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Challenges in the diagnosis of NASH
HISTOLOGICAL CLASSIFICATIONS IN NAFLD: HOW
AND WHEN TO TRUST THE PATHOLOGIST?
Pierre Bedossa
Department of Pathology, Hôpital Beaujon,
University Paris-Denis Diderot, France
Email: pierre.bedossa@bjn.aphp.fr
Take-home messages
• Liver biopsy is the only diagnostic procedure that can reliably differentiate NASH from NAFL
despite its usual limitations, mainly sampling error.
• NASH is the association of liver fat, hepatocyte ballooning and lobular inflammation. In the absence
of any one of these three lesions the diagnosis is NAFL.
• Although the distinction of NAFL and NASH is clinically relevant, NAFLD displays a continuous
spectrum of histological lesions, a spectrum that can be reported simply with the SAF score.
• SAF score assesses, semi-quantitatively and separately, steatosis, activity and fibrosis in a simple and
reproducible manner.
• The FLIP algorithm increases agreement for the overall diagnosis of NASH between observers.
Introduction
NAFLD covers a spectrum of histological lesions ranging from steatosis to a complex pattern with
associated hepatocyte injury, inflammation and fibrosis. Despite the usual limitations of the liver biopsy
in assessment of any chronic liver diseases, it is the only diagnostic procedure that can reliably assess
these various patterns and their association, allowing the distinction between NASH and NAFL, a
distinction that is essential for prognostic risk stratification [1, 2]. Therefore, whether the liver biopsy
(and the pathologist) is reliable may appear as a central question in NAFLD.
When to trust the pathologist?
Histopathologic evaluation of liver biopsy samples remains central to all investigations in NAFLD.
However, it is an invasive procedure that carries a low but real risk of morbidity and mortality. The
main limitations and advantages of liver biopsy are summarized in Table 1. Thus, and considering the
huge number of patients with potential NAFLD, liver biopsy should be reserved for selected patients.
Unfortunately, liver biopsy may sometimes fail to provide significant information because of limitations
related to the procedure itself. Indeed since the volume of a needle biopsy sample represents only a very
minor fraction of the whole liver, sampling variation is a relevant issue to consider, a risk that is inversely
proportional to the length of the biopsy [3]. While a 25 mm biopsy is considered optimal for assessing
and quantitating detailed lesions, a 15mm long biopsy usually provides robust information for a global
evaluation. These recommendations, developed in the context of chronic viral hepatitis, may be less
relevant in NAFLD. Indeed in NAFLD, and contrary to chronic hepatitis, the lesions tend to show a
very robust and characteristic lobular systematization affecting mainly the centrilobular zone. Since the
size of a liver lobule is 0.5-1 mm, the threshold for the minimally required length of a biopsy might be
lower but this needs to be formally demonstrated.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 19
HISTOLOGICAL CLASSIFICATIONS IN NAFLD: HOW
AND WHEN TO TRUST THE PATHOLOGIST?
Pierre Bedossa
Department of Pathology, Hôpital Beaujon,
University Paris-Denis Diderot, France
Email: pierre.bedossa@bjn.aphp.fr
Take-home messages
• Liver biopsy is the only diagnostic procedure that can reliably differentiate NASH from NAFL
despite its usual limitations, mainly sampling error.
• NASH is the association of liver fat, hepatocyte ballooning and lobular inflammation. In the absence
of any one of these three lesions the diagnosis is NAFL.
• Although the distinction of NAFL and NASH is clinically relevant, NAFLD displays a continuous
spectrum of histological lesions, a spectrum that can be reported simply with the SAF score.
• SAF score assesses, semi-quantitatively and separately, steatosis, activity and fibrosis in a simple and
reproducible manner.
• The FLIP algorithm increases agreement for the overall diagnosis of NASH between observers.
Introduction
NAFLD covers a spectrum of histological lesions ranging from steatosis to a complex pattern with
associated hepatocyte injury, inflammation and fibrosis. Despite the usual limitations of the liver biopsy
in assessment of any chronic liver diseases, it is the only diagnostic procedure that can reliably assess
these various patterns and their association, allowing the distinction between NASH and NAFL, a
distinction that is essential for prognostic risk stratification [1, 2]. Therefore, whether the liver biopsy
(and the pathologist) is reliable may appear as a central question in NAFLD.
When to trust the pathologist?
Histopathologic evaluation of liver biopsy samples remains central to all investigations in NAFLD.
However, it is an invasive procedure that carries a low but real risk of morbidity and mortality. The
main limitations and advantages of liver biopsy are summarized in Table 1. Thus, and considering the
huge number of patients with potential NAFLD, liver biopsy should be reserved for selected patients.
Unfortunately, liver biopsy may sometimes fail to provide significant information because of limitations
related to the procedure itself. Indeed since the volume of a needle biopsy sample represents only a very
minor fraction of the whole liver, sampling variation is a relevant issue to consider, a risk that is inversely
proportional to the length of the biopsy [3]. While a 25 mm biopsy is considered optimal for assessing
and quantitating detailed lesions, a 15mm long biopsy usually provides robust information for a global
evaluation. These recommendations, developed in the context of chronic viral hepatitis, may be less
relevant in NAFLD. Indeed in NAFLD, and contrary to chronic hepatitis, the lesions tend to show a
very robust and characteristic lobular systematization affecting mainly the centrilobular zone. Since the
size of a liver lobule is 0.5-1 mm, the threshold for the minimally required length of a biopsy might be
lower but this needs to be formally demonstrated.
The International Liver Congress™ 2015 • Vienna, Austria • April 22–23, 2015 19
