| Abstract|| |
Background: Hepatitis C Virus (HCV) infection is a common universal problem especially in the Arab World. Objective: To assess the significance of persistently normal liver enzymes in patients who were anti HCV positive and suggest the proper approach for this group of patients. Method: 56 patients who were anti HCV positive with persistently normal liver enzymes for more than one year underwent liver biopsy to assess their liver histology after excluding other possible causes of chronic liver disease. METAVIR scoring system was used and the degree of fibrosis (F0-F4) was considered as reflection of severity. Results: Out of 56 patients, only 52 patients had liver biopsies; 44 (84.6%) patients had abnormal liver histology and eight (15.4%) patients had normal liver biopsy. Out of the 44 patients with abnormal liver biopsy, 23 (44.2%) patients had mild histology (F1-F2); 15 (28.8%) patients had severe histology (F3); two (3.8%) patients had cirrhosis (F4); four (7.7%) patients had non-specific changes (Al/FO). Conclusion: Normal liver enzymes in patients who were anti HCV positive does not carry prognostic implication and patients should have a liver biopsy to assess their liver histology, though the chance of having mild histology with minimal inflammation is more than 50%.
Keywords: Hepatitis C virus, METAVIR, Liver biopsy, Liver enzymes
|How to cite this article:|
Akbar HO. Significance of normal liver enzymes in patients with hepatitis C virus. Saudi J Gastroenterol 2002;8:9-13
| Introduction|| |
Non-A, non-B hepatitis was first recognized in 1975 and subsequently Hepatitis C virus (HCV) serologic test became first available in 1989  . HCV is a single-stranded linear RNA virus related to the viruses of the family Flaviviridae  . HCV is a major cause of post transfusion Non-A, Non-B hepatitis (80-95%).
Currently, there are at least six different genotypes that has been identified, prevalence of which varies among different parts of the world . Transmission of the virus is mainly parentral; however, sporadic cases are frequent. Chronic infection is characterized by fluctuating levels of liver enzymes and eventually 80% of cases develop chronic liver disease and 20% develop liver cirrhosis. On the other hand, patients with chronic liver disease secondary to HCV are usually asymptomatic or with minimal symptoms such as fatigue, anorexia and right upper quadrant pain.
Patients with HCV-related chronic liver disease are usually detected by positive hepatitis C serology (HCV-Ab) while investigating for abnormal liver enzymes. However, patients with persistently normal liver enzymes and positive anti HCV constitute a unique group to the consulting physician with different possible management approaches of either: reassurance that this is a carrier state with no liver involvement; or proceed for liver biopsy to determine the severity of liver involvement histologically.
| Materials and Methods|| |
This is a prospective study where anti HCV positive patients using ELISA II or ELISA III with persistently normal liver enzymes for at least six months were followed up in the clinic every three months for minimum of one year. Candidates on initial visit were checked for presence of risk factors and symptoms related to liver disease as well as possibility for the existence of other causes of chronic liver disease. In addition, the following investigations were done: complete blood count, blood glucose, liver enzymes [alanine aminotranferase alanine and aspartate aminotranferase (ALT), AST], albumin, total bilirubin, coagulation profile (prothrombin time), hepatitis B serology (HBsAg), antinuclear antibody, schistosoma complement fixation test as well as abdominal ultrasound. Patients had also qualitative HCV ribonucleic acid (RNA) polymerase chain reaction (PCR) test (Roche diagnostic) at the initial visit or during follow up as well as quantitative HCV (RNA) using branched-branched-deoxy nucleio acid (DNA) signal amplification assay (Chiron diagnostic). Patients during subsequent visits were assessed for the development of new symptoms as well as repeat of liver enzymes. Patients younger than 18 years; with possibility of the presence of other causes of chronic liver disease or who develops abnormal liver enzymes during follow-up period were excluded from the study. At the end of one year follow-up, all patients with persistently normal liver enzymes had liver biopsy after a written consent and checking coagulation profile, platelets and abdominal ultrasound. Liver biopsy results were reported using METAVIR scoring system  . A (Grade) used for necro-inflamatory activity (A0-A3) and F (Stage) used for degree of fibrosis (F0-F4). Severity assessed by the degree of fibrosis, was reported as normal (A0/F0), nonspecific (Al/FO), mild (Al-A2/F1-F2), severe (A2-A3/F3), and cirrhosis (F4). Statistical package software system (SPSS) for analysis was used. Descriptive statistics were done. T-test, Chi-square test and Fisher's exact test were used as appropriate. P-value was set at <0.05 for statistical significance.
| Results|| |
Seventy-two patients were initially included in the study between 1994-1999 (followed up at King Abdulaziz University Hospital, Jeddah, K.S.A.). Five patients were subsequently excluded from the study because they were HBsAg positive and one patient was tested positive for schistosoma by complement fixation test. Seven patients failed to follow-up and hence, did not complete the whole one-year follow-up. An additional three patients were also excluded because of increased liver enzymes during follow-up period. As a result, only fifty-six patients were left with persistently normal liver enzymes that were followed for one year. Fifty two patients agreed to have liver biopsy at the end of one year, while the remaining four patients refused. Twenty three patients were female (41%) and 33 patients were male (59%). Age range was from 21-63 years.
Eighteen patients were complaining of fatigue, one patient had itching and two patients had right upper quadrant discomfort post prandially with normal abdominal ultrasound [Table - 1]. Forty one patients (73%) had no recognized risk factor for acquiring HCV, nine patients (17%) had previous history of blood transfusion while two patients were married to a spouse with HCV-antibodies [Table - 2]. Eight patients with persistently normal liver enzymes had a normal liver biopsy (A0/F0) while four patients had non-specific changes (Al/FO). Twenty three patients had a liver biopsy with mild changes (Al-A2/Fl-F2). On the other hand, 15 patients had severe changes (A2-A3/F3) and another two patients had liver cirrhosis (F4) [Table - 3]. In the study, 15.4% of the patients had a normal liver histology, 7.7% had nonspecific changes, 44.2% had a mild liver histology (F1-F2) and 32.7% had a severe liver histology including cirrhosis (F3- F4).
None of the patients who had a normal liver biopsy or non-specific changes were symptomatic. Seven patients with normal liver histology had a quantitative RNA using b-DNA signal amplification less than 0.2 meq/ml while only two patients with non-specific changes had a similar result and none in patients with stage F 1 or more.
Mean quantitative viral load among patients with normal or non-specific histology was 0.35 meq/ml as compared to 6.81 meq/ml in patients with abnormal histology (P= 0.016). On the other hand, quantitative viral load among patients with different stages (F1-F4) was not statistically different (P 0.98).
| Discussion|| |
Twenty-five percent of patients with chronic liver disease secondary to HCV have persistently normal liver enzymes. In addition, 27%-59% of blood donors with positive HCV antibodies have normal liver enzymes with 54-65% having detectable HCV RNA by PCR ,, . In a survey of the members of the American Association for the study of liver disease, only 40% of the members participated in the survey recommended liver biopsy for patients with HCV and persistently normal liver enzymes  . Comparing the results of this study with similar other studies [Table - 4], 66.1% of the patients had mild liver histology (non specific, chronic persistent hepatitis [CPH]) compared to 51.9% in this study. 27% had more severe liver histology (chronic active hepatitis [CAH], cirrhosis) compared to 32.7% in this study, while cirrhosis was reported in one case and in two cases in this study  . On the other hand, only 7% had normal liver biopsy, as compared to 15% in this study. Investigating the relationship between alanine amino transferase (ALT) level and the severity of liver histology, there was no statistically significant relation, which in turn confirms that liver enzymes in patients with HCV does not help to access disease severity ,,, .
Previous studies have shown that virologic characteristics do not differ from patients with normal or increased liver enzymes together with no difference in distribution of genotypes among affected patients  . The exact mechanism of liver damage in patients with hepatitis C is not yet well understood including cytopathic effect, immune complex mediated and cytotoxic T-cell response. The hepatitis C virus unlike hepatitis B virus, lack deoxynucleic acid (DNA) intermediate and hence cannot be integrated into the host genome. Also, HCV antibody is neither neutralizing nor protective. In most patients with other causes of chronic liver disease, increase liver enzymes is an indication of on-going cell damage with the release of these intracellular enzymes (amino transferases), while with the above group of patients despite the presence of viraemia (proved by PCR) and ongoing liver damage (proved by abnormal liver histology), they did not show this increase in liver enzymes. It is possible that the dramatic fluctuation of ribonucleic acid (RNA) levels in patients with HCV may have a temporal relation with the ALT fluctuation, which in turn may be correlated with the hepatocyte injury in infected patients with increased liver enzymes in contrast to patients with normal liver enzymes who may have a persistently stable HCV-RNA levels  . Another possibility of having normal liver enzymes in patients with chronic liver disease secondary to HCV may be related to host factors particularly immunologic, where possible equilibrium between HCV replication and host immune response results in weak or no cell mediated response directed to HCV infected cells .
| Conclusion|| |
In this study, almost 85% of the patients with HCV and persistently normal liver enzymes have got abnormal liver histology of variable degree of severity. Hence, patients with HCV infection with persistently normal liver enzymes does not rule out absence of chronic liver disease but is more likely to be associated with mild liver histology . The approach to patients with HCV with normal or increased liver enzymes should be the same and the liver biopsy remains the only method for assessment of the severity of liver involvement. On the other hand, in patients with HCV and normal liver enzymes, a persistently negative viral load assessed by PCR test may denies the need of liver biopsy in this group.
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Hisham Osman Akbar
Assistant Professor and Consultant Gastroenterologist, King Abdulaziz University Hospital, P.0. Box 80215, Jeddah 21589
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3], [Table - 4]