HKASLD 27th Annual Scientific Meeting 2014
IgG4-related HPB disease – an
update on an emerging condition
Dr George Webster
University College London and
Royal Free Hospitals
London, UK
Clinical Overview
• Background
• Clinical presentation
• Diagnostic criteria
• Clinical mimics
• Management
• Disease course
Autoimmune Pancreatitis (AIP) +
IgG4-related disease
Publications 2000-2012
Year
Public
ations p
er
year
300
400
100
200
500
600
What have we learnt?
• Autoimmune Pancreatitis (AIP) is a
Worldwide disease and we’ve
missed/misdiagnosed it for years
“AIP – is it relevant in the West?” Varadarajulu, S., Cotton, P. B. Gastroenterology 2003
What have we learnt?
• AIP is one component of a multisystem IgG4-related fibroinflammatory disease
• ‘IgG4-related disease’ (IgG4-RD) Stone JH et al N Engl J Med 2012;366:539-51
HISORt criteria for AIP
Category Criteria
Histology At least 1 of following:
• Periductal lymphoplasmacytic infiltrate with obliterative phlebitis
and storiform fibrosis
• Lymphoplasmacytic infiltrate with > 10 IgG4+ plasma cells/HPF
Pancreatic
Imaging
Typical: diffuse gland enlargement; diffuse attenuated pancreatic duct.
Others: focal mass/stricture; atrophy; calcification; pancreatitis
Serology Elevated serum IgG4
Other
organs
Hilar/intrahepatic strictures; persistent biliary stricture; parotid/lacrimal
gland; mediastinal lymphadenopathy; retroperitoneal fibrosis
Response
to Steroid
treatment
Resolution/marked improvement of pancreatic/extrapancreatic
manifestation
Chari et al Clin Gastroenterol Hepatol 2006; 4: 1010-6.
Non-histological proven AIP Worldwide
Japan USA Germany Italy UK
N 127 28 36 87 28
% male 83% 79% 42% 62% 82%
Jaundice 61% 79% 14% 44% 64%
Pain 13% 50% 33% 20% 18%
Acute
Pancreatitis
2% 25% 64% 32% 0%
Other organ
involvement
63% 75% 44% 15% 82%
IBD 3% 11% 8% 30% 14%
↑ IgG4 91% 85% 59% 50% 54%
Kamisawa T et al Pancreas 2011 N=697 Worldwide
Within the spectrum of IgG4-RD
• Kuttner’s tumour
• Mikulicz syndrome
• Autoimmune pancreatitis
• Retroperitoneal fibrosis
• Inflammatory pseudotumour
• Inflammatory aortic aneurysm/aortitis
• Reidel’s thyroiditis
• Eosinophilic angiocentric fibrosis
• Idiopathic hypocomplementemic tubulointerstitial nephritis
Stone JH et al N Engl J Med 2012;366:539-51
UK Prospective Cohort
• Two site prospective data collection (UCL and Oxford)
• All patients referred from 2003 to 2013 and diagnosed with IgG4-related
AIP (type I AIP) or IgG4-related sclerosing cholangitis (IgG4-SC)
• Median FU 33.6 months (range 6.8-132.2)
• Diagnostic criteria used:
• HISORt in AIP and IAC
• ICDC for AIP Criteria Sensitivity Specificity
Japanese 2002/6 80% 89%
Korean 2007 89% 89%
Asian 2008/10 82% 89%
HISORt 2006/8 92% 97%
ICDC 2011 95.1% 100%
Baseline Characteristics
Age Demographics of cohort
Age (years)
Num
be
r o
f p
atien
ts
1-10
11-2
0
21-3
0
31-4
0
41-5
0
51-6
0
61-7
0
71-8
0
81-9
0
0
10
20
30
40
Presenting symptom % (116 patients)
Obstructive Jaundice 74%
Abdominal pain 36%
Acute pancreatitis 3%
Pancreas 91%
Renal 11%
Liver/biliary
58%
Salivary
Glands 19%
Retroperitoneal
Fibrosis 4%
Neurological 3%
Diffuse
lymphadenopathy
43%
Pulmonary 6%
IBD 9%
IgG4-related disease UCL + Oxford experience
N=116
Extra-HPB disease
in 36%
Arthropathy 6% Thyroid 8%
Vitiligo, Coeliac, psoriasis,
alopecia, PMR 1%
Huggett M et al Am J Gastroenterol. 2014;109:1675-83
Ocular 2%
What have we learnt?
• No single diagnostic test for
IgG4-RD
How do we make the
diagnosis?
• Clinical presentation
• Disease associations
• Laboratory
• Imaging
• Pathology
Always a
combination
of features
• ↑ IgG4 initially reported >95% sensitive and specific
for IgG4-RD/AIP
• Recent studies report elevated IgG4 in 63-82%.
• Raised tissue IgG4 in presence of normal serum
levels Deheregoda M et al Clin Gastro Hepatol
2006
• ↑ serum IgG4 in 3-10% of patients with non-AIP
pancreatic disease (including pancreatic tumour).
Ghazale A et al. Am J Gastroenterol 2007
Serum IgG4
Multi-organ involvement in IgG4-RD
Biliary
Renal, retroperitoneal
Pituitary
Pancreatic
• Similar pathological features in all
involved tissues
• Lymphoplasmacytic infiltrate
• Storiform (matted/whorled) fibrosis
• Obliterative phlebitis
• Eosinophil infiltrate
• 10-50 IgG4+ plasma cells per HPF
• IgG4+ plasma cells: IgG+ plasma
cells ratio > 50%
• High yield from duodenal papilla
Pathological features of IgG4-related disease
Moon SH et al GIE 2010
Deheregoda M et al Clin Gastro Hep 2006
Pancreas H + E
IgG4 immunostain
HISORt diagnostic criteria for IgG4-SC
Stricture(s) of intra-hepatic, proximal extra-hepatic, or intra-
pancreatic ducts, with:
Previous
pancreatic/biliary
resection or core
biopsy of
pancreas showing
features of
AIP/IgG4-SC
Classical
imaging
findings of
AIP +
elevated
serum IgG4
Two or more of:
•Elevated serum IgG4
•Suggestive pancreatic imaging
•Other organ involvement
•Biliary Bx: > 10 IgG4+ cells/HPF
Combined with following findings
after 4 weeks of steroids:
•Markedly improved biliary
strictures allowing stent removal
•Liver enzymes < x2 ULN
•Decreasing IgG4 + CA19-9
Definite diagnosis
of IgG4-SC
Ghazale et al Gastroenterology
2008:134:706-715
A B C
What have we learnt?
• IgG4-RD mimics cancer:
– AIP/IgG4-related pancreatitis v pancreatic cancer
– IgG4-sclerosing cholangitis v cholangiocarcinoma
IgG4-SC in patients resected for presumed
malignant bile duct strictures
Erdogan D et al. Br J Surg 2008:95;727-34
• 185 resections; 1984-2005
• 32/185 (17%) benign histology
• 15/32 (47%) lymphoplasmacytic
infiltrate
• IgG4+ plasma cells
• ie. Nearly 50% of ‘benign’ resections
likely to be due to IgG4-RD.
• Emphasises need for preoperative
histology (eg Cholangioscopy)
Cholangiographic classification of IgG4-SC
Type 1 Type 2 Type 3 Type 4
Common Differential Diagnoses
• Pancreatic Ca
• CCA
• AIP
• Acute/chronic
pancreatitis
• PSC
• CCA
• PSC
• PSC
• CCA
Nakazawa T, et al Pancreas. 2006;32:229.
Cholangiogram in Type 2-4 IgG4-SC v PSC and CCA Factors favouring diagnosis
IgG4-SC v CCA
Biliary patency despite concentric strictures
Complete biliary obstruction
Multifocal strictures
Mild upstream dilatation
IgG4-SC v PSC
Long, segmental biliary strictures Band-like strictures and beading
Low bile duct stricture Pseudodiverticulum
Peripheral duct pruning
Nakazawa et al Pancreas 2005
Oh et al J Gastroenterol Hepatol 2010
Tabata et al Gut Liver 2013
“Cholangiocarcinoma – need
histological diagnosis”
Diagnosis
“IgG4-associated Cholangitis”
IgG4+ plasma
cells
What have we learnt?
• Response to steroids may be dramatic,
but relapse is common
Management of IgG4-RD
• No randomised data on role of steroids
• Rapid, sometimes dramatic, improvement within 4/52 of starting steroids (eg Prednisolone 40mg OD)
• Clinical relapse after initial course of steroids in 24-68%.
• Treatment of relapse poorly defined:
• Maintenance steroids
• Steroids + Azathioprine
• Rituximab
Response to steroids Pancreatic Anatomy
• Consistent resolution in pancreatic mass
• Improvement in pancreatic duct stricturing
Treatment response in IgG4
sclerosing cholangitis
Patient 2 Patient 6
3 months
steroids
2 months
steroids
.
IgG4-sclerosing cholangitis Steroid response
Pre-steroids 3/12 post-steroids
Sequential MRCPs of remission
and relapse in IgG4-SC
6/12 Pred
18 months At diagnosis (0 months)
Off steroids
16/12
Pred + AZA
28 months 30 months
Predictors of relapse
• Diffuse pancreatic enlargement
• Extrapancreatic biliary disease
(IgG4-SC)
• Other organ involvement
• Genetic factors (eg substitution of
aspartic acid at position 57 of DQβ1
gene)
• Lack of maintenance steroids
• High pre-treatment serum IgG4, and
failure to normalise?
• Absence of surgical resection Chari ST et al Gastroenterology2008;134: :625-8
Park DH et al Gastroenterology 2008;134:440-8
Sandanayake et al Clin Gastro Hepatol 2009;7:1089-96
Sah RP et al Gastroenterology
2010;139:140-8
What have we learnt?
• Clinical course of Ig4-RD is poorly
defined, difficult to predict, but may
progress to end-stage organ failure
High risk of Complications
Organ dysfunction % of cohort
Cirrhosis and liver failure 5%
Exocrine pancreatic insufficiency 53%
Endocrine pancreatic insufficiency - Diabetes 37%
Renal impairment - stage 2-4 CKD 12%
PV/SV thrombosis 9%
Liver transplant 0.9%
Huggett M et al Am J Gastroenterol. 2014 Oct;109(10):1675-83
Increased risk of Any Cancer
• 7.7% (9/116) diagnosed with cancer at or after diagnosis
• Increased risk of ANY CANCER at or after diagnosis
OR 2.25 (CI 1.12-3.94) p=0.018
• 3 patients with pancreato-biliary carcinomas
+ 3.4% (4/116) diagnosed with cancer in 3 years prior to
diagnosis
Huggett M et al Am J Gastroenterol. 2014 Oct;109(10):1675-83
Clinical Overview of IgG4-related disease
Summary
• IgG4-SC is one component of a multisystem IgG4-related
disease
• IgG4-SC may mimic PSC or cholangiocarcinoma
• Established diagnostic criteria incorporate clinical,
laboratory, radiographic, and pathological parameters
• Steroid therapy may be associated with prompt clinical and
cholangiographic improvement. Disease relapse may
occur, and role of long-term immunosuppression remains
uncertain.
• Long term clinical course, including other organ dysfunction
+ cancer, requires particular attention
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