Medicine chapters
Approach to jaundice: haemolytic, obstructive and inherited hyperbilirubinaemias
How bilirubin is made and cleared, how to sort jaundice into haemolytic, hepatocellular and obstructive types, and the inherited hyperbilirubinaemias: Gilbert, Crigler-Najjar, Dubin-Johnson and Rotor.
- Jaundice is visible when bilirubin rises above about 50 µmol/L (3 mg/dL); sort it into pre-hepatic (haemolytic), hepatic and post-hepatic (obstructive).
- Unconjugated rise with normal liver tests = haemolysis or Gilbert; conjugated rise with dark urine and pale stools = cholestasis, so get an ultrasound first to look for dilated ducts.
- Gilbert (common, benign, worse on fasting) and Crigler-Najjar are unconjugated; Dubin-Johnson (black liver) and Rotor are conjugated.
On this page
Overview
Jaundice (icterus) is yellow colouring of the skin, sclera and mucous membranes from a raised serum bilirubin. It becomes visible when bilirubin is above about 50 µmol/L (3 mg/dL).
Jaundice is a sign, not a diagnosis. The task is to decide whether the problem is too much bilirubin made (haemolysis), poor handling by the liver (hepatitis, cirrhosis, inherited defects) or blocked outflow (stones, tumour, stricture). A few simple tests (conjugated fraction, urine, liver enzymes and an ultrasound) usually sort this out.
Bilirubin metabolism in brief
- Old red cells are broken down in the spleen. Haem → biliverdin → unconjugated bilirubin.
- Unconjugated bilirubin is fat-soluble and water-insoluble. It travels in blood bound to albumin, so it is not filtered by the kidney.
- The liver cell takes it up and conjugates it with glucuronic acid using UDP-glucuronosyl transferase (UGT1A1).
- Conjugated bilirubin is water-soluble. It is pumped into bile across the canalicular membrane by MRP2.
- In the gut, bacteria turn it into urobilinogen. Most leaves in faeces as stercobilin (brown stool colour). A little is reabsorbed and passed in urine.
Only conjugated bilirubin can appear in urine. So bilirubinuria = conjugated hyperbilirubinaemia (liver or biliary disease), never pure haemolysis.
Converting units
Bilirubin 85 µmol/L. To convert to mg/dL, divide by 17.
85 ÷ 17 = 5 mg/dL → clearly visible jaundice
Classification of jaundice
| Type | Main defect | Bilirubin type | Examples |
|---|---|---|---|
| Pre-hepatic | Too much bilirubin made | Unconjugated | Haemolytic anaemias, ineffective erythropoiesis (e.g. megaloblastic anaemia), large haematoma |
| Hepatic: unconjugated | Poor uptake or conjugation | Unconjugated | Gilbert, Crigler-Najjar, neonatal jaundice, drugs such as rifampicin |
| Hepatic: conjugated | Poor excretion or liver cell damage | Mixed or conjugated | Viral, drug and alcoholic hepatitis, cirrhosis, Dubin-Johnson, Rotor, intrahepatic cholestasis |
| Post-hepatic (obstructive) | Bile cannot reach the gut | Conjugated | Common bile duct stones, carcinoma of pancreas head or ampulla, cholangiocarcinoma, strictures, sclerosing cholangitis, pancreatic pseudocyst |
Haemolytic jaundice
- Red cell breakdown increases the bilirubin load. A normal liver copes with most of it, so the jaundice is mild (usually about 68–102 µmol/L, 4–6 mg/dL).
- Acholuric: unconjugated bilirubin is albumin-bound and cannot pass into urine.
- More bilirubin reaches the gut, so urinary urobilinogen rises and stools are normal or dark.
- Clues: anaemia, splenomegaly, pigment gallstones, leg ulcers (sickle cell), family history (spherocytosis, thalassaemia, G6PD deficiency).
- Tests: raised reticulocytes, raised LDH, low haptoglobin, blood film (spherocytes, bite cells, fragments), direct antiglobulin (Coombs) test. Liver enzymes, ALP and albumin are normal.
Obstructive (cholestatic) jaundice
- Conjugated bilirubin backs up into blood and spills into urine: dark urine.
- No bile reaches the gut: pale, clay-coloured stools and steatorrhoea; urinary urobilinogen falls or disappears.
- Bile salts in the skin cause pruritus.
- Fat-soluble vitamin loss, especially vitamin K, gives a prolonged prothrombin time that corrects with parenteral vitamin K (unlike liver cell failure).
- Liver tests: ALP and GGT high, transaminases only mildly raised.
Extrahepatic vs intrahepatic cholestasis
- Extrahepatic (large duct) obstruction: stone, tumour or stricture. Ultrasound shows dilated ducts. Needs drainage.
- Intrahepatic cholestasis: failure of bile secretion inside the liver (hepatitis, drugs such as chlorpromazine or oestrogens, primary biliary cholangitis, pregnancy, sepsis). Ducts are not dilated. Treat the cause.
Pointers to the cause
| Feature | Suggests |
|---|---|
| Colicky pain, fever, rigors and jaundice (Charcot triad) | Common bile duct stone with cholangitis |
| Painless, progressive jaundice, weight loss, older patient | Carcinoma of pancreatic head, ampulla or bile duct |
| Palpable, non-tender gallbladder with painless jaundice | Carcinoma of pancreas head (Courvoisier law) |
| Jaundice that fluctuates, with anaemia and melaena | Ampullary carcinoma |
| Middle-aged woman, itch, raised ALP, antimitochondrial antibody | Primary biliary cholangitis |
Courvoisier law: in painless obstructive jaundice, a palpable gallbladder is unlikely to be due to stones. Stones cause chronic inflammation, so the gallbladder becomes fibrosed and shrunken, not distended.
Inherited (congenital) hyperbilirubinaemias
These are non-haemolytic. Liver enzymes are normal.
| Syndrome | Bilirubin | Defect | Key features | Treatment |
|---|---|---|---|---|
| Gilbert | Unconjugated | Reduced UGT1A1 activity (promoter repeat in the gene) | Very common; mild jaundice with fasting, illness, exertion; normal reticulocytes | None: reassure |
| Crigler-Najjar type I | Unconjugated (very high) | Absent UGT1A1 | Severe neonatal jaundice, kernicterus; no response to phenobarbital | Phototherapy, liver transplant |
| Crigler-Najjar type II | Unconjugated (lower) | Reduced UGT1A1 | Survive to adulthood; bilirubin falls with phenobarbital | Phenobarbital |
| Dubin-Johnson | Conjugated | MRP2 canalicular pump defect | Black (pigmented) liver; worse with pregnancy or the pill; urine coproporphyrin mostly isomer I | None; benign |
| Rotor | Conjugated | Defective hepatic storage and uptake | Like Dubin-Johnson but no pigment in the liver | None; benign |
Gilbert syndrome
- The commonest inherited hyperbilirubinaemia; Kumar quotes 2–7% of the population.
- Usually found by chance: raised unconjugated bilirubin (about 17–102 µmol/L, 1–6 mg/dL), all other liver tests normal, no signs of liver disease.
- Bilirubin rises on fasting (for example during Ramadan) and during minor illness.
- Reticulocyte count is normal, which excludes haemolysis.
- Diagnosis is clinical; the aim is reassurance and avoiding needless tests.
- Clinical point: reduced glucuronidation increases toxicity of drugs cleared this way, such as irinotecan.
Raised unconjugated bilirubin + normal enzymes + normal reticulocytes + worse with fasting = Gilbert syndrome.
Crigler-Najjar syndrome
- Very rare. Type I: no enzyme at all; bilirubin is very high from birth and causes kernicterus. Phenobarbital does not help because there is no enzyme to induce. Liver transplantation is the only cure.
- Type II: some enzyme remains. Bilirubin is lower and phenobarbital (an enzyme inducer) lowers it.
Phenobarbital test: bilirubin falls → enzyme is present (type II or Gilbert); no change → enzyme is absent (type I).
Dubin-Johnson and Rotor syndromes
- Both are autosomal recessive, cause mild conjugated hyperbilirubinaemia, and have a good prognosis.
- Dubin-Johnson: defective MRP2 export pump; liver looks black from pigment deposition. Jaundice may first appear with the combined pill or pregnancy.
- Rotor: similar picture but no liver pigment.
Gilbert and Crigler-Najjar are unconjugated. Dubin-Johnson and Rotor are conjugated. Remember "Dubin and Rotor = Direct (conjugated)".
Approach to the jaundiced patient
History
- Age and duration: young with a short prodrome suggests viral hepatitis; elderly with weight loss suggests cancer.
- Pain, fever, rigors: stones, cholangitis or liver abscess.
- Drugs in the previous 2–3 months, including herbal and over-the-counter products; alcohol.
- Blood-borne virus risks: injections with reused needles, transfusion, dental work, tattoos, IV drug use, sexual exposure.
- Travel and water: hepatitis A and E outbreaks.
- Family history of jaundice (Gilbert, haemolytic anaemias).
- Dark urine, pale stools, itch: cholestasis.
Examination
- Signs of chronic liver disease (spider naevi, palmar erythema, ascites, splenomegaly) suggest acute-on-chronic disease.
- Smooth tender liver: hepatitis or obstruction. Knobbly, hard liver: cirrhosis or metastases.
- Palpable gallbladder: pancreatic cancer. Splenomegaly with anaemia: haemolysis or portal hypertension.
- Kayser-Fleischer rings in a young patient: Wilson disease.
Investigations
| Test | Haemolytic | Hepatocellular | Obstructive |
|---|---|---|---|
| Main bilirubin type | Unconjugated | Mixed | Conjugated |
| Urine bilirubin | Absent | Present | Present |
| Urine urobilinogen | Increased | Normal or increased | Absent or reduced |
| Stool colour | Normal or dark | Normal or pale | Pale |
| ALT/AST | Normal | Very high | Mildly raised |
| ALP/GGT | Normal | Mildly raised | Very high |
| Other | Reticulocytes up, haptoglobin low | Viral markers, autoantibodies | Dilated ducts on ultrasound |
- Full blood count, film and reticulocytes: haemolysis.
- Liver tests and prothrombin time/INR: pattern and severity.
- Viral markers (HAV IgM, HBsAg and IgM anti-HBc, anti-HCV, HEV IgM): the most useful blood tests in acute jaundice.
- Abdominal ultrasound: the key first imaging test. It shows whether ducts are dilated (a common bile duct up to about 6 mm is normal), the level of block and often the cause.
- MRCP: non-invasive picture of the bile and pancreatic ducts; the usual next test after ultrasound.
- ERCP: now mainly therapeutic (remove stones, place stents, sphincterotomy).
- CT or endoscopic ultrasound: stage pancreatic or ampullary tumours.
- Liver biopsy: when the cause stays unclear and ducts are not dilated.
In jaundice, ultrasound comes first to separate obstructive (dilated ducts) from non-obstructive causes.
Management principles
- Treat the cause: stop the offending drug, treat viral hepatitis, remove duct stones by ERCP, plan surgery or stenting for tumours.
- Before any procedure in obstructive jaundice: give parenteral vitamin K, keep the patient well hydrated (risk of kidney injury) and cover cholangitis with antibiotics.
- Pruritus: colestyramine.
- Cholangitis (fever, rigors, jaundice, pain): IV fluids, antibiotics and urgent biliary drainage by ERCP.
- Gilbert: reassurance only.
Prolonged prothrombin time that corrects with vitamin K points to cholestasis (malabsorption). If it does not correct, the liver cells cannot make clotting factors: liver cell failure.
Expect: the bilirubin level at which jaundice is seen; urine and stool findings that separate haemolytic from obstructive jaundice (acholuria, urobilinogen); the enzyme behind Gilbert syndrome and its triggers; Crigler-Najjar types and the phenobarbital response; black liver in Dubin-Johnson versus Rotor; conjugated vs unconjugated types; Courvoisier law; ultrasound as the first test; vitamin K before procedures; Charcot triad for cholangitis.
Quick revision
- Visible jaundice: bilirubin above about 50 µmol/L (3 mg/dL).
- Unconjugated is albumin-bound and never in urine; conjugated can appear in urine.
- Haemolytic: mild, acholuric, urobilinogen up, haptoglobin down, enzymes normal.
- Obstructive: dark urine, pale stools, itch, ALP and GGT high, urobilinogen absent.
- Ultrasound first; MRCP next; ERCP to treat.
- Gilbert: reduced UGT1A1, fasting rise, normal reticulocytes, no treatment.
- Crigler-Najjar I: absent enzyme, kernicterus, transplant; type II responds to phenobarbital.
- Dubin-Johnson: conjugated, MRP2, black liver. Rotor: conjugated, no pigment.
- Painless jaundice with a palpable gallbladder: pancreatic head cancer.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Why is there no bilirubin in the urine in haemolytic jaundice?
The excess bilirubin is unconjugated and tightly bound to albumin, so the kidney cannot filter it.
How is Gilbert syndrome confirmed?
By a mildly raised unconjugated bilirubin with normal liver enzymes and a normal reticulocyte count, often rising after fasting or illness. No treatment is needed.
What is the difference between Dubin-Johnson and Rotor syndromes?
Both give a benign conjugated hyperbilirubinaemia, but in Dubin-Johnson the liver contains dark pigment and the defect is in the MRP2 canalicular pump, while the liver in Rotor syndrome is not pigmented.
What is the first investigation for a patient with dark urine and pale stools?
An abdominal ultrasound, to see whether the bile ducts are dilated and where the block is.