Autoimmune pancreatitis is the pancreatic manifestation of a systemic disorder that affects various organs, including the bile duct, retroperitoneum, kidney, and parotid and lacrimal glands. It represents a recently described subset of chronic pancreatitis that is immune mediated and has unique histologic, morphologic, and clinical characteristics. A hallmark of the disease is its rapid response to corticosteroid treatment. Although still a rare disease, autoimmune pancreatitis is increasingly becoming recognized clinically, leading to evolution in the understanding of its prognosis, clinical characteristics, and treatment.
Autoimmune pancreatitis (AIP) represents a unique
subset of chronic inflammatory pancreatic disease with
distinct clinical, morphologic, and histopathologic features
that typically responds dramatically to steroid treatment
[1-3]. Named in 1995 by Yoshida and colleagues [4-5], the
clinical characteristics of the disease had been described as
early as 1961. It took several decades for it to be accepted as
Pancreatic Association still debated its existence . In the
last 5 years, however,AIPhas generated significant interest
it is increasingly being recognized and its existence is no
longer in doubt.
Sarles and colleagues  in 1961 were the first to
describe an autoimmune phenomenon in relation to
“sclerosis of the pancreas”. Although treatment with
this spurred interest in this entity over the next several
decades. Several terms were then used to subsequently
describe the disease, including “chronic sclerosing
“nonalcoholic duct-destructive pancreatitis,” “sclerosing
pancreatitis,” “sclerosing pancreaticocholangitis,” and
“autoimmune chronic pancreatitis” [7-9]. In 1991,
Kawaguchi and colleagues  described a variant of
cholangitis extensively involving the pancreas. This
description was quickly followed by several other reports
269 Apollo Medicine, Vol. 7, No. 4, December 2010
Consultant Gastroenterologist, Department of Gastroenterology, Apollo BGS Hospital, Kuvempu Nagar,
Mysore 570 023, India.
Autoimmune pancreatitis is the pancreatic manifestation of a systemic disorder that affects various organs,
including the bile duct, retroperitoneum, kidney, and parotid and lacrimal glands. It represents a recently
described subset of chronic pancreatitis that is immune mediated and has unique histologic, morphologic, and
clinical characteristics.Ahallmark of the disease is its rapid response to corticosteroid treatment.Although still
a rare disease, autoimmune pancreatitis is increasingly becoming recognized clinically, leading to evolution in
the understanding of its prognosis, clinical characteristics, and treatment.
Key words:Auto immune Pancreatitis (AIP), Serum IgG4, CT Scan, MRI, Steroids.
Ito and colleagues  subsequently described the first
three cases of AIP that were successfully treated with
corticosteroids. In a seminal study published in 2001,
Hamano, et al. reported that elevated serum IgG4 levels
were associated with sclerosing pancreatitis and that
treatment with corticosteroid therapy successfully
decreased these levels. The first diagnostic criteria were
proposed by the Japanese Pancreas Society in 2001 and
subsequently modified in 2006 [13-14]. Chari, et al.  in
2006 proposed new diagnostic criteria, which included
organ involvement and response to corticosteroids.
AIP has been defined as “the pancreatic manifestation
of a systemic fibroinflammatory disease which affects not
only the pancreas but also various other organs including
bile duct, salivary glands, the retroperitoneum and lymph
nodes. Organs affected by AIP have a lymphoplasmacytic
infiltrate rich in IgG4 positive cells and the inflammatory
process responds to steroid therapy” . The systemic
disease of which AIP is a manifestation has been called
IgG4-related systemic disease (ISD) in recognition that all
rich in IgG4-positive cells [15-16].
Almost all data describing the epidemiology of AIP
come from Japan. In 2002, Nishimori and colleagues 
randomly surveyed Japanese hospitals on how many
the diagnostic criteria for AIP as proposed by the Japan
Apollo Medicine, Vol. 7, No. 4, December 2010 270
Pancreas Society. Based on this survey, the prevalence of
patients who hadAIP in Japan was estimated to be 0.82 per
100,000. AIP was predominantly seen in men past middle
age (older than 45 years). Other Japanese series have
described the prevalence of disease between 5% and 6% of
all patients who have chronic pancreatitis [18-19].
The prevalence ofAIPin the United States is unknown,
because no extensive population-based studies have been
performed. BecauseAIP often mimics pancreatic cancer in
its initial presentation, the best estimates of prevalence of
AIP are in patients undergoing resection for presumed
pancreatic cancer because of obstructive jaundice or a
pancreatic mass. In three recent studies, 43 of 1808 (2.4%)
pancreatic resections were reported to have
lymphoplasmacytic sclerosing pancreatitis (LPSP) on
histologic examination of the resected specimen.. Another
retrospective evaluation of 245 pathology specimens at the
Mayo Clinic from patients who underwent resection for
benign pancreatic disease revealed that 27 (11%)
representedAIPwith a “tumefactive” presentation.
Males are nearly twice as likely as females to develop
AIP and the average age of onset is in the fifth decade .
In fact, 85% of patients are older than 50 years of age .
Currently, the pathogenesis of AIP is unknown,
although it almost certainly reflects an immune-mediated
process. Genetic susceptibility to AIP has been linked to
both the HLA-DRB1"0405-DQB1"0401 in the class II and
theABCF1 proximal to C3-2-11 telomeric of HLA-E in the
genetic association of Fc receptor-like 3 polymorphisms
withAIPin Japanese patients .
The trigger for AIP remains elusive. It is hypothesized
that HLA-DR antigens on the pancreatic ductal and acinar
cells may serve as antigens recognized by CD4+ producing
interferon-c and CD8+ T lymphocytes, leading to
subsequent inflammation. Polymorphisms of the cytotoxic
of the T-cell immune response, have been demonstrated in
patients who haveAIP .An etiologic role for antigenic
has also been proposed. Like many immune-mediated
diseases, AIP has been linked to many other autoimmune
conditions, such as Sjögren syndrome, retroperitoneal
fibrosis, and primary sclerosing cholangitis (PSC) [23-25].
The work by Kamisawa and colleagues, however , has
shown that these associated conditions are in fact
manifestations of a new clinicopathological entity, IgG4-
infiltration with abundant IgG4-positive plasma cells. For
example, unlike Sjögren syndrome, Reidel thyroiditis and
IgG4-associated nephritis . Whether AIP is truly
associated with any other distinct autoimmune disorder
needs confirmation in case-control studies.
Most patients who haveAIP are male and older than 50
years[17,19,20]. The male/female predominance is
in the subset of AIP associated with parotid gland
involvement, however http://www.mdconsult.com/das/
is typically in the sixth decade, AIP has been described in
patients in their 30s .
The clinical presentation ofAIPmay include pancreatic
or extrapancreatic manifestations:
Upper abdominal discomfort or pain
Acute pancreatitis (rare)
Hilar or abdominal lymphadenopathy
Chronic thyroiditis, Interstitial nephritis
The most common presentation, seen in over two thirds
of patients with an acute presentation, is obstructive
jaundice associated with a biliary stricture and a focal mass
or diffuse enlargement of the pancreas . The major
cancer, often leading to surgical resection. Other pancreatic
mani-festations include the presence of a pancreatic mass,
diffuse or focal enlargement of the pancreas in the absence
of obstructive jaundice, and new onset or worsening of
chronic pancreatitis, abdominal pain and attacks of acute
pancreatitis are uncommon manifestations of AIP. Most
patients with AIP have no or mild abdominal pain or
discomfort that is controlled by nonnarcotic analgesics.
The pancreatic manifestations of AIP thus can mimic
pancreatic cancer, acute pancreatitis, painless chronic
pancreatitis, or unexplained pancreatic functional
271 Apollo Medicine, Vol. 7, No. 4, December 2010
not seen in AIP; however, long-standing or recurrent AIP
can be associated with stone formation.
Classically, the predominant histologic feature of AIP
has been dense infiltration of the periductal space with
plasma cells and T lymphocytes. Associated with this
infiltrate is acinar destruction, obliterative phlebitis
involving the major and minor veins, and storiform or
“whirling” fibrosis of the pancreatic parenchyma, which
can extend to contiguous peripancreatic soft tissue. This
constellation of histopathologic findings defines LPSP
AIP has been associated with involvement of several
other organs. These extrapancreatic manifestations of AIP
can be seen in up to 49% of patients and include biliary
strictures, sclerosing cholangitis, sialadenitis, retro-
peritoneal fibrosis, hilar or abdominal lymphadenopathy,
bowel disease. The extrapancreatic manifestations may
occur concurrently with pancreatic disease, may be present
before the recognition of pancreatic disease, or can occur
weeks to months after their initial presentation [27,29].
Table 1 summarizes the common, atypical, and rare
clinical features encountered inAIP.
to be indurated and firm, the fibroinflammatory process
within the pancreas can mimic pancreatic ductal
adenocarcinoma because it is commonly localized in the
head of the pancreas ( Fig. 1) . The involved area is firm
the fibrosis can sometimes be seen infiltrating the
peripancreatic soft tissue. When AIP involves the head of
the pancreas, involvement of the main pancreatic duct
results in proximal stenosis or obstruction and distal
greater than 90% of the cases) and appears thickened and
stenotic with proximal dilatation. Unlike other forms of
chronic pancreatitis, such as alcoholic pancreatitis and
Table 1. Clinical features of autoimmune pancreatitis
Feature Typical (>50%) Less common (10-50%) Rare (<10%)
Presenting Obstructive jaundice Abdominal pain, weight loss, Clinical acute pancreatitis,
complaint diabetes, steatorrhea asymptomatic
Histology LPSP IDCP Extensive fibrosis, minimal
Pancreatic Diffusely enlarged gland Parenchymal atrophy, intraductal Pseudocyst
imaging with delayed and rim calcification
narrowed pancreatic duct
Serology Elevated serum IgG4 Normal serum IgG4 levels
Other organ Bile duct, kidneys, Retroperitoneum, salivary Mesenteritis, inflammatory
involvement lymphadenopathy gland bowel disease
Response to Complete Incomplete Refractory to steroids
Abbreviation: IDCP, idiopathic duct-centric chronic pancreatitis.
Data from Lara LP, Chari ST.Autoimmune pancreatitis. Curr Gastroenterol Rep 2005;7:101–6.
Fig. 1. Gross appearance of AIP. A cross section through the
pancreas is shown. Dense, white fibrotic tissue has
replaced the normal pancreatic parenchyma. There is
enhancement of the process around the common bile
duct (*). There are foci of fat necrosis present in this
example (yellow flecks).
Apollo Medicine, Vol. 7, No. 4, December 2010 272
(Fig. 2) [10,30]. A less common histopathologic variant
termed idiopathic duct-centric chronic pancreatitis is
characterized by a neutrophilic infiltrate with occasional
microabscesses and rare obliterative phlebitis [9,31].
Nearly a third of patients who haveAIPdevelop pancreatic
calcification and atrophy and the appearance can resemble
usual chronic calcific pancreatitis.
Pathologic features of autoimmune pancreatitis
Firm, tumor-like mass within the head of the pancreas
Lymphoplasmacytic inflammation with associated
fibrosis (periductal or lobular)
Increased numbers of IgG4-positive plasma cells (>10/
Neutrophilic infiltrate within the lobules and ducts with
bular fibrosis without significant inflammation
Not typically seen
Calcifications or stones
Fig.2 Histopathologic features of AIP. (A) Low magnification showing a fibroinflammatory process diffusely involving and
destroying the pancreatic parenchyma (hematoxylin-eosin, original magnification _40). (B) Periductal inflammation and
fibrosis extends into the adjacent parenchyma; the ductal epithelium is relatively spared (hematoxylin-eosin, original
magnification _100). (C) On higher magnification, destruction of the normal acini by plasma cells (arrows), lymphocytes,
and fibroblasts can be seen; the acinar cells contain pink cytoplasmic granules (hematoxylin-eosin, original magnification
_400). (D) Obliterative venulitis is a characteristic finding in AIP. Here, the vein lumen (*) is nearly obliterated by the
inflammatory process; an uninvolved artery is present in the lower right corner (hematoxylin-eosin, original.
273 Apollo Medicine, Vol. 7, No. 4, December 2010
sid=1077935416/ N/644914/If08000150001.fig - top
Because elevated IgG4 serum levels are typically
identified in patients withAIP, the presence of IgG4 plasma
cells, detected by immunohistochemistry, is another
characteristic histopathologic finding of AIP and can be
used as a diagnostic tool in AIP and related sclerosing
diseases.Adense infiltration of IgG4-positive plasma cells
in the pancreas is characteristic of AIP (Fig. 3). In the
Japanese literature, ‘‘dense’’ is defined as greater than 30
IgG4-positive cells per high-power field (hpf). A recent
publication by the Mayo Clinic divides the IgG4-positive
infiltrate into mild (<10/hpf), moderate (11–30/hpf), and
marked (>30/hpf). They found that patients withAIP often
had moderate or marked infiltration by IgG4-positive
plasma cells in their pancreatic tissue.This was particularly
true in classic LPSP, in which 16 (94%) of 17 cases showed
elevated numbers of IgG4-positive cells, compared with 5
(42%) of 12 cases of IDCP, highlighting yet another
difference between these two histologic variants of AIP.
Both sets of researchers rarely found IgG4 staining in
patients with chronic alcoholic pancreatitis and pancreatic
ductal adenocarcinoma. Based on these studies of IgG4
staining in AIP, another diagnostic feature of AIP is the
presence of a lymphoplasmacytic infiltrate with greater
than10 IgG4-positive cells/hpf in the pancreas.
Although several distinguishing imaging features of
AIP have been proposed in the literature, the lack of
familiarity of this entity by radiologists and referring
clinical services often results in an errant diagnosis of
The characteristic appearance of AIP observed by
various imaging modalities is that of a diffusely enlarged
pancreas, forming a sausage-shaped gland with featureless
borders (Fig.4) [1,32]. Other classic features that may be
present include delayed and prolonged contrast
enhancement, a rimlike capsule surrounding the gland on
delayed enhancement sequences (the hypoattenuation
halo), a nondilated, ectatic pancreatic duct, and the absence
of peripancreatic fat hypoenhancement, calcifications,
stones, and pseudocysts are typically not seen.
On CT, in addition to appearing diffusely enlarged
enhancement and can have a capsulelike low-density rim
surrounding the pancreas. In a large study by Sahani and
colleagues, uniform pancreatic enlargement and
isoenhancement were common features in most patients
with diffuseAIP; peripancreatic infiltration, when present,
was minimal. Absence of normal pancreatic clefts and a
subtle rim of hypoattenuation were thought to be caused by
within the head and uncinate process, was difficult to
distinguish from pancreatic carcinoma.
MRI characteristically reveals enlargement of the
pancreas with decreased signal intensity on T1-weighted
MR images, increased signal intensity onT2-weighted MR
images, and, occasionally, a hypointense capsule-like rim
(Fig 4 B) . Magnetic resonance cholangiopancreato-
graphy (MRCP) is often helpful in characterizing the
the pancreatic duct is not well visualized. Narrowing of the
anterior superior pancreaticoduodenal artery, posterior
superior pancreaticoduodenal artery, and transpancreatic
AIP patients .
Increasingly, endoscopic ultrasound has been used to
evaluate patients for AIP [34,35]. Not only can the
parenchyma and biliary and pancreatic ducts be visualized,
EUS also provides an opportunity to obtain Trucut biopsy
indeterminate biliary strictures. Levy and colleagues 
have reported on the diagnostic usefulness ofTrucut biopsy
in three patients who had suspected pancreatic
adenocarcinoma with planned surgical resection following
indeterminate fine-needle aspiration. In two of the patients,
pancreatitis was diagnosed. In all patients, unnecessary
surgery was avoided.
On endoscopic retrograde cholangiopancreatography
(ERCP), the pancreatic duct has an irregular contour and
can be either segmentally or diffusely narrowed . If the
Fig. 3 Numerous IgG4-positive plasma cells are present in
this case of AIP (IgG4 immunostain).
Apollo Medicine, Vol. 7, No. 4, December 2010 274
proximal duct is strictured, there is often dilation of the
ERCP, MRCP may not be able to detect the irregular
narrowing of the main pancreatic duct, but the MRCP
findings of skipped, nonvisualized main pancreatic duct
lesions, in conjunction with other imaging studies, are
useful in supporting a diagnosis of AIP .Cholangiography
has been shown to be an accurate method to differentiate
AIP from primary sclerosing cholongitis (PSC). Nakazawa
and colleagues  reported that bandlike stricture, beaded
were significantly more frequent in patients who had PSC.
In contrast, segmental stricture, long stricture with
prestenotic dilatation, and stricture of the distal common
bile duct were significantly more common in sclerosing
cholangitis with AIP. Increased uptake with whole-body
(18)F-fluorodeoxyglucose positron emission tomography
is seen in the pancreas and extrapancreatic lesions of
patients who haveAIP[38-40].
FEATURES OF AUTOIMMUNE PANCREATITIS BY
VARIOUS IMAGING MODALITIES
Diffusely or focally enlarged pancreas
With structuring of the main pancreatic duct, can see
dilatation of the upstream pancreatic or common bile
Typically absent: calcifications, pancreatic duct stones,
Diffuse pancreatic enlargement, uniform enhancement,
minimal pancreatic infiltration
The focally enlarged pancreas can mimic pancreatic
Capsule-like low-density rim surrounding the pancreas
Global pancreatic enlargement decreased T1 signal,
increased T2 signal, peripancreatic decreased signal
Fig. 4. Images from a 42-year-old woman with mild abdominal pain and history of undifferentiated connective tissue disease.
(A) Contrast-enhanced CT shows global pancreatic enlargement.The pancreas enhances uniformly. (B) Fat saturation
T1-weighted image shows diffuse pancreatic enlargement (asterisk). (C) Contrast-enhanced CT performed after steroid
treatmentshows a decrease in size of the pancreas (compare measure bar with Fig. 1A).
275 Apollo Medicine, Vol. 7, No. 4, December 2010
Segmental or diffuse irregular narrowing of the main
Skipped, nonvisualized main pancreatic duct lesions ±
Segmental or diffuse irregular narrowing of the main
pancreatic duct may not be seen
provide targeted fineneedleaspirates or core biopsies to
aid in the distinction between carcinoma
Increased numbers of circulating immunoglobulins,
specifically immunoglobulin subclass 4, are a hallmark of
the disease [9,16]. In a landmark study, Hamano and
colleagues  reported that serum IgG4 levels were highly
(95%) sensitive and highly (97%) specific for AIP. In a
recent study of 510 patients from the United States 
including 45 who hadAIP, 135 who had pancreatic cancer,
62 who had no pancreatic disease, and 268 who had other
pancreatic diseases, the sensitivity, specificity, and positive
diagnosis of AIP were 76%, 93%, and 36%, respectively.
When using a cutoff of twice the upper limit of normal for
serum IgG4 (>280 mg/dL), the corresponding values were
of non-AIP patient groups, including 10% of patients who
had ductal adenocarcinoma, had elevated IgG4 levels .
In addition, serum IgG4 levels, even in the presence of
classic histologic findings ofAIP, can be normal (Table 2)
Elevated titers of many autoantibodies have been
described in AIP. Autoantibodies against carbonic
anhydrase II and IV and lactoferrin are detected in most
patients who haveAIP [41,42]. Involvement of antinuclear
. Autoantibodies to the pancreatic secretory trypsin
inhibitor have been shown to be elevated in nearly 50% of
AIP patients compared with controls . None of these
autoantibodies have prediction characteristics that equal
that of IgG4. Levels of total IgG and gamma globulins are
also increased in AIP. In our experience, however, it is
unusual to have elevated serum levels of IgG or gamma
a combination of serum IgG4 levels and autoantibody titers
of antinuclear antibodies and rheumatoid factor modestly
The authors do not routinely use autoantibody titers to
OTHER ORGAN INVOLVEMENT
Other organs are often involved in AIP; their
involvement may be diagnosed before, simultaneous with,
to 100% of all patients presenting with AIP [1,44], and has
recently been termed IAC http://www.mdconsult.com/das/
1.html?issn=0889-8553 - r08000150042. IAC affects both
intra- and extrahepatic bile ducts, with the distal common
bile duct being the most common site of involvement .
Biliary imaging may not necessarily reveal involvement,
even when present microscopically . Histologically, a
lymphoplasmacytic infiltrate surrounds the bile ducts in a
pattern similar to that seen in the pancreas and IgG4-
positive staining is often present , http://
N/644914/1.html?issn=0889-8553 - r08000150095.
AIP coexisting with PSC has been described, although
Table 2. IgG4 level in patients who have different diseases of the pancreas
AIP Normal Pancreatic Benign pancreatic Chronic
pancreas cancer tumor pancreatitis
Numbera* 45 62 135 64 79
Mean IgG4 ± SM 550 ± 99 49 ± 6 68 ± 9 47 ± 5 46 ± 5
Range 16–2890 3–263 3–1140 3–195 3–231
Proportion elevated 76% 4.8% 9.6% 4.7% 6.3%
Ghazale A, Chari ST, Smyrk TC, et al. Value of serum IgG4 in the diagnosis of autoimmune pancreatitis and in distinguishing it from
pancreatic cancer.Am J Gastroenterol 2007;102(8):1646-1653.
Apollo Medicine, Vol. 7, No. 4, December 2010 276
this is likely not primary sclerosing cholangitis but IgG4-
proportion of patients who have aggressive PSC, serum
IgG4 levels are elevated suggesting a possible role for
corticosteroid therapy. One should be cautious in
diagnosing IAC simply based on elevated serum IgG4
levels, however, because false-positive elevations may
occur in true PSC. IAC differs from PSC in that there is
generally less intrahepatic involvement, the strictures can
be transient under observation, the strictures are usually
Inflammatory bowel disease, which is present in 70% of
PSC, is less common (6%) in IAC. Analogous to the
involvement, inflammation of the biliary tree typically
responds to corticosteroid treatment, although the specific
response of each duct segment is still being evaluated .
In addition to the biliary system, multiple other organs
may be involved in ISD. Hamano and colleagues reviewed
the frequency, distribution, clinical characteristics, and
hadAIPand found the most frequent extrapancreatic lesion
was hilar lymphadenopathy (80.4%), followed by
extrapancreatic bile duct lesions (73.9%), lacrimal and
salivary gland lesions (39.1%), hypothyroidism (22.2%),
lacrimal and salivary gland lesions were found to have
significantly higher IgG4 levels than those who did not.
Both intrinsic (tubulointestinal fibrosis) and extrinsic
(hydro-nephrosis secondary to retroperitoneal fibrosis)
renal disease have been associated with AIP, as has
of the liver [27,44,48].
features suggestive of AIP, but stopped short of providing
were proposed by the Japan Pancreas Society in 2002 and
later modified in 2006.These guidelines were developed to
distinguish between AIP and pancreatic adenocarcinoma.
To make the diagnosis of AIP based on the Japanese
guidelines, it is mandatory that findings on radiography be
consistent withAIP. These findings include the presence of
diffuse or segmental narrowing of the main pancreatic duct
with irregular wall diagnosed by endoscopic retrograde
pancreatogram and diffuse or localized enlargement of the
pancreas on abdominal ultrasonography, CT, or MRI. In
addition, one of serologic (high serum c-globulin, IgG, or
antibodies and rheumatoid factor) or histologic (marked
interlobular fibrosis and prominent infiltration of
lymphocytes and plasma cells in the periductal area,
occasionally with lymphoid follicles in the pancreas)
of AIP. The Japanese criteria do not take into account that
AIP has unique histologic features, characteristic findings
on IgG4 immunostaining of the organs involved, other
organ involvement, or response to steroids.
In 2006, Chari and colleagues  published an alternate
set of guidelines based on the Mayo Clinic experience with
AIP. These criteria, known by the mnemonic HISORt,
recognize characteristic features of AIP on pancreatic
histology and imaging, serology, other organ involvement,
and response to corticosteroid therapy. Based on the
or presence of 10 or more IgG4-positive cells per high-
power field (HPF) on immunostain of lymphoplasmacytic
infiltrate with storiform fibrosis; (b) typical pancreatic
imaging with elevated serum IgG4 ≥140 mg/dL, or (c)
unexplained pancreatic disease with negative workup for
other pancreatic diseases, especially malignancy, with
elevated serum IgG4 levels ≥140 mg/dL or other organ
involvement confirmed by presence of abundant IgG4-
positive cells, and resolution/marked improvement in
pancreatic or extrapancreatic manifestations with steroid
therapy (Table 3). By including additional features, these
ASAIAN CONSENSUS CRITERIA
Lymohoplasmacytic infiltration with fibrosis and
–positive cell infiltration.
Imaging: Both of the following
Diffuse, segmental or focal enlargement of the gland, with
or without a mass or hypoattenuated rim
Diffuse, segmental, or focal pancreatic duct narrowing,
with or with out stenosis of the bile duct
Serology: one of the following
High levels of total IgG or IgG4
Detection of autoantibodies (ANA, RF)
Response to glucocorticoid therapy: included as optional
with a negative workup for pancreatobiliary cancer
The cornerstone of treatment of AIP is the use of
277 Apollo Medicine, Vol. 7, No. 4, December 2010
Table 3. Mayo Clinic HISORt criteria for the diagnosis of autoimmune pancreatitis
At least one of the following:
• Periductal lymphoplasmacytic infiltrate with obliterative phlebitis and storiform fibrosis
• Lymphoplasmacytic infiltrate with storiform fibrosis with abundant (≥10 IgG4 cells/HPF)
• Typical: diffusely enlarged gland with delayed rim enhancement, diffusely irregular, attenuated main
• Other: focal pancreatic mass/enlargement, focal pancreatic ductal stricture, pancreatic atrophy,
• Elevated serum IgG4 level (normal 8–140 mg/dL)
Other organ involvement
• Hilar/intrahepatic biliary strictures, persistent distal biliary stricture, parotid/lacrimal gland involvement,
mediastinal lymphadenopathy, retroperitoneal fibrosis
Response to steroid therapy
• Resolution/marked improvement of pancreatic/extrapancreatic manifestation with corticosteroid therapy
GroupA: diagnostic pancreatic histology
Presence of one or more of the following criteria:
• Specimen demonstrating the full spectrum of LPSP
• ≥10 IgG4 cells/HPF on immunostain of pancreatic lymphoplasmacytic infiltrate
Group B: typical imaging + serology
Presence of all of the following criteria:
• CT or MRI scan showing diffusely enlarged pancreas with delayed and rim enhancement
• Pancreatogram showing diffusely irregular pancreatic duct
• Elevated serum IgG4 levels
Group C: response to corticosteroids
Presence of all of the following criteria:
• Unexplained pancreatic disease after negative workup for other causes
• Elevated serum IgG4 or other organ involvement confirmed by presence of abundant IgG4-positive cells
• Resolution/marked improvement in pancreatic or extrapancreatic manifestations with corticosteroid
*Patients meeting criteria for one or more of the groups haveAIP.
Data from Chari ST, Smyrk TC, Levy MJ, et al. .
corticosteroids with multiple authors reporting dramatic
response rates with prolonged therapy [1,9,48]. A word of
caution, however, is that it is imperative to thoroughly rule
out other possible causes of pancreatic disease, most
notably pancreatic malignancy, before initiating
Although spontaneous remissions do occur in AIP, the
use of corticosteroids seems to hasten recovery and may
prevent recurrences.There are several reasons, therefore, to
initiate treatment ofAIPwith corticosteroids. For one, if the
diagnosis remains in doubt and malignancy has been
excluded, response to corticosteroids can be a reasonable
method of diagnosing AIP. The clinical suspicion for AIP
should be high before initiation of therapy, however, and
patients should be followed closely for any symptoms (e.g.,
profound weight loss, anorexia, night sweats) more
consistent with malignancy thanAIP. Treatment can also be
Apollo Medicine, Vol. 7, No. 4, December 2010 278
a means of reducing clinical symptoms from acute
pancreatic (pancreatic endocrine insufficiency, rarely acute
pancreatitis) or extrapancreatic (jaundice from biliary
strictures, sialadenitis) manifestations of disease http://
N/644914/1.html?issn=0889-8553 - r08000150062,
[48,49]. In addition, there can sometimes be structural
improvement, for example in the pancreatic duct, with
corticosteroid therapy The degree of structural response
depends on the extent of fibrosis versus inflammation;
patients who have more inflammatory injury typically have
a greater structural response and extensive fibrosis may not
allow complete remission to occur .
The exact corticosteroid treatment protocol for patients
who have AIP is not standardized; however, most
practitioners initiate therapy with between 30 and 40 mg of
prednisone daily.These doses are usually effective to induce
remission; it is unclear if starting at lower doses would be
equally effective. Resolution of symptoms is generally
rapidly achieved within 2 to 3 weeks of corticosteroid
initiation. It usually takes several weeks to months for
evidence of serologic (normalization of IgG4) or radiologic
remission. Occasionally, because of fibrotic involvement of
tissue, radiologic remission is not seen, especially in
proximal biliary strictures resembling cholangiocarcinoma,
intrahepatic strictures resembling PSC, and retroperitoneal
fibrosis. Progression toward normalization of serum IgG4
levels can be used to guide treatment in these instances.
Because histologic specimens are often difficult to obtain,
we generally do not use histology as a marker for remission.
At the Mayo Clinic, we treat patients diagnosed with
AIP with a prolonged steroid taper. Patients are started on
40 mg/d of prednisone for 4 weeks. After 4 weeks, their
clinical response is gauged and repeat cross-sectional
imaging and serologic evaluation are performed to check for
response. If clinical, serologic, or radiographic response is
documented, the prednisone dose is tapered 5 mg/wk until
gone. In patients in whom a biliary stent has been placed,
this usually can be removed at 6 to 8 weeks following
initiation of therapy. IgG4 levels are also followed and in
patients who have AIP, a decrease in IgG4 (although not
necessarily normalization) should occur within 4 weeks of
b o d y / 2 2 5 1 3 9 9 4 2 - 1 2 / j o rg = j o u r n a l & s o u r c e =
If08000150005.fig - top
Recently, in patients who present with jaundice
because of biliary stricturing disease who do not wish to
undergo initial endoscopic retrograde
cholongiopancreatography with stent placement, we have
occasionally treated with a large initial bolus of
intravenous corticosteroids. Although our experience is
limited and at this time anecdotal, jaundice does seem to
respond rapidly to this treatment, thus obviating the need
for biliary stent placement. Further prospective studies are
needed to determine if large initial doses of corticosteroids
are an effective alternative to initial biliary stent placement
in newly diagnosedAIP.
Between 30% and 40% of patients have clinical or
radiographic relapse following treatment with prolonged
corticosteroids requiring retreatment with a second
prolonged course [1,25,48,49]. These relapses generally
occur in the short term; data on long-term relapse are
lacking. Relapse may be symptomatic, radiologic,
serologic, or histologic. The presence of symptoms
(recurrent abdominal pain, weight loss, and so forth) is often
a clue to relapse within the pancreas; only in the presence of
symptoms is cross-sectional imaging repeated. Serologic
relapse alone can be seen in patients who do not have
clinical symptoms or radiologic changes; whether or not this
represents a subclinical disease relapse is unclear at this
time. It is also unclear if certain types of organ involvement
are more prone to relapse than others. For example, Ghazale
and colleagues  found that in patients who had IAC
treated with 11 weeks of corticosteroids, proximal biliary
involve-ment (proximal extrahepatic and intrahepatic
biliary strictures) relapsed with a rate of 65% compared with
a 25% relapse rate in those who had intrapancreatic
stricturing of the distal common bile duct.
In a certain subset of patients who have relapse after a
second prolonged course of steroids, either chronic
prednisone therapy or use of another agent, such as
azathioprine or 6-mercaptopurine, may be necessary. In
Japan, it is often standard of care to continue patients on a
chronic low dose (2.5–10 mg/d) of prednisone indefinitely
[48,49].Although there are only case reports evaluating the
efficacy of long-term treatment of AIP with immuno-
modulating therapy, we have had favorable, although
limited, experience with these medications . As more
experience is gained about the long-term pathogenesis of
AIP, recommendations on the use of chronic suppressive
therapy needs to be developed. In addition, because there is
such a high frequency of short-term relapse, whether
maintenance therapy should be used in all patients, and what
type of maintenance therapy should be used, remains to be
It is unclear at this time whether corticosteroid therapy
alters the long-term natural history of disease, prevents the
development of future pancreatic or extrapancreatic
involvement and organ dysfunction, or is adequate as a long-
term suppressive strategy.
279 Apollo Medicine, Vol. 7, No. 4, December 2010
Increasingly, we are evaluating patients in whom AIP
has been inaccurately diagnosed. The misdiagnosis occurs
in the setting of patients who have other unrelated
conditions, such as pancreatic adenocarcinoma, being
treated inappropriately with corticosteroids. We have also
seen several patients who had functional abdominal pain
complaints treated with prolonged courses of high-dose
corticosteroids without evidence of AIP. Conversely,
multiple patients have undergone therapies, such as
pancreatic head resections or partial hepatectomy, without
consideration of an autoimmune cause.
It is therefore important that AIP be considered in the
differential diagnosis of patients who have chronic
pancreatitis or biliary strictures. It is imperative, however,
that a thorough evaluation be performed for other causes of
initiation of corticosteroid therapy. Once corticosteroid
therapy has been initiated, patients should be followed
closely for signs of worsening or refractory disease
symptoms; it is highly unusual for AIP not to quickly
respond to appropriate corticosteroid therapy. In addition,
patients who do not meet the Japanese Pancreas Society or
Mayo HISORt guidelines, corticosteroid therapy is likely
There are limited data about the long-term outcome of
most comprehensive report on prognosis when they
evaluated 42 patients who had AIP, 19 of whom received
corticosteroid treatment at the time of diagnosis. In the 23
patients who did not have corticosteroid treatment initially,
16 developed unfavorable events, including obstructive
jaundice attributable to distal bile duct stenosis in 4,
growing pseudocyst in 1, and sclerogenic changes of
extrapancreatic bile duct in 9, over an average observation
23 months in the initial treatment group, 6 patients
developed unfavorable events consisting of interstitial
pneumonia in 3 and recurrence of obstructive jaundice in 3.
Their conclusions were that early introduction of
corticosteroids is important to prevent subsequent disease
out” of disease, rendering the pancreas usually somewhat
atrophic following treatment . The degree of residual
pancreatic exocrine or endocrine insufficiency is likely
related to the degree of gland fibrosis at the time of
At this time, given the relatively recent description and
active investigation of AIP, there are no data regarding the
addition, it has not been investigated whether life
expectancy is altered by the course of this disease.
There are several lines of investigation that need to be
cause of this disease and its relationship with IgG4 is
imperative. Specifically, the antigenic trigger of CD4 and
CD8 T-cell activation needs to be identified. Clinically,
specific attention to the wide-ranging effects of IgG4-
related systemic disease. It is not currently known whether
different manifestations of IgG4-related disease have
unique or alternate prognoses. The role of corticosteroids,
specifically their role in changing the natural history of
it will be important to determine if treatment helps to
prevent future organ dysfunction. Furthermore, the role of
chronic suppressive therapy, either with corticosteroids or
another immune-modulating drug, in preventing relapse
and affecting long-term prognosis is yet to be determined.
AIP is a unique subtype of recently identified chronic
pancreatitis that is immune mediated and represents one
manifestation of a systemic IgG4-related disease process.
Although a rare condition, it is important to recognize
because it responds often dramatically to immune system–
modulating treatment. Diagnosing AIP can sometimes be
challenging, however, and it is imperative that clinicians be
cautious when considering this diagnosis in patients
suspected of having a pancreatic malignancy. As clinical
experience with AIP increases, refinement of diagnostic
criteria and development of standardized therapeutic
protocols should allow further optimization of care for our
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