Hyperglucagonemia (High Blood Glucagon Levels)

Almost all vital processes of the body require energy. Carbohydrates in food are broken into simpler units, mainly glucose. This glucose is utilized by cells to derive energy. Optimum concentration of glucose in the blood is required for healthy  functioning. It is maintained by hormones secreted from the pancreas – insulin and glucagon. Changes in the ratio of these hormones, disturbances in its secretion and diminished effect can lead to disruption in regulating the blood glucose levels.

What is hyperglucagonemia?

Hyperglucagonemia is excess of glucagon in the blood. It is a common occurrence in diabetics. However, various tumors especially of the pancreas may also increase glucagon concentration in the blood. Glucagon raises the blood glucose levels, therefore an excess of this hormone can cause very high blood glucose levels if it is not counteracted by insulin. Overall this is a rare condition and more frequently seen in the chronic stage as a result of pancreatic tumor (glucagonoma). It tens to affect older people over the age of 55 years of age. Hyperglucagonemia can be life threatening due to it effects on blood clotting or the spread of malignant tumors of the glucagon-producing cells of the pancreas (glucagonoma).

Hyperglucagonemia Pathophysiology

Glucose breakdown provides the major source of energy for cells. The blood glucose level is regulated by the relative activities of insulin and glucagon. Insulin helps in utilization of glucose and removes it from blood. On the contrary, glucagon breaks down stored proteins into glucose and increases its level in blood (gluconeogenesis). In a way insulin and glucagon function with a mutual feedback. Various factors lead to increased glucagon secretion. A reduced glucose concentration in blood serves as the most important trigger for glucagon secretion.

Glucagon in diabetes

Blood glucose concentration may be affected by hormones but it is regulated by specific areas in the brain. This entire system is jointly referred as neuroendocrine system. Upon sensing reduced glucose level (hypoglycemia), the feeding center in the hypothalamus of the brain of the brain evokes a hunger response to induce food intake. Reduced glucose amounts depress activation of brain satiety center. Unopposed functioning of appetite area of the brain leads to overeating (hyperphagia) and thereby increases blood glucose level.

In diabetic conditions, energy requirements are met by utilizing protein and fat reserves. Glucagon increases breakdown of proteins and fats (lipolysis). Increased mobilization of stored proteins and fats causes significant loss of body weight, a common sign of diabetes mellitus. Accelerated protein breakdown and reduced synthesis, causes protein depletion. Depletion of proteins is often associated with impaired functioning (wasting) of any organ and poor resistance to infections.

The manifestations of disordered fat metabolism are so prominent that diabetes appears more of a lipid disease than of carbohydrate metabolism. Fat metabolism causes formation of ketone bodies. During fasting, ketone bodies are used as energy source. However, the presence of abundant ketone bodies causes extensive loss of electrolytes (salts) and water from the body. The resulting dehydration could lead to unconsciousness or coma, referred to as diabetic ketoacidotic coma.

Glucagon from pancreatic tumors

In cases of a pancreatic tumor that affects the glucagon-secreting cells (glucagonoma) the excessively secreted glucagon becomes free from the feedback mechanism of insulin. However, it does not amount to an increase in blood glucose level unless glucose metabolism by liver is impaired. Under normal conditions, glucagon is degraded in the liver. Glucagon is released first in the portal veins and carried to liver, before being released in peripheral circulation. It explains the spread of the pancreatic tumor towards liver. Disruption of liver functioning also increases peripheral glucagon levels (glucose intolerance), owing to its reduced degradation.

Hyperglucagonemia Causes

• Tumors associated with glucagonoma are usually malignant and can spread all over the body. Excessive secretion from these tumorous pancreatic alpha cells could cause hyperglaucogonemia.
• Genetic pre-disposition for tumors of endocrine glands (multiple endocrine neoplasia – MEN) have an increased risk of presenting glucagonoma.
• Diabetes mellitus and more frequently as a complication of acute diabetic emergencies.
• Diseases of the pancreas like pancreatitis.
• Sudden or severe stress to the body as is seen with trauma, burns, septicemia (“blood poisoning”) and a myocardial infarction (heart attack).
• Raised cortisol in conditions like Cushing syndrome.
• Kidney failure.
• Liver cirrhosis.

Hyperglucagonemia Symptoms

Hyperglucagonemia show four prominent symptoms, known as the 4 D’s – dermatosis, diabetes, deep vein thromboisis (DVT) and depression.

Dermatosis

Characterstic rashes appear around oral and genital areas and may spread across fingers and legs. It is known as necrolytic migratory erythrema (NME). The skin lesions often present as dark pigmented, fragile blisters or skin crusting.

Diabetes

High glucagon levels alone could not increase glucose concentration in blood. Spread of pancreatic tumor to liver, impairs glucagon degradation. Reduced glucose utilization signals appetite center of the brain causing overeating (hyperphagia). Collectively, the raised glucose levels and overeating increases the blood glucose level.

Deep vein thrombosis (DVT)

Blood clots form in a deep veins of the leg and usually manifests as swelling with pain. It often resolves spontaneously but sometime the clot travels to other body parts (embolism) along the venous flow. The presence of such clots in the lungs interferes with the normal breathing process and usually proves fatal (pulmonary embolism).

Depression

Large amounts of water and electrolytes escape from the body, owing to abnormally high levels of glucagon. Severe forms of dehydration affects normal brain functioning. Depression and irritability are among the most common indicators of deranged mental status in a patients with hyperglucagonemia.

Other signs and symptoms

• Excessive thirst
• Frequent urination
• Increased appetite
• Inflamed mouth and tongue
• Significant weight loss

Hyperglucagonemia Diagnosis

Common signs such as the typical skin lesions  described above along with high blood glucose levels or impaired glucose tolerance may raise the suspicion of hyperglucagonemia. This may warrant further testing.

Diagnostic tests include:

• Blood glucagon level over 1000 pg/ml (normal range is 50-200 pg/ml) positively suggests glucagonoma.
• Fasting blood glucose level and glucose tolerance test to establish diabetes mellitus.
• Studying cells (biopsy) of skin lesions (NME lesions) to differentiate it from normal skin lesions arising from nutritional deficiencies.
• CT scan of the abdomen to detect blood clots.

Hyperglucagonemia Complications

Usually the malignant pancreatic tumors spread to liver and disrupt its functions. Once glucose metabolism is affected, it leads to an increase in blood glucose concentration and its associated symptoms. At the time of diagnosis, almost 60% of these tumors retain the property to spread (metastasis) to other body parts. Once spread to other organs, both successful removal of the tumor and its treatment becomes complicated. Due to the likelihood of blood clot formation, there is the risk of pulmonary embolism which can be fatal.

Hyperglucagonemia Treatment

• Glucagon release is inhibited by somatostatin, a pancreatic hormone having complementary functions. Biopsy reports of the pancreatic tumors show presence of somatostatin receptors on the cell surface. Presently, octreotide, an analogue of somatostatin is being used for hyperglucagonemia.
• Malignant pancreatic tumors are slow growing and do not respond to chemotherapy. Therefore, surgical  removal of the pancreas is warranted. In cases of pancreatic tumors metastasized to liver, surgical intervention does not help. Chemotherapy may therefore be necessary.
• Severe skin rashes may be treated with antibiotics, steroids and aminoacid and zinc supplementation.
• Low doses of the anticoagulant heparin may be administered as a prophylactic measure to prevent venous blood clotting and other related fatal effects.