Liver injury in patients with substance use disorder

INTRODUCTION

It is well established that certain substances, whether natural or synthetic, result in liver injury when ingested. The problem of liver injury in patients with substance use disorder (SUD) is of emerging importance, given the epidemic of illicit substance use (SU). The purpose of this review is to briefly summarize the clinical approach to acute liver injury; to explore the relationship between SU and liver injury; to understand the potential for hepatotoxicity from drugs used to treat SUD; and finally, to propose an approach to SUD in patients with liver disease.

CLINICAL APPROACH TO ACUTE LIVER INJURY

DILI accounts for more than half of all cases of acute liver failure in the United States.¹ It occurs through one of 3 mechanisms; namely, direct, indirect, and idiosyncratic. Direct DILI is characterized by a predictable, dose-dependent response, as seen in the prototypical example of acetaminophen toxicity.¹ In contrast, idiosyncratic DILI is associated with an unpredictable, nonreproducible reaction that has a variable latency period. Indirect DILI causes liver injury not through direct hepatotoxicity of the drug but rather by means of the biological action of the drug itself. For example, antipsychotic drugs that are associated with increased adiposity and weight gain may result in fatty liver disease.¹

The diagnostic approach to DILI is illustrated in Figure 1.

FIGURE 1.

Diagnostic approach to substance-induced liver injury. Abbreviations: ALT, alanine transaminase; ALP, alkaline phosphatase; AST, aspartate transaminase.

SUBSTANCE USE AND LIVER INJURY

Approximately 46.8 million (16.7%) Americans aged 12 years and older reported suffering from SUD in 2022.² Several illicit substances have been linked with liver injury (Table 1).

TABLE 1.

Overview of commonly used illicit substances and their associated hepatotoxicity

Drug	Proposed mechanism of DILI	Clinical findings	Outcomes	References
Cannabis	Precise mechanism is unknown Undergoes extensive hepatic metabolism	Rare cases of hepatocellular necrosis and acute liver failure Case reports have demonstrated worsening hepatic steatosis and fibrosis in patients with chronic hepatitis C	Clinical resolution with the removal of the drug, supportive care, and administration of NAC	3,4
Cocaine	Metabolized into norcocaine, a hepatotoxic metabolite Ischemic hepatitis	Hepatocellular pattern of injury Case reports typically showed AST/ALT elevations 10–12 × ULN. Patients commonly presented with high-grade fever and rhabdomyolysis	Clinical resolution with the removal of the drug, supportive care, and administration of NAC	5
Heroin, opioids	No clearly established hepatotoxic effects			6
Kratom	One mechanism proposes the metabolism of mitragynine, an indole alkaloid, yields toxic metabolites that may deplete glutathione, leading to hepatocyte damage by reactive oxygen species	Cholestatic or mixed pattern of injury Case reports typically showed ALT/AST elevation > 3 × ULN, with mild ALP elevation 2–3 × ULN. Liver biopsies usually showed acute cholestatic injury	Clinical resolution with removal of the drug and supportive care	7
Methamphetamine, Methylenedioxy-methamphetamine (MDMA)	Proposed mechanisms: Metabolism of MDMA yielding hepatotoxic reactive metabolites, oxidative stress Vasospasm-induced hepatic ischemia Hyperthermia-induced mitochondrial dysfunction	Hepatocellular injury Case reports demonstrate peak ALT/AST levels ranging from 2000 to 5000	Improvement with supportive care and administration of NAC in mild cases Acute liver failure may occur in more severe cases, necessitating liver transplantation	8
Phencyclidine	Malignant hyperthermia Ischemic hepatitis due to severe hypotension	Hepatocellular pattern of injury Case reports showed peak ALT/AST elevations > 9000, with subsequent rapid improvement with supportive care Hyperthermia, rhabdomyolysis and renal impairment were also observed	Improvement with supportive care	9

Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; NAC, N-Acetylcysteine; ULN, upper limit of normal.

Cannabis

Marijuana, a derivative of cannabis, is one of the most commonly used substances across the world due to the psychoactive component delta-9-tetrahydrocannabinol. It has not been strongly linked to liver injury. There are, however, a few case reports of hepatic failure due to cannabis use.^3,4

Cocaine

Cocaine-induced hepatotoxicity has been reported as a part of systemic toxicity associated with the drug characterized by hyperthermia, disseminated intravascular coagulation, acute renal failure, and acute liver injury.⁵ The pathophysiology of cocaine-induced hepatotoxicity involves the direct toxic effects of norcocaine, a metabolite of cocaine, and cocaine-induced vasoconstriction leading to ischemic injury.

Heroin (and Opioids)

Current evidence for heroin and opioid-related hepatic injury remains equivocal. This is in part due to confounding factors typically present in heroin users, including a disproportionately higher prevalence of alcohol use disorder and viral hepatitis acquired through intravenous drug use.⁶

Kratom

Kratom is derived from Mitragyna speciosa, a tree found in Southeast Asia, and has partial µ-opioid agonist effects.⁷ It has no therapeutic indication for use in the United States. Though uncommon, case reports have identified a link between Kratom and liver injury, usually with a cholestatic pattern.⁷

Methamphetamine

Methamphetamine and methylenedioxy-methamphetamine are stimulants that act by upregulating catecholamines. These drugs are hepatotoxic, often leading to acute liver failure in otherwise young, healthy individuals by means of mechanisms as outlined in Table 1.⁸

Phencyclidine

Phencyclidine, a potent hallucinogen, is a synthetic analog of ketamine. Phencyclidine overdose has been linked to malignant hyperthermia and acute liver injury.⁹ The pattern of liver injury resembles hepatic ischemia or “shock liver” due to severe hypotension and hypoxia and is characterized by acute hepatic necrosis.⁹

HEPATOTOXICITY OF COMMON CONTAMINANTS

Individuals with SUD remain at risk of liver injury not only from the illicit substances used, but also from contaminants frequently present in these substances. Kratom is commonly contaminated with toxic metals such as lead and nickel.¹⁰ These heavy metals are known to cause hepatic injury by inducing oxidative stress.¹¹ Toxic metal contamination has also been linked to heroin and cannabis. Additionally, cannabis is sometimes contaminated with pesticides containing known carcinogens.¹² Roughly 70% of cocaine used in the United States is contaminated with levamisole, an anthelminthic agent used in animals, which has been associated with cases of mild, self-limited liver injury.^13,14 Fentanyl is an occasional adulterant found in methamphetamine, heroin, and methylenedioxy-methamphetamine, though this has not been linked to clinically significant livery injury.

HEPATOTOXICITY FROM DRUGS USED TO TREAT SUD

Buprenorphine & Naloxone

Buprenorphine, a partial µ-opioid receptor agonist, is one of the main pharmacologic agents utilized in medication-assisted treatment of opioid use disorder.¹⁵ When used sublingually, at recommended doses, buprenorphine is generally well tolerated. However, when used intravenously and at supratherapeutic doses, it has been linked with acute liver injury. Case reports have also demonstrated liver injury occurring at therapeutic doses in susceptible patients; notably, individuals with chronic hepatitis C.¹⁵ Naloxone, an opioid antagonist often used in combination with buprenorphine as a part of medication-assisted treatment, has not been linked to liver injury (Table 2).

TABLE 2.

Overview of pharmacologic agents used in treatment of substance use disorder and their associated hepatotoxicity

Drug	Proposed mechanism of DILI	Clinical findings	Outcomes	References
Buprenorphine	Unknown	Hepatocellular injury Case report demonstrated ALT elevation 300 × ULN, prolonged PT, and renal impairment	Most cases appear to be self-limited Severe hepatitis with acute liver failure may occur	10
Gabapentin (Used off label for cannabis use disorder)	Unknown	Mixed pattern of liver injury Case reports demonstrate peak ALT/AST levels ranging from 300 to 800. One case showed primarily cholestatic injury, with significantly elevated ALP in the 1200s.	Clinical resolution with removal of the drug	13
Methadone	No clearly established hepatotoxic effects			11
Naltrexone	Unknown	Mild, asymptomatic hepatocellular injury Case reports do not show liver enzyme elevation at therapeutic doses	Spontaneous resolution often occurs without discontinuation of the drug	12
Topiramate (used off label for cocaine use disorder)	Induction of CYP3A4, or inhibition of CYP2C19 enzymes by topiramate potentiates hepatotoxic effects of other medications (eg, antipsychotics)	Hepatocellular injury Case reports demonstrate ALT/AST elevations ranging from 3 to 6 × ULN	Clinical resolution with removal of the drug and supportive care	14

Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; PT, prothrombin time; ULN, upper limit of normal.

Methadone

Methadone is a full µ-opioid receptor agonist used in the treatment of opioid use disorder.¹⁶ It has not been linked to clinically significant hepatic injury. Patients taking methadone have a higher prevalence of chronic liver disease compared with the general population due to high-risk lifestyle practices, including intravenous drug use predisposing them to hepatitis B, C, and other pathogens.¹⁶

Naltrexone

Naltrexone is an opioid antagonist used in the treatment of opioid and alcohol use disorder. The Food and Drug Administration had previously issued a black box warning regarding the potential for hepatotoxicity when ingested in supratherapeutic doses. However, this warning has since been removed. When administered at recommended dosages, naltrexone is not associated with liver injury.¹⁷

AN APPROACH TO SUD IN PATIENTS WITH LIVER DISEASE

The prevalence of marijuana and opioid use has been estimated at 29% and 22%, respectively, in patients with chronic hepatitis C.¹⁸ Additionally, cocaine use is seen in about 26% of this patient population.¹⁸ Among patients with cirrhosis, the estimated prevalence of marijuana use is 3%–10%, cocaine 5%, and opioids 4%–5%.¹⁸ SUD has been implicated in the exacerbation of some chronic liver diseases, as seen in buprenorphine-induced liver injury in patients with chronic hepatitis C.¹⁵

Addiction specialists have been introduced into the liver transplant evaluation process to evaluate and develop treatment plans to reduce alcohol-associated risks.¹⁹ However, a similar process regarding other SU in these patients is lacking.¹⁹ Current evidence suggests that alcohol relapse rates are higher in postliver transplant patients who had been abstinent for at least 6 months before transplantation compared with patients who were abstinent for less than 6 months pretransplantation.²⁰

Recent data indicates that the most prevalent SU in liver transplantation candidates is cannabis.²¹ Despite widespread social acceptance, cannabis use remains a contentious topic in liver transplantation.²² Limited data and the need for the assessment of the harms and benefits of cannabis challenge liver transplant centers to formulate an equitable SU policy pertaining to liver transplant candidates with active cannabis use.²²

Treatment of SUD in these patients requires a multidisciplinary approach, with the primary goal of abstinence and harm reduction, while additional support from an addiction specialist can help improve psychosocial functioning, which can lead to increased insight, healthy emotional coping skills, and increased prevention skills against recurrence of SU.²³

EVIDENCE-BASED ASSESSMENT INSTRUMENTS FOR SUD

Screening, brief intervention, and referral to treatment (SBIRT) provide a framework to health care systems to screen for and assess SUD.²⁴ SBIRT is utilized for prevention and identifying SU, although health care settings have been inconsistent with its use.²⁵ Screening tools listed in Table 3 are commonly used with SBIRT.

TABLE 3.

Screening tools for substance use disorder

Evidence-based screening instruments for substance use disorder
Screening tool	Substance	Number of items, time to complete, and format
Drug Abuse Screening Test (DAST-10)a Available in languages other than English18	Prescribed/OTC medications Nonprescription psychoactive drugs	Ten-item questionnaire Typically completed in less than 8 min Can be clinician or self-administered
Cut down, Annoyed, Guilty, Eye-Opener-adapt to include drugs (CAGE-AID)a 18	Most psychoactive drugs	Four-item questionnaire Typically completed in 2–3 min Can be clinician or self-administered
Cut down, Annoyed, Guilt, Eye-Opener-adapt to include drugs (Family CAGE-AID)a 18	Most psychoactive drugs	Four-item questionnaire Typically completed in 2–3 min Can be clinician or self-administered
Alcohol, Smoking, and Substance Involved Test (ASSIST) Available in languages other than English18	Alcohol, tobacco, and all other psychoactive drugs	Eight-item questionnaire Clinician administered

^aDoes not apply to alcohol or tobacco.

Abbreviation: OTC, Over the counter.

Diagnosing SUD in liver transplant patients is typically performed before liver transplant by an addiction specialist.²⁶ Training and clinical focus of the addiction specialist may be more adept at evoking an accurate and thorough history of SU than other clinicians.²⁶ Unlike markers for liver graft health, such as liver enzymes and drug levels, there are no absolute biomarkers for SUD.²⁶ Through a biopsychosocial lens, the addictions specialist turns to the standardized diagnostic criteria of the Diagnostic and Statistical Manual of Mental Health Disorders to diagnose SUD (Table 4).²⁶

TABLE 4.

Diagnosing and determining severity of substance use disorder

Diagnostic criteria for substance use disorder
Using in larger amounts or for longer than intended
Wanting to cut down or stop using but unable to
Majority of time is spent getting, using, or recovering from the substance
Craving
Unable to meet major obligations due to use
Continuous use despite negative consequences
Giving up important activities because of use
Continuous use, even when put in danger
Continuous use worsens physical/psychological symptoms
Increased tolerance
Withdrawal symptoms

Note: Fewer than 2 symptoms=no disorder; 2–3 symptoms=mild disorder; 4–5 symptoms=moderate disorder; 6 or more symptoms=severe disorder.

NONPHARMACOLOGICAL APPROACH TO TREATMENT OF SUD

Behavioral treatment programs integrated within primary care or hepatology office visits could improve abstinence and mitigate the recurrence of SU. Patients who continue in behavior treatment programs after liver transplantation show a decrease in recurrence of SU.²³

Motivational approaches should be tailored to the patient’s level of motivation to change.²⁷ Motivational interviewing (MI) accepts that people with problematic behaviors have different levels of readiness for behavior change.²⁸ Motivational interviewing is an evidence-based, person-centered approach that does not require patients to be highly motivated at treatment initiation.²⁷ It originated in the field of addiction treatment but is widely used across many disciplines.²⁸ Providers can use the Open-ended, Affirmation, Reflection, Summarize basic principles of motivational interviewing to form a partnership with the patient, in which the provider does not assume the role of the expert (Table 5).²⁸

TABLE 5.

Basic principles of motivational interviewing

OARS
Open-ended questions
Affirmations
Reflective listening
Summary

CONCLUSION

SUD is endemic in many cities across the United States and throughout the world. Idiosyncratic DILI is sometimes observed with SU and occasionally with some of the pharmacologic treatments for SU. The clinical approach starts with a focused history and physical examination, followed by appropriate liver biochemical tests and imaging as needed. To more effectively treat SUD and thereby mitigate its harmful effects on the liver and overall health, it is paramount that clinicians utilize screening tools such as the well-established SBIRT.

CONFLICTS OF INTEREST

The authors have no conflicts to report.