4th April 2024

Pancreatic Endocrine Disorders

Multiple endocrine neoplasia types 1 & 2

Introduction

Multiple endocrine neoplasia (MEN) is a group of rare autosomal dominant inherited tumour disorders that manifest with specific organ dysfunction. MEN-1 is caused by a mutation of the MEN1 gene and MEN-2 by a mutation of the RET proto-oncogene. 

MEN-1

Background

Primary hyperparathyroidism is present in approximately 90% of patients. 40 to 70% of patients have functioning or non-functioning pancreatic neuroendocrine tumours, which include insulinomas, gastrinomas, VIPomas, and somatostatinomas. Pituitary adenomas are present in 30 to 40% of MEN-1 patients.

Patients, therefore, may present with symptoms of hyperparathyroidism and of a pituitary adenoma. Hyperparathyroidism leads to hypercalcaemia manifesting as ‘bones, stones and groans’. These symptoms are the most common presenting feature. Those with pituitary adenomas may have symptoms of hyperprolactinaemia (erectile dysfunction, infertility, galactorrhoea, headaches), acromegaly, hyperthyroidism and hypercortisolism. Pituitary adenomas cause both visual and endocrinologic symptoms. Patients may experience gradual vision loss, hyperprolactinaemia (erectile dysfunction, infertility, galactorrhoea, headaches), acromegaly, hyperthyroidism and hypercortisolism.

Diagnosis

The criteria for diagnosis involve any one of the following:

• Two or more MEN-1 associated endocrine tumours 
• One or more MEN-1 associated tumours and a first degree relative with MEN-1
• MEN1 mutation

Treatment

Treatment is focused on medical management of the manifestations of MEN and consideration of surgical removal of tumours.

MEN-2

Background

MEN-2 is extremely rare. MEN-2a and 2b both are associated with a high risk for early onset medullary thyroid carcinoma and phaeochromocytomas. Phaeochromocytomas can be screened with serum free metanephrines and normetanephrines. MEN-2a, in addition, has an increased association with parathyroid adenomas or hyperplasia.

Diagnosis

• MEN2A is diagnosed clinically by 2 or more specific endocrine tumours
• MEN2b is diagnosed clinically with medullary thyroid carcinoma < 40 years old, mucosal neuromas and a marfanoid habitus 
• If clinical features are inconclusive, RET genetic testing can be used

Treatment

Treatment for medullary thyroid carcinoma is thyroidectomy and lymph node dissection. However, patients with the RET gene may be offered a prophylactic thyroidectomy and then follow up calcitonin levels. Calcitonin is released by C cells of the thyroid and it opposes the action of PTH. Phaeochromocytomas are removed by adrenalectomy.

The table below summarises the features of the main types of MEN:

Pancreatic neuroendocrine tumours

Introduction

There are various pancreatic neuroendocrine tumours which include insulinomas, gastrinomas, VIPomas and somatostatinomas.

Insulinoma

This is the most common pancreatic neuroendocrine tumour arising from β cells of the islet of Langerhans. There is an association with MEN-1. High insulin levels lead to hypoglycaemia manifesting as double vision, weakness, confusion and sweating. As insulin is produced in equal amounts as C-peptide the latter is expected to rise in those with insulinomas. Provided Whipple’s criteria is met (hypoglycaemia associated with low blood sugar and resolution of symptoms with glucose administration) then diagnosis is by a supervised 72 hour fast with frequent blood tests and a CT scan of the pancreas. Management consists of surgical excision, however if patients are not surgical candidates, diazoxide and somatostatin can be given.

Gastrinoma

Gastrinomas are gastrin secreting tumours most commonly found in the duodenum or pancreas, causing a rare syndrome called Zollinger-Ellison. This leads to gastroduodenal ulceration, abdominal pain, diarrhoea and malabsorption. Screening is by measuring fasting gastrin levels. For diagnosis, a secretin stimulation test may be performed or through histology via tumour sampling. There is an association with MEN-1. Treatment of choice is to remove it surgically when possible; generally, this is when the disease is localised but not in MEN-1. Medical management involves protein pump inhibitors or somatostatin analogues for the hypersecretion of gastric acid. Several chemotherapeutic agents can be used for those with metastatic disease. 

VIPoma

The VIPoma tumour secretes vasoactive intestinal peptide hormone (VIP). VIP causes inhibition of gastric acid and it stimulates the secretion of water into pancreatic juice and bile and ultimately increases motility. Excess of VIP manifests as watery diarrhoea. Diagnosis is via VIP levels. There is an association with MEN-1. The tumour has a high malignant risk, therefore surgery is the treatment of choice.

Somatostatinoma

Somatostatinomas secrete somatostatin and are found in the pancreas or upper small intestine. Somatostatin is a growth hormone inhibiting hormone and inhibits the release of a variety of hormones including growth hormone, thyroid stimulating hormone, and prolactin. It also suppresses the release of hormones in the GI system.  This type of tumour can cause diabetes, gallstones and diarrhoea. 

The table below summarises gastrointestinal hormones and their source:

Obesity and metabolic syndrome

Obesity is defined as a BMI over 30kg/m². However, abdominal obesity may be a more reliable indicator of obesity related complications. Management involves initially physical activity, dietary advice and behavioural intervention. Drug treatment if the prior fails involve orlistat or liraglutide as options. Orlistat is a lipase inhibitor and liraglutide is a GLP-1 agonist. Referral for weight loss surgery may be indicated if the patient has a BMI of over 40, or between 35 to 40 with other significant diseases. 

Metabolic syndrome is becoming increasingly more common globally. It consists of a combination of conditions, including hypertension, insulin resistance, impaired glucose tolerance, obesity and high cholesterol, which can increase the risk of cardiovascular disease.

References

• Eng C. Multiple Endocrine Neoplasia Type 2. 1999 Sep 27 [Updated 2019 Aug 15]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1257/
• Gorrigan, R., Druce, M. (2021) Multiple endocrine neoplasia syndromes. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/866 
• Iglesias, P. and Díez, J., 2014. MANAGEMENT OF ENDOCRINE DISEASE: A clinical update on tumor-induced hypoglycemia. European Journal of Endocrinology, 170(4), pp.R147-R157.
• National Institute for Health and Care Excellence (NICE) (2017) Obesity.  Available at: https://cks.nice.org.uk/topics/obesity/).
• Pisegna, J. (2022) Zollinger-Ellison syndrome. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/408 
• Ro, C., Chai, W., Yu, V. and Yu, R., 2013. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chinese Journal of Cancer, [online] 32(6), pp.312-324. Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845620/>.
• Sinnot, B. (2022). Phaeochromocytoma. BMJ Best Practice.
  https://bestpractice.bmj.com/topics/en-gb/163
• Thakker, R., 2012. Clinical Practice Guidelines for Multiple endocrine neoplasia Type 1 (MEN1). The Journal of Clinical Endocrinology &amp; Metabolism, 97(9), pp.2990-3011.
• Wehmeier, K., Grundy, S. (2022) Metabolic syndrome. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/212