Autoimmune pancreatitis overview

# Overview
In 1995, Yoshida proposed the term "autoimmune pancreatitis" for the first time. Autoimmune pancreatitis is also known as primary inflammatory pancreatitis, lymphoplasmacytic sclerosing pancreatitis, pseudotumorous pancreatitis, chronic pancreatitis with irregular narrowing of the main pancreatic duct, idiopathic chronic pancreatitis, and nonalcoholic duct destructive chronic pancreatitis. Autoimmune pancreatitis (AIP) may be classified into two types; type 1 AIP and type 2 AIP or idiopathic duct-centric pancreatitis. Type 1  AIP meets the HISORt criteria, involves pancreas as one part of a systemic IgG4-positive disease. Type 2 consists of granulocytic lesions, does not involve IgG4-positive cells, has no systemic involvement, and is usually associated with inflammatory bowel disease. Th1-type CD4+ T cells are thought to play an important role in the pathogenesis of autoimmune pancreatitis (AIP) via autoimmune reaction against carbonic anhydrase type II or lactoferrin. Autoimmune pancreatitis may be associated with systemic autoimmune conditions such as IgG4-associated cholangitis, chronic sclerosing sialadenitis (Kuttner's tumor), Mikulicz's disease (IgG4-related plasmacytic exocrinopathy), mediastinal fibrosis, adenopathy, chronic periaortitis, idiopathic retroperitoneal fibrosis, tubulointerstitial nephritis, IgG4-associated pseudolymphoma, ulcerative colitis and hypergammaglobulinemia. Diffuse pancreatic gland enlargement may be seen on gross examination. Microscopic findings suggestive of autoimmune pancreatitis may include Interlobular ducts surrounded by the infiltration of inflammatory cells and fibrosis. Immunohistochemistry stains may show CD4+ T cells (mainly), some CD8+ T cells, B cells and HLA-DR antigen expression on pancreatic duct or acinar cells. Autoimmune pancreatitis is idiopathic in origin and has no clear etiology. Autoimmune pancreatitis is thought to be due to some autoimmune reaction against pancreas and might be associated with other autoimmune diseases. Autoimmune pancreatitis needs to be differentiated from other diseases such as alcoholic chronic pancreatitis, pancreatic cancer, chronic pancreatitis, inflammatory bowel disease, dumping syndrome, celiac disease, Whipple's disease, tropical sprue and colon carcinoma. In North America, 2.5% of pancreatoduodenectomies are done because of AIP being misdiagnosed as pancreatic cancer. The symptoms of autoimmune pancreatitis usually develop in the fifth decade of life, and start with symptoms such as painless jaundice, dark urine, and mild abdominal pain. During the later course of disease, patients may present with abdominal mass mimicking pancreatic cancer. If left untreated, patients with autoimmune pancreatitis may progress to develop pancreatic insufficiency, diabetes, and pancreatic calcifications or stones. The prognosis is usually good; about 2/3rd of patients show good response to glucocorticoids with complete recovery, 25% may require a second course of glucocorticoids, and a few patients with autoimmune pancreatitis may require continuous treatment. Autoimmune pancreatitis is diagnosed by revised HISORt criteria, proposed by Mayo clinic, that includes histology, pancreatic imaging, serology, other organ involvement, and response to steroid treatment. Patients with autoimmune pancreatitis may do not have a positive history of alcohol abuse. Common symptoms of autoimmune pancreatitis include mild abdominal pain, abdominal mass/pancreatic mass, painless jaundice, weight loss, and diabetes mellitus. Laboratory findings consistent with the diagnosis of autoimmune pancreatitis may include increased serum IgG4 levels and hypergammaglobulinemia (>2 times the upper limit of normal in most patients), antilactoferrin antibody, anticarbonic anhydrase II antibody, other autoantibodies (ANA), rheumatoid factor (RF), IgG4-positive plasma cells, elevated serum alkaline phosphatase levels (ALP), elevated serum aminotransferases, ESR, and CA19-9. CT scan findings suggestive of autoimmune pancreatitis may include diffusely enlarged pancreas with featureless borders, delayed enhancement with or without a capsule-like rim and rarely calcifications may be seen. ERCP or MRCP findings in autoimmune pancreatitis may include a narrowed main and dorsal pancreatic duct, diffuse and irregular narrowing of the pancreatic duct (beaded appearance), focal stricture of the pancreatic duct, proximal or distal common bile duct and irregular narrowing of the intrahepatic ducts. Glucocorticoids are found to play an important role in the management of autoimmune pancreatitis via several ways such as efficacy in alleviating symptoms, decreasing the size of the pancreas, reversing histopathologic features in patients with AIP,  and mprovement of lab findings. Immunomodulatory drugs such as azathioprine are usually used when, AIP patients have no response to steroid management, relapse occurs and patients cannot be weaned off steroids. Surgery is usually considered when pain management fails with medical and endoscopic therapies. The goals of surgery include effective pain relief, and to preserve long-term pancreatic function. Surgery for chronic pancreatitis tends to be divided into two areas - resectional and drainage procedures. Dilated pancreatic duct may be managed with lateral pancreaticojejunostomy (LPJ) and lateralpancreaticojejunostomy with localized pancreatic head resection. Nondilated pancreatic duct is usually managed with pancreaticoduodenectomy, duodenal-preserving pancreatic head resection (DPPHR), distal pancreatectomy (DP) and total pancreatectomy (TP). Patients should be managed appropriately and timely with glucocorticoids and immunomodulatory drugs to prevent complications such as pancreatic insufficiency, diabetes, and pancreatic calcifications or stones.

# Historical Perspective
The concept of pancreas and pancreatic duct was first described by Johannes Wirsung of Padua in 1642. In 1761, Giovanni Morgagni described the clinical syndrome of severe upper abdominal pain, vomiting, and collapse. He is also credited with the earliest pathological recognition of cancer of the pancreas. In 1948, Eliason and Welty described distal pancreatectomy (DP). In 1980, Beger described duodenal-preserving pancreatic head resection (DPPHR) technique for chronic pancreatitis to decrease the morbidity of pancreatic head resection. In 1961, Sarles proposed autoimmunity as a pathogenetic mechanism of pancreatitis. In 1995, Yoshida proposed the term "autoimmune pancreatitis" for the first time. Autoimmune pancreatitis is also known as primary inflammatory pancreatitis, lymphoplasmacytic sclerosing pancreatitis, pseudotumorous pancreatitis, chronic pancreatitis with irregular narrowing of the main pancreatic duct, idiopathic chronic pancreatitis, and nonalcoholic duct destructive chronic pancreatitis. In 2009, the two types of autoimmune pancreatitis were first identified as type 1 (lymphoplasmacytic sclerosing pancreatitis) and type 2 (idiopathic duct-centric pancreatitis).

# Classification
Autoimmune pancreatitis (AIP) may be classified into two types; type 1 AIP and type 2 AIP or idiopathic duct-centric pancreatitis. Type 1  AIP meets the HISORt criteria, involves pancreas as one part of a systemic IgG4-positive disease. Type 2 consists of granulocytic lesions, does not involve IgG4-positive cells, has no systemic involvement, and is usually associated with inflammatory bowel disease.

# Pathophysiology
Th1-type CD4+ T cells are thought to play an important role in the pathogenesis of autoimmune pancreatitis (AIP) via autoimmune reaction against carbonic anhydrase type II or lactoferrin. Autoimmune pancreatitis may involve fibrosis of peripancreatic vessels leading to obliterative vasculitis and phlebitis similar to that occuring in pancreatic cancer. Autoimmune pancreatitis may be associated with systemic autoimmune conditions such as IgG4-associated cholangitis, chronic sclerosing sialadenitis (Kuttner's tumor), Mikulicz's disease (IgG4-related plasmacytic exocrinopathy), mediastinal fibrosis, adenopathy, chronic periaortitis, idiopathic retroperitoneal fibrosis, tubulointerstitial nephritis, IgG4-associated pseudolymphoma, ulcerative colitis and hypergammaglobulinemia. Diffuse pancreatic gland enlargement may be seen on gross examination. Microscopic findings suggestive of autoimmune pancreatitis may include Interlobular ducts surrounded by the infiltration of inflammatory cells and fibrosis. Immunohistochemistry stains may show CD4+ T cells (mainly), some CD8+ T cells, B cells and HLA-DR antigen expression on pancreatic duct or acinar cells.

# Causes
Autoimmune pancreatitis is idiopathic in origin and has no clear etiology. Autoimmune pancreatitis is thought to be due to some autoimmune reaction against pancreas and might be associated with other autoimmune diseases.

# Differentiating Autoimmune pancreatitis from Other Diseases
Autoimmune pancreatitis needs to be differentiated from other diseases such as alcoholic chronic pancreatitis, pancreatic cancer, chronic pancreatitis, inflammatory bowel disease, dumping syndrome, celiac disease, Whipple's disease, tropical sprue and colon carcinoma.

# Epidemiology and Demographics
Autoimmune pancreatitis is a world wide entitiy but it's incidence has been found to be recently increased in Japan. In North America, 2.5% of pancreatoduodenectomies are done because of AIP being misdiagnosed as pancreatic cancer. The mean age of patients with AIP is 59 yr (range, 4575 yr). In autoimmune pancreatitis, the male-to-female ratio was found to be 15:2. Autoimmune pancreatitis usually involves elderly male population.

# Risk Factors
There are no established risk factors found to be associated with autoimmune pancreatitis. Patients with systemic autoimmune diseases such as Sjogren syndrome and Primary sclerosing cholangitis may be associated with an increased risk of autoimmune pancreatitis.

# Screening
There is insufficient evidence to recommend routine screening for autoimmune pancreatitis.

# Natural History, Complications, and Prognosis
The symptoms of autoimmune pancreatitis usually develop in the fifth decade of life, and start with symptoms such as painless jaundice, dark urine, and mild abdominal pain. During the later course of disease, patients may present with abdominal mass mimicking pancreatic cancer. If left untreated, patients with autoimmune pancreatitis may progress to develop pancreatic insufficiency, diabetes, and pancreatic calcifications or stones. The prognosis is usually good; about 2/3rd of patients show good response to glucocorticoids with complete recovery, 25% may require a second course of glucocorticoids, and a few patients with autoimmune pancreatitis may require continuous treatment.

# Diagnosis

## Diagnostic Criteria
Autoimmune pancreatitis is diagnosed by revised HISORt criteria, proposed by Mayo clinic, that includes histology, pancreatic imaging, serology, other organ involvement, and response to steroid treatment.

## History and Symptoms
Patients with autoimmune pancreatitis may do not have a positive history of alcohol abuse. Common symptoms of autoimmune pancreatitis include mild abdominal pain, abdominal mass/pancreatic mass, painless jaundice, weight loss, and diabetes mellitus. Less common symptoms may include symptoms related to other autoimmune diseases such as Sjogren's syndrome, primary sclerosing cholangitis (PSC), inflammatory bowel disease (IBD), and retroperitoneal fibrosis. Autoimmune pancreatitis may have  extra-pancreatic involvement such as bile duct, salivary gland, retroperitoneum, kidneys, and orbit depending upon the various stages of autoimmune pancreatitis.

## Physical Examination
Patients with acute on chronic autoimmune pancreatitis may assume a characteristic position in an attempt to relieve their abdominal pain. Patients with steatorrhea or advanced disease may present with loss of subcutaneous fat, temporal wasting, sunken supraclavicular fossa, and other physical signs of malnutrition.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of autoimmune pancreatitis may include increased serum IgG4 levels and hypergammaglobulinemia (>2 times the upper limit of normal in most patients), antilactoferrin antibody, anticarbonic anhydrase II antibody, other autoantibodies (ANA), rheumatoid factor (RF), IgG4-positive plasma cells, elevated serum alkaline phosphatase levels (ALP), elevated serum aminotransferases, ESR, and CA19-9.

## Electrocardiogram
There are no ECG findings associated with autoimmune pancreatitis.

## X-ray
There are no x-ray findings associated with autoimmune pancreatitis.

## Ultrasound
Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) may be used to obtain histologic specimens from pancreas.

## CT scan
CT scan findings suggestive of autoimmune pancreatitis may include diffusely enlarged pancreas with featureless borders, delayed enhancement with or without a capsule-like rim and rarely calcifications may be seen.

## MRI
MRI findings suggestive of autoimmune pancreatitis may include diffusely enlarged pancreas with featureless borders and delayed enhancement with or without a capsule-like rim.

## Other Imaging Findings
ERCP or MRCP findings in autoimmune pancreatitis may include a narrowed main and dorsal pancreatic duct, diffuse and irregular narrowing of the pancreatic duct (beaded appearance), focal stricture of the pancreatic duct, proximal or distal common bile duct and irregular narrowing of the intrahepatic ducts.

## Other Diagnostic Studies
Other diagnostic studies for autoimmune pancreatitis usually include pancreatic biopsy, which may demonstrate extensive fibrosis. Endoscopic ultrasound-guided trucut biopsy (EUS-TCB) is usually avoided due to increased risk of complications and limited diagnostic ability.

# Treatment

## Medical Therapy
Glucocorticoids are found to play an important role in the management of autoimmune pancreatitis via several ways such as efficacy in alleviating symptoms, decreasing the size of the pancreas, reversing histopathologic features in patients with autoimmune pancreatitis (AIP), and mprovement of lab findings. About 2/3rd of patients show good response to glucocorticoids with complete recovery, 25% may require a second course of glucocorticoids, and a few patients with autoimmune pancreatitis may require continuous treatment. Immunomodulatory drugs such as azathioprine are usually used when, AIP patients have no response to steroid management, relapse occurs and patients cannot be weaned off steroids.

## Surgery
Surgery is usually considered when pain management fails with medical and endoscopic therapies. The goals of surgery include effective pain relief, and to preserve long-term pancreatic function. Surgery for chronic pancreatitis tends to be divided into two areas - resectional and drainage procedures. Dilated pancreatic duct may be managed with lateral pancreaticojejunostomy (LPJ) and lateralpancreaticojejunostomy with localized pancreatic head resection. Nondilated pancreatic duct is usually managed with pancreaticoduodenectomy, duodenal-preserving pancreatic head resection (DPPHR), distal pancreatectomy (DP) and total pancreatectomy (TP).

## Primary Prevention
There are no established measures for the primary prevention of autoimmune pancreatitis.

## Secondary Prevention
Patients should be managed appropriately and timely with glucocorticoids and immunomodulatory drugs to prevent complications such as pancreatic insufficiency, diabetes, and pancreatic calcifications or stones.