MEN Syndromes & Endocrine Pancreas

The endocrine pancreas

Four islet cell types. Alpha cells make glucagon, beta cells make insulin (and amylin), delta cells make somatostatin, and PP (F) cells make pancreatic polypeptide. In the classic islet picture, beta cells cluster centrally and alpha cells sit at the periphery. Each cell type can give rise to a functioning neuroendocrine tumor whose syndrome is simply an excess of its hormone.

Somatostatin is the universal "off switch" of GI and pancreatic hormones, so a somatostatin-secreting tumor mimics losing all of them at once.

Multiple endocrine neoplasia

Genetics. All MEN syndromes are autosomal dominant. MEN1 results from loss of the MEN1 tumor suppressor gene, which encodes menin (chromosome 11). MEN2A and MEN2B result from gain-of-function mutations of the RET proto-oncogene, a receptor tyrosine kinase (chromosome 10).

MEN1 = tumor suppressor (menin); MEN2 = oncogene (RET).

MEN1 (Wermer): the three P's. Parathyroid hyperplasia is the earliest and most common manifestation and causes hypercalcemia. Pancreatic islet tumors, especially gastrinoma and insulinoma, are the next feature, and pituitary adenomas, most commonly prolactinomas, complete the triad. A patient with hypercalcemia, recurrent duodenal ulcers and galactorrhea with amenorrhea has all three.

MEN2A (Sipple). Medullary thyroid carcinoma, pheochromocytoma and parathyroid hyperplasia, all from a RET mutation.

MEN2B. Medullary thyroid carcinoma and pheochromocytoma plus mucosal and GI neuromas (bumpy lips and tongue) with a marfanoid habitus, but no primary hyperparathyroidism. It is the most aggressive MEN syndrome, with the earliest-onset medullary carcinoma, and is also RET-driven.

Medullary thyroid carcinoma. It arises from the parafollicular C cells, secretes calcitonin, and shows amyloid stroma derived from calcitonin. It is the hallmark of both MEN2 subtypes, and rising calcitonin (and CEA) tracks the disease after treatment.

Prophylactic thyroidectomy. Because medullary carcinoma is nearly inevitable in MEN2, RET carriers identified by genetic testing undergo prophylactic thyroidectomy, earliest in MEN2B. Pheochromocytoma must always be screened for and treated before any surgery, because an unrecognized tumor can release catecholamines during anesthesia and cause a lethal hypertensive crisis.

Other familial pheochromocytoma syndromes. Von Hippel-Lindau disease and neurofibromatosis type 1 also predispose to pheochromocytoma but lack medullary thyroid carcinoma.

Insulinoma and the hypoglycemia workup

Insulinoma. A beta-cell tumor and the most common functioning islet-cell tumor; most are small, solitary and benign. Patients have fasting hypoglycemia with adrenergic symptoms (sweating, tremor, palpitations) and neuroglycopenic symptoms (confusion, odd behavior, seizures), and may gain weight from frequent eating.

Whipple triad. Diagnosis rests on (1) symptoms of hypoglycemia, (2) a documented low plasma glucose (below 55 mg/dL) at the time of symptoms, and (3) relief when glucose is given. Labs show inappropriately high insulin, C-peptide and proinsulin during hypoglycemia. Surgical resection is curative; diazoxide, which opens β-cell K+ channels and blocks insulin release, is used when surgery is not possible.

Separating the causes. Insulin and C-peptide are cleaved from proinsulin in equal amounts, so endogenous insulin brings C-peptide with it and injected insulin does not. Sulfonylurea abuse drives the patient's own β cells and therefore mimics an insulinoma, but the drug is detectable in serum.

Other functioning islet-cell tumors

Gastrinoma (Zollinger-Ellison syndrome). A gastrin-secreting tumor of the duodenum or pancreas drives massive acid secretion: refractory or recurrent peptic ulcers, ulcers in unusual sites such as the distal duodenum and jejunum, and diarrhea (acid inactivates pancreatic enzymes, causing steatorrhea). Confirm with a high fasting gastrin and a positive secretin stimulation test. Gastrinoma is associated with MEN1.

Normally secretin lowers gastrin; in gastrinoma it paradoxically raises it.

Glucagonoma. An alpha-cell tumor producing the 6 D's: Dermatitis (necrolytic migratory erythema), Diabetes (hyperglycemia), DVT, Depression, Diarrhea and Declining weight. Treat with octreotide and resection.

VIPoma. Vasoactive intestinal peptide causes WDHA syndrome (Verner-Morrison, "pancreatic cholera"): Watery Diarrhea that is large-volume, tea-colored and secretory (it persists with fasting), Hypokalemia, and Achlorhydria. The somatostatin analog octreotide controls symptoms.

Somatostatinoma. A delta-cell tumor whose somatostatin suppresses insulin (diabetes), CCK (gallstones and steatorrhea) and gastrin (achlorhydria). The classic triad is diabetes, gallstones and steatorrhea.