What an endoscopist should know about immunoglobulin-G4-associated disease of the

What an endoscopist should know about
immunoglobulin-G4-associated disease of the
pancreas and biliary tree
L. Maillette de Buy Wenniger, E. A. Rauws, U. Beuers
Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The
DOI http://dx.doi.org/
Endoscopy 2012; 44: 66–73
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0013-726X
Autoimmune pancreatitis (AIP) and IgG4-associated cholangitis (IAC) are the recently recognized pancreatobiliary manifestations of IgG4associated systemic disease (ISD). Clinically, ISD
of the pancreas and/or biliary tree may mimic
pancreatic cancer, sclerosing cholangitis, or cholangiocarcinoma. Patients often present with abdominal pain, weight loss, jaundice, itch, and biochemical signs of pancreatitis and cholestasis. Tomography may reveal enlargement of the pancreas or may mimic malignant pancreatic lesions,
and cholangiopancreatography may disclose irregularities of the pancreatic duct and stenoses of
the distal and/or proximal common bile duct and
intrahepatic bile ductules. Serum immunoglobu-
lin G4 (IgG4) is elevated in most patients but, unlike tissue IgG4-loaded plasma cell infiltrates, is
not diagnostic of the disease. The application of
consensus diagnostic criteria for laboratory investigations, imaging, and histologic findings can
identify patients who qualify for corticosteroid
treatment. The excellent response to immunosuppressive therapy suggests an immune-mediated etiology of the disease, but the exact pathophysiological mechanisms are still under investigation. Relapse may occur after tapering down of
corticosteroids, which supports the rationale of
maintenance immunosuppression after remission has been induced.
Immunoglobulin-G4-associated disease
of the pancreas and biliary tree
IgG4-associated sclerosing or systemic
Endoscopic evaluation of the biliary tree and pancreatic duct can yield important information
about stenoses that restrict the normal flow of
bile and pancreatic secretions respectively towards the intestinal lumen. One of the least common and only recently acknowledged types of
sclerotic disease of these ducts is characterized
by a marked increase of serum immunoglobulin
G4 (IgG4) in most patients. Although rare, identification of this patient group is of crucial importance, especially to distinguish them from those
with malignant pancreaticobiliary disease. This
review aims to provide a practical overview of
the current knowledge of IgG4-associated disease
of the pancreas and the biliary tree: when to think
of the diagnosis, how to confirm the diagnosis,
and how to treat patients with IgG4-associated
pancreatic and biliary disease.
IgG4-associated sclerosing or systemic disease
(ISD) [1] is a recently established umbrella term
for a range of organ abnormalities that are all
associated with elevated IgG4 serum levels and/
or IgG4-positive plasma cell infiltrates in different
tissues. High IgG4 serum levels were first reported by Hamano et al. in 2001 in patients with sclerosing pancreatitis, and have since then been
associated with autoimmune pancreatitis (AIP)
[2]. Careful evaluation of patients with AIP now
suggests that AIP should be classified into type 1,
typically seen in older males and associated with
high IgG4, and type 2, which is found in younger
patients who do not have raised IgG4 levels [3].
As type 2 AIP is thought not to belong to the spectrum of IgG4-associated disease, in this review we
will focus only on type 1 AIP.
The list of organs that can be affected by ISD has
expanded from the pancreas [4 – 6], the biliary
tree, gallbladder, and liver [7], the retroperitoneum [8, 9], the salivary, parotid, and lacrimal
glands [10, 11], and the kidney [12], to the lungs
[13, 14], the lymphatic system, the prostate [15,
Corresponding author
Prof. Dr. Ulrich Beuers
Department of
Gastroenterology and
G4-213 Academic Medical
University of Amsterdam
P O Box 22700
1100 DE Amsterdam
The Netherlands
Fax: +31-20-6917033
[email protected]
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Hypotheses on the pathophysiology
of IgG4-associated disease
Under normal conditions IgG4 makes up 5 % of total circulating
IgGs. Induction of IgG4 is thought to be mainly associated with
helminthic infections, some allergy-like conditions, and other situations of ongoing antigen exposure: beekeepers, for example,
first develop a predominantly IgG1-mediated response to the
bee venom, which is gradually overruled by an IgG4-driven reaction.
Immunoglobulin G4 antibodies differ functionally from other IgG
subclasses in their anti-inflammatory activity. This includes poor
ability to induce complement and cell activation because of low
affinity for C1q (the q fragment of the first component of complement) and Fc receptors [28]. Consequently, IgG4 has become the
preferred subclass for immunotherapy in which recruitment of
host effector function is undesirable. IgG4 was formerly thought
to be a monovalent antibody, but this paradigm may need revision. IgG4 seems to be capable of dimerizing with IgG4 of other
species via Fab-arm exchange [29]. This was shown to occur in
vivo for natalizumab, a therapeutic antibody approved for use in
humans, thus forming bispecific antibodies [30].
The pathophysiology of IgG4-associated diseases is elusive [31]. A
derailment of the immune system is assumed to be causing overactive proliferation and infiltration of the target organs by IgG4loaded plasma cells. However, the initiation of this cascade is un-
Table 1 List of possible localizations of immunoglobulin-G4-associated
systemic disease.
ISD localizations (adapted from
Suggested additional
ISD localizations
Biliary tree, gallbladder, and liver
Lymphatic system (especially hilus)
Salivary, parotid, and lacrimal
Intestine, stomach, ileal pouch
Vascular system (aortitis)
Nervous system, eye (uveitis)
Thyroid gland
Pituitary gland
ISD, immunoglobulin-G4-associated systemic disease.
known. One possibility would be that the immune system crossreacts with self antigens in a way similar to classical autoimmune
disease, predominantly relying on T-helper-1 cells. Evidence for
molecular mimicry of plasminogen-binding protein of Helicobacter pylori to carbonic anhydrase II has been provided recently in
patients with AIP when an antibody against this peptide was
identified [32]. Potential methodological shortcomings of this
study included the lack of a control group of patients with an active H. pylori infection, and the fact that the H. pylori infection
status of the investigated patients was not reported [33].
Another explanation of the apparent increase (which in itself is
still under debate) in cases of IgG4-associated disease would be
the plummeting rates of helminthic infections due to improved
hygiene, leading to an increased risk of inappropriate overproduction of IgG4. Under preindustrial conditions IgG4 is thought
to be an important antibody in the control of these parasites
[34], and (sub)total removal of encounters with these parasitic
animals could sensitize individuals towards aberrant reactions
analogous to allergies [35]. The cytokine profile of ISD could fit
such a T-2-driven reaction [36].
Whether IgG4 has a direct role in the pathogenesis of ISD is still
unclear, and the finding of high IgG4 levels could be an epiphenomenon. Still, the finding of tissue reactivity of IgG4 from patient
sera suggests that the immunoglobulins may have a pivotal function in the maintenance of the pathological process, and possibly
even in its initiation [37]. In patients who respond to therapy the
serum IgG4 levels fall [7], supporting a relationship between IgG4
load and disease activity.
When to consider IgG4-associated pancreaticobiliary
disease, and how to differentiate it from pancreatic
or biliary malignancy
The cholestatic and some gastrointestinal symptoms of IgG4associated disease of the pancreas and biliary tree are the result
of stenoses of the pancreatic duct and/or biliary tree. Although
isolated involvement of either the pancreas or the bile ducts has
been reported, most patients already have ISD lesions in both
duct systems on presentation or would develop them during the
further course of the disease. Pancreaticobiliary ISD symptoms
often include jaundice (approx. 75 % of all cases), weight loss,
and abdominal or back pain. Anorexia, steatorrhea, and new-onset diabetes are also reported in significant percentages. Typical-
Maillette de Buy Wenniger L et al. What an endoscopist should know about IgG4ssociated disease of the pancreas and biliary tree … Endoscopy 2012; 44: 66–73
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16], the stomach [17, 18], the intestine [18] including ileal pouches [19], the nervous system [20], the thyroid gland [21], the pituitary gland [22], and the aorta leading to aneurysms [23, 24]
" Table 1). Lesions in any of these organs are characterized by
infiltrating T cells and IgG4-bearing plasma cells. Obliterative
phlebitis is often present, and as the disease advances, fibrosis/
sclerosis of the tissue ensues.
In this review we focus on IgG4-associated disease of the organs
that can be evaluated using upper endoscopic techniques, i. e., the
pancreas (type 1 autoimmune pancreatitis, AIP 1) [26] and the
biliary tree (IgG4-associated cholangitis, IAC) [7, 27]. Nevertheless, endoscopists should be aware of the possibility of other organ involvement in IgG4-associated disease of the pancreaticobiliary system: recognizing these associated ISD locations may
support the diagnosis of pancreaticobiliary ISD. Given the strong
similarities between the clinical presentation, age of peak incidence, and initial findings of laboratory, radiological, and endoscopic investigations, IgG4-associated disease should always be
seen as a differential diagnosis to the statistically more likely diagnosis of pancreatic cancer or to the profoundly less favorable
diagnosis of cholangiocarcinoma or primary sclerosing cholangitis (PSC). Only histological evaluation of the affected organs can
eventually indisputably confirm either of these diagnoses, and
most of the early cases of IgG4-associated pancreaticobiliary disease were only diagnosed retrospectively on resection specimens
after surgery for suspected pancreatic malignancy. Knowing that
the standard treatment with corticosteroids for ISD would negatively affect the prognosis of patients who turn out to have a malignant disease, it is of the uttermost importance to perform a full
work-up in all suspected cases, including laboratory investigations, imaging techniques including endoscopic ultrasonography,
and, if possible, biopsies of the pancreas and of affected bile ducts
by the endoscopic route. Consensus criteria for the diagnosis of
ISD should be stringently applied in all cases.
Clinical action
Findings in anamnesis not entirely typical of pancreatic cancer or
biliary cancer, e. g.:
Determine serum IgG4
Earlier episode of pancreatitis-like complaints
Earlier unexplained pseudotumors
Table 2 Diagnostic cues suggesting the possibility of immunoglobulin-G4-associated disease
rather than pancreatic or biliary
Recently developed diabetes
Other organ involvement (dry mouth, dry eyes, kidney involvement)
Radiological findings not typical of pancreatic or biliary cancer
" Table 3)
Determine serum IgG4
Endoscopic findings not typical of cancer, e. g.:
Determine serum IgG4 and screen for PSC (PANCA)
Multiple intrahepatic biliary strictures, mimicking PSC rather
than a classical hilar biliary malignancy (watch out for Klatskin
tumor in a patient with undiagnosed PSC)
Wall irregularities along whole trajectory of pancreatic duct
Pathological examination of biopsy/brush material obtained by
endoscopy shows no malignant cells
Request immunohistochemical staining for
IgG4-positive cells
No malignant cells found in frozen section during (Whipple)
surgery for suspected pancreatic/biliary malignancy, or no
malignant disease found on pathological evaluation of resection
Determine IgG4; request immunohistochemical staining for IgG4-positive cells of resection
specimen; and initiate steroid treatment if patient has recurrence of cholestatic complaints
and matches HISORt criteria
Patient diagnosed with pancreatic/biliary cancer without treatment options still alive approx. 3 – 6 months after diagnosis
Determine serum IgG4
IgG4, immunoglobulin G4; PSC, primary sclerosing cholangitis; P-ANCA, perinuclear anti-neutrophil cytoplasmic antibodies; HISORt, histology,
imaging, serology, other organ involvement, and response to therapy.
ly, the disease is found in men above 60 years of age (range 40 –
80 years), with a reported male:female ratio of up to 8:1. The clinical signs and symptoms are often highly suggestive of pancreatic
head cancer, but may provide subtle cues that point towards
" Table2). Dynamic CT or MRI shows
IgG4-associated disease (●
the diffuse enlargement of the pancreas that is typical of AIP
" Fig. 1), but may also further raise the suspicion of pancreatic
cancer in cases where inflammatory changes mimic a pancreatic
Swelling of the inflamed pancreas may lead to compression of the
common bile duct, inhibiting normal bile flow in patients with
IgG4-associated pancreaticobiliary disease. Hilar involvement of
bile ducts in IAC rather mimics hilar cholangiocarcinoma (Klatskin tumor).
immune-mediated diseases as well. Elevated levels of CA19 – 9,
an established tumor marker, have been documented in up to
18 % of AIP patients.
Findings during endoscopy
Endoscopy is often part of the clinical work-up of patients with
pancreaticobiliary ISD. Endoscopic retrograde cholangiopancreatography (ERCP) typically reveals strictures of not only the pan" Fig. 2) but also the biliary tree (●
" Fig. 3). The
creatic duct (●
most common finding is distal common bile duct involvement
(in 90 %), but typical strictures can be observed anywhere in the
Laboratory investigations
Case series report elevated levels of alkaline phosphatase in 80
% – 90 % of patients, and γ-glutamyltransferase is often also
elevated. Serum activities of pancreatic enzymes are normal in
about 60 % of cases. The finding of markedly raised IgG4 levels (>
280 mg/dL – twice the upper limit of normal) is highly suggestive
of IgG4-associated disease, but moderately raised IgG4 levels
(140 mg/dL < IgG4 < 280 mg/dL) are not pathognomonic of ISD.
IgG4 levels above 140 mg/dL show a moderate sensitivity of 70
% – 80 % for diagnosing AIP. The added value of measuring total
IgG levels is still under discussion [38]. Fluctuations in IgG4 levels
provide a rationale for repeated serum IgG4 measurements.
Based on serum markers only, discrimination between pancreatic cancer, cholangiocarcinoma, and IgG4-associated disease with
adequate certainty remains difficult in most cases. Elevated levels of IgG4 are reported in about 50 % – 80 % of AIP and IAC patients, but mildly elevated levels were also found in 9 % of a retrospective cohort of patients with PSC and in 10 % of pancreatic
cancer patients [39], and elevated IgG4 can be observed in other
Fig. 1 CT of pancreas suggestive of autoimmune pancreatitis in a woman
with markedly elevated serum levels of immunoglobulin G4 (IgG4). The
pancreas has a sausage-like appearance, and an enhanced rim is visible.
Maillette de Buy Wenniger L et al. What an endoscopist should know about IgG4ssociated disease of the pancreas and biliary tree … Endoscopy 2012; 44: 66–73
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Fig. 2 Pancreatic duct made visible during endoscopy in the same patient
" Fig. 1. The duct wall shows irregularities.
as in ●
" Fig. 3. The pancreatic tail is swollen.
CT of the same patient as in●
may be further made likely by the finding of IgG4-positive plasma cells in a pancreatic core biopsy or biliary biopsies of the lesions. In patients with a dominant bile duct stenosis, stent placement may relieve cholestasis.
What to biopsy and how to interpret histology
Fig. 3 Endoscopic retrograde cholangiogram of a man presenting with
cholestasis combined with markedly elevated IgG4 levels.
biliary tree, and especially the intrahepatic stenoses that are seen
in approximately 10 % of cases may mimic those in PSC. It is important to note that these strictures may come and go, even during the natural course of the disease.
In clinical practice endoscopy is not likely to provide the definitive diagnosis of ISD. Still, in cases suggestive of IAC or pancreatitis ERCP may give an opportunity to gather extra arguments that
favor the benign disease over pancreatic cancer or cholangiocarcinoma. The presence of (multiple) pancreaticobiliary strictures,
in combination with appropriate findings on ultrasonography,
" Fig. 4) may help in reaching a diagnosis, which
CT, or MRI (●
Pancreatic biopsy under EUS guidance may be of diagnostic value; a core biopsy should be performed since fine-needle aspiration provides no reliable information [41]. The exact value of biliary biopsies is still under debate, but strong IgG4-positive infiltrates in transpapillary, intraductal biopsies of the bile duct have
been shown in cases of both AIP and IAC, whereas they were absent in cases of pancreatic malignancy [7, 42]. The finding of
IgG4-positive infiltration in papillary biopsies was reported to
be specific, although not very sensitive, but this finding should
be confirmed in an independent large study group [43 – 45]. Performing a liver biopsy is not strictly necessary for diagnosing AIP
or IAC, but the finding of more than 10 IgG4-positive cells per
high power field may help to differentiate between IAC and PSC
in cases where tissue is available [46, 47].
Central to the diagnosis of ISD in pancreatic, biliary, or liver tissue
is the immunohistochemical staining of more than 10 IgG4-positive cells per high power field, although IgG4-positive cells may
also be seen in lymphoplasmacytic infiltrates of other etiologies
[48]. Routine histochemistry may reveal lymphoplasmacytic infiltration of the tissue, obliterative phlebitis and storiform fibrosis (swirling fibrosis centered around ducts and veins), and
sclerosis in advanced cases. The finding of dense IgG4-positive infiltration is a strong indicator of IgG4-associated disease, which
in combination with other investigations can result in a definite
diagnosis of IgG4-associated pancreaticobiliary disease.
Diagnosing IgG4-associated pancreaticobiliary disease
IgG4-associated sclerosing disease is a systemic disease that is
histologically defined by IgG4-positive plasma cell infiltrates in
many organs, often in the presence of elevated serum IgG4 levels,
and responds to systemic administration of corticosteroids [49].
At present, the HISORt [7, 50] criteria (histology, imaging, serology, other organ involvement, and response to therapy) and Japa-
Maillette de Buy Wenniger L et al. What an endoscopist should know about IgG4ssociated disease of the pancreas and biliary tree … Endoscopy 2012; 44: 66–73
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Fig. 4
Diagnosing IgG4-associated diseasepancreaticobiliary
Type 1 autoimmune pancreatitis
IgG4-associated cholangitis
Clinical suspicion of pancreatic disease
Stricture(s) of intrahepatic, proximal extrahepatic
or intrapancreatic ducts, with:
Absence of classical
imaging for AIP
Negative work-up
for cancer
Classical imaging for AIP
and one of the following:
▪ Elevated serum IgG4
▪ Other organ involvement
▪ Compatible FNA
One of the following:
▪ Serum IgG4 > 2 x ULN
▪ (Histologically) proven
other ISD-spectrum
organ involvement
Two of the following:
▪Elevated serum IgG4
evidence for other
organ involvement
▪Compatible FNA
Previous pancreatic/biliary
resection or core biopsy
of pancreas showing
diagnostic features of
Definite diagnosis
of AIP
Response to 2 weeks of
adequate steroid
▪Significant decrease in
serum IgG4
▪Markedly improved
morphology as
objectivated by imaging
(CT, ultrasound, MRCP)
Classical imaging findings
of AIP and elevated serum
Definite diagnosis
of IAC
In all cases of non-response to
adequate steroid treatment:
▪ Withdraw steroids!
▪Reconsider presence of malignant
Two or more of the
▪ Elevated serum IgG4
▪ Suggestive pancreatic
imaging findings
▪ Other organ involvement
▪ Bile duct biopsy with >10
IgG4 positive cells/hpf
Combined with following
findings after 4 weeks of
adequate steroid
▪ Markedly improved
biliary strictures allowing
stent removal
▪ Liver enzymes < 2 x ULN
▪ Significant decrease in
serum IgG4 and CA19.9
Fig. 5 Summary of HISORt (histology, imaging, serology, other organ involvement, and response to therapy) diagnostic criteria for autoimmune pancreatitis
(AIP) and IgG4-associated cholangitis (IAC) [7, 50], adapted from Alderlieste et al. [27]. FNA, fine-needle aspiration; ISD, IgG4-associated systemic disease; CT,
computed tomography; MRI, magnetic resonance imaging; MRCP, magnetic resonance cholangiopancreatography; ULN, upper limit of normal.
nese consensus criteria [25] are ubiquitously applied for diagnos" Fig. 5). These criteria are valuable tools in clining AIP and IAC (●
ical practice, but cannot exclude other disorders with 100 % accuracy before the successful induction of prolonged disease remission by immunosuppressive treatment.
The most relevant differential diagnoses of pancreaticobiliary ISD
are pancreatic cancer and cholangiocarcinoma. Given the strong
resemblance of the clinical presentations of pancreatic cancer
and AIP, and the knowledge that pancreatic cancer, with an incidence of about 10 per 100 000, is about 10 times more common
than AIP, clinicians should be extremely alert to any indications
that argue for the presence of malignancy.
The risk of cholangiocarcinoma is much lower, but in patients
suspected of having IAC who show intrahepatic strictures on
cholangiography it is important to consider the possibility of cholangiocarcinoma against a background of PSC. PSC can barely be
distinguished from IAC by cholangiography, especially in cases
where the intrahepatic bile ducts are affected. The view, however, that PSC and IAC/AIP may be manifestations of the same disease spectrum, appears questionable [51]. Still, as IgG4-associated pancreaticobiliary disease, unlike PSC, typically responds to
steroid treatment, clinicians should always consider the possibility of ISD in patients presenting with PSC-like features at an advanced age. Incidental reports of ISD in even young children [52]
suggest the possibility that a subset of patients previously diagnosed as having PSC or autoimmune hepatitis and who respond
swiftly to steroid treatment actually have a liver-dominant form
of ISD [53].
Other differential diagnoses of ISD of the pancreas and biliary
tract are chronic alcohol-induced pancreatitis, gallstone disease,
microlithiasis and sludge, and the extremely rare eosinophilic
pancreatitis or cholangitis [54].
Treatment options for ISD
Corticosteroids form the cornerstone of treatment of any IgG4associated disease, and are generally effective. Some patients
have been reported to improve spontaneously without any treatment, but the data on the natural course of AIP and IAC are too
limited so far [1, 55].
Before the initiation of immunosuppressive therapy, manifest
biliary obstructions should be taken care of by endoscopic stenting. Antibiotic prophylaxis should be given when hilar and intrahepatic bile ducts are affected. Blood glucose levels should be
controlled as a significant proportion of patients develop (temporary) de novo diabetes. Patients who already have established
diabetes should be instructed to expect and actively manage deregulation of their blood glucose, especially during the first
weeks of corticosteroid therapy.
An initial dose of 40 mg/day of prednisolone (or approx. 0.6 mg/
kg) is usually applied, and is effective in nearly all bona fide cases
of AIP and IAC. In patients who do not show any improvement
(radiologically after 2 weeks for AIP, or as measured by decreasing IgG4 levels and cholestatic markers after 4 weeks for IAC;
" Fig. 6 and ●
" Fig. 7) the suspicion of malignant or other disease
" Fig. 8) should be raised. Steroid use should be quickly tapered
in these cases and discontinued.
Patients should be closely followed in the months after the initiation of immunosuppressive therapy. As clinical signs and symptoms improve and serum levels of IgG4 and alkaline phosphatase
Maillette de Buy Wenniger L et al. What an endoscopist should know about IgG4ssociated disease of the pancreas and biliary tree … Endoscopy 2012; 44: 66–73
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" Fig. 3 and ●
" Fig.4 after a course of
Fig. 7 CT of the same patient as in ●
high-dose prednisolone. The pancreatic swelling has changed into a nearly
atrophic pancreas.
Fig. 6 Endoscopic retrograde cholangiogram of a patient with primary
sclerosing cholangitis (PSC), illustrating the difficulty of distinguishing PSC
from IgG4-associated cholangitis on the basis of the cholangiogram alone.
decrease the dose of prednisolone can be tapered by 5 mg every
1 – 2 weeks to 15 mg/day, which is then the recommended dose
for a period of about 3 – 6 months to induce remission of the disease and to prevent relapse. Thereafter, steroid use can be further
tapered down to a maintenance regime of 5 mg/day, which can be
stopped as guided by the clinical course or continued as a safeguard against relapse for a maximum of 3 years (counting from
the start of therapy). Biliary stents can often be removed after
1 – 2 months, and diabetes mellitus regularly improves.
Under optimal treatment regimens the short-term prognosis of
IgG4-associated systemic disease is good, but, as the concept of
ISD is still young, firm predictions about its long-term prognosis
cannot be made. The consensus is that ISD in itself represents a
relatively benign pathology that is unrelated to malignant disease. In a recent series of 111 patients followed up for ISD,
though, 3 patients developed non-Hodgkin lymphoma 3 – 5 years
after the diagnosis [56]. The publication of a few additional case
reports about the occurrence of malignant disease of B-cell origin
[57] as well as one case of T-cell lymphoma [58] could indicate an
elevated risk of hematologic malignancy, possibly due to the intense activation of the immune cells and the associated proliferation during IgG4-mediated disease activity. Clinical vigilance for
hematological malignancies during the follow-up of ISD patients
is thus warranted [58].
Fig. 8 Magnetic resonance cholangiopancreatogram of the same patient
" Fig. 3, ●
" Fig. 4, and ●
" Fig. 6 after prednisolone treatment, showas in ●
ing nearly complete remission of the previously observed bile duct strictures.
Reacting to relapse
Relapse rates after a successful course of steroids vary greatly
among the reported case series: figures from 10 % to over 50 %
have been described. Early predictors of relapse appear to be rising serum levels of alkaline phosphatase and IgG4, and possibly
enlargement of the pancreas on imaging. Upon (the suspicion
of) relapse, steroid therapy can be reinitiated, or the dose can be
stepped up to the initial dose (0.6 mg/kg per day).
Escape treatments for steroid-refractory ISD all rely on suppression of the immune system. In these cases prednisolone is often
used to induce remission and azathioprine or mycophenolate
mofetil is subsequently used for long-term immunosuppression.
Budesonide may be of value as it generally has fewer systemic
Maillette de Buy Wenniger L et al. What an endoscopist should know about IgG4ssociated disease of the pancreas and biliary tree … Endoscopy 2012; 44: 66–73
Table 3 Radiological findings suggestive of pancreaticobiliary immunoglobulin-G4-associated systemic disease [25].
Delayed-phase enhancement of enlarged pancreas on dynamic CT or MRI
Capsule-like rim surrounding pancreas with low density on CT or hypoin" Fig. 1)
tense on T2-weighted MRI (●
Diffuse or multiple signal intense areas on diffusion-weighted MRI
Low apparent diffusion coefficient (ADC) on MRI [40]
Abnormal extrapancreatic FDG uptake (lymph nodes, salivary glands) on
FDG-PET (beware confusion with metastases)
Hypoechoic pancreas with focal or diffuse parenchymal swelling on endoscopic ultrasonography
Intrapancreatic, extrahepatic, or intrahepatic biliary strictures on ERCP
" Fig. 2 and ●
" Fig. 3)
Thickened gallbladder wall on ultrasonography
MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission
scanning; ERCP, endoscopic retrograde cholangiopancreatography.
side effects than prednisolone, but it may fail to suppress disease
manifestations outside the biliary tract. A more specific approach
may lie in the depletion of the IgG4-producing B-cell pool: rituximab, a monoclonal antibody directed against CD20 on B lymphocytes, was reported to induce remission swiftly in a steroidrefractory case and in patients with IgG4-associated systemic
disease [59, 60].
Summary and outlook
Autoimmune pancreatitis and IgG4-associated cholangitis are
the pancreaticobiliary manifestations of IgG4-associated systemic disease. The possibility of IgG4-associated pancreaticobiliary
disease should be considered especially in elderly men presenting with jaundice, abdominal pain, and weight loss, in whom
imaging reveals a diffusely swollen pancreas and distal stricturing of the common bile duct, but malignant cells are absent in
pancreatic or biliary biopsies or biliary brush material obtained
during endoscopy. In men above 55 years of age in whom findings are suggestive of pancreatic or biliary malignancy, but histology has been negative for carcinoma, IgG4 levels should be assessed. Markedly elevated IgG4 levels ( > 2 × upper limit of normal)
are suggestive of IgG4-associated pancreaticobiliary disease. The
pathogenesis of IgG4-associated disease remains elusive, but
using consensus diagnostic criteria enables clinicians to distinguish pancreaticobiliary IgG4-associated disease from its main
differential diagnoses, pancreatic or bile duct cancer, with an important role for the finding of an IgG4-positive infiltrate in biopsies of the pancreas or bile ducts. Using oral corticosteroid therapy, remission of disease can be obtained and maintained in the
majority of patients.
Endoscopists have an important role in the integrated care of
these patients, especially by relieving cholestasis by biliary stenting in the acute phase of disease or by performing biopsies and
imaging of the lesions in pancreas and/or bile ducts during the diagnostic work-up and evaluation of therapy.
Prospective follow-up of patients with IgG4-associated disease
will, hopefully, yield more definite insight in the etiology, response to therapy, and prognosis of this only recently recognized
disease entity. Since serum IgG4 levels alone have proven to be
insufficient as a diagnostic biomarker, the hunt is on for the identification of sensitive and specific blood-derived markers for ISD.
Histology will probably remain a crucial diagnostic tool, but
there is a need for a clear consensus on which tissue to biopsy
and what criteria to use in its evaluation. The clinical application
of nonsteroid immunosuppressive medication as maintenance
therapy as well as the use of targeted B-cell depletion therapy deserves further investigation. Eventually, immunological studies
may identify the cell biological mechanisms that are causative of
IgG4-associated systemic disease.
Lucas Maillette de Buy Wenniger and Erik A. Rauws have no potential conflicts of interest to declare. Ulrich Beuers has received
lecture fees from Falk Foundation, Gilead, Roche, and Zambon. He
has received a research grant from Zambon and has performed
clinical trials with Dr. Falk Pharma. He has signed a consultant
agreement with Intercept (obeticholic acid).
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