HBV DNA 水平波动的低病毒血症乙型肝炎患者肝纤维化患病率较

StephenW

HBV DNA 水平波动的低病毒血症乙型肝炎患者肝纤维化患病率较低

Faisal M Sanai1, Ahmad H Alhouthali1, Hamdan S Alghamdi2, Feras Badriq3, Eisa A Sanai1, Mohammed K Mujalled1, Waleed Khayyat3, Motaz S Attar3, Basil S Bagadeem3, Alaa M Meer1, Waleed Alshumrani4, Khalid Albeladi1, Ibrahim AlTraif2, Saleh Alqahtani5
1 沙特阿拉伯吉达阿卜杜勒阿齐兹国王医疗城内科胃肠病科
2 沙特·本·阿卜杜勒阿齐兹国王健康科学大学医学院，国民警卫队卫生事务部阿卜杜拉国王国际医学研究中心，吉达；沙特阿拉伯利雅得阿卜杜勒阿齐兹国王医学城肝胆科和器官移植中心肝病科
3 沙特·本·阿卜杜勒阿齐兹国王健康科学大学医学院，国民警卫队卫生事务部阿卜杜拉国王国际医学研究中心，沙特阿拉伯吉达
4 吉达阿卜杜勒阿齐兹国王医疗城内科胃肠病科；沙特·本·阿卜杜勒阿齐兹国王健康科学大学医学院，阿卜杜拉国王国际医学研究中心，国民警卫队卫生事务部，沙特阿拉伯吉达
5 沙特阿拉伯利雅得费萨尔国王专科医院和研究中心肝移植中心；胃肠病学和肝病学部，约翰霍普金斯大学，巴尔的摩，马里兰州，美国

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Faisal M Sanai 博士
阿卜杜勒阿齐兹国王医疗城内科胃肠病学部，邮政信箱 22490，吉达 - 21423
沙特阿拉伯
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DOI: 10.4103/sjg.sjg_48_22
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背景：在慢性乙型肝炎病毒（HBV）患者中，HBV DNA 的波动是一个“灰色地带”，阻碍了对非活动携带者的准确识别。我们旨在评估这种波动是否会影响慢性 HBV 患者中显着肝纤维化（Metavir F2-4）的存在。方法：纳入连续、未经治疗的 HBeAg 阴性携带者 (n = 234)，其 HBV DNA (n = 73) 波动高于或低于 2000 IU/mL 水平，并与没有波动的那些 (n = 161) 进行比较。基于持续低（<2,000 IU/mL，n = 137）和更高 HBV DNA（2,000-20,000 IU/mL，n = 24）的患者，进一步分析了没有 HBV DNA 波动的患者。肝纤维化（通过瞬时弹性成像评估）与病毒学和生化特征相关。结果：整个队列的平均年龄为 47.8 ± 11.1 岁，其中 107 人 (45.7%) 为男性。在中位 60 个月（四分位距 [IQR] 34-82）的随访期间，73 名（31.2%）患者的 HBV DNA 平均波动为 1.6 ± 0.9。第一次波动的中位时间为 14.5 (IQR 5.0–33.7) 个月。与没有波动的患者相比，波动病毒血症患者的 log10 qHBsAg (3.1 ± 0.8 vs. 2.7 ± 1.0, P = 0.022) 和 HBV DNA (3.4 ± 0.5 vs. 2.7 ± 0.8, P < 0.001) 更高。与没有波动性病毒血症的患者相比，波动性病毒血症患者发生 F2-4 纤维化的可能性较小（8.2%）（18.2%，优势比 [OR]：0.407，95% 置信区间 [CI]：0.161–1.030；P = 0.052 ）。男性波动较小，占 HBV DNA 波动患者的 37.0%（P = 0.071）。与没有波动的人相比（14.9%；P = 0.030），HBV DNA 水平明显较高的人（26.0%）发生波动的频率更高。结论：波动的 HBV DNA 水平经常发生，但与明显的纤维化无关。 HBV DNA 水平的微小波动不太可能具有临床相关性。

StephenW

Lower prevalence of hepatic fibrosis in low viremic hepatitis B patients with fluctuating HBV DNA levels

Faisal M Sanai1, Ahmad H Alhouthali1, Hamdan S Alghamdi2, Feras Badriq3, Eisa A Sanai1, Mohammed K Mujalled1, Waleed Khayyat3, Motaz S Attar3, Basil S Bagadeem3, Alaa M Meer1, Waleed Alshumrani4, Khalid Albeladi1, Ibrahim AlTraif2, Saleh Alqahtani5
1 Department of Medicine, Gastroenterology Unit, King Abdulaziz Medical City, Jeddah, Saudi Arabia
2 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Jeddah; Department of Hepatobiliary Sciences and Organ Transplant Center, Division of Hepatology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
3 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
4 Department of Medicine, Gastroenterology Unit, King Abdulaziz Medical City, Jeddah; College of Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
5 Liver Transplant Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia; Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, Maryland, United States

Correspondence Address:
Dr. Faisal M Sanai
Gastroenterology Unit, Department of Medicine, King Abdulaziz Medical City, PO Box 22490, Jeddah - 21423
Saudi Arabia
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DOI: 10.4103/sjg.sjg_48_22
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Background: In chronic hepatitis B virus (HBV) patients, fluctuations in HBV DNA serve as a “gray area” and impede the accurate identification of inactive carriers. We aimed to assess if such fluctuations impact the presence of significant hepatic fibrosis (Metavir F2-4) in chronic HBV patients. Methods: Consecutive, untreated HBeAg-negative carriers (n = 234) with fluctuating HBV DNA (n = 73) above or below a level of 2000 IU/mL were included and compared to those without fluctuations (n = 161). Patients without fluctuating HBV DNA were further analyzed based on those with persistently low (<2,000 IU/mL, n = 137) and higher HBV DNA (2,000–20,000 IU/mL, n = 24). Hepatic fibrosis (assessed by transient elastography) was correlated with virologic and biochemical profiles. Results: The mean age of the overall cohort was 47.8 ± 11.1 years, of whom 107 (45.7%) were male. During a median of 60 months (interquartile range [IQR] 34–82) of follow-up, 73 (31.2%) patients had a mean of 1.6 ± 0.9 fluctuations in HBV DNA. The median time to the first fluctuation was at 14.5 (IQR 5.0–33.7) months. Patients with fluctuating viremia had higher log10 qHBsAg (3.1 ± 0.8 vs. 2.7 ± 1.0, P = 0.022) and HBV DNA (3.4 ± 0.5 vs. 2.7 ± 0.8, P < 0.001) compared to those without fluctuations. Patients with fluctuant viremia were less likely to have F2-4 fibrosis (8.2%) compared to those without fluctuant viremia (18.2%, odds ratio [OR]: 0.407, 95% confidence interval [CI]: 0.161–1.030; P = 0.052). Males tended to have less fluctuation constituting 37.0% of patients with fluctuating HBV DNA (P = 0.071). Fluctuations occurred more frequently in those with predominantly higher HBV DNA levels (26.0%) compared to those without fluctuations (14.9%; P = 0.030). Conclusions: Fluctuating HBV DNA levels occur frequently but are not associated with significant fibrosis. Minor fluctuations in HBV DNA levels are unlikely to be of clinical relevance.

StephenW

https://doi.org/10.4103/sjg.sjg_48_22

StephenW

Fluctuating hepatitis B viremia: Full of sound and fury, signifying nothing?

Henry H Nguyen, Samuel S Lee
Liver Unit, University of Calgary Cumming School of Medicine, Canada

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Date of Web Publication        05-Aug-2022


How to cite this article:
Nguyen HH, Lee SS. Fluctuating hepatitis B viremia: Full of sound and fury, signifying nothing?. Saudi J Gastroenterol 2022;28:319-21

How to cite this URL:
Nguyen HH, Lee SS. Fluctuating hepatitis B viremia: Full of sound and fury, signifying nothing?. Saudi J Gastroenterol [serial online] 2022 [cited 2022 Sep 12];28:319-21. Available from: https://www.saudijgastro.com/text.asp?2022/28/5/319/353463

See accompanying article on page 341



Most of us treasure stability, especially when it comes to a key laboratory value such as hepatitis B viremia in the management of patients with chronic hepatitis B (CHB). Thus, an unstable, fluctuating viral load in such a situation is potentially unsettling, perhaps even full of sound and fury. But what does it really signify?

The management of CHB is complex and the decision to start viral suppression therapy is dependent on clinical factors including HBV DNA levels, liver inflammation, and/or fibrosis. In this issue of the Saudi Journal of Gastroenterology, Sanai et al.[1] retrospectively evaluated CHB patients with negative HBe antigen and fluctuating HBV DNA levels (2000 to 20000 IU/mL) vs those without fluctuation (persistently below 2000 IU/mL), comparing their risk of developing of significant hepatic fibrosis. They observed no significant association with HBV DNA levels and liver fibrosis. Interestingly, in the group with fluctuant viremia, F2-F4 fibrosis was lower compared to those without fluctuant viremia (~8% vs 18%). These results were collected from academic centers in the two largest Saudi cities.

The observations made by Sanai et al. although largely negative, highlight the complex pathophysiology of CHB infection, the need to factor in the role of host immune responses and the potential for concurrent underlying chronic liver diseases that may have ultimately affected the end-organ liver disease readout of fibrosis. The concept of differential host immune response in driving liver injury is well characterized for early hepatitis B infection. During this early phase of infection, high levels of HBV DNA, indicative of viral replication, are occurring in the setting of normal serum biochemistry and minimal liver fibrosis.[2] The lack of hepatocellular injury in this stage is thought to be in part driven by an attenuated immune response limiting the degree of direct hepatocyte injury. In later stages, which is more representative of the population in the study by Sanai et al., whereby HBe antigen is negative, using a normal ALT to evaluate for the absence of hepatocellular injury may be insufficient for identifying true underlying immune response and hepatocyte injury in the liver environment. One study has highlighted that although rare, in patients with a normal ALT and HBV DNA <20,000 IU/mL, evidence of active liver disease can still be present on histology.[3] Given the invasive nature of liver biopsy, evaluating the effects of fluctuation of HBV DNA on the inflammatory response in the liver environment was understandably not possible in this study. Development of reliable biomarkers identifying patients with active immune response at the liver tissue level beyond what is reflected by ALT levels is needed in CHB. This will allow for better evaluation of overall disease activity in the liver environment. The complex issues in managing CHB, including emerging biomarkers of disease activity/liver damage and the role of the host immune response in CHB have been reviewed elsewhere.[4],[5],[6]

Another area of potential interest includes that of the luminal microbiota and its effect on host immune response within the liver. The concept of host microbiota mediating differential immune function has been previously described and well characterized in pre-clinical models.[7],[8] Studies have highlighted perturbations in microbial composition in the setting of CHB and its effect on liver injury[9],[10] thought to occur via various mechanisms within the gut-liver axis. Avenues include luminal components translocating the gastrointestinal tract and signaling with innate receptors in the hepatic environment, such as lipopolysaccharide-Toll Like Receptor 4, flagellin- Toll Like Receptor 5, and various cell wall components – Toll Like Receptor 2 interactions. The roles of luminal derived metabolites are also of importance and have been discussed elsewhere in the context of different forms of chronic liver diseases.[11],[12],[13]

Moreover, in this study the use of a liver stiffness measurement by transient elastography as a non-invasive means of monitoring liver fibrosis reflects real-world management of patients with CHB. The authors minimized inter-observer variability by utilizing single operators at the study centers. The lack of association in fibrosis level change by transient elastography in relation to fluctuant HBV DNA levels may be potentially masked by underlying non-alcoholic steatohepatitis (NASH); a condition that is highly prevalent globally with modeling and epidemiological data suggesting ~30% of the world's population being affected by the year 2030.[14] NASH and NAFLD are particularly prevalent in the Middle Eastern population.[15] The authors did evaluate the body mass index, presence of diabetes, and dyslipidemia between the HBV fluctuant and non-fluctuant groups and highlighted no significant difference. They also included Controlled Attenuation Parameter score calculated from the transient elastography, which correlates to liver steatosis, and showed no difference between the groups. Although these clinical and noninvasive variables have been previously shown to be associated with NAFLD/NASH, they are not diagnostic of NASH and cannot be used in place of a biopsy to completely rule out the presence of underlying liver inflammation or fibrosis. As such, it is a possibility that HBV DNA fluctuations may drive liver injury but any difference in this observed endpoint was blunted by concurrent NASH. Again, this highlights the need for better biomarkers to reflect immune activity in the setting of CHB.

One of the major conclusions of this study is that apparent viremia fluctuations, especially defined in the authors' manner as any value that crosses the 2000 IU/mL cutoff threshold for 'inactive carriage', are probably clinically insignificant, at least in terms of fibrosis or disease progression. In addition to the above factors, an important methodological/technical note must be emphasized in this regard. That issue is the significance of changes on logarithmic base 10 values. Most human brains cannot easily or intuitively grasp numbers expressed as log-10 values. For example, if hepatitis B DNA levels increase from 2000 to 4000 IU/mL, this absolute doubling may appear quite significant. However, in log-10 terms that is only a modest increase from 3.3 to 3.6. Thus, the results of this study, along with all others that use PCR-based HBV-DNA assays such as the Abbott platform, which is widely used globally, must be carefully considered in view of the natural inherent variability, as this extent of 0.3 log difference is within the accepted coefficient of variability of the assay.[16]

In summary, Sanai et al. found no significant difference in fibrosis score on transient elastography in patients with fluctuating HBV DNA levels vs those without fluctuation. Their study highlights the importance of considering both viral and host factors when evaluating end organ outcomes, and suggests that small logarithmic variations in viremia are clinically insignificant.

StephenW

https://doi.org/10.4103/sjg.sjg_307_22