Design and Validation of a Histological Scoring System
for Nonalcoholic Fatty Liver Disease
David E. Kleiner,1Elizabeth M. Brunt,2Mark Van Natta,3Cynthia Behling,4Melissa J. Contos,5Oscar W. Cummings,6
Linda D. Ferrell,7Yao-Chang Liu,8Michael S. Torbenson,9Aynur Unalp-Arida,3Matthew Yeh,10Arthur J. McCullough,11
and Arun J. Sanyal12for the Nonalcoholic Steatohepatitis Clinical Research Network13
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence
titis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH
Clinical Research Network designed and validated a histological feature scoring system that
addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score
(NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of
which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hep-
atocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as
present or absent. An anonymized study set of 50 cases (32 from adult hepatology services,
18 from pediatric hepatology services) was assembled, coded, and circulated. For the vali-
dation study, agreement on scoring and a diagnostic categorization (“NASH,” “borderline,”
adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular
inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regres-
sion, five features were independently associated with the diagnosis of NASH in adult
biopsies: steatosis (P ? .009), hepatocellular ballooning (P ? .0001), lobular inflammation
(P ? .0001), fibrosis (P ? .0001), and the absence of lipogranulomas (P ? .001). The
proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular
ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD
and NASH with reasonable inter-rater reproducibility that should be useful for studies of
both adults and children with any degree of NAFLD. NAS of >5 correlated with a diagnosis
of NASH, and biopsies with scores of less than 3 were diagnosed as “not NASH.”
Abbreviations: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NIDDK, National Institute of Diabetes & Digestive & Kidney Diseases;
NIH, National Institutes of Health; H&E, hematoxylin and eosin; NAS, NAFLD activity score.
From the1Laboratory of Pathology, National Cancer Institute, Bethesda, MD;2Saint Louis University Liver Center, Department of Pathology, Saint Louis University
CA;5Department of Pathology, Virginia Commonwealth University, Richmond, VA;6Department of Pathology, University Hospital, Indianapolis, IN;7Department of
Pathology, University of California San Francisco, San Francisco, CA;8Department of Pathology, and11Division of Gastroenterology, MetroHealth Medical Center,
and12Department of Internal Medicine, Division of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University Medical Center, Richmond,
VA.13A list of members of the Nonalcoholic Steatohepatitis Clinical Research Network is located in the Appendix.
Received November 12, 2004; accepted February 25, 2005.
Supported by the National Institute of Diabetes & Digestive & Kidney Diseases (grants 1U01DK061718, 1U01DK061728, 1U01DK061731, 1U01DK061732,
1U01DK061734, 1U01DK061737, 1U01DK061738, 5U01DK061730, 7U01DK061713, and N01HR761019) and the National Institute of Child Health and
Address reprint requests to: David E. Kleiner, Laboratory of Pathology, National Cancer Institute, Bldg 10, Room 2N212, MSC 1516, Bethesda, MD 20892. E-mail:
KleinerD@mail.nih.gov; fax: 301-480-9488.
Copyright © 2005 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
Potential conflict of interest: Nothing to report.
complex known as metabolic syndrome.1-4Prevalence es-
timates of NAFLD have used a variety of laboratory and
most common form of chronic liver disease in adults in
the “epidemic” of obesity in developed countries.5-9
Ludwig et al.10are credited with solidifying the no-
atohepatitis (NASH) in a seminal manuscript published
in 1980. Now recognized as a progressive form of fatty
liver disease, NASH has been documented to have the
potential to progress to cirrhosis and hepatocellular carci-
noma.3,5NASH may be a leading cause of “cryptogenic
cirrhosis” in which etiologically specific clinical labora-
NAFLD is also gaining recognition as a significant form
of liver disease in pediatric populations, which in some
patients may progress to cirrhosis in adulthood.12,13
Whereas laboratory test abnormalities and radio-
graphic findings may be suggestive of NAFLD, histolog-
ical evaluation remains the only means of accurately
assessing the degree of steatosis, the distinct necroinflam-
matory lesions and fibrosis of NASH, and distinguishing
NASH from “simple” steatosis, or steatosis with inflam-
mation.14Matteoni et al.15showed that cirrhosis devel-
shown the combination of lesions of steatosis, inflamma-
tion, ballooning, and Mallory’s hyaline or fibrosis,
whereas only 4% of patients with simple steatosis and
none of the patients with steatosis and inflammation
alone had evidence of cirrhosis during the 10 years of
A system for semiquantitative evaluation for the
unique lesions recognized for NASH proposed by Brunt
terminology used in chronic hepatitis for semiquantita-
tive evaluation, commonly referred to as “grading” and
“staging.”17The proposed system was based on the con-
cept that the histological diagnosis of NASH rests on a
constellation of features rather than any individual fea-
ture. However, it was developed for NASH and was not
developed to encompass the entire spectrum of NAFLD
as defined by Matteoni et al.15A different semiquantita-
tive feature-based scoring system for NAFLD was used in
a recently published treatment trial from Promrat et al.18
Neither of these systems was designed to evaluate pediat-
ric NAFLD, which may show different histological fea-
tures than adult NASH.12
onalcoholic fatty liver disease (NAFLD) is in-
creasingly recognized as the hepatic manifesta-
tion of insulin resistance and the systemic
Beginning in 2002, the National Institute of Diabetes
& Digestive & Kidney Diseases (NIDDK) sponsored the
development of a multicenter cooperative Clinical Re-
search Network for NASH.19Among the goals of the
network were: (1) to form a database for long-term natu-
ral history observations of patients with NAFLD; (2) to
collect clinical samples for metabolic, immunological,
molecular, and genetic studies of NAFLD focusing on
defining the etiology of this disease; and (3) to evaluate
promising therapies for NASH in both adult and pediat-
histological evaluation that would encompass the spec-
trum of NAFLD, that could be applied to pediatric
NAFLD, and that would allow for assessment of changes
to accomplish this task.
Materials and Methods
The Pathology Subcommittee, composed of patholo-
gists from each Clinical Research Network Clinical Cen-
ter (total of eight), a pathologist from the National
Institutes of Health (NIH), two principal investigators
from Clinical Centers, the NIDDK project scientist, and
the principal investigator from the Data Coordinating
for case review. A study set was assembled from cases
“rule out” NAFLD or NASH. Cases were specifically in-
cluded to cover the range of possible diagnoses: (1) diag-
nostic of steatohepatitis, (2) borderline or possible
steatohepatitis, and (3) not diagnostic of steatohepatitis.
trichrome stains submitted. The study set cases were
stripped of all clinical information except for the designa-
tion as “adult” or “pediatric,” and the pathologists were
blinded to even this piece of information. The Institute
Review Boards at each Clinical Center, the Data Coordi-
nating Center, and the Office of Human Subjects Re-
search of the NIH approved the research plan.
Scoring System Definition. The Committee re-
evaluation method for each of the recognized features of
NAFLD. The Committee agreed that only H&E and
the evaluation. The histological features were grouped
into five broad categories: steatosis, inflammation, hepa-
system of evaluation is detailed in Table 1, and examples
of ballooning, microvesicular steatosis, and megamito-
chondria are shown in Figs. 1 and 2.
1314KLEINER ET AL.HEPATOLOGY, June 2005
Table 1. NASH Clinical Research Network Scoring System Definitions and Scores in Study Set
% Responses in Category for Study Set Cases
Adult (n ? 576)Pediatric (n ? 162)
Grade Low- to medium-power evaluation of parenchymal involvement
Predominant distribution pattern
Perisinusoidal or periportal
Mild, zone 3, perisinusoidal
Moderate, zone 3, perisinusoidal
Perisinusoidal and portal/periportal
Lobular inflammationOverall assessment of all inflammatory foci
?2 foci per 200? field
2-4 foci per 200? field
?4 foci per 200? field
Small aggregates of macrophages
Usually in portal areas or adjacent to central veins
Assessed from low magnification
None to minimal
Greater than minimal
Liver cell injury
Few balloon cells
Many cells/prominent ballooning
None to rare†
None to rare†
None to rare†
Mallory’s hyalineVisible on routine stains
None to rare†
None to rare†
*Ballooning classification: few indicates rare but definite ballooned hepatocytes as well as case that are diagnostically borderline; examples are shown in Fig. 1.
Examples of patches of microvesicular steatosis and megamitochondria are shown in Fig. 2.
†The “None to rare” category is meant to alleviate the need for time-consuming searches for rare examples or deliberation over diagnostically borderline changes.
If the feature is identified after a reasonable search, it should be coded as “many.”
‡Diagnostic classification was not available on 2 sets of adult biopsy observations, reducing the total of such observations to 512.
HEPATOLOGY, Vol. 41, No. 6, 2005KLEINER ET AL.1315
For the validation study, the pathologists were addi-
as “NASH,” “borderline,” or “not NASH.” The biopsy
specimens were made anonymous and randomized by an
NIH employee not involved in the study. The adult cases
were reviewed by each pathologist at his or her home
were circulated once.
Statistical Analyses. Pediatric and adult cases were
analyzed separately. Weighted kappa scores were used to
measure the degree of inter-rater and intra-rater agree-
ment betweenand within
correlation coefficients derived from components of vari-
ance models.20Chi-square tests were used to compare
univariate associations of histological features with diag-
nosis of steatohepatitis. Multivariate associations with di-
agnosis of steatohepatitis were assessed by using multiple
logistic regression models using generalized estimating
equations with robust variance estimation and exchange-
able correlation to account for correlations due to multi-
ple readings within and between raters.21Adjusted
percentage distributions for each histological feature,
holding other features constant and retaining the univar-
iate marginal distributions, were calculated from the lo-
gistic regression model coefficients for comparison with
the unadjusted univariate distributions of features. All
statistical analyses were carried out by the Data Coordi-
nating Center (M. Van N.) using SAS 8.0 (SAS Institute
Inc., Cary, NC) and Stata 7.0 (Stata Corp., College Sta-
A total of 50 anonymous liver biopsy specimens
formed the validation study set. The study set was chosen
to sample the range of pathological conditions seen in
pediatric and adult NAFLD. The 32 cases from adults
576 sets of observations; the 18 pediatric cases were each
read once, for a total of 162 sets of observations. Each
Fig. 1. Scoring of ballooning injury. (A) There is mild steatosis but no ballooning degeneration. All pathologists scored this case as “0” for
ballooning injury. (B) In no study set case was there absolute concordance among the nine pathologists for a ballooning score of 1. During the second
round of reviews, this case was scored as 1? ballooning injury by 8 of the 9 pathologists. This field shows several scattered balloon cells that are
not much larger than the surrounding steatotic hepatocytes but with the same cytoplasmic characteristics as more obvious balloon cells, such as
those seen in panel C. (C) This field is taken from a case scored as 2? ballooning injury by all pathologists. There is a contiguous patch of hepatocytes
showing prominent ballooning injury, sharply contrasted against the more normal hepatocytes in the field. (All photomicrographs: Hematoxylin and
eosin; original magnification ?600).
Fig. 2. Microvesicular steatosis and megamitochondria. (A) Contigu-
ous patch of microvesicular steatosis from case of steatohepatitis. This
case would be scored positively for this feature. (B) Photomicrograph of
cells with easily identified megamitochondria (arrows). This case would
be scored positively for this feature, although it is not necessary to see
so many positive cells in a single field. (All photomicrographs: Hema-
toxylin and eosin; original magnification ?400).
1316 KLEINER ET AL.HEPATOLOGY, June 2005
possible score was used at least once during the course of
the validation. The distribution of recorded scores is
shown in Table 1.
Analysis of agreement on features in the adult cases
showed reasonable agreement on the scores for the major
scoring categories of steatosis grade, fibrosis, ballooning
for the adult study set of 0.5 and above (Table 2). Agree-
ment was not as strong for the inflammatory changes or
for steatosis location; both lobular and portal inflamma-
tion had interrater kappa values of 0.45. The interrater
agreement on the diagnosis of steatohepatitis was 0.61.
There was absolute agreement on the diagnosis between
the nine pathologists on six cases and agreement among
eight of the nine on a further five cases. The intra-rater
agreement was higher in all categories than the interrater
Feature scoring agreement on the pediatric cases in the
study set was not as robust as in the adult study set, with
lower weighted kappa scores in all categories except ste-
atosis (0.64). Some of the results were statistically no bet-
ter than chance (microvesicular steatosis, pigmented
macrophages, lipogranulomas and megamitochondria,
and glycogenated nuclei); this may be caused in part by
the low level of agreement on the presence or absence of
frequency of observation of one of the two scores. Many
of the pediatric cases appeared to have more zone 1 ste-
atosis, more “periportal only” fibrosis, less ballooning,
and rare Mallory’s hyaline. In particular, there was dis-
agreement between pathologists on the diagnosis of ste-
or no ballooning or lobular inflammation.
Although it is accepted that steatohepatitis is a pattern
to define exact diagnostic criteria that all pathologists
agree on to precisely distinguish NAFLD cases with ste-
atohepatitis from those with only steatosis and inflamma-
tion.14Data generated by the NASH Network study on
assigned feature scores allowed statistical examination of
which individual features were useful in discriminating
definite steatohepatitis from the other two categories.
Both crude and adjusted analyses were performed to ad-
dress these questions; the results are shown in Table 3.
Several features showed significant association with the
diagnosis of steatohepatitis on both analyses and for both
adults and children, including lobular inflammation, bal-
looning degeneration, and fibrosis. In the adult cases, the
degree of steatosis showed a trend toward significance in
the crude analysis but was clearly associated with the di-
degree of steatosis above the 5% cutoff was not associated
with the diagnosis of NASH in either analysis.
Portal inflammation, location of steatosis, Mallory’s
hyaline, and megamitochondria were associated with ste-
atohepatitis on crude analysis but, when analyzed in the
adjusted model, were not significantly associated. In this
a ballooning score of 2; this may be why this feature was
not independently associated with steatohepatitis.
The proportion of adult cases categorized as steato-
hepatitis for the most significant features is shown in Fig.
3. Although no single feature or score was absolutely as-
sociated with a diagnosis of steatohepatitis, the severity of
some individual findings did show association. Patholo-
gists had somewhat varied criteria for steatohepatitis and
tended to emphasize or require some features more than
others. Even so, the mere presence of a combination of
features was not sufficient for a diagnosis of steatohepati-
tis. For example, only 68% of adult cases with steatosis,
ballooning, and lobular inflammation (a common set of
minimal criteria14) were diagnosed as NASH. Among the
individual pathologists, this percentage varied from 56%
to 79%. Adding fibrosis increased this fraction to 82%,
to meet these criteria yet still were diagnosed as steato-
hepatitis. These results emphasize how difficult it is to
reduce the histopathological diagnosis of steatohepatitis
to the presence or absence of specific features, indepen-
dent of the variability that is part of any observation.
Based on both the agreement data and the multiple
regression analysis, we would propose a NAFLD Activity
Table 2. Inter- and Intra-rater Variability
Agreement (Kappa Score)
(18 cases, 9
NOTE. All values represent weighted kappa statistics where appropriate.
HEPATOLOGY, Vol. 41, No. 6, 2005 KLEINER ET AL.1317
Table 3. Logistic Regression Analysis of Features of NAFLD With Respect to the Diagnosis of NASH
Histologic Feature of NAFLDCategory
Percent With Diagnosis of NASH
Adult (n ? 512 Readings From 32
Pediatric (n ? 162 Readings From 18
Overall diagnosis of NASH (outcome)
Mild, zone 3
Moderate, zone 3
Zone 3 & periportal
Lobular inflammationNo foci
None to minimal
None to rare
None to rare
None to rare
Mallory bodiesNone to rare
None to rare
*Adjusted percent with NASH diagnosis calculated from a logistic regression model for correlated data with NASH diagnosis as the outcome and indicator variables
for each histological feature. Marginal totals for adjusted percentages were fixed to equal the unadjusted marginal totals, and odds ratios from the adjusted percentages
equal those from the logistic regression model.
†Combined 5 observations in the ?5% category with 5%-33% category because there were no events in the ?5% category.
‡P values were derived from comparisons of percentages with diagnosis of NASH across categories of each histological feature and were calculated from chi-square
tests (unadjusted percentages) or from Wald’s tests from the logistic regression model (adjusted percentages).
§Not calculable because 2 of 2 observations in large lipogranulomas-present category had the event.
1318KLEINER ET AL. HEPATOLOGY, June 2005
Score (NAS), which specifically includes only features of
active injury that are potentially reversible in the short
term. The score is defined as the unweighted sum of the
scores for steatosis (0-3), lobular inflammation (0-3), and
ballooning (0-2); thus ranging from 0 to 8. Fibrosis,
which is both less reversible and generally thought to be a
the activity score. The separation of fibrosis from other
grading for both NASH16and chronic hepatitis.17
The relationship of the NAS to the diagnosis of steato-
other hand, most cases with scores of ?5 were diagnosed
as steatohepatitis. Cases with activity scores of 3 and 4
were divided almost evenly between the 3 diagnostic cat-
egories. A similar analysis of pediatric case scores showed
nearly identical results (data not shown).
The aims of this study were to devise and validate a
feature-based semiquantitative scoring system to be used
in clinical trials and natural history studies of NAFLD.
The feature scoring system described used the recognized
group of histological features for evaluation. This system
was based on and further refined the grading proposal of
Brunt et al.16In particular, the fibrosis staging system was
between delicate (1A) and dense (1B) perisinusoidal fi-
brosis, and to detect portal-only fibrosis, without perisi-
nusoidal fibrosis (stage 1C). Minimal steatosis (score 0)
(under 5%) was separated from mild (5%-33%) steatosis
(score 1) to avoid giving weight to this feature when very
little steatosis is present. A minimum of 5% steatosis was
NAFLD in biopsy specimens from both adults and chil-
dren. Evaluation of ballooning was limited to three cate-
gories (none, few, and many) after discussion among the
Committee pathologists as to what might be the most
reproducible cutoff points. Lobular inflammation was as-
sessed semiquantitatively on a scale that is the same as the
method of Brunt et al.16The proposed system differed
from the previous methods in that the histologically dis-
tinct lesions of NAFLD were assessed and summed to
provide an NAFLD Activity Score (NAS), in contrast
ment to grade severity16or to make disease categories.22
None of the features was weighted in this analysis; future
studies may identify elements that indeed deserve greater
With respect to these major disease features, the cur-
rent system had fair to good interobserver reproducibility
in both adult and pediatric cases and was equivalent to
previously reported interobserver reproducibility studies
in fatty liver disease.22,23Each of the major features (ste-
sis) showed independent correlation with a diagnosis of
steatohepatitis. Based on this observation and the repro-
ducibility studies, we defined a NAS for evaluating histo-
logical changes after therapeutic intervention trials. It is
important to note that the primary purpose of the NAS is
numeric values replace the pathologist’s diagnostic deter-
mination of steatohepatitis. The NAS has also not been
nor should it be taken as an absolute severity scale.
With respect to other features assessed in this scoring
system, some were more reproducible than others. The
less reproducible features were considered an optional
part of the scoring system, and for the purposes of the
Fig. 4. Fraction of adult cases with activity scores by diagnosis. For
each activity score, the fraction of observations with a particular diag-
nostic categorization is shown. The total number of observations for each
activity score is shown across the top of the graph.
Fig. 3. Fraction of adult cases of NAFLD diagnosed as steatohepatitis.
For each subscore of steatosis grade, lobular inflammation, ballooning
injury, and fibrosis, the histogram shows the fraction of times the
observer made the diagnosis of definite steatohepatitis. For example, of
all of the cases in which a 2? score for ballooning injury was made, 80%
were diagnosed as definite steatohepatitis. Similarly, only 11% of the
time that a fibrosis score of 0 was made did the observer diagnose the
case as definite steatohepatitis.
HEPATOLOGY, Vol. 41, No. 6, 2005 KLEINER ET AL.1319
in group review sessions, where differences in observa-
One of the findings of this study was the lesser degree
of interobserver agreement in scoring the features of the
pediatric cases of NAFLD submitted for review. As has
been previously reported in pediatric NAFLD,12,13,24,25
pediatric study cases included a significant proportion
with only periportal fibrosis. This feature is considered
unusual in adults, although it has been reported.26Pedi-
tion, less ballooning, and only rare Mallory’s hyaline
when compared with adult cases. The only pediatric case
titis resembled “typical” adult steatohepatitis, with prom-
inent ballooning, moderate lobular inflammation, and
Mallory’s hyaline. We postulate that the increased vari-
ability of scores was attributable to different patterns of
disease in pediatric NAFLD, and we will continue to
study this in the cases accrued by the NASH Clinical
Research Network. Nevertheless, the scoring system that
was developed covers the range of features in pediatric
One concern for any new scoring system is how it
applies in actual clinical trials. Although the data are not
presented here, this method for scoring and the activity
score (NAS) were used in a blinded re-review of biopsy
specimens from two recently published therapeutic tri-
als.18,27The conclusions that could be drawn regarding
histological changes were essentially the same as those in
by the NASH Network.
In summary, we have designed and validated a semi-
quantitative scoring system that is useful for assessing the
range of histological features of NAFLD. The system is
simple and requires only routine histochemical stains
(H&E and Masson trichrome stains), so that the system
can be used by practicing pathologists. Of course, other
special stains for additional analyses may be used at the
discretion of each pathologist. The method proposed
showed reasonable interrater agreement among experi-
enced hepatopathologists similar to other studies of vari-
ability in fatty liver disease.22,23Multiple regression
analysis of the scores with respect to the diagnosis of
NASH confirmed previous observations that the diagno-
ical feature, but rather involves assessment of multiple
independent features. As a reflection of this fact, the NAS
was able to discriminate between NASH and non-NASH
fatty liver disease in this patient population. To make it
easy for other pathologists to make use of this system, it is
our plan to show examples of the lesions on the NASH
Clinical Research Network web site.
Appendix: Members of the Nonalcoholic Steatohepatitis
Clinical Research Network
Case Western Reserve University, Cleveland, OH: Yao-Chang Liu,
M.D.; Arthur J. McCullough, M.D. (Principal Investigator); Duke
University Medical Center, Durham, NC: Anna Mae Diehl, M.D.
(Principal Investigator); Marcia Gottfried, M.D.; Michael S. Torben-
son, M.D.; Indiana University School of Medicine, Indianapolis, IN:
Naga Chalasani, M.D. (Principal Investigator); Oscar W. Cummings,
M.D.; Johns Hopkins University Center for Clinical Trials (Data Coor-
dinating Center), Baltimore, MD: Pat Belt, B.S.; Aynur U¨nalp-Arida,
M.D., Ph.D.; Mark Van Natta, M.H.S.; James Tonascia, PhD (Prin-
cipal Investigator) National Cancer Institute (NCI), Bethesda, MD:
David E. Kleiner, M.D., Ph.D. (Co-Lead Pathologist); National Insti-
tute of Child Health and Human Development (NICHD), Bethesda,
MD: Gilman D. Grave, MD (Project Scientist) National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD:
Jay Hoofnagle, M.D. (Project Scientist); Patricia R. Robuck, Ph.D.
(Project Scientist); St Louis University Hospital, St. Louis, MO: Eliza-
beth M. Brunt, M.D. (Co-Lead Pathologist); Brent A. Tetri, M.D.
(Principal Investigator); University of California San Diego, San Diego,
CA: Cynthia Behling, M.D.; Joel E. Lavine, M.D., Ph.D. (Principal
Nathan M. Bass, M.D., Ph.D. (Principal Investigator); Linda D. Fer-
rell, M.D.; University of Washington, Seattle, WA: Kris V. Kowdley,
M.D. (Principal Investigator); Matthew Yeh, M.D., Ph.D. Virginia
Commonwealth University, Richmond, VA: Melissa J. Contos, M.D.;
Arun J. Sanyal, M.D. (Principal Investigator)
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