Pi Is 0168827823050584

Review
IgG4-related cholangitis – a mimicker of fibrosing and

malignant cholangiopathies
Remco Kersten1,†, David C. Trampert1,†, Toni Herta1,2, Lowiek M. Hubers1, Lucas J. Maillette de Buy Wenniger3,
Joanne Verheij4, Stan F.J. van de Graaf1, Ulrich Beuers1,*
Summary
IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroin-
flammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic
predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been
described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in
cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-
3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expan-
sions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-
cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+
SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary
diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially
invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria
comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to
prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance
and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators
can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the patho-
genesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
© 2023 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under
the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Introduction revealed an enlarged, dark brown-green discoloured liver with a

IgG4-related disease (IgG4-RD) is a rare systemic fibroin- smooth surface, marked fibrotic longitudinal thickening (up to
flammatory disorder of unknown pathogenesis which can affect 3 mm) of the common hepatic duct wall and the right and left
almost every secretory organ in the human body.1,2 Since its first hepatic ducts (without any microscopic evidence of malignancy),
description as a multiorgan fibroinflammatory autoimmune dis- cystic dilatation of the intrahepatic ducts (without intrahepatic
ease in 2003,3 numerous manifestations of the head and neck, stenoses or pruning), a small gallbladder, an indurated and
thorax, abdomen, and pelvic organs have been reported enlarged pancreas, but a barely enlarged spleen and no evidence
(Table 1).1 Already in the 19th century, various organ manifesta- of colitis. These findings are compatible with IRC and IgG4-RD of
tions of IgG4-RD such as Mikulicz’s disease, Küttner’s tumour or the digestive tract rather than a first description of primary
Riedel’s struma were described for the first time. IgG4-related sclerosing cholangitis (PSC) as assumed over decades. Case
cholangitis (IRC), although only described in 2004 as IgG4- reports from 60 years ago documented the combined appear-
related sclerosing cholangitis with or without hepatic inflamma- ance of sclerosing cholangitis with Riedel’s struma and retro-
tory pseudotumour4 and defined in 2007 as IgG4-associated peritoneal fibrosis, a typical organ pattern of IgG4-RD
cholangitis,5 was most probably first reported 140 years earlier. manifestations.7 In the late nineties, the first five men with a
In 1867, a 60-year-old previously healthy factory employee from ‘sclerosing pancreato-cholangitis’ were described as respond-
Basel (Switzerland) developed severe, and after a few months ing well to glucocorticosteroids, today fulfilling the diagnostic
fatal, hepatobiliary injury with jaundice and weight loss.6 Autopsy criteria of IRC and type 1 autoimmune pancreatitis (AIP).8,9
Keywords: Autoimmune pancreatitis; biliary bicarbonate umbrella; cholangiocarcinoma; CCA; IgG4-RD; IgG4-related disease; primary sclerosing
cholangitis; PSC.
Received 12 April 2023; received in revised form 24 July 2023; accepted 14 August 2023; available online 18 August 2023
* Corresponding author’s Address: Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, Amsterdam University
Medical Centers, AMC, C2-327, P.O. Box 22600, NL-1100 DD Amsterdam, The Netherlands; Tel.: +31-20-566 24 22, fax: +31-20-566 95 82.
E-mail address: u.h.beuers@amsterdamumc.nl (U. Beuers).
†
These authors contributed equally to this work and share first authorship.
https://doi.org/10.1016/j.jhep.2023.08.005
Journal of Hepatology, December 2023. vol. 79 j 1502–1523

Review
Keypoints
Genetic predisposition and blue-collar work are risk factors for development of IRC.
Oligoclonal expansions of IgG4+ plasmablasts in IRC disappear upon treatment.
IRC autoantigens annexin A11 and laminin 511-E8 strengthen cholangiocyte defence.
Multiple T cell lineages have a pathogenic role in IgG4-RD.
The HISORt criteria are the standard for the diagnosis of IRC.
Glucocorticosteroids and immunomodulators are cornerstones of IRC treatment.
IRC with or without inflammatory pseudotumour is the major field. Herein, we review the actual state of knowledge on the
hepatobiliary manifestation of IgG4-RD.1,2 The clinical presen- pathophysiology, clinical presentation, diagnosis (and differ-
tation of IRC may mimic other hepatobiliary diseases such as ential diagnosis) and treatment of IRC, one of the major man-
PSC or cholangiocarcinoma (CCA). IRC is an under-recognised ifestations of systemic IgG4-related disease.
and often misdiagnosed disease as no single accurate diag-
nostic test is available to distinguish IRC from PSC or CCA.
The pathogenesis of IgG4-related cholangitis
Misdiagnosis of IRC carries the risk of inappropriate medical
and potentially invalidating surgical interventions.10 IRC is (and IgG4-RD)
mainly diagnosed in elderly men and is closely associated with The potential role of genetic, microbial and
type 1 AIP, the most frequent manifestation of IgG4-RD of the environmental factors
digestive tract, in >90% of affected individuals in well- The pathogenesis of IgG4-RD is largely unknown, but it is
characterized cohorts.2,11 conceivable that both host and environmental factors influence
In recent years, IRC has drawn remarkable clinical and sci- susceptibility and disease progression (Fig. 1). Similar to other
entific attention and notable advances have been made in the autoimmune diseases, certain HLA variants are associated with
Table 1. Organ manifestations of IgG4-RD associated with IRC.

Organ Nomenclature160 Involvement in IRC*,11,96,97,148,150,161–164
Pancreas Type I AIP (IgG4-related pancreatitis) 92%
Salivary glands IgG4-related sialadenitis 5%, 13%, 17%, 18%, 26%
Parotid glands IgG4-related parotitis
Submandibular glands IgG4-related submandibular gland disease
Kidney IgG4-related kidney disease (subtypes) 1%, 5%, 9%, 11%, 26%
Tubuli Tubulointerstitial nephritis
Glomeruli Membranous glomerulonephritis
Pyelum Renal pyelitis
Retroperitoneum IgG4-related retroperitoneal fibrosis 3%, 5%, 7%, 9%, 10%, 17%
Lymph nodes IgG4-related lymphadenopathy 2%, 4%, 8%, 9%, 15%, 43%
Lacrimal glands IgG4-related dacryoadenitis 8%
Lung IgG4-related lung disease 1%, 6%, 7%
Eyes IgG4-related ophthalmic disease 2%, 15%
Aorta IgG4-related aortitis/periaortitis 1%, 6%
Arteries IgG4-related periarteritis 6%
Gallbladder IgG4-related cholecystitis 2%, 7%
Pleura IgG4-related pleuritis 5%
Hypophysis IgG4-related hypophysitis 2%
Stomach** IgG4-related gastric disease 2%
Prostate IgG4-related prostatitis 2%
Joints** IgG4-related synovitis 1%
Liver*** IgG4-related hepatopathy 1%
Testis** IgG4-related testicular disease ?
Pachymeninges IgG4-related pachymeningitis ?
Thyroid gland IgG4-related thyroiditis ?
Mediastinum IgG4-related mediastinitis ?
Pericardium IgG4-related pericarditis ?
Breast IgG4-related mastitis ?
Mesentery IgG4-related mesenteritis ?
Intestine** IgG4-related intestinal disease ?
Ileal pouch** IgG4-related pouchitis ?
Skin IgG4-related skin disease ?
The different organs that can be affected by IgG4-RD (left column), their official nomenclature (middle column), and the percentage of people with IRC affected by IgG4-RD in the
respective organs.
*Reported percentages likely differ due to cohort varieties in case-ascertainment (biopsy proven yes/no, imaging modality used, extent of search of other organ involvement), size of
the cohort and ethnicities.
**No official nomenclature established.
***Debated whether a distinct IgG4-RD manifestation or a consequence of IRC.
Journal of Hepatology, December 2023. vol. 79 j 1502–1523 1503

Blue collar work
Toxin exposure
Aetiology
Direct tissue damage?

Malignancy
DAMPs/PAMPs?
Molecular mimicry?
Microbiome? Immune Malignancy

dysregulation
Healthy cholangiocyte IRC cholangiocyte

Glycochenodeoxycholate Glycochenodeoxycholic acid
HCO3-
HCO3- HCO3-
HCO3-
HCO3- HCO3- HCO3- H+ H+
Bicarbonate H+
HCO3-
Impaired bicarbonate
Cl- HCO3- HCO3-
umbrella HCO3- HCO3- HCO3- + umbrella?
H H+
ANO1 SLC4A2 ANO1 SLC4A2
Ca 2+ Cl-
Annexin A11
Pathogenesis
ITGA6B1 Disrupted barrier Annexin A11

function? autoantibodies
Laminin 511 Laminin 511-E8
autoantibodies
Oligoclonal IgG4+ Tregs

PDGF plasmablasts
IL-33 IL-13 BAFF

Tph TGF-β IL-10
CD4+ SLAMF7+ CTLs
IL-4 Perforin IL-1β Basophils

IL-21 TGF-β Granzyme A
M2 macrophages Dendritic cells
CD8+ CTLs
Tfh2
Galectin-3 Prohibitin 1
FCγR2B autoantibodies? autoantibodies?
Fig. 1. Pathogenic concept of IgG4-related cholangitis. (Upper) Hypothesised aetiological factors that lead to the characteristic immunological dysregulation of
IRC. Exposure to (occupational) toxins during blue-collar work, autoantigens and/or DAMPs/PAMPs which are possibly released by malignancies and the microbiome
are hypothesised to function as aetiological agents, possibly through mechanisms of molecular mimicry. (Lower) The immune dysregulation and its potential effect on
cholangiocellular function. After activation of the innate immune system by aetiological agents, an extensive dysregulation of the adaptive immune system occurs in
IRC. Oligoclonal IgG1+ and IgG4+ plasmablasts could produce autoantibodies against annexin A11, laminin 511-E8, galectin-3 and prohibitin 1. Autoantibodies against
annexin A11 may disrupt the protective bicarbonate umbrella by inhibiting the trafficking of the Cl− channel ANO1 to the apical cholangiocyte membrane. Autoan-
tibodies against laminin 511-E8 may block its binding to membrane receptors (ITGA6B1), thereby impairing cholangiocellular barrier function. The role of galectin-3 and
prohibitin 1 autoantibodies is unclear at present but could potentially be in the immunological context of B and T cells. Additionally, oligoclonal IgG4+ plasmablasts
could perpetuate the immune dysregulation due to stimulation and reactivation of oligoclonal CD4+ SLAMF7+ cytotoxic T cells and could contribute to the formation of
storiform fibrosis by secreting PDGF. ANO1, anoctamin 1; BAFF, B-cell activation factor; Ca2+, calcium; CD4, cluster of differentiation; Cl−, chloride; CTLs, cytotoxic T
lymphocytes; DAMPs, damage-associated molecular patterns; FCcR2B, Fc c receptor 2 B; HCO3−, bicarbonate; IL, interleukin; IRC, IgG4-related cholangitis; ITGA6B1,
integrin a6b1; PAMPs, pathogen-associated molecular patterns; SLAMF7, signalling lymphocytic activation molecule family member 7; SLC4A2, solute carrier family 4
member 2; Tfh, follicular T helper 2 cells; TGF-b, Transforming growth factor-b; Tph, peripheral T helper cells; Tregs, regulatory T cells. Image created with BioRender.
1504 Journal of Hepatology, December 2023. vol. 79 j 1502–1523

Review
IgG4-RD, suggesting that antigen presentation and recognition exposing the immune system to autoantigens and damage-
play an important role.12 A recent genome-wide association associated molecular patterns which fuel an autoimmune
study among 835 Japanese citizens with various manifesta- response. (ii) Alternatively, toxic substances could trigger
tions of IgG4-RD identified HLA-DRB1, but also the non-HLA autoreactive B and T cells through molecular mimicry. (iii)
gene FCGR2B as susceptibility loci for IgG4-RD.13 Notably, Toxins could cause genetic and epigenetic changes, skewing
FCcR2B is the only FCc receptor family member expressed in B the immune response towards autoimmunity. (iv) Toxin expo-
cells. It has inhibitory functions in contrast to other FCc sure could lead to the development of malignancies,23 which
receptors and is thought to play a role in the elimination of have been proposed to play a role in the pathogenesis of
autoreactive B cells.14 Thus, FCGR2B gene variants may IgG4-RD. Nonetheless, toxin exposure would lead to a break in
weaken suppressive effects on the immune response and in- self-tolerance with both B and T cells at play.
crease susceptibility to autoimmunity.14 Another recent
genome-wide association study found that IL1R1 genetic The potential role of malignancies
polymorphisms contributed to IgG4-related periaortitis/peri-
Malignancy prior to the onset of IgG4-RD is a possible pre-
arteritis, suggesting the possibility that certain genetic factors
disposing factor in a subset of patients with multi-organ IgG4-
might affect the risk of specific IgG4-RD manifestations.15
RD.24 A history of malignancy was three times more prevalent
Additionally, in a small cohort of individuals with type I AIP,
in people with manifestations of IgG4-RD (mainly outside the
polymorphisms in CTLA4 (a gene coding for an inhibitory re-
digestive tract – 19% type I AIP) compared to matched con-
ceptor expressed on activated memory T cells) were identi-
trols.24 In a recent Japanese study, 32% of people with IRC
fied.16 For IRC, comparable findings are not yet reported, and
had a history of malignancy before the development of
are therefore of particular interest when designing future ge-
IgG4-RD.25 One might speculate about the potential patho-
netic analyses.
physiological mechanisms linking malignant disease to the
The potential pathogenic role of the human microbiota in
subsequent development of IgG4-RD: (i) Cancer-induced
the development of IRC has recently been addressed. Faecal
autoimmunity has been discussed for several rheumatic dis-
analysis from people with IRC, PSC and healthy controls
eases and appears plausible as a stimulus for an abnormal
revealed reduced alpha diversity and a shift in microbial
immune response against tumour autoantigens in antigen-
communities in IRC and PSC.17 Notably, next to common
expressing organs. (ii) Cancer and IgG4-RD might share the
variations in microbial composition and metabolic activity in
same risk factors (such as toxin exposure) or have pathological
IRC and PSC, integrative analyses also identified distinct
pathways in common. (iii) Medical therapies administered to
host-microbe associations. A dysregulated response to
treat malignancies might induce tumour destruction and
the intestinal microbiome has previously been hypothesized
tumour destruction-related autoimmune responses against
to play a role in the pathogenesis of IRC via activation of
tumour peptides, leading to IgG4-RD of non-affected organs.
Toll-like receptors,18 and intestinal dysbiosis plays an
essential role in the development of type I AIP in experimental
mouse models.19 The potential role of autoantigens
We identified ‘blue-collar work’ and long-term, often lifelong Our finding of dominant oligoclonal IgG4+ B cell populations in
exposure to occupational toxins as independent risk factors for sera and affected tissues of patients with IRC raised the sus-
the development of IRC and type I AIP.20,21 An occupational picion that the immune response in IgG4-RD could be targeting
history of ‘blue-collar work’ was reported by 68% of patients specific autoantigens.26 This has led to the discovery of
with IgG4-RD, compared to only 39% of age- and sex-matched numerous autoantigens and autoantibodies (Table 2). Most of
controls (odds ratio [OR] 3.66; CI 2.18–6.13; n = 404; p these autoantibodies are not disease specific. In IRC, the
<0.0001). Industrial contaminants appeared to potentially drive presence of autoantibodies against annexin A11, laminin 511-
the elevated risk, including asbestos and VDGF (vapours, E8, galectin-3 and prohibitin 1 has been confirmed, in line
dusts, industrial gases and fumes).20 Typical work environ- with the expression of these autoantigens in cholangiocytes
ments included exposure to oil products, metal industry, truck (Figs 1 and 2).
driving, automobile repair, woodworking or painting. Notably, The potential pathogenicity of these autoantibodies has
these work profiles are strongly male dominated. We speculate been strongly supported by the observation that mice injected
that male-dominated ‘blue-collar work’ may contribute to the with IgG isolated from sera of patients with IgG4-RD develop
remarkable overrepresentation of men (80-85%) among people typical organ lesions.27 Furthermore, patients who were posi-
with IRC and type 1 AIP. In line with our findings, cigarette tive for multiple autoantibodies were shown to have more se-
smoking was recently identified to be more common among a vere disease,28 and autoantibody levels decreased upon
large group of patients from a rheumatology unit with different successful treatment.29,30 With regard to the pathogenicity of
organ manifestations of IgG4-RD compared to matched con- IgG subtypes, some data suggest a more detrimental role for
trols, but this relation was primarily seen in people with IgG1 and a possible protective role of IgG4 autoantibodies.27,31
IgG4-related retroperitoneal fibrosis.22 Nevertheless, these Autoantibodies could potentially contribute to the patho-
data suggest that smoking, like VDGF, may be a potential genesis of IRC by directly affecting the function of the targeted
modifiable risk factor. autoantigen, or by eliciting an excessive immune response after
How exposure to (occupational) toxins plays a role in the binding of the autoantibody.
pathogenesis of IgG4-RD can only be speculated upon at this The first identified IgG4/IgG1 target autoantigen in IRC is
time: (i) Chemical agents might directly damage tissues, annexin A11.31 Annexin A11 has been implicated in Ca2+-

Table 2. Identified autoantigens in IgG4-RD.
Autoantigen Organ manifestation Positivity Positivity in other diseases Detection Autoantibody
in IgG4-RD method subtype
Carbonic Type I AIP 21% Sjögren’s syndrome165 ELISA IgG
anhydrase I165 Aplastic anaemia like syndrome166
Behçet’s disease167
Carbonic Type I AIP 25%-73% Primary sclerosing cholangitis ELISA IgG
anhydrase II165 Sjögren’s syndrome165
Diabetes type II168
Carbonic Type I AIP 27% Sjögren’s syndrome169 ELISA IgG
anhydrase IV169 Pancreatic cancer169
Systemic lupus erythematosus170
Lactoferrin171–172 Type I AIP 54%-76% Sjögren’s syndrome171 ELISA IgG
Primary sclerosing cholangitis173
Pancreatic Type I AIP 42% (ELISA) - ELISA IgG
secretory trypsin 31% (WB) WB IgG1
inhibitor172
Amylase alpha- Type I AIP 100% Diabetes type I and II174 ELISA IgG
2A174
Heat shock Type I AIP 92% Diabetes type I175 ELISA IgG
protein 10175 Chronic alcohol-related pancreatitis175
Pancreatic cancer175
Trypsinogen176 Type I AIP 79% Chronic (alcohol-related) pancreatitis176 ELISA IgG
Plasminogen Type I AIP 95% Pancreatic cancer177 DELFIA IgG
binding
protein177
Type IV Type I AIP 55% Crohn’s disease178 WB/ELISA IgG
collagen178 Pancreatic cancer178
IL-1RA179 Type I AIP, aorta, kidney, lacrimal-, 16% Systemic lupus erythematosus ELISA IgG1, IgG2, IgG3,
salivary glands, liver, retroperitoneum Rheumatoid arthritis IgG4
Prohibitin 156 Type I AIP 74% Primary sclerosing cholangitis* ELISA IgG
Mikulicz’s disease 53% Sjögren’s syndrome56
Retroperitoneum 55% Behçet disease180
Other probable IgG4-RD 90% Idiopathic pulmonary fibrosis28
IRC 62%*
Laminin 511- Type I AIP 51% Idiopathic pulmonary fibrosis28 ELISA IgG (IgG1, IgG4)
E829 IRC 13%* IgG
Integrin alpha6 Type I AIP 16% - ELISA IgG
beta129
Galectin-330 Type I AIP, IRC, lacrimal and salivary glands 28% (IgG4) Idiopathic pulmonary fibrosis30 ELISA IgG4, IgE
Lungs, retroperitoneum, kidney 10% (IgE) Systemic lupus erythematosus181
Retroperitoneum, kidney, IRC 13%* (IgG) Crohn’s disease182
Annexin A1131 Type I AIP, IRC 18% Idiopathic pulmonary fibrosis28 WB IgG1, IgG4
Systemic lupus erythematosus183
Antiphospholipid syndrome183
Overview of the identified autoantigens in IgG4-RD (first column), the IgG4-RD organ manifestations in which they were detected (second column), percentage of patients tested
positive in the respective organ manifestation (third column), respective autoantibody positivity in other diseases (fourth column), detection method used (fifth column) and the
autoantibody subtype detected (sixth column).
AIP, autoimmune pancreatitis; DELFIA, dissociation-enhanced lanthanide fluorescence immunoassay; ELISA, enzyme-linked immunosorbent assay; IRC, IgG4-related cholangitis;
WB, western blot.
*Submitted for publication.
dependent membrane trafficking in various cell types.32,33 In HCO3− umbrella as it creates the Cl− gradient necessary for
cholangiocytes, this process is important for the maintenance apical HCO3− secretion. The membrane insertion of ANO1 by
of an apical defence mechanism against the toxic effects of annexin A11 was markedly inhibited after human chol-
glycine-conjugated bile acids, referred to as the ‘biliary HCO3− angiocytes were incubated with cholestatic IRC serum with
umbrella’.34–36 Glycine-conjugated bile acid permeation due to high titers of anti-annexin A11 IgG1 and IgG4 autoantibodies,
an impaired biliary HCO3− umbrella likely contributes to the but not after incubation with cholestatic PSC control sera.40
progressive bile duct destruction found in immune-mediated Thus, IgG1/IgG4-mediated autoreactivity against annexin A11
cholangiopathies.37–39 Annexin A11 is predominantly may contribute to the pathogenesis of IRC by weakening the
expressed in cholangiocytes within the human liver, the cell biliary HCO3− umbrella.
type that is mainly affected in IRC. Furthermore, in human Autoantibodies against laminin 511-E8 were previously
cholangiocytes annexin A11 mediates the plasma membrane detected in just over 50% of patients with type I AIP.29 We also
insertion of the Ca2+-sensitive Cl− channel anoctamin-1 confirmed the presence of laminin 511-E8 autoantibodies in
(ANO1). ANO1 is crucial for the formation of a stable biliary IRC (submitted for publication).41 Laminins are heterotrimeric

Review
Single cell RNA expression values of IgG4-RD autoantigens in target organs clustered by cell type
LG 1
PH 3
1
1
A5
B1
S
C
XA
B1
AL
nTPM values nTPM values
M
AN
LA
LA
LA
500 80
Plasma cells Plasma cells
B cells 400 B cells

60
T cells 300
T cells
Salivary duct cells 40 Salivary duct cells

200
Respiratory ciliated cells Respiratory ciliated cells
20
Respiratory basal cells 100 Respiratory basal cells
Club cells Club cells

0 0
Alveolar cells type 1 Alveolar cells type 1
Alveolar cells type 2 Alveolar cells type 2
Cholangiocytes Cholangiocytes
Hepatocytes Hepatocytes
Pancreatic ductal cells Pancreatic ductal cells
Proximal enterocytes Proximal enterocytes
Distal enterocytes Distal enterocytes
Intestinal goblet cells Intestinal goblet cells
Paneth cells Paneth cells
Proximal tubular cells Proximal tubular cells
Distal tubular cells Distal tubular cells
Collecting duct cells Collecting duct cells
Prostatic glandular cells Prostatic glandular cells
Prostatic basal cells Prostatic basal cells
Fig. 2. Cellular gene expression of autoantigens in target organs of IgG4-RD. Single-cell RNA expression of the confirmed IRC autoantigens annexin A11
(ANXA11), galectin-3 (LGALS3), prohibitin 1 (PHB1) (left heatmap) and the laminin 511 gene constituents LAMA5, LAMB1 and LAMC1 (right heatmap). Note the
relatively low expression of the IgG4-RD autoantigens in hepatocytes compared to cholangiocytes. Publicly available single cell RNA-sequencing data was acquired
from the single cell atlas as part of the human protein atlas platform in March 2023. Inclusion criteria of the datasets, clustering of cells, defining cell types and
normalisation are described in detail (https://www.proteinatlas.org/about/assays+annotation#singlecell_rna). Data are presented as nTPM. The dark red expression
values of LGALS3 exceed the scale of 500 nTPM. ANXA11, annexin A11; IRC, IgG4-related cholangitis; LAMA5, laminin alpha 5; LAMB1, laminin beta 1; LAMC1,
laminin gamma 1; LGALS3, galectin-3; PHB1, prohibitin 1; nTPM, normalized transcripts per million.
extracellular matrix proteins, with laminin 511-E8 being the additional interest are the findings that laminin 511 regulates
truncated form of laminin 511 and an important binding partner barrier function and impairs leukocyte migration in endothelial
for integrin a6b1.42,43 Notably, of the type I AIP patient sera cells.45 In turn, tight junction-associated barrier function was
where no anti-laminin 511-E8 antibodies were detected, four impaired in vitro by IL-4 (which is enriched in IRC bile) via
patients had autoantibodies directed against integrin a6b1.29 activation of claudin-2-mediated paracellular pore pathways.46
Laminin 511-E8 promotes cholangiocyte differentiation of hu- Given the reported functions of laminin 511 and the apparent
man induced pluripotent stem cells, thereby upregulating cholangiocyte barrier dysfunction in IRC, we recently
secretory components of the biliary HCO3− umbrella, such as identified autoantibodies against laminin 511-E8 in a subset of
the apical cAMP-sensitive Cl−/HCO3− channel CFTR (cystic people with IRC and observed, in vitro, that laminin 511-E8
fibrosis transmembrane conductance regulator), the G protein- helped protect human cholangiocytes against T lymphocyte-
coupled bile acid receptor 1 (GPBAR1, also known as TGR5) induced barrier dysfunction and toxic bile acids (submitted
and the basolateral secretin receptor.44 Further supporting a for publication).41
role for laminin 511 in epithelial fluid secretion is the increased Galectin-3 is a carbohydrate binding lectin recently identi-
diameter of laminin 511-E8-treated cholangiocyte cysts.44 Of fied as an autoantigen in IgG4-RD. High expression of galectin-

3 was found in both the serum and affected tissue of patients Their activation leads to an increased production of IgG4 by
with IgG4-RD; galectin-3 was indirectly related to disease ac- plasmablasts via BAFF (B cell activating factor), IL-33 and
tivity but remained high during glucocorticosteroid therapy.47 IL-13.64–66 Notably, CD163+ M2 macrophages and plasmacy-
Anti-galectin-3 autoantibodies were identified in an IgG4-RD toid dendritic cells play a role in inflammation and fibrosis for-
cohort and were predominantly of the IgG4 and IgE isotype, mation via secretion of IL-33.19,67–69 The innate and adaptive
but not the IgG1 isotype.30 Galectin-3 sorts proteins into ves- immune systems are thoroughly interconnected and their
icles for transport to the apical plasma membrane, thereby crosstalk is extensive in IgG4-RD.70 Antigen presentation by
exerting a function comparable to annexin A11.48 Similar to the innate immune system has been hypothesized to initiate the
laminin 511, galectin-3 interacts with integrin b1 and regulates aberrant B and T cell responses in IgG4-RD.71
its apical sorting.49 Galectin-3 appears to be involved in biliary
inflammation, as Lgals3 knockout or galectin-3 inhibitor treat- The potential role of T cells
ment led to an absence of bile duct damage with reduced Where initial research implicated T helper 2 cells in the patho-
mononuclear cell infiltrates, granulomas and fibrosis compared genesis of IgG4-RD, this paradigm has been questioned.72,73
to controls in mouse models of ‘autoimmune cholangitis’.50 Pathogenic roles for regulatory T cells (Tregs), follicular T help-
Using a murine model of xenobiotic-induced primary biliary er 2 (Tfh2) cells, peripheral T helper (Tph) cells, and CD4+
cholangitis (PBC), the deletion of Lgals3 exacerbated the PBC- SLAMF7+ / CD8+ cytotoxic T lymphocytes have recently
like phenotype, increasing periportal inflammation (with more been described.
pro-inflammatory lymphocytes), granuloma formation and Tregs play an important role in the regulation of self-
fibrosis.51 Additionally, galectin-3 may inhibit the differentiation tolerance and secrete the anti-inflammatory cytokines IL-10
of B cells towards immunoglobulin-secreting plasma cells, and and TGF-b, which promote IgG4 class switching and
galectin-3 has an ascribed profibrotic role in various fibrotic fibrosis.74,75 Increased infiltration of Tregs in the bile ducts in
diseases.52–54 Collectively, for immune-mediated cholestatic IRC correlates with the amount of IgG4-positive cells, whilst
liver diseases, a protective role for galectin-3 is not incon- this is not the case in PBC, PSC and autoimmune hepatitis.76,77
ceivable. This role may be hampered in IRC by specific auto- With respect to gene expression, higher ratios of IL-4/IFN-c, IL-
antibodies targeting galectin-3. 5/IFN-c, IL-10/CD4 and TGF-b/CD4 were observed in affected
Prohibitins 1 and 2 are scaffold proteins involved in a wide tissues in IRC samples compared to PSC and PBC samples,
array of cellular functions, such as proliferation, survival, suggesting that Tregs are involved in IgG4 class switching
metabolism, mitochondrial dynamics and inflammation.55 Pro- and fibrosis.77
hibitin 1 autoantibodies have been detected in the presence of Tfh2 cells have recently drawn attention in IgG4-RD. They
various organ manifestations of IgG4-RD,56 but also other differ from T helper cells in that they stimulate antigen-specific
immune-mediated disorders including PSC and Sjögren’s B cell proliferation, somatic hypermutation, isotype class
syndrome (Table 2). Notably, expression of prohibitin 1 is switching and germinal centre development.78 Tfh2 cells ex-
reduced in patients with PBC, biliary atresia and Alagille syn- press BCL6, CXCR5, CXCR13 and PD-1 and secrete the cy-
drome.57 Additionally, in bile duct-ligated mice, prohibitin 1 tokines IL-4 and IL-21.79 IL-21 allows for plasmablast and
knockout resulted in increased bile duct proliferation and liver plasma cell differentiation, whilst IL-4 induces isotype class
fibrosis.57 From an immunological viewpoint, prohibitin 1 is switching.74,80 Evidence supporting a key role for Tfh2 cells in
involved in IgG1 production by B cells and survival of IgG4-RD are: (i) Tfh2 cells promote the differentiation of naïve B
T cells.58,59 cells towards IgG4-secreting plasmablasts, (ii) the Tfh2 cell
subset is increased in blood and positively correlates with
Antigen recognition by the innate immune system disease activity, number of affected organs and serum IgG4
Activation of the innate immune system is a prerequisite for levels and (iii) Tfh2 cells decrease after glucocorticosteroid
formation of the aforementioned autoantibodies by the adap- treatment.81 In IRC, circulating and tissue-infiltrating Tfh2 cells
tive immune system. Considering the tendency of IgG4-RD to are expanded and correlate with disease activity.82
affect epithelia of the digestive tract, such as the bile ducts that Tph cells, like Tfh2 cells, are implicated in the immune
are frequently exposed to environmental stressors, it has been response of IRC. Tph cells lack CXCR5 and therefore do not
speculated that damage-/pathogen-associated molecular pat- enter lymph nodes but form ectopic lymphoid structures that
terns could activate the innate immune system in IgG4- are often seen in IgG4-RD.79 Tph cells are increased in active
RD.18,60,61 Chronic exposure to (occupational) toxins, bacteria IRC, correlate with serum IgG4 levels and disease severity, and
and self-antigens could function as damage-/pathogen-asso- their levels decrease upon treatment.83 As Tph cells are able to
ciated molecular patterns, possibly through mechanisms of travel to the site of inflammation and form ectopic lymphoid
molecular mimicry. Notably, mice that are injected with an structures that could maintain the inflammatory process,
activator of the innate immune system (polyinosinic poly- they may even play a more critical role than their Tfh2 coun-
cytidylic acid) develop lesions typical of type I AIP, IRC and terparts in IRC.83 Notably, Tph-like cells express cytotoxic
IgG4-related sialadenitis, in conjunction with the formation of mediators, such as granzyme and perforin, that can cause
autoantibodies directed against lactoferrin, carbonic anhydrase tissue damage.84,85
II and pancreatic secretory trypsin inhibitor.62 In addition, two types of CTLs may play a critical role in
The innate immune system is activated via Toll-like re- IgG4-RD. The presence of dominant oligoclonal subsets of
ceptors and NLRs (nucleotide-binding oligomerization domain- CD8+ CTLs in both the blood and affected tissues was recently
like receptors) on monocytes, CD163+ M2 macrophages and demonstrated.86 These CD8+ CTLs express granzyme A
basophils in various organ manifestations of IgG4-RD.60,61,63,64 and preferentially induce apoptosis in mesenchymal cells.

Review
Independently, both blood and affected tissues are dominated cytokines (IL-33, IL-1b) that activate fibroblasts and lead to
by oligoclonal expansion of CD4+ SLAMF7+ CTLs, which are fibrosis formation.67,68 Understanding the pathogenic mecha-
characterized by their ability to secrete granzyme A, perforin nisms of storiform fibrosis formation in IRC and its potential
and IFN-c to kill target cells and secrete cytokines such as reversibility will be relevant in preventing disease complications
IL-1b.87,88 Notably, CD4+ SLAMF7+ CTLs decrease upon rit- and end-stage liver disease.
uximab treatment. CD4+ SLAMF7+ CTLs do not express
CD2088 which implies that B cells can regulate the mainte- Clinical presentation, diagnosis and differential
nance of effector/memory CD4+ T cells in IgG4-RD.89 The diagnosis of IRC
relevance of CD4+ SLAMF7+ CTLs and CD8+ CTLs has yet to IRC typically affects males aged 50-60 years or above.1,2 They
be demonstrated in IRC. present with obstructive jaundice, substantial weight loss and
episodes of upper abdominal pain or discomfort.1,2 Cholestatic
The potential role of B cells pruritus is reported by a minority of affected individuals (e.g.
The B cell lineage, including plasmablasts, plays a critical role in 13% in a Japanese cohort).96 The close association of IRC and
the pathogenesis of IgG4-RD, but the exact nature of its contri- type 1 AIP can explain an endocrine pancreatic insufficiency
bution is still uncertain. In IRC- and type 1 AIP-dominated IgG4- (type 3c pancreatogenic diabetes mellitus) and exocrine
RD, we have shown that the B cell receptor repertoire of patients pancreatic insufficiency, which are often detected in the pres-
contains oligoclonal expansions of IgG4+ plasmablasts which ence of IRC.97 Fever or night sweats are not typical in adults
exhibit signs of affinity maturation, suggesting an antigen-driven (for children and adolescents see below), but may also indicate
response.26 Independent studies have confirmed that these a bacterial cholangitis in IRC or an underlying malignancy.98
IgG4+ plasmablasts disappear upon treatment of IgG4-RD.26,90 The diagnosis of IRC is challenging as the clinical presen-
At relapse, the IgG4+ plasmablasts that reappear were distinct tation may mimic other hepatobiliary diseases such as PSC
from the ones present during the initial peak of disease activity, and CCA (Table 3). Furthermore, no single validated and
indicating that new naïve B cells are recruited by CD4+ T cells to adequate diagnostic test is available to accurately diagnose
undergo repeated rounds of mutation and selection driven by a IRC. Diagnosing IRC therefore requires a comprehensive work-
self-reactive disease process.90 up. The importance of this work-up is underlined by the fact
At present it is unclear whether IgG4+ B cells play a that up to one-third of patients with IRC, often with accom-
pathogenic role in IRC and IgG4-RD in general. IgG4+ B cells panying inflammatory pseudotumours, undergo unnecessary,
could produce potentially pathogenic IgG4 autoantibodies31,40 extensive abdominal surgery for suspected malignancy (e.g.
or could stimulate and reactivate CD4+ CTLs as suggested by extended hemihepatectomy; pylorus-preserving pan-
the finding that rituximab treatment reduces clonally expanded creatoduodenectomy or Whipple’s procedure) before the
CD4+ SLAMF7+ CTLs.91 They could also actively affect tissue diagnosis of IRC is made histopathologically.10,11,99 Vice versa,
fibrosis92 corresponding with the finding that rituximab treat- 10-15% of the resection specimens from these surgical pro-
ment decreased ELF (enhanced liver fibrosis) scores and cedures may reveal fibroinflammatory lesions without malig-
myofibroblast volume in people with IgG4-RD.93 An alternative nancy. In a considerable portion of these patients, histological
is that IgG4 produced by IgG4+ B cells solely functions to and clinical evidence for IgG4-RD that explains the preopera-
dampen an excessive IgG1-mediated immune response in IRC, tive clinical and imaging findings can be found, obviating the
type 1 AIP and IgG4-RD in general.27,31,40 need for major surgery.10,11,99
In comparison to plasmablasts, other cell types of the B cell Hepatic inflammatory pseudotumours in the context of IRC
lineage have been understudied. Increases in circulating were first described in 20044 and further analysis100,101
memory B cells have been shown to precede disease demonstrated striking histomorphological similarity and glu-
relapse,94 and CD21low memory B cells were reported to be cocorticosteroid responsiveness comparable to the inflamma-
increased in patients with IgG4-RD.91 tory pseudotumours found in the pancreas in association with
type 1 AIP.4,102 Thus, hepatic inflammatory pseudotumours
Formation of storiform fibrosis with histomorphological features of IgG4-RD are widely regar-
ded as one manifestation of IRC.
The aetiology and exact pathophysiological processes that
To ensure a comprehensive work-up, various diagnostic
lead to storiform fibrosis formation in IgG4-RD and IRC have
algorithms have been developed, of which the HISORt criteria
not been clarified. However, given the roles of the above
are now regarded as the diagnostic standard. These criteria
described immune cells, the following cell types and mecha-
comprise histology (H), imaging (I), serology (S), other organ
nisms could play important roles:84,95 (i) CD4+ SLAMF7+ CTLs,
manifestations of IgG4-RD (O), and response to glucocorti-
CD8+ CTLs and Tph cells could induce tissue damage by
costeroid therapy (Rt).11,103 Fig. 3 presents an overview of the
secreting cytotoxic mediators such as granzymes and perfor-
diagnostic work-up and Table 3 summarizes diagnostic fea-
ins. In addition, the secretion of profibrotic cytokines such as
tures of the most relevant alternative cholangiopathies when a
IL-1b and TGF-b by these cells would lead to the activation of
diagnosis of IRC is considered.
an excessive wound healing response. (ii) B cells from patients
with IgG4-RD express extracellular matrix remodelling enzymes
Histology
and are able to secrete PDGFB (platelet-derived growth factor
subunit B), leading to collagen production by fibroblasts.92 (iii) Histological evaluation of biopsies or surgical resection speci-
M2 macrophages and plasmacytoid dendritic cells secrete mens to distinguish IRC from CCA or other benign

1510
Table 3. Differential diagnosis of IgG4-related cholangitis and respective HISORt characteristics.

Feature IRC PSC CCA Fibrohistiocytic Follicular SC-GEL
pseudotumours cholangitis
Clinical Male 50-75 years of age Male <40 years Identical to IRC Sex equally affected Sex equally Mostly minors
presentation affected
(H) Histology Lymphoplasmacellular infiltrate Onion skin fibrosis Dysplasia or Histiocytic infiltrate Extensive Neutrophil infiltration
Obliterative phlebitis Mucosal ulceration malignant cells Fibrovenous occlusion lymphoid follicles epithelium
Storiform fibrosis Fibro-obliterative bile ducts Neutrophil aggregates
Xanthogranulomatous inflammation Xanthogranulomatous
inflammation
IgG4+ plasma cells: No obliterative phlebitis IgG4+/IgG+ <0.4 IgG4+/IgG+ <0.4184 No obliterative IgG4+/IgG+ <0.4184–186
Biopsy: >10/HPF No storiform fibrosis phlebitis
Resection: >50/HPF IgG4+/IgG+ typically <0.4184 No storiform

IgG4+/IgG+ ratio >0.4 fibrosis
IgG4+/IgG+
<0.4184,185
(I) Imaging Bile duct strictures:111,115,187,188 Bile duct strictures:187,188 Bile duct strictures:115 Mass forming:184 Bile duct Bile duct strictures:186
- Long band-shaped strictures - Circumscribed short strictures - Short bile duct - Mass in biliary tree 20% strictures:184,185 - Diffuse stricturing
- Absence of short bile duct stenosis - Beaded biliary tree stricture - Mass in liver parenchyma - (Peri)hilar duct
80% stricture
Bile duct thickness:116 Bile duct thickness: Bile duct thickness:
- Single wall CBD >2.5 mm in - Single wall CBD <2.5 mm111 - Caveat: intraluminal
stricturing area, >0.8 mm in CCA
non-stricturing area
Mass forming:184
- Mass in biliary tree 100%
- Mass in liver parenchyma 0%
(S) Serology Serum IgG4: Serum IgG4: Serum IgG4: Serum IgG4: Serum IgG4: Serum IgG4:186,199,200
- >ULN 80%121 - >ULN 15%-25%125,127 - >ULN 13.5%124 - Unknown - <ULN in all case - <ULN in all case
- >4x ULN pathognomonic124 - >1 and <2x ULN: IgG4/IgG1 reports185,193–197 reports
- >1 and <2x ULN: IgG4/IgG1 ratio: ratio <0.24125
>0.24125
IgG2 high (PPV 91%)126 IgG2 <
− normal and IgG1 high CA19-9 >ULN 75%191 CA19-9 >ULN 10%-20%100,192 p-ANCA: unknown p-ANCA 50%186,199
pANCA <10%189 (PPV 85%)126 CA19-9 >ULN 40% CA19-9 unknown
CA19-9 >ULN 30%-50%127,161 p-ANCA 40%190 (mild)185,193,195–198
CA19-9 >ULN 12.5%127
(O) Other Type I AIP >90%2 IBD 80% Metastases Concomitant hepatobiliary Follicular Type 2 AIP?
organs IBD 0%-10%96,130,201,202 disease (e.g. choledocholithiasis) pancreatitis185 IBD >80%
(see Table 1) Prior (hepatobiliary) malignancy203
(Rt) Response Responsive to glucocorticosteroids Caveat: variant PSC-AIH Caveat: improvement Spontaneous improvement Unknown Responsive to UDCA
to therapy Caveat: response in PSC with of inflammatory Responsive to antibiotics, NSAIDs and
high IgG4204 component glucocorticosteroids
Differential diagnoses to be considered in the work-up of IRC and their characteristic HISORt features differentiating them from other biliary diseases such as PSC, CCA, fibrohistiocytic pseudotumours, follicular cholangitis and SC-GEL.
These features can be weighed in the work-up of IRC to come to a working or definitive diagnosis.
AIH, autoimmune hepatitis; AIP, autoimmune pancreatitis; CA19-9, cancer antigen 19-9; CBD, common bile duct; CCA, cholangiocarcinoma; HPF, high-power field; IBD, inflammatory bowel disease; IRC, IgG4-related cholangitis;
NSAIDs, non-steroidal anti-inflammatory drugs; pANCA, perinuclear anti-neutrophil cytoplasmic antibodies; PPV, positive predictive value; PSC, primary sclerosing cholangitis; SC-GEL, sclerosing cholangitis with granulocytic epithelial
lesion; UDCA, ursodeoxycholic acid; ULN, upper limit of normal.
Review
H Histology
• Lymphoplasmacellular infiltrate Presence of biliary strictures
• Obliterative phlebitis
• Storiform fibrosis
• IgG4+ plasma cells:
- Biopsy: >10/HPF
- Resection: >50/HPF
- IgG4+/IgG+ plasma cell ratio >0.4
A: Previous histology B: Imaging + serology C: Pathognomonic D: Miscellaneous
Imaging compatible with IRC or type 1 1. Classical imaging findings of serology Two or more of the following:
I AIP type 1 AIP Serum IgG4 >4 xULN • Serology: elevated serum IgG4
1. Non-invasive imaging: CT/MRCP+MRI
+ • Imaging: findings suggestive of type 1 AIP
2. EUS, ERCP, cholangioscopy +
2. Elevated serum IgG4 • Other organ involvement
histopathology
• Bile duct biopsy: IgG4+ plasma cells >10/HPF
Suggestive of IRC:
• Bile duct wall thickening
- Longitudinal, >2.5 mm, band-shaped
- >0.8 mm in non-strictured areas
• Absence of short bile duct stenoses
S Serology
Probable IRC:
• Serum IgG4
Assess response to steroid therapy
- >4x ULN pathognomonic
- 1-2x ULN: IgG4/IgG1 ratio >0.24
indicative of IRC
• Serum IgG2 high
• Future: single accurate diagnostic test?
O Other organs Definitive IRC: Follow up:

• History of organ resection, biopsy material Start treatment:
• Careful history and physical examination Imaging: improved biliary strictures
• Remission induction with prednisone (0.5-0.6 mg/kg/day)
• Imaging and histology upon indication Biochemical: ALP, γGT, bilirubin ↓
• After 2-4 weeks: consider immunomodulator for maintenance of remission and
• Assess pancreatic involvement including Serology: IgG4
steroid sparing effect
exo- and endocrine function
• Refractory patients: reconsider diagnosis; consider rituximab
• Future: role for whole body PET-CT?
Rt Response to therapy
Every effort should be made to rule out biliary or pancreatic malignancy before starting corticosteroid therapy
After 2-4 weeks of induction therapy
• Biochemical: ALP, gGT, bilirubin Features contradictory of IRC diagnosis:
• Serology: serum IgG4 • Non-response to prednisone therapy (biochemical, serological, imaging)
• Imaging: improved biliary strictures • Pancreatic duct dilatation with pancreatic atrophy
• Atypical brush cytology (positive FISH)
• Future: role for whole body PET-CT?
Fig. 3. Diagnosis of IgG4-related cholangitis according to the modified HISORt criteria. Patients who have biliary strictures and suspected IRC should have a
work-up according to the HISORt criteria (left column). Based on the outcome of the HISORt work-up, the flow-diagram on the right is followed. Patients can be divided
into four categories: patients falling into category A, B or C are assumed to have ‘definitive IRC’ upon which glucocorticosteroid therapy is started and an immu-
nomodulator added when glucocorticosteroids are tapered. Patients falling into category D are defined as ‘probable IRC’ and should be given a trial of glucocorti-
costeroid therapy and have their response assessed. Of note, every effort should be made to rule out either biliary or pancreatic malignancy. AIP, autoimmune
pancreatitis; ALP, alkaline phosphatase; CT, Computed tomography; ERCP, endoscopic retrograde cholangiopancreaticography; EUS, endoscopic ultrasonography;
cGT, gamma-glutamyltransferase; FISH, fluorescence in situ hybridization; HISORt, histology, imaging, serology, other organs, response to therapy; HPF, high-power
field; IRC, IgG4-related cholangitis; MRCP, magnetic resonance cholangiopancreaticography. PET-CT, Positron emission tomography-computed tomography; ULN,
upper limit of normal.
cholangiopathies usually shows characteristic fibro- had extrahepatic bile duct involvement.107 Bile duct biopsies can
inflammatory lesions in the bile duct wall in IRC. These lesions in some cases demonstrate IRC (sensitivity 52%, specificity
consist of (i) a dense lymphoplasmacellular infiltration rich in 96%), but are too superficial to assess the criterion of obliterative
IgG4+ plasma cells, CD4+ T lymphocytes and eosinophilic phlebitis.108 In patients with concomitant symptomatic type 1
granulocytes, (ii) typical histopathological features such as AIP, histological assessment of duodenal papillary biopsies
obliterative phlebitis (with partial or complete venous obliteration might provide supportive diagnostic information, but papillary
or inflammatory para-arterial nodules), and (iii) particularly in biopsies are controversial due to a considerable sampling error
advanced stages of the disease a cartwheel-shaped storiform and the risk of post-biopsy pancreatitis.108,109 Obtaining
fibrosis (Fig. 4).104,105 The number of IgG4+ plasma cells and the adequate pathological specimens (endoscopic retrograde
ratio of IgG4+/IgG+ plasma cells per high power field (HPF) are of cholangiopancreaticography-brush, cholangioscopic biopsies,
secondary importance, since biopsies from patients with PSC or liver needle biopsies) of lesions that are highly suspicious for
CCA can also contain IgG4+ plasma cells.104 The general CCA is essential in the work-up of IRC.
consensus is that >10 IgG4+ plasma cells per HPF in biopsy
specimens and >50 IgG4+ plasma cells per HPF in resection
specimens are indicative of IRC.98,104 An IgG4+/IgG+ ratio Imaging
greater than 0.4 fits the diagnosis of IRC, although ratios of >0.7 Imaging of the liver and biliary tree by MRI/magnetic resonance
are more commonly seen in IRC.106 The HPF with the highest cholangiopancreaticography (MRCP), CT, endoscopic ultra-
number of cells in the specimen is decisive as IgG4+ cell distri- sound (EUS), intraductal ultrasound, or cholangioscopy may
bution may be patchy. Acquiring histological material for the show bile duct strictures with wall thickening of the extrahe-
diagnosis of IRC comes with pitfalls. Liver needle biopsies are patic, perihilar, and/or intrahepatic bile ducts, and/or lesions
hampered by a lack of sensitivity but seem to be useful in patients suspicious for malignancy like inflammatory pseudotu-
with intrahepatic bile duct involvement as 57% of patients mours.110,111 A recent multicentre analysis from Japan and the
demonstrated >10 IgG4+ per HPF vs. 8% of patients that only US disclosed that – next to elevated serum IgG4 – EUS and

A B C
#
Fig. 4. Histopathologic characteristics of IgG4-related cholangitis. Characteristic findings of IRC on histopathology of a resection specimen: (A) Dense lym-
phoplasmacellular infiltrate (arrow), a few eosinophils within the infiltrate (#) and storiform fibrosis (circle) demonstrated by H&E staining at 40x magnification. (B) Dense
infiltrate of >50 IgG4+ plasma cells per HPF demonstrated by immunohistochemistry at 40x magnification (IgG4+ plasma cells coloured brown after staining with an
IgG4-specific monoclonal antibody). (C) Obliterative phlebitis (arrow) demonstrated by H&E staining at 40x magnification (modified from Herta, Verheij, Beuers. Der
Internist. 2018; 59: 560-566). HPF, high-power field; IRC, IgG4-related cholangitis.
intraductal ultrasound are useful imaging modalities for the the upper limit of normal (ULN) is pathognomonic, as moderately
diagnosis of IRC.112 The pattern of bile duct involvement has elevated IgG4 serum levels are also observed in PSC (15%),
led to the differentiation of IRC into type 1 (distal stricture of the CCA or pancreatic adenocarcinoma (<4x ULN).2,122–125 When
common bile duct), type 2 (intrahepatic segmental or diffuse serum IgG4 levels are >1.4 g/L (ULN) and <2.8 g/L (2xULN) in
bile duct alterations and distal stricture of the common bile sclerosing cholangitis, incorporating the IgG4/IgG1 ratio with a
duct, with prestenotic dilatation [type 2a], or without pre- cut-off of 0.24 improves the positive predictive value and spec-
stenotic dilatation [type 2b]), type 3 (hilar and distal stricture of ificity to distinguish IRC from PSC.125 Elevated serum IgG2 may
the common bile duct), and type 4 (hilar stricture of the com- also distinguish IRC from PSC,126 although this observation re-
mon bile duct) (Fig. 5).113,114 A type 1 pattern is most common quires further confirmation. Carbohydrate antigen 19-9 (CA19-9)
and found in one out of two cases.114 Bile duct wall thickening does not enable differentiation of IRC from CCA or pancreatic
is an important imaging criterion for the differentiation of IRC adenocarcinoma since CA19-9 serum levels may be markedly
from PSC, as it results in longer and more band-shaped con- elevated in all conditions.127 Newer biomarkers are of potential
strictions in IRC, in contrast to the circumscribed and short diagnostic value, although diagnostic accuracy and feasibility in
strictures found in PSC. A single-wall common bile duct routine clinical practice remain to be validated. We identified
thickness >2.5 mm on MRI has been proposed as a diagnostic affinity maturated, class-switched IgG4+ B cell receptor clones
criterion for IRC over PSC.111 Notably, the absence of short bile by next-generation sequencing in blood and affected tissue of
duct strictures is also a helpful radiological sign suggestive of people with IRC.26 The detection of these clones probably allows
IRC over CCA.115 On intraductal sonography, circular sym- for a reliable differentiation of active IRC from PSC, CCA and
metric wall thickness with smooth inner and outer margins of pancreatic adenocarcinoma.26 A similar observation was re-
the bile duct wall are suggestive of IRC, while a wall thickness ported for circulating plasmablast counts90 in individuals with
of >0.8 mm in non-strictured areas is highly suggestive of multi-organ involvement of IgG4-RD.128 In contrast, we could not
IRC.116 Positron emission tomography with computed tomog- confirm the formerly proposed diagnostic value of serum IgG4/
raphy (PET-CT) is gaining considerable traction for diagnosing IgG RNA ratio in a prospective cohort study.129 A metabolomic
IgG4-RD and assessing treatment response, but its usefulness approach to distinguish IRC from PSC holds promise but re-
(also considering radiation exposure and costs) is still under quires validation in other cohorts, while its value for dis-
debate.117,118 In one study, combined PET-CT did not lead to tinguishing IRC from malignancies needs to be proven.130
an increased detection of bile duct involvement compared to
conventional radiology, whereas another study detected 11% Other organ involvement
more IRC involvement using PET-CT.119 Numerous organs including various glands can be affected in
Starting with non-invasive imaging modalities such as IgG4-RD, as summarized in Table 1. In addition to the strong
contrast-enhanced MRI/MRCP or CT is advisable. Subse- association of IRC with type 1 AIP (>90%) and vice versa (30-
quently, invasive imaging methods such as EUS and endo- 60%),11,131 various other organ manifestations have been
scopic retrograde cholangiopancreaticography (with brush, observed in people with IRC. A carefully taken medical history
biopsy or cholangioscopy) can be employed to obtain patho- and meticulous physical examination may disclose former and
logical samples from sites where there is a suspicion of ma- present extrahepatic manifestations of IgG4-RD, such as IgG4-
lignancy.112 Notably, inter-observer variability is moderate in related sialadenitis or prostatitis, which may have gone undi-
most imaging studies.115,120 Imaging findings that distinguish agnosed or have disappeared over time without specific
IRC from PSC and CCA can be found in Fig. 5. treatment. In case biopsies have been taken from potentially
affected organs in the past, specific staining with monoclonal
Serology and serum biomarkers anti-IgG4 antibodies and histopathological revision for other
Up to 75-80% of individuals with IRC present with elevated IgG4 characteristic features of IgG4-RD such as dense lympho-
serum levels.1,2,121 However, only an elevation of more than 4x plasmacellular infiltrates, obliterative phlebitis and storiform

Review
IRC PSC CCA
Distal CCA
Type 1 Type 2a Type 2b
MRCP
findings
Type 4 Klatskin tumor
Type 3
Circumscribed short strictures

Long, band-shaped strictures Beaded biliary tree
Suggestive
Absence of short bile duct strictures Pruned biliary tree
MRCP Short bile duct stricture
Single-wall CBD thickness >2.5 mm Skipped bile duct lesions
findings
Continuous bile duct wall thickness from distal bile duct to hilar region Outpouching diverticulum
Single-wall CBD thickness <2.5 mm
IRC PSC CCA
Bile duct thickness Outpouching

>0.8 mm in non-strictured area Smooth inner Invasive
diverticulum
and outer margins Irregular bile
Irregular bile duct wall
duct wall
IDUS
findings
Asymmetric abnormalities
Symmetric abnormalities Asymmetric abnormalities
Disappearance three layers
Intact three layers (inner wall, cholangiocytes, outer wall) Disappearance three layers
Fig. 5. Imaging findings in IgG4-related cholangitis, primary sclerosing cholangitis and cholangiocarcinoma. Cholangiographic features of IRC, PSC and CCA
on MRCP imaging. IRC can be classified according to its cholangiographic subtype: type 1, distal stenosis; type 2a, distal stenosis and diffuse intraductal chol-
angiopathy with prestenotic dilatation; type 2b, distal stenosis and diffuse intrahepatic cholangiopathy without prestenotic dilatation; type 3, distal and hilar bile duct
stricture; type 4, hilar bile duct stricture. Suggestive imaging findings for IRC, PSC and CCA are listed in the row below. Imaging by IDUS can potentially differentiate
between IRC, PSC and CCA. Distinctive features are depicted in the respective figures. A step-up approach from non-invasive imaging (CT, MRI/MRCP) to endoscopic
imaging (EUS, ERCP, cholangioscopy) and obtaining pathological specimens is advised in the work-up of IRC. CBD, common bile duct; CCA, cholangiocarcinoma;
ERCP, endoscopic retrograde cholangiopancreaticography; EUS, endoscopic ultrasound; IDUS, intraductal ultrasonography; IRC, IgG4-related cholangitis; MRCP,
magnetic resonance cholangiopancreaticography; PSC, primary sclerosing cholangitis; SSC, secondary sclerosing cholangitis; SC-GEL, sclerosing cholangitis with
granulocytic epithelial lesion.
fibrosis appear mandatory. Careful examination of all lymph radiography.117–119 PET-CT might therefore be considered in
node stations is non-invasive and could be of help to find rare cases when the diagnosis of IRC is uncertain, and the
enlarged lymph nodes which are easily accessible for biopsy. involvement of other organs and easily accessible biopsy sites
With regards to findings on abdominal imaging, extrabiliary needs to be assessed. Still, considering exposure to radioac-
organ involvement, particularly of the pancreas, is a charac- tive material, high costs and the lack of proven diagnostic
teristic feature of IRC. The pancreas might appear enlarged and benefit in larger cohorts, PET-CT is not recommended as part
sausage-shaped, hypoechoic on ultrasound, with an oedema- of a routine diagnostic work-up in people suspected of
tous swelling of the surrounding fat tissue (halo) and multifocal suffering from IRC.
strictures of the pancreatic duct. Inflammatory pseudotumours
that raise suspicion of pancreatic malignancy may also
occur.110 Next to pancreatic abnormalities, renal abnormalities Response to therapy
and gallbladder wall thickening are more frequently observed in Glucocorticosteroids, at a dose equivalent to 30-40 mg/day or
association with IRC when compared to PSC.111 The role for 0.5-0.6 mg/kg/day of predniso(lo)ne, are the first-line treatment
whole body imaging in identifying other organ involvement is for IRC.132,133 In the vast majority of cases, improvement of not
unclear at present. In small cohorts of patients with type I only clinical, but also biochemical (bilirubin, alkaline phospha-
AIP and IRC, whole body PET-CT led to more frequent tase, gamma-glutamyltransferase and elevated CA19-9 levels),
detection of other involved organs compared to conventional and imaging findings can be observed within 2 to 4 weeks of

predniso(lo)ne therapy, with treatment response supporting the medium-dose prednisone (0.5-0.6 mg/kg) is as effective as
diagnosis of IRC. Serum IgG4 might improve moderately in this high-dose prednisone (0.8-1 mg/kg/day) for inducing remis-
timeframe as the biological half-life of IgG4 is around 21 days. sion.135 Treatment responsiveness to glucocorticosteroid
Response to glucocorticosteroid therapy is, therefore, regar- therapy is a nearly universal feature of IgG4-RD. Yet, disease
ded as a diagnostic hallmark that distinguishes IRC from ma- recurrence after tapering and cessation of treatment is seen in
lignancies such as CCA. An IgG4-RD responder index has at least 50% of affected individuals.11 To decrease the cumu-
previously been proposed by rheumatologists for study and lative glucocorticosteroid dose and reduce the risk of relapse,
research purposes to quantify treatment response in systemic treatment regimens for remission induction of IRC and type 1
IgG4-RD.134 It is unclear, however, whether the IgG4-RD AIP have added immunomodulators to glucocorticosteroids
responder index has additive value in the aforementioned after the initial glucocorticosteroid response has been docu-
analysis of therapeutic response in major manifestations of the mented as a confirmation of the diagnosis of IgG4-RD. These
digestive tract, IRC and type 1 AIP. regimens are comparable to those widely and effectively used
Together, the HISORt criteria form a pragmatic approach for for the treatment of autoimmune hepatitis.136 Observational
the diagnosis of IRC (Fig. 3).11 A ‘definitive IRC’ can be studies are available for azathioprine, iguratimod and metho-
assumed when (A) IgG4-RD of either the bile ducts or pancreas trexate.137 Three clinical trials have assessed the additive effect
has previously been histologically proven or, (B) imaging find- of mycophenolate mofetil, leflunomide and cyclophosphamide,
ings typical for AIP (sausage-like shape, focal pancreatic mass/ all of which led to higher remission rates and lower relapse
enlargement without pancreatic duct dilatation, multiple rates (Table 4).138–140 A retrospective analysis comparing
pancreatic masses, focal pancreatic duct stricture without cyclophosphamide and mycophenolate did not demonstrate
upstream dilatation, pancreatic atrophy) are supported by superiority of one drug over another in terms of remission in-
elevated serum IgG4 levels.11 (C) Based on the high specificity duction.141 Alternatively, remission induction with the anti-
of IgG4 serum levels >4x ULN,124,125 we advocate for the CD20 antibody rituximab has proven to be successful in a
addition of a third category to the HISORt flow diagram being single-arm observational study and larger cohorts of patients
group C with elevated serum IgG4 levels >4x ULN.124,125 Glu- with IRC.142,143 However, relapse rates after rituximab induc-
cocorticosteroid therapy can be started in cases falling into tion are still considerable and rituximab must be used with
group A, B or C. A fourth group (D) categorized as having caution in IRC given the potentially increased and prolonged
‘probable IRC’ would need to fulfil two or more of the following risk of infections in the context of typical complications of IRC
criteria: elevated serum IgG4, imaging findings suggestive of such as bacterial cholangitis, cholecystitis and bile duct-
type 1 AIP, other organ involvement, or a bile duct biopsy derived liver abscesses. A recently performed network anal-
showing >10 IgG4+ plasma cells per HPF. Here, a time-limited ysis found that glucocorticosteroids plus an immunomodulator
trial course of glucocorticosteroids is justified and should only were associated with higher remission rates in IgG4-RD
be continued when treatment response within weeks is docu- compared to glucocorticosteroids only (OR 3.4), an immuno-
mented (Fig. 3). modulator only (OR 55.3) or rituximab induction treatment only
Non-response to glucocorticosteroids should always (OR 7.4).144 Currently, there is no evidence for one immuno-
question a diagnosis of IRC. However, fibrotic bile duct stric- modulator over another. Standard practice in our clinic is to
tures in long-lasting IRC can lead to persistent symptoms and induce remission with medium-dose prednisolone for 4 weeks,
might not resolve upon immunosuppression. Still, exclusion of after which prednisolone is tapered down and an immuno-
malignancy remains a major diagnostic challenge in these pa- modulator (azathioprine, starting dose 50 mg daily; alterna-
tients before a course of glucocorticosteroids is started. tively, 6-mercaptopurine or mycophenolate mofetil) is added at
Although the HISORt criteria form a useful pragmatic approach mostly moderate doses. In addition to rituximab, various other
to the diagnosis of IRC, there is an unmet need for validated new drugs, mainly monoclonal antibodies, have been devel-
diagnostic tests that can accurately diagnose IRC and distin- oped to more specifically dampen autoimmune reactions and
guish it from PSC and malignancies such as CCA and autoantibody effects; these new drugs are being tested in
pancreatic adenocarcinoma. registered trials in IgG4-RD (Table 5).
(ii) Maintaining remission can currently be achieved via four
strategies: (a) low-dose glucocorticosteroids plus an immuno-
Therapeutic options in IRC and IgG4-RD modulator, (b) low-dose glucocorticosteroids only, (c) an
In IRC, prevention or alleviation of organ damage and treatment immunomodulator only, or (d) rituximab maintenance therapy.
of signs and symptoms such as jaundice, weight loss, Remission induction and maintenance therapy with low-dose
abdominal complaints, and pruritus are the primary therapeutic prednisone for 3 years resulted in a markedly lower relapse
aims. Lack of treatment can lead to bacterial cholangitis, liver rate (23.3%) compared to remission induction with only 26
abscesses, cholecystitis, biliary fibrosis, cirrhosis and death. weeks of prednisone treatment (57.9%) in type 1 AIP.145
Treatment of IRC is based on (i) remission induction, (ii) remis- Additionally, a recently performed retrospective analysis
sion maintenance and (iii) long-term management.2,122,132,133 demonstrated that low-dose prednisone maintenance (>3
(i) Remission is induced with medium-dose predniso(lo)ne years) improved survival in patients with IRC.25 The recently
(0.5-0.6 mg/kg/day) for 4 weeks after which glucocorticoste- performed network analysis (see above) showed that gluco-
roids are progressively tapered down by 5 mg every 2 weeks corticosteroids plus an immunomodulator lowered relapse
until a maintenance dose of < −7.5 mg/day is reached.
133
The rates in IgG4-RD compared to glucocorticosteroid mono-
maximum dose, duration and rate of tapering down can be therapy (OR 0.39), whereas rituximab maintenance treatment
varied depending on the extent of disease, comorbidities, and was associated with the lowest relapse rate (OR 0.10).144 For
indicators of relapse.132,133 A recent trial demonstrated that IRC with the inherent risk of bacterial superinfection, i.e.

Table 4. Overview of performed clinical studies in IgG4-RD.
Authors Intervention Comparator Design No. of No. of IRC Endpoints Follow-up Outcome
patients patients (months)
Wu et al.135 High-dose predni- Medium-dose RCT, open-label 40 14 Remission rate 6 95% vs. 80% (p = 0.157)
sone (0.8-1.0 mg/ prednisone (0.5-
kg/day) 0.6 mg/kg/day)
Wang et al.138 GC + leflunomide GC RCT, open-label 66 13 Relapse rate 12 18% vs. 42%
Time to relapse HR 0.35, 95% CI [0.13-0.90]
Yunyun et al.139 GC + mycopheno- GC RCT, open-label 79 30 Remission rate 12 76% vs. 51%
late mofetil Relapse rate 21% vs. 40%
Yunyun et al.140 GC + GC RCT, open-label 104 29 Remission rate 12 88% vs. 60%
cyclophosphamide Relapse rate 12% vs. 38.5%
Masamune et al.145 GC induction + GC induction + 26 RCT, open-label 49 25 Relapse rate 36 57.9% vs. 23.3%
maintenance week taper
Carruthers et al.143 RTX induction - Single arm, open-label 30 10 Disease response 6 77%
Remission rate 47%
141
Luo et al. GC + GC + mycophenolate Retrospective cohort 155 34 Complete response 12 56% vs. 50%
cyclophosphamide mofetil Relapse rate 4% vs. 15%
Ebbo et al.205 RTX induction + - Retrospective cohort 33 13 Clinical response 25 93.5%
maintenance Relapse rate 42%
142
Majumder et al. RTX induction + RTX induction Retrospective cohort 43 14 Relapse rate 36 11% vs. 45%
maintenance
Lanzilotta et al.206 RTX induction and/ - Meta-analysis 101 101 Remission rate 19 89%
or maintenance Relapse rate 21%
AE rate 25%
Omar et al.144 RTX maintenance GC Network analysis 1,169 392 Remission rate 3-60 OR = 3.53, 95% CI [0.13-94.51]
Relapse rate OR = 0.10, 95% CI [0.01-1.63]
AE rate OR = 7.69, 95% CI [0.02-N]
Omar et al.144 RTX induction GC Network analysis 1,169 392 Remission rate 3-60 OR = 0.45, 95% CI [0.12-1.67]
AE rate OR = 0.94, 95% CI [0.03-26.0]
Omar et al.144 GC + GC Network analysis 1,169 392 Remission rate 3-60 OR = 3.36, 95% CI [1.44-7.83]
immunomodulator Relapse rate OR = 0.39, 95% CI [0.20-0.80]
AE rate OR = 1.04, 95% CI [0.08-12.5]
Omar et al.144 Immunomodulator GC Network analysis 1,169 392 Remission rate 3-60 OR = 0.06, 95% CI [0.02-0.18]
AE rate OR = 0.47, 95% CI [0.02-9.13]
Clinical studies in IgG4-RD that have included patients with IRC, listed by first author (first column), their intervention and comparator (second and third column), study design (fourth column), total number of included patients and
number of IRC patients (fifth and sixth column), endpoints assessed (seventh column), follow-up time in months (eighth column) and the respective outcome of the intervention vs. comparator when applicable (ninth column).
AE, adverse event; GC, glucocorticosteroids; HR, hazard ratio; OR, odds ratio; RCT, randomised controlled trial; RTX, rituximab.
Review
1515
Table 5. Overview of registered ongoing clinical studies in IgG4-related cholangitis.
NCT identifier Intervention Comparator Target Design Sample Outcome Follow-up
size (months)
NCT05662241 Obexelimab Placebo CD19- Randomized, blinded 200 Time to flare 12
FCcR2B
NCT05625581 Tofacitinib + Cyclophosphamide + JAK1-JAK3 Case-control, open- 40 Remission rate 6
glucocorticosteroid glucocorticosteroid label
NCT04660565 Belimumab + Prednisone BAFF Randomized, open- 60 Risk of flare 12
prednisone label
NCT05728684 CM310 - IL4RA Single group, open- 20 Response rate 3
label
NCT04540497 Inebilizumab Placebo CD19 Randomized, blinded 190 Time to flare 12
NCT04918147 Elotuzumab + Prednisone SLAMF7 Randomized, blinded 75 Response 11
prednisone
NCT04520451 Rilzabrutinib Glucocorticosteroid BTK Randomized, open- 25 Flare 4
label, cross-over occurrence
NCT04124861 - Immunosuppressant Glucocorticosteroid + - Randomized, open- 138 Recurrence rate 18
monotherapy immunosuppressant label
- No therapy
NCT05746689 Sirolimus + prednisone - mTOR Single group, open- 20 Relapse rate 12
label
List of ongoing registered clinical studies in IRC with NCT identifier, intervention, comparator, pharmacological target, study design, sample size, primary outcome measure and
follow-up time.
BAFF, B cell activation factor; BTK, Bruton’s tyrosine kinase; CD19, cluster of differentiation 19; FCcR2B, Fc c receptor 2B; IL4RA, interleukin-4 receptor alpha; JAK1, janus kinase 1;
JAK3, janus kinase 3; mTOR, mammalian target of rapamycin; NCT, national clinical trial; SLAMF7, signalling lymphocytic activation molecule family member.
bacterial cholangitis, we currently prefer long-term strategies malignancy and management of their therapy-induced side
(a) and (c) for the majority of our patients. Still, further studies effects. Currently, life-long surveillance is advised for patients
comparing different treatment options in IRC are warranted. with IRC.132,133
The optimal duration of maintenance therapy has not been As IRC is associated with type I AIP in >90%, monitoring of
established, but at least 2-3 years appears reasonable based exocrine and endocrine pancreatic function is recommended.
on available data, and long-term treatment beyond 3 years may Exocrine pancreatic insufficiency has been reported to occur in
be warranted in individuals with a high risk of relapse, including up to 53% of individuals with IRC and faecal elastase tests
those with multiorgan IgG4-RD, markedly elevated serum IgG4, should be performed when indicated (e.g. steatorrhea, weight
involvement of hilar and intrahepatic bile ducts in IRC, multiple loss).97,122 Endocrine pancreatic dysfunction leading to dia-
strictures, or thicker bile duct walls.11 Expert consensus in- betes mellitus type 3c has been reported to occur in 37% of
dicates that maintenance treatment of IgG4-RD should be patients in one IRC cohort, but the long-term incidence may be
patient-tailored based on predictors of relapse, comorbidities even higher.
and the risk of (developing) glucocorticosteroid-induced Development of biliary cirrhosis in IRC has been reported in
side effects.132,133 4.5%148 to 7.5%,11 but may be even more frequent in some
A potential role for ursodeoxycholic acid (UDCA) in the cohorts with advanced disease. Of note, the risk of developing
maintenance treatment of IRC has not been studied so far.2,133 cirrhosis might be particularly relevant in people with proximal
Anticholestatic, hepato- and cholangioprotective effects of bile duct involvement (up to 9% in 5 years). No published studies
UDCA have been shown for a number of fibrosing chol- have reported follow-up strategies to monitor fibrosis progres-
angiopathies including PBC and PSC,133,146 and its beneficial sion in IRC, but annual transient elastography appears as an
effect on transplant-free survival in PBC is clearly documented. advisable measure in line with recommendations for PSC and
Putative mechanisms of action of UDCA in fibrosing chol- PBC.133,146 Current disease-specific cut-off values for transient
angiopathies have been intensely studied and discussed,147 elastography in IRC are yet to be established. IRC-related biliary
with the evidence suggesting that UDCA might provide bile cirrhosis should be managed according to current clinical
duct protection in addition to immunosuppressive treatment guidelines, including semi-annual screening for HCC and vari-
and thereby exert an additional glucocorticosteroid-sparing ces. The occurrence of splanchnic and portal vein thrombosis in
effect in IRC. up to 9% of patients with IRC is noteworthy97 and should be
When relevant advanced fibrotic bile duct strictures in IRC treated according to the EASL clinical practice guidelines.149
do not adequately respond (any longer) to glucocorticosteroid The risk of malignancy in IRC has been reported variably in
treatment, endoscopic intervention under antibiotic prophylaxis different cohorts. A large Japanese study identified malignancies
with balloon dilatation and – if unresponsive to balloon dilata- in 25/527 (4.7%) patients with IRC during a follow-up of 4.1
tion alone – short-term stenting may be needed to guarantee years, which was comparable to an age/gender-matched control
adequate bile flow into the duodenum.132,133 population.96 Other studies have reported an increased risk, with
(iii) Long-term management of IRC. Depending on the clin- 11%-21.5% of patients experiencing a malignancy during their
ical course, patients with IRC are seen at a 6-12-month interval disease course.25,97,150 Notably, a prominent increase in
in the outpatient clinic to assess the development of potential pancreatic and biliary tract malignancies was observed.25,150
biliary and hepatic damage, other organ involvement,122 risk of Maintenance treatment with glucocorticosteroids has been

Review
reported to improve survival in individuals with IRC, possibly by UDCA.122,158,159 Rapid response to therapy was reported in 19/
reducing relapse rates and inflammatory activity, and thereby the 23 (82%) cases, with relapse after tapering of glucocorticoste-
occurrence of malignancies.25 roids in 13/23 (56%).157 In case of relapse, a new course of
Renal impairment in individuals with IRC occurs in up to predniso(lo)ne, and the initiation of maintenance therapy (e.g.,
12%, and is monitored by creatinine and estimated glomerular azathioprine 1-2 mg/kg/day), is recommended.122,158
filtration rate, especially in patients who have kidney, ureter or
retroperitoneal involvement of IgG4-RD.97 Collaboration with Outlook for future research
experienced nephrologists/urologists is crucial for success- Insights into the pathophysiology and clinical course of IRC
ful management. have led to considerable advances in its diagnosis and man-
Additional long-term management depends on the treat- agement during the last two decades. Still, gaps in our basic
ment modality chosen. Patients treated with long-term gluco- knowledge and in the clinical management of IRC remain.
corticosteroids should be assessed for osteoporosis risk (DEXA
[dual x-ray absorptiometry] scan) and given calcium/vitamin D Pathophysiology
supplements. Endocrine pancreatic function should be moni-
tored by HbA1c on a regular basis and exocrine pancreatic Identification of potential aetiological agents and unravelling of
function by faeces elastase measurement. Additional man- molecular mechanisms leading to the dysregulated immune
agement advice can be found in current guidelines.133,151–153 reaction that is characteristic of IRC are unmet needs. The
potential pathogenic role of IgG1 and IgG4 autoantibodies
IRC and IgG4-RD in children needs to be further assessed. The mechanisms of storiform
fibrosis formation also need to be unravelled.
IgG4-RD has rarely been reported in paediatric patients and
might, in some cases, represent systemic IgE-mediated allergic Diagnosis
reactions with elevated serum IgG4. There are only a few case
reports on IRC and hepatic fibroinflammatory masses, in pa- The development of an accurate diagnostic test that can
tients aged 3-17 of whom 50% were girls.154–156 A similar age distinguish IRC from both PSC and CCA is an unmet need and
range and gender distribution was reported in the only system- would prevent a considerable number of misdiagnoses and
atic review on IgG4-RD in children.157 Intermittent abdominal unjustified surgical and oncological interventions. A potential
pain, mild jaundice, weight loss, and – in contrast to most adult role of PET-CT in the diagnostic work-up of IgG4-RD, i.e.
patients – fever were described as typical clinical symptoms in assessing other organ involvement, has to be critically inves-
children with presumed IRC. Due to the absence of consensus tigated considering radiation load and costs.
on paediatric diagnostic criteria, the diagnosis should be based
on adult criteria.122 Elevated IgG4 serum levels were found in 16/ Treatment
23 (70%) children with histologically confirmed IgG4-RD,157 but Prospective, randomized-controlled clinical trials comparing
the appropriate diagnostic cut-off in children remains unknown. the most effective and safe immunomodulators in IRC would
Transabdominal ultrasonography may demonstrate hepato- be desirable. The long-term course of IRC needs to be firmly
megaly, dilated bile ducts, enlarged abdominal lymph nodes, established and patients at risk for a complicated disease
hepatic masses, or pancreatic alterations.155 Imaging can be course who are in need of more intensive therapy need to be
expanded by non-invasive, radiation-free modalities (MRI/ identified. Adequate follow-up strategies to monitor fibrosis
MRCP) in unclear cases. Histology is not mandatory for the progression and detect malignancies early should be investi-
diagnosis of hepatobiliary IgG4-RD as malignancy is rare in gated. Therapeutic options, based on recent advances in
children.122 Only a clear distinction from other paediatric auto- understanding the pathophysiology of IgG4-RD, should be
immune liver diseases such as autoimmune hepatitis or juvenile expanded to reduce glucocorticosteroid-induced side effects
sclerosing cholangitis may require a liver biopsy.158 Still, the and to improve remission and relapse rates (Table 5 for cur-
number of IgG4+ plasma cells per HPF for the diagnosis of IgG4- rent trials evaluating novel therapeutic approaches in IRC).
RD in children is unknown. Treatment of IgG4-RD in children International collaboration will be pivotal to achieve
is based on glucocorticosteroids, immunomodulators, and these aims.
Affiliations
1
Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the
Netherlands; 2Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany; 3Department of Ophthalmology, Amsterdam
University Medical Centers, the Netherlands; 4Department of Pathology, Amsterdam University Medical Centers, the Netherlands
Abbreviations ratio; PBC, primary biliary cholangitis; PDGFB, platelet-derived growth factor
subunit B; PET-CT, positron emission tomography with computed tomography;
AIP, autoimmune pancreatitis; ANO1, anoctamin 1; BTK, Bruton’s tyrosine ki-
PPAR, peroxisome proliferator-associated receptor; PSC, primary sclerosing
nase; CA19-9, carbohydrate antigen 19-9; CCA, cholangiocarcinoma; CTL,
cholangitis; SC-GEL, sclerosing cholangitis with granulocytic epithelial lesions;
cytotoxic T cell; EUS, endoscopic ultrasound; HCC, hepatocellular carcinoma;
SLAMF7, signalling lymphocytic activation molecule family member 7; Tfh2,
HPF, high power field; IgG4-RD, IgG4-related disease; IRC, IgG4-related chol-
follicular T helper 2 cells; Tph, peripheral T helper cells; Tregs, regulatory T cells;
angitis; LAMA5, laminin a5; LAMB1, laminin b1; LAMC1, laminin c1; LGALS3,
UDCA, ursodeoxycholic acid; ULN, upper limit of normal.
galectin-3; MRCP, magnetic resonance cholangiopancreaticography; OR, odds

Financial support (London, England) 1999;354:43–44. https://doi.org/10.1016/s0140-6736(99)
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The group’s research on IgG4-related cholangitis was supported by a ZonMw
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Open Competition grant of the Netherlands Organization for scientific research
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(NWO), grants from the Netherlands Digestive Foundation (MLDS), from Dr. Falk
cholangiocarcinoma: a 30-year tertiary care experience. Am J Gastroenterol
GmbH for investigator-initiated experimental research, from the German patient
2018;113:765–772. https://doi.org/10.1038/s41395-018-0036-5.
organisation ’Deutsche Morbus Crohn/Colitis ulcerosa Vereinigung’ (DCCV,
[11] Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al.
section PSC), from the American patient organisation ’PSC partners seeking a
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therapy. Gastroenterology 2008;134:706–715. https://doi.org/10.1053/j.
from a South-African PSC patient foundation (Stichting AMC Foundation #20837)
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matol 2020;30:17–23. https://doi.org/10.1080/14397595.2019.1621000.
Gastroenterology (NVGE, to RK, DT, LMW).
[13] Terao C, Ota M, Iwasaki T, Shiokawa M, Kawaguchi S, Kuriyama K, et al.
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Review

IgG4-related cholangitis – a mimicker of fibrosing and

Introduction revealed an enlarged, dark brown-green discoloured liver with a

Journal of Hepatology, December 2023. vol. 79 j 1502–1523

Table 1. Organ manifestations of IgG4-RD associated with IRC.

Journal of Hepatology, December 2023. vol. 79 j 1502–1523 1503

Direct tissue damage?

Microbiome? Immune Malignancy

Healthy cholangiocyte IRC cholangiocyte

ITGA6B1 Disrupted barrier Annexin A11

Oligoclonal IgG4+ Tregs

IL-33 IL-13 BAFF

CD4+ SLAMF7+ CTLs

IL-4 Perforin IL-1β Basophils

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B cells 400 B cells

Salivary duct cells 40 Salivary duct cells

Club cells Club cells

Alveolar cells type 1 Alveolar cells type 1

Alveolar cells type 2 Alveolar cells type 2

Pancreatic ductal cells Pancreatic ductal cells

Proximal enterocytes Proximal enterocytes

Distal enterocytes Distal enterocytes

Intestinal goblet cells Intestinal goblet cells

Paneth cells Paneth cells

Proximal tubular cells Proximal tubular cells

Distal tubular cells Distal tubular cells

Collecting duct cells Collecting duct cells

Prostatic glandular cells Prostatic glandular cells

Prostatic basal cells Prostatic basal cells

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Table 3. Differential diagnosis of IgG4-related cholangitis and respective HISORt characteristics.

Resection: >50/HPF IgG4+/IgG+ typically <0.4184 No storiform

O Other organs Definitive IRC: Follow up:

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IRC PSC CCA

Circumscribed short strictures

IRC PSC CCA

Bile duct thickness Outpouching

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