Hangzhou, 15 March Ulrich Beuers Department of Gastroenterology and Hepatology Academic Medical Center University of Amsterdam

Transcription

1 Clinical Aspects of Primary Biliary Cirrhosis Hangzhou, 15 March 2008 Ulrich Beuers Department of Gastroenterology and Hepatology Academic Medical Center University of Amsterdam

2 Epidemiology of Primary Biliary Cirrhosis Prevalence (per ) Gender (f : m) 9 : 1 Age at manifestation Hepatocyte Bile ducts PBC in China Posters # 41, 57, 60, 66, 69, 74

3 Diagnostic Criteria of Primary Biliary Cirrhosis Florid, nonsuppurative cholangitis Hepatocyte Cholestatic enzyme pattern AP, γgt Bile ducts Autoantibodies AMA (M2)

4 Clinical Findings in Primary Biliary Cirrhosis (> 50% asymptomatic at time of diagnosis) Fatigue Pruritus Abdominal discomfort Dry eye, dry mouth Xanthelasma Jaundice Osteoporosis Fat malabsorption Sherlock and Summerfield, 1979

5 Primary Biliary Cirrhosis - Associated Immune-mediated Disorders - Autoimmune thyreopathies Sjögren syndrome CREST syndrome Rheumatoid Arthritis Lupus erythematodes Fibrosing alveolitis Renal tubular acidosis Celiac disease Autoimmune hemolytic anemia Autoimmune thrombocytopenic purpura...

6 Model of Progression of Primary Biliary Cirrhosis Reversible Irreversible 100 % Bile ducts Bile duct loss Cholestasis Fibrosis Degree of severity Wiesner R Histological Stage 1. Portal inflammation 2. Periportal inflammation, ductular proliferation 3. Fibrosis 4. Zirrhosis

7 Primary Biliary Cirrhosis Pathogenesis Immune-mediated bile duct injury Gershwin & Mackay, Hepatology 2008;47:737 Aggravation of bile duct injury by hydrophobic bile acids Cholestasis with retention of hydrophobic bile acids in liver Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure

8 Primary Biliary Cirrhosis: Pathogenesis Immune-mediated bile duct injury Therapy Placebo-controlled trials Aggravation of bile duct injury by hydrophobic bile acids Cholestasis with retention of hydrophobic bile acids in liver Ursodeoxycholic acid (13-15 mg/kg/d) Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure Beuers et al., Hepatology 1998;28:1449

9 UDCA improves Transplant-free Survival in PBC Metaanalysis of randomized, placebo-controlled long-term studies Poupon 1994 Vuoristo 1995 Kilmurry 1996 Pares 2000 Jorgensen 2002 Combes 2004 Total UDCA better OR (95% CI) Placebo better Follow-up: UDCA dose: > 2 years mg/kg/d Shi et al., Am J Gastroenterol 2006;101:1529 n = 1038

10 Effect of UDCA on Survival in Early Stage (I-II) Primary Biliary Cirrhosis Probability of survival [%] Patient survival with UDCA and without LTx Estimated survival (Mayo-Score) n = Corpechot et al., Gastroenterology 2005;128:300 Survival of a control population (matched for age, gender, and time of follow-up) Time [years]

11 Effect of UDCA on Survival in Late Stage (III-IV) Primary Biliary Cirrhosis 100 Probability of survival 80 [%] n = Corpechot et al., Gastroenterology 2005;128:300 Patient survival with UDCA and without LTx Estimated survival (Mayo-Score) Time [years] 0.57 Survival of a control population (matched for age, gender, and time of follow-up) 0.48

12 Effect of UDCA on Survival in Primary Biliary Cirrhosis - Patients with good biochemical response to UDCA - Probability of survival PBC patients with good biochemical response Good responders to UDCA: Alk. phosphatase after 1 year: - decrease > 40% - normalization n = 117 Pares et al., Gastroenterology 2006;130:715

13 Potential Mechanisms and Sites of Action of UDCA in Cholestatic Liver Diseases Stimulation of hepatocellular secretion Bile acids Stimulation of cholangiocellular secretion Beuers, Nature Clin Pract Gastroenterol Hepatol 2006;3:318 Apoptosis Necrosis Antiapoptotic effects Decrease of bile cytotoxicity

14 Effect of UDCA on Survival in Primary Biliary Cirrhosis - Patients without adequate biochemical response to UDCA - Probability of survival PBC patients without adequate biochemical response n = 64 Pares et al., Gastroenterology 2006;130:715

15 AIH-PBC Overlap Syndrome AIH 8-9 % PBC ALT > 5xN IgG > 2xN or ASMA + Moderate/severe periportal lymphocytic piecemeal necrosis 2 out of 3 criteria required AP > 2 x N or GGT > 5 x N AMA + Florid bile duct lesion Beuers & Rust, Semin Liver Dis 2005;25:311 Chazouilleres et al., Hepatology 1998;28:296

16 Primary Biliary Cirrhosis: Future Therapy Pathogenesis Immunologic bile duct injury Aggravation of bile duct injury by hydrophobic bile acids Budesonide? Leuschner et al., Gastroenterology 1999; 117:918 Rautiainen et al., Hepatology 2005; 41:747 Hempfling et al., Hepatology 2003; 38:126 Cholestasis with retention of hydrophobic bile acids in liver Ursodeoxycholic acid (13-15 mg/kg/d) Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure

17 Primary Biliary Cirrhosis: Future Therapy Pathogenesis Immunologic bile duct injury Budesonide? RCT Aggravation of bile duct injury by hydrophobic bile acids Immunosuppressive agents? MMF Sirolimus Nuclear receptor agonists? Bezafibrate 6E-CDCA Statins Cholestasis with retention of hydrophobic bile acids in liver Ursodeoxycholic acid (13-15 mg/kg/d) Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis Liver failure Liver transplantation

18 Decreasing Need of Liver Transplantation in Primary Biliary Cirrhosis PBC Corpechot et al. Hepatology 2007;46:963

19 Recurrence of Autoimmune Liver Disease after Liver Transplantation AIH 22 % PBC 18 % PSC 11 % (no difference by type of primary immunosuppression) Gautam et al. Liver Transpl 2006;12:1813

20 Clinical Findings in Primary Biliary Cirrhosis Fatigue Pruritus Abdominal discomfort Dry eye, dry mouth Xanthelasma Jaundice Osteoporosis Fat malabsorption Sherlock and Summerfield, 1979

21 Fatigue in Primary Biliary Cirrhosis Daytime somnolence Hypersomnolence ESS: Epworth Sleepiness Scale n=48, each Newton et al., Hepatology 2006;44:91

22 Fatigue in Primary Biliary Cirrhosis Daytime somnolence Hypersomnolence Modafinil for treatment of daytime somnolence and fatigue in PBC Jones & Newton, Aliment Pharmacol Ther 2007;25:471 Newton et al., Hepatology 2006;44:91

23 Pruritus in Primary Biliary Cirrhosis < 70 % of patients women > men aggravated by pregnancy & estrogen treatment Sherlock and Summerfield, 1979

24 Potential Pruritogens in Primary Biliary Cirrhosis accumulate in the systemic circulation are biotransformed in the liver are secreted into bile and undergo enterohepatic cycling

25 Therapy of Pruritus in Primary Biliary Cirrhosis 1 st line : Evidence Cholestyramine (1-2 x 4 g/d, max. 16 g/d) III C 2 nd line : Rifampicin (2 x mg/d) II C 3 rd line : 4 th line : Tandon et al. Am J Gastroenterol 2007;102:1528 Naltrexone (25-50 mg/d) II C Tandon et al. Am J Gastroenterol 2007;102:1528 Sertraline ( mg/d) II C Mayo et al. Hepatology 2007;45:666 I: High quality randomized controlled studies II: Randomized controlled study, cohort or case-control studies, metaanalysis III: Descriptive studies, expert opinion, clinical experience C: Improvement in symptoms Clin Infect Dis 1994;18:421 (modified) Guidelines AASLD: Heathcote, Hepatology 2000;31:1005 (modified)

26 Refractory Pruritus in Primary Biliary Cirrhosis - Experimental Therapeutic Approaches - Albumin dialysis Plasma separation / anion absorption Nasobiliary drainage Pares et al., Am J Gastroenterol 2004;99:1105 Pusl et al., J Hepatol 2006;45:887 Beuers et al, Hepatology 2006;44:280

27 Clinical Aspects of Primary Biliary Cirrhosis Diagnosis AP, γgt AMA (M2) Florid bile duct lesion Fatigue Symptoms Pruritus Therapy Standard Future strategies PBC UDCA (13-15 mg/kg/d) Budesonide? LTx Other immunosuppressives? Nuclear receptor ligands? AIH / PBC UDCA + Azathioprin / Corticosteroids Fatigue Modafinil? Pruritus Cholestyramine Cannabinoids? Rifampicin Apheresis / Albumin dialysis? Naltrexone Nasobiliary drainage? Sertraline LTx?