Enterprise Interest Nothing to declare

Enterprise Interest Nothing to declare

29 th European Congress of Pathology, Amsterdam, Sept 2 nd -6 th, 2017 What s new in alcohol-mediated liver injury? Carolin Lackner Institute of Pathology Medical University of Graz Austria

Burden of disease due to alcohol misuse Alcohol accounts for 6.5 % of all deaths (men:11%, women: 1.8%) o 50% of all deaths from cirrhosis 11.6% of all disability-adjusted life years (men: 17.3 %, women: 4.4%) ~50% of all liver transplantations in Europe Alcohol-related mortality is disproportionally high in young European males (25%) and females (10%) Rehm J, Lancet 2009 WHO Global Status Report on Alcohol and Health 2014

Disparities between research & burden in liver diseases 6.7 Attention-to-Burden Index, ABI 1.7-1.2-9.7 Ndugga N, BMJ Open 2017

Normal liver Types of alcoholic liver disease Steatosis Fibrosis Decompensation: 20-40% Clin AH 28d mortality: 35% Cirrhosis 80-90% HCC 20-40% Alcoholic hepatitis 8-20% 8-20% Bataller R, Semin Liver Dis 2015

Clinical presentation of ALD Severely ill Jaundiced Cirrhotic Decompensated Early/compensated No/mild symptoms Low 30d survival rate High 30d survival rate

Histology in the management of decompensated ALD Prognosis assessment MDF/MELD/ABIC/GAHS SHORT-TERM mortality risk HIGH LOW Steroids indicated: Liver biopsy Standard care Diagnosis/exclusion of AH Prognosis, early detection of infection/aclf Response to steroids

Histological diagnosis of AH

Alcoholic hepatitis Steatosis Ballooning Lobular inflammation

Fibrosis progression in ALD Stage 21 34 CAB

Histological definitions of alcoholic hepatitis Fibrosis Lob inflam PMC Lob.Inflam mononucl & PMC Mallory- Denk bodies Necrosis Ballooning Steatosis International Group Lancet 1981 MacSween RMN Semin Liver Dis 1986 Periven. Lefkowitch J Clin Liver Dis 2005 Brunt B MacSweens Pathology of the Liver

Histological confirmation of clinical AH Reference Altamirano J Gastroenterology 2014 Spahr L BMC Gastroenterol 2011 Clinical AH n AH on histology n (%) 181 121 (67) 234 211 (91) Dominguez A Am J Gastroenterol 2008 Mookerjee R/Lackner C J Hep 2011 Bissonnette J Hepatology 2017 131 115 (88) 68 34 (50) 83 / 68 46 (55) / 48 (71)

Histological diagnoses in patients with clinical AH Bissonnette J, Hepatology 2017 Cohort n AH on histology Test 83 46 Validation 68 48 Histological diagnosies in patients without AH on histology Alc cirrhosis : 35 Steatosis + fibrosis: 1 Susp. BSEP mutation: 1 Viral/drug induced chronic hepatitis: 1 Alc cirrhosis/fibrosis: 14 Alc foamy degeneration: 2 Hypoxic hepatitis: 3 Infectious mononucleosis: 1

Histological factors associated with infection & prediction of short-term mortality

Cholestasis Ductular CH Canalicular CH

Predictors of short-term outcome in ALD Author Reference n Diagnosis Follow up Outcome Infection Katoonizadeh A/ Laleman W, Gut 2010 54 ACLF 48 hr Age, SIRS Ductular CH, MDB SIRS Ductular CH Spahr L, BMC Gastroent 2011 163 Clin AH, No sepsis 90 d Age, MDF Canalicular CH Mookerjee R/Lackner C, J Hep 2011 68 Decomp ALD +/-SIRS 28 d SIRS AH grade SIRS neg pat. Canalicular CH Altamirano J, Gastroenterol 2014 121 Clin&hist AH 90 d Fibrosis Megamitochondria CH, PMN Canalicular/ Ductular CH

Altamirano J, Gastroenterology 2014 ALCOHOLIC HEPATITIS HISTOLOGIC SCORE: AHHS

Role of histology in the management of early/compensated ALD? Asymptomatic or oligosymptomatic Frequently overlooked condition Poorly characterized Utility of long-term mortality predictors Frequent In Austria: 160-320 000 Guide intervention (abstinence councelling) people to prevent at risk? fibrosis progression, decompensation & complications

Decompensation PREVENTABLE!! Early/compensated ALD

Predictors of long-term outcome in ALD Author Reference Pessione F Liver Int 2003 Cortez-Pinto H Dig Dis Sci 2003 n Patients Follow up 122 Cirrhosis 5 yr 82 Clinical AH 12 yr Prognostic factors Age, CPS,GI-bleeding, HBV, HCV, smoking, alcohol abuse AH Mallory-Denk bodies Septal fibrosis / cirrhosis Elphick DA Am J Gastroenterol 2007 41 Biopsy within 1 mt of decomp 2 yr CPS, MDF Masson S Liver Int 2013 134 Septal fibrosis & Cirrhosis 15 yr Alcohol abuse, smoking, age Bilirubin

Predictors of long-term mortality in ALD Early/compensated (n=60) Decompensated (n=132) Fibrosis stage F3-4 0.007 Pericell fibrosis Sex Bilirubin INR 52% of cases P Present Female p 0.002 0.019 <0.001 <0.001 Variables entered Fibrosis stage, ductular reaction, ASH abstinence, INR, albumin, platelet count Variables entered Pericellular fibrosis, canalicular cholestasis, ductular cholestasis, ASH, abstinence, sex, bilirubin, INR, albumin, leukocyte count, platelet count, sodium Lackner C, Spindelboeck W, J Hep 2017

What s new in alcoholic liver disease? Conclusion Histology is an important guide in the management of ALD Decompensated Histological confirmation of clinical AH selects patients for steroid treatment Ductular/canalicular cholestasis are evolving early markers of infection and sepsis Early/compensated Massively understudied but very frequent liver disease High prevalence of stage 3 & 4 fibrosis (apprx. 50%) Histological fibrosis stage may be the most important independent factor for prediction of long-term outcome Early diagnosis is pivotal to prevent disease progression