barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
50 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 51
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
NOTES
liver cirrhosis whereas others do not, even after several decades of exposure to ethanol, suggesting the
major impact of cofactors for fibrosis progression. Overweight and obesity are well-documented risk factors
for the development of cirrhosis (2). Alcoholic and non-alcoholic fatty liver disease share similar pathways
of hepatocyte injury (e.g. activation of type 1 liver macrophages, resistance to adiponectin) and obesity is
associated with a more rapid progression of hepatic fibrosis in experimental models (3). As example, in
a series of more than 1,600 patients with an alcohol intake greater than 50g/day, liver biopsy found liver
cirrhosis in 60% of overweight patients, as compared to 35% in non overweight (2). The risk of alcoholic
liver disease is higher when alcohol is consumed outside mealtimes, leading to a risk of hepatic injury,
cirrhosis and hepatocellular carcinoma (4). This is probably related to a more rapid absorption of ethanol
and to changes in gut permeability, as may be observed in binge drinking. The deleterious impact of drinking
outside mealtimes also seems to be related to changes in gastric alcohol dehydrogenase and hepatic
glutathione (4).
Regarding binge drinking, its definition is not consensual but the National Institute on Alcohol Abuse
and Alcoholism has proposed the threshold of 5 drinks in the space of 2 hours (4 drinks for women). To
date, we have no robust data that prove the negative impact of binge drinking on fibrosis progression (5).
However, some experimental studies have suggested that binge drinking is associated with increased gut
permeability that leads to the release of endotoxin and cytokines, therefore enhancing liver inflammation
and fibrosis. Another key effect of binge drinking on the liver is mitochondrial dysfunction, caused either by
lipid peroxidation and selective depletion of mitochondrial (5).
Several studies indicate that cigarette smoking worsens fibrosis in liver diseases, especially in hepatitis
C, hepatitis B and primary biliary cirrhosis (6). It must be acknowledged that no data are available in
the specific setting of alcoholic liver disease. Tobacco is also a well-documented risk factor of HCC with
risk-ratio ranging from 1.49 to 9.6, regardless of the cause (6). Thus, more attention must be paid to
obtain tobacco withdrawal in patients suffering from chronic liver diseases, especially in alcoholic liver
disease when considering the synergic risk of tobacco on oral, pharyngeal and esophageal cancers in
heavy drinkers.
In this patient, episodes of binge drinking, alcohol consumption outside meals, cigarette smoking and
obesity may have promoted the evolution of fibrosis to cirrhosis.
Question 2: What is your feeling about sobriety when considering the results of GGT, MCV and AST
Answer:
Elevation in γ-glutamyltransferase (GGT) and mean corpuscular volume (MCV) are currently considered as
indicators for chronic alcohol abuse, but no single laboratory marker can be considered as diagnostic in this
setting (7). The sensitivity and specificity of GGT for chronic alcohol consumption above 50 g/day are 73%
and 75% respectively, and it is important to point out that the specificity of γ-glutamyltransferase is far lower
in patients with advanced fibrosis. However, the rate of GGT is usually higher in patients with alcoholic liver
cirrhosis, as compared with patients with other liver diseases. Lastly, elevated GGT is frequently observed
in obese patients, especially in men (8). Elevation in mean corpuscular volume is related to a direct toxicity
of ethanol on the erythrocyte membrane. The diagnostic accuracy of an elevated MCV is not very different
from that of GGT, with respective sensitivity and specificity at 52% and 85% (7). However, the relatively good
specificity must be tempered by the possibility of other causes for macrocytosis in cirrhotics, in particular
low folate concentration in serum (due to a certain degree of malnutrition) and/or acquired injuries of the
erythrocyte membrane (such as spur cells or burr cells), which may cause hemolysis and disturbed MCV.
Elevation in transaminases, especially aspartate amino transferase (AST) is commonly seen in alcoholic
liver disease and its sensitivity is around 50% with specificity at 80%. The AST/ALT ratio is usually greater
than 1 but this is commonly seen in patients with advanced liver disease, especially cirrhosis, regardless
of the cause (9).
In this patient, measurement of carbohydrate deficient transferrin (CDT) can be proposed but its good
specificity (92%) is hampered by a sensitivity that is not better than that of GGT (69%). Thus, this parameter
is mainly interesting when elevated.
Question 3: You recommend liver biopsy to establish the diagnosis of cirrhosis but the patient refuses to
undergo the procedure. Which alternative tools can be used to assess liver fibrosis
Answer:
Liver biopsy is still the gold standard for the diagnosis of alcoholic liver disease. However, when considering
the morbidity of this invasive procedure and the number of patients with abnormal liver tests related to
chronic alcohol consumption, it is unrealistic to propose liver biopsy to all patients. It seems reasonable
to screen heavy drinkers for fibrosis using non-invasive tools. Fibrotest ® , FibrometerA ® and Hepascore ®
are the three combinations of biomarkers that have proven their relevance in compensated alcoholic
liver disease (10). The diagnostic accuracy of these three markers was comparable in terms of fibrosis
extent in a recent prospective study of more than 200 patients who had undergone liver biopsy (10). The
respective areas under the ROC curve were 0.83 for the three scores for the diagnosis of fibrosis greater
or equal than F2 and were the following for the diagnosis of cirrhosis: 0.94 (Fibrotest ® ), 0.94 (FibrometerA ® )
and 0.92 (Hepascore ® ). These performances were superior to that of APRI, Forns and FIB4 scores but
were not improved by their combination of one to another. Transient elastography (Fibroscan ® ) has also
demonstrated to be a valid and reproducible non-invasive tool for the assessment of fibrosis in alcoholic liver
disease. However, it must be kept in mind that it is not only influenced by fibrosis, but also by inflammation,
cholestasis and abstinence or alcohol relapse. Nevertheless, two large studies have shown good AUROC
curves: 0.92 (11) and 0.87 (12) for the diagnosis of cirrhosis. However, cut-offs for the definition of cirrhosis
are far higher than those used for hepatitis C and the optimal value which predicts a METAVIR score F4 is
still to be determined (19.5 kPa in (11) and 22.6 in (12)). In this patient, it seems reasonable to evaluate liver
fibrosis using Fibrotest ® , FibrometerA ® or Hepascore ® and to take measurements of liver stiffness using
Fibroscan ® .
Question 4: Which pharmacological strategy do you recommend for sobriety maintenance
Answer:
Persistence of craving episodes in this patient argues for a pharmacological support to reach long-term
abstinence. Disulfiram inhibits the liver enzyme aldehyde dehydrogenase, leading to the accumulation of
acetaldehyde and to a flushing reaction characterized by tachycardia, nausea, vomiting, and hypotension.
Despite some heterogeneity between studies, a meta-analysis on more than 1,500 patients has shown that
disulfiram used in a supervised manner was more efficient than placebo to reach abstinence Disulfiram has
not been evaluated in patients with liver cirrhosis and systemic effects related to the pharmacological effect
of disulfiram must lead to be very cautious in its use in these patients. A systematic review published in 2010
(13) has compelled 24 randomized controlled trials and has demonstrated that acamprosate, a glutamate
antagonist, is effective in promoting abstinence in increasing abstinence duration by 11% as compared to
placebo. Acamprosate was not associated with any hepatotoxicity but none of the studies included in this
meta-analysis had included patients with liver cirrhosis. Naltrexone is an opioid antagonist that has been
proved to maintain abstinence in several studies, especially when its long-acting injectable form is used
(14). In the most recent series on more than 600 patients (14), the 380 mg monthly dose of naltrexone was
more likely to maintain abstinence than the 190 mg dose or than the placebo (the 380 mg dose reducing
heavy drinking by 25% as compared to placebo). There was no evidence for hepatotoxicity in this series
but patients with transaminases greater than 3 times the upper limit of the normal value were excluded from
the study. Lastly, naltrexone in combination with behavioural intervention seems to be more efficient than
acamprosate in a large study in patients without alcoholic liver disease (15).
Thus, naltrexone and acamprosate are promising drugs but they have not been tested in cirrhotic patients
with alcoholic liver disease and are potentially responsible for hepatotoxicity in these patients, as well as