Krawczyk, Marcin

Lammert, Frank

Liebe, Roman

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A vaccine for Beethoven's vulnerable liver

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Eur J Clin Invest. 2023;53:e14035.    | 1 of 3https://doi.org/10.1111/eci.14035wileyonlinelibrary.com/journal/eciReceived: 24 April 2023 | Accepted: 22 May 2023DOI: 10.1111/eci.14035  C O M M E N T A R YA vaccine for Beethoven's vulnerable liverRoman Liebe1  |   Frank Lammert2 |   Marcin Krawczyk3,41Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Otto- von- Guericke University, Magdeburg, Germany2Hannover Medical School (MHH), Hannover, Germany3Department of Medicine II, Saarland University Medical Center, Homburg, Germany4Laboratory of Metabolic Liver Disease, Medical University of Warsaw, Warsaw, PolandCorrespondenceMarcin Krawczyk, Department of Medicine II, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg, Germany.Email: marcin.krawczyk@uks.euKeywords: Alcoholic liver disease, HBV, Liver cirrhosisDear EJCI Editor,The recent report1 presenting a thorough analysis of Ludwig van Beethoven's genome has made headlines in scientific and non- scientific journals. The famous com-poser is known to have suffered, among other ailments, from cirrhosis, and the study by Begg et al.1 adds a few exciting new details to this picture. In brief, the authors showed that Beethoven carried a combination of genetic variants (i.e. HFE p.His63Asp and p.Cys282Tyr as well as PNPLA3 p.I148M) that rendered his liver particularly vul-nerable to external noxae, here iron, alcohol and caloric overload.2 Hence, regular alcohol consumption, proba-bly combined with rich food over many years is likely to represent the major cause for his chronic liver disease. Interestingly, Begg et al.1 also performed a metagenomic analysis of Beethoven's hair locks and found that in the last months of his life, he might have suffered from hepa-titis B virus (HBV) infection.Although the mass media and the authors of the report1 seem to have focused on the analysis of Beethoven's ge-nome, the detection of HBV infection should not be over-seen as it might be highly relevant to Beethoven's death, but also to our everyday liver patients. Apparently, the composer experienced a first episode of jaundice 6 years before his death in 1827, possibly a first sign of decompen-sation. The fact that it took a couple of decades of chronic alcohol consumption on the background of his high- risk genotype to develop clinical liver disease shows the organ's enormous regenerative capacity. This proverbial resilience has been known for a long time and features prominently in the Prometheus saga from 800 BC, which Beethoven refers to in his ballet ‘The Creatures of Prometheus Op. 43’, composed in 1801. One could speculate that during the last months of his life, the composer might have suf-fered from acute- on- chronic liver failure (ACLF) caused by the HBV infection on top of his alcohol- induced pro-gressive liver damage. This additional insult precipitated the lethal deterioration of liver function (Figure 1). ACLF is a new disease entity,3 defined as acute liver failure in patients with chronic liver diseases. Bajaj et al.4 described ACLF ‘as a potentially reversible condition in patients with chronic liver disease with or without cirrhosis that is as-sociated with the potential for multiple organ failure and mortality within 3 months in the absence of treatment of the underlying liver disease, liver support, or liver transplanta-tion’. The data available in Begg's paper1 are not sufficient to determine if Beethoven suffered from multiple organ failure or only liver failure. Of note, acute viral infections have been identified as precipitating events of ACLF.5,6 In terms of hepatitis B, acute infection is rare but can re-sult in rapid dysfunction of pre- injured liver, and flares of chronic HBV infection have been described as triggers of ACLF.7 Patients with HBV- ACLF have been reported to suffer from high short- term mortality,8 in line with the data from the metagenomic analyses revealing the viral infection, and Beethoven's rapid demise.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.2 of 3 |   LIEBE et al.Begg's study1 is a major success of molecular ge-netic analyses. However, we reckon the observation that Beethoven suffered from HBV infection and that ACLF can be triggered by acute viral infections deserves more prominence. This finding might be used as a motivational lever to promote wider acceptance for vaccination against viral infections. Indeed, as highlighted by the pandemic and reviewed recently by Jeng et al.,9 vaccinations rep-resent an effective means to prevent severe viral infec-tions. Regardless of how long Beethoven suffered from HBV infection, one can imagine that prior vaccination against HBV, if it had been available at the time, might have prevented the acute deterioration of his vulnerable liver, which was challenged by the “devil's triangle” of gene variants, environmental toxins, and virus. This rep-resents an important positive message, which is urgently needed in view of the persisting vaccine hesitancy follow-ing COVID- 19.10ACKNO WLE DGE MENTSPortrait of Beethoven by Stieler was reproduced in Figure 1 with kind permission of Beethoven Haus Bonn. Open Access funding enabled and organized by Projekt DEAL.CONFLICT OF INTEREST STATEMENTThe authors have no conflict of interest to declare.ORCIDRoman Liebe   https://orcid.org/0000-0002-3199-5595 Marcin Krawczyk   https://orcid.org/0000-0002-0113-0777 REFERENCES 1. Begg TJA, Schmidt A, Kocher A, et al. Genomic analyses of hair from Ludwig van Beethoven. Curr Biol. 2023;33:1431- 1447.e22. doi:10.1016/j.cub.2023.02.041 2. Krawczyk M, Liebe R, Lammert F. Toward genetic prediction of nonalcoholic fatty liver disease trajectories: PNPLA3 and be-yond. Gastroenterology. 2020;158:1865- 1880. 3. Jalan R, Moreau R, Arroyo V. Acute- on- chronic liver failure. N Engl J Med. 2020;383:893- 894. 4. Bajaj JS, O'Leary JG, Lai JC, et al. Acute- on- chronic liver failure clinical guidelines. Am J Gastroenterol. 2022;117:225- 252. 5. Li Q, Wang J, Lu M, Qiu Y, Lu H. Acute- on- chronic liver fail-ure from chronic- hepatitis- B. who is the behind scenes. Front Microbiol. 2020;11:583423. 6. Trebicka J, Fernandez J, Papp M, et al. PREDICT identifies pre-cipitating events associated with the clinical course of acutely decompensated cirrhosis. J Hepatol. 2021;74:1097- 1108. 7. Yuan L, Zeng BM, Liu LL, et al. Risk factors for progression to acute- on- chronic liver failure during severe acute exacerbation of chronic hepatitis B virus infection. World J Gastroenterol. 2019;25:2327- 2337. 8. Li H, Chen LY, Zhang NN, et al. Characteristics, diagnosis and prognosis of acute- on- chronic liver failure in cirrhosis associ-ated to hepatitis B. Sci Rep. 2016;6:25487.F I G U R E  1  showing the hypothetical sequential impact of PNPLA3 and HFE risk genotype, chronic alcohol abuse and HBV infection on LvB's liver, based on a figure by Jalan et al.11 Despite a vicious combination of PNPLA3 risk genotype and chronic alcohol consumption, the organ proves its proverbial regenerative capacity and resilience to maintain sufficient function over 30+ years of abuse. 13652362, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/eci.14035 by Universitaet Des Saarlandes, Wiley Online Library on [08/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License   | 3 of 3LIEBE et al. 9. Jeng WJ, Papatheodoridis GV, Lok ASF. Hepatitis B. Lancet. 2023;401:1039- 1052. 10. Wiysonge CS, Ndwandwe D, Ryan J, et al. Vaccine hesitancy in the era of COVID- 19: could lessons from the past help in divin-ing the future? Hum Vaccin Immunother. 2022;18:1- 3. 11. Jalan R, Gines P, Olson JC, et al. Acute- on chronic liver failure. J Hepatol. 2012;57:1336- 1348.How to cite this article: Liebe R, Lammert F, Krawczyk M. A vaccine for Beethoven's vulnerable liver. Eur J Clin Invest. 2023;53:e14035. doi:10.1111/eci.14035 13652362, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/eci.14035 by Universitaet Des Saarlandes, Wiley Online Library on [08/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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A vaccine for Beethoven's vulnerable liver

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