Autoimmune pancreatitis

Autoimmune pancreatitis may cause a variety of symptoms and signs, which include pancreatic and biliary (bile duct) manifestations, as well as systemic effects of the disease. Two-thirds of patients present with either painless jaundice due to bile duct obstruction or a "mass" in the head of the pancreas, mimicking carcinoma. As such, a thorough evaluation to rule out cancer is important in cases of suspected AIP.[4]

Type 1 AIP typically presents in a 60–70-year-old male with painless jaundice. In some cases, imaging reveals a mass in the pancreas or diffuse pancreatic enlargement.[4] Narrowing in the pancreatic duct called strictures may occur.[4] Rarely, Type 1 AIP presents with acute pancreatitis.[4] Type 1 AIP presents with manifestations of autoimmune disease (IgG4 related) in at least half of cases. The most common form of systemic involvement is cholangitis, which occurs in up to 80 percent of cases of Type 1 AIP. Additional manifestations include inflammation in the salivary glands (chronic sclerosing sialadenitis), in the lungs resulting in scarring (pulmonary fibrosis) and nodules, scarring within the chest cavity (mediastinal fibrosis) or in the anatomic space behind the abdomen (retroperitoneal fibrosis) and inflammation in the kidneys (tubulointerstitial nephritis).[4]

AIP is characterized by the following features:

1. Scleral Icterus (yellow eyes), jaundice (yellow skin) which is usually painless, usually without acute attacks of pancreatitis.
2. Relatively mild symptoms, such as minimal weight loss or nausea.
3. Increased serum levels of gamma globulins, immunoglobulin G (IgG) or IgG4.
4. The presence of serum autoantibodies such as anti-nuclear antibody (ANA), anti-lactoferrin antibody, anti-carbonic anhydrase II antibody, and rheumatoid factor (RF).
5. Contrast-enhanced CT demonstrates a diffusely enlarged (sausage-shaped) pancreas.
6. Diffuse irregular narrowing of the main pancreatic duct, and stenosis of the intrapancreatic bile duct on endoscopic retrograde cholangiopancreatography (ERCP).
7. Rare pancreatic calcification or cyst formation.
8. Marked responsiveness to treatment with corticosteroids.

Histopathologic examination of the pancreas reveals a characteristic lymphoplasmacytic infiltrate of CD4- or CD8-positive lymphocytes and IgG4-positive plasma cells, and exhibits interstitial fibrosis and acinar cell atrophy in later stages. At the initial stages, typically, there is a cuff of lymphoplasma cells surrounding the ducts but also more diffuse infiltration in the lobular parenchyma. However, localization and the degree of duct wall infiltration are variable. Whereas histopathologic examination remains the primary method for differentiation of AIP from acute and chronic pancreatitis, lymphoma, and cancer. By Fine Needle Aspiration (FNA) the diagnosis can be made if adequate tissue is obtained. In such cases, lymphoplasmacytic infiltration of the lobules are the key finding. Rarely, granulomatous reaction could be observed. It has been proposed that a cytologic smear primarily composed of acini rich in chronic inflammatory cells (lymphocytes, plasma cells), with rare ductal epithelial cells lacking atypia, favors the diagnosis of AIP. The sensitivity and the specificity of these criteria for differentiating AIP from neoplasia are unknown. In cases of systemic manifestation of AIP, the pathologic features are similar in other organs.[5]

Although the exact mechanism explaining the clinical manifestations of autoimmune pancreatitis remain for an important part obscure, most professionals would agree that the development of IgG4 antibodies, recognizing an epitiope on the membrane of pancreatic ancinar cells is an important factor in the pathophysiology of the disease. These antibodies are postulated to provoke an immune response against these ancinar cells resulting in pancreatic inflammation and destruction.[5] Knowing the auto-antigens involved would allow early diagnosis of the disease, its differentiation from a diagnosis of pancreatic cancer, and potentially even prevention, but unfortunately these remain obscure. An earlier publication suggested that the human ubiquitin-protein ligase E3 component n-recognin 2 (UBR2) was an important antigen [6] but follow up studies suggested this finding is likely to be an artifact.[7] Hence improved diagnosis, understanding and treatment of autoimmune pancreatitis awaits the identification of the auto-antigens involved.

AIP often completely resolves with steroid treatment. The failure to differentiate AIP from malignancy may lead to unnecessary pancreatic resection, and the characteristic lymphoplasmacytic infiltrate of AIP has been found in up to 23% of patients undergoing pancreatic resection for suspected malignancy who are ultimately found to have benign disease. In this subset of patients, a trial of steroid therapy may have prevented a Whipple procedure or complete pancreatectomy for a benign disease which responds well to medical therapy.[11] "This benign disease resembles pancreatic carcinoma both clinically and radiographically. The diagnosis of autoimmune pancreatitis is challenging to make. However, accurate and timely diagnosis may preempt the misdiagnosis of cancer and decrease the number of unnecessary pancreatic resections."[12] Autoimmune pancreatitis responds dramatically to corticosteroid treatment.[12]

If relapse occurs after corticosteroid treatment or corticosteroid treatment is not tolerated, immunomodulators may be used. Immunomodulators such as azathioprine, and 6-mercaptopurine have been shown to extend remission of autoimmune pancreatitis after corticosteroid treatment. If corticosteroid and immunomodulator treatments are not sufficient, rituximab may also be used. Rituximab has been shown to induce and maintain remission.[13]

AIP does not affect long-term survival.[3]

AIP is relatively uncommon,[14] with an overall global prevalence less than 1 per 100,000. Type 1 AIP is more common in East Asia, whereas type 2 is relatively more common in the US and Europe. The prevalence of AIP may be increasing in Japan.[15] Type 1 AIP occurs three times more often in men than women.[4]

As the number of published cases of AIP has increased, efforts have been focused on defining AIP as a distinct clinical and pathologic entity and toward developing some generally agreed upon diagnostic criteria and nomenclature. Terms frequently encountered are autoimmune or autoimmune-related pancreatitis, lymphoplasmacytic sclerosing pancreatitis, idiopathic tumefactive chronic pancreatitis, idiopathic pancreatitis with focal irregular narrowing of the main pancreatic duct, and non-alcoholic duct destructive chronic pancreatitis. There are also a large number of case reports employing descriptive terminology such as pancreatitis associated with Sjögren's syndrome, primary sclerosing cholangitis, or inflammatory bowel disease. Some of the earliest cases were reported as pancreatic pseudotumor or pseudolymphoma.