Modern Pathology (2007) 20, S40–S48

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Pathology of fatty liver disease

Elizabeth M Brunt
Department of Pathology, Saint Louis University School of Medicine, St Louis, MO, USA

Fatty liver disease is currently recognized as a common cause of liver test elevation, paralleling the worldwide
‘epidemic’ of obesity in adults and children. In many clinical practices, there is recognition that liver biopsy
evaluation is the only means of diagnosis (or exclusion) of fatty liver disease, as neither laboratory tests nor
imaging studies to date can provide complete data related to amount of steatosis, inflammation, liver cell injury,
fibrosis, and architectural remodeling. Liver biopsy evaluation also provides a means of ‘grading and staging’
the lesions of fatty liver disease and of detecting clinically unsuspected processes. Liver biopsy evaluation is
often the primary end point in clinical trials of treatment, thus, standardization of diagnosis and methods of
grading and staging have become important. In this review, these concepts as well as the pathophysiologic
bases for them are discussed.
Modern Pathology (2007) 20, S40–S48. doi:10.1038/modpathol.3800680

Keywords: fatty liver disease; insulin resistance; grading; staging

The normal adult human liver may have up to 5% of Nonalcoholic fatty liver disease (NAFLD)
its mass as lipid. The size of triglyceride droplets
(macrovesicular or microvesicular) may be a clue to Background
the underlying cause of the accumulation. When The significance of excess fat accumulation in the
discussing ‘fatty liver disease’, most often we are liver was recognized by pathologists in the 19th
referring to diseases that are characterized by century. Associations of hepatic steatosis and cirro-
predominantly large droplet steatosis (macrovesi- hosis with obesity, diabetes and alcohol have been
cular steatosis), or mixed large and small droplet documented in numerous large studies of American
steatosis. Small droplets that do not fill the entire and European pathologists in the 20th century.
hepatocyte are usually included in the macrovesi- Although not the first to use the term, credit is due
cular category. Several primary liver diseases, such to the study from the Mayo Clinic published in 1980
as hepatitis C and Wilson disease, hepatocellular for establishing the moniker ‘NASH’ in the nomen-
adenoma and carcinoma, and certain drugs and clature of fatty liver disease.1 In this study, Ludwig
toxins, such as steroids and alcohol, commonly et al1 carefully established the nonalcoholic nature
show these forms of steatosis (Figure 1a). In contrast, of the 20 subjects with liver biopsies; 90% were
‘true’ microvesicular steatosis consists of much obese, 65% were women, 25% were diabetic and/or
smaller, uniform fat droplets dispersed throughout hyperlipidemic, and 15% had hypertension. The
the hepatocyte, and often requires special stains subjects had been accrued based on a liver biopsy
such as oil red O to detect (Figure 1b). This latter with features that had been characterized as ‘alco-
form is a manifestation of severe, recent liver injury, hol-like’. Over the course of the next decade, the
such as in Reye’s syndrome and acute fatty liver of concept of NAFLD became accepted, in no small
pregnancy and other processes of deranged mito- part due to pathologists’ contributions in clinico-
chondrial b oxidation. pathologic studies. Today, we recognize that hepatic
steatosis cannot be ignored as 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 NAFLD and nonalcoholic steatohepatitis (NASH).
Correspondence: Dr EM Brunt, MD, Department of Pathology, In addition, in the setting of liver transplantation,
Saint Louis University School of Medicine, 4th Floor, FDT 3635 large amounts of large droplet fat have been
Vista Avenue, St Louis, MO 63110, USA.
E-mail: bruntem@slu.edu associated with initial poor function of the liver
Received 14 July 2006; accepted 26 July 2006 graft.
 Pathology of fatty liver disease
EM Brunt
S41

Figure 1 (a) Steatosis can be seen in varying amounts in a variety of liver diseases. The etiology of the steatosis may be due to a toxin,
hepatitis C viral infection or host factors, but often cannot be determined by histologic evaluation. This is an example of steatosis, large
and small droplet type, in hepatitis C in an overweight, diabetic individual. (b) Microvesicular steatosis is often initially considered as
swollen, ‘ballooned’ hepatocytes. As shown in this example of acute fatty liver of pregnancy, the hepatocytes are enlarged and the
cytoplasm is reticulated by the small aggregates of steatosis. Because of the significance of the clinical situations in which microvesicular
steatosis is the dominant finding, stains on frozen sections are highly recommended for confirmation (photograph courtesy of Dr Linda
Ferrell).

The epidemic of obesity throughout the world has study, 21% of 742 such patients were found to have
brought awareness of NAFLD to the forefront of NAFLD. Each of these types of studies have
hepatology and medicine in the past quarter cen- recognized drawbacks and liver tissue evaluation
tury. Currently, NAFLD is ‘billed’ as the most remains the ‘gold standard’ in the clinico-pathologic
common form of chronic liver disease for adults in diagnosis of NAFLD for confirmation (or exclusion)
the United States and is growing to be such in Asia. of the diagnosis, for distinguishing NAFLD and
The problem is now recognized in both adults and NASH, and to establish severity of inflammation
children. In all populations, obese and diabetic and fibrosis.8
subjects are at higher risk than lean, nondiabetic Studies have confirmed that routine clinical tests
individuals. It is unethical and impractical to per- alone may misdiagnose (overdiagnose) NASH in a
form population screening with liver biopsies, so significant proportion of cases,9 and that not all
several methods have been used to determine ‘unexplained’ liver test abnormalities are the result
prevalence of NAFLD. Three cited studies are based of fatty liver disease.10 In Skelly et al’s10 study, liver
on the data collected from the third National Health biopsy made a clinically significant and previously
and Nutrition Evaluation Survey;2–4 all three studied unsuspected diagnosis in 13% of cases, confirmed
ALT values in nonalcoholic subjects without ser- cryptogenic liver disease in 9% and documented
ologic markers of liver disease; some additionally normal liver in 6%. Recent reports of liver disease in
included values for AST2 and GGT,3 and only one diabetics also confirm the value of tissue evaluation
specifically excluded diabetics.4 These studies to identify entities other than fat, such as glycogenic
found ‘unexplained’ elevated liver tests in US adults hepatopathy, characterized by diffuse glycogeno-
in 5.45, 23 and 2.8%, respectively. The latter study sis,11 and diabetic hepatosclerosis, which consists of
showed that 68% of those could be accounted for by dense perisinusoidal fibrosis and basement mem-
increased body mass index (BMI).4 An Italian brane deposition12 (Figure 2a and b). Neither of
population survey based on ultrasound evaluation these entities is characterized by significant steato-
of a cohort of 257 nondiabetic adults with no sis. These studies also emphasize the value of
serologic evidence of liver disease showed evidence adequate clinical information, as both of these
of steatosis (‘bright liver’) in 58%.5 This study also entities occur in the setting of insulin-dependent
showed that the risk of steatosis was related to diabetes rather than obesity.
obesity and alcohol use. Another imaging study6
that measured hepatic triglyceride content in a
multiethnic cohort of 2287 subjects in the US Role of Liver Biopsy
documented steatosis in 30% of subjects; interest-
ingly, 79% of these subjects had normal ALT values. Histologic evaluation has also played an important
The ethnic distribution of steatosis reflected the role in broadening the concept of NAFLD from a
well-documented ethnic distribution of NAFLD- liver disease of only obese individuals with elevated
related cirrhosis: Hispanic4Caucasian4African ALT, to an entity that can involve lean indivi-
American. A novel approach to detect prevalence duals,13,14 or subjects with normal ALT values as
has come from evaluation of newly diagnosed liver well.15 Most studies of NAFLD focus on subjects in
disease patients in a large clinic setting;7 in this whom other forms of liver disease have been

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 Pathology of fatty liver disease
EM Brunt
S42

Figure 2 (a) Glycogenic hepatopathy. The hepatocyte cytoplasm is markedly expanded by excess glycogen, imparting a ‘glassy’
appearance. The parenchyma is diffusely involved. Small amounts of steatosis may also be present. (b) Diabetic hepatosclerosis, with
patches of dense perisinusoidal fibrosis (trichrome stain).

excluded, but some have documented NAFLD/ and thus in ‘grade’ and ‘stage’ have been shown in
NASH in subjects with concurrent chronic liver recent studies.28,29 As in all liver diseases, the type
disease.16–18 A feature that often leads to diagnostic of liver biopsy (for instance, wedge biopsy, intra-
difficulties for clinicians is the presence of abnormal operative biopsy, etc) available for evaluation and
ANA, ASMA and AMA in the setting of NAFLD. preparation of the tissue are significant considera-
Several studies to date that have shown from 3 to tions. Wedge biopsies may overestimate fibrosis if
40% of otherwise characteristic NAFLD/NASH only parenchyma immediately adjacent to the liver
subjects are positive for one of these antibodies, capsule is over-represented. Intra-operative biopsies
but the question of the significance of antibodies carried out after significant amounts of time under
remains largely unanswered. anesthesia have a risk of ‘surgical hepatitis’, which
Liver pathology has also played a key role in the is characterized by clusters of polymorphonuclear
growing studies to evaluate clinical ‘markers’ of leukocytes, often found around the terminal hepatic
disease, such as adiponectin levels19 and the HAIR venules. When lobular inflammation is a key
(hypertension, ALT, Insulin Resistance) score.20 component of a score, as it is in NAFLD and NASH,
Clinical studies to evaluate predictors of fibrosis, these lesions can be troublesome. Finally, the use of
by definition, have relied on liver biopsy evalua- the sponge in processing liver biopsies for histology
tion.21,22 Differing results in these studies may be is to be discouraged because of resultant mechanical
because of some degree of differing histologic artefacts including irregular indentations and trian-
criteria and methods utilized for the evaluation of gular-shaped holes in the liver biopsy.
fibrosis evaluation. Biopsy studies have estimated
the rate of progression of fibrosis in NAFLD from
0.08 stages/year23 to 0.28 stages/year.24 It is recog- Use of ‘Special Stains’
nized that cirrhosis occurs in 19–33% of subjects
with documented NASH;25 a recent study showed Many liver pathology texts emphasize the value of
significantly increased rates of cirrhosis and mor- considering a variety of stains as ‘routine’ and not
tality in 132 subjects with NAFLD and diabetes ‘special’ for evaluation; these typically include
followed for 10 years compared with nondiabetic hematoxylin and eosin, trichrome (or an equivalent)
subjects with NAFLD.26 for fibrosis, reticulin (or an equivalent) for evalua-
Experienced pathologists recognize that sample tion of architecture, periodic acid Schiff with
size, technique of obtaining the biopsy and proces- diastase for evaluation of globules, basement mem-
sing are all important considerations in liver branes and vessel walls, and an iron stain. Most find
biopsies. Documentation of differences in grading the trichrome particularly helpful to identify the
and staging in chronic hepatitis in relationship to early lesions of pericentral and perisinusoidal
biopsy length have been reviewed, and it has been fibrosis seen in NASH. The other stains help to
proposed that a 2 cm or more core with at least 11 exclude other diagnostic possibilities. Globules of
complete portal tracts is probably necessary in order a-1-antitrypsin and small amounts of either hepato-
to grade and stage a case reliably.27 In NAFLD, this cellular iron or reticulo-endothelial iron may be
topic is also of great interest as the biopsy evaluation missed without the use of the periodic acid
is such an integral component of the diagnosis. Schiff with diastase and iron stains, respectively.
Differences in the lesions within the parenchyma, Iron stain is also useful in distinguishing iron from

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 Pathology of fatty liver disease
EM Brunt
S43
lipochrome pigment, copper and bile. Stains for syndrome’ shares a common link of insulin resis-
copper or copper-associated protein are also con- tance,36 is variably defined and includes central
sidered useful by some if there is any concern of (truncal) adiposity, abnormal glucose tolerance or
chronic bile duct or cholestatic injury, or Wilson diabetes, dyslipidemia and systemic hypertension.37
disease. The regular use of ‘special stains’ adds very The ‘two-hit’ hypothesis of Day and James,38
little to overall cost of the liver biopsy as each is not although continually modified, remains a central
expensive, and if requested at the time of initial paradigm in thinking of the complex pathogenesis of
processing, will not result in wasting tissue by NAFLD/NASH. Briefly, insulin resistance and hy-
having to resurface the block. perinsulinemia (in combination with other factors
including low adiponectin levels and elevated
TNFa) result in and perpetuate hepatic steatosis;
Histologic Criteria for NAFLD/NASH the fatty liver is considered more vulnerable to
injury from a ‘second hit(s)’, and self-perpetuating
Of equal significance for diagnosis and studies in cycles of cell injury and fibrogenic stimuli are
NAFLD are histologic criteria. Results of a blinded initiated. There may be other ‘hits’ that lead to
study of biopsies with clinico-pathologic correla- fibrosis and cirrhosis, and possibly, ultimately to
tions highlights the value of utilizing careful criteria hepatocellular carcinoma. Several likely gene can-
to distinguish NAFLD and NASH.30 Ludwig’s didates are actively being studied39 for each of the
original, often-quoted manuscript continues to serve putative steps of the process; at least 23 have been
as a benchmark reference for pathologists in this shown to be involved in NAFLD40 and hundreds
disease.1 more are under investigation in fat metabolism and
A survey of an international group of hepato- insulin interactions.36
pathologists who have published in the field on The lesions of NAFLD/NASH can be understood
their criteria for diagnosing NASH31 illustrates the in terms of the recognized and putative pathophy-
differences in opinions that exist in the field today. siology:39 the imbalance of free fatty acid delivery to
However, a common theme from each is that the the liver with overfeeding and insulin resistance
diagnosis relies on a combination of lesions, a relative to export and oxidation results in steatosis;
pattern of injury as it were, rather than a particular reactive oxygen species, by-products of microsomal
single lesion. The lesions most often noted to be and peroxisomal oxidation, result in mitochondrial
included were steatosis, hepatocyte ballooning, damage, decreased ATP, increased apoptosis, lipid
lobular inflammation and perisinusoidal fibrosis; peroxidation and cytokine release. Investigators
zone 3 accentuation and Mallory’s hyaline were also have noted specific lesions in association with each
noted by some. Two studies of observer variability of these steps. One of the first patterns recognizable
have now shown that experienced liver pathologists in prefibrotic NASH in adults is the predominance
who agree in advance what to study, and what the of steatosis and injury in acinar zone 3; two groups
lesions ‘look like’ can have good or excellent have shown zonal localization of DNA damage,
agreement on the lesions of interest in NAFLD: products of oxidative damage41 and expression of
steatosis, ballooning, lobular inflammation and CYP 2E142 in zone 3. Steatosis, while predominantly
fibrosis;32,33 this is particularly true in adult biopsies macrovesicular, may be mixed large and small
compared with pediatric biopsies. Although the droplet steatosis. Liver cell injury is most often
literature is not entirely concordant, it is likely that noted in the form of ballooning with cell swelling;
most would agree that the finding of fat alone, or fat this was the key histologic feature that differentiated
and inflammation alone, with no evidence of progressive NAFLD (Types 3 and 4) with an
ballooning would qualify for definitive NAFLD, increased risk of cirrhosis and liver-related death
but not for NASH. The additional finding of in the study by Matteoni et al.43 Lobular inflamma-
ballooning would strongly support the diagnosis of tion is typically present, but mild and commonly
active NASH, whereas the presence of zone 3 peri- mixed in nature. Portal inflammation is typically
sinusoidal fibrosis would support a diagnosis of absent or mild, and when significant, it has been
previous/remote NASH, or can be seen in ongoing recommended that co-existent liver disease be
NASH. considered.44 Increased portal inflammation has
Clinico-pathologic and pathophysiology corre- also recently been identified as a feature of resolu-
lates. In considering the histologic findings of tion from the results of a recent treatment trial.45
NAFLD, it is important to consider the both clinical Other features that may be present in NAFLD/NASH
context in which this liver disease exists and the include Mallory’s hyaline, which can be detected by
pathophysiology of the process. NAFLD has come to immunohistochemical stains against ubiquitin and
be recognized as the ‘hepatic manifestation of the p62, acidophil bodies, megamitochondria and gly-
metabolic syndrome’14 from several studies docu- cogenated nuclei. Hepatocellular and sinusoidal
menting the close associations of the histologic lining cell iron are rarely discussed except in
findings with critical clinical features34,35 that have focused studies of iron and NAFLD, but may be
come to be grouped together because of a shared risk present if carefully examined. Fibrosis is initially
of increased cardiovascular disease. The ‘metabolic present in acinar zone 3 in a perisinusoidal,

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 Pathology of fatty liver disease
EM Brunt
S44

Figure 3 (a) Nonalcoholic steatohepatitis is characterized by zone 3 accentuation of the lesions of steatosis (large and small droplet type),
ballooning and lobular inflammation. There may also be a component of portal chronic inflammation (not illustrated). The findings in
this biopsy are indistinguishable from alcoholic steatohepatitis. (b) The earliest stage of fibrosis in NASH is zone 3 perisinusoidal
collagen deposition in a ‘chickenwire’ pattern (central zone on right, portal tract on left). This pattern is also seen in alcoholic liver
disease, and therefore is not useful in distinguishing the two (trichrome stain).

‘chickenwire’ pattern with sparing of the portal and 52 biopsies from 51 clinical cases of NASH that
periportal areas. Two studies utilizing evaluation of recognized the constellation of lesions of NASH
stellate cell activation by immunohistochemistry (Table 1a and 1b). Steatosis was present by defini-
noted zone 3 accentuation in human liver biopsies tion and did not necessarily affect the grade,
of NASH.46,47 With progression, portal and peripor- although greater amounts were typically present in
tal fibrosis may occur, as well as various forms of more severe cases. The lesions that correlated with a
bridging fibrosis. Cirrhosis is a known complication ‘gestalt’ grade of mild, moderate and severe steato-
of NASH. The physiologically altered liver with hepatitis were ballooning, lobular and portal in-
cirrhosis may or may not retain any or all of the flammation. Fibrosis was evaluated for two
active lesions of NASH; hence, many cases of components: zone 3 perisinusoidal fibrosis and
‘cryptogenic’ cirrhosis may have developed from portal-based fibrosis. It was noted that some cases
‘burned-out’ NASH.48 What is not known is in had only the former, while cases with any portal-
whom and how to accurately predict histological based fibrosis also had the former, or had bridging
progression of fibrosis, that is, ‘natural history’ of fibrosis, hence the staging system as proposed.
NAFLD (Figure 3a and b); however, new concepts in In 2002, the NIDDK sponsored NASH Clinical
the pathogenesis of fibrosis have been suggested. Research Network sponsored the Pathology Com-
Very recently, a study in hepatitis C49 has been mittee to develop a scoring system that would
broadened to NASH50 to introduce the idea that the encompass the entire spectrum of NAFLD and
portal fibrosis of chronic liver disease correlates provide a feature-based scoring system for the entire
with the periportal ductular reaction, which may be spectrum of NAFLD that could be applied to
‘driven’ by hepatocyte proliferative arrest as mea- treatment trials in adults and children (Table 2a
sured by senescence markers. The putative cause(s) and 2b). The system was developed and validated by
of hepatocyte proliferative arrest are speculated to the nine pathologists of the group after two blinded
be viral infection, steatosis, insulin resistance and readings of 32 adult biopsies and one blinded
increased body mass. reading of 18 pediatric biopsies.33 This is a scoring
system in which the components, steatosis, lobular
inflammation and hepatocellular ballooning, are
Grading and Staging each semiquantitated, then added together for an
aggregate activity score. The fibrosis score is a
The concept of semiquantitative ‘grading’ and modification of the ‘Brunt’ fibrosis score above with
‘staging’ the necroinflammatory lesions, fibrosis additional subclassifications of stage 1 to account
and architectural alterations in chronic hepatitis is for delicate (1a) or dense (1b) perisinusoidal fibrosis
well established. Batts and Ludwig51 describe the and stage 1c to include ‘portal only’ fibrosis when
portal-based nature of these lesions for viral, auto- noted. Biopsies with NAFLD Activity Scores (NAS)
immune and some forms of metabolic chronic liver above 5 were nearly all correlated with a histologic
disease. Clearly, the lesions of NASH are different diagnosis of ‘definite NASH’, whereas those of 0–2
from those of portal-based injury of chronic hepati- were all diagnosed as ‘definitely not NASH’; this
tis. Thus, a system for grading and staging NASH was true in both adults and pediatric biopsies. A
was proposed in 199952 based on a blinded review of word of caution was noted: ‘ythe primary purpose

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 Pathology of fatty liver disease
EM Brunt
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Table 1a NASH activity grade Table 2a Grading for NAFLDa

Grade Steatosis Ballooning Inflammation NAS Steatosisb Ballooning Inflammation, lobularc

Mild, 1–2 (up to 66%) Minimal L: 1–2 0 o5% (0) None (0) None (0)
Grade 1 P: none-mild 3 5–33% (1) Rare or few (1) 1–2 foci per 20  field (1)
Moderate, 2–3 (433%; Present L: 2 6 34–66% (2) Many (2) 2–4 foci/20  field (2)
Grade 2 may be 466%) P: mild– 8 466% (3) Many (2) 44 foci/20  field (3)
moderate
Severe, 3 Marked L: 3 NAS: NAFLD activity score.
Grade 3 P: mild– a
The number in parentheses is the NAS score for each histologic
moderate feature. This is an example of how the composite NAS is derived for
any case of NAFLD; in any case, the combinations of lesions may
Steatosis Grade 1: r33%; Grade 2: 433% o66%; Grade 3: Z66%. differ, and thus, the NAS would also.
L ¼ lobular, P ¼ portal. b
Steatosis estimated by percent of fat in hepatocytes by examination
Adapted from Brunt et al.52 at 4  and 10  .
c
Includes all types of inflammatory cells in clusters in lobule
(mononuclears, neutrophils, eosinophils).
Table 1b Staging of fibrosis for NASH

Stage Histologic description Table 2b Staging for NAFLD

0 No fibrosis Stage Histologic description

1 Zone 3 perisinusoidal fibrosis only
2 Zone 3 plus portal/periportal fibrosis
0 No fibrosis
3 As above with bridging fibrosis
1a Zone 3 perisinusoidal fibrosis, requires trichrome
4 Cirrhosis stain to identify
1b Zone 3 perisinusoidal fibrosis, seen easily on H&E
Adapted from Brunt et al.52 1c Periportal/portal fibrosis only
2 Zone 3 plus portal/periportal fibrosis
3 As above with bridging fibrosis
4 Cirrhosis
of the NAS is to assess overall histological change; it
is not intended that numeric values replace the Adapted from Kleiner et al.33
pathologist’s diagnostic determination of steato-
hepatitis’.33
A third scoring system was published in 200553
Resolution of NAFLD
based on a review of 25 biopsies of predominantly
Hispanic women by two blinded pathologists. The Recent clinical treatment trials are affording us
system is a multistep process of deriving an activity opportunities we had not realized in the past, as
score (that is derived from adding lobular inflamma- most are now being done with biopsies before and
tion and necrosis plus Mallory bodies, plus hepato- after intervention. One of the most interesting
cyte ballooning, plus perisinusoidal fibrosis) to findings to date is the fact that some patients can
portal fibrosis scores to determine grades from 1 to have ‘spontaneous’ resolution of the lesions of
3. The authors showed good k scores between the NASH without specific clinical intervention, other
two pathologists and strong correlations and rele- than, perhaps, increased awareness of having a
vant clinical tests. serious liver disease. This has been shown so far
in three studies.45,56,59 Other findings that have been
documented in clinical trials are shown in Table 3.
NAFLD and Alcoholic Liver Disease (ALD) Most45,56–58 studies, but not all59 have shown
complete resolution of the features of NASH with
It is often stated in the literature that NASH is treatment; some have shown new findings, such as a
histologically ‘identical’ to ASH, but is that really shift in inflammation that favors increased portal
true? There are several lesions of alcoholic liver inflammation45 or no change in portal inflamma-
disease that, to date, are not known in NAFLD,54 tion.56 Fibrosis score decreased57 or the nature of
including sclerosing hyaline necrosis, the veno- fibrosis changed.45 Notable differences in these
occlusive lesion first described by Goodman and studies are the numbers of patients and the length
Ishak,55 and alcoholic foamy degeneration. On the of time of observation.
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 Pediatric NAFLD
obesity, diabetes and alcohol are all likely contribut-
ing factors (Figure 4). In addition, most of the Pediatric obesity and NAFLD are problems of
standard literature in liver pathology notes that growing significance in our country and throughout
Mallory hyaline and neutrophilic infiltrates may be the world; the lesions of pediatric NAFLD, in many
more prominent in ALD. cases, are different than in adult cases; a recent

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 Pathology of fatty liver disease
EM Brunt
S46
study has classified the lesions into types 1 and 2 Differential Diagnoses
based on similarities, or lack thereof, with adult
NAFLD.60 The major differences with adult NAFLD Finally, we all are faced with biopsies from patients
are greater steatosis, little or no hepatocellular with clinically phenotypic NAFLD, but without
ballooning or Mallory’s hyaline, and portal accent- fatty liver disease or even steatosis in the biopsy.
uation over zone 3 accentuation in pediatric cases. Several questions arise in such biopsies. Do
This is a fledgling field that will continue to grow in the lesions of NAFLD wax and wane? Do all the
the future. lesions of NAFLD/NASH (necessarily) ‘disappear’
with progression to cirrhosis or regression or
do some features, 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,
rarely, a lesion suggestive of PSC. The pathologist
may also need to consider the possibility of
autoimmune liver disease, iron overload or even
Wilson disease.
Finally, even though the concept of the ‘Metabolic
Syndrome’ is being questioned about its role in
cardiovascular risk,61 this cluster of clinical findings
currently retains a significant role in NAFLD.
Perhaps with what we are learning in pathology, it
Figure 4 Sclerosing hyaline necrosis. The terminal hepatic is time for us to begin to broaden our ‘spectrum’
venule is obliterated (upper left-center) and only visualized on of pathology to include not only steatosis
special stains, which may highlight the remnants of the vein wall. and steatohepatitis with cirrhosis but also the
Many of the surrounding hepatocytes have undergone necrosis,
and several of the remaining hepatocytes are ballooned and/or
minimal lesions (or ‘normal’) and hepatocellular
have Mallory’s hyaline with surrounding neutrophils, a lesion carcinoma in the setting of both cirrhotic and
known as satellitosis. noncirrhotic liver.

Table 3 Histologic findings of recent clinical trials

Recent treatment trials: primary histologic findings

Study (n) Tx Post-tx bx (n) Histologic findings reported

Neuschwander- 30 overweight Rosi 22 45% no longer NASH; improved grade, steatosis, inflammation,
Tetri et al45 48 weeks ballooning (P ¼ 0.004)
Shift toward increased portal CI (P ¼ 0.02)
No change in fibrosis score, shift from dense to delicate
perisinusoidal fibrosis (P ¼ 0.02)

Promrat et al56 18 overweight, Pio 18 67% had histologic response; decreased steatosis, ballooning,
nondiabetic 48 weeks lobular inflammation, Mallory’s hyaline, fibrosis (Po0.05)
No change in portal inflammation

Lindor et al59 166 multicenter Urso v 107 Both groups had decreased steatosis, and no significant change
Placebo 104 weeks in inflammation or fibrosis
No statistical differences between groups

Dixon et al57 36 morbid LAGB 36 83% no longer NASH; significant improvement in steatosis,
obesity; 12 36–204 weeks inflammation, fibrosis (Po0.001). No change in portal
steatosis only inflammation
Fibrosis: stage Z2: 78%-13% (Po0.001)

Huang et al58 23 overweight Diet to 15 60% had histologic response; compared with nonresponders,
reduce 48 weeks significant improvement in steatosis (P ¼ 0.003), total score
IR (Po0.0001)

Tx, therapy; bx, biopsy; n, number; Rosi, rosiglitazone; Pio, pioglitazone; Urso, ursodeoxycholic acid; LAGB, laparoscopic adjustable gastric
binding; IR, insulin resistance; CI, chronic inflammation.

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