GASTROENTEROLOGY 2004;126:1409 –1415
CLINICAL MANAGEMENT
Loren Laine, M.D.
Clinical Management Editor
University of Southern California
Los Angeles, California
Chronic Hepatitis C With Normal Aminotransferase Levels
AIJAZ AHMED and EMMET B. KEEFFE
From the Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
Clinical Case
A 43-year-old woman is referred for management of
chronic hepatitis C. After donating blood, the pa-
tient was informed that she had hepatitis C virus
(HCV) infection. She initially saw her primary care
physician who ordered a complete blood count, pro-
thrombin time, and hepatic function panel. On re-
ferral evaluation, the patient has no symptoms or
signs of chronic liver disease, and all of the labora-
tory tests arranged by her primary physician were
normal.
Background
Chronic hepatitis C is estimated to affect 170
million individuals worldwide, and at least 2.7 million
persons in the United States are viremic with detectable
HCV RNA.1 Most patients with chronic hepatitis C
remain asymptomatic and without significant liver dis-
ease for 2 or more decades following infection.2 Natural
history studies suggest that approximately 20% of pa-
tients with chronic hepatitis C progress to cirrhosis in
the first 20 years of infection.1,2 The risk of cirrhosis in
patients with persistently normal alanine aminotransfer-
ase (ALT) levels in the setting of chronic hepatitis C is
even lower.3–5 Currently, liver biopsy is the most reliable
method of staging the severity of hepatic fibrosis. Al-
though peginterferon plus ribavirin combination therapy
has resulted in significant improvement in the sustained
virological response rate to approximately 50% overall,
therapeutic efficacy remains less than optimal.6 –9 In ad-
dition, treatment is expensive (approximately $30,000/
year for drug costs alone) and associated with significant
adverse effects.10
Definition of Normal ALT
The criteria for a persistently normal ALT level in
patients with chronic hepatitis C varies from one study to
the other, with no universally accepted definition.3,4 The
absolute ALT level, number of tests performed, time
interval between testing, total duration of observation,
and coexisting other liver chemistry abnormalities may
be crucial.3,4 The normal range for any laboratory test is
typically estimated by obtaining samples from a popu-
lation of “healthy” individuals (some of whom may have
undiagnosed chronic hepatitis C or fatty liver), and the
upper limit of the test is set at 2 standard deviations
above the mean population value. In most clinical trials,
patients with persistently normal ALT levels are defined
on the basis of 2 or 3 normal ALT levels obtained at
intervals of at least 1 month during a 6-month period of
time preceding antiviral therapy.3,4
Epidemiology of HCV Infection With
Normal ALT
Blood Donor Population
In the United States, approximately 0.4% of vol-
unteer blood donors test positive for anti-HCV.11,12
Screening is performed with anti-HCV testing, and pa-
tients with a detectable anti-HCV undergo confirmatory
testing for the presence of HCV RNA by polymerase
chain reaction. Blood donor volunteers who test positive
for anti-HCV are informed by blood bank personnel of
their serologic status and advised to consult their per-
sonal physicians for evaluation. Routine screening of
blood donors has facilitated the identification of many
individuals with detectable anti-HCV who are asymp-
tomatic and have no history of liver disease. In the blood
donor population, approximately 25% of patients with
chronic hepatitis C have persistently normal ALT lev-
els.11,12 The majority of volunteer blood donors are un-
aware of underlying chronic hepatitis C before attempt-
ing to donate blood and, at the time of blood donation,
deny a history of high-risk behavior for acquiring HCV.
© 2004 by the American Gastroenterological Association
0016-5085/04/$30.00
doi:10.1053/j.gastro.2004.02.073
1410 AHMED AND KEEFFE
Table 1. Normal ALT: Degree of Hepatic Fibrosis
Year Author (ref) N minimal (%)
1997 Hoofnagle et al.26a 223
2000 Shiffman et al.13b 37
2002 Pradat et al.17c 66
aLiteraturereview to 1997.
bInstitutionalreview.
cMulticenter European experience.
On closer questioning in one study, however, 35% of
donors admitted to use of illicit parenteral drugs in the
past, and 20% had exposure to blood or blood prod-
ucts.11
General Population
It is estimated that approximately 20% of pa-
tients with chronic hepatitis C have persistently normal
ALT levels.4 In published studies, the proportion of
patients with chronic hepatitis C who have persistently
normal ALT levels has varied from 8% to 33%.11,13–18
Although the presence of persistently normal ALT levels
does not exclude the presence of advanced liver disease or
even cirrhosis, the great majority of patients have histo-
logically mild liver disease (stage 0 to 1 fibrosis).17–25
The prevalence of cirrhosis in patients with chronic
hepatitis C in the setting of normal ALT levels varies
from 0.5% to 6% (Table 1).13,17,26
Natural History of HCV Infection with
Normal ALT
One of the major problems encountered by most
investigators in studying the natural history of chronic
hepatitis C is the inability to identify infected patients
when they are asymptomatic and have normal ALT lev-
els. In addition, patients with chronic hepatitis C and
persistently normal ALT levels have been excluded from
registration clinical trials.6 – 8 These patients are difficult
to diagnose, and a small proportion come to medical
attention with an incidental diagnosis or, more rarely,
late after the development of cirrhosis with end-stage
liver disease. It has been shown that patients with
chronic hepatitis C and normal ALT levels have signifi-
cantly lower hepatocyte proliferation rates, lower apopto-
sis rates, and milder histologic damage as compared with
patients with elevated ALT levels.27 In patients with
normal ALT levels, the rate of fibrosis progression is
much slower than those with elevated ALT lev-
els.11,16,23,24
In a recent European retrospective collaborative trial,
864 patients with chronic hepatitis C were studied to
determine the correlation between ALT levels and his-
GASTROENTEROLOGY Vol. 126, No. 5
Normal to Mild to
moderate (%) Advanced (%)
37 63 0.5
63 31 6
35 63 2
tological findings on biopsy.17 Only 8% of patients had
persistently normal ALT levels, a lower proportion com-
pared to prior studies.13–16,18 Histological scores were
determined using the METAVIR system. In the subset
of patients with persistently normal ALT levels, 85%
had mild liver disease (stage 0 –1 fibrosis).17 Therefore,
only a small proportion (i.e., 15%) of patients with
chronic hepatitis C and persistently normal ALT levels
had moderate (stage 2) or advanced (stage 3 to 4) fibrosis.
In contrast, among patients with elevated ALT levels,
only 25% had mild liver disease; approximately 50% of
patients with elevated ALT levels had stage 2 fibrosis,
and about 25% had stage 3 or 4 fibrosis.
A few investigators have reported that chronic hepa-
titis C in patients with persistently normal ALT levels is
consistently associated with signs of histologic damage
and histologic severity that does not differ from patients
with elevated ALT levels.19,25,28 It is difficult to compare
these contradictory results due to differences in study
designs. Large, prospective studies are lacking in this
patient population as patients with persistently normal
ALT levels typically evade early diagnosis and have been
excluded from registration trials. Moreover, the progres-
sion of fibrosis in patients with chronic hepatitis C can be
variable and nonlinear.29 There may be rapid progression
of fibrosis associated with flares of hepatitis C,29 and the
factors associated with this rapid progression have varied
with study designs (longitudinal versus cross-sectional
studies).11,29 –33
Potential Management Strategies
Whether to treat or follow expectantly patients
with chronic hepatitis C and persistently normal ALT
levels and/or mild histologic liver disease is unclear. The
utility of liver biopsy in this patient population has not
been studied in a large number of patients. The obser-
vation that patients with persistently normal ALT levels
and mild necroinflammation have a slower rate of fibrosis
progression has reinforced the recommendation that pa-
tients with mild disease activity and scant hepatic fibro-
sis can delay antiviral therapy until newer treatments
May 2004 CLINICAL MANAGEMENT 1411

Table 2. Normal ALT: Pros and Cons of Peginterferon Plus Table 3. Normal ALT: Factors to Consider in Individualized
Ribavirin Antiviral Therapy Management of Chronic Hepatitis C
Pros HCV genotype (better response with genotypes 2 or 3 vs.
Interruption or delay in the progression of liver disease genotype 1)
Prevention of risk of HCV-related future complications Serum HCV RNA level (better response with less than vs. greater
Higher sustained virological response based on larger proportion than 1 ⫻ 106 IU/mL)
of patients with mild fibrosis Histologic stage of disease (better response with stage 0–1 vs.
No evidence of posttreatment ALT flares stage 3–4)
Favorable cost-effectiveness analyses Patient motivation and preference
Cons Complications and symptoms of HCV infection
Favorable natural history without treatment Quality of life
Lack of large prospective treatment trials Presence of comorbid illnesses
Majority of experience retrospective with limited number of Age
patients Disease duration
Definition of normal ALT uncertain and variable from study to
study
Adverse effects of antiviral therapy
undergo initial and/or follow-up liver biopsies to assess
disease progression.5 According to the NIH consensus
statement, the decision to treat patients with persistently
with greater efficacy and fewer side effects become avail- normal ALT levels should take into account several pre-
able.11,16,23,24 On the other hand, some patients with dictive factors that may influence the outcome of ther-
mild disease are not interested in the wait and watch apy, such as genotype, viral load, and presence of hepatic
approach. For example, a health care provider (e.g., sur- fibrosis, as well as general considerations, such as patient
geon, nurse), a prospective mother planning pregnancy, preferences and motivation for therapy, symptoms, qual-
or an individual with nonhepatic manifestations of ity of life, severity of comorbid illnesses, patient age, and
chronic hepatitis C such as cryoglobulinemia may want disease duration (Table 3).
to pursue antiviral therapy to eradicate HCV infection In contrast to the data presented at the 1997 NIH
irrespective of the degree of hepatic fibrosis. The results consensus conference, it is now apparent that ALT levels
of peginterferon plus ribavirin registration trials have appear to have no effect on the likelihood of response to
supported this approach by demonstrating a significantly antiviral therapy for chronic hepatitis C.36 In patients
higher sustained virological response among patients with persistently normal ALT levels, the sustained viro-
with minimal or no fibrosis (57%) compared with those logical response with interferon monotherapy and stan-
with bridging fibrosis or cirrhosis (44%).6 Therefore, dard interferon plus ribavirin combination therapy ap-
preemptive treatment of mild disease may be more effi- pear to be comparable to reported studies in patients
cacious than delaying treatment until progression to with elevated ALT levels (Table 4).36 – 40 Zeuzem et al.41
more advanced liver disease. On the other hand, the recently reported preliminary results of a an interna-
majority of patients with persistently normal ALT levels tional, multicenter, randomized controlled study using
will not progress to advanced liver disease over the next peginterferon alfa-2a 180 ␮g/week plus ribavirin 800
1–2 decades, based on available natural history studies, mg/day combination therapy for either 24 or 48 weeks in
and can safely await newer therapy (Table 2). HCV-infected patients with persistently normal ALT
The 1997 National Institutes of Health (NIH) Con- levels and demonstrated treatment efficacy comparable to
sensus Development Conference on Hepatitis C con- previous trials in patients with elevated ALT levels.6 –9
cluded that treatment of chronic hepatitis C in the The overall sustained virological response was 30% and
setting of persistently normal ALT levels was not bene-
ficial, and should not routinely be undertaken.34 In 2002,
the second NIH Consensus Development Conference on Table 4. Normal ALT: Response to Interferon Plus Ribavirin
Hepatitis C recommended that patients with persistently Antiviral Therapy
normal ALT levels and minimal or no fibrosis on liver Sustained virological
Year Author (ref) N ALT response (%)
biopsy should be reassured of a favorable prognosis,
undergo periodic monitoring, and may not need antiviral 2000 Gordon et al.36 44 ⬍1.3 36
2001 Lee et al.37 19 ⬍1.5 47
therapy in light of the adverse effects of treatment.5 2001 Di Bisceglie et al.38 24 Normal 25
However, it was also stated, with support from an Eu- 2002 Jacobson et al.39 56 Normal 32
ropean consensus conference,35 that decisions to treat 2002 Sponseller et al.40 24 Normal 50
such patients should be individualized, and based on NOTE. Standard interferon, 3 million units 3 times per week.
patients’ preferences and willingness or unwillingness to Table adapted from Bacon et al.4
1412 AHMED AND KEEFFE
52% for the 24-week and 48-week treatment groups,
respectively, versus 0% for an untreated control group.41
For patients with genotype 1, the sustained virological
response was 13% in the 24-week treatment group and
40% in the 48-week group; for patients with genotypes
2 and 3, the sustained virological response was 72% and
78% in the 24-week and 48-week groups, respectively.
Patients who relapsed after completion of treatment were
noted to have mild, transient ALT elevations; only one
patient had a posttreatment flare with ALT levels greater
than 10 times upper limit of normal. In a related study,
patients in the untreated control group were followed for
72 weeks to study the short-term natural history of
patients with persistently normal ALT levels in the
setting of chronic hepatitis C.42 Transient elevation of
ALT levels were noted in over 50% of control patients.
This is an important observation and provides further
data suggesting that the definition of persistently normal
ALT levels in HCV population be reevaluated.
Cost-Effectiveness and Quality of Life in
Patients With Normal ALT
A significant impairment in health-related qual-
ity of life was noted in a broad spectrum of patients with
chronic hepatitis C when compared with healthy con-
trols.43 In this report, there were no differences in quality
of life between HCV patients with persistently normal
ALT levels versus those with elevated ALT levels.43 In
another study, the issues of quality of life and cost-
effectiveness were analyzed using a computer-based pro-
gram in a simulated population of patients with chronic
hepatitis C and histologically mild liver disease.44 Com-
parison was made between preemptive standard inter-
feron plus ribavirin combination therapy without a liver
biopsy, watchful waiting with a biopsy every 3 years, and
combination therapy initiated only on evidence of mod-
erate to severe histologic findings, and no treatment. It
was demonstrated that preemptive treatment with inter-
feron plus ribavirin reduces the future risk of cirrhosis to
16% as compared with 27% with no treatment, or 18%
with watchful waiting and biopsy every 3 years. Preemp-
tive immediate treatment should increase life expectancy
by 1.0 quality-adjusted life-year as compared to watchful
waiting with serial biopsies. In addition, preemptive
treatment provided a saving of $5100 over the patient’s
lifetime when compared to watchful waiting with re-
peated liver biopsies.44
Liver Biopsy in Patients With Normal ALT
The issue of whether patients with chronic hepa-
titis C and persistently normal ALT levels should un-
dergo a liver biopsy remains controversial. It is difficult
GASTROENTEROLOGY Vol. 126, No. 5
Table 5. Normal ALT: Routine Versus Selective Liver Biopsy
Benefits of Routine Liver Biopsy
Gold standard for grading and staging the severity of liver
disease to assist in the timing of antiviral therapy, especially
in patients with genotype 1 who have a lower sustained
virological response and require longer duration of therapy
Diagnosis of coexisting liver diseases (uncommon)
Identification of the small number of patients with cirrhosis who
may benefit from screening for hepatocellular carcinoma
Basis for Selective Liver Biopsy
High sustained virological response rate in patients with
genotypes 2 and 3, making routine liver biopsy optional
Invasive procedure with risk of complications
Favorable cost-effectiveness analysis to treat without biopsy
Patient preference to not undergo biopsy, with or without
treatment
to recommend a liver biopsy on a routine basis to pa-
tients with persistently normal ALT levels since the
progression rate of fibrosis, although somewhat variable,
is generally slow.27 On the other hand, information
obtained from a liver biopsy may provide useful data to
help decide between monitoring and antiviral therapy
(Table 5). The option of performing a liver biopsy should
be discussed with all patients who have persistently
normal ALT levels in the setting of chronic hepatitis C.
A liver biopsy may be useful in patients with persistently
normal ALT levels who are interested in conservative
management and express the desire to defer antiviral
therapy. Patients with histologically mild liver disease
can be reassured, while the small proportion of patients
with more significant histological findings who may
benefit from antiviral therapy can be identified. Patients
who opt against liver biopsy must understand that there
is a small risk, i.e., approximately 15% based on the data
of Pradat et al.,17 that they may have moderate to ad-
vanced liver disease despite persistently normal ALT
levels. Patients who wish to undergo antiviral therapy,
particularly those with genotype 2 or 3, may quite
reasonably opt not to have a liver biopsy before starting
antiviral therapy based on the high sustained virological
response rate of 75%– 80%.6 – 8 Thus, liver biopsy should
be used selectively rather than routinely in patients with
chronic hepatitis C, especially those with normal ALT
levels. The indication for liver biopsy, as well as the
potential benefits of antiviral therapy, needs further
study in this subset of patients.
Recommended Management
Strategy
It may be prudent to recommend expectant man-
agement without the use of current antiviral therapy to
patients with persistently normal ALT levels and/or mild
May 2004
Figure 1. Normal ALT: individualized management of chronic hepati-
tis C.
liver disease confirmed by liver biopsy.4,5 However, pa-
tients with biopsy-proven moderate or advanced liver
disease should be encouraged to undergo treatment.4,5
On the other hand, patients with mild liver disease have
a significantly better sustained virological response with
antiviral therapy compared with those with more ad-
vanced liver disease.6 Furthermore, preemptive use of
antiviral therapy in patients with mild liver disease may
be cost-effective, improve quality of life, and prolong
life.44 Thus, it remains controversial whether a patient
with chronic HCV infection with persistently normal
ALT levels should undergo liver biopsy, or whether a
patient with mild histological disease by liver biopsy
should be treated. It appears that the sustained virolog-
ical response for patients with persistently normal ALT
levels who undergo treatment, however, are comparable
to those with elevated ALT levels in the absence of
advanced fibrosis (Table 4).36 – 41 In summary, the deci-
sion regarding whether to treat or follow conservatively
patients with chronic hepatitis C and persistently normal
ALT levels should be individualized based on the pres-
ence or absence of factors predicting a successful out-
come, as well patient preferences and general medical
condition (Table 3) and should follow standard treatment
guidelines (Figure 1).
CLINICAL MANAGEMENT 1413
Evolution of Case
Initial Evaluation
A review of medical records on this 43-year-old
woman with chronic hepatitis C revealed normal ALT
levels on an annual basis over the previous 5 years. She
most likely acquired HCV infection 25 years ago at the
age of 18 as a result of injection drug use over a 1-year
period, and she reported a history of jaundice at that
time. No other risk factors were identified. She drank
alcohol only rarely on special social occasions. She had no
comorbid medical conditions. She worked full-time as an
accountant and was a single mother, and exercised 5 days
per week. Viral studies confirmed HCV infection with a
serum HCV RNA level of 560,000 IU/mL and genotype
1b. Hepatitis A and B serologies were consistent with
lack of immunity, and she underwent hepatitis A and B
vaccination. The patient was unsure whether to proceed
with antiviral therapy to eradicate HCV infection or
defer treatment to maintain her active lifestyle.
The efficacy, duration, and adverse effects of peginter-
feron plus ribavirin therapy were discussed with the
patient. The role of liver biopsy and it complications
were also reviewed. She ultimately requested a liver
biopsy to facilitate a decision regarding management
options, and biopsy showed mild histologic liver disease
with grade 1 inflammation and stage 0 fibrosis.
Subsequent Management
Conservative management without antiviral ther-
apy was recommended to the patient, based on the
presence of mild histologic liver disease, excellent quality
of life with lack of symptoms, and a demanding work
and home schedule. The importance of continuing her
healthy lifestyle was also stressed. She was given the
option of a follow-up liver biopsy in 5 years, based on the
expected slow progression of her liver disease.
Conclusion
Persistently normal ALT levels are found in ap-
proximately 20% of patients with chronic hepatitis C. In
this subset of patients, the disease is generally but not
always mild, and the natural history is likely to be
benign over the next 1–2 decades. The role of liver
biopsy and long-term benefits of peginterferon plus riba-
virin combination therapy needs to be further evaluated
in these patients, but preliminary data suggests that the
response to antiviral therapy is similar to the response in
patients with elevated ALT levels. In addition, the def-
inition of normal ALT levels in chronic hepatitis C needs
re-evaluation. Pending data from future studies, empha-
1414 AHMED AND KEEFFE
sis should be placed on individualizing management in
this patient subpopulation.
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