LOs 3 & 4 — Carbohydrate, Lipid, Cholesterol & Protein Metabolism

Carbohydrate Metabolism

Process	Metabolic State	Hormonal Control	Outcome
Glycogenesis
Glycogenolysis
Gluconeogenesis
Glycolysis

Acute liver failure → profound ___ because ___

Liver uses ___ (not GLUT4) for glucose uptake because it is ___ (insulin-independent/dependent)

Lipid Metabolism & Lipoproteins

VLDL is made by ___ and carries ___; degraded to ___ → ___

HDL produced by ___ + ___; performs ___ cholesterol transport

NAFLD/NASH mechanism: insulin resistance → ↑___ delivery to liver + ↓___ + ↓___ export → ___ accumulation

Lipoprotein	Origin	Primary Cargo	Key Clinical Point
Chylomicrons
VLDL
LDL
HDL

Cholesterol Metabolism & Statins (LO 4)

5 main uses of cholesterol: ___, ___, ___, ___, ___

Rate-limiting step: HMG-CoA → ___ catalyzed by ___

High dietary cholesterol → ___ (suppresses/stimulates) HMG-CoA reductase via ___

Statins mechanism: competitive inhibit ___ → ↓hepatic cholesterol → ↑___ → ↑LDL clearance → ↓serum LDL

Statin side effects: ___, ___

Familial hypercholesterolemia = mutation in ___ → ↑LDL despite normal ___

Protein Metabolism & Liver Failure Consequences

Liver makes all plasma proteins EXCEPT ___ (made by ___)

Albumin t½ = ___ days → ↓albumin indicates ___ (acute/chronic) liver dysfunction

Clotting factor NOT made by liver: Factor ___ (made by ___)

Factor with shortest t½ = Factor ___; rises first in ___; why it's an early marker of liver failure

Urea cycle: NH₃ → ___ (in hepatocytes only); failure → ___ → hepatic encephalopathy; treatment = ___ + ___

First-pass effect: oral drug absorbed → ___ → ___ → substantial metabolism before reaching systemic circulation

Signs of Liver Failure (HY)

⚠️ Step 1 Favorite: Know ALL 6 consequences of hepatocyte failure

Lost Function	Consequence / Clinical Sign
↓ Albumin
↓ Clotting factors (II, VII, IX, X)
↓ Urea cycle
↓ Gluconeogenesis/glycogenolysis
↓ Estrogen metabolism
↓ Bile production

LO 5 — Bilirubin Metabolism & 4 Types of Jaundice

Bilirubin Pathway — Step by Step

Step	Location	Process	Product
1–3		Aged RBCs → Hgb → heme → biliverdin → ___
4		Unconjugated bilirubin bound to ___ → transported to liver
5		Uptake via ___; conjugated with ___ by ___
6		Secreted via ___ into bile → duodenum
7–8		Bacteria → urobilinogen → ___ (stool) + ___ (urine, ~20% reabsorbed)

Unconjugated bilirubin: fat or water soluble? Can it be filtered by kidneys? Can it cross BBB?

Conjugated bilirubin: solubility? Appearance in urine → ___ urine; cannot cross ___

4 Types of Jaundice — Lab Differentiation

Type	Mechanism	Direct Bili	Indirect Bili	Urine Bili	Urobilinogen	Stool
Hemolytic (Pre-hepatic)
Hepatocellular (Intrahepatic)
Obstructive (Post-hepatic)
Neonatal (Physiologic)

⚠ Obstructive jaundice classic triad: dark urine + clay-colored stools + pruritus. Courvoisier sign = painless jaundice + palpable non-tender gallbladder → pancreatic head malignancy until proven otherwise.

Congenital Hyperbilirubinemias

Condition	Defect	Bili Type	Key Clinical Feature
Gilbert Syndrome
Crigler-Najjar Type I
Crigler-Najjar Type II
Dubin-Johnson
Rotor Syndrome

LOs 6–10 — Bile, EHC, Secretion, Regulation & Clinical Predictions

Bile Composition (LO 6)

Component	% of Solutes	Function / Note
Bile salts
Phospholipids (lecithin)
Cholesterol
Conjugated bilirubin

Primary bile acids (made in liver from cholesterol): ___ + ___; rate-limiting enzyme: ___

Gallstone formation: when ___ exceeds ___ + ___ → cholesterol crystallizes → ___ gallstones (___% of stones)

Conjugation & Secondary Bile Acids (LO 7)

Bile acids conjugated with ___ or ___ → bile salts; significance: ↓pKa → ___ at intestinal pH → cannot be ___ reabsorbed

Secondary bile acids formed by gut bacteria via 7α-dehydroxylation: cholic acid → ___; chenodeoxycholic acid → ___

Enterohepatic Circulation Sequence (LO 7)

Step 1: Hepatocytes synthesize primary bile acids → conjugate with ___ → bile salts → secreted to ___

Step 2: Bile salts enter duodenum via ___ → emulsify ___ throughout small intestine

Step 3: ___% of bile salts actively reabsorbed in ___ via ASBT transporter

Step 4: Absorbed bile salts → ___ vein → liver reconjugates → cycle repeats ___× per day

Total bile acid pool ≈ ___ g; liver synthesizes only ___ g/day to replace fecal losses

Bile acid sequestrants (cholestyramine) mechanism: bind ___ in gut → ↑CYP7A1 → ↑cholesterol → bile acid synthesis → ↓serum ___

Bile Secretion & Gallbladder Concentration (LO 8)

Stage 1 (hepatocytes): bile salts secreted via ___ pump; organic anions via ___

Stage 2 (cholangiocytes): secrete ___ and water stimulated by ___ via cAMP/CFTR

Gallbladder concentrates bile ___-fold by absorbing ___, ___, ___, and water

Between meals: sphincter of Oddi ___ → bile diverted to ___ (capacity ~___ mL)

Regulation of Bile Secretion (LO 9)

⚠ CCK contracts the gallbladder AND relaxes the sphincter of Oddi. Secretin stimulates ductal HCO₃⁻ but does NOT contract the gallbladder.

Regulator	Cell / Source	Stimulus	Effect on Bile/Gallbladder
CCK
Secretin
Bile salts (choleresis)
Vagal stimulation
Somatostatin

Clinical Predictions (LO 10)

Cholecystectomy: bile now delivered ___ (continuously/in bolus); total bile production ___; symptoms with large fatty meals: ___

Ileal resection: ASBT destroyed → bile salts ___ in feces → pool ___ → insufficient ___ → steatorrhea + ___ diarrhea + fat-soluble vitamin ___

Ileal resection also impairs ___ absorption (absorbed in terminal ileum with ___) → ___ anemia

Cholecystectomy vs. ileal resection: which causes steatorrhea? ___. Why the other does not: ___

Practice Questions — GI14 USMLE-Style

Q1. A patient with acetaminophen overdose develops acute liver failure. Liver biopsy shows centrilobular necrosis. Which zone of the hepatic acinus is injured, and why is it preferentially affected?

A. Zone 1 — first to receive toxic metabolites via portal blood
B. Zone 2 — intermediate oxygen tension increases susceptibility
C. Zone 3 — highest CYP2E1 concentration + lowest O₂ tension
D. Zone 3 — direct toxin absorption from the central vein
E. Zone 1 — highest oxygen exposure activates APAP to NAPQI

✅ C — Zone 3 (centrilobular) is preferentially damaged by acetaminophen because it has the highest concentration of CYP2E1 (the enzyme that converts APAP to toxic NAPQI) and the lowest O₂ tension (last to receive blood from the portal triad). At therapeutic doses, NAPQI is detoxified by glutathione; overdose depletes glutathione → centrilobular necrosis. Zone 1 is preferentially damaged by viral hepatitis (first to receive virus-containing portal blood).

Q2. A patient with cirrhosis develops confusion, asterixis, and a flapping hand tremor. Labs show NH₃ of 180 μg/dL. Which two medications would you prescribe and why?

A. Lactulose + rifaximin
B. Neomycin + vancomycin
C. Lactulose + metronidazole
D. Cholestyramine + lactulose
E. Rifaximin + proton pump inhibitor

✅ A — Hepatic encephalopathy results from impaired urea cycle → NHaccumulation → CNS toxicity (asterixis, confusion). Lactulose: acidifies colon → converts NH₃ → NH₄⁺ (trapped, non-absorbable) + cathartic effect to expel it. Rifaximin: non-absorbable antibiotic → reduces ammonia-producing gut bacteria. Together they reduce serum ammonia. Neomycin was historically used but rifaximin has better evidence and safety profile.

Q3. A 45-year-old woman with cirrhosis has ascites (SAAG = 1.4 g/dL) and bilateral leg edema. A classmate says "the edema is from low albumin — remove albumin-rich fluid and she'll get better." What is wrong with this reasoning?

A. SAAG <1.1 indicates malignancy, not portal hypertension
B. Ascites requires portal hypertension in addition to ↓oncotic pressure; removing fluid doesn't address portal HTN
C. Bilateral leg edema in cirrhosis is always from DVT, not albumin
D. Albumin levels are always normal in cirrhosis because the liver compensates
E. Ascites in cirrhosis is due to infection, not portal hypertension

✅ B — SAAG ≥1.1 g/dL indicates a portal hypertension etiology (here SAAG = 1.4). Ascites requires portal hypertension as the primary driver — hypoalbuminemia alone (e.g., nephrotic syndrome) causes leg edema but NOT ascites. The triad for cirrhotic ascites: (1) portal HTN → ↑hydrostatic pressure, (2) hypoalbuminemia → ↓oncotic pressure, (3) splanchnic vasodilation + RAAS activation → Na/H₂O retention. Treating only albumin without addressing portal HTN is insufficient.

Q4. A physician prescribes atorvastatin to a patient with an LDL of 190 mg/dL. The patient asks why the drug helps. Which sequence correctly describes statin's mechanism?

A. Statin blocks LDLR → less LDL cleared → LDL falls because less is produced
B. Statin blocks HMG-CoA reductase → ↓hepatic cholesterol → upregulate LDLR → ↑LDL clearance from plasma
C. Statin blocks MRP2 → ↓cholesterol secretion into bile → LDL falls
D. Statin activates SREBP-1c → ↑cholesterol synthesis but ↑LDL receptor too → net LDL falls
E. Statin blocks lipoprotein lipase → TG cleared faster → LDL falls indirectly

✅ B — Statins competitively inhibit HMG-CoA reductase → ↓endogenous hepatic cholesterol synthesis → hepatocytes sense low intracellular cholesterol → SREBP-2 activated → upregulate LDL receptors (LDLR) on hepatocyte surface → ↑LDL uptake from plasma → ↓serum LDL by 30–50%. Side effects: myopathy (↑CK), rhabdomyolysis (rare), transaminase elevation. Familial hypercholesterolemia = LDLR mutation → statins less effective alone.

Q5. A 28-year-old man has recurrent mild jaundice after fasting and a recent illness. Bilirubin = 3.0 mg/dL (all indirect). Direct bilirubin, LFTs, CBC, and hemolysis panel are all normal. What is the diagnosis and mechanism?

A. Dubin-Johnson syndrome — defective MRP2 secretion of conjugated bilirubin
B. Gilbert syndrome — mildly reduced UGT1A1 promoter activity triggered by fasting/stress
C. Crigler-Najjar Type II — severely reduced UGT1A1 activity
D. Hemolytic anemia — RBC destruction overwhelming conjugation
E. Rotor syndrome — defective OATP1B1/B3 uptake of bilirubin

✅ B — Gilbert syndrome is the most common congenital cause of unconjugated hyperbilirubinemia (5–10% of population). UGT1A1 promoter has a TATA box repeat → mildly reduced activity (30–50%) → unconjugated (indirect) bilirubin accumulates, especially during fasting, illness, exercise, or stress. Completely benign. No treatment needed. Key distinguisher from hemolysis: no anemia, no ↑reticulocytes, no ↑LDH, normal haptoglobin.

Q6. A patient presents with dark urine, pale clay-colored stools, and intense pruritus for 3 weeks. Labs: total bilirubin 12 mg/dL (direct 10, indirect 2), ALP ↑↑↑, GGT ↑↑, ALT/AST mildly elevated. What type of jaundice is this, and what additional sign should you look for?

A. Hemolytic jaundice — look for splenomegaly and reticulocytosis
B. Obstructive jaundice — look for Courvoisier sign (palpable non-tender gallbladder)
C. Hepatocellular jaundice — look for spider angiomata and asterixis
D. Neonatal jaundice — look for unconjugated hyperbilirubinemia only
E. Gilbert syndrome — look for fasting as a precipitant

✅ B — Classic obstructive (post-hepatic) jaundice: ↑↑direct bili, dark urine (bilirubinuria — conjugated bili filtered by kidneys), pale/clay stools (no bilirubin reaching gut → no stercobilin), pruritus (bile salt skin deposition), markedly ↑ALP (cholestasis marker). Courvoisier sign (painless jaundice + palpable non-tender gallbladder) = pancreatic head malignancy until proven otherwise (gallstones cause fibrosis/scarring of GB wall, preventing distension — Courvoisier's law).

Q7. A patient undergoes extensive terminal ileal resection for Crohn's disease. Which of the following is NOT an expected consequence?

A. Steatorrhea
B. Fat-soluble vitamin deficiency (A, D, E, K)
C. Bile acid (cholerheic) diarrhea
D. Vitamin B₁₂ deficiency → megaloblastic anemia
E. Improved fat digestion due to ↑hepatic bile acid synthesis compensating for lost reabsorption

✅ E — The liver CANNOT compensate adequately through increased synthesis. The hepatic capacity to synthesize bile acids de novo is limited (~0.5 g/day). Terminal ileal resection eliminates the ASBT transporter responsible for 95% reabsorption → rapid depletion of the bile acid pool → insufficient intraluminal bile acid concentration → steatorrhea + fat-soluble vitamin deficiency + bile acid diarrhea + B₁₂ deficiency. This is a key distinction from cholecystectomy (reservoir only, bile acid pool intact).

Q8. A medical student is tested on bile secretion regulation. She writes: "Both CCK and secretin contract the gallbladder." What is incorrect in her statement, and what does secretin actually do?

A. She's correct — both hormones contract the gallbladder
B. CCK relaxes the gallbladder; secretin contracts it
C. Only CCK contracts the gallbladder; secretin stimulates ductal HCO₃⁻ secretion but does NOT contract the gallbladder
D. Secretin contracts the gallbladder only in the fasted state
E. Neither CCK nor secretin contracts the gallbladder — vagal stimulation is the sole driver

✅ C — The classic trap: secretin does NOT contract the gallbladder. CCK (released by I cells when fat/protein enters duodenum) → contracts gallbladder smooth muscle + relaxes sphincter of Oddi → bile delivered to duodenum. Secretin (released by S cells when H⁺ enters duodenum) → stimulates cholangiocytes and pancreatic ductal cells to secrete HCO₃⁻-rich fluid → alkalinizes duodenum. Secretin = "the bicarb hormone," not the bile-contracting hormone.

Vessel	Flow Rate & % of Total	O₂ Saturation	Content / Source
Portal Vein
Hepatic Artery

Zone	Location	O₂ Status	Primary Functions	Vulnerable to
Zone 1 (Periportal)
Zone 2 (Midzonal)
Zone 3 (Centrilobular)

Feature	Ascites	Peripheral Edema
Location
Required component
SAAG

Type	Example Causes	LFTs / Liver Function
Pre-hepatic
Intra-hepatic (sinusoidal)
Post-hepatic

Overview of the Liver — Active Recall