Gastrointestinal hormone levels

The hormones and where they come from

Hormone	Cell	Site	Main action
Gastrin	G cell	Gastric antrum	inc gastric acid, parietal cell trophic
GIP	K cell	Duodenum + upper jejunum	Incretin; inc insulin, inc lipid storage
GLP-1	L cell	Ileum + colon (density inc distally)	Incretin; inc insulin, dec glucagon, dec gastric emptying, satiety
Somatostatin	D cell	Diffuse	Universal inhibitor
CCK	I cell	Duodenum/jejunum	Gallbladder contraction, pancreatic enzymes, satiety
Secretin	S cell	Duodenum	Pancreatic bicarbonate; inhibits gastrin
Motilin	M cell	Duodenum	Migrating motor complex (erythromycin agonist)
Ghrelin	P/D1 cell	Gastric fundus	Orexigenic - the only one that is
VIP	Neurons	Gut/pancreas	Secretory diarrhoea, vasodilation
PYY	L cell	Ileum/colon	Satiety, "ileal brake"

Functioning GEP-NETs are rare: ~1-4 per million/yr
- Gastrinoma and insulinoma are the commonest
- VIPoma, glucagonoma, somatostatinoma each <0.1 per million
~20-25% of gastrinomas occur in MEN1
Overall NET incidence rising (detection), now ~5-7 per 100,000
Most "gut hormone levels" ordered in practice are gastrin - and most raised results are PPI-related, not tumour

Oral glucose produces a far greater insulin response than IV glucose at matched glycaemia
- Accounts for ~50-70% of the insulin response to an oral load in health
- Mediated by GIP + GLP-1
Glucose-dependent - incretin action ceases as glucose falls
- -> incretin-based drugs do not cause hypoglycaemia alone
In T2DM
- Incretin effect is markedly reduced
- GIP action is largely lost (beta-cell resistance)
- GLP-1 action is preserved at pharmacological doses -> the entire rationale for GLP-1 RA therapy
Both are degraded within minutes by DPP-4 -> short native half-life; DPP-4 inhibitors raise endogenous levels modestly
Bariatric surgery (esp. RYGB) delivers nutrients to distal L cells -> exaggerated GLP-1/PYY -> weight loss and remission of diabetes independent of restriction; also the mechanism of post-bariatric hypoglycaemia**

Autonomous secretion by a neuroendocrine tumour
Loss of physiological feedback - achlorhydria removes the acid brake on gastrin

Must be off PPI for 1-2 weeks (cover with high-dose H2 blocker) - PPIs are by far the commonest cause of hypergastrinaemia and generate false positives
Interpret only alongside gastric pH

Gastrin	Gastric pH	Interpretation
>10x ULN + pH <2	acidic	Gastrinoma - diagnostic
Raised + pH >4	achlorhydric	Secondary: PPI, atrophic gastritis/pernicious anaemia, H. pylori, post-vagotomy, renal failure, short gut
Equivocal (1-10x) + acid	acidic	Secretin stimulation test: gastrin rise >120 pg/mL = gastrinoma (paradoxical - secretin normally inhibits gastrin)

At the time of hypoglycaemia (glucose <3.0 mmol/L):
- Insulin inappropriately detectable, C-peptide raised, proinsulin raised, BOHB suppressed
- Sulfonylurea screen negative
Exogenous insulin: insulin high with C-peptide suppressed**
Sulfonylurea: insulin and C-peptide both high - indistinguishable from insulinoma without the drug screen

Others

VIPoma - VIP >75-100 pmol/L + secretory diarrhoea (>3 L/day, persists with fasting), hypokalaemia, achlorhydria ("WDHA")
Glucagonoma - glucagon >500-1000 pg/mL + necrolytic migratory erythema, diabetes, weight loss, DVT
Somatostatinoma - the inhibitory triad: diabetes + gallstones + steatorrhoea
Carcinoid - 24-hr urinary 5-HIAA; avoid bananas, avocado, walnuts, pineapple, paracetamol
Chromogranin A - falsely raised by PPIs, renal impairment, atrophic gastritis, heart failure - poor specificity; better for monitoring than diagnosis

CT/MRI pancreas, EUS, Ga-68 DOTATATE PET (somatostatin receptor imaging - superior to octreotide scan)
Insulinoma is often DOTATATE-negative -> GLP-1 receptor PET (exendin) or EUS
MEN1 screen: calcium, PTH, prolactin, MEN1 genetics

Gastrinoma - high-dose PPI (e.g. esomeprazole 40-80 mg bd), titrated to basal acid output; lifelong if metastatic
Insulinoma - frequent carbohydrate, diazoxide (+ thiazide for fluid retention), somatostatin analogue, everolimus
VIPoma - aggressive fluid and potassium replacement, octreotide
Glucagonoma - octreotide, zinc/amino acid replacement for NME, VTE prophylaxis
Carcinoid syndrome - octreotide/lanreotide; telotristat for refractory diarrhoea

Tumour-directed

Surgical resection is the only cure - enucleation for insulinoma, exploration for gastrinoma
Somatostatin analogue (octreotide LAR, lanreotide) - antiproliferative in SSTR-positive well-differentiated NETs
PRRT - Lu-177 DOTATATE for progressive SSTR-positive metastatic disease
Everolimus, sunitinib, capecitabine/temozolomide
Liver-directed therapy for hepatic-predominant disease

GLP-1 RA - semaglutide, dulaglutide, liraglutide; exenatide
Dual GIP/GLP-1 - tirzepatide (greater HbA1c and weight effect than GLP-1 RA alone)
DPP-4 inhibitors - sitagliptin, linagliptin (weight-neutral, modest effect)
GLP-1 RAs delay gastric emptying -> withhold before endoscopy/anaesthesia per current Australian peri-procedural advice

Stop PPIs; check renal function; confirm the syndrome clinically first. Unselected "gut hormone screens" generate mostly false positives.

MEN1 - parathyroid + pituitary + pancreatic NET (gastrinoma commonest, usually duodenal and multiple)
MEN2, von Hippel-Lindau, neurofibromatosis type 1 (duodenal somatostatinoma), tuberous sclerosis
Pernicious anaemia / autoimmune atrophic gastritis -> hypergastrinaemia -> type 1 gastric NET
Chronic PPI use
Bariatric surgery - altered incretin profile, post-bariatric hypoglycaemia
Short bowel syndrome, coeliac disease
Carcinoid heart disease (right-sided valvular fibrosis)

Well-differentiated NETs are indolent - median survival in metastatic disease measured in years
Grading drives everything
- G1 Ki-67 <3%, G2 3-20%, G3 >20%; neuroendocrine carcinoma is a different disease (platinum-based chemotherapy)
Insulinoma ~90% benign and solitary and curable by enucleation
Gastrinoma ~60-90% malignant; liver metastases determine survival
MEN1-associated gastrinomas: multiple, duodenal, rarely cured surgically
Complications
- Refractory peptic ulceration, perforation, oesophagitis (ZES)
- Profound hypokalaemia and dehydration (VIPoma)
- Thromboembolism (glucagonoma)
- Carcinoid crisis on induction of anaesthesia (pre-treat with octreotide)
- Hypoglycaemic brain injury (insulinoma)

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