Il danno epatico da alcol

Il danno epatico da alcol
Giovanni Addolorato
Unità Operativa di Alcologia,
UOC di Medicina Interna e Gastroenterologia,
Università Cattolica di Roma - Policlinico “Agostino Gemelli”
Dipartimento Politiche Antidroga, Presidenza del Consiglio dei Ministri
Giovanni Addolorato
Unità Operativa di Alcologia,
UOC di Medicina Interna e Gastroenterologia,
Università Cattolica di Roma - Policlinico “Agostino Gemelli”
- Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi
conflitto d’interesse in relazione a questa presentazione
- la presentazione contiene discussione di farmaci in studio e ad
uso off-label (Baclofen)
Alcohol Unit: drink
1 drink = 12-14 g pure alcohol
What is light-to-moderate drinking?
- Men: Up to 2 drinks per day
- Women: Up to 1 drink per day
PATOLOGIE ALCOL - RELATE
CARDIOPATIA
ENCEFALOPATIA
MIELOPATIA
INFEZIONI
ULCERA GASTRICA
E DUODENALE
EPATOPATIA
PANCREATITE
IMPOTENZA
NEOPLASIE
TUBO DIGERENTE
MIOPATIA E
MALNUTRIZIONE
ALCOL E FEGATO
RISCHIO DI EPATOPATIA CRONICA
20
Epatopatia cronica alcolica
20
Cirrosi alcolica
Maschi
Femmine
Maschi
Femmine
16
Rischio relativo
Rischio relativo
16
12
8
12
8
4
4
0
0
<1
1-6
7-13
14-27
28-41 42-69
>/=70
<1
1-6
7-13
14-27
28-41 42-69
>/=70
Becker et al, Hepatology 1996
Relationship between daily alcohol consumption
and non-cirrhotic (NCLD) and cirrotic (CLD) alcohol induced liver
Damage as derived from the cohort Dionysos population.
No
Alcohol intake
damage
(g per day)
(%)
Teetotaler
99,9
NCLD CLD
(%)
(%)
OR for
NCLD
OR for
CLD
0
0,04
0
0
0
0
< 30
99,3
0,5
0,15
31-60
97,2
1,8
1
61-90
93
4,7
2,3
20,2
25
91-120
91,6
3,5
4,9
15,1
52,9
>120
86,5
7,8
5,7
35,8
63,2
7,5
10,9
Bellentani et al, Gut 1997
ALCOL E FEGATO
L’abuso alcolico rimane la più frequente causa di cirrosi epatica nei Paesi
Occidentali
Tilg & Day, Nat Clin Pract Gastroenterol Hepatol 2007
21%
36%
HCV
ALCOL
HBV
CBP
HCV+ALCOL
HBV + ALCOL
EMOCROMATOSI
CRIPTOGENETICA
Bellentani S et al, Hepatology 1994
HCV
HCV+ALCOL
ALCOL
HBV + ALCOL
HBV
ALTRO
Sagnelli E et al, J Med Virol 2001
ALCOL E FEGATO
PATOGENESI DEL DANNO
Alcol &
Metaboliti
ALCOL E FEGATO
PATOGENESI DEL DANNO EPATICO
ACETALDEIDE
ADDOTTI
PROTEICI
reazioni
immunitarie
NECROSI
EPATOCITI
ALCOL
stress
ossidativo
perossidazione
lipidica
FIBROSI
↑ permeabilità
intestinale
ENDOTOSSINE
cellule di
Kuppfer
Gramenzi et al, Aliment Pharm Ther 2006
Oxidative damage and alcohol intake caused by
free radical intermediates
Addolorato et al. Dig Dis Sci, 2001
ALCOL E FEGATO
PATOGENESI DEL DANNO
Alcol &
Metaboliti
Genere
Razza
Modalità
Nutrizione
Virus
Co-fattori
ALCOL E FEGATO
IL SUBSTRATO GENETICO
• GENERE
• RAZZA
• MODALITA’ DI ASSUNZIONE
↓ volume di distribuzione
↓ ADH gastrica
<
estrogeni
↑ risposta immunitaria
ALCOL E FEGATO
IL SUBSTRATO GENETICO
• GENERE
• RAZZA
• MODALITA’ DI ASSUNZIONE
<
<
ALCOL E FEGATO
MODALITÀ DI ASSUNZIONE
30.000 morti /anno
prevalenza di vino
prima causa di morte fino a 24 anni
prevalenza di birra
prevalenza di superalcolici
“BINGE DRINKING”
VINO DURANTE IL PASTO
ALCOL E FEGATO
MODALITÀ DI ASSUNZIONE
p < 0.001
Assunzione prolungata di bevande alcoliche
> 30 g/die
FUORI DEI PASTI
p < 0.001
SOLO AI PASTI
Bellentani et al, Gut 1997
ALCOL, DANNO METABOLICO E NUTRIZIONE
• in pazienti con abuso alcolico:
- incrementata REE
- ridotta FM
- incrementato WHR
- incrementata ECW
- ridotta ICW
Spesa energetica/kg peso corporeo
**
0.18
0.15
g/min
Kcal/24 h/Kg
*
Velocità di ossidazione dei substrati
0.12
0.09
CONTROLLI
ALCOLISTI
**
0.06
0.03
0
LIP
CHO
Addolorato et al, Am J Gastroenterol 2000
Distribuzione del grasso corporeo: WHR
WHR 1,1
1
*
* P < 0.01
*
0,9
** P < 0.001
0,8
0,7
0,6
Addolorato et al, J Internal Med 1998
Uomini
Donne
A) SOCIAL DRINKER BEHAVIOUR
ATP SYNTHESIS
CH3 -CH2 -OH
(ETHANOL)
NAD+
ADH
CH3 -CHO + NADH + H+
(ACETALDEHYDE)
FATTY ACIDS
MITOCHONDRIA
NADPH +
H+ +
MEOS
B) CHRONIC ALCOHOL ABUSE
Hypothalamic pituitary
CH3 -CH2 -OH
(ETHANOL)
O2
CH3 -CHO + NADP+
(ACETALDEHYDE)
GLUCOCORTICOIDS
adrenal axis activation
ADH
NAD+
REDUCED FAT MASS
AND ALTERATION OF
FAT DEPOSITION
CH3 -CHO + NADH + H+
(ACETALDEHYDE)
stress
FR
MITOCHONDRIA
ADAPTATION/
REARRANGEMENT
GIANT MITOCHONDRIA
NADPH + H+ + O2
CH3 -CHO + NADP+
(ACETALDEHYDE)
HEAT
W/H
ATP SYNTHESIS
Oxidative
MEOS
INDUCTION
H2 O + CO2
FAT
OXIDATION
FAT OXIDATION
FR
ACETATE
CATECHOLAMINE RELEASE CARDIAC OUTPUT
ENERGY EXPENDITURE
Addolorato et al. J Int Med 1998
Gasbarrini G et al, Ann Ital Med Int 2003
ALCOL E FEGATO
DANNO EPATICO
0 – 30%
Fegato normale
60 – 100%
Steatosi epatica
20 – 40%
Steatoepatite
EASL Clinical Practical Guidelines, J Hepatol 2012
10 – 15%
Fibrosi/Cirrosi
ALCOL E FEGATO
COMORBILITÀ HCV
Alcol
HCV
OR
0
+
1
9,2
25 – 50
+
+
+
+
0,9
9,5
4,5
26,1
13,0
133,4
15,0
147,2
S index
(g/die)
75 – 100
125 – 150
>175
Rischio di sviluppare cirrosi
1,1
2,2
6,5
6,6
Corrao & Aricò, Hepatology 1998
Moderate Alcohol Consumption and HCV
• Investigation of 78 HCV-infected patients with alcohol consumption
<40g/d, who underwent two liver biopsies in a mean interval of 6.3
years. Progressive fibrosis with increased:
- total alcohol consumption
- daily alcohol consumption
- frequency of drinking occasions
Westin et al., J Viral Hepatol 2002
• Prospective study with 260 HCV-infected patients showed that even
moderate alcohol consumption, as low as 31-50 g/day in men and 2150 g/day in women, may aggravate histological lesions.
Hezode et al., Aliment Pharmacol Ther, 2006
HCV e alcol: sinergismo
Incremento di fibrosi e di rischio di HCC: meccanismi
- Aumentata produzione di radicali liberi dell’ossigeno
- Accumulo di ferro
- Induzione di steatosi
- Modulazione della risposta immunitaria e dell’apoptosi
- Danno diretto sul DNA
As reviewed in:
Singal & Anand, J Clin Gastroenterol 2007
Mueller et al., Word J Gastroenterol 2009
McCartney & Beard. World J Gastroenterol 2010
- Effetto sulla viremia: aumentata replicazione virale in
presenza di uso/abuso alcolico
Addolorato et al, Alcohol Res 2000
Zhang et al, Hepatology 2003
What is light-to-moderate drinking? [1 drink = 12-14 g pure alcohol]
- Men: Up to 2 drinks per day
- Women: Up to 1 drink per day
When is "low-risk" drinking still too much?
- taking medications that interact with alcohol
- medical condition that can be made worse by drinking
e.g. liver disease (such as HCV), bipolar disorder, abnormal heart
rhythm, and chronic pain.
- underage
- planning to drive a vehicle or operate machinery
- pregnant or trying to become pregnant
Treatment of ALD
 Nutrition and Antioxidants
 Steroid (prednisolon)
 Pentossifillin
 Anti-TNFα (infliximab, etanercept)
 Propiltiouracil
 Colchicin
 NCB1 agonist/antagonist
Total
alcohol abstinence
• The
most effective management strategy for alcoholics with ALD is to
achieve total alcohol abstinence
Medical and surgical treatments for ALD have limited success when
drinking continues Tilg & Day. Nat Clin Pract Gastroenterol Hepatol 2007
•
Persistent alcohol intake has been associated with increased mortality in
patients with liver cirrhosis Pessione et al. Liver Int 2003
•
Effective Anticraving Medications for Alcohol
Dependence
Medication
Mechanism of Action
Naltrexone (Nalorex® and Vivitol®);
Nalmefene ?
Mu opioid receptor inhibitor
?OPRM1 (label)
Acamprosate (Campral®)
Glutamate receptor modulation (label)
Ondansetron (Zofran®)
Serotonin- 3 receptor antagonist (off-label)
Type B/SERT & 3-UTR
Sodium Oxybate (GHB) (Alcover®)
GABA-B/ GHB agonist (label in Italy and
Austria)
Baclofen (Lioresal® and Liofen®)
GABA-B antagonist (off-label)
Alcohol dependent; Severe liver disease
Topiramate (Topamax®)
GABA/Glutamate modulator
Heavy current drinkers (off-label)
Addolorato et al, Nature Neuropsychopharmacol 2012
Baclofen and liver cirrhosis
Baclofen showed its safety and efficacy in achieving and maintaining
alcohol abstinence in alcohol-dependent patients with liver cirrhosis
Trial profile
p = 0.0002
CAD: 30.8 ± 5.5
p = 0.001
CAD: 62.8 ± 5.4
Kaplan–Meier survival
analysis of proportion
of lapse and relapse
Number at risk refers to
proportion remaining free
for lapse and relapse
Pilot study at Loma Linda University Medical Center, US
• Baclofen used for 5-8 months in 14 patients with severe alcoholic hepatitis
• 13/14 patients completely stopped drinking/craving and one patient
reported a significant reduction in alcohol consumption
• There was a significant reduction in total bilirubin (p=.0057) and AST
(p=.0438) and there was a trend for reduced ALT (p=.083). No side effects
were reported
Yamini & Runyon. Alcohol Alcohol 2014
Pilot study at Royal Alexandria Hospital Paisley, Glasgow, UK
• Baclofen used ‘off label’ in > 50 patients
• the dose required was lower in those patients with advanced alcoholic liver
disease; patients reduce/stop drinking/craving. No side effects were reported
Heydtmann. Alcohol Clin Exp Res 2011
Alcoholic liver disease
• When
abstinence fail to improve
liver function or the patient
develop a severe liver damage (e.g.
acute alcoholic hepatitis), OLT is the
most effective therapy
Steatosis
Steatohepatitis
Cirrhosis
Liver transplantation in alcohol‐related cirrhosis
Management of alcoholic liver disease,
Journal of Hepatology, 2012
Management strategies in alcoholic liver disease,
Nature, 2007
Alcoholic liver disease, Hepatology 2010
Indicazioni al trapianto in Italia
Pazienti adulti
Mirante VG et Al. AISF 2000
Liver transplantation in alcohol‐related cirrhosis
Primary indications of Liver Transplantation in 297 Cirrhosis in Liver Transplant Centre, Gemelli Hospital, Roma ‐ 1995‐2009
31 %
Ethical problems
AASLD Practice Guidelines, Hepatology 2010
The 6‐months rule
Liver transplantation in alcoholic hepatitis
Mathurin et al, NEJM 2011
Results
Number of patients, divided by etiologies, who underwent liver transplantation between
1995 and 2009. Trend of transplantation for alcoholic cirrhosis.
Results: recidivism and survival
∆ = 0.2
Kaplan‐Meier analysis. Estimated survival probability curves for patients followed and not followed at the AAU, together with p‐
values from log‐rank tests at different times of observation (p<0.0001 at 8yrs). Difference in the estimated survival probability for patients followed and not followed at the AAU, along with the related confidence bands. (95% CI: ‐0.09:‐0.47; p=0.005). Results: pre‐OLT alcohol abstinence time
Advanced ALD is a widely accepted indication for OLT and the survival rate after OLT is
not different (or better) than other indications
Moralistic view (self‐inflicted disease, risk of recidivism, ecc) should not undetermine OLT
procedure in these patients
Alcoholic patients should be followed before and after liver transplantation by clinicians
with expertise in alcohol use disorder management, within LT Unit
Abstinence time before transplantation could be shortened in select patients when
clinical condition do not allow 6‐ month waiting time
A. Ferrulli, A. Mirijello, L. Leggio, G. Vassallo,
M. Antonelli, C. D’Angelo, G. Gasbarrini, A. Gasbarini
Grazie per l’attenzione

Download Report