- Open Access
Effects of lamivudine on serum albumin levels correlate with pretreatment HBV-DNA levels in cirrhotic patients
© Nakamuta et al; licensee BioMed Central Ltd. 2007
- Received: 07 July 2005
- Accepted: 01 May 2007
- Published: 01 May 2007
Lamivudine treatment has been recently demonstrated to increase the serum albumin levels in cirrhotic patients with hepatitis B virus (HBV) infection, but the precise mechanism remains unclear. We hypothesized that the improvement of hypoalbuminemia by lamivudine may be attributable to the reduction of HBV replication itself, rather than to cessation of hepatitis. In order to confirm this hypothesis, in this study we evaluated factors which correlated with the increase in serum albumin levels. Fifty-four patients (Child-Pugh A/B/C, 35/9/10) with HBV-related liver cirrhosis who had been treated with lamivudine for more than 12 months were evaluated. We analyzed the correlation between the increase in serum albumin levels at month 12 after starting treatment (Δ-albumin) and various pretreatment variables. We also analyzed the correlation between Δ-albumin and the reduction in serum levels of HBV-DNA (Δ-HBV-DNA) or alanine aminotransferase (Δ-ALT) at month 12.
The average Δ-albumin was 0.38 g/dL and only serum HBV-DNA levels before treatment correlated significantly with Δ-albumin. We also analyzed the correlation in patients whose alanine aminotransferase levels were normalized after 12 months so that the possible influence of breakthrough hepatitis could be excluded. Even among this subgroup of patients, there was no significant correlation between Δ-albumin and either pretreatment alanine aminotransferase levels or Δ-ALT. In contrast, in patients whose serum HBV-DNA was undetectable at month 12, we found a significant correlation between Δ-albumin and both pretreatment serum HBV-DNA levels and Δ-HBV-DNA.
Our results demonstrated that albumin levels are associated with pretreatment HBV-DNA but not with alanine aminotransferase levels.
- Cirrhotic Patient
- Serum Albumin Level
- Alanine Aminotransferase Level
- Lamivudine Treatment
Chronic hepatitis B is an important cause of morbidity and mortality resulting from cirrhosis-related liver failure and hepatocelluar carcinoma (HCC) [1–3]. Lamivudine, a nucleoside analogue with potent antiviral effects against hepatitis B virus (HBV), has been shown to be effective both in patients with chronic hepatitis and also those with liver cirrhosis [4–6]. In cirrhotic patients, decreased HBV-DNA loads following lamivudine treatment result in decreased serum levels of alanine aminotransferase (ALT), increased serum albumin levels, and improvement of the Child-Pugh score [7–13]. The underlying mechanism for the increase in albumin levels after lamivudine treatment has not been determined. It has been suggested that the improvement of hypoalbuminemia may be attributable to the cessation of hepatic inflammation. However, earlier treatments such as glycyrrhizin, ursodeoxycholic acid [14, 15], predonisolone , and Stronger Neo-Minophagen C therapy , all of which reduce ALT levels in viral cirrhotic patients, do not result in improvement of hypoalbuminemia. Furthermore, it has been shown that there is no significant correlation between serum ALT levels and HBV-DNA loads in patients with HBV [18–20]. We hypothesized that the improvement of hypoalbuminemia by lamivudine may be attributable to the reduction of HBV replication itself, rather than to cessation of hepatitis. In order to confirm this hypothesis, we evaluated several laboratory parameters in cirrhotic patients treated with lamivudine that could influence serum albumin levels.
Characteristics of the patients
53.0 ± 9.1
54.9 ± 4.6
49.5 ± 9.1
52.6 ± 8.8
3.85 ± 0.43
3.12 ± 0.38
2.94 ± 0.57
3.56 ± 0.6
0.90 ± 0.43
1.25 ± 0.35
3.09 ± 1.28
118.2 ± 125.5
62.7 ± 43.2
80.6 ± 96.8
102.0 ± 113.0
Platelet (× 104/μL)
11.8 ± 5.3
7.3 ± 3.2
6.3 ± 2.5
10.0 ± 5.2
HBV-DNA (log copies/mL)
5.0 ≤ x < 7.0
To identify the factors associated with increased serum albumin levels, correlations between the increase in serum albumin levels at 12 months after the start of treatment (Δ-albumin) and basic variables before treatment were examined using the data for all patients. In this analysis, only HBV-DNA load correlated significantly with Δ-albumin (t = 2.66, r2 = 0.120089, p = 0.0103), whereas age, sex, HBeAg, ALT, bilirubin, platelet count, and Child-Pugh classification did not (Table 1).
This study demonstrated the followings: 1) HBV-DNA, but not ALT levels, before lamivudine treatment was associated with increased serum albumin levels at 12 months after treatment (Δ-albumin); 2) Even among those patients who showed cessation of hepatitis following treatment, there was no correlation between either pretreatment ALT levels or Δ-ALT and Δ-albumin; 3) In contrast, in the analysis of subjects with undetectable HBV-DNA levels after treatment, there was significant correlation between both pretreatment HBV-DNA levels and Δ-HBV-DNA and Δ-albumin. Taken together, these results suggest that the improvement of hypoalbuminemia following lamivudine treatment is attributable to a reduction of HBV replication, but not to cessation of hepatitis.
We do not deny the idea that cessation of hepatitis, which is represented by lowering of serum ALT levels, contributed to and increase of serum albumin levels. In true, we think that replicative HBV and inflammation are closely related; however, in our study, HBV reduction statistically showed more effect improving serum albumin levels than decreasing the inflammation marker ALT. This may happen perhaps because, in cirrhotic patients, fibrosis is the main pathological change (compared with inflammation), and the correlation between, on the one hand, serum albumin or HBV-DNA levels and, on the other hand, ALT levels was in some degree weakened as the cirrhotic change proceed. Therefore, in cirrhotic patients, Δ-ALT is within a narrower range and ALT levels cannot influence albumin levels significantly.
How does lowering of HBV load induces the increase of albumin levels in an inflammation-independent manner? Hui et al.  recently showed that emergence of phenotypic resistance of HBV-DNA was associated with a rapid decline in serum albumin levels following prolonged lamivudine treatment, although they did not report whether a correlation existed between serum ALT levels and serum HBV loads. In a series of studies in woodchucks and Hep G2 cells, Kosovsky et al. demonstrated that HBV replication inversely correlated with cell proliferation and DNA synthesis by hepatocytes [21–23]. Yang et al. has analyzed gene expression profiles of HepG2 cells with or without HBV . However, whether HBV replication directly influences the ability of infected hepatocytes to synthesize protein is still unclear and further studies are needed.
Correlations between Δ-albumin and basic variables before treatment
A total of 54 cirrhotic patients with HBV infection were evaluated, including 38 males and 16 females, ranging in age from 28 to 71 years (mean 52.6 years) (Table 1). Informed consent was obtained from each patient prior to their entering the study. Liver cirrhosis was diagnosed based on liver biopsy (n = 11), laboratory data, ultrasonography, and/or computed tomography. Patients were classified as Child-Pugh class A, B and C (35, 9, and 10 patients, respectively). For all patients, the existence of serum HBV-DNA was confirmed by TMA assay (103.7–108.7 genome equivalents/mL; 3.7–8.7 log genome equivalents [LGE]/mL) (Chugai Diagnostic Science, Tokyo, Japan) or by a Roche Monitor kit (102.6–107.6 copies/ml; 2.6–7.6 log copies/mL) (Roche Diagnostics, Tokyo, Japan) before treatment. HBe-Ag was positive in 29 patients and negative in 25 patients. Patients with fatty liver, viral hepatitis C, a history of alcohol abuse, or autoimmune disorders such as autoimmune hepatitis and primary biliary cirrhosis were excluded. None of the patients had a prior history of treatment for hepatocellular carcinoma.
Patients had been treated with lamivudine (100 mg, once a day) without interruption for more than twelve months at Kyushu University Hospital and its affiliated hospitals. Basic laboratory data, such as platelet counts, serum ALT levels, bilirubin, albumin, serum HBV-DNA load (Roche Monitor kit: Roche Diagnostics) and HBe-Ag were determined at least every 3 months.
Data are expressed as mean ± SD, and statistical comparisons were performed using chi-squared test for categorical data and one-way ANOVA for numeric data. In cases where the serum HBV-DNA load was less than 2.6 log copies/mL, it was entered as 2.6 log copies/mL. For the analysis of correlations between two continuous variables, a simple regression model was used. For the analysis of discontinuous variables, such as sex and HBe-Ag, statistical differences were confirmed using Mann-Whitney U test or Kruskal-Wallis test.
In addition to the authors, the Kyushu University Liver Disease Study Group includes the following individuals: R Sugimoto (Harasanshin Hospital, Fukuoka), H Amagase and S Tominaga (Mihagino Hospital, Kitakyushu), K Yanagita (Saiseikai Karatsu Hospital, Karatsu), K Ogiwara (Kyushu Rosai Hospital, Kitakyushu), M Tokumatsu (Saiseikai Fukuoka Hospital, Fukuoka), S Tabata (Hayashi Hospital, Fukuoka), M Yokota (National Kyushu Cancer Center, Fukuoka), H Tanaka (Chihaya Hospital, Fukuoka), S Nagase (Fukuoka Teishin Hospital, Fukuoka), S Tsuruta (Nakabaru Hospital, Fukuoka), S Tada (Moji Rosai Hospital, Kitakyushu), M Nagano (Kyushu Koseinenkin Hospital, Kitakyushu), M Honda (Nishi-Fukuoka Hospital, Fukuoka), T Umeno (Sawara Hospital, Fukuoka), T Sugimura (National Hospital Organization Fukuoka Higashi Hospital, Fukuoka), S Ueno (Kitakyushu Municipal Wakamatsu Hospital, Kitakyushu), K Miki (Kitakyushu Municipal Moji Hospital, Kitakyushu), H Okubo (Shineikai Hospital, Kitakyushu), H Fujimoto (Mitusbishikagaku Hospital, Kitakyushu), N Higuchi (Shin-Nakama Hospital, Kitakyushu), S Shigematsu (Kouseikan Hospital, Saga), and N Higashi (National Hospital Organization Beppu Hospital, Ohita). We would like to thank them for their assistance.
- Ganem D, Prince AM: Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med. 2004, 350: 1118-1129. 10.1056/NEJMra031087.View ArticlePubMedGoogle Scholar
- Lai CL, Ratziu V, Yuen M-F, Poynard T: Viral hepatitis B. Lancet. 2003, 362: 2089-2094. 10.1016/S0140-6736(03)15108-2.View ArticlePubMedGoogle Scholar
- Tang ZY: Hepatocellular carcinoma-cause, treatment and metastasis. World J Gastroenterol. 2001, 7: 445-454.PubMedGoogle Scholar
- Ooga H, Suzuki F, Tsubota A, Arase Y, Suzuki Y, Akuta N, Sezaki H, Hosaka T, Someya T, Kobayashi M, Saitoh S, Ikeda K, Kobayashi M, Matsuda M, Satoh J, Kumada H: Efficacy of lamivudine treatment in Japanese patients with hepatitis B virus-related cirrhosis. J Gastroenterol. 2004, 39: 1078-1084. 10.1007/s00535-004-1450-6.View ArticlePubMedGoogle Scholar
- Cetin K, Sabahattin K, Kadir D, Ahmet D, Ziyaettin D, Selim B, Muruvvet B, Fatih B, Gungor B, Zeynel M, Yilmaz C, Atilla O: Lamivudine treatment in patients with hepatitis B virus induced liver cirrhosis. Hepatogastroenterology. 2003, 50 (Suppl 2): ccxcv-ccxcvii.PubMedGoogle Scholar
- Yao FY, Terrault NA, Freise C, Maslow L, Bass NM: Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort. Hepatology. 2001, 34: 411-416. 10.1053/jhep.2001.26512.View ArticlePubMedGoogle Scholar
- Hui JM, George J, Liddle C, Lin R, Samarasinghe D, Crewe E, Farrell GC: Changes in serum albumin during treatment of chronic hepatitis B with lamivudine: effects of response and emergence of drug resistance. Am J Gastroenterol. 2002, 97: 1003-1009. 10.1111/j.1572-0241.2002.05621.x.View ArticlePubMedGoogle Scholar
- Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, Leduc R, Peltekian K, Wong F, Margulies M, Heathcote EJ: Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology. 2000, 31: 207-210. 10.1002/hep.510310130.View ArticlePubMedGoogle Scholar
- Yao FY, Bass NM: Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatology. 2000, 33: 301-307. 10.1016/S0168-8278(00)80371-2.View ArticleGoogle Scholar
- Kapoor D, Guptan RC, Wakil SM, Kazim SN, Kaul R, Agarwal SR, Raisuddin S, Hasnain SE, Sarin SK: Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis. J Hepatology. 2000, 33: 308-312. 10.1016/S0168-8278(00)80372-4.View ArticleGoogle Scholar
- Sponseller CA, Bacon BR, Di Bisceglie AM: Clinical improvement in patients with decompensated liver disease caused by hepatitis B after treatment with lamivudine. Liver Transpl. 2000, 6: 715-720. 10.1053/jlts.2000.18501.View ArticlePubMedGoogle Scholar
- Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, Wartin P, Dienstag J, Adams P, Dickson R, Anschuetz G, Bell S, Condreay L, Brown N, The Lamivudine North American Transplant Group: A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001, 33: 424-432. 10.1053/jhep.2001.21554.View ArticlePubMedGoogle Scholar
- Andreone P, Biselli M, Gramenzi A, Cursaro C, Morelli MC, Sama C, Lorenzini S, Spinucci G, Porzio F, Felline F, Di Giammarino L, Bernardi M: Efficacy of lamivudine therapy for advanced liver disease in patients with precore mutant hepatitis B virus infection awaiting liver transplantation. Transplantation. 2002, 74: 1119-1124. 10.1097/00007890-200210270-00011.View ArticlePubMedGoogle Scholar
- Scotto G: The ursodeoxycholic acid for the treatment of HCV infections. Infez Med. 1997, 5: 168-173.PubMedGoogle Scholar
- Matsuda Y, Inada M, Maeda H, Matsuyama T: Improvement of alanine aminotransferase by administration of suplatast tosilate plus ursodeoxycholic acid in patients with resistance to ursodeoxycholic acid monotherapy on hepatitis C virus-related chronic liver disease. Intern Med. 2002, 41: 774-779.View ArticlePubMedGoogle Scholar
- Lee SD, Tong MJ, Wu JC, Lin HC, Tsai YT, Lo KJ: A randomised double-blind placebo-controlled trial of prednisolone therapy in HBeAg and HBV DNA positive Chinese patients with chronic active hepatitis B. J Hepatol. 1991, 12: 246-250. 10.1016/0168-8278(91)90946-9.View ArticlePubMedGoogle Scholar
- Miyake K, Tango T, Ota Y, Mitamura K, Yoshiba M, Kako M, Hayashi S, Ikeda Y, Hayashida N, Iwabuchi S, Sato Y, Tomi T, Funaki N, Hashimoto N, Umeda T, Miyazaki J, Tanaka K, Endo Y, Suzuki H: Efficacy of Stronger Neo-Minophagen C compared between two doses administered three times a week on patients with chronic viral hepatitis. J Gastroenterol Hepatol. 2002, 17: 1198-1204. 10.1046/j.1440-1746.2002.02876.x.View ArticlePubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- Sakugawa H, Nakasone H, Nakayoshi T, Kawakami Y, Yamashiro T, Maeshiro T, Kinjo F, Saito A: Correlation between serum transaminase activity and virus load among patients with chronic liver disease type B. Hepatol Res. 2001, 21: 159-168. 10.1016/S1386-6346(01)00085-7.View ArticlePubMedGoogle Scholar
- Chun YK, Kim JY, Woo HJ, Oh SM, Kang I, Ha J, Kim SS: No significant correlation exists between core promoter mutations, viral replication, and liver damage in chronic hepatitis B infection. Hepatology. 2000, 32: 1154-1162. 10.1053/jhep.2000.19623.View ArticlePubMedGoogle Scholar
- Kosovsky MJ, Khaoustov VI, Rushton M, Yoffe B: Induction of hepatitis B virus gene expression at low temperature. Biochim Biophys Acta. 2000, 1490: 63-73.View ArticlePubMedGoogle Scholar
- Fourel I, Cullen JM, Saputelli J, Aldrich CE, Schaffer P, Averett DR, Pugh J, Mason WS: Evidence that hepatocyte turnover is required for rapid clearance of duck hepatitis B virus during antiviral therapy of chronically infected ducks. J Virol. 1994, 68: 8321-8330.PubMed CentralPubMedGoogle Scholar
- Kajino K, Jilbert AR, Saputelli J, Aldrich CE, Cullen J, Mason WS: Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte. J Virol. 1994, 68: 5792-5803.PubMed CentralPubMedGoogle Scholar
- Yang J, Bo CB, Yao J, Yang NM, Wang SQ: Diffeentially expressed cellular genes following HBV: potential targets of anti-HBV drugs?. J Viral Hepatitis. 2005, 12: 357-363. 10.1111/j.1365-2893.2005.00611.x.View ArticleGoogle Scholar
- Wang JH, Lu SN, Lee CM, Lee JF, Chou YP: Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis. Scand J Gastroenterol. 2002, 37: 366-369. 10.1080/003655202317284309.View ArticlePubMedGoogle Scholar
- Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R: Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002, 51: 597-599. 10.1136/gut.51.4.597.PubMed CentralView ArticlePubMedGoogle Scholar
- Kagawa T, Watanabe N, Kanouda H, Takayama I, Shiba T, Kanai T, Kawazoe K, Takashimizu S, Kumaki N, Shimamura K, Matsuzaki S, Mine T: Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant. World J Gastroenterol. 2004, 10: 1686-1687.PubMed CentralView ArticlePubMedGoogle Scholar
- Bruno R, Sacchi P, Filice C, Filice G: Acute liver failure during lamivudine treatment in a hepatitis B cirrhotic patient. Am J Gastroenterol. 2001, 96: 265-10.1111/j.1572-0241.2001.03501.x.View ArticlePubMedGoogle Scholar
- Hadziyannis SJ, Papatheodoridis GV, Dimou E, Laras A, Papaioannou C: Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2000, 32: 847-851. 10.1053/jhep.2000.17915.View ArticlePubMedGoogle Scholar
- Nakamuta M, Kotoh K, Tanabe Y, Kajiwara E, Shimono J, Masumoto A, Maruyama T, Furusyo N, Nomura H, Sakai H, Takahashi K, Azuma K, Shimoda S, Enjoji M, Hayashi J, Kyushu University Liver Disease Study Group: Body surface area is an independent factor contributing to the effects of lamivudine treatment. Heptol Res. 2005, 31: 13-17. 10.1016/j.hepres.2004.11.004.View ArticleGoogle Scholar
- Kuwahara R, Kumashiro R, Inoue H, Tanabe R, Tanaka E, Hino T, Ide T, Koga Y, Sata M: Adefovir dipivoxil as a treatment for hepatic failure caused by lamivudine-resistant HBV strains. Dig Dis Sci. 2004, 49: 300-303. 10.1023/B:DDAS.0000017455.39171.56.View ArticlePubMedGoogle Scholar
- Wiegand J, Tischendorf JJ, Nashan B, Klempnauer J, Flemming P, Niemann P, Rohde P, Manns MP, Trautwein C, Tillmann HL: Severe exacerbation of chronic hepatitis B after emergence of lamivudine resistance in a cirrhotic patient: immediate switch to adefovir dipivoxil appears to be indicated. J Gastroenterol. 2004, 42: 15-18. 10.1055/s-2004-812683.Google Scholar
- Tong MJ, Tu SS: Treatment of patients with chronic hepatitis B with adefovir dipivoxil. Semin Liver Dis. 2004, 24 (Suppl 1): 37-44. 10.1055/s-2004-828677.View ArticlePubMedGoogle Scholar
- Kotoh K, Nakamuta M, Fukushima M, Matsuzaki C, Enjoji M, Sakai H, Nawata H: High relative fat-free mass is important for maintaining serum albumin levels in patients with compensated liver cirrhosis. World J Gastroenterol. 2005, 11: 1356-1360.PubMed CentralView ArticlePubMedGoogle Scholar
- Arroyo V: Pathophysiology, diagnosis and treatment of ascites in cirrhosis. Ann Hepatol. 2002, 1: 72-79.PubMedGoogle Scholar
- Tseng P, Lu S-N, Tung H-D, Wang J-H, Changchien C-S, Lee C-M: Determinants of early mortality and benefits of lamivudine therapy in patients with hepatitis B virus-related decompensated liver cirrhosis. J Viral Hepatitis. 2005, 12: 386-392. 10.1111/j.1365-2893.2005.00608.x.View ArticleGoogle Scholar
- Mahmood S, Niiyama G, Kamei A, Izumi A, Nakata K, Ikeda H, Suehiro M, Kawanaka M, Togawa K, Yamada G: Influence of viral load and genotype in the pregression of hepatitis B-associated liver cirrhosis to hepatocellular carcinoma. Liver Int. 2005, 25: 220-225. 10.1111/j.1478-3231.2005.01077.x.View ArticlePubMedGoogle Scholar
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