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Alcoholic Hepatitis
and the Effect of Alcohol on other Types
of Hepatitis
Helmut K. Seitz
Centre for Alcohol Research, University of Heidelberg,
Germany
&
Department of Medicine, Salem Medical Centre,
Heidelberg, Germany
Seminar for laeger i alkohol- og stofmisbrugsbehandlingen
Vaerlose, Denmark, 12.-13.November 2014
Alcohol Research Center
University of Heidelberg
Alkoholforschungszentrum
Universität Heidelberg
Alkoholforschungszentrum
Universität Heidelberg
Natural Course of Alcoholic Liver Disease
LTX
Decompensation
(20-40 %)
Hepatocellular Cancer
(3-10 %)
Alcoholic
Steatohepatitis
(10-35 %)
Alcoholic Fibrosis (20-40 %)
Alcoholic Cirrhosis (8-20 %)
Healthy Liver
Alcoholic Fatty Liver (90-100 %)
Alcoholic
Hepatitis
70
% 4
0 %
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Definition
• One has to distinguish between a mild Alcoholic Steatohepatitis
(ASH) with elevation of serum transaminase activities and the
clinical feature of an Alcoholic Hepatitis (AH). The first has a good
prognosis with alcohol abstinence, while AH has a poor prognosis
with high mortality.
• Severe AH is a Clinical Syndrom with Jaundice, and Signs of
Hepatic Decompensation due to Alcohol.
• In approximately 30% AH is present in Alcoholic Cirrhosis.
• Alcoholic Steatohepatits (ASH) is a histologic Diagnosis with
Steatosis, Hepatocellular Balooning, and Infiltration of Neutrophils.
Alcohol Research Center
University of Heidelberg
Alcoholic Hepatitis (AH)
AH is a clinical Syndrom characterized by
jaundice, anorexia, and hepatomegaly
with extensive hepatocellular necrosis,
inflammation and Fibrosis.
AH represents a spectrum of clinical Symptoms and is frequently present in
cirrhosis (acute on chronic disease).
Mortality depends on the severity of the disease.
MILD MODERATE SEVERE
30 day
Mortality
20% >40%
68%
PROGNOSIS
_
_ _ 8 year
Cirrhosis
Development
Morgan MY, 1994
Alcohol Research Center
University of Heidelberg
Risk Factors
1. Non-genetic Risik factors of AH:
Massive Alcohol Abuse
Female Gender
Overweight and Obesety
2. Genetic Risk Factors have not been identified so far.
Alcohol Research Center
University of Heidelberg
Alcoholic Steatohepatitis
PVF
Mallory-Denk-
Bodies
Alcohol Research Center
University of Heidelberg
Diagnostics
Typical Clinical Feature
(Signs of Hepatic Decompensation: Jaundice, Fever, Ascites, HE,
Bleeding, Weight Loss, Malnutrition)
Alcohol History
Laboratory: DeRitis Ratio (AST>ALT; often >2, often not higher than 300U/l)
Histology: According to EASL Guidelines Liver Biopsy (konventional or
transjugular) is recommended but not mandatory.
Fibrosis: Transient Elastography
Alcohol Research Center
University of Heidelberg
Differential Diagnosis
DILI
Sepsis
Ischemic Hepatit is
Alcohol Research Center
University of Heidelberg
Prognosis
Discriminant function 1)
1) Maddrey et al. Gastroenterology 75,193:1978
2) Wiesner et al. Gastroenterology 124,91:2003
MELD 2)
4,6 x (PTT Patient – PTT Controls) + Bilirubin (mg %)
32= 1 month mortality 50 %
9,57 x loge (Krea mg %) + 3,78 x loge (Bili mg %) +
11,2 x loge (INR) + 6,43
21 = 3 month mortality 20 %
Alcohol Research Center
University of Heidelberg
Glasgow Alcoholic Hepatitis Score
> 14.5 7.25-14.5 < 7.25 Bilirubin (mg%)
> 2.0 1.5-2.0 < 1.5 PT ratio
- > 5 < 5 Urea (mmol/l)
- > 15 < 15 WCC (109/l)
- > 50 < 50 AGE
3 2 1
SCORE
OVERALL ACCURACY
OUTCOME ON DAY 84
57 % vs. 78 % day 6-9
53 % vs. 75 % day 1 GAHS vs. DF
Forrest et al.GUT 2005;54:1174-79
Alcohol Research Center
University of Heidelberg
Treatment of Severe AH
Alcohol Research Center
University of Heidelberg
Nutritional Therapy – What is confirmed?
Established
– oral/enteral diet: improved malnutrition and
complications (A), mortality questionable
influenced in Alcohol Hepatitis (B)
– enteral diet through NG-tube: effectiv, no
increased complications, poor compliance
(B)
– parenteral diet: unsufficient data
Stickel et al, Aliment Pharm Ther 2003;18:357
No proven advantage on survival by:
o parenteral Nutrition
o branched-chain amino acids
o Anabole Steroids
o Vitamin Substitution
Alcohol Research Center
University of Heidelberg
Steroids: meta analysis
• data of the last 3 RCTs
• 102 Placebos, 113 steroids
• All: DF >32, without
infections, without bleeding
• 28 days survival 85 % vs.
65 % (p<0.001)
• Only 1/5 has an advantage
• Age and creatinine have
also to be considered
Mathurin et al 2002
Alcohol Research Center
University of Heidelberg
Who responds to steroids?
• 238 patients
• all DF > 32
• all treated with steroids
• ECBL = Early Change of Bilirubin Levels after 7 days of therapy
• highly significant for 6 months survival
Mathurin 2003
Louvet 2007
Alcohol Research Center
University of Heidelberg
Steroid Therapy: Summary
• Steroids should be used in AH with DF>32 and GASH>9.
• Prerequisite: no GI bleeding, no infection (treatment of the
infection has priority).
• Problem: septic complications
• If ECBL appears within 7 days , therapy has to be continued,
otherwise stop therapy.
Alcohol Research Center
University of Heidelberg
• AH no LTX
• Alcoholic Cirrhosis: 6 Month
Abstinence
Organ Availability!
Present Concept of Liver Transplantation in
ALD
Alcohol Research Center
University of Heidelberg
Time of Abstinence before LTX Survival Died +
< 6 mo (n = 11) 7 4
6 to 24 mo (n = 29) 25 4
> 24 mo (n = 33) 20 13
Total 52 21
+ p NS
Kumar S, et al. Hepatology. Vol 11, No 2, 1990
Effect of Abstinence on Post-Transplant
Survival in Patients with Alcoholic Cirrhosis
Alcohol Research Center
University of Heidelberg
Time of Abstinence before
LTX Total n (%) Drinking n (%) P Value
< 6 months 18 (6.6) 9 (50.0)
6 - < 12 months 64 (23.5) 15 (23.4) 0.001
12 months 190 (69.9) 30 (15.8)
Total 272 (100) 54 (19.9)
Pfitzmann R, et al. Liver Transpl. 13:197-205, 2007
Time of Abstinence before LTX and
Relapse after LTX
Alcohol Research Center
University of Heidelberg
a. Frequency: 2nd frequent cause
b. Survival: Similar or better compared to other etiologies
c. Relapse: Yes
The Incidence depends on Definition.
In general no major problem. May, however,
have an influence on survival.
Therapy is available.
LTX in ALD: The Facts
Alcohol Research Center
University of Heidelberg
Mathurin P. et al, N Engl J Med ;2011;365:1790-800
Survival of Patients with Severe AH and
LTX without Abstinence prior to LTX
Alcohol Research Center
University of Heidelberg
Mathurin P. et al, N Engl J Med ;2011;365:1790-800
Survival of Patients with Severe AH and LTX
without Abstinence prior to LTX
Alcohol Research Center
University of Heidelberg
Rapid onset of jaundice ,
poor liver function ,
active, most recent alcohol abuse
Exclusion of other causes of acute liver
failure
Prognosis-Scores (MDF, MELD,GAHS)
Low Risk:
MDF<32; MELD<18; GAHS<8
Increased Risk:
MDF≥32; MELD≥ 18; GAHS≥ 8
Hepatic Encephalopathy
Exclusion / Treatment of Infections
Malnutrition
•Nutrition Therapy (35kcal/kg; 1,5g/kg Proteine)
•Prednisolon 40mg/tgl. ± N-acetylcystein
Stop: No Response following 7 days of Treatment
•Possiblyl Pentoxifyllin (2 x 400mg/tgl. for 4 Weeks) Nutritional Therapy
(35kcal/kg; 1,5g/kg Protein)
Responder
(Lille Score<0,45)
Non- Responder
(Lille Score≥0,45)
Treatment for 28 days
Supportive Care, Treatment of Alcoholism, Follow up (HCC Screening)
LTX???
Adequate nutritional
status
Alcohol Research Center
University of Heidelberg
Laboratory AFL/ASH
AFL: Frequently increased Serum -GT activity,
occasionally up to 4000 U/L.
ASH: Elevated Serum AST Activity (< 300 U/L) and
Serum -GT activity :often extremely high
AST/ALT-Ratio > 1
Alcohol Research Center
University of Heidelberg
Ethylglucuronid as a highly sensitive Marker for
Alcohol Consumption
Alcohol Research Center
University of Heidelberg
Ethylglucuronide:
Healthy individuals: 1 Glas of Wine/1 Bottle of Beer
EtG ca. 20h measurable in the urine,
ca. 0.1-0.5mg/l
Alcoholics: Begin of Detoxification : 2mg/l
after 24h Detoxification: 0.5 – 2mg/l
0.5mg/l
CDT: ca. 1week 60g ethanol /day (1 bottle of wine)
Albermann Int J Legal Med. 2012 Sep;126(5):757-64.
Amount of Ethanol?
Alcohol Research Center
University of Heidelberg
Case Report II
Male, 59 years, LTx 2 years ago due to HCV Cirrhosis.
April 2013: jaundice, HCV-RNA 9 Mill IU/ml, Bili:10 mg%, GOT 412
U/l, GPT 470 U/L, GGT: 3039 U/L, AP:214 U/l
Histology: Steatosis, cholestatic HCV Relaps
Therapy: Sofosbuvir + RBV for 24 weeks, HCV RNA negativ
Laboratory: GOT: 89 U/L, GPT: 76 U/L, GGT: 800 U/L, Bili: 1.8mg%
Histology: no hepatitis, severe steatosis
EtG: > 2000 µg/g Creatinine
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Natural Course of Alcoholic Liver Disease
• Amount of Alcohol
• Genetics
• Gender
• Other Liver Diseases (HepB/C,
Hemochromatosis, NASH)
• Obesity / Malnutrition
• Iron
• Drugs + Toxins (Cannabis)
• Vitamin A
• Smoking
LTX
Decompensation
(20-40 %)
Hepatocellular Cancer
(3-10 %)
Alcoholic
Steatohepatitis
(10-35 %)
Alcoholic Fibrosis (20-40 %)
Alcoholic Cirrhosis (8-20 %)
Healthy Liver
Alcoholic Fatty Liver (90-100 %)
Alcoholic
Hepatitis
70
% 4
0 %
Alcohol Research Center
University of Heidelberg
Mallory Bodies, not only
peripherally (NASH), but also
centrally (ASH) found. Signs of
endogenous and exogenous
toxic damage
HE-stain
Round cell infiltrates by lymphocytes.
Typical for chronic Hepatitis C
Ballooning and fatty
hepatocytes
Casuistic Alcohol Research Center
University of Heidelberg
Ladewig-stain
Pseudolobuli
chicken wire fibrosis.
septa
Casuistic Alcohol Research Center
University of Heidelberg
Casuistic
Mallory Bodies
Mallory Bodies
Mallory Bodies
Alcohol Research Center
University of Heidelberg
Etiology of chronic liver disease
Center of Disease Control and Prevention (Singal & Anand, 2007)
Hepatitis C +
Alcohol
14%
Hepatitis C
26%
Alcohol
24%Cryptogenic
17%
Others
5%
Hepatitis B +
Alcohol
3%
Hepatitis B
11%
Alcohol Research Center
University of Heidelberg
Effect of Alcohol on Various Liver Diseases
• Hepatitis C
• Hepatitis B
• Non-Alcoholic Fatty Liver Disease
• Hereditary Hemochromatosis
• Drug Induced Liver Injury
Alcohol Research Center
University of Heidelberg
1. INFLUENCE OF ALCOHOL ON THE PREVALENCE
OF HCV INFECTION
2. HEPATIC INTERACTIONS OF ALCOHOL AND HCV
VIRUSREDUPLICATION
FIBROSIS
HEPATOCELLULAR CARCINOMA
3. INFLUENCE OF ALCOHOL ON THE RESPONSE OF
HCV TREATMENT
Alcohol Research Center
University of Heidelberg
Alcoholic liver disease and HCV prevalence
0
20
40
60
80
100
% Anit-HCV
positive
Alcoholic
fibrosis
Cirrhosis HCC
Takase et al., Alcohol Alcohol Suppl 1993;1A:77-84.
Alcohol Research Center
University of Heidelberg
1. INFLUENCE OF ALCOHOL ON THE PREVALENCE
OF HCV INFECTION
2. HEPATIC INTERACTIONS OF ALCOHOL AND HCV
VIRUSREDUPLICATION
FIBROSIS, CIRRHOSIS
HEPATOCELLULAR CARCINOMA
3. INFLUENCE OF ALCOHOL ON THE RESPONSE OF
HCV TREATMENT
Alcohol Research Center
University of Heidelberg
Impact of alcohol consumption on serum
HCV-RNA level
Pessione et al. Hepatology 1998; 27: 1717-1722
Serum HCV-RNA (mEq x 105)
0
80
120
140
100
60
40
0 1-69 70-139 140-209 ≥ 210
SRAC g/Week
Serum HCV-RNA (mEq x 105)
0
80
120
140
100
60
40
Alcohol Research Center
University of Heidelberg
Effect of alcohol reduction on serum HCV-RNA
Cromie et al. J Hepatol 1996; 25: 821-826
Copies/ml x 105
35
30
25
0
40
10
Start of Study
39-100 g daily
20
15
5
After 4 months
0-50 g daily
p = 0,018
Alcohol Research Center
University of Heidelberg
Relative Risk (RR) for advanced fibrosis (FF) cirrhosis
(Ci), and decompensated cirrhosis (dCi) in Patients
with chronic HCV Infection and heavy Alcohol Abuse
(210-560 g/week)
Singal & Anand Clin Gastroenterol 2007; 41: 761-772
0
2,5
3
4
2
3,5
RR
FF
fortgeschrittene
Fibrose
Ci
Zirrhose
dCi
dekompensierte
Zirrhose
1,5
1
0,5
Alcohol Research Center
University of Heidelberg
Alcohol and Liver Fibrosis
Patienten (%)
0
60
100
80
0 1-20 21-30 31-50
40
20
Alkohol (g/d)
Fibrosestadium
0-1
2-4
Hézode et al. Aliment Pharmacol Therap 2003;17:1031-37
Alcohol Research Center
University of Heidelberg
Effect of Alcohol intake on the progression of hepatitis C
Patients Result
2.235 HCV 0; < 50; > 50 > 50 Progression of fibrosis
(p < 0,001) Poynard 1997
Roudot-Thoraval 1997
6.664 HCV
> 5 (f); >6 (m) drinks; > 1 J Higher prevalence of cirrhosis
(35 vs. 18 %; p < 0,001)
Serfaty 1997 168 HCV with &
without Ci < 30; 30-80; > 80; > 5 J
Higher prevalence of cirrhosis
(p < 0,05)
Ostapowicz 1998 234 HCV Calculation of total
alcohol intake p < 0,02
Pessione 1998 233 HCV Quantification of weekly alcohol
intake
Weekly alcohol correlates
with fibrosis score (p < 0,006)
176 HCV 40 (f); > 60 (m); > 5 J Faster progress of cirrhosis
(58 % vs. 10 %; p < 0,001) Wiley et al.
Carrao 1998 702 HCV 0; 25; 50; 75; 100; >125 RR for decompensated cirrhosis
= 9,2 (-50); 26,1 (-100); 133 (<125)
Thomas 2000 1.667 IDU + HCV Quantification Risk for ESLD 3,6 bei
>260 g/wkly comp. to < 90 g/wkly
Alcohol (g/d)
Harris 2001 636 HCV > 80 RR cirrhosis: HCV 7,8;
HCV + alcohol 31,1
Author
Alcohol Research Center
University of Heidelberg
Fibrosis, alcohol and HCV
Wiley et al., Hepatology 28:805, 1998
Alcohol Research Center
University of Heidelberg
0
1
2
3
4
0 5 10 15 20
Years of exposure
Fib
rosis
Gra
de
HCV + alcohol
HCV alone
Poynard et al. Lancet 1997; 349: 825-832
Fibrosis RR > 50 g Ethanol/day = 2,4 (p = 0,0001)
Alcohol and progression of hepatitis C
Patients: 78 with two liver biopsies at an mean
interval of 6.3 years.
Alcohol: < 40 g/d (median 5 g/d,1-12 g/d)
Result: Increase in progressive fibrosis:
1. Higher total alcohol
(15,4 kg vs. 3,9 kg; p = 0.007)
2. Higher daily alcohol consumption
(5,7 g vs. 2,6 g per day; p = 0,03)
3. Higher drinking frequency
(35 vs. 8 days per year; p = 0,006)
Westin et al. J Viral Hepat 2002; 9: 235-241
Alcohol Research Center
University of Heidelberg
Odds ratio of HCC for patients with various amount of alcohol
intake with and without hepatitis C Alcohol Hepatitis C
Author / Country Case / Controls
(Quantity)
Odds ratio
(95 % Ci)
Case / Controls
(Quantity)
Odds ratio
(95 % Ci)
Tagger et al., Italy
Daily alcohol intake (g/d)
< 40
40-80
> 80
31 / 219
27 / 157
102 / 203
1.0 (reference)
1.5 (0.7-2.9)
7.3 (4.0-13.1)
47 / 18
32 / 7
42 / 5
26.1 (12.6-54)
62.6 (23.3-168)
126 (42.8-373)
Hassan et al., USA
Daily alcohol intake (g/d)
No
Yes
< 80 g/d
> 80 g/d
40 / 136
75 / 94
33 / 63
42 / 31
1.0 (reference)
2.4 (1.3-4.4)
1.7 (0.9-3.7)
4.5 (1.4-14.8)
19.1 (4.1-89.1)
53.9 (7.0-415.7)
Alcohol Research Center
University of Heidelberg
Relative risk of HCC through alcohol consumption,
with and without hepatitis B/C-infection
Donato et al. Am J Epidemiol 2002; 155: 323-331
20
0
40 60 80 100 120
alcohol consumption
(g/day)
Log (Odds Ratio)
with HCV-infection 15
10
5
140
with HBV-Infection
without HCV-/HBV-
infection
Alcohol Research Center
University of Heidelberg
Is there any dose of alcohol that causes no further
damage in hepatitis C? 1. Fibrogenesis is dose-dependent and starts already with small amounts of
alcohol (less than 30 g per day). There is no safe dose of alcohol for patients
with HCV infection, obese patients and diabetics are particularly at risk. (Monto
et al, Hepatology 39, 826-34:2004).
2. HCV patients with a history of excessive alcohol consumption have a 2-3-fold
increased risk to develop severe liver diseases compared to HCV patients
without alcohol consumption in the past (Delarocque-Astagneau et al, Ann
Epidemiol 15,551-557:2005).
3. It is still not clear how long a patient needs to restrain from alcohol to allow the
negative effects of alcohol to dissappear. (Tabone et al, J Viral Hepat 9,288-
294:2002).
4. The abstinence rate seems to be higher in alcoholics with HCV infection than in
alcoholics without HCV infection (Rifai et al, Psychosomatics 47,112:2006).
Alcohol Research Center
University of Heidelberg
1. INFLUENCE OF ALCOHOL ON THE PREVALENCE
OF HCV INFECTION
2. HEPATIC INTERACTIONS OF ALCOHOL AND HCV
VIRUSREDUPLICATION
FIBROSIS, CIRRHOSIS
HEPATOCELLULAR CARCINOMA
3. INFLUENCE OF ALCOHOL ON THE RESPONSE OF
HCV TREATMENT
Alcohol Research Center
University of Heidelberg
Alcohol and Anti-HCV Treatment
Alcoholics have a lower response rate to
treatment with Interferon
(10 studies between 1994-2005).
Alcohol Research Center
University of Heidelberg
Influence of alcohol on the Hepatitis – C - Therapy
Vir
olo
gic
al a
nd
bio
ch
em
ica
l tr
ea
tme
nt
res
po
ns
e (
%)
0
30
40
Alcoholics Non-alcoholics
20
10
ALT HCV RNA ALT HCV RNA
Mochida et al. Alcoholism Clin Exp Res 1996; 20: 371A-77A
Alcohol Research Center
University of Heidelberg
Inhibiting effect of alcohol or bad compliance ?
In 726 patients, alcohol consumption during the past 12 months was
closely linked with a higher rate of discontinued therapy. (40% vs.
26%, p=0.002).
After correction the response rate was comparably similar (25% vs.
23%,NS) (Anand et al, Gastroenterology 130,1607:2006)
Bad compliance in alcoholics is probably the main reason
for a lower response rate compared to HCV treatment
Conclusion:
Alcohol Research Center
University of Heidelberg
Alcohol and Anti-HCV Treatment
Summary
1. Alcoholics have an increased prevalence of HCV infection (life style,
immunosuppression?)
2. High alcohol consumption (> 50 g/day) stimulates 1) hepatic fibrogenesis
with an increased risk for cirrhosis and 2) hepatic carcinogenesis with an
increased risk for HCC.
3. A threshold level is difficult to state. Women reveal a deterioration of hepatic
histology already at a lower alcohol intake as compared to men. It is unclear
how long ethanol abstinence needs to be perfrormed to prevent the negative
effect of ethanol.
4. Alcoholics have a relatively low success rate of antiviral therapy, possibly
due to poor compliance.
5. Mechanisms explaining the negative effect of ethanol on hepatitis C include:
1) Stimulation of HCV replication and an increased generation of
quasispecies,
2) Immunomodulation,
3) increased oxidative stress due to various mechanisms,
4) increased fat accumulation.
Alcohol Research Center
University of Heidelberg
Effect of Alcohol on Various Liver Diseases
• Hepatitis C
• Hepatitis B
• Non-Alcoholic Fatty Liver Disease
• Hereditary Hemochromatosis
• Drug Induced Liver Injury
Alcohol Research Center
University of Heidelberg
Effect of alcohol on the development of a hepatocellular
carcinoma (cirrhosis) in HBSAG positive male patients
Alcohol Research Center
University of Heidelberg
Ohnishi et al., Cancer 49,672 1982
Amount of alcohol HCC
(ml/day)
Number of
patients
Age (years)
Kein 7 (8) 61 ± 7 (49 ± 14)
< 24 20 (10) 49 ± 9 (39 ± 8)
25 – 75 5 (5) 43 ± 7 (35 ± 8)
75 – 125 12 (8) 50 ± 9 (43 ± 6)
> 125 3 52 ± 6
Patients Alcohol
RR
(compared to
no alcohol)
Reference
N = 400
chron. Hep B
≥ 3 days / week
> 15 years 3 – 5
Chen CJ, et al.
Hepatology
1991;13:398-406.
N = 341
HBSAg + 27 g / day 5
Oshima A, et al.
Int J Cancer
1984;34:775-9.
Risk of HCC in Patients with Hepatitis B and
Ethanol Consumption
Alcohol Research Center
University of Heidelberg
Effect of Alcohol on Various Liver Diseases
• Hepatitis C
• Hepatitis B
• Non-Alcoholic Fatty Liver Disease
• Hereditary Hemochromatosis
• Drug Induced Liver Injury
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Alcohol and nutrition
Moderate alcohol consumption
• Alcoholaddition
• 6-10 % of daily energie
• Metabolism by ADH
• Increase in weight
Alcohol Research Center
University of Heidelberg
Steatosis at ultrasound
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
C HD O O+HD
16
46
76
94,5
Bellentani & Tribelli. J Hepatol 2001; 35:591
HD = Ethanol > 60g/d O = BMI > 25kg/m2
Alcohol Research Center
University of Heidelberg
Obesity as a risk factor of ALD progression
Fibrosis ≤ 2
(n=151)
Fibrosis > 2
(n=117)
P
Age 50 ± 1 57 ± 1 <0.001
Female sex (%) 17 30 <0.01
BMI 23 ± 0.3 25 ± 0.4 <0.005
Alcohol (g/d) 110 ± 7 110 ± 6 NS
Alcohol (duration) 24 ± 1 30 ± 1 <0.005
Glucose 5.3 ± 0.1 7 ± 0.5 <0.01
Triglycerides 1.7 ± 0.3 1.5 ± 02 NS
Cholesterol 2.4 ± 0.1 2.3 ± 0.1 NS
Perl‘s grade 0.86 ± 0.06 1.18 ± 0.09 <0.005
Raynard et al. Hepatology 2002;35:635-8
0
20
40
60
80
100
120
140
Normal (BMI 21) Obese (BMI 29)
cirrhosis (%)
alcohol (g/d)
Naveau et al. Hepatology 1997;25:108-11
N=1,432
N=172
Alcohol Research Center
University of Heidelberg
Factors associated with HCC in NASH
(n = 195)
Alcohol Research Center
University of Heidelberg
Hazard Ratio
Characteristic (95% Confidence Interval) P Value
Age at time of cirrhosis diagnosis 1.07 (1.02-1.1) 0.012
Male sex 2.08 (0.94-4.6) 0.071
Non-Caucasian 0.92 (0.12-6.8) 0.93
BMI 0.94 (0.89-0.99) 0.025
Ever smoked 0.87 (0.39-1.9) 0.73
Any alcohol consumption 3.6 (1.5-8.3) 0.003
Diabetes mellitus 1.00 (0.40-2.5) 0.99
Ascha et al, Hepatology 2010; 1:1972-1978
Alcohol
Social Alcohol Intake compared with no Alcohol
Intake in the Development of HCC in HCV and
NASH
Alcohol Research Center
University of Heidelberg
Ascha et al, Hepatology 2010; 1:1972-1978
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Effect of Alcohol on Various Liver Diseases
• Hepatitis C
• Hepatitis B
• Non-Alcoholic Fatty Liver Disease
• Hereditary Hemochromatosis
• Drug Induced Liver Injury
Alcohol Research Center
University of Heidelberg
Iron Deposition in ALD and Hepatitis C
HCV ALD
Alkoholforschungszentrum
Universität Heidelberg
no of subjects
death or hospitalisation related to cirrhosis or HCC
per 100.000 person-years hazard ratio
Transferrin saturation
15-30% 4658 76 1
30-35% 1355 100 1.3
35-40% 906 101 1.3
40-50% 815 175 2.3
>50% 326 311 4.1
<15% 707 101 1.3
Alcohol consumption
>2 drinks/day 5499 346 4.1
Alcohol consumption and Tf-S
>2 drink/day + Tf-S>40% 2483 480 6.9
Data from National Health and Nutrition Examination Survey (NHANES I), Ioannou et al. Clin Gastro and Hepatol. 2007
Iron overload is a prognostic factor for liver
disease
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Gut 2000; 46:277-282
Effect of Alcohol on Various Liver Diseases
• Hepatitis C
• Hepatitis B
• Non-Alcoholic Fatty Liver Disease
• Hereditary Hemochromatosis
• Drug Induced Liver Injury
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Mol.Med 17, 1285-94, 2011
Histology and Liver Collagen Accumulation in
Alcohol-Treated wild type and CB1-/- Mice
Alcohol Research Center
University of Heidelberg
Patsenker et al. Mol Med. 2011 Aug 19;17(11-12):1285 - 94.
WT/no EtOH WT/EtOH
CB1-/-,EtOH CB1-/-,no EtOH
Alcohol and Cocaine
Cocaethylen
Cocaine + Ethanol
Cocaine alone
JPET 283,164-176, 1997
Kokaethylen
Kokain
+ Alcohol
100 mg Cocaine intranasal + Alcohol (0.8 g/kg)
Alcohol Research Center
University of Heidelberg
Hepatotoxicity of Ethanol plus Cocaine in
Mice
Drug Alcohol Dep 31:253, 1993
0
2
4
6
8
10
12
14
Con
jug
ate
d D
ien
es
Ctrl/
NaCl
Ctrl/
ETOH
Coc/
NaCl
Coc/
ETOH
0
2000
4000
6000
8000
10000
12000
14000
SG
PT
U/L
Ctrl/
NaCl
Ctrl/
ETOH
Coc/
NaCl
Coc/
ETOH
Alcohol Research Center
University of Heidelberg
Effect of Alcohol and
Cocaine on the
Cardiovascular System
placebo ( ), alcohol (), cocaine () and the
combination of alcohol and
cocaine ().
Alcohol Research Center
University of Heidelberg
Methotrexate
Injury to
stellate cells
Hepatocellular
necrosis
Injury to
limiting plate
Perioportal
fibrosis
Portal-portal
fibrosis
Steatosis
Cirrhosis
Fibroblast
activation
Centrizonal
fibrosis
Central-portal
fibrosis
Alcohol
Alcohol Research Center
University of Heidelberg
NADH+H+
NAD+
ADH
NAD+ NADH+H+
ALDH
Mitochondrium
Ethanol Acetaldehyde Acetate
Ethanol Metabolism
Cyp2E1
Microsomes
Cyp2E1
Drugs Metabolites
Procarcinogens Carcinogens
Vitamin A Metabolites
(toxic & apoptotic)
Alcohol Research Center
University of Heidelberg
alcoholic fatty liver after 14 days of alcohol abstinence
Cytochrom P450 2E1 – Induction by Alcohol
Alcohol Research Center
University of Heidelberg
Alcohol consumption and CYP2E1 activity
Oneta C, Lieber CS, Ji JJ, Rüttiman S, Rosman J, Seitz HK. J-Hepatol 2002;36:47-52
Alcohol Research Center
University of Heidelberg
Inhibition of Meprobamate Metabolism by Ethanol
50
100
150
200
Ethanol 0 10 mM
p<0,01
50 mM
p<0,01
100 mM
p<0,01
ngM
B /
g L
eber
/Std
Rubin et al, Am J. Med., 49, 801-6, 1970
Alcohol Research Center
University of Heidelberg
Chronic Ethanol Consumption enhances
Clearance
10
100
0 6 12 18 24
Stunden
Me
pro
ba
ma
t im
Blu
t %
Cm
ax
vor Alkohol nach Alkohol
Amer J Med 51:346-351, 1971
• Alcohol in a Dosis of 16% of total Calories during 1 month to 4 volunteers (ca. 50 g Alcohol/day)
• Meprobamat (Meprodil®) – Clear T1/2
• Pentobarbital
– Clear , T1/2
• Alcohol
– Elimination (13.8 → 23.8 mg/100ml/h)
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Metabolism of Isoniacid
Alcohol Research Center
University of Heidelberg
Isoniacid
Acetylisoniacid
Acetylhydrazin
Diacetylhydrazin
NAT2 (PM)
Hydrolyse
NAT2 (PM)
Hepatotoxins
CYP2E1 (PM)
Hepatotoxicity of Isoniacid
Risk factors
• Acetylator-Phenotype
• CYP4502E1
– Genotyp (Wildtype c1/c1 )
– Activity (Alcohol)
• Alcohol consumption
• Rifampicin (Enzyme induction)
• Age
Huang et al.,Hepatology 37:924, 2003
0%
5%
10%
15%
20%
25%
30%
fast slow
Incidence of transaminases >2x Norm
CYP4502E1 Genotype c2/c2 od c1/c2 c1/c1
Acetylators
Alcohol Research Center
University of Heidelberg
Äthanol und Mikrosomen
S
Normal Leber Mikrosomen
Akuter Äthanol Leber Mikrosomen
Chronischer Äthanol Leber Mikrosomen
Nach Entzug Leber Mikrosomen
S
E
S
E
S
P
A
P
A
P
P
Alcohol Research Center
University of Heidelberg
Interactions with Alcohol
Alcohol acute
• Frequently with oxidative
metabolized drugs:
Clearance decreases
Half life time increases
Bioavailability increases
• (Central acting drugs,
Antidiabetics, Nitrates)
• Acetylation increases
Alcohol chronic
Deterioration of Liver Function
Induction of CYP2E1
• Effects: partly moderate decrease
of half life time and increase of
clearance (approximately 10%) (ß-
blockers, anticoagulants )
Dosisadaptation
• However:
• Increased Toxicity of Isoniazide,
Paracetamol, Cocaine
Alcohol Research Center
University of Heidelberg
CASE
40-year old patients suffers from depression and takes the following
drugs:
Amitryptilin (Saroten, Tryptizol), Ranitidin (Zantic), Ketoprofen
(Fastum), Paracetamol
Recently Fluoxetin (zB Fluctine) (40mg/day) was added..
On december 16th she visited a christmas party together with her
husband. Here she consumes a hot alcoholic beverage. She returns
home by 3 a.m. and takes one tablet of of amitryptiline before sleep. .
At 4.30 a.m. her husband wakes up due to her heavy breathing. He
realizes that she is unconscious.
In the Hospital her alcohol blood level is 1.3 g/l. EKG shows
supraventricular tachycardia and a prolongated QRS interval. The
patients is still unconscious and is transfered to the ICU.
Alcohol Research Center
University of Heidelberg
At the present levels of Fluoxetin
plus Metabolite 95% of fast
metabolizers shift to phenotypic
slow CYP2D6 metabolizers.
A blood alcohol level of 1.3 g/L
interfers with the First-Pass
Metabolism of Amitryptilin and the
bioavailability is increased by a
factor of 2.
Bloood Levels of Amitryptilin Alcohol Research Center
University of Heidelberg
Interaction between ethanol and xenobiotic metabolism at
the CYP2E1 site
Drugs Chemicals Carcinogens
Chemotherpeutics:
5 FU, Cyclophosphamid
Anesthetics:
Enfluoran,Isofluran,Methox
yfluran,Sevofluran
Central acting drugs:
Barbiturate, Meprobamat,
Tranquilizer
Acetaminophen
(Paracetamol)
Phenytoin
Propranolol
Isoniacid
Rifamipicin, Tolbutamide
Methadon
Warfarin
Aceton,
Butanol,
Pentanol
Anililn
Benzen,
Bromobenzen
CCI4
Solvents
Vinyle chloride
Acetyl Amino Fluorene,
2-Amino Fluorene
4-Amino Biphenyl
Aflatoxin
Amino Acid, Pyrrolyzates
Benzo (2) Pyrene
Dimethylhydrazine
Nitrosamine
Others
Vitamine A
Universität Heidelberg
AFZ
Alcohol Research Center
University of Heidelberg
0
100
200
300
400
500
600
700
800
900
Normal Liver Fatty liver Alcoholic liver Cirrhosis
hepatic
vita
min
e A
(µ
g/g
wet w
eig
ht)
< 0.001 < 0.001 < 0.001
Liver autopsy
diabetes
Alcoholic liver disease and vitamine A
Concentration in the liver
Leo und Lieber, 1982
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Retinoids, Ethanol and Cancer
RETINOL RETINAL RETINOIC ACID
RETINOIC ACID
ETHANOL
CYP2E1
ADH ALDH
METABOLITES
(apoptotic)
AP-1 GENE EXPRESSION
HYPERPROLIFERATION
Alcohol Research Center
University of Heidelberg
Summary and Conclusion
• Chronic alcohol consumption is a risk factor for the deterioration of various types of liver disease such as hepatitis B and C, NAFLD, HH and DILI including cannabis and vitamin A associated liver fibrosis.
• Depending on the underlying liver disease this negative effect of alcohol is time and dose dependent, but may occur already at much lower alcohol intake as compared to an alcohol dose necessary to initiate alcoholic liver disease itself.
• As a consequence alcohol intake should be avoided or at least limited and certainly not consumed chronically under these conditions.
Alcohol Research Center
University of Heidelberg
PRM-INDUCED DNA
FRAGMENTATION IN HEP G2 CELLS
Dan et al. FASEB J 19;1-4, 2005
Alcohol Research Center
University of Heidelberg
Control (120h) PRM (24h) PRM (48h)
PRM (72h) PRM (96h) PRM (120h)
B
0
5
10
15
20
25
Control 24 48 72 96 120
Time (h)
% o
f S
ub-G
1
PRM – INDUCED TOXICITY
Dan et al. FASEB J 19;1-4, 2005
Alcohol Research Center
University of Heidelberg
C AST C AST
A LDH
B LDH
0
10
20
30
40
50
60
70
80
90
100
0 3 6 12 24
Time (h)
LD
H le
akage (
%)
PRM
Control
C AST D AST
0
10
20
30
40
50
60
70
80
90
0,02 0,04 0,075 0,15 0,3
PRM Concentration ( m M)
AS
T le
akage (
%)
PRM
Control
0
3
6
9
12
15
0 3 6 12 24
Time (h)
AS
T le
akage (
x-f
old
to c
ontr
ol)
80
m
0
10
20
30
40
50
60
70
LD
H le
akage (
%)
PRM
Control
0.02 0.04 0.075 0.15 0.3
PRM concentration ( M)
Dan et al. FASEB J 19;1-4, 2005
A
Control (24 h) PRM (1 h) PRM (3 h)
PRM (6 h) PRM (12 h) PRM (24 h)
PRM (6h) PRM (12h) PRM (24h)
Control (120h) PRM (1h) PRM (3h)
Alcohol Research Center
University of Heidelberg
EFFECT OF PRM ON MITOCHONDRIAL MEMBRANE
POTENTIAL
Alkohol als Risiko-Faktor für Paracetamol Hepatotoxizität
Ann Intern Med 104:399, 1986
toxic range
for non-
alcoholics
Experimentell:
• Akuter Alkohol schützt vor
Toxizität
• Chronischer Alkohol erhöht
Toxizität
Universität Heidelberg
AFZ
100
1000
10000
100000
0 10 20 30
Dose of Paracetamol g/24h
AS
T I
U/L
Paracetamol, GSH-Metabolite und Plasma GSH Plasma GSH wurde nach 2 g Paracetamol in 5 Alkoholikern und 5 Kontrollen gemessen
Velez und Lauterburg, Gut 29:1153, 1988
p<0.02 vs baseline
Mercaptur-
säure Addukt
Cystein
Addukt
Universität Heidelberg
AFZ
2g Paracetamol
0
100
200
300
µm
ol/
6h
Controls Alcoholics
0
2
4
6
8
10
0 2 4
Time after Paracetamol (h)
Pla
sma
GS
H n
mo
l/m
l
Controls Alcoholic Subjects
Pharmakodynamische Interaktion mit Antihistaminikum Hydroxyzin (Atarax) 50 mg + 0.3 g/kg Alkohol (ca. 0.5 Promille)
-5
0
5
10
15
20
25
30
35
0 2 4 6
Stunden
Mo
tor
Re
actio
n T
ime
(m
s)
Plazebo Plazebo+ETOH
Hydroxizin Hydroxizin+ETOH
Clin Ther 2003;25:1518-38
Universität Heidelberg
AFZ
% p
ositiv
e c
ells
for ed
A
Correlation between 4HNE, CYP2E1 and
etheno-DNA-adducts in liver biopsies
% p
ositiv
e c
ells
for ed
A
CYP2E1 staining intensity
1 2 3
0 2
0 4
0 6
0 8
0
1 2 3
0 2
0 4
0 6
0 8
0
4-HNE staining intensity
r = 0.846, p<0.01 r = 0.93, p<0.01
Alcohol Research Center
University of Heidelberg
Wang et al. Hepatology 2009;50:453-61
H.K. Seitz & F. Stickel 2007
Alcohol Research Center
University of Heidelberg
HCV, alcohol and oxidative stress
Inflammation / Liver Damage
NFκB
STAT-3
Products of
Lipid peroxidation
Fibrosis
HCV
Mitochondrial
Damage,
Steatosis
ROS
HCC
Ethanol
Iron
Alcohol Research Center
University of Heidelberg
Mechanisms of Alchohol-HCV Interaction
• HCV Replication (intracellular signal transduction)
(Plumlee et al. 2005)
• HCV Genomes (quasi species) (Takahashi et al. 2001)
• Apoptosis (Szabo 2003)
• Immunomodulation (Geissler at al. 1997)
• Oxidative stress (cytochrome P-4502E1, Iron, glutathion)
(Seitz and Stickel 2007)
• Steatosis (Serfaty et al. 2002)
Alcohol Research Center
University of Heidelberg
Liver histology in rats following the administration
of various diets
Wang Y, Seitz HK, Wang XD, ACER 34, 567-573, 2010
Alcohol Research Center
University of Heidelberg
A
D
B
F E
C A B
D
Control diet
Control diet
High fat diet High fat diet
with alcohol
E F High fat diet High fat diet
with alcohol
Interactions with Alcohol
acute alcohol
• In most cases due to
oxidatively metabolized
drugs:
Decreasing clearance
Increasing half-life
Increasing bioavailability
• (antipsychotic drugs, anti
diabetic drugs, nitrates)
• Increasing acetylization
chronic alcohol consumption
Decreasing liver function
Induction of CYP2E1
• Result: partially low half-life and
increase in clearance (ca 10%)
(ß-blockers, anticoagulants)
• evt. dosis adaptation
• But:
Increase in toxicity of Isoniazid,
Paracetamol, Cocaine
Alcohol Research Center
University of Heidelberg
Glassen K, Seitz HK 2010
Alcohol Research Center
University of Heidelberg
Wölk und Wedemeyer, Hepatology 2008; 47: 343-5
Hepatitis C und Fettstoffwechsel
Alcohol as a risk factor for für
paracetamol hepatotoxicity
Ann Intern Med 104:399, 1986
toxic range
for non-
alcoholics
experimental:
• Acute alcohol protects against
toxicity
• Chronic alcohol increases
toxicity
Alcohol Research Center
University of Heidelberg
100
1000
10000
100000
0 10 20 30
Dose of Paracetamol g/24h
AS
T I
U/L
0
2
4
6
8
10
0 2 4
Time after Paracetamol (h)
Pla
sm
a G
SH
nm
ol/
ml
Controls Alcoholic Subjects
Paracetamol, GSH-Metabolite and Plasma GSH Plasma GSH has been found in 5 alcoholics and 5 controls after administration of 2 g
paracetamol
Velez und Lauterburg, Gut 29:1153, 1988
p<0.02 vs baseline
Mercaptur-
acid adduct
Cysteine
adduct
2g Paracetamol
0
100
200
300
µm
ol/
6h
Controls Alcoholics
Alcohol Research Center
University of Heidelberg
εdA and εdC correlate in liver biopsies
% positive cells for edC 0 20 40 60 80
% p
ositiv
e c
ells
for ed
A
0 2
0 4
0 6
0 8
0
r = 0.97, p<0.01
Alcohol Research Center
University of Heidelberg
Wang et al. Hepatology 2009;50:453-61
Alkohol und HCV-Replikation
Plumlee et al. Virology Journal 2005; 2: 89
ETHANOL
- Membranproteine?
- Fluidität? Hemmung v. IFNAR?
Hemmung v. Jak?
SOCS Induktion?
↓ Stat1 Y701 ↑ Stat1 S727 ↑ p38 MAPK
↑ Antiviraler
Signalweg
IFN
↓ Antiviraler
Signalweg
↓ HCV Replikation ↑ HCV Replikation
Andere Signalproteine?
X
Mitogen-Aktivierte-Protein-Kinase (MAPK),
Signaltransduktoren und Aktivatoren der Transkription (STAT) Janus associated kinase (JaK)
Suppressors of cytokine signalling (SOCS) Interferon-Alpha Rezeptor (IFNAR)
Alcohol Research Center
University of Heidelberg
• Design: patients with AH (DF > 32)
• Double-blind, Placebo-controlled (3 x 400 mg /d)
over 28 days
• primary end points:
• short term survival, HRS
Akriviadis et al., Gastroenterology2000;119:1637
0
10
20
30
40
50
60
70
80
90
100
PTX CTR
28 days mortality
p = 0,037
%
Result:
• improved survival, less HRS.
• decreased TNFα level
• higher effects through steroids
than expected
Pentoxifyllin in AH Alcohol Research Center
University of Heidelberg
ethanol
ROS
(H2O2)
iron accumulation
Iron Accumulation by Ethanol
toxicity
hepcidin
iron absorption
iron release
TfR1
iron uptake
Alcohol Research Center
University of Heidelberg
Isolated GGT-Elevation
1. Alcohol
2. NAFLD
3. Drugs
4. Myocardial Infarction, Insuff.
5. Acute Pankreatitis
6. Hypothyreodism
7. Anorexia nervosa
8. Myotonic Muscle Dystrophia
9. Guillain-Barre Syndrome
10. Porphyria Cutanea Tarda
11. Neurologic Diseases
12. Malignant Diseases / Radiotherapy
Alcohol Research Center
University of Heidelberg
Comparison of CDT, GGT, MCV
in Alcoholic Liver Disease
Marker Sensitivity(%) Specifity (%)
CDT 61 92
GGT 85 18
MCV 70 66
Bell et al., Alc Clin Exp Res 17, 246:1993
Alcohol Research Center
University of Heidelberg
Prevalence of Fractures
(Rips, vertebra, clavicle)
0
10
20
30
40
Alcohol.
Cirrhosis
Other
Cirrhosis
Controls Alcohol
Intoxication
p < 0.02 p < 0.001
Moreau et al., Alcoholism Clin Exp Res 16,141:1992
Alcohol Research Center
University of Heidelberg
Patients
with
fractu
res
Specifity and Sensitivity of Various Markers in
ALD
Marker Specifity (%) Sensitivity (%)
Gamma-GT 17 85
MCV 36 66
Thorax Fractur 96 27
Moreau et al., Alcoholism Clin Exp Res 16,141:1992
Alcohol Research Center
University of Heidelberg
Case Report I
Female, 62 years, LTx 3 years ago due to PSC with
elevated serum transaminase activities.
BMI: 17 kg/m2, no DM, normal lipids, graft intact.
Liver Biopsy: massive steatosis, no PSC
Ethylglucuronid: > 2000 µg/g Creatinine
Alcohol Research Center
University of Heidelberg
Case Report III
Male, 42 years, LTx 3 years ago due to PSC, Recurrence of PSC in the
transplant.
Laboratory: GOT: 42U/L, GPT: 42U/L, GGT: 279 U/L, AP: 301 U/L
EtG: 475 µg/g Creatinine
The day before: Champion of Pistol shooting
Alcohol Research Center
University of Heidelberg
Matrix Metalloproteinases mRNA in Alcohol-
Induced Liver Injury in wild type and CB1-/-
Mice
Alcohol Research Center
University of Heidelberg
Patsenker et al. Cannabinoid Receptor Type I Modulates Alcohol-Induced
Liver Fibrosis. Mol Med. 2011 Aug 19;17(11-12):1285 - 94.
Fibrosis related mRNA Transcript in Alcohol-
Induced Liver Injury in wild type and CB1-/- Mice
Alcohol Research Center
University of Heidelberg
Patsenker et al. Cannabinoid Receptor Type I Modulates Alcohol-Induced
Liver Fibrosis. Mol Med. 2011 Aug 19;17(11-12):1285 - 94.
CB1 and CB2 Expression in Human ALD
Alcohol Research Center
University of Heidelberg
Patsenker et al. Cannabinoid Receptor Type I Modulates Alcohol-Induced
Liver Fibrosis. Mol Med. 2011 Aug 19;17(11-12):1285 - 94.
Hepatic Inflammation after Alcohol-Induced
Liver Injury in wild Type and CB1-/- Mice
Alcohol Research Center
University of Heidelberg
Patsenker et al. Cannabinoid Receptor Type I Modulates Alcohol-Induced
Liver Fibrosis. Mol Med. 2011 Aug 19;17(11-12):1285 - 94.
Laboratory Pitfalls
Serum GGT Activity
Serum Transaminase Activity (AST/ALT)
Serum Ferritin
Alcohol Research Center
University of Heidelberg
Histologic Prognostic Factors
Little or no Megamitochondria
Reduced Infiltration of PMNs
Increased Number of Progenitor Cells
Cholestasis
Alcohol Research Center
University of Heidelberg
PARENTERAL NUTRITION
7 RCTs ; n = 244
21-30 days outcome:
Improvement in albumine and nitrogen balance.
No survival benefit.
Alcohol Research Center
University of Heidelberg
LTX in Alcoholic Cirrhosis with and without
Alcoholic Hepatitis
Tome et al. J Hep 36,793,2002
Alcohol Research Center
University of Heidelberg
Alcohol consumption and fibrosis
Poynard et al. Lancet 1997; 349: 825-832
4.0
1.0
<10 11-20 21-30 31-40 >40
Duration of infection (years)
Grade of fibrosis
>50 g
Alcohol per
day
0-49 g
Alcohol per
day
n=1.039
Alcohol Research Center
University of Heidelberg
Alcohol consumption and fibrosis
Poynard et al. Lancet 1997; 349: 825-832
4.0
1.0
<30 31-40 41-50 51-60 >60
Age at biopsy (years)
Grade of fibrosis
>50 g
Alcohol per
day
0-49 g
Alcohol per
day
n=1.574
Alcohol Research Center
University of Heidelberg
Alcohol, HCC & HCV infection
Study Result
HCV & HCC > 80 x 10 J HCC with alcohol earlier as
without (p < 0,05) Matsuda et al. 1995
Kuwana et al. 1997
HCV & HCC
> 80 Alcohol with RR =1,9
Tagger et al. 1999 CCRS 0-40; 41-80; >80 RR for HCV + 26, 63, 126
Kwon et al. 2000 RS (AC) > 80; > 5 J 34 % with AC + HCV vs. 6%
with AC without HCV
Khan u. Yatsuhashi 2000
RS (HCV) < 80; > 80 1,5x - 2,5x increased risk for HCC
HCV und HCC > 65; > 5 J Alcohol with RR = 3,04 Aizawa et al. 2000
Donato et al. 2002 CCRS > 60 2x increased risk for HCC
Hassan et al. 2002 HBCCS > 80 RR: Alcohol = 4, HCV =15,
Alcohol + HCV = 54
Alcohol (g/d) Author
75
343
915
162
120
153
1.150
345
N
Alcohol Research Center
University of Heidelberg
Effect of Acetaldehyde, H2O2, Hypoxia and Endo- and
Exocannabinoids on CB1 and Fibrosis-related mRNA in
HSC
Alcohol Research Center
University of Heidelberg
Patsenker et al. Cannabinoid Receptor Type I Modulates Alcohol-Induced
Liver Fibrosis. Mol Med. 2011 Aug 19;17(11-12):1285 - 94.
PREVALENCE
The Prevalence of AH is Population dependent.
A 20% Prevalence has been reported in a Biopsy Study with more than
1500 Alcoholic Patients.
Approximately 6% of all Patients with Hepatic Decompensation and
25% o an Acute on Chronic Liver Failure reveal AH (EASL
Guidelines 2012).
Alcohol Research Center
University of Heidelberg
Cause of liver disease regarding 1.829 patients with
cirrhosis & 217 patients with HCC
De Bac et al. Hepatology 1994; 20: 1225-30. ; Morgan et al. Gastroenterology 2004; 127(Suppl 1): S87-S96
Cause of cirrhosis
HBV
HCV
Alcohol
Alcohol + HCV
HBV + HCV
75 ( 4.1)
873 (47.7)
159 ( 8.7)
387 (21.2)
58 ( 3.2)
12 ( 5.5)
90 (41.5)
16 ( 7.4)
62 (28.6)
5 ( 2.3)
12/75 (16.0)
90/873 (10.3)
16/159 (10.1)
62/387 (16.0)*
5/58 ( 8.6)
Cirrhosis
Quantity (%)
Quantity HCC (% of
217 patients with
HCC)
% cirrhotic
patients with
HCC
* p < 0,005 vs. Alkohol und vs. Hepatitis C
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Occurence of Death according to the Presence or
Absence of stainable hepatic Iron in Patients with
Alcoholic Cirrhosis
Alcohol Research Center
University of Heidelberg
Threshold of Hepatic Iron Score=1 Threshold of Hepatic Iron Score=5
Ganne-Carrie et al., Gut 2000; 46:277-282
Lille Score and Response to Steroid Therapy
Alcohol Research Center
University of Heidelberg
Alcohol is a severe risk factor in the
progression of hepatitis C
1. Fibrogenesis is dose-dependent and starts already with small
amounts of alcohol (less than 30 g per day). There is no safe
dose of alcohol for patients with HCV infection, obese patients
and diabetics are particularly at risk. (Monto et al, Hepatology
39, 826-34:2004).
2. HCV patients with a history of excessive alcohol consumption
have a 2-3-fold increased risk to develop severe liver diseases
compared to HCV patients without alcohol consumption in the
past (Delarocque-Astagneau et al, Ann Epidemiol 15,551-
557:2005).
Alcohol Research Center
University of Heidelberg
Alcohol Research Center
University of Heidelberg
Lin et al, J Hep 2013; 58: 730-735
Effect of HBV DNA load in alcoholic
cirrotics on HCC incidence
Effect of antiviral therapy in alcoholic
cirrotics with HBV infection on HCC
incidents
GAHS, Steroids & 28 Days Mortality
• 188 patients with ASH
all DF >32
• GAHS > 9 at 64 %
• patients with GAHS < 9
have an excellent
prognosis without therapy
• GAHS > 9 = poor
prognosis without steroids
Forrest Gut 2007
Alcohol Research Center
University of Heidelberg
Naveau S et al Hepatology 2004
Corticosteroid group 82 %
Infliximab group 61 %
100 %
80 %
60 %
40 %
20 %
0 % 0 10 20 30 40 50 60
Days
TNFα Antibodies: Reduced Survival in the French
Randomized Controlled Study
3 doses 10 mg / kg in 15 days!
Alcohol Research Center
University of Heidelberg