Cholestatic Liver Disease Differential
On this page
Direct answer
Cholestatic liver disease is impaired bile flow, recognised by a predominantly raised alkaline phosphatase (ALP) with a matching rise in gamma-glutamyl transferase (GGT). The commonest intrinsic causes are primary biliary cholangitis, which is antimitochondrial antibody positive in middle-aged women, and primary sclerosing cholangitis, which is linked with ulcerative colitis. Drug-induced, infiltrative and extrahepatic obstruction must be excluded before a diagnosis is made.
What you must remember
- R ratio: the ALT multiple of normal divided by the ALP multiple of normal; above 5 suggests hepatocellular injury, below 2 suggests cholestasis, and 2 to 5 is mixed.
- Confirming a hepatic source: a raised GGT with raised ALP confirms liver origin, whereas bone disease raises ALP with a normal GGT.
- Primary biliary cholangitis: middle-aged women, antimitochondrial antibody (M2) positive, treated with ursodeoxycholic acid at 13 to 15 mg/kg/day.
- Primary sclerosing cholangitis: predominantly men with ulcerative colitis, often p-ANCA positive, with multifocal strictures on MRCP.
- Drug-induced cholestasis: amoxicillin-clavulanate, flucloxacillin, chlorpromazine, oral contraceptives and anabolic steroids are classic causes.
- Infiltrative causes: sarcoidosis, lymphoma, tuberculosis, amyloidosis and metastatic disease.
- Extrahepatic obstruction: choledocholithiasis, cholangiocarcinoma and carcinoma of the pancreatic head, all of which dilate the ducts.
- Imaging rule: dilated bile ducts on ultrasound point to obstruction, whereas normal ducts point to an intrahepatic cause.
A woman with itching and a raised ALP
A 52-year-old woman has had itching for six months, with raised ALP and GGT but near-normal transaminases. She has no jaundice and no weight loss, and her liver ultrasound shows no dilated ducts.
| Cause | Typical clue | Key test |
|---|---|---|
| Primary biliary cholangitis | Middle-aged woman, pruritus | Antimitochondrial antibody, response to ursodeoxycholic acid |
| Primary sclerosing cholangitis | Man with ulcerative colitis | MRCP showing beaded, multifocal strictures |
| Drug-induced | New medicine, rash or hypersensitivity | Drug history, improvement after withdrawal |
| Infiltrative | Systemic illness, granulomas | Biopsy, staging imaging |
| Choledocholithiasis | Colicky pain, fever | Dilated ducts on ultrasound, MRCP or ERCP |
| Pancreatic or biliary cancer | Weight loss, painless jaundice | CT or MRCP, then biopsy |
The R ratio places the pattern, and the table then sorts causes by clinical clue and the next test. In practice, antimitochondrial antibody is sent first and ultrasound is the first imaging, because a dilated duct changes the pathway. If the ducts are dilated, the question becomes where the obstruction lies, while normal ducts shift the focus to intrahepatic causes such as primary biliary cholangitis, sclerosing cholangitis and infiltration.
Where the examiner tests the cholestatic pattern
Most errors come from attributing a raised ALP to the wrong organ or from applying the wrong treatment.
- Trap: calling every raised ALP bone disease without checking GGT Correct: GGT confirms a hepatic source, because bone disease raises ALP with a normal GGT.
- Trap: giving high-dose ursodeoxycholic acid to a patient with PSC and expecting PBC-style benefit Correct: high-dose therapy does not improve outcome in PSC, so management is supportive, endoscopic and ultimately transplantation.
- Trap: overlooking amoxicillin-clavulanate in a patient with a new cholestatic picture Correct: it is a leading cause of drug-induced cholestasis, and stopping the drug is the first step.
Frequently asked questions
Which antibody is most strongly linked with primary biliary cholangitis?
Antimitochondrial antibody, particularly the M2 subtype, is the antibody most strongly associated with primary biliary cholangitis, and it supports the diagnosis when ALP is raised. Anti-gp210 and anti-sp100 antibodies are more specific markers in patients who are antimitochondrial negative.
What is the typical MRCP finding in primary sclerosing cholangitis?
MRCP in primary sclerosing cholangitis typically shows multifocal strictures alternating with dilatations, often described as a beaded appearance of the intrahepatic and extrahepatic ducts. This pattern helps distinguish it from a single obstructing lesion such as a stone or cancer.
Which drugs are classic causes of cholestatic jaundice?
Amoxicillin-clavulanate, flucloxacillin, chlorpromazine, oral contraceptives and anabolic steroids are classic causes of drug-induced cholestasis. The diagnosis is made only after other causes are excluded, and stopping the offending drug is the first step in management.
How is the R ratio calculated and interpreted?
The R ratio is the ALT multiple of normal divided by the ALP multiple of normal, with each value taken against its own upper limit. A value above 5 suggests a hepatocellular pattern, a value below 2 suggests a cholestatic pattern, and a value between 2 and 5 suggests a mixed pattern.
Why is ursodeoxycholic acid used in primary biliary cholangitis?
Ursodeoxycholic acid is the first-line drug in primary biliary cholangitis, usually given at 13 to 15 mg/kg/day, and it improves biochemistry and slows disease progression. Patients who respond poorly are offered second-line therapy such as bezafibrate, elafibranor or seladelpar, because obeticholic acid has been withdrawn from several markets.