GI Lectures 16 & 17: Digestion & Absorption I & II
HoyaDocs — GI Block | USMLE Step 1 Preparation
GI Lectures 16 & 17 — Overview
Digestion & Absorption I & II · HoyaDocs GI Block
Page Summaries
Small intestine anatomy (villi, microvilli, lacteals, goblet cells) · Unstirred water layer · Principal digestive enzymes table · Transport mechanisms · Role of fiber
Practice Qs: 1
Salivary/pancreatic amylase → brush border saccharidases · SGLT1/GLUT5/GLUT2 · Lactose intolerance · HCl/pepsin/enterokinase/pancreatic proteases · PepT1 & cytoplasmic peptidases
Practice Qs: 2–5, 14
Lingual/gastric/pancreatic lipase · Co-lipase · Bile salt micelles · Chylomicrons (apoB-48) · Abetalipoproteinemia · Enterohepatic circulation · Ileal resection consequences
Practice Qs: 6–8, 15
Na+/Cl-/HCO3-/K+ absorption · Iron (DMT1/ferritin/transferrin) · Calcium (CaBP/vitamin D/PTH) · Fat-soluble vitamins · B12 pathway (TC1 → IF → terminal ileum → TC2) · Colon & diarrhea
Practice Qs: 9–13
Official Learning Objectives Map
GI Tract Structure & Digestion Overview
LOs 1–5 · Small intestine anatomy, principal digestive enzymes, transport mechanisms, fiber
- LO1: Draw and label small intestine structure (villi, microvilli, lacteals, goblet cells, crypts)
- LO2: Functional significance of each component and the unstirred water layer
- LO3: Principal digestive enzymes — location, substrate, product
- LO4: Mechanisms of absorption (active, passive, facilitated, co-transport)
- LO5: Why fiber is not digested
▼ Small Intestine Structure
The small intestine achieves enormous absorptive surface area (~250 m²) through three levels of amplification:
- Plicae circulares (valves of Kerckring): Permanent circular folds of mucosa and submucosa — increase area ~3×
- Villi: Finger-like projections of mucosa (0.5–1.5 mm tall) — increase area ~10×; each villus contains a central lacteal (lymphatic capillary) and a capillary network
- Microvilli (brush border): Dense apical membrane projections (~1 µm tall) on each enterocyte — increase area ~20×; contain brush border enzymes (saccharidases, peptidases, lipase)
Combined amplification: ~600-fold compared to a smooth tube of the same length.
| Component | Function | Step 1 Relevance |
|---|---|---|
| Villi | Absorptive surface; each has central lacteal + capillaries | Villous atrophy in celiac disease → malabsorption |
| Microvilli (brush border) | Enzyme-rich membrane; final digestion of carbs & proteins | Disaccharidase deficiency → lactose intolerance |
| Lacteals | Absorb chylomicrons (too large for capillaries) | Lymphangiectasia → protein-losing enteropathy |
| Goblet cells | Secrete mucus to protect epithelium and lubricate contents | Reduced in celiac; increased in IBD |
| Crypts of Lieberkühn | Contain stem cells; site of secretion (Cl⁻, water) | Crypt hyperplasia in celiac; source of secretory diarrhea |
| Paneth cells | Located at crypt base; secrete defensins and lysozyme | Innate immunity of the gut epithelium |
- Villous atrophy + crypt hyperplasia → celiac disease (anti-tTG, anti-endomysial Ab; HLA-DQ2/DQ8)
- PAS-positive macrophages in lamina propria → Whipple's disease (Tropheryma whipplei)
- Dilated lacteals → intestinal lymphangiectasia → fat and protein malabsorption
▼ Unstirred Water Layer
Immediately adjacent to the brush border lies an unstirred water layer (UWL) — a thin, relatively stagnant aqueous film (~100–500 µm thick) through which all absorbed molecules must diffuse before reaching the enterocyte membrane.
- The UWL is a rate-limiting step for absorption of highly lipophilic compounds
- Bile salt micelles ferry lipid digestion products across the UWL, dramatically increasing effective lipid absorption
- Without micelles, fat-soluble nutrients cannot traverse the UWL efficiently → steatorrhea
- The UWL also creates a microclimate of slightly lower pH near the brush border (due to Na+/H+ exchange), which facilitates proton-coupled transport of di/tripeptides via PepT1
Students often think micelles are absorbed whole. They are not. Micelles carry lipids across the UWL; lipid products then passively diffuse across the enterocyte membrane while bile salts stay in the lumen and are recycled in the terminal ileum.
▼ Principal Digestive Enzymes
Memorize this table — this is directly tested. Know the source, substrate, and product for each enzyme.
| Enzyme | Source | Substrate | Product(s) |
|---|---|---|---|
| Salivary amylase (ptyalin) | Parotid/submandibular glands | Starch (α-1,4 glycosidic bonds) | Oligosaccharides, maltose, maltotriose |
| Lingual lipase | Tongue (von Ebner's glands) | Triglycerides (short- & medium-chain) | Diglycerides + fatty acids |
| Gastric lipase | Gastric chief cells | Triglycerides (mainly short/medium-chain) | Diglycerides + fatty acids |
| Pepsin | Gastric chief cells (as pepsinogen; activated by HCl) | Proteins (preferential: Phe, Trp, Tyr bonds) | Large peptide fragments |
| Pancreatic amylase | Exocrine pancreas | Starch, glycogen (α-1,4 bonds) | Maltose, maltotriose, α-limit dextrins |
| Pancreatic lipase | Exocrine pancreas (+ co-lipase) | Triglycerides (sn-1,3 positions) | 2-monoglyceride + 2 free fatty acids |
| Trypsin | Pancreas (trypsinogen) → activated by enterokinase | Proteins; Arg/Lys peptide bonds | Peptides (also activates other zymogens) |
| Chymotrypsin | Pancreas (activated by trypsin) | Proteins; aromatic AA bonds (Phe, Trp, Tyr, Leu) | Peptides |
| Elastase | Pancreas (activated by trypsin) | Elastin; Ala, Gly, Ser peptide bonds | Peptides |
| Carboxypeptidases A & B | Pancreas (activated by trypsin) | C-terminal amino acids | Free amino acids + shorter peptides |
| Enterokinase (enteropeptidase) | Duodenal brush border | Trypsinogen | Trypsin (then activates all other zymogens) |
| Lactase | Brush border (jejunum) | Lactose (galactose-glucose) | Galactose + glucose |
| Sucrase-isomaltase | Brush border (jejunum) | Sucrose; α-limit dextrins | Fructose + glucose; glucose |
| Maltase | Brush border | Maltose, maltotriose | Glucose |
| Aminopeptidase / dipeptidases | Brush border & cytoplasm | Di/tripeptides, N-terminal AAs | Free amino acids |
- Made by duodenal brush border; the master activator of the protease cascade
- Cleaves trypsinogen → trypsin; trypsin then activates chymotrypsinogen, proelastase, and procarboxypeptidases
- Congenital enterokinase deficiency → failure to thrive, protein malabsorption, hypoproteinemia — presents like pancreatic exocrine insufficiency but amylase/lipase levels are normal
▼ Mechanisms of Intestinal Transport
| Mechanism | Energy | Carrier | Examples in GI |
|---|---|---|---|
| Primary active transport | ATP (directly) | Pump (ATPase) | Na+/K+-ATPase on basolateral membrane — drives all Na+ co-transport |
| Secondary active (co-transport) | Na+ gradient (indirectly) | Carrier protein | SGLT1 (glucose + Na+), PepT1 (di/tripeptides + H+), ASBT (bile acids + Na+) |
| Facilitated diffusion | None (↓ conc gradient) | Carrier protein | GLUT5 (fructose apical), GLUT2 (basolateral exit for all sugars) |
| Passive diffusion | None (↓ conc gradient) | None (lipid bilayer) | Lipid digestion products, water (via osmosis), unconjugated bile acids |
| Paracellular transport | Electrochemical gradient | Tight junctions | Water, Cl⁻ (passive paracellular route in proximal SI) |
The Na+/K+-ATPase on the basolateral membrane keeps intracellular Na+ low. This drives secondary active transport of glucose (SGLT1), amino acids, and peptides (PepT1) across the apical brush border — even against their concentration gradients. Cholera toxin disrupts this by locking CFTR open → massive Cl⁻/water secretion, not Na+ failure.
▼ Fiber & Cellulose
Dietary fiber consists primarily of cellulose, a glucose polymer linked by β-1,4 glycosidic bonds.
- Human digestive enzymes (amylase, maltase, etc.) can only cleave α-glycosidic bonds
- No β-glucosidase (cellulase) is produced by the human GI tract → cellulose passes through undigested
- Colonic bacteria ferment some soluble fiber → short-chain fatty acids (SCFAs: butyrate, propionate, acetate) → energy source for colonocytes
- Insoluble fiber (cellulose) adds bulk, reduces transit time, and binds water in stool
"Alpha we Absorb, Beta we Bypass" — humans absorb α-linked sugars (starch, glycogen) but bypass β-linked sugars (cellulose, chitin). Ruminants have cellulases from gut bacteria; we don't.
Carbohydrate & Protein Digestion/Absorption
LOs 6–10 · Amylases, brush border saccharidases, SGLT1/GLUT5/GLUT2, lactose intolerance, proteases, PepT1
- LO6: Carbohydrate digestion — salivary → pancreatic amylase → brush border saccharidases
- LO7: Monosaccharide absorption — SGLT1, GLUT5, GLUT2
- LO8: Disaccharidase deficiency consequences — osmotic diarrhea, gas
- LO9: Protein digestion — HCl/pepsin, enterokinase cascade, pancreatic proteases, brush border peptidases
- LO10: Amino acid and di/tripeptide absorption (PepT1); cytoplasmic peptidases
▼ Carbohydrate Digestion
Dietary carbohydrates arrive as starch (~50–60%), sucrose (~30%), and lactose (~10%). Digestion is a sequential, two-phase process: luminal (salivary + pancreatic amylase) → brush border (saccharidases).
Phase 1 — Luminal Digestion
- Salivary amylase (ptyalin) begins starch digestion in the mouth and proximal stomach; inactivated by gastric acid (pH < 4) — accounts for only ~5% of total digestion
- Pancreatic amylase (secreted into duodenum) is the dominant luminal amylase; cleaves internal α-1,4 bonds → maltose, maltotriose, and α-limit dextrins (which contain α-1,6 branch points)
- Neither amylase can cleave the α-1,6 branch points of starch — that requires isomaltase
Phase 2 — Brush Border Digestion
- Maltase: maltose + maltotriose → glucose
- Sucrase-isomaltase complex: sucrose → glucose + fructose; α-limit dextrins → glucose
- Lactase (β-galactosidase): lactose → glucose + galactose; highest activity in jejunum; lowest activity at birth, declines with age in most populations
- End products entering the enterocyte: glucose, galactose, fructose (all monosaccharides)
- Starch must be fully hydrolyzed to monosaccharides before absorption; oligosaccharides and disaccharides are not transported across the enterocyte membrane
- Only monosaccharides are absorbed: glucose, galactose (via SGLT1), fructose (via GLUT5)
▼ Carbohydrate Absorption (SGLT1 / GLUT5 / GLUT2)
Three transporters handle all monosaccharide absorption from the gut lumen into the portal blood:
| Transporter | Location | Substrates | Mechanism | Step 1 Note |
|---|---|---|---|---|
| SGLT1 | Apical brush border | Glucose + Galactose | Secondary active co-transport with Na+ (2 Na+ : 1 sugar) | Driven by Na+/K+-ATPase; fails in glucose-galactose malabsorption (SGLT1 mutation) |
| GLUT5 | Apical brush border | Fructose only | Facilitated diffusion (no Na+ needed) | High-fructose corn syrup → GLUT5 saturation → fructose reaches colon → osmotic diarrhea |
| GLUT2 | Basolateral membrane | Glucose, Galactose, Fructose | Facilitated diffusion (into portal blood) | All three monosaccharides exit via GLUT2; this is the final step before portal absorption |
- SGLT1 = glucose AND galactose (not fructose) — requires Na+
- GLUT5 = fructose only — no Na+ required
- GLUT2 = all three exit basolaterally — no Na+
- Glucose-galactose malabsorption (AR) = SGLT1 mutation → osmotic diarrhea with glucose OR galactose; fructose is fine (GLUT5 unaffected)
"SGLT1 = Sodium Goes with Glucose & gaLacTose 1" (secondary active, Na+ driven)
"GLUT5 = FructoSe (5 letters)" — facilitated, no Na+
"GLUT2 = TwO leave" — all three exit basolaterally via GLUT2
▼ Disaccharidase Deficiency & Lactose Intolerance
Primary lactase deficiency is the most common disaccharidase deficiency — physiologic decline in lactase activity after weaning, especially prevalent in non-Northern European populations.
Pathophysiology of Symptoms
- Undigested lactose remains in the lumen → osmotic effect: draws water into lumen → watery diarrhea
- Lactose reaches the colon → colonic bacteria ferment it → H₂, CO₂, short-chain fatty acids → bloating, cramping, flatulence
- Symptoms begin 30–60 minutes after lactose ingestion
- Diagnosis: hydrogen breath test (↑H₂ after lactose load) or empirical dietary trial
Secondary Disaccharidase Deficiency
- Any condition causing villous atrophy or brush border damage can secondarily reduce all disaccharidase activity: celiac disease, Crohn's disease, rotavirus enteritis, giardiasis
- Note: sucrase-isomaltase deficiency is a separate AR disorder — rare; sucrose ingestion causes diarrhea; starch digestion also impaired
- Osmotic diarrhea (e.g., lactose intolerance): stops with fasting; stool osmolar gap > 50 mOsm/kg; caused by unabsorbed solutes in lumen
- Secretory diarrhea (e.g., cholera, VIPoma): continues despite fasting; normal stool osmolar gap; caused by active Cl⁻/water secretion
▼ Protein Digestion
Dietary protein (~50–100 g/day) undergoes a three-stage cascade of proteolysis: gastric → pancreatic → brush border/cytoplasmic.
Stage 1 — Gastric
- HCl (parietal cells): denatures proteins (unfolds) → more peptide bonds accessible; converts pepsinogen → pepsin (autocatalytic at pH < 5)
- Pepsin: endopeptidase; cleaves Phe, Trp, Tyr, and Leu bonds → large polypeptide fragments; accounts for ~10–15% of total protein digestion; inactivated at duodenal pH > 5
Stage 2 — Pancreatic (in Duodenum)
The critical enterokinase (enteropeptidase) cascade:
- Duodenal brush border enterokinase cleaves trypsinogen → trypsin
- Trypsin then activates: chymotrypsinogen → chymotrypsin; proelastase → elastase; procarboxypeptidase A & B → carboxypeptidases A & B; trypsinogen → more trypsin (autocatalytic)
- Trypsin: cleaves Lys/Arg bonds (basic AA)
- Chymotrypsin: cleaves aromatic AA bonds (Phe, Trp, Tyr, Leu)
- Elastase: cleaves Ala, Gly, Ser bonds
- Carboxypeptidases A & B: exopeptidases; cleave from C-terminus
- Products: oligopeptides (30%), tripeptides, dipeptides, and free amino acids (70%)
Enterokinase, not trypsin itself, is the initiating activator. Without enterokinase (e.g., congenital deficiency), no pancreatic protease becomes active → severe protein malabsorption despite normal pancreatic function. Contrast with pancreatitis (premature intrapancreatic trypsin activation).
Also: trypsin inhibitor (SPINK1) normally prevents premature trypsin activation in the pancreatic duct. SPINK1 mutations → chronic pancreatitis.
▼ Protein Absorption
Amino acids and small peptides are absorbed across the brush border by multiple transporters:
- Free amino acids: multiple Na+-dependent cotransporters (grouped by AA type: neutral, basic, acidic, imino) + some Na+-independent carriers; enter portal blood via basolateral transporters
- Di- and tripeptides: absorbed intact via PepT1 (H+-peptide cotransporter) — uses the proton gradient created by the Na+/H+ antiporter in the brush border microclimate; di/tripeptides are absorbed MORE efficiently than free AAs
- Cytoplasmic peptidases then hydrolyze di/tripeptides to free amino acids within the enterocyte before they exit basolaterally
- Hartnup disease (AR): defective neutral amino acid transporter (intestinal + renal); tryptophan malabsorption → niacin deficiency → pellagra-like rash, ataxia, psychiatric symptoms; di/tripeptide absorption is intact (PepT1 unaffected) → symptoms are mild/variable
- Cystinuria (AR): defective basic AA transporter (cystine, ornithine, arginine, lysine — "COAL"); forms cystine kidney stones; intestinal absorption also impaired but clinical manifestations are renal
Lipid Digestion & Absorption
LOs 11–16 · Lipases, co-lipase, bile salts, micelles, chylomicrons, abetalipoproteinemia, enterohepatic circulation
- LO11: Lipid digestion — lingual/gastric/pancreatic lipase, co-lipase, bile salts
- LO12: Micelle formation and crossing the unstirred water layer
- LO13: Intracellular re-esterification, chylomicron assembly (apoB-48), secretion into lacteals
- LO14: Abetalipoproteinemia — mechanism, features, consequences
- LO15: Enterohepatic circulation of bile acids — conjugated vs. unconjugated reabsorption
- LO16: Consequences of ileal resection
▼ Lipid Digestion
Dietary fat is primarily triglycerides (TGs). Because fats are hydrophobic, digestion requires a stepwise process of emulsification → enzymatic hydrolysis → micellar solubilization before absorption.
Step 1 — Lingual & Gastric Lipase
- Lingual lipase (von Ebner's glands): begins TG hydrolysis in mouth; active at pH 2–7.5 → continues in stomach; preferentially hydrolyzes short- and medium-chain FA at sn-3 position → diacylglycerol + FA
- Gastric lipase (gastric chief cells): active at pH 3–6; primarily short/medium-chain TGs; accounts for ~10–30% of total TG digestion in adults; critical in neonates (pancreatic lipase immature) and pancreatic exocrine insufficiency
- Gastric churning creates a coarse emulsion of TG droplets → increases surface area for further digestion
Step 2 — Pancreatic Lipase + Co-lipase
- Bile salts displace pancreatic lipase from the lipid-water interface → co-lipase (secreted by pancreas as pro-co-lipase; activated by trypsin) anchors pancreatic lipase at the interface, restoring activity
- Pancreatic lipase cleaves sn-1 and sn-3 ester bonds of TG → 2-monoglyceride + 2 free fatty acids (the dominant products)
- Pancreatic lipase accounts for ~70–80% of TG digestion; it requires an alkaline pH (>6.5) — this is why bicarbonate secretion by the pancreas is essential
Without co-lipase, bile salts inhibit pancreatic lipase by competitively occupying the lipid interface. Co-lipase anchors pancreatic lipase to the droplet surface. Orlistat (weight-loss drug) works by irreversibly inhibiting pancreatic lipase → prevents TG digestion → steatorrhea as side effect.
▼ Bile Salts & Micelle Formation
Bile salts (amphipathic molecules — hydrophilic face + hydrophobic face) serve two key roles in fat digestion: emulsification and micelle formation.
- Emulsification: Bile salts coat large TG droplets → break them into smaller droplets (1–2 µm) → increased surface area for lipase action
- Micelle formation: After lipase action, bile salts surround 2-monoglycerides, free fatty acids, cholesterol, and fat-soluble vitamins → form mixed micelles (4–8 nm diameter, cylindrical) with hydrophobic core + hydrophilic exterior
- Micelles transport lipid digestion products across the unstirred water layer to the brush border; at the brush border surface, the products diffuse out of the micelle and passively cross the lipid bilayer into the enterocyte
- Bile salts remain in the lumen after releasing their contents — they are recycled in the terminal ileum (enterohepatic circulation)
- Any condition reducing bile salt delivery to the duodenum (cholestasis, biliary obstruction, ileal disease) → ↓ micelle formation → steatorrhea + fat-soluble vitamin deficiency (A, D, E, K)
- Vitamin K deficiency → ↑ PT (clotting factor synthesis requires vitamin K)
- Vitamin D deficiency → ↓ Ca²+ absorption → osteomalacia/rickets
- Vitamin A deficiency → night blindness
▼ Lipid Absorption & Chylomicron Assembly
Once lipid products (2-monoglycerides, free fatty acids, cholesterol, fat-soluble vitamins) arrive at the brush border, they diffuse passively across the enterocyte membrane (the lipid bilayer is permeable to hydrophobic molecules).
Intracellular Processing
- Inside the enterocyte, free fatty acids and 2-monoglycerides are carried to the smooth endoplasmic reticulum (SER) by fatty acid binding proteins
- In the SER: re-esterification — 2-MAG + 2 FA → triglyceride (via monoacylglycerol pathway, the dominant route in enterocytes)
- TG, cholesterol esters, fat-soluble vitamins, and phospholipids are assembled into chylomicrons using apolipoprotein B-48 (apoB-48) — made from editing of the apoB-100 mRNA (unique to intestine)
- Chylomicrons are packaged in the Golgi → exocytosed at the basolateral membrane → enter lacteals (not portal capillaries — too large, ~75–1200 nm)
- Lacteals → mesenteric lymphatics → thoracic duct → left subclavian vein → systemic circulation
Short- & Medium-Chain Fatty Acids — Exception
- Short-chain (C<8) and medium-chain (C8–C12) fatty acids are sufficiently water-soluble to bypass micelles and be absorbed directly into portal blood (not packaged into chylomicrons)
- Clinical application: MCT oil is used in patients with fat malabsorption (abetalipoproteinemia, lymphangiectasia) because it bypasses the chylomicron pathway
Lipids → enterocyte (passive diffusion) → SER re-esterification → chylomicron (apoB-48) → basolateral exocytosis → lacteal → thoracic duct → left subclavian vein. This is why a fatty meal causes chylous-appearing lymph (chyle) and a turbid plasma sample (chylomicronemia) after eating.
▼ Abetalipoproteinemia & Steatorrhea
Abetalipoproteinemia (AR) is caused by a defect in microsomal triglyceride transfer protein (MTP), which is required to load apoB-48 onto chylomicrons. Without functional MTP, chylomicrons cannot be assembled.
- Fat digestion is normal; lipids enter enterocytes normally
- Re-esterification occurs in SER but chylomicrons cannot be exported → fat accumulates in enterocytes (vacuoles visible on biopsy)
- Steatorrhea (foul-smelling, fatty, floating stools)
- Fat-soluble vitamins (A, D, E, K) cannot be absorbed → night blindness, osteomalacia, neurologic symptoms (vitamin E deficiency → spinocerebellar degeneration → ataxia)
- Acanthocytes (spur cells) on peripheral blood smear — altered red cell membrane lipid composition
- Very low serum cholesterol and triglycerides (no chylomicrons or VLDL)
- Treatment: low-fat diet + high-dose fat-soluble vitamin supplementation; MCT oil for calories
Familial hypobetalipoproteinemia = heterozygous truncating mutations in APOB gene → reduced (not absent) apoB-48 and apoB-100. Milder phenotype than abetalipoproteinemia. Abetalipoproteinemia = MTP gene mutation → no assembly of any apoB-containing lipoprotein.
▼ Enterohepatic Circulation of Bile Acids
The body conserves bile acids by recycling them 6–10 times per day. The terminal ileum is the site of active reabsorption of conjugated bile acids.
The Recycling Loop
- Liver synthesizes primary bile acids (cholic acid, chenodeoxycholic acid) from cholesterol → conjugated with glycine or taurine (→ bile salts) → secreted in bile → stored in gallbladder
- Meal stimulates CCK → gallbladder contraction → bile salts enter duodenum → emulsify fat + form micelles
- Terminal ileum: conjugated bile salts actively reabsorbed via ASBT (apical sodium-dependent bile acid transporter) — Na+/bile acid co-transport; enters portal blood → hepatic re-uptake → re-secreted (the "loop")
- Colonic bacteria deconjugate remaining bile salts → unconjugated bile acids (secondary: deoxycholic acid, lithocholic acid) reabsorbed by passive diffusion in colon
- ~5% of bile acids are lost in feces daily — replenished by hepatic de novo synthesis
Ileal Resection — Consequences
- Loss of active bile acid reabsorption → ↑ bile acids in colon → cholerheic (bile acid) diarrhea (bile acids stimulate colonic water secretion)
- If resection > ~100 cm: bile acid pool depleted → ↓ micelle formation → fat malabsorption & steatorrhea
- Reduced micelles → ↓ absorption of fat-soluble vitamins (A, D, E, K) and vitamin B12 (ileum also required for B12-IF complex absorption)
- Increased hepatic bile acid synthesis (upregulated to compensate) but often insufficient
- ↑ oxalate absorption (unbound by calcium in lumen) → enteric hyperoxaluria → calcium oxalate kidney stones
Terminal ileum resection causes both (1) bile acid malabsorption (→ steatorrhea if large resection) AND (2) vitamin B12 malabsorption (→ megaloblastic anemia). The two things the terminal ileum is uniquely responsible for. Cholestyramine (bile acid sequestrant) can help bind bile acids in the colon to reduce diarrhea — but worsens fat malabsorption.
Water, Electrolytes & Micronutrients
LOs 17–21 · Na+/Cl-/HCO3-/K+ absorption, iron, calcium, fat-soluble vitamins, B12, colon, diarrhea
- LO17: Water and electrolyte absorption — Na+, Cl−, HCO3−, K+ mechanisms
- LO18: Iron absorption — ferrireductase, DMT1, ferritin, ferroportin, transferrin
- LO19: Calcium absorption — calbindin, vitamin D, PTH
- LO20: Fat-soluble vitamins (ADEK) and B12 pathway (TC1 → IF → terminal ileum → TC2)
- LO21: Role of colon; osmotic vs. secretory diarrhea
▼ Water & Electrolyte Absorption
The GI tract handles ~9 L/day of fluid (2 L dietary + 7 L secretions): ~7 L absorbed by small intestine, ~1.5–2 L by colon; only ~100–200 mL lost in stool. Na+ absorption drives water absorption osmotically.
| Ion | Small Intestine Mechanism | Colon Mechanism | Step 1 Key Point |
|---|---|---|---|
| Na+ | ① SGLT1 (glucose/galactose co-transport) ② Na+/H+ antiporter (NHE3) ③ Paracellular diffusion (jejunum) ④ Na+-AA co-transport | ENaC (epithelial Na+ channel) — aldosterone-upregulated; electrogenic | ORS (oral rehydration solution) exploits SGLT1; works even in cholera |
| Cl− | Passive paracellular (jejunum); Cl−/HCO3− exchanger (ileum, alkaline secretion) | Cl−/HCO3− exchanger; CFTR (Cl− secretion — reversed in secretory diarrhea) | Cholera toxin locks CFTR open → massive Cl− (and water) secretion → rice-water stools |
| HCO3− | Secreted by pancreas into duodenum (neutralizes gastric acid); Cl−/HCO3− exchanger in ileum secretes HCO3− | Secreted into lumen (stool pH slightly alkaline) | Pancreatic HCO3− deficiency (chronic pancreatitis) → impaired TG digestion (lipase needs pH > 6.5) |
| K+ | Passive paracellular absorption (follows electrical gradient) | Secreted (K+ channel) when Na+ is absorbed electrogenically; net K+ loss in secretory diarrhea → hypokalemia | Diarrhea → hypokalemia; especially secretory diarrhea |
- WHO ORS: Na+ 75, Cl− 65, K+ 20, citrate 10, glucose 75 mEq/L (osmolarity ~245)
- Glucose drives SGLT1-mediated Na+ absorption in the small intestine — this pathway is intact in cholera (toxin only locks CFTR, not SGLT1)
- One of the most impactful medical discoveries of the 20th century — saves millions of lives/year from diarrheal diseases
▼ Iron Absorption
Iron is absorbed primarily in the duodenum and proximal jejunum. Body iron stores tightly regulate absorption since there is no active excretion mechanism.
Heme Iron (Most Bioavailable)
- From meat (hemoglobin, myoglobin); absorbed intact by heme carrier protein (HCP1)
- Inside enterocyte: heme oxygenase releases Fe2+
- Bioavailability ~25%; not affected by gastric pH or chelators
Non-Heme Iron (Lower Bioavailability)
- Fe3+ → Fe2+: ferrireductase (duodenal cytochrome B, DcytB) on brush border converts Fe3+ (ferric, dietary) to Fe2+ (ferrous)
- Fe2+ + H+ → enterocyte: DMT1 (divalent metal transporter 1) — H+-coupled co-transport (requires acidic microenvironment; explains why achlorhydria → iron deficiency)
- Inside enterocyte: Fe2+ is either stored as ferritin (if body stores replete — cells shed into lumen, iron lost) OR exported via ferroportin on the basolateral membrane
- Hephaestin (ferroxidase) on basolateral membrane re-oxidizes Fe2+ → Fe3+ for loading onto transferrin in blood
- Transferrin (β-globulin, made by liver) carries Fe3+ in blood (2 iron-binding sites); delivers to bone marrow, liver, etc.
Regulation
- Hepcidin (liver peptide hormone): ↑ when body iron stores high → binds ferroportin → causes internalization and degradation → ↓ Fe export from enterocytes (and macrophages) → ↓ serum iron
- Iron deficiency: ↓ hepcidin → ↑ ferroportin expression → ↑ absorption
- Vitamin C (ascorbic acid) reduces Fe3+ → Fe2+ in the gut → enhances non-heme iron absorption
- Tannins (tea, coffee) and phytates chelate iron → ↓ absorption
- PPIs → ↓ gastric acid → ↓ DcytB activity (needs low pH) → ↓ Fe2+ availability → iron deficiency with chronic PPI use
- Gastrectomy / achlorhydria → same mechanism
- Hemochromatosis (HFE mutation): ↓ hepcidin signaling → unregulated ↑ ferroportin → excessive iron absorption → iron deposition in liver, heart, pancreas, skin, joints ("bronze diabetes")
▼ Calcium Absorption
Calcium is absorbed in the duodenum and proximal jejunum via two mechanisms: active (transcellular) and passive (paracellular).
Active (Transcellular) Absorption — Duodenum
- Ca2+ enters enterocyte via TRPV6 (and TRPV5) channels on the apical membrane, driven by low intracellular Ca2+
- Inside cell: Ca2+ binds calbindin D9k (CaBP, calcium-binding protein) → shuttled across cytoplasm (prevents toxic intracellular Ca2+ accumulation)
- Ca2+ exits basolaterally via PMCA1b (Ca2+-ATPase, active) and NCX1 (Na+/Ca2+ exchanger)
- This pathway is upregulated by 1,25-(OH)₂-vitamin D (calcitriol) → increases expression of TRPV6, calbindin, PMCA
Passive (Paracellular) Absorption
- Occurs throughout the small intestine when luminal Ca2+ is high (large dietary load)
- Does not require vitamin D; depends on electrochemical gradient and tight junction permeability
Regulation
- Vitamin D (1,25-(OH)₂-D3): primary regulator of active Ca2+ absorption; upregulates all transcellular components
- PTH: indirectly increases Ca2+ absorption by stimulating renal 1α-hydroxylase → ↑ calcitriol → ↑ intestinal Ca2+ absorption; also ↓ urinary Ca2+ excretion
- Gastric acid: converts insoluble Ca2+ salts to soluble Ca2+ → available for absorption; achlorhydria → ↓ Ca2+ absorption
↓ Vitamin D → ↓ calbindin → ↓ Ca2+ absorption → ↓ serum Ca2+ → ↑ PTH (secondary hyperparathyroidism) → bone resorption → rickets (children) / osteomalacia (adults). Fat malabsorption (any cause) → fat-soluble vitamin D malabsorption → same chain.
▼ Vitamin Absorption & the B12 Pathway
Fat-Soluble Vitamins (A, D, E, K)
- Require bile salts and micelles for absorption — absorbed by passive diffusion from micelles in the proximal small intestine
- Incorporated into chylomicrons → transported via lymphatics
- Any cause of fat malabsorption (cholestasis, pancreatic insufficiency, ileal resection) → fat-soluble vitamin deficiency
| Vitamin | Deficiency Consequence | Step 1 Note |
|---|---|---|
| A (retinol) | Night blindness, Bitot's spots, xerophthalmia, immune impairment | Measles → vitamin A depletion → severe disease |
| D (cholecalciferol) | Rickets (children), osteomalacia (adults), secondary hyperparathyroidism | Synthesis requires sunlight (7-dehydrocholesterol → D3); hydroxylation in liver (25) then kidney (1-α) |
| E (tocopherol) | Hemolytic anemia (neonates), spinocerebellar degeneration, posterior column signs | Main antioxidant for cell membranes; deficiency in abetalipoproteinemia |
| K (phylloquinone) | ↑ PT/INR, bleeding; neonatal hemorrhagic disease | Required for γ-carboxylation of factors II, VII, IX, X, protein C/S; warfarin antagonizes vitamin K |
Vitamin B12 — The Unique Pathway
Vitamin B12 absorption is a multi-step process and each step is a potential exam question:
- Dietary B12 is bound to protein; gastric acid + pepsin free it
- Free B12 binds transcobalamin I (TC1, R-protein) secreted in saliva → TC1-B12 complex travels to duodenum
- Pancreatic proteases digest TC1 → B12 released → binds intrinsic factor (IF) secreted by gastric parietal cells
- IF-B12 complex travels to terminal ileum → binds cubilin receptor → endocytosis into ileal enterocytes
- Inside enterocyte: IF degraded; B12 released → binds transcobalamin II (TC2) → secreted into portal blood → delivered to all cells
- Pernicious anemia: autoimmune destruction of parietal cells → no IF → no B12 absorption → megaloblastic anemia + subacute combined degeneration of the spinal cord (posterior + lateral columns)
- Gastrectomy: removes parietal cells → same result; B12 supplementation required lifelong
- Chronic pancreatitis: no pancreatic proteases → TC1 not cleaved → B12 stays bound to TC1 (not IF) → not absorbed; mild B12 deficiency possible
- Terminal ileum resection / Crohn's of terminal ileum: no IF-B12 receptor → B12 malabsorption
- D. latum (fish tapeworm): competes for B12 in the gut → deficiency
- Veganism: no dietary B12 → deficiency over years (B12 stores last 3–5 years)
▼ Role of Colon & Diarrhea
Colonic Functions
- Absorbs remaining ~1.5–2 L of water per day (capacity ~5 L/day before diarrhea)
- Na+ absorbed via electrogenic ENaC (aldosterone-sensitive); K+ secreted → diarrhea causes hypokalemia
- Bacterial fermentation of undigested carbohydrates → SCFAs (butyrate, propionate, acetate) → energy source for colonocytes (butyrate preferred fuel)
- Slow transit → more water absorption → formed stool; fast transit → less absorption → watery stool
Diarrhea Classification
| Type | Mechanism | Key Feature | Classic Examples |
|---|---|---|---|
| Osmotic | Unabsorbed solutes draw water into lumen | Stops with fasting; ↑ stool osmolar gap (>50) | Lactose intolerance, lactulose, Mg2+-based laxatives, SGLT1 deficiency |
| Secretory | Active Cl−/water secretion (CFTR); | Continues despite fasting; normal osmolar gap | Cholera (CT), VIPoma, carcinoid, C. difficile toxin A |
| Exudative / Inflammatory | Mucosal damage → blood, pus, protein in stool | Fever, bloody stool, ↑ WBCs | IBD, invasive bacteria (Shigella, Salmonella, Campylobacter, EHEC) |
| Malabsorptive | Failure of nutrient/fat absorption → osmotic + motility effects | Steatorrhea, weight loss, fat-soluble vitamin deficiency | Celiac disease, pancreatic insufficiency, Whipple's, giardiasis |
| Motility | Abnormal intestinal transit (fast or slow) | Often post-meal urgency or pseudo-obstruction | IBS-D, hyperthyroidism, post-vagotomy |
Stool osmolar gap = 290 − 2×([Na+] + [K+]). Normal <50 mOsm/kg (ions account for most osmolarity). Gap >125 = osmotic diarrhea (nonabsorbed solutes contributing to osmolarity). Gap <50 = secretory (ions the dominant solutes — electrolytes being actively secreted).
Practice Questions
15 USMLE-Style MCQs — Digestion & Absorption I & II
Question 1
A medical student is reviewing the structural basis of absorptive efficiency in the small intestine. Which structural feature of the enterocyte is primarily responsible for the approximately 20-fold increase in apical surface area per cell and houses the final enzymatic steps of carbohydrate and protein digestion?
A. Plicae circulares
B. Villi
C. Microvilli (brush border)
D. Lacteals
E. Crypts of Lieberkühn
Microvilli are the dense apical membrane projections (~1 µm tall) present on each enterocyte. They increase the apical surface area by approximately 20-fold and bear brush border enzymes including lactase, sucrase-isomaltase, maltase, aminopeptidases, and dipeptidases — the final step in carbohydrate and protein digestion before absorption. Plicae circulares (A) and villi (B) provide larger-scale amplification but do not bear enzymes on their surface. Lacteals (D) absorb chylomicrons. Crypts (E) are secretory structures containing stem cells.
Question 2
A 45-year-old woman undergoes a Whipple procedure (pancreaticoduodenectomy) for pancreatic head adenocarcinoma, resulting in loss of exocrine pancreatic secretion into the duodenum. Which step of carbohydrate digestion would be most severely impaired?
A. Salivary amylase digestion of starch in the mouth
B. Brush border lactase activity on lactose
C. Pancreatic amylase cleavage of starch to oligosaccharides and maltose
D. SGLT1-mediated glucose uptake in the jejunum
E. GLUT2-mediated basolateral glucose export
Pancreatic amylase is the dominant luminal amylase, accounting for the vast majority of starch digestion. Salivary amylase (A) begins starch digestion but is inactivated by gastric acid and accounts for only ~5% of total digestion. Brush border enzymes (B) are unaffected by pancreatic insufficiency — they are expressed by enterocytes, not secreted by the pancreas. SGLT1 (D) and GLUT2 (E) are transport proteins on the enterocyte and would not be impaired by loss of pancreatic secretion.
Question 3
Glucose is absorbed across the apical membrane of the enterocyte via SGLT1 co-transport. This is an example of which transport mechanism, and what drives it?
A. Primary active transport driven directly by ATP hydrolysis
B. Secondary active transport driven by the Na+ electrochemical gradient
C. Facilitated diffusion via a carrier protein
D. Passive diffusion down a concentration gradient
E. Pinocytosis requiring clathrin-coated vesicles
SGLT1 co-transports 2 Na+ ions and 1 glucose molecule into the enterocyte. The Na+ electrochemical gradient (low intracellular Na+ maintained by basolateral Na+/K+-ATPase) provides the energy — this is secondary active transport. The Na+/K+-ATPase is the primary active transporter that ultimately drives the whole system. Facilitated diffusion (C) is the mechanism used by GLUT5 (fructose) and GLUT2 (basolateral); it requires no Na+ or energy. Glucose can move against its own concentration gradient via SGLT1, which distinguishes it from passive mechanisms.
Question 4
A 22-year-old woman develops abdominal cramping, bloating, and watery diarrhea within 30 minutes of consuming a glass of milk. She reports feeling well otherwise and has no blood in her stool. A hydrogen breath test following lactose administration is positive. Which statement best explains the mechanism of her diarrhea?
A. Lactase deficiency → lactose activates Cl⁻ secretion via CFTR → secretory diarrhea
B. Lactase deficiency → undigested lactose in lumen → osmotic water retention → osmotic diarrhea; bacterial fermentation → gas
C. Lactase deficiency → impaired SGLT1 transport → reduced Na+ absorption → secretory diarrhea
D. Autoimmune destruction of enterocytes → villous atrophy → global malabsorption
E. Lactose directly stimulates mast cell degranulation in the gut → inflammatory diarrhea
Lactase deficiency → undigested lactose remains in the small intestinal lumen → acts as an osmotic agent → draws water into lumen → watery diarrhea. Lactose reaching the colon is fermented by bacteria → H₂, CO₂, short-chain fatty acids → bloating, cramping, flatulence. This is an osmotic diarrhea (stops with fasting; elevated stool osmolar gap). CFTR-mediated secretion (A, C) describes secretory diarrhea, which continues with fasting. Autoimmune villous atrophy (D) describes celiac disease. Mast cell involvement (E) would suggest an IgE-mediated food allergy.
Question 5
A 6-month-old infant is found to have absent enterokinase (enteropeptidase) activity due to a rare congenital deficiency. Which of the following best describes the downstream consequence of this defect?
A. Impaired carbohydrate digestion due to failure of pancreatic amylase secretion
B. Failure to activate trypsinogen → all pancreatic proteases remain inactive → severe protein malabsorption
C. Defective micelle formation due to impaired bile acid secretion
D. Selective malabsorption of fructose due to GLUT5 downregulation
E. Increased gastric pepsin activity compensates for the defect
Enterokinase is the master initiator of the pancreatic protease activation cascade. It cleaves trypsinogen → trypsin; trypsin then activates chymotrypsinogen, proelastase, and procarboxypeptidases. Without enterokinase, no protease is activated → severe protein malabsorption, hypoproteinemia, failure to thrive. Note that pancreatic enzymes are secreted normally; the defect is in activation, not secretion. Carbohydrate and fat digestion are unaffected (those pathways don't require enterokinase). Pepsin (E) is insufficient to compensate for loss of all pancreatic proteases.
Question 6
A patient with chronic pancreatitis develops steatorrhea and greasy, foul-smelling stools. Which mechanism is the primary cause of fat malabsorption in this condition?
A. Impaired bile acid synthesis by the liver
B. Loss of pancreatic lipase and bicarbonate → impaired TG hydrolysis and suboptimal intraluminal pH
C. Defective apoB-48 synthesis by enterocytes
D. Loss of terminal ileum bile acid reabsorption
E. Impaired lingual lipase activity in the mouth
Chronic pancreatitis destroys exocrine pancreatic tissue → loss of pancreatic lipase (and co-lipase) → failure to hydrolyze TGs to 2-MAG + free fatty acids. Additionally, loss of pancreatic HCO₃⁻ → low duodenal pH → pancreatic lipase further inactivated (requires pH > 6.5) and bile salts precipitate (pKa ~6) → impaired micelle formation. All downstream events (micelle formation, enterocyte uptake, chylomicron assembly) depend on prior TG hydrolysis. Bile acid synthesis (A) and apoB-48 (C) are intact. Terminal ileum dysfunction (D) would cause bile acid malabsorption and secondarily impair fat absorption, but this is not the mechanism in chronic pancreatitis.
Question 7
A 42-year-old man with Crohn's disease affecting the terminal ileum undergoes surgical resection of 120 cm of terminal ileum. Which combination of deficiencies is most expected?
A. Iron deficiency anemia and vitamin C deficiency
B. Fat malabsorption and vitamin B12 deficiency, with risk of oxalate kidney stones
C. Lactose intolerance and folate deficiency
D. Protein malabsorption and hyperkalemia
E. Calcium malabsorption and hypomagnesemia only
The terminal ileum has two unique absorptive functions: (1) active reabsorption of conjugated bile acids (ASBT transporter) and (2) absorption of the IF-B12 complex (cubilin receptor). With 120 cm of resection, the bile acid pool is depleted → impaired micelle formation → fat malabsorption and fat-soluble vitamin deficiency. B12 malabsorption → megaloblastic anemia and subacute combined degeneration of the cord (if untreated). Additionally, fat malabsorption → intraluminal fat binds calcium → less Ca²+ available to bind oxalate → oxalate freely absorbed → hyperoxaluria → calcium oxalate kidney stones ("enteric hyperoxaluria"). Iron (A) is absorbed in the duodenum, not the ileum. Lactose intolerance and folate deficiency (C) relate to proximal small intestine.
Question 8
A 9-year-old boy presents with failure to thrive, fatty diarrhea, and neurological symptoms including ataxia and loss of proprioception. Laboratory evaluation reveals very low serum cholesterol, absent serum triglycerides, and acanthocytes on peripheral smear. Intestinal biopsy shows lipid vacuoles in enterocytes. What is the underlying defect?
A. Congenital absence of pancreatic lipase
B. Defective microsomal triglyceride transfer protein (MTP) → failure to assemble apoB-48-containing chylomicrons
C. Loss of SGLT1 function → glucose-galactose malabsorption
D. Autoimmune destruction of parietal cells → vitamin B12 deficiency
E. Primary bile acid synthesis defect → impaired micelle formation
This is the classic presentation of abetalipoproteinemia (AR). MTP is required to transfer lipids onto apoB-48 during chylomicron assembly in the enterocyte SER. Without MTP, lipids enter the enterocyte normally but cannot be packaged → fat accumulates (lipid vacuoles on biopsy). No chylomicrons (or VLDL, which uses apoB-100) enter the blood → absent serum TG and very low cholesterol. Acanthocytes result from abnormal red cell membrane lipid composition. Neurological symptoms are due to vitamin E deficiency (fat-soluble; cannot be exported in chylomicrons). Treatment: very low fat diet + high-dose fat-soluble vitamins + MCT oil.
Question 9
A cholera patient presents with profuse "rice-water" diarrhea and severe volume depletion. Oral rehydration solution containing sodium and glucose is administered. Which transport mechanism explains why ORS works despite active intestinal secretion?
A. ENaC-mediated Na+ absorption in the colon is intact and compensates
B. SGLT1-mediated Na+-glucose co-transport remains functional and drives Na+ and water absorption even when CFTR is constitutively active
C. Glucose stimulates CCK → inhibits cAMP → reverses CFTR opening
D. Fructose absorption via GLUT5 draws Na+ through tight junctions paracellularly
E. Oral glucose suppresses V. cholerae toxin production
Cholera toxin activates Gs protein permanently → ↑ adenylyl cyclase → ↑ cAMP → PKA phosphorylates CFTR → constitutive Cl⁻ and water secretion. However, SGLT1 on the apical membrane is unaffected by cAMP. Providing glucose + Na+ in ORS exploits SGLT1 to absorb Na+ (and osmotically drive water absorption) simultaneously. This net absorption can partially offset secretory losses. ORS does not reverse cholera toxin action — it simply uses an intact absorption pathway that runs in parallel. This is one of medicine's great clinical insights: even in the face of massive secretory diarrhea, absorption can continue via SGLT1.
Question 10
A 28-year-old woman with iron deficiency anemia is counseled on dietary iron. Which statement correctly describes the mechanism of non-heme iron uptake from the intestinal lumen into the duodenal enterocyte?
A. Fe3+ (ferric) is directly transported across the brush border by DMT1
B. Fe3+ is reduced to Fe2+ by ferrireductase (DcytB) at the brush border, then transported by DMT1 via H+-coupled co-transport
C. Fe2+ diffuses passively across the lipid bilayer of the brush border
D. Fe3+ binds ferritin on the brush border and is endocytosed intact
E. Iron absorption occurs primarily in the terminal ileum via a vitamin D-dependent mechanism
Dietary non-heme iron is mostly in the Fe3+ (ferric) form, which is insoluble at intestinal pH. Duodenal cytochrome B (DcytB, a ferrireductase) on the brush border reduces Fe3+ → Fe2+ (ferrous). Fe2+ is then transported into the enterocyte by DMT1 via H+-coupled co-transport (the proton gradient comes from the NHE3 Na+/H+ exchanger creating a slightly acidic microenvironment). DMT1 cannot transport Fe3+ (A). Iron does not passively diffuse (C) — it requires a carrier. Ferritin is an intracellular storage protein, not a membrane receptor (D). Iron absorption is in the duodenum/proximal jejunum, not the terminal ileum (E).
Question 11
A 35-year-old woman with primary biliary cholangitis develops fat-soluble vitamin deficiency and hypocalcemia. A bone densitometry scan shows osteomalacia. Which mechanism best explains the calcium malabsorption in this patient?
A. PTH deficiency directly impairing colonic Ca2+ reabsorption
B. Impaired micelle formation → fat-soluble vitamin D malabsorption → ↓ calcitriol → ↓ calbindin expression → impaired transcellular Ca2+ absorption
C. Loss of DMT1 function in the duodenum affecting both iron and calcium transport
D. High luminal pH dissolving calcium salts → excessive passive Ca2+ absorption
E. Destruction of goblet cells → loss of mucus protecting Ca2+ absorption
Biliary obstruction/cholangitis reduces bile salt delivery to the duodenum → impaired micelle formation → fat-soluble vitamins (including vitamin D) cannot be absorbed → ↓ circulating calcitriol (1,25-(OH)₂-D3) → ↓ expression of TRPV6 channels and calbindin in enterocytes → impaired transcellular Ca2+ absorption in the duodenum → hypocalcemia → secondary hyperparathyroidism → bone resorption → osteomalacia. PTH deficiency (A) would not occur here — PTH rises reactively. DMT1 (C) transports iron (Fe2+), not calcium. High luminal pH (D) would reduce Ca2+ solubility, not increase absorption. Goblet cells (E) have no role in Ca2+ absorption.
Question 12
A 58-year-old man presents with fatigue, glossitis, and tingling in his feet. Labs show macrocytic anemia (MCV 112 fL) and low serum B12. He has a history of autoimmune thyroiditis. Anti-parietal cell and anti-intrinsic factor antibodies are positive. Which step in B12 absorption is directly impaired?
A. Release of B12 from dietary protein by gastric acid
B. Binding of B12 to transcobalamin I (TC1/R-protein) in saliva
C. Cleavage of TC1 by pancreatic proteases in the duodenum
D. Binding of free B12 to intrinsic factor (IF), preventing IF-B12 complex formation
E. Release of B12 from IF within the terminal ileal enterocyte
This is pernicious anemia. Anti-parietal cell antibodies destroy gastric parietal cells → no intrinsic factor (IF) secreted. Anti-IF antibodies (blocking type) directly prevent B12 from binding IF. Without IF, the B12-IF complex cannot form → no binding to cubilin receptor in the terminal ileum → B12 not absorbed. Note that TC1 (B) still binds B12 in the saliva, but when TC1 is cleaved by pancreatic proteases (C) in the duodenum, free B12 cannot find IF → passes through unabsorbed. The result is megaloblastic anemia + subacute combined degeneration (posterior column + corticospinal tract). Treatment: IM hydroxocobalamin or high-dose oral B12 (some passive absorption).
Question 13
A 65-year-old man with a 3-cm VIPoma (vasoactive intestinal peptide-secreting tumor) presents with profuse watery diarrhea (6–10 L/day), hypokalemia, and achlorhydria (WDHA syndrome). A stool sample collected during a fast shows high-volume watery stool with a stool osmolar gap of 20 mOsm/kg. Which type of diarrhea is this?
A. Osmotic diarrhea — unabsorbed VIP draws water into lumen
B. Exudative diarrhea — VIPoma causes mucosal inflammation
C. Secretory diarrhea — VIP activates adenylyl cyclase → ↑ cAMP → Cl⁻ and water secretion into lumen
D. Malabsorptive diarrhea — VIPoma destroys pancreatic lipase
E. Motility diarrhea — VIP accelerates GI transit via smooth muscle stimulation only
VIPoma (Verner-Morrison syndrome / WDHA: Watery Diarrhea, Hypokalemia, Achlorhydria) causes profuse secretory diarrhea. VIP binds its receptor → activates adenylyl cyclase → ↑ cAMP → PKA → phosphorylation of CFTR and other channels → massive Cl⁻ and water secretion into the gut lumen. Key features of secretory diarrhea: (1) continues with fasting (unlike osmotic), (2) low stool osmolar gap (<50 mOsm/kg) because electrolytes dominate the stool osmolarity, (3) large-volume watery stools, (4) hypokalemia (K+ secreted with the large volumes). Osmotic diarrhea (A) stops with fasting and has a high osmolar gap. VIPoma does not cause mucosal damage (B) or fat malabsorption (D).
Question 14
Researchers study sugar transport in a patient with a novel mutation selectively inactivating SGLT1. Which finding would be expected in this patient?
A. Impaired fructose absorption; glucose and galactose absorbed normally
B. Impaired glucose and galactose absorption; fructose absorption unaffected
C. Impaired glucose absorption only; galactose uses an alternative SGLT2 transporter in the jejunum
D. Impaired absorption of all three monosaccharides because GLUT2 depends on SGLT1 function
E. Glucose absorbed normally via GLUT5 when SGLT1 is absent
SGLT1 transports both glucose and galactose across the apical brush border (2 Na+: 1 sugar co-transport). Inactivation of SGLT1 prevents both glucose and galactose from entering the enterocyte via this route → osmotic diarrhea with glucose or galactose ingestion. Fructose uses a completely separate transporter, GLUT5 (facilitated diffusion), which does not depend on Na+ or SGLT1 → fructose absorption is unaffected. SGLT2 (C) is the renal glucose transporter (proximal tubule), not a small intestinal transporter. GLUT2 (D) is the basolateral exit transporter — it would not function without glucose/galactose entering first, but fructose would still exit normally via GLUT2. GLUT5 (E) does not transport glucose.
Question 15
A 7-year-old boy presents with steatorrhea, failure to thrive, and fat-soluble vitamin deficiencies. Peripheral blood smear shows acanthocytes. Serum lipid panel reveals absent chylomicrons and VLDL, very low LDL, and undetectable apolipoprotein B. His pancreatic enzyme levels are normal. Which dietary modification and supplement would be most appropriate?
A. Gluten-free diet and oral folic acid
B. Low-fat diet with MCT oil supplementation, plus high-dose fat-soluble vitamins (A, D, E, K)
C. High-fat diet to overcome the absorption defect by mass action
D. Lactose-free diet and iron supplementation
E. Low-protein diet to prevent enterokinase activation cascade overload
This is abetalipoproteinemia (absent apoB-48 and apoB-100 → no chylomicrons or VLDL). Normal pancreatic enzymes confirm digestion is intact; the defect is in chylomicron assembly (MTP deficiency). Management: (1) Low-fat diet — restricts long-chain TG, which cannot be exported in chylomicrons; (2) MCT oil — medium-chain fatty acids bypass the chylomicron pathway, absorbed directly into portal blood; (3) High-dose fat-soluble vitamins (A, D, E, K) — water-miscible preparations are used because regular fat-soluble preparations cannot be absorbed; vitamin E supplementation is critical to prevent the progressive spinocerebellar degeneration. Gluten-free diet (A) treats celiac disease. High fat (C) would worsen symptoms.
Question 16
A 30-year-old woman is found to have intestinal lymphangiectasia — a condition in which the lacteals of the small intestine are chronically dilated and rupture, leaking their contents into the intestinal lumen. Which combination of findings would be most expected?
A. Hyperproteinemia and hyperlipidemia due to lymphatic backup
B. Steatorrhea, fat-soluble vitamin deficiency, and protein-losing enteropathy (hypoalbuminemia, edema)
C. Impaired glucose and galactose absorption with normal fat digestion
D. Iron deficiency anemia due to blocked duodenal absorption
E. Megaloblastic anemia only, due to obstruction of B12-bearing lymph
Lacteals are the lymphatic capillaries within each villus. Their unique function is to absorb chylomicrons (which are too large for blood capillaries) and transport them via lymph → thoracic duct → systemic circulation. When lacteals rupture or are chronically obstructed: (1) chylomicrons leak back into the intestinal lumen → steatorrhea; (2) fat-soluble vitamins (A, D, E, K) that traveled with chylomicrons are also lost; (3) lymph is protein-rich → protein loss into the gut lumen → hypoalbuminemia and edema (protein-losing enteropathy). Glucose and galactose (C) are absorbed into blood capillaries via SGLT1 and GLUT2, not through lacteals — unaffected. Iron (D) is absorbed directly into portal blood. B12 (E) also enters portal blood after terminal ileal absorption, not via lymphatics.
Question 17
A biochemist isolates a pancreatic serine protease from duodenal fluid. In vitro testing shows the enzyme cleaves peptide bonds on the C-terminal side of aromatic amino acid residues (phenylalanine, tyrosine, tryptophan) and leucine. Which enzyme has been isolated?
A. Trypsin
B. Elastase
C. Chymotrypsin
D. Carboxypeptidase A
E. Enterokinase (enteropeptidase)
Each pancreatic protease has a characteristic cleavage specificity: Chymotrypsin cleaves after large, hydrophobic aromatic residues (Phe, Tyr, Trp) and Leu. Trypsin (A) cleaves after positively charged residues Lys and Arg. Elastase (B) cleaves after small, neutral residues Ala, Gly, and Ser. Carboxypeptidase A (D) is an exopeptidase that removes the C-terminal amino acid residue (prefers aromatic and aliphatic C-terminal AAs); it cannot cleave internal peptide bonds. Enterokinase (E) is a duodenal brush border enzyme that specifically activates trypsinogen by cleaving a short N-terminal propeptide — it is not a general protease. Memorize: "Trypsin = Lys/Arg (positive charge); Chymotrypsin = Phe/Tyr/Trp/Leu (big & hydrophobic); Elastase = Ala/Gly/Ser (small)."
Question 18
A nutritionist counsels a patient that dietary fiber provides no caloric energy from human digestive enzymes, yet it is still partially metabolized in the GI tract. Which statements correctly explain both facts?
A. Cellulose has α-1,4 glycosidic bonds; human amylase cleaves these bonds but too slowly to extract significant energy
B. Cellulose has β-1,4 glycosidic bonds, which human enzymes cannot cleave; colonic bacteria ferment some soluble fiber → short-chain fatty acids (SCFAs) → absorbed by colonocytes
C. Cellulose is composed of fructose units linked by β-1,4 bonds; GLUT5 cannot transport the products
D. Fiber activates a hepatic enzyme that converts cellulose to glycogen; the glycogen is then metabolized normally
E. Fiber is digested by lingual lipase in the mouth; its products are excreted unchanged in bile
Cellulose is a polymer of glucose linked by β-1,4 glycosidic bonds. Human salivary and pancreatic amylases, as well as brush border saccharidases, can only cleave α-glycosidic bonds (as in starch/glycogen). No human enzyme produces the β-glucosidase (cellulase) activity needed to digest cellulose → passes through the small intestine unabsorbed. In the colon, anaerobic bacteria ferment soluble fiber → short-chain fatty acids (butyrate, propionate, acetate). Butyrate is the preferred fuel for colonocytes and has anti-inflammatory and anti-neoplastic effects. Insoluble fiber (cellulose) adds fecal bulk and reduces colonic transit time. Option A incorrectly states the bond type is α. Option C incorrectly identifies cellulose as a fructose polymer.
Question 19
A 7-year-old boy develops intermittent cerebellar ataxia, a pellagra-like rash on sun-exposed skin, and psychiatric symptoms. Urine amino acid chromatography shows massive neutral aminoaciduria (elevated alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tryptophan). His serum amino acid levels are low-normal. He is eating a varied diet with adequate protein. Which mechanism explains why this patient can still absorb some protein despite the transporter defect?
A. SGLT1 can transport neutral amino acids when glucose is absent from the lumen
B. GLUT2 on the basolateral membrane pumps amino acids from blood into enterocytes
C. Di- and tripeptides containing neutral amino acids are absorbed intact via PepT1 (H+-peptide cotransporter), bypassing the defective free amino acid transporter
D. Colonic bacteria synthesize neutral amino acids from dietary fiber that are then absorbed
E. Gastric pepsin absorbs amino acids directly across the gastric mucosa
This is Hartnup disease (AR), caused by loss-of-function mutations in SLC6A19 (B0AT1), the brush border transporter for free neutral amino acids. Tryptophan malabsorption is the most clinically significant consequence: insufficient tryptophan → insufficient niacin (nicotinamide) synthesis → pellagra-like features (rash, ataxia, psychiatric symptoms). However, the same neutral amino acids can be absorbed as di- or tripeptides via PepT1 — a completely separate H+-coupled cotransporter that recognizes peptide bonds, not individual amino acids. This explains why symptoms are intermittent and relatively mild: high-protein diets (more peptides) lessen symptoms. The renal tubular transporter is also affected → neutral aminoaciduria (though serum levels may be near-normal due to partial intestinal compensation via PepT1). Treatment: high-protein diet + nicotinamide supplementation.
Question 20
A student studying cholestasis draws a diagram of fat digestion. She marks the step where, after pancreatic lipase has hydrolyzed triglycerides into 2-monoglycerides and free fatty acids, a critical transport vehicle carries these products from the intestinal lumen to the brush border for absorption. This transport vehicle then releases its contents at the enterocyte surface and does not enter the cell. What is this vehicle and why is it necessary?
A. Chylomicrons — they carry lipids from the enterocyte to the lymph and are recycled back to the lumen
B. Mixed micelles formed by bile salts — they are amphipathic vesicles that carry lipid digestion products across the unstirred water layer to the brush border, where products diffuse passively into the cell while bile salts remain in the lumen
C. VLDL particles secreted by the liver — they pick up fatty acids from the portal blood and ferry them back to the enterocyte
D. Fatty acid binding proteins (FABP) in the intestinal lumen — they are secreted by goblet cells and carry fatty acids through the aqueous lumen
E. Pancreatic co-lipase — it escorts fatty acids across the unstirred water layer after dissociating from pancreatic lipase
The unstirred water layer (UWL) adjacent to the brush border is an aqueous film through which all absorbed molecules must diffuse. Lipid digestion products (2-monoglycerides, free fatty acids, cholesterol, fat-soluble vitamins) are hydrophobic and cannot diffuse through the aqueous UWL efficiently on their own. Bile salt micelles — amphipathic cylindrical structures with a hydrophobic core — dissolve these lipid products and carry them across the UWL to the brush border. At the brush border, the slightly more hydrophilic surface causes lipid products to diffuse out of the micelle and passively cross the enterocyte lipid bilayer. Bile salts remain in the lumen and travel to the terminal ileum for active reabsorption (enterohepatic circulation). This is why cholestasis (↓ bile salts) → no micelles → fat malabsorption even when pancreatic lipase is intact. Chylomicrons (A) are assembled inside the enterocyte and travel away from the gut. FABP (D) exists intracellularly, not in the lumen. Co-lipase (E) anchors lipase at the fat droplet surface; it does not escort fatty acids across the UWL.
Question 21
A researcher administers a drug that specifically and completely blocks the basolateral Na+/K+-ATPase of all small intestinal enterocytes. Which group of absorptive processes would be MOST directly and immediately impaired?
A. Passive diffusion of long-chain fatty acids and fat-soluble vitamins into enterocytes
B. Fructose uptake via GLUT5 and basolateral glucose export via GLUT2
C. Glucose and galactose uptake via SGLT1, amino acid uptake via Na+-coupled cotransporters, and dipeptide/tripeptide uptake via PepT1 (indirectly, via NHE3 dependence)
D. Chylomicron assembly and exocytosis into lacteals
E. Calcium absorption via TRPV6 and calbindin-mediated transcellular transport only
The basolateral Na+/K+-ATPase is the engine that drives all secondary active co-transport in the intestine. By continuously pumping 3 Na+ out of the enterocyte (and 2 K+ in), it keeps intracellular Na+ low. This creates the electrochemical gradient that drives: SGLT1 (Na+-glucose/galactose co-transport) and all Na+-amino acid cotransporters at the apical brush border. PepT1 uses an H+ gradient (generated by NHE3, which itself depends on the Na+ gradient), so it is also ultimately impaired when the Na+ gradient collapses. Fatty acid diffusion (A) is passive and requires no pump. GLUT5 (B) is Na+-independent facilitated diffusion; GLUT2 is also facilitated diffusion — both are unaffected by Na+/K+-ATPase blockade. Chylomicron assembly (D) occurs in the SER/Golgi and is independent of the Na+ gradient. Calcium absorption via TRPV6 (E) is driven by low intracellular Ca2+ (maintained by PMCA Ca2+-ATPase, a separate pump) — though the Na+/Ca2+ exchanger (NCX) on the basolateral membrane would be secondarily impaired by loss of Na+ gradient. Answer C captures the broadest and most immediate effect.