EASL Clinical Practice Guidelines

Immunoglobulin G4-associated cholangitis

Diagnosis

Immunoglobulin G4-associated cholangitis (IAC) is a recently described biliary disease of unknown etiology that presents with biochemical and cholangiographic features indistinguishable from PSC, frequently involves the extrahepatic bile ducts, responds to anti-inflammatory therapy, is often associated with autoimmune pancreatitis and other fibrosing conditions, and is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts and liver tissue [[153], [154], [155], [156], [157], [158], [159]]. In contrast to PSC, IAC is not associated with IBD. Preliminary data suggest that immunopathogenesis of IAC strikingly differs from other immune-mediated cholestatic liver diseases like PSC and PBC in that T helper 2 (Th2) and T regulatory (Treg) cytokines were markedly overexpressed in IAC patients [158]. In the largest cohorts of 53 and 17 IAC patients, respectively [[159], [157]], median age at diagnosis of the mostly male patients (7/8) was around 60 years.

The diagnosis of IAC was recently proposed to be definitive if a patient with biliary stricture(s) in the intrahepatic, proximal extrahepatic and/or intrapancreatic bile ducts

  1. has recently undergone pancreatic/biliary surgery or core biopsy of the pancreas showing diagnostic features of autoimmune pancreatitis (AIP)/IAC; or
  2. shows classical imaging findings of AIP and elevated IgG4; or
  3. fulfils two of the following criteria (elevated serum IgG4; suggestive pancreatic imaging findings; other organ manifestations including sclerosing sialadenitis, retroperitoneal fibrosis, or gastrointestinal involvement and abdominal lymphadenopathy with infiltration of IgG4-positive plasma cells; >10 IgG4-pos. plasma cells per high power field in bile duct biopsies) and shows an adequate response to a 4-week course of corticosteroid treatment to allow stent removal without relapse of obstructive cholestasis, to reach serum liver tests <2× ULN, and to present decreasing IgG4 and CA 19-9 [159].
Although not yet cross-validated in an independent cohort of IAC patients, this diagnostic recommendation may temporarily serve as a guideline for diagnosis of IAC.

Treatment

Immunosuppressive treatment has been shown to exert a marked effect on inflammatory activity of IAC, and complete long-term remission after three months of treatment has been reported. However, the extent of disease may affect the long-term response, and a retrospective analysis showed that patients with alterations of proximal extrahepatic and intrahepatic bile ducts are prone to a higher risk of relapse after stop of treatment than patients with distal bile duct strictures only [159]. Thus, corticosteroids are regarded as the initial treatment of choice in this disease, and azathioprine at doses up to 2 mg/kg/d should be considered in those with proximal and intrahepatic stenoses and those after relapse during/after corticosteroid therapy. Treatment duration of 3 months may be sufficient for some patients, but long-term maintenance therapy at low doses may be required when disease activity has not completely come to a standstill or has relapsed.

Recommendations

  1. IAC is a corticosteroid-responsive (II-2/C2) sclerosing cholangitis of unknown immunopathogenesis which, unlike PSC, affects mostly older patients and has a good long-term prognosis after adequate response to immunosuppressive treatment (II-2/C2).
  2. The diagnosis of IAC is proposed to be made in patients with cholangiographic findings typical of sclerosing cholangitis on the basis of (i) histological features of autoimmune pancreatitis (AIP)/IAC or (ii) classical imaging findings of AIP and elevated IgG4; or (iii) two diagnostic biochemical, histological and imaging criteria and an adequate response to a 4-week course of corticosteroid treatment to allow biliary stent removal without relapse of obstructive cholestasis, and to reach serum liver tests <2× ULN (III/C2).
  3. Long-term treatment of IAC with corticosteroids and/or azathioprine may be needed after relapse or for inadequate response (III/C2).