Autoimmune Pancreatitis (AIP) is an increasingly recognized type of
chronic pancreatitis
Chronic pancreatitis is a long-standing inflammation of the pancreas that alters the organ's normal structure and functions. It can present as episodes of acute inflammation in a previously injured pancreas, or as chronic damage with persistent pa ...
that can be difficult to distinguish from
pancreatic carcinoma
Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancre ...
but which responds to treatment with
corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involve ...
, particularly
prednisone
Prednisone is a glucocorticoid medication mostly used to immunosuppressive drug, suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium ...
. Although autoimmune pancreatitis is quite rare, it constitutes an important clinical problem for both patients and their clinicians: the disease commonly presents itself as a tumorous mass which is diagnostically indistinguishable from pancreatic cancer, a disease that is much more common in addition to being very dangerous. Hence, some patients undergo pancreatic surgery, which is associated to substantial mortality and morbidity, out of the fear by patients and clinicians to undertreat a malignancy. However, surgery is not a good treatment for this condition as AIP responds well to immunosuppressive treatment. There are two categories of AIP: Type 1 and Type 2, each with distinct clinical profiles.
Type 1 AIP is now regarded as a manifestation of
IgG4-related disease
IgG4-related disease (IgG4-RD), formerly known as IgG4-related systemic disease, is a chronic inflammatory condition characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of fibrosis (scarring) and ...
,
and those affected have tended to be older and to have a high relapse rate. Type 1 pancreatitis, is as such as manifestation of IgG4 disease, which may also affect bile ducts in the liver, salivary glands, kidneys and lymph nodes. Type 2 AIP seems to affect only the pancreas, although about one-third of people with type 2 AIP have associated inflammatory bowel disease. AIP occurring in association with an
autoimmune disorder
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
has been referred to as "secondary" or "syndromic" AIP. AIP does not affect long-term survival.
Signs and symptoms
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.
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.
Narrowing in the pancreatic duct called strictures may occur.
Rarely, Type 1 AIP presents with
acute pancreatitis
Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes in order of frequency include: 1) a gallstone impacted in the common bile duct beyond the point where the pancreatic duct joins it; 2) heavy alcohol use; 3) systemic disease; ...
.
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
Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failu ...
) and
nodules, scarring within the chest cavity (
mediastinal fibrosis) or in the anatomic space behind the abdomen (
retroperitoneal fibrosis
Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures. It may present wi ...
) and inflammation in the kidneys (
tubulointerstitial nephritis
Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules ...
).
AIP is characterized by the following features:
# Scleral Icterus (yellow eyes),
jaundice
Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...
(yellow skin) which is usually painless, usually without acute attacks of
pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...
.
# Relatively mild symptoms, such as minimal weight loss or nausea.
# Increased serum levels of gamma globulins,
immunoglobulin G
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...
(IgG) or IgG4.
# The presence of serum autoantibodies such as
anti-nuclear antibody
Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human pro ...
(ANA), anti-
lactoferrin
Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, su ...
antibody, anti-
carbonic anhydrase
The carbonic anhydrases (or carbonate dehydratases) () form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid (i.e. bicarbonate and hydrogen ions). The active site ...
II antibody, and
rheumatoid factor
Rheumatoid factor (RF) is the autoantibody that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG-Fc. RF and IgG join to form immune com ...
(RF).
# Contrast-enhanced CT demonstrates a diffusely enlarged (sausage-shaped) pancreas.
# Diffuse irregular narrowing of the main pancreatic duct, and stenosis of the intrapancreatic bile duct on
endoscopic retrograde cholangiopancreatography
Endoscopic retrograde cholangiopancreatography (ERCP) is a technique that combines the use of endoscopy and fluoroscopy to diagnose and treat certain problems of the biliary or pancreatic ductal systems. It is primarily performed by highly skille ...
(ERCP).
# Rare pancreatic calcification or cyst formation.
# Marked responsiveness to treatment with corticosteroids.
Histopathology
Histopathologic examination of the pancreas reveals a characteristic lymphoplasmacytic infiltrate of
CD4- or
CD8
CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...
-positive
lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
and IgG4-positive
plasma cells
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
, and exhibits interstitial fibrosis and
acinar cell
Centroacinar cells are spindle-shaped cells in the exocrine pancreas. They represent an extension of the intercalated duct into each pancreatic acinus. These cells are commonly known as duct cells, and secrete an aqueous bicarbonate solution und ...
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
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
, 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
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adap ...
,
plasma cells
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
), with rare ductal
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
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.
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.
[ 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 ] but follow up studies suggested this finding is likely to be an artifact. Hence improved diagnosis, understanding and treatment of autoimmune pancreatitis awaits the identification of the auto-antigens involved.
Diagnosis
Criteria
Most recently the fourteenth Congress of the International Association of Pancreatology developed the International Consensus Diagnostic Criteria (ICDC) for AIP. The ICDC emphasizes five cardinal features of AIP which includes the imaging appearance of pancreatic parenchyma and the pancreatic duct, serum IgG4 level, other organ involvement with IgG4-related disease, pancreatic histology and response to steroid therapy.
In 2002, the Japanese Pancreas Society proposed the following diagnostic criteria for autoimmune pancreatitis:
::I. Pancreatic imaging studies show diffuse narrowing of the main pancreatic duct with irregular wall (more than 1/3 of length of the entire pancreas).
::II. Laboratory data demonstrate abnormally elevated levels of serum gamma globulin and/or IgG
Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...
, or the presence of autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
.
::III. Histopathologic examination of the pancreas shows fibrotic changes with lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
and plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific substan ...
infiltrate.
For diagnosis, criterion I (pancreatic imaging) must be present with criterion II (laboratory data) and/or III (histopathologic findings).
Mayo Clinic has come up with five diagnostic criteria called HISORt criteria which stands for histology, imaging, serology, other organ involvement, and response to steroid therapy.
Radiologic features
Computed tomography (CT) findings in AIP include a ''diffusely enlarged hypodense'' pancreas or a focal mass that may be mistaken for a pancreatic malignancy.[ A low-density, ''capsule-like rim on CT'' (possibly corresponding to an inflammatory process involving peripancreatic tissues) is thought to be an additional characteristic feature (thus the mnemonic: ''sausage-shaped''). ]Magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...
(MRI) reveals a diffusely decreased signal intensity and delayed enhancement on dynamic scanning. The characteristic ERCP
Endoscopic retrograde cholangiopancreatography (ERCP) is a technique that combines the use of endoscopy and fluoroscopy to diagnose and treat certain problems of the biliary or pancreatic ductal systems. It is primarily performed by highly skille ...
finding is segmental or diffuse irregular narrowing of the main pancreatic duct, usually accompanied by an extrinsic-appearing stricture of the distal bile duct. Changes in the extrapancreatic bile duct similar to those of primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may ha ...
(PSC) have been reported.
The role of endoscopic ultrasound
Endoscopic ultrasound (EUS) or echo-endoscopy is a medical procedure in which endoscopy (insertion of a probe into a hollow organ) is combined with ultrasound to obtain images of the internal organs in the chest, abdomen and colon. It can be used t ...
(EUS) and EUS-guided fine-needle aspiration
Fine-needle aspiration (FNA) is a diagnostic procedure used to investigate lumps or masses. In this technique, a thin (23–25 gauge (0.52 to 0.64 mm outer diameter)), hollow needle is inserted into the mass for sampling of cells that, aft ...
(EUS-FNA) in the diagnosis of AIP is not well described, and EUS findings have been described in only a small number of patients. In one study, EUS revealed a diffusely swollen and hypoechoic pancreas in 8 of the 14 (57%) patients, and a solitary, focal, irregular mass was observed in 6 (46%) patients. Whereas EUS-FNA is sensitive and specific for the diagnosis of pancreatic malignancy, its role in the diagnosis of AIP remains unclear.
Treatment
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
A pancreaticoduodenectomy, also known as a Whipple procedure, is a major surgical operation most often performed to remove cancerous tumours from the head of the pancreas. It is also used for the treatment of pancreatic or duodenal trauma, or chro ...
or complete pancreatectomy
In medicine, a pancreatectomy is the surgical removal of all or part of the pancreas. Several types of pancreatectomy exist, including pancreaticoduodenectomy (Whipple procedure), distal pancreatectomy, segmental pancreatectomy, and total pancr ...
for a benign disease which responds well to medical therapy. "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." Autoimmune pancreatitis responds dramatically to corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
treatment.
If relapse occurs after corticosteroid treatment or corticosteroid treatment is not tolerated, immunomodulators
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
may be used. Immunomodulators such as azathioprine
Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus, ...
, and 6-mercaptopurine
Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's dise ...
have been shown to extend remission of autoimmune pancreatitis after corticosteroid treatment. If corticosteroid and immunomodulator treatments are not sufficient, rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in non-geriatric p ...
may also be used. Rituximab has been shown to induce and maintain remission.
Prognosis
AIP does not affect long-term survival.
Epidemiology
AIP is relatively uncommon, 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. Type 1 AIP occurs three times more often in men than women.
Controversies in nomenclature
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
Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may ha ...
, or inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammation, inflammatory conditions of the colon (anatomy), colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine a ...
. Some of the earliest cases were reported as pancreatic pseudotumor or pseudolymphoma.
References
External links
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, Orphanet = 103919
Pancreas disorders
Autoimmune diseases
IgG4-related disease
Steroid-responsive inflammatory conditions