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

BARCELONA . SPAIN
104 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 105
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
an acute deterioration of alcoholic cirrhosis with a systemic inflammatory response (SIRS) suggestive of
steatohepatitis, showed that ASH was present only in 50% [6]. Among 234 patients with a clinical suspicion
of ASH, in whom particular care was taken to exclude infection, liver biopsy showed diagnoses other than
ASH in 10% [5]. Based on liver biopsy in 1,604 patients admitted with alcohol abuse in France, with or
without symptoms of liver disease, ASH was present in 44 % of the 411 patients with cirrhosis and 12 % of
the 996 patients without cirrhosis [7].
HISTOLOGICAL FEATURES OF ASH
Steatohepatitis is defined by the coexistence of steatosis, hepatocyte ballooning and an inflammatory
infiltrate with PMNs. These criteria are common to ASH and NASH. Similarly, the presence of Mallory’s
bodies, and mega mitochondria, although not specific to alcoholic steatohepatitis, are often associated with
the elementary lesions described above, both in ASH and NASH. At standard histological examination, no
single criteria can differentiate ASH from NASH (which by the way was initially called “pseudo-alcoholic
hepatitis”). However, lesions of steatohepatitis may appear more pronounced in patients with ASH compared
with NASH. In addition, the presence of these lesions in a patient with ALD suggests active drinking.
CLINICAL MANIFESTATIONS AND EVALUATION
When symptomatic, ASH usually presents with progressive jaundice. However, ASH should be suspected
in patients with alcohol abuse presenting with any of the features of liver decompensation, such as ascites,
encephalopathy or gastrointestinal bleeding. An enlarged liver is often present, which may be tender or
even painful in rare cases. ASH is often be associated with SIRS, exceptionally with high fever, with or
without infection. Weight loss, muscle wasting and malnutrition can be at the front scene. Besides palmar
erythema and finger clubbing, spider angiomas and gynecomasty are believed to be especially prevalent
when alcohol is the cause of steatohepatitis. Extrahepatic manifestations of alcohol toxicity, such as parotid
gland enlargement, Dupuytren’s contracture, peripheral neuropathy or alcohol-related CNS disorders,
cardiomyopathy, or history of pancreatitis may help in the diagnosis of alcohol abuse.
At liver function tests, AST levels, which may be normal in asymptomatic forms, are typically elevated to
1-6 times the upper limit of the normal range. The AST/ALT ratio is usually greater than 2 which can also
be seen in advanced fibrosis related to other causes of chronic liver disease [8]. Low serum albumin, a
prolonged prothombin time and elevated international normalized ratio (INR) reflect the severity of liver
dysfunction. Besides the possibility of leucopenia as seen in cirrhosis, neutrophilia, sometimes of high level,
is a frequent feature of ASH.
Imaging studies of the liver, in addition to detecting signs of advanced stages of ALD such as a dysmorphic
liver, portal-systemic collaterals and splenomegaly, may evidence liver “arterialization”, related to increased
resistance to portal venous blood flow and the resulting dilatation of the hepatic artery. In some cases, liver
“arterialization” in ASH may translate into hypervascular, although benign, regeneration nodules.
Infection is a permanent concern in patients with ASH. Active infection: In a cohort of 246 patients with
severe ASH, a quarter of the patients were infected at admission, and another quarter became infected
while receiving corticosteroids [9]. Even though the patient may have normal body temperature, systematic
infection screening should include blood and urine cultures, ascites examination, and chest X-ray. These
should be performed at admission and repeated if the clinical condition of the patient deteriorates or when
an important therapeutic step is considered.
Due to the high incidence of acute renal failure related to the hepatorenal syndrome (HRS) in severe ASH,
repeat checks of renal function are also recommended in patients with ASH.
The hepatic venous pressure gradient, measured at the time of transvenous liver biopsy, is an accurate
reflection of portal pressure in ASH and carries prognostic information. Sharp portal pressure increases
have been reported to reflect the severity of ASH. Clinically significant portal hypertension may emerge
rapidly during the course of ASH, while the healing process can be accompanied by a marked decrease in
portal pressure over a few weeks.
Caution with the use of transient elastography to estimate fibrosis is recommended in patients with a clinical
diagnosis of alcoholic hepatitis. In addition to fibrosis, inflammation, cholestasis or liver congestion, and
recent alcohol consumption behavior may interfere with liver stiffness measurements [10, 11].
PROGNOSTIC SCORES
Prognostic scores have been developed mainly to select patients with “severe” ASH, i.e. at high risk of
early (1, 2, or 3 months) mortality, in order to initiate randomized trials with mortality as an end-point.
The Maddrey Discriminant Function (MDF = bilirubin (mg/dL) + 4.6 x (patient PT - control PT)) was
developed in 1978 and is still used to stratify patients into severe and non-severe forms of ASH. MDF ≥
32 has been used in most randomized controlled trials to define “severe ASH” and demonstrate treatment
efficacy in this category [12, 13]. In the absence of treatment, the 1-month spontaneous survival of patients
with a DF ≥32 has fluctuated between 50 and 65 % [13, 14]. Although the most widespread and simple to
interpret, MDF is limited by difficulties in standardizing prothrombin time, presence of only two categories
(severe/non-severe) and lack of dynamic information to assess treatment response.
The Model for End-Stage Liver Disease (MELD), widely used in liver diseases, has been evaluated
to assess the severity of ASH. Although useful as a continuous measure of severity of ASH, no clearly
validated cut-off point has been established that differentiates severe from non-severe ASH. In one recent
retrospective report of largely untreated patients with ASH, a MELD score > 21 was associated with a
3-month mortality of 20% [15]. Although relatively easy to calculate and standardize, it has not been
prospectively validated.
The Glasgow Alcoholic Hepatitis Score (GAHS) [16] was also derived to assess severity of ASH in
patients with suspected ASH (not all patients had biopsies). It is based on 5 laboratory values and can be
calculated at day 1 or days 6-9 to give dynamic information. In patients with a MDF ≥ 32 patients and GAHS
≥ 9, 28-day survival was 52% if untreated and 78% if treated with steroids. In patients with GAHS 0.45 vs 85% in those with a Lille score
< 0.45 [18]. Applying Lille score to individual patients data from 5 recent RCTs in patients with severe
ASH, allowed the definition of three groups of response to corticosteroids and corresponding survival at 28
days. Complete responders, defined as Lille score 0.56, had
50% survival under steroids, which was slightly inferior to the 56% survival in patients not receiving steroids