Rita Garcia Martinez

Juan Rodés

Grupo investigación enfermedades hepáticas y digestivas

Hospital General Universitario Gregorio Marañon

Medico especialista Medicina Interna-Hepatología

H. Vall d’Hebron

(2002-2007)

Medicina Interna

Hepatología

Investigadora Predoctoral

Medicina Interna-Hepatología

H. Vall d’Hebron

(2007-2010)

Cirrosis Encefalopatía

hepatica

FUNCION COGNITIVA & TRASPLANTE

HEPATICO

Investigadora Postdoctoral

Liver Failure Group

University College London

(2010-2013)

Cirrosis Albúmina

BASES FISIOPATOLOGICAS

ALBUMINA EN CIRROSIS

Cognitive Function after Liver Transplantation:

Implications of Hepatic Encephalopathy

Supervisor: Juan Cordoba

Universitat Autonoma Barcelona

Financiación: Contrato post-MIR Rio Hortega

(2007-2010)

BACKGROUND

Hepatic Encephalopathy (HE): brain dysfunction

Clinical manifestations: wide spectrum of neuropsychiatric abnormalities

ranging from subclinical alterations to coma

Vilstrup H. J Hepatol 2014

Ferenci P. Hepatology 2002

World Health Organization 2010

liver failure

portosystemic shunts

BACKGROUND: HE, pathogenesis: ammonia

Cordoba J. Semin Liver Dis 2008

BACKGROUND: HE, cerebral abnormalities: astrocytes

Jalan R. Int J Biochem Cell Biol 2003

Albrecht J.Hepatololgy 2006

Haussinger D. J Hepatol 2000

GLU

GLN

GLN

GLN GLN

GLN GLN

GLN

GLN

GLN

GS

NH4+

Capillary Astrocyte

Astrocyte

H2O

H2O H2O

H2O

NH4+

Imaging: structure

frequency

resonance

Spectroscopy: molecules

BACKGROUND: HE, 1H Magnetic resonance

o Low-grade brain

edema

o WML volume

o Manganese

deposition

o Cerebral volume

o Spectroscopic

alterations:

• Glutamate

• Glutamine

• Choline

• Mio-inositol

BACKGROUND: liver transplantation

European Liver Transplant Registry 2014

Restores normal liver function (if successful)

Significantly rose during last 2-3 decades

Improvement life expectancy of patients after LT

Successful liver transplant:

Rovira A . Curr Opin Neurol 2002

Improvement neuradiological manifestations of HE

o Low-grade brain edema

o WML volume

o Spectroscopic alterations

o Manganese deposition

Córdoba J et al. J Hepatol 2001

Improvement cognitive function

BACKGROUND: HE in the age of liver transplantation

Successful liver transplant:

Systematic & sensitive assessment of brain function after LT:

Cognitive improvement

Year Author N

(CH)

Control group

(Healthy control

HC)

Follow-up

(months)

Neuropshycological

test Neuroimagen Results

Link

Clinical

condition

1990 Tarter N=62 HC=38

Crohn disease=22 15 27 test no

12/27 worse CH vs HC

4/27 worse CH vs Crohn No

1991 Arria N=13

(OH) HC=13 12 16 test no >1 test impaired 10%-20% CH OH?????

2003 O´Carroll N=70

N=31 HC=30

12

36 4 test no

Improvement at 1 year

Stable at 3 year -

2003 Lewis N=12 HC=25 120 6 test No 4/6 worse CH vs HC No

2004 Mechtcheriakov N=14 HC=32 21 8 test no VMCP worse CH vs HC No

2004 Mattarozzi N=13 HC=9 18 16 test no memory span worse CH vs HC No

Heterogeneous outcomes, not completely reversible, no explanation

BACKGROUND: HE in the age of LT

BACKGROUND: HE in the age of LT

n=25 n= 14 n=20

Sotil EU. Liver Transplant 2009

Cognitive function after LT according to pre-transplant HE

BACKGROUND: HE and brain atrophy

Brain Computed Tomography

Zeneroli ML. J Hepatol 1987

Chronic HE

(n=18)

Acute HE

(n=15)

Alcoholic 87% 0%

Non-alcoholic 50% 0%

BACKGROUND: HE, summary

CLASSICALLY: reversible

Metabolic origin (treatable)

Clinical recovery between

episodes

RECENTLY: sequels?

Permanent cognitive

impairment after bouts of

HE detectable in LT

recipients

Brain atrophy

Double nature of HE?

Reversible: metabolic origin

Permanent: structural damage

STUDY: aim

To describe the cognitive outcome after LT

To describe the brain volume and brain metabolites

after LT

To analyze the role of prior OHE on both cognitive function and

brain volume after LT

STUDY: design

70 Patients

11 died after-LT 7 declined to participate

Liver transplantation

March’04-October’07

52 Patients NPS

1-2 months 6-12 months

Neuropsychological assessment:

- 20 tests, normalized (age, gender, education)

Clinical evaluation

MR assessment (since March’06):

- Brain volume normalized (standard cranial size)

- Spectroscopy 24 Patients MR

STUDY: methods, neuropsychological assessment (NPS)

AVL

Symbol digit-T

Grooved Pegboard-T

Hooper-T

Trail A-T

JLO-T

COWAT-T

FAST T-T...

MEMORY

ATTENTION

EXECUTIVE FUNCTION

MOTOR FUNCTION

VISUOSPATIAL FUNCTION

GLOBAL COGNITIVE FUNCTION

50 60 40 30 70

µ -1SD -2SD +1SD +2SD

20 tests

Normalized using μ and SD healthy people same age, gender and education

T-VALUES

50+10[ ]

(x- μ)

SD

STUDY: patients

Neuropsychological study (n=52)

• Age 54±10 42 ♂ / 10 ♀ DM 14 • Etiology 25 viral 16 alcohol 8 viral+alcohol 3 others • Prior HE 24 • MELD 17±6 • Immunosuppressant FK 25 FK+MMF20 FK+mTOR 6 CyA+MMF 1

Episodes: 1±2 Time HE-LT: 22±33 months Maximal severity HE: I-II 20, III-IV 4

MR study (n=24)

• Age 54±9 18 ♂ / 6 ♀ DM 9 • Etiology 13 viral 8 alcohol 3 others • Prior HE 12 • MELD 17±6 • Immunosuppressant FK 7 FK+MMF 12 FK+mTOR 6 CyA+MMF 1

Episodes: 1±2 Time HE-LT: 20±29 months Maximal severity HE: I-II 11, III-IV 1

STUDY : results

STUDY: results

STUDY: results

STUDY: results

STUDY: results

STUDY: summary

Cognitive function after LT is influenced by pretransplant conditions

Hepatic encephalopathy is associated with neuropsychological sequels,

predominantly on motor function

The structural basis for permanent damage is supported by the

association between hepatic encephalopathy and decreased normalized

brain volume

Decreased brain volume could be related to loss of neurons

HE: REVERSIBILITY – LIVER TRANSPLANT

Successful liver transplant:

Systematic & sensitive assessment of brain function after LT:

Pre-LT OHE impacts on post LT attention and executive functions

Campagna F Liver Transplant 2014

n=23

n=42

HE: CLINICAL RELEVANCE OF PERSISTENT DEFICITS

Studies in LT recipients:

Improvement of cognitive function is the norm

Deficits are detected by sensitive diagnostic tests

Quantified:

9-13% LT recipients cognitive impairment, mild

prior OHE seems to be involved, additive effects with other factors

Studies in LT recipients: limitations

Exclusion of patients with neuropsychiatric disorders/dementia

Exclusion of patients without successful outcome

Do we have the real picture of the degree of reversibility???

Persistent deficits even if mild may contribute to cognitive decline and QoL

Albumin biology in liver failure

Supervisor: Rajiv Jalan

University College London

Financiación:

Beca Juan Rodes –AEEH

Sheila Sherlock EASL fellowship

Beca Estancia Extranjero Sociedad Catalana Digestologia

(2010-2013)

Detoxification Efficiency

Control Cirrhotic AcLF 0

100

200

*** ***

% o

f re

fere

nce

po

pu

lati

on

Hepatology 2009

In cirrhosis, albumin is inefficient: hypoalbumineamia and dysfunction

Albumin in Spontaneous Bacterial Peritonitis

N Engl J Med 1999

Decrease incidence of renal failure

Decease mortality

Hepatology 2013

Albumin: multifunctional protein acting through pleiotropic effects

SD Sham (n=6)

SD BDL (n=7)

NAR Sham (n=8)

NAR BDL (n=7)

6 weeks

o Hemodynamics

o Inflammation

o Cardiorenal

function: PRA

o Organ function

o Survival

surgery

Endpoints

Rodent model of chronic liver failure: bile duct ligation

• Analbumaemic rats (NAR)

• Control rats (SD)

AIM:

METHODS:

To explore mechanisms of action of albumin in liver failure

J Hep 2015

NAR BDL worst hemodynamics, endothelial function and survival

Analbuminaemia was associated to worse phagocytic capacity in PBMCs

On HUVEC cells: Albumin prevents LPS-induced activation

A

B

Untreated FITC-Alb 1h FITC-Alb 3h FITC-Alb 6h

40x

10x

HSA 1h LPS 6h Control LPS 6h

C

Albumin is internalized by HUVECs

Albumin has antioxidant effect on HUVECs & reduces cell stress

UCL

Rajiv Jalan

Nathan Davies

Raj Moorkerjee

Liver Failure Group

Juan Cordoba

Servicio Medicina Interna-Hepatología

Institut de Recerca-Malalties Hepàtiques

COMPLICACIONES DE LA CIRROSIS

Encefalopatía hepática

Otros problemas neurológicos en pcte cirrótico

Disfunción circulatoria

Infecciones/respuesta inmune en cirrosis

LINEAS DE INTERES:

Rafael Bañares

Javier Vaquero

Servicio de Medicina Digestiva

Grupo investigación enfermedades hepáticas y digestivas