Host Factors in the Natural History of Chronic Hepatitis B: Role of Genetic Determinants

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Abstract

Background

The host immune system plays an important role in hepatitis B virus (HBV) infection manifestation. Genetic polymorphisms of several inflammatory cytokines, including TNF- α and IL-10, have been associated with chronic hepatitis B (CHB) progression, although with contradicting results. CHB progression can be categorized into four phases, immune tolerance (IT), immune clearance (IC), low/no replicative (LR), and e-negative hepatitis (ENH), with HBeAg seroconversion as an important milestone. Here, we determined the association of TNF- α (rs1800629) and IL-10 (rs1800896 and rs1800872) SNPs in the context of CHB natural history progression, particularly to HBeAg seroconversion, in Indonesian CHB patients.

Methods

A total of 287 subjects were recruited and categorized into distinct CHB phases based on HBeAg, viral load, and ALT levels. TNF- α and IL-10 SNPs were determined using PCR-RFLP and confirmed with direct sequencing. The association between SNP genotypes with CHB dynamics was determined using logistic regression presented as odds ratio (OR) with 95% CI.

Results

No significant association was found between IL-10 -592A/C polymorphism and progression of IT and IC to LR, IT and IC to ENH, and LR to ENH phases in all the gene models. IL-10 rs1800896 and TNF- α rs1800629 could not be analyzed using logistic regression. Subjects' age (≥40 years old) was significantly associated with IT and IC to LR (OR: 2.191, 95% CI 1.067–4.578, P = 0.034), IT and IC to ENH (OR: 7.460, 95% CI 3.316–18.310, P < 0.001), and LR to ENH (OR: 5.252, 95% CI 2.010–14.858, P = 0.001). Male gender was associated with LR to ENH (OR: 4.077, 95% CI 1.605–11.023, P = 0.004).

Conclusions

Age and male gender were associated with CHB phase progression instead of the TNF- α and IL-10 polymorphisms. It would be beneficial to study not only the effect of host determinants but also the viral factor to understand the mechanisms of CHB phase progression.

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Most cited references 51

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Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update

S. K. Sarin, M. Kumar, G K Lau … (2015)

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

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Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.

Francesco Donato, F Bortolotti, Giovanna Fattovich (2008)

The natural history of chronic hepatitis B virus (HBV) infection and disease is complex and highly variable. We review the natural history of chronic hepatitis B with emphasis on the rates of disease progression and factors influencing the course of the liver disease. Chronic hepatitis B is characterized by an early replicative phase (HBeAg positive chronic hepatitis) and a late low or non-replication phase with HBeAg seroconversion and liver disease remission (inactive carrier state). Most patients become inactive carriers after spontaneous HBeAg seroconversion with good prognosis, but progression to HBeAg negative chronic hepatitis due to HBV variants not expressing HBeAg occurs at a rate of 1-3 per 100 person years following HBeAg seroconversion. The incidence of cirrhosis appears to be about 2-fold higher in HBeAg negative compared to HBeAg positive chronic hepatitis. In the cirrhotic patient the 5-year cumulative risk of developing hepatocellular carcinoma is 17% in East Asia and 10% in the Western Europe and the United States and the 5-year liver related death rate is 15% in Europe and 14% in East Asia. There is a growing understanding of viral, host and environmental factors influencing disease progression, which ultimately could improve the management of chronic hepatitis B.

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Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches.

Joseph Lau, Elias Zintzaras (2008)

The aim of the study was to consider statistical and methodological issues affecting the results of meta-analysis of genetic association studies for pertinent gene-disease associations. Although the basic statistical issues for performing meta-analysis are well described in the literature, there are remaining methodological issues. An analysis of our database and a literature review were performed to assess issues such as departure of Hardy-Weinberg equilibrium, genetic contrasts, sources of bias (replication validity, early extreme contradictory results, differential magnitude of effect in large versus small studies, and "racial" diversity), utility of cumulative and recursive cumulative meta-analyses. Gene-gene-environment interactions and methodological challenges of genome-wide association studies are discussed. Departures from Hardy-Weinberg equilibrium can be handled using sensitivity analysis or correction procedures. A spectrum of genetic models should be investigated in the absence of biological justification. Cumulative and recursive cumulative meta-analyses are useful to explore heterogeneity in risk effect in time. Exploration of bias leading to heterogeneity provides insight to postulated genetic effects. In the presence of bias, results should be interpreted with caution. Meta-analysis provides a robust tool to investigate contradictory results in genetic association studies by estimating population-wide effects of genetic risk factors in diseases and explaining sources of bias and heterogeneity.

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Author and article information

Contributors

David H. Muljono:

ORCID: https://orcid.org/0000-0002-5542-106X

Journal

Journal ID (nlm-ta): Int J Hepatol

Journal ID (iso-abbrev): Int J Hepatol

Journal ID (publisher-id): IJH

Title: International Journal of Hepatology

Publisher: Hindawi

ISSN (Print): 2090-3448

ISSN (Electronic): 2090-3456

Publication date Collection: 2022

Publication date (Electronic): 23 August 2022

Volume: 2022

Electronic Location Identifier: 6046677

Affiliations

¹Post Graduate School, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia

²Eijkman Center for Molecular Biology, National Research and Innovation Agency, Jakarta, Indonesia

³Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia

⁴Faculty of Medicine and Health, University of Sydney, Sydney, Australia

Author notes

Academic Editor: Mircea-Catalin Fortofoiu

Author information

Turyadi https://orcid.org/0000-0002-1388-4920

Billy Witanto https://orcid.org/0000-0001-5077-3923

Korri E. El-Khobar https://orcid.org/0000-0002-9383-931X

M. Luthfi Parewangi https://orcid.org/0000-0001-9257-9344

M. Rezki Rasyak https://orcid.org/0000-0002-4016-4072

Dhita P. Wibowo https://orcid.org/0000-0003-2237-2094

Meta D. Thedja https://orcid.org/0000-0002-2948-4905

Irawan Yusuf https://orcid.org/0000-0001-9891-131X

Muh. Nasrum Massi https://orcid.org/0000-0002-3347-6529

Ilhamjaya Patellongi https://orcid.org/0000-0002-1100-4360

Din Syafruddin https://orcid.org/0000-0001-7141-2545

David H. Muljono https://orcid.org/0000-0002-5542-106X

Article

DOI: 10.1155/2022/6046677

PMC ID: 9427277

SO-VID: 4b1f641d-dc7b-4e6e-8293-be2cb2a65aea

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 29 March 2022

Date accepted : 27 July 2022

Funding

Funded by: Ministry of Research and Technology/National Research and Innovation Agency, Indonesia

Host Factors in the Natural History of Chronic Hepatitis B: Role of Genetic Determinants

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Karger: Gastroenterology

Most cited references 51

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update

Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.

Synthesis of genetic association studies for pertinent gene-disease associations requires appropriate methodological and statistical approaches.

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