IgG4 Cholangiopathy: A Diagnostic and Therapeutic Challenge
IgG4 Cholangiopathy: A Diagnostic and Therapeutic Challenge
Patients presenting with IgG4-related cholangiopathy are typically men aged 50-60 years, and more than 75% will present with common bile duct obstruction and jaundice.
Coexisting pancreatic disease, biliary strictures, bile duct masses, or head of pancreas mass can all be found. Characteristic clinical findings also include epigastric abdominal pain, jaundice, weight loss, and epigastric tenderness. Pancreatic insufficiency with steatorrhea can develop, and new-onset diabetes mellitus is present in approximately 50% of those with concomitant autoimmune pancreatitis. Association with other IgG4-related disorders (such as axillary lymphadenopathy or salivary gland enlargement) may be helpful clues that the patient has IgG4-related cholangiopathy.
Stricturing of the intrapancreatic portion of the distal common bile duct is the most frequent bile duct finding. Narrowing of the ducts at the biliary hilum may also be seen, raising questions of cholangiocarcinoma, sclerosing cholangitis, or other causes of bile duct strictures.
Obtaining biopsies of the distal common bile duct, pancreas, or ampulla to look for IgG4 plasma cells may assist in diagnosis of IgG4 cholangiopathy.
Serum IgG4 elevation is the laboratory hallmark of IgG4 cholangiopathy. IgG4 normally accounts for 5% of total circulating IgG. In a study of 1412 patients, IgG4 levels ≥ 135 mg/dL were 80% sensitive and 86% specific for the diagnosis of autoimmune pancreatitis and/or IgG4 cholangiopathy. Serum levels > 300 mg/dL are highly specific. However, mild elevation of serum IgG4 alone is not specific and occurs in patients with cholangiocarcinoma, especially those with underlying sclerosing cholangitis. Serum IgG4 levels may decline with immunosuppressive therapy, although normalization of levels is unlikely.
In addition to elevation of serum IgG4, nonspecific increases of total gamma-globulin and IgG and such non-organ-specific autoantibodies as antinuclear antibody and rheumatoid factor can be present. Peripheral eosinophilia occurs in as many as 15% of patients with IgG4-related disorders. Laboratory evidence of cholestasis with elevation of alkaline phosphatase, bilirubin, and gamma-glutamyltransferase, coupled with modest elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, are frequently present in IgG4 cholangiopathy. An elevated bilirubin level favors the diagnosis of IgG4 cholangiopathy over sclerosing cholangitis.
The biliary tract changes associated with IgG4 cholangiopathy are similar to those seen in sclerosing cholangitis, and cholangiography alone may not reliably separate IgG4-associated cholangiopathy from sclerosing cholangitis or cholangiocarcinoma. IgG4 cholangiopathy is more likely to produce simultaneous strictures of the intrapancreatic portion of the distal common bile duct and of the hepatic hilum, and the association with autoimmune pancreatitis may help with diagnosis. IgG4 cholangiopathy can produce both short and long segmental strictures of biliary ducts with proximal duct dilation, although changes may be limited to the distal common bile duct. Peripheral hepatic bile duct involvement can occur, along with large bile duct involvement.
Endoscopic ultrasonography with needle biopsy of the head of the pancreas may exclude pancreatic carcinoma as a cause of segmental narrowing of the intrapancreatic bile duct. Intraductal ultrasonography may identify bile-duct wall thickening in nonstenotic bile duct segments and assist in differentiation of IgG4 cholangiopathy from cholangiocarcinoma. Gallbladder wall thickening affects 25% of patients with IgG4 disease.
In patients with cholangiopathy and pancreatic involvement, CT shows diffuse or focal pancreatic edema, pancreatic enlargement, focal pancreatic masses, pancreatic atrophy, or peripancreatic hypoattenuation. This pancreas rim or "capsule" is evident in 12%-40% of cases of autoimmune pancreatitis. Focal changes of the pancreas can mimic pancreatic carcinoma. Delayed enhancement of the pancreas on CT and lack of proximal pancreatic duct dilation may be helpful in differentiating autoimmune pancreatitis from pancreatic carcinoma.
Endoscopic ultrasonography of IgG4 cholangiopathy can identify biliary wall thickening with luminal preservation and a normal hyperechoic outer wall of the duct. Narrowing of the portal, splenic, or superior mesenteric veins develops in up to 70% of patients with IgG4-related disease of the pancreas and common bile duct. However, the changes of sclerosing cholangitis and IgG4 cholangiopathy can be difficult to separate at endoscopic ultrasonography. Obtaining biopsies of the bile duct, pancreas, or duodenal papilla, which are evaluated for IgG4 cells, may assist in diagnosis.
The histologic hallmark of IgG4-related disease is tissue infiltration with IgG4 plasma cells.The finding of more than 10 IgG4-positive plasma cells per high-power field at tissue microscopy may establish the diagnosis. Bile duct inflammation is typically dense and transmural, and is associated with eosinophils, fibrosis, and obliterative phlebitis. Liver histology of patients with IgG4 cholangiopathy shows more portal and lobular inflammation than sclerosing cholangitis with portal areas containing plasma cells and eosinophils, perivenular inflammation, and limited inflammation of the bile ducts. IgG4 plasma cells are often present. Other manifestations include sclerosis of portal areas with minimal inflammation, lobular hepatitis, and cholestasis.
Clinical Features of IgG4 Cholangiopathy
Patients presenting with IgG4-related cholangiopathy are typically men aged 50-60 years, and more than 75% will present with common bile duct obstruction and jaundice.
Coexisting pancreatic disease, biliary strictures, bile duct masses, or head of pancreas mass can all be found. Characteristic clinical findings also include epigastric abdominal pain, jaundice, weight loss, and epigastric tenderness. Pancreatic insufficiency with steatorrhea can develop, and new-onset diabetes mellitus is present in approximately 50% of those with concomitant autoimmune pancreatitis. Association with other IgG4-related disorders (such as axillary lymphadenopathy or salivary gland enlargement) may be helpful clues that the patient has IgG4-related cholangiopathy.
Stricturing of the intrapancreatic portion of the distal common bile duct is the most frequent bile duct finding. Narrowing of the ducts at the biliary hilum may also be seen, raising questions of cholangiocarcinoma, sclerosing cholangitis, or other causes of bile duct strictures.
Obtaining biopsies of the distal common bile duct, pancreas, or ampulla to look for IgG4 plasma cells may assist in diagnosis of IgG4 cholangiopathy.
Laboratory Markers
Serum IgG4 elevation is the laboratory hallmark of IgG4 cholangiopathy. IgG4 normally accounts for 5% of total circulating IgG. In a study of 1412 patients, IgG4 levels ≥ 135 mg/dL were 80% sensitive and 86% specific for the diagnosis of autoimmune pancreatitis and/or IgG4 cholangiopathy. Serum levels > 300 mg/dL are highly specific. However, mild elevation of serum IgG4 alone is not specific and occurs in patients with cholangiocarcinoma, especially those with underlying sclerosing cholangitis. Serum IgG4 levels may decline with immunosuppressive therapy, although normalization of levels is unlikely.
In addition to elevation of serum IgG4, nonspecific increases of total gamma-globulin and IgG and such non-organ-specific autoantibodies as antinuclear antibody and rheumatoid factor can be present. Peripheral eosinophilia occurs in as many as 15% of patients with IgG4-related disorders. Laboratory evidence of cholestasis with elevation of alkaline phosphatase, bilirubin, and gamma-glutamyltransferase, coupled with modest elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, are frequently present in IgG4 cholangiopathy. An elevated bilirubin level favors the diagnosis of IgG4 cholangiopathy over sclerosing cholangitis.
Radiologic Evaluation
The biliary tract changes associated with IgG4 cholangiopathy are similar to those seen in sclerosing cholangitis, and cholangiography alone may not reliably separate IgG4-associated cholangiopathy from sclerosing cholangitis or cholangiocarcinoma. IgG4 cholangiopathy is more likely to produce simultaneous strictures of the intrapancreatic portion of the distal common bile duct and of the hepatic hilum, and the association with autoimmune pancreatitis may help with diagnosis. IgG4 cholangiopathy can produce both short and long segmental strictures of biliary ducts with proximal duct dilation, although changes may be limited to the distal common bile duct. Peripheral hepatic bile duct involvement can occur, along with large bile duct involvement.
Endoscopic ultrasonography with needle biopsy of the head of the pancreas may exclude pancreatic carcinoma as a cause of segmental narrowing of the intrapancreatic bile duct. Intraductal ultrasonography may identify bile-duct wall thickening in nonstenotic bile duct segments and assist in differentiation of IgG4 cholangiopathy from cholangiocarcinoma. Gallbladder wall thickening affects 25% of patients with IgG4 disease.
In patients with cholangiopathy and pancreatic involvement, CT shows diffuse or focal pancreatic edema, pancreatic enlargement, focal pancreatic masses, pancreatic atrophy, or peripancreatic hypoattenuation. This pancreas rim or "capsule" is evident in 12%-40% of cases of autoimmune pancreatitis. Focal changes of the pancreas can mimic pancreatic carcinoma. Delayed enhancement of the pancreas on CT and lack of proximal pancreatic duct dilation may be helpful in differentiating autoimmune pancreatitis from pancreatic carcinoma.
Endoscopic ultrasonography of IgG4 cholangiopathy can identify biliary wall thickening with luminal preservation and a normal hyperechoic outer wall of the duct. Narrowing of the portal, splenic, or superior mesenteric veins develops in up to 70% of patients with IgG4-related disease of the pancreas and common bile duct. However, the changes of sclerosing cholangitis and IgG4 cholangiopathy can be difficult to separate at endoscopic ultrasonography. Obtaining biopsies of the bile duct, pancreas, or duodenal papilla, which are evaluated for IgG4 cells, may assist in diagnosis.
Histology of IgG4-Related Disease
The histologic hallmark of IgG4-related disease is tissue infiltration with IgG4 plasma cells.The finding of more than 10 IgG4-positive plasma cells per high-power field at tissue microscopy may establish the diagnosis. Bile duct inflammation is typically dense and transmural, and is associated with eosinophils, fibrosis, and obliterative phlebitis. Liver histology of patients with IgG4 cholangiopathy shows more portal and lobular inflammation than sclerosing cholangitis with portal areas containing plasma cells and eosinophils, perivenular inflammation, and limited inflammation of the bile ducts. IgG4 plasma cells are often present. Other manifestations include sclerosis of portal areas with minimal inflammation, lobular hepatitis, and cholestasis.
Source...