Medical Liver Disease: Problem Diagnoses for Practicing Pathologists
Dr. Grace Kim
Dr. Linda D. Ferrell
Dr. Sanjay Kakar
Section 5 -
Nonalcoholic Fatty Liver Disease
University of California
San Francisco, CA
NAFLD is a common liver disease and encompasses a wide spectrum of pathologic changes ranging from
simple steatosis at one end to steatohepatitis, fibrosis and cirrhosis at the other. In patients with
risk factors for NAFLD like obesity and type 2 diabetes, it is estimated that 50-70% will show steatosis,
20-30% will progress to steatohepatitis and 2-3% will eventually develop cirrhosis . The occurrence
of cirrhosis, overall mortality and liver-related mortality in NAFLD patients has been reported as 5-15%,
12-36% and 2-7% respectively, and is significantly higher than the general population
Role of Liver Biopsy:
Studies increasingly support a "two-hit" hypothesis, where simple steatosis is the first step and has
a very small (<5%) risk of progression to advanced fibrosis. On the other hand, patients with
steatohepatitis, which constitutes the "second hit", progress to cirrhosis in around 25% of cases .
Hence it is critical to separate steatohepatitis from steatosis. There are no clinical or radiological
tests that can reliably diagnose steatohepatitis. Use of liver function tests alone can lead to
overdiagnosis of NASH in a significant number of cases. Serum transaminases often correlate poorly with
histological activity. Radiological techniques can demonstrate steatosis, but cannot detect
steatohepatitis . In several epidemiological and clinical studies, unexplained increase in ALT and
AST has been assumed to have fatty liver disease. In a study of 354 patients with clinically unexplained
liver test abnormalities, Skelly et al showed that 66% had fatty liver disease on liver biopsy . The
remaining cases were either normal, had a different clinical diagnosis or remained cryptogenic. Hence
the diagnosis of steatohepatitis can be reliably made only on biopsy. The role of liver biopsy in fatty
liver disease is to establish the diagnosis, distinguish steatosis from steatohepatitis, determine the
extent of activity and fibrosis, and evaluate for other coexisting disease processes The rest of the
discussion in this category is devoted to pathologic features
and diagnostic problems encountered
in nonalcoholic steatohepatitis (NASH).
(1) Steatosis: The fat occurs in macrovesicular or mixed patterns; predominantly
microvesicular steatosis is not characteristic of steatohepatitis. An upper limit of 5% is widely used
as a cutoff for defining significant steatosis . Minor degrees of steatosis have been considered
'normal', but an opposing view holds any degree of steatosis to be pathological. Steatosis is present in
nearly 100% of cases, but may not be necessary for diagnosis in certain situations like
(a) steatohepatitic cirrhosis; fat often disappears after onset of significant fibrosis or cirrhosis
(b) steatohepatitis associated with drugs like amiodarone may show minimal steatosis
(2) Inflammation: Mild mixed acinar inflammation is considered the hallmark of
steatohepatitis. Neutrophils, usually in small numbers, can surround the ballooned hepatocytes
(satellitosis). Mild acinar and portal mononuclear inflammation including lymphocytes and histiocytes is
also common. Occasional lipogranulomas, eosinophils, pigmented Kupffer cells and microgranulumoas may be
(3) Hepatocellular injury (in addition to steatosis) is a prerequisite for the diagnosis of
steatohepatitis. Evidence of hepatocellular injury most often occurs in the form of hepatocellular
ballooning or pericellular fibrosis.
(a) Hepatocellular ballooning, characterized by swelling and rarefaction of
cytoplasm of zone 3 hepatocytes is a characteristic finding of steatohepatitis. This can be accompanied
by cytoplasmic Mallory hyaline in zone 3 hepatocytes, but is often poorly formed. Scattered acidophil
bodies are common but are not a conspicuous finding.
(b) Pericellular fibrosis. The pericellular, chickenwire or spider-web
pattern of fibrosis results from collagen deposition in the space of Disse and often starts in the zone 3
of the acinus. Portal-based fibrosis can accompany pericellular fibrosis. Fibrosis in the periportal
region has been reported in NASH associated with diabetes and in children.
Table 1. Histologic features of nonalcoholic steatohepatitis. Adapted from AASLD
conference summary on NASH, 2002
- Steatosis, predominantly macrovesicular,
concentrated in zone 3
- Mild mixed acinar inflammation
- Hepatocelluar injury in the form of
- Hepatocellular ballooning, often most
prominent in zone 3, and/or
- Pericellular fibrosis
|Often present, not essential for diagnosis|
- Glycogenated nuclei in zone 1
- Lipogranulomas in the acinus or portal tracts
- Occasional acidophil bodies
|May be present, not essential for diagnosis|
- Mallory hyaline in zone 3, typically
- Mild iron deposits in hepatocytes or
- Giant mitochondria
- Predominantly microvesicular steatosis
- Prominent portal and/or acinar inflammation,
numerous plasma cells
- Prominent bile ductular proliferation, cholestasis
- Perivenular fibrosis, sclerosing hyaline sclerosis
- Marked lobular inflammation
Minimum criteria: The minimum findings necessary for the diagnosis of SH include:
(1) Macrovesicular steatosis, (not considered necessary for diagnosis in certain
situations described above).
(2) Evidence of hepatocellular injury in the form of hepatocellular ballooning (with or
without acidophil bodies or Mallory hyaline) or pericellular fibrosis. When present along with
steatosis, pericellular fibrosis provides evidence of prior steatohepatitic injury and is sufficient for
the diagnosis even in the absence of hepatocellular ballooning or inflammation.
(3) Acinar inflammation (often mild and mixed) is required for the diagnosis by some
pathologists and is mentioned as a necessary criterion in the AASLD summary conference on NASH .
However, many hepatopathologists believe that the first two criteria are enough to make the diagnosis.
Steatosis with scattered inflammatory cells in the absence of hepatocellular injury (hepatocyte
ballooning or pericellular fibrosis) have low rate of progression to fibrosis, and is not considered
enough for the diagnosis of steatohepatitis.
Histological Course of NASH
There are a limited number of studies that have examined histological features in NASH patients in
sequential biopsies. There is a wide variability in progression of disease among different patients. In
most cases, disease progression is slow and increase in stage of fibrosis is seen in 30-40% of patients
over 3-5 years
Rapid progression to advanced fibrosis and cirrhosis can be seen in a minority
of patients. Diabetes, high body mass index and high AST levels have been shown to be predictive of
Fibrosis remains stable in 35-50% of patients or may regress in 15-30%. Reduction
in fibrosis stage may be due to sampling error or may represent true regression of fibrosis. The
severity of steatosis, hepatocellular ballooning and inflammation generally regresses over time
independent of progression of fibrosis . Hence typical features of steatohepatitis may be lost by
the time cirrhosis develops (see later).
Diagnostic Considerations in Steatohepatitis
(1) Alcoholic vs. Nonalcoholic
In majority of instances, it is not histologically possible to distinguish alcoholic vs. nonalcoholic
SH. In general, NASH is characterized by more prominent steatosis and less severe signs of
hepatocellular injury like ballooning and inflammation. Glycogenated nuclei in zone 1 have been
described in 70-80% of NASH compared to ~10% in alcoholic SH . Abundant Mallory hyaline and
prominent neutrophilic infiltrate strongly favor alcoholic etiology for SH . Several features like
obliteration of central veins, canalicular cholestasis and extensive microvesicular steatosis can occur
in alcoholic SH, but have not been observed in NASH.
(2) Risk Factors
A vast majority of NASH cases can be attributed to obesity, type 2 diabetes and hyperlipidemia. Type
1 diabetes is not a significant risk factor unless the blood glucose is poorly controlled. The major
risk factors for NASH are associated with insulin resistance and are components of the metabolic
syndrome. The diagnosis of metabolic syndrome is based on the evaluation of 5 components: obesity,
hypertension, hypertryglyceridemia, low HDL and hyperglycemia (presence of 3 or more is generally
accepted as metabolic syndrome). Metabolic syndrome is present in 22% of the population and carries
increased risk of cardiovascular morbidity and mortality as well as increased risk of progressive
fibrosis in NASH. Among the NASH patients, nearly 90% have metabolic syndrome
Drug-related SH is uncommon and only a few drugs are associated with this pattern of liver injury
. Amiodarone is the best known example and is a very effective
antiarrhythmic drug. Majority of patients have asymptomatic abnormalities of liver function tests, but
1-3% of patients with long-term amiodarone use develop more serious toxicity with typical histological
features of NASH . The biopsy often shows prominent Mallory hyaline (occasionally in zone 1} and
neutrophilic satellitosis, while steatosis is less conspicuous. Reversal of liver injury often occurs
with discontinuation of the drug, but may be delayed by weeks or months. In addition, amiodarone is also
associated with a different type of lipid accumulation called phospholipidosis characterized by
accumulation of drug in the lysosomes. On liver biopsy, these cells appear as 'foamy hepatocytes'. Similar changes can occur in Kupffer cells that appear as foamy cells in the
sinusoids. Perhexiline maleate (Pexid), an antianginal drug, and diethylaminoethoxyhexestrol (Coralgil), a vasodilator, were extensively used in
Europe and Japan respectively. Both drugs can cause NASH and phospholipidoses similar to amiodarone.
Table 2. Risk factors for NASH
Metabolic diseases (acquired)
Metabolic diseases (genetic)
- Diabetes, type 2
- Rapid weight loss
- Wilson disease
- Jejunoileal bypass
Questionable etiologic association; may exacerbate NASH
- Perhexiline maleate
- Calcium channel blockers (like nifedipine, verapamil and diltiazem)
The evidence linking other drugs to NASH is tenuous. Drugs like tamoxifen,
steroids, estrogen and diethylstilbesterol often lead to hepatic
steatosis, but steatohepatitis is rare. These drugs may exacerbate or precipitate steatohepatitis in
patients with risk factors for NASH rather than play an etiological role. The evidence linking NASH and
calcium channel blockers like nifedipine is also anecdotal. Risk factors for
NASH were present in many reported cases creating uncertainty about the association of these drugs with
steatohepatitic injury. Methotrexate is well known to cause steatosis,
portal-based fibrosis and eventually cirrhosis in some patients with long term use. However, typical
features of NASH like ballooned hepatocytes and pericellular fibrosis are not seen with methotrexate use.
It has been suggested that methotrexate can exacerbate SH.
Three metabolic disorders that can mimic NASH warrant special mention. Diabetic patients with poor
glycemic control can develop glycogenic hepatopathy, characterized by swollen
hepatocytes and glycogenated nuclei similar to NASH . However, it occurs more commonly in type 1
diabetes as opposed to type 2 diabetes in NASH. Fat, Mallory hyaline, significant inflammation and
pericellular fibrosis are usually absent or inconspicuous in glycogen hepatopathy. The term diabetic hepatosclerosis has been suggested to describe dense perisinusoidal
fibrosis and basement membrane deposition that occur in patients with long standing insulin-dependent
diabetes . It is associated with severe microvascular disease in other organs and may represent a
form of hepatic microangiopathy. In addition to sinusoidal fibrosis, perivenular fibrosis and hyaline
thickening of small hepatic artery branches may be present. Features typical of NASH such as steatosis
or hepatocellular ballooning are not seen. These patients often have elevated alkaline phosphatase, a
finding unusual for NASH . Wilson disease is
more often associated with steatosis, but histologic features of steatohepatitis with Mallory hyaline can
occur. The non-zonal distribution of fat and Mallory hyaline in Wilson disease, 'chronic hepatitis-like'
pattern of inflammation and portal-based fibrosis are helpful in the differential diagnosis.
(3) Pediatric NASH
NAFLD is reportedly increasing in pediatric patients and affects more than 1-2% of adolescents. A
strong association with male gender, Hispanic race and insulin resistance has been reported. Majority of
patients are obese and metabolic abnormalities like hypertryglyceridemia and hypercholesterolemia are
Some of the diagnostic features for adult NASH are often not seen in children (7,8,9,10).
Steatosis is often severe but may lack zone 3 predominance. Ballooned hepatocytes, Mallory hyaline,
acinar inflammation and neutrophilic infiltrate may be mild or absent, while portal-based chronic
inflammation may be prominent. Portal-based fibrosis in the absence of pericellular fibrosis can occur.
Advanced fibrosis can occur in pediatric NASH; cirrhosis is less common than in adults but has been
A recent study has proposed that pediatric steatohepatitis can be classified as types 1 and 2 based on
histological features . Type 1 NASH shows the classic histological features with zone 3 predominance
of steatosis and fibrosis while type 2 NASH shows variant features like portal-based inflammation and
fibrosis. Half of the pediatric patients with NASH in this series showed type 2 features. Type 2 NASH
was more frequent in boys and in children of Asian, Native American and Hispanic ethnicity. Children
with type 2 NASH have a high incidence of severe obesity. Review of NASH studies in adults suggests that
type 2 NASH may also occur in adults, especially in patients with extreme obesity.
(4) NASH in Conjunction with Other Liver Diseases
In view of the increasing incidence of fatty liver disease, it is evident that NASH can coexist with
other liver diseases. The features of NASH are sufficiently distinctive to allow diagnosis in the
presence of another liver disease. Histologic features of steatohepatitis are present in around 5% of
patients with another liver disease even in the absence of significant alcohol consumption . This
overlap is often encountered in hepatitis C, perhaps because both are common diseases. Macrovesiclular
steatosis occurs in approximately 40% of patients with chronic hepatitis C, but is generally mild (except
genotype 3a) and is either non-zonal or predominiantly in zone 1. Ballooned hepatocytes in zone 3 and
pericellular fibrosis are not seen hepatitis C. On the other hand, lymphoid aggregates, periportal
activity, prominent acidophil bodies and portal-based fibrosis are not typically features of NASH.
Coexisting NASH may accelerate the progression of fibrosis in patients with hepatitis C .
(5) Unusual Histologic Features
(a) Extensive microvesicular steatosis. Some degree of microvesicular
steatosis is often observed in NASH. However, exclusive or predominant microvesicular steatosis should
prompt consideration of other etiologies like alcohol foamy liver degeneration, Reyes's syndrome (in
children), acute fatty liver of pregnancy and genetic diseases like carnitine deficiency. Adverse effect
of drugs/toxins like cocaine, tetracycline, valproic acid and zidovudine can also lead to predominantly
(b) Prominent portal inflammation. Mild portal inflammation can be
observed in NASH. However, portal inflammation exceeding acinar changes is unusual and should trigger
the consideration of other hepatitic processes like viral and autoimmune hepatitis. The presence of
lymphoid aggregates (as in hepatitis C) and numerous plasma cells (as in autoimmune hepatitis) are
unusual in NASH. Serum autoantibodies have been detected in 23-36% of NASH patients and can lead to
clinical confusion with autoimmune hepatitis. Antinuclear antibodies (ANA) and anti-smooth muscle
have been reported in 20% and 3-5% of cases respectively
Both antibodies are
present in rare cases . These patients generally show typical histological features of NASH and do
not benefit from steroid therapy.
(c) Portal-based fibrosis. Mild portal fibrosis has been commonly
described in NASH. However, portal-based fibrosis in the absence of or out of proportion to pericellular
fibrosis is not a typical feature and should invoke another etiology as the cause of fibrosis Exceptions
include NASH in children, which is often associated with portal-based fibrosis in the absence of
pericellular fibrosis. In some patients with type 2 diabetes, the pericellular fibrosis may first appear
in the periportal region (zone 1).
(d) Bile ductular reaction. Mild degree of ductular reaction occurs
commonly as a nonspecific finding. However, prominent bile ductular reaction, bile duct injury and duct
loss are not part of the spectrum of NASH.
(e) Increased hepatic iron. A mild increase of iron in hepatocytes
(generally nonzonal) or sinusoidal cells has been described in 15-55% of biopsies showing typical NASH.
Serum ferritin is an acute phase reactant and can be elevated in these patients raising the clinical
suspicion for genetic hemochromatosis. However, genetic hemochromatosis is characterized by a more
intense iron deposition that predominantly occurs in hepatocytes and is more pronounced in the periportal
region; the typical histological features of NASH are not observed in hemochromatosis. The role of iron
in progression of fibrosis is uncertain, but the present evidence suggests that it is unlikely to be
(6) Grading and Staging
Although several different grading and staging schemes have been proposed, modified Brunt
classification is the most widely used
The combination of steatosis, hepatocellular ballooning
and inflammation in the grading scheme can create problems since these three features do not change in
conjunction. It is not uncommon for NASH biopsies to show marked (>66%) steatosis but minimal
hepatocellular ballooning and inflammation. It has been advocated that steatosis can be graded
separately (mild, moderate, severe) and features of hepatocellular injury (like ballooned hepatocytes and
inflammation) be used for the grading of steatohepatitis. Since pediatric NASH has features different
from adult NASH and often shows portal-based inflammation and fibrosis, different grading and staging
strategies have to be devised.
Table 3. Grading of steatohepatitis
|Steatosis: up to 66%, predominantly macrovesicular|
Ballooning: occasional, zone 3
Lobular inflammation: Scattered, mixed
Portal inflammation: none or mild
|Steatosis: any degree, macrovesicular or mixed|
Ballooning: present, zone 3
Lobular inflammation: Neutrophils often present, +/- chronic inflammation
Portal inflammation: none, mild or moderate
|Steatosis: usually >66%, often mixed|
Ballooning: marked, predominantly in zone 3
Lobular inflammation: Scattered mixed inflammation; neutrophils often prominent in zone 3
Portal inflammation: mild or moderate; not predominant or marked
|Staging of steatohepatitis|
|Stage 1 ||Zone 3 perivenular or pericellular fibrosis, focal or extensive|
|Stage 2 ||As in stage 1 plus portal fibrosis, focal or extensive|
|Stage 3 ||Bridging fibrosis, focal or extensive|
|Stage 4 ||Cirrhosis (+/- residual pericellular fibrosis)|
(7) NASH-Related Cirrhosis
Cirrhosis in NAFLD may retain the characteristic histological features of NASH, but the phenomenon of
'burnt-out' cirrhosis is well documented. Biopsy-proven cases of NASH may lose the diagnostic features
with progression to cirrhosis . Based on correlation with clinical risk factors for NASH, it is
believed that a large proportion of otherwise cryptogenic cirrhosis may be related to NASH . A high
incidence of obesity and type 2 diabetes has been found in cryptogenic cirrhosis. It has been speculated
that remodeling of hepatic architecture in cirrhosis leads to shunting of gut-derived lipoproteins from
the portal to systemic circulation, diverting blood-borne lipids away from the liver.
Patients with steatohepatitic cirrhosis are at risk for hepatocellular carcinoma
incidence of HCC in cryptogenic cirrhosis ranges from 18-27%. The precise risk in NASH-related cirrhosis
is not known, but is speculated to be similar to hepatitis C –related cirrhosis.
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