LIVER TRANSPLANTATION 18:1310-1315, 2012

ORIGINAL ARTICLE

Detection of Alcohol Consumption in Patients with Alcoholic Liver Cirrhosis During the Evaluation Process for Liver Transplantation Johann-Martin Hempel,1 Gertrud Greif-Higer,1 Thomas Kaufmann,2 and Manfred E. Beutel1 Departments of 1Psychosomatic Medicine and Psychotherapy, and 2Forensic Medicine, University Hospital of Mainz, Mainz, Germany

Alcoholic liver cirrhosis (ALC) is a commonly accepted indication for liver transplantation (LT). Any alcohol consumption is considered a contraindication for LT. However, the assessment of abstinence in everyday practice mostly relies on patient self-reporting, which must be considered highly unreliable. After consumption, ethanol is eliminated by alcohol dehydrogenase, with methanol accumulating in the blood. Methanol, which is known to be a sensitive and specific indicator for recent alcohol consumption, has not been used for verifying alcohol consumption in LT assessments yet. Therefore, the purpose of this study was to test the feasibility of using methanol testing to identify recent alcohol consumption in LT candidates during routine and short-notice appointments. We compared methanol and ethanol measurements with self-reported alcohol consumption for 41 patients with ALC during the evaluation process before they were accepted onto the waiting list. In 32 of the 92 blood samples drawn from these 41 patients during the study, a relapse was detected by the methanol test. Both the ethanol test results and the self-reported data were positive in only 3 cases. Thus, the methanol test identified 29 additional cases of alcohol consumption. Furthermore, the methanol test discovered recent alcohol consumption in 5 of 10 transplant patients when both self-reported data and ethanol test results were negative. As a part of blood alcohol analysis, the methanol test is more sensitive than self-reporting and ethanol testing for the detection of recent alcohol consumption. Also, short-notice appointments for blood alcohol analysis reveal more cases of alcohol relapse than routine, long-term appointments. The measurement of methanol as a sensitive screening test for recent alcohol consumption should be implemented both in law and in daily, routine practice. Liver Transpl 18:1310-1315, 2012. V 2012 AASLD. C

Received November 9, 2011; accepted May 4, 2012.

See Editorial on Page 1267 Alcoholic liver cirrhosis (ALC) is a commonly accepted indication for liver transplantation (LT). If these patients remain abstinent, their prognosis is superior to that of patients with liver cirrhosis of other etiologies. However, continued alcohol consumption is considered an absolute contraindication for LT.1-4 Therefore, the high percentages of relapse cases before LT (19%-50%)5,6 and after LT (11%-80%)7-20 pose a serious problem.21-25 To ensure abstinence by the patient, a strict and systematic investigation is required. In everyday practice, however, no reliable methods are available for testing absti-

nence: neither self-reporting nor conventional indicators for alcohol consumption (eg, blood ethanol) can confirm or exclude recent alcohol intake with sufficient reliability. Recent studies using ethyl glucuronide have provided promising results.6,26 For obvious reasons, selfreporting is not reliable because the denial of alcohol consumption is a typical symptom of addictive behavior. Because of its short half-life and increased elimination in alcoholics, ethanol is also an unreliable method of testing.8,27-29 Since the 1980s, blood alcohol analysis has been established in forensic medicine for testing the blood levels of ethanol and other alcohols (eg, methanol, propanol-2, and acetone). Methanol is part of almost

Abbreviations: ADH, alcohol dehydrogenase; ALC, alcoholic liver cirrhosis; LT, liver transplantation; SEC, serum ethanol concentration; SMC, serum methanol concentration; T0, time 0; T1, time 1; T2, time 2. Address reprint requests to Johann-Martin Hempel, M.D., Department of Psychosomatic Medicine and Psychotherapy, University Hospital of Mainz, Langenbeckstrasse 1, Mainz, Germany D-55131. Tel: þ49 6131 176777; E-mail: [email protected] DOI 10.1002/lt.23468 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

C 2012 American Association for the Study of Liver Diseases. V

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every alcoholic beverage in different concentrations. Also, methanol is produced by the body only at very low concentrations. The serum methanol concentration (SMC) may be increased only moderately (up to a factor of 2) after the consumption of large quantities of fruits and products containing pectin.30 The normal endogenous SMC is approximately 0.95 6 0.45 mg/L. If the serum ethanol concentration (SDC) exceeds 0.2 to 0.5 mg/L, methanol cannot be eliminated by alcohol dehydrogenase (ADH) because of the competitive inhibition of ethanol. Therefore, methanol accumulates after a certain delay and can be detected in the blood of patients. If the SEC drops below 0.2 to 0.5 mg/L, methanol begins to be catabolized by ADH, and it can be detected up to 48 hours after alcohol consumption. The information gained from blood alcohol analysis goes beyond simple proof of alcohol consumption; depending on the duration of alcohol ingestion and the serum concentration of several alcohol metabolites, conclusions can also be drawn about the time of alcohol ingestion and the type of alcoholic beverage.30-33 The feasibility of blood alcohol analysis in routine clinical practice was investigated in a previous crosssectional field study over a period of 3 years (G.G.H. and T.K., 2004–2007).34,35 In that study, 309 patients with or without a background of alcoholism underwent a blood alcohol analysis at our clinic so that we could compare the results of the ethanol test with the results of the methanol test. The methanol test was positive for 142 of the 594 specimens (23.9%), whereas the ethanol test was positive for only 22 specimens (3.7%). This glaring difference indicated the feasibility and sensitivity of the methanol test not only for forensic use but also for routine clinical practice. The purpose of this prospective field study was to test the applicability of the methanol test for identifying recent alcohol consumption in LT candidates. Therefore, we compared methanol and ethanol measurements with self-reported alcohol consumption.

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a complete physical examination, a routine laboratory test, and an analysis of blood alcohol metabolites such as ethanol, methanol, propanol-2, and acetone. Each patient’s mental health and alcohol consumption were assessed in detail with a semistructured interview by a mental health professional who specialized in psychosomatic medicine and addiction. The consumption of large quantities of fruit was precisely questioned, documented, and eliminated in all cases. 2. Time 1 (T1). This routine control appointment was arranged at the LT clinic while the patient either was still being evaluated or was already on the waiting list for LT. This appointment included a quick physical examination, standard laboratory tests, and blood alcohol analysis. Alcohol consumption was precisely questioned and documented. The consumption of large quantities of fruit was precisely questioned, documented, and eliminated in all cases. 3. Time 2 (T2). This surprise appointment required patients to show up within 48 hours so that they would be unable to stop drinking in advance of the examination and avoid being caught in the act. The T2 appointment included the same measures followed during the T1 appointment.

Dropouts Altogether, 21 consecutive patients attended all 3 appointments. There were 20 dropouts: 7 patients who died, 9 patients who underwent LT before the study’s completion, 1 patient who underwent transplantation and died afterward, and 3 noncompliant patients who did not show up for appointments. Therefore, we had 41 patients at T0, 30 patients at T1, and 21 patients at T2.

Materials

PATIENTS AND METHODS This study was designed as a prospective field study.

Subjects We recruited 41 consecutive patients (12 females and 29 males) who were diagnosed with ALC either alone or in combination with hepatitis B or C or hepatocellular carcinoma; the median age was 53 years. All patients were included in the study at the beginning of the evaluation process before they were assigned to the waiting list for LT.

Process/Follow-Up There were 3 appointments: 1. Time 0 (T0). This appointment was held at the beginning of the evaluation process and included

We analyzed a total of 92 blood specimens and related self-reports. Because of the dropouts, we analyzed the results of the 21 patients who completed all 3 assessments in order to prevent bias in the test results, to allow a follow-up study of single patients, and to be able to compare the examination methods in each case. Because the specimens were analyzed at the Institute of Forensic Medicine (Johannes Gutenberg University, Mainz, Germany), we received the test results after some delay.

Technique From every patient, we collected 2 blood samples in serum tubes. For the blood alcohol analysis, we used a high-resolution headspace gas chromatography system developed by Bonte and modified by Wolf et al.36,37

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TABLE 1. All Methanol and Ethanol Test Results

TABLE 2. All Methanol Test Results and Self-Reported Alcohol Consumption

Methanol Test

Ethanol test Sum

Negative Positive

Negative

Positive

Sum

60 (65) 0 (0) 60 (65)

29 (32) 3 (3) 32 (35)

89 (97) 3 (3) 92 (100)

NOTE: The data are presented as numbers and percentages. All percentages are based on the total number of blood samples (n ¼ 92).

Methanol Test

Selfreport Sum

Negative Positive

Negative

Positive

Sum

58 (63) 2 (2) 60 (65)

31 (34) 1 (1) 32 (35)

89 (97) 3 (3) 92 (100)

NOTE: The data are presented as numbers and percentages. All percentages are based on the total number of blood samples (n ¼ 92).

Ethanol The ethanol test was considered positive when any quantity of ethanol was detected.

Methanol Considering the elimination kinetics of methanol published in the literature, we developed a 3-step model for determining a positive result from the methanol test led by Kaufmann: 1. All results with an SMC < 1.5 mg/L were interpreted to be negative because acute alcohol intake could not be proven reliably. 2. All results with an SMC of 1.5 to 2.99 mg/L strongly indicated recent alcohol consumption. The methanol test was considered positive if other factors that could increase SMC (eg, the consumption of large quantities of fruit or other products containing pectin) were excluded by the medical history. 3. With an SMC
3 mg/L, the methanol test was regarded to be highly positive, and the intake of alcohol was considered proven.

Figure 1. Self-reported alcohol consumption and results of ethanol and methanol tests for 21 assessed patients.

Self-Report

RESULTS

We used the Alcohol Use Disorders Identification Test–Consumption,38 which is a reliable and valid measure for examining the exact frequency and quantity of alcohol consumption.39 At T0, alcohol consumption self-reporting was considered positive if the last ingestion of alcohol occurred within the last 48 hours.

Comparison of Methanol and Ethanol Test Results and Self-Reported Alcohol Consumption

Ethics All patients provided informed consent for blood testing by blood alcohol analysis. They were assured that the results would not have an impact on their listing for LT. The experimental procedures were approved a priori by the ethics committee of the Statutory Physician Board of Rhineland-Palatine.

Statistics For statistical evaluations, we used SPSS 17.0 (IBM, Armonk, NY) with McNemar’s test and the j concordance index.

As Table 1 shows, the methanol test was positive for 32 of the 92 cases (35%). The ethanol test was positive for only 3 of the 92 cases (3%); these 3 cases were also identified by the methanol test. Thus, in 29 of the 92 cases, the methanol test revealed alcohol consumption that could not be proven by the ethanol test (P < 0.001 by McNemar’s test). Table 2 compares the methanol test results and self-reported alcohol consumption. According to the self-reports, only 3 of the 92 cases (3%) were positive. One of these patients was captured by the methanol test. In 2 cases, when alcohol had been consumed more than 48 hours previously, the methanol test was negative. The methanol test was positive for 32 of the 92 cases (35%). Thus, in 31 of the 92 cases, the methanol test revealed alcohol consumption that could not be proven by self-reporting (P < 0.001 by McNemar’s test).

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TABLE 3. Transplant Patients (n 5 10): Comparison of Test Results From Routine Appointments (T0 and T1) and Short-Notice Appointments (T2) T0 Appointment Patient Number 3 8 10 17 18 21 24 29 30 32

Self-Report

T1 Appointment Self-Report

T2 Appointment Self-Report

and Ethanol

Methanol

and Ethanol

Methanol

and Ethanol

Methanol

Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative

Positive Negative Negative Negative Negative Positive Positive Negative Positive Negative

Negative Negative Negative Negative Negative LT LT Negative LT LT

Negative Negative Negative Negative Negative LT LT Negative LT Deceased

Negative LT Negative LT Negative LT LT LT LT Deceased

Positive LT Negative LT Positive LT LT LT LT Deceased

Analysis of 21 Consecutively Assessed Patients Figure 1 shows the self-report, ethanol test, and methanol test results for these 21 patients at the 3 measurement points. At T0, there were no positive self-reports, the ethanol test was positive in 2 cases, and the methanol test was positive in 5 cases. At T1, 2 self-reports were positive, the ethanol test was negative in all cases, and the methanol test was positive in 6 cases. At T2, there was positive self-report, the ethanol test was negative in all cases, and the methanol test was positive in 11 cases. Altogether, the methanol test revealed alcohol consumption at T0 in 3 patients, at T1 in 4 patients, and at T2 in 10 patients who were identified by neither self-reporting nor ethanol testing.

Analysis of 10 Transplant Patients The group of 10 patients who underwent transplantation during the course of this study deserves closer attention. As Table 3 shows, none of these patients indicated alcohol consumption in their self-reports, and there was not a single positive ethanol test; however, the methanol test proved alcohol consumption in 5 patients: 1 of these patients (patient 3) even tested positive twice. Also, in comparison with routine, longterm appointments, the short-notice appointments for blood alcohol analysis revealed 2 cases of alcohol relapse (patients 3 and 18).

DISCUSSION This study has demonstrated that as a part of blood alcohol analysis, the methanol test is more sensitive than the methods used hitherto for monitoring abstinence and drinking in patients with ALC before LT, even when the patients are explicitly advised about the testing procedure. The methanol test revealed considerably more relapses (32 versus 3) than self-reporting and ethanol testing at all 3 appointments.

As for the 21 patients who were assessed consecutively at all 3 appointments, it was shown in daily practice that a surprise control appointment revealed more relapses than routine appointments (11 at T2, 5 at T0, and 6 at T1). The patients could suspend drinking for a few days before routine visits to prevent the detection of blood alcohol. In accordance with the study protocol, a positive methanol test result did not have an impact on listing. This may also be a reason for the fairly high rate of identified relapses. Our study population did not contain a specific control group. Also, the methanol test does not have 100% sensitivity and specificity. Therefore, our test results need to be validated in more studies before this test becomes a part of standard practice. However, as our study has proved, the methanol test can lead to the better detection of alcohol relapse and better monitoring of abstinence in patients with ALC who are awaiting LT. The methanol test also provides important hints to the staff about the need for addiction therapy for the underlying condition of alcoholism. The requirement of abstinence from alcohol for the successful treatment of ALC is reflected in LT legislation and in the specifications of the guidelines of the German Medical Association, which defines alcohol dependency as a contraindication for LT. Given the shortage of donor organs for LT and the unfavorable prognosis of patients who relapse after LT, we have an obligation to monitor the abstinence of patients more closely. In conclusion, using objective measurements of methanol, we found a disturbingly high rate of noncompliance with abstinence that contradicted patients’ self-reports, short-lived ethanol measurements, and the assessment of an experienced addiction professional. Therefore, we must assume that there is a high rate of active concealment. Given the gap between claims of abstinence and the high number of identified relapses, we strongly

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recommend the implementation of a sensitive screening test for recent alcohol consumption (eg, the methanol test) both in law and in daily, routine practice.

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