Liver functions and bilirubin
Liver functions, bilirubin metabolism, jaundice and liver failure
Liver functions, the route of bilirubin from red cell to stool, and how blood, urine and stool findings classify jaundice, for FCPS Part 1. Also covers inherited hyperbilirubinaemias, kernicterus, encephalopathy and hepatitis serology.
Liver functions
- Synthesis: albumin (low in chronic disease, causing oedema and ascites); clotting factors, including the vitamin K-dependent II, VII, IX and X; fibrinogen; transport proteins; angiotensinogen; acute phase proteins.
- Carbohydrate: after an overnight fast, hepatic glycogenolysis keeps glucose normal for the first 12–24 hours; gluconeogenesis takes over as glycogen runs out. Acute liver failure (for example paracetamol) loses both, causing hypoglycaemia, which marks severe disease and needs continuous dextrose.
- Protein and nitrogen: the urea cycle turns ammonia into urea.
- Lipid: cholesterol, lipoprotein and bile acid synthesis. Alcohol shifts NADH/NAD⁺ so fatty acid oxidation falls and triglyceride builds up: steatosis (fatty liver) is the earliest and commonest alcohol change, reversible with abstinence, followed by alcoholic hepatitis and cirrhosis.
- Storage: glycogen, vitamins A, D and B12, iron, copper.
- Drug metabolism: phase I (cytochrome P450 oxidation, reduction, hydrolysis) and phase II (glucuronidation, sulphation, acetylation, glutathione conjugation).
- Hormones: inactivates oestrogen (spider naevi, gynaecomastia, palmar erythema in cirrhosis), aldosterone and insulin; 25-hydroxylates vitamin D.
- Immune: Kupffer cells clear bacteria and endotoxin from portal blood.
Structure and zones
- Blood arrives from the portal vein (about 75% of flow) and hepatic artery (25%, but about half the oxygen), mixes in sinusoids and drains to the central vein.
- Acinus (Rappaport): zone 1 (periportal) has the best oxygen and is hit first by viral hepatitis and portal toxins; zone 3 (centrilobular) has the least oxygen and the most P450, so it is damaged first by ischaemia, paracetamol, alcohol and right heart failure.
- Stellate (Ito) cells in the space of Disse store vitamin A and become fibroblasts in cirrhosis.
- First-pass metabolism and shunting: high-extraction oral drugs (propranolol, morphine, lidocaine) are largely removed on first pass. In cirrhosis with portosystemic collaterals, blood bypasses hepatocytes, so oral bioavailability rises sharply and a normal dose causes exaggerated bradycardia and hypotension.
Bilirubin metabolism
- Macrophages (mainly splenic) break down haem: haem oxygenase gives biliverdin, iron and CO; biliverdin reductase gives unconjugated bilirubin. About 80% comes from senescent red cells.
- Unconjugated bilirubin is water-insoluble, carried bound to albumin, and never appears in urine. Being lipid-soluble, free unconjugated bilirubin can cross the immature blood–brain barrier.
- Hepatocytes take it up through an organic anion transporter (OATP), then UDP-glucuronyl transferase (UGT1A1) conjugates it with glucuronic acid.
- Conjugated bilirubin is water-soluble and actively secreted into the canaliculus by MRP2, the rate-limiting step.
- Colonic bacteria convert it to urobilinogen; some is reabsorbed and excreted in urine, most becomes stercobilin, which colours stool.
- Large haematoma or haemolysis: breakdown of haem increases bilirubin load beyond conjugating capacity, giving mild unconjugated jaundice with normal enzymes and no bilirubin in urine, typically a few days after major bruising.
- Rifampicin competes for hepatic uptake and transiently raises unconjugated bilirubin in the first days of TB treatment without hepatitis. A rising ALT with jaundice on anti-TB drugs is true hepatotoxicity: stop the drugs and reintroduce them one at a time.
Classifying jaundice
| Feature | Pre-hepatic (haemolysis) | Hepatocellular | Post-hepatic (obstructive) |
|---|---|---|---|
| Bilirubin type | Unconjugated | Both | Conjugated |
| Urine bilirubin | Absent (acholuric) | Present | Present, dark urine |
| Urine urobilinogen | Increased | Variable | Absent |
| Stools | Normal or dark | Normal or pale | Pale, clay-coloured |
| ALP, GGT | Normal | Mildly raised | Markedly raised |
| ALT, AST | Normal | Markedly raised | Mildly raised |
| Extra clues | Low haptoglobin, high LDH and reticulocytes | Low albumin, high INR | Itching (bile salts), high cholesterol |
- Haemolytic causes in exam stems: Coombs-positive haemolysis on methyldopa; G6PD deficiency after primaquine or other oxidant antimalarials; falciparum malaria; delayed transfusion reaction about a week after transfusion; sickle cell disease with leg ulcers.
- Cholestasis: primary biliary cholangitis (middle-aged women, anti-mitochondrial antibodies), carcinoma of the pancreatic head, strictures, stones, drugs.
- Obstetric (intrahepatic) cholestasis: severe itching of palms and soles in the third trimester without rash, raised serum bile acids and mildly raised ALT; the main risk is stillbirth, so delivery is planned.
- Vitamin K in obstruction: without bile, fat-soluble vitamin K is malabsorbed, so the PT is prolonged. If it corrects with parenteral vitamin K, the cause is malabsorption; if not, hepatocellular synthesis has failed.
Inherited hyperbilirubinaemias
| Condition | Defect | Bilirubin | Features |
|---|---|---|---|
| Gilbert syndrome | Reduced UGT1A1 (promoter variant) | Unconjugated, mild | Very common; jaundice with fasting, illness or stress; benign |
| Crigler–Najjar type I | Absent UGT1A1 | Unconjugated, very high | Kernicterus in infancy; liver transplant |
| Crigler–Najjar type II | Severely reduced UGT1A1 | Unconjugated | Responds to phenobarbital |
| Dubin–Johnson | Defective canalicular MRP2 | Conjugated | Black liver; benign |
| Rotor syndrome | Defective hepatic storage | Conjugated | Benign, no pigment |
Neonatal jaundice and kernicterus
- Physiological jaundice appears after 24 hours and settles in 1–2 weeks: large red cell mass with shorter survival, immature UGT and increased enterohepatic circulation. Breastfed babies may have mild, prolonged unconjugated jaundice.
- Jaundice in the first 24 hours is always pathological: Rh or ABO haemolysis, G6PD deficiency, spherocytosis.
- Kernicterus: free unconjugated bilirubin deposits in the basal ganglia (globus pallidus), hippocampus and brainstem nuclei, causing lethargy, hypertonia, arching (opisthotonus), a high-pitched cry, then athetoid cerebral palsy and deafness.
- Prolonged jaundice beyond 2 weeks with pale stools and conjugated bilirubin suggests biliary atresia.
- Phototherapy converts unconjugated bilirubin to water-soluble isomers excreted without conjugation.
Liver tests and liver failure
- ALT is more liver-specific than AST; AST:ALT above 2 suggests alcohol. ALP comes from bile ducts, bone and placenta; raised GGT confirms a hepatic source.
- Prothrombin time/INR is the best single marker of synthetic function and prognosis in acute liver failure, because factor VII has the shortest half-life (about 6 hours). Albumin changes over weeks. PT/INR also monitors warfarin (target INR 2–3 for most indications).
- Hepatic encephalopathy: gut-derived ammonia escapes hepatic clearance. In the brain, astrocytes detoxify ammonia to glutamine, which accumulates osmotically and swells them (cerebral oedema), and neurotransmission is disturbed. Look first for a precipitant: infection (including SBP), GI bleeding, constipation, dehydration, electrolyte imbalance or sedatives. Treat with lactulose and rifaximin.
- Spontaneous bacterial peritonitis: ascitic neutrophils above 250/mm³; IV ceftriaxone (a third-generation cephalosporin) plus albumin.
- Hepatorenal syndrome: renal vasoconstriction in cirrhosis; rising creatinine, very low urine sodium, normal kidneys, no response to albumin and stopping diuretics; treat with terlipressin plus albumin.
- Severe alcoholic hepatitis: Maddrey discriminant function above 32; prednisolone may improve short-term survival once infection and bleeding are excluded.
Viral hepatitis essentials
| Virus | Spread | Course |
|---|---|---|
| A | Faecal–oral (street food, water) | Acute only |
| E | Faecal–oral | Acute; severe, even fatal, in pregnancy |
| B | Blood, sexual, vertical | Chronic in 5% of adults, 90% of neonates |
| C | Blood: unsafe injections and reused needles in Pakistan | Mostly chronic (about 75–85%) |
- HBV serology: HBsAg means infection; IgM anti-HBc means acute infection; HBeAg means high replication and infectivity; anti-HBs means immunity. HBsAg, IgM anti-HBc and HBeAg positive with anti-HBs negative is acute hepatitis B, highly infectious.
Remember Unconjugated: albumin-bound, urine-free, brain-toxic. Conjugated: water-soluble, dark urine, pale stool.
Exam trap Unconjugated bilirubin never appears in urine, however high it is.
How FCPS asks about this
- Enzyme conjugating bilirubin: UDP-glucuronyl transferase (UGT1A1); reduced in Gilbert syndrome.
- Haemolytic (prehepatic) jaundice: unconjugated bilirubin, raised urine urobilinogen, no urine bilirubin, low haptoglobin.
- Obstructive jaundice: conjugated bilirubin, dark urine, pale stools, no urobilinogen, high ALP; PT corrects with parenteral vitamin K.
- Black liver with mild conjugated hyperbilirubinaemia: Dubin–Johnson, defective MRP2.
- Kernicterus: unconjugated bilirubin deposited in the basal ganglia.
- Best test of severity in acute liver failure: PT/INR.
- Paracetamol damage: zone 3; hypoglycaemia from lost glycogenolysis and gluconeogenesis.
Test yourself on this topic
5 of the 83 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
A man with cirrhosis and ascites has rising creatinine, very low urine sodium and no improvement after stopping diuretics and giving albumin for 2 days. The kidneys look normal on ultrasound. What is the treatment?
Answer: Terlipressin with albumin
Hepatorenal syndrome is functional kidney failure in advanced liver disease: splanchnic vasodilatation reduces effective blood volume, and intense renal vasoconstriction follows. Diagnosis requires no response to volume expansion with albumin, no shock or nephrotoxins and normal kidney imaging. Treatment is a vasoconstrictor (terlipressin) with albumin; liver transplant is definitive.
Hepatorenal syndrome
- Functional kidney failure
- Splanchnic vasodilatation
- No response to albumin
- Terlipressin + albumin; transplant
Remember Cirrhosis with failing but normal-looking kidneys: HRS.
Exam trap Exclude SBP, which often triggers HRS.
Why the other options are wrong
- High-dose furosemide Diuretics worsen it.
- Kidney biopsy and steroids Kidney structure is normal.
- NSAIDs Worsen kidney function.
- More large-volume paracentesis only Does not treat it.
An elderly woman has a raised alkaline phosphatase with normal GGT, bilirubin and transaminases. What is the most likely source of the ALP?
Answer: Bone
ALP comes mainly from liver (biliary epithelium) and bone (osteoblasts), with smaller amounts from intestine and placenta (raised in the third trimester). A raised ALP with a raised GGT points to the hepatobiliary tree; a raised ALP with normal GGT points to bone: Paget disease (very high ALP, normal calcium), osteoblastic metastases (prostate), osteomalacia, healing fractures, hyperparathyroidism, and growing children. ALP isoenzymes can confirm the source.
Isolated ALP rise
- ALP + GGT ↑ → liver (cholestasis)
- ALP ↑, GGT normal → bone
- Bone causes: Paget, metastases, osteomalacia, growth
- Also: pregnancy (placental)
Remember GGT tells you whether ALP came from the liver.
Why the other options are wrong
- Bile ducts GGT would also be raised.
- Hepatocytes Transaminases would rise.
- Pancreas Not a source of ALP.
- Kidney Minor source.
A 55-year-old man with alcoholic cirrhosis, albumin 24 g/L and ascites needs an umbilical hernia repair. His INR is 2.2 and stays at 2.1 after three days of intravenous vitamin K. What is the cause of the raised INR?
Answer: Failing hepatic synthesis of factors
Most clotting factors, including the vitamin K-dependent factors II, VII, IX and X and fibrinogen, are made by hepatocytes. In cirrhosis, the failing liver cannot make enough of them even when vitamin K is supplied, so parenteral vitamin K does not correct the INR. This failure to correct separates synthetic failure from vitamin K malabsorption due to cholestasis. A high INR in cirrhosis is a marker of liver function and a component of the Child–Pugh and MELD scores.
INR in cirrhosis
- Liver makes clotting factors
- No correction with IV vitamin K
- Marker of synthetic function
- Part of Child–Pugh and MELD
Remember Vitamin K fails: the factory is broken.
Exam trap A high INR in cirrhosis does not mean the patient is protected from thrombosis.
Why the other options are wrong
- Malabsorption of vitamin K IV vitamin K bypasses absorption and would have corrected this.
- Antibodies against factor VII Factor VII inhibitors are very rare.
- Consumption of factors in the ascites Ascites does not consume clotting factors.
- Warfarin taken without telling the team Warfarin effect is reversed by IV vitamin K.
A 60-year-old woman with advanced cirrhosis has a blood urea of 1.8 mmol/L (BUN 5 mg/dL) with a normal creatinine and a high ammonia. Which of the following explains the low urea?
Answer: Reduced hepatic urea cycle capacity
The urea cycle runs almost entirely in hepatocytes, where ammonia from gut bacteria and amino acid breakdown is converted to urea for excretion. In advanced liver disease, urea synthesis falls, so blood urea is low while ammonia rises. Poor protein intake and fluid overload can lower urea further. Because urea depends on liver function, a normal urea in cirrhosis can hide kidney impairment, and creatinine is the better guide to renal function.
Urea and the liver
- Urea cycle is hepatic
- Liver failure: low urea
- High ammonia at the same time
- Use creatinine for kidney function
Remember Low urea with high ammonia: the liver's urea factory is failing.
Exam trap A normal urea in cirrhosis does not mean normal kidneys.
Why the other options are wrong
- Increased renal urea excretion The kidney is not over-excreting urea.
- Excess protein intake High protein intake would raise urea.
- Dilution by intravenous fluids Can contribute but does not explain the high ammonia.
- Kidney converting urea to ammonia Not a recognised mechanism.
Two weeks after successful stenting of a malignant bile duct stricture, a man's urine is clear and his stools are normal in colour, but his eyes are still yellow and serum bilirubin has fallen only by half. Which of the following explains the slow fall?
Answer: Bilirubin bound covalently to albumin
In prolonged cholestasis, some conjugated bilirubin in plasma becomes covalently attached to albumin, forming delta bilirubin. It is not filtered by the kidney and is cleared only as the albumin is broken down, with a half-life of about 2–3 weeks. So after the obstruction is relieved, free conjugated bilirubin disappears quickly and the urine clears, while delta bilirubin keeps the patient mildly jaundiced for weeks. A blocked stent would bring back dark urine and pale stools.
Delta bilirubin
- Conjugated bilirubin bound to albumin
- Not filtered into urine
- Half-life of albumin, 2–3 weeks
- Jaundice fades slowly after drainage
Remember Urine clears first; eyes clear weeks later.
Exam trap A slow fall in bilirubin with clear urine does not mean the stent has failed.
Why the other options are wrong
- Stent blockage with sludge Clear urine and normal stools show bile is flowing.
- Unconjugated bilirubin from haemolysis No evidence of haemolysis is given.
- Hepatocyte conjugation still failing Conjugation is not the problem in obstruction.
- Bilirubin stored in the skin and sclera Tissue staining does not explain the serum level.
Where this sits in the CPSP syllabus
- Paper 1: Gastrointestinal system and liver, Liver functions; bilirubin metabolism and jaundice
- Surgery & Allied, Paper 2: Gastrointestinal system and liver, Liver functions; bilirubin metabolism and jaundice
- Medicine & Allied, Paper 2: Gastrointestinal system and liver, Liver functions; bilirubin metabolism and jaundice
- Medicine & Allied, Paper 2: Haematopoietic and lymphoid disorders, Jaundice: pathophysiology and types
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