Endocrinology: NETS and Hypoglycaemia (Complete)

• Neuroendocrine tumours: Neuroendocrine Tumours | Carcinoid Syndrome | Pancreatic NETs | Treating NETs
• Inherited syndromes: MEN1 | MEN2 | Other Familial Endocrine Syndromes
• Hypoglycaemia without diabetes: Hypoglycaemia without Diabetes: Approach | Investigating Hypoglycaemia | Insulinoma | Factitious Hypoglycaemia | Other Causes
• Revision: Drug Reference Table | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧬 Neuroendocrine tumours and hypoglycaemia are linked by the insulinoma - a pancreatic NET that presents as low blood glucose. This chapter covers NETs and carcinoid syndrome, the inherited multiple endocrine neoplasia syndromes, and how to investigate hypoglycaemia in someone who does not have diabetes.
Your four questions for every patient: Is there a hormone syndrome, or just a mass? What grade and how far has it spread? Could this be inherited (MEN1, MEN2, VHL)? If hypoglycaemic - is it real, and what did the critical sample show?

Neuroendocrine Tumours

Mechanism: Tumours of neuroendocrine cells, which are spread throughout the body and can secrete hormones and amines. Phaeochromocytoma and medullary thyroid cancer are also neuroendocrine tumours, but are covered in other chapters.

Common sites:

• Small intestine (especially the ileum). Pancreas.
• Appendix - often found incidentally by pathology after appendicectomy.
• Rectum. Stomach. Lung (bronchial carcinoid).

Key features:

• Function: Most are "non-functioning" and present with a mass, metastases or as incidental findings.
• Functioning" tumours cause hormone syndromes.

Investigations:

• Biochemistry:
  • 24-hour urine 5-HIAA (or plasma 5-HIAA) for serotonin-secreting tumours. Avoid bananas, tomatoes, avocados, pineapple, walnuts and some drugs beforehand.
  • Chromogranin A - a general marker. Falsely raised by PPIs, renal failure and atrophic gastritis.
  • Specific hormones - gastrin, insulin, glucagon, VIP - guided by symptoms.
• Imaging:
  • CT and MRI.
  • Somatostatin receptor PET-CT (e.g. Ga-68 DOTATATE) - most well-differentiated NETs express somatostatin receptors. It also predicts response to somatostatin-based treatment.
  • FDG-PET for high-grade tumours.
  • Endoscopic ultrasound for pancreatic NETs.
• Biopsy for grade (Ki-67).
• Echocardiogram in carcinoid syndrome.

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Carcinoid Syndrome

Mechanism: Serotonin, tachykinins and other substances released by a NET (usually small intestinal) reach the general circulation. Normally the liver inactivates them, so the syndrome usually means liver metastases. The exceptions are primary tumours that drain directly into the systemic circulation - lung and ovary.

Clinical pattern:

• Flushing - face and upper body, often triggered by alcohol, stress or food.
• Diarrhoea - watery, secretory.
• Bronchospasm (wheeze). Abdominal pain.
• Carcinoid heart disease: Causes fibrosis of the right-sided valves, causing tricuspid regurgitation and pulmonary stenosis, with right heart failure. The left heart is spared unless there is a PFO or lung primary - the lungs inactivate serotonin.
• Pellagra - dermatitis, diarrhoea, dementia - from niacin deficiency, as tryptophan is diverted into serotonin.

Diagnosis:

• Raised urine or plasma 5-HIAA.
• CT or MRI of the liver.
• Ga-68 DOTATATE PET.
• Echocardiogram - and NT-proBNP to screen for heart involvement.

Management:

• Somatostatin analogues - octreotide or lanreotide - control symptoms in most patients and slow tumour growth.
• Telotristat ethyl for refractory diarrhoea.
• Niacin supplements.
• Valve replacement for carcinoid heart disease.
• Avoid triggers.
• Prevent carcinoid crisis around surgery, embolisation or anaesthesia, with octreotide cover.

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Pancreatic NETs

Most pancreatic NETs are non-functioning. The functioning ones are named after the hormone they make:

• Insulinoma (commonest functioning): Fasting hypoglycaemia - see Insulinoma. Usually small, single and benign.
• Gastrinoma - Zollinger–Ellison syndrome:
  • Location: Pancreas or duodenum.
  • Clinical pattern: Excess gastric acid causes multiple, severe or recurrent peptic ulcers, ulcers in unusual places (distal duodenum, jejunum), and diarrhoea (acid inactivates lipase).
  • Diagnosis: Raised fasting gastrin with acidic gastric pH. PPIs raise gastrin, so interpret with specialist advice - do not simply stop the PPI in someone with severe ulcer disease. Secretin stimulation test.
  • Malignancy: Over half are malignant.
  • MEN1: About 25% have it.
  • Treatment: High-dose PPI and surgery where possible.
• Glucagonoma:
  • Necrolytic migratory erythema - a migrating, blistering rash around the groin and perineum.
  • Diabetes. Weight loss. Anaemia. VTE. Glossitis.
• VIPoma - Verner–Morrison or "WDHA" syndrome:
  • Watery Diarrhoea - large volumes, persists despite fasting.
  • Hypokalaemia. Achlorhydria.
  • Dehydration, acidosis, hypercalcaemia, flushing.
• Somatostatinoma (rare): Diabetes, gallstones, steatorrhoea - inhibition of insulin, gallbladder contraction and pancreatic enzymes.
• Non-functioning pancreatic NETs:
  • Present with a mass, jaundice or liver metastases.
  • Small (under 2 cm) incidental tumours may be monitored.

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Treating NETs

Treatment is decided by a specialist NET multidisciplinary team:

• Surgery: The only cure - resection of the primary and, where possible, metastases. Removing the primary can also prevent obstruction and ischaemia from small bowel tumours.
• Somatostatin analogues:
  • Drugs: Octreotide LAR (e.g. 30 mg IM every 4 weeks), lanreotide (120 mg deep SC every 4 weeks), or short-acting SC octreotide.
  • Effect: Control hormone symptoms, and slow growth of well-differentiated tumours.
  • Side effects: Gallstones, steatorrhoea, abdominal cramps, glucose changes.
• Peptide receptor radionuclide therapy (PRRT): Lutetium-177 dotatate delivers radiation to somatostatin receptor-positive tumours. NICE TA539 covers progressive, unresectable, well-differentiated gastroenteropancreatic NETs.
• Targeted drugs: Everolimus and sunitinib for progressive pancreatic NETs; everolimus for lung and GI NETs.
• Liver-directed treatment: Embolisation, ablation, selective internal radiation.
• Chemotherapy: Capecitabine and temozolomide for pancreatic NETs. Platinum and etoposide for neuroendocrine carcinomas.
• Hormone-specific control: High-dose PPI (gastrinoma), diazoxide (insulinoma), telotristat (carcinoid diarrhoea).
• Follow-up: Long-term imaging and markers - recurrence can occur many years later.

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MEN1

Mechanism: Multiple endocrine neoplasia type 1 is an autosomal dominant loss-of-function mutation in the MEN1 gene (which encodes menin, a tumour suppressor). Tumours develop in several endocrine glands, often at a young age.

The "3 Ps":

• Parathyroid (about 95%): Primary hyperparathyroidism from multigland hyperplasia. Usually the first feature, often in the 20s–30s.
• Pancreas and duodenum (about 40–70%):
  • Gastrinoma - commonest functioning, often multiple and duodenal.
  • Insulinoma.
  • Non-functioning NETs - the main cause of death.
• Pituitary (about 30–40%): Prolactinoma most often, then non-functioning, GH or ACTH tumours.
• Others:
  • Adrenal cortical tumours.
  • Thymic and bronchial carcinoids - thymic carcinoids are aggressive, especially in male smokers.
  • Skin - angiofibromas, collagenomas, lipomas.
  • Meningiomas.

Diagnosis: Any of:

• Two of the three main tumours.
• One main tumour plus a first-degree relative with MEN1.
• A MEN1 mutation.

Who to test genetically:

• Primary hyperparathyroidism under 30, or multigland disease.
• Gastrinoma.
• Multiple pancreatic NETs.
• A family history.

Management:

• Parathyroids: Subtotal or total parathyroidectomy (with autotransplantation) - recurrence is common.
• Other tumours: Treated on their own merits.
• Lifelong surveillance: Calcium, PTH, prolactin, IGF-1, fasting gut hormones, and MRI of the pancreas and pituitary - from about age 5 in mutation carriers.
• Family screening (cascade testing).

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MEN2

Mechanism: An autosomal dominant gain-of-function mutation in the RET proto-oncogene. The specific mutation (codon) predicts how early and how aggressive the medullary thyroid cancer will be.

MEN2A (the common form):

• Medullary thyroid cancer - nearly 100%.
• Phaeochromocytoma - about 50%, often bilateral.
• Primary hyperparathyroidism - about 20–30%.
• Also cutaneous lichen amyloidosis and Hirschsprung's disease.

MEN2B (rarer, more aggressive):

• Medullary thyroid cancer - very early and aggressive.
• Phaeochromocytoma.
• Mucosal neuromas - lips, tongue, eyelids.
• Marfanoid habitus.
• Intestinal ganglioneuromatosis - constipation, megacolon.
• No hyperparathyroidism.

Management:

• Genetic testing: Everyone with medullary thyroid cancer should have RET testing, and positive relatives too.
• Prophylactic total thyroidectomy in RET carriers, timed by the codon:
  • MEN2B - within the first year of life.
  • High-risk MEN2A - by about 5 years.
  • Lower-risk MEN2A - guided by calcitonin.
• Calcitonin (and CEA) are tumour markers for medullary thyroid cancer.
• Screening: For phaeochromocytoma (plasma metanephrines) and calcium.
• Always exclude phaeochromocytoma before any surgery - including thyroidectomy and pregnancy delivery. If present, remove it first with alpha-blockade.

💡 Clinical Pearl: MEN1 = the 3 Ps (parathyroid, pancreas, pituitary). MEN2A = medullary thyroid cancer, phaeo, parathyroid. MEN2B = medullary thyroid cancer, phaeo, mucosal neuromas and a marfanoid build - but no parathyroid disease.

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Other Familial Endocrine Syndromes

• Von Hippel–Lindau (VHL gene):
  • Retinal and CNS (cerebellar, spinal) haemangioblastomas.
  • Clear cell renal carcinoma and renal cysts.
  • Phaeochromocytoma.
  • Pancreatic NETs and cysts.
  • Endolymphatic sac tumours.
  • Polycythaemia (EPO from tumours).
• Neurofibromatosis type 1 (NF1):
  • Café-au-lait macules, axillary freckling.
  • Neurofibromas, Lisch nodules.
  • Phaeochromocytoma.
  • Duodenal somatostatinoma and GIST.
• Succinate dehydrogenase (SDHx) mutations:
  • Paragangliomas (head and neck, abdomen) and phaeochromocytomas.
  • SDHB carries a high risk of malignancy.
  • Also GIST and renal cancer.
• Carney complex (PRKAR1A):
  • Spotty skin pigmentation.
  • Cardiac myxomas.
  • Primary pigmented nodular adrenal disease (Cushing's).
  • GH-secreting pituitary tumours.
  • Testicular and thyroid tumours.
• MEN4 (CDKN1B): An MEN1-like phenotype without an MEN1 mutation.
• Autoimmune polyendocrine syndromes:
  • APS-1 (AIRE gene): Mucocutaneous candidiasis, hypoparathyroidism, Addison's disease.
  • APS-2: Addison's disease plus autoimmune thyroid disease and/or type 1 diabetes - commoner, in adults.
• Genetic testing: About 30–40% of phaeochromocytomas and paragangliomas have a germline mutation, so all patients with one should be offered genetic testing.

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Hypoglycaemia without Diabetes: Approach

Why it is rare: In people without diabetes, hypoglycaemia is very uncommon, because insulin switches off and glucagon, adrenaline, cortisol and GH switch on as glucose falls. True hypoglycaemia therefore means something is overriding these defences. Be very weary of diagnosis hypoglycaemia simple because people fast. People undergo starvation do not succumb to hypoglycaemic. Blaming odd symptoms on unverified "low blood sugar" can lead to missing other diagnoses e.g. epilepsy.

Confirm it is real - Whipple's triad:

• Symptoms of hypoglycaemia.
• A low plasma glucose measured at the time - typically below 3.0 mmol/L, measured in the lab. Capillary meters are unreliable at low levels.
• Symptoms relieved when glucose is raised.

Symptoms:

• Autonomic: Sweating, tremor, palpitations, hunger, anxiety.
• Neuroglycopenic: Confusion, odd behaviour, slurred speech, focal weakness, seizures, coma. Often misdiagnosed as epilepsy, stroke, psychiatric illness or intoxication.

A practical split:

• Unwell patients (most hospital cases):
  • Drugs - alcohol, quinine, pentamidine, quinolones, beta-blockers, salicylates, accidental insulin or sulfonylurea.
  • Critical illness - sepsis, liver failure, renal failure, heart failure, starvation, malaria.
  • Hormone deficiency - cortisol, GH.
  • Non-islet cell tumour hypoglycaemia.
• Apparently well patients:
  • Insulinoma.
  • Post-bariatric hypoglycaemia.
  • Insulin autoimmune syndrome.
  • Factitious or accidental insulin or sulfonylurea.

💡 Clinical Pearl: Hypoglycaemia that happens after fasting or exercise suggests insulinoma. Hypoglycaemia 1–3 hours after meals in someone who has had bariatric surgery suggests post-bariatric hypoglycaemia.

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Investigating Hypoglycaemia

The critical sample: Take blood during a spontaneous hypoglycaemic episode (glucose below 3.0 mmol/L), before giving glucose if it is safe to do so. Measure:

• Plasma glucose (lab).
• Insulin.
• C-peptide - released with the body's own insulin, but not present in injected insulin.
• Proinsulin.
• Beta-hydroxybutyrate (ketones are suppressed by insulin).
• Sulfonylurea screen.
• Insulin antibodies.
• Cortisol.

Supervised 72-hour fast: The gold standard if spontaneous episodes cannot be captured. Done on a ward with glucose checks; the fast is stopped and bloods taken when hypoglycaemia occurs. Most insulinomas show within 48 hours.

💡 Clinical Pearl: Some insulin assays do not detect modern insulin analogues. If factitious insulin use is suspected and insulin looks normal, discuss with the laboratory.

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Insulinoma

• What it is: An insulin-secreting pancreatic NET - the commonest functioning pancreatic NET. About 1–4 cases per million people a year.
• The "rule of 10s": About 90% are benign, 90% are single, and 90% are under 2 cm. About 10% are associated with MEN1 (often multiple).
• Clinical pattern:
  • Fasting or exercise-induced hypoglycaemia - e.g. confusion before breakfast or after missing a meal.
  • Weight gain from eating to avoid symptoms.
  • Often misdiagnosed for years as epilepsy, psychiatric illness or "funny turns".
• Diagnosis:
  • Biochemistry first: Hypoglycaemia with inappropriately high insulin, C-peptide and proinsulin, low ketones and a negative sulfonylurea screen.
  • Then localisation: CT or MRI, endoscopic ultrasound. GLP-1 receptor PET is highly sensitive (specialist centres). Somatostatin receptor PET is less sensitive for benign insulinomas.
• Management:
  • Surgical removal (enucleation or partial pancreatectomy) cures most.
  • Before or instead of surgery:
    • Frequent meals and a bedside glucose plan.
    • Diazoxide (inhibits insulin release) - causes fluid retention, so it is often given with a thiazide; also causes hirsutism.
  • Somatostatin analogues - with caution, as they can worsen hypoglycaemia by suppressing glucagon.
  • Everolimus or PRRT for malignant insulinoma.

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Factitious Hypoglycaemia

• What it is: Hypoglycaemia caused by deliberate, covert use of insulin or sulfonylureas. It occurs more often in:
  • Healthcare workers.
  • People with access to diabetes drugs - family members with diabetes.
  • People with a psychiatric history or factitious disorder.
• Fabricated or induced illness (by a carer, especially in children) is a safeguarding issue.
• Accidental: Dispensing errors - e.g. gliclazide supplied instead of another drug - and confusion in older people. Always check the actual tablets.
• Clues:
  • Injected insulin: High insulin with low C-peptide.
  • Sulfonylurea: High insulin and C-peptide with a positive sulfonylurea screen - the screen must be specifically requested.
• Management:
  • Make sure the patient is safe.
  • Approach non-judgementally, with senior and psychiatric involvement.
  • Involve safeguarding if a child or vulnerable adult may be at risk.
  • Document carefully.
• Sulfonylurea overdose: Hypoglycaemia can recur for days. Give octreotide (which blocks insulin release) as well as glucose, and admit for monitoring.

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Other Causes

• Post-bariatric hypoglycaemia:
  • Timing: Typically 1–3 years after gastric bypass, occurring 1–3 hours after meals.
  • Mechanism: Rapid glucose absorption, a big GLP-1 surge, then excess insulin.
  • Treatment:
    • Small, low-glycaemic meals, with sugars avoided.
    • Acarbose.
    • Then specialist options - diazoxide, somatostatin analogues, feeding tube into the remnant stomach, or surgical reversal in severe cases.
• Non-islet cell tumour hypoglycaemia (NICTH):
  • Cause: Large tumours - mesothelioma, solitary fibrous tumours, hepatocellular carcinoma, sarcomas - secrete incompletely processed "big IGF-2", which acts like insulin.
  • Biochemistry: Insulin and C-peptide are suppressed; IGF-2:IGF-1 ratio above about 10.
  • Treatment: Remove or debulk the tumour. Glucocorticoids (e.g. prednisolone) or GH can help.
• Insulin autoimmune syndrome (Hirata disease):
  • Cause: Antibodies to insulin bind it after meals and release it later, causing hypoglycaemia.
  • Who: Commoner in East Asian people. Triggered by drugs with sulfhydryl groups (e.g. methimazole, alpha-lipoic acid).
  • Course: Often self-limiting.
• Alcohol: Blocks gluconeogenesis - hypoglycaemia after binge drinking with poor food intake. Ketosis may be present. Give thiamine as well as glucose.
• Liver failure, sepsis, renal failure, starvation, malaria (and quinine treatment).
• Adrenal insufficiency and hypopituitarism: Especially in children. Check cortisol.
• Drugs: Quinine, pentamidine, quinolones, high-dose salicylates, beta-blockers (which also mask warning symptoms), ACE inhibitors (rarely).
• Nesidioblastosis: Diffuse beta-cell overgrowth - neonates (congenital hyperinsulinism) and some adults after bypass.
• Reactive (idiopathic) postprandial symptoms without documented low glucose: not true hypoglycaemia - Whipple's triad is not met.

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Drug Reference Table

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Spot the Diagnosis

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Exam-style Scenarios

1. A 58-year-old man has flushing and diarrhoea. CT shows liver lesions and an ileal mass; echo shows tricuspid regurgitation.
Answer: Carcinoid syndrome from a small bowel NET with liver metastases, and carcinoid heart disease.

• Urine 5-HIAA, biopsy for Ki-67, Ga-68 DOTATATE PET.
• Somatostatin analogue.
• NET MDT.
• Octreotide cover for any procedure.

2. A 29-year-old woman has medullary thyroid cancer. Her father had a "blood pressure tumour" removed.
Answer: Likely MEN2A.

• RET genetic testing.
• Exclude phaeochromocytoma (plasma metanephrines) before thyroidectomy; remove it first if present.
• Check calcium and PTH.
• Cascade testing of relatives.

3. A 35-year-old woman has early-morning confusion that improves with breakfast, and recent weight gain. During a hypoglycaemic episode: glucose 2.1, insulin and C-peptide raised, ketones low, sulfonylurea screen negative.
Answer: Insulinoma.

• Localise with CT, MRI and endoscopic ultrasound.
• Surgical removal.
• Check calcium and prolactin for MEN1.

4. An 82-year-old man has recurrent hypoglycaemia. He does not have diabetes. Insulin and C-peptide are raised; the sulfonylurea screen is positive.
Answer: Sulfonylurea-induced hypoglycaemia - possibly a dispensing error.

• Check the actual tablets he is taking.
• Admit; glucose infusion and octreotide.
• Monitor for 24–72 hours.
• Report the error.

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Key Points

• Most NETs are slow-growing; grade (Ki-67) guides outlook and treatment.
• Carcinoid syndrome usually means liver metastases. Check 5-HIAA and screen the right heart.
• Ga-68 DOTATATE PET finds most well-differentiated NETs and predicts response to somatostatin-based treatment.
• NET treatment centres on surgery and somatostatin analogues; give octreotide cover for procedures.
• MEN1 is the 3 Ps; MEN2 is medullary thyroid cancer plus phaeo. Exclude phaeo before any surgery.
• Offer genetic testing to everyone with a phaeochromocytoma or paraganglioma.
• Hypoglycaemia without diabetes: confirm Whipple's triad, and take the critical sample - insulin, C-peptide, ketones, sulfonylurea screen.
• High insulin with low C-peptide means injected insulin.

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Guidelines and Further Reading

• UK and Ireland Neuroendocrine Tumour Society (UKINETS) guidance
• ENETS guidance papers on gastroenteropancreatic NETs
• Clinical practice guidelines for MEN1 (Thakker et al.) and revised American Thyroid Association guidelines for medullary thyroid cancer
• Endocrine Society guideline: Evaluation and management of adult hypoglycaemic disorders
• NICE TA539: Lutetium-177 dotatate for unresectable or metastatic neuroendocrine tumours
• BNF / BNFc - for current doses

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