indicators are low hemoglobin and a hematocrit number. Sometimes there is a decrease in serum iron.

As for folic acid and vitamin B ₁₂, their levels remain within the normal range. The second feature of anemia is resistance to vitamin therapy and iron preparations. Thrombosis and embolism in glucagonome take place in 10% of patients, and it is still not clear whether they are a property of the syndrome or the result of the tumor process as such, which is often observed in oncology in general. More than 20% of patients reported diarrhea, rarely steatorrhea. The first - usually periodic, in severity can be from minor to debilitating.

[10], [11], [12], [13]

Diagnostics of the glucagon

In most patients with glucagon, glucagon levels are more than 1000 pg / ml (normally less than 200). However, moderate increases in the hormone can be observed with kidney failure, acute pancreatitis, severe stress and fasting. Correlation with symptoms is necessary. Patients should perform CT of the abdominal cavity and endoscopic ultrasound; if CT is uninformative, MRI can be used.

Among the laboratory indicators, a special place is occupied by the study of immunoreactive glucagon. The latter can be increased in diabetes mellitus, pheochromocytoma, liver cirrhosis, glucocorticoid hypercorticism, renal insufficiency, but glucagon levels exceeding in tens and hundreds of times its normal values are known at present only with glucagon-secreting neoplasms of the pancreas. Other laboratory-specific indicators of glucagonome syndrome are hypocholesterolemia, hypoalbuminemia, hypoaminoacidemia. The latter has a special diagnostic significance, since it is detected in almost all patients.

Glucagon is usually large. Only 14% do not exceed 3 cm in diameter, while more than 30% of patients have a primary focus of 10 cm or more. In the overwhelming majority of cases (86%), alpha-cell malignancies are malignant, 2/3 of which at the time of diagnosis already have metastases. Most often (43%), the tumor is found in the tail of the pancreas, less often (18%) - in its head. Topical diagnosis of glucagon and its metastases does not cause any particular difficulties. The most effective in this regard are visceral arteriography and computed tomography.

Glucagon secretion can be part of the syndrome of multiple endocrine neoplasia type I. Certain signs of glucagonoma syndrome, for example diabetes or dermatitis, are observed with entero-glucagon secretion lesions of other organs.

[14], [15], [16], [17], [18]

Treatment of the glucagon

Resection of the tumor leads to regression of the symptoms. Incompatible tumors, the presence of metastases or recurrent tumors are subject to combined treatment with streptozocin and doxorubicin, which lower the levels of circulating immunoreactive glucagon, lead to regression of symptoms and improve the condition (50%), but hardly affect the survival time. Octreotide injections partially suppress glucagon secretion and reduce erythema, but glucose tolerance can also decrease due to decreased insulin secretion.

Octreotide quickly enough leads to the disappearance of anorexia and weight loss caused by the catabolic effect of glucagon excess. With the effectiveness of the drug, patients can be transferred to the prolonged octreotide 20-30 mg intramuscularly once a month. Patients taking octreotide should additionally take pancreatic enzymes because of the overwhelming effect of octreotide on the secretion of pancreatic enzymes.

Local applications, oral or parenteral use of zinc lead to regression of erythema, but erythema may resolve after simple hydration or intravenous administration of amino or fatty acids, suggesting that erythema is caused uniquely not by zinc deficiency.

Treatment of patients with glucagonoma - surgical and chemotherapeutic. A quarter of all surgical procedures terminate due to a metastatic process with trial laparotomy, but an attempt to remove the primary focus should be undertaken under any circumstances, as reducing the tumor mass creates more favorable conditions for chemotherapy. The drugs of choice for glucagon are streptozotocin (streptozocin) and dacarbazine, which allow years to maintain remission of the malignant process.