XVII JORNADAS DE AVANCES EN HEPATOLOGÍA
18-19 Mayo 2018, Málaga
“Fallo hepático agudo sobre crónico: prevención y tratamiento ”prevención y tratamiento ”
Pere GinèsServei d’Hepatologia, Hospital Clínic
Barcelona
Disclosures
Ferring Pharmaceuticals: Advisory Board & ConsultancyMallinckrodt: Consultancy
Martin Pharmaceuticals: ConsultancyGrifols S.A: Research Funding
Novartis: Advisory Board & Consultancy
1. Definition and Rationale
2. Clinical Pattern
3. Alterations in immune function and inflammation
ACUTE-ON-CHRONIC LIVER FAILURE
inflammation
4. Prevention
5. Management
1. Definition and Rationale
2. Clinical Pattern
3. Alterations in immune function and inflammation
ACUTE-ON-CHRONIC LIVER FAILURE
inflammation
4. Prevention
5. Management
ACUTE KIDNEY INJURY INFLUENCES MORTALITY RELATED TO LIVER FAILURE IN CIRRHOSIS
Pro
babi
lity
of d
eath
at 3
mon
ths
0.5
1.0
0.9
0.8
0.7
0.6n=300
Fagundes C et al., J Hepatol 2012
Pro
babi
lity
of d
eath
at 3
mon
ths
0.4
0.3
0.2
0.1
0.0
0 20 25 30155 10
Serum bilirubin (mg/dL)
No AKIAKI
1. Definition and Rationale
2. Clinical Pattern
3. Alterations in immune function and inflammation
ACUTE-ON-CHRONIC LIVER FAILURE
inflammation
4. Prevention
5. Management
3
4
5
6
15
20
25
30
35
2
3
4
30
40
50
60
70
80
ACLF ON COMPENSATED CIRRHOSISOrgan function and CLIF-C-ACLF Score
Bilirubin INR & Creat. CLIF-C-ACLF OF(n)
0
1
2
0
5
10
15
0
1
0
10
20
30
ACLF ON DECOMPENSATED CIRRHOSISOrgan function and CLIF-C-ACLF
1
2
3
4
5
10
15
20
25
1
2
3
10
20
30
40
50
60
Bilirubin INR, Creat. OF(n)CLIFC-ACLF
00
5
00
10
1. Definition and Rationale
2. Clinical Pattern
3. Alterations in immune function and inflammation
ACUTE-ON-CHRONIC LIVER FAILURE
inflammation
4. Natural history. Outcome
5. Management
ACUTE-ON-CHRONIC LIVER FAILURESIRS, Multiogran Failure, and survival
Michelena et al. Hepatology, 2015
CytokineAcute decompensation without
ACLFn=29
ACLFn=26
P AUCROC (95% IC)
VCAM-1 (ng/mL) 1263 (1063-2023) 2399 (1791-3501) <0.00 01 0.780 (0.655-0.905)VEGF-A (pg/mL) 74 (49-169) 201 (112-252) 0.001 0.771 (0 .644-0.897)
Fractalkine (pg/mL) 4.4 (3.6-6.4) 6.7 (5.5-8.2) 0.001 0. 756 (0.625-0.887)MIP-1α (pg/mL) 3.7 (3.0-5.8) 5.7 (4.9-12.0) 0.002 0.749 (0.61 5-0.882)
RANTES (pg/mL) 396 (143-1124) 137 (71-208) 0.002 0.739 ( 0.603-0.874)Eotaxin (pg/mL) 36 (29-51) 58 (38-69) 0.004 0.727 (0.58 9-0.864)
IP-10 (pg/mL) 38 (29-54) 69 (43-101) 0.004 0.724 (0.580 -0.868)GM-CSF (pg/mL) 46 (43-52) 42 (40-45) 0.008 0.709 (0.564 -0.854)
IL-1β (pg/mL) 4.3 (3.2-5.6) 2.6 (1.8-3.7) 0.012 0.698 (0.554-0.842)
ACUTE-ON-CHRONIC LIVER FAILURE Plasma levels of cytokines
IL-1β (pg/mL) 4.3 (3.2-5.6) 2.6 (1.8-3.7) 0.012 0.698 (0.554-0.842)IL-2 (pg/mL) 21 (15-36) 15 (4-22) 0.015 0.691 (0.546-0. 836)
ICAM-1 (ng/mL) 1315 (993-2393) 1831 (1317-2944) 0.087 0 .635 (0.485-0.784)MCP-1 (pg/mL) 18 (12-33) 27 (16-45) 0.086 0.635 (0.487- 0.784)
PDGF-BB (pg/mL) 99 (37-245) 47 (16-121) 0.157 0.611 (0.459-0.763)IFN-γ (pg/mL) 13 (9-28) 9 (5-21) 0.177 0.606 (0.452-0.760)IL-6 (pg/mL) 45 (19-81) 59 (30-233) 0.175 0.607 (0.455-0.758)IL-7 (pg/mL) 1.6 (1.5-1.7) 1.5 (1.5-1.7) 0.241 0.592 (0.436-0.748)
MIP-1β (pg/mL) 122 (95-160) 114 (77-160) 0.273 0.586 (0.432-0.740)IL-10 (pg/mL) 2.1 (0.7-4.4) 1.1 (0.08-5.0) 0.300 0.582 (0.425-0.738)
G-CSF (pg/mL) 36 (22-65) 49 (22-83) 0.680 0.532 (0.376-0.689)IL-13 (pg/mL) 4.8 (4.5-7.8) 4.8 (4.5-5.4) 0.495 0.446 (0.293-0.599)
Solé et al. Sci Rep 2016
Enriched processes/pathways Num Cytokines involved Types of cytokines P
Cell movement of monocytes 9Eotaxin, MIP-1 α, RANTES, GM-CSF, Fractalkine, IP-10, IL1- β,IL-
2,VCAM-18.44e-20
Leukocyte migration 10Eotaxin, MIP-1 α, RANTES, GM-CSF, Fractalkine, IP-10, IL-1 β, IL-2,
VCAM-1,VEGF-A1.82e-18
Migration of phagocytes 8 MIP-1 α, RANTES, GM-CSF, Fractalkine, IP-10, IL-1 β, IL-2, VCAM-1 3.93e -17
Chemotaxis of mononuclear leukocytes
8 Eotaxin, MIP-1 α, RANTES, GM-CSF, Fractalkine, IP-10, IL-1 β, IL-2 1.25e-16
Chemotaxis of monocytes 7 Eotaxin, MIP-1 α, RANTES, GM-CSF, Fractalkine, IP-10, IL-1 β 1.45e-15
Migration of monocytes 6 MIP-1 α, RANTES, GM-CSF, Fractalkine, IL-2,VCAM-1 7.58e -14
Migration of mononuclear leukocytes 7 MIP-1 α, RANTES, GM-CSF, Fractalkine, IP-10, IL-2, VCAM-1 3 .45e-13
ACUTE-ON-CHRONIC LIVER FAILURESystemic inflammation. Functional enrichment analysis
Cell movement of natural killer cells 5 MIP-1 α, RANTES, Fractalkine, IP-10, IL-2 5.88e -13
Activation of macrophages 5 MIP-1 α, RANTES, GM-CSF, IL-1β, IL-2 1.97e-12
Transmigration of phagocytes 5 MIP-1 α, RANTES, GM-CSF, IL-1β, VCAM-1 9.08e-12
Binding of professional phagocytic cells
5 Eotaxin, MIP-1 α, RANTES, IP-10, VCAM-1 2.62e -11
Neovascularization 4 GM-CSF, IL-1 β, IL-2, VEGF-A 4.28e -11
Necrosis 9Eotaxin, MIP-1 α, RANTES, GM-CSF, Fractalkine, IL-1 β, IL-2,VCAM-
1, VEGF-A8.39e-11
Chronic inflammatory disorder 9Eotaxin, MIP-1 α, RANTES, GM-CSF, IP-10, IL-1β, IL-2, VCAM-1,
VEGF-A9.40e-11
Cell viability 6 GM-CSF, IP-10, IL-1 β, IL-2, VCAM-1, VEGF-A 3.46e -8
Solé et al. Sci Rep 2016
1. Definition and Rationale
2. Clinical Pattern
3. Alterations in immune function and inflammation
ACUTE-ON-CHRONIC LIVER FAILURE
inflammation
4. Prevention
5. Management
LIVERHOPESimvastatin and Rifaximin for prevention of ACLF in cirrhosis
Potential mechanisms of action
1. Definition and Rationale
2. Clinical Pattern
3. Alterations in immune function and inflammation
ACUTE-ON-CHRONIC LIVER FAILURE
inflammation
4. Prevention
5. Management