Year : 2002 | Volume
: 8 | Issue : 1 | Page : 9--13
Significance of normal liver enzymes in patients with hepatitis C virus
Hisham Osman Akbar
Department of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
Hisham Osman Akbar
Assistant Professor and Consultant Gastroenterologist, King Abdulaziz University Hospital, P.0. Box 80215, Jeddah 21589
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%.
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Akbar HO. Significance of normal liver enzymes in patients with hepatitis C virus.Saudi J Gastroenterol 2002;8:9-13
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Akbar HO. Significance of normal liver enzymes in patients with hepatitis C virus. Saudi J Gastroenterol [serial online] 2002 [cited 2021 Apr 11 ];8:9-13
Available from: https://www.saudijgastro.com/text.asp?2002/8/1/9/33377
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 0.98).
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 .
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.
|1||Kuo G, Choo Q-L, Alter Hj, Gitnick GL, Redeker AG, Purcell H, Miyamura T, et al. An Assay for circulating antibodies. Science 1989; 244:362-4|
|2||Miller RH, Purcell RH. Hepatitis C virus shares amino acid sequence similarity with pestiviruses and falviviruses as well as members of two plant virus super groups. Prc Nat'l Acad Sci USA 1990, 87:2057-61|
|3||Simmonds P, Holmes EC, Cha T.A., Chan SW, McOmish F, Irvine B, Beal E, et al. Classification of Hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. Jgen Virol 1993: 74-2391-9|
|4||Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24: 2189-93.|
|5||Esteban JI, Lopez-Talavera JI, Genesca J, Madoz P, Viladomiu L, Nuniz E, Martin-Vega C, et al. High rate of Infectivity and Liver Disease in Blood Donors with antibodies to Hepatitis C virus. Ann Intern Med 1991;115:443-9|
|6||Prieto M, Olaso C, Verdu C, Cordoba J, Gisbert C, Rayon M, Carrasco d, et al. Does the Healthy Hepatitis C Virus Carriers state really exist? An analysis using PCR. Hepatology 1995, 22:413-7|
|7||Shakil AO, Conry-Cantelina C, Alter HJ, Hayashi P, Kleiner DE, Tedeschi V, et al. Volunteer blood donors with antibodies to hepatitis C virus: Clinical, biochemical, virologic, and histologic features. Ann Intern Med 1995; 123:330-7|
|8||Everhart JE, Stolar M, Hooffnagle JH. Management of hepatitis C: a national survey of gastroenterologists and hepatologists. Hepatology 1997, 26 (supp 1): 785-825|
|9||Stanley AJ, Haydon GH, Piris J, Jarvis LM, Hayes PC. Assessment of liver histology in patients with hepatitis C and normal transaminase levels. Eur J Gastroenterol Hepatol, Sept. 1996, 8: 869-72|
|10||Alberti A. Norsica G, Chemello L. CavalleoHo D, Noventa F, Pontisso P, Ruol A. Hepatitis C Viraemia and Liver Disease in Symptom Free Individuals with Anti-HCV. Lancet 1992; 340:697-8|
|11||Healey CJ, chapman RWG, Fleming KA. Liver Histology in Hepatitis C Infection: A comparison between patients with persistently normal or abnormal transaminase. Gut 1995; 37:274-8|
|12||Kodama T, Tamaki T, Katabami S, Katamuma A, Yamashita K, et al. Histological findings in assymptomatic hepatitis C virus carriers. J GastroenteroL Hepatol 1993; 8:403-5|
|13||Naito M. Hayashi N, Hagiwara H, Hiramatsu N, Kasahara A. Fusamoto H. Kamada T. Serum hepatitis C virus RNA quantity and histological features of hepatitis C virus carriers with persistently normal ALT levels. Hepatology 1994; 19:871-5|
|14||VanThiel DH, Caraceni P, Molloy PJ, Hassanein T, Kania RJ, Gurakar A, Friedlander L. Chronic hepatitis C in patients with normal or near normal alanine aminotransferase level: the role of interferon alpha 2b therapy. J Hepatol (Denmark), Nov 1995, 23(5): 503-8|
|15||Haber MM, West AB, Haber AD, Reuben A. Relationship of amnitransferases to liver histological status in chronic hepatitis C. Anm J Gastroenterol 1995; 90:1250-7|
|16||McCormick SE, Goodman ZD, Maydonovitch CL, Sjogren MH. Evaluation of liver histology, ALT elevation and HCV RNA titre in patients with chronic hepatitis C. Am J GastroenteroL 1996; 91:1516-22|
|17||Alter HJ. TOC or not TOC: These are the questions. Blood. 1995; 85:1681-1695|
|18||Marcellin P. Martinot M, Boyer N, Levy S. Treatment of hepatitis C patients with normal aminotransferases levels. Clinics in liver disease, Nor 1999; 3: 843-52.|