Predictors for advanced liver fibrosis in chronic hepatitis B virus infection with persistently normal or mildly elevated alanine aminotransferase

Wang,Dexin; Zhang,Ping; Zhang,Min

doi:10.3892/etm.2017.5219

Predictors for advanced liver fibrosis in chronic hepatitis B virus infection with persistently normal or mildly elevated alanine aminotransferase

Authors:
- Dexin Wang
- Ping Zhang
- Min Zhang
View Affiliations

Affiliations: Department of Medicine, The Sixth People's Hospital of Qingdao, Qingdao, Shandong 266033, P.R. China
Published online on: September 29, 2017 https://doi.org/10.3892/etm.2017.5219
Pages: 5363-5370
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to evaluate the predictors for advanced liver fibrosis in patients with chronic hepatitis B virus (HBV) infection with persistently normal alanine aminotransferase (PNALT), or persistently or intermittently mildly elevated ALT (PIEALT). A total of 305 patients were included in the present study. Liver biopsies were evaluated using the METAVIR scoring system. Liver stiffness (LS) was measured using Fibroscan. Multivariate logistic regression and the area under the receiver operating characteristic curve (AUROC) were used to examine the diagnostic value of the predictors for advanced liver fibrosis. HBV DNA viral load in the PNALT group was significantly lower compared with the PIEALT group (4.57±1.68 vs. 5.71±1.69 log10 IU/ml; P<0.001). Body mass index and LS were also significantly lower in the PNALT group compared with the PIEALT group (P<0.001). The proportion of patients with liver fibrosis was significantly higher in the PIEALT group compared with the PNATL group (P=0.001). High ALT levels were an independent predictor for liver fibrosis, with an odds ratio (OR) of 2.69 (P=0.002). Male sex (OR=0.34, P=0.007), high ALT levels (OR=2.37, P=0.029) and a high HBV DNA load (OR=1.39, P=0.005) were independent predictors for advanced liver fibrosis. The AUROC was 0.65 (P=0.003) when using ALT levels to predict advanced liver fibrosis. ALT levels at ≥0.88 upper limit of normal (ULN; 35 IU/l) were considered as positive for advanced liver fibrosis, the sensitivity and specificity were 87.8 and 47.4%, respectively. The AUROC was 0.64 (P=0.004) when using the HBV DNA value to predict advanced liver fibrosis. When an HBV DNA value of ≥4.99 log10 IU/ml was considered as positive for advanced liver fibrosis, the sensitivity and specificity were 78.0 and 49.5%, respectively. The AUROC was 0.72 (P<0.001) when combining ALT, HBV DNA load and sex into a formulation to predict advanced liver fibrosis. When the formulation score at >‑2.22 was considered as positive for advanced liver fibrosis, the sensitivity and specificity were 61.5 and 70.7%, respectively. Therefore, normal ALT levels do not always indicate the absence of hepatic fibrosis. A combination of ALT levels, sex and serum HBV DNA load may more effectively identify patients with CHB at high risk of developing fibrosis. These patients may benefit from liver biopsy.

View Figures

View References

1	Clements CJ, Baoping Y, Crouch A, Hipgrave D, Mansoor O, Nelson CB, Treleaven S, van Konkelenberg R and Wiersma S: Progress in the control of hepatitis B infection in the Western Pacific Region. Vaccine. 24:1975–1982. 2006. View Article : Google Scholar : PubMed/NCBI
2	Liaw YF: Antiviral therapy of chronic hepatitis B: Opportunities and challenges in Asia. J Hepatol. 51:403–410. 2009. View Article : Google Scholar : PubMed/NCBI
3	Ott JJ, Stevens GA, Groeger J and Wiersma ST: Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 30:2212–2219. 2012. View Article : Google Scholar : PubMed/NCBI
4	Liaw YF, Kao JH, Piratvisuth T, Chan HL, Chien RN, Liu CJ, Gane E, Locarnini S, Lim SG, Han KH, et al: Asian-Pacific consensus statement on the management of chronic hepatitis B: A 2012 update. Hepatol Int. 6:531–561. 2012. View Article : Google Scholar : PubMed/NCBI
5	Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, et al: Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update. Hepatol Int. 10:1–98. 2016. View Article : Google Scholar : PubMed/NCBI
6	Rukunuzzaman M and Karim MB: Chronic hepatitis B in children - a review. Mymensingh Med J. 24:649–656. 2015.PubMed/NCBI
7	Bravo AA, Sheth SG and Chopra S: Liver biopsy. N Engl J Med. 344:495–500. 2001. View Article : Google Scholar : PubMed/NCBI
8	Peng J, Cai S, Yu T, Chen Y, Zhu Y and Sun J: Aspartate aminotransferase to platelet ratio index-a reliable predictor of therapeutic efficacy and improvement of Ishak score in chronic hepatitis B patients treated with nucleoside analogues. Scand J Clin Lab Invest. 76:133–142. 2016. View Article : Google Scholar : PubMed/NCBI
9	Zeng J, Cai S, Liu J, Xue X, Wu X and Zheng C: Dynamic changes in liver stiffness measured by transient elastography predict clinical outcomes among patients with chronic hepatitis B. J Ultrasound Med. 36:261–268. 2017. View Article : Google Scholar : PubMed/NCBI
10	Cai S, Cao J, Yu T, Xia M and Peng J: Effectiveness of entecavir or telbivudine therapy in patients with chronic hepatitis B virus infection pre-treated with interferon compared with de novo therapy with entecavir and telbivudine. Medicine (Baltimore). 96:e70212017. View Article : Google Scholar : PubMed/NCBI
11	European Association for the Study of Liver: EASL clinical practical guidelines: Management of alcoholic liver disease. J Hepatol. 57:399–420. 2012. View Article : Google Scholar : PubMed/NCBI
12	Cai SH, Lv FF, Zhang YH, Jiang YG and Peng J: Dynamic comparison between Daan real-time PCR and Cobas TaqMan for quantification of HBV DNA levels in patients with CHB. BMC Infect Dis. 14:852014. View Article : Google Scholar : PubMed/NCBI
13	Castera L: Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis. J Viral Hepat. 16:300–314. 2009. View Article : Google Scholar : PubMed/NCBI
14	Poynard T and Bedossa P: Age and platelet count: A simple index for predicting the presence of histological lesions in patients with antibodies to hepatitis C virus. METAVIR and CLINIVIR Cooperative Study Groups. J Viral Hepat. 4:199–208. 1997. View Article : Google Scholar : PubMed/NCBI
15	Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, et al: Transient elastography: A new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 29:1705–1713. 2003. View Article : Google Scholar : PubMed/NCBI
16	Cai S, Yu T, Jiang Y, Zhang Y, Lv F and Peng J: Comparison of entecavir monotherapy and de novo lamivudine and adefovir combination therapy in HBeAg-positive chronic hepatitis B with high viral load: 48-week result. Clin Exp Med. 16:429–436. 2016. View Article : Google Scholar : PubMed/NCBI
17	Sharaiha RZ, Kumta NA, Saumoy M, Desai AP, Sarkisian AM, Benevenuto A, Tyberg A, Kumar R, Igel L, Verna EC, et al: Endoscopic sleeve gastroplasty significantly reduces body mass index and metabolic complications in obese patients. Clin Gastroenterol Hepatol. 15:504–510. 2017. View Article : Google Scholar : PubMed/NCBI
18	Ou H, Cai S, Liu Y, Xia M and Peng J: A noninvasive diagnostic model to assess nonalcoholic hepatic steatosis in patients with chronic hepatitis B. Therap Adv Gastroenterol. 10:207–217. 2017. View Article : Google Scholar : PubMed/NCBI
19	Wang L, Chen S and Xu K: IL-17 expression is correlated with hepatitis B-related liver diseases and fibrosis. Int J Mol Med. 27:385–392. 2011.PubMed/NCBI
20	Bai Q, An J, Wu X, You H, Ma H, Liu T, Gao N and Jia J: HBV promotes the proliferation of hepatic stellate cells via the PDGF-B/PDGFR-β signaling pathway in vitro. Int J Mol Med. 30:1443–1450. 2012. View Article : Google Scholar : PubMed/NCBI
21	Fagone P, Mangano K, Mammana S, Pesce A, Pesce A, Caltabiano R, Giorlandino A, Portale TR, Cavalli E, et al: Identification of novel targets for the diagnosis and treatment of liver fibrosis. Int J Mol Med. 36:747–752. 2015. View Article : Google Scholar : PubMed/NCBI
22	Fagone P, Mangano K, Pesce A, Portale TR, Puleo S and Nicoletti F: Emerging therapeutic targets for the treatment of hepatic fibrosis. Drug Discov Today. 21:369–375. 2016. View Article : Google Scholar : PubMed/NCBI
23	Zhang Q, Xu M, Qu Y, Li Z, Zhang Q, Cai X and Lu L: Analysis of the differential expression of circulating microRNAs during the progression of hepatic fibrosis in patients with chronic hepatitis B virus infection. Mol Med Rep. 12:5647–5654. 2015. View Article : Google Scholar : PubMed/NCBI
24	Lambrecht J, Jan Poortmans P, Verhulst S, Reynaert H, Mannaerts I and van Grunsven LA: Circulating ECV-associated miRNAs as potential clinical biomarkers in early stage HBV and HCV induced liver fibrosis. Front Pharmacol. 8:562017. View Article : Google Scholar : PubMed/NCBI
25	Zheng J, Zhou Z, Xu Z, Li G, Dong P, Chen Z, Lin D, Chen B and Yu F: Serum microRNA-125a-5p, a useful biomarker in liver diseases, correlates with disease progression. Mol Med Rep. 12:1584–1590. 2015. View Article : Google Scholar : PubMed/NCBI
26	Yuen MF, Yuan HJ, Wong DK, Yuen JC, Wong WM, Chan AO, Wong BC, Lai KC and Lai CL: Prognostic determinants for chronic hepatitis B in Asians: Therapeutic implications. Gut. 54:1610–1615. 2005. View Article : Google Scholar : PubMed/NCBI
27	Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R and Bose S: Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology. 134:1376–1384. 2008. View Article : Google Scholar : PubMed/NCBI
28	Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM and Murad MH: American Association for the Study of Liver Diseases: AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 63:261–283. 2016. View Article : Google Scholar : PubMed/NCBI
29	Xue X and Cai S: Comment on ‘assessment of liver stiffness in pediatric fontan patients using transient elastography’. Can J Gastroenterol Hepatol. 2016:93439602016. View Article : Google Scholar : PubMed/NCBI
30	Tai DI, Lin SM, Sheen IS, Chu CM, Lin DY and Liaw YF: Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time. Hepatology. 49:1859–1867. 2009. View Article : Google Scholar : PubMed/NCBI
31	Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, Vianello L, Zanuso F, Mozzi F, Milani S, et al: Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 137:1–10. 2002. View Article : Google Scholar : PubMed/NCBI
32	Lin CL, Liao LY, Liu CJ, Yu MW, Chen PJ, Lai MY, Chen DS and Kao JH: Hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology. 45:1193–1198. 2007. View Article : Google Scholar : PubMed/NCBI
33	Kumar M, Sharma P, Garg H, Kumar R, Bhatia V and Sarin SK: Transient elastographic evaluation in adult subjects without overt liver disease: Influence of alanine aminotransferase levels. J Gastroenterol Hepatol. 26:1318–1325. 2011. View Article : Google Scholar : PubMed/NCBI
34	Yasuda M, Shimizu I, Shiba M and Ito S: Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. Hepatology. 29:719–727. 1999. View Article : Google Scholar : PubMed/NCBI
35	Lemoine M, Thursz M, Mallet V and Shimakawa Y: Diagnostic accuracy of the gamma-glutamyl transpeptidase to platelet ratio (GPR) using transient elastography as a reference. Gut. 66:195–196. 2017. View Article : Google Scholar : PubMed/NCBI
36	Li Q, Lu C, Li W, Huang Y and Chen L: The independent predictors of significant liver histological changes in chronic hepatitis B virus infection patients with persistently high-normal or low-normal alanine transaminase levels. Discov Med. 23:19–25. 2017.PubMed/NCBI