LO 1–4 — Hunger, Satiety & Salivary Secretion

Hunger & Satiety Hormones

Hormone	Source	Released When	Effect	Mechanism
Ghrelin	Gastric fundus (X/A-like cells)	Fasting / pre-meal (peaks just before meals)	↑ Hunger	Stimulates NPY/AgRP neurons → ↑ appetite, ↑ food intake, ↑ fat storage
PYY & GLP-1	L-cells of distal ileum and colon	Post-meal (fat/CHO)	↓ Appetite	Inhibits NPY/AgRP neurons → ↓ appetite (ileal brake); PYY also slows GI transit
Leptin	Adipocytes (white fat); proportional to fat mass	∝ fat mass	↓ Appetite	Inhibits NPY/AgRP + activates POMC/CART neurons → ↓ appetite + ↑ energy expenditure
GLP-1 incretin	L-cells (ileum/colon)	Post-meal nutrients	↓ Blood glucose	↑ Insulin secretion (glucose-dependent incretin effect)

⚠ Step 1 trap: Ghrelin is the only hunger-stimulating gut hormone. PYY, GLP-1, CCK, leptin all reduce appetite. In obesity: leptin is HIGH but there is leptin resistance.

Three Major Salivary Glands

Gland	Type	Primary Product	% of Total
Parotid	Purely serous	α-amylase (ptyalin)	~25%
Submandibular	Mixed (serous + mucous)	α-amylase + mucin	~70% of total saliva
Sublingual	Predominantly mucous	Mucin (mucus glycoproteins)	~5%

Two-Stage Salivary Production Model

Stage 1 — Acinar cells: Produce a primary secretion that is

Isotonic (plasma-like)

(tonicity), similar to plasma in electrolyte composition.
Stage 2 — Ductal cells: Na⁺ is

Reabsorbed (water cannot follow → becomes hypotonic)

; K⁺ is

Secreted into lumen (K+ > plasma)

into the lumen; HCO₃^⁻ is

Secreted (HCO3- neutralizes acid in esophagus)

(neutralizes esophageal acid).
Net result: Final saliva is always

Hypotonic (always, at all flow rates)

to plasma, even at high flow rates.

Autonomic Control of Salivary Secretion

Division	CN / Origin	Effect	Key Clinical Point
PSNS → Parotid	CN IX (glossopharyngeal) via otic ganglion	Sustained, large-volume, CN VII (facial) via submandibular ganglion secretion via ACh (M3)	Atropine → Watery (large-volume) (blocks M3)
PSNS → Submandb/Sublng	Xerostomia (dry mouth)		Atropine → Watery (large-volume) (blocks M3)
SNS	T1–T3 → superior cervical ganglion	Brief viscous blip then Vasoconstriction → cessation	Dry mouth under stress
Aldosterone effect	Salivary ducts	↑ Na+ reabsorption + ↑ K+ secretion (identical to renal collecting duct) (same mechanism as renal collecting duct)

LO 5–6 — Gastric Cell Types, HCl Mechanism & Mucosal Protection

Gastric Gland Cell Types — Complete Reference

Cell Type	Location	Product(s)	Stimulated By
Surface Mucous Cells	Surface + pit	Alkaline mucus (thick gel; pH 6-7 at surface despite luminal pH 2)	Prostaglandins, ACh
Parietal (Oxyntic)	Upper-mid body	HCl + Intrinsic Factor (IF)	ACh (M3), Histamine (H2), Gastrin (CCK2) — all three required for maximal acid
Chief (Zymogenic)	Base of gland	Pepsinogen I & II (+ gastric lipase); pepsinogen activated by HCl → pepsin	ACh, secretin, ↓pH
G Cells	Pyloric antrum	Gastrin	Peptides/AAs in lumen, vagal ACh/GRP, stomach distension
D Cells	Throughout (antrum + fundus)	Somatostatin (the primary 'off switch' for acid)	Low luminal pH (<3), fat, secretin
ECL Cells	Fundus / oxyntic gland	Histamine (+ serotonin); histamine amplifies parietal cell HCl via H2 receptor	Gastrin, ACh

HCl Secretion Mechanism — Parietal Cell

Step 1: CO₂ + H₂O → H₂CO₃ via

Carbonic anhydrase

(inside parietal cell)
Step 2: H₂CO₃ → H⁺ + HCO₃^⁻
Step 3: H⁺ pumped into lumen via

H+/K+-ATPase (the rate-limiting step in HCl secretion)

[the rate-limiting step]
Step 4: HCO₃^⁻ exits basolateral via

HCO3-/Cl- antiporter (exchanges intracellular HCO3- for extracellular Cl-)

→ blood = "alkaline tide"
Step 5: Cl^⁻ exits apically → combines with H⁺ → HCl secreted

"Alkaline tide" definition

Post-meal rise in blood HCO3- (one HCO3- enters blood per H+ secreted)

PPI mechanism (vs. H2 blocker)

PPIs irreversibly block H+/K+-ATPase; H2 blockers block histamine signaling upstream

Mucosal Protection & Pernicious Anemia

NSAIDs: COX inhibition → ↓ ___ → mucosal injury

Prostaglandins (PGE2, PGI2)

Misoprostol = ___ analog; used for ___ prophylaxis

PGE1 analog; NSAID-induced ulcer prophylaxis

Pernicious anemia: anti-parietal cell Ab destroy ___; lose HCl + ___

Parietal cells; HCl + intrinsic factor (IF)

IF-B12 complex absorbed at ___

Terminal ileum (cubam receptor for IF-B12 complex)

Achlorhydria → hypergastrinemia mechanism (why?)

No HCl → no luminal pH ↓ → no somatostatin → G cells disinhibited → hypergastrinemia

Esophageal mucosa = ___ epithelium (no surface mucous cells)

Stratified squamous (no surface mucous cells; very vulnerable to acid)

LO 7–11 — Three Phases, H. pylori & Drug Targets

Three Phases of Gastric Secretion

Phase	Trigger	Key Mediators	% of Acid	Net Effect
Cephalic	Sight/smell/taste/thought of food (before food enters stomach)	Vagus (CN X) → ACh + GRP → parietal cells + G cells → gastrin	30–40%	↑ HCl
Gastric	Food in stomach: distension + peptides/AAs in antrum	ACh, Gastrin, Histamine	50–60%	↑ HCl (dominant)
Intestinal	Chyme in duodenum	Secretin, CCK, GIP + enterogastric reflex	5–10% (mostly inhibitory)	↓ HCl (inhibitory)

Stimulators & Inhibitors of HCl

Stimulator/Inhibitor	Receptor / Source	2nd Messenger	Key Notes
Histamine (HAG)	H2 receptor	cAMP → PKA (most potent direct stimulator)	Most potent direct stimulator
ACh (HAG)	M3 (muscarinic) receptor → IP3/Ca2+	IP3/Ca²⁺	Vagal + ENS neurons
Somatostatin (inhibitor)	D cells (paracrine)	↓ cAMP	Triggered by luminal pH < 3 (somatostatin released at pH <3 by D cells) ; the primary "off switch"
Secretin (inhibitor)	S cells (duodenum)	cAMP	Released when duodenal pH < 4.5 (secretin released at duodenal pH <4.5) ; ↑ pancreatic HCO₃^⁻

H. pylori Pathophysiology

🚨 H. pylori = #1 cause of peptic ulcer disease worldwide (WHO Class I carcinogen)

Urease mechanism → forms ___ → alkaline microenvironment

Ammonia (NH3) + CO2; creates alkaline microenvironment around bacteria

Mucinase → disrupts ___

Mucus-bicarbonate barrier (allows acid/pepsin direct mucosal access)

Antral H. pylori → chain: ↓ D cells → ↓ ___ → ↑ gastrin → ↑ HCl → ___

Somatostatin → gastrin → DU (duodenal ulcer)

Corpus H. pylori → destroys parietal cells → ↑ gastrin but ↓ HCl → ___ risk

Gastric ulcer (GU) + gastric cancer/adenocarcinoma

MALT lymphoma: can regress with ___

H. pylori eradication (MALT lymphoma can fully regress)

Triple therapy = ___

PPI + clarithromycin + amoxicillin (or metronidazole) × 7–14 days

Pharmacological Targets

Drug Class	Mechanism	Key Step 1 Fact
PPIs (omeprazole)	Irreversibly block H+/K+-ATPase (proton pump) ; prodrug activated by Acid in secretory canaliculi (prodrug activation; must take before meals)	Most effective; take before meals (pumps must be active)
H2 Blockers	Block H2 receptor receptor → ↓ cAMP	Cimetidine: inhibits CYP450 enzymes (drug interactions with warfarin, theophylline) + causes gynecomastia
Misoprostol	PGE1 analog → ↓ parietal cell cAMP + ↑ mucus/HCO₃^⁻	NSAID prophylaxis + abortifacient (uterine contractions)
Truncal vagotomy	Eliminates Cephalic phase (30–40% of acid; requires drainage procedure — pyloroplasty)	Requires drainage procedure (pyloroplasty); impairs gastric emptying

LO 12–14 — Exocrine Pancreas, SI Secretions, Colonic & GI Hormone Table

Pancreatic Cell Types

Cell Type	Stimulated By	Product	Key Detail
Acinar cells	CCK (I-cells) + vagal ACh	Digestive enzymes (as zymogens stored in granules)	Stored as zymogen granules
Centroacinar / Ductal	Secretin (S-cells) + VIP	HCO3--rich, enzyme-poor fluid (via CFTR — cAMP-mediated)	Via CFTR channels; neutralizes duodenal acid

Enzyme Activation Cascade

Step 1:

Enterokinase

(brush border, duodenum — NOT pancreatic) activates trypsinogen → Trypsin
Step 2: Trypsin activates

All other zymogens (chymotrypsinogen, proelastase, procarboxypeptidase, pro-colipase, prophospholipase A2)

(all other zymogens — chymotrypsinogen, proelastase, procarboxypeptidase, pro-colipase, prophospholipase A2)
Special cases: Amylase =

No zymogen — secreted in active form

(no zymogen needed); Lipase requires

Colipase (activated by trypsin from pro-colipase; anchors lipase to lipid droplet)

(cofactor, activated by trypsin) to anchor to lipid droplet in bile

CF (CFTR mutation): pancreatic consequence

Thick secretions block pancreatic ducts → autodigestion → exocrine pancreatic insufficiency → steatorrhea + fat-soluble vitamin deficiency (ADEK)

Acute pancreatitis: phospholipase A2 → fat necrosis → sequesters Ca²⁺ → ___

Hypocalcemia (Ca2+ binds fatty acids → saponification → Chvostek's/Trousseau's signs)

Small Intestinal Cell Types

Cell	Location	Secretion	Step 1 Key Point
Goblet Cells	Throughout SI + colon (↑ distally)	Mucin (mucus glycoproteins)	More numerous in colon; MUC2 in colon
Paneth Cells	Crypts of small intestine ONLY (absent from normal colon)	α-defensins (cryptdins), lysozyme — antimicrobial peptides	Paneth cell metaplasia in colon = Crohn's clue
Brunner's Glands	Submucosa of the duodenum only (unique location in GI tract)	Alkaline mucus (HCO3--rich) + urogastrone (EGF)	Stimulated by Secretin (primary stimulator) ; inhibited by SNS
Enterocytes (brush border)	Villi	Brush border enzymes (enterokinase, disaccharidases, peptidases)	Enterokinase here activates trypsinogen

CFTR & Secretory Diarrhea

Cholera toxin mechanism (molecular target)

ADP-ribosylates Gsα → locks in active (GTP-bound) state → constitutive adenylate cyclase → ↑↑ cAMP → CFTR wide open → massive Cl- secretion → 'rice-water' diarrhea

E. coli heat-stable toxin (ST): mechanism

Activates guanylate cyclase → ↑ cGMP → ↑ CFTR activity → secretory diarrhea

Colonic Secretions & GI Hormone Master Table

Colon: net secretor of ___ and ___

HCO3- and K+

HCO₃⁻/Cl⁻ exchange: HCO₃⁻ neutralizes ___

Short-chain fatty acids (SCFAs) from bacterial fermentation (butyrate, propionate, acetate)

Prolonged diarrhea → acid-base disturbance

Hyperchloremic metabolic acidosis (non-anion gap) + hypokalemia

Motilin: source; released during ___; initiates ___

M cells (duodenum/jejunum); fasting (interdigestive period); migrating motor complex (MMC) — 'intestinal housekeeper'

GI Hormone Clinical Syndromes

Syndrome	Hormone / Cell	Classic Triad / Key Features
Zollinger-Ellison	↑ Gastrin (gastrinoma)	Multiple peptic ulcers (distal duodenum), diarrhea/steatorrhea (acid inactivates lipase), ↓ response to PPIs; associated with MEN1
VIPoma (WDHA)	↑ VIP → ↑ cAMP → CFTR	WDHA: Watery Diarrhea, Hypokalemia, Achlorhydria; treat with octreotide + surgery
Carcinoid Syndrome	↑ Serotonin (EC cells)	Flushing, diarrhea, wheezing, tricuspid regurgitation; ↑ urine 5-HIAA; occurs after liver metastasis
Somatostatinoma	↑ Somatostatin	'Inhibitory syndrome': diabetes (↓ insulin) + gallstones (↓ CCK → bile stasis) + steatorrhea (↓ pancreatic lipase)

Practice Questions — LO 1–14 Integration

Select the best answer, then reveal the explanation.

Q1. A 28-year-old woman with obesity undergoes Roux-en-Y gastric bypass. Six months later she reports markedly reduced hunger. Which of the following best explains the hormonal changes responsible?

A. Increased ghrelin from the bypassed gastric fundus
B. Decreased PYY and GLP-1 due to reduced caloric intake
C. Decreased ghrelin + increased PYY and GLP-1 due to altered anatomy
D. Increased leptin from enlarged adipose stores

C — Decreased ghrelin + increased PYY/GLP-1. The bypassed fundus produces less ghrelin (less hunger drive). Food passes rapidly to the distal gut → robust L-cell stimulation → ↑ PYY + GLP-1 → satiety. Six months post-op she has lost weight → less fat → less leptin (opposite of D). Choice A reverses the ghrelin direction.

Q2. A researcher collects saliva at rest (low flow) and after maximal gustatory stimulation (high flow). Which correctly describes how electrolytes change with increasing flow rate?

A. Na+ decreases; K+ increases; osmolarity rises to isotonic
B. Na+ increases; K+ decreases slightly; saliva remains hypotonic
C. Na+ increases; K+ increases; osmolarity becomes isotonic
D. Na+ and K+ unchanged; only HCO3- changes

B — Na+ increases; K+ decreases slightly; always hypotonic. At low flow, ducts have more time to reabsorb Na+ and secrete K+ → very low Na+, very high K+. At high flow, less ductal modification → Na+ rises toward plasma levels, K+ falls slightly. Saliva is always hypotonic regardless of flow rate — it never reaches isotonicity.

Q3. A 65-year-old woman prescribed oxybutynin (anticholinergic) for overactive bladder develops dry mouth. What is the mechanism?

A. Activation of H2 receptors on acinar cells
B. Blockade of M3 muscarinic receptors on acinar cells, reducing IP3/Ca2+ signaling
C. Stimulation of α1-adrenergic receptors causing vasoconstriction
D. Blockade of CN IX at the otic ganglion

B — M3 muscarinic blockade → xerostomia. Parasympathetic ACh acting on M3 receptors (IP3/Ca2+) is the dominant driver of salivary secretion. Anticholinergics block M3 → eliminate sustained watery saliva → xerostomia. Note: vagus (CN X) does NOT control salivary glands — that's CN VII (submandibular/sublingual) and CN IX (parotid).

Q4. A 52-year-old woman has macrocytic anemia, subacute combined degeneration, and markedly elevated serum gastrin. Anti-parietal cell antibodies are positive. Why is her gastrin elevated?

A. Gastrinoma in the pancreas
B. Loss of HCl eliminates acid-mediated inhibition of G cells
C. Excess vagal stimulation of G cells via GRP
D. D-cell hyperplasia causing excess somatostatin

B — Loss of HCl removes the normal acid feedback on G cells. Anti-parietal cell antibodies destroy parietal cells → no HCl (achlorhydria) + no intrinsic factor. Normally pH <3 triggers D cells → somatostatin → inhibits G cells. Without HCl, pH stays high → no somatostatin → G cells tonically active → hypergastrinemia. This is pernicious anemia. Choice A (gastrinoma) would not show anti-parietal cell antibodies.

Q5. A new acid-suppressing drug is a prodrug activated by gastric acid that then irreversibly forms a disulfide bond with its target. Which target and mechanism does this describe?

A. Carbonic anhydrase in the parietal cell cytoplasm
B. H2 receptor on parietal cell → reducing cAMP
C. HCO3-/Cl- antiporter on basolateral membrane
D. H+/K+-ATPase (proton pump) — the rate-limiting step in HCl secretion

D — H+/K+-ATPase (PPI mechanism). PPIs are prodrugs activated by acid in the secretory canaliculi of parietal cells → sulfenamide form → irreversibly binds cysteine residues of H+/K+-ATPase. The proton pump is the rate-limiting step in HCl secretion — no H+ reaches the lumen without it. PPIs are the most effective acid suppressants because they target the final, obligatory step. H2 blockers block histamine signaling upstream of the pump.

Q6. Sham feeding (seeing and smelling food without eating) significantly increases gastric acid. Which phase is this, and what happens after truncal vagotomy?

A. Gastric phase; persists after vagotomy via gastrin
B. Intestinal phase; eliminated by secretin after vagotomy
C. Cephalic phase; completely eliminated by truncal vagotomy
D. Cephalic phase; partially preserved by ENS local reflexes

C — Cephalic phase; completely eliminated by truncal vagotomy. The cephalic phase is 100% vagal (CN X): cortex → dorsal vagal nucleus → vagus → stomach → ACh + GRP → parietal cells + G cells → ↑ gastrin. Contributes 30–40% of meal acid. Truncal vagotomy severs CN X → no cephalic-phase acid response. The gastric phase has a vagal component but local ENS and gastrin can maintain it; the intestinal phase is primarily hormonal.

Q7. A patient develops acute pancreatitis secondary to a gallstone obstructing the pancreatic duct. Which of the following best explains why hypocalcemia develops?

A. Trypsin degrades PTH in the bloodstream
B. Phospholipase A2 causes fat necrosis → Ca2+ binds fatty acids (saponification) → hypocalcemia
C. Amylase release damages the parathyroid glands
D. Lipase deficiency prevents absorption of dietary calcium

B — Phospholipase A2 activation → fat necrosis → saponification → Ca2+ sequestration. In pancreatitis, zymogens activate prematurely inside the pancreas. Phospholipase A2 digests fat cells → fatty acids are released → Ca2+ binds fatty acids forming calcium soaps (saponification) → Ca2+ sequestered in the peritoneum → hypocalcemia → Chvostek's + Trousseau's signs. Elastase separately digests vessel walls → hemorrhagic pancreatitis → Cullen's sign (periumbilical) or Grey Turner's sign (flank).

Q8. A patient has a pancreatic tumor causing watery diarrhea (8 L/day), hypokalemia, and achlorhydria. What is the diagnosis and what is the specific molecular mechanism of diarrhea?

A. Somatostatinoma; ↓ CCK → ↓ pancreatic enzymes → osmotic diarrhea
B. Gastrinoma (ZES); ↑ gastrin → acid inactivates lipase → secretory diarrhea
C. VIPoma; VIP → ↑ cAMP → CFTR-mediated Cl- secretion → isotonic secretory diarrhea
D. Carcinoid; serotonin → ↑ gut motility → transit diarrhea

C — VIPoma (WDHA syndrome). VIP binds VPAC receptors → ↑ adenylate cyclase → ↑↑ cAMP → PKA → CFTR channels open → massive Cl- secretion → Na+ + water follow → voluminous secretory diarrhea. VIP also: inhibits parietal cells → achlorhydria; stimulates colonic K+ secretion → hypokalemia. WDHA = Watery Diarrhea, Hypokalemia, Achlorhydria. Treatment: octreotide (somatostatin analog) + surgical resection. This is also called "pancreatic cholera" because the mechanism mirrors cholera toxin's effect on CFTR.

GI Secretions I & II — Active Recall