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Dear colleagues,
With recent dramatic improvements in treating hepatitis C, alcoholic liver disease has now become the leading indication for LT. Determining candidacy for a transplanted liver is a rigorous process and there has always been concern for relapse to alcohol use and its effect on the implanted graft. But, have we been too strict in restricting access in such patients?
Drs. Mitchell Mah’moud and John Aita explore this topic with a concise review of the current literature through an ethical lens. After alcohol, the most commonly used psychotropic drug is marijuana. Marijuana has traditionally been a barrier to candidacy for LT but, as with alcohol, should transplant centers relax this restriction, especially with ongoing legalization across the United States? Dr. Mohamed Shoreibah and colleagues explore this topic though a cogent review of the literature assessing the impact of marijuana use on liver transplant outcomes. We hope these essays will help your medical practice and ongoing advocacy for your patients.
We welcome your thoughts on X at @AGA_GIHN.
Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, Conn., and chief of endoscopy at West Haven VA Medical Center in Connecticut. He is an associate editor for GI & Hepatology News.
Liver transplantation in the setting of alcohol-related liver disease
BY MITCHELL MAH’MOUD, MD, FACG, AGAF, FAASLD, AND JOHN AITA, MD
Alcohol-related liver disease (ALD), with its subset of severe alcohol-associated hepatitis (SAH), currently accounts for most liver transplantation (LT) recipients in the United States. Patients with SAH, particularly those with a MELD-NA of at least 35, have a 70%-75% mortality rate within 6 months. The ethics of liver transplantation in the setting of SAH are complex and still controversial. With liver transplantation in general, there are more patients with various disorders listed for transplant than available organs. There may also be concern regarding a posttransplant return to harmful alcohol use leading to graft dysfunction or loss. Ultimately, in ethics terms, there is an inherent conflict between the values of beneficence (the obligation to act for an individual patient’s benefit) and justice (fair and equitable treatment of a society).
The past decade has yielded supportive data depicting adequate posttransplant (LT) survival in select SAH patients. Previously, 6 months of alcohol sobriety was typically mandated by LT centers. Reasons for this requirement included (a) documentation of sobriety (including enrollment in an alcohol rehabilitation program) and (b) determination of maximal recovery (such that transplant may not be indicated). Present day information shows poor correlation between the 6-month alcohol sobriety period and reduced posttransplant alcohol use. In particular, the ACCELERATE-AH study, in which patients with severe alcoholic hepatitis underwent LT before 6 months of abstinence, demonstrated post-LT survival rates of 94% at 1 year and 84% at 3 years, similar to post-LT survival rates of other LT recipients. Although other factors may play into a transplant committee’s decision to require a period of sobriety before liver transplant evaluation, these data suggest that a “one size fits all” mandatory sobriety period prior to LT evaluation is now incongruent with normative medical practice.
One overarching principle of LT is that society provides organs to those patients with the greatest need. An inherent effect of listing select patients with SAH for liver transplant is that it potentially increases the wait time (and therefore the mortality risk) for other liver disease patients. Unfortunately, alcohol use disorder (AUD) has increased significantly in recent years among younger patients (from 2001 to 2013), and some patients may even be at greater risk of ALD (e.g., PNPLA3, TM6SF2, polymorphisms or post gastric bypass) with even mild/moderate use compared to other individuals . LT should not be considered a cure for AUD but rather a treatment for SAH that carries a high mortality rate but comparable post-LT survival to other indications for LT. Data from the ACCELERATE-AH trial revealed a cumulative incidence of any alcohol use at 1 year of approximately 25% and at 3 years of 34% for post-LT patients with SAH. This is roughly equivalent to reported disease recurrence rates of 10%-40% over 1-10 years post-LT for AIH, PBC and PSC and 7%-33% for MASLD. Despite these data, concern for reemergence of metabolic syndrome has never been an impediment when evaluating patients for LT due to end-stage liver disease from MASLD. LT centers may have a selection pathway that permits judicious transplant evaluation for SAH patients who, in the context of beneficence, are felt to greatly benefit from liver transplant in the near term (and are felt unlikely to recover without transplant) while, in the spirit of the ethical tenet of justice, also yield the best suitability for the donated organ (meaning the organ was put to good use with adequate graft survival). In this setting, a liver transplant program may utilize tools such as S-DAT, the PACT scoring system and TERS in identifying candidates with SAH for LT and those who are likely to relapse post-LT.
The optimal role of liver transplant in SAH patients is still emerging, but recent evidence suggests that the post-LT survival rate and alcohol-relapse rate appear to be acceptable. Nonetheless, the need to prevent harmful and sustained alcohol use post LT is vital since it is considered the strongest predictor of graft loss and death. Recent observations have also highlighted younger age and consumption of >10 drinks/day within 6 months of LT as predictors of sustained alcohol use post-LT. Hence, early identification of sustained alcohol use post-LT coupled with timely interventions based on abstinence-promoting behavioral and pharmacologic therapy should remain the goal of all transplant centers to avoid relapse and alcohol related deaths. In addition, incorporating addiction treatment centers into post-LT management should be considered standard of care to provide continued therapy for AUD in all patients post-LT. As in the DAA era of hepatitis C therapies, the role of LT in the setting of SAH may dwindle as emerging SAH-specific therapies evolve resulting in adequate transplant-free survival. Until then, it is beneficial to refine the guidelines periodically across all the UNOS regions on patient selection for LT in SAH, consistent with ethical principles of beneficence and justice. Finally, despite the concern about return to harmful drinking post LT, the need to destigmatize AUD and explain the purpose of LT for SAH through public education is vital.
Dr. Mah’moud is professor of medicine in the division of gastroenterology at Duke University School of Medicine, Durham, N.C., and a gastroenterologist with RMG Gastroenterology in North Carolina. Dr. Aita is gastroenterologist with Cleveland Clinic Indian River Hospital in Vero Beach, Fla. Dr. Mah’moud disclosed serving on the advisory board of CLDF, and receiving research support from Intercept Pharma and Gilead Scientific, but not in a capacity related to this article.
References
Tapper E. BMJ. 2018;362: k2817
Louvet A. Lancet Gastro Hep. 2022;7(5):416-25
Lee B. Gastroenterology. 2018;155:422-30
Shroff H. Hot Topics in Hepatology: Chicago ALF Debate. Clinical Liver Disease (2020 vol 16, No.5: 178-85)
High Stakes: Navigating the Hazy Intersection of Marijuana and Liver Transplants
BY JOVEN TRISTEZA, MD, THOMAS RULI, MD, AND MOHAMED SHOREIBAH, MD
Marijuana is currently illegal at the federal level and is listed as a schedule I substance. However, marijuana for medical and recreational use has been legalized by several states, leading to an increase in its use. This unclear and disparate status of marijuana has created a smoky situation for patients being evaluated for liver transplant. Multiple studies have shown marijuana to provide medical benefits, while other studies in liver transplant patients have shown that it does not affect posttransplant outcomes. Those studies have helped inform decision-making for liver transplant selection committees across the country, where marijuana use is evaluated in the context of the patient’s medical and social history, as well as the history of other substance use. Though we do not encourage its use, we do not believe that marijuana use should be the singular reason to deny a patient listing for liver transplant.
Marijuana has been studied extensively regarding its effects on the human body. The main compounds in marijuana are tetrahydrocannabinol, or THC, and cannabidiol, or CBD. These compounds exhibit many effects that we observe clinically through the endocannabinoid system. Beneficial effects related to the gastrointestinal tract include relief from nausea and vomiting and stimulation of appetite in patients with anorexia. Other benefits outside the GI tract include alleviation of chronic pain and management of some forms of drug-resistant epilepsy. Ongoing studies are investigating the role of marijuana in other medical conditions.1,2 At least equally notable are marijuana’s potential adverse effects, which include tachycardia, hypertension, agitation, nausea, psychosis, and hallucinations.2 Marijuana may also increase the risk of heart failure, acute myocardial infarction, and stroke.3
The exact effect of marijuana on the liver remains inconclusive. Receptors for endocannabinoids have been associated with steatosis and fibrosis in some studies. However, some evidence also suggests that marijuana may reduce inflammation in the liver.2 Small, prospective studies have not been able to link marijuana use with hepatic laboratory abnormalities, and there is currently no significant association between marijuana and liver disease, injury, or cirrhosis. Of particular relevance to liver transplant recipients is marijuana’s effect on cytochrome P450 enzyme function, especially CYP3A4 which is the CYP class that metabolizes tacrolimus, a common immunosuppressant used in liver transplant patients. Marijuana inhibits CYP3A4 which could increase tacrolimus levels, potentially leading to morbidity. One strategy to mitigate this process is closer monitoring of tacrolimus levels for patients using marijuana.
The once-presumed increased risk of fungal infection — particularly Aspergillus — for liver transplant patients who use marijuana has been refuted. Furthermore, there have been concerns by liver transplant selection committees that marijuana use may be related to a greater risk of post–liver transplant noncompliance, infections, or even death. However, marijuana use on its own has not been associated with these concerns in the liver transplant population.4
The practice of excluding marijuana users from being listed for liver transplant does not appear to be evidence based. In a 2018 study focusing on US transplant centers, 40% of centers would not accept any marijuana use, and only 28% would list those who were taking medical marijuana for transplant. Interestingly, eight states have passed legislation prohibiting withholding transplant evaluation for marijuana users if it is solely based on their marijuana use.5 In the 5 years since that study was published, there have been major changes in the legality of marijuana. A future study of interest could assess how these changes have affected the position of transplant centers.
The sociopolitical and transplant medicine worlds alike continue to adapt to the legalization of marijuana. While marijuana use is associated with adverse effects, its potential for benefit for a variety of medical conditions is an evolving area that has shown promise. It is therefore logical to view marijuana as a pharmacologic agent with potential for risks and benefits, but not necessarily a sole reason to exclude patients from listing for liver transplant. The current data are reassuring in that those who use marijuana and receive liver transplantation are not at higher risk of posttransplant complications, infections, or death when compared to those who do not use it. Should marijuana use exist in the context of substance use disorder or other behavioral and mental health issues, then the case warrants careful multidisciplinary evaluation prior to consideration for liver transplant. The aim of our discourse is not to encourage the use of marijuana in patients being considered for liver transplant but rather to discourage their exclusion from listing solely on the basis of marijuana use. In the pursuit of an equitable organ allocation system, our hope is that this work facilitates a more informed discussion and a change in policy in liver transplant programs that may still consider marijuana use an exclusion criterion.
Joven Tristeza, MD, and Thomas Ruli, MD, are residents in internal medicine at the University of Alabama at Birmingham; Mohamed Shoreibah, MD, is a specialist in gastroenterology and hepatology at the University of Alabama at Birmingham where he also serves on the faculty of the internal medicine residency program. The authors have no conflicts of interest.
REFERENCES
1. Cox, EJ. Pharmacology & Therapeutics. 2019;201:25-38.
2. Maselli, DB. Clinical Gastroenterology and Hepatology. 2021;19(9):1748-1758.e2.
3. Page, RL. Circulation. 2020;142(10):e131-e152.
4. Panchani, N. The American Journal of the Medical Sciences. 2023;365(2):115-120.
5. Zhu, J. Transplantation. 2018;102(3):433-439.
Dear colleagues,
With recent dramatic improvements in treating hepatitis C, alcoholic liver disease has now become the leading indication for LT. Determining candidacy for a transplanted liver is a rigorous process and there has always been concern for relapse to alcohol use and its effect on the implanted graft. But, have we been too strict in restricting access in such patients?
Drs. Mitchell Mah’moud and John Aita explore this topic with a concise review of the current literature through an ethical lens. After alcohol, the most commonly used psychotropic drug is marijuana. Marijuana has traditionally been a barrier to candidacy for LT but, as with alcohol, should transplant centers relax this restriction, especially with ongoing legalization across the United States? Dr. Mohamed Shoreibah and colleagues explore this topic though a cogent review of the literature assessing the impact of marijuana use on liver transplant outcomes. We hope these essays will help your medical practice and ongoing advocacy for your patients.
We welcome your thoughts on X at @AGA_GIHN.
Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, Conn., and chief of endoscopy at West Haven VA Medical Center in Connecticut. He is an associate editor for GI & Hepatology News.
Liver transplantation in the setting of alcohol-related liver disease
BY MITCHELL MAH’MOUD, MD, FACG, AGAF, FAASLD, AND JOHN AITA, MD
Alcohol-related liver disease (ALD), with its subset of severe alcohol-associated hepatitis (SAH), currently accounts for most liver transplantation (LT) recipients in the United States. Patients with SAH, particularly those with a MELD-NA of at least 35, have a 70%-75% mortality rate within 6 months. The ethics of liver transplantation in the setting of SAH are complex and still controversial. With liver transplantation in general, there are more patients with various disorders listed for transplant than available organs. There may also be concern regarding a posttransplant return to harmful alcohol use leading to graft dysfunction or loss. Ultimately, in ethics terms, there is an inherent conflict between the values of beneficence (the obligation to act for an individual patient’s benefit) and justice (fair and equitable treatment of a society).
The past decade has yielded supportive data depicting adequate posttransplant (LT) survival in select SAH patients. Previously, 6 months of alcohol sobriety was typically mandated by LT centers. Reasons for this requirement included (a) documentation of sobriety (including enrollment in an alcohol rehabilitation program) and (b) determination of maximal recovery (such that transplant may not be indicated). Present day information shows poor correlation between the 6-month alcohol sobriety period and reduced posttransplant alcohol use. In particular, the ACCELERATE-AH study, in which patients with severe alcoholic hepatitis underwent LT before 6 months of abstinence, demonstrated post-LT survival rates of 94% at 1 year and 84% at 3 years, similar to post-LT survival rates of other LT recipients. Although other factors may play into a transplant committee’s decision to require a period of sobriety before liver transplant evaluation, these data suggest that a “one size fits all” mandatory sobriety period prior to LT evaluation is now incongruent with normative medical practice.
One overarching principle of LT is that society provides organs to those patients with the greatest need. An inherent effect of listing select patients with SAH for liver transplant is that it potentially increases the wait time (and therefore the mortality risk) for other liver disease patients. Unfortunately, alcohol use disorder (AUD) has increased significantly in recent years among younger patients (from 2001 to 2013), and some patients may even be at greater risk of ALD (e.g., PNPLA3, TM6SF2, polymorphisms or post gastric bypass) with even mild/moderate use compared to other individuals . LT should not be considered a cure for AUD but rather a treatment for SAH that carries a high mortality rate but comparable post-LT survival to other indications for LT. Data from the ACCELERATE-AH trial revealed a cumulative incidence of any alcohol use at 1 year of approximately 25% and at 3 years of 34% for post-LT patients with SAH. This is roughly equivalent to reported disease recurrence rates of 10%-40% over 1-10 years post-LT for AIH, PBC and PSC and 7%-33% for MASLD. Despite these data, concern for reemergence of metabolic syndrome has never been an impediment when evaluating patients for LT due to end-stage liver disease from MASLD. LT centers may have a selection pathway that permits judicious transplant evaluation for SAH patients who, in the context of beneficence, are felt to greatly benefit from liver transplant in the near term (and are felt unlikely to recover without transplant) while, in the spirit of the ethical tenet of justice, also yield the best suitability for the donated organ (meaning the organ was put to good use with adequate graft survival). In this setting, a liver transplant program may utilize tools such as S-DAT, the PACT scoring system and TERS in identifying candidates with SAH for LT and those who are likely to relapse post-LT.
The optimal role of liver transplant in SAH patients is still emerging, but recent evidence suggests that the post-LT survival rate and alcohol-relapse rate appear to be acceptable. Nonetheless, the need to prevent harmful and sustained alcohol use post LT is vital since it is considered the strongest predictor of graft loss and death. Recent observations have also highlighted younger age and consumption of >10 drinks/day within 6 months of LT as predictors of sustained alcohol use post-LT. Hence, early identification of sustained alcohol use post-LT coupled with timely interventions based on abstinence-promoting behavioral and pharmacologic therapy should remain the goal of all transplant centers to avoid relapse and alcohol related deaths. In addition, incorporating addiction treatment centers into post-LT management should be considered standard of care to provide continued therapy for AUD in all patients post-LT. As in the DAA era of hepatitis C therapies, the role of LT in the setting of SAH may dwindle as emerging SAH-specific therapies evolve resulting in adequate transplant-free survival. Until then, it is beneficial to refine the guidelines periodically across all the UNOS regions on patient selection for LT in SAH, consistent with ethical principles of beneficence and justice. Finally, despite the concern about return to harmful drinking post LT, the need to destigmatize AUD and explain the purpose of LT for SAH through public education is vital.
Dr. Mah’moud is professor of medicine in the division of gastroenterology at Duke University School of Medicine, Durham, N.C., and a gastroenterologist with RMG Gastroenterology in North Carolina. Dr. Aita is gastroenterologist with Cleveland Clinic Indian River Hospital in Vero Beach, Fla. Dr. Mah’moud disclosed serving on the advisory board of CLDF, and receiving research support from Intercept Pharma and Gilead Scientific, but not in a capacity related to this article.
References
Tapper E. BMJ. 2018;362: k2817
Louvet A. Lancet Gastro Hep. 2022;7(5):416-25
Lee B. Gastroenterology. 2018;155:422-30
Shroff H. Hot Topics in Hepatology: Chicago ALF Debate. Clinical Liver Disease (2020 vol 16, No.5: 178-85)
High Stakes: Navigating the Hazy Intersection of Marijuana and Liver Transplants
BY JOVEN TRISTEZA, MD, THOMAS RULI, MD, AND MOHAMED SHOREIBAH, MD
Marijuana is currently illegal at the federal level and is listed as a schedule I substance. However, marijuana for medical and recreational use has been legalized by several states, leading to an increase in its use. This unclear and disparate status of marijuana has created a smoky situation for patients being evaluated for liver transplant. Multiple studies have shown marijuana to provide medical benefits, while other studies in liver transplant patients have shown that it does not affect posttransplant outcomes. Those studies have helped inform decision-making for liver transplant selection committees across the country, where marijuana use is evaluated in the context of the patient’s medical and social history, as well as the history of other substance use. Though we do not encourage its use, we do not believe that marijuana use should be the singular reason to deny a patient listing for liver transplant.
Marijuana has been studied extensively regarding its effects on the human body. The main compounds in marijuana are tetrahydrocannabinol, or THC, and cannabidiol, or CBD. These compounds exhibit many effects that we observe clinically through the endocannabinoid system. Beneficial effects related to the gastrointestinal tract include relief from nausea and vomiting and stimulation of appetite in patients with anorexia. Other benefits outside the GI tract include alleviation of chronic pain and management of some forms of drug-resistant epilepsy. Ongoing studies are investigating the role of marijuana in other medical conditions.1,2 At least equally notable are marijuana’s potential adverse effects, which include tachycardia, hypertension, agitation, nausea, psychosis, and hallucinations.2 Marijuana may also increase the risk of heart failure, acute myocardial infarction, and stroke.3
The exact effect of marijuana on the liver remains inconclusive. Receptors for endocannabinoids have been associated with steatosis and fibrosis in some studies. However, some evidence also suggests that marijuana may reduce inflammation in the liver.2 Small, prospective studies have not been able to link marijuana use with hepatic laboratory abnormalities, and there is currently no significant association between marijuana and liver disease, injury, or cirrhosis. Of particular relevance to liver transplant recipients is marijuana’s effect on cytochrome P450 enzyme function, especially CYP3A4 which is the CYP class that metabolizes tacrolimus, a common immunosuppressant used in liver transplant patients. Marijuana inhibits CYP3A4 which could increase tacrolimus levels, potentially leading to morbidity. One strategy to mitigate this process is closer monitoring of tacrolimus levels for patients using marijuana.
The once-presumed increased risk of fungal infection — particularly Aspergillus — for liver transplant patients who use marijuana has been refuted. Furthermore, there have been concerns by liver transplant selection committees that marijuana use may be related to a greater risk of post–liver transplant noncompliance, infections, or even death. However, marijuana use on its own has not been associated with these concerns in the liver transplant population.4
The practice of excluding marijuana users from being listed for liver transplant does not appear to be evidence based. In a 2018 study focusing on US transplant centers, 40% of centers would not accept any marijuana use, and only 28% would list those who were taking medical marijuana for transplant. Interestingly, eight states have passed legislation prohibiting withholding transplant evaluation for marijuana users if it is solely based on their marijuana use.5 In the 5 years since that study was published, there have been major changes in the legality of marijuana. A future study of interest could assess how these changes have affected the position of transplant centers.
The sociopolitical and transplant medicine worlds alike continue to adapt to the legalization of marijuana. While marijuana use is associated with adverse effects, its potential for benefit for a variety of medical conditions is an evolving area that has shown promise. It is therefore logical to view marijuana as a pharmacologic agent with potential for risks and benefits, but not necessarily a sole reason to exclude patients from listing for liver transplant. The current data are reassuring in that those who use marijuana and receive liver transplantation are not at higher risk of posttransplant complications, infections, or death when compared to those who do not use it. Should marijuana use exist in the context of substance use disorder or other behavioral and mental health issues, then the case warrants careful multidisciplinary evaluation prior to consideration for liver transplant. The aim of our discourse is not to encourage the use of marijuana in patients being considered for liver transplant but rather to discourage their exclusion from listing solely on the basis of marijuana use. In the pursuit of an equitable organ allocation system, our hope is that this work facilitates a more informed discussion and a change in policy in liver transplant programs that may still consider marijuana use an exclusion criterion.
Joven Tristeza, MD, and Thomas Ruli, MD, are residents in internal medicine at the University of Alabama at Birmingham; Mohamed Shoreibah, MD, is a specialist in gastroenterology and hepatology at the University of Alabama at Birmingham where he also serves on the faculty of the internal medicine residency program. The authors have no conflicts of interest.
REFERENCES
1. Cox, EJ. Pharmacology & Therapeutics. 2019;201:25-38.
2. Maselli, DB. Clinical Gastroenterology and Hepatology. 2021;19(9):1748-1758.e2.
3. Page, RL. Circulation. 2020;142(10):e131-e152.
4. Panchani, N. The American Journal of the Medical Sciences. 2023;365(2):115-120.
5. Zhu, J. Transplantation. 2018;102(3):433-439.
Dear colleagues,
With recent dramatic improvements in treating hepatitis C, alcoholic liver disease has now become the leading indication for LT. Determining candidacy for a transplanted liver is a rigorous process and there has always been concern for relapse to alcohol use and its effect on the implanted graft. But, have we been too strict in restricting access in such patients?
Drs. Mitchell Mah’moud and John Aita explore this topic with a concise review of the current literature through an ethical lens. After alcohol, the most commonly used psychotropic drug is marijuana. Marijuana has traditionally been a barrier to candidacy for LT but, as with alcohol, should transplant centers relax this restriction, especially with ongoing legalization across the United States? Dr. Mohamed Shoreibah and colleagues explore this topic though a cogent review of the literature assessing the impact of marijuana use on liver transplant outcomes. We hope these essays will help your medical practice and ongoing advocacy for your patients.
We welcome your thoughts on X at @AGA_GIHN.
Gyanprakash A. Ketwaroo, MD, MSc, is associate professor of medicine, Yale University, New Haven, Conn., and chief of endoscopy at West Haven VA Medical Center in Connecticut. He is an associate editor for GI & Hepatology News.
Liver transplantation in the setting of alcohol-related liver disease
BY MITCHELL MAH’MOUD, MD, FACG, AGAF, FAASLD, AND JOHN AITA, MD
Alcohol-related liver disease (ALD), with its subset of severe alcohol-associated hepatitis (SAH), currently accounts for most liver transplantation (LT) recipients in the United States. Patients with SAH, particularly those with a MELD-NA of at least 35, have a 70%-75% mortality rate within 6 months. The ethics of liver transplantation in the setting of SAH are complex and still controversial. With liver transplantation in general, there are more patients with various disorders listed for transplant than available organs. There may also be concern regarding a posttransplant return to harmful alcohol use leading to graft dysfunction or loss. Ultimately, in ethics terms, there is an inherent conflict between the values of beneficence (the obligation to act for an individual patient’s benefit) and justice (fair and equitable treatment of a society).
The past decade has yielded supportive data depicting adequate posttransplant (LT) survival in select SAH patients. Previously, 6 months of alcohol sobriety was typically mandated by LT centers. Reasons for this requirement included (a) documentation of sobriety (including enrollment in an alcohol rehabilitation program) and (b) determination of maximal recovery (such that transplant may not be indicated). Present day information shows poor correlation between the 6-month alcohol sobriety period and reduced posttransplant alcohol use. In particular, the ACCELERATE-AH study, in which patients with severe alcoholic hepatitis underwent LT before 6 months of abstinence, demonstrated post-LT survival rates of 94% at 1 year and 84% at 3 years, similar to post-LT survival rates of other LT recipients. Although other factors may play into a transplant committee’s decision to require a period of sobriety before liver transplant evaluation, these data suggest that a “one size fits all” mandatory sobriety period prior to LT evaluation is now incongruent with normative medical practice.
One overarching principle of LT is that society provides organs to those patients with the greatest need. An inherent effect of listing select patients with SAH for liver transplant is that it potentially increases the wait time (and therefore the mortality risk) for other liver disease patients. Unfortunately, alcohol use disorder (AUD) has increased significantly in recent years among younger patients (from 2001 to 2013), and some patients may even be at greater risk of ALD (e.g., PNPLA3, TM6SF2, polymorphisms or post gastric bypass) with even mild/moderate use compared to other individuals . LT should not be considered a cure for AUD but rather a treatment for SAH that carries a high mortality rate but comparable post-LT survival to other indications for LT. Data from the ACCELERATE-AH trial revealed a cumulative incidence of any alcohol use at 1 year of approximately 25% and at 3 years of 34% for post-LT patients with SAH. This is roughly equivalent to reported disease recurrence rates of 10%-40% over 1-10 years post-LT for AIH, PBC and PSC and 7%-33% for MASLD. Despite these data, concern for reemergence of metabolic syndrome has never been an impediment when evaluating patients for LT due to end-stage liver disease from MASLD. LT centers may have a selection pathway that permits judicious transplant evaluation for SAH patients who, in the context of beneficence, are felt to greatly benefit from liver transplant in the near term (and are felt unlikely to recover without transplant) while, in the spirit of the ethical tenet of justice, also yield the best suitability for the donated organ (meaning the organ was put to good use with adequate graft survival). In this setting, a liver transplant program may utilize tools such as S-DAT, the PACT scoring system and TERS in identifying candidates with SAH for LT and those who are likely to relapse post-LT.
The optimal role of liver transplant in SAH patients is still emerging, but recent evidence suggests that the post-LT survival rate and alcohol-relapse rate appear to be acceptable. Nonetheless, the need to prevent harmful and sustained alcohol use post LT is vital since it is considered the strongest predictor of graft loss and death. Recent observations have also highlighted younger age and consumption of >10 drinks/day within 6 months of LT as predictors of sustained alcohol use post-LT. Hence, early identification of sustained alcohol use post-LT coupled with timely interventions based on abstinence-promoting behavioral and pharmacologic therapy should remain the goal of all transplant centers to avoid relapse and alcohol related deaths. In addition, incorporating addiction treatment centers into post-LT management should be considered standard of care to provide continued therapy for AUD in all patients post-LT. As in the DAA era of hepatitis C therapies, the role of LT in the setting of SAH may dwindle as emerging SAH-specific therapies evolve resulting in adequate transplant-free survival. Until then, it is beneficial to refine the guidelines periodically across all the UNOS regions on patient selection for LT in SAH, consistent with ethical principles of beneficence and justice. Finally, despite the concern about return to harmful drinking post LT, the need to destigmatize AUD and explain the purpose of LT for SAH through public education is vital.
Dr. Mah’moud is professor of medicine in the division of gastroenterology at Duke University School of Medicine, Durham, N.C., and a gastroenterologist with RMG Gastroenterology in North Carolina. Dr. Aita is gastroenterologist with Cleveland Clinic Indian River Hospital in Vero Beach, Fla. Dr. Mah’moud disclosed serving on the advisory board of CLDF, and receiving research support from Intercept Pharma and Gilead Scientific, but not in a capacity related to this article.
References
Tapper E. BMJ. 2018;362: k2817
Louvet A. Lancet Gastro Hep. 2022;7(5):416-25
Lee B. Gastroenterology. 2018;155:422-30
Shroff H. Hot Topics in Hepatology: Chicago ALF Debate. Clinical Liver Disease (2020 vol 16, No.5: 178-85)
High Stakes: Navigating the Hazy Intersection of Marijuana and Liver Transplants
BY JOVEN TRISTEZA, MD, THOMAS RULI, MD, AND MOHAMED SHOREIBAH, MD
Marijuana is currently illegal at the federal level and is listed as a schedule I substance. However, marijuana for medical and recreational use has been legalized by several states, leading to an increase in its use. This unclear and disparate status of marijuana has created a smoky situation for patients being evaluated for liver transplant. Multiple studies have shown marijuana to provide medical benefits, while other studies in liver transplant patients have shown that it does not affect posttransplant outcomes. Those studies have helped inform decision-making for liver transplant selection committees across the country, where marijuana use is evaluated in the context of the patient’s medical and social history, as well as the history of other substance use. Though we do not encourage its use, we do not believe that marijuana use should be the singular reason to deny a patient listing for liver transplant.
Marijuana has been studied extensively regarding its effects on the human body. The main compounds in marijuana are tetrahydrocannabinol, or THC, and cannabidiol, or CBD. These compounds exhibit many effects that we observe clinically through the endocannabinoid system. Beneficial effects related to the gastrointestinal tract include relief from nausea and vomiting and stimulation of appetite in patients with anorexia. Other benefits outside the GI tract include alleviation of chronic pain and management of some forms of drug-resistant epilepsy. Ongoing studies are investigating the role of marijuana in other medical conditions.1,2 At least equally notable are marijuana’s potential adverse effects, which include tachycardia, hypertension, agitation, nausea, psychosis, and hallucinations.2 Marijuana may also increase the risk of heart failure, acute myocardial infarction, and stroke.3
The exact effect of marijuana on the liver remains inconclusive. Receptors for endocannabinoids have been associated with steatosis and fibrosis in some studies. However, some evidence also suggests that marijuana may reduce inflammation in the liver.2 Small, prospective studies have not been able to link marijuana use with hepatic laboratory abnormalities, and there is currently no significant association between marijuana and liver disease, injury, or cirrhosis. Of particular relevance to liver transplant recipients is marijuana’s effect on cytochrome P450 enzyme function, especially CYP3A4 which is the CYP class that metabolizes tacrolimus, a common immunosuppressant used in liver transplant patients. Marijuana inhibits CYP3A4 which could increase tacrolimus levels, potentially leading to morbidity. One strategy to mitigate this process is closer monitoring of tacrolimus levels for patients using marijuana.
The once-presumed increased risk of fungal infection — particularly Aspergillus — for liver transplant patients who use marijuana has been refuted. Furthermore, there have been concerns by liver transplant selection committees that marijuana use may be related to a greater risk of post–liver transplant noncompliance, infections, or even death. However, marijuana use on its own has not been associated with these concerns in the liver transplant population.4
The practice of excluding marijuana users from being listed for liver transplant does not appear to be evidence based. In a 2018 study focusing on US transplant centers, 40% of centers would not accept any marijuana use, and only 28% would list those who were taking medical marijuana for transplant. Interestingly, eight states have passed legislation prohibiting withholding transplant evaluation for marijuana users if it is solely based on their marijuana use.5 In the 5 years since that study was published, there have been major changes in the legality of marijuana. A future study of interest could assess how these changes have affected the position of transplant centers.
The sociopolitical and transplant medicine worlds alike continue to adapt to the legalization of marijuana. While marijuana use is associated with adverse effects, its potential for benefit for a variety of medical conditions is an evolving area that has shown promise. It is therefore logical to view marijuana as a pharmacologic agent with potential for risks and benefits, but not necessarily a sole reason to exclude patients from listing for liver transplant. The current data are reassuring in that those who use marijuana and receive liver transplantation are not at higher risk of posttransplant complications, infections, or death when compared to those who do not use it. Should marijuana use exist in the context of substance use disorder or other behavioral and mental health issues, then the case warrants careful multidisciplinary evaluation prior to consideration for liver transplant. The aim of our discourse is not to encourage the use of marijuana in patients being considered for liver transplant but rather to discourage their exclusion from listing solely on the basis of marijuana use. In the pursuit of an equitable organ allocation system, our hope is that this work facilitates a more informed discussion and a change in policy in liver transplant programs that may still consider marijuana use an exclusion criterion.
Joven Tristeza, MD, and Thomas Ruli, MD, are residents in internal medicine at the University of Alabama at Birmingham; Mohamed Shoreibah, MD, is a specialist in gastroenterology and hepatology at the University of Alabama at Birmingham where he also serves on the faculty of the internal medicine residency program. The authors have no conflicts of interest.
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