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 />
98 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 99<br />
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012<br />
ALCOHOLIC HEPATITIS OR DECOMPENSATED CIRRHOSIS:<br />
DIAGNOSTIC AND PROGNOSTIC ISSUE<br />
Frederik Nevens<br />
Leuven, Belgium<br />
E-mail: frederik.nevens@uzleuven.be<br />
KEY POINTS<br />
• There are different types <strong>of</strong> chronic liver failure: chronic hepatic decompensation and acuteon-chronic<br />
liver failure.<br />
• Multiorgan failure occur be<strong>for</strong>e sepsis in ACLF and <strong>the</strong>re<strong>for</strong>e scores as <strong>the</strong> SOFA score predict<br />
outcome better than MELD.<br />
• One <strong>of</strong> <strong>the</strong> most frequent precipitating events <strong>of</strong> ACLF is severe alcoholic hepatitis.<br />
• Prognostic scores used <strong>for</strong> patients with ASH are disease-specific: modified Maldrey’s<br />
discrimination function, <strong>the</strong> Lille score, <strong>the</strong> Glasgow alcoholic hepatitis score and <strong>the</strong> ABIC<br />
and <strong>the</strong> non disease-specific score: MELD.<br />
• Early control <strong>of</strong> ASH by corticosteroids prevents evolution to ACLF.<br />
• During corticosteroid treatment a Lille score at day 7 ≤ 0.16 select responders.<br />
Alcohol can provoke different types <strong>of</strong> liver injury. The most critical ill patients are patients suffering<br />
from severe alcoholic hepatitis (ASH) (mostly superimposed on alcoholic cirrhosis) and patients with a<br />
decompensated cirrhosis. Recently a new clinical syndrome has been described : acute-on-chronic liver<br />
failure (ACLF).<br />
GENERAL ASPECTS OF LIVER FAILURE AND PROGNOSIS<br />
There are different types <strong>of</strong> liver failure. It is important to recognize <strong>the</strong>m since <strong>the</strong>y all have a different<br />
prognosis and require a different <strong>the</strong>rapeutic approach. Traditionally liver failure is divided in acute liver<br />
failure (ALF) which occurs suddenly in a patient without a previous liver disease and chronic liver failure<br />
due to chronic hepatic decompensation (CHD) which is found in patients with end-stage cirrhosis as a<br />
result <strong>of</strong> a slowly progression <strong>of</strong> <strong>the</strong>ir underlying liver disease. Since <strong>the</strong> introduction <strong>of</strong> albumin dialysis<br />
ano<strong>the</strong>r subtype <strong>of</strong> chronic liver failure is recognized : ACLF. This is an acute and rapid deterioration within<br />
weeks <strong>of</strong> a patient with a well-compensated chronic liver disease and is clinically characterized by deep<br />
jaundice, renal impairment, hepatic encephalopathy and rapidly evolving multiorgan failure (1). In patients<br />
with alcoholic cirrhosis admitted to <strong>the</strong> hospital <strong>for</strong> a complication, ACLF has a 3 month mortality <strong>of</strong> 60 %<br />
versus 20 % in case <strong>of</strong> end-stage CHD (2) (Fig1). Spontaneous reactivation <strong>of</strong> hepatitis B presenting as<br />
ACLF in <strong>the</strong> absence <strong>of</strong> liver transplantation has a 3 month mortality <strong>of</strong> 80% illustrating <strong>the</strong> severity <strong>of</strong> this<br />
syndrome (3).<br />
The most important clinical complication in all <strong>the</strong>se conditions <strong>of</strong> liver failure which directly affects outcome,<br />
is sepsis and multiorgan failure. A low threshold to start antibiotics has significantly improved <strong>the</strong> outcome<br />
<strong>of</strong> patients with ALF (4). In case <strong>of</strong> CHD sepsis occur late in <strong>the</strong> progression <strong>of</strong> <strong>the</strong> disease at <strong>the</strong> moment <strong>of</strong><br />
severe impairment <strong>of</strong> liver function (5). In this situation prognosis at admission <strong>of</strong> <strong>the</strong> hospital is especially<br />
related to <strong>the</strong> degree <strong>of</strong> liver dysfunction and <strong>the</strong>re<strong>for</strong>e MELD score is accurate to predict <strong>the</strong> mortality in<br />
this condition. In ACLF multiorgan failure occur be<strong>for</strong>e sepsis at an early stage <strong>of</strong> <strong>the</strong> clinical syndrome.<br />
In this regard we found in a recent prospective study that in ACLF <strong>the</strong> SOFA score was <strong>the</strong> best score to<br />
predict outcome at admission in <strong>the</strong> hospital (2).<br />
The exact path<strong>of</strong>ysiology <strong>of</strong> ACLF is still unclear. In most cases <strong>of</strong> ACLF <strong>the</strong>re is a discordance between <strong>the</strong><br />
severity <strong>of</strong> jaundice on <strong>the</strong> one hand and <strong>the</strong> degree <strong>of</strong> o<strong>the</strong>r features <strong>of</strong> liver impairment on <strong>the</strong> o<strong>the</strong>r hand.<br />
This resulted to <strong>the</strong> toxin accumulation hypo<strong>the</strong>sis. Since albumin dialysis removes both water soluble and<br />
non soluble toxins a beneficial effect in ACLF was expected and indeed an improvement in haemodynamic<br />
instability and hepatic encephalopathy was observed. (6, 7, 8) None <strong>of</strong> <strong>the</strong>se devices however could<br />
improve yet overall survival. Currently an excessive pro-inflammatory response to bacterial components is<br />
thought to play an important role linking <strong>the</strong> gut, liver and systemic circulation in this syndrome (9).<br />
A crucial role in <strong>the</strong> onset <strong>of</strong> ACLF are <strong>the</strong> precipitating events. This is illustrated by <strong>the</strong> fact that early<br />
and aggressive control <strong>of</strong> <strong>the</strong>se triggers allow reversal <strong>of</strong> ACLF. A common precipitating event <strong>of</strong> ACLF<br />
is variceal haemorrhage. Prophylactic use <strong>of</strong> antibiotics has significantly improved <strong>the</strong> outcome <strong>of</strong> <strong>the</strong>se<br />
patients and in this regard it has been recently demonstrated that in high risk patients early control <strong>of</strong><br />
variceal haemorrhage by TIPS prevents ACLF (10). A similar observation came recently from India. Early<br />
suppression <strong>of</strong> HBV viremia with ten<strong>of</strong>ovir prevented <strong>the</strong> development <strong>of</strong> multiorgan failure in patients with<br />
spontaneous reactivation <strong>of</strong> Hepatitis B presenting as ACLF (3). The most common trigger in <strong>the</strong> Western<br />
countries <strong>of</strong> ACLF is severe alcoholic hepatitis and this will be discussed more in detail below.<br />
DIFFERENT TYPES OF LIVER FAILURE IN PATIENTS WITH ALCOHOLIC LIVER DISEASE<br />
a.Severe ASH as a trigger <strong>for</strong> ACLF<br />
One <strong>of</strong> <strong>the</strong> most important cause <strong>of</strong> chronic liver failure is alcohol. CHD is <strong>the</strong> most frequent subtype and is<br />
characterized in <strong>the</strong> initial stage by <strong>the</strong> complications <strong>of</strong> portal hypertension and mild to moderate jaundice.<br />
The one year mortality in case <strong>of</strong> <strong>the</strong> appearance <strong>of</strong> ascites is 29% and if hepatic encephalopathy occurs<br />
this is 64 % (11). The prognosis is predominantly affected by abstinence. ACLF is less frequent but in<br />
tertiary hospitals ACLF can account <strong>for</strong> more than 40 % <strong>of</strong> <strong>the</strong> emergency hospitalization due to alcoholic<br />
cirrhosis (2). In Western countries <strong>the</strong> percentage <strong>of</strong> alcoholic cirrhosis included in <strong>the</strong> studies with albumin<br />
dialysis (MARS <strong>of</strong> Prome<strong>the</strong>us) <strong>for</strong> <strong>the</strong> treatment <strong>of</strong> ACLF range from 39 to 92% (8, 12, 13). In patients with<br />
alcoholic cirrhosis ACLF can be induced by several precipitation events but <strong>the</strong> most frequent one is severe<br />
ASH, which occurred in around 25 % <strong>of</strong> our patients with ACLF (2).<br />
b.Prognostic scores used <strong>for</strong> patients with ASH<br />
Severe ASH is characterized by a rapid onset <strong>of</strong> jaundice, elevated AST (< 300 IU/ml), AST/ALT ratio > 2,<br />
bilirubin > 5 mg/dl, elevated INR and neutrophilia (14). As has been demonstrated <strong>for</strong> variceal haemorrhage<br />
and exacerbation <strong>of</strong> HBV, <strong>the</strong> best way to reverse ACLF is a rapid control <strong>of</strong> ASH in patients <strong>of</strong> which<br />
spontaneous recuperation is doubtful. There<strong>for</strong>e prognostic scores are <strong>of</strong> importance.<br />
There are different scores which assess <strong>the</strong> severity <strong>of</strong> ASH (Table 1). There are <strong>the</strong> disease-specific<br />
prognostic models (modified Maddry’s discrimination function, <strong>the</strong> Glasgow alcoholic hepatitis score and<br />
<strong>the</strong> ABIC score) and <strong>the</strong>re is <strong>the</strong> non disease-specific prognostic model: MELD. In 2 retrospective studies it<br />
was found that a MELD score <strong>of</strong> > 21 was a useful clinical tool to assess mortality <strong>of</strong> <strong>the</strong>se patients (15,16).<br />
In one <strong>of</strong> <strong>the</strong> studies also a decrease in MELD by 2 points at day 7 was associated with a good prognosis.<br />
Still one <strong>of</strong> <strong>the</strong> most commonly used disease-specific score to predict outcome <strong>of</strong> ASH is <strong>the</strong> modified<br />
Maddry’s discriminant function (DF) (17). Patients with a DF < 32 have a spontaneous survival at 28 days<br />
around 90 %; if <strong>the</strong> DF is ≥ 32 <strong>the</strong> spontaneous 2 month survival is only 50 % - 65 %. These patients mostly<br />
progress to <strong>the</strong> systemic inflammatory response syndrome and multisystem organ failure which is also<br />
seen in o<strong>the</strong>r types <strong>of</strong> ACLF.<br />
In patients with severe ASH without contraindication (gastro-intestinal bleeding, hepatorenal syndrome,<br />
sepsis and HBV) corticosteroids seems to improve outcome. A recent meta-analysis <strong>of</strong> individual data from<br />
5 randomized trials demonstrated that 28-day survival was higher in corticosteroid-treated patients (80%<br />
vs 66%) (18). Two disease-specific scores assessed which patients might benefit from corticosteroids: <strong>for</strong><br />
<strong>the</strong> Maddrey score <strong>the</strong> cut-<strong>of</strong>f is ≥ 32.and <strong>for</strong> <strong>the</strong> Lille score this is ≥0.45 (19). Ano<strong>the</strong>r score which allow to<br />
select <strong>the</strong> best candidates <strong>for</strong> treatment is <strong>the</strong> Glasgow score (20). The Glasgow alcoholic hepatitis score