Rita Garcia Martinez Juan Rodés Grupo investigación ... · Neuroimagen Results Link Clinical...
Transcript of Rita Garcia Martinez Juan Rodés Grupo investigación ... · Neuroimagen Results Link Clinical...
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