الفهرس 
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Abstract
Most clinical studies in the field ofhepatology, including response to
therapeutic trials, employ serum alanine aminotransferase (ALT) as the most
indicative marker of hepatocellular damage in acute and chronic hepatitis.
However, in chronic hepatitis C virus (HCV) and hepatitis B virus (HBV)
infections, serum ALT has been shown not to be a satisfactory marker of
histologic disease activity because of ALT activity fluctuation in these
patients.
Chronic hepatitis C and B are progressive diseases, which may progress
to cirrhosis and hepatocellular carcinoma.
In chronic HCV and HBV infections, serum aminotransferases have
been shown not to be satisfactory markers of disease activity since, significant
histologic lesions may be present in patients with normal values of
aminotransferases.
Recently, alpha glutathione S-transferase (a-GST) has been proposed as
an alternative marker of hepatocellular damage. Mainly because it appears to
be a very stable serum marker, and it is unaffected by gross muscle damage,
extrahepatic inflammation or haemolysis and thus appears to be more liver
specific than aminotransferases activities.
a-GST is a small enzyme (MW 50 KD) present in high concentration in
hepatocytes cytosol, has a short half life «90 minutes) and is uniformly
distributed in the liver lobule (both periportal and centrilobular). These
characteristics suggest that, a-GST might be a more sensitive indicator of
hepatocellular damage particularly, damage due to chronic viral hepatitis.
The work was carried out to assess the clinical utility of a-GST in
monitoring of disease activity in patients with chronic hepatitis. 130 subjects
were included in this study, comprising 50 patients having chronic hepatitis C,
50 patients having chronic hepatitis Band 30 healthy control group. Control
group was clinically, sonographically and serologically free.
All subjects were subjected to full history taking, full clinical
examination and laboratory investigations, which included:
(1) Routine laboratory investigations, which included urine analysis, stool
analysis, complete blood picture, liver function tests (ALT, AST, serum
bilirubin, alkaline phosphatase, prothrombin time and concentrations).
(289)
Summary and Conclusion ...
(2) Fasting and two hour’s postprandial blood sugar, renal function tests, xray
chest and ECG.
(3) Hepatitis viral seromarkers (OOsAg, OOc antibody (IgG), OOeAg,
OOeAb, HCV-RNA, OOV-DNA and anti-HCY.
(4) a-Glutathione S-transferase serum level.
(5) Abdominal ultrasonography.
(6) Gastrointestinal endoscopy (proctosigmoidoscopy and upper
gastrointestinal endoscopy).
(7) Liver biopsy and histopathological evaluation (grading and staging),
when it was possible.
Our patients were classified into:
Group (I) : Consisted of 50 patients with chronic hepatitis C.
Group (2) : Consisted of 50 patients with chronic hepatitis B.
The COO patients were divided into the following groups according to
the recent classification of viral hepatitis B, which is based on the viral
replication markers and liver cell inflammation:
Group (A) : Chronic OOV infection ”immune tolerant stage”.
Group (B) : Chronic VOO ”immune elimination stage”.
Group (C) : Chronic VOO ”dormant or inactive stage”.
Furthermore, group B was divided into 2 groups:
BI : Typical cases (wild type) of group B.
B2 : Atypical cases (pre-core mutant) of group B.
In addition:
Group B I and C : were subdivided according to the presence or absence of
schistosomiasis into the following subgroups :
Bns : Non schistosomal cases of group B I.
Bs : Schistosomal cases of group B1.
Cns : Non schistosomal cases of group C.
Cs : Schistosomal cases of group C.
The OOeAglHBeAb system and serum OOV-DNA were used to define
the state of viral replication, while liver function tests as well as a-GST were
used as indicators of liver cell inflammation.
(290)
Summary and Conclusion ...
Analysis of risk factors in HCY patients revealed that surgery and
dental care was reported by 3l/50 (62%) subjects followed by history of tarter
emetic-injections in 23/51 (46%) while blood transfusion was reported in 2/50
(4%) subjects indicating that non-transfusion routes are equally important in
the transmission ofHCY virus. Also, risk factors in HBY revealed surgery and
dental procedures in 24 (48%), antibilharzial injections in 20 (40%) and no
evidence of risk factor in 11(22%) while blood transfusion in 5 (10%) patients.
In group (1) :
Anti-HCY antibodies were positive in the 50 subjects using ELISA (2nd
generation), whereas PCR was reactive in 46/50 (92%). This negative PCR
subjects had normal ALT levels, normal abdominal ultrasound and minimal to
moderate liver histology indicating HCY healthy carrier state.
Among the studied HCY subjects, 16/50 (32%) had normal LAT values.
Histopathology revealed features of chronic active hepatitis in 13/16 (26%).
Activity was mild in 1l/16 (68.8%), moderate in 2/16 (12.5%) and minimal
histology in another three 3/16 (6%). a-GST was elevated in 1l/16 (68.8%),
i.e. a-GST is more sensitive in detecting HCY healthy carriers.
a-GST, ALT, AST and bilirubin levels were significantly increased
when compared with that of the control group. Serum albumin and total
protein showed statistical, significant decrease when compared with that of the
control group. Direct relation between ALT, a-GST, AST and severity of liver
disease was found.
According to the presence or absence of schistosomiasis, HCY patients
were classified into two groups and compared histo-pathologically. It was
found that the group with schistosomiasis showed a more severe liver disease.
a-GST, ALT and AST levels were higher in bilharzia1 than nonbilharzial
patients and significantly higher in cirrhotic patients than noncirrhotics,
probably reflecting the more severe liver damage in bilharzial and
cirrhotic patients.
Prothrombin concentration and platelet count were studied versus the
pathology to determine the relation between them. It was found that values of
prothrombin concentration and platelet count were affected in advanced liver
disease but with no significance in early cases.
(291)
Summary and Conclusion ...
The diagnostic sensitivity, specificity and accuracy of a-GST, ALT and
AST in HeV group were calculated. It was found that sensitivity of a-GST =
84%, ALT = 68% and AST = 62% and these results showed that a-GST is
more sensitive than AST or ALT.
As regard specificity, of a-GST was 90%, of ALT was 85% and of AST
was 75% and these results indicate that a-GST is more specific than AST or
ALT.
As regard accuracy, ofa-GSTwas 90%, of ALT was 80% and of AST
was 68% and these results indicate that a-GST is more sensitive, specific and
accurate than AST or ALT in assessment of chronic hepatitis e liver damage.
The sensitivity combination of AST, ALT and a-GST tests was also
calculated. When AST was considered with ALT or a-GST, there was no
increase in sensitivity. In contrast, when ALT was associated with a-GST,
diagnostic sensitivity was increased (from 84% to 94%).
Histopathologic hepatitis activity showed direct correlation with age,
ALT, a-GST, AST and serum albumin. a-GST showed direct correlation with
ALT, AST, total serum bilirubin, histologic grading, staging and cirrhosis.
Independent predictors of hepatitis activity were a-GST, ALT, AST and
serum albumin.
In conclusion, a-GST appeared to be a more sensitive and specific
marker than aminotransferases in chronic hepatitis e virus infected patients.
The association of serum a-GST with ALT determination improves the
biochemical assessment of liver damage in these patients with chronic
hepatitis e. This suggests that sequential determination of serum a-GST
concentration and ALT activities might provide a sensitive measurements of
treatment efficacy.
In group (2) patients:
a-GST and liver functions were significantly higher-in group (2)
patients than control. The highest levels of serum HBV-DNA were detected in
group ”A” (representing the high replicative immune tolerant stage) with no
signs of liver cell injury and normal liver biopsy.
Group BI patients representing the typical cases of immune-elimination
stage, showed a positive correlation between the DNA level, serum
aminotransferases and a-GST levels.
Summary and Conclusion ...
The patients of group B2 compnsmg the suggested pre-core- mutant
infected cases that are lacking the HBeAg, showed non significant lower
levels of DNA than those of group BI (wild type) and negative correlation
with ALT level and a-GST.
The study showed that all the HBeAg positive cases were DNApositive.
However, DNA was detected in low levels in some cases of group BI
who were negative for HBeAg denoting that HBeAg/HBeAb is not totally
reliable as a parameter of viremia.
A positive correlation was found between HBV-DNA titre in the DNApositive
groups and HBeAg positivity, while a negative correlation was found
with HBeAb positivity.
Patients in group C in the present study, representing the cases who
were in an inactive or dormant phase ofCHB, did not show any level of viral
replication either by HBeAg detection or HBV-DNA estimation. Most of the
cases of group Chad normal levels of liver function tests and a-GST except
some cases that showed elevated liver enzymes and a-GST which could be
attributed to either, undetectable low levels of viral replication, ongoing selfsustaining
process of hepatic injury, occurrence of cirrhosis or concomitant
undiagnosed HCV infection.
The present study showed non-significant difference in the DNA level
between schistosomal and non-schistosomal subgroups. On the other hand, it
was found a significant difference as regards the liver function tests and a-
GST, where schistosomiasis and cirrhosis elevated the parameters of liver cell
injury (ALT, AST & a-GST) and reduced the parameters of liver synthetic
functions (serum albumin and prothrombin).
ALT levels were normal in 18/50 (36%) patients. Histopathology
revealed mild chronic active hepatitis in 13 (72.2%) and minimal hepatitis in 5
(10%) subjects. a-GSTwas elevated in 13/18 (72.2%) patients, i.e. a-GST is
more accurate and sensitive.
The diagnostic sensitivity, specificity and accuracy of a-GST, ALT and
AST in this group were calculated. Sensitivity, of a-GST was 82%, of ALT
was 66% and AST was 62% indicating that a-GST is more sensitive.
Specificity of a-GST was89.2%, of ALTwas 84.2 and of AST was 75%
indicating that a-GST is more specific. Accuracy, of a-GST was 88.8%, of
ALTwas 79% and of AST was 68% indicating that a-GST is more accurate.
(293)
Summary and Conclusion •..
So, a-GST is more sensitive, specific and accurate for assessment of chronic
hepatitis B hepatocellular damage.
The sensitivity combination of AST; ALT and a-GST was estimated,
when AST was considered with ALT and a-GST, there was no increase in
sensitivity. In contrast, when ALT was associated with a-GST, diagnostic
sensitivity increased from 82% to 92%.
Histopathologic hepatitis activity showed direct significant correlation
with age, a-GST, ALT, AST, serum albumin and bilirubin. a-GST showed
direct significant correlation with ALT, AST, total serum bilirubin, histologic
grading, staging and cirrhosis. Independent predictors of hepatitis activity
were a-GST, ALT, AST and serum albumin.
In conclusion : a-GST is more sensitive, specific and accurate marker
than aminotransferases in chronic hepatitis B viral infection. The association
of a-GST and ALT serum levels assessment improves the biochemical
assessment of hepatocellular damage in chronic hepatitis B, which might
provide a sensitive non-invasive measurement of treatment efficacy. a-GST
was significantly elevated in patients with advanced liver disease, particularly
with severe activity merging into cirrhosis when compared to patients without.
Also, a-GST was significantly higher in chronic hepatitis with periportal
fibrosis compared to patients without schistosomal hepatic fibrosis. Elevation
of a-GST was parallel to severity of hepatitis activity (grading and staging of
chronic hepatitis B & C).
Summary and Conclusion •..
CONCLUSIONS
from this study it was concluded that:
(1) a.-Glutathione S-transferase (a.-GST) serum levels were significantly
higher in patients with chronic hepatitis B and C than control, significantly
higher in chronic hepatitis with cirrhosis in comparison to those without
and statistically non-significantly higher in chronic HCV patients than
HBV patients.
(2) a.-GST is more sensitive, specific, accurate and non-invasive marker than
aminotransferases (ALT and AST) in detecting hepatocellular damage
especially in patients with normal ALT levels and minimal hepatitis
(healthy carriers). So, patients who are viremic with normal ALT levels,
a.-GST system are activated if minimal hepatitis activity started to occur.
(3) When hepatitis activity increases, markers of liver cell injury increase
(namely ALT, AST, serum bilirubin and a.-GST) and markers of hepatic
synthetic function (serum albumin and prothrombin concentration)
decrease at advanced liver disease stage especially in mixed pathology,
late cirrhosis and decompensated hepatitis.
(4)In patients with positive seromarkers of viremia and normal serum ALT
levels, minimal and mild to moderate hepatitis activity was found by
histopathologic liver assessment. a.-GST was found to be high in these
patients, so, a.-GST can detect silent forms ofHBV and/or HCV related
minimal hepatic activity with normal ALT levels and during periods of
ALT normality during intermittently raised ALT levels, because chronic
hepatitis is the hallmark of chronic viral hepatitis B and C.
(5)a.-GST could be used as a surrogate marker in possible HCV or HBV
infection with normal ALT and with minimal hepatic necro-inflammation.
So, it is advised to use it in detecting and screening possible HCV or HBV
infection in habitual blood donors.
(6) Hepatitis activity was directly correlated with age of the patients, duration
of the disease, markers of liver cell injury (a.-GST, ALT and AST) and
total serum bilirubin.
(7) Independent predictors of histopathologic activity in chronic viral hepatitis
were a.-GST, ALT, AST levels and serum albumin, so, these non-invasive
(295)
Summary and Conclusion ...
predictors can detect histologic hepatitis activity and a-GST is the most
important test in the three models.
(8) The combination of a-GST and ALT serum levels estimation increase the
sensitivity for detection of hepatocellular integrity and injury in patients
with chronic Band C hepatitis.
(9) a-GST serum levels were directly correlated with serum levels of ALT,
AST and hepatitis histopathologic activity (grading ofnecroinflammation
and staging of architectural alterations).
(10) Grading scores of hepatitis activity were significantly correlated with
serum levels of a-GST, ALT, AST and total serum bilirubin, So, the
numerical scoring system could be included in the future studies ofHCV
or HBV to assess their clinical usefulness in diagnosis and assessment of
hepatitis activity.
(11) Raised ALT serum levels indicate hepatocellular damage in chronic
hepatitis but are not specific for any hepatotropic virus (HCV or HBV),
HCV might cause severe necro-inflammation than HBV, however, ALT
levels are not the optimal tool to assess liver damage, because it is known
that HCV or HBV infection with normal or low ALT levels may hide a
well-developed cirrhosis and chronic liver damage in 32-36% of patients.
(12) Anti-HCV immunoassays are suboptimal, PCR is time consuming, not
routine in most laboratories, expensive with contamination potential and
variability has been observed among different laboratories on the same
serum samples, So, it will be advantageous, therefore that the use of a-
GST assay is preferred in diagnosis ofHCV and HBV infection because it
is simple, fast, sensitive, specific, with less cost and effort.
(13) HCV-RNA levels determination is the single sensitive and reliable
predictor of HCV viremia, and is detected in 92% of HCV infected
patients.
(14) No statistical correlation was found between circulating HCV-RNA
levels, histopathology of hepatitis (grading and staging scores), different
grades and stages of chronic active hepatitis. So, HCV -RNA levels can’t
predict disease activity. HCV-RNA levels were lower in cirrhotic patients.
Also, there was no statistical correlation between HCV -RNA levels and
liver biochemistry (levels of ALT, AST, a-GST, total serum bilirubin,
serum albumin and prothrombin concentration).
(296)
Summary and Conclusion ...
(15) HBV-DNA estimation IS the most sensitive marker for HBVreplication,
as it is far more reliable than HBeAg and it correlates well
with the serological and biochemical markers of the virus.
(16) HCV-RNA or HBV-DNA estimation were of no practical importance in
predicting histologic activity, so patients with positive anti-HCV and/or
HBs antignemia could be assessed for histological activity by using the
following equations:
(a) For HCV, hepatitis histologic activity = a-GST serum level (0.76) +
ALT serum level (0.68) + AST level (0.51) - serum albumin (0.55) +
2.13.
(b)For HBV, histopathologic disease activity = a-GST level (0.89) + ALT
level (0.59) + AST level (0.59) - serum albumin (0.52) + 4.33.
(17) The inapperent parenteral route of infection seems to have a role in
transmission of HCV or HBV infection and no evidence of risk factors is
found in a good number of patients indicating that community acquired
infection has a role in viral transmission.
(18) Association of chronic viral hepatitis with schistosomal periportal
fibrosis are associated with more severe liver disease.
(19) Hepatic histologic evaluation continues to be required for clinical
assessment of chronic hepatitis activity, although, there is a correlation
between ALT levels and degree of hepatic injury, yet, this relation alone is
weak and a-GST + ALT levels estimation can replace this invasive biopsy
procedure (especially before starting antiviral therapy or for follow up of
treatment response).