Autoimmune Hepatitis, Primary Biliary Cholangitis & Primary Sclerosing Cholangitis
Match the patient, the antibody and the duct picture to the right treatment
Three autoimmune liver diseases
The target sets the pattern. Autoimmune hepatitis (AIH) attacks hepatocytes and produces a hepatocellular pattern with a raised IgG. Primary biliary cholangitis (PBC) destroys small intrahepatic bile ducts, and primary sclerosing cholangitis (PSC) scars intra- and extrahepatic ducts; both produce a cholestatic pattern with a raised ALP. Demographics, antibodies and duct imaging separate them.
| Feature | AIH | PBC | PSC |
|---|---|---|---|
| Typical patient | Young or middle-aged woman; other autoimmunity | Woman aged ~40–60; Sjögren, thyroid disease | Man aged ~30–40; ulcerative colitis in ~70% |
| Pattern | ↑ALT/AST, ↑IgG | ↑ALP, ↑IgM | ↑ALP |
| Serology | ANA, anti-smooth muscle (type 1); anti-LKM1 (type 2) | AMA (~95%) | p-ANCA (nonspecific); AMA negative |
| Diagnosis | Biopsy: interface hepatitis, plasma cells | AMA + ↑ALP; biopsy rarely needed | MRCP: multifocal strictures, beading |
| Treatment | Prednisone or budesonide + azathioprine | Lifelong ursodiol; second-line add-on if needed | No effective drug; transplant |
Autoimmune hepatitis
Presentation. AIH mostly affects young or middle-aged women, often with another autoimmune disease—Hashimoto thyroiditis, type 1 diabetes, celiac disease, ulcerative colitis. It may surface as an incidental ALT rise, chronic fatigue and arthralgia, an acute hepatitis with ALT above 1000, or acute liver failure; about a third of adults already have cirrhosis at diagnosis.
Serology. Polyclonal hypergammaglobulinemia with a raised IgG is characteristic. Type 1 AIH, the usual adult form, has ANA and/or anti-smooth muscle (anti-actin) antibodies. Type 2, mainly in children and often more aggressive, has anti-liver-kidney microsomal type 1 antibodies (anti-LKM1, directed against CYP2D6). Anti-soluble liver antigen (anti-SLA) is highly specific when present.
Biopsy. Histology is usually required: interface hepatitis—lymphoplasmacytic inflammation eroding the limiting plate—with abundant plasma cells, hepatocyte rosettes and emperipolesis. Viral hepatitis, Wilson disease and drug injury must be excluded; nitrofurantoin and minocycline can produce an AIH-like picture that often resolves once the drug is stopped.
Treatment. Induce remission with prednisone plus azathioprine. Budesonide can replace prednisone when there is no cirrhosis; in cirrhosis, portosystemic shunting bypasses its first-pass hepatic metabolism and raises systemic exposure. Check thiopurine methyltransferase (TPMT) activity before azathioprine, because low activity causes severe myelosuppression. The goal is biochemical remission—normal ALT and IgG—followed by long-term maintenance, since relapse after withdrawal is common. Mycophenolate is the usual second-line drug; transplantation is reserved for acute liver failure or decompensated cirrhosis.
Primary biliary cholangitis
Presentation. PBC is a granulomatous, nonsuppurative destruction of small intrahepatic bile ducts (the "florid duct lesion") in women aged roughly 40–60. Fatigue and pruritus lead, although many patients are found through an incidental ALP rise; jaundice comes late. Antimitochondrial antibody (AMA) against the E2 subunit of pyruvate dehydrogenase (anti-PDC-E2) is positive in about 95%, and IgM is raised.
Diagnosis. An ALP at least 1.5 times the upper limit of normal plus an AMA titer ≥1:40, with normal ducts on ultrasound, establishes PBC without biopsy. Biopsy is reserved for AMA-negative disease—where PBC-specific ANA (anti-sp100, anti-gp210) helps—or suspected overlap with AIH.
Associations and complications. Sjögren syndrome, autoimmune thyroiditis with hypothyroidism, Raynaud phenomenon and limited scleroderma (CREST), and celiac disease travel with PBC. Complications include osteoporosis (DEXA at diagnosis and periodically); hyperlipidemia with xanthelasma and xanthomas, mostly HDL and lipoprotein X without a clear rise in cardiovascular risk; fat-soluble vitamin (A, D, E, K) deficiency with steatorrhea; and eventually cirrhosis, portal hypertension (variceal screening once present) and hepatocellular carcinoma.
Treatment. Ursodeoxycholic acid, 13–15 mg/kg/day for life, improves liver tests, slows progression and prolongs transplant-free survival. Response is judged at 12 months; an inadequate response prompts an add-on PPAR agonist (elafibranor or seladelpar, or an off-label fibrate such as bezafibrate or fenofibrate); obeticholic acid, the former FXR-agonist add-on, worsens pruritus, caused serious liver injury and has been withdrawn from the market. Treat pruritus first with cholestyramine, taken at least 4 hours apart from ursodiol and other drugs, then rifampin (with liver-test monitoring), naltrexone or sertraline. Transplantation is indicated for decompensated cirrhosis or intractable pruritus.
Primary sclerosing cholangitis
Presentation. PSC is a fibrosing inflammation of intra- and extrahepatic bile ducts, mostly in men in their 30s–40s; about 70% have inflammatory bowel disease, usually ulcerative colitis. It may be found as an asymptomatic ALP rise in a patient with colitis or present with fatigue, pruritus, jaundice or bacterial cholangitis. Atypical p-ANCA is common but nonspecific, and AMA is negative.
Diagnosis. MRCP is the test of choice, showing multifocal strictures alternating with dilations ("beading"). Diagnostic ERCP is avoided because of pancreatitis and cholangitis risk and is kept for intervention. Biopsy shows concentric "onion-skin" periductal fibrosis and is needed only for small-duct PSC, in which the cholangiogram is normal.
| Cancer | Risk | Surveillance |
|---|---|---|
| Cholangiocarcinoma | Lifetime ~10–20% | MRCP or ultrasound ± CA 19-9 every 6–12 months |
| Gallbladder cancer | Polyps carry high malignant potential | Annual imaging; cholecystectomy for polyps ≥8 mm |
| Colorectal cancer (with IBD) | Higher than colitis alone | Colonoscopy at PSC diagnosis, then annually |
| Hepatocellular carcinoma | Once cirrhosis develops | Ultrasound every 6 months |
Dominant strictures. New jaundice, rising bilirubin, worsening pruritus or cholangitis with a dominant stricture on MRCP calls for ERCP with brush cytology (± FISH) to exclude cholangiocarcinoma, plus balloon dilation; bacterial cholangitis is treated with antibiotics.
Treatment. No medical therapy alters the natural history. Ursodiol may improve liver tests but not survival, and high doses (28–30 mg/kg/day) increased serious adverse outcomes. Liver transplantation is the only definitive treatment—for decompensated cirrhosis, recurrent cholangitis or intractable pruritus—and PSC can recur in the graft. Colectomy for colitis does not change the course of PSC.
IgG4-related sclerosing cholangitis and overlap
The steroid-responsive mimic. IgG4-related sclerosing cholangitis can resemble PSC or hilar cholangiocarcinoma but typically affects older men and accompanies type 1 autoimmune pancreatitis—a diffusely enlarged, "sausage-shaped" pancreas—and other organ involvement such as salivary gland enlargement and retroperitoneal fibrosis. Serum IgG4 is usually raised, and tissue shows IgG4-positive plasma cells with storiform fibrosis. It responds dramatically to corticosteroids; relapses are treated with azathioprine or rituximab.
Measure IgG4 at least once in every patient labeled PSC—the mimic is treatable, PSC is not.
Overlap syndromes. Features of AIH can coexist with PBC or PSC (AIH–sclerosing cholangitis overlap is especially common in children); these patients usually need immunosuppression added to therapy for the cholestatic disease.