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

BARCELONA . SPAIN
54 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 55
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
HISTOPATHOLOGICAL ASSESMENT OF ALCOHOLIC LIVER DISEASE
Tania Roskams
Leuven, Belgium
E-mail: tania.roskams@uz.kuleuven.ac.be
KEY POINTS
• Know the typical features of alcoholic liver disease (ALD) and the differences with other
common etiologies of liver disease.
• Understand the histopathological features which are most important in the prognostic
assessment of ALD, in particular to make the differential diagnosis of so-called acute-onchronic
liver disease and chronic decompensated liver disease.
INTRODUCTION
In the setting of alcoholic steatohepatitis (ASH), the clinician takes a liver biopsy to know 1) the etiology
of the disease 2) eventual additional factors, 3) the stage of the disease, 4) the activity of the disease, 5)
in case of sudden deterioration in the end stage the clinician wants to know if this is decompensation of
end-stage cirrhosis or so-called acute-on-chronic liver disease. These different aspects will be discussed
during this talk.
When receiving a needle biopsy of the liver the first feature a pathologist assesses is the architecture. A
special fibrous tissue stain is necessary: e.g. sirius red or Masson’s trichrome. In alcoholic or non-alcoholic
steatohepatitis, a fine threadery perisinusoidal, pericellular type of fibrosis is seen, resulting in the
typical chicken wire fibrosis. This type of fibrosis is caused by direct activation of stellate cells, which are
located in the immediate vicinity of hepatocytes. Since alcohol is metabolized in the centrolobular area, the
fibrosis starts in this area, followed by periportal fine threadery fibrosis. Centrolobular fibrosis can affect the
draining centrolobular veins and cause outflow block at microscopical level. Paraportal shunt vessels and
dilated sinusoids are signs of portal hypertension.
The fine threadery perisinusoidal and pericellular type of fibrosis differs from biliary fibrosis, which is the
result of ductular reaction associated with activation of periductular fibroblasts resulting in porto-portal
septa. The fine threadery fibrosis in NASH also differs from the type of fibrosis in viral or auto-immune
hepatitis which is the results of interface hepatitis or confluent necrosis following the blood stream from
which inflammatory cells diapede: from portal tracts to central veins: that’s why in hepatitis portal-central
septa are seen, which is not the case in biliary type of fibrosis.
The next structures to be examined are the portal tracts. In ASH little inflammation is seen compared to
viral or auto-immune hepatitis and the infiltrate which is present is mainly composed of polymorphonuclear
leucocytes. Portal phlebosclerosis is commonly seen, especially in more advanced stages of the
disease. At the interface with the parenchyma ductular reaction is often seen as a sign of regeneration,
because alcohol inhibits the regenerative capacity of the hepatocytes, hence activating the progenitor
cell compartment (Roskams et al 2003). It can also be the results of secondary sclerosing cholangitis
which is also quite common in the more advanced stages of disease, either secondary to the liver
fibrosis or secondary to sclerosing pancreatitis. Features are similar to primary sclerosing cholangitis:
thickened basement membranes, ductular reaction and cholangiolitis, but ductopenia is lacking. A special
histopathological features is ductular bilirubinostasis: ductules at the interface of the portal tracts with
the surrounding parenchyma are dilated and contain bilirubin plugs. This is an early sign of infection before
clinical signs are obvious.
The parenchyma in (N)ASH shows steatosis: microvesicular, mediovesicular and finally macrovesicular.
In alcoholic disease, the steatosis is localized in the centrolobular area since alcohol is metabolized
there, while in (N)ASH steatosis is distributed more randomly and associated with glycogenated nuclei.
Ballooning of hepatocytes and formation of Mallory-Denk bodies (MDB) are also typical for ASH. MDB
surrounded by polymorphs are called satellitosis and are a sign of active alcohol use. To objectivate
MDB an immunohistochemical stain for ubiquitin can be used. Also the presence of satellitosis is better
objectivated using this stain. Megamitochondria are a sign of active metabolization of alcohol. Hepatocytic
bilirubinostasis is a sign of decompensation of the hepatocyte function.
Acute on chronic liver failure
In the context of chronic liver insufficiency, the term “acute-on-chronic liver failure” (ACLF) was introduced
about a decade ago in an attempt to demarcate a syndrome with a similar clinical context and onset, but
with heterogeneity in etiology of underlying liver disease and rapidity of clinical presentation (Jalan 2002 and
Laleman 2006). Although ACLF, in its first (only) working definition, was described as an acute deterioration
in liver function in a patient with previously well-compensated liver disease due to the effects of a precipitating
event, yet this entity remains poorly defined. Clinically, this syndrome is characterized by jaundice, hepatic
encephalopathy, hemodynamic instability and/or hepatorenal syndrome, and leads to a mortality of 50 to
90% because of the combined impact of these manifestations The importance of this syndrome resides
in the conceptual suggestion of reversibility or recompensation since if the patient can tide over the acute
episode of liver failure and associated subsequent multi-organ dysfunction; he could re-emerge above the
critical threshold of functional liver cell mass and as such preclude the need for transplantation (Jalan 2002,
Sen 2002 and Laleman 2006). In this way, ACLF has to be distinguished from chronic relentless hepatic
decompensation (CHD), which usually occurs in patients with end-stage cirrhosis as a result of progression
of their underlying liver disease. Because this is deemed irreversible due to loss of regeneration potential,
liver transplantation is the only therapeutic option. Accordingly the key elements in ACLF compared to
the CHD state are the ability to recompensate (reversibility) and the presence of a precipitating hit, which
initiates a cascade of devastating events. Whether this reversibility is related to regeneration potential has
not been investigated yet. Therefore in a previous study (Katoonizadeh et al 2010) we aimed to address
this question. In addition, we investigated the importance of early clinical characteristics, the identification
and relative role of precipitating factors and a wide spectrum of histological parameters (Table). Upon
histological proof of cirrhosis and use of the clinical working definition, we were able to characterize two
different groups of patients in our homogenous population of patients with alcoholic cirrhosis. In an
attempt to elucidate the different outcome despite relatively similar clinical presentation, we reviewed the
two essential elements characterizing ACLF, namely regeneration potential and the influence of precipitating
events. Regenerative ability was studied in the 2 groups by evaluating the degree of activation of HPCs and
hepatocytes replication. Our results showed that HPCs were equally highly activated in both groups, while
the number of proliferating hepatocytes was comparably low. Accordingly, difference in regenerative ability
seems – at least histologically – not to explain the disparity in survival and challenges the quintessence of
“regenerative potential” in the definition of ACLF. Although we admit to certain shortcomings related to the
manner of assessment, at present histological assessment, however, remains by far the most ‘simple’, most
clinically accessible and direct index of regenerative potential.
If we next consider the effect of a potential precipitating event, we documented a key role for an apparently
triggered and dysregulated inflammatory response. Our investigations revealed that in patients
with ACLF features of infection such as SIRS and ductular bilirubinostasis at biopsy were early
characteristics of ACLF.
Increased susceptibility to infections in patients with (alcoholic) cirrhosis has already previously been reported
and is now generally accepted (Wong 2005). In clinical practice, however, the problem is the lack of a highlysensitive,
cheap, easily and rapidly available detection assays for detection of infection. In this setting,
positive SIRS criteria, used and validated already earlier in septic shock and multi-organ failure (Muckart
1997), might represent an alternative approach and early additive tool. In our study, we clearly showed that