Hormonal or enzymatic control of the alimentary tract, including control of acid and pancreatic secretion

Two secretory systems

Two secretory systems, both under neural + endocrine + paracrine control:
- Gastric acid - parietal cell H+/K+ ATPase
- Pancreatic exocrine - ductal bicarbonate (secretin) + acinar enzymes (CCK, vagus)
Three phases of digestion: cephalic (~30%, vagal), gastric (~50-60%, distension + peptides), intestinal (~10%, largely inhibitory)

Basal acid output ~2-5 mmol/h; maximal ~15-25 mmol/h
Pancreas secretes ~1.5-2 L/day at pH 8, containing ~20 g enzyme protein
Steatorrhoea requires >90% loss of exocrine pancreatic function - the enormous reserve is why chronic pancreatitis presents so late

Secretagogue	Source	Route	Receptor	Second messenger
Acetylcholine	Vagus	Neural	M3	Ca2+
Histamine	ECL cell	Paracrine	H2	cAMP
Gastrin	Antral G cell	Endocrine	CCK-B/CCK-2	Ca2+

*All three converge on the H+/K+ ATPase (proton pump) - the final common path, and why PPIs work where H2 blockers plateau*
Gastrin acts MOSTLY INDIRECTLY - stimulating ECL cells to release histamine
- Hence H2 blockers blunt gastrin- and ACh-driven secretion too (potentiation)
Gastrin release: peptides/amino acids in the antrum, distension, gastrin-releasing peptide (GRP) from vagal fibres
- *Vagal control of gastrin is via GRP, NOT acetylcholine - which is why vagotomy does not abolish gastrin release*

SOMATOSTATIN from antral D cells is the master brake
- Low antral pH (<3) -> D cell somatostatin -> inhibits G cell gastrin AND ECL histamine AND the parietal cell directly (negative feedback)
- *Loss of this feedback explains the hypergastrinaemia of achlorhydria, atrophic gastritis, pernicious anaemia and PPI therapy*
Secretin, GIP, CCK, prostaglandin E2 (the mucosal protection NSAIDs remove)
Fat and acid in the duodenum -> enterogastrone effect -> dec acid, dec gastric emptying

Hormone	Released from	Trigger	Action
Secretin	S cells, duodenum	ACID (pH <4.5) in the duodenum	DUCTAL water + BICARBONATE (neutralises chyme, provides the pH optimum for pancreatic enzymes)
CCK	I cells, duodenum/jejunum	FAT and PROTEIN (long-chain fatty acids, amino acids)	ACINAR enzyme secretion, gallbladder contraction, sphincter of Oddi relaxation, dec gastric emptying, satiety
Vagus (ACh)	Cephalic phase	Sight/smell/taste	Enzyme secretion (~25% of the meal response)

Enzymes secreted as ZYMOGENS
- Enterokinase (duodenal brush border) -> trypsinogen to TRYPSIN -> activates all the rest (chymotrypsinogen, proelastase, procarboxypeptidase, prophospholipase)
- *Amylase and lipase are secreted ALREADY ACTIVE*
- Protection: zymogen packaging, pancreatic secretory trypsin inhibitor (SPINK1), trypsin autolysis (PRSS1)
  - Mutations in PRSS1 and SPINK1 cause hereditary pancreatitis - premature intra-acinar activation

Motilin - fasting; drives the migrating motor complex (erythromycin is a motilin agonist -> prokinetic)
GIP and GLP-1 - incretins: glucose-dependent insulin release
- *The incretin effect - oral glucose evokes far more insulin than the same IV load* - the basis of GLP-1 agonists and DPP-4 inhibitors
Ghrelin - fundus, the only orexigenic gut hormone, rises pre-prandially
PYY, oxyntomodulin - ileal brake, satiety
VIP - secretomotor; VIPoma -> WDHA (watery diarrhoea, hypokalaemia, achlorhydria)

Fasting gastrin
- Very high + HIGH acid output / low gastric pH -> ZOLLINGER-ELLISON (gastrinoma)
- Very high + LOW acid (achlorhydria) -> atrophic gastritis, pernicious anaemia, or PPI therapy
- *Stop the PPI for 1-2 weeks before measuring gastrin - and cover with an H2 blocker*
- Secretin stimulation test: *secretin paradoxically INCREASES gastrin in gastrinoma* (>120 ng/L rise), but suppresses it in normal G cells
Faecal elastase-1 <200 microg/g - exocrine pancreatic insufficiency (<100 = severe)
Urea breath test - H. pylori urease activity
Hydrogen/methane breath tests - carbohydrate malabsorption and bacterial overgrowth
Chromogranin A - neuroendocrine tumour marker (falsely raised by PPIs, renal impairment, atrophic gastritis)
Gastric acid studies (basal/maximal acid output) - largely historical

Target	Drug	Effect
H+/K+ ATPase	PPI (omeprazole, esomeprazole, pantoprazole)	Irreversible; needs an active pump -> take 30-60 min BEFORE food; full effect at 3-5 days
H2 receptor	Famotidine, ranitidine (withdrawn - NDMA)	Fast, but tachyphylaxis within days
K+-competitive acid blocker	Vonoprazan	Faster, more sustained, no food dependence; not widely available in Australia
M1/M3	Pirenzepine	Historical
Somatostatin receptor	Octreotide, lanreotide	VIPoma, gastrinoma, carcinoid, variceal bleeding, high-output fistula
CCK-B	(Netazepide)	Investigational, for ECL hyperplasia
Motilin receptor	Erythromycin	Prokinetic in gastroparesis and pre-endoscopy
GLP-1 receptor	Semaglutide, tirzepatide	Incretin effect exploited for diabetes and obesity
Prostaglandin	Misoprostol	Replaces the mucosal PGE2 NSAIDs suppress
Enzyme replacement	Creon (pancrelipase)	*Take WITH meals; give a PPI to stop gastric acid denaturing lipase*

Consequences of long-term acid suppression - the exam angle

Hypergastrinaemia -> ECL hyperplasia (gastric carcinoid only with very prolonged, profound suppression)
Rebound acid hypersecretion on stopping - taper
dec absorption of iron, B12, calcium, magnesium -> deficiency, fracture risk
inc enteric infection - **C. difficile, Campylobacter, Salmonella; SIBO**
Interstitial nephritis, hypomagnesaemia
Deprescribe where the indication has lapsed

Zollinger-Ellison syndrome - and MEN1 in ~20-25%: parathyroid, pituitary, pancreas
Pernicious anaemia / autoimmune atrophic gastritis - anti-parietal cell and anti-intrinsic factor antibodies -> achlorhydria, hypergastrinaemia, type 1 gastric carcinoid, B12 and iron deficiency
*H. pylori* - antral gastritis -> inc gastrin -> duodenal ulcer; corpus gastritis -> atrophy -> dec acid -> gastric cancer
Chronic pancreatitis, cystic fibrosis, pancreatic cancer, coeliac disease - exocrine insufficiency
VIPoma, glucagonoma, somatostatinoma, carcinoid - functioning neuroendocrine tumours
Hereditary pancreatitis - PRSS1, SPINK1, CFTR, CTRC
Post-gastrectomy/vagotomy - dumping, B12 deficiency, bile reflux gastritis

Massive functional reserve in both systems
- >90% of exocrine pancreatic function must be lost before steatorrhoea appears
- Acid secretion falls with age and with atrophic gastritis
Chronic hypergastrinaemia -> ECL hyperplasia -> type 1 gastric carcinoids (indolent, multiple, usually managed endoscopically)
Untreated exocrine insufficiency -> steatorrhoea, weight loss, fat-soluble vitamin deficiency, osteoporosis (in ~2/3 of chronic pancreatitis)
- *Under-treatment is common - most patients are prescribed too little enzyme and no PPI*
Gastrinoma - ~60-90% malignant; prognosis is determined by hepatic metastases, not the acid, which is controllable with high-dose PPI

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