Igg4-Related Disorder and Endocrine Diseases: A Review of the Literature

Abstract

IgG4-related disorders (IgG4-RD) are a new entity of multi-organ disorders that share common fibro-inflammatory histopathologic characteristics and elevated IgG4 levels in serum and tissue. Autoimmune pancreatitis and Mikulicz syndrome are major entities, however many syndromes are part of IgG4-RD including eosinophilic angiocentric fibrosis, fibrosing mediastinitis, hypertrophic pachymeningitis, inflammatory pseudotumour, multifocal fibrosclerosis (commonly affecting the orbits, thyroid gland, retroperitoneum, mediastinum, and other tissues and organs), periaortitis and peri-arteritis, inflammatory aortic aneurysm, retroperitoneal fibrosis (Ormond’s disease), Riedel’s thyroiditis, and sclerosing mesenteritis. In this review we detail the link between IgG4-RD and endocrine disorders and then examine the link between diabetes and IgG4-RD. We study the increased risk of IgG4-RD after using dulaglutide. We concluded that IgG4-RD should be suspected in patients with progressive thyroiditis with mass effect and very high antibody titers. The relationship between IgG4-RD and diabetes is still controversial.

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Diabetes & Metabolism
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ISSN: 2155-6156
Bashier et al., J Diabetes Metab 2015, 6:12
http://dx.doi.org/10.4172/2155-6156.1000631
Volume 6 • Issue 12 • 1000631
J Diabetes Metab
ISSN: 2155-6156 JDM, an open access journal
Review Article
Abstract
IgG4-related disorders (IgG4-RD) are a new entity of multi-organ disorders that share common bro-inammatory
histopathologic characteristics and elevated IgG4 levels in serum and tissue. Autoimmune pancreatitis and Mikulicz
syndrome are major entities, however many syndromes are part of IgG4-RD including eosinophilic angiocentric
brosis, brosing mediastinitis, hypertrophic pachymeningitis, inammatory pseudotumour, multifocal brosclerosis
(commonly affecting the orbits, thyroid gland, retroperitoneum, mediastinum, and other tissues and organs), peri-
aortitis and peri-arteritis, inammatory aortic aneurysm, retroperitoneal brosis (Ormond’s disease), Riedel’s
thyroiditis, and sclerosing mesenteritis.
In this review we detail the link between IgG4-RD and endocrine disorders and then examine the link between
diabetes and IgG4-RD. We study the increased risk of IgG4-RD after using dulaglutide.
We concluded that IgG4-RD should be suspected in patients with progressive thyroiditis with mass effect and
very high antibody titers. The relationship between IgG4-RD and diabetes is still controversial.
Igg4-Related Disorder and Endocrine Diseases: A Review of the Literature
Alaaeldin M Bashier1*, Ghita Hari2 and Elamin I Abdelgadir3
1Endocrine Division, Medical department, Dubai Hospital, UAE
2Rheumatology division, Dubai Hospital, Dubai UAE
3Endocrine division, Dubai Hospital, Dubai, UAE
*Corresponding author: Alaaeldin M Bashier, Endocrine Division, Medical
department, Dubai Hospital, P.O. Box 94132, UAE, Tel : +971554154445; E-mail:
alaminibrahim@hotmail.com
Received October 28, 2015; Accepted December 05, 2015; Published December
10, 2015
Citation: Bashier AM, Hari G, Abdelgadir EI (2015) Igg4-Related Disorder
and Endocrine Diseases: A Review of the Literature. J Diabetes Metab 6: 631.
doi:10.4172/2155-6156.1000631
Copyright: © 2015 Bashier AM, et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
Keywords: IgG4; yroiditis; Pancreatitis; Diabetes mellitus;
Hypophysitis
Abbreviations: IgG4-RD: IgG4 Related Disorders; AIP:
Autoimmune Pancreatitis; MD: Mikulicz Disease; GLP-1: Glucagon
Like Peptide 1
Introduction
In 2001, Hamano et al. [1] described elevated levels of IgG4 in
the sera of patients presenting with autoimmune pancreatitis. A few
years later, IgG4-positive cells were described in other organs of
these patients, and the term IgG4-related disorders was suggested.
is refers to an immune-mediated multi-organ group of disorders
previously regarded as isolated single-organ diseases. e link between
these diseases has been gradually established in view of the common
bro-inammatory histopathologic characteristics and the elevation
of IgG4 in the serum and tissues. Currently, IgG4-RD are described
as “a bro-inammatory condition characterized by a tendency for
formation of tumefactive lesions, a dense lymphoplasmacytic inltrate
rich in IgG4-positive plasma cells, storiform brosis, frequent, but not
invariable elevations of serum IgG4 levels, and a swi initial response
to glucocorticoids provided that tissue brosis has not supervened” [2].
Autoimmune pancreatitis (AIP) and the Mikulicz disease (MD)
are major entities of IgG4-related disease. AIP is a form of chronic
pancreatitis that presents with painless obstructive jaundice. Extra-
pancreatic sclerosing manifestations were more frequent than
previously thought in AIP patients. is could aect the bile duct, liver,
gallbladder, retroperitoneum, salivary and lachrimal glands. Extensive
IgG4 and plasma cell inltration were also detected in the aected
tissues [3]. Mikulicz disease (MD) presents with bilateral, painless, and
symmetrical swelling of the lachrimal and salivary glands leading to
dryness of the eyes and mouth—this presentation is easily confused
with Sjogren’s syndrome [4].
e diagnosis of IgG4-related disorder is based on typical histology
makeup (dense lymphoplasmacytic inltrates, storiform brosis, mild
eosinophilic inltration, and obliterative phlebitis), a high count of
IgG4-positive plasma cells per high-power eld (HPF), and high IgG4/
IgG ratio. However, non-histologic criteria for diagnosis of IgG4-
related disease (IgG4-RD) have been proposed [5]. e following
two criteria are the most established: IgG4 plasma level of >135 mg/
dl and an IgG4/IgG plasma cell ratio of >40% with more than 10
IgG4-positive plasma cells per HPF. Stricter criteria for diagnosis
were proposed by Deshpande et al. [6]. is group suggested that the
critical histopathological features include a dense lymphoplasmacytic
inltrate, a storiform pattern of brosis, and obliterative phlebitis. e
proposed terminology scheme for the diagnosis of IgG4-RD is based
primarily on the morphological appearance on biopsy. e tissue IgG4
counts and IgG4:IgG ratios are secondary in importance. is means
that the prominent IgG4+ plasma cells in the absence of one or more
of the characteristic morphological features are usually not sucient
for diagnosis [6].
ere are some histologic criteria that are inconsistent with
IgG4-RD including the presence of epithelioid cell granulomas
(this excludes IgG4-RD), giant cells, and a prominent neutrophilic
inltrate. e presence of neutrophils, necrosis and giant cells suggests
granulomatosis with polyangiitis [6].
Based on these criteria, many other conditions are now considered
to be part of the IgG4-RD including eosinophilic angiocentric brosis
(aecting the orbits and upper respiratory tract), brosing mediastinitis,
hypertrophic pachymeningitis, idiopathic hypocomplementemic
tubulointerstitial nephritis with extensive tubulointerstitial deposits,

Citation: Bashier AM, Hari G, Abdelgadir EI (2015) Igg4-Related Disorder and Endocrine Diseases: A Review of the Literature. J Diabetes Metab 6:
631. doi:10.4172/2155-6156.1000631
Page 2 of 5
Volume 6 • Issue 12 • 1000631
J Diabetes Metab
ISSN: 2155-6156 JDM, an open access journal
al. [16] included patients with IgG4-RD and found high antithyroid
antibodies in 41%, hypothyroidism in 21%, but none with Riedel’s
thyroiditis. Many other studies did not show any thyroid abnormalities
[17-19].
Cameselle-Teijeiro et al. [20] studied a case of Riedel’s thyroiditis in
2014 by applying both the classic criteria and the recent stricter criteria
to diagnosis the IgG4-RD spectrum [6]. is suggested that Riedel’s
thyroiditis be included within the IgG4-RD spectrum.
Based on this data, we suggest that IgG4-RD should be considered
in any patient with an aggressive form of thyroiditis including
Hashimoto’s thyroiditis. Suspected patients should be analyzed for a
IgG4/IgG ratio with immunostaining when indicated.
IgG4-RD and the pituitary gland
ere are many published cases of IgG4-RD aecting the pituitary
gland. Almost all cases involved middle-aged or elderly men presenting
with various degrees of hypopituitarism and diabetes insipidus and
demonstrating a thickened pituitary stalk and/or pituitary mass.
Pituitary swelling and the mass eect shrank remarkably in response
to glucocorticoid therapy even at lower doses that that prescribed
as a replacement for adrenocortical insuciency. e presence of
IgG4-related systemic disease and elevated serum IgG4 levels before
glucocorticoid therapy were the main clues to a correct diagnosis of
IgG4-related infundibulo-hypophysitis [21].
MRI shows a thickened pituitary stalk, swelling of the pituitary
gland or mass formation. e pituitary stalk was markedly enhanced
with gadolinium or had no enhancement in the pituitary gland. e
“bright” signal seen in the posterior portion of the pituitary on T1-
weighed imaging was absent in cases involving central diabetes insipidus
and in several cases without clinical diabetes insipidus. Hypertrophic
pachymeningitis and orbital lesions including pseudotumor formation
were seen in a few cases. ese MRI ndings are not specic for
IgG4-RD and can be seen in lymphocytic hypophysitis, sarcoidosis,
tuberculosis and Wegener’s granulomatosis [21].
To dierentiate between lymphocytic hypophysitis (LYH) and
IgG4-RD, the serum IgG4 level should be checked. Values >140 mg/
dl indicate IgG4-RD. Moreover, LYH occurs more frequently in young
females particularly during pregnancy or post-partum with a peak
incidence between 30-40 years of age. e presence of an autoimmune
disorder as well as anti-pituitary antibodies also suggests LYH [22-24].
ere are no specic diagnostic criteria for IgG4-related
hypophysitis, however Leporati et al. [25] suggested ve criteria
to diagnose IgG4-related hypophysitis. e rst is mononuclear
inltration of the pituitary gland, which is rich in lymphocytes and
plasma cells with more than 10 IgG4-positive cells per HPF. e second
is a sellar mass and/or thickened pituitary stalk on pituitary MRI when
pituitary histopathology is unavailable. e third is biopsy-proven
IgG4-positive lesions in other organs. e fourth is increased serum
IgG4 levels (>140 mg/dL), and the h is shrinkage of the pituitary
mass and symptom improvement with steroids. Moreover, the authors
suggested that the diagnosis is established when any of the following
are fullled: criterion 1 alone or criterion 2 and 3 or criterion 2, 4, and
5. ese criteria were proposed before the most recent guidelines and
stricter criteria are applied to the diagnosis of IgG4-RD.
When serum IgG4 is high, systemic surveys to detect other organs
should be considered using the gallium scintigraphy and/or FDG/
PET [18]. Care should be taken when measuring serum IgG4 because
there are many conditions that are associated with high IgG4 including
Inammatory pseudotumour (aecting the orbits, lungs, kidneys,
and other organs), Küttner’s tumor (aecting the submandibular
glands), multifocal brosclerosis (commonly aecting the orbits,
thyroid gland, retroperitoneum, mediastinum, and other tissues and
organs), periaortitis and periarteritis, inammatory aortic aneurysm,
retroperitoneal brosis (Ormond’s disease), Riedel’s thyroiditis, and
sclerosing mesenteritis. ese disorders are usually seen in older males
with atopic conditions. Many organs can be aected can result in a
tumor eect especially in the lungs, orbits and pituitary gland [7,4].
ere are no specic guidelines for treatment of IgG4-RD, however
there is an agreement that all cases of symptomatic active IgG4-RD
require treatment—some very urgently. e consensus states that
glucocorticoids are the rst line for all active untreated IgG4-RD unless
there is a contraindication. Following successful induction, certain
patients would benet from maintenance therapy. Retreatment with
steroids may be considered in patients who relapse o treatment
following successful induction. Steroid-sparing agents should be
considered following relapse [8].
ere has been controversy regarding the initial use of combination
steroids and steroid-sparing agents. is is because glucocorticoid
monotherapy will ultimately fail to control the disease, and long-term
glucocorticoid toxicities are a high risk to patients.
A response to treatment is oen seen within 2-4 weeks and oen
sooner. e dose is tapered over 8 weeks once signicant improvement
is seen. In cases that are resistant to steroids ritoximab (B cell depleting
agent), azathioprine, mycophenolate are reasonable choices [9].
IgG4-RDs are associated with an increased risk of cancers including
non-Hodgkin’s lymphoma [10]. ere are also cases of pancreatic
cancer and salivary duct carcinoma, pulmonary adenocarcinoma, small
cell carcinoma of the lung, and gastrointestinal clear cell sarcoma [11].
IgG4-related Disorders in Endocrine Practice
IgG4-related disorders and the thyroid
Riedel’s thyroiditis is a part of IgG4-RD. In 2010, Dahlgren et
al. [12], described three patients with Riedel’s thyroiditis based on a
bro-inammatory process. ey found that the three patients had
high IgG4/IgG ratios and very high levels of IgG4 per high power eld.
Li et al. [13] further studied the IgG4-related thyroiditis in a series of
patients with Hashimoto’s thyroiditis that underwent surgery. Staining
for IgG4 was positive in histopathology sections in 19 patients. Positive
patients were older, male, and had more progression and higher levels
of circulating antithyroid antibodies.
Salook et al. [14] reported a patient who presented with an acute
elevation in T4 and suppressed TSH associated with neck pain. e
patient had already been diagnosed with Hashimoto’s thyroiditis
and was on a stable dose of thyroxine. Due to pressure symptoms,
the patient underwent surgery and histopathology revealed extensive
brotic processes, heavy plasmocytic inltrates, and storiform brosis.
is immunostained strongly for IgG and IgG4, and the IgG4/IgG ratio
was over 80%. e serum IgG4 level was 737 mg/dl (normal, 3–201)
with normal IgG1 and IgG3 levels and borderline IgG2 levels (805,
normal 169–786 mg/dl). us, he was diagnosed with IgG4-related
thyroiditis.
Considering thyroid diseases to be an IgG4-RD is still controversial;
Pusztaszeri et al. described a patient with an expanding nodule that
on histopathology showed features suggestive of IgG4-RD, however
plasma IgG4 levels were normal [15]. Another study by Hamano et

Citation: Bashier AM, Hari G, Abdelgadir EI (2015) Igg4-Related Disorder and Endocrine Diseases: A Review of the Literature. J Diabetes Metab 6:
631. doi:10.4172/2155-6156.1000631
Page 3 of 5
Volume 6 • Issue 12 • 1000631
J Diabetes Metab
ISSN: 2155-6156 JDM, an open access journal
Wegener’s granulomatosis, multicenteric Castleman’s disease, and
idiopathic plasmacytic lymphadenopathy [26].
Treatment with prednisolone 30-50 mg per day resulted in
signicant improvement in all reported cases of hypophysitis except for
one case that responded to an alternative treatment with azathioprine
[7].
IgG4-RD and diabetes
To date, no data has linked diabetes with IgG4-RD; however
we know that the immune system plays a role in the development
of diabetes, and diabetes does aect the immune system to activate
oxidative stress pathways. Moreover, some medications used for
treatment of diabetes result in immune modulation
Auto-immune pancreatitis: Auto-immune pancreatitis (AIP)
could be the link between diabetes and IgG4-RD. AIP is a chronic form
of pancreatitis that results in painless jaundice, dark urine, and pale
stool. It may also present with unexplained weight loss and extreme
weakness. Systemic symptoms such as weight loss and fever are
rare. Newly diagnosed type 2 diabetes malabsorption and pancreatic
calcication and stones may be seen in some cases [18,28].
e rst suggestion that pancreatitis could be related to an auto-
immune process came from Sarles et al. [29] in 1961. However, the
concept of auto-immune pancreatitis was introduced by Yoshida et al.
[30] in 1995. e autoimmune association of AIP is based on association
with other autoimmune disorders like sclerosing cholangitis, primary
biliary cirrhosis, Sjogren’s syndrome, and inammatory bowel
disease [31]. Autoantibodies commonly associated with AIP include
antinuclear antibodies, rheumatoid factor, anticarbonic anhydrase II,
and antilactoferrin [28].
ere are two types of AIP—type 1 is IgG4-related and oen
aects males over 60 years of age; the male-to-female ratio is 4-7.5 :1
[32]. Patients might have associated sclerosing cholangitis, salivary
gland involvement (sialadenitis), retroperitoneal brosis, or lung
involvement. Type 2 AIP usually aects men or women over 40; 30% of
them might have an associated inammatory bowel disease [33].
Imaging studies show an enlarged pancreas—mostly the pancreatic
head. e ERCP (endoscopic retrograde cholangiopancreatography)
shows irregular narrowing of the pancreatic duct with or without
stenosis of the common bile duct [34].
Many criteria have been developed to diagnose AIP and avoid
surgery in cases that are steroid responsive [35]. ese criteria include
the Asian diagnostic criteria for auto-immune pancreatitis as well as
the Mayo clinic diagnostic criteria (the HISORt criteria). ere are
four Asian criteria. Criterion I is a diuse pancreatic parenchyma and
segmental/focal enlargement of the gland occasionally with a mass or
hypoattenuated rim. ere may also be pancreato-biliary ducts with
diuse/segmental/focal duct narrowing oen with stenosis of the bile
duct. Criterion II is high levels of serum IgG or IgG4 or detection
of antibodies. Criterion III is lymphocytic inltration with brosis
and abundant IgG4+ cells on pancreatic biopsy. Criterion IV is the
presence of lymphocytic sclerosing pancreatitis in histopathology of
resected pancreas including storiform brosis, lymphocytic inltration,
periductal inammation, obliterative phlebitis, and numerous IgG4+
cells. One optional criterion is response to steroids. is suggests that
these should be tried in patients to fulll criterion I. e diagnosis
of auto-immune pancreatitis is fullled if we have criterion I+II or
criterion I + III or criterion I + II + III, or criterion IV alone [36].
e Mayo clinic’s criteria are similar to the Asian criteria. Criterion
H (histology) is periductal lymphocytic inltrates, obliterative
phlebitis, storiform brosis, lymphocytic inltrates, storiform
brosis, and abundant IgG4+ cells (> 10 HPF). Criterion I (imaging)
is a diusely enlarged gland with delayed rim enhancement and
diusely irregular attenuated pancreatic ducts. Criterion I also
includes focal pancreatic mass enlargement, focal pancreatic duct
stricture, pancreatic atrophy, pancreatic calcication, and pancreatitis.
Criterion S (serology) includes elevated serum IgG4 (normal 8-140 mg/
dl). Criterion O (other organ involvement) includes hilar/intrahepatic
biliary strictures, persistent distal biliary stricture, parotid lacrimal
gland involvement, mediastinal lymphadenopathy, or retroperitoneal
brosis. Criterion R (response to steroid therapy) includes resolution
or marked improvement of pancreatic/extrapancreatic manifestations
with steroid therapy. It is suggested that the diagnosis of AIP is fullled
if we had criterion H or criteria I + S, or a strong clinical suspicion of
AIP + criterion S and/or O + criterion R [36,37].
Anti-diabetes agents and IgG4-RD: As diabetes progresses,
eventually one or perhaps more than one injectable drugs are added
including insulin or glucagon like peptide-1 agonist (GLP-1). A recent
concern in clinical practice is how to reduce the frequency of the
injections to improve patient adherence and convenience.
e endogenously produced GLP-1 hormone is rapidly degraded
by the dipeptydil peptidase IV enzyme (DPP IV) or ltered through
the kidneys. is usually only takes three minutes [38]. e current
challenge is to protect synthetic GLP-1 from the DPP IV proteolytic
eects to prolong the half-life of the drug. Increasing the molecular size
of those agents protects them from being ltered via the kidney. Current
examples of high molecular weight GLP-1 agonists include once daily
liraglutide or albiglutide or dulaglutide or exenatide LAR once weekly.
e extension of the GLP-1 activity was attained by adding albumin in
case of albiglutide and immunoglobulin for dulaglutide. is provided
a half-life of 90 hours with a steady-state trough of up to two weeks;
dulaglutide is approved for once weekly injection [39-42].
Dulaglutide is GLP- composed of two identical disulde-linked
chemical chains. Each chain is formed with a human peptide analogue
(GLP-1) covalently attached to an Fc fragment of a modied human
immunoglobulin (IgG4). e attachment is via a linker peptide in each
chain. e aim of this special biochemical engineering is to protect GLP-
1 from deactivation by the DPP IV enzyme. is increases solubility,
reduces renal clearance, and increases the pharmacodynamics duration
[43-45].
Immunogenicity
Altered immune response is a major concern especially when new
recombinant hormones are tested in clinical trials. One very eective
weekly GLP-1 agonist is tapsoglutide, which has been pulled from the
market aer reports of severe hypersensitivity reactions [46]; 35% of
patients receiving exenatide had a low titer of anti-drug antibodies [47].
In liraglutide, 8.6% of LEAD trial patients had anti-drug antibodies
[37]. e highest incidences of anti-drug antibodies were encountered
in the duration trials of the exenatide once weekly (Bydureon) where it
reached 43-54% in dierent trials [48-50].
In the albiglutide studies, only 2.5% developed antibodies, but
these antibodies remained intact for only a short period [51]. is is
not the case in dulaglutide. e peptide portion of dulaglutide was
designed to be as high as 90% homologous to endogenous human GLP-
1. Nonetheless, immunoadhesion of the Fc protein to an end organ
molecule (receptors, an enzyme, or ligand) helps inhibit autoimmune

Citation: Bashier AM, Hari G, Abdelgadir EI (2015) Igg4-Related Disorder and Endocrine Diseases: A Review of the Literature. J Diabetes Metab 6:
631. doi:10.4172/2155-6156.1000631
Page 4 of 5
Volume 6 • Issue 12 • 1000631
J Diabetes Metab
ISSN: 2155-6156 JDM, an open access journal
and inammatory processes against it [43,52,53]. In the AWARD 1
trial—a multicenter trial comparing dulaglutide to exenatide—added
pioglitazone and metformin (n=987); dulaglutide led to antibodies in
1.8% while the exenatide-treated group developed antibodies in 48%
of the patients [53]. Another trial from Japan compared dulaglutide
to placebo (dulaglutide group n= 108 showed zero incidences of
antibodies over 12 weeks. is is, by far, considered a revolutionary
addition to the GLP-1 agonist agents.
Conclusion
IgG4-RD are newly discovered disorders associated with storiform
brosis, high serum levels of IgG4, and high IgG4/IgG ratios. Many
endocrine disorders are related to IgG4 including Riedel’s thyroiditis
as well as some cases of Hashimoto’s thyroiditis and hypophysitis
with diabetes insipidus or panhypopituitarism. IgG4-RD should be
suspected in patients with progressive thyroiditis with a mass eect and
very high antibody titers.
Competing Interests
Authors declare that they have no competing interests.
Authors’ Contributions
A B: came with the idea of the paper, shared in writing the IgG4-RD
and endocrine disorders as well as the immune system and diabetes,
edited and revised the manuscript.
G H: shared in writing the introduction edited and revised the
manuscript.
E A: shared in writing Anti-diabetes agents and IgG4-RD, edited
and revised the manuscript.
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Citation: Bashier AM, Hari G, Abdelgadir EI (2015) Igg4-Related Disorder and Endocrine Diseases: A Review of the Literature. J Diabetes Metab 6:
631. doi:10.4172/2155-6156.1000631
Page 5 of 5
Volume 6 • Issue 12 • 1000631
J Diabetes Metab
ISSN: 2155-6156 JDM, an open access journal
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Citation: Bashier AM, Hari G, Abdelgadir EI (2015) Igg4-Related Disorder
and Endocrine Diseases: A Review of the Literature. J Diabetes Metab 6: 631.
doi:10.4172/2155-6156.1000631
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