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Reply to: “Liver stiffness, fatty liver disease and atrial fibrillation in the Rotterdam study: Some issues”

Published:August 15, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.030

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      To the Editor:
      We thank Tsai et al. for their interest in our recent publication demonstrating that liver stiffness was associated with atrial fibrillation, whereas fatty liver disease was not.
      • van Kleef L.A.
      • Lu Z.
      • Ikram M.A.
      • de Groot N.M.S.
      • Kavousi M.
      • de Knegt R.J.
      Liver stiffness, but not fatty liver disease, is associated with atrial fibrillation: the Rotterdam Study.
      ,
      • Tsai W.-C.
      • Yu M.-L.
      • Dai C.-Y.
      Liver stiffness, fatty liver disease and atrial fibrillation in the Rotterdam study: some issues.
      First, the authors mentioned in their letter the low sensitivity of a single 10-second ECG for the diagnosis of atrial fibrillation. We agree that the diagnostic accuracy of a 10-second ECG alone is generally poor. Therefore, in this study, we defined atrial fibrillation using a comprehensive approach comprising not only the 10-second 12-lead ECG at the study visit but also objective data obtained from other health care professionals by linking electronic medical records with our study database. To prevent arbitrariness in the diagnosis of atrial fibrillation, research physicians, supervised by an experienced cardiologist, confirmed each diagnosis by an independent reading of the ECG. Based on the prevalence of atrial fibrillation in our study, this approach seems to detect most participants with atrial fibrillation.
      Notably, this comprehensive approach may explain the relatively high prevalence of atrial fibrillation in this elderly population compared to the study by Feinberg et al., mentioned by the authors.
      • Feinberg W.M.
      • Blackshear J.L.
      • Laupacis A.
      • Kronmal R.
      • Hart R.G.
      Prevalence, age distribution, and gender of patients with atrial fibrillation: analysis and implications.
      We would like to note that this study originates from 1995 while there is evidence that the prevalence of atrial fibrillation has increased in the last decades, either due to better sensitivity of diagnostic strategies or an increase in the prevalence of risk factors for atrial fibrillation.
      • Schnabel R.B.
      • Yin X.
      • Gona P.
      • Larson M.G.
      • Beiser A.S.
      • McManus D.D.
      • et al.
      50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study.
      Moreover, recent studies have a larger sample size, and the prevalence seems more accurate for our data collection period. Indeed, a study among over 200.000 Swedes demonstrated that the prevalence of atrial fibrillation based on ICD-10 codes was 4.2% among those aged 60–69 years and 9.7% among those aged 70–79 years old. We would like to note that the population in Sweden is comparable to the Netherlands and that these findings perfectly align with our results.
      Secondly, they mentioned the potential issue of not evaluating risk factors for atrial fibrillation in this study, such as obesity and BMI, as well as thyroid disorders, valvular disease and chronic obstructive pulmonary disease. Unfortunately, because of overfitting, we could not specifically investigate all potential covariates in the associations and we endorse future studies investigating the potential impact of these conditions on the association between atrial fibrillation and liver stiffness. Regarding BMI, it was a deliberate choice not to utilize BMI because of the increasing concerns about the predictive ability of BMI in elderly populations. Sarcopenia, a condition common in the elderly, could result in favourable BMI levels while only muscle mass is lost and not fat mass whilst being a risk factor for NAFLD.
      • Wijarnpreecha K.
      • Panjawatanan P.
      • Aby E.
      • Ahmed A.
      • Kim D.
      Nonalcoholic fatty liver disease in the over-60s: impact of sarcopenia and obesity.
      Waist circumference is a better proxy for metabolic health and is therefore used in this study.
      • Ross R.
      • Neeland I.J.
      • Yamashita S.
      • Shai I.
      • Seidell J.
      • Magni P.
      • et al.
      Waist circumference as a vital sign in clinical practice: a Consensus Statement from the IAS and ICCR Working Group on Visceral Obesity.
      Nonetheless, we repeated our primary analysis with additional adjustment for BMI and the results remained consistent. Moreover, we would like to note that waist circumference has a better predictive value for atrial fibrillation compared to BMI in men, whereas BMI was a slightly better predictor in women.
      The final comment by the authors is about the controlled attenuation parameter (CAP). First of all, we note that our data originates from 2009-2014, when CAP was not yet available on commercial devices. However, validating these findings using CAP would be interesting, as CAP may have better accuracy for detecting mild steatosis.
      • Cao Y-t
      • Xiang L-l
      • Qi F.
      • Zhang Y-j
      • Chen Y.
      • Zhou X-q
      Accuracy of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) for assessing steatosis and fibrosis in non-alcoholic fatty liver disease: a systematic review and meta-analysis.
      Yet, it seems highly unlikely that missing out on some individuals with only mild steatosis resulted in a complete distortion of associations. Last, the FAST score was mentioned; this is a composite of liver stiffness, CAP and AST (aspartate aminotransferase) that has been used to predict the presence of NASH-fibrosis.
      • Newsome P.N.
      • Sasso M.
      • Deeks J.J.
      • Paredes A.
      • Boursier J.
      • Chan W.K.
      • et al.
      FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.
      This score is likely to encounter the same issues as liver stiffness alone and might not discriminate between venous congestion and NASH-fibrosis. Because of the important role attributed to liver stiffness in this algorithm, validation of the diagnostic accuracy of the FAST score is required in populations at risk of venous congestion.
      In conclusion, we believe that the potential issues mentioned by Tsai et al. have not had any impact on our conclusion that atrial fibrillation was associated with liver stiffness and not with fatty liver disease. However, additional studies are warranted to investigate the exact impact of the association between atrial fibrillation and fatty liver disease on current elastography-based risk stratification algorithms.

      Financial support

      Financial support was provided by the Foundation for Liver and Gastrointestinal Research, Rotterdam, the Netherlands. The funding source did not influence study design, nor the writing of the report and decision to submit for publication.

      Authors’ contributions

      Writing of the manuscript: LvK and RdK. Critical review of the manuscript, approval of final version approval of submission: LvK, MK, and RdK.

      Conflicts of interest

      RdK is a speaker for Echosens, consultant for AbbVie and received grants from Abbvie, Gilead and Janssen. The remaining authors reported no relevant conflicts.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the supplementary data to this article:

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