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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Toxicological urinalysis is a highly sensitive and specific test that detects recent substance use. It has been established for substance misuse treatment but has not been routinely used at liver transplantation (LT) centers. Patients with a history of substance misuse are required to be abstinent from alcohol and illicit drugs before they are listed for LT. In this cross-sectional study, we sought to determine the prevalence of recent substance use in LT candidates via toxicological urinalysis. One hundred nine adults who were admitted for an LT assessment provided data, and they were categorized by the etiology of their liver disease [alcohol-related liver disease (ALD), hepatitis C virus (HCV), or other liver diseases]. Urine was toxicologically screened for drugs and their metabolites as well as the urinary alcohol metabolites ethyl glucuronide and ethyl sulfate. The prevalence of alcohol metabolites in patients with ALD was 20%. Licit and illicit substances together provided a positive toxicological result in 30% of the patients. Positive results were more common among patients with HCV (40%) and ALD (38%) versus patients with other liver diseases (18%). During the clinical assessment, 4% of the patients with ALD or HCV self-reported current alcohol or illicit drug use. These results correspond to the findings of other studies and emphasize the uncertainty of self-reported substance use data for LT candidates. Liver Transpl 17:1200–1204, 2011. © 2011 AASLD.

Liver transplantation (LT) for end-stage liver disease is a well-established lifesaving treatment option that provides recipients with improved quality of life and longevity.1, 2 The success of LT has traditionally been related to survival. Survival rates have continuously improved; across the United States, the United Kingdom, and Ireland, the 1-, 5-, 10-, and 20-year patient survival rates are 90%, 70%, 65%, and 50%, respectively.2-4 Furthermore, longitudinal data have shown remarkable improvements in quality-of-life domains after LT.1

The consideration of candidates for LT whose liver disease etiology is related to substance misuse remains controversial. Surveys of public and professional attitudes toward organ allocation to patients with different causes of liver disease have demonstrated that abstinent patients with a history of alcohol dependence or injecting drug use are considered a low priority in comparison with other patient groups.5, 6 There is also evidence suggesting that patients with chronic alcohol-related liver disease (ALD) are not being referred for an LT assessment even though they are considered good candidates within the transplant community.5, 7 In practice, patients with a history of substance misuse who are assessed for LT must currently be abstaining from alcohol and illicit drugs (except for occasional cannabis use, which is not contraindicated in the UK guidelines8, 9); after the LT assessment, alcohol or illicit drug use is a contraindication for transplantation. The UK guidelines also stipulate that any policy concerning alcohol abuse should be consistent for all etiologies of liver disease. In our program, abstinence from alcohol is not mandatory before transplantation when the liver disease is unrelated and the alcohol consumption patterns are within the recommended limits for the general population. To monitor substance use, some programs call in patients on short notice for random screening while they are on the waiting list. This practice is recommended by established UK guidelines for patients with a history of substance misuse, ALD, or hepatitis C virus (HCV) but not for patients with other liver disease etiologies.8, 9

The number of studies reporting the prevalence of alcohol use in patients with ALD on the LT waiting list is limited, and there is only 1 published study of drug use by patients on the waiting list.10 The use of toxicological analyses such as random blood alcohol tests and urinary ethyl glucuronide tests has increased the rate of detection of alcohol use in LT candidates in comparison with self-reported rates.11-13 The testing of urine for direct alcohol metabolites (ethyl glucuronide and ethyl sulfate) is a toxicological development that is gaining popularity as a sensitive and specific test for detecting recent alcohol consumption.14-16 The detection time for ethyl glucuronide and ethyl sulfate in urine (range ∼40-90 hours, median = 65 hours) is considerably longer than the detection time for ethanol and depends on the dose.14 A positive result for ethyl glucuronide can be obtained after a single session of alcohol consumption.15 Ethyl glucuronide is sensitive to bacteria in urine and can provide false-negative and false-positive results, but ethyl sulfate is not sensitive in this way.17, 18 When ethyl glucuronide and ethyl sulfate analyses are combined, they provide a highly sensitive and specific tool for objectively identifying recent alcohol consumption.15

Current clinical practice relies on self-reported information from the patient and on the family and the referrer for the validity of the patient's abstinence. Toxicological analysis is used when there is a clinical perception of ongoing substance use; it is not used for all LT candidates. There are still clinical concerns about the practical implications of managing positive drug and alcohol screens for all patients with liver disease and about the interpretation of biochemical results. Therefore, we proposed this anonymous study to determine the prevalence of recent drug and alcohol use in a population of patients being assessed for LT.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

The study was approved by the East London and The City Research Ethics Committee (reference 09/H0704/49).

Participants

This cross-sectional study used 109 urine specimens routinely provided by adult patients with chronic liver disease who were admitted for an assessment for LT at King's College Hospital between January 21, 2010 and September 21, 2010. The patients were referred by a hepatologist or gastroenterologist when they were considered suitable for an assessment for LT. Their admission was planned, and they underwent a series of investigations based on their medical history, collateral history, and self-reports. Upon admission, the patients routinely provided 24-hour urine specimens for the analysis of their renal function, and all patients who provided 24-hour urine specimens were included. The patients were kept unaware that the urine specimens were going to be toxicologically analyzed so that selection bias would be avoided. The urine specimens were rendered anonymous, and the results did not affect clinical decision making with respect to transplant candidacy.

The liver disease etiology was determined and was recorded as ALD, HCV, or other liver disease for the purposes of this study. The other liver disease category included cholestatic, vascular, metabolic, and cryptogenic liver diseases. Seven candidates with HCV and a history of alcohol misuse were considered to have HCV. The only other retained information was the age and sex of the patient.

Procedures

Collection and Measurement of the Metabolites of Substance Use

Two aliquots of each patient's urine (3-5 mL) were stored in a freezer until the toxicological analysis. Urinary drugs and their metabolites were screened with a cloned enzyme donor immunoassay19 on a Beckman Coulter Olympus AU640 analyzer. The reagents for the cloned enzyme donor immunoassay were obtained from Microgenics GmbH (a part of the ThermoFisher Scientific group). The following drugs and metabolites were analyzed during the drug screening process, and the results were recorded as positive or negative according to the designated cutoff values: amphetamines (500 ng/mL), barbiturates (300 ng/mL), benzodiazepines (300 ng/mL), cannabis (multilevel tetrahydrocannabinol assay; 25 ng/mL), cocaine (calibrated with the benzoylecgonine metabolite; 300 ng/mL), a methadone metabolite (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; 100 ng/mL), and opiates (1000 ng/mL). The urine creatinine level was measured as a marker of the urine concentration and integrity. Positive results for amphetamines and opiates were confirmed with liquid chromatography mass spectrometry.

Measurements of the direct alcohol metabolites ethyl glucuronide and ethyl sulfate in urine were performed by a liquid chromatography/tandem mass spectrometry method with cutoff values of 0.2 and 0.1 mg/L, respectively.20, 21 High-value samples were diluted into a linear range, and the results were multiplied by the dilution factor. Current research indicates that liver cirrhosis has no significant effect on ethyl glucuronide levels.22

Statistical Methods

All patients who provided 24-hour urine specimens were included in the study, so the true prevalence of recent substance use in this patient group was obtained. Descriptive statistics were used to summarize the sample characteristics according to the study measurements. Fisher's exact test was used to compare the proportions of ALD or HCV patients and patients with other liver diseases who had positive toxicological screens. The results were analyzed with the Statistical Package for the Social Sciences (version 17.0).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

One hundred nine patients with chronic liver disease who were assessed for LT provided data for this study. The demographics are shown in Table 1. The majority were male (67%), and other liver disease was the most common etiology of liver disease (40%). The mean age was 52.6 years (standard deviation = 9.3 years).

Table 1. Participant Characteristics
Liver DiseasePatients [n (%)]Males [n (%)]Females [n (%)]Age (Years)
RangeMean (Standard Deviation)
ALD40 (37)28 (26)12 (11)40-6853.5 (7.2)
HCV25 (23)22 (20)3 (3)31-6352 (5.9)
Other44 (40)23 (21)21 (19)25-7152.1 (11.9)
Total109 (100)73 (67)36 (33)25-7152.6 (9.3)

Prevalence of Drug and Alcohol Metabolites in Urine

Twenty percent of ALD patients were positive for alcohol metabolites; therefore, LT would have been contraindicated according to current guidelines (Table 2). Patients with ALD were significantly more likely to have positive results for alcohol metabolites than patients with other liver diseases (20% versus 5%, P = 0.04 by Fisher's exact test). ALD patients also most frequently had positive results for opiates (20%) and benzodiazepines (15%), whereas 20% of HCV patients had positive test results for cannabis. Overall, ALD and HCV patients were more likely than patients with other liver diseases to have positive toxicological results (38%, 40%, and 18% positive, respectively), although these differences did not reach statistical significance.

Table 2. Prevalence of Substance Use by Liver Disease
SubstanceLiver Disease [n (%)]
ALD (n = 40)HCV (n = 25)Other (n = 44)Total (n = 109)
  • NOTE: Some patients used more than 1 substance.

  • *

    A toxicological analysis that was positive for ethyl glucuronide and ethyl sulfate was considered evidence of alcohol use.

Alcohol*8 (20)0 (0)2 (5)10 (9)
Any drug12 (30)10 (40)8 (18)30 (28)
 Amphetamines0 (0)0 (0)0 (0)0 (0)
 Benzodiazepines6 (15)2 (8)3 (7)11 (10)
 Barbiturates0 (0)1 (4)0 (0)1 (1)
 Cocaine metabolite0 (0)1 (4)0 (0)1 (1)
 Methadone metabolite0 (0)1 (4)0 (0)1 (1)
 Opiates8 (20)2 (8)5 (11)15 (14)
 Cannabis0 (0)5 (20)2 (5)7 (6)
Any substance15 (38)10 (40)8 (18)33 (30)

Overall, there was no sex difference: 29% of males (21/73) and 33% of females (12/36) had positive toxicological results (P = 0.7), and 17% of females (6/36) and 5% of males (4/73) had positive results for alcohol metabolites (P = 0.08).

Polysubstance use was encountered: 2% of the patients (2/109) provided samples with 3 substance use classes (alcohol, benzodiazepines, and opiates), and 8% of the patients (9/109) provided samples with 2 substance metabolites. Three of the 15 opiate class–positive specimens were not specified by the laboratory; 8 were codeine, 2 were dihydrocodeine, and 2 were morphine. These opiate class–positive results potentially indicated the recent use of opioid analgesics. All the detected drug metabolites possibly originated from prescribed or illicit drug use, and opiate metabolites may originate from over-the-counter medications. There were no positive results for amphetamines. In the course of the clinical assessment, only 3% of patients with ALD self-reported current alcohol use, and 5% of patients with HCV reported current drug use.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This cross-sectional study demonstrates that urine toxicological screening increases the detection of recent substance use in LT candidates in comparison with self-reports. The analysis found a significant association between LT candidates with ALD and positive urinalysis findings for alcohol metabolites. According to the urine drug screen analysis, the overall prevalence rate of drug use was 28%; however, because the toxicology results were rendered anonymous, it was not possible to determine whether the positive results were due to licit or illicit substance use.

At LT centers, recent substance use remains a significant concern for clinicians and contributes to the decision to list or not list a patient for transplantation. Current guidelines recommend that patients with ALD or a history of substance misuse be abstinent before transplantation. These guidelines have been adopted because of the limited availability of donated organs, the potential harm to grafted livers from substance use, and the negative opinions associated with LT recipients who relapse. Despite the clinical expectation of abstinence, there are no established protocols for assessing or monitoring this. This study's toxicological results would have contraindicated LT for 8 ALD patients (20%) who were positive for alcohol metabolites and for 1 patient with HCV (4%) who was cocaine metabolite–positive. LT would have been contraindicated for 8% of all the patients according to their presentation. Overall, 30% of the patients had positive toxicological results for licit or illicit substance use. In future clinical practice, positive toxicological results may trigger an additional evaluation to determine the source of the drug; if the source is found to be illicit, removal from the transplant wait list might result.

Some drugs, such as analgesics, benzodiazepines, and barbiturates, are associated with reduced clearance in patients with cirrhosis.23 The LT candidates commonly used opiates (14%) or benzodiazepines (10%) despite the advice of hepatology specialists to avoid these substances because of their potential to precipitate hepatic encephalopathy.24 In comparison with the other patients, ALD patients had a notably higher prevalence of using opiates (20%) and benzodiazepines (15%). There could be many reasons for this finding, and no causal relationship can be established. It is worth considering the neurobiological actions of alcohol, which are emulated by benzodiazepines and opioids.25, 26 Hypothetically, the results of this study could depict patients who substituted benzodiazepines and opioids for alcohol. Such patients would require a close assessment and management by a substance misuse specialist.

Previous studies of pre-LT substance use have focused primarily on alcohol, and the participants have been defined by a diagnosis of ALD.10-13 These methodologies have not accurately reflected the overall rate of substance use in all LT candidates. By using urine samples from routinely provided specimens, we determined the true prevalence rate for this cross-section of all LT candidates. There are 4 published studies on alcohol use in patients with ALD listed for LT. The pretransplant rates of alcohol use established in these studies are 15%,11 17%,13 25%,10 and 50%.12 In this study, we found that 20% of the ALD patients were positive for alcohol metabolites. Although the results of Erim et al.'s study12 are relative outliers, the results from these other studies are remarkably similar.

Urine drug screening is frequently employed for the routine screening of nontransplant patients at high risk for the effects of substance use.27, 28 Traditional blood alcohol biomarkers are indirect biomarkers, have variable specificities, are difficult to interpret in individuals with cirrhosis, and do not produce positive results after a single session of drinking.15, 29, 30 Toxicological urinalysis is cost-effective, sensitive, and specific and improves the detection rates of substance use, but the window of opportunity for detecting substance use is limited. The detected prevalence rate is probably an underestimation of the true rate of substance use if this is measurable over a longer period of time (eg, hair analysis31, 32). Because the admission for these patients is planned, it is also possible that patients may cease using alcohol and illicit drugs before admission to avoid detection; therefore, the results may be biased. Furthermore, toxicological analysis detects metabolites from more commonly used substances but is not all-encompassing, and it has not been performed to detect other drugs that may affect liver disease (eg, cathinones).33

This study has a number of limitations, including the lack of clinical correlations. This could be addressed further in a prospective, open study, but that approach can also suffer from selection bias, with compliant patients more likely to consent to the study. There is also no information on important outcomes such as alcohol and illicit drug use after transplantation and any impact that this might have on graft function.

Despite the clinical implications of substance use in LT candidates, there are surprisingly few published studies on substance use in this patient group. This likely reflects the limited clinical reasons for concern about the effectiveness of existing approaches to assessing abstinence from alcohol. This study's results emphasize the uncertainty of self-reported data and promote the clinical acquisition of objective evidence to corroborate a patient's report. A finding of current substance use should not be an endpoint for LT candidates; rather, patients should be referred for substance use management, continue with their liver disease management, and be reevaluated for LT in the future. Because of the limited amount of existing research, it may be beneficial in the future to examine the relationship between patient clinical data and a variety of objective substance use measures in LT candidates.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES