Gastroenterology: Anatomy Physiology Pharmacology

• Anatomy: The Gut Wall and Enteric Nervous System | Mouth, Oesophagus and Stomach | Small Intestine | Large Intestine, Rectum and Anus | Blood Supply of the Gut | Portal Venous System | Liver | Gallbladder and Bile Ducts | Pancreas | Peritoneum and Abdominal Regions
• Physiology: Swallowing | Gastric Acid and Mucosal Protection | Digestion and Absorption | Iron, B12, Folate and Vitamins | Fluid, Electrolytes and Diarrhoea | Motility, Defecation and Vomiting | Gut Hormones | What the Liver Does | Bilirubin and Bile Acids | Gut Defences and the Microbiome | Portal Hypertension and Ascites | Normal Values and LFT Patterns
• Pharmacology: Acid Suppression | Helicobacter pylori Eradication | Antiemetics | Laxatives | Antidiarrhoeals and IBS Drugs | IBD Drugs — Aminosalicylates, Steroids and Immunomodulators | IBD Drugs — Biologics and Small Molecules | Drugs for Liver Disease | Drugs for Alcohol-Related Disease | Pancreatic Enzymes and Bile Acid Drugs | Prescribing in Liver Disease | Drug-Induced Liver Injury | Drugs That Harm the Gut
• Revision: Drug Reference Table | Spot the Answer | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🍽️ Gastrointestinal anatomy, physiology and pharmacology — the gut digests food, absorbs nutrients and water, and gets rid of waste; the liver processes almost everything absorbed, including most drugs. Knowing the blood supply, the portal circulation, where things are absorbed and what the liver does explains most GI symptoms, blood tests and complications. Most GI drugs reduce acid, stop vomiting, change bowel movement, calm gut inflammation or treat liver disease.
Your four questions for every drug: How does it work? What is it used for? What are the important side effects and safety issues? What does it interact with, and how is it monitored?

The Gut Wall and Enteric Nervous System

• Four layers from inside out:
  • Mucosa — epithelium (absorbs and secretes), lamina propria (immune cells), muscularis mucosae. Most cancers and inflammation start here.
  • Submucosa — blood vessels, lymphatics, the submucosal (Meissner's) plexus (controls secretion and blood flow).
  • Muscularis propria — inner circular and outer longitudinal muscle, with the myenteric (Auerbach's) plexus between them (controls movement).
  • Serosa (peritoneum) — or adventitia where there is no peritoneum (oesophagus, retroperitoneal parts) — the oesophagus has no serosa, so cancer spreads and leaks more easily.
• Enteric nervous system — the "gut brain" (about as many neurons as the spinal cord); works on its own but is adjusted by the autonomic nerves:
  • Parasympathetic (vagus, and sacral nerves S2–S4 for the distal colon) — increases movement and secretion.
  • Sympathetic — slows movement, closes sphincters, reduces blood flow.
  • Loss of the myenteric plexus — achalasia (oesophagus), Hirschsprung's disease (colon, from birth), Chagas disease.
• Interstitial cells of Cajal — the gut's pacemaker cells (origin of GIST tumours — KIT-positive, treated with imatinib).
• Visceral pain — poorly localised, felt in the midline according to embryological origin (foregut — epigastric; midgut — around the umbilicus; hindgut — suprapubic); becomes localised when the parietal peritoneum is inflamed (e.g. appendicitis moving to the right iliac fossa).

Mouth, Oesophagus and Stomach

• Oesophagus — about 25 cm long, from C6 (cricopharyngeus) to the stomach at about T10–T11; about 40 cm from the incisors to the gastro-oesophageal junction at endoscopy.
  • Upper third — skeletal muscle; lower third — smooth muscle (so myasthenia and stroke affect the top; achalasia and scleroderma the bottom).
  • Three narrowings where food and tablets stick — cricopharyngeus (15 cm), where the aortic arch and left main bronchus cross (25 cm), and the diaphragm (40 cm).
  • Lower oesophageal sphincter — a high-pressure zone helped by the diaphragm crura; weakened by hiatus hernia, smoking, alcohol, fatty food, pregnancy, calcium channel blockers, nitrates and anticholinergics → reflux.
  • Lining — squamous epithelium; in Barrett's oesophagus it changes to columnar (intestinal metaplasia) from chronic acid — risk of adenocarcinoma.
  • Lower oesophageal veins link portal and systemic veins — varices in portal hypertension.
• Stomach — cardia, fundus, body, antrum and pylorus:
  • Parietal cells (body and fundus) — acid and intrinsic factor.
  • Chief cells — pepsinogen.
  • G cells (antrum) — gastrin.
  • ECL cells — histamine (stimulates parietal cells).
  • D cells — somatostatin (inhibits acid).
  • Mucous cells — protective mucus and bicarbonate.
• Blood supply of the stomach — all from the coeliac trunk (left and right gastric along the lesser curve; gastroepiploic arteries along the greater curve; short gastrics to the fundus). A posterior duodenal ulcer can erode the gastroduodenal artery → major bleeding.
• Vagus nerve — stimulates acid secretion and gastric emptying (vagotomy reduces both).

Small Intestine

• About 6 metres long — duodenum (about 25 cm), jejunum (about 2.5 m), ileum (about 3.5 m). A huge surface area (folds, villi and microvilli — about 30 m²) for absorption.
• Duodenum — C-shaped around the head of the pancreas; mostly retroperitoneal; the bile duct and pancreatic duct open at the ampulla of Vater (second part). Brunner's glands make alkaline mucus.
• Jejunum — thicker wall, more folds, long vasa recta; absorbs most nutrients.
• Ileum — more fat in the mesentery, lymphoid tissue (Peyer's patches); the terminal ileum absorbs vitamin B12 and bile acids (the reason Crohn's disease and ileal resection cause B12 deficiency and bile acid diarrhoea).
• Ileocaecal valve — slows emptying into the colon and limits backflow of bacteria (its removal increases bacterial overgrowth).
• Villus atrophy (coeliac disease) — flattened villi, fewer brush border enzymes → malabsorption (iron, folate, calcium) and lactose intolerance; mainly affects the duodenum and jejunum, so duodenal biopsy confirms it.
• Meckel's diverticulum — remnant of the vitelline duct; "rule of 2s" (2% of people, 2 feet from the ileocaecal valve, 2 inches long, may contain 2 types of ectopic tissue — gastric and pancreatic); can cause painless bleeding in children (technetium scan).
• Short bowel syndrome — usually under about 200 cm of small bowel left; loss of fluid, magnesium and nutrients; may need parenteral nutrition.

Large Intestine, Rectum and Anus

• About 1.5 metres — caecum and appendix, ascending, transverse, descending and sigmoid colon, rectum, anal canal.
• Intraperitoneal parts (have a mesentery — can twist) — transverse and sigmoid colon (sigmoid volvulus, especially in older people with chronic constipation), caecum in some people (caecal volvulus). Ascending and descending colon are retroperitoneal.
• Features — taeniae coli (three bands of longitudinal muscle, which meet at the appendix base), haustra, appendices epiploicae.
• Appendix — base at McBurney's point (one-third of the way from the anterior superior iliac spine to the umbilicus); tip position varies (retrocaecal appendicitis can cause atypical pain).
• Functions — absorbs water and salt (about 1–1.5 L a day), stores faeces, ferments fibre into short-chain fatty acids (fuel for colon cells).
• Rectum — about 12–15 cm; stretch receptors give the urge to defecate.
• Dentate (pectinate) line in the anal canal — the boundary between gut-derived and skin-derived tissue:
  • Above — columnar lining, visceral nerves (painless) — internal haemorrhoids are painless; adenocarcinoma; drains to internal iliac and portal veins and nodes.
  • Below — squamous lining, somatic nerves (painful) — anal fissures, external haemorrhoids and squamous cancer are painful; lymph drains to the inguinal nodes.
• Anal sphincters — internal (smooth muscle, involuntary — tight in fissures, relaxed by GTN and diltiazem) and external (skeletal, voluntary — pudendal nerve; damaged in childbirth → faecal incontinence).

Blood Supply of the Gut

• Coeliac trunk branches — left gastric, splenic, common hepatic.
• Watershed areas (between two arterial territories) — the splenic flexure and the rectosigmoid junction — most vulnerable to ischaemic colitis in low blood pressure (left-sided pain and bloody diarrhoea in older people).
• Acute mesenteric ischaemia — usually SMA embolism (AF) or thrombosis; pain out of proportion to the examination, raised lactate (late); CT angiography urgently.
• Chronic mesenteric ischaemia — "intestinal angina": pain 15–30 minutes after eating, fear of food, weight loss.
• Rectum and anus — superior rectal (from IMA), middle rectal and inferior rectal arteries (from internal iliac).
• Gut blood flow is about 25% of cardiac output at rest, rising after meals; it falls early in shock (the gut is sacrificed to protect the brain and heart).

Portal Venous System

• Portal vein — formed behind the neck of the pancreas by the superior mesenteric vein and the splenic vein (the inferior mesenteric vein usually joins the splenic vein).
• Carries nutrient-rich blood from the gut, spleen and pancreas to the liver — about 75% of liver blood flow (the hepatic artery supplies the other 25%, but about half the oxygen).
• First-pass metabolism — drugs absorbed from the gut go through the liver before reaching the body — so some drugs are much less active when swallowed (e.g. GTN is given under the tongue; morphine and propranolol have low oral availability).
• Portosystemic anastomoses — places where portal and systemic veins connect; they enlarge in portal hypertension:
  • Lower oesophagus and gastric fundus (left gastric to azygos veins) — varices — life-threatening bleeding.
  • Umbilicus (paraumbilical to abdominal wall veins) — caput medusae.
  • Rectum (superior rectal to middle and inferior rectal) — rectal varices (different from haemorrhoids).
  • Retroperitoneum — relevant in surgery.
• Portal vein thrombosis — in cirrhosis, cancer, pancreatitis, clotting disorders (myeloproliferative — JAK2); Budd–Chiari syndrome — blocked hepatic veins (pain, ascites, big liver).
• Hepatic veins drain the liver into the IVC (three main veins — right, middle and left).

Liver

• The largest internal organ (about 1.5 kg) — under the right ribs, held by the falciform ligament; the bare area touches the diaphragm.
• Couinaud segments — 8 functional segments, each with its own portal and arterial branch and bile duct — allows surgical removal of parts of the liver. The right and left halves are divided by a line through the gallbladder and IVC (Cantlie's line), not the falciform ligament.
• Porta hepatis — the portal vein, hepatic artery and common bile duct (the portal triad) enter and leave here.
• Microscopic structure — the acinus:
  • Blood flows from the portal triads (zone 1 — most oxygen) through the sinusoids to the central vein (zone 3 — least oxygen).
  • Zone 3 has the most CYP450 enzymes and least oxygen — first damaged by paracetamol (NAPQI), ischaemia (shock liver) and alcohol.
  • Zone 1 — damaged by some toxins and in viral hepatitis.
• Cells:
  • Hepatocytes — metabolism, synthesis, bile production.
  • Kupffer cells — macrophages that filter bacteria from portal blood.
  • Hepatic stellate cells — store vitamin A; become activated and lay down collagen in liver injury → fibrosis and cirrhosis.
  • Sinusoidal endothelial cells — leaky "windows" let proteins pass between blood and hepatocytes.
• Regeneration — the healthy liver can regrow after up to about two-thirds is removed (the basis of living donor transplants).
• Liver pain — from stretching of the capsule (hepatitis, congestion in heart failure, Budd–Chiari).

Gallbladder and Bile Ducts

• Bile duct tree — right and left hepatic ducts → common hepatic duct → joined by the cystic duct → common bile duct (CBD; normal diameter under about 6 mm, larger in older people and after cholecystectomy) → passes behind the duodenum and through the head of the pancreas → joins the pancreatic duct at the ampulla of Vater, controlled by the sphincter of Oddi.
• Gallbladder — stores and concentrates bile (about 30–50 mL); contracts after fatty meals (stimulated by CCK) — the reason biliary pain follows fatty food.
• Calot's triangle — cystic duct, common hepatic duct and the underside of the liver; contains the cystic artery (usually from the right hepatic artery) — identified in cholecystectomy to avoid bile duct injury.
• Gallbladder pain — felt in the right upper quadrant and epigastrium, referred to the right shoulder tip (diaphragm irritation) or between the shoulder blades. Murphy's sign — pain stops breath-in when pressing under the right ribs (acute cholecystitis).
• Gallstones in the CBD — obstructive jaundice, cholangitis (Charcot's triad — fever, jaundice, RUQ pain), pancreatitis (stone at the ampulla).
• Courvoisier's law — a palpable, non-tender gallbladder with painless jaundice is unlikely to be gallstones — think cancer of the pancreatic head or distal bile duct.

Pancreas

• Position — retroperitoneal (except the tail), behind the stomach at about L1–L2: head in the curve of the duodenum, uncinate process behind the superior mesenteric vessels, neck over the portal vein, body across the aorta, tail at the splenic hilum.
• Pancreatic pain radiates to the back and is eased by sitting forward.
• Exocrine function — about 1.5 L a day of juice:
  • Bicarbonate (from duct cells, stimulated by secretin) neutralises stomach acid.
  • Enzymes (from acinar cells, stimulated by CCK) — lipase, amylase, and proteases made as inactive precursors (trypsinogen is activated by enteropeptidase in the duodenum; trypsin then activates the others).
  • Acute pancreatitis — enzymes activated too early inside the pancreas → self-digestion; main causes are gallstones and alcohol (also high triglycerides, high calcium, drugs, ERCP, trauma).
• Exocrine insufficiency — appears when about 90% of function is lost — fatty, pale, floating stools (steatorrhoea), weight loss, fat-soluble vitamin deficiency; measure faecal elastase. Causes — chronic pancreatitis, cancer, cystic fibrosis, pancreatic surgery.
• Endocrine function — the islets (insulin, glucagon) — covered in the Endocrine Anatomy, Physiology and Pharmacology chapter.
• Pancreatic cancer in the head blocks the bile duct early (painless jaundice); in the body and tail it presents late (back pain, weight loss, new diabetes).

Peritoneum and Abdominal Regions

• Peritoneum — two layers: parietal (lines the abdominal wall — sharp, well-localised pain) and visceral (covers organs — dull, poorly localised pain). The space between normally holds a little fluid; excess fluid is ascites.
• Peritonitis — inflamed parietal peritoneum: guarding, rigidity, rebound tenderness, lying still; from a perforation (free gas under the diaphragm on erect chest X-ray) or infection.
• Retroperitoneal organs ("SAD PUCKER") — suprarenal (adrenal) glands, aorta and IVC, duodenum (most), pancreas (most), ureters, colon (ascending and descending), kidneys, oesophagus, rectum. Retroperitoneal bleeding may show as flank bruising (Grey Turner's sign).
• Greater omentum — hangs from the stomach; walls off infection ("the abdominal policeman"); site of cancer deposits ("omental cake").
• Lesser sac — behind the stomach; fluid collects here in pancreatitis (pseudocysts).
• Nine regions — right and left hypochondrium, epigastrium, right and left lumbar (flank), umbilical, right and left iliac fossa, suprapubic (hypogastrium) — used to describe where pain or masses are.
• Inguinal canal — indirect hernias pass through the deep ring (lateral to the inferior epigastric vessels); direct hernias push through the posterior wall (Hesselbach's triangle, medial to the vessels); femoral hernias (below and lateral to the pubic tubercle) are most likely to strangulate.

Swallowing

• Three phases:
  • Oral (voluntary) — chewing, forming a bolus, pushing it back with the tongue.
  • Pharyngeal (reflex, under 1 second) — soft palate closes the nose, larynx rises and the epiglottis covers the airway, breathing stops briefly, the upper oesophageal sphincter opens. Controlled by the brainstem (cranial nerves V, VII, IX, X, XII).
  • Oesophageal — peristalsis carries the bolus down; the lower oesophageal sphincter relaxes.
• Oropharyngeal dysphagia (difficulty starting a swallow, coughing, choking, nasal regurgitation) — stroke, Parkinson's, motor neurone disease, myasthenia, dementia — risk of aspiration pneumonia; speech and language therapy assessment.
• Oesophageal dysphagia (food sticks after swallowing):
  • Solids then liquids, progressive — a stricture or cancer (urgent endoscopy).
  • Solids and liquids from the start — a motility problem (achalasia — failure of the lower sphincter to relax; spasm).
  • Food bolus impaction in a young man with atopy — eosinophilic oesophagitis.
• Tablets and swallowing — some drugs cause pill oesophagitis if they stick (doxycycline, bisphosphonates, potassium, iron, NSAIDs) — take with plenty of water while upright.

Gastric Acid and Mucosal Protection

• Acid secretion — parietal cells pump hydrogen ions into the stomach via the proton pump (H+/K+ ATPase) — the final common pathway (the target of PPIs).
• Three stimulants acting on parietal cells:
  • Acetylcholine (vagus, M3 receptors).
  • Gastrin (from G cells — stimulated by protein and stomach stretch).
  • Histamine (from ECL cells, H2 receptors — the target of H2 blockers).
• Phases — cephalic (sight and smell of food — vagus), gastric (food in the stomach — about two-thirds of acid), intestinal.
• Inhibition — somatostatin, low stomach pH (negative feedback on gastrin), fat and acid in the duodenum.
• Acid's jobs — kills microbes, activates pepsin, helps absorb iron, B12 (releases it from food) and calcium. Low acid (PPIs, atrophic gastritis) → infections (C. difficile, Salmonella), bacterial overgrowth, poor iron and B12 absorption; high gastrin.
• Mucosal protection — mucus and bicarbonate layer, tight cell junctions, rapid cell renewal, good blood flow, and prostaglandins (made by COX-1 — they increase mucus, bicarbonate and blood flow).
• Why NSAIDs cause ulcers — they block COX-1, so protective prostaglandins fall; aspirin also damages cells directly and stops platelets working (more bleeding).
• Helicobacter pylori — a spiral bacterium that survives acid by making urease (turns urea into ammonia — the basis of the urea breath test); causes gastritis, duodenal and gastric ulcers, gastric cancer and MALT lymphoma.
• Zollinger–Ellison syndrome — a gastrin-secreting tumour (gastrinoma, sometimes with MEN 1) → multiple or unusual ulcers, diarrhoea; very high gastrin off PPIs.

Digestion and Absorption

• Carbohydrates:
  • Salivary and pancreatic amylase break starch into sugars; brush border enzymes (lactase, sucrase, maltase) finish the job.
  • Glucose and galactose are absorbed with sodium by SGLT1 — the reason oral rehydration solution contains both sugar and salt (glucose pulls sodium and water in, even in cholera).
  • Fructose is absorbed by a separate carrier (GLUT5) — limited capacity (fructose and sorbitol cause diarrhoea in large amounts).
  • Lactase deficiency (common worldwide; after gastroenteritis or coeliac disease) — undigested lactose → bloating, wind and diarrhoea.
• Proteins — pepsin (stomach), then trypsin, chymotrypsin and others (pancreas), then brush border peptidases; absorbed as amino acids and small peptides.
• Fats:
  • Bile acids emulsify fat into small droplets; pancreatic lipase breaks triglycerides into fatty acids and monoglycerides.
  • These form micelles with bile acids and are absorbed in the jejunum.
  • Inside cells, fats are rebuilt and packaged into chylomicrons, which enter the lymphatics (lacteals) — not the portal vein.
  • Fat malabsorption (no bile, no lipase, damaged lining) → steatorrhoea and deficiency of the fat-soluble vitamins A, D, E and K (bruising and raised INR from vitamin K deficiency).
• Malabsorption — think where:
  • Lumen — no bile (cholestasis), no enzymes (pancreatic insufficiency), bacterial overgrowth.
  • Lining — coeliac disease, Crohn's, infections (Giardia), radiation enteritis, short bowel.
  • After the lining — lymphatic blockage (lymphangiectasia, lymphoma).

Iron, B12, Folate and Vitamins

• Refeeding syndrome — on restarting feeding after starvation, insulin drives phosphate, potassium and magnesium into cells → dangerous low levels (heart failure, arrhythmias, weakness); start feeding slowly and replace electrolytes and thiamine (NICE CG32).

Fluid, Electrolytes and Diarrhoea

• Daily fluid traffic — about 2 L drunk plus about 7 L secreted (saliva, gastric juice, bile, pancreatic juice, intestinal juice) = about 8–9 L entering the small bowel; the small bowel absorbs about 7 L and the colon about 1–1.5 L; only about 100–200 mL leaves in stool.
• Electrolytes in GI losses:
  • Vomiting or NG drainage — loss of acid and chloride → metabolic alkalosis, low chloride, low potassium (mostly from kidney losses driven by aldosterone).
  • Diarrhoea — loss of bicarbonate and potassium → metabolic acidosis (normal anion gap), low potassium.
  • High-output stomas and fistulas — sodium and magnesium loss, dehydration, AKI.
  • Villous adenoma of the rectum — potassium-rich mucus (low potassium).
• Types of diarrhoea:
  • Osmotic — unabsorbed substances pull water in (lactose intolerance, magnesium, lactulose, sorbitol, malabsorption) — stops when fasting; raised stool osmotic gap.
  • Secretory — the gut actively secretes chloride and water (cholera toxin raises cAMP and opens CFTR chloride channels; VIPoma, carcinoid, bile acids, laxative misuse) — continues when fasting; large volume.
  • Inflammatory — blood, pus, fever (IBD, Shigella, Campylobacter, C. difficile).
  • Motility-related — IBS, hyperthyroidism, diabetic autonomic neuropathy.
• Oral rehydration solution uses SGLT1 (glucose–sodium co-transport) — works even in secretory diarrhoea, because this pathway is undamaged.

Motility, Defecation and Vomiting

• Peristalsis — co-ordinated contraction behind and relaxation in front of the bolus (enteric reflex).
• Gastric emptying — liquids empty quickly; solids are ground first (about 2–4 hours); fat, acid and high calorie meals slow emptying. Gastroparesis (diabetes, opioids, GLP-1 agonists, after surgery) — early fullness, vomiting of old food.
• Migrating motor complex — "housekeeping" waves every 90–120 minutes between meals that sweep debris and bacteria along (driven by motilin — erythromycin is a motilin agonist, used to speed gastric emptying); loss → bacterial overgrowth.
• Gastrocolic reflex — eating triggers colonic movement (urge to open the bowels after meals — used in bowel training, strong in IBS).
• Defecation — rectal stretch → urge; internal sphincter relaxes (reflex); the external sphincter and puborectalis relax voluntarily; abdominal straining. Problems — constipation (slow transit, outlet obstruction — dyssynergia), faecal incontinence (sphincter damage, neurological), overflow diarrhoea from faecal impaction in older people.
• Vomiting — co-ordinated by the vomiting centre in the brainstem, with inputs that explain antiemetic choice:
  • Chemoreceptor trigger zone (area postrema — outside the blood–brain barrier; D2, 5-HT3, NK1 receptors) — drugs, toxins, uraemia, high calcium, pregnancy.
  • Gut (vagal 5-HT3 receptors) — chemotherapy, radiotherapy, gastroenteritis, bowel obstruction, gastric stasis.
  • Vestibular system (H1 and muscarinic receptors) — motion sickness, vertigo, labyrinthitis.
  • Cortex — anxiety, smells, raised intracranial pressure, anticipation.

Gut Hormones

What the Liver Does

• Makes proteins:
  • Albumin (half-life about 3 weeks — falls slowly; also low in inflammation, nephrotic syndrome, malnutrition) — low albumin → oedema and ascites.
  • Clotting factors — most of them, including the vitamin K-dependent factors II, VII, IX and X. Factor VII has the shortest half-life (about 6 hours), so the INR rises within hours in acute liver failure — the best quick marker of liver function. (The liver also makes anticoagulant proteins — so patients with cirrhosis are not "auto-anticoagulated" and still get clots.)
• Glucose control — stores glycogen, makes glucose (gluconeogenesis) — hypoglycaemia in acute liver failure.
• Ammonia removal — the urea cycle turns ammonia from gut bacteria and protein breakdown into urea; liver failure and portosystemic shunting → high ammonia → hepatic encephalopathy. Urea is often low in liver failure.
• Fat and cholesterol — makes cholesterol, lipoproteins and bile acids; fat build-up causes fatty liver (MASLD).
• Bilirubin — conjugation and excretion into bile (see the next section).
• Drug and hormone metabolism:
  • Phase 1 — oxidation by cytochrome P450 enzymes (CYP3A4, 2D6, 2C9, 2C19, 1A2) — the site of many drug interactions (inducers and inhibitors).
  • Phase 2 — conjugation (glucuronidation, sulfation, acetylation, glutathione) to make drugs water-soluble for excretion.
  • Breaks down oestrogen (gynaecomastia and spider naevi in cirrhosis), aldosterone and insulin.
• Storage — glycogen, vitamins A, D and B12, iron (haemochromatosis), copper (Wilson's disease).
• Immune role — Kupffer cells clear gut bacteria; liver failure → infection risk (spontaneous bacterial peritonitis, sepsis).
• Signs of chronic liver disease explained — jaundice (bilirubin), bruising (clotting factors), oedema and ascites (albumin, portal pressure), confusion and flap (ammonia), spider naevi, palmar erythema and gynaecomastia (oestrogen), splenomegaly and low platelets (portal hypertension).

Bilirubin and Bile Acids

• Bilirubin pathway:
  • Old red cells are broken down → haem → unconjugated bilirubin (not water-soluble; carried on albumin; not in urine).
  • The liver conjugates it (enzyme UGT1A1) → conjugated bilirubin (water-soluble) → bile → gut.
  • Gut bacteria convert it to urobilinogen → stercobilin (makes stool brown); some urobilinogen is reabsorbed and passed in urine.
• Types of jaundice:
  • Pre-hepatic (haemolysis, Gilbert's syndrome) — unconjugated; no bilirubin in urine; normal stool and urine colour. Gilbert's (reduced UGT1A1, about 5% of people) — mild jaundice with fasting or illness; harmless; affects irinotecan metabolism.
  • Hepatic (hepatitis, cirrhosis) — mixed.
  • Post-hepatic (obstructive) — gallstones, cancer of the pancreatic head, strictures, PSC — conjugated; dark urine, pale stools, itch (bile salts in skin); raised ALP and GGT; dilated ducts on ultrasound.
• Bile — bile acids, cholesterol, phospholipids, bilirubin and bicarbonate; about 500–600 mL a day. Gallstones form when bile has too much cholesterol relative to bile acids (cholesterol stones), or too much bilirubin (pigment stones — haemolysis).
• Enterohepatic circulation — about 95% of bile acids are reabsorbed in the terminal ileum and recycled to the liver several times a day.
  • Ileal disease or resection → bile acid diarrhoea (colon irritated by bile acids — treat with colestyramine or colesevelam); larger losses → fat malabsorption, gallstones and oxalate kidney stones.
  • Drugs also undergo enterohepatic recycling (e.g. some oestrogens, mycophenolate) — interrupted by antibiotics and bile acid binders.

Gut Defences and the Microbiome

• Barriers — stomach acid, mucus, tight junctions, rapid lining turnover (every 3–5 days), antimicrobial peptides (Paneth cells), secretory IgA, gut-associated lymphoid tissue (Peyer's patches), Kupffer cells in the liver.
• The microbiome — trillions of bacteria, mainly in the colon: digest fibre into short-chain fatty acids, make vitamin K and some B vitamins, train the immune system, and block harmful bacteria.
• Disrupted microbiome:
  • Antibiotics (especially clindamycin, cephalosporins, co-amoxiclav and quinolones) and PPIs → C. difficile infection.
  • Small intestinal bacterial overgrowth — slow motility (diabetes, scleroderma), blind loops after surgery, low acid; bloating, diarrhoea, B12 deficiency (bacteria use it) with raised folate (bacteria make it).
  • Bacterial translocation in cirrhosis → spontaneous bacterial peritonitis.
• Faecal microbiota transplant — for recurrent C. difficile infection (NICE).
• IBD — an abnormal immune response to gut bacteria in genetically susceptible people (e.g. NOD2 in Crohn's); smoking worsens Crohn's but is "protective" in UC.
• Coeliac disease — an immune reaction to gluten (gliadin) in people with HLA-DQ2 or DQ8; tissue transglutaminase is the autoantigen (tTG-IgA test — check total IgA, as IgA deficiency gives false negatives; patient must be eating gluten).

Portal Hypertension and Ascites

• Portal hypertension — raised pressure in the portal vein (hepatic venous pressure gradient over 5 mmHg; over 10 mmHg is clinically significant — varices and ascites develop; bleeding risk over 12 mmHg).
• Causes — cirrhosis (most), portal vein thrombosis (pre-hepatic), Budd–Chiari syndrome and right heart failure (post-hepatic), schistosomiasis (worldwide).
• Mechanism — scarred liver resists flow, plus increased blood flow into the portal system from splanchnic vasodilatation (nitric oxide) — so treatment both lowers resistance and reduces inflow (non-selective beta-blockers reduce cardiac output via beta-1 and allow splanchnic vasoconstriction via beta-2 blockade; terlipressin constricts splanchnic vessels).
• Consequences — varices, ascites, splenomegaly (low platelets), encephalopathy (blood bypasses the liver), portal hypertensive gastropathy.
• How ascites forms — portal hypertension raises pressure in the sinusoids → fluid leaks; splanchnic vasodilatation lowers the effective blood volume → RAAS, sympathetic system and ADH are activated → the kidneys retain sodium and water (low urine sodium) and dilute the blood (hyponatraemia). The basis of treatment with spironolactone and salt restriction.
• Hepatorenal syndrome — extreme kidney vasoconstriction from the same process → AKI without kidney damage; treated with terlipressin and albumin.
• Serum–ascites albumin gradient (SAAG) — serum albumin minus ascitic albumin:
  • 11 g/L or more — portal hypertension (cirrhosis, heart failure, Budd–Chiari).
  • Under 11 g/L — not portal hypertension (peritoneal cancer, TB, pancreatitis, nephrotic syndrome).
• Spontaneous bacterial peritonitis — ascitic neutrophils over 250 cells/mm³; may be silent — tap the ascites of every cirrhotic patient admitted.

Normal Values and LFT Patterns