igg4-related hpb disease an update on an emerging condition · aneurysm/aortitis •reidel’s...

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

[email protected]

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


• 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%


• 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


• 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


• 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


• 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

igg4-related hpb disease an update on an emerging condition · aneurysm/aortitis •reidel’s...

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