ICU · first-part-physiology

GI and Hepatic Physiology — Comprehensive (Splanchnic Circulation, Liver Metabolism, Gut Barrier, Bile)

Also known as GI physiology · Hepatic physiology · Splanchnic circulation · Liver metabolism · Gut barrier · Bacterial translocation · Bilirubin metabolism · Bile formation · Gut origin of MODS · Hepatic drug metabolism · Enterohepatic circulation · Gut microbiome

GI and hepatic physiology — the integrated splanchnic circulation, liver metabolic functions, gut barrier, and bile physiology that underpin multiple organ dysfunction in critical illness. SPLANCHNIC CIRCULATION: receives ~25% of cardiac output — mesenteric arteries (coeliac, SMA, IMA) supply the gut → gut capillaries → PORTAL VEIN (75% of liver blood flow, oxygen-poor, nutrient-rich) + HEPATIC ARTERY (25%, oxygen-rich) form the liver's DUAL blood supply → hepatic sinusoids → central vein → hepatic vein → IVC. The gut is a LOW-FLOW vulnerable organ — in shock (any type) splanchnic vasoconstriction (alpha-1, angiotensin II, vasopressin) diverts flow to heart/brain → mesenteric ischaemia → mucosal injury → bacterial/endotoxin translocation across the disrupted gut barrier → portal bacteremia → Kupffer cell activation → cytokine storm (TNF-alpha, IL-1, IL-6) → systemic inflammatory response → multiple organ dysfunction syndrome (MODS) — the 'gut motor' of MODS. LIVER METABOLIC FUNCTIONS: (1) GLUCOSE HOMEOSTASIS — glycogen storage (100 g), glycogenolysis (glycogen → glucose-1-phosphate → glucose), gluconeogenesis (lactate, amino acids, glycerol → glucose); the liver is the glycostat — maintains plasma glucose 4-7 mmol/L. (2) PROTEIN SYNTHESIS — albumin (oncotic pressure, drug binding), ALL clotting factors EXCEPT von Willebrand factor (made by endothelium) and factor VIII (mostly endothelial) — factors II, VII, IX, X (vitamin K-dependent), I (fibrinogen), V, XI, XII, XIII; complement proteins; acute-phase proteins (CRP, ferritin). (3) DRUG METABOLISM — PHASE I: cytochrome P450 (CYP3A4, CYP2D6, CYP1A2, CYP2C9) — oxidation/reduction/hydrolysis (adds or exposes a functional group, often makes drug MORE active or reactive); PHASE II: conjugation (glucuronidation, sulphation, acetylation, glutathione conjugation) — attaches a polar group → water-soluble metabolite for renal/biliary excretion. BOTH phases are IMPAIRED in cirrhosis (reduced CYP activity + portosystemic shunting reduces first-pass metabolism → drug accumulation). (4) BILIRUBIN METABOLISM — senescent RBCs (reticuloendothelial system) → haem oxygenase cleaves haem → biliverdin → biliverdin reductase → UNCONJUGATED (indirect) bilirubin — FAT-SOLUBLE, albumin-bound, cannot be excreted in urine → hepatocyte uptake → conjugated with GLUCURONIC ACID (UGT1A1) → CONJUGATED (direct) bilirubin — WATER-SOLUBLE → excreted in bile → gut bacteria deconjugate → UROBILINOGEN → most excreted in stool (STERCOBILIN = brown colour); ~10% reabsorbed (enterohepatic circulation) → re-excreted in bile OR urine as urobilinogen. (5) AMMONIA METABOLISM — gut bacteria produce NH3 from protein/urea → portal blood → hepatocyte UREA CYCLE (carbamoyl phosphate synthetase-I → ornithine cycle) → urea → kidney excretion. In liver failure the urea cycle FAILS → NH3 accumulates → crosses blood-brain barrier → astrocyte glutamine synthesis (glutamine synthetase) → osmotic astrocyte swelling → cerebral oedema + hepatic encephalopathy. GUT BARRIER: the single-cell-thick intestinal epithelium + mucus layer (goblet cells) + tight junctions (claudins, occludin, zonula occludens) + antimicrobial peptides (defensins, RegIIIgamma) + gut-associated lymphoid tissue (GALT — Peyer's patches, lamina propria lymphocytes, secretory IgA) + commensal microbiome (10^13 organisms) — DISRUPTED in critical illness by ischaemia/reperfusion, antibiotics (dysbiosis), proton pump inhibitors (bacterial overgrowth), altered motility (ileus), parenteral nutrition → bacterial translocation → MODS. BILE: hepatocytes synthesise primary bile acids (cholic, chenodeoxycholic acid) from cholesterol → conjugated with glycine/taurine → secreted into canaliculi → gallbladder storage → released post-prandially (CCK) → emulsify dietary fat (form mixed micelles) → 95% reabsorbed in terminal ileum (enterohepatic circulation, 6-10 cycles/day) → also the excretory route for conjugated bilirubin, cholesterol, and lipophilic drug metabolites. CHOLESTASIS (intrahepatic [sepsis, drugs, PBC] or extrahepatic [gallstones, stricture, tumour]) → conjugated bilirubin back-up → jaundice + pruritus (bile acid skin deposition) + malabsorption of fat-soluble vitamins (A, D, E, K).