Current Concepts in Liver Pathology: An Update, Part I
Moderator: Dr. Paulette Bioulac-Sage
Section 4 -
Pathology of Fatty Liver Disease
Elizabeth M. Brunt
Department of Pathology, Saint Louis University School of Medicine
St. Louis, MO
The normal adult human liver may have up to 5%
of its mass as lipid. The size of triglyceride droplets may be a clue to the underlying cause of the
accumulation: "true" microvesicular steatosis, which often requires special stains such as oil red O to
detect, a manifestation of severe, recent liver injury, such as in Reye's syndrome and acute fatty liver
of pregnancy, results from deranged mitochondrial b oxidation. When discussing "fatty liver disease",
most often we are referring to diseases that are characterized by predominantly large droplet steatosis,
(macrovesicular steatosis) or mixed large and small droplet steatosis. Several primary liver diseases,
such as hepatitis C and Wilson disease, hepatocellular adenoma and carcinoma, and certain drugs and
toxins, such as steroids and alcohol, commonly show these forms of steatosis.
Nonalcoholic Fatty Liver Disease.
The fact that excess fat
accumulation in the liver is significant was recognized by insightful pathologists of the 19th
century. Associations of hepatic steatosis and cirrhosis with obesity, diabetes and alcohol have been
documented in numerous large studies of American and European pathologists in the 20th
century. Credit is due to the study from the Mayo Clinic published in 1980 for establishing the moniker,
NASH, in the nomenclature of liver disease. In
that study , the 20 subjects had been accrued based on liver biopsy with features
characterized as "alcohol-like". Ludwig et al carefully established the nonalcoholic nature of the 20
subjects, as well as clinical findings common to them: 90% were obese, 65% were women, 25% were diabetic
and/or hyperlipidemic and 15% had hypertension. Over the course of the next decade, the concept of
nonalcoholic fatty liver disease became accepted, in no small part due to pathologists' contributions in
clinico-pathologic studies. Today, we recognize that hepatic steatosis is not to be considered a
necessarily benign process or a mere histologic oddity, but rather is a significant finding or marker for
potentially progressive liver disease. Most often, we see steatosis in the setting of alcohol-related
liver disease, and hepatitis C (especially genotype 3), and in nonalcoholic fatty liver disease and
nonalcoholic steatohepatitis (NAFLD and NASH). In the setting of the allograft liver, large amounts of
macrosteatosis have been associated with initial poor function.
The contemporary epidemic of obesity throughout the world has brought awareness of NAFLD
to the forefront of hepatology and medicine. Currently, NAFLD is "billed" as the most common form of
chronic liver disease for adults in the United States and is growing to be such in Asia. The problem is
recognized in adults and children. In all populations, obese and diabetic subjects are at higher risk
than lean, nondiabetic individuals. Several methods have been used to determine prevalence of NAFLD; all
studies have recognized the shortcomings of laboratory tests and various imaging studies. Three cited
studies are based on the data collected from the 3rd National Health and Nutrition Evaluation
Survey; all three studied ALT values in nonalcoholic subjects without serologic markers of liver disease;
some additionally included values for AST 
and GGT , and only one specifically
excluded diabetics . The studies found "unexplained" elevated liver tests in US adults in
5.45%, 23% and 2.8% respectively. An Italian population survey based on ultrasound evaluation of a
cohort of 257 nondiabetic adults with no serologic evidence of liver disease showed evidence of steatosis
("bright liver") in 58% ; the risk of steatosis was related to obesity and alcohol use. A
recent study  calculated hepatic triglyceride content in a multiethnic cohort of 2,287
subjects in the US and documented steatosis in 30% of subjects; interestingly, 79% of these subjects had
normal ALT values. The ethnic distribution of steatosis reflected the well-documented ethnic
distribution of NAFLD-related cirrhosis: Hispanic>Caucasian>African American. A novel approach to
detect prevalence has come from evaluation of newly diagnosed liver disease patients in a large clinic
setting ; in this study 21% of 742 such patients were found to have NAFLD. Each of these
types of studies have recognized drawbacks and liver tissue evaluation remains the "gold standard" in the
clinico-pathologic diagnosis of NAFLD for confirmation (or exclusion) of the diagnosis, for
distinguishing NAFLD and NASH, and to establish severity of inflammation and fibrosis .
Studies have confirmed that routine clinical tests alone may misdiagnose (over or
underdiagnose) NASH in a significant proportion of cases  and that not all "unexplained"
liver test abnormalities are the result of fatty liver disease [10.] In Skelly et al's study,
liver biopsy confirmed NAFLD in two-thirds of the cases, but made a clinically significant and previously
unsuspected diagnosis in 13% of cases, confirmed cryptogenic liver disease in 9% and documented normal
liver in 6%.
Liver Pathology Evaluation in NAFLD.
Histologic evaluation has also played
an important role in broadening the concept of NAFLD from one of a liver disease of only obese
individuals with elevated ALT, to one that can involve lean individuals
subjects with normal ALT values . Most studies of NAFLD focus on subjects in whom other
forms of liver disease have been excluded, but some have documented NAFLD/NASH in subjects with
concurrent chronic liver disease
the question of the significance of abnormal ANA, ASMA
and AMA remains largely unanswered as there are several studies to date that have shown from 3% to 40% of
otherwise characteristic NAFLD/NASH subjects with positivity of one of these values.
Liver pathology has also played a key role in the growing studies to evaluate clinical
"markers" of disease, such as adiponectin levels  and the HAIR score (hypertension,
ALT, Insulin Resistance) . Clinical studies to evaluate predictors of
fibrosis, by definition, have relied on liver biopsy evaluation
Differing results in
these studies may be result to some degree from differing histologic criteria and methods of fibrosis
evaluation utilized. Biopsy studies have estimated rate of fibrosis progression in NAFLD from 0.08
to 0.28 stages/year . It is recognized that cirrhosis occurs in
19-33% of subjects with documented NASH ; a recent study showed significantly increased rates
of cirrhosis and mortality in 132 subjects with NAFLD and diabetes followed for 10 years compared with
nondiabetic subjects with NAFLD .
Experienced pathologists recognize that sample size, technique of obtaining the biopsy,
and processing are all important considerations in liver biopsies. Documentation of differences in
grading and staging in chronic hepatitis in relationship to biopsy length have been
reviewed . In NAFLD, this topic is also of great interest as the biopsy evaluation is such
an integral component of the diagnosis. Differences in the lesions within the parenchyma, and thus in
"grade" and "stage" have been shown in recent studies
As in all liver diseases, the
type of liver biopsy (for instance, wedge biopsy, intra-operative biopsy, etc) available for evaluation
and preparation of the tissue are also significant considerations that will be discussed.
Histologic Criteria: NAFLD, NASH, cirrhosis.
Results of a blinded study of
biopsies with clinico-pathologic correlations highlights the value of utilizing careful criteria to
distinguish NAFLD and NASH.  Ludwig's original work continues to serve as a benchmark
reference for pathologists in this disease .
A survey of an international group of hepatopathologists who have published in the field
on their criteria for diagnosing NASH  illustrates the differences in opinions that exist in
the field today. A common theme, however, is that the diagnosis relies on a combination of lesions,
rather than a particular single lesion. The lesions most often noted to be included were steatosis,
hepatocyte ballooning, lobular inflammation, and perisinusoidal fibrosis; zone 3 accentuation and
Mallory's hyaline were also noted by some. Two studies of observer variability have now shown that
experienced liver pathologists who agree in advance what to study, have good or excellent agreement on
the lesions of interest in NAFLD: steatosis, ballooning, lobular inflammation and fibrosis
This is particularly true in adult biopsies compared with pediatric biopsies .
In considering the histologic findings of NAFLD, it is important to consider the clinical
context in which this liver disease exists. NAFLD has come to be recognized as the "hepatic
manifestation of the metabolic syndrome";  several studies have documented the close
associations of the histologic findings with the critical clinical features
come to be grouped together because of a shared risk of increased cardiovascular disease. The "metabolic
syndrome" shares a common link of insulin resistance , is variably defined and includes
central (truncal) adiposity, abnormal glucose tolerance or diabetes, dyslipidemia, and systemic
The "two-hit" hypothesis of Day and James  although continually
modified, remains a central paradigm in thinking of the complex pathogenesis of NAFLD/NASH. Briefly,
insulin resistance and hyperinsulinemia (in combination with other factors including low adiponectin
levels and elevated TNF a) result in and perpetuate hepatic steatosis; the fatty liver is considered more
vulnerable to injury from a "second hit(s)" and self-perpetuating cycles of cell injury and fibrogenic
stimuli are initiated. Several likely gene candidates are actively being studied  for each
of the putative steps of the process; at least 23 have been shown to be involved in NAFLD and
hundreds more are under investigation in fat metabolism and insulin interactions .
The lesions of NAFLD/NASH can be understood in terms of the recognized and putative
pathophysiology . The imbalance of free fatty acid delivery to the liver with overfeeding
and insulin resistance relative to export and oxidation results in steatosis; reactive oxygen species,
by-products of microsomal and peroxisomal oxidation, result in mitochondrial damage, decreased ATP,
increased apoptosis, lipid peroxidation and cytokine release. Investigators have noted specific lesions
in association with each of these steps. One of the first patterns recognizable in pre-fibrotic NASH in
adults is the predominance of steatosis and injury in acinar zone 3; two groups have shown zonal
localization of DNA damage, products of oxidative damage 
and expression of CYP 2E1 
in zone 3. Steatosis, while predominantly macrovesicular, may be mixed large and small droplet
steatosis. Liver cell injury is most often noted in the form of ballooning with cell swelling; this was
the key histologic feature that differentiated progressive NAFLD (Types 3 and 4) with an increased risk
of cirrhosis and liver-related death in the study by Matteoni et al . Lobular inflammation
is typically present, but mild and commonly mixed in nature. Portal inflammation is absent or mild; when
significant, it has been recommended one consider co-existent liver disease . Increased
portal inflammation has also recently been identified as a feature of resolution from the results of a
recent treatment trial . Other features that may be present in NAFLD/NASH include Mallory's
hyaline, which can be detected by immunohistochemical stains against ubiquitin and p62, acidophil bodies,
megamitochondria and glycogenated nuclei. Hepatocellular and sinusoidal lining cell iron are rarely
discussed except in focused studies of iron and NAFLD, but may be detected if carefully examined.
Fibrosis is initially present in acinar zone 3 in a perisinusoidal, "chickenwire" pattern with sparing of
the portal and periportal areas. Two studies utilizing evaluation of stellate cell activation by
immunohistochemistry noted zone 3 accentuation in human liver biopsies of NASH
progression, portal and periportal fibrosis may occur, as well as various forms of bridging fibrosis.
Cirrhosis is a known complication of NASH. The physiologically altered liver with cirrhosis may or may
not retain any or all of the active lesions of NASH; hence, many cases of "cryptogenic" cirrhosis may
have developed from "burned-out" NASH. 
Grading and Staging.
The concept of semi-quantitative
"grading" and "staging" the necroinflammatory lesions, fibrosis and architectural alterations in chronic
hepatitis is well established. The cartoon published by Batts and Ludwig demonstrates the
portal-based nature of these lesions for viral, autoimmune and some forms of metabolic chronic liver
disease. Clearly, the lesions of NASH are different from those of portal-based injury of chronic
hepatitis; a system for grading and staging NASH was proposed in 1999  based on a blinded
review of 52 biopsies from 51 clinical cases of NASH that recognized the constellation of lesions of
NASH. Steatosis was present by definition and did not necessarily affect the grade, although greater
amounts were typically present in more severe cases. The lesions that correlated with a "gestalt" grade
of mild, moderate and severe were ballooning, lobular and portal inflammation. Fibrosis was evaluated
for two components: zone 3 perisinusoidal fibrosis and portal-based fibrosis. It was noted that some
cases had only the former, while cases with any portal-based fibrosis also had the former, or had
bridging fibrosis, hence the staging system as proposed. In 2002, the NIDDK sponsored NASH Clinical
Research Network sponsored the Pathology Committee to develop a scoring system that would encompass the
entire spectrum of NAFLD and provide a feature-based scoring system for the entire spectrum of NAFLD that
could be applied to treatment trials in adults and children . This is a scoring system in
which the components, steatosis, lobular inflammation and hepatocellular ballooning, are each
semi-quantitated, then added together for an aggregate activity score. The fibrosis score is a
modification of the "Brunt" fibrosis score with subclassification of stage 1 to account for delicate (1a)
or dense (1b) perisinusoidal fibrosis and addition of stage 1c to include "portal only" fibrosis when
noted. Biopsies with NAFLD Activity Scores (NAS) above 5 were nearly all correlated with an histologic
diagnosis of "definite NASH", whereas those of 0-2 were all diagnosed as "definitely not NASH"; this was
true in both adults and pediatric biopsies. A word of caution was noted: "…the primary purpose of the
NAS is to assess overall histological change; it is not intended that numeric values replace the
pathologist's diagnostic determination of steatohepatitis."  A third scoring system was
published in 2005  based on a review of 25 biopsies of predominantly Hispanic women by two
blinded pathologists. The system is a multistep process of deriving an activity score (that is derived
from adding lobular inflammation and necrosis plus Mallory bodies, plus hepatocyte ballooning, plus
perisinusoidal fibrosis) to portal fibrosis scores to determine grade from 1-3. The authors showed good
kappa scores between the two pathologists and strong correlations and relevant clinical tests.
New Concepts in Fibrogenesis.
Very recently, a study in
hepatitis C  has been broadened to NASH  to introduce the concept that the
portal fibrosis of chronic liver disease correlates with the periportal ductular reaction, which may be
"driven" by hepatocyte proliferative arrest as measured by senescence markers. The putative cause(s) of
hepatocyte proliferative arrest are speculated to be viral infection, steatosis, insulin resistance,
increased body mass.
NAFLD and ALD.
It is often stated in the literature that NASH
is histologically "identical" to ASH, but is that really true? There are several lesions of alcoholic
liver disease that, to date, are not known in NAFLD , including sclerosing hyaline necrosis,
the veno-occlusive lesion first described by Goodman and Ishak , and alcoholic foamy
degeneration. On the other hand, there are several biopsies of fatty liver disease for which the
pathologist cannot be sure of the true etiology of liver disease, and cases in which obesity, diabetes
and alcohol are all likely contributing factors.
Resolution of NAFLD.
Recent clinical treatment trials are
affording us opportunities we had not realized in the past, as most are now being done with biopsies
before and after intervention. One of the most interesting findings to date is the fact that some
patients can have "spontaneous" resolution of the lesions of NASH without specific clinical intervention,
other than, perhaps, increased awareness of having a serious liver disease. This has been shown so far
in three studies. Most
studies, but not all have shown complete
resolution of the features of NASH with treatment; some have shown new findings, such as a shift in
inflammation that favors increased portal inflammation  or no change in portal
Fibrosis score decreased or the nature of fibrosis
changed . Notable differences in these studies are the numbers of patients, the types of
patients (bariatric vs nonbariatric) and the length of time of observation.
Pediatric obesity and NAFLD are problems of
growing significance in our country and throughout the world; the lesions of pediatric NAFLD, in many
cases, are different than in adult cases; a recent study has classified the lesions into types 1 and 2
based on similarities, or lack thereof, with adult NAFLD . The major differences with adult
NAFLD are greater steatosis, little or no hepatocellular ballooning or Mallory's hyaline, and portal
accentuation over zone 3 accentuation. This is a fledgling field that will continue to grow in the
Finally, we all are faced with
biopsies from patients with clinically phenotypic NAFLD but without fatty liver disease or even steatosis
in the biopsy. Several questions arise in such biopsies: do the lesions of NAFLD wax and wane? Do all
the lesions of NAFLD/NASH (necessarily) "disappear" with progression to cirrhosis or regression or do
some, such as fibrosis, remain? Further, is it possible that other causes of liver abnormalities can be
detected by biopsy? Examples of cases that are seen in my experience include the following: (1)
"nonspecific" findings with evidence of prior hepatocellular injury; (2) globules of A1AT in unsuspected
A1AT deficiency and (3) evidence of chronic cholestasis and sometimes, ie rarely, a lesion suggestive of
PSC. Even though the concept of the "Metabolic Syndrome" is under
questioning as a valid concept for cardiovascular risk , the cluster of findings currently
retain a significant role in thinking of NAFLD. Perhaps with what we are learning in pathology, it is
time for us to begin to broaden our "spectrum" of pathology to include not only steatosis and
steatohepatitis with cirrhosis, but also the minimal lesions (or "normal") and hepatocellular carcinoma
in the setting of both cirrhotic and noncirrhotic liver.
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