update on an emerging condition Dr George Webster University - - PowerPoint PPT Presentation

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 george.webster@uclh.nhs.uk

Clinical Overview

• Background
• Clinical presentation
• Diagnostic criteria
• Clinical mimics
• Management
• Disease course

Autoimmune Pancreatitis (AIP) + IgG4-related disease

Publications 2000-2012

Year Publications per 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

• rgans

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) Number of patients

1

• 1

1 1

• 2

2 1

• 3

3 1

• 4

4 1

• 5

5 1

• 6

6 1

• 7

7 1

• 8

8 1

• 9

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

• f 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

• f 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

• ccur, and role of long-term immunosuppression remains

uncertain.

• Long term clinical course, including other organ dysfunction

+ cancer, requires particular attention