Autoimmune Pancreatitis

DEFINITION, ETIOLOGY, PATHOGENESisTop

Autoimmune pancreatitis (AIP) is a distinct form of chronic pancreatitis due to an autoimmune etiology. It can occur as a primary pancreatic condition or as part of a systemic disease (immunoglobulin G4 [IgG4]-related disease). Although the incidence and prevalence of AIP remain largely unknown in Europe and North America, the condition is being increasingly recognized. AIP can manifest as a mass indistinguishable from pancreatic cancer or as diffuse pancreatic inflammation. Unlike other pancreatic conditions, AIP usually responds dramatically to glucocorticoid therapy. It is estimated to constitute ~5% of all cases of chronic pancreatitis. Three types of AIP are distinguished:

1) Type 1 is a pancreatic manifestation of a systemic autoimmune disease called IgG4-related disease. It is usually characterized by an increased serum concentration of IgG4 with lymphoplasmacytic inflammation and fibrosis of the pancreas and other organs (simultaneous or even after several years): bile ducts, gallbladder, liver, salivary and lacrimal glands, retroperitoneal space, intestinal mesentery, aorta, mediastinum, kidneys, bladder, thyroid, nipple, lung, central nervous system, prostate, and/or lymph nodes.

2) Type 2 is characterized by neutrophilic infiltration in the epithelium of the pancreatic duct. It is confined to the pancreas and is not accompanied by an increased concentration of IgG4. It is often associated with other autoimmune conditions, such as inflammatory bowel disease.

3) Type 3 is a recently recognized form of AIP caused by pancreatic injury due to the use of immune checkpoint inhibitors for a broad spectrum of malignancies. It may manifest as an asymptomatic elevation of lipase levels or clinical pancreatitis. The diagnosis is made based on a temporal relationship with exposure to immune checkpoint inhibitors and absence of other causes of pancreatitis. 

CLINICAL FEATURES AND NATURAL HISTORYTop

The clinical features of AIP are variable. As AIP may present with symptoms and imaging features suggestive of pancreatic cancer, the latter needs to be excluded. The most common symptom of AIP is obstructive jaundice (30%-50% of patients) caused by stricture of the common bile duct due to inflammatory edema of the head of the pancreas or “fibrotic inflammation” of the bile ducts. Jaundice varies in severity, while abdominal pain is usually mild. More than 50% of patients with type 1 AIP have other organ involvement. An asymptomatic course with abnormal imaging and laboratory findings is possible. Relapse is more frequent in AIP type 1 than in type 2.

With time pancreatic lesions resembling those typical of chronic pancreatitis are seen: parenchymal atrophy, calcification, and/or dilation of the pancreatic ducts. Exocrine pancreatic insufficiency and diabetes may also develop.

DIAGNOSISTop

Diagnostic Tests

There is no single diagnostic test for AIP. Guidelines regarding the diagnostic criteria for AIP vary globally. The HISORt (histology, imaging, serology, other organ involvement, and response to therapy) criteria from the Mayo Clinic require a combination of histology, imaging, serology, other organ involvement, and response to glucocorticoids for the diagnosis of AIP.

1. Laboratory tests: There are no abnormalities that are specific for AIP; hyperbilirubinemia, increased activity of cholestatic enzymes, periodic lipase and amylase elevation, increased levels of cancer antigen (CA) 19-9 (especially in biliary tract involvement); quite commonly autoantibodies against carbonic anhydrase (ACAs), lactoferrin II (ALF), smooth muscles (SMAs), antimitochondrial autoantibodies (AMAs), antinuclear autoantibodies (ANAs), and rheumatoid factor (RF) are seen, but their significance is not clear. An increased concentration of IgG4 has the greatest diagnostic significance as a single parameter—a value of 2-fold the upper limit of normal may indicate type 1 AIP. However, IgG4 is not specific to AIP.

2. Imaging: Pancreatic lesions may be diffuse or focal. On ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI), diffuse lesions are characterized by the enlargement of the pancreas and loss of normal organ architecture, known as “sausage-shaped pancreas.” In 10% to 40% of patients, CT and MRI show lower tissue attenuation (“halo”) on the periphery of the pancreas, which is considered specific to AIP. On dynamic CT and MRI, a delayed enhancement of the pancreatic parenchyma is observed. Pseudocysts and pancreatic calcifications are not typical findings in AIP. Focal AIP with mass formation is more difficult to distinguish from pancreatic cancer. Delayed parenchyma enhancement, a characteristic rim, and numerous masses are helpful in differentiation. CT may also show extrapancreatic lesions such as retroperitoneal fibrosis. Endoscopic ultrasonography (EUS) shows pancreatic enlargement, focal or diffuse decreased echogenicity, and hyperechoic punctiform images that may correspond to compressed ducts. EUS can be used to perform biopsy. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic retrograde cholangiopancreatography (ERCP) show long (>1/3 of the length) and numerous strictures of the main pancreatic duct and no or slight (<5 mm) dilatation of the duct proximal to the stricture; these features are less characteristic for pancreatic cancer. Stricturing in the biliary tree may also be seen in IgG4-associated cholangitis. The role of ERCP in the diagnostic workup is limited due to its invasive nature.

3. Histology: Type 1 AIP typically shows lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Type 2 AIP shows idiopathic duct-centric pancreatitis with granulocytic epithelial lesions. Type 3 AIP shows CD8+ T-cell infiltration.

4. Response to glucocorticoids: Resolution or marked improvement of pancreatic or extrapancreatic manifestations in response to glucocorticoid treatment suggests the possibility of AIP. Yet, the response to glucocorticoids does not exclude the possibility of pancreatic cancer.

Differential Diagnosis

1. Pancreatic cancer.

2. Cholangiocarcinoma.

3. Primary sclerosing cholangitis.

4. Alcoholic chronic pancreatitis.

5. Lymphomas, multiple myeloma, pancreatic metastases of renal cancer.

TREATMENTTop

Glucocorticoid therapy provides rapid improvement in >90% of patients. Use prednisone or prednisolone: initially 30 to 40 mg/d or 0.6 mg/kg of body weight/d, usually for 2 to 4 weeks; reduce the dose every 1 to 2 weeks by 5 mg/d until discontinuation within 3 months. Lack of a quick response (usually after 1-2 weeks) suggests diagnosis other than AIP.

Data on the treatment of patients with relapses (~30% of patients with type 1 AIP and ~10% of patients with type 2 AIP) are limited. Immunosuppressants and immunomodulators such as azathioprine, mercaptopurine, or mycophenolate are often used to avoid extended glucocorticoid treatment. In recurrent jaundice due to biliary obstruction, bile duct stenting may be necessary. Rituximab may be used for induction of remission and as maintenance therapy in patients with relapsing type 1 AIP.