Hyperglucagonemia (Glucagonoma Syndrome) 

Updated: Feb 18, 2019
Author: George T Griffing, MD; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

Hyperglucagonemia is a state of excess glucagon secretion. In healthy individuals, insulin has a suppressive effect on alpha-cell function and on glucagon secretion. The most common cause of hyperglucagonemia is an absence or deficiency of the restraining influence of insulin on glucagon production. Although rare, hyperglucagonemia can be caused by an autonomous secretion of glucagon by a tumor of pancreatic alpha cells (glucagonoma syndrome). Most patients are middle-aged and may appear wasted and ill.[1, 2, 3, 4, 5, 6, 7, 8, 9]

The glucagon levels usually are in excess of 500 pg/mL (normal levels are < 60 pg/mL). 

Hyperglucagonemia 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. 

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.[14, 6, 7, 9]

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 diabetes mellitus associated with glucagonoma syndrome tends to be mild and usually can be controlled with diet and/or oral hypoglycemic agents. Typically, the associated anemia is normochromic normocytic, although macrocytic anemia has been described in some patients. Venous thrombosis is thought to occur in as many as 30% of patients with glucagonoma syndrome. 

Diagnosis is aided by the typical skin appearance of patients with NME and by the evaluation of a skin biopsy.

Glucagon should be tested by RIA of a fasting plasma sample. Hormones that may be elevated in glucagonoma syndrome include insulin, VIP, gastrin, pancreatic polypeptide, 5-HT, calcitonin, adrenocorticotropic hormone, and adrenocorticotropic hormone (ACTH). 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. 

Transabdominal ultrasonography is noninvasive and may be the initial imaging modality of choice for the detection of pancreatic tumors, but it has 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.31 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.

Surgery is the treatment of choice for glucagonoma syndrome. Surgical treatment includes the following:

  • Resection of a localized tumor, including, in selected cases, through laparoscopic surgery[21, 22, 23]

  • Cytoreduction or debulking of large and nonresectable metastatic tumors

  • Hepatic artery embolization

Medical treatment of glucagonoma syndrome includes therapy for NME, treatment of diabetes, treatment of hyperglucagonemia, and treatment of islet cell tumor. 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]  NME has been documented to respond to surgical resection of the glucagonoma, to therapy with octreotide, and to chemotherapy, all of which lead to reduction in glucagon levels.[15, 16, 18, 19, 20, 1, 21, 22, 24]   The control of diabetes in glucagonoma syndrome usually can be achieved with diet, oral hypoglycemic agents, or, in some cases, insulin. Octreotide is the therapeutic agent of choice for hyperglucagonemia. The most commonly used treatment for islet cell tumor is combination chemotherapy with streptozocin and 5-fluorouracil, which is reported to cause tumor shrinkage in as many as 10% of patients. 

Complications include deep venous thrombosis, hypercalcemia when glucagonoma syndrome occurs as part of MEN type 1 syndrome,[12, 13]  adverse effects of therapy (eg, gallstone formation from octreotide), and complications of diabetes mellitus.

Pathophysiology

Glucagon is a 29–amino acid polypeptide with a molecular weight of 3500 daltons; it is manufactured by the alpha cells of the pancreatic islets. Produced as proglucagon, it undergoes posttranslational processing that turns it into glucagon and the major proglucagon fragment (MPGF).[25] In the pancreatic α-cells, glucagon is stored as amyloidlike fibrils.[26] In the intestinal wall's Langerhans cells, proglucagon undergoes post-translational processing to create the following products:

  • Glicentin - A 69-amino acid polypeptide that contains the amino acid sequence of glucagon but does not bind to glucagon receptors or have any of the actions of glucagon

  • Oxyntomodulin – Stimulates gastric acid production and acts via the glucagonlike peptide I receptors in the arcuate nucleus to induce satiety; the administration of oxyntomodulin to animals and humans causes weight loss by reducing food intake in combination with increasing energy expenditure[27]

  • Glucagonlike peptide (GLP) I and II - GLP I (also known as incretin) is a potent stimulator of insulin secretion. It is thought to play an important role in early, anticipatory insulin secretion during a meal, before the increase in arterial blood glucose causes glucose-stimulated insulin secretion (GSIS), which usually occurs about 15 minutes from the start of a meal.[28]

The secretion of glucagon is increased by hypoglycemia, increased sympathetic activity, catecholamines, and alanine. It is inhibited or decreased by hyperglycemia, insulin, and somatostatin.[29, 30]

Glucagon mediates catabolism, and along with cortisol, growth hormone, and the catecholamines (epinephrine, norepinephrine), it plays a key role in glucose counterregulation in response to hypoglycemia. Indeed, the hyperglycemic actions of the other counterregulatory hormones are mediated through the increased production of glucagon.[31] To this end, glucagon analogues have been synthesized and are life-saving medications used in the treatment of hypoglycemia.[32, 33]

Isolated deficiency of glucagon may cause hypoglycemia and impair response to spontaneous and induced hypoglycemia. Hypoglycemia is a powerful stimulator of glucagon secretion. Glucagon secretion increases when blood glucose concentration falls below 50-60 mg/dL and decreases to a nadir at a blood glucose concentration of about 150 mg/dL, usually within 45-90 minutes following a meal. However, hyperglycemia does not suppress glucagon production without the accompanying physiologic increase in insulin secretion.

Insulin and glucagon are the 2 main hormones involved in fuel metabolism. Insulin primarily is anabolic in its actions and is involved in glycogen and protein synthesis, incorporating triglycerides into adipose tissue, increasing glucose uptake and utilization in insulin-sensitive tissues, and promoting glycolysis. Insulin inhibits gluconeogenesis, ketogenesis, and lipolysis. Conversion of the glycerol released from lipolysis into plasma glucose also is inhibited.

Glucagon promotes glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. Glucagon agonism has also been shown to exert effects on lipid metabolism, energy balance, and food intake. The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, in particular, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity.[34, 35] Insulin and glucagon plasma levels vary in a reciprocal manner in healthy individuals. A small increase in the glucagon level stimulates insulin secretion independent of hyperglycemia, and a relatively small increase in the insulin level suppresses the secretion of glucagon.

Insulin directly inhibits glucagon release by binding to the insulin receptor on an alpha cell and having a suppressive effect on the cell's function.[36] Glucagon, on the other hand, not only stimulates insulin secretion directly, by binding to its receptor on the beta cell, but also stimulates secretion indirectly, through induction of hyperglycemia by glycogenolysis, by gluconeogenesis, and by decreasing nonessential peripheral utilization of glucose.

Despite the high glucagon levels associated with type 2 diabetes, diabetic ketoacidosis usually does not occur. Perhaps this is because the circulating insulin concentration, although not sufficient to suppress the hepatic glucose–producing effects of glucagon, is sufficient to inhibit lipolysis and ketogenesis. Hepatic glucose production and lipolysis are known to be more sensitive to insulin than the stimulation of peripheral glucose utilization. However, less insulin is required to suppress lipolysis than to suppress hepatic glucose production.

The role of glucagon in the development of diabetic ketoacidosis is through suppression of malonyl coenzyme A (CoA) levels. Malonyl CoA is an inhibitor of carnitine palmityltransferase (CPT-I), an enzyme that catalyses the rate-limiting step in the transfer of fatty acids across the mitochondrial membrane for beta oxidation; malonyl CoA is therefore an inhibitor of ketogenesis.

CPT-I transesterifies fatty acyl CoA to fatty acyl carnitine, allowing it to cross the mitochondrial membrane and undergo beta oxidation. By decreasing malonyl CoA levels, glucagon indirectly disinhibits CPT-I, causing ketosis. In the absence of glucagon, ketone production is minimal. However, diabetic ketoacidosis does not occur, as a rule, in glucagonoma syndrome, perhaps because the available insulin is sufficient to suppress lipolysis and ketogenesis.

A syndrome of marked hyperglucagonemia and pancreatic α-cell hyperplasia without a tumor has been described. Genetic studies shown the glucagon gene to be normal, but the glucagon receptor sequence showed a homozygous missense mutation (P86S) in the extracellular domain.[37]

Epidemiology

 

The frequency of glucagonoma syndrome is 1 case out of 20,000,000 population. The international frequency is 1 case out of 20,000,000 population. For persons with glucagonoma syndrome, the median age at presentation is 55 years. Mortality related to glucagonoma syndrome most commonly is due to the complication of deep venous thrombosis.

Glucagonomas are slow-growing tumors with an indolent course. Approximately 50-60% of the tumors are malignant and have, by the time of diagnosis, metastasized to the liver. Even with liver metastases, some patients live over 20 years without therapy.[38] ​ Metastasis to the liver, complications of deep venous thrombosis, and the catabolic effects of the tumor are the usual causes of death and shortened survival.

 

 

 

 

Presentation

History

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]

Physical

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.

Causes

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.

 

DDx

 

Workup

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.

 

Treatment

Medical Care

Medical treatment of glucagonoma syndrome includes therapy for NME, treatment of diabetes, treatment of hyperglucagonemia, and treatment of islet cell tumor.

NME has been documented to respond to surgical resection of the glucagonoma, to therapy with octreotide, and to chemotherapy, all of which lead to reduction in glucagon levels.[15, 16, 18, 19, 20, 1, 21, 22, 24]  Amino acid supplementation and total parenteral nutrition, even in the presence of elevated glucagon levels, are shown to lead to dramatic improvement of NME. NME is reported to respond to omega-3 triglyceride therapy. The response of NME to zinc supplementation and to topical zinc has been described, but the role of zinc deficiency in the etiology of NME remains unclear. Other agents used in the treatment of NME include tetracycline and hydrocortisone topical creams.

The control of diabetes in glucagonoma syndrome usually can be achieved with diet, oral hypoglycemic agents, or, in some cases, insulin.

Octreotide is the therapeutic agent of choice for hyperglucagonemia. It is used alone, in combination with chemotherapy, or in conjunction with hepatic artery embolization. A long-acting analogue of somatostatin, octreotide, which has a half-life of 3 hours, can be employed preoperatively prior to the surgical resection or debulking of large metastatic tumors. The drug acts by blocking the secretion and effects of glucagon[45] and is particularly effective in the treatment of NME and diarrhea.

The most commonly used treatment for islet cell tumor is combination chemotherapy with streptozocin and 5-fluorouracil, which is reported to cause tumor shrinkage in as many as 10% of patients. Other chemotherapeutic agents used in combination include doxorubicin, dacarbazine, cisplatin, etoposide, lomustine, cyclophosphamide, and interferon. Chemotherapeutic agents are occasionally used in combination with octreotide.

In rapidly progressive disease, a multimodality approach has been advocated, with the use of surgery or hepatic artery embolization, octreotide, and chemotherapy.

Surgical Care

Surgery is the treatment of choice for glucagonoma syndrome. Surgical treatment includes the following:

  • Resection of a localized tumor, including, in selected cases, through laparoscopic surgery[21, 22, 23]

  • Cytoreduction or debulking of large and nonresectable metastatic tumors

  • Hepatic artery embolization - This procedure can be used alone or in combination with the somatostatin analogue octreotide or with chemotherapy for unresectable hepatic metastases. Hepatic artery embolization works on the principle that most of the blood supply to the tumor is derived from the hepatic artery, whereas the blood supply to the healthy liver parenchyma comes from the portal vein. Embolization of the hepatic artery leads to tumor necrosis.

  • Liver transplantation[46]

Preoperatively, patients may require the following:

  • Total parenteral nutrition with amino acid, fatty acid, and zinc supplementation

  • Blood transfusion - In cases of severe anemia

  • Proper treatment and control of diabetes

  • Heparin - For the prophylaxis of deep venous thrombosis

  • Treatment with octreotide

 

Octreotide acetate (Sandostatin)

Long-acting, cyclic somatostatin analogue that has a half-life of about 2-3 h, with a biologic effect of 1 mo. Short-acting somatostatin must be injected bid-tid to maintain continuous 24-h activity. Both bind with high affinity to somatostatin receptors. Octreotide inhibits the release of GH, glucagon, insulin, gastrin, 5-HT, VIP, secretin, motilin, and pancreatic polypeptide. It suppresses the secretion of TSH and leads to a decreased response of LH to GnRH stimulation.

Octreotide is currently approved for use in acromegaly, carcinoid syndrome, VIPomas, congenital hyperinsulinism (nesidioblastosis), and the treatment of hyperglucagonemia in glucagonoma syndrome. Worsening of diabetes is possible because octreotide also may inhibit insulin release.