HKASLD 27 th 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 600 Publications per year 500 400 300 200 100 Year
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 Typical: diffuse gland enlargement; diffuse attenuated pancreatic duct. Imaging Others: focal mass/stricture; atrophy; calcification; pancreatitis Serology Elevated serum IgG4 Other Hilar/intrahepatic strictures; persistent biliary stricture; parotid/lacrimal organs gland; mediastinal lymphadenopathy; retroperitoneal fibrosis Response Resolution/marked improvement of pancreatic/extrapancreatic to Steroid manifestation treatment 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 2% 25% 64% 32% 0% Pancreatitis Other organ 63% 75% 44% 15% 82% involvement 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 Criteria Sensitivity Specificity • ICDC for AIP 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 40 Number of patients 30 20 10 0 0 0 0 0 0 0 0 0 0 1 2 3 4 5 6 7 8 9 - - - - - - - - - 1 1 1 1 1 1 1 1 1 1 2 3 4 5 6 7 8 Age (years) Presenting symptom % (116 patients) Obstructive Jaundice 74% Abdominal pain 36% Acute pancreatitis 3%
IgG4-related disease UCL + Oxford experience Ocular 2% Neurological 3% Salivary Glands 19% Arthropathy 6% Thyroid 8% Renal 11% Pulmonary 6% Retroperitoneal Liver/biliary Fibrosis 4% 58% Diffuse lymphadenopathy 43% IBD 9% Pancreas 91% N=116 Vitiligo, Coeliac, psoriasis, alopecia, PMR 1% Extra-HPB disease in 36% Huggett M et al Am J Gastroenterol. 2014;109:1675-83
What have we learnt? • No single diagnostic test for IgG4-RD
How do we make the diagnosis? • Clinical presentation • Disease associations Always a • combination Laboratory of features • Imaging • Pathology
Serum IgG4 • ↑ I gG4 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
Multi-organ involvement in IgG4-RD Pituitary Biliary Pancreatic Renal, retroperitoneal
Pathological features of IgG4-related disease Pancreas H + E • 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 immunostain • IgG4+ plasma cells: IgG+ plasma cells ratio > 50% Deheregoda M et al Clin Gastro Hep 2006 • High yield from duodenal papilla Moon SH et al GIE 2010
HISORt diagnostic criteria for IgG4-SC Stricture(s) of intra-hepatic, proximal extra-hepatic, or intra- pancreatic ducts, with: A B C Previous Classical Two or more of: • Elevated serum IgG4 pancreatic/biliary imaging resection or core findings of • Suggestive pancreatic imaging biopsy of AIP + • Other organ involvement pancreas showing elevated • Biliary Bx: > 10 IgG4+ cells/HPF features of serum IgG4 Combined with following findings AIP/IgG4-SC after 4 weeks of steroids: • Markedly improved biliary Definite diagnosis strictures allowing stent removal of IgG4-SC • Liver enzymes < x2 ULN • Decreasing IgG4 + CA19-9 Ghazale et al Gastroenterology 2008:134:706-715
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 Nakazawa T, et al Pancreas. 2006;32:229. Type 1 Type 2 Type 3 Type 4 Common Differential Diagnoses • Pancreatic Ca • PSC • PSC • PSC • CCA • CCA • CCA • AIP • Acute/chronic pancreatitis
Cholangiogram in Type 2-4 IgG4-SC v PSC and CCA Factors favouring diagnosis IgG4-SC v CCA Biliary patency despite concentric Complete biliary obstruction strictures 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 ” IgG4+ plasma cells Diagnosis “ IgG4-associated Cholangitis ”
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 2 months steroids steroids
IgG4-sclerosing cholangitis Steroid response Pre-steroids 3/12 post-steroids
Sequential MRCPs of remission and relapse in IgG4-SC 18 months At diagnosis (0 months) 6/12 Pred Off steroids 30 months 16/12 28 months Pred + AZA
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 Sah RP et al Gastroenterology 2010;139:140-8 • 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
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 % of cohort Organ dysfunction 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
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