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

BARCELONA . SPAIN
62 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 63
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
elastography, serum markers seem to be limited in patients with ALD to those that are not accessible by TE.
Transient elastography
Assessment of liver stiffness (LS) by transient elastography (TE) has revolutionized the diagnosis of fibrosis/
cirrhosis in patients with ALD [13, 23, 24]. Although TE/Fibroscan was the first technique widely used
alternative techniques such as ARFI or magnetic resonance elastography are currently under investigation
and seem to be comparable with regard to accuracy (Fig. 6). Major advantage of TE is that the results are
a) noninvasive b) immediate (results obtained within 10 min) c) can be performed in >90% of patients, and
d) has a very small sample error of less than 5% [25] (Fig. 7). These characteristics render TE an ideal tool
for diagnosis, screening and follow up of ALD patients. LS of 8 and 12.5 kPa represent generally accepted
cut-off values for F3 and F4 fibrosis whereas LS values below 6 kPa are considered as normal and exclude
ongoing liver disease (Fig. 8 and 9). LS highly correlates with portal pressure and esophageal varices and
HCC are likely at values > 20 kPa [26, 27].
The major studies solely focusing on ALD patients demonstrated the usefulness of TE for fibrosis stage F3
and F4 with an AUROC>0.92 [16, 28-30]. However, especially in those studies that did not consider the
degree of steatohepatitis, cut off values for F3 and F4 fibrosis were considerably higher as compared to
patients with HCV infection (Fig. 10). Meanwhile, several conditions are known that increase LS irrespective
of fibrosis stage which include: hepatic infiltration with tumor cells, all inflammatory conditions (hepatitis)
[31, 32], deposition of amyloid [33], liver congestion [34], and mechanic cholestasis [35] (Fig. 11 and
12). Histological subanalysis confirmed that besides fibrosis stage conditions of increased pressure and
typical features of ALD such as ballooning, Mallory-Denk body deposition and perisinusoidal inflammatory
infiltrates highly correlate with LS but not steatosis [29] of the demonstrated thatThe knowledge of these
conditions has led to more optimized diagnostic algorithms in using and interpreting TE in the clinical
context [13]. This is especially required for ALD patients since these patients may present with a variety of
clinical features (steatosis, steatohepatitis, cardiaque insufficiency, cholestasis, HCC) that all may interfere
with TE.
First preliminary studies indicate that 1. TE will also help us to discriminate between relapsers and
abstainers, 2. TE may even directly affect drinking behaviour most likely in non-addicted patients not being
aware of their individual fibrosis risk and 3. TE will allow us to screen the population for cirrhosis to obtain
first robust prevalence data on alcoholic liver cirrhosis.
Thus, a small study on 23 heavy drinkers admitted for alcohol detoxification over 7 days were followed up
by TE over 60 days [36] (Fig. 16). Liver stiffness significantly decreased (-20%) in abstinent patients but
increased (32%) in those who continued to drink. In another important study, liver stiffness was measured
by TE in 1190 subjects >45 years old from a general population attending for a medical check-up were
consecutively enrolled in the study [1] (Fig. 17). All subjects were submitted to medical examination and
laboratory tests in addition to LSM, performed on the same day by a single operator. Subjects with LS values
>8 kPa were referred to a liver unit for further investigations. 89 (7.5%) had LSM >8 kPa including nine
patients with LSM >13 kPa. Despite the fact that normal liver tests were observed in 43% of them, a specific
cause of chronic liver disease was found in all cases. ALD was the cause in 27 patients either alone or in
combination with NAFLD. Liver biopsy could be obtained for 27 patients, including all nine patients with LS
>13 kPa. Liver biopsy confirmed liver cirrhosis in these 9 patients with LS>13 kPA due to ALD (n=5), chronic
hepatitis C (n=3) or chronic hepatitis B (n=1). The 18 remaining biopsies showed liver fibrosis in all cases
except one (isolated steatosis), with ALD and NAFLD being present in six and eight cases, respectively.
Importantly, three of the patients with confirmed cirrhosis due to ALD stopped drinking immediately until
now. The study indicates that 1. TE is a useful and specific procedure to screen for cirrhosis in the general
population, 2. advanced fibrosis and cirrhosis is much higher in the general population as assumed so far
(up to 7%) and 3. a significant proportion of patients with alcoholic cirrhosis have normal lab tests but will
stop drinking immediately upon diagnosis of advanced liver disease.
Figure 1: Gommorrhi silberfärbung, sample error, several papers estimated 15-50%
The major confounding condition in ALD patients that increases LS is steatohepatitis.
This problem was addressed in a recent study on 101 biopsy proven patients with ALD [29]. Sequential LS
analysis before and after normalization of serum transaminases was performed in a learning cohort of 50
patients with ALD admitted for alcohol detoxification (Fig. 13 and 14). LS decreased in almost all patients
within a mean observation interval of 5.3 days. The decrease in LS correlated best with the decrease in
AST. No significant changes in LS were observed below AST levels of 100 U/L. By excluding those patients
with AST > 100 U/L at the time of LS assessment in a second validation cohort of 101 biopsy proven ALD
patients, AUROC for the detection of F3 and F4 fibrosis could be both increased to 0.94. Meanwhile, these
observations have been confirmed in two independent study populations.
The actual diagnostic algorithm for TE to screen ALD patients is as follows (Fig. 15). If TE can be correctly
performed (>70%) with the M probe advanced fibrosis can be robustly excluded in typically >40% of patients.
Patients with increased LS>8 kPa should undergo simultaneous abdominal ultrasound and laboratory tests
that should include AST levels. If morphological abnormalities, congestion or cholestasis can be excluded
by ultrasound and AST levels are 100 U/l, patients should abstain from alcohol
until transaminases have normalized and LS can be reassessed. Likewise, interventions can be applied
to patients with congestion (diuretics) or mechanic cholestasis (biliary drainage). Only if LS>30 kPa, the
diagnosis of liver cirrhosis can be established with certainty despite the presence of severe steatohepatitis.
In cases of invalid measurements with the M probe, most patients can be successfully measured with the
XL probe (>95%). The role of alternative tools to assess liver stiffness such as ARFI and MRE or serum
markers in the remaining patients needs to be addressed in the future.
In addition, the accuracy of liver biopsy in assessing fibrosis is limited due to sampling error and interobserver
variability [2, 3, 4, 5, 6]. 2 Abdi W, Millan JC, Mezey E. Sampling variability on percutaneous liver biopsy.
Arch Intern Med