Liver disease of less common aetiology - primary sclerosing cholangitis (PSC)
Description
- Chronic fibro-inflammatory disease of intra- and/or extrahepatic bile ducts -> multifocal strictures + intervening dilatation -> biliary cirrhosis
- Cholestatic biochemistry: inc ALP and GGT, with fluctuating bilirubin
Subtypes
| Large-duct (classic) ~90% | Intra- and/or extrahepatic strictures on MRCP |
| Small-duct ~10% | Normal cholangiogram, PSC on biopsy. Better prognosis; low cholangiocarcinoma risk |
| PSC-AIH overlap | More common in children/young adults; steroid-responsive |
| IgG4-related sclerosing cholangitis | A mimic, not a subtype - steroid-responsive, must not be missed |
- Progressive and, unlike PBC, has no effective medical therapy
Epidemiology
- Prevalence ~10-15/100,000; Northern European ancestry
- M:F ~2:1 (the opposite of PBC and AIH)
- Median age at diagnosis ~40 - younger than PBC
- ~70% of PSC patients have IBD (usually ulcerative colitis)
- Only ~10% of IBD patients have PSC
- Rare in Aboriginal and Torres Strait Islander and East Asian populations
Aetiopathogenesis
- Immune-mediated bile duct injury in a genetically susceptible host; strong HLA associations (HLA-B8, DR3, DR52a)
- Proposed "leaky gut" model: gut-primed lymphocytes aberrantly home to the liver via MAdCAM-1/CCL25
- Cholangiocyte injury -> periductal "onion-skin" concentric fibrosis -> ductopenia -> cholestasis -> biliary cirrhosis
- No autoantibody is causal, and none is diagnostic
The PSC-IBD phenotype - distinct from ordinary UC
- Pancolitis, rectal sparing, backwash ileitis
- Often quiescent colitis with severe liver disease, or vice versa
- Markedly higher colorectal cancer risk, right-sided predominance
- Colitis activity and liver disease run independently - colectomy does not improve PSC
Diagnosis
Presentation
- ~50% asymptomatic - found on an incidental raised ALP, often during IBD workup
- Fatigue, pruritus, right upper quadrant pain, jaundice
- Recurrent bacterial cholangitis - fever, rigors, jaundice, pain
- Later: cirrhosis, portal hypertension, malabsorption, metabolic bone disease
MRCP - the diagnostic test
- Multifocal short strictures with intervening dilatation -> "beaded" appearance of intrahepatic and/or extrahepatic ducts
- Non-invasive; ERCP is reserved for assessing or treating a dominant stricture given its procedural risk (post-ERCP pancreatitis, cholangitis)
- Ultrasound to exclude calculi and to survey for gallbladder polyps
Serology - no diagnostic antibody exists
- Atypical perinuclear ANCA positive in 26-94% - neither specific nor prognostic
- A positive ANA or ASMA, or raised immunoglobulins, raises AIH overlap -> consider biopsy
- IgG4 in everyone - to exclude IgG4-related sclerosing cholangitis (steroid-responsive and reversible)
- AMA negative (positive suggests PBC)
Liver biopsy
- Not required in classic large-duct disease
- Indicated for suspected small-duct PSC (normal MRCP with cholestatic LFTs) or suspected AIH overlap
- Classic finding: periductal concentric "onion-skin" fibrosis (present in a minority of samples)
Everyone with a new diagnosis
- Colonoscopy with biopsies even if asymptomatic - to look for the IBD that is present in ~70%
- Fibrosis staging (elastography); DEXA; fat-soluble vitamins
- Baseline CA 19-9 (imperfect; also rises with cholangitis and biliary obstruction)
Differentials - secondary sclerosing cholangitis
- IgG4-related sclerosing cholangitis (the one you must not miss)
- Choledocholithiasis; prior biliary surgery; ischaemic cholangiopathy
- AIDS cholangiopathy (cryptosporidium, CMV); recurrent pyogenic cholangitis
- Intra-arterial chemotherapy; critical illness/COVID cholangiopathy; histiocytosis
Management
There is no medical therapy proven to alter the natural history. Management is surveillance, complication control and transplantation.
Disease-modifying - what there is
- UDCA: not recommended as routine therapy in PSC
- Improves biochemistry but no proven survival benefit; high-dose UDCA (28-30 mg/kg/day) caused harm (more deaths, transplants, varices) in a randomised trial - do not use high dose
- Some clinicians use moderate dose (13-15 mg/kg) - practice varies; it is not guideline-mandated
- Immunosuppression only for AIH overlap or IgG4 disease - not for classic PSC
- Investigational: norursodeoxycholic acid, FXR agonists, vancomycin
Dominant stricture
- Suspect with rising bilirubin, worsening pruritus, cholangitis, or a rapid rise in ALP
- ERCP with brush cytology + FISH to exclude cholangiocarcinoma, then balloon dilatation (stenting no better and more complications)
- Antibiotic prophylaxis with every ERCP
Cholangitis
- Blood cultures, IV antibiotics, biliary drainage
- Recurrent episodes -> rotating/prophylactic antibiotics; a transplant indication in its own right
Symptom and complication control
- Pruritus: cholestyramine -> rifampicin -> naltrexone -> sertraline (as for PBC)
- Fat-soluble vitamin (ADEK) replacement; steatorrhoea
- Osteoporosis - calcium, vitamin D, DEXA every 2-3 years, bisphosphonate
- Vaccinate against hepatitis A and B
Surveillance - the core of management
| Target | Test | Interval |
|---|---|---|
| Cholangiocarcinoma / gallbladder cancer | MRCP +/- CA 19-9 | Annually |
| Gallbladder polyp | Ultrasound | Annually. *Cholecystectomy for any polyp >=8 mm - a high proportion are malignant* |
| Colorectal cancer (if IBD) | Colonoscopy | Annually, from the time of PSC diagnosis - not after 8 years |
| Cirrhosis | HCC surveillance, varices | 6-monthly ultrasound; endoscopy by stage |
- Investigate for cholangiocarcinoma on any sudden worsening of jaundice, weight loss, or other change in clinical status
Transplantation
- The only effective treatment. Indications: decompensated cirrhosis, recurrent bacterial cholangitis, intractable pruritus, and selected early hilar cholangiocarcinoma (neoadjuvant protocol)
- PSC recurs in the graft in ~8-20%
- Colitis may flare or first appear after transplant; colorectal cancer risk continues - keep annual colonoscopy going
Associations
- IBD - ~70%, usually ulcerative colitis (Crohn colitis less often). Only ~10% of IBD has PSC
- Cholangiocarcinoma, gallbladder carcinoma, colorectal cancer, HCC
- Autoimmune pancreatitis / IgG4-related disease (as a mimic and an overlap)
- Coeliac disease, type 1 diabetes, autoimmune thyroid disease
- Sarcoidosis
- Osteoporosis / hepatic osteodystrophy
- Peristomal varices after colectomy with ileostomy
Natural history & complications
- Median transplant-free survival ~12-20 years from diagnosis; highly variable
- Progressive, with fluctuating cholestasis; no reliable predictor of an individual course
Prognostic factors
| Good | Poor |
|---|---|
| Younger age at diagnosis | Extensive or dominant biliary strictures |
| Female sex | Recurrent cholangitis |
| Reduced or normal ALP | Coexisting ulcerative colitis (rather than Crohn) |
| Small-duct disease | Synthetic dysfunction; cirrhosis with portal hypertension |
- PSC-AIH overlap runs a course worse than classic AIH but better than classic PSC
- Mayo risk score, Amsterdam-Oxford model, ALP normalisation - prognostic tools
Complications
- Cholangiocarcinoma in 10-20% - highest risk in the first year after diagnosis; often at the hilum; frequently unresectable
- Gallbladder carcinoma - hence the 8 mm polyp threshold
- Colorectal cancer - markedly increased, right-sided
- HCC (only with cirrhosis)
- Recurrent bacterial cholangitis, choledocholithiasis (pigment stones)
- Portal hypertension, fat-soluble vitamin deficiency, metabolic bone disease
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