|
Clinical Features of Hepatitis C-Infected Patients
With Persistently Normal Alanine Transaminase Levels
in the Southwestern United States
Hepatology,
November 1999, p. 1307-1311, Vol. 30, No. 5
M. Mazen Jamal1, Anurag Soni1,
Patrick G. Quinn1, Donald E. Wheeler2,
Sanjeev Arora1, and David E. Johnston1
From the Divisions of 1Gastroenterology
and 2Pathology, University of New Mexico
Health Sciences Center, Albuquerque, NM.
ABSTRACT
Approximately one third of patients with chronic
hepatitis C virus (Hepatitis C Virus) infection have normal alanine
transaminase (ALT) levels. We studied the
clinical, biochemical, virological, and histological
features in patients with persistently normal ALT.
A case-control study was conducted on 275 patients
with chronic Hepatitis C Virus infection, including 75 patients
with persistently normal ALT and 200 patients
with abnormal ALT. Persistently normal ALT was
defined as 4 consecutive ALT values in each
patient within a period of 12 months.
The average age of the patients was 44 years
(range 18 to 69 years). More non-Hispanic
whites had persistently normal ALT. The
mean serum ferritin level was significantly lower
in patients with persistently normal ALT as
compared with abnormal ALT (128 ± 92 ng/mL
and 224 ± 128 ng/mL), respectively (P
= .017). The mean Hepatitis C Virus-RNA level was
significantly lower in patients with persistently
normal ALT as compared with abnormal ALT (12 × 105 ± 2.8 × 106
copies/mL and 33 × 105 ± 8.0 × 106),
respectively (P = .02). Histologically,
patients with persistently normal ALT had
less severe portal inflammation (P < .05),
lobular inflammation (P = .003),
piecemeal necrosis (P = .002), fibrosis
(P < .05), lower prevalence of
cirrhosis (P = .007), as well as a
slower fibrosis progression rate (P < .001).
Chronic hepatitis C patients with
persistently normal ALT have low-activity grade and
stage on liver biopsy. In these patients the hepatitis
C RNA level was lower compared with
abnormal ALT patients, which may explain
the slower fibrosis progression rate. (HEPATOLOGY 1999;30:1307-1311.)
INTRODUCTION
Hepatitis C viral infection often causes chronic
liver disease and leads to serious consequences
including cirrhosis and hepatocellular carcinoma.
The development of serological and virological tests
to detect hepatitis C infection has contributed
greatly to our understanding of the natural
history and clinical features of this
infection.
Evaluation of hepatitis C infection involves
standard biochemical tests. Elevation of alanine
transaminase (ALT) is indicative of
hepatocellular inflammation and necrosis and
considered to be a hallmark of chronic hepatitis C
infection. However, up to a third of
patients infected with hepatitis C have normal
ALT levels.
Therefore, ALT level may not always predict
histological evidence of chronic hepatitis C.
The aim of this study is to evaluate the
clinical, biochemical, virological, and
histological features of chronic hepatitis C patients
with persistently normal ALT and to compare
the results in patients with abnormal ALT.
PATIENTS AND METHODS
A case-control study was conducted at the
University of New Mexico Health Sciences Center from
1995 to 1997. During this time, 275 consecutive
patients were eligible for the study. Case and control
patients participated in a structured interview
conducted by a Research Coordinator who was
blinded to the study. Data collected included:
age, race, sex, risk factors, symptoms (depression,
fatigue, weakness, and abdominal pain), comorbid
illnesses (rheumatoid arthritis, diabetes
mellitus, coronary artery disease, chronic renal
failure, and congestive heart failure), and alcohol
consumption history. Information about
alcohol consumption included both frequency of
drinking and amount consumed. Laboratory data included
complete blood count, serum biochemistry,
prothrombin time, iron, total iron binding
capacity, and ferritin. The ALT measurements were
performed on a Johnson & Johnson Vitros
950 Chemistry system (Rochester, NY)
using Vitros chemistry calibrator kit 3 and
Vitros reagents. Reference interval for
women was 9 to 52 (SI U/L) and for men was
21 to 72 (SI U/L). The reference intervals
are the central 95% of results from a study
of 2,445 healthy adults after excluding 5%
of the extreme values. The hepatitis C virus (Hepatitis C Virus)-RNA
viral load measurement was performed using
a second generation reverse-transcription polymerase
chain reaction (RT-PCR) assay (Roche Amplicor Monitor
Kit, Branchburg, NJ). The assay involves
measurements made on patients' serum
samples diluted serially: 1:1, 1:5, 1:25, 1:125, 1:625,
and compared against serially diluted control serum.
This assay is reported to have
approximately a 3-fold variability (0.311 log).
Hepatitis C Virus genotyping was performed at the Tricore Specialty
Labs (Albuquerque, NM). The assay for genotyping
uses extraction of Hepatitis C Virus RNA, RT coupled with
PCR to specifically amplify a 450-nucleotide portion
of the NS5b region of the Hepatitis C Virus-RNA genome, which is
then directly sequenced.
An ABI 377 automatic sequencer (PE Biosystems,
Perkin-Elmer, Foster City, CA) was used for
cycle sequencing.
Eligibility
and Definitions. All patients were
positive for hepatitis C antibody by enzyme-linked
immunosorbent assay (ELISA II; Abbott Laboratory,
Evanston, IL); had positive hepatitis C RNA
by quantitative PCR (Hepatitis C Virus Monitor; Roche
Diagnostic Systems, Branchburg, NJ); and had negative
autoimmune markers (antinuclear and
antismooth muscle antibodies). All the patients
had an Hepatitis C Virus- genotype test. Patients younger than 18 years,
those with previous treatment with interferon
alfa, those with fluctuating ALT level
(patients with even one abnormal value with others
being within the normal range on serial ALT testing),
liver transplant patients, those with
undetectable Hepatitis C Virus RNA, those with hepatitis
B surface antigen and patients with hepatocellular
carcinoma, and hemochromatosis were all
excluded. The patients were divided into
two groups based on ALT level. Group I consisted of 75 patients
with persistently normal serum ALT level, which
was defined as at least 4 normal ALT
values within 12 months and at least 3 normal
levels within 6 months. Group II had 200 patients
with abnormal serum ALT level. Duration of
infection was defined as the duration since
the first exposure to a blood-borne risk factor (time
since a blood transfusion or first exposure
to intravenous drug use [IDU]). This could
be determined in 67 out of 75 patients
(89.3%) in the persistently normal ALT
group and 180 out of 200 (90%) in
the abnormal ALT group. All patients signed a consent
form to participate in the study and the
study was approved by the institutional
review committee of the University of New Mexico.
Liver Biopsy
Specimen Preparation and Evaluation.
All liver biopsy specimens were fixed in 10%
neutral-buffered formalin. Sections were cut at 3- to
4-µm thickness and stained with
hematoxylin-eosin, prussian blue (for Iron), and
Masson's trichrome stain and reviewed by a
staff pathologist who was blinded with
respect to the clinical data. Biopsy specimens were
graded with respect to the degree of
piecemeal necrosis, portal and lobular inflammation,
and fibrosis according to a revised scoring system.
Fibrosis progression rate was defined as the
ratio of the fibrosis score over the
estimated duration of the infection.
Statistical
Analysis. The statistical analysis was
performed using SAS/STAT Software (SAS Institute,
Carey, NC). Any P value less than .05 was
taken to be indicative of statistical
significance. Continuous variables were
analyzed by unpaired t tests and nonparametric
tests. Binary variables were analyzed using
 2
tests and Fisher's exact test. Quantitative variables
were expressed as means ± SD;
the median and interquartile were used for alcohol
consumption because the distribution was not
normal. The multivariate statistical
analysis using logistic regression included
biologically relevant variables and those
that showed a P value of less than .20 in
the univariate analysis. Odds ratio and their 95%
confidence interval were used to indicate
the strength of influence. In the multivariate
model, fibrosis progression rate was coded as
dichotomous variable using the code 0 or
1 to indicate a rate of  the
mean value or a rate greater than the mean.
RESULTS
Four hundred forty-three patients were diagnosed
with hepatitis C in the Gastroenterology clinic
between June 1995 and June 1997. Two
hundred seventy-five patients were eligible for the
study and 168 patients were excluded for
the following reasons: 89 patients
with previous treatment with interferon; 44 patients
with negative Hepatitis C Virus RNA; 15 patients had
fluctuating ALT level; 8 patients with
a history of liver transplantation; 4 patients
younger than 18 years; 3 patients with
hepatitis B; 2 patients with acquired
immune deficiency syndrome; 2 patients with
autoimmune hepatitis; and 1 patient
with hemochromatosis.
Demographics.
Demographic features of the two groups are shown in
Table 1.
There was no significant difference between the two
groups based on age and sex. Average age of
the patients in the two groups was 44 years.
There were more non-Hispanic whites in the
persistently normal ALT group (P = .03).
Subanalysis of the ALT level in Hispanics and
non-Hispanic whites in the two groups did not show any
significant difference. The mean level of
ALT in the persistently normal ALT group in
Hispanics and non-Hispanic whites was 38.3 ± 12.9 and
37.8 ± 12.0, respectively. There
was no significant difference between the
patients of the two groups in terms of duration of
infection, or the risk factors for hepatitis C. Average
alcohol consumption was the same in both
groups even when we took into consideration
heavy alcohol consumption (>50 g/d).
| table 1.
Demographics of Patients With Persistently Normal and Abnormal
ALT |
|
| No.
of Patients |
Normal ALT
|
Abnormal ALT
|
P
Value |
| N = 75 |
N = 200 |
|
| Average age-mean ± SD |
44Y (44.2 ± 9.2) |
44Y (43.9 ± 10.3) |
NS |
| Race |
|
|
.03 |
| White (%) |
47 |
42 |
| Hispanic (%) |
44 |
54 |
| Others (%) |
9 |
4 |
| Sex |
|
|
NS |
| Male (%) |
60 |
58 |
| Female (%) |
40 |
42 |
| Duration of infection
(mean ± SD) |
21Y (21.2 ± 10.6) |
20Y (20.7 ± 9.7) |
NS |
| Average alcohol consumption (median,
interquartile) |
25.7* (0, 51.7) |
25.7 (0, 51.7) |
NS |
| Alcohol consumption (20-50 g/d) |
21/75 (28%) |
54/200 (27%) |
NS |
| Alcohol consumption (>50 g/d) |
24/75 (32%) |
58/200 (29%) |
NS |
| Risk factors |
| IDU (%) |
46/75 (62) |
128/200 (64) |
NS |
| Blood transfusion (%) |
21/75 (28) |
52/200 (26) |
NS |
| Others (%) |
8/75 (10) |
20/200 (10) |
NS |
|
Abbreviation: NS, not significant.
* g/D.
n = 67.
n = 180. |
Biochemical
Data. The biochemical data of the two
groups are shown in Table 2.
There was no significant difference in both groups in
regards to serum iron level, total
iron-binding capacity, iron saturation, albumin,
bilirubin, and prothrombin time. However, the serum
ferritin and the Hepatitis C Virus-RNA levels in the two
groups were significantly different. Mean
serum ferritin levels for persistently normal ALT and
abnormal ALT patients were 128 ± 92 ng/dL
and 224 ± 128 ng/dL, respectively
(P = .017). Hepatitis C Virus-RNA level was
12 × 105 ± 2.8 × 106
and 33 × 105 ± 8.0 × 106,
respectively (P = .02). To examine
carefully whether the difference in mean
values is more than the intrinsic variability of the
RT-PCR assay we applied logarithm to the
base 10 and found a 1.4-order difference
in means of the log-transformed values and this is
more than the reported intrinsic variability for
this assay. The transformed-log values for
persistently normal ALT and abnormal ALT
groups were 4.06 ± 2.0 and 5.67 ± 1.6, respectively,
with P < .001.
| table 2.
Biochemistry of Patients With Persistently Normal and Abnormal
ALT |
|
| No.
of Patients |
Normal ALT
|
Abnormal ALT
|
P
Value |
| N = 75 |
N = 200 |
|
| ALT value in males (U/L)
mean ± SD |
45.6 ± 13.0 |
151.8 ± 47.6 |
<.001 |
| ALT value in females (U/L)
mean ± SD |
35.3 ± 6.1 |
112.8 ± 33.5 |
<.001 |
| Iron (µg/dL) mean ± SD |
109 ± 76 |
127 ± 60 |
NS |
| TIBC (µg/dL) mean ± SD |
339 ± 80 |
358 ± 71 |
NS |
| Iron saturation (%)
mean ± SD |
32% ± 16.9% |
37% ± 6.8% |
NS |
| Ferritin (ng/mL) mean ± SD |
128 ± 92 |
224 ± 128 |
.017 |
| Bilirubin (mg/dL) mean ± SD |
1.00 ± 0.5 |
1.05 ± 0.5 |
NS |
| Albumin (g/L) mean ± SD |
3.8 ± 0.5 |
3.9 ± 0.5 |
NS |
| PT (sec) mean ± SD |
12.0 ± 1.1 |
12.7 ± 1.2 |
NS |
| RNA (copies/mL) mean ± SD |
12 × 105 ± 2.8 × 10
6 |
33 × 105 ± 8.0 × 10
6 |
.02 |
|
| Abbreviations: TIBC, total iron
binding capacity; PT, prothombin time. |
Symptoms and
Comorbid Illnesses. There was no
significant difference in the presenting symptoms or
the presence of comorbid illnesses in the patients of
the two groups (Table 3).
Although there was no statistically significant difference
in terms of depression as a symptom, there was a trend
towards depression being more common in the
subjects with abnormal ALT (P = .08).
| table 3.
Symptoms and Comorbid Diseases in Both Groups |
|
No.
of
Patients |
Normal ALT
|
Abnormal ALT
|
P
Value |
| N = 75 |
N = 200 |
|
| Depression |
28% |
38% |
.08 |
| Fatigue |
62% |
71% |
NS |
| RUQ pain |
13% |
17% |
NS |
| Weakness |
49% |
49% |
NS |
| RA |
12% |
10% |
NS |
| DM |
5% |
8% |
NS |
| CAD |
5% |
5% |
NS |
| CRF |
2% |
1% |
NS |
| CHF |
1% |
1% |
NS |
|
| Abbreviations: RA, rheumatoid
arthritis; DM, diabetes mellitus; CAD, coronary artery disease;
CRF, chronic renal failure; CHF, congestive heart failure. |
Genotype.
There was no significant difference in Hepatitis C Virus genotype
between the two groups (Fig.1).
Genotype 1b was most commonly encountered in
our patients followed up by Genotype 3. Four
patients in each group had mixed viral
infection.
 Fig. 1. Comparison of the
percentage of the different genotype distribution in the two
groups. Persistently normal ALT group ( )
and abnormal ALT group ( ). |
Histological
Features. Patients with persistently
normal ALT had histologically less severe liver
disease as compared with those with abnormal ALT (Fig.2).
The mean scores for portal inflammation in patients
with persistently normal and abnormal ALT were
(1.4 ± 0.73) and (1.8 ± 0.8),
respectively, (P < .05), for piecemeal
necrosis (0.87 ± 0.78) and (1.44 ± 0.87)
(P = .002), for lobular inflammation
(0.97 ± 0.41) and (1.40 ± 0.73)
(P = .003), and for fibrosis (1.4 ± 1.66)
and (2.05 ± 1.63), respectively, (P < .05).
Six percent of patients with persistently
normal ALT had cirrhosis compared with 19%
in the abnormal ALT group (P= .007). Fibrosis
progression rate per year was evaluated in
67 patients from group I and 180 patients
from group II (in whom duration of infection was
known). The fibrosis progression rate in
both groups was (0.08 ± 0.07) and
(0.15 ± 0.1), respectively, (P < .001).
We analyzed the fibrosis progression rate
per year after excluding the patients with alcohol
consumption of more than 50 g/d and it
remained significantly lower in
persistently normal ALT group (0.05 ± 0.06)
compared with the abnormal ALT group (0.11 ± 0.10)
(P < .001). A subanalysis of
the fibrosis progression rate per year in patients
with alcohol consumption of more than 50 g/d
again was significantly lower in the
persistently normal ALT group (0.13 ± 0.11)
compared with the abnormal ALT group (0.23 ± 0.22)
(P < .001). Multivariate analysis
was performed using logistic regression with fibrosis
progression rate as a binary outcome variable.
We developed our model by repetitive
elimination and inclusion of predictive variables.
In our model age, ALT and alcohol were
predictive factors of fibrosis progression.
Alcohol, race, sex, ferritin, or RNA levels were not
found to be confounding variables. The odds ratio (OR)
and 95% CI for ALT level and alcohol were
3.7 (1.4, 9.7) P = .008, and
1.8 (1.2, 2.9) P < .05, respectively.
For age, the OR and 95% CI per decade were
1.9 (1.2, 3.0) P = .006. The
histological grading was analyzed in the
two groups and further subanalysis was
performed to compare Hispanics and non-Hispanic whites
with regard to the mean grading score
(Table 4).
The mean grading score for these two groups
was 4.15 ± 2.1 and 6.6 ± 2.9, respectively,
(P = .003). The mean grading
score in Hispanics in the two groups was
4.12 ± 2.05 and 7.2 ± 2.8, respectively,
(P < .001), and for the
non-Hispanic whites was 4.2 ± 2.15 and
6.1 ± 2.9, respectively, (P < .001).
There was no statistical difference between Hispanics
and non-Hispanic whites in the persistently
normal ALT group with regard to the mean
grading score. There was no difference in the iron-stain
grade on liver biopsy between the two groups.
 Fig. 2. Comparison of the mean
score of histological features between the persistently normal and
abnormal ALT groups. The mean score for portal inflammation is
(1.4 ± 0.73) and (1.8 ± 0.8), for
piecemeal necrosis is (0.87 ± 0.78) and
(1.44 ± 0.87), for lobular inflammation is
(0.97 ± 0.41) and (1.4 ± 0.73),
and for fibrosis is (1.4 ± 1.66) and
(2.05 ± 1.63), respectively. Persistently normal
ALT group () and the abnormal ALT group ( ). |
DISCUSSION
The clinical characteristics of chronic Hepatitis C Virus-infected
patients with persistently normal ALT are not
completely defined. Controversies still
exist regarding the severity of disease on liver
biopsy in these patients.
A clear understanding of these features is
important in making rational therapeutic decisions
regarding the care of these patients. A
crucial aspect of this study is our
definition of persistently normal ALT, which is at
least 4 consecutive, normal ALT values
within a period of 12 months and at
least 3 values within 6 months. This
decreases the chance of including patients
with fluctuating ALT level, which would have inflated
our case population and confounded the results.
Our study highlights several important features of
Hepatitis C Virus-infected patients with persistently normal ALT
level. It is important to note that there
were no healthy hepatitis C carriers in our study
(i.e., no normal biopsy specimens) in contrast
to a previous study.15
We found histologically significant liver disease even
in patients with persistently normal ALT,
although it was less severe compared with
subjects with persistently abnormal ALT. Using
the revised scoring system we have shown significantly
less severe portal inflammation, piecemeal
necrosis, and lobular inflammation as well
as degree of fibrosis, and incidence of cirrhosis in
patients with persistently normal ALT
compared with patients with abnormal ALT.
Similar results were reported by other investigators,
which are in contrast to the findings of at
least 1 study
showing moderate to severe disease in
persistently normal ALT patients.
One of the main results in our study was the
estimate of fibrosis progression rate suggesting a
slower progression of liver fibrosis in the
normal ALT group, even after excluding patients with
heavy alcohol consumption (>50 g/d). However, our
results showed that alcohol hastened
fibrosis progression equally in persistently normal
and abnormal ALT groups, but did not contribute to the
difference between the two groups. Therefore, we
suggest that the natural history of Hepatitis C Virus
infection in patients with persistently normal
ALT is associated with delay in the development of
severe liver disease.
Genotyping has become an important tool in the
armamentarium of a hepatologist. It is important both
as a prognostic tool and also in
determining the duration of treatment compared with
a more favorable genotype. There have been
studies on genotype distribution in
patients with persistently normal ALT with varied
results.
We did not find any difference in genotype
distribution among patients of the two
groups. These differences maybe attributed to
geographical variation and differences in mode of
transmission of infection as have been
pointed out in the past. To determine the
replicative level of Hepatitis C Virus in patients infected with the
virus, quantification of the Hepatitis C Virus RNA in the
serum by RT-PCR assay is routinely done.
There is evidence that Hepatitis C Virus cytopathogenicity may contribute
to hepatocellular damage in liver cells with elevated
level of Hepatitis C Virus RNA, thereby suggesting a
correlation between Hepatitis C Virus-RNA level and
severity of liver disease.
Higher Hepatitis C Virus-RNA levels have also been
reported in patients with chronic active hepatitis
compared with those with chronic persistent
hepatitis C.
In our study we found that patients with
persistently normal ALT had significantly
lower Hepatitis C Virus-RNA levels thereby signifying less severe
disease. It is interesting, although not surprising,
that subjects with persistently normal ALT
have a significantly lower serum ferritin
level because it has been reported that a high ferritin
level is associated with more severe hepatitis and
advanced liver disease.
Many Hepatitis C Virus-positive patients with elevated
aminotransferase activity have a serum
ferritin level above the normal range, but only
a minority of these patients have iron overload.
Two studies found a close relationship
between serum ALT activity and ferritin
level.
Therefore, we feel that a high ferritin level
in a chronic Hepatitis C Virus-infected patient maybe indicative of
more severe disease.
Contrary to previous reports,
our study shows no sex difference between the
persistently normal and abnormal ALT groups, which
might be a limitation of our study. However, based on
multivariate analysis, sex was not found to
be a confounding variable for fibrosis progression.
It is not clear why more Hispanic patients have an
abnormal ALT level. It has been postulated that
race might play a role in progression of
Hepatitis C Virus-related chronic liver disease.
A vast majority of chronic Hepatitis C Virus patients either have
asymptomatic disease or report nonspecific symptoms.
Fatigue is a common complaint and other
symptoms include depression, weakness, nausea, anorexia,
abdominal discomfort, and difficulty with
concentration. We analyzed some of these
symptoms and found no association between any
individual symptom and type of chronic Hepatitis C Virus infection.
However, there was a trend towards
depression being more common in abnormal ALT
patients compared to their persistently normal ALT
counterparts. The analysis also included
comorbid chronic illnesses that might have
a role in expression of some of these nonspecific
symptoms. Patients in both groups were
matched in terms of the chronic comorbid illnesses
studied. Therefore, depression, though nonspecific,
might be an important clinical symptom marker of
more severe disease.
It is difficult to estimate the duration of
infection in a majority of subjects owning to multiple
risk factors. However, it is easier to
predict the duration of disease in subjects who have
had a single blood transfusion or used intravenous
drugs for a short duration of time. There
has been a suggestion that the mode of
transmission of infection influences the severity
of liver disease. Patients who acquired the
infection through a blood transfusion had
more severe disease compared with the other
risk factors. 29-31 However, because there
was no difference between the two groups, as
far as mode of transmission is concerned, this
variable would not influence the disease
course and confound our results.
In conclusion, our report showed that patients with
persistently normal ALT have less severe hepatitis and
less advanced disease histologically, which
supports the concept that the lower level of
viremia may play a role in slowing down the
progression of disease.
Abbreviations
Abbreviations: ALT, alanine transaminase; Hepatitis C Virus,
hepatitis C virus; RT-PCR, reverse-transcription
polymerase chain reaction.
FOOTNOTES
Received May 13, 1999; accepted August 10, 1999.
Address reprint requests to: M. Mazen Jamal, M.D.,
Division of Gastroenterology and Hepatology,
University of New Mexico Health Sciences Center, 2211 Lomas
Blvd. NE, ACC-5, Albuquerque, NM 87131-5271. E-mail:
mmjamal@salud.unm.edu;
fax (505) 272-6839.
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