IgG4 Cholangiopathy: A Diagnostic and Therapeutic Challenge

Rowen K. Zetterman, MD


July 15, 2014

In This Article

IgG4 Cholangiopathy: A Complex Disease

IgG4 cholangiopathy belongs to a spectrum of systemic inflammatory disorders that affect multiple organ systems and are associated with elevated serum IgG4 levels or bile duct inflammation that includes IgG4 plasma cells.[1] The manifestations of these systemic inflammatory disorders (known as "IgG4-related diseases"[2]) include diffuse inflammatory changes or pseudotumors of involved organs. Infiltration of T-cells and IgG4 plasma cells, coupled with a storiform pattern of fibrosis and obliterative venous vascular changes, contribute to tissue manifestations.

Autoimmune pancreatitis and IgG4 cholangiopathy are the most common disorders[3]; they frequently occur together, although cholangiopathy can occur in the absence of autoimmune pancreatitis.[4] Other manifestations include sialadenitis, lacrimal gland disease, retroperitoneal fibrosis, inflammatory pseudotumors of the liver, interstitial lung disease, generalized lymphadenopathy of the abdomen, retro-orbital fibrosis, and prostate and thyroid fibrosing disorders.[2,5,6] Pseudotumors of the kidney due to IgG4 immune complex-related tubulointerstitial nephritis also develop in conjunction with autoimmune pancreatitis.[7] An association of IgG4 cholangiopathy with inflammatory bowel disease can be found, adding to the diagnostic confusion of whether concomitant bile duct disease is a consequence of sclerosing cholangitis or IgG4 cholangiopathy.[8]

Cholangiopathy and Autoimmune Pancreatitis

IgG4 cholangiopathy frequently occurs in conjunction with autoimmune pancreatitis, the pancreatic expression of IgG4-related disease. Pancreatic manifestations of IgG4-related disease include diffuse pancreatic swelling, mass lesions, pseudocysts, and pancreatic ductal stenosis,[5,9,10] Of patients with chronic pancreatitis, 6% have an autoimmune origin that results in destruction of pancreatic acini, obliterative venous disease, pancreatic fibrosis, and IgG4 plasma cell infiltration.[11]

Two types of autoimmune pancreatitis are observed.[12,13]

Subtype 1

Subtype 1 is an IgG4-associated systemic disorder with pancreatic involvement; it is more common in men, especially older men.[14] The symptoms are nonspecific and include mild epigastric abdominal pain, epigastric tenderness, and associated weight loss. Pancreatic involvement is diffuse, with pancreatic swelling, or is seen as a mass on radiologic imaging. IgG4-related pancreatitis must be considered as a cause of pancreatic mass to avoid unnecessary resection for suspected cancer.

In addition to pancreatic involvement, IgG4-related disease of other organs is present in up to 60% of patients.[12] Serum IgG4 levels are typically elevated.

Ultrasonography may identify a diffusely hypoechoic, swollen, sausage-shaped pancreas. Focal hypoechoic areas suggestive of tumor may be apparent. Stenosis of the intrapancreatic portion of the distal common bile duct from IgG4 cholangiopathy results in obstructive jaundice in 40% of patients.[15] CT may show delayed contrast enhancement of the pancreas, a low-density rim surrounding the pancreas that is suggestive of a "capsule," diffuse pancreatic swelling, or a mass lesion. Cholangiography may reveal diffuse narrowing of the pancreatic duct, with limited dilation of the normal proximal pancreatic duct.

Subtype 1 IgG4-related autoimmune pancreatitis is typically responsive to steroid therapy, although relapse after treatment is common[13] and is more likely in those with proximal bile duct involvement and diffuse pancreatic swelling.[12] Long-term immunosuppressive maintenance therapy may be required.

Subtype 2

Subtype 2 IgG4-related autoimmune pancreatitis is typically a pancreas-specific disorder not associated with increased serum IgG4.[13] The disease is equally distributed in men and women, and it is associated with a younger age at onset of pancreatitis (in one third of patients) or obstructive jaundice. Inflammatory bowel disease is more likely in subtype 2 than in subtype 1 IgG4 cholangiopathy.

Serum IgG4 levels are typically normal and serum amylase levels elevated in patients with subtype 2 disease. Pancreatic histology reveals less fibrosis, less obliterative phlebitis, and infiltration by fewer IgG4 plasma cells. The histologic characteristic of subtype 2 is a granulocytic-epithelial lesion with granulocytic cell infiltration of the pancreas, coupled with pancreatic duct obstruction and an absence of IgG4 plasma cells.[16]

Subtype 2 autoimmune pancreatitis is responsive to steroid therapy and less frequently relapses after treatment than does subtype 1.


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