Biliary tree and gallbladder

What it normally does

• Bile is mostly water, with bile salts, phospholipid (mainly phosphatidylcholine), cholesterol, conjugated bilirubin and electrolytes. Cholesterol does not dissolve in water. It stays in solution only because bile salts and phospholipid wrap it into mixed micelles and vesicles, so what keeps bile liquid is a ratio, not a concentration: enough bile salt and phospholipid for the cholesterol present. Bile salts are also the osmotic engine that pulls water into the canaliculus (bile salt-dependent flow), so bile secretion is driven by the same molecules that keep it stable.

  Explains why gallstones form when the liver secretes cholesterol out of proportion to bile salt and phospholipid — and why the classic risk factors (obesity, rapid weight loss, oestrogen, ileal disease) all shift that one ratio.

• Between meals the sphincter of Oddi is tonically contracted, so most bile backs up the cystic duct into the gallbladder (the gallbladder still empties partially with each migrating motor complex, so filling between meals is not absolute). The gallbladder holds only about 30-50 mL, but it actively absorbs sodium out of the bile with water following, concentrating it five- to tenfold. It is a muscular bag with one narrow outlet — the cystic duct, roughly 3 mm wide with a spiral mucosal fold (valve of Heister) — and a dependent pouch at the neck (Hartmann pouch) where a stone naturally comes to rest.

  Explains why stones form and grow in the gallbladder rather than in the ducts, and why a stone wedged at the neck produces a closed, distending, inflamed organ — acute cholecystitis.

• Fat and amino acids arriving in the duodenum release cholecystokinin (CCK) from I cells. CCK contracts gallbladder smooth muscle through CCK1 receptors and relaxes the sphincter of Oddi, with vagal reinforcement, so concentrated bile squirts into the duodenum through the ampulla — which the pancreatic duct also drains into, a shared final common channel. Bile salts emulsify fat and carry the products, plus the fat-soluble vitamins A, D, E and K, to the brush border in micelles. About 95% of bile salts are then recaptured in the terminal ileum by a specific transporter (ASBT) and returned to the liver in the portal vein; the pool cycles about two to three times per meal, six to ten times a day (enterohepatic circulation).

  Explains pain 30-60 minutes after a fatty meal, pale greasy stool and a rising INR when bile cannot reach the gut, gallstones after ileal resection or in Crohn disease, and why a stone at the shared ampulla can inflame the pancreas.

• Old red cells yield haem, which becomes unconjugated bilirubin: water-insoluble, carried on albumin, and therefore not filtered by the kidney. The hepatocyte conjugates it with glucuronic acid (UGT1A1), which makes it water-soluble, then pumps it into the canaliculus (MRP2). In the colon, bacteria convert it to urobilinogen and then stercobilin — that is what makes stool brown.

  Explains the whole picture of obstructive jaundice in one step: conjugated bilirubin is water-soluble, so when it cannot get out through the duct it refluxes into blood and spills into urine — dark urine, pale stool, yellow patient.

What goes wrong

• Gallstones (cholelithiasis) and biliary colic← from “Bile is mostly water, with bile salts, phospho…”

  The liver secretes cholesterol out of proportion to bile salt and phospholipid, so bile becomes supersaturated. Crystals nucleate, and a gallbladder that empties sluggishly holds them long enough to grow into stones. That is the 80% — cholesterol and mixed stones. The rest are pigment stones: black calcium bilirubinate stones, which form in the gallbladder in chronic haemolysis or cirrhosis, and brown stones, which form mostly within the ducts in infected, stagnant bile — above a stricture, after biliary instrumentation, or with parasitic infestation. Pain happens when a stone rolls into the neck or cystic duct as the gallbladder contracts — classically after a fatty, CCK-releasing meal, though attacks also wake patients at night with no meal at all: the gallbladder squeezes against a blocked outlet, wall tension rises, and it hurts until the stone falls back.

  A ratio problem, not a calcium problem. The classic risk factors — female sex, middle age, obesity, parity and oestrogen — plus rapid weight loss, very low energy diets and bariatric surgery, and terminal ileal disease or resection, which strips bile salts out of the pool. Silent stones are left alone; symptomatic stones come out.

  You would find: Severe constant epigastric or right upper quadrant pain 30-60 minutes after a fatty meal, often to the right shoulder tip or interscapular region, with nausea and vomiting; it plateaus and settles within a few hours. Despite the name it is not colicky. Between attacks the examination and the bloods are normal — that is the point. Ultrasound is the test: a mobile echogenic focus with an acoustic shadow. About 10-15% of Australian adults have stones and roughly 80% never know; only about 1-2% per year become symptomatic, and once symptomatic they usually recur. Cholecystectomy is one of the commonest general surgical operations in the country. Obesity and type 2 diabetes both drive stone formation and both fall disproportionately on Aboriginal and Torres Strait Islander communities; combined with the distance to elective surgical lists, people in remote areas more often present first with a complication than for a planned operation.

• Acute cholecystitis← from “Between meals the sphincter of Oddi is tonical…”

  A stone impacts at the neck or in the cystic duct and stays. The gallbladder cannot empty but keeps secreting mucus, so it distends. Retained concentrated bile salts and lysolecithin injure the mucosa — this starts as chemical, not bacterial, inflammation — and wall oedema then impairs perfusion in the cystic artery territory. Bacteria from the duodenum colonise the stagnant bile secondarily. Left long enough: empyema, gangrene, perforation. If the stone in the neck or cystic duct compresses the common hepatic duct from outside, you get jaundice from a gallbladder stone (Mirizzi syndrome). About 5-10% of cases have no stone at all — acalculous cholecystitis in the critically ill, ventilated or parenterally fed patient, where nothing is eaten, so no CCK is released and the gallbladder does not empty — but wall hypoperfusion in shock and sepsis matters at least as much as the stasis, which is why this form gangrenes and perforates so readily.

  Biliary colic that would not stop. Pain over 6 hours plus fever plus a positive Murphy equals cholecystitis; a jaundiced patient with these features has a duct problem too until proven otherwise.

  You would find: Right upper quadrant pain now lasting more than 6 hours, with fever, anorexia and local tenderness. Murphy sign: the patient catches their breath as the inflamed fundus meets your fingers on inspiration. Neutrophil leucocytosis and CRP up. Crucially the bilirubin is usually normal or only slightly raised — the common bile duct is open. Ultrasound: stone at the neck, wall thicker than 3 mm, pericholecystic fluid, sonographic Murphy sign. Management is admission, fluids, analgesia, antibiotics and cholecystectomy, usually on that admission and ideally within the first few days.

• Choledocholithiasis and obstructive (post-hepatic) jaundice← from “Old red cells yield haem, which becomes unconj…”

  A stone passes the cystic duct and lodges in the common bile duct — or a tumour of the pancreatic head or the duct itself compresses it. Conjugated bilirubin is already water-soluble, so when it cannot reach the gut it refluxes across the hepatocyte into blood and is filtered into urine. Nothing reaches the colonic bacteria, so no stercobilin is made. Bile salts also never reach the duodenum, so fat and the fat-soluble vitamins A, D, E and K are not absorbed. Back-pressure and retained bile acids make duct epithelium produce more alkaline phosphatase.

  Dark urine plus pale stool means the block is after conjugation. Painless progressive jaundice with weight loss is pancreatic head cancer until proven otherwise; painful fluctuating jaundice is a stone.

  You would find: Yellow sclerae, dark urine, pale stool, itch. Cholestatic bloods: bilirubin and ALP up, GGT up with it (which confirms the ALP is biliary and not bone), transaminases comparatively modest. Prolonged INR that corrects with parenteral vitamin K — that is malabsorption, not liver failure, and it is a genuinely useful discriminator. A palpable, non-tender gallbladder in a jaundiced patient points to malignancy rather than stones, because a stone-diseased gallbladder is fibrosed and cannot distend (Courvoisier). Ultrasound finds gallbladder stones reliably but detects only about a quarter to a half of duct stones, so a normal ultrasound does not exclude one — a duct dilated above 6 mm is the clue, and MRCP or endoscopic ultrasound settles it. ERCP is how the stone comes out.

• Ascending cholangitis← from “Fat and amino acids arriving in the duodenum r…”

  Bile normally flows one way and flushes the duct clean. Block the outlet and the duct becomes a closed space; gut organisms — Escherichia coli, Klebsiella, Enterococcus, anaerobes — colonise the stagnant column. Because there is no exit, pressure inside the duct rises above the pressure in the hepatic sinusoids and forces bacteria and endotoxin back into the sinusoids and the bloodstream (cholangiovenous reflux). That is why this becomes septic shock in hours rather than staying a local infection, and why antibiotics alone do not fix it: nothing sterilises a pressurised, undrained space.

  Obstruction plus infection under pressure. The definitive treatment is drainage; antibiotics buy time. Any jaundiced patient with fever and rigors is a cholangitis until the duct is imaged — do not wait for the full triad.

  You would find: Charcot triad — fever with rigors, right upper quadrant pain, jaundice — is highly specific but insensitive: the complete triad is present in only about a quarter of patients in modern series (older textbook figures of 50-70% overstate it), so its absence does not exclude cholangitis. Add hypotension and confusion and it is Reynolds pentad, meaning a patient in trouble now. Cholestatic LFTs, high neutrophils and lactate, positive blood cultures. Treatment is resuscitation, antibiotics and urgent biliary decompression by ERCP, typically within 24 hours and sooner if shocked. In rural and remote Australia this is a retrieval problem as much as a medical one, because ERCP lives in tertiary centres.

• Gallstone pancreatitis← from “Fat and amino acids arriving in the duodenum r…”

  The bile duct and the pancreatic duct share a final common channel at the ampulla. A small stone passing through — usually one that has already dropped into the duodenum by the time you look — transiently obstructs that channel, pancreatic secretion backs up, and trypsinogen is activated inside the acinar cell instead of in the gut. The gland then digests itself. Small stones and a wide cystic duct are the dangerous combination, because they are the ones that travel.

  One anatomical junction explains it. Lipase makes the diagnosis, ALT names the cause, ultrasound finds the stones, and the operation prevents the next one.

  You would find: Severe constant epigastric pain boring through to the back, relieved by sitting forward, with vomiting. Lipase more than three times the upper limit of normal. An ALT above about 150 U/L (roughly three times normal) in acute pancreatitis points hard at a gallstone cause. Gallstones and alcohol account for most cases in Australia. There is no drug that treats the pancreatitis — fluids, analgesia and early enteral nutrition — and the definitive treatment is removing the gallbladder, ideally on the same admission for mild disease, because recurrence rates before cholecystectomy are high.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.