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Detection of unreported alcohol consumption in fatty liver disease

Published:October 26, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.016

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      • Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease
        Journal of HepatologyVol. 77Issue 4
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          Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) cannot reliably be distinguished by routine diagnostics, and the role of alcohol consumption in metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear. We investigated alcohol consumption in patients with presumed NAFLD and ALD using novel objective alcohol markers.
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      • Are there any reliable predictors of unreported alcohol consumption in individuals with MAFLD?
        Journal of Hepatology
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          We have read with positive interest the study by Staufer et al. dealing with a very interesting topic, namely the role of alcohol consumption in metabolic dysfunction-associated fatty liver disease (MAFLD).1 This study assessed and compared the accuracy of five tests – ethylglucuronide in hair (hEtG) and urine, carbohydrate deficient transferrin, mean corpuscular volume, gamma-glutamyltransferase – and two scores, AUDIT-C and ANI (ALD/NAFLD index), for diagnosing regular moderate or excessive ethanol intake.
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      • Considerations in the search for under-reported alcohol consumption in NAFLD
        Journal of Hepatology
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          We congratulate Staufer et al. for examining a controversial topic in the field.1 Alcohol consumption in NAFLD/MAFLD has definitely been “the elephant in the room” for a long time. This important paper urges the field to include objective alcohol markers as an important quality variable in future cohort studies and treatment trials. However, even though the study is important to the field and highlights the importance of objective alcohol markers, there are some points to be made. First, the “gold standard” definition was based on patient interview using AUDIT-C.
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      Conflict of interest statement

      BM has no conflict to declare with respect to this work. KS discloses speaker fees as well as travel support from Vifor Pharma, employee of Versantis AG. MT discloses grant support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda and UltraGenyx, honoraria for consulting from Abbvie, Albireo, BiomX, Boehringer Ingelheim, Falk, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire, speaker fees from Falk Foundation, Gilead, Intercept, MSD and Roche, as well as travel support from Abbvie, Falk, Gilead, Intercept, Janssen, Roche.

      Authors´ contributions

      KS, BM, MT drafted the manuscript. All authors approved the final version of the manuscript prior to submission.

      Financial support

      none.
      With great interest we have read the letters by Colli et al
      • Colli A.
      • Fraquelli M.
      • Casazza G.
      Are there any reliable predictors of unreported alcohol consumption in MAFLD patients?.
      and Hagström et al
      • Hagstrom H.
      • Ekstedt M.
      Considerations in the search for under-reported alcohol consumption in NAFLD.
      in response to our study on alcohol intake in non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction – associated fatty liver disease (MAFLD)
      • Staufer K.
      • Huber-Schonauer U.
      • Strebinger G.
      • Pimingstorfer P.
      • Suesse S.
      • Scherzer T.M.
      • et al.
      Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease.
      , and would like to thank the authors for their thoughtful comments.
      The primary intent of our study was to improve the understanding of alcohol intake in presumed NAFLD and MAFLD patients by its systematic assessment using established means while additionally introducing highly sensitive and specific measures of alcohol intake such as ethyl glucuronide in hair (hEtG) and urine (uEtG). These have not been used in the context of fatty liver disease so far, but have been established previously in other clinical contexts, i.e., the liver transplant setting
      • Staufer K.
      • Andresen H.
      • Vettorazzi E.
      • Tobias N.
      • Nashan B.
      • Sterneck M.
      Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption.
      , and forensic contexts. Accurate assessment of alcohol consumption is a prerequisite to accurately diagnose and treat patients. This is particularly important in clinical settings where access to treatment directly correlates with chance of survival (e.g. liver transplant) or patient selection for clinical trials to assess treatment efficacy (e.g. treatment of non-alcohol steatohepatitis, NASH).
      We like to clarify, that in our study direct (uEtG, hEtG) and indirect (mean corpuscular volume, gamma-glutamyl transferase, carbohydrate deficient transferrin) alcohol markers were assessed for their accuracy to detect repeated moderate and excessive alcohol consumption using predefined and pre-established cut-offs. Especially for hEtG cut-off values were used that have been previously established and recommended by the Society of Hair Testing

      Testing SoH. Consensus for the Use of Alcohol Markers in Hair for Assessment of both Abstinence and Chronic Excessive Alcohol Consumption. 2016.

      . The Receiver Operating Characteristic (ROC) curve and the area under the curve (AUC) thus have been calculated treating direct and indirect markers as binary predictors. For a binary predictor the AUC (accounting for ties) is estimated as (sensitivity + specificity) * 0.5
      • Muschelli J.
      ROC and AUC with a Binary Predictor: a Potentially Misleading Metric.
      and has been correctly estimated. While AUC is the most popular ROC index used to compare markers, it cannot detect the difference among two paired markers if their distribution has the same location and differs only in shapes
      • Yin J.
      • Tian L.
      Joint confidence region estimation for area under ROC curve and Youden index.
      ,
      • Yin J.
      • Samawi H.
      • Tian L.
      Joint inference about the AUC and Youden index for paired biomarkers.
      . As the Youden index represents the overall diagnostic accuracy it provides additional information to allow one to compare the overall performance of different markers. Using more than one index to compare markers is recommended
      • Yin J.
      • Tian L.
      Joint confidence region estimation for area under ROC curve and Youden index.
      ,
      • Yin J.
      • Samawi H.
      • Tian L.
      Joint inference about the AUC and Youden index for paired biomarkers.
      . Besides that, we thank the authors for their scrutiny and have revised Table 3 for column permutation accordingly.
      Quantifying the amount of alcohol intake especially in patients with liver disease is challenged by the persistent social stigma that goes along with alcohol-related liver disease fostering under-reporting of alcohol consumption. Especially in clinical settings (outside of the forensic context) where we aim to assess alcohol intake as only or additional risk factor for liver damage, we need to use objective alcohol markers as diagnostic anchor to enable and support frank physician – patient interactions to enable appropriate medical care. Since all alcohol markers including phosphatidyl-ethanol (PEth) like other diagnostic tools may have limitations in diagnostic accuracy
      • Beck O.
      • Mellring M.
      • Lowbeer C.
      • Seferaj S.
      • Helander A.
      Measurement of the alcohol biomarker phosphatidylethanol (PEth) in dried blood spots and venous blood-importance of inhibition of post-sampling formation from ethanol.
      we should be cautious considering them as “the one and only truth”, especially in the context of insurance or employment issues, or when appropriate medical care may be delayed or withheld. In patients where reported alcohol consumption and alcohol marker test results are congruent, diagnostic accuracy cannot be further improved. In patients where alcohol marker test results show higher intake than indicated we need to involve the patient while excluding confounding factors that might have led to false positive results. Although hEtG can be false positive in patients using EtG containing hair treatment or due to heavily impaired kidney function
      • Staufer K.
      • Yegles M.
      Biomarkers for detection of alcohol consumption in liver transplantation.
      , this did not occur in the present study. In contrast, only one patient indicated EtOH consumption > 10g/d, that was detected by uEtG only, but not hEtG.
      In summary, patients with fatty liver disease need a comprehensive diagnostic work-up including sensitive and specific alcohol markers to facilitate appropriate medical care (Suppl Figure 1 in
      • Staufer K.
      • Huber-Schonauer U.
      • Strebinger G.
      • Pimingstorfer P.
      • Suesse S.
      • Scherzer T.M.
      • et al.
      Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease.
      ), and to accurately identify patients eligible for clinical trials on novel therapeutics, especially in the treatment of NASH. We believe that objective alcohol markers could foster de-stigmatization of alcohol intake and alcohol-related liver disease when integrated as part of an empathetic and cooperative physician-patient relation.

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        Are there any reliable predictors of unreported alcohol consumption in MAFLD patients?.
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        Considerations in the search for under-reported alcohol consumption in NAFLD.
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