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

BARCELONA . SPAIN
106 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 107
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
(NS). Thus, the Lille score is particularly useful to establish a stopping rule in non-responders at day 7 of
steroid therapy (see below).
TREATMENT IN ALL FORMS OF ASH
Alcohol abstinence
Alcohol abstinence improves clinical outcomes at all stages of ALD, including ASH. Therefore, abstinence
should be the chief vital goal in ASH. The pursuit of abstinence deserves the full, multidisciplinary medical
support, as discussed in another part of this syllabus. It should be pointed out that, except baclofen, no
pharmacological therapy has been tested in the setting of ASH or decompensated cirrhosis. Specifically,
disulfiram and naltrexone should be avoided in patients with ASH because of possible hepatotoxicity.
Acamprosate and topiramate have not been tested in patients with cirrhosis. Of note, the only published
clinical trial testing baclofen in patients with ALD [19] included a majority of decompensated, Child C
patients, probably a number of whom had superimposed ASH.
Withdrawal syndrome
Because most patients with ASH maintain active drinking until hospital admission, systematic evaluation
and management of withdrawal are mandatory in patients with ASH. We encourage the use of clinical
scores, such as the revised clinical institute withdrawal assessment for alcohol scale [20] at regular intervals
after admission. Specific to decompensated ALD is the risk of hepatic encephalopathy. We encourage the
use of repeat doses of short-lived benzodiazepines, titrated to the alcohol withdrawal score.
Malnutrition
Some degree of malnutrition is nearly universal in ASH. Simple bedside methods such as the Subjective
Global Assessment (SGA), or anthropometry to assess muscle wasting will identify patients at particular
risk of undernutrition [21]. B-complex vitamins should be supplemented and intravenous thiamine should
be administered whenever glucose infusion is used. A daily protein intake of 1.5 g/kg of body weight should
be ensured, irrespective of the presence of encephalopathy. Liposoluble vitamins deficiency should be
compensated. When the recommended protein-caloric intake is difficult to achieve orally, nutrition may be
considered.
No consistent mortality benefit with various nutritional interventions has been shown. One study comparing
enteral feeding to steroids in the short-term treatment of severe ASH did not show any significant difference
in 28-days mortality [22]. However, early deaths were more frequent in the group treated with TEN, while late
mortality was higher in the steroid group. Since denutrition can be associated with depletion of glutathion
stores, speculations on a possible synergistic effect of nutrition and steroids may be seen in light of recent
data on N-acetylcysteine and corticosteroids combination [39].
Renal function
Renal dysfunction is frequent during the course of severe ASH and represents an important predictor of
infection and survival. The most frequent cause of acute renal failure is the hepatorenal syndrome (HRS).
To best prevent the HRS, adequate volume expansion should be ensured, diuretics avoided whenever
serum creatinine is not strictly normal, non-steroidal anti-inflammatory drugs and radiocontrast agents
should be proscribed. Use of vasoactive drugs should be discussed early in the course of HRS, similar to
HRS in other settings.
Infections
Bacterial infection is frequent and difficult to diagnose, since SIRS criteria are common at admission due
to the inflammatory state associated with ASH. Empirical use of antibiotic administration, although widely
used, is not warranted. Instead, infection screening should be systematic at admission (1 in 4 patients
admitted for ASH is infected at admission) and repeated at regular intervals.
Long-term management of non-alcoholic cofactors
Alcohol and obesity are supra-additive factors of chronic liver disease [23]. It seems intuitive that in the
long-term management of patients initially presenting with ASH, it may be relevant to pay attention to nonalcoholic
cofactors of steatohepatitis, such as insulin resistance, small intestinal bacterial overgrowth, or
drugs (amiodarone, tamoxifen, NSAIDs, methotrexate..). However, no trial has yet shown the value of
correcting metabolic or other factors of steatohepatitis in the long-term outcome of these patients.
SPECIFIC MEASURES IN SEVERE ASH
Corticosteroids
Starting with the seminal study by Maddrey in 1978 [12], the history of corticosteroid trials in alcoholic
hepatitis looks like a long winding road. Inconsistencies may have been in part related to heterogeneity
between studies and the fact that a number of patients with a clinical diagnosis of alcoholic hepatitis did not
have a liver biopsy to confirm ASH. The analysis of individual data from the five most recent randomized
controlled trials [4, 13, 14, 22, 24] showed that patients allocated to corticosteroid treatment had higher
28-day survival than patients allocated to non-corticosteroid treatment [25]. This result should now be
acknowledged, and corticosteroids have become the first-line therapy of severe ASH. These studies also
contributed to delineate the limitations to corticosteroid use in ASH :
1. The efficacy of corticosteroids is demonstrated only in patients with biopsy-proven ASH, at a dose of
40mg/day for 28 days. Steroids may be harmful in conditions other than ASH, which may represent 10-30%
of patients with a clinical diagnosis of alcoholic hepatitis, dominated by infection-related decompensation of
ALD. Again, when the greatest care has been taken, including systematic cultures, to rule out infection, ASH
will eventually not be confirmed at liver biopsy in 10% of the patients with a clinical diagnosis of alcoholic
hepatitis [5].
2. The effect of corticosteroids on survival seems to be restricted to severe ASH, as defined by an MDF
≥ 32 [26-29]. Thus, treatment of non-severe ASH, by steroids is not warranted.
3. Only about 60 % of patients with severe forms of SAH benefit from corticosteroids. Thus, early identification
of non-responders to corticosteroids (i.e. about 40% of the patients), is important to define stopping rules
and limit the exposure to steroids [18]. Based on the meta-analysis of individual patient data from five RCTs
of patients with a DF >32 or encephalopathy, a Lille score ≥ 0.56 at 7 days upon corticosteroids, defines
non-response to steroids [18, 25]. In non-responders, not only survival at 28 days is limited to about 50%,
but steroid therapy is.
4. Infection is a contraindication for corticosteroid treatment. However, this is only relevant to active,
uncontrolled infection. In fact, corticosteroids may be started after infection has been controlled [9].
Pentoxifylline
Pentoxifylline is an antioxidant and a weak anti-TNF agent. In patients with severe ASH (DF ≥32) treated
with pentoxifylline, 6-month survival was higher than in those receiving placebo. The survival benefit was
not accompanied by significant changes in liver function but related to a lower incidence of the HRS [30].
The effect of pentoxifylline on preventing the HRS was confirmed by other trials [31, Tyagi P, 2011 #1425].