Cover Story

Defining the Roadmap to Success for Patients With Alcohol-Related Liver Disease

Humans have enjoyed the intoxicating effects of alcohol as early as the Neolithic period around 10,000 BC. Unfortunately, research also suggests that the development of liver injury and disease related to alcohol use has existed almost as far back as the discovery of fermented beverages. Today, rates of problematic drinking, alcohol-related liver disease, and the subsequent outcomes of liver transplantation or mortality continue to rise both in the U.S. and globally.

While the exact prevalence is unknown, recent estimates suggest that 4.65% of adult Americans meet DSM-IV criteria for alcohol abuse and 3.81% meet the criteria for alcohol dependence. Fatty liver develops in 90% of individuals who drink more than 60g of alcohol per day but can also develop in those who drink less. According to a 2014 report from the World Health Organization, harmful alcohol use causes approximately 3.3 million deaths annually, corresponding to 5.9% of all deaths. The report also noted that harmful alcohol use correlated with 139 million disability-adjusted life years and 5.1% of the global burden of disease and injury.

Many experts consider ALD to be approaching epidemic levels if not already there and that requires increased attention. Because addiction is a chronic medical disorder that often exists alongside psychiatric disorders such as depression and anxiety, it is essential to keep in mind that prevention, treatment and management of ALD require a multi-disciplinary approach.

Keys to Management

For patients who present with ALD, the only effective medical treatment to improve long-term outcomes is controlling the risk factor of harmful alcohol consumption.

“Recognizing that patients with ALD suffer from two diseases including liver disease and alcohol use disorder, the management of these patients should be under an integrated program between hepatologists and addiction specialists to improve the long-term outcome of these patients and manage this epidemic,” Ashwani K. Singal, MD, MS, FACG, FAASLD, from the department of medicine at the University of South Dakota Sanford School of Medicine and division of transplant hepatology at the Avera McKennan University Hospital and Transplant Institute in South Dakota, told Healio Gastroenterology and Liver Disease. “We can see this as an epidemic as it is becoming the number one cause of liver disease all over the world. There are some centers in the U.S. where integrated care models exist in practice. However, in most centers, such a model does not exist, and studies are needed to develop strategies and logistics of creating such models in managing patients with ALD and alcohol-related hepatitis.”

Ashwani K. Singal

Singal discussed ALD in clinical practice from two points of view: identifying patients with risk factors and addressing rehabilitation prior to disease as point one, and managing patients with established ALD as point two.

The opportunities available to identify patients with ALD in primary or family care centers and in rehabilitation centers include noninvasive screening such as elevated liver enzymes along with ultrasound abnormalities. While ALD can be distinct from nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, they share similar signs and can often manifest together. From there, Singal explained, the key is to refer these patients to the right specialists including hepatologists and addiction specialists while also educating the patient on their risks for liver disease.

For patients presenting with ALD, often in the hospital with established complications such as cirrhosis or alcoholic hepatitis, there is unfortunately no currently approved medical treatment, so the only controllable risk factor is the harmful alcohol consumption. Singal also highlighted some important differences between ALD-related complications like cirrhosis and the diagnosis of alcohol-related hepatitis.

“Alcohol-related hepatitis is a unique clinical syndrome that can have a very high short-term mortality because these patients can progress to or present with acute-on-chronic liver failure,” he said. “Although there are not many attractive medications available at this time that can change that outcome, corticosteroids are something that in individual cases can improve the short-term mortality. On the long-term, however, it will still be important to address the alcohol consumption.”

The Looming Epidemic

The mean alcohol consumption in the world is approximately 6.2 liters of pure alcohol per person per year and up to 10.9 liters per year throughout Europe. Over the last decade, rates of alcohol consumption and subsequent liver disease, especially alcohol-related cirrhosis, have increased in many regions throughout the world with a few managing to reduce their rates.

One study presented at the 2019 International Liver Congress revealed marked increases in the prevalence of alcohol-related cirrhosis in North American men between 2013 and 2017. Prevalence rates increased significantly from 107.7 cases per 100,000 to 158.2 cases and was highest at 309.5 cases among men aged 60 years to 79 years compared with men aged 80 years or older. While incidence of alcohol-related cirrhosis remained relatively stable during the study period, the incidence rates were found to be highest in men aged 40 years to 59 years (97.4 per 100,000) compared with men aged 80 years or older.

“Over the last two decades, efforts to increase awareness of heavy drinking and improve access to care for alcoholic cirrhosis patients have been implemented,” Hassan Azhari, MD, from the University of Calgary in Canada, said during his presentation at the meeting. “However, the impact of these efforts has not been fully evaluated. We undertook this study to describe the epidemiology of alcoholic cirrhosis in a large North American cohort.”

According to the 2018 EASL clinical practice guidelines for managing alcohol-related liver disease, there was a slight decrease in the overall level of alcohol consumption in Europe between 1990 and 2014 due to decreases in the richest countries in the central western European Union and Mediterranean parts of the region. However, alcohol consumption levels remained stable for the past 25 years in central eastern EU and increased during the last two decades in the United Kingdom, Finland, and the eastern and southeastern parts of the WHO European Regions.

Prevention as Intervention

Douglas A. Simonetto

“As gastroenterologists, we are well-trained to recognize and manage alcohol-related liver disease and its complications,” Douglas A. Simonetto, MD, from the division of gastroenterology and hepatology at the Mayo Clinic College of Medicine in Minnesota, told Healio Gastroenterology and Liver Disease. “However, less attention is usually paid to the underlying problem of alcohol use disorder (AUD). Comprehensive psychosocial history and counselling are an essential part of our job given that alcohol abstinence is the most effective treatment of ALD.”

In a study published in Clinical Gastroenterology and Hepatology, Simonetto and colleagues found that early alcohol rehabilitation reduced 30-day hospital readmission, alcohol relapse and mortality among patients hospitalized for alcohol-related hepatitis.

Results from both a test cohort and validation cohort showed that 30-day readmission rates (test, P = .02; validation, P = .07), 30-day alcohol relapse rates (test, P , .001; validation, P , .001), and overall mortality rates (adjusted HR = 0.2; 95% CI, 0.05-0.56) were lower in those who attended alcohol rehabilitation compared with patients who did not.

“Early diagnosis of ALD and early AUD treatment are the key for better outcomes. Unfortunately, advanced liver disease or alcohol-related hepatitis may progress despite sustained alcohol abstinence, thus identifying patients at risk early is paramount,” Simonetto said. “Patients admitted with alcohol-related liver disease should not be discharged from the hospital without a treatment plan for AUD in place. In the outpatient setting, set aside enough time to discuss treatment of AUD and involve an addiction expert or counselor with experience treating patients with underlying liver disease if possible.”

Simonetto also addressed the stigma surrounding AUD, which can lead patients to underreport their alcohol consumption and refuse the assistance of psychiatrists or addiction counselors. Speaking to a patient about addiction treatment can be challenging initially, he explained, but should be addressed the same way one would comfortably discuss management of ascites or hepatic encephalopathy.

“As gastroenterologists we have the advantage of being able to explain to patients the potential complications of ALD and risk of disease progression in detail, but if we don’t highlight treatment options for AUD then patients may not appreciate their importance,” he said. “Additionally, rather than asking patients whether they are interested in meeting with a psychiatrist, we should first lay the pharmacological and nonpharmacological options available and then refer to addiction experts to help implement them.”

Changing Landscape of Liver Transplantation

Liver transplantation remains the final options for patients with severe complications from ALD, especially alcohol-related hepatitis. With rates of ALD as the indication for LT increasing, researchers and clinicians are looking for ways to improve selection and posttreatment outcomes.

“While rates of alcohol misuse and alcohol-associated liver disease have definitely increased, alcohol has always been a dominant cause of liver disease,” Brian P. Lee, MD, from the Department of Gastroenterology and Hepatology at the University of California San Francisco, told Healio Gastroenterology and Liver Disease. “Now that hepatitis C has declined due to antiviral therapy, and transplant providers are more accepting of ‘early liver transplantation’ for ALD, this has led to become the most common indication for liver transplant in the United States.”

Brian P. Lee

To minimize the risk for alcohol relapse posttransplant that can lead to further disease development, most transplant centers have required a minimum of 6 months abstinence before liver transplantation will be considered for a patient with ALD. However, many experts are arguing against this decision as a blanket criterion for all patients and discussing “early LT” options for those with ALD. The American College of Gastroenterology clinical guideline for ALD specifically states in its recommendations that “the decision on LT evaluation should not be based solely on minimum 6 months of alcohol abstinence, and other criteria should be taken into consideration.”

Lee provided details regarding the ACCELERATE-AH consortium study that confirmed a prior European pilot experience. Results revealed that early LT in patients with severe alcoholic hepatitis can achieve good intermediate survival with a probability of 3-year survival of 84% and a rate of sustained alcohol use of 17%. Additionally, these patients had rates of alcohol use matching historic transplant cohorts for alcohol-associated cirrhosis.

“The caveat is that these patients are very carefully selected — they are at high-risk of short-term mortality without transplant, and expected to adhere to lifelong abstinence based on their psychosocial profile despite a short duration of sobriety,” Lee said. “Also, given that early transplant for alcoholic hepatitis is a relatively new indication for transplant, long-term outcomes are largely unknown. Lastly, whether these results can be generalized to the broader ALD population (not just alcoholic hepatitis) is understudied.”

While most of the patients in the study who underwent early LT remained abstinent after transplant, Lee advised that sustained alcohol posttransplant was the strongest predictor of graft failure and patient mortality, so interventions to prevent and treat posttransplant alcohol use are critical.

“The ACCELERATE-AH study found that most patients with alcohol use after transplant were able to regain sobriety (ie, slips),” he said. “Most centers routinely monitor for alcohol use after transplant at each posttransplant visit with a combination of clinical interview supplemented by biochemical testing that can detect recent alcohol use (either ethyl glucuronide or phosphatidylethanol). Biochemical tests can be sent with routine posttransplant tests and can be a helpful tool to assist with monitoring alcohol use. Building a strong therapeutic relationship with patients is important to maximize patient openness and willingness to engage in recommended interventions.”

Monitoring Relapse

As Lee mentioned, monitoring for relapse is as important for a patient who underwent LT to treat ALD as is the early conversations with a patient at risk for developing ALD. This must be done with care and understanding, however, as a patient may feel punished rather than aided.

Robert M. Weinrieb

“Once a person is caught in the cycle of their addiction, it becomes very difficult for them to break out of that cycle successfully on their own,” Robert M. Weinrieb, MD, FACLP, chief psychiatric consultant at the Penn Transplant Institute, told Healio Gastroenterology and Liver Disease. “In other words, most of our patients are quite ashamed of the reason they need a transplant, but that was not enough to get them to change their behaviors, nor can they rearrange their genetics.”

Weinrieb explained that while LT patients with AUD have a responsibility to themselves, their families and to society, they cannot change what led them to their addiction. When the decision is made to treat a patient with transplantation for AUD, it is important to provide them with a “roadmap to learn better ways of coping and managing their lives” in the same way a patient with diabetes uses insulin and the knowledge of their disease to be successful in their own health care.

“Patients must be informed from the outset that we are going to monitor their sobriety, not because we want to ‘catch them’ and take them off the list, but because we understand that AUDs can be tricky, and when patients are first learning to manage their AUD, monitoring them is another means of support,” Weinrieb said. “Secondly, we need to know how to ask them about relapse without making them feel even more ashamed or criticized than they already do. We’ve gained their trust; we need a plan to get them back on track and involving their support network will strengthen that plan.”

Weinrieb mirrored Lee’s points about using phosphatidylethanol, a blood test that confirms alcohol use within the prior 3 weeks to 4 weeks, in both pre- and posttransplant patients with AUD. This can help determine those best suited for LT and for early LT. With these tests, Weinrieb said that more unreported drinking has been uncovered lately than previously recognized.

“If we can use that information to guide people toward adequate treatment for their AUD, then I’d say we are using it ethically and hopefully, effectively,” he said. – by Talitha Bennett

Disclosures: Lee, Simonetto and Weinrieb report no relevant financial disclosures. Singal reports he was on the speakers bureau for Bayer, and Bristol-Meyers Squibb and Gilead; has served on advisory boards for AbbVie, Bayer, Eisai, Exact Sciences, Gilead, Roche and Wako Diagnostics; serves as a consultant to Bayer, Glycotest, Eisai and Roche; and has received research funding from AbbVie and Gilead.

Humans have enjoyed the intoxicating effects of alcohol as early as the Neolithic period around 10,000 BC. Unfortunately, research also suggests that the development of liver injury and disease related to alcohol use has existed almost as far back as the discovery of fermented beverages. Today, rates of problematic drinking, alcohol-related liver disease, and the subsequent outcomes of liver transplantation or mortality continue to rise both in the U.S. and globally.

While the exact prevalence is unknown, recent estimates suggest that 4.65% of adult Americans meet DSM-IV criteria for alcohol abuse and 3.81% meet the criteria for alcohol dependence. Fatty liver develops in 90% of individuals who drink more than 60g of alcohol per day but can also develop in those who drink less. According to a 2014 report from the World Health Organization, harmful alcohol use causes approximately 3.3 million deaths annually, corresponding to 5.9% of all deaths. The report also noted that harmful alcohol use correlated with 139 million disability-adjusted life years and 5.1% of the global burden of disease and injury.

Many experts consider ALD to be approaching epidemic levels if not already there and that requires increased attention. Because addiction is a chronic medical disorder that often exists alongside psychiatric disorders such as depression and anxiety, it is essential to keep in mind that prevention, treatment and management of ALD require a multi-disciplinary approach.

Keys to Management

For patients who present with ALD, the only effective medical treatment to improve long-term outcomes is controlling the risk factor of harmful alcohol consumption.

“Recognizing that patients with ALD suffer from two diseases including liver disease and alcohol use disorder, the management of these patients should be under an integrated program between hepatologists and addiction specialists to improve the long-term outcome of these patients and manage this epidemic,” Ashwani K. Singal, MD, MS, FACG, FAASLD, from the department of medicine at the University of South Dakota Sanford School of Medicine and division of transplant hepatology at the Avera McKennan University Hospital and Transplant Institute in South Dakota, told Healio Gastroenterology and Liver Disease. “We can see this as an epidemic as it is becoming the number one cause of liver disease all over the world. There are some centers in the U.S. where integrated care models exist in practice. However, in most centers, such a model does not exist, and studies are needed to develop strategies and logistics of creating such models in managing patients with ALD and alcohol-related hepatitis.”

Ashwani K. Singal

Singal discussed ALD in clinical practice from two points of view: identifying patients with risk factors and addressing rehabilitation prior to disease as point one, and managing patients with established ALD as point two.

The opportunities available to identify patients with ALD in primary or family care centers and in rehabilitation centers include noninvasive screening such as elevated liver enzymes along with ultrasound abnormalities. While ALD can be distinct from nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, they share similar signs and can often manifest together. From there, Singal explained, the key is to refer these patients to the right specialists including hepatologists and addiction specialists while also educating the patient on their risks for liver disease.

PAGE BREAK

For patients presenting with ALD, often in the hospital with established complications such as cirrhosis or alcoholic hepatitis, there is unfortunately no currently approved medical treatment, so the only controllable risk factor is the harmful alcohol consumption. Singal also highlighted some important differences between ALD-related complications like cirrhosis and the diagnosis of alcohol-related hepatitis.

“Alcohol-related hepatitis is a unique clinical syndrome that can have a very high short-term mortality because these patients can progress to or present with acute-on-chronic liver failure,” he said. “Although there are not many attractive medications available at this time that can change that outcome, corticosteroids are something that in individual cases can improve the short-term mortality. On the long-term, however, it will still be important to address the alcohol consumption.”

The Looming Epidemic

The mean alcohol consumption in the world is approximately 6.2 liters of pure alcohol per person per year and up to 10.9 liters per year throughout Europe. Over the last decade, rates of alcohol consumption and subsequent liver disease, especially alcohol-related cirrhosis, have increased in many regions throughout the world with a few managing to reduce their rates.

One study presented at the 2019 International Liver Congress revealed marked increases in the prevalence of alcohol-related cirrhosis in North American men between 2013 and 2017. Prevalence rates increased significantly from 107.7 cases per 100,000 to 158.2 cases and was highest at 309.5 cases among men aged 60 years to 79 years compared with men aged 80 years or older. While incidence of alcohol-related cirrhosis remained relatively stable during the study period, the incidence rates were found to be highest in men aged 40 years to 59 years (97.4 per 100,000) compared with men aged 80 years or older.

“Over the last two decades, efforts to increase awareness of heavy drinking and improve access to care for alcoholic cirrhosis patients have been implemented,” Hassan Azhari, MD, from the University of Calgary in Canada, said during his presentation at the meeting. “However, the impact of these efforts has not been fully evaluated. We undertook this study to describe the epidemiology of alcoholic cirrhosis in a large North American cohort.”

According to the 2018 EASL clinical practice guidelines for managing alcohol-related liver disease, there was a slight decrease in the overall level of alcohol consumption in Europe between 1990 and 2014 due to decreases in the richest countries in the central western European Union and Mediterranean parts of the region. However, alcohol consumption levels remained stable for the past 25 years in central eastern EU and increased during the last two decades in the United Kingdom, Finland, and the eastern and southeastern parts of the WHO European Regions.

Prevention as Intervention

Douglas A. Simonetto

“As gastroenterologists, we are well-trained to recognize and manage alcohol-related liver disease and its complications,” Douglas A. Simonetto, MD, from the division of gastroenterology and hepatology at the Mayo Clinic College of Medicine in Minnesota, told Healio Gastroenterology and Liver Disease. “However, less attention is usually paid to the underlying problem of alcohol use disorder (AUD). Comprehensive psychosocial history and counselling are an essential part of our job given that alcohol abstinence is the most effective treatment of ALD.”

In a study published in Clinical Gastroenterology and Hepatology, Simonetto and colleagues found that early alcohol rehabilitation reduced 30-day hospital readmission, alcohol relapse and mortality among patients hospitalized for alcohol-related hepatitis.

PAGE BREAK

Results from both a test cohort and validation cohort showed that 30-day readmission rates (test, P = .02; validation, P = .07), 30-day alcohol relapse rates (test, P , .001; validation, P , .001), and overall mortality rates (adjusted HR = 0.2; 95% CI, 0.05-0.56) were lower in those who attended alcohol rehabilitation compared with patients who did not.

“Early diagnosis of ALD and early AUD treatment are the key for better outcomes. Unfortunately, advanced liver disease or alcohol-related hepatitis may progress despite sustained alcohol abstinence, thus identifying patients at risk early is paramount,” Simonetto said. “Patients admitted with alcohol-related liver disease should not be discharged from the hospital without a treatment plan for AUD in place. In the outpatient setting, set aside enough time to discuss treatment of AUD and involve an addiction expert or counselor with experience treating patients with underlying liver disease if possible.”

Simonetto also addressed the stigma surrounding AUD, which can lead patients to underreport their alcohol consumption and refuse the assistance of psychiatrists or addiction counselors. Speaking to a patient about addiction treatment can be challenging initially, he explained, but should be addressed the same way one would comfortably discuss management of ascites or hepatic encephalopathy.

“As gastroenterologists we have the advantage of being able to explain to patients the potential complications of ALD and risk of disease progression in detail, but if we don’t highlight treatment options for AUD then patients may not appreciate their importance,” he said. “Additionally, rather than asking patients whether they are interested in meeting with a psychiatrist, we should first lay the pharmacological and nonpharmacological options available and then refer to addiction experts to help implement them.”

Changing Landscape of Liver Transplantation

Liver transplantation remains the final options for patients with severe complications from ALD, especially alcohol-related hepatitis. With rates of ALD as the indication for LT increasing, researchers and clinicians are looking for ways to improve selection and posttreatment outcomes.

“While rates of alcohol misuse and alcohol-associated liver disease have definitely increased, alcohol has always been a dominant cause of liver disease,” Brian P. Lee, MD, from the Department of Gastroenterology and Hepatology at the University of California San Francisco, told Healio Gastroenterology and Liver Disease. “Now that hepatitis C has declined due to antiviral therapy, and transplant providers are more accepting of ‘early liver transplantation’ for ALD, this has led to become the most common indication for liver transplant in the United States.”

Brian P. Lee

To minimize the risk for alcohol relapse posttransplant that can lead to further disease development, most transplant centers have required a minimum of 6 months abstinence before liver transplantation will be considered for a patient with ALD. However, many experts are arguing against this decision as a blanket criterion for all patients and discussing “early LT” options for those with ALD. The American College of Gastroenterology clinical guideline for ALD specifically states in its recommendations that “the decision on LT evaluation should not be based solely on minimum 6 months of alcohol abstinence, and other criteria should be taken into consideration.”

Lee provided details regarding the ACCELERATE-AH consortium study that confirmed a prior European pilot experience. Results revealed that early LT in patients with severe alcoholic hepatitis can achieve good intermediate survival with a probability of 3-year survival of 84% and a rate of sustained alcohol use of 17%. Additionally, these patients had rates of alcohol use matching historic transplant cohorts for alcohol-associated cirrhosis.

PAGE BREAK

“The caveat is that these patients are very carefully selected — they are at high-risk of short-term mortality without transplant, and expected to adhere to lifelong abstinence based on their psychosocial profile despite a short duration of sobriety,” Lee said. “Also, given that early transplant for alcoholic hepatitis is a relatively new indication for transplant, long-term outcomes are largely unknown. Lastly, whether these results can be generalized to the broader ALD population (not just alcoholic hepatitis) is understudied.”

While most of the patients in the study who underwent early LT remained abstinent after transplant, Lee advised that sustained alcohol posttransplant was the strongest predictor of graft failure and patient mortality, so interventions to prevent and treat posttransplant alcohol use are critical.

“The ACCELERATE-AH study found that most patients with alcohol use after transplant were able to regain sobriety (ie, slips),” he said. “Most centers routinely monitor for alcohol use after transplant at each posttransplant visit with a combination of clinical interview supplemented by biochemical testing that can detect recent alcohol use (either ethyl glucuronide or phosphatidylethanol). Biochemical tests can be sent with routine posttransplant tests and can be a helpful tool to assist with monitoring alcohol use. Building a strong therapeutic relationship with patients is important to maximize patient openness and willingness to engage in recommended interventions.”

Monitoring Relapse

As Lee mentioned, monitoring for relapse is as important for a patient who underwent LT to treat ALD as is the early conversations with a patient at risk for developing ALD. This must be done with care and understanding, however, as a patient may feel punished rather than aided.

Robert M. Weinrieb

“Once a person is caught in the cycle of their addiction, it becomes very difficult for them to break out of that cycle successfully on their own,” Robert M. Weinrieb, MD, FACLP, chief psychiatric consultant at the Penn Transplant Institute, told Healio Gastroenterology and Liver Disease. “In other words, most of our patients are quite ashamed of the reason they need a transplant, but that was not enough to get them to change their behaviors, nor can they rearrange their genetics.”

Weinrieb explained that while LT patients with AUD have a responsibility to themselves, their families and to society, they cannot change what led them to their addiction. When the decision is made to treat a patient with transplantation for AUD, it is important to provide them with a “roadmap to learn better ways of coping and managing their lives” in the same way a patient with diabetes uses insulin and the knowledge of their disease to be successful in their own health care.

PAGE BREAK

“Patients must be informed from the outset that we are going to monitor their sobriety, not because we want to ‘catch them’ and take them off the list, but because we understand that AUDs can be tricky, and when patients are first learning to manage their AUD, monitoring them is another means of support,” Weinrieb said. “Secondly, we need to know how to ask them about relapse without making them feel even more ashamed or criticized than they already do. We’ve gained their trust; we need a plan to get them back on track and involving their support network will strengthen that plan.”

Weinrieb mirrored Lee’s points about using phosphatidylethanol, a blood test that confirms alcohol use within the prior 3 weeks to 4 weeks, in both pre- and posttransplant patients with AUD. This can help determine those best suited for LT and for early LT. With these tests, Weinrieb said that more unreported drinking has been uncovered lately than previously recognized.

“If we can use that information to guide people toward adequate treatment for their AUD, then I’d say we are using it ethically and hopefully, effectively,” he said. – by Talitha Bennett

Disclosures: Lee, Simonetto and Weinrieb report no relevant financial disclosures. Singal reports he was on the speakers bureau for Bayer, and Bristol-Meyers Squibb and Gilead; has served on advisory boards for AbbVie, Bayer, Eisai, Exact Sciences, Gilead, Roche and Wako Diagnostics; serves as a consultant to Bayer, Glycotest, Eisai and Roche; and has received research funding from AbbVie and Gilead.