Jaundice
Red flags
Acute liver failure - jaundice + coagulopathy + encephalopathy
- INR >=1.5 with any encephalopathy in a patient without known cirrhosis
- -> discuss with a liver transplant unit the same day. Do not wait for a diagnosis
- Hypoglycaemia, lactic acidosis, rapidly rising bilirubin with falling transaminases (loss of viable hepatocytes, not recovery)
- Paracetamol history - including staggered/therapeutic-excess ingestion. Start NAC on suspicion
Ascending cholangitis - obstruction + infection
- Charcot triad: fever + RUQ pain + jaundice. Reynolds pentad adds hypotension + confusion
- -> blood cultures, IV antibiotics, and biliary decompression by ERCP within 24-48 h (within hours if septic shock)
Other immediate concerns
- Painless jaundice with weight loss -> pancreatic or biliary malignancy until proven otherwise
- Jaundice + fever + rash + eosinophilia 2-8 weeks after a new drug -> DRESS
- Jaundice + anaemia + reticulocytosis + dark urine -> haemolysis, consider intravascular causes and TTP
- Jaundice in pregnancy -> HELLP, acute fatty liver of pregnancy - both obstetric emergencies
- New jaundice in known cirrhosis -> decompensation; look for SBP, variceal bleed, HCC, portal vein thrombosis, drug or alcohol trigger
Differential by mechanism
Bilirubin >~40-50 micromol/L before jaundice is clinically visible. Sclerae first, then skin.
1. Pre-hepatic (unconjugated, no bilirubin in urine)
- Haemolysis - autoimmune, hereditary spherocytosis, G6PD, sickle cell, thalassaemia, mechanical valve, TTP/HUS, malaria
- Bilirubin rarely >85 micromol/L from haemolysis alone unless there is coexisting liver disease
- Ineffective erythropoiesis - megaloblastic anaemia, MDS
- Impaired conjugation - Gilbert syndrome (UGT1A1, ~5-8% of population, rises with fasting/illness, otherwise entirely normal LFTs), Crigler-Najjar
- Resorption of a large haematoma
2. Hepatocellular (conjugated + unconjugated; ALT/AST >> ALP)
- Viral - hepatitis A, B, C, D, E; EBV, CMV, HSV
- Drug/toxin - paracetamol, alcohol, antibiotics (amoxicillin-clavulanate, flucloxacillin - often cholestatic), anti-TB drugs, statins, herbals, checkpoint inhibitors, amanita
- Alcohol-related hepatitis - AST:ALT >2, both usually <300
- Ischaemic hepatitis - shock liver; ALT in the thousands, rises and falls within days
- Autoimmune hepatitis, Wilson disease (young, low ALP:bilirubin ratio, haemolysis, Kayser-Fleischer rings), haemochromatosis, alpha-1 antitrypsin
- MASLD/MASH (formerly NAFLD)
- Budd-Chiari, veno-occlusive disease
- Sepsis-associated cholestasis, TPN
3. Cholestatic - intrahepatic (ALP and GGT >> ALT)
- Primary biliary cholangitis (AMA), primary sclerosing cholangitis (ANCA in ~80%; IBD association)
- Drug-induced cholestasis - flucloxacillin, amoxicillin-clavulanate, erythromycin, anabolic steroids, COCP
- Infiltration - lymphoma, granuloma (sarcoid, TB), amyloid, metastases
- Intrahepatic cholestasis of pregnancy, benign recurrent intrahepatic cholestasis
- Dubin-Johnson / Rotor - isolated conjugated hyperbilirubinaemia with otherwise normal LFTs
4. Post-hepatic - extrahepatic obstruction (ALP >> ALT, dilated ducts)
- Choledocholithiasis - commonest; painful, fluctuating
- Malignancy - pancreatic head, cholangiocarcinoma, ampullary, gallbladder, nodal; painless, progressive
- Benign stricture, post-surgical injury, IgG4-related sclerosing cholangitis (steroid-responsive, mimics malignancy)
- Chronic pancreatitis, parasites (Ascaris, liver flukes)
- Mirizzi syndrome - stone in the cystic duct compressing the CHD
In children - conjugated hyperbilirubinaemia
Always pathological. Categories:
- Extrahepatic biliary obstruction - the three main causes are gallstones, primary sclerosing cholangitis, and pancreatic pathology
- In infants: biliary atresia - the time-critical diagnosis; choledochal cyst**
- Inflammatory - neonatal/autoimmune hepatitis
- Immune dysregulation
- Malignancy
- Toxin/medication - TPN, drugs
- Metabolic - alpha-1 antitrypsin deficiency, galactosaemia, tyrosinaemia, Alagille, progressive familial intrahepatic cholestasis, Wilson
- Infection - TORCH, sepsis, UTI
Focused history
Characterise
- Onset and speed; fluctuating (stone) vs progressive (tumour) vs episodic (Gilbert with fasting)
- Pain - RUQ colic (stone), epigastric radiating to back (pancreatic), painless (malignancy)
- Dark urine + pale stools = conjugated (cholestatic or obstructive)
- Normal-coloured urine with jaundice = unconjugated - haemolysis or Gilbert
- Pruritus - cholestasis; may precede jaundice by months in PBC
- Fever and rigors -> cholangitis
Cause-seeking
- Every drug, dose and start date in the last 3 months - prescribed, over-the-counter, herbal, bodybuilding supplements. And paracetamol quantity
- Alcohol - quantify in standard drinks per week, and ask specifically about the last 6 weeks
- Risk factors for viral hepatitis: IV drug use, tattoos, transfusion before 1990, country of birth, sexual history, occupational exposure, shellfish and travel (HAV/HEV)
- Metabolic: weight, diabetes, dyslipidaemia
- Family history - Gilbert, haemochromatosis, Wilson, alpha-1 antitrypsin
- Autoimmune history - thyroid, coeliac, IBD (PSC)
- Surgery - previous cholecystectomy, bariatric surgery
- Pregnancy and gestation
- Weight loss, anorexia, night sweats -> malignancy
Focused examination
Signs of chronic liver disease
- Splenomegaly, caput medusae, oesophageal varices (and ascites, spider naevi, palmar erythema, gynaecomastia, testicular atrophy, Dupuytren, leuconychia)
Signs of acute liver injury
- Tender hepatomegaly, abdominal discomfort
Signs pointing to a cause
- Track marks - viral hepatitis risk factor
- Lymphadenopathy - viral or haematological malignant cause
- Kayser-Fleischer rings (Wilson), slate-grey pigmentation (haemochromatosis), xanthelasma (PBC), scratch marks
- Palpable, non-tender gallbladder with jaundice (Courvoisier) -> malignant obstruction
- Virchow node, umbilical nodule, cachexia -> malignancy
Signs of liver failure
- Confusion / encephalopathy, asterixis, fetor hepaticus
- Bruising, bleeding
- Hypotension, hypoglycaemia
Bedside
- Weight, BMI, temperature, urinalysis (bilirubin and urobilinogen), glucose
Investigation strategy
Step 1 - the pattern separates the differential in one line
- LFT: is this hepatocellular or cholestatic?
- R factor = (ALT / ULN) / (ALP / ULN) - >5 hepatocellular, <2 cholestatic, 2-5 mixed
- Split (fractionated) bilirubin
- Unconjugated predominant -> haemolysis or Gilbert. Stop and look at the blood, not the liver
- Conjugated -> hepatocellular or cholestatic
Step 2 - first-line bloods
- FBE + film, reticulocytes, LDH, haptoglobin, DAT (haemolysis)
- INR and albumin - synthetic function, and the prognostic markers
- UEC, glucose, lipase
- Paracetamol level in any acute presentation
Step 3 - imaging
- Abdominal ultrasound first in every jaundiced patient - answers the critical question: are the ducts dilated?
- Dilated -> obstruction -> MRCP (or EUS for a small distal lesion), then ERCP for therapy
- Not dilated -> intrahepatic disease -> serological workup
- Ducts may not be dilated in early obstruction or in PSC - repeat or proceed to MRCP if suspicion is high
- CT for staging a mass; not a good test for stones
Step 4 - the liver screen (if ducts are not dilated)
- Viral: hepatitis A IgM, HBsAg, anti-HBc, anti-HCV + HCV RNA, hepatitis E, EBV, CMV
- Autoimmune: AMA (PBC), ANA and anti-smooth muscle antibody (autoimmune hepatitis), immunoglobulins (IgG in AIH, IgM in PBC, IgG4), ANCA - positive in ~80% of PSC
- Metabolic: ferritin and transferrin saturation (haemochromatosis), caeruloplasmin and 24h urinary copper (Wilson - in anyone under 40), alpha-1 antitrypsin level and phenotype
- Coeliac serology, TSH
- Tumour markers (CA19-9, AFP) - interpret with care; CA19-9 rises in benign obstruction
Step 5
- Transient elastography (FibroScan) or ELF for fibrosis staging
- Liver biopsy when the diagnosis remains unclear, for staging, or where results will change management
- Transjugular route if ascites or coagulopathy
Management
Immediate
- Acute liver failure: ICU, transplant unit referral, N-acetylcysteine (benefit even in non-paracetamol ALF), manage cerebral oedema, treat hypoglycaemia, avoid sedation, do not correct INR with FFP - it removes the key prognostic marker
- Cholangitis: blood cultures, IV antibiotics per Therapeutic Guidelines, fluid resuscitation, and biliary drainage - ERCP within 24-48 h, urgently if septic
- Cease every potentially hepatotoxic drug and any alcohol
By cause
- Obstruction - ERCP with sphincterotomy and stone extraction, or stenting for malignancy; cholecystectomy on the same admission for gallstone disease
- Malignancy - MDT, staging, tissue diagnosis, resectability assessment; stent for palliation
- Viral hepatitis - antivirals for HBV, DAA for HCV; supportive for HAV/HEV
- Autoimmune hepatitis - prednisolone + azathioprine
- PBC - ursodeoxycholic acid 13-15 mg/kg/day, then obeticholic acid or a fibrate for non-responders
- Alcohol-related hepatitis - abstinence, thiamine, nutrition, corticosteroid if Maddrey DF >32
- Paracetamol - NAC by nomogram, or empirically for staggered ingestion
Symptomatic
- Pruritus: cholestyramine (separate from other drugs by 4 h), rifampicin, naltrexone, sertraline
- Fat-soluble vitamin replacement (A, D, E, K) in prolonged cholestasis
- Nutrition; avoid sedatives and nephrotoxins
Do not
- Do not attribute jaundice to Gilbert syndrome unless the bilirubin is unconjugated and all other LFTs are normal
- Do not delay ultrasound waiting for serology
Traps
- Jaundice with normal-coloured urine is unconjugated - the problem is haematological, not hepatic
- A falling ALT with rising bilirubin and INR in fulminant hepatitis is hepatocyte death, not recovery. It is the worst sign in the note
- Isolated raised bilirubin with everything else normal in a well young adult is Gilbert syndrome - no imaging, no biopsy, no follow-up
- Normal-calibre ducts on ultrasound do not exclude obstruction, especially early or in PSC
- Alcohol-related hepatitis rarely produces an AST above 300-400 - a transaminase in the thousands means something else (paracetamol, ischaemia, virus)
- ALP rises in pregnancy, bone disease and childhood - confirm hepatic origin with GGT
- Isolated raised GGT is usually enzyme induction (alcohol, phenytoin) and is not by itself liver disease
- Amoxicillin-clavulanate cholestasis may begin weeks AFTER the course finished
- Test caeruloplasmin in every patient under 40 with unexplained liver disease - Wilson disease is treatable and fatal if missed
- Correcting the INR in acute liver failure removes the transplant unit's best prognostic marker - ask before you give FFP
Talk track
- "My first task is to decide whether this patient is sick right now: I would look for encephalopathy, coagulopathy and features of cholangitis, because those two diagnoses change the next hour."
- "Then I would split the bilirubin. If it is unconjugated with otherwise normal liver enzymes, I am looking at haemolysis or Gilbert syndrome and the workup is haematological."
- "If it is conjugated, the liver function tests tell me whether the pattern is hepatocellular or cholestatic - I would calculate the R factor."
- "The single most important early investigation is an abdominal ultrasound, to answer one question: are the bile ducts dilated? Dilated ducts mean obstruction and take me toward MRCP and ERCP. Non-dilated ducts take me to a full liver screen."
- "Alongside that I would take a meticulous drug and alcohol history, including over-the-counter and herbal preparations, and check a paracetamol level."
- "In anyone under 40 I would specifically send caeruloplasmin, because Wilson disease is treatable and easily missed."
- "The findings that would worry me most are painless jaundice with weight loss, and a rising INR - the first suggests malignancy, the second liver failure."
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