Autoimmune (IgG4) Cholangitis

Published on 19/07/2015 by admin

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Last modified 22/04/2025

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 Strictures long and smooth without irregularity and may cause proximal biliary dilatation

• MR: MRCP images nicely demonstrate irregularity and strictures of intrahepatic or extrahepatic bile ducts (most commonly affecting distal CBD)

image Affected segments demonstrate concentric ductal wall thickening with hyperenhancement on T1WI C+
image Stricture long and smooth (without irregularity)
image Findings of concomitant autoimmune pancreatitis

– Enlarged pancreas with abnormal signal (hypointense on T1WI and hyperintense on T2WI)
– Rim of peripheral hypoenhancement and low T2WI signal with delayed enhancement
– Multiple discontiguous pancreatic duct strictures on MRCP, which may resolve after administration of secretin
• CT: Circumferential focal or diffuse bile duct wall thickening with hyperenhancement of affected segments

PATHOLOGY

• Frequently associated with imaging findings of autoimmune pancreatitis and other manifestations of IgG4-related sclerosing disease
• Exact pathophysiology not well understood, but some evidence for both autoimmune and allergic mechanisms

CLINICAL ISSUES

• Typically affects middle-aged and elderly males
• Diagnosis based on a combination of imaging, histopathology, serologic (↑ IgG4) markers and clinical response to steroids/azathioprine
• May improve spontaneously, progress, or relapse, although relapse rate after therapy may be high (> 50%)
• Treatment with steroids typically effective, although other immunomodulators utilized in refractory cases
image
(Left) CECT of a jaundiced patient shows a thickened, slightly dilated common bile duct (CBD) image and an enlarged, sausage-shaped pancreas image. The appearance of the pancreas is consistent with autoimmune pancreatitis (AIP), and an elevated IgG4 indicates that the bile duct thickening is due to IgG4-related sclerosing cholangitis (ISC).

image
(Right) ERCP in same patient shows a stricture image of the distal CBD, the most common manifestation of ISC. ISC and AIP resolved after steroid and azathioprine therapy.
image
(Left) Coronal CECT in a patient with known autoimmune pancreatitis (not shown) demonstrates tapered narrowing of the distal CBD image with wall hyperenhancement, compatible with autoimmune cholangitis.

image
(Right) Coronal CECT in a patient with known autoimmune pancreatitis demonstrates wall thickening, hyperenhancement, and narrowing of the CBD image with proximal biliary dilatation image, in keeping with IgG4-related cholangitis.

TERMINOLOGY

Synonyms

• IgG4-related sclerosing disease (IRSD), IgG4-related sclerosing cholangitis (ISC)

Definitions

• IRSD: Spectrum of disorders characterized by tumor-like lymphoplasmacytic infiltration and varying degrees of fibrosis in different organs

image Pancreas is most commonly affected organ (autoimmune pancreatitis) followed by salivary glands and biliary tree
• ISC: Biliary manifestations of IRSD frequently associated with autoimmune pancreatitis (AIP)

image Manifested as wall thickening and biliary strictures

IMAGING

General Features

• Best diagnostic clue

image Bile duct wall thickening and strictures in setting of autoimmune pancreatitis
• Location

image ISC classified based upon stricture location

– Type 1: Distal (intrapancreatic) common bile duct (CBD)

image Most common type: May mimic pancreatic adenocarcinoma or cholangiocarcinoma
– Type 2: Strictures distributed throughout intra- and extrahepatic ducts

image May mimic primary sclerosing cholangitis
– Type 3: Strictures of duct bifurcation and distal duct

image May mimic cholangiocarcinoma
– Type 4: Isolated hilar stricture

image May mimic cholangiocarcinoma
• Size

image Variable: Focal or diffuse involvement of biliary tree
• Morphology

image Concentric bile duct wall thickening and hyperenhancement
image Typically long smooth stricture with upstream biliary ductal dilatation

Radiographic Findings

• ERCP

image Distal CBD stricture and irregularity of main pancreatic duct (due to concomitant AIP) most frequent findings
image Strictures of intra- and extrahepatic ducts rarely occur without pancreatic duct involvement
image Long, smooth strictures (particularly of distal CBD) without irregularity

CT Findings

• Circumferential focal or diffuse bile duct wall thickening

image Most commonly affects distal CBD, but can affect any portion of biliary tree
image Hyperenhancement of affected bile duct: Enhancement may persist during delayed phase
image No vascular invasion, metastatic disease, or other secondary findings of malignancy
• No clear association between ISC and malignancy, but involved sites in biliary tree may rarely appear mass-like and mimic malignancy (inflammatory pseudotumor)
• Diffuse gallbladder wall thickening (due to either lymphoplasmacytic infiltration and transmural fibrosis or superimposed cholecystitis)
• Findings of concomitant autoimmune pancreatitis

image Focal, multifocal, or diffuse (sausage-shaped) pancreatic enlargement with hypodense pancreatic capsule
image Enlargement of pancreas with a paucity of peripancreatic inflammation, fluid, or stranding
image Less enhancement than expected in arterial phase; parenchyma/capsule may show delayed enhancement
image Diffuse or segmental narrowing of pancreatic duct (may produce multiple discrete strictures)
image Rarely may be focal in morphology and mimic malignancy
• Additional extrabiliary manifestations of IRSD: Lymphadenopathy, sclerosing mesenteritis, retroperitoneal fibrosis, renal involvement

MR Findings

• MRCP images nicely demonstrate irregularity and strictures of intrahepatic or extrahepatic bile ducts 

image Affected segments demonstrate concentric ductal wall thickening with hyperenhancement on T1WI C+
image Ductal dilatation upstream from sites of narrowing or stricture
image Sites of stricture tend to be long and smooth (without wall irregularity)
• Diffuse gallbladder wall thickening
• Findings of concomitant autoimmune pancreatitis

image Enlarged pancreas with abnormal signal (hypointense on T1WI and hyperintense on T2WI)
image Rim of peripheral hypoenhancement and low T2WI signal with delayed enhancement
image Multiple discontiguous pancreatic duct strictures on MRCP, which may resolve after administration of secretin

Ultrasonographic Findings

• Intrahepatic biliary ductal dilatation
• Bile duct wall thickening: No specific sonographic features to differentiate autoimmune cholangitis from other forms of cholangitis
• Gallbladder wall thickening
• Focal or diffuse enlargement/hypoechogenicity of pancreas (concomitant autoimmune pancreatitis)

Imaging Recommendations

• Best imaging tool

image MRCP, ERCP

DIFFERENTIAL DIAGNOSIS

Primary Sclerosing Cholangitis

• Irregular strictures affecting both intra- and extrahepatic bile ducts with alternating sites of dilatation, stricture, and normal-appearing ducts

image Classically produces “beaded” strictures with “pruning” of the biliary tree in the more chronic setting
• Usually seen in younger patients with a more indolent course than ISC
• Unlike PSC, ISC more commonly affects distal CBD and tends to demonstrate longer segment strictures
• Associated with inflammatory bowel disease (uncommon in ISC)

Ascending Cholangitis

• Usually results from biliary obstruction (most often due to choledocholithiasis)
• Thickening and hyperenhancement of bile ducts with upstream biliary dilatation and heterogeneous liver parenchymal enhancement
• Patients are typically septic and febrile

Benign Biliary Stricture

• Benign stricture of CBD due to prior biliary catheterization or passed stone
• No mural thickening, hyperenhancement, or imaging features of autoimmune cholangitis

Cholangiocarcinoma

• Focal irregular mural thickening or intraductal papillary mass

image Involved sites may demonstrate delayed contrast enhancement due to fibrous stroma of tumor
• Other signs of malignancy often present, including vascular encasement, lymphadenopathy, and metastases

AIDS Cholangiopathy

• Opportunistic infections affecting biliary tree in AIDS patients with very low CD4 counts (usually < 100)
• Papillary stenosis frequent, with tapered narrowing of distal CBD and upstream biliary dilatation
• Long segment extrahepatic duct strictures and gallbladder wall thickening may be present, while involvement of intrahepatic biliary tree can closely mimic PSC

Pancreatic Adenocarcinoma

• Presence of distal CBD stricture and narrowing/irregularity of pancreatic duct due to autoimmune pancreatitis in ISC may raise concern for pancreatic adenocarcinoma
• No discrete mass present in most cases of ISC, but focal autoimmune pancreatitis may be very difficult to distinguish from malignancy

PATHOLOGY

General Features

• Etiology

image Exact pathophysiology not well understood
image Some evidence for both autoimmune and allergic mechanisms
• Associated abnormalities

image Frequently associated with autoimmune pancreatitis
image Involvement of other organs in setting of IRSD

Staging, Grading, & Classification

• Other sites of involvement in IRSD

image Most common: Autoimmune pancreatitis, autoimmune sclerosing cholangitis, sialadenitis (Mikulicz disease), nephritis, lymphadenopathy
image Less common: Cholecystitis, orbital pseudotumor, dacryoadenitis, retroperitoneal fibrosis, Riedel thyroiditis, interstitial pneumonitis, sclerosing mesenteritis, vasculitis, hypophysitis
• 60-90% have multiple organ involvement (2/3 had involvement of ≥ 3 organs in one study)

image In a retrospective study of 57 patients with IRSD, 36/57 (∼ 65%) had involvement of ≥ 3 organs

Gross Pathologic & Surgical Features

• Ductal wall thickening and stricture

image Intrapancreatic common bile duct is the most commonly involved segment

Microscopic Features

• Ductal wall thickening
• Periductal inflammation with IgG4-positive plasma cells and T cells
• Fibrosis

CLINICAL ISSUES

Presentation

• Most common signs/symptoms

image Jaundice
image ↑ alkaline phosphatase
image ↑ serum IgG4 level

– Very small subset of PSC patients (< 10%) may also have elevated IgG4 levels
image Signs/symptoms of associated autoimmune pancreatitis: Epigastric pain, ↑ amylase/lipase
• Other signs/symptoms

image Signs/symptoms related to involvement of other organs in setting of IRSD
image 40% of patients have history of allergy or asthma
• Clinical profile

image Diagnosis is made based on a combination of imaging, histopathology, elevated IgG4, and clinical response to steroids/azathioprine

Demographics

• Age

image Middle-age and elderly (most often 5th and 6th decades)
• Gender

image M > F (up to 8:1)

Natural History & Prognosis

• May improve spontaneously, progress, or relapse, although relapse rate after therapy may be high (> 50%)
• No known association with cholangiocarcinoma or pancreatic cancer

Treatment

• Immunosuppression effective, though no randomized trials performed
• Steroids most often induce long-term remission, although relapse may occur, particularly if there is extensive biliary and extrabiliary involvement

image Other immunomodulator drugs (i.e., azathioprine) utilized for refractory or recurrent disease
image If therapy effective, clinical and cholangiographic improvement seen within 6 weeks of treatment
• Biliary stenting of extrahepatic strictures

DIAGNOSTIC CHECKLIST

Image Interpretation Pearls

• Imaging features of ISC and PSC may overlap, although demographics and course of disease are different for each

image PSC seen in younger patients with more indolent course
image ISC has more acute presentation, is seen in older patients, responds to steroids, and may be associated with extrabiliary manifestations of IRSD
image Some authors suggest that ISC and PSC are not completely separate conditions and indeed may be variations of same disease spectrum
image
(Left) CECT of an elderly man with jaundice shows thickening of the proximal right and left hepatic ducts image and mild intrahepatic biliary ductal dilatation.

image
(Right) Cholangiogram of the same patient shows strictures image of the proximal right and left hepatic ducts. The patient’s serum IgG4 was not elevated, but the strictures improved with empiric steroid therapy. An elevated IgG4 is a highly sensitive and specific marker for ISC, though IgG4 levels may vary widely during the disease course.
image
(Left) Axial CECT of a middle-aged woman with jaundice and abdominal pain shows a diffusely enlarged pancreatic body/tail image and mild thickening of the common duct image post stent placement.

image
(Right) ERCP of the same patient shows a hilar stricture image. The patient had an elevated IgG4, and these imaging findings were found to represent AIP and ISC. The patient also had Riedel thyroiditis, a finding indicating a systemic fibrosclerosing process. The stricture and AIP improved after steroid therapy.
image
(Left) MRCP of an elderly man with jaundice shows a proximal common duct-hilar stricture image and mild intrahepatic biliary dilatation. The location of the stricture strongly suggested cholangiocarcinoma, but an elevated serum IgG4 and positive IgG4 staining at cytology indicated ISC.

image
(Right) ERCP of the same patient shows a complex stricture image extending into the proximal right and left hepatic ducts. A preoperative diagnosis of ISC may be difficult if imaging findings of AIP are absent.
image
Numerous IgG4(+) plasma cells image are demonstrated by immunohistochemical stain performed on a bile duct biopsy, confirming the diagnosis of IgG4-associated cholangitis. (Courtesy H. Wang, MD, PhD.)

image
A biopsy of a strictured extrahepatic bile duct of a different patient shows dense lymphoplasmacytic infiltrates, typical histologic findings of IgG4-associated cholangitis. A coexistent pancreatic head lesion initially prompted an imaging diagnosis of a pancreatic carcinoma and a malignant biliary stricture. (Courtesy H. Wang, MD, PhD.)

SELECTED REFERENCES

1. Joshi, D, et al. Review article: biliary and hepatic involvement in IgG4-related disease. Aliment Pharmacol Ther. 2014. [ePub].

 

Zen, Y, et al. IgG4 Cholangiopathy. Int J Hepatol. 2012; 2012:472376.

Nakazawa, T, et al. Diagnostic procedures for IgG4-related sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2011; 18(2):127–136.

Okazaki, K, et al. Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease. J Gastroenterol. 2011; 46(3):277–288.

Vlachou, PA, et al. IgG4-related sclerosing disease: autoimmune pancreatitis and extrapancreatic manifestations. Radiographics. 2011; 31(5):1379–1402.

Naitoh, I, et al. Clinical significance of extrapancreatic lesions in autoimmune pancreatitis. Pancreas. 2010; 39(1):e1–e5.

Alderlieste, YA, et al. Immunoglobulin G4-associated cholangitis: one variant of immunoglobulin G4-related systemic disease. Digestion. 2009; 79(4):220–228.

Itoh, S, et al. Lymphoplasmacytic sclerosing cholangitis: assessment of clinical, CT, and pathological findings. Clin Radiol. 2009; 64(11):1104–1114.

Webster, GJ, et al. Autoimmune pancreatitis/IgG4-associated cholangitis and primary sclerosing cholangitis—overlapping or separate diseases? J Hepatol. 2009; 51(2):398–402.

Ghazale, A, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008; 134(3):706–715.

Kamisawa, T, et al. IgG4-related sclerosing disease. World J Gastroenterol. 2008; 14(25):3948–3955.

Chari, ST, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006; 4(8):1010–1016. [quiz 934].

Kamisawa, T, et al. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006; 41(7):613–625.

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