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Substance Use Disorder Is Associated With Alcohol-Associated Liver Disease in Patients With Alcohol Use Disorder

  • Author Footnotes
    ∗ Co-authorship.
    Augustin G.L. Vannier
    Footnotes
    ∗ Co-authorship.
    Affiliations
    MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Author Footnotes
    ∗ Co-authorship.
    Vladislav Fomin
    Footnotes
    ∗ Co-authorship.
    Affiliations
    MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Raymond T. Chung
    Affiliations
    MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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  • Suraj J. Patel
    Affiliations
    MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Author Footnotes
    ∗ Co-authorship.
    Esperance Schaefer
    Footnotes
    ∗ Co-authorship.
    Affiliations
    MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Author Footnotes
    ∗ Co-authorship.
    Russell P. Goodman
    Footnotes
    ∗ Co-authorship.
    Affiliations
    MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Author Footnotes
    ∗ Co-authorship.
    Jay Luther
    Correspondence
    Correspondence: Address correspondence to: Jay Luther, MD, Director, Division of Gastroenterology, MGH Alcohol Liver Center, Massachusetts General Hospital.
    Footnotes
    ∗ Co-authorship.
    Affiliations
    MGH Alcohol Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

    Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
    Search for articles by this author
  • Author Footnotes
    ∗ Co-authorship.
Open AccessPublished:February 08, 2022DOI:https://doi.org/10.1016/j.gastha.2022.02.004

      Background and Aims

      Substance use disorder (SUD) commonly associates with alcohol use disorder (AUD), and certain substances have independently been shown to drive liver injury. In this work, we sought to determine if coexisting SUD in patients with AUD is associated with the presence of alcohol-associated liver disease (ALD).

      Methods

      We performed a cross-sectional analysis using the Mass General Brigham Biobank to identify patients based on International Classification of Diseases, Tenth Revision, codes. We performed multivariate analyses accounting for a wide range of demographic and clinical variables to evaluate the association between SUD and ALD. We subsequently used the same method to evaluate the association between SUD and hepatic decompensation.

      Results

      We identified 2848 patients with a diagnosis of AUD; 9.0% of them had ALD, and 25.2% had a history of SUD. In multivariate analyses, patients with SUD were more frequently diagnosed with ALD than those without SUD (odds ratio [OR] = 1.95, P = .001). Furthermore, the number of concurrent SUDs was positively associated with the diagnosis of ALD (OR = 1.33, P < .001). Independent of the presence of other SUDs, opioid use disorder in patients with AUD was associated with ALD (OR = 1.902, P = .02). In subsequent analyses, we found that sedative use disorder was associated with hepatic decompensation (OR = 2.068, P = .03).

      Conclusion

      In patients with AUD, SUD, and particularly opioid use disorder, was independently associated with the diagnosis of ALD.

      Keywords

      Abbreviations used in this paper:

      ALD (alcohol-associated liver disease), AUD (alcohol use disorder), ICD-10 (International Classification of Diseases, Tenth Revision), MGB (Massachusetts General Brigham), OR (odds ratio), SUD (substance use disorder)

      Introduction

      Excessive alcohol use is highly prevalent and contributes to significant morbidity and mortality in society.
      Substance Abuse and Mental Health Services Administration (SAMHSA)
      National Survey on Drug Use and Health 2018, 2019 (NSDUH-2016-DS0001). Table 2.1B—tobacco product and alcohol use in lifetime, past year, and past month among persons aged 12 or older, by age group: percentages..
      Centers for Disease Control and Prevention (CDC)
      Alcohol and public health: alcohol-related disease impact (ARDI). Annual average for United States 2011-2015 alcohol-attributable deaths due to excessive alcohol use, all ages. Methodology: according to the CDC, due to scientific updates to ARDI, estimates of alcohol-attributable deaths or years of potential life lost generated in the current version of ARDI should not be compared with estimates that were generated using the ARDI default reports or analyses in the ARDI Custom Data Portal prior to July 30, 2020.
      • Grant B.F.
      • Goldstein R.B.
      • Saha T.D.
      • et al.
      Epidemiology of DSM-5 alcohol use disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions III.
      It is well-established that excessive alcohol intake increases the risk for developing alcohol-associated liver disease (ALD),
      World Health Organization
      ,
      • Rehm J.
      • Taylor B.
      • Mohapatra S.
      • et al.
      Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
      a leading cause of morbidity among alcohol users.
      • Rehm J.
      • Taylor B.
      • Mohapatra S.
      • et al.
      Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
      While most patients with excessive alcohol use do not experience severe liver injury, a minority can develop alcohol-related hepatitis or cirrhosis. Severe alcohol-related hepatitis, the most aggressive form of ALD, carries a dismal prognosis.
      • Goyal S.K.
      • Dixit V.K.
      • Jain A.K.
      • et al.
      Assessment of the model for end-stage liver disease (MELD) score in predicting prognosis of patients with alcoholic hepatitis.
      • Testino G.
      • Leone S.
      Acute alcoholic hepatitis: a literature review and proposal of treatment.
      • Deltenre P.
      • Trépo E.
      • Fujiwara N.
      • et al.
      Gene signature-MELD score and alcohol relapse determine long-term prognosis of patients with severe alcoholic hepatitis.
      Similarly, patients with cirrhosis, and in particular, those who have experienced a liver-related decompensating event, face high 2-year mortality rates.
      • D'amico G.
      • Morabito A.
      • D'amico M.
      • et al.
      Clinical states of cirrhosis and competing risks.
      Accordingly, identifying modifiable risk factors for advanced liver disease among patients with alcohol use disorder (AUD) is critical.
      In recent years, the use of nonalcohol substances, such as marijuana, opioids, benzodiazepines, and cocaine, has increased and resuled in significant burden on patients and the medical system.

      Key substance use and mental health indicators in the United States: results from the 2018 National Survey on Drug Use and Health, 2018. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. https://www.samhsa.gov/data/report/2018-nsduh-annual-national-report. Accessed March 7, 2022.

      ,
      • Verna E.C.
      • Schluger A.
      • Brown Jr., R.S.
      Opioid epidemic and liver disease.
      Due to common epidemiologic, socioeconomic, and psychiatric drivers, there is frequently a comorbidity between AUD and other substance use disorders (SUDs).
      • Connor J.P.
      • Gullo M.J.
      • White A.
      • et al.
      Polysubstance use: diagnostic challenges, patterns of use and health.
      • Arnaout B.
      • Petrakis I.L.
      Diagnosing co-morbid drug use in patients with alcohol use disorders.
      • Soyka M.
      Alcohol use disorders in opioid maintenance therapy: prevalence, clinical correlates and treatment.
      • Smyth B.P.
      • Hannigan A.
      • Cullen W.
      Cocaine use in young adults: correlation with early onset cannabis, alcohol and tobacco use.
      In addition, it has been demonstrated that hospitalized patients with ALD have a significantly higher prevalence of nonalcohol SUDs than hospitalized patients without underlying liver diseases.
      • Jinjuvadia R.
      • Jinjuvadia C.
      • Puangsricharoen P.
      • et al.
      Concomitant psychiatric and nonalcohol-related substance use disorders among hospitalized patients with alcoholic liver disease in the United States.
      Notably, for each of these substances, there exist mechanistic data demonstrating their ability to independently drive hepatotoxicity, thereby potentially accentuating the negative effect of alcohol on the liver in patients with AUD.
      • Perino L.E.
      • Warren G.H.
      • Levine J.S.
      Cocaine-induced hepatotoxicity in humans.
      • Vitcheva V.
      Cocaine toxicity and hepatic oxidative stress.
      • Smith H.S.
      Opioid metabolism.
      • Atici S.
      • Cinel I.
      • Cinel L.
      • et al.
      Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model.
      Because of the increased frequency of nonalcohol substance use in patients with AUD and the potential hepatotoxicity of these substances, we hypothesize that patients with AUD and other substance use history will be more frequently diagnosed with ALD than those with AUD and no history of other substance use. In this work, we leverage a large and well-characterized cohort of patients with AUD who exhibit varying degrees of liver injury and substance use patterns to examine the association between substance use and the presence and severity of ALD.

      Methods

      Patient Cohort

      For this cross-sectional associative study, we identified eligible patients in the Massachusetts General Brigham (MGB) Biobank,
      • Gainer V.S.
      • Cagan A.
      • Castro V.M.
      • et al.
      The biobank portal for partners personalized medicine: a query tool for working with consented biobank samples, genotypes, and phenotypes using i2b2.
      which is a large integrated database comprised of over 125,000 consented subjects within the MGB health-care system. Robust demographic, clinical, social, and demographic data are available for each patient and accessible through an online platform. Data are derived from the electronic health record and health surveys. All patients included in the database provided informed consent. To identify patients with AUD, we queried the MGB Biobank for patients with the following International Classification of Diseases, Tenth Revision, (ICD-10) diagnoses: alcohol abuse (F10.1) or alcohol dependence (F10.2). We included all patients with one of these diagnoses that also completed an alcohol questionnaire to quantify their alcohol use.

      Demographic and Clinical Factors

      We collected the following demographic and clinical data on our cohort: sex, age, race, ethnicity, body mass index, viral hepatitis status, drinking history, history of nicotine dependence, substance use history, psychiatric disorder history, and the receipt of medical addiction therapy or psychotherapy (Table A1). For lab testing, the most recent values were used in our analyses. Alcohol consumption was quantified from a patient-completed questionnaire, which asked the following question: “During the past year, how many alcoholic drinks (glass/bottle/can of beer; 4oz glass of wine; drink or shot of liquor) did you usually drink in a typical week?”. Participants were given the following options: (1) none, or less than one per month, (2) 1–3 per month, (3) 2–4 per week, (4) 5–6 per week, (5) 1–2 per day, (6) 3–4 per day, (7) 5–6 per day, or (9) more than 6 per day. We converted these categorical responses into a linear score (0–8) for our multivariate analyses. Viral hepatitis was assessed through analysis of lab testing and diagnosis history. Patients were classified as having hepatitis B if they had a positive hepatitis B antigen test or a diagnosis of chronic hepatitis B in their medical chart. Patients were classified as having hepatitis C if they had a positive hepatitis C antibody test or a diagnosis of hepatitis C in their medical chart. Patients that were missing either a hepatitis C antibody test or a hepatitis B antigen test and were not diagnosed with viral hepatitis were considered untested for the purpose of our multivariate analyses.

      Definition of SUD

      We identified the subset of patients with AUD who also had a history of a SUD. We determined that patients had a SUD if they had an ICD-10 code in their chart that supported a diagnosis of abuse of or dependence of the following substances: cocaine (F14.1 & F14.2), opioids (F11.1 & F11.2), cannabis (F12.1 & F12.2), other stimulant (F15.1 & F15.2), inhalants (F18.1 & F18.2), and sedatives, hypnotic or anxiolytic (F13.1 & F13.2). Stimulants include substances such as amphetamines, while sedatives, hypnotic or anxiolytic, refer to benzodiazepines and barbiturates.

      Definitions of ALD

      We identified patients with ALD by looking for one of the following ICD-10 diagnoses: alcoholic hepatitis (K70.1), alcoholic fibrosis and sclerosis (K70.2), alcoholic cirrhosis of liver (K70.3), alcoholic hepatic failure (K70.4), other cirrhosis (K74.69), or unspecified cirrhosis (K74.60). We did not include patients with only an ICD diagnosis of either alcoholic fatty liver (K70.0) or alcoholic liver disease-unspecified (K70.9), as a high number of patients with moderate and extensive alcohol use develop hepatic steatosis, which is of unclear clinical significance with regard to liver-related morbidity and mortality.
      • Parker R.
      The natural history of alcohol-related liver disease.
      Hepatic decompensation was defined by a diagnosis of hepatorenal (K76.7) or hepatopulmonary syndrome (K76.81), hepatic encephalopathy/failure (K72.0, K72.1, K72.2, K72.9), hepatocellular carcinoma (C22.0), ascites (R18), and esophageal varices with bleeding (I85.01, I85.11).

      Statistical Analyses

      Continuous variables were summarized using means compared using the t test with Welch correction; categorical variables were expressed as numbers and percentages and compared using the Fisher exact test. We also performed univariate logistic regressions to determine the odds ratio (OR) and 95% confidence interval of having ALD for each risk factor, demographic characteristic, and SUD. Multivariate logistic regressions were adjusted for the following variables: demographics, risk factors for AUD (homelessness, psychiatric disorders, nonalcohol SUDs), specific AUD diagnosis (abuse, dependence or both), the receipt of medical addiction therapy, psychotherapy, alcohol use history (as assessed by questionnaire), and concurrent liver diseases that may contribute to the development and progression of ALD (hepatitis B and hepatitis C virus positivity, nonalcoholic steatohepatitis, biliary cholangitis, autoimmune hepatitis, chronic passive liver congestion, alpha-1 antitrypsin deficiency, and hemochromatosis). All analyses were conducted using GraphPad Prism (San Diego, CA).

      Results

      Patient Demographics

      Our analysis consisted of 2848 patients with AUD who had completed an alcohol use questionnaire (Figure). Demographic data are provided in Table 1. We found no difference in the severity of AUD, based on diagnostic coding of alcohol abuse, in patients with AUD with or without SUD (81% vs 78%, respectively, P > .05). Many patients had multiple SUDs (Figure A1)
      Figure thumbnail gr1
      FigureFlowchart of patient selection. The flow diagram details the method for patient selection in our analyses.
      Table 1Demographics of the Cohort
      VariableAll patients (2848)AUD (2129)AUD + SUD (719)P value
      All P values refer to a Fisher exact test (categorical variables) or a t test with Welch correction (linear variables) comparing patients with both SUD and AUD to those with only AUD.
      Age56.759.049.9<.001
      Male sex (%)1574 (55.2%)1185 (55.6%)389 (54.1%).5
      White (%)2524 (88.6%)1909 (89.6%)615 (85.5%).003
      BMI28.528.528.3.5
      Viral hepatitis209 (7.3%)100 (4.6%)109 (15.1%)<.001
      Homeless (%)112 (3.9%)28 (1.3%)84 (11.6%)<.001
      Psychotherapy (%)1102 (38.6%)649 (30.4%)453 (63%)<.001
      Psychiatric disorder (%)2374 (83.3%)1686 (79.1%)688 (95.6%)<.001
      Nicotine dependence (%)994 (34.9%)609 (28.6%)385 (53.5%)<.001
      MAT (%)1113 (39%)724 (34%)389 (54.1%)<.001
      BMI, body mass index; MAT, medical addiction therapy.
      a All P values refer to a Fisher exact test (categorical variables) or a t test with Welch correction (linear variables) comparing patients with both SUD and AUD to those with only AUD.

      SUD Is Associated With the Presence of ALD in Patients With AUD

      Given the potential biological contribution of substance use to liver disease,
      • Perino L.E.
      • Warren G.H.
      • Levine J.S.
      Cocaine-induced hepatotoxicity in humans.
      • Vitcheva V.
      Cocaine toxicity and hepatic oxidative stress.
      • Smith H.S.
      Opioid metabolism.
      • Atici S.
      • Cinel I.
      • Cinel L.
      • et al.
      Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model.
      we first sought to determine if there was an association between the presence of SUD in patients with AUD and a diagnosis of ALD. We found that patients with a history of any drug disorder were more often diagnosed with ALD than those without a history of a drug disorder (OR = 1.95, P = .001) (Table 2). In subgroup analyses, AUD patients with concurrent opioid disorder (OR = 1.90, P = .01) were more frequently diagnosed with ALD. Notably, we found no association between ALD and sedative, stimulant, cocaine, or cannabis disorder (Table 2). Furthermore, we found a positive association between the number of SUDs and the diagnosis of ALD (OR = 1.33, P < .001). Taken together, we found a positive association between the presence of SUD and ALD in patients with AUD, especially in those patients with a history of opioid disorder.
      Table 2SUD Is Independently Associated With Increased Odds of Having Alcohol-Associated Liver Disease in Patients With AUD
      Substance use disorderOdds ratio95% CIP value
      Any SUD1.951.31–2.89.001
      Number of SUDs1.331.14–1.55<.001
      Cannabis1.570.92–2.63.09
      Cocaine1.330.72–2.40.4
      Inhalant1.210.66–2.18.5
      Opioid1.901.13–3.17.01
      Other0.500.18–1.26.2
      Sedative1.250.59–2.56.6
      CI, confidence interval.

      Sedative Use Disorder, But Not Other Substance Use Diagnoses, Associates With Hepatic Decompensation in Patients With AUD

      Given the wide spectrum of ALD, we next sought to determine if there was an association between SUD and hepatic decompensation in patients with AUD. While we did not find an association between SUD and hepatic decompensation (OR = 1.08, P = .68), there was a positive association between sedative use disorder and hepatic decompensation (OR = 2.07, P = .03) (Table 3). We did not find an association between ALD and the number of SUDs or the presence of cannabis, cocaine, inhalant, or sedative use disorder. Taken together, we conclude that a diagnosis of sedative use disorder was associated with hepatic decompensation in patients with AUD.
      Table 3Sedative Use Disorder, But Not Other SUDs, Is Independently Associated With Increased Odds of Hepatic Decompensation in Patients With AUD
      Substance use disorderOdds ratio95% CIP value
      Any SUD1.080.74–1.56.7
      Number of SUDs1.110.94–1.29.2
      Cannabis0.910.53–1.50.7
      Cocaine0.840.45–1.50.6
      Inhalant1.230.68–2.16.5
      Opioid1.050.62–1.74.9
      Other1.080.43–2.43.9
      Sedative2.071.04–3.95.03
      CI, confidence interval.

      Discussion

      In this cross-sectional study, we found a positive association between the presence of ALD and a history of SUD in a large cohort of patients with AUD. Notably, opioid use disorder significantly associated with the presence of ALD. Moreover, we found that an increasing number of SUD diagnoses in a patient with AUD also associated with ALD. Finally, we also found that sedative use disorder, but not other SUDs, associated with hepatic decompensation in patients with AUD. These associations were identified in multivariate analyses, suggesting drug use may independently contribute to liver injury in patients with AUD.
      It is well established that there is an association between alcohol use and liver disease, ranging from reversible hepatic steatosis to steatohepatitis and to chronic hepatic fibrosis. The wide spectrum of liver diseases observed in patients with AUD highlights the numerous factors independent of quantity of alcohol consumed that may contribute to liver injury. While many of these factors are nonmodifiable, there is an urgent and unmet need to identify modifiable risk factors in these patients. We hypothesized that concurrent drug use would represent a key variable in driving liver disease in patients with AUD. This hypothesis was based on established data that highlight the ability of certain substances to mechanistically drive liver injury. In particular, opioids are metabolized in the liver and may accentuate liver injury through lipid peroxidation and mitochondrial injury.
      • Desai A.
      • Marion G.
      • Nephew L.D.
      • et al.
      Contemporary trends in hospitalizations for comorbid chronic liver disease and substance use disorders.
      Furthermore, hepatocytes have numerous opioid receptors that drive pathways that may contribute to liver injury.
      • Masini A.
      • Gallesi D.
      • Giovanni F.
      • et al.
      Membrane potential of hepatic mitochondria after acute cocaine administration in rats--the role of mitochondrial reduced glutathione.
      Opioids have been implicated in altering bile acid metabolism as well, which could potentially effect liver homeostasis.
      • Tang Bo
      • Zhang Y.
      • Liang R.
      • et al.
      Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway.
      Accordingly, there is biological plausibility to support our observed findings that substance use associates with liver disease in patients with AUD.
      Previous work has highlighted an increase in SUD prevalence among patients with ALD. An analysis of the National Inpatient Sample data from 2011 found an increased likelihood for hospitalized patients with ALD to have SUD compared with hospitalized patients without ALD.
      • Jinjuvadia R.
      • Jinjuvadia C.
      • Puangsricharoen P.
      • et al.
      Concomitant psychiatric and nonalcohol-related substance use disorders among hospitalized patients with alcoholic liver disease in the United States.
      A more recent analysis of the National Inpatient Sample data found that compared with the patients with chronic liver disease, patients with comorbid chronic liver disease and SUD were more likely to have ALD.
      • Verna E.C.
      • Schluger A.
      • Brown Jr., R.S.
      Opioid epidemic and liver disease.
      Our study builds on these data in multiple ways. First, we study the effect of SUD on liver diseases in only those patients with AUD. Second, we demonstrate the association of individual SUDs with ALD. Finally, we show the effect of SUDs on hepatic decompensation in patients with AUD.
      Patients with AUD often use other recreational drugs. A recent cross-sectional study demonstrated that 8% of those who use alcohol engage in other drugs, and among those who have AUD, 15% have another SUD including hard drugs and marijuana.
      • Saha T.D.
      • Grant B.F.
      • Chou S.P.
      • et al.
      Concurrent use of alcohol with other drugs and DSM-5 alcohol use disorder comorbid with other drug use disorders: sociodemographic characteristics, severity, and psychopathology.
      Those with concurrent SUDs tend to be male, have lower annual incomes, have more severe AUD, and tend to have more comorbid psychiatric disorders.
      • Saha T.D.
      • Grant B.F.
      • Chou S.P.
      • et al.
      Concurrent use of alcohol with other drugs and DSM-5 alcohol use disorder comorbid with other drug use disorders: sociodemographic characteristics, severity, and psychopathology.
      In our analysis, most patients with AUD did not have a concurrent SUD, and controlling for alcohol use did not eliminate the association between hard drug use and liver disease.
      It is impossible to examine the effect of drug use simply from a biologic perspective without recognizing the societal context that these patients live in and the stigma they experience. Many people who inject drugs feel judged by the health-care system and, even prior to engaging in it, feel like their complaints will be dismissed or they will be turned away.
      • Whitfield J.B.
      • Masson S.
      • Liangpunsakul S.
      • et al.
      Obesity, diabetes, coffee, tea, and cannabis use alter risk for alcohol-related cirrhosis in 2 large cohorts of high-risk drinkers.
      ,
      • Muncan B.
      • Walters S.M.
      • Ezell J.
      • et al.
      “They look at us like junkies”: influences of drug use stigma on the healthcare engagement of people who inject drugs in New York City.
      Studies utilizing qualitative interviews of people with SUD revealed that they use the coping strategies of delaying care or seeking care with alternative medicine.
      • Muncan B.
      • Walters S.M.
      • Ezell J.
      • et al.
      “They look at us like junkies”: influences of drug use stigma on the healthcare engagement of people who inject drugs in New York City.
      These feelings are not simply imagined; in reality, many health-care providers do harbor negative feelings toward people who use drugs.
      • Paquette C.E.
      • Syvertsen J.L.
      • Pollini R.A.
      Stigma at every turn: health services experiences among people who inject drugs.
      This results in reduced collaboration between professionals and patients, short and more task-oriented visits. Patients under these circumstances are less likely to complete treatment. Thus, even if drug use does not biologically contribute to liver disease, its stigmatizing effects can create a schism in health-care equity.
      • Muncan B.
      • Walters S.M.
      • Ezell J.
      • et al.
      “They look at us like junkies”: influences of drug use stigma on the healthcare engagement of people who inject drugs in New York City.
      Our study has several limitations. First, the observational and cross-sectional nature of our study limits the findings to associations and may have potential cofounders not accounted for on statistical analysis. This is an inherent limitation of an associative study; by adjusting for many factors in our multivariate analyses, we limit this effect as much as possible. Necessarily, however, we cannot be sure that we have completely avoided residual confounding. Second, the determination of AUD and SUD was made by ICD-10 codes, and each patient may not have been fully evaluated by a provider concentrating in addiction medicine. However, while detailed SUD histories taken by addiction specialists would have reduced the noise in our cohort, this should not sum to produce the associations that we demonstrated in this study. Rather, greater noise introduced by imperfect coding increases statistical uncertainty and makes such associations more difficult to demonstrate.
      Despite these limitations, we conclude that in our cohort of patients with AUD, SUD was independently associated with the presence of ALD. Prospective cohort studies are warranted to conclusively establish the altered risk of patients with concurrent SUD and AUD to develop ALD.

      Authors' Contributions:

      Augustin Vannier: Conceptualization, design, investigation, formal analysis, drafting and editing manuscript. Vladislav Fomin: Conception, design, investigation, drafting and editing manuscript. Raymond T. Chung: Conceptualization, design, editing manuscript, supervision. Suraj J. Patel: Conceptualization, design, editing manuscript, supervision. Esperance Schaefer: Conceptualization, design, editing manuscript, supervision. Russell P. Goodman: Conceptualization, design, editing manuscript, supervision. Jay Luther: Conceptualization, design, drafting and editing manuscript, supervision.

      Supplementary Materials

      References

        • Substance Abuse and Mental Health Services Administration (SAMHSA)
        National Survey on Drug Use and Health 2018, 2019 (NSDUH-2016-DS0001). Table 2.1B—tobacco product and alcohol use in lifetime, past year, and past month among persons aged 12 or older, by age group: percentages..
        U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality, 2019
        • Centers for Disease Control and Prevention (CDC)
        Alcohol and public health: alcohol-related disease impact (ARDI). Annual average for United States 2011-2015 alcohol-attributable deaths due to excessive alcohol use, all ages. Methodology: according to the CDC, due to scientific updates to ARDI, estimates of alcohol-attributable deaths or years of potential life lost generated in the current version of ARDI should not be compared with estimates that were generated using the ARDI default reports or analyses in the ARDI Custom Data Portal prior to July 30, 2020.
        (Accessed September 24, 2020.)
        • Grant B.F.
        • Goldstein R.B.
        • Saha T.D.
        • et al.
        Epidemiology of DSM-5 alcohol use disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions III.
        JAMA Psychiatry. 2015; 72: 757-766
        • World Health Organization
        Poznyak V. Rekve D. Global status report on alcohol and health 2018. WHO, Geneva2018
        • Rehm J.
        • Taylor B.
        • Mohapatra S.
        • et al.
        Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
        Drug Alcohol Rev. 2010; 29: 437-445
        • Goyal S.K.
        • Dixit V.K.
        • Jain A.K.
        • et al.
        Assessment of the model for end-stage liver disease (MELD) score in predicting prognosis of patients with alcoholic hepatitis.
        J Clin Exp Hepatol. 2014; 4: 19-24
        • Testino G.
        • Leone S.
        Acute alcoholic hepatitis: a literature review and proposal of treatment.
        Minerva Med. 2018; 109: 290-299
        • Deltenre P.
        • Trépo E.
        • Fujiwara N.
        • et al.
        Gene signature-MELD score and alcohol relapse determine long-term prognosis of patients with severe alcoholic hepatitis.
        Liver Int. 2019; 40: 565-570
        • D'amico G.
        • Morabito A.
        • D'amico M.
        • et al.
        Clinical states of cirrhosis and competing risks.
        J Hepatol. 2018; 68: 563-576
      1. Key substance use and mental health indicators in the United States: results from the 2018 National Survey on Drug Use and Health, 2018. U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality. https://www.samhsa.gov/data/report/2018-nsduh-annual-national-report. Accessed March 7, 2022.

        • Verna E.C.
        • Schluger A.
        • Brown Jr., R.S.
        Opioid epidemic and liver disease.
        JHEP Rep. 2019; 1: 240-255
        • Connor J.P.
        • Gullo M.J.
        • White A.
        • et al.
        Polysubstance use: diagnostic challenges, patterns of use and health.
        Curr Opin Psychiatry. 2014; 27: 269-275
        • Arnaout B.
        • Petrakis I.L.
        Diagnosing co-morbid drug use in patients with alcohol use disorders.
        Alcohol Res Health. 2008; 31: 148
        • Soyka M.
        Alcohol use disorders in opioid maintenance therapy: prevalence, clinical correlates and treatment.
        Eur Addict Res. 2015; 21: 78-87
        • Smyth B.P.
        • Hannigan A.
        • Cullen W.
        Cocaine use in young adults: correlation with early onset cannabis, alcohol and tobacco use.
        Ir Med J. 2016; 109: 468
        • Jinjuvadia R.
        • Jinjuvadia C.
        • Puangsricharoen P.
        • et al.
        Concomitant psychiatric and nonalcohol-related substance use disorders among hospitalized patients with alcoholic liver disease in the United States.
        Alcohol Clin Exp Res. 2018; 42: 397-402
        • Perino L.E.
        • Warren G.H.
        • Levine J.S.
        Cocaine-induced hepatotoxicity in humans.
        Gastroenterology. 1987; 93: 176-180
        • Vitcheva V.
        Cocaine toxicity and hepatic oxidative stress.
        Curr Med Chem. 2012; 19: 5677-5682
        • Smith H.S.
        Opioid metabolism.
        Mayo Clin Proc. 2009; 84: 613-624
        • Atici S.
        • Cinel I.
        • Cinel L.
        • et al.
        Liver and kidney toxicity in chronic use of opioids: an experimental long term treatment model.
        J Biosci. 2005; 30: 245-252
        • Gainer V.S.
        • Cagan A.
        • Castro V.M.
        • et al.
        The biobank portal for partners personalized medicine: a query tool for working with consented biobank samples, genotypes, and phenotypes using i2b2.
        J Pers Med. 2016; 6: 11
        • Parker R.
        The natural history of alcohol-related liver disease.
        Curr Opin Gastroenterol. 2020; 36: 164-168
        • Desai A.
        • Marion G.
        • Nephew L.D.
        • et al.
        Contemporary trends in hospitalizations for comorbid chronic liver disease and substance use disorders.
        Clin Transl Gastroenterol. 2021; 12: e00372
        • Masini A.
        • Gallesi D.
        • Giovanni F.
        • et al.
        Membrane potential of hepatic mitochondria after acute cocaine administration in rats--the role of mitochondrial reduced glutathione.
        Hepatology. 1997; 25: 385-390
        • Tang Bo
        • Zhang Y.
        • Liang R.
        • et al.
        Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway.
        Int J Mol Med. 2011; 28: 1077-1085
        • Saha T.D.
        • Grant B.F.
        • Chou S.P.
        • et al.
        Concurrent use of alcohol with other drugs and DSM-5 alcohol use disorder comorbid with other drug use disorders: sociodemographic characteristics, severity, and psychopathology.
        Drug Alcohol Depend. 2018; 187: 261-269
        • Whitfield J.B.
        • Masson S.
        • Liangpunsakul S.
        • et al.
        Obesity, diabetes, coffee, tea, and cannabis use alter risk for alcohol-related cirrhosis in 2 large cohorts of high-risk drinkers.
        Am J Gastroenterol. 2021; 116: 106-115
        • Muncan B.
        • Walters S.M.
        • Ezell J.
        • et al.
        “They look at us like junkies”: influences of drug use stigma on the healthcare engagement of people who inject drugs in New York City.
        Harm Reduct J. 2020; 17: 1-9
        • Paquette C.E.
        • Syvertsen J.L.
        • Pollini R.A.
        Stigma at every turn: health services experiences among people who inject drugs.
        Int J Drug Policy. 2018; 57: 104-110