Current Concepts in the Management and Treatment of PBC & PSC Michael A Heneghan, MD, MMedSc, FRCPI. Institute of Liver Studies, King s College Hospital, London
A family affair? Central vein Hepatocytes Portal triad Granulomatous lymphocytic cholangitis PBC AIH Small duct SC Periductal onionskin fibrosis Large duct SC Lympho-plasmacytic infiltrate Biliary strictures and dilatation Duodenum Hirschfield; BMJ 2009
PBC AIH PSC AIP/IgG4RD Examples of Presentation NON-SPECIFIC Asymptomatic cholestasis Fatigue/Pruritus Asymptomatic transaminitis Jaundice, arthralgia Asymptomatic Cholangitis Abdominal pain Diabetes Jaundice Pancreatic mass Fleeting cholangiopathy Specific Investigations NON-SPECIFIC POOR TREATMENT OUTCOME PREDICTORS Anti-mitochondrial antibodies (M2 fraction) Liver biopsy showing active granulomatous duct lesions Raised globulins Autoantibodies (ANA/SMA/LKM) Liver biopsy showing interface hepatitis and lymphoplasmacytic infiltrate Cholangiography Liver biopsy showing periductal sclerosis Elevated IgG4 levels Pancreatic imaging changes Cholangiopathy Retroperitoneal fibrosis Typical histological or radiological appearance DESCRIPTIVE Untreated natural history CONCERNING Medical intervention NON-SPECIFIC Granulomatous cholangitis Hepatitis Periductal sclerosis Sclerosing cholangitis Stable disease in some Progressive portal hypertension and/or chronic liver failure Ursodeoxycholic acid CHINESE HERBAL REMEDY Mild disease in some Liver failure (acute or chronic with portal hypertension) Prednisolone and Azathioprine EFFECTIVE BUT INEXACT Cholangitis Portal hypertension Biliary cirrhosis, portal hypertension and liver failure No proven therapy CAREER WAITING TO BE MADE Relapsing and remitting course Chronic pancreatitis Secondary biliary cirrhosis Prednisolone ATYPICAL AUTOIMMUNITY
Using GWAS to identify genetic predisposition in hepatic autoimmunity Many Genetic associations of PBC, AIH, PSC shared with other autoimmune disorders Pleiotropy Some loci implicated in multiple disorders Webb GJ J Autoimmun 2015
Fig. 2 Genetic overlap between PSC and IBD 163 IBD Loci 16 PSC Loci (Includes independent MHC Signals) Journal of Hepatology 2013 59, 571-582DOI: (10.1016/j.jhep.2013.03.015) Boberg et al. J Hepatol 2013
Importance of IL-2 Pathway: From GWAS
Total make up of risk in PSC made up of uncertain contributions
Relative Sibling risk of selected AID s Disease Relative sibling risk Primary Sclerosing Cholangitis 9 39 Crohn's disease 5 35 Type I diabetes mellitus 15 Primary biliary cirrhosis 10 Psoriasis 4 12 Rheumatoid arthritis 5 10 Ulcerative colitis 6 9 Ulcerative colitis in PSC siblings 8
November 2015 Nomenclature change What's in a name? that which we call a rose, By any other name would smell as sweet;
Fig. 2 Incidence of PSC & PBC per 100,000 Journal of Hepatology 2012 56, 1181-1188DOI: (10.1016/j.jhep.2011.10.025) Boonstra et al. J Hepatol 2012;56:1181-8.
Fig. 3 Prevalence of PSC & PBC per 100,000 Journal of Hepatology 2012 56, 1181-1188DOI: (10.1016/j.jhep.2011.10.025) Boonstra et al. J Hepatol 2012;56:1181-8.
Fig. 4 Temporal trends in PBC prevalence. Boonstra et al. J Hepatol 2012;56:1181-8. Journal of Hepatology 2012 56, 1181-1188DOI: (10.1016/j.jhep.2011.10.025)
Criteria to define response to UDCA in PBC Duration of response Origin Decrease in alkaline phosphatase to <2 times ULN Decrease in alkaline phosphatase 40% from baseline or to normal value Decrease in alkaline phosphatase to <3 times ULN, decrease in aspartate aminotrasferase to <2 times ULN, and normal bilirubin 6 months Mayo Clinic 1 year Spanish 40 1 year Paris I 61 59 and 60 Normalisation of bilirubin or albumin 1 year Dutch 62 Decrease in alkaline phosphatase to <1 67 times ULN Decrease in alkaline phosphatase to <1 5 times ULN or aspartate aminotrasferase <1 5 times ULN, and normal bilirubin 2 years Toronto 63 1 year Paris II 64
Potential Surrogate end-points in PSC Number of hard endpoints too low Level 1 Death/Liver Transplant/Cirrhosis Complications Requires >2500 patient years of follow-up Liver Biopsy Alk Phos Level 2 Transient Elastography Supplemented by MRI/ELF Testing Ponsioen et al. Hepatology 2015
Potential Therapeutic Targets in PBC Nuclear receptor target Farnesoid X receptor Peroxisome proliferator-activated receptor α Vitamin D receptor Membrane receptor target Fibroblast growth factor 4 G-protein-coupled BA receptor TGR5 Apical sodium bile salt transporter Obeticholic acid Bezafibrate, fenofibrate Vitamin D Fibroblast growth factor 19, fibroblast growth factor 19 analogue NGM 282 TGR5 agonist Int-777 Apical sodium bile salt transporter inhibitors
Figure 3 Impact of failure to respond in PBC. Mayo Dutch Combination of Mayo & Dutch Criteria Laemmers et al. Gastroenterology 2014;147:1338-49.
Figure 1 Obeticholic Acid in UDCA non-responsive patients Hirschfield et al. Gastroenterology 2015;148:751-61.
Figure 2 Effect of OCA in DB study & extension Hirschfield et al. Gastroenterology 2015;148:751-61.
Figure 4 Pruritus severity in PBC patients as % of patients Double Blind Phase Open Label Extension Phase Gastroenterology 2015 148, 751-761.e8DOI: (10.1053/j.gastro.2014.12.005)
Demographic and Clinical Characteristics of the Participants at Baseline. (POISE Study Group) Nevens F et al. N Engl J Med 2016;375:631-643.
Primary Composite End Point in the Double-Blind and Open- Label Extension Phases, According to Trial Group. Nevens F et al. N Engl J Med 2016;375:631-643.
Alkaline Phosphatase and Total Bilirubin Levels in the Double- Blind and Open-Label Extension Phases Nevens F et al. N Engl J Med 2016;375:631-643.
Farnesoid X Receptor Activation and Plasma Bile Acid Levels in the Double-Blind Phase, According to Trial Group. Nevens F et al. N Engl J Med 2016;375:631-643.
Nevens F et al. N Engl J Med 2016;375:631-643. Incidence of Adverse Events of > 10%
Combined UDCA and fenofibrate in PBC patients with incomplete UDCA response may improve outcomes Incomplete response defined by Toronto Criteria Failure of Alk Phos < 1.67 X Normal Cheung et al. AP&T 2015
Decompensation free and transplant-free survival in patients treated with FF & UDCA v UDCA Cheung et al. AP&T 2015
PSC: greatest need in Hepatology Symptomatic at presentation Asymptomatic at presentation Transplantation-free survival (+95% Cl) for 211 patients with PSC Journal of Hepatology (2009) 158 164
Liver Tx free survival Small duct vs. Large duct PSC Bjornsson, et al., Gastroenterol 2008;134:978
Prevalence of PSC in UC World J Gastroenterol. 2008 January 21; 14(3): 331 337.
Are the days of UDCA over? Anti-cholestatic effects Stimulate BA and organic Anion secretion at hepatocyte level Stimulates Biliary HCO3- Secretion Stablisation of a biliary HCO3- umbrella
The Biliary HCO3- Umbrella
RCT: UDCA (23mg/kg/d) vs Placebo in PSC p=0.368 Olsson et al., Gastroenterol 2005;129:1464
High dose UDCA vs Placebo HEPATOLOGY, Vol. 50, No. 3, 2009
Still relatively few patients studied HEPATOLOGY, Vol. 50, No. 3, 2009
Risk Factors for Neoplasia in Inflammatory Bowel Disease Patients With Pancolitis Am J Gastroenterol. 2010
Cumulative colon cancer risk Cumulative risk (95% CI) of colorectal cancer for 211 patients with PSC with (----- ) or without ( ) concurrent IBD. Journal of Hepatology (2009) 158 164
Dominant strictures and IBD No dominant stenosis Dominant stenosis Journal of Hepatology Volume 53, Issue 2, August 2010, Pages 313-317
What do I do Annually/Semi-Annually? Bloods: DISEASE SEVERITY Bilirubin, INR, Platelets, Creatinine, Albumin ALP, ALT, IgG Discuss UDCA: DISEASE MODIFICATION Bit of a saga but Give ciprofloxacin prescription: PRAGMATIC MANAGEMENT Preventative strategies: CHRONIC DISEASE Imaging/Colonoscopy: PRE-MALIGNANT DISEASE Annual/Semi-annual imaging (ultrasound) AFP/CA19.9 Gallbladder malignancy Low threshold for cholecystectomy Cirrhosis Hepatocellular carcinoma surveillance Variceal surveillance Colonoscopy if IBD every 12 months The IBD of PSC is not classic IBD Bone Density 2-3 yearly
What don t I do Annual MRCP Will offer periodic MRCP to help estimate disease progression but not routine screening CA19.9 monitoring (Understand limitations) Elevated when jaundiced Lewis Antigen (Non-secretors) produce 0/ very low levels Routine ERCP If new jaundice then consider intervention Refer for transplant until they need one Diagnose overlap syndromes unless obvious
Take home messages Distinct chronic inflammatory and progressive biliary diseases Large bile duct inflammatory and fibrosing cholangitis Auto-inflammatory disease Contrasting environmental and genetic risk factors to PBC New genetic discoveries provide novel insights into disease mechanisms and herald disease-specific therapy