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Dynamics of liver stiffness in chronic hepatitis B patients with concurrent metabolic-associated fatty liver disease

  • Danny Con
    Correspondence
    Corresponding author. Address: Department of Gastroenterology, Box Hill Hospital, 8 Arnold Street, Box Hill, 3128, Victoria, Australia; Tel.: +61 3 8804 9999.
    Affiliations
    Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia
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  • Daniel Clayton-Chubb
    Affiliations
    Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia
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  • John Lubel
    Affiliations
    Department of Gastroenterology, Alfred Health, Melbourne, Victoria, Australia

    Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Victoria, Australia
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  • Rohit Sawhney
    Affiliations
    Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia

    Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Victoria, Australia
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  • Stephen Bloom
    Affiliations
    Department of Gastroenterology, Eastern Health, Melbourne, Victoria, Australia

    Faculty of Medicine, Nursing and Health Science, Monash University, Melbourne, Victoria, Australia
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Published:February 19, 2021DOI:https://doi.org/10.1016/j.jhep.2021.02.013

      Linked Article

      To the Editor:
      We read with interest the article by Mak et al.
      • Mak L.Y.
      • Hui R.W.
      • Fung J.
      • Liu F.
      • Wong D.K.
      • Cheung K.S.
      • et al.
      Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B.
      and commend their work exploring the diverse relationship between hepatic steatosis and chronic hepatitis B (CHB). Through prospective follow-up of 330 patients with normal alanine aminotransferase (ALT) and low viraemia, Mak et al. showed persistent severe steatosis (controlled attenuation parameter ≥280 dB/m) was associated with progression of fibrosis category after 3 years. As modern nucleos(t)ide analogues are able to achieve effective long-term viral/biochemical suppression and attenuate fibrosis development,
      • Con D.
      • Goodwin T.
      • Majeed A.
      • Roberts S.
      • Kemp W.
      Comparison of 48-week efficacy of tenofovir vs. entecavir for patients with chronic hepatitis B: a network meta-analysis.
      the focus of CHB management has shifted to address non-viral risk factors such as concurrent steatosis – with approximately 30% prevalence amongst patients with CHB
      • Machado M.V.
      • Oliveira A.G.
      • Cortez-Pinto H.
      Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients.
      – and metabolic dysfunction-associated fatty liver disease (MAFLD).
      • Eslam M.
      • Newsome P.N.
      • Sarin S.K.
      • Anstee Q.M.
      • Targher G.
      • Romero-Gomez M.
      • et al.
      A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.
      Although Mak et al. provided useful insight into the effects of severe steatosis on virologically quiescent CHB, the broader relationship between these two conditions remains elusive. We aimed to provide additional insight by modelling serial liver stiffness measurements (LSM) over time and comparing their trajectories amongst patients with or without concurrent MAFLD.
      We retrospectively identified all non-cirrhotic patients with CHB at a tertiary Australian centre. Patients were followed up from first review between 01/01/2010–31/12/2016 until 31/08/2020 or loss-to-follow-up. Steatosis was diagnosed radiologically (diffusely increased echogenicity on ultrasound) and MAFLD was diagnosed using new criteria.
      • Eslam M.
      • Newsome P.N.
      • Sarin S.K.
      • Anstee Q.M.
      • Targher G.
      • Romero-Gomez M.
      • et al.
      A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.
      Transient elastography was performed by a certified operator in accordance with best clinical practice for quality and probe selection.
      • Kemp W.
      • Levy M.
      • Weltman M.
      • Lubel J.
      Australian Liver Association (ALA) expert consensus recommendations for the use of transient elastography in chronic viral hepatitis.
      The median of ≥10 successful measurements was recorded. Multivariable general linear mixed-effects regression (random intercept at the patient level) was used to model LSM, BMI, ALT and viral load using optimal order polynomial time covariates (by Akaike’s information criterion) and time interaction terms. Each model was controlled for baseline age, sex, LSM, ALT, BMI, viral load, antiviral status, prior antiviral exposure and metabolic risk factors. Analysis was performed in Stata/IC 16.1 (StataCorp LP, USA, 2020).
      Of 660 patients (median follow-up 6.0 years; IQR 4.1–8.3), 172 (26%) had concurrent MAFLD. Data comprised 1,997 LSM, 10,647 ALT and 8,223 DNA measurements. Patients with MAFLD were of similar age (median 45.5 vs. 43.0 years, p = 0.09), but were more commonly male (65% vs. 44%, p <0.001). There was no significant difference (MAFLD vs. non-MAFLD) in the proportion who were HBeAg positive (19% vs. 25%, p = 0.21), on antiviral therapy at baseline (7% vs. 12%, p = 0.18) or commenced on therapy during follow-up (25% vs. 29%, p = 0.49). Most (61%) were never on antiviral therapy. Interestingly, we found that although average LSM was 15% higher initially (95% CI 7–24%, p <0.001) amongst patients with concurrent MAFLD, this improved over time such that there was no significant difference after 2–3 years (Fig. 1). Although LSM is known to be elevated in obesity, the trajectory of LSM in patients with MAFLD did not appear to correlate with BMI, but instead mirrored the trajectory of HBV DNA and ALT, reflective of the underlying virological and biochemical response. On average, DNA was 35% lower in patients with MAFLD (95% CI 14–51%, p = 0.003), and this difference remained over time. ALT decreased in all patients over time but was 13% higher in patients with MAFLD on entry (95% CI 4–23%, p = 0.003), and remained higher throughout follow-up. Of note, a similar degree of improvement in LSM was not observed in patients without MAFLD, despite no difference in the rate of change in ALT or viral load between MAFLD and non-MAFLD patients.
      Figure thumbnail gr1
      Fig. 1Estimated trends in liver stiffness (LSM), BMI, ALT and HBV DNA over time using general linear mixed effects regression in patients with chronic hepatitis B, stratified by presence of concurrent MAFLD (n = 660).
      Both optimal order polynomial fit with 95% confidence bands as well as linear fit for comparison are shown. (A) LSM; (B) BMI; (C) ALT; (D) HBV DNA. (This figure appears in color on the web.)
      Perhaps the most striking finding of these data is the lack of any apparent worsening of LSM on average over time – in fact, LSM improved in patients with MAFLD, with similar findings when analysing only untreated patients (data not shown). However, our cohort was substantially different to the cohort by Mak et al. as we included all patients with CHB, the majority of whom had elevated HBV DNA and ALT throughout follow-up. This perhaps suggests viraemia and/or raised ALT has a more pronounced influence on LSM, and that the effect of steatosis is unmasked only after viral and biochemical suppression. Another explanation could be the influence of improved lifestyle changes not captured in our data; however, BMI did not substantially change over time. Although we were limited by the lack of controlled attenuation parameter measurements to quantify steatosis degree, ultrasound is less sensitive for steatosis so the patients in our cohort were likely to have moderate-to-severe steatosis. Thus, our results are markedly different from Mak et al. who showed the rate of fibrosis progression appeared highest in patients with persistent severe steatosis (41%) and new onset severe steatosis (35%). However, data for milder degrees of steatosis were not provided. It remains speculative whether the negative effects of steatosis on liver fibrosis outweigh the apparent protective effects, since concurrent steatosis attenuates viraemia,
      • Hui R.W.H.
      • Seto W.K.
      • Cheung K.S.
      • Mak L.Y.
      • Liu K.S.H.
      • Fung J.
      • et al.
      Inverse relationship between hepatic steatosis and hepatitis B viremia: results of a large case-control study.
      ,
      • Hu D.
      • Wang H.
      • Wang H.
      • Wang Y.
      • Wan X.
      • Yan W.
      • et al.
      Non-alcoholic hepatic steatosis attenuates hepatitis B virus replication in an HBV-immunocompetent mouse model.
      accelerates HBsAg seroclearance,
      • Mak L.Y.
      • Hui R.W.
      • Fung J.
      • Liu F.
      • Wong D.K.
      • Cheung K.S.
      • et al.
      Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B.
      and possibly even improves the rate of response to antiviral therapy.
      • Li J.
      • Le A.K.
      • Chaung K.T.
      • Henry L.
      • Hoang J.K.
      • Cheung R.
      • et al.
      Fatty liver is not independently associated with the rates of complete response to oral antiviral therapy in chronic hepatitis B patients.
      Additional prospective studies are required to further clarify the unique relationship between steatosis and CHB.

      Financial support

      This study was not directly funded and there are no other financial disclosures to declare.

      Authors’ contributions

      DC: conceptualization, data collection, statistical analysis, data interpretation, manuscript drafting. DCC: data collection, data interpretation. JL: data collection, data interpretation, revision of manuscript critically for important intellectual content. RS: conceptualization, data interpretation, revision of manuscript critically for important intellectual content. SB: conceptualization, data interpretation, revision of manuscript critically for important intellectual content.

      Conflicts of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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