barcelona . spain - European Association for the Study of the Liver
barcelona . spain - European Association for the Study of the Liver
barcelona . spain - European Association for the Study of the Liver
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BARCELONA . SPAIN<br />
50 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 51<br />
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012<br />
NOTES<br />
liver cirrhosis whereas o<strong>the</strong>rs do not, even after several decades <strong>of</strong> exposure to ethanol, suggesting <strong>the</strong><br />
major impact <strong>of</strong> c<strong>of</strong>actors <strong>for</strong> fibrosis progression. Overweight and obesity are well-documented risk factors<br />
<strong>for</strong> <strong>the</strong> development <strong>of</strong> cirrhosis (2). Alcoholic and non-alcoholic fatty liver disease share similar pathways<br />
<strong>of</strong> hepatocyte injury (e.g. activation <strong>of</strong> type 1 liver macrophages, resistance to adiponectin) and obesity is<br />
associated with a more rapid progression <strong>of</strong> hepatic fibrosis in experimental models (3). As example, in<br />
a series <strong>of</strong> more than 1,600 patients with an alcohol intake greater than 50g/day, liver biopsy found liver<br />
cirrhosis in 60% <strong>of</strong> overweight patients, as compared to 35% in non overweight (2). The risk <strong>of</strong> alcoholic<br />
liver disease is higher when alcohol is consumed outside mealtimes, leading to a risk <strong>of</strong> hepatic injury,<br />
cirrhosis and hepatocellular carcinoma (4). This is probably related to a more rapid absorption <strong>of</strong> ethanol<br />
and to changes in gut permeability, as may be observed in binge drinking. The deleterious impact <strong>of</strong> drinking<br />
outside mealtimes also seems to be related to changes in gastric alcohol dehydrogenase and hepatic<br />
glutathione (4).<br />
Regarding binge drinking, its definition is not consensual but <strong>the</strong> National Institute on Alcohol Abuse<br />
and Alcoholism has proposed <strong>the</strong> threshold <strong>of</strong> 5 drinks in <strong>the</strong> space <strong>of</strong> 2 hours (4 drinks <strong>for</strong> women). To<br />
date, we have no robust data that prove <strong>the</strong> negative impact <strong>of</strong> binge drinking on fibrosis progression (5).<br />
However, some experimental studies have suggested that binge drinking is associated with increased gut<br />
permeability that leads to <strong>the</strong> release <strong>of</strong> endotoxin and cytokines, <strong>the</strong>re<strong>for</strong>e enhancing liver inflammation<br />
and fibrosis. Ano<strong>the</strong>r key effect <strong>of</strong> binge drinking on <strong>the</strong> liver is mitochondrial dysfunction, caused ei<strong>the</strong>r by<br />
lipid peroxidation and selective depletion <strong>of</strong> mitochondrial (5).<br />
Several studies indicate that cigarette smoking worsens fibrosis in liver diseases, especially in hepatitis<br />
C, hepatitis B and primary biliary cirrhosis (6). It must be acknowledged that no data are available in<br />
<strong>the</strong> specific setting <strong>of</strong> alcoholic liver disease. Tobacco is also a well-documented risk factor <strong>of</strong> HCC with<br />
risk-ratio ranging from 1.49 to 9.6, regardless <strong>of</strong> <strong>the</strong> cause (6). Thus, more attention must be paid to<br />
obtain tobacco withdrawal in patients suffering from chronic liver diseases, especially in alcoholic liver<br />
disease when considering <strong>the</strong> synergic risk <strong>of</strong> tobacco on oral, pharyngeal and esophageal cancers in<br />
heavy drinkers.<br />
In this patient, episodes <strong>of</strong> binge drinking, alcohol consumption outside meals, cigarette smoking and<br />
obesity may have promoted <strong>the</strong> evolution <strong>of</strong> fibrosis to cirrhosis.<br />
Question 2: What is your feeling about sobriety when considering <strong>the</strong> results <strong>of</strong> GGT, MCV and AST<br />
Answer:<br />
Elevation in γ-glutamyltransferase (GGT) and mean corpuscular volume (MCV) are currently considered as<br />
indicators <strong>for</strong> chronic alcohol abuse, but no single laboratory marker can be considered as diagnostic in this<br />
setting (7). The sensitivity and specificity <strong>of</strong> GGT <strong>for</strong> chronic alcohol consumption above 50 g/day are 73%<br />
and 75% respectively, and it is important to point out that <strong>the</strong> specificity <strong>of</strong> γ-glutamyltransferase is far lower<br />
in patients with advanced fibrosis. However, <strong>the</strong> rate <strong>of</strong> GGT is usually higher in patients with alcoholic liver<br />
cirrhosis, as compared with patients with o<strong>the</strong>r liver diseases. Lastly, elevated GGT is frequently observed<br />
in obese patients, especially in men (8). Elevation in mean corpuscular volume is related to a direct toxicity<br />
<strong>of</strong> ethanol on <strong>the</strong> erythrocyte membrane. The diagnostic accuracy <strong>of</strong> an elevated MCV is not very different<br />
from that <strong>of</strong> GGT, with respective sensitivity and specificity at 52% and 85% (7). However, <strong>the</strong> relatively good<br />
specificity must be tempered by <strong>the</strong> possibility <strong>of</strong> o<strong>the</strong>r causes <strong>for</strong> macrocytosis in cirrhotics, in particular<br />
low folate concentration in serum (due to a certain degree <strong>of</strong> malnutrition) and/or acquired injuries <strong>of</strong> <strong>the</strong><br />
erythrocyte membrane (such as spur cells or burr cells), which may cause hemolysis and disturbed MCV.<br />
Elevation in transaminases, especially aspartate amino transferase (AST) is commonly seen in alcoholic<br />
liver disease and its sensitivity is around 50% with specificity at 80%. The AST/ALT ratio is usually greater<br />
than 1 but this is commonly seen in patients with advanced liver disease, especially cirrhosis, regardless<br />
<strong>of</strong> <strong>the</strong> cause (9).<br />
In this patient, measurement <strong>of</strong> carbohydrate deficient transferrin (CDT) can be proposed but its good<br />
specificity (92%) is hampered by a sensitivity that is not better than that <strong>of</strong> GGT (69%). Thus, this parameter<br />
is mainly interesting when elevated.<br />
Question 3: You recommend liver biopsy to establish <strong>the</strong> diagnosis <strong>of</strong> cirrhosis but <strong>the</strong> patient refuses to<br />
undergo <strong>the</strong> procedure. Which alternative tools can be used to assess liver fibrosis<br />
Answer:<br />
<strong>Liver</strong> biopsy is still <strong>the</strong> gold standard <strong>for</strong> <strong>the</strong> diagnosis <strong>of</strong> alcoholic liver disease. However, when considering<br />
<strong>the</strong> morbidity <strong>of</strong> this invasive procedure and <strong>the</strong> number <strong>of</strong> patients with abnormal liver tests related to<br />
chronic alcohol consumption, it is unrealistic to propose liver biopsy to all patients. It seems reasonable<br />
to screen heavy drinkers <strong>for</strong> fibrosis using non-invasive tools. Fibrotest ® , FibrometerA ® and Hepascore ®<br />
are <strong>the</strong> three combinations <strong>of</strong> biomarkers that have proven <strong>the</strong>ir relevance in compensated alcoholic<br />
liver disease (10). The diagnostic accuracy <strong>of</strong> <strong>the</strong>se three markers was comparable in terms <strong>of</strong> fibrosis<br />
extent in a recent prospective study <strong>of</strong> more than 200 patients who had undergone liver biopsy (10). The<br />
respective areas under <strong>the</strong> ROC curve were 0.83 <strong>for</strong> <strong>the</strong> three scores <strong>for</strong> <strong>the</strong> diagnosis <strong>of</strong> fibrosis greater<br />
or equal than F2 and were <strong>the</strong> following <strong>for</strong> <strong>the</strong> diagnosis <strong>of</strong> cirrhosis: 0.94 (Fibrotest ® ), 0.94 (FibrometerA ® )<br />
and 0.92 (Hepascore ® ). These per<strong>for</strong>mances were superior to that <strong>of</strong> APRI, Forns and FIB4 scores but<br />
were not improved by <strong>the</strong>ir combination <strong>of</strong> one to ano<strong>the</strong>r. Transient elastography (Fibroscan ® ) has also<br />
demonstrated to be a valid and reproducible non-invasive tool <strong>for</strong> <strong>the</strong> assessment <strong>of</strong> fibrosis in alcoholic liver<br />
disease. However, it must be kept in mind that it is not only influenced by fibrosis, but also by inflammation,<br />
cholestasis and abstinence or alcohol relapse. Never<strong>the</strong>less, two large studies have shown good AUROC<br />
curves: 0.92 (11) and 0.87 (12) <strong>for</strong> <strong>the</strong> diagnosis <strong>of</strong> cirrhosis. However, cut-<strong>of</strong>fs <strong>for</strong> <strong>the</strong> definition <strong>of</strong> cirrhosis<br />
are far higher than those used <strong>for</strong> hepatitis C and <strong>the</strong> optimal value which predicts a METAVIR score F4 is<br />
still to be determined (19.5 kPa in (11) and 22.6 in (12)). In this patient, it seems reasonable to evaluate liver<br />
fibrosis using Fibrotest ® , FibrometerA ® or Hepascore ® and to take measurements <strong>of</strong> liver stiffness using<br />
Fibroscan ® .<br />
Question 4: Which pharmacological strategy do you recommend <strong>for</strong> sobriety maintenance<br />
Answer:<br />
Persistence <strong>of</strong> craving episodes in this patient argues <strong>for</strong> a pharmacological support to reach long-term<br />
abstinence. Disulfiram inhibits <strong>the</strong> liver enzyme aldehyde dehydrogenase, leading to <strong>the</strong> accumulation <strong>of</strong><br />
acetaldehyde and to a flushing reaction characterized by tachycardia, nausea, vomiting, and hypotension.<br />
Despite some heterogeneity between studies, a meta-analysis on more than 1,500 patients has shown that<br />
disulfiram used in a supervised manner was more efficient than placebo to reach abstinence Disulfiram has<br />
not been evaluated in patients with liver cirrhosis and systemic effects related to <strong>the</strong> pharmacological effect<br />
<strong>of</strong> disulfiram must lead to be very cautious in its use in <strong>the</strong>se patients. A systematic review published in 2010<br />
(13) has compelled 24 randomized controlled trials and has demonstrated that acamprosate, a glutamate<br />
antagonist, is effective in promoting abstinence in increasing abstinence duration by 11% as compared to<br />
placebo. Acamprosate was not associated with any hepatotoxicity but none <strong>of</strong> <strong>the</strong> studies included in this<br />
meta-analysis had included patients with liver cirrhosis. Naltrexone is an opioid antagonist that has been<br />
proved to maintain abstinence in several studies, especially when its long-acting injectable <strong>for</strong>m is used<br />
(14). In <strong>the</strong> most recent series on more than 600 patients (14), <strong>the</strong> 380 mg monthly dose <strong>of</strong> naltrexone was<br />
more likely to maintain abstinence than <strong>the</strong> 190 mg dose or than <strong>the</strong> placebo (<strong>the</strong> 380 mg dose reducing<br />
heavy drinking by 25% as compared to placebo). There was no evidence <strong>for</strong> hepatotoxicity in this series<br />
but patients with transaminases greater than 3 times <strong>the</strong> upper limit <strong>of</strong> <strong>the</strong> normal value were excluded from<br />
<strong>the</strong> study. Lastly, naltrexone in combination with behavioural intervention seems to be more efficient than<br />
acamprosate in a large study in patients without alcoholic liver disease (15).<br />
Thus, naltrexone and acamprosate are promising drugs but <strong>the</strong>y have not been tested in cirrhotic patients<br />
with alcoholic liver disease and are potentially responsible <strong>for</strong> hepatotoxicity in <strong>the</strong>se patients, as well as