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

LIVERHOPEList of participant countries

LIVERHOPESimvastatin and Rifaximin for prevention of ACLF in cirrhosis

Potential mechanisms of action

LIVERHOPEHypothesis

1. Definition and Rationale

2. Clinical Pattern

3. Alterations in immune function and inflammation

ACUTE-ON-CHRONIC LIVER FAILURE

inflammation

4. Prevention

5. Management

Accepted treatments

• Liver Transplantation

•Standard supportive therapy

Potential treatments under investigation

ACUTE-ON-CHRONIC LIVER FAILURE

Potential treatments under investigation

• Plasmapheresis

• Artificial liver support

• Stem cell transplantation

• Granulocyte-colony stimulating factor