Biochemical Effects on the Liver of 1 Month of Alcohol Abstinence in Moderate Alcohol Consumers

Biochemical Effects on the Liver of 1 Month of Alcohol Abstinence in Moderate Alcohol Consumers Abstract In this study, 16 moderate alcohol consumers without structural liver disease ceased alcohol intake for 1 month and underwent liver measurements at three time points. Gamma-glutamyl transferase, although within the normal range, decreased significantly after abstinence and increased after the resumption of alcohol consumption. Short summary: In this study in healthy moderate alcohol consumers, we observe that one month of alcohol abstinence results in decreased gamma-glutamyl transferase levels, which return to baseline levels after resumption of alcohol consumption. INTRODUCTION Liver steatosis and inflammation are features of the early stages of alcoholic liver disease, and may ultimately lead to liver fibrosis and cirrhosis. Liver steatosis is frequently present in the general population, particularly in those with metabolic syndrome and obesity, and has been labelled non-alcoholic fatty liver disease (NAFLD) (Younossi et al., 2016). The risk of liver damage from alcohol consumption is dose dependent (Askgaard et al., 2015), but even when consumed in moderation, alcohol contributes to the progression of liver disease in patients with NAFLD (Boyle et al., 2018). Alcohol consumption in the European Union is the highest in the world, with an average of 27 g per adult per day, twice as high as the global average (Laramée et al., 2013). The UK Chief Medical Officer has recently updated the advice on alcohol intake. The advised maximum alcohol intake has been reduced for men from 32 g/day and for women from 24 g/day to 112 g/week for both. The advice also recommends spreading the intake evenly over 3 or more days, and incorporating alcohol-free days into each week (Department of Health, United Kingdom, 2016). The Health Council in the Netherlands has revised its advice from recommending a maximum of 140 g/week to suggesting that it is better not to drink at all (Health Counsil, the Netherlands, 2015). Public and social media initiatives to raise awareness about the health risks associated with alcohol consumption have become increasingly popular. Dry January in the UK, Tournée Minérale in Belgium and IkPas in the Netherlands are examples of public health campaigns challenging people to abstain from alcohol for one month. Total cessation of alcohol consumption is a critical determinant in reducing mortality in alcoholic liver disease, especially when liver cirrhosis is already present (Xie et al., 2014). However, the benefits of short-term abstinence remain largely intuitive, and scientific evidence of these benefits in non-dependent alcohol consumers without established liver disease is scarce. Four weeks of abstinence in patients with alcoholic liver disease has been found to result in a reduction in liver stiffness and improvement in liver biochemistry (Gianni et al., 2017). A recent UK study showed that Dry January resulted in a lower body weight, better glucose homoeostasis and reduced liver stiffness in participants with an average alcohol intake of 252 ± 13 g/week (Mehta et al., 2015). It is unclear whether beneficial effects can be achieved in participants with a moderate alcohol intake (well within the limits set by the guidelines). To this end, we investigated whether one month of alcohol abstinence improves liver health in moderate alcohol consumers. METHODS Design We performed a prospective controlled intervention study from November 2016 to January 2017. Approval was granted by the institutional review board (NL56238.091.15) of the Radboudumc, and all of the participants gave informed consent. Study population The intervention group consisted of 16 adult participants (10 males; 6 females), who had a moderate alcohol intake, with a maximum of 210 g/week. Nine adults who were teetotallers (four males; five females) served as a control group. We excluded patients with established liver disease. Intervention The intervention consisted of 28 days of alcohol abstinence. All of the participants underwent an extensive health evaluation at three time points: before the intervention (T0), directly after the intervention (T4) and at 4-week follow-up (T8). Outcome parameters alcohol intake The participants reported their average alcohol use in the previous month in standard units per week, which were converted to a mean alcohol intake in g/week. One standard unit was estimated at 10 g of pure alcohol. Liver measurements Liver stiffness in kilopascals (kPa) was measured with two modalities: transient elastography (Fibroscan®) and shear wave elastography (Applio 500 Toshiba®) (Friedrich-Rust et al., 2016). Liver fat was measured using computer-aided quantitative ultrasonography (CAUS) on conventional ultrasound images. Liver fat percentage was calculated from residual attenuation (in decibels per centimetre per Megahertz), as previously described (Thijssen et al., 2008; Weijers et al., 2016). The diameter of the abdominal fat layer in millimetres (mm) was measured by ultrasound on the midclavicular line near the seventh intercostal space. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) (all in U/L), ferritin (in ug/L) and carbohydrate deficient transferrin (CDT) (in %) were assayed on automated analysers. Statistical analyses As tests for normal data distribution are inaccurate in a small sample, all analyses were performed with parametric and non-parametric statistics. A two-sided level of P < 0.05 on both tests was considered statistically significant. Data are presented as medians with an interquartile range (IQR: 25th−75th percentile) or as numbers; percentages (n, %), and P-values from the non-parametric tests are shown. The interaction between time and group in terms of liver biochemistry was tested with a multivariate general linear model for repeated measures. All repeated measures within groups were also tested with a paired-samples T-test and Wilcoxon matched-pair signed rank test. Analyses were performed with the SPSS software (version 22; SPSS Inc.; Chicago, IL, USA). RESULTS Group characteristics The intervention group drank a median of 120 g (IQR: 63–120 g) alcohol/week before the intervention, while the control group did not drink any alcohol. The age, gender, body composition and demographics of the two groups were comparable (Table 1). Table 1. Group characteristics baseline   Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS    Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS  Number, percentage, median and IQR (25th −75th percentile) are shown. *Measured with bio-impedance analysis. NS, not significant; P-value >0.05. Table 1. Group characteristics baseline   Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS    Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS  Number, percentage, median and IQR (25th −75th percentile) are shown. *Measured with bio-impedance analysis. NS, not significant; P-value >0.05. Intervention and follow-up All of the participants reported absolute alcohol abstinence during the intervention period. CDT mirrored alcohol consumption and remained unchanged in the controls (T0: 1.39% (1.33–1.45%) and T4 1.35% (1.32–1.48%)). CDT decreased during abstinence (T0: 1.50% (1.29–1.67%) to T4 1.38% (1.22–1.46%), P = 0.008). During the follow-up, participants in the intervention group resumed alcohol consumption, averaging 138 g (IQR: 75–159 g) alcohol/week, a higher intake than before the intervention period. The liver after the intervention The liver measurements of all of the participants at baseline were within the normal range. Liver stiffness (measured with both modalities) and liver fat percentage were similar between and within groups across all time points (Fig. 1A and B). The median thickness of abdominal fat was 18.7 mm (IQR: 13.2–27.0 mm) in the intervention group and 16.2 mm (IQR: 11.2–22.6 mm) in the control group (P = 0.108). The median thickness remained stable within and between groups at T0, T4 and T8 (Fig. 1C). The liver biochemistry values of one participant in the control group exceeded the upper limit of the normal range at all three time points, but the values were included in the final analysis. In the intervention group, GGT decreased from 24.6 U/L (IQR: 20.1–33.1 U/L) at T0 to 21.0 U/L (IQR: 15.6–26.3 U/L) at T4 and rose again to 23.1 U/L (IQR: 20.0–32.4 U/L) at T8 (P = 0.001 and P = 0.010, respectively). The values remained unchanged in the control group; 21.1 U/L (IQR: 15.2–41.1 U/L) at T0; 20.6 U/L (IQR: 15.0–38.5 U/L) at T4; 22.7 U/L (IQR: 15.2–47.2 U/L) at T8 (P = 0.953 and P = 0.441, respectively; Fig. 1D). In a multivariate analysis, time and group interacted significantly with change in GGT at T4 (P = 0.011). AST, ALT and ALP did not change with the intervention, and did not differ between the intervention group and the control group. The laboratory values at all three time points are shown in Supplementary Table S1. The intervention group had higher ferritin levels at baseline than the controls: 106.8 ug/L (IQR: 51.8–281.6 ug/L) vs. 55.5 ug/L (IQR: 21.4–99.9 ug/L), P = 0.027). The intervention did not change the ferritin levels. At T4, the ferritin levels were 86.2 ug/L (IQR: 52.0–307.0 ug/L) in the intervention group, compared to 53.0 ug/L (IQR: 22.0–69.4 ug/L) in the control group, and remained unchanged after four weeks of resumed alcohol consumption (T8): 120.4 ug/L (IQR: 41.0–300.1 ug/L) vs. 39.7 ug/L (IQR: 25.7–78.8 ug/L) (Fig. 1E). Fig. 1. View largeDownload slide Median values with interquartile range of measurements at T0, T4 and T8 are shown for the interventional group (black circles) and controls (open squares). (A) shows liver stiffness (kPa), (B) liver fat percentage (%), (C) thickness of abdominal fat (mm), (D) GGT levels (U/l) and (E) ferritin levels (ug/l). Statistically significant differences of repeated measures of GGT at T4 and T8 in interventional group are stated with corresponding P-values in (D). Fig. 1. View largeDownload slide Median values with interquartile range of measurements at T0, T4 and T8 are shown for the interventional group (black circles) and controls (open squares). (A) shows liver stiffness (kPa), (B) liver fat percentage (%), (C) thickness of abdominal fat (mm), (D) GGT levels (U/l) and (E) ferritin levels (ug/l). Statistically significant differences of repeated measures of GGT at T4 and T8 in interventional group are stated with corresponding P-values in (D). DISCUSSION We found that one month of abstinence from alcohol resulted in a significant decrease in GGT levels in a group of moderate alcohol consumers. Resumption of moderate alcohol consumption resulted in a return to the values seen at baseline. All of the observed changes were within the range of normal values, but the effect size was larger in two participants with a higher alcohol intake (120 g/week). It is tempting to speculate that GGT might serve as a biomarker of abstinence. GGT is an important factor in maintaining high concentrations of glutathione—a strong mitochondrial anti-oxidant—in the liver tissue during oxidative stress (Whitfield, 2001). GGT increases with increasing alcohol intake. With the enzymatic conversion of alcohol to acetaldehyde, reactive oxygen species (ROS) are released in the liver (van Beek et al., 2014). Both acetaldehyde and ROS are toxic to hepatocytes, and are associated with oxidative stress and cell death (Ajakaiye et al., 2011). The decrease in GGT observed in this study, albeit modest in absolute numbers, most likely reflects reduced oxidative stress. Measurements of liver stiffness and liver fat percentage remained unchanged after alcohol cessation. This contrasts with the reduction in liver stiffness found in a UK study (Mehta et al., 2015), although in comparison with our study, participants had a higher alcohol intake at baseline and a higher degree of hepatic steatosis. It is possible that elastography lacks the sensitivity to detect small but relevant changes in liver architecture that result from alcohol cessation in moderate consumers. Such early changes may be reflected by GGT levels (Whitfield, 2001). The design of this study has several limitations. First, both groups were small, and the number of participants and distribution of data per group differed, possibly affecting the statistical analyses between groups. Nonetheless, significant differences were already present immediately after the intervention in the small intervention group, suggesting that the results would withstand scrutiny in larger studies. The use of a control group with stable measurements at the different time points reduces the risk of measurement intravariability as an explanation for the observed differences. Secondly, we could not correct for all possible confounders during the intervention, such as diet and lifestyle changes. The participants did not report changes in physical activity, but it is possible that alcohol abstinence is associated with an (unreported) improved life style. We did not add a third group that did not cease moderate drinking, as this was a pilot study. A follow-up study with randomization of the intervention and larger numbers of participants is needed to confirm our results. Finally, alcohol intake was self-reported by the participants, possibly leading to recall bias. As the participants acted as their own controls in our within-subject repeated measures design, changes in reports may be more important than the accuracy of reports. Framing our findings from a societal perspective. The scientific evidence that alcohol significantly impairs health, even in low volumes, is irrefutable (Stockwell et al., 2016). Nonetheless, alcohol consumption remains deeply anchored within the culture of European societies. More than three quarters of European citizens consume alcohol on a regular basis, resulting in a total annual health burden of 125 billion Euros (Laramée et al., 2013). The efficacy of public warning campaigns is limited, although promising initiatives have been launched (Hassan and Shiu, 2018). Increasing taxes, restrictions on the sale of alcohol and bans on alcohol advertising may be cost-effective measures to reduce alcohol consumption (Anderson et al., 2012). Lifestyle interventions such as Dry January have been shown to have both short-term and long-lasting effects (de Visser et al., 2016, 2017). The positive message of the possibility of improving liver health through abstinence could be advocated by policy makers to meet the challenge of reducing the societal burden of alcohol consumption. In conclusion, we found that 1 month of alcohol abstinence resulted in a decrease in GGT (within the normal range) in moderate alcohol consumers without apparent pre-existing liver damage. SUPPLEMENTARY MATERIAL Supplementary data are available at Alcohol And Alcoholism online ACKNOWLEDGEMENTS We would like to thank Rebecca van Veen and Denise Janssen-Bell for performing ultrasounds. Conflict of Interest Statement None declared. REFERENCES Ajakaiye M, Jacob A, Wu R, et al.  . ( 2011) Alcohol and hepatocyte-Kupffer cell interaction (review). Mol Med Rep  4: 597– 602. Google Scholar PubMed  Anderson P, Moller L, Galea G. ( 2012) Alcohol in the European Union. Consumption, Harm and Policy Approaches . World Health Organization, Copenhagen, Denmark. http://www.euro.who.int/__data/assets/pdf_file/0003/160680/e96457.pdf. Askgaard G, Gronbaek M, Kjaer MS, et al.  . ( 2015) Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study. J Hepatol  62: 1061– 7. Google Scholar CrossRef Search ADS PubMed  Boyle M, Masson S, Anstee QM. ( 2018) The bidirectional impacts of alcohol consumption and the metabolic syndrome: cofactors for progressive fatty liver disease. J Hepatol  68: 251– 67. Google Scholar CrossRef Search ADS PubMed  de Visser RO, Robinson E, Bond R. ( 2016) Voluntary temporary abstinence from alcohol during ‘Dry January’ and subsequent alcohol use. Health Psychol  35: 281– 89. Google Scholar CrossRef Search ADS PubMed  de Visser RO, Robinson E, Smith T, et al.  . ( 2017) The growth of ‘Dry January’: promoting participation and the benefits of participation. Eur J Public Health  27: 929– 31. Google Scholar CrossRef Search ADS PubMed  Department of Health, United Kingdom ( 2016) UK Chief Medical Officers’ Low Risk Drinking Guidelines. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/545937/UK_CMOs__report.pdf Friedrich-Rust M, Poynard T, Castera L. ( 2016) Critical comparison of elastography methods to assess chronic liver disease. Nat Rev Gastroenterol Hepatol  13: 402– 11. Google Scholar CrossRef Search ADS PubMed  Gianni E, Forte P, Galli V, et al.  . ( 2017) Prospective evaluation of liver stiffness using transient elastography in alcoholic patients following abstinence. Alcohol Alcoho  52: 42– 7. Google Scholar CrossRef Search ADS   Hassan L, Shiu E. ( 2018) Communicating messages about drinking. Alcohol Alcohol  53: 1– 2. Google Scholar CrossRef Search ADS PubMed  Health Counsil, the Netherlands ( 2015) Guideline Healthy Food Consumption. https://www.gezondheidsraad.nl/sites/default/files/201524_richtlijnen_goede_voeding_2015.pdf Laramée P, Kusel J, Leonard S, et al.  . ( 2013) The economic burden of alcohol dependence in Europe. Alcohol Alcohol  48: 259– 69. Google Scholar CrossRef Search ADS PubMed  Mehta G, MacDonald S, Maurice J, et al.  . ( 2015) Short term abstinence from alcohol improves insulin resistance and fatty liver phenotype in moderate drinkers. Hepatology  62: 267A. Stockwell T, Zhao J, Panwar S, et al.  . ( 2016) Do ‘Moderate’ drinkers have reduced mortality risk? A systematic review and meta-analysis of alcohol consumption and all-cause mortality. J Stud Alcohol Drugs  77: 185– 98. Google Scholar CrossRef Search ADS PubMed  Thijssen JM, Starke A, Weijers G, et al.  . ( 2008) Computer-aided B-mode ultrasound diagnosis of hepatic steatosis: a feasibility study. IEEE Trans Ultrason Ferroelectr Freq Control  55: 1343– 54. Google Scholar CrossRef Search ADS PubMed  van Beek JHDA, de Moor MHM, Geels LM, et al.  . ( 2014) The association of alcohol intake with gamma-glutamyl transferase (GGT) levels: evidence for correlated genetic effects. Drug Alcohol Depend  134: 99– 105. Google Scholar CrossRef Search ADS PubMed  Weijers G, Wanten G, Thijssen JM, et al.  . ( 2016) Quantitative ultrasound for staging of hepatic steatosis in patients on home parenteral nutrition validated with magnetic resonance spectroscopy: a feasibility study. Ultrasound Med Biol  42: 637– 44. Google Scholar CrossRef Search ADS PubMed  Whitfield JB. ( 2001) Gamma glutamyl transferase. Crit Rev Clin Lab Sci  38: 263– 355. Google Scholar CrossRef Search ADS PubMed  Xie YD, Feng B, Gao Y, et al.  . ( 2014) Effect of abstinence from alcohol on survival of patients with alcoholic cirrhosis: a systematic review and meta-analysis. Hepatol Res  44: 436– 49. Google Scholar CrossRef Search ADS PubMed  Younossi ZM, Koenig AB, Abdelatif D, et al.  . ( 2016) Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatol  64: 73– 84. Google Scholar CrossRef Search ADS   © The Author(s) 2018. Medical Council on Alcohol and Oxford University Press. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Alcohol and Alcoholism Oxford University Press

Biochemical Effects on the Liver of 1 Month of Alcohol Abstinence in Moderate Alcohol Consumers

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Abstract

Abstract In this study, 16 moderate alcohol consumers without structural liver disease ceased alcohol intake for 1 month and underwent liver measurements at three time points. Gamma-glutamyl transferase, although within the normal range, decreased significantly after abstinence and increased after the resumption of alcohol consumption. Short summary: In this study in healthy moderate alcohol consumers, we observe that one month of alcohol abstinence results in decreased gamma-glutamyl transferase levels, which return to baseline levels after resumption of alcohol consumption. INTRODUCTION Liver steatosis and inflammation are features of the early stages of alcoholic liver disease, and may ultimately lead to liver fibrosis and cirrhosis. Liver steatosis is frequently present in the general population, particularly in those with metabolic syndrome and obesity, and has been labelled non-alcoholic fatty liver disease (NAFLD) (Younossi et al., 2016). The risk of liver damage from alcohol consumption is dose dependent (Askgaard et al., 2015), but even when consumed in moderation, alcohol contributes to the progression of liver disease in patients with NAFLD (Boyle et al., 2018). Alcohol consumption in the European Union is the highest in the world, with an average of 27 g per adult per day, twice as high as the global average (Laramée et al., 2013). The UK Chief Medical Officer has recently updated the advice on alcohol intake. The advised maximum alcohol intake has been reduced for men from 32 g/day and for women from 24 g/day to 112 g/week for both. The advice also recommends spreading the intake evenly over 3 or more days, and incorporating alcohol-free days into each week (Department of Health, United Kingdom, 2016). The Health Council in the Netherlands has revised its advice from recommending a maximum of 140 g/week to suggesting that it is better not to drink at all (Health Counsil, the Netherlands, 2015). Public and social media initiatives to raise awareness about the health risks associated with alcohol consumption have become increasingly popular. Dry January in the UK, Tournée Minérale in Belgium and IkPas in the Netherlands are examples of public health campaigns challenging people to abstain from alcohol for one month. Total cessation of alcohol consumption is a critical determinant in reducing mortality in alcoholic liver disease, especially when liver cirrhosis is already present (Xie et al., 2014). However, the benefits of short-term abstinence remain largely intuitive, and scientific evidence of these benefits in non-dependent alcohol consumers without established liver disease is scarce. Four weeks of abstinence in patients with alcoholic liver disease has been found to result in a reduction in liver stiffness and improvement in liver biochemistry (Gianni et al., 2017). A recent UK study showed that Dry January resulted in a lower body weight, better glucose homoeostasis and reduced liver stiffness in participants with an average alcohol intake of 252 ± 13 g/week (Mehta et al., 2015). It is unclear whether beneficial effects can be achieved in participants with a moderate alcohol intake (well within the limits set by the guidelines). To this end, we investigated whether one month of alcohol abstinence improves liver health in moderate alcohol consumers. METHODS Design We performed a prospective controlled intervention study from November 2016 to January 2017. Approval was granted by the institutional review board (NL56238.091.15) of the Radboudumc, and all of the participants gave informed consent. Study population The intervention group consisted of 16 adult participants (10 males; 6 females), who had a moderate alcohol intake, with a maximum of 210 g/week. Nine adults who were teetotallers (four males; five females) served as a control group. We excluded patients with established liver disease. Intervention The intervention consisted of 28 days of alcohol abstinence. All of the participants underwent an extensive health evaluation at three time points: before the intervention (T0), directly after the intervention (T4) and at 4-week follow-up (T8). Outcome parameters alcohol intake The participants reported their average alcohol use in the previous month in standard units per week, which were converted to a mean alcohol intake in g/week. One standard unit was estimated at 10 g of pure alcohol. Liver measurements Liver stiffness in kilopascals (kPa) was measured with two modalities: transient elastography (Fibroscan®) and shear wave elastography (Applio 500 Toshiba®) (Friedrich-Rust et al., 2016). Liver fat was measured using computer-aided quantitative ultrasonography (CAUS) on conventional ultrasound images. Liver fat percentage was calculated from residual attenuation (in decibels per centimetre per Megahertz), as previously described (Thijssen et al., 2008; Weijers et al., 2016). The diameter of the abdominal fat layer in millimetres (mm) was measured by ultrasound on the midclavicular line near the seventh intercostal space. Gamma-glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) (all in U/L), ferritin (in ug/L) and carbohydrate deficient transferrin (CDT) (in %) were assayed on automated analysers. Statistical analyses As tests for normal data distribution are inaccurate in a small sample, all analyses were performed with parametric and non-parametric statistics. A two-sided level of P < 0.05 on both tests was considered statistically significant. Data are presented as medians with an interquartile range (IQR: 25th−75th percentile) or as numbers; percentages (n, %), and P-values from the non-parametric tests are shown. The interaction between time and group in terms of liver biochemistry was tested with a multivariate general linear model for repeated measures. All repeated measures within groups were also tested with a paired-samples T-test and Wilcoxon matched-pair signed rank test. Analyses were performed with the SPSS software (version 22; SPSS Inc.; Chicago, IL, USA). RESULTS Group characteristics The intervention group drank a median of 120 g (IQR: 63–120 g) alcohol/week before the intervention, while the control group did not drink any alcohol. The age, gender, body composition and demographics of the two groups were comparable (Table 1). Table 1. Group characteristics baseline   Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS    Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS  Number, percentage, median and IQR (25th −75th percentile) are shown. *Measured with bio-impedance analysis. NS, not significant; P-value >0.05. Table 1. Group characteristics baseline   Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS    Intervention (n = 16)  Controls (n = 9)  P-value  Gender (n, % male)  10 (62.5)  4 (44.4)  NS  Age (years)  55 (IQR: 42–64)  58 (IQR: 26–61)  NS  Alcohol (g/week)  120 (IQR: 63–120)  0  <0.001  Alcohol frequency (days/week)  3 (IQR: 3–4)  0  <0.001  -Smokers (n, % current/past)  2 (12.5)/10 (62.5)  0/4 (44.4)    Comorbiditity (n, %)  6 (37.5)  3 (33.3)  NS  -Cardiovascular/Diabetes  3 (50.0)  2 (66.7)    -Other  3 (50.0)  1 (33.3)    -BMI  24.3 (IQR: 22.6–27.2)  22.3 (IQR: 19.7–26.9)  NS  -Mean arterial blood pressure (mmHg)  93.7 (IQR: 86.0–98.9)  75.3 (IQR: 67.8–98.8)  NS  -Body fat (%)*  27.9 (IQR: 24.1–32.6)  30.2 (21.9–36.7)  NS  -Highest education (% college degree)  13 (81.3)  9 (100)  NS  -Family situation (% household with partner)  14 (87.5)  7 (77.8)  NS  -Employment (% employed/retired)  13 (81.3)/2 (12.5)  6 (66.7)/2 (22.2)  NS  Number, percentage, median and IQR (25th −75th percentile) are shown. *Measured with bio-impedance analysis. NS, not significant; P-value >0.05. Intervention and follow-up All of the participants reported absolute alcohol abstinence during the intervention period. CDT mirrored alcohol consumption and remained unchanged in the controls (T0: 1.39% (1.33–1.45%) and T4 1.35% (1.32–1.48%)). CDT decreased during abstinence (T0: 1.50% (1.29–1.67%) to T4 1.38% (1.22–1.46%), P = 0.008). During the follow-up, participants in the intervention group resumed alcohol consumption, averaging 138 g (IQR: 75–159 g) alcohol/week, a higher intake than before the intervention period. The liver after the intervention The liver measurements of all of the participants at baseline were within the normal range. Liver stiffness (measured with both modalities) and liver fat percentage were similar between and within groups across all time points (Fig. 1A and B). The median thickness of abdominal fat was 18.7 mm (IQR: 13.2–27.0 mm) in the intervention group and 16.2 mm (IQR: 11.2–22.6 mm) in the control group (P = 0.108). The median thickness remained stable within and between groups at T0, T4 and T8 (Fig. 1C). The liver biochemistry values of one participant in the control group exceeded the upper limit of the normal range at all three time points, but the values were included in the final analysis. In the intervention group, GGT decreased from 24.6 U/L (IQR: 20.1–33.1 U/L) at T0 to 21.0 U/L (IQR: 15.6–26.3 U/L) at T4 and rose again to 23.1 U/L (IQR: 20.0–32.4 U/L) at T8 (P = 0.001 and P = 0.010, respectively). The values remained unchanged in the control group; 21.1 U/L (IQR: 15.2–41.1 U/L) at T0; 20.6 U/L (IQR: 15.0–38.5 U/L) at T4; 22.7 U/L (IQR: 15.2–47.2 U/L) at T8 (P = 0.953 and P = 0.441, respectively; Fig. 1D). In a multivariate analysis, time and group interacted significantly with change in GGT at T4 (P = 0.011). AST, ALT and ALP did not change with the intervention, and did not differ between the intervention group and the control group. The laboratory values at all three time points are shown in Supplementary Table S1. The intervention group had higher ferritin levels at baseline than the controls: 106.8 ug/L (IQR: 51.8–281.6 ug/L) vs. 55.5 ug/L (IQR: 21.4–99.9 ug/L), P = 0.027). The intervention did not change the ferritin levels. At T4, the ferritin levels were 86.2 ug/L (IQR: 52.0–307.0 ug/L) in the intervention group, compared to 53.0 ug/L (IQR: 22.0–69.4 ug/L) in the control group, and remained unchanged after four weeks of resumed alcohol consumption (T8): 120.4 ug/L (IQR: 41.0–300.1 ug/L) vs. 39.7 ug/L (IQR: 25.7–78.8 ug/L) (Fig. 1E). Fig. 1. View largeDownload slide Median values with interquartile range of measurements at T0, T4 and T8 are shown for the interventional group (black circles) and controls (open squares). (A) shows liver stiffness (kPa), (B) liver fat percentage (%), (C) thickness of abdominal fat (mm), (D) GGT levels (U/l) and (E) ferritin levels (ug/l). Statistically significant differences of repeated measures of GGT at T4 and T8 in interventional group are stated with corresponding P-values in (D). Fig. 1. View largeDownload slide Median values with interquartile range of measurements at T0, T4 and T8 are shown for the interventional group (black circles) and controls (open squares). (A) shows liver stiffness (kPa), (B) liver fat percentage (%), (C) thickness of abdominal fat (mm), (D) GGT levels (U/l) and (E) ferritin levels (ug/l). Statistically significant differences of repeated measures of GGT at T4 and T8 in interventional group are stated with corresponding P-values in (D). DISCUSSION We found that one month of abstinence from alcohol resulted in a significant decrease in GGT levels in a group of moderate alcohol consumers. Resumption of moderate alcohol consumption resulted in a return to the values seen at baseline. All of the observed changes were within the range of normal values, but the effect size was larger in two participants with a higher alcohol intake (120 g/week). It is tempting to speculate that GGT might serve as a biomarker of abstinence. GGT is an important factor in maintaining high concentrations of glutathione—a strong mitochondrial anti-oxidant—in the liver tissue during oxidative stress (Whitfield, 2001). GGT increases with increasing alcohol intake. With the enzymatic conversion of alcohol to acetaldehyde, reactive oxygen species (ROS) are released in the liver (van Beek et al., 2014). Both acetaldehyde and ROS are toxic to hepatocytes, and are associated with oxidative stress and cell death (Ajakaiye et al., 2011). The decrease in GGT observed in this study, albeit modest in absolute numbers, most likely reflects reduced oxidative stress. Measurements of liver stiffness and liver fat percentage remained unchanged after alcohol cessation. This contrasts with the reduction in liver stiffness found in a UK study (Mehta et al., 2015), although in comparison with our study, participants had a higher alcohol intake at baseline and a higher degree of hepatic steatosis. It is possible that elastography lacks the sensitivity to detect small but relevant changes in liver architecture that result from alcohol cessation in moderate consumers. Such early changes may be reflected by GGT levels (Whitfield, 2001). The design of this study has several limitations. First, both groups were small, and the number of participants and distribution of data per group differed, possibly affecting the statistical analyses between groups. Nonetheless, significant differences were already present immediately after the intervention in the small intervention group, suggesting that the results would withstand scrutiny in larger studies. The use of a control group with stable measurements at the different time points reduces the risk of measurement intravariability as an explanation for the observed differences. Secondly, we could not correct for all possible confounders during the intervention, such as diet and lifestyle changes. The participants did not report changes in physical activity, but it is possible that alcohol abstinence is associated with an (unreported) improved life style. We did not add a third group that did not cease moderate drinking, as this was a pilot study. A follow-up study with randomization of the intervention and larger numbers of participants is needed to confirm our results. Finally, alcohol intake was self-reported by the participants, possibly leading to recall bias. As the participants acted as their own controls in our within-subject repeated measures design, changes in reports may be more important than the accuracy of reports. Framing our findings from a societal perspective. The scientific evidence that alcohol significantly impairs health, even in low volumes, is irrefutable (Stockwell et al., 2016). Nonetheless, alcohol consumption remains deeply anchored within the culture of European societies. More than three quarters of European citizens consume alcohol on a regular basis, resulting in a total annual health burden of 125 billion Euros (Laramée et al., 2013). The efficacy of public warning campaigns is limited, although promising initiatives have been launched (Hassan and Shiu, 2018). Increasing taxes, restrictions on the sale of alcohol and bans on alcohol advertising may be cost-effective measures to reduce alcohol consumption (Anderson et al., 2012). Lifestyle interventions such as Dry January have been shown to have both short-term and long-lasting effects (de Visser et al., 2016, 2017). The positive message of the possibility of improving liver health through abstinence could be advocated by policy makers to meet the challenge of reducing the societal burden of alcohol consumption. In conclusion, we found that 1 month of alcohol abstinence resulted in a decrease in GGT (within the normal range) in moderate alcohol consumers without apparent pre-existing liver damage. SUPPLEMENTARY MATERIAL Supplementary data are available at Alcohol And Alcoholism online ACKNOWLEDGEMENTS We would like to thank Rebecca van Veen and Denise Janssen-Bell for performing ultrasounds. Conflict of Interest Statement None declared. REFERENCES Ajakaiye M, Jacob A, Wu R, et al.  . ( 2011) Alcohol and hepatocyte-Kupffer cell interaction (review). Mol Med Rep  4: 597– 602. Google Scholar PubMed  Anderson P, Moller L, Galea G. ( 2012) Alcohol in the European Union. Consumption, Harm and Policy Approaches . 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Alcohol and AlcoholismOxford University Press

Published: May 3, 2018

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