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"Clinical and histologic spectrum of nonalcoholic
fatty liver disease associated with
normal ALT values"
Hepatology, June 2003, Volume 37,
Number 6
Pouneh Mofrad Division of
Gastroenterology, Hepatology, and
Nutrition, Department of Internal
Medicine; Virginia Commonwealth
University, Richmond, VA.
Nonalcoholic fatty liver disease (NAFLD)
has recently been recognized to be one
of the leading causes of chronic liver
disease. This histology of this
condition is characterized by either
predominantly macrovesicular steatosis
alone or steatohepatitis. The latter
condition includes steatosis along
with varying combinations of findings,
including cytologic ballooning,
Mallory's hyaline, pericellular
fibrosis, and scattered inflammatory
infiltrate. By definition,
nonalcoholic fatty liver and
nonalcoholic steatohepatitis (NASH)
occur in individuals who do not
consume alcohol in amounts generally
considered to be harmful to the liver.
The serum ALT value has long been used
as a surrogate marker of liver injury.
It is, however, well known that the
ALT values do not correlate well with
the severity of liver disease noted on
liver biopsy in subjects with chronic
liver disease. This is particularly
true when one considers the stage of
fibrosis present in an individual
patient. The present study confirms
this to be true also for NAFLD
Several published series have provided
detailed information on the histologic
and clinical spectrum of findings in
patients with NAFLD. The majority of
subjects in these studies were
identified by the presence of elevated
liver enzymes. It is, however, known
that both fatty liver and NASH may
exist without elevation of alanine
aminotransferase (ALT). Although the
full spectrum of NAFLD is known to
occur in the presence of normal ALT
levels, there have been no previous
studies that have focused on those
with NAFLD and normal ALT values or
contrasted their clinical and
histologic features with those having
abnormal ALT levels. Based on an upper
limit of normal as 40 IU/L for ALT, a
recent study has also suggested that
some individuals with high
"normal" ALT levels may have
underlying NAFLD. We performed a
retrospective study to (1)
characterize the clinical and
histologic features of those with
NAFLD and normal ALT values, (2)
compare the spectrum of NAFLD
associated with normal versus elevated
ALT levels, and (3) determine whether
there were differences in the clinical
or histologic spectrum of NAFLD
between those with a low normal versus
high normal ALT value.
ABSTRACT: A retrospective study was
performed to (1) characterize the
clinical and histologic features of
those with nonalcoholic fatty liver
disease (NAFLD) and normal alanine
aminotransferase (ALT) values, (2)
compare the spectrum of NAFLD
associated with normal versus elevated
ALT levels, and (3) determine whether
there were differences in the clinical
or histologic spectrum of NAFLD
between those with a low normal versus
high normal ALT value. A total of 51
subjects with NAFLD and normal ALT
were identified and compared with 50
consecutive subjects with NAFLD and
elevated ALT. The major indications
for liver biopsy in those with normal
ALT were unexplained hepatomegaly (n =
21) and evaluation as a potential
donor for living donor liver
transplantation (n = 16). The 2 groups
were comparable with respect to age,
gender distribution, and ethnicity.
Approximately 80% of cases in both
groups had at least 1 feature of the
metabolic syndrome, the major risk
factor for NAFLD. The 2 groups were
also comparable with respect to the
grade of the individual histologic
parameters of NAFLD. A total of 12
subjects with normal ALT levels had
bridging fibrosis, whereas 6 had
cirrhosis. Diabetes was the only
factor independently associated with
an increased risk of advanced fibrosis
(bridging fibrosis or cirrhosis) by
multivariate analysis (relative risk:
2.3, P < .01). The mean steatosis
(1.6 vs. 2.16, P < .04) and
perisinusoidal fibrosis scores (0.35
vs. 0.9, P < .049) were lower in
those with low normal (<30 IU/L)
ALT versus high normal ALT. However,
the prevalence of advanced fibrosis
was similar (5 of 15 vs. 13 of 36,
respectively). In conclusion, (1) the
entire histologic spectrum of NAFLD
can be seen in individuals with normal
ALT values, (2) the histologic
spectrum in these individuals is not
significantly different from those
with elevated ALT levels, and (3) a
low normal ALT value does not
guarantee freedom from underlying
steatohepatitis with advanced
fibrosis.
It is interesting to note the
relatively high prevalence of bridging
fibrosis or cirrhosis in those with
NAFLD and normal ALTs. This may be at
least partly due to the bias inherent
in a retrospective analysis. The
differences in the rates of advanced
fibrosis among those undergoing biopsy
for hepatomegaly versus asymptomatic
and apparently healthy individuals
being evaluated as transplant donors
indeed support this possibility. On
the other hand, the data from the
transplant donor group also indicate
that the absence of any obvious
symptoms, signs, or ALT values
suggestive of liver disease does not
guarantee the absence of clinically
significant liver disease, i.e.,
advanced stage chronic liver disease.
In this respect, these data
corroborate and extend the existing
literature regarding other chronic
liver diseases, e.g., hepatitis C and
normal ALT values.
An important question is the
following: How does one identify
subjects with clinically significant
NAFLD in the absence of symptoms,
signs, or abnormal ALT values? It is
clearly both unreasonable and
impractical to perform routine liver
biopsies for this purpose. Although
much more work needs to be done to
determine who should be screened for
NAFLD and how such individuals should
be evaluated, the current studies
suggest that those with hepatomegaly,
especially in the presence of
diabetes, are more likely to have
clinically significant underlying
pathology.
In summary, patients with NAFLD and
normal ALT values may have
steatohepatitis and advanced fibrosis.
Diabetes is an independent predictor
of advanced fibrosis. Although further
work remains to be done to answer the
clinical questions raised by these
data, this study is an initial step
toward the identification,
characterization, and management of
NAFLD in patients with normal ALTs.
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