Microvesicular Steatosis: Current Issues in Pathology
Elizabeth M. Brunt
Saint Louis University School of Medicine
St. Louis, Missouri
Macrovesicular steatosis, defined as intracytoplasmic vacuoles that eccentrically displace the hepatocyte
nucleus, is a common in finding in liver biopsies, as up to 5% of liver mass may be fat. Marked steatosis,
a histologic feature of aberrant lipid metabolism, is indicative of liver involvement by a wide variety of
systemic disorders, toxic or drug-induced liver injury, and of various specific liver diseases, including
hepatitis C infection, Wilson's disease, and galactosemia.
"Fat people have fat livers" (Ludwig,1997); numerous historical and current studies have documented that
obesity (primarily in the form of central/visceral fat) correlates with degree of hepatic steatosis and may
be associated with progressive fibrosis in many forms of liver disease (viral hepatitis C, alcohol) and
nonalcoholic fatty liver disease(s). There is currently a recognized epidemic of obesity and its related
metabolic consequences. Concurrently, there is increasing awareness that nonalcoholic fatty liver disease
is a significant form of progressive chronic liver disease in adults and in children. Some authorities have
stated that nonalcoholic fatty liver disease may be the most common liver disease in North America. Rather
than the relatively benign process this was once considered, nonalcoholic steatohepatitis, the
necroinflammatory progression of nonalcoholic fatty liver disease, is known to potentially result in
cirrhosis with its attendant complications including hepatocellular carcinoma, and liver-related morality.
Recent studies have documented that many cases of otherwise cryptogenic cirrhosis may in fact be the result
of "burned-out" fatty liver disease in which loss of histologically-identifiable hepatocellular steatosis
has occurred.
Obesity- and nonobesity-related clinical associations that predispose to various forms of fatty liver
disease, clinical features related to predisposition to progressive fibrosis, and the basic pathophysiologic
mechanisms by which steatosis may progress to steatohepatitis with liver damage are areas of active
investigation . In addition, as there remain no laboratory, serologic or imaging test(s) for confirmation
(or exclusion) of the diagnosis of steatohepatitis, liver biopsy evaluation continues to serve a significant
role in clinical diagnosis and determination of extent of ongoing liver cell injury, inflammation, and
fibrosis. Therefore, the role of pathologists in both clinical care and investigative studies continues to
be significant.
Current issues in pathology in nonalcoholic fatty liver disease relate to definition(s) of the constellation
of findings necessary for and included in the diagnosis of steatohepatitis, the means by which activity and
fibrosis are quantified, and specific diagnostic nomenclature. Various approaches to semi-quantitative
evaluation have been proposed in order to focus on the histologic findings that distinguish steatohepatitis
from other forms of chronic liver disease. Concordance studies have shown the difficulties for pathologists
to agree on lesions of significance. Means of quantification and assignment of significance to amounts of
steatosis and fibrosis vary markedly in studies focused on the importance of these findings; lack of
agreement in these areas is a reflection of the challenges encountered currently.
Finally, terminology of the rubrics NAFLD and NASH is being questioned for several reasons. Pathologists
cannot always distinguish the lesions of marked steatohepatitis as deriving from alcohol or the nonalcoholic
syndromes and clinically-based studies are not concordant in definitions of "nonalcoholic" use. On the
other hand, there are lesions seen in ALD that are not present in NAFLD, and vice versa. Perhaps it is time
to formally consider a nomenclature that more reflects our growing understanding of the complex metabolic
derangements that may result in steatohepatitis, removes the (non-)association with alcohol when
appropriate, and parallels terminology of other forms of chronic liver disease in which the diagnosis of
steatosis or steatohepatitis is followed by assignment of known clinical conditions. Unlinking the
terminology of fatty liver disease from "alcohol" may also be useful in allowing natural history studies of
the various entities that may result in the same histological features.
Selected References
Burt AD, Mutton A, Day C. Diagnosis and interpretation of steatosis and steatohepatitis. Semin Diagn
Pathol 15:246, 1998.
Falck-Ytter Y, Younoussi ZM, Marchesini G, and McCullough AJ. Clinical features and natural history of
nonalcoholic steatosis syndromes. Semin Liver Dis 21:17, 2001.
