01Core principlesThe concepts and mechanisms needed to understand the subject.
Bilirubin comes mainly from haem breakdown. Unconjugated bilirubin travels albumin-bound to the liver, hepatocytes conjugate it to a water-soluble form, and canaliculi excrete it into bile. Jaundice becomes visible when bilirubin accumulates, but the colour alone cannot locate the defect. The useful clinical task is to combine direct and indirect fractions with blood-count evidence, hepatocellular and cholestatic enzymes, synthetic function, symptoms and imaging.
The pre-hepatic, hepatic and post-hepatic model is a reasoning framework rather than three sealed boxes. Haemolysis can coexist with sepsis-related cholestasis; a common-duct stone can transiently raise ALT markedly before ALP peaks; infiltrative liver disease can produce a cholestatic pattern without an extrahepatic blockage. State what the evidence supports, recognise overlap, and pursue the dangerous mechanism first.
Urine and stool findings reflect bilirubin handling. Unconjugated bilirubin is albumin-bound and is not filtered into urine. Conjugated bilirubin is water-soluble, so cholestasis may cause dark bilirubin-containing urine. Reduced bile pigment reaching the gut can make stool pale. These clues support classification but do not replace blood tests and imaging.
Key points
- Pre-hepatic jaundice usually increases unconjugated bilirubin because bilirubin production exceeds hepatic uptake and conjugation, most often through haemolysis or ineffective erythropoiesis.
- Hepatic jaundice may disturb uptake, conjugation, hepatocyte integrity or canalicular export, so bilirubin fractions and enzyme patterns can be mixed rather than neatly categorical.
- Post-hepatic jaundice causes conjugated bilirubin to reflux into blood; dark urine, pale stool, pruritus and a cholestatic ALP/GGT pattern support impaired bile flow.
- Start with fractionated bilirubin, ALT, ALP, GGT, albumin, full blood count and INR when illness is significant; compare previous results and interpret the whole pattern and clinical context.
- For isolated unconjugated hyperbilirubinaemia, examine haemoglobin, reticulocytes, LDH and haptoglobin before assuming Gilbert syndrome; haemolysis changes the management.
- Ultrasound tests for duct dilatation and structural liver disease, but a non-dilated duct does not exclude early, intermittent or intrahepatic cholestasis.
- Adults aged 40 or over with jaundice meet NICE criteria for a suspected pancreatic-cancer pathway referral; illness severity can require same-day hospital assessment instead.
02Mechanisms and patternsImportant relationships and how to distinguish them.
Predominantly unconjugated bilirubin with anaemia, reticulocytosis, raised LDH and low haptoglobin supports increased red-cell breakdown; ALP is not raised by haemolysis itself.
ALT or AST predominance with variable conjugated bilirubin suggests hepatocyte injury from viral, toxic, ischaemic, autoimmune or metabolic disease; INR and glucose indicate functional consequence.
ALP predominance supported by GGT, conjugated hyperbilirubinaemia, pruritus, dark urine or pale stool points toward impaired bile formation or flow.
Intermittent isolated unconjugated hyperbilirubinaemia during fasting or illness with normal blood count and liver enzymes is compatible with Gilbert syndrome after haemolysis is excluded.
Hypotension, fever, confusion, bleeding or hypoglycaemia matters more urgently than the bilirubin category because it may reveal sepsis or failing hepatic synthesis.
03Interpreting evidenceInformation, measurements and their limitations.
Consider the information, its meaning and its limitations before deciding what follows.
- 01
Fractionated bilirubin and urine dipstick - Why
- Separate predominantly conjugated from unconjugated accumulation and determine whether bilirubin is entering urine.
- Interpretation and limitations
- Urinary bilirubin supports a conjugated component; an isolated indirect rise directs attention to haemolysis and conjugation disorders, but laboratory fractions are not perfectly disease-specific.
- 02
Full blood count, reticulocytes, LDH and haptoglobin - Why
- Test whether accelerated erythrocyte destruction explains unconjugated jaundice.
- Interpretation and limitations
- Falling haemoglobin, reticulocytosis, raised LDH and consumed haptoglobin form a haemolytic pattern; a blood film and direct antiglobulin test then refine the cause.
- 03
ALT, ALP and GGT - Why
- Describe hepatocellular versus cholestatic biochemical predominance and confirm whether an ALP rise is likely hepatobiliary.
- Interpretation and limitations
- ALT predominance supports hepatocyte injury; ALP with GGT supports cholestasis. Bone disease may raise ALP without GGT, while mixed disease and changing obstruction blur the ratio.
- 04
Albumin, INR and glucose - Why
- Assess hepatic synthetic reserve and metabolic failure rather than injury alone.
- Interpretation and limitations
- A rising INR or hypoglycaemia in acute jaundice is dangerous; low albumin is less acute and may reflect chronic liver disease, inflammation, renal loss or malnutrition.
- 05
Abdominal ultrasound - Why
- Look for duct dilatation, stones, gallbladder abnormality, liver morphology, focal lesions and portal hypertension.
- Interpretation and limitations
- Dilated ducts support mechanical obstruction and determine further biliary imaging. Normal calibre does not exclude an early stone, hilar lesion, sclerosing cholangitis or drug-related cholestasis.
- 06
Cause-directed liver screen - Why
- Identify viral, autoimmune and iron-related liver disease when a hepatic or intrahepatic cholestatic process remains possible.
- Interpretation and limitations
- The BSG adult screen includes hepatitis B surface antigen, hepatitis C antibody with PCR if positive, AMA, SMA, ANA, immunoglobulins, ferritin and transferrin saturation alongside ultrasound.
04Applied reasoningWorked examples connecting principles to decisions.
01Worked case: localise a bilirubin riseUse fractions, haemolysis markers and imaging togetherA 36-year-old develops scleral icterus after a viral illness: bilirubin is 82 micromol/L, conjugated bilirubin 9 micromol/L, ALT 27 U/L, ALP 91 U/L, haemoglobin 86 g/L, reticulocytes 9%, LDH raised and haptoglobin undetectable.+
- 1Calculate that the bilirubin is predominantly unconjugated and note that ALT and ALP do not show hepatocellular or cholestatic injury.
- 2Integrate anaemia, reticulocytosis, raised LDH and low haptoglobin: increased red-cell destruction is the actual demonstrated mechanism, so classify this as pre-hepatic jaundice.
- 3Review the blood film, direct antiglobulin test, medicines, transfusion history and infection context; the direct antiglobulin test is positive and haematology confirms warm autoimmune haemolysis.
- 4After treatment directed by haematology, haemoglobin rises and bilirubin falls with the haemolysis markers; this biochemical response verifies the mechanism rather than an assumed diagnosis of Gilbert syndrome.
02Obstructive routeMap the biliary level before interventionConjugated jaundice, pale stools and cholestatic enzymes are accompanied by duct dilatation on ultrasound.+
- 1Assess fever, pain, observations and mental state immediately for cholangitis and escalate urgent drainage when infection or instability is present.
- 2Obtain cross-sectional imaging appropriate to the suspected cause before elective instrumentation, preserving anatomy needed for resectability planning.
- 3Discuss malignant or complex hilar obstruction with the specialist HPB team before selecting the duct, route and stent.
- 4Verify effective decompression using symptoms, bilirubin trend, inflammatory markers and a clear plan for recurrent obstruction.
03Hepatic routeMeasure function while identifying injuryALT predominance and jaundice occur without duct dilatation.+
- 1Review timing of prescribed, over-the-counter and recreational exposures, alcohol, travel, infection risks and autoimmune symptoms.
- 2Measure INR and glucose promptly because enzyme height does not quantify remaining liver function.
- 3Send a targeted acute and chronic liver aetiology screen and discuss severe or unexplained disease with hepatology.
- 4Trend bilirubin, INR, glucose, renal function and mental state; deteriorating synthesis overrides a reassuring fall in ALT.
05Checking understandingVerify the reasoning, revisit uncertainties and apply feedback.
- Trend bilirubin fractions with ALT, ALP and GGT when the pattern is evolving; different half-lives mean biochemical peaks need not occur together.
- Repeat INR, glucose, renal function, acid-base status and conscious level in acute hepatic illness because organ failure can develop while transaminases fall.
- For haemolysis, follow haemoglobin, reticulocyte response, LDH and haptoglobin alongside the cause-specific plan; bilirubin alone cannot demonstrate recovery.
- After biliary intervention, record clinical improvement, bilirubin trajectory and recurrent fever or pain, and ensure ownership of stent exchange or removal.
- Do not use repeated liver panels as the only strategy for an unexplained abnormality; complete the indicated aetiology and structural assessment.
06Special situationsVariants, exceptions and circumstances that change the usual approach.
ALP needs provenance
Pregnancy, growth and bone disease can raise ALP; a parallel GGT rise makes a hepatobiliary source more likely but does not locate the lesion.
ALT can spike in obstruction
Acute transient common-duct obstruction may initially look hepatocellular, so symptom timing and serial ultrasound or duct imaging matter.
Synthetic tests answer another question
Albumin and INR assess aspects of function, whereas ALT and ALP mainly report injury or cholestasis; neither set replaces the other.
Fraction is a direction
A mixed fraction is common in sepsis and liver disease; avoid forcing a complex patient into a single mechanistic label.
Age threshold changes referral
NICE places jaundice at age 40 or over on the suspected pancreatic-cancer pathway even without pain or a palpable gallbladder.
07Common pitfallsFrequent interpretation and management errors.
- 01
Calling all jaundice obstructive without fractionating bilirubin can miss haemolysis and expose the patient to irrelevant biliary procedures.
- 02
Calling an isolated unconjugated rise Gilbert syndrome before reviewing anaemia and haemolysis markers can miss an active red-cell disorder.
- 03
Interpreting a normal ultrasound as proof that there is no cholestasis ignores early obstruction and intrahepatic duct disease.
- 04
Equating a lower ALT with recovery can be dangerous when INR, glucose, lactate, renal function or cognition is worsening.
- 05
Waiting for outpatient cancer referral in a patient with fever or physiological compromise fails to address immediate cholangitis or organ failure.