6.6 Glucagonoma

Glucagonomas are neuroendocrine tumours arising from the α cells of the islets of Langerhans, which result in excessive secretion of glucagon and peptides derived from preproglucagon. Post-translational modification of proglucagon is tissue specific and results in various glucagon peptides (1). It is the ratio of insulin to glucagon that controls the balance of gluconeogenesis and glycogenolysis in the liver. Glucagon stimulates hepatic gluconeogenesis and inhibits both glycolysis and glycogen synthesis. It increases production of free fatty acids from triglyceride breakdown by activating hormone-sensitive lipase; these undergo fatty oxidation in the liver via acetyl CoA, forming ketone bodies. The increase in free fatty acids from lipolysis inhibits hepatic lipogenesis. Glucagon also increases muscle proteolysis, resulting in an increase in amino acid supply to the liver.

The incidence of glucagonomas is estimated to be only 1 per 20 million (2). The current data is either based upon single case reports or a few small series of cases. The majority of glucagonomas are sporadic, with only 3% associated with multiple endocrine neoplasia (MEN) (3). Table 6.6.1 illustrates the clinical features of 22 patients from the Hammersmith Hospital between 1970 and 1999. The median age of presentation is 64 years for sporadic tumours and 33 years for those associated with MEN. The earlier age of onset noted in those with glucagonomas associated with MEN may be due to the fact these patients may present with other disease-associated symptoms, e.g. hypercalcaemia of hyperparathyroidism. Alternatively, they may be detected through screening for neuroendocrine tumours.

The term glucagonoma syndrome was first used in 1974 with the description of a series of cases of glucagon-secreting pancreatic tumours associated with necrolytic migratory erythema, weight loss, diabetes mellitus, and stomatitis (4). Not all glucagonomas are symptomatic and they may be identified solely through screening of MEN patients. The nutrient deficiencies arising due to hyperglucagonoma and the secretion from the tumour of glucagon-like peptides 1 and 2, as well as cosecretion of other hormones such as pancreatic polypeptide, give rise to a spectrum of clinical features (5).

This painful pruritic rash is a typical feature of the glucagonoma syndrome and one of the most common presenting signs, occurring in 72% of patients (6). Although characteristic for the glucagonoma syndrome, NME is not pathognomic (Fig. 6.6.1). The initial lesions of NME are erythematous plaques which may be associated with bullae. These lesions form erosions and crusts which eventually heal to leave central areas of hyperpigmentation and induration. The lesions demonstrate the koebner phenomenon, i.e. occurring at sites of trauma (4). Skin biopsy histology reveals necrolysis of the upper dermis and vacuolization of keratinocytes (7). The occurrence of NME does not correlate with metastases and has been noted in 60% of patients with benign glucagonoma.

The exact pathogenesis of NME remains unclear. There have been several postulated theories; the condition appears to be a multifactorial disease caused by a combination of zinc, amino acid, and fatty acid deficiencies (8). The glucagonoma syndrome shares a number of clinical features with vitamin B_2, B_3, B_6, and B₁₂ deficiency. Indeed vitamin B deficiency may arise as a result of hyperglucagonaemia (5). There have been several cases of NME reported that were secondary to intravenous glucagon treatment, suggesting that NME is a direct consequence of glucagon action on the skin (9, 10). NME has also been associated with conditions other than glucagonoma, e.g. coeliac disease and cirrhosis; both of these conditions may have raised glucagon or glucagon-like peptides levels (6).

Diabetes mellitus is common in sporadic glucagonomas, occurring in 55% of patients at presentation and eventually developing in 75% of cases. Of these three-quarters require insulin therapy (11). Although rare, diabetic ketoacidosis has been reported (12).

Weight loss or cachexia is a common presenting complaint, occurring in 72% of patients with metastases and 40% with local disease (6) Similar rates of 71% were noted in a review from the Mayo clinic of 21 patients with glucagonoma (11). Normocytic normochromic anaemia was noted in approximately a third of patients; and is probably the result of direct bone marrow suppression by glucagon (6). Diarrhoea occurs in approximately one-fifth of patients (6, 11); of these, 50% also have elevated gastrin and pancreatic polypeptide levels (6). Involvement of the mucous membranes may lead to the development of stomatitis, glossitis, and chelitis in a third of cases (6). Psychiatric symptoms occur in 20% of patients and may vary from depression to paranoid delusions (6). Thromboembolism is a major source of morbidity and mortality in the glucagonoma syndrome and occurs in up to 11% of cases (6) and may account for up to 50% of deaths (13).

Over 80% of patients with sporadic tumours have metastases at presentation (6, 11). Hepatic metastases usually involve both lobes of the liver and are multiple in two-thirds of cases; of the single hepatic metastases 75% occur in the right lobe (6). Of primary tumours, 41% are confined to the tail of the pancreas, 14% involve the head and body, 14% occur in the head alone, and 9% in the body alone (6). Sensitive imaging modalities and hepatic angiography may allow an increased detection of the primary tumour site (6).

Raised fasting plasma glucagon immunoreactivity is the basis for diagnosis. The reference range at the Hammersmith Clinical Chemistry Gut Hormone Laboratory is fasting plasma glucagon level below 50 pmol/l. False-positive results may occur due to other causes of a raised fasting plasma glucagon such as renal or hepatic failure, drugs, and prolonged fasting (14). Plasma glucagon levels may be elevated to various degrees ranging from only 1.5 to 150 times the upper limit of normal (6). Thus, if clinically supported, a marginally elevated plasma glucagon level may still be suspicious (15).

A raised fasting plasma gastrin level is noted in one-fifth of patients at presentation and may be associated with the Zollinger–Ellison syndrome (16). Plasma gastrin levels should be monitored regularly since they may rise up to 6 years after initial diagnosis. Other hormones may also be elevated, for example insulin, 5-hydroxyindoleacetic acid, human pancreatic polypeptide, chromogranin, and vasoactive intestinal peptide. It is therefore important an annual assessment of fasting gut hormone profile should be undertaken (6).

Biochemical investigations may reveal hypoproteinaemia, hypoalbuminaemia, and hypocholesterolaemia (13). Specific nutritional deficiencies, e.g. zinc deficiency, should be screened for (13), although plasma levels of trace elements may not reflect tissue levels (6).

Contrast-enhanced CT and visceral angiography are the imaging modalities of choice and are more sensitive than abdominal ultrasound in tumour detection (17) (Fig. 6.6.2). The usefulness of MRI in tumour or metastases detection is as yet unclear (6).

A multidisciplinary approach to treatment is required. Nutritional assessment, correction of any deficiencies and implementation of weight maintenance strategies is imperative. Where required, diabetic control should be optimized. Anticoagulation therapy should be instigated although there are currently no guidelines regarding which anticoagulant to use or the extent of anticoagulation required.

Surgical resection, either of the tumour itself or distal pancreatectomy and splenectomy in local disease, is the treatment of choice and offers 5-year survival rates of over 66% (6). However, 90% of patients have metastases at presentation and these commonly extend beyond lymph node metastases (6). Nevertheless, surgical resection or debulking of the tumour or distal pancreatectomy and splenectomy may offer good symptom relief (6). Unfortunately, symptoms return in a quarter of patients by 1 year, and 1-year survival rates are only 50% (6).

Hepatic artery embolization allows devascularization of hepatic metastases and symptomatic relief in 80% of patients; this may not correlate with a fall in plasma glucagon (18). Prior to the procedure, the patency of the portal vein must be established to ascertain whether there is adequate supply to the normal liver parenchyma. Complications of the procedure include massive peptide release, the effects of this may be minimized with the use of octreotide. Vasodilating peptides and contrast load may lead to severe hypotension, thus optimal fluid balance must be maintained both pre- and postembolization. Additionally there are risks of infection in the necrotic tissue and of hepatic abscess formation (6).

Somatostatin analogues such as octreotide are the mainstay of medical therapy and provide rapid symptomatic relief, especially of NME (19), although they are less effective in control of weight loss and diabetes (20). Somatostatin inhibits growth hormone and other pituitary and pancreatic hormones. It has been demonstrated to both reduce plasma glucagon levels and shrink tumour size but its use was restricted by its very short plasma half-life. Octreotide is a somatostatin analogue with a longer plasma half-life of 2 h with intravenous administration. It is effective in reducing plasma glucagon levels, although tumour shrinkage or suppression of growth has not been demonstrated (21). Patients may require increasingly higher doses of octreotide after 6 months to control symptoms (6). Lanreotide is a longer-acting somatostatin analogue, which can be administered every 2 weeks, and has been shown to be effective (22) requires further evaluation in a larger number of cases. Patients should be monitored for symptoms of gall stone formation as cholestasis is noted in 50% of patients (6).

Chemotherapeutic agents such as streptozocin and 5-fluorouracil have been used in the treatment of glucagonoma. Streptozocin is a nitrosourea antibiotic with selective toxicity to pancreatic B cells, demonstrated in animals, and 5-fluorouracil inhibits DNA synthesis (6). Chemotherapy has a very limited role in management in those with symptoms persisting at 6 months and patients tend to survive for less than a year (6).

Patients with benign disease have a 85% survival rate at a mean follow-up of 4.7 years. Those with malignant disease treated with combination therapy have a 60% survival rate with a mean follow-up of 4.8 years.