Liver physiology and bilirubin
Liver physiology, bilirubin and bile
The liver receives a dual blood supply, makes most plasma proteins, buffers blood glucose and clears bilirubin and many drugs into bile. CPSP asks you to classify jaundice, explain inherited and neonatal hyperbilirubinaemia, follow bile salts round the enterohepatic circulation, and explain how liver-specific contrast agents and nuclear tracers work.
Blood supply and flow
- The portal vein brings about 75% of liver blood flow (nutrient-rich); the hepatic artery brings about 25% (but half the oxygen). A meal increases portal flow, which falsely raises liver stiffness on elastography, so patients fast first.
- Portal venous gas flows out to the periphery (within 2 cm of the capsule); biliary gas stays central near the porta, because bile flows towards the hilum.
- Portal vein embolisation diverts portal flow to the future remnant, which hypertrophies before major hepatectomy.
- After a TIPS, portal blood bypasses hepatocytes, so ammonia escapes clearance (encephalopathy).
- Normal hepatic vein Doppler is triphasic (transmitted right atrial pulsations); a stiff cirrhotic liver damps them to a monophasic trace.
Metabolic and synthetic functions
| Function | Detail | Clinical or imaging link |
|---|---|---|
| Glucose | Glycogenolysis for the first 12–24 hours of fasting, then gluconeogenesis | Hypoglycaemia in liver failure; preterm and growth-restricted babies have small glycogen stores |
| Proteins | Albumin, clotting factors (II, VII, IX, X need vitamin K), transferrin, binding globulins | Immunoglobulins are not made in the liver (globulin rises in cirrhosis) |
| Urea cycle | Converts ammonia to urea | Low urea with high ammonia in advanced cirrhosis |
| Lipids | VLDL export; LDL receptors (fewer in hypothyroidism) | Oestrogen raises VLDL output in late pregnancy; fatty liver when fatty acid delivery and lipogenesis rise |
| SHBG | Synthesis suppressed by insulin | More unbound oestrogen and testosterone in obesity and PCOS |
| Kupffer cells | Phagocytose particles | Tc-99m sulphur colloid scan; in cirrhosis, "colloid shift" to spleen and marrow |
- On unenhanced CT the normal liver is denser than the spleen; fatty liver is lower than the spleen.
- In pregnancy alkaline phosphatase rises from the placental isoenzyme, with normal bilirubin, ALT and bile acids.
Bilirubin metabolism
- Haem from old red cells (and from a large haematoma) becomes biliverdin, then unconjugated bilirubin, which is lipid-soluble and travels bound to albumin.
- Hepatocyte uptake (OATP transporters) is followed by conjugation with glucuronic acid by UDP-glucuronyl transferase (UGT1A1), then excretion into canaliculi by MRP2, the rate-limiting step.
- Gut bacteria convert conjugated bilirubin to urobilinogen; some is reabsorbed and appears in urine, the rest becomes stercobilin (stool colour).
- Conjugated bilirubin is water-soluble and appears in urine. Unconjugated bilirubin is not, but the free fraction crosses membranes: the blood–brain barrier (kernicterus) and the placenta (the mother clears fetal bilirubin, so babies with haemolysis are not jaundiced until after birth).
- In prolonged cholestasis some bilirubin binds albumin covalently (delta bilirubin), so jaundice fades slowly after the obstruction is relieved.
Types of jaundice
| Feature | Pre-hepatic (haemolysis, haematoma) | Hepatocellular | Obstructive |
|---|---|---|---|
| Main bilirubin | Unconjugated | Mixed | Conjugated |
| Urine bilirubin | Absent (acholuric) | Present | Present, dark urine |
| Urine urobilinogen | Increased | Variable | Absent |
| Stool | Normal or dark | Normal | Pale |
| Enzymes | Normal | ALT high | ALP and GGT high; itching |
Inherited and hormonal causes
| Condition | Defect | Pattern |
|---|---|---|
| Gilbert syndrome | Reduced UGT1A1 | Mild unconjugated rise with fasting or illness |
| Crigler–Najjar | Absent (type 1) or severe lack of UGT1A1 | Severe unconjugated, kernicterus risk |
| Dubin–Johnson | MRP2 defect | Conjugated; black liver |
| Cholestasis of pregnancy, combined pill | Oestrogen impairs canalicular export | Itching, raised bile acids; bile acids stimulate fetal colonic motility (meconium) |
- Neonatal jaundice: immature UGT, short red cell life and more enterohepatic return. Poor breastfeeding slows stools, increasing reabsorption. Congenital hypothyroidism delays UGT maturation.
Bile and the enterohepatic circulation
- Primary bile acids (cholic, chenodeoxycholic) are conjugated with glycine or taurine, forming bile salts that make micelles for fat and fat-soluble vitamin absorption.
- The gallbladder concentrates bile by active Na⁺ absorption with water following, so bile salts rise but osmolality stays the same. CCK contracts it; fasting for about 6 hours lets it fill for ultrasound.
- About 95% of bile salts are reabsorbed in the terminal ileum and return in portal blood.
| Ileal loss | Effect |
|---|---|
| Short (under about 100 cm) | Bile acids reach the colon and cause secretory diarrhoea |
| Long (over about 100 cm) | Pool too small for micelles: steatorrhoea; unbound oxalate absorbed, causing oxalate stones |
| Any significant length | B12 deficiency |
- Obstructive jaundice prevents vitamin K absorption; the INR corrects with IV vitamin K.
- Most gallstones are cholesterol stones with little calcium, so they are not seen on plain X-ray.
Agents that follow hepatocyte pathways
- Gadoxetate enters hepatocytes through OATP and leaves via MRP2; normal liver is bright on the 20-minute hepatobiliary phase. Focal nodular hyperplasia contains hepatocytes with poorly draining ductules, so it stays bright.
- HIDA scan: the tracer shares the bilirubin uptake pathway, so very high bilirubin reduces uptake. Phenobarbital beforehand induces excretion, helping to separate biliary atresia from neonatal hepatitis.
- Indocyanine green is excreted unchanged into bile; retention at 15 minutes measures hepatic function before resection.
- Iodinated contrast in the gallbladder a day after CT in kidney failure is vicarious hepatic excretion.
Remember Pale stools, dark urine and no urinary urobilinogen mean bile is not reaching the gut.
Exam trap Gilbert syndrome raises unconjugated bilirubin; Dubin–Johnson raises conjugated bilirubin with a black liver.
Exam trap The liver makes albumin and clotting factors but not immunoglobulins.
Test yourself on this topic
5 of the 24 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Only about 10–15% of gallstones are radio-opaque on a plain abdominal radiograph. What is the main reason most gallstones are radiolucent?
Answer: Most are cholesterol with little calcium
Most gallstones in adults are cholesterol or mixed stones, formed when bile is supersaturated with cholesterol relative to bile salts and lecithin. Cholesterol contains little calcium, so only stones with enough calcium are radio-opaque. Black pigment stones, made of calcium bilirubinate in haemolysis and cirrhosis, are more often visible. By contrast about 90% of renal stones contain calcium and are radio-opaque.
Gallstones on X-ray
- Mostly cholesterol stones
- Only 10–15% radio-opaque
- Calcium content makes them visible
- Ultrasound: echo and shadow
Remember A normal X-ray does not exclude gallstones.
Exam trap Relying on a plain film to exclude gallstones.
Why the other options are wrong
- Bile absorbs the X-ray beam Bile has soft-tissue density.
- The gallbladder lies behind the ribs Ribs do not hide them on X-ray.
- Stones dissolve in concentrated bile Stones do not dissolve in bile.
- Bowel gas always hides the gallbladder Gas may overlap but is not the main reason.
A man with advanced cirrhosis has low albumin, low clotting factors and low transferrin. His total globulin, however, is raised. Which plasma protein is not made by the liver?
Answer: Immunoglobulin G
The liver makes most plasma proteins, including albumin, clotting factors, fibrinogen, transferrin and many complement factors. Immunoglobulins are made by plasma cells. In cirrhosis, gut antigens bypass Kupffer cell clearance through portosystemic shunts and stimulate antibody production, so immunoglobulins often rise while liver-made proteins fall. A reversed albumin:globulin ratio is therefore common.
Liver proteins
- Liver makes albumin, clotting factors
- Also transferrin, fibrinogen
- Immunoglobulins: plasma cells
- Cirrhosis: globulin rises
Remember Low albumin plus high globulin: think cirrhosis.
Exam trap A high total protein in cirrhosis does not mean good liver synthesis.
Why the other options are wrong
- Albumin Made by the liver.
- Fibrinogen Made by the liver.
- Transferrin Made by the liver.
- Prothrombin Made by the liver.
Before a major hepatectomy, a man has an indocyanine green clearance test: 15 minutes after injection, 25% of the dye remains in his blood (normal under 10%). Which property makes ICG a measure of liver function?
Answer: It is excreted unchanged into bile
Indocyanine green binds plasma proteins, is taken up almost entirely by hepatocytes and is excreted unchanged into bile without enterohepatic recirculation. Its clearance therefore depends on hepatic blood flow and hepatocyte uptake and excretion. High retention at 15 minutes indicates reduced functional reserve and a higher risk of liver failure after resection. It is not handled by the kidney.
ICG clearance
- Taken up by hepatocytes only
- Excreted unchanged into bile
- No enterohepatic return
- High retention: poor reserve
Remember ICG retention: a quick measure of liver reserve.
Exam trap Low hepatic blood flow also raises ICG retention.
Why the other options are wrong
- It is filtered and secreted by the kidney It is not cleared by the kidneys.
- It is conjugated with glucuronic acid It is not conjugated.
- It is metabolised by CYP2E1 It is not metabolised.
- It is stored in Kupffer cells Kupffer cells do not clear it.
Two patients have gas in the liver on CT. In one, branching gas reaches within 2 cm of the liver capsule; in the other, gas is confined to central branching channels near the porta hepatis. Why does portal venous gas lie peripherally?
Answer: Portal blood flows out to the periphery
Portal venous blood flows from the hilum outwards into ever smaller branches towards the sinusoids, so gas bubbles in the portal vein are carried to the periphery of the liver. Bile flows the other way, from peripheral ductules towards the hilum, so air in the bile ducts (pneumobilia) collects centrally. Peripheral portal venous gas suggests serious disease such as bowel ischaemia, while pneumobilia is common after sphincterotomy.
Gas in the liver
- Portal flow: hilum to periphery
- Portal gas: peripheral
- Bile flow: periphery to hilum
- Pneumobilia: central
Remember Gas goes where the fluid flows.
Exam trap Peripheral liver gas is an emergency sign; central gas is often benign.
Why the other options are wrong
- Bile flows from the periphery to the hilum Explains central pneumobilia, not peripheral gas.
- Gas rises to the anterior capsule Position changes do not explain the branching pattern.
- Portal veins lie outside the liver They branch within the liver.
- Hepatic veins drain to the capsule Hepatic veins drain to the IVC, not the capsule.
A man with cirrhosis has a transjugular intrahepatic portosystemic shunt (TIPS) placed for refractory ascites, with good flow from the portal vein into the hepatic vein. A week later he is confused with a flapping tremor. What is the mechanism?
Answer: Portal blood bypasses the hepatocytes
Portal blood carries ammonia and other nitrogenous toxins from gut bacteria. Normally periportal hepatocytes convert ammonia to urea and perivenous cells capture the rest as glutamine. A TIPS sends portal blood straight into the hepatic vein, bypassing much of this clearance, so ammonia reaches the brain, where astrocytes swell as they make glutamine. Hepatic encephalopathy occurs in a significant minority after TIPS.
TIPS and encephalopathy
- Portal blood full of ammonia
- Liver makes urea and glutamine
- TIPS bypasses hepatocytes
- Ammonia reaches the brain
Remember A shunt that saves the belly can cloud the mind.
Exam trap A well-functioning shunt increases, not lowers, the risk of encephalopathy.
Why the other options are wrong
- Bleeding into the brain from the procedure No focal signs or haemorrhage are described.
- Contrast nephropathy causing uraemia Uraemia would not give this picture after a working shunt.
- Stent infection with sepsis No fever or sepsis.
- Hepatic artery occlusion by the stent Not a usual complication.
Where this sits in the CPSP syllabus
- Diagnostic Radiology, Paper 2: Gastrointestinal physiology, Liver physiology and bile
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