Research Article

Relationship of HBeAg Status with ALT DNA Level and Liver Histology in Chronic Hepatitis B Patients


  • Ayşe İNCİ
  • Muzaffer FİNCANCI
  • Utku Murat KALAFAT

Received Date: 29.11.2014 Accepted Date: 21.05.2015 Viral Hepat J 2015;21(2):52-55


Chronic hepatitis B (CHB) infection is a highly prevalent and important health problem. Hepatitis B virus (HBV) infection is a very important public health problem in our country. Our country is in a mid-hepatitis B virus-endemic area. Hepatitis B virus (HBV) is enveloped DNA virus which causes acute and chronic infections. Liver biopsy is the gold standard procedure for documenting liver damage in chronic hepatitis. In this study, our aim was to determine the relationship of positive or negative HBeAg status in chronic hepatitis B patients with ALT (alanine aminotransferase), DNA level and liver histology.

Materials and Methods:

We retrospectively evaluated medical records of 230 hepatitis B patients who underwent liver biopsy in our clinic. Demographic properties, biopsy results, liver enzymes, HBV DNA levels and serological indications were evaluated. HBV DNA was investigated by quantitation of DNA using real-time polymerase chain reaction (PCR) and serological markers by enzyme immunoassay (EIA). Patients were separated into 2 groups according to their HBeAg status (group 1= HBeAg-positive; group 2= HBeAg-negative).


Two hundred and thirty patients participated in the study. The average age of patients in group 1 and group 2 was 36.42±11.76 and 47.01±12.15, respectively. There was a statistically significant difference in average age between the groups (p<0.000). The average ALT level was higher in HBeAg-positive group (p<0.000). There was no significant difference in fibrosis score between the groups, however, histologic activity index (HAI) was higher in group 2 than in group 1. When the correlation between ALT and HAI was evaluated, a significant and positive correlation was found only in HBeAg negative-patients while no significant correlation could be detected between ALT and fibrosis in both groups. There was not any significant correlation between DNA and fibrosis in group 1 while positive correlation was detected in group 2.


We assume that when evaluating HBV infections, serological tests, HBV DNA level, liver enzymes, previous treatments and clinical status of the patient should be considered as a whole.

Keywords: Hepatitis B virus, DNA, biopsy


Chronic hepatitis B virus (HBV) infection is an important, widespread health problem. Approximately, 600.000 people die of liver failure, cirrhosis, and hepatocellular carcinoma (HCC) every year (1). Currently, it is possible to diagnose and follow patients with confidence by monitoring various parameters of hepatitis (2).

Four stages of chronic HBV infection include immune tolerance, immune clearance (response), inactive carrier state, and reactivation. The immune response stage shows active inflammation in the liver biopsy and increasing enzyme levels with liver damage. During this period, the patient has hepatitis B e antigen (HBeAg)-positive chronic B hepatitis (3).

Chronic HBV infection can be HBeAg positive or negative. Patients are HBeAg-positive in the early stages of chronic hepatitis B and become HBeAg-negative in the advanced stages. The number of HBeAg-negative cases has increased over the last 10 years as a result of aging HBV-infected population (4). Most HBeAg-negative chronic HBV screening has been conducted in the Mediterranean region, although it has increased worldwide (5).

During patient monitoring, it is necessary to discuss the biochemical, virological, and clinical features separately according to the e antigen status (6).

The serum transaminase levels can increase at different rates because of the damage to the liver parenchyma. Measurement of aspartate transaminase (AST) and alanine aminotransferase (ALT), indicators of inflammation, is an inexpensive test and  frequently used in the clinical practice (7).

Liver biopsy is the gold standard for following and treating chronic HBV. The modified histologic activity index (HAI), necroinflammatory activity, and prevalence of fibrosis are evaluated separately. The modified HAI is scored as follows: 0) no fibrosis, 1) fibrous expansion in some portal areas, with or without short fibrous septa, 2) fibrous expansion in most portal areas, with or without short fibrous septa, 3) fibrous expansion in most portal areas and rare portal-portal (P-P) bridge formation, 4) fibrous expansion in portal areas and obvious bridge formation, 5) obvious bridge formation and rare nodules, and 6) potential or definite cirrhosis (8).

This study determined the relationships of positive and negative HBeAg status in chronic hepatitis B patients with ALT and DNA levels and liver histology.

Materials and Methods

This retrospective study enrolled 230 chronic hepatitis B patients who were treated and followed at İstanbul Education and Research Hospital, Department of Infectious Disease and Clinical Microbiology and underwent liver biopsy. The included patients were known to be HBsAg-positive for more than 6 months, had not been treated before the biopsy, and were not co-infected with hepatitis C virus (HCV) or human immunodeficiency virus (HIV).

Patient age, gender, biopsy results, liver enzyme levels before the biopsy, HBV DNA levels, and serological indicators were evaluated. Liver histology was evaluated by pathologists using the Ishak scoring system. The patients were divided into HBeAg-positive (group 1) and HBeAg-negative (group 2) groups.

Student’s t-test was used to compare the means between the groups. The relationships between the histopathological findings and the ALT and DNA levels were evaluated using Spearman’s correlation coefficient. Statistical significance was taken as p<0.05.


The study enrolled 230 patients: 177 (77%) were HBeAg-negative and 53 (23%) were HBeAg-positive. The mean age of the HBeAg-negative patients was significantly higher than the HBeAg-positive patients (36.42±11.76 vs. 47.01±12.15 years; p<0.000). The mean ALT level was higher in the HBeAg-positive group (129.03±89.62 vs. 76.35±75.06; p<0.000). The HAI was higher in the HBeAg-negative subjects (6.25±2.3 vs. 7.39±2.88; p=0.004) (Table 1). There was no significant difference in the fibrosis score between the groups (1.81±1.06 vs. 2.11±1.19; p=0.098).

A significant positive correlation was found between ALT and HAI only in the HBeAg-negative patients (p=0.005, r=0.209). No significant correlation was found between ALT and fibrosis. A significant positive correlation between DNA and HAI was found only in the HBeAg-negative patients (p=0.007, r=0.201). No significant correlation was found between DNA and fibrosis in group 1, while a positive correlation was found in group 2 (p=0.011, r=0.191; Table 2).


The natural course of chronic HBV infection and disease is complicated and quite variable (9). Over all age groups, 2-10% of acute HBV infection progresses to chronic infection. Chronic HBV infection is an important risk factor for hepatocellular cancer (HCC), especially in patients with cirrhosis. Their HCC risk is increased 390-fold when compared with the normal population (10).

To treat chronic HBV infection appropriately, the stage of the disease must be known and HBV DNA and ALT levels are important parameters in the treatment approach (11).

In our series, 77% of the subjects were HBeAg-negative. In other studies, the proportion of HBeAg-negative cases ranged from 16.4 to 76.7% (5,6,12,13,14,15,16,17,18,23,25).

Comparing HBeAg-positive and -negative patients, the latter tended to be older, had a higher HAI, and lower average ALT and DNA levels. There was no significant difference in the mean fibrosis score between the groups.

Peng et al. (5) observed that HAI was significantly higher in HBeAg-negative subjects, while the ALT levels were lower, albeit not significantly. Our results are compatible with these results.

Acar et al. reported that the average age of HBeAg-negative patients was 25.87±5.99 years and this was significantly higher than that of HBeAg-positive patients. They also reported lower ALT levels in HBeAg-negative patients, as in our study, and they found no significant difference in the mean fibrosis scores (6). However, the HAI scores in HBeAg-negative patients and in HBeAg-positive patients in their study was significantly different than those in our subjects (4.06±2.02 and 4.78±2.40 vs. 6.25±2.3 and 7.39±2.88) (p=0.001).

Yalçın et al. (17) found no significant difference in the HBeAg status and fibrosis scores in HBeAg-negative and -positive subjects, as in our study, but found higher HAI scores in HBeAg-negative patients.

In our study, the DNA level was significantly higher in the HBeAg-positive patients compared with the HBeAg-negative group, as in other studies (17,19,20).

We observed that the ALT and DNA levels were not correlated with the histopathological findings in the HBeAg-positive patients, although the DNA level was higher than in HBeAg-negative cases; the HAI and fibrosis scores also increased and the ALT level was correlated with the HAI, but not with the fibrosis scores (Table 3).

The changes in the ALT and DNA levels are an important indicator of histopathological activity for diagnosing cirrhosis and HCC stage. We believe that serological tests, HBV DNA level, liver enzymes, and the clinical status of the patient must be evaluated regardless of whether the patient receives therapy or not.

Ethics Committee Approval: None, Informed Consent: Consent form was filled out by all participants, Concept: Ayşe İnci, Muzaffer Fincancı, Utku Murat Kalafat, Design: Ayşe İnci, Utku Murat Kalafat, Data Collection or Processing: Ayşe İnci, Utku Murat Kalafat, Analysis or Interpretation: Ayşe İnci, Muzaffer Fincancı, Utku Murat Kalafat, Literature Search: Ayşe İnci, Utku Murat Kalafat, Writing: Ayşe İnci, Peer-review: External and internal peer-reviewed, Conflict of Interest: No conflict of interest was declared by the authors, Financial Disclosure: The authors declared that this study has received no financial support.

1. World Health Organization. Hepatitis B vaccines. Wkly Epidemiolo Rec.No. 40, 2009, 84, 405-420.
2. Tosun S. Metanalysis of hepatitis B epidemiyology puplishes. Tabak F, Tosun S.(eds) Viral Hepatit 2013. Istanbul: Istanbul Medical Publishing, Association of Fighting with Viral Hepatitis, 2013:25-81.
3. Sonsuz A. Chronic Hepatitis B and C.I.U Cerrahpasa Medical Faculty Continuing Medical Training Activiy Symposym Series No:58, November 2007; p.79-90.
4. Zarski JP, Marcellin P, Leroy V, Trepo C, Samuel D, Ganne-Carrie N, Barange K, Canva V, Doffoel M, Cales P; Fédération nationaledes Pôles de référence et des Réseaux Hépatites. Characteristics of patients with chronic hepatitis B in France: predominant frequency of HBe antigen negative cases. J Hepatol. 2006;45:355-360.
5. Peng J, Luo K, Zhu Y, Guo Y, Zhang L, Hou J. Clinical and histological characteristics of chronic hepatitis B with negative hepatitis B e-antigen. Chin Med J (Engl). 2003;116:1312-1317.
6. Acar A,Turhan V, Karacaer Z, Öncül O, Görenek L. Correlation of HBeAg/Anti-HBe status with liver hıstology and ALT/AST levels in young adult hepatitis B patients. AJC. 2009:3:231-234
7. Pehlivan Y, Koruk M, Gülşen MT, Savaş C, Kadayıfçı A. The Relation Between AST/ALT ratio and stage of the disease in chronic hepatitis. Gaziantep Medicine Journal. 2008;14:28-31.
8. Aydın O,Yıldız L, Kefeli M, Barış S, Kandemir B. Reproducibility of ishac modified histological activity index between one an multi observer at chronical viral hepatitis. Turkish Pathology Journal. 2005;21:58-61.
9. Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol. 2008;48:335-352.
10. Gürbüz AK. Getting chronical at hepatitis B virüs - Clinic and ordinary course at hepatitis Updated. Gastroentherology. 2003;7:50-54.
11. Leblebicioğlu H. Checking index of chronical hepatit treatment. In: Tabak F, Tosun S (eds). Viral Hepatit 2013. İstanbul: Istanbul Medical Publishing: Association of Fighting with Viral Hepatitis; 2013: p.303-307.
12. Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Muñoz AE, Adrover R, Cocozzella D, Fernandez N, Estepo C,Mendizabal M, Romero GA, Levi D, Schroder T, Paz S, Fainboim H, Mandó OG, Gadano AC, Silva MO. Efficacy and safety of long term entecavir in chronic hepatitis B treatment naïve patients in clinical practice. Ann Hepatol. 2014;13:327-336.
13. Chan HL, Leung NW, Hussain M, Wong ML, Lok AS. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong. Hepatology. 2000;31:763-768.
14. Aygün C,Gözel N, Demirel U, Yalnız M, Özercan İH, Bahçecioğlu İH. Relation of liver fibrosis with serum GGT level at chronical viral hepatitis B diagnosed patient. Fırat Medical Journal. 2010;15:74-78.
15. Demir NA,Kölgelier S, Demir LS, Sümer Ş,Dikici N, Özçimen S, İnkaya AÇ. Evaluation of treatment result with 245mg/day tenofovir Disoproksil Fumarat for one year at hepatitis B patients. Nobel Med.2013;9:57-62.
16. İnci A, Fincancı M, Müderrisoğlu C. Investigation of anti-hepatitis delta virus and anti-hepatitis C virus in patients with hepatitis B virus infection. İstanbul Med J. 2013;14:109-111.
17. Yalcin K, Degertekin H, Yildiz F, Celik Y. Markers of disease activity in chronic hepatitis B virus infection. Clin Invest Med. 2003;26:27-34.
18. Shao J, Wei L, Wang H, Sun Y, Zhang LF, Li J, Dong JQ. Relationship between hepatitis B virus DNA levels and liver histology in patients with chronic hepatitis B. World J Gastroenterol 2007;13:2104-24107.
19. Xie Y, Zhao H, Dai WS, Xu DZ. HBV DNA level and antigen concentration in evaluating liver damage of patients with chronic hepatitis B. Hepatobiliary Pancreat Dis Int. 2003;2:418-422.
20. Ortatatlı M, Gümral R, Özbek A, Kenar L. Relation between. liver damage and serum and tissue viral load and serology at hepatitis B patients. DOI: 10.4328/JCAM.1534.
21. Özkara S, Tosun İ, Sari B, Kiliç G, Vardar Aker F, Sezikli M, Güzelbulut F, Bor E. The correlation of serum transaminase values with fibrosis staging and necroinflam-matory activity scores in chronic Hepatitis. Turkiye Klinikleri J Med Sciences. 2011;31:68-74.
22. Seto WK, Lai CL, Ip PP, Fung J, Wong DK, Yuen JC, Hung IF, Yuen MF. A large population histology study showing the lack of association between ALT elevation and significant fibrosis in chronic hepatitis B. PLoS ONE. 2012;7:32622.
23. Ahmad N, Alam S, Mustafa G, Adnan AB, Baig RH, Khan M. e-antigen-negative chronic hepatitis B in Bangladesh. Hepatobiliary Pancreat Dis Int. 2008;7:379-382.
24. Sari A, Dere Y, Pakoz B, Calli A, Unal B, Tunakan M. Relation of hepatitis B core antigen expression with histological activity, serum HBeAg, and HBV DNA levels. Indian J Pathol Microbiol. 2011;54:355-358.
25. Kaya S, Yönem Ö, Özdemir L, Sümer Z. Relation between HBV serological indicators with HBV DNA quantity and serum alanine İnönü University Medical Faculty Journal 2006;13:21-24.
26. Yuen MF, Ng IO, Fan ST, Yuan HJ, Wong DK, Yuen JC, Sum SS, Chan AO, Lai CL. Significance of HBV DNA levels in liver histology of HBeAg and Anti-HBe positive patients with chronic hepatitis B. Am J Gastroenterol. 2004;99:2032-2037.