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Statins and the liver: Not harmful and perhaps beneficial
, including glucose intolerance and hyperlipidemia. A lingering concern about potential hepatotoxicity has resulted in widespread reluctance to prescribe statins to treat hyperlipidemia in patients with liver disease; however, their safety in this setting has been documented in the literature as well as in clinical practice. Therefore, statins should not be withheld in patients with liver disease when indicated — with a few caveats. Baseline liver chemistries should be obtained. After initiation of statin therapy, a modest rise in serum aminotransferase levels may occur but is not an indication to discontinue the drug. In fact, monitoring of liver biochemical tests more frequently than is appropriate for any patient with chronic liver disease is unnecessary. The role of statins in cirrhosis may even expand, as recent reports suggest that statin use in patients with cirrhosis may slow the progression of liver disease and reduce the frequency of complications, such as hepatocellular carcinoma. These observations, however, require confirmation before statins can be suggested for any indication other than treating hyperlipidemia in patients with chronic liver disease, and statins are generally not appropriate in patients with decompensated cirrhosis.
Pearls from the Pros was published in Gastro Hep Advances .
Dr. Friedman is the Anton R. Fried, MD, Chair of the Department of Medicine at Newton-Wellesley Hospital in Newton, Mass., and assistant chief of medicine at Massachusetts General Hospital, and a professor of medicine at Harvard Medical School and Tufts University, Boston. Dr. Martin is chief of the division of digestive health and liver diseases at the University of Miami, where he is the Mandel Chair of Gastroenterology. The authors disclose no conflicts.
, including glucose intolerance and hyperlipidemia. A lingering concern about potential hepatotoxicity has resulted in widespread reluctance to prescribe statins to treat hyperlipidemia in patients with liver disease; however, their safety in this setting has been documented in the literature as well as in clinical practice. Therefore, statins should not be withheld in patients with liver disease when indicated — with a few caveats. Baseline liver chemistries should be obtained. After initiation of statin therapy, a modest rise in serum aminotransferase levels may occur but is not an indication to discontinue the drug. In fact, monitoring of liver biochemical tests more frequently than is appropriate for any patient with chronic liver disease is unnecessary. The role of statins in cirrhosis may even expand, as recent reports suggest that statin use in patients with cirrhosis may slow the progression of liver disease and reduce the frequency of complications, such as hepatocellular carcinoma. These observations, however, require confirmation before statins can be suggested for any indication other than treating hyperlipidemia in patients with chronic liver disease, and statins are generally not appropriate in patients with decompensated cirrhosis.
Pearls from the Pros was published in Gastro Hep Advances .
Dr. Friedman is the Anton R. Fried, MD, Chair of the Department of Medicine at Newton-Wellesley Hospital in Newton, Mass., and assistant chief of medicine at Massachusetts General Hospital, and a professor of medicine at Harvard Medical School and Tufts University, Boston. Dr. Martin is chief of the division of digestive health and liver diseases at the University of Miami, where he is the Mandel Chair of Gastroenterology. The authors disclose no conflicts.
, including glucose intolerance and hyperlipidemia. A lingering concern about potential hepatotoxicity has resulted in widespread reluctance to prescribe statins to treat hyperlipidemia in patients with liver disease; however, their safety in this setting has been documented in the literature as well as in clinical practice. Therefore, statins should not be withheld in patients with liver disease when indicated — with a few caveats. Baseline liver chemistries should be obtained. After initiation of statin therapy, a modest rise in serum aminotransferase levels may occur but is not an indication to discontinue the drug. In fact, monitoring of liver biochemical tests more frequently than is appropriate for any patient with chronic liver disease is unnecessary. The role of statins in cirrhosis may even expand, as recent reports suggest that statin use in patients with cirrhosis may slow the progression of liver disease and reduce the frequency of complications, such as hepatocellular carcinoma. These observations, however, require confirmation before statins can be suggested for any indication other than treating hyperlipidemia in patients with chronic liver disease, and statins are generally not appropriate in patients with decompensated cirrhosis.
Pearls from the Pros was published in Gastro Hep Advances .
Dr. Friedman is the Anton R. Fried, MD, Chair of the Department of Medicine at Newton-Wellesley Hospital in Newton, Mass., and assistant chief of medicine at Massachusetts General Hospital, and a professor of medicine at Harvard Medical School and Tufts University, Boston. Dr. Martin is chief of the division of digestive health and liver diseases at the University of Miami, where he is the Mandel Chair of Gastroenterology. The authors disclose no conflicts.
AGA CPU updates usage of vasoactive drugs, IV albumin, for cirrhosis
The publication, authored by Vincent Wai-Sun Wong, MBChB, MD, and colleagues, includes 12 best-practice-advice statements concerning 3 common clinical scenarios: variceal hemorrhage, ascites and spontaneous bacterial peritonitis, and acute kidney injury and hepatorenal syndrome.
These complications of liver decompensation “are manifestations of portal hypertension with a [consequent] vasodilatory–hyperdynamic circulatory state, resulting in progressive decreases in effective arterial blood volume and renal perfusion,” the update authors wrote in November in Gastroenterology. “Because a potent vasoconstrictor, terlipressin, was recently approved by the United States Food and Drug Administration and because recent trials have explored use of intravenous albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and intravenous albumin in these 3 specific scenarios.”
Variceal Hemorrhage
Comprising 70% of all upper GI hemorrhage in patients with cirrhosis, and carrying a 6-week mortality rate as high as 43%, Dr. Wong and colleagues advise immediate initiation of vasoactive drugs upon suspision of variceal hemorrhage, ideally before therapeutic and/or diagnostic endoscopy.
“The goals of management of acute variceal hemorrhage include initial hemostasis, preventing early rebleeding, and reducing in-hospital and 6-week mortality,” they wrote, noting that vasoactive drugs are effective at stopping bleeding in up to 8 out of 10 cases.
In patients with acute variceal hemorrhage undergoing endoscopic hemostasis, vasoactive agents should be continued for 2-5 days to prevent early rebleeding, according to the second best-practice-advice statement.
The third statement suggests octreotide as the drug of choice for variceal hemorrhage due to its favorable safety profile.
“Nowadays, vasopressin is no longer advised in patients with acute variceal hemorrhage because of a high risk of cardiovascular adverse events,” the update authors noted.
Ascites and Spontaneous Bacterial Peritonitis
In cases requiring large-volume (greater than 5 L) paracentesis, intravenous albumin should be administered at time of fluid removal, according to the update. In these patients, albumin reduces the risk of post-paracentesis circulatory dysfunction (defined as an increase in plasma renin activity), thereby reducing the risk of acute kidney injury.
Intravenous albumin should also be considered in patients with spontaneous bacterial peritonitis as this can overcome associated vasodilatation and decreased effective arterial blood volume, which may lead to acute kidney injury if untreated. In contrast, because of a demonstrated lack of efficacy, albumin is not advised in infections other than spontaneous bacterial peritonitis, unless associated with acute kidney injury.
Long-term albumin administration should be avoided in patients with cirrhosis and uncomplicated ascites, whether they are hospitalized or not, as evidence is lacking to support a consistent beneficial effect.
The update also advises against vasoconstrictors in patients with uncomplicated ascites, bacterial peritonitis, and after large-volume paracentesis, again due to a lack of supporting evidence.
Acute Kidney Injury and Hepatorenal Syndrome
In hospitalized patients with cirrhosis and ascites presenting with acute kidney injury, Dr. Wong and colleagues called albumin “the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with acute kidney injury,” however, the authors caution the dose of albumin “should be tailored to the volume status of the patient.”
The update authors suggested that terlipressin and norepinephrine are suitable options for patients with cirrhosis and the hepatorenal syndrome; however, they suggest terlipressin above the others based on available evidence and suggested concomitant albumin administration as it may further improve renal blood flow by filling the central circulation.
Terlipressin also has the advantage (over norepinephrine) of being administrable via a peripheral line without the need for intensive care unit monitoring, the update authors wrote. The agent is contraindicated in patients with hypoxia or with coronary, peripheral, or mesenteric ischemia, and it should be used with caution in patients with ACLF grade 3, according to the publication. Risks of terlipressin may also outweigh benefits in patients with a serum creatine greater than 5 mg/dL and those listed for transplant with a MELD score of 35 or higher.
The Clinical Practice Update was commissioned and supported by AGA. The authors disclosed relationships with Advanz, Boehringer Ingelheim, 89bio, and others.
The publication, authored by Vincent Wai-Sun Wong, MBChB, MD, and colleagues, includes 12 best-practice-advice statements concerning 3 common clinical scenarios: variceal hemorrhage, ascites and spontaneous bacterial peritonitis, and acute kidney injury and hepatorenal syndrome.
These complications of liver decompensation “are manifestations of portal hypertension with a [consequent] vasodilatory–hyperdynamic circulatory state, resulting in progressive decreases in effective arterial blood volume and renal perfusion,” the update authors wrote in November in Gastroenterology. “Because a potent vasoconstrictor, terlipressin, was recently approved by the United States Food and Drug Administration and because recent trials have explored use of intravenous albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and intravenous albumin in these 3 specific scenarios.”
Variceal Hemorrhage
Comprising 70% of all upper GI hemorrhage in patients with cirrhosis, and carrying a 6-week mortality rate as high as 43%, Dr. Wong and colleagues advise immediate initiation of vasoactive drugs upon suspision of variceal hemorrhage, ideally before therapeutic and/or diagnostic endoscopy.
“The goals of management of acute variceal hemorrhage include initial hemostasis, preventing early rebleeding, and reducing in-hospital and 6-week mortality,” they wrote, noting that vasoactive drugs are effective at stopping bleeding in up to 8 out of 10 cases.
In patients with acute variceal hemorrhage undergoing endoscopic hemostasis, vasoactive agents should be continued for 2-5 days to prevent early rebleeding, according to the second best-practice-advice statement.
The third statement suggests octreotide as the drug of choice for variceal hemorrhage due to its favorable safety profile.
“Nowadays, vasopressin is no longer advised in patients with acute variceal hemorrhage because of a high risk of cardiovascular adverse events,” the update authors noted.
Ascites and Spontaneous Bacterial Peritonitis
In cases requiring large-volume (greater than 5 L) paracentesis, intravenous albumin should be administered at time of fluid removal, according to the update. In these patients, albumin reduces the risk of post-paracentesis circulatory dysfunction (defined as an increase in plasma renin activity), thereby reducing the risk of acute kidney injury.
Intravenous albumin should also be considered in patients with spontaneous bacterial peritonitis as this can overcome associated vasodilatation and decreased effective arterial blood volume, which may lead to acute kidney injury if untreated. In contrast, because of a demonstrated lack of efficacy, albumin is not advised in infections other than spontaneous bacterial peritonitis, unless associated with acute kidney injury.
Long-term albumin administration should be avoided in patients with cirrhosis and uncomplicated ascites, whether they are hospitalized or not, as evidence is lacking to support a consistent beneficial effect.
The update also advises against vasoconstrictors in patients with uncomplicated ascites, bacterial peritonitis, and after large-volume paracentesis, again due to a lack of supporting evidence.
Acute Kidney Injury and Hepatorenal Syndrome
In hospitalized patients with cirrhosis and ascites presenting with acute kidney injury, Dr. Wong and colleagues called albumin “the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with acute kidney injury,” however, the authors caution the dose of albumin “should be tailored to the volume status of the patient.”
The update authors suggested that terlipressin and norepinephrine are suitable options for patients with cirrhosis and the hepatorenal syndrome; however, they suggest terlipressin above the others based on available evidence and suggested concomitant albumin administration as it may further improve renal blood flow by filling the central circulation.
Terlipressin also has the advantage (over norepinephrine) of being administrable via a peripheral line without the need for intensive care unit monitoring, the update authors wrote. The agent is contraindicated in patients with hypoxia or with coronary, peripheral, or mesenteric ischemia, and it should be used with caution in patients with ACLF grade 3, according to the publication. Risks of terlipressin may also outweigh benefits in patients with a serum creatine greater than 5 mg/dL and those listed for transplant with a MELD score of 35 or higher.
The Clinical Practice Update was commissioned and supported by AGA. The authors disclosed relationships with Advanz, Boehringer Ingelheim, 89bio, and others.
The publication, authored by Vincent Wai-Sun Wong, MBChB, MD, and colleagues, includes 12 best-practice-advice statements concerning 3 common clinical scenarios: variceal hemorrhage, ascites and spontaneous bacterial peritonitis, and acute kidney injury and hepatorenal syndrome.
These complications of liver decompensation “are manifestations of portal hypertension with a [consequent] vasodilatory–hyperdynamic circulatory state, resulting in progressive decreases in effective arterial blood volume and renal perfusion,” the update authors wrote in November in Gastroenterology. “Because a potent vasoconstrictor, terlipressin, was recently approved by the United States Food and Drug Administration and because recent trials have explored use of intravenous albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and intravenous albumin in these 3 specific scenarios.”
Variceal Hemorrhage
Comprising 70% of all upper GI hemorrhage in patients with cirrhosis, and carrying a 6-week mortality rate as high as 43%, Dr. Wong and colleagues advise immediate initiation of vasoactive drugs upon suspision of variceal hemorrhage, ideally before therapeutic and/or diagnostic endoscopy.
“The goals of management of acute variceal hemorrhage include initial hemostasis, preventing early rebleeding, and reducing in-hospital and 6-week mortality,” they wrote, noting that vasoactive drugs are effective at stopping bleeding in up to 8 out of 10 cases.
In patients with acute variceal hemorrhage undergoing endoscopic hemostasis, vasoactive agents should be continued for 2-5 days to prevent early rebleeding, according to the second best-practice-advice statement.
The third statement suggests octreotide as the drug of choice for variceal hemorrhage due to its favorable safety profile.
“Nowadays, vasopressin is no longer advised in patients with acute variceal hemorrhage because of a high risk of cardiovascular adverse events,” the update authors noted.
Ascites and Spontaneous Bacterial Peritonitis
In cases requiring large-volume (greater than 5 L) paracentesis, intravenous albumin should be administered at time of fluid removal, according to the update. In these patients, albumin reduces the risk of post-paracentesis circulatory dysfunction (defined as an increase in plasma renin activity), thereby reducing the risk of acute kidney injury.
Intravenous albumin should also be considered in patients with spontaneous bacterial peritonitis as this can overcome associated vasodilatation and decreased effective arterial blood volume, which may lead to acute kidney injury if untreated. In contrast, because of a demonstrated lack of efficacy, albumin is not advised in infections other than spontaneous bacterial peritonitis, unless associated with acute kidney injury.
Long-term albumin administration should be avoided in patients with cirrhosis and uncomplicated ascites, whether they are hospitalized or not, as evidence is lacking to support a consistent beneficial effect.
The update also advises against vasoconstrictors in patients with uncomplicated ascites, bacterial peritonitis, and after large-volume paracentesis, again due to a lack of supporting evidence.
Acute Kidney Injury and Hepatorenal Syndrome
In hospitalized patients with cirrhosis and ascites presenting with acute kidney injury, Dr. Wong and colleagues called albumin “the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with acute kidney injury,” however, the authors caution the dose of albumin “should be tailored to the volume status of the patient.”
The update authors suggested that terlipressin and norepinephrine are suitable options for patients with cirrhosis and the hepatorenal syndrome; however, they suggest terlipressin above the others based on available evidence and suggested concomitant albumin administration as it may further improve renal blood flow by filling the central circulation.
Terlipressin also has the advantage (over norepinephrine) of being administrable via a peripheral line without the need for intensive care unit monitoring, the update authors wrote. The agent is contraindicated in patients with hypoxia or with coronary, peripheral, or mesenteric ischemia, and it should be used with caution in patients with ACLF grade 3, according to the publication. Risks of terlipressin may also outweigh benefits in patients with a serum creatine greater than 5 mg/dL and those listed for transplant with a MELD score of 35 or higher.
The Clinical Practice Update was commissioned and supported by AGA. The authors disclosed relationships with Advanz, Boehringer Ingelheim, 89bio, and others.
FROM GASTROENTEROLOGY
Fewer than 1 out of 4 patients with HCV-related liver cancer receive antivirals
, and rates aren’t much better for patients seen by specialists, based on a retrospective analysis of private insurance claims.
The study also showed that patients receiving DAAs lived significantly longer, emphasizing the importance of prescribing these medications to all eligible patients, reported principal investigator Mindie H. Nguyen, MD, AGAF,, of Stanford University Medical Center, Palo Alto, California, and colleagues.
“Prior studies have shown evidence of improved survival among HCV-related HCC patients who received DAA treatment, but not much is known about the current DAA utilization among these patients in the general US population,” said lead author Leslie Y. Kam, MD, a postdoctoral scholar in gastroenterology at Stanford Medicine, who presented the findings in November at the annual meeting of the American Association for the Study of Liver Diseases.
To generate real-world data, the investigators analyzed medical records from 3922 patients in Optum’s Clinformatics Data Mart Database. All patients had private medical insurance and received care for HCV-related HCC between 2015 and 2021.
“Instead of using institutional databases which tend to bias toward highly specialized tertiary care center patients, our study uses a large, national sample of HCV-HCC patients that represents real-world DAA treatment rates and survival outcomes,” Dr. Kam said in a written comment.
Within this cohort, fewer than one out of four patients (23.5%) received DAA, a rate that Dr. Kam called “dismally low.”
Patients with either compensated or decompensated cirrhosis had higher treatment rates than those without cirrhosis (24.2% or 24.5%, respectively, vs. 16.2%; P = .001). The investigators noted that more than half of the patients had decompensated cirrhosis, suggesting that HCV-related HCC was diagnosed late in the disease course.
Receiving care from a gastroenterologist or infectious disease physician also was associated with a higher treatment rate. Patients managed by a gastroenterologist alone had a treatment rate of 27.0%, while those who received care from a gastroenterologist or infectious disease doctor alongside an oncologist had a treatment rate of 25.6%, versus just 9.4% for those who received care from an oncologist alone, and 12.4% among those who did not see a specialist of any kind (P = .005).
These findings highlight “the need for a multidisciplinary approach to care in this population,” Dr. Kam suggested.
Echoing previous research, DAAs were associated with extended survival. A significantly greater percentage of patients who received DAA were alive after 5 years, compared with patients who did not receive DAA (47.2% vs. 35.2%; P less than .001). After adjustment for comorbidities, HCC treatment, race/ethnicity, sex, and age, DAAs were associated with a 39% reduction in risk of death (adjusted hazard ratio, 0.61; 0.53-0.69; P less than .001).
“There were also racial ethnic disparities in patient survival whether patients received DAA or not, with Black patients having worse survival,” Dr. Kam said. “As such, our study highlights that awareness of HCV remains low as does the use of DAA treatment. Therefore, culturally appropriate efforts to improve awareness of HCV must continue among the general public and health care workers as well as efforts to provide point of care accurate and rapid screening tests for HCV so that DAA treatment can be initiated in a timely manner for eligible patients. Continual education on the use of DAA treatment is also needed.”
Robert John Fontana, MD, AGAF, professor of medicine and transplant hepatologist at the University of Michigan, Ann Arbor, described the findings as “frustrating,” and “not the kind of stuff I like to hear about.
“Treatment rates are so low,” Dr. Fontana said, noting that even among gastroenterologists and infectious disease doctors, who should be well-versed in DAAs, antivirals were prescribed less than 30% of the time.
In an interview, Dr. Fontana highlighted the benefits of DAAs, including their ease-of-use and effectiveness.
“Hepatitis C was the leading reason that we had to do liver transplants in the United States for years,” he said. “Then once these really amazing drugs called direct-acting antivirals came out, they changed the landscape very quickly. It really was a game changer for my whole practice, and, nationally, the practice of transplant.”
Yet, this study and others suggest that these practice-altering agents are being underutilized, Dr. Fontana said. A variety of reasons could explain suboptimal usage, he suggested, including lack of awareness among medical professionals and the public, the recency of DAA approvals, low HCV testing rates, lack of symptoms in HCV-positive patients, and medication costs.
This latter barrier, at least, is dissolving, Dr. Fontana said. Some payers initially restricted which providers could prescribe DAAs, but now the economic consensus has swung in their favor, since curing patients of HCV brings significant health care savings down the line. This financial advantage—theoretically multiplied across 4-5 million Americans living with HCV—has bolstered a multi-institutional effort toward universal HCV screening, with testing recommended at least once in every person’s lifetime.
“It’s highly cost effective,” Dr. Fontana said. “Even though the drugs are super expensive, you will reduce cost by preventing the people streaming towards liver cancer or streaming towards liver transplant. That’s why all the professional societies—the USPSTF, the CDC—they all say, ‘OK, screen everyone.’ ”
Screening may be getting easier soon, Dr. Fontana predicted, as at-home HCV-testing kits are on the horizon, with development and adoption likely accelerated by the success of at-home viral testing during the COVID-19 pandemic.
Beyond broader screening, Dr. Fontana suggested that greater awareness of DAAs is needed both within and beyond the medical community.
He advised health care providers who don’t yet feel comfortable diagnosing or treating HCV to refer to their local specialist.
“That’s the main message,” Dr. Fontana said. “I’m always eternally hopeful that every little message helps.”
The investigators and Dr. Fontana disclosed no conflicts of interest.
, and rates aren’t much better for patients seen by specialists, based on a retrospective analysis of private insurance claims.
The study also showed that patients receiving DAAs lived significantly longer, emphasizing the importance of prescribing these medications to all eligible patients, reported principal investigator Mindie H. Nguyen, MD, AGAF,, of Stanford University Medical Center, Palo Alto, California, and colleagues.
“Prior studies have shown evidence of improved survival among HCV-related HCC patients who received DAA treatment, but not much is known about the current DAA utilization among these patients in the general US population,” said lead author Leslie Y. Kam, MD, a postdoctoral scholar in gastroenterology at Stanford Medicine, who presented the findings in November at the annual meeting of the American Association for the Study of Liver Diseases.
To generate real-world data, the investigators analyzed medical records from 3922 patients in Optum’s Clinformatics Data Mart Database. All patients had private medical insurance and received care for HCV-related HCC between 2015 and 2021.
“Instead of using institutional databases which tend to bias toward highly specialized tertiary care center patients, our study uses a large, national sample of HCV-HCC patients that represents real-world DAA treatment rates and survival outcomes,” Dr. Kam said in a written comment.
Within this cohort, fewer than one out of four patients (23.5%) received DAA, a rate that Dr. Kam called “dismally low.”
Patients with either compensated or decompensated cirrhosis had higher treatment rates than those without cirrhosis (24.2% or 24.5%, respectively, vs. 16.2%; P = .001). The investigators noted that more than half of the patients had decompensated cirrhosis, suggesting that HCV-related HCC was diagnosed late in the disease course.
Receiving care from a gastroenterologist or infectious disease physician also was associated with a higher treatment rate. Patients managed by a gastroenterologist alone had a treatment rate of 27.0%, while those who received care from a gastroenterologist or infectious disease doctor alongside an oncologist had a treatment rate of 25.6%, versus just 9.4% for those who received care from an oncologist alone, and 12.4% among those who did not see a specialist of any kind (P = .005).
These findings highlight “the need for a multidisciplinary approach to care in this population,” Dr. Kam suggested.
Echoing previous research, DAAs were associated with extended survival. A significantly greater percentage of patients who received DAA were alive after 5 years, compared with patients who did not receive DAA (47.2% vs. 35.2%; P less than .001). After adjustment for comorbidities, HCC treatment, race/ethnicity, sex, and age, DAAs were associated with a 39% reduction in risk of death (adjusted hazard ratio, 0.61; 0.53-0.69; P less than .001).
“There were also racial ethnic disparities in patient survival whether patients received DAA or not, with Black patients having worse survival,” Dr. Kam said. “As such, our study highlights that awareness of HCV remains low as does the use of DAA treatment. Therefore, culturally appropriate efforts to improve awareness of HCV must continue among the general public and health care workers as well as efforts to provide point of care accurate and rapid screening tests for HCV so that DAA treatment can be initiated in a timely manner for eligible patients. Continual education on the use of DAA treatment is also needed.”
Robert John Fontana, MD, AGAF, professor of medicine and transplant hepatologist at the University of Michigan, Ann Arbor, described the findings as “frustrating,” and “not the kind of stuff I like to hear about.
“Treatment rates are so low,” Dr. Fontana said, noting that even among gastroenterologists and infectious disease doctors, who should be well-versed in DAAs, antivirals were prescribed less than 30% of the time.
In an interview, Dr. Fontana highlighted the benefits of DAAs, including their ease-of-use and effectiveness.
“Hepatitis C was the leading reason that we had to do liver transplants in the United States for years,” he said. “Then once these really amazing drugs called direct-acting antivirals came out, they changed the landscape very quickly. It really was a game changer for my whole practice, and, nationally, the practice of transplant.”
Yet, this study and others suggest that these practice-altering agents are being underutilized, Dr. Fontana said. A variety of reasons could explain suboptimal usage, he suggested, including lack of awareness among medical professionals and the public, the recency of DAA approvals, low HCV testing rates, lack of symptoms in HCV-positive patients, and medication costs.
This latter barrier, at least, is dissolving, Dr. Fontana said. Some payers initially restricted which providers could prescribe DAAs, but now the economic consensus has swung in their favor, since curing patients of HCV brings significant health care savings down the line. This financial advantage—theoretically multiplied across 4-5 million Americans living with HCV—has bolstered a multi-institutional effort toward universal HCV screening, with testing recommended at least once in every person’s lifetime.
“It’s highly cost effective,” Dr. Fontana said. “Even though the drugs are super expensive, you will reduce cost by preventing the people streaming towards liver cancer or streaming towards liver transplant. That’s why all the professional societies—the USPSTF, the CDC—they all say, ‘OK, screen everyone.’ ”
Screening may be getting easier soon, Dr. Fontana predicted, as at-home HCV-testing kits are on the horizon, with development and adoption likely accelerated by the success of at-home viral testing during the COVID-19 pandemic.
Beyond broader screening, Dr. Fontana suggested that greater awareness of DAAs is needed both within and beyond the medical community.
He advised health care providers who don’t yet feel comfortable diagnosing or treating HCV to refer to their local specialist.
“That’s the main message,” Dr. Fontana said. “I’m always eternally hopeful that every little message helps.”
The investigators and Dr. Fontana disclosed no conflicts of interest.
, and rates aren’t much better for patients seen by specialists, based on a retrospective analysis of private insurance claims.
The study also showed that patients receiving DAAs lived significantly longer, emphasizing the importance of prescribing these medications to all eligible patients, reported principal investigator Mindie H. Nguyen, MD, AGAF,, of Stanford University Medical Center, Palo Alto, California, and colleagues.
“Prior studies have shown evidence of improved survival among HCV-related HCC patients who received DAA treatment, but not much is known about the current DAA utilization among these patients in the general US population,” said lead author Leslie Y. Kam, MD, a postdoctoral scholar in gastroenterology at Stanford Medicine, who presented the findings in November at the annual meeting of the American Association for the Study of Liver Diseases.
To generate real-world data, the investigators analyzed medical records from 3922 patients in Optum’s Clinformatics Data Mart Database. All patients had private medical insurance and received care for HCV-related HCC between 2015 and 2021.
“Instead of using institutional databases which tend to bias toward highly specialized tertiary care center patients, our study uses a large, national sample of HCV-HCC patients that represents real-world DAA treatment rates and survival outcomes,” Dr. Kam said in a written comment.
Within this cohort, fewer than one out of four patients (23.5%) received DAA, a rate that Dr. Kam called “dismally low.”
Patients with either compensated or decompensated cirrhosis had higher treatment rates than those without cirrhosis (24.2% or 24.5%, respectively, vs. 16.2%; P = .001). The investigators noted that more than half of the patients had decompensated cirrhosis, suggesting that HCV-related HCC was diagnosed late in the disease course.
Receiving care from a gastroenterologist or infectious disease physician also was associated with a higher treatment rate. Patients managed by a gastroenterologist alone had a treatment rate of 27.0%, while those who received care from a gastroenterologist or infectious disease doctor alongside an oncologist had a treatment rate of 25.6%, versus just 9.4% for those who received care from an oncologist alone, and 12.4% among those who did not see a specialist of any kind (P = .005).
These findings highlight “the need for a multidisciplinary approach to care in this population,” Dr. Kam suggested.
Echoing previous research, DAAs were associated with extended survival. A significantly greater percentage of patients who received DAA were alive after 5 years, compared with patients who did not receive DAA (47.2% vs. 35.2%; P less than .001). After adjustment for comorbidities, HCC treatment, race/ethnicity, sex, and age, DAAs were associated with a 39% reduction in risk of death (adjusted hazard ratio, 0.61; 0.53-0.69; P less than .001).
“There were also racial ethnic disparities in patient survival whether patients received DAA or not, with Black patients having worse survival,” Dr. Kam said. “As such, our study highlights that awareness of HCV remains low as does the use of DAA treatment. Therefore, culturally appropriate efforts to improve awareness of HCV must continue among the general public and health care workers as well as efforts to provide point of care accurate and rapid screening tests for HCV so that DAA treatment can be initiated in a timely manner for eligible patients. Continual education on the use of DAA treatment is also needed.”
Robert John Fontana, MD, AGAF, professor of medicine and transplant hepatologist at the University of Michigan, Ann Arbor, described the findings as “frustrating,” and “not the kind of stuff I like to hear about.
“Treatment rates are so low,” Dr. Fontana said, noting that even among gastroenterologists and infectious disease doctors, who should be well-versed in DAAs, antivirals were prescribed less than 30% of the time.
In an interview, Dr. Fontana highlighted the benefits of DAAs, including their ease-of-use and effectiveness.
“Hepatitis C was the leading reason that we had to do liver transplants in the United States for years,” he said. “Then once these really amazing drugs called direct-acting antivirals came out, they changed the landscape very quickly. It really was a game changer for my whole practice, and, nationally, the practice of transplant.”
Yet, this study and others suggest that these practice-altering agents are being underutilized, Dr. Fontana said. A variety of reasons could explain suboptimal usage, he suggested, including lack of awareness among medical professionals and the public, the recency of DAA approvals, low HCV testing rates, lack of symptoms in HCV-positive patients, and medication costs.
This latter barrier, at least, is dissolving, Dr. Fontana said. Some payers initially restricted which providers could prescribe DAAs, but now the economic consensus has swung in their favor, since curing patients of HCV brings significant health care savings down the line. This financial advantage—theoretically multiplied across 4-5 million Americans living with HCV—has bolstered a multi-institutional effort toward universal HCV screening, with testing recommended at least once in every person’s lifetime.
“It’s highly cost effective,” Dr. Fontana said. “Even though the drugs are super expensive, you will reduce cost by preventing the people streaming towards liver cancer or streaming towards liver transplant. That’s why all the professional societies—the USPSTF, the CDC—they all say, ‘OK, screen everyone.’ ”
Screening may be getting easier soon, Dr. Fontana predicted, as at-home HCV-testing kits are on the horizon, with development and adoption likely accelerated by the success of at-home viral testing during the COVID-19 pandemic.
Beyond broader screening, Dr. Fontana suggested that greater awareness of DAAs is needed both within and beyond the medical community.
He advised health care providers who don’t yet feel comfortable diagnosing or treating HCV to refer to their local specialist.
“That’s the main message,” Dr. Fontana said. “I’m always eternally hopeful that every little message helps.”
The investigators and Dr. Fontana disclosed no conflicts of interest.
AT THE LIVER MEETING
Taste and smell changes linked with worse QOL and cognition in cirrhosis, renal failure
than those who do not exhibit these sensory changes, according to investigators.
Clinicians should screen for changes in taste and smell among patients at risk of cognitive changes, and offer nutritional interventions to support body weight and QOL, reported principal investigator Jasmohan S. Bajaj, MD, AGAF, of Virginia Commonwealth University, Richmond, and colleagues.
“Cirrhosis is linked with poor nutrition, which could partly be due to anorexia in hepatic encephalopathy (HE) and coexistent renal failure,” the investigators wrote in their abstract, which Dr. Bajaj presented in November at the annual meeting of the American Association for the Study of Liver Diseases.
“We wanted to measure how changes in the brain in cirrhosis affect patients’ abilities to smell and taste, and study how that affects their quality of life,” Dr. Bajaj said in a written comment.
To this end, the investigators conducted an observational study involving 59 participants, among whom 22 were healthy, 21 had cirrhosis, and 16 had renal failure requiring dialysis.
“Prior studies individually have shown changes in taste and smell for these two organ failures,” Dr. Bajaj said. “We studied them together as well and linked these to quality of life and individual cognitive tests.”
Of note, individuals with past or current COVID-19, or with current or recent alcohol or tobacco use, were excluded.
Compared with healthy individuals, participants with cirrhosis or renal failure had significantly worse performance on a taste discrimination test, with perceptions of sweet and sour most affected.
Cognitive measurement with Psychometric Hepatic Encephalopathy Score (PHES) and Stroop tests showed that scores were worse for patients with disease than those without. Taste discrimination significantly correlated with both cognitive test scores, regardless of HE or dialysis, whereas smell only correlated with the Stroop test.
Multivariable analysis revealed that better PHES scores and smell discrimination were linked with better taste discrimination. Similarly, better PHES scores and taste discrimination contributed to better smell discrimination. Eating impairment was associated with worse Stroop scores and worse olfactory-related QOL, suggesting that sensory changes, cognitive changes, and eating behaviors were all correlated.
“Health care providers ought to be alert to changes in patients’ eating habits, diet and weight as their liver and kidney disease worsen and as their brain function changes,” Dr. Bajaj said. “Nutritionists and others may be able to assist patients with a healthy diet and suggest ways to improve patients’ reports of their quality of life. Taste and smell are just a few aspects of the complicated assessment of health-related quality of life, brain dysfunction, and nutritional compromise in cirrhosis. We need to be mindful to not just focus on these aspects but to individualize care.”
Adrian M. Di Bisceglie, MD, hepatologist and emeritus professor of internal medicine at Saint Louis University, said the study was “well done,” and called the findings “an interesting little tidbit” that would probably not change his practice as a physician, but could be valuable for designing nutritional interventions.
In an interview, Dr. Di Bisceglie explained that a well-balanced diet with adequate caloric intake can help slow the muscle wasting that occurs with the condition, but creating a tasty menu can be challenging when patients are asked to restrict their sodium intake as a means of reducing fluid retention.
“Salt contributes substantially to the enjoyment of food,” Dr. Di Bisceglie said.
Although the study did not specifically report the salt level in patients’ diets, Dr. Di Bisceglie said the findings highlight the need for low-salt strategies to improve palatability. For example, he suggested increasing umami, or savory flavor, as this can be accomplished without adding a significant amount of salt.
When asked if changes in taste or smell might be used as simple screening tools to detect cognitive impairment in patients with cirrhosis, Dr. Di Bisceglie said that this might be “possible,” but is probably unnecessary.
“There is an easy bedside test that we’ve been using for decades [to predict hepatic encephalopathy], which is reading,” Dr. Di Bisceglie said, noting that patients with cognitive deficits often describe reading paragraphs repeatedly without comprehending what they have read.
The investigators and Dr. Di Bisceglie disclosed no conflicts of interest.
than those who do not exhibit these sensory changes, according to investigators.
Clinicians should screen for changes in taste and smell among patients at risk of cognitive changes, and offer nutritional interventions to support body weight and QOL, reported principal investigator Jasmohan S. Bajaj, MD, AGAF, of Virginia Commonwealth University, Richmond, and colleagues.
“Cirrhosis is linked with poor nutrition, which could partly be due to anorexia in hepatic encephalopathy (HE) and coexistent renal failure,” the investigators wrote in their abstract, which Dr. Bajaj presented in November at the annual meeting of the American Association for the Study of Liver Diseases.
“We wanted to measure how changes in the brain in cirrhosis affect patients’ abilities to smell and taste, and study how that affects their quality of life,” Dr. Bajaj said in a written comment.
To this end, the investigators conducted an observational study involving 59 participants, among whom 22 were healthy, 21 had cirrhosis, and 16 had renal failure requiring dialysis.
“Prior studies individually have shown changes in taste and smell for these two organ failures,” Dr. Bajaj said. “We studied them together as well and linked these to quality of life and individual cognitive tests.”
Of note, individuals with past or current COVID-19, or with current or recent alcohol or tobacco use, were excluded.
Compared with healthy individuals, participants with cirrhosis or renal failure had significantly worse performance on a taste discrimination test, with perceptions of sweet and sour most affected.
Cognitive measurement with Psychometric Hepatic Encephalopathy Score (PHES) and Stroop tests showed that scores were worse for patients with disease than those without. Taste discrimination significantly correlated with both cognitive test scores, regardless of HE or dialysis, whereas smell only correlated with the Stroop test.
Multivariable analysis revealed that better PHES scores and smell discrimination were linked with better taste discrimination. Similarly, better PHES scores and taste discrimination contributed to better smell discrimination. Eating impairment was associated with worse Stroop scores and worse olfactory-related QOL, suggesting that sensory changes, cognitive changes, and eating behaviors were all correlated.
“Health care providers ought to be alert to changes in patients’ eating habits, diet and weight as their liver and kidney disease worsen and as their brain function changes,” Dr. Bajaj said. “Nutritionists and others may be able to assist patients with a healthy diet and suggest ways to improve patients’ reports of their quality of life. Taste and smell are just a few aspects of the complicated assessment of health-related quality of life, brain dysfunction, and nutritional compromise in cirrhosis. We need to be mindful to not just focus on these aspects but to individualize care.”
Adrian M. Di Bisceglie, MD, hepatologist and emeritus professor of internal medicine at Saint Louis University, said the study was “well done,” and called the findings “an interesting little tidbit” that would probably not change his practice as a physician, but could be valuable for designing nutritional interventions.
In an interview, Dr. Di Bisceglie explained that a well-balanced diet with adequate caloric intake can help slow the muscle wasting that occurs with the condition, but creating a tasty menu can be challenging when patients are asked to restrict their sodium intake as a means of reducing fluid retention.
“Salt contributes substantially to the enjoyment of food,” Dr. Di Bisceglie said.
Although the study did not specifically report the salt level in patients’ diets, Dr. Di Bisceglie said the findings highlight the need for low-salt strategies to improve palatability. For example, he suggested increasing umami, or savory flavor, as this can be accomplished without adding a significant amount of salt.
When asked if changes in taste or smell might be used as simple screening tools to detect cognitive impairment in patients with cirrhosis, Dr. Di Bisceglie said that this might be “possible,” but is probably unnecessary.
“There is an easy bedside test that we’ve been using for decades [to predict hepatic encephalopathy], which is reading,” Dr. Di Bisceglie said, noting that patients with cognitive deficits often describe reading paragraphs repeatedly without comprehending what they have read.
The investigators and Dr. Di Bisceglie disclosed no conflicts of interest.
than those who do not exhibit these sensory changes, according to investigators.
Clinicians should screen for changes in taste and smell among patients at risk of cognitive changes, and offer nutritional interventions to support body weight and QOL, reported principal investigator Jasmohan S. Bajaj, MD, AGAF, of Virginia Commonwealth University, Richmond, and colleagues.
“Cirrhosis is linked with poor nutrition, which could partly be due to anorexia in hepatic encephalopathy (HE) and coexistent renal failure,” the investigators wrote in their abstract, which Dr. Bajaj presented in November at the annual meeting of the American Association for the Study of Liver Diseases.
“We wanted to measure how changes in the brain in cirrhosis affect patients’ abilities to smell and taste, and study how that affects their quality of life,” Dr. Bajaj said in a written comment.
To this end, the investigators conducted an observational study involving 59 participants, among whom 22 were healthy, 21 had cirrhosis, and 16 had renal failure requiring dialysis.
“Prior studies individually have shown changes in taste and smell for these two organ failures,” Dr. Bajaj said. “We studied them together as well and linked these to quality of life and individual cognitive tests.”
Of note, individuals with past or current COVID-19, or with current or recent alcohol or tobacco use, were excluded.
Compared with healthy individuals, participants with cirrhosis or renal failure had significantly worse performance on a taste discrimination test, with perceptions of sweet and sour most affected.
Cognitive measurement with Psychometric Hepatic Encephalopathy Score (PHES) and Stroop tests showed that scores were worse for patients with disease than those without. Taste discrimination significantly correlated with both cognitive test scores, regardless of HE or dialysis, whereas smell only correlated with the Stroop test.
Multivariable analysis revealed that better PHES scores and smell discrimination were linked with better taste discrimination. Similarly, better PHES scores and taste discrimination contributed to better smell discrimination. Eating impairment was associated with worse Stroop scores and worse olfactory-related QOL, suggesting that sensory changes, cognitive changes, and eating behaviors were all correlated.
“Health care providers ought to be alert to changes in patients’ eating habits, diet and weight as their liver and kidney disease worsen and as their brain function changes,” Dr. Bajaj said. “Nutritionists and others may be able to assist patients with a healthy diet and suggest ways to improve patients’ reports of their quality of life. Taste and smell are just a few aspects of the complicated assessment of health-related quality of life, brain dysfunction, and nutritional compromise in cirrhosis. We need to be mindful to not just focus on these aspects but to individualize care.”
Adrian M. Di Bisceglie, MD, hepatologist and emeritus professor of internal medicine at Saint Louis University, said the study was “well done,” and called the findings “an interesting little tidbit” that would probably not change his practice as a physician, but could be valuable for designing nutritional interventions.
In an interview, Dr. Di Bisceglie explained that a well-balanced diet with adequate caloric intake can help slow the muscle wasting that occurs with the condition, but creating a tasty menu can be challenging when patients are asked to restrict their sodium intake as a means of reducing fluid retention.
“Salt contributes substantially to the enjoyment of food,” Dr. Di Bisceglie said.
Although the study did not specifically report the salt level in patients’ diets, Dr. Di Bisceglie said the findings highlight the need for low-salt strategies to improve palatability. For example, he suggested increasing umami, or savory flavor, as this can be accomplished without adding a significant amount of salt.
When asked if changes in taste or smell might be used as simple screening tools to detect cognitive impairment in patients with cirrhosis, Dr. Di Bisceglie said that this might be “possible,” but is probably unnecessary.
“There is an easy bedside test that we’ve been using for decades [to predict hepatic encephalopathy], which is reading,” Dr. Di Bisceglie said, noting that patients with cognitive deficits often describe reading paragraphs repeatedly without comprehending what they have read.
The investigators and Dr. Di Bisceglie disclosed no conflicts of interest.
AT THE LIVER MEETING
COVID livers are safe for transplant
, based on a national study with the longest follow-up to date.
Using livers from deceased patients with COVID-19 could be an opportunity expand organ availability, reported principal investigator Nadim Mahmud, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Findings were presented in November at the annual meeting of the American Association for the Study of Liver Diseases.
“During the COVID-19 pandemic, a few centers trialed transplanting solid organs from COVID-19 positive donors with promising initial results,” presenting author Roy X. Wang, MD, of the University of Pennsylvania, said in a written comment. “However, these were smaller experiences with short follow-up that were not exclusively focused on liver transplantation. We wanted to explore the safety of liver transplantation from COVID-19 positive donors using a large national dataset with the longest follow up time to date.”
The dataset included 13,096 COVID-negative donors and 299 COVID-positive donors who died between July 2020 and July 2022, with cases and controls matched via propensity scoring. COVID-positive donors were significantly more likely to be younger and have died of brain death. Beyond this difference in age, no significant demographic differences were detected.
After 1 year of follow-up, no statistically significant differences in patient survival (subhazard ratio, 1.11; log-rank P = .70) or allograft survival (hazard ratio, 1.44; log-rank P = .14) were detected when comparing livers transplanted from positive versus negative donors.
“Our findings support and expand upon the results from earlier studies,” Dr. Wang concluded. “Liver transplant from COVID-19-positive donors has acceptable short-term outcomes and may represent an opportunity to expand organ access.”
Still, more work is needed to assess other clinical metrics and long-term outcomes, he added.
“While we were able to show similar patient and graft survival post-transplant between COVID-19-positive and negative donors, rates of other complications were not investigated such as episodes of rejection, liver injury, and hospitalizations,” Dr. Wang said. “Due to data limitations, we are only able to report on outcomes up to 1 year post transplant. Additional investigation will be needed to continue monitoring future outcomes and identifying any differences between recipients of COVID-19-positive and negative donors.”
Timucin Taner, MD, PhD, division chair of transplant surgery at Mayo Clinic, Rochester, Minnesota, said the study is important because it reaffirms the majority opinion among transplant physicians: These livers are safe.
In an interview, Dr. Taner suggested that Dr. Wang’s call for longer term data is “mostly science speak,” since 1 year of follow-up should be sufficient to determine liver viability.
“If a liver from a COVID-19 donor behaved well for a year, then chances are it’s not going to behave badly [later on] because of the virus at the time of donation,” Dr. Taner said.
He said the reported trends in usage of COVID-positive livers reflect early hesitancy that waned with rising vaccination rates, and recognition that the virus could not be spread via liver donation.
“To date, the only transmission [of SARS-CoV-2] from a transplant has been from a lung transplant,” Dr. Taner said, “and that was back in the days that we didn’t know about this. Other organs don’t transmit the disease, so they are easily usable.”
These new data should further increase confidence among both health care providers and patients, he added.
“[This study is] reassuring to the patients on the waitlist that these organs are very safe to use,” Dr. Taner said. “We as the transplant society are comfortable using them without any hesitation.”
The investigators and Dr. Taner disclosed no conflicts of interest.
, based on a national study with the longest follow-up to date.
Using livers from deceased patients with COVID-19 could be an opportunity expand organ availability, reported principal investigator Nadim Mahmud, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Findings were presented in November at the annual meeting of the American Association for the Study of Liver Diseases.
“During the COVID-19 pandemic, a few centers trialed transplanting solid organs from COVID-19 positive donors with promising initial results,” presenting author Roy X. Wang, MD, of the University of Pennsylvania, said in a written comment. “However, these were smaller experiences with short follow-up that were not exclusively focused on liver transplantation. We wanted to explore the safety of liver transplantation from COVID-19 positive donors using a large national dataset with the longest follow up time to date.”
The dataset included 13,096 COVID-negative donors and 299 COVID-positive donors who died between July 2020 and July 2022, with cases and controls matched via propensity scoring. COVID-positive donors were significantly more likely to be younger and have died of brain death. Beyond this difference in age, no significant demographic differences were detected.
After 1 year of follow-up, no statistically significant differences in patient survival (subhazard ratio, 1.11; log-rank P = .70) or allograft survival (hazard ratio, 1.44; log-rank P = .14) were detected when comparing livers transplanted from positive versus negative donors.
“Our findings support and expand upon the results from earlier studies,” Dr. Wang concluded. “Liver transplant from COVID-19-positive donors has acceptable short-term outcomes and may represent an opportunity to expand organ access.”
Still, more work is needed to assess other clinical metrics and long-term outcomes, he added.
“While we were able to show similar patient and graft survival post-transplant between COVID-19-positive and negative donors, rates of other complications were not investigated such as episodes of rejection, liver injury, and hospitalizations,” Dr. Wang said. “Due to data limitations, we are only able to report on outcomes up to 1 year post transplant. Additional investigation will be needed to continue monitoring future outcomes and identifying any differences between recipients of COVID-19-positive and negative donors.”
Timucin Taner, MD, PhD, division chair of transplant surgery at Mayo Clinic, Rochester, Minnesota, said the study is important because it reaffirms the majority opinion among transplant physicians: These livers are safe.
In an interview, Dr. Taner suggested that Dr. Wang’s call for longer term data is “mostly science speak,” since 1 year of follow-up should be sufficient to determine liver viability.
“If a liver from a COVID-19 donor behaved well for a year, then chances are it’s not going to behave badly [later on] because of the virus at the time of donation,” Dr. Taner said.
He said the reported trends in usage of COVID-positive livers reflect early hesitancy that waned with rising vaccination rates, and recognition that the virus could not be spread via liver donation.
“To date, the only transmission [of SARS-CoV-2] from a transplant has been from a lung transplant,” Dr. Taner said, “and that was back in the days that we didn’t know about this. Other organs don’t transmit the disease, so they are easily usable.”
These new data should further increase confidence among both health care providers and patients, he added.
“[This study is] reassuring to the patients on the waitlist that these organs are very safe to use,” Dr. Taner said. “We as the transplant society are comfortable using them without any hesitation.”
The investigators and Dr. Taner disclosed no conflicts of interest.
, based on a national study with the longest follow-up to date.
Using livers from deceased patients with COVID-19 could be an opportunity expand organ availability, reported principal investigator Nadim Mahmud, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Findings were presented in November at the annual meeting of the American Association for the Study of Liver Diseases.
“During the COVID-19 pandemic, a few centers trialed transplanting solid organs from COVID-19 positive donors with promising initial results,” presenting author Roy X. Wang, MD, of the University of Pennsylvania, said in a written comment. “However, these were smaller experiences with short follow-up that were not exclusively focused on liver transplantation. We wanted to explore the safety of liver transplantation from COVID-19 positive donors using a large national dataset with the longest follow up time to date.”
The dataset included 13,096 COVID-negative donors and 299 COVID-positive donors who died between July 2020 and July 2022, with cases and controls matched via propensity scoring. COVID-positive donors were significantly more likely to be younger and have died of brain death. Beyond this difference in age, no significant demographic differences were detected.
After 1 year of follow-up, no statistically significant differences in patient survival (subhazard ratio, 1.11; log-rank P = .70) or allograft survival (hazard ratio, 1.44; log-rank P = .14) were detected when comparing livers transplanted from positive versus negative donors.
“Our findings support and expand upon the results from earlier studies,” Dr. Wang concluded. “Liver transplant from COVID-19-positive donors has acceptable short-term outcomes and may represent an opportunity to expand organ access.”
Still, more work is needed to assess other clinical metrics and long-term outcomes, he added.
“While we were able to show similar patient and graft survival post-transplant between COVID-19-positive and negative donors, rates of other complications were not investigated such as episodes of rejection, liver injury, and hospitalizations,” Dr. Wang said. “Due to data limitations, we are only able to report on outcomes up to 1 year post transplant. Additional investigation will be needed to continue monitoring future outcomes and identifying any differences between recipients of COVID-19-positive and negative donors.”
Timucin Taner, MD, PhD, division chair of transplant surgery at Mayo Clinic, Rochester, Minnesota, said the study is important because it reaffirms the majority opinion among transplant physicians: These livers are safe.
In an interview, Dr. Taner suggested that Dr. Wang’s call for longer term data is “mostly science speak,” since 1 year of follow-up should be sufficient to determine liver viability.
“If a liver from a COVID-19 donor behaved well for a year, then chances are it’s not going to behave badly [later on] because of the virus at the time of donation,” Dr. Taner said.
He said the reported trends in usage of COVID-positive livers reflect early hesitancy that waned with rising vaccination rates, and recognition that the virus could not be spread via liver donation.
“To date, the only transmission [of SARS-CoV-2] from a transplant has been from a lung transplant,” Dr. Taner said, “and that was back in the days that we didn’t know about this. Other organs don’t transmit the disease, so they are easily usable.”
These new data should further increase confidence among both health care providers and patients, he added.
“[This study is] reassuring to the patients on the waitlist that these organs are very safe to use,” Dr. Taner said. “We as the transplant society are comfortable using them without any hesitation.”
The investigators and Dr. Taner disclosed no conflicts of interest.
AT THE LIVER MEETING
More than one-third of adults in the US could have NAFLD by 2050
, according to investigators.
These findings suggest that health care systems should prepare for “large increases” in cases of hepatocellular carcinoma (HCC) and need for liver transplants, reported lead author Phuc Le, PhD, MPH, of the Cleveland Clinic, and colleagues.
“Following the alarming rise in prevalence of obesity and diabetes, NAFLD is projected to become the leading indication for liver transplant in the United States in the next decade,” Dr. Le and colleagues wrote in their abstract for the annual meeting of the American Association for the Study of Liver Diseases. “A better understanding of the clinical burden associated with NAFLD will enable health systems to prepare to meet this imminent demand from patients.”
To this end, Dr. Le and colleagues developed an agent-based state transition model to predict future prevalence of NAFLD and associated outcomes.
In the first part of the model, the investigators simulated population growth in the United States using Census Bureau data, including new births and immigration, from the year 2000 onward. The second part of the model simulated natural progression of NAFLD in adults via 14 associated conditions and events, including steatosis, nonalcoholic steatohepatitis (NASH), HCC, liver transplants, liver-related mortality, and others.
By first comparing simulated findings with actual findings between 2000 and 2018, the investigators confirmed that their model could reliably predict the intended epidemiological parameters.
Next, they turned their model toward the future.
It predicted that the prevalence of NAFLD among US adults will rise from 27.8% in 2020 to 34.3% in 2050. Over the same timeframe, prevalence of NASH is predicted to increase from 20.0% to 21.8%, proportion of NAFLD cases developing cirrhosis is expected to increase from 1.9% to 3.1%, and liver-related mortality is estimated to rise from 0.4% to 1% of all deaths.
The model also predicted that the burden of HCC will increase from 10,400 to 19,300 new cases per year, while liver transplant burden will more than double, from 1,700 to 4,200 transplants per year.
“Our model forecasts substantial clinical burden of NAFLD over the next three decades,” Dr. Le said in a virtual press conference. “And in the absence of effective treatments, health systems should plan for large increases in the number of liver cancer cases and the need for liver transplant.”
During the press conference, Norah Terrault, MD, president of the AASLD from the University of Southern California, Los Angeles, noted that all of the reported outcomes, including increasing rates of liver cancer, cirrhosis, and transplants are “potentially preventable.”
Dr. Terrault went on to suggest ways of combating this increasing burden of NAFLD, which she referred to as metabolic dysfunction–associated steatotic liver disease (MASLD), the name now recommended by the AASLD.
“There’s no way we’re going to be able to transplant our way out of this,” Dr. Terrault said. “We need to be bringing greater awareness both to patients, as well as to providers about how we seek out the diagnosis. And we need to bring greater awareness to the population around the things that contribute to MASLD.”
Rates of obesity and diabetes continue to rise, Dr. Terrault said, explaining why MASLD is more common than ever. To counteract these trends, she called for greater awareness of driving factors, such as dietary choices and sedentary lifestyle.
“These are all really important messages that we want to get out to the population, and are really the cornerstones for how we approach the management of patients who have MASLD,” Dr. Terrault said.
In discussion with Dr. Terrault, Dr. Le agreed that increased education may help stem the rising tide of disease, while treatment advances could also increase the odds of a brighter future.
“If we improve our management of NAFLD, or NAFLD-related comorbidities, and if we can develop an effective treatment for NAFLD, then obviously the future would not be so dark,” Dr. Le said, noting promising phase 3 data that would be presented at the meeting. “We are hopeful that the future of disease burden will not be as bad as our model predicts.”
The study was funded by the Agency for Healthcare Research and Quality. The investigators disclosed no conflicts of interest.
, according to investigators.
These findings suggest that health care systems should prepare for “large increases” in cases of hepatocellular carcinoma (HCC) and need for liver transplants, reported lead author Phuc Le, PhD, MPH, of the Cleveland Clinic, and colleagues.
“Following the alarming rise in prevalence of obesity and diabetes, NAFLD is projected to become the leading indication for liver transplant in the United States in the next decade,” Dr. Le and colleagues wrote in their abstract for the annual meeting of the American Association for the Study of Liver Diseases. “A better understanding of the clinical burden associated with NAFLD will enable health systems to prepare to meet this imminent demand from patients.”
To this end, Dr. Le and colleagues developed an agent-based state transition model to predict future prevalence of NAFLD and associated outcomes.
In the first part of the model, the investigators simulated population growth in the United States using Census Bureau data, including new births and immigration, from the year 2000 onward. The second part of the model simulated natural progression of NAFLD in adults via 14 associated conditions and events, including steatosis, nonalcoholic steatohepatitis (NASH), HCC, liver transplants, liver-related mortality, and others.
By first comparing simulated findings with actual findings between 2000 and 2018, the investigators confirmed that their model could reliably predict the intended epidemiological parameters.
Next, they turned their model toward the future.
It predicted that the prevalence of NAFLD among US adults will rise from 27.8% in 2020 to 34.3% in 2050. Over the same timeframe, prevalence of NASH is predicted to increase from 20.0% to 21.8%, proportion of NAFLD cases developing cirrhosis is expected to increase from 1.9% to 3.1%, and liver-related mortality is estimated to rise from 0.4% to 1% of all deaths.
The model also predicted that the burden of HCC will increase from 10,400 to 19,300 new cases per year, while liver transplant burden will more than double, from 1,700 to 4,200 transplants per year.
“Our model forecasts substantial clinical burden of NAFLD over the next three decades,” Dr. Le said in a virtual press conference. “And in the absence of effective treatments, health systems should plan for large increases in the number of liver cancer cases and the need for liver transplant.”
During the press conference, Norah Terrault, MD, president of the AASLD from the University of Southern California, Los Angeles, noted that all of the reported outcomes, including increasing rates of liver cancer, cirrhosis, and transplants are “potentially preventable.”
Dr. Terrault went on to suggest ways of combating this increasing burden of NAFLD, which she referred to as metabolic dysfunction–associated steatotic liver disease (MASLD), the name now recommended by the AASLD.
“There’s no way we’re going to be able to transplant our way out of this,” Dr. Terrault said. “We need to be bringing greater awareness both to patients, as well as to providers about how we seek out the diagnosis. And we need to bring greater awareness to the population around the things that contribute to MASLD.”
Rates of obesity and diabetes continue to rise, Dr. Terrault said, explaining why MASLD is more common than ever. To counteract these trends, she called for greater awareness of driving factors, such as dietary choices and sedentary lifestyle.
“These are all really important messages that we want to get out to the population, and are really the cornerstones for how we approach the management of patients who have MASLD,” Dr. Terrault said.
In discussion with Dr. Terrault, Dr. Le agreed that increased education may help stem the rising tide of disease, while treatment advances could also increase the odds of a brighter future.
“If we improve our management of NAFLD, or NAFLD-related comorbidities, and if we can develop an effective treatment for NAFLD, then obviously the future would not be so dark,” Dr. Le said, noting promising phase 3 data that would be presented at the meeting. “We are hopeful that the future of disease burden will not be as bad as our model predicts.”
The study was funded by the Agency for Healthcare Research and Quality. The investigators disclosed no conflicts of interest.
, according to investigators.
These findings suggest that health care systems should prepare for “large increases” in cases of hepatocellular carcinoma (HCC) and need for liver transplants, reported lead author Phuc Le, PhD, MPH, of the Cleveland Clinic, and colleagues.
“Following the alarming rise in prevalence of obesity and diabetes, NAFLD is projected to become the leading indication for liver transplant in the United States in the next decade,” Dr. Le and colleagues wrote in their abstract for the annual meeting of the American Association for the Study of Liver Diseases. “A better understanding of the clinical burden associated with NAFLD will enable health systems to prepare to meet this imminent demand from patients.”
To this end, Dr. Le and colleagues developed an agent-based state transition model to predict future prevalence of NAFLD and associated outcomes.
In the first part of the model, the investigators simulated population growth in the United States using Census Bureau data, including new births and immigration, from the year 2000 onward. The second part of the model simulated natural progression of NAFLD in adults via 14 associated conditions and events, including steatosis, nonalcoholic steatohepatitis (NASH), HCC, liver transplants, liver-related mortality, and others.
By first comparing simulated findings with actual findings between 2000 and 2018, the investigators confirmed that their model could reliably predict the intended epidemiological parameters.
Next, they turned their model toward the future.
It predicted that the prevalence of NAFLD among US adults will rise from 27.8% in 2020 to 34.3% in 2050. Over the same timeframe, prevalence of NASH is predicted to increase from 20.0% to 21.8%, proportion of NAFLD cases developing cirrhosis is expected to increase from 1.9% to 3.1%, and liver-related mortality is estimated to rise from 0.4% to 1% of all deaths.
The model also predicted that the burden of HCC will increase from 10,400 to 19,300 new cases per year, while liver transplant burden will more than double, from 1,700 to 4,200 transplants per year.
“Our model forecasts substantial clinical burden of NAFLD over the next three decades,” Dr. Le said in a virtual press conference. “And in the absence of effective treatments, health systems should plan for large increases in the number of liver cancer cases and the need for liver transplant.”
During the press conference, Norah Terrault, MD, president of the AASLD from the University of Southern California, Los Angeles, noted that all of the reported outcomes, including increasing rates of liver cancer, cirrhosis, and transplants are “potentially preventable.”
Dr. Terrault went on to suggest ways of combating this increasing burden of NAFLD, which she referred to as metabolic dysfunction–associated steatotic liver disease (MASLD), the name now recommended by the AASLD.
“There’s no way we’re going to be able to transplant our way out of this,” Dr. Terrault said. “We need to be bringing greater awareness both to patients, as well as to providers about how we seek out the diagnosis. And we need to bring greater awareness to the population around the things that contribute to MASLD.”
Rates of obesity and diabetes continue to rise, Dr. Terrault said, explaining why MASLD is more common than ever. To counteract these trends, she called for greater awareness of driving factors, such as dietary choices and sedentary lifestyle.
“These are all really important messages that we want to get out to the population, and are really the cornerstones for how we approach the management of patients who have MASLD,” Dr. Terrault said.
In discussion with Dr. Terrault, Dr. Le agreed that increased education may help stem the rising tide of disease, while treatment advances could also increase the odds of a brighter future.
“If we improve our management of NAFLD, or NAFLD-related comorbidities, and if we can develop an effective treatment for NAFLD, then obviously the future would not be so dark,” Dr. Le said, noting promising phase 3 data that would be presented at the meeting. “We are hopeful that the future of disease burden will not be as bad as our model predicts.”
The study was funded by the Agency for Healthcare Research and Quality. The investigators disclosed no conflicts of interest.
AT THE LIVER MEETING
Food insecurity increases risk of adolescent MASLD
, according to a recent study.
These findings suggest that more work is needed to ensure that eligible adolescents can access Supplemental Nutrition Assistance Program (SNAP) benefits and have opportunities to engage in physical activities through school-associated programs, reported principal investigator Zobair M. Younossi, MD, MPH, professor and chairman of the Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, and colleagues.
Dr. Younossi presented the findings in November during a press conference at the annual meeting of the American Association for the Study of Liver Diseases.
“Food insecurity among children is about 10.2% in the United States,” Dr. Younossi said. “[Food insecurity has] been shown to be a risk factor for MASLD among adults, but the data and children and adolescents are really lacking at the moment.”
To address this knowledge gap, Dr. Younossi and colleagues analyzed data from 771 adolescents aged 12-18 years in the National Health and Nutrition Examination Survey (2017-2018). Among these participants, 9.8% reported food insecurity and 10.8% had MASLD. Rates of obesity and central obesity were 22.5% and 45.4%, respectively, while 1.0% had diabetes and 20.9% had prediabetes.
Among adolescents facing food insecurity, more than half (51.5%) did not eat enough food, a vast majority (93.2%) could not access a balanced meal, and almost all (98.9%) relied upon low-cost food for daily sustenance.
The prevalence of MASLD in the food insecure group was almost twice as high as in the food secure group (18.7% vs 9.9%), and advanced fibrosis was about 9 times more common (2.8% vs. 0.3%). Food insecure participants were also more likely to come from a low-income household (70.4% vs. 25.7%) and participate in SNAP (62.4% vs. 25.1%).
Adjusting for SNAP participation, demographic factors, and metabolic disease showed that food insecurity independently increased risk of MASLD by more than twofold (odds ratio [OR], 2.62; 95% CI, 1.07–6.41). The negative effect of food insecurity was almost twice as strong in participants living in a low-income household (OR, 4.79; 95% CI, 1.44–15.86).
“The association between food insecurity and MASLD/NAFLD is most likely the result of not being able to eat a balanced meal and more likely having to purchase low-cost food,” Dr. Younossi said. “Together, these factors may lead to a cycle of overeating along with the overconsumption of ultra-processed foods and sugar-sweetened food and beverages.”
He went on to suggest that more work is needed to remove “systemic and structural barriers” that prevent eligible adolescents from participating in SNAP, while offering support so they can participate in “more physical activity in school and in after-school programs.”
Elliot Benjamin Tapper, MD, associate professor of medicine at the University of Michigan, Ann Arbor, recently published a similar study in the Journal of Clinical Gastroenterology linking food scarcity and MASLD in adults.
In an interview, Dr. Tapper praised this new study by Dr. Younossi and colleagues because it “identifies a serious unmet need” among younger individuals, who may stand to benefit most from early intervention.
“The goal [of screening] is to prevent the development of progressive disease,” Dr. Tapper said. “Our current guidelines for screening for advanced liver disease and people with risk factors focus exclusively on adults. If you waited longer, then there’s a risk that these [younger] people [in the study] would have progressed to a later stage of disease.”
Dr. Tapper predicted increased enthusiasm for MAFLD screening among adolescents in response to these findings, but he cautioned that conventional educational intervention is unlikely to yield significant benefit.
“If you’re food insecure, you can’t go out and buy salmon and olive oil to follow the Mediterranean diet,” Dr. Tapper said. In this era, where the people who are at risk tomorrow are young and food insecure, we have to come up with a way of tailoring our interventions to the means that are available to these patients.”
To this end, health care providers need to collaborate with individuals who have personally dealt with food scarcity to implement practicable interventions.
“Referral to social work has to be paired with some kind of standard teaching,” Dr. Tapper said. “How would I use social and nutritional assistance programs to eat in a liver-healthy way? What can I avoid? [Educational materials] should be written by and edited by people with lived experience; i.e., people who have food insecurity or have walked a mile in those shoes.”
Dr. Younossi disclosed relationships with Merck, Abbott, AstraZeneca, and others. Dr. Tapper disclosed relationships with Takeda, Novo Nordisk, Madrigal, and others.
, according to a recent study.
These findings suggest that more work is needed to ensure that eligible adolescents can access Supplemental Nutrition Assistance Program (SNAP) benefits and have opportunities to engage in physical activities through school-associated programs, reported principal investigator Zobair M. Younossi, MD, MPH, professor and chairman of the Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, and colleagues.
Dr. Younossi presented the findings in November during a press conference at the annual meeting of the American Association for the Study of Liver Diseases.
“Food insecurity among children is about 10.2% in the United States,” Dr. Younossi said. “[Food insecurity has] been shown to be a risk factor for MASLD among adults, but the data and children and adolescents are really lacking at the moment.”
To address this knowledge gap, Dr. Younossi and colleagues analyzed data from 771 adolescents aged 12-18 years in the National Health and Nutrition Examination Survey (2017-2018). Among these participants, 9.8% reported food insecurity and 10.8% had MASLD. Rates of obesity and central obesity were 22.5% and 45.4%, respectively, while 1.0% had diabetes and 20.9% had prediabetes.
Among adolescents facing food insecurity, more than half (51.5%) did not eat enough food, a vast majority (93.2%) could not access a balanced meal, and almost all (98.9%) relied upon low-cost food for daily sustenance.
The prevalence of MASLD in the food insecure group was almost twice as high as in the food secure group (18.7% vs 9.9%), and advanced fibrosis was about 9 times more common (2.8% vs. 0.3%). Food insecure participants were also more likely to come from a low-income household (70.4% vs. 25.7%) and participate in SNAP (62.4% vs. 25.1%).
Adjusting for SNAP participation, demographic factors, and metabolic disease showed that food insecurity independently increased risk of MASLD by more than twofold (odds ratio [OR], 2.62; 95% CI, 1.07–6.41). The negative effect of food insecurity was almost twice as strong in participants living in a low-income household (OR, 4.79; 95% CI, 1.44–15.86).
“The association between food insecurity and MASLD/NAFLD is most likely the result of not being able to eat a balanced meal and more likely having to purchase low-cost food,” Dr. Younossi said. “Together, these factors may lead to a cycle of overeating along with the overconsumption of ultra-processed foods and sugar-sweetened food and beverages.”
He went on to suggest that more work is needed to remove “systemic and structural barriers” that prevent eligible adolescents from participating in SNAP, while offering support so they can participate in “more physical activity in school and in after-school programs.”
Elliot Benjamin Tapper, MD, associate professor of medicine at the University of Michigan, Ann Arbor, recently published a similar study in the Journal of Clinical Gastroenterology linking food scarcity and MASLD in adults.
In an interview, Dr. Tapper praised this new study by Dr. Younossi and colleagues because it “identifies a serious unmet need” among younger individuals, who may stand to benefit most from early intervention.
“The goal [of screening] is to prevent the development of progressive disease,” Dr. Tapper said. “Our current guidelines for screening for advanced liver disease and people with risk factors focus exclusively on adults. If you waited longer, then there’s a risk that these [younger] people [in the study] would have progressed to a later stage of disease.”
Dr. Tapper predicted increased enthusiasm for MAFLD screening among adolescents in response to these findings, but he cautioned that conventional educational intervention is unlikely to yield significant benefit.
“If you’re food insecure, you can’t go out and buy salmon and olive oil to follow the Mediterranean diet,” Dr. Tapper said. In this era, where the people who are at risk tomorrow are young and food insecure, we have to come up with a way of tailoring our interventions to the means that are available to these patients.”
To this end, health care providers need to collaborate with individuals who have personally dealt with food scarcity to implement practicable interventions.
“Referral to social work has to be paired with some kind of standard teaching,” Dr. Tapper said. “How would I use social and nutritional assistance programs to eat in a liver-healthy way? What can I avoid? [Educational materials] should be written by and edited by people with lived experience; i.e., people who have food insecurity or have walked a mile in those shoes.”
Dr. Younossi disclosed relationships with Merck, Abbott, AstraZeneca, and others. Dr. Tapper disclosed relationships with Takeda, Novo Nordisk, Madrigal, and others.
, according to a recent study.
These findings suggest that more work is needed to ensure that eligible adolescents can access Supplemental Nutrition Assistance Program (SNAP) benefits and have opportunities to engage in physical activities through school-associated programs, reported principal investigator Zobair M. Younossi, MD, MPH, professor and chairman of the Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, and colleagues.
Dr. Younossi presented the findings in November during a press conference at the annual meeting of the American Association for the Study of Liver Diseases.
“Food insecurity among children is about 10.2% in the United States,” Dr. Younossi said. “[Food insecurity has] been shown to be a risk factor for MASLD among adults, but the data and children and adolescents are really lacking at the moment.”
To address this knowledge gap, Dr. Younossi and colleagues analyzed data from 771 adolescents aged 12-18 years in the National Health and Nutrition Examination Survey (2017-2018). Among these participants, 9.8% reported food insecurity and 10.8% had MASLD. Rates of obesity and central obesity were 22.5% and 45.4%, respectively, while 1.0% had diabetes and 20.9% had prediabetes.
Among adolescents facing food insecurity, more than half (51.5%) did not eat enough food, a vast majority (93.2%) could not access a balanced meal, and almost all (98.9%) relied upon low-cost food for daily sustenance.
The prevalence of MASLD in the food insecure group was almost twice as high as in the food secure group (18.7% vs 9.9%), and advanced fibrosis was about 9 times more common (2.8% vs. 0.3%). Food insecure participants were also more likely to come from a low-income household (70.4% vs. 25.7%) and participate in SNAP (62.4% vs. 25.1%).
Adjusting for SNAP participation, demographic factors, and metabolic disease showed that food insecurity independently increased risk of MASLD by more than twofold (odds ratio [OR], 2.62; 95% CI, 1.07–6.41). The negative effect of food insecurity was almost twice as strong in participants living in a low-income household (OR, 4.79; 95% CI, 1.44–15.86).
“The association between food insecurity and MASLD/NAFLD is most likely the result of not being able to eat a balanced meal and more likely having to purchase low-cost food,” Dr. Younossi said. “Together, these factors may lead to a cycle of overeating along with the overconsumption of ultra-processed foods and sugar-sweetened food and beverages.”
He went on to suggest that more work is needed to remove “systemic and structural barriers” that prevent eligible adolescents from participating in SNAP, while offering support so they can participate in “more physical activity in school and in after-school programs.”
Elliot Benjamin Tapper, MD, associate professor of medicine at the University of Michigan, Ann Arbor, recently published a similar study in the Journal of Clinical Gastroenterology linking food scarcity and MASLD in adults.
In an interview, Dr. Tapper praised this new study by Dr. Younossi and colleagues because it “identifies a serious unmet need” among younger individuals, who may stand to benefit most from early intervention.
“The goal [of screening] is to prevent the development of progressive disease,” Dr. Tapper said. “Our current guidelines for screening for advanced liver disease and people with risk factors focus exclusively on adults. If you waited longer, then there’s a risk that these [younger] people [in the study] would have progressed to a later stage of disease.”
Dr. Tapper predicted increased enthusiasm for MAFLD screening among adolescents in response to these findings, but he cautioned that conventional educational intervention is unlikely to yield significant benefit.
“If you’re food insecure, you can’t go out and buy salmon and olive oil to follow the Mediterranean diet,” Dr. Tapper said. In this era, where the people who are at risk tomorrow are young and food insecure, we have to come up with a way of tailoring our interventions to the means that are available to these patients.”
To this end, health care providers need to collaborate with individuals who have personally dealt with food scarcity to implement practicable interventions.
“Referral to social work has to be paired with some kind of standard teaching,” Dr. Tapper said. “How would I use social and nutritional assistance programs to eat in a liver-healthy way? What can I avoid? [Educational materials] should be written by and edited by people with lived experience; i.e., people who have food insecurity or have walked a mile in those shoes.”
Dr. Younossi disclosed relationships with Merck, Abbott, AstraZeneca, and others. Dr. Tapper disclosed relationships with Takeda, Novo Nordisk, Madrigal, and others.
AT THE LIVER MEETING
Prognostic tool identifies alcohol relapse risk after liver transplant
, based on data from 140 individuals.
Alcohol relapse after liver transplant ranges from 4% to as high as 95% among patients with alcoholic liver disease (ALD) and better tools are needed to identify those at increased risk, Jiten P. Kothadia, MD, of the University of Tennessee Health Science Center, Memphis, said in a presentation given in October at the annual meeting of the American College of Gastroenterology.
Dr. Kothadia and colleagues evaluated the effectiveness of the Social Determinant Acuity Tool (S-DAT), which stratified patients in terms of successful post-liver transplant outcomes from excellent (S-DAT scores 0-6) to poor candidates (scores 35-40). The S-DAT categories included cognitive function, mental health, social support, coping skills, financial status, compliance, alcohol abuse, substance abuse, reliability, legal issues, understanding the transplant process, and desire for transplant.
The study population included 140 adults with alcoholic liver disease who underwent a liver transplant between January 2016 and November 2021 at a single center. Before surgery, all patients underwent a thorough psychosocial evaluation using the S-DAT. The mean age of the participants was 53.4 years, 107 were male, and 67.9% had abstained from alcohol for more than 6 months prior to transplant.
The primary outcome of post-liver transplant alcohol relapse was defined as any alcohol use regardless of the amount or frequency, based on patient interviews or blood or urine tests.
Overall, the rate of relapse was 23.6%; and the rate within a year was 18.6%. In a multivariate analysis, S-DAT score was a significant predictor of relapse (odds ratio [OR] 1.65, P = .000). Other independent predictors of relapse were post-LT alcohol treatment (OR 7.11, P = .02), smoking history (OR 0.15, P = .03), and marital status (OR 60.28, P = .000). The area under the receiver operative curves (AUROC) for the S-DAT score to predict alcohol relapse within 1 year after LT was 0.77.
The sensitivity of the S-DAT for predicting relapse risk was 96.2%, and specificity was 40.4%; positive and negative predictive values were 26.9% and 97.9%, respectively.
The high sensitivity and negative predictive values of the S-DAT make it a useful screening tool for identifying patients at low risk of alcohol relapse after a liver transplant, Dr. Kothadia said in an interview. “Our score will guide risk-based interventions post-LT to reduce post-LT relapse and improve long-term outcomes.”
The findings included only data from a single center, which may limit generalizability, Dr. Kothadia said. The tool is not yet clinically available, he noted.
“We would like to perform external validation of our S-DAT score as it stresses the importance of these psychosocial variables,” and to confirm the findings in larger, multicenter, prospective clinical trials, he said.
The study received no outside funding. Dr. Kothadia indicated no relevant financial relationships.
, based on data from 140 individuals.
Alcohol relapse after liver transplant ranges from 4% to as high as 95% among patients with alcoholic liver disease (ALD) and better tools are needed to identify those at increased risk, Jiten P. Kothadia, MD, of the University of Tennessee Health Science Center, Memphis, said in a presentation given in October at the annual meeting of the American College of Gastroenterology.
Dr. Kothadia and colleagues evaluated the effectiveness of the Social Determinant Acuity Tool (S-DAT), which stratified patients in terms of successful post-liver transplant outcomes from excellent (S-DAT scores 0-6) to poor candidates (scores 35-40). The S-DAT categories included cognitive function, mental health, social support, coping skills, financial status, compliance, alcohol abuse, substance abuse, reliability, legal issues, understanding the transplant process, and desire for transplant.
The study population included 140 adults with alcoholic liver disease who underwent a liver transplant between January 2016 and November 2021 at a single center. Before surgery, all patients underwent a thorough psychosocial evaluation using the S-DAT. The mean age of the participants was 53.4 years, 107 were male, and 67.9% had abstained from alcohol for more than 6 months prior to transplant.
The primary outcome of post-liver transplant alcohol relapse was defined as any alcohol use regardless of the amount or frequency, based on patient interviews or blood or urine tests.
Overall, the rate of relapse was 23.6%; and the rate within a year was 18.6%. In a multivariate analysis, S-DAT score was a significant predictor of relapse (odds ratio [OR] 1.65, P = .000). Other independent predictors of relapse were post-LT alcohol treatment (OR 7.11, P = .02), smoking history (OR 0.15, P = .03), and marital status (OR 60.28, P = .000). The area under the receiver operative curves (AUROC) for the S-DAT score to predict alcohol relapse within 1 year after LT was 0.77.
The sensitivity of the S-DAT for predicting relapse risk was 96.2%, and specificity was 40.4%; positive and negative predictive values were 26.9% and 97.9%, respectively.
The high sensitivity and negative predictive values of the S-DAT make it a useful screening tool for identifying patients at low risk of alcohol relapse after a liver transplant, Dr. Kothadia said in an interview. “Our score will guide risk-based interventions post-LT to reduce post-LT relapse and improve long-term outcomes.”
The findings included only data from a single center, which may limit generalizability, Dr. Kothadia said. The tool is not yet clinically available, he noted.
“We would like to perform external validation of our S-DAT score as it stresses the importance of these psychosocial variables,” and to confirm the findings in larger, multicenter, prospective clinical trials, he said.
The study received no outside funding. Dr. Kothadia indicated no relevant financial relationships.
, based on data from 140 individuals.
Alcohol relapse after liver transplant ranges from 4% to as high as 95% among patients with alcoholic liver disease (ALD) and better tools are needed to identify those at increased risk, Jiten P. Kothadia, MD, of the University of Tennessee Health Science Center, Memphis, said in a presentation given in October at the annual meeting of the American College of Gastroenterology.
Dr. Kothadia and colleagues evaluated the effectiveness of the Social Determinant Acuity Tool (S-DAT), which stratified patients in terms of successful post-liver transplant outcomes from excellent (S-DAT scores 0-6) to poor candidates (scores 35-40). The S-DAT categories included cognitive function, mental health, social support, coping skills, financial status, compliance, alcohol abuse, substance abuse, reliability, legal issues, understanding the transplant process, and desire for transplant.
The study population included 140 adults with alcoholic liver disease who underwent a liver transplant between January 2016 and November 2021 at a single center. Before surgery, all patients underwent a thorough psychosocial evaluation using the S-DAT. The mean age of the participants was 53.4 years, 107 were male, and 67.9% had abstained from alcohol for more than 6 months prior to transplant.
The primary outcome of post-liver transplant alcohol relapse was defined as any alcohol use regardless of the amount or frequency, based on patient interviews or blood or urine tests.
Overall, the rate of relapse was 23.6%; and the rate within a year was 18.6%. In a multivariate analysis, S-DAT score was a significant predictor of relapse (odds ratio [OR] 1.65, P = .000). Other independent predictors of relapse were post-LT alcohol treatment (OR 7.11, P = .02), smoking history (OR 0.15, P = .03), and marital status (OR 60.28, P = .000). The area under the receiver operative curves (AUROC) for the S-DAT score to predict alcohol relapse within 1 year after LT was 0.77.
The sensitivity of the S-DAT for predicting relapse risk was 96.2%, and specificity was 40.4%; positive and negative predictive values were 26.9% and 97.9%, respectively.
The high sensitivity and negative predictive values of the S-DAT make it a useful screening tool for identifying patients at low risk of alcohol relapse after a liver transplant, Dr. Kothadia said in an interview. “Our score will guide risk-based interventions post-LT to reduce post-LT relapse and improve long-term outcomes.”
The findings included only data from a single center, which may limit generalizability, Dr. Kothadia said. The tool is not yet clinically available, he noted.
“We would like to perform external validation of our S-DAT score as it stresses the importance of these psychosocial variables,” and to confirm the findings in larger, multicenter, prospective clinical trials, he said.
The study received no outside funding. Dr. Kothadia indicated no relevant financial relationships.
FROM ACG 2023
Liver-resident T cells provide early protection against Listeria infection
, according to investigators.
These finding suggest that gamma delta T17 cells could be a target for novel cell-based therapies against liver diseases, reported lead author Yanan Wang, PhD, of Shandong University, Jinan, China, and colleagues.
“Gamma delta T cells are located in mucosal tissues and other peripheral lymphoid tissues and are considered to act as the first line of defense within the immune system,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Several studies have reported that IL-17A produced by gamma delta T cells plays a critical role in host defense after Listeria monocytogenes [infection] in the liver. However, in those studies, the details of the phenotypes, dynamic changes, proliferation activity, and cytokine production of the responding gamma delta T cell populations in the overall process of hepatic infection are unclear, and how they accumulated into the infection sites has not been elucidated.”
To address this knowledge gap, Dr. Wang and colleagues conducted a series of experiments involving gamma delta T cells from murine liver samples.
First, using single-cell RNA-sequencing (scRNA-seq), the investigators identified six clusters of hepatic gamma delta T cells.
“[This first step] revealed the unique gene expression characteristics and indicated the possible important roles in immune responses of hepatic gamma delta T17 cells,” they noted.
Next, the investigators measured expression of CD44 and CD27 in liver gamma delta cells.
“Expression of CD44 and CD27 has been used to distinguish IL-17A–, interferon gamma–producing, and other subsets of gamma delta T cells in the thymus, lymph nodes, lungs, and other peripheral lymphoid tissues,” they wrote.
These efforts revealed three subsets of hepatic gamma delta T cells, of which CD44hiCD27– gamma delta T cells were most abundant. Further analysis revealed expression profiles consistent with liver residency.
The next phases of the study characterized the immune roles of hepatic gamma delta T cells.
A comparison of Listeria monocytogenes infection in wild-type versus T-cell antigen receptor knockout mice, for example, showed that knockout mice had significantly more weight loss than did wild-type mice, greater bacterial load in the liver, and shorter survival times.
“As expected, the proportion and absolute numbers of gamma delta T cells in the liver of wild-type mice increased at day 3 and reached a peak at day 7 after infection,” the investigators wrote. “These data suggested that hepatic gamma delta T cells proliferated after infection and contributed to Lm clearance.”
Parabiosis experiments showed that the increased number of CD44hiCD27– gamma delta T cells in the livers of Listeria monocytogenes-infected mice were due to migration and proliferation of liver-resident gamma delta T cells instead of circulating gamma delta T cells. A transwell assay revealed that Kupffer cells and monocyte-derived macrophages promoted migration of CD44hiCD27– gamma delta T cells upon infection.
“Our study provides additional insight into liver-resident lymphocytes and will aid in targeting such tissue-resident lymphocyte populations to promote local immune surveillance,” the investigators concluded.
The study was supported by grants from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The investigators disclosed no conflicts of interest.
, according to investigators.
These finding suggest that gamma delta T17 cells could be a target for novel cell-based therapies against liver diseases, reported lead author Yanan Wang, PhD, of Shandong University, Jinan, China, and colleagues.
“Gamma delta T cells are located in mucosal tissues and other peripheral lymphoid tissues and are considered to act as the first line of defense within the immune system,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Several studies have reported that IL-17A produced by gamma delta T cells plays a critical role in host defense after Listeria monocytogenes [infection] in the liver. However, in those studies, the details of the phenotypes, dynamic changes, proliferation activity, and cytokine production of the responding gamma delta T cell populations in the overall process of hepatic infection are unclear, and how they accumulated into the infection sites has not been elucidated.”
To address this knowledge gap, Dr. Wang and colleagues conducted a series of experiments involving gamma delta T cells from murine liver samples.
First, using single-cell RNA-sequencing (scRNA-seq), the investigators identified six clusters of hepatic gamma delta T cells.
“[This first step] revealed the unique gene expression characteristics and indicated the possible important roles in immune responses of hepatic gamma delta T17 cells,” they noted.
Next, the investigators measured expression of CD44 and CD27 in liver gamma delta cells.
“Expression of CD44 and CD27 has been used to distinguish IL-17A–, interferon gamma–producing, and other subsets of gamma delta T cells in the thymus, lymph nodes, lungs, and other peripheral lymphoid tissues,” they wrote.
These efforts revealed three subsets of hepatic gamma delta T cells, of which CD44hiCD27– gamma delta T cells were most abundant. Further analysis revealed expression profiles consistent with liver residency.
The next phases of the study characterized the immune roles of hepatic gamma delta T cells.
A comparison of Listeria monocytogenes infection in wild-type versus T-cell antigen receptor knockout mice, for example, showed that knockout mice had significantly more weight loss than did wild-type mice, greater bacterial load in the liver, and shorter survival times.
“As expected, the proportion and absolute numbers of gamma delta T cells in the liver of wild-type mice increased at day 3 and reached a peak at day 7 after infection,” the investigators wrote. “These data suggested that hepatic gamma delta T cells proliferated after infection and contributed to Lm clearance.”
Parabiosis experiments showed that the increased number of CD44hiCD27– gamma delta T cells in the livers of Listeria monocytogenes-infected mice were due to migration and proliferation of liver-resident gamma delta T cells instead of circulating gamma delta T cells. A transwell assay revealed that Kupffer cells and monocyte-derived macrophages promoted migration of CD44hiCD27– gamma delta T cells upon infection.
“Our study provides additional insight into liver-resident lymphocytes and will aid in targeting such tissue-resident lymphocyte populations to promote local immune surveillance,” the investigators concluded.
The study was supported by grants from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The investigators disclosed no conflicts of interest.
, according to investigators.
These finding suggest that gamma delta T17 cells could be a target for novel cell-based therapies against liver diseases, reported lead author Yanan Wang, PhD, of Shandong University, Jinan, China, and colleagues.
“Gamma delta T cells are located in mucosal tissues and other peripheral lymphoid tissues and are considered to act as the first line of defense within the immune system,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Several studies have reported that IL-17A produced by gamma delta T cells plays a critical role in host defense after Listeria monocytogenes [infection] in the liver. However, in those studies, the details of the phenotypes, dynamic changes, proliferation activity, and cytokine production of the responding gamma delta T cell populations in the overall process of hepatic infection are unclear, and how they accumulated into the infection sites has not been elucidated.”
To address this knowledge gap, Dr. Wang and colleagues conducted a series of experiments involving gamma delta T cells from murine liver samples.
First, using single-cell RNA-sequencing (scRNA-seq), the investigators identified six clusters of hepatic gamma delta T cells.
“[This first step] revealed the unique gene expression characteristics and indicated the possible important roles in immune responses of hepatic gamma delta T17 cells,” they noted.
Next, the investigators measured expression of CD44 and CD27 in liver gamma delta cells.
“Expression of CD44 and CD27 has been used to distinguish IL-17A–, interferon gamma–producing, and other subsets of gamma delta T cells in the thymus, lymph nodes, lungs, and other peripheral lymphoid tissues,” they wrote.
These efforts revealed three subsets of hepatic gamma delta T cells, of which CD44hiCD27– gamma delta T cells were most abundant. Further analysis revealed expression profiles consistent with liver residency.
The next phases of the study characterized the immune roles of hepatic gamma delta T cells.
A comparison of Listeria monocytogenes infection in wild-type versus T-cell antigen receptor knockout mice, for example, showed that knockout mice had significantly more weight loss than did wild-type mice, greater bacterial load in the liver, and shorter survival times.
“As expected, the proportion and absolute numbers of gamma delta T cells in the liver of wild-type mice increased at day 3 and reached a peak at day 7 after infection,” the investigators wrote. “These data suggested that hepatic gamma delta T cells proliferated after infection and contributed to Lm clearance.”
Parabiosis experiments showed that the increased number of CD44hiCD27– gamma delta T cells in the livers of Listeria monocytogenes-infected mice were due to migration and proliferation of liver-resident gamma delta T cells instead of circulating gamma delta T cells. A transwell assay revealed that Kupffer cells and monocyte-derived macrophages promoted migration of CD44hiCD27– gamma delta T cells upon infection.
“Our study provides additional insight into liver-resident lymphocytes and will aid in targeting such tissue-resident lymphocyte populations to promote local immune surveillance,” the investigators concluded.
The study was supported by grants from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The investigators disclosed no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Nano drug delivery could overcome toxicity in HCC to enable safer, more effective therapy
leading to safer treatment and better outcomes, according to a recent review.
Nanomedicines homing in on the Wnt/beta-catenin signaling pathway could be particularly impactful, Mamatha Bhat, MD, PhD, a hepatologist and clinician-scientist at Toronto General Hospital Research Institute, and colleagues reported, as this is one of the most up-regulated pathways in HCC.
To date, however, agents addressing this pathway have been hindered by off-target toxicity, suggesting that more work is needed to develop the right payload for nanoparticle delivery, the investigators wrote in Gastro Hep Advances.
“Although nanotherapeutics offers an unmatched improvement in drug delivery, due to the limited impact and treatment-resistance demonstrated by the current systemic therapies, there is currently no approved nanomedicine for the treatment of HCC,” the investigators wrote. “Therefore, it is of utmost importance to dig deeper into understanding the signaling pathways that govern hepatocarcinogenesis and identify novel targets that can be used to develop more specific and targeted nanotherapies.”
Their review focused on the Wnt/beta-catenin signaling pathway, but first, Dr. Bhat and colleagues discussed the characteristics of inorganic versus lipid nanoparticles, as these differences can determine liver uptake.
Inorganic nanoparticles have a high surface-to-volume ratio, leading to increased surface charges that enhance cellular uptake. However, they are prone to oxidation, requiring surface modifications or short circulation times to prevent degradation. These nanoparticles are limited in delivering chemotherapeutic drugs and peptides, and are not suitable for encapsulating nucleic acids.
In contrast, lipid nanoparticles are preferred for targeted delivery in HCC, according to the investigators. They have a natural affinity for apolipoprotein E (apo E), resembling lipoproteins, which aids in specific liver cell targeting. When lipid nanoparticles enter the bloodstream, they interact with apo E–rich lipoproteins like HDL cholesterol and LDL cholesterol, leading to formation of complexes recognized by LDL cholesterol receptors on liver cells. This triggers receptor-mediated endocytosis, internalizing apo E–lipid nanoparticle complexes into HCC cells.
The other major variable is the selected treatment target. Dr. Bhat and colleagues made the case for the Wnt/beta-catenin signaling pathway based on alterations found in approximately two-thirds of patients with HCC.
“Aberrant activation of this pathway and mutations in genes encoding key components are characteristic to hepatocarcinogenesis and promote tumor growth and dedifferentiation,” they wrote.
Although beta-catenin itself makes for an obvious molecular target, especially considering known associations with drug resistance, its flat structure lacks deep binding pockets that would be suitable for small-molecule inhibitors, and any available pockets may be altered by numerous posttranscriptional modifications. Instead, beta-catenin could be indirectly modulated by nanoparticle-mediated siRNA therapy, as this would allow for precise delivery of siRNA to cancer cells, minimizing off-target toxicity.
Alternative approaches could involve targeting proteasomal degradation of beta-catenin, transcriptional coactivators of beta-catenin, or different oncogenes in HCC, all of which are described in further detail in the review, along with promising preclinical findings.
“With ongoing advancements in nanotechnology, there is optimism that it will continue to play a vital role in overcoming the challenges associated with HCC management and contribute to further advancements in therapeutic outcomes for patients,” the authors concluded.
One coauthor disclosed external funding by a Mitacs Elevate postdoctoral fellowship in collaboration with Highland Therapeutics. The remaining authors disclosed no conflicts of interest.
Hepatocellular Carcinoma (HCC) remains a major health problem associate with increasing prevalence and mortality rates worldwide. Around 50-60% of HCC patients are exposed to systemic therapies during their natural history. Atezolizumab plus bevacizumab (median OS: 19.2mo, ORR 30%), and durvalumab plus tremelimumab (median OS: 16.4mo, ORR: 20%) are considered first line treatment options for advanced HCC, and sorafenib or lenvatinib are recommended for patients with any contraindication for immune checkpoint inhibitors. These therapies are indicated for ‘all comers’ an no molecular markers /personalize medicine is currently available for this cancer. The lack of precision oncology relates to the fact that the most common mutations ( i.e TERT, TP53,CTNNB1) are unactionable targets. In this scenario, advances in precision oncology are an unmet medical need.
The Wnt/B-catenin signaling pathway is a master regulator of oncogenesis in HCC and defines one of the molecular subclasses characterized by CTNNB1 mutations (~25-30%) or AXIN1 mutations (~5-10%). Most of these tumors have an immune excluded/desert phenotype. Thus, targeting this pathway is expected to provide a primary antitumoral effect along with an immune-modulatory effect rescuing cases with an immune excluded phenotype.
In this review, the authors discuss the applicability of precision oncology in HCC targeting the WNT/B-catenin pathway by inhibiting the interaction with transcriptional coactivators of B-catenin such as CBP and TCF or by enhancing the proteasomal degradation of B-catenin, reducing pathway activation, with drugs like Tankyrase inhibitors and casein kinase 1a activators. These approaches are challenging due to its associated off-target toxicity and its complexity. To overcome these caveats, the author propose to utilization of nanotechnology to deliver Wnt inhibitors, an approach that currently requires further research to refine the most promising strategies and drugs suitable for clinical implementation.
Josep M. Llovet, MD, PhD, FAASLD, director, Mount Sinai Liver Cancer Program in New York, and head of translational research in the Liver Cancer Group, Liver Unit, IDIBAPS, Hospital Clínic Barcelona. Dr. Llovet receives research support from Bayer Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen.
Hepatocellular Carcinoma (HCC) remains a major health problem associate with increasing prevalence and mortality rates worldwide. Around 50-60% of HCC patients are exposed to systemic therapies during their natural history. Atezolizumab plus bevacizumab (median OS: 19.2mo, ORR 30%), and durvalumab plus tremelimumab (median OS: 16.4mo, ORR: 20%) are considered first line treatment options for advanced HCC, and sorafenib or lenvatinib are recommended for patients with any contraindication for immune checkpoint inhibitors. These therapies are indicated for ‘all comers’ an no molecular markers /personalize medicine is currently available for this cancer. The lack of precision oncology relates to the fact that the most common mutations ( i.e TERT, TP53,CTNNB1) are unactionable targets. In this scenario, advances in precision oncology are an unmet medical need.
The Wnt/B-catenin signaling pathway is a master regulator of oncogenesis in HCC and defines one of the molecular subclasses characterized by CTNNB1 mutations (~25-30%) or AXIN1 mutations (~5-10%). Most of these tumors have an immune excluded/desert phenotype. Thus, targeting this pathway is expected to provide a primary antitumoral effect along with an immune-modulatory effect rescuing cases with an immune excluded phenotype.
In this review, the authors discuss the applicability of precision oncology in HCC targeting the WNT/B-catenin pathway by inhibiting the interaction with transcriptional coactivators of B-catenin such as CBP and TCF or by enhancing the proteasomal degradation of B-catenin, reducing pathway activation, with drugs like Tankyrase inhibitors and casein kinase 1a activators. These approaches are challenging due to its associated off-target toxicity and its complexity. To overcome these caveats, the author propose to utilization of nanotechnology to deliver Wnt inhibitors, an approach that currently requires further research to refine the most promising strategies and drugs suitable for clinical implementation.
Josep M. Llovet, MD, PhD, FAASLD, director, Mount Sinai Liver Cancer Program in New York, and head of translational research in the Liver Cancer Group, Liver Unit, IDIBAPS, Hospital Clínic Barcelona. Dr. Llovet receives research support from Bayer Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen.
Hepatocellular Carcinoma (HCC) remains a major health problem associate with increasing prevalence and mortality rates worldwide. Around 50-60% of HCC patients are exposed to systemic therapies during their natural history. Atezolizumab plus bevacizumab (median OS: 19.2mo, ORR 30%), and durvalumab plus tremelimumab (median OS: 16.4mo, ORR: 20%) are considered first line treatment options for advanced HCC, and sorafenib or lenvatinib are recommended for patients with any contraindication for immune checkpoint inhibitors. These therapies are indicated for ‘all comers’ an no molecular markers /personalize medicine is currently available for this cancer. The lack of precision oncology relates to the fact that the most common mutations ( i.e TERT, TP53,CTNNB1) are unactionable targets. In this scenario, advances in precision oncology are an unmet medical need.
The Wnt/B-catenin signaling pathway is a master regulator of oncogenesis in HCC and defines one of the molecular subclasses characterized by CTNNB1 mutations (~25-30%) or AXIN1 mutations (~5-10%). Most of these tumors have an immune excluded/desert phenotype. Thus, targeting this pathway is expected to provide a primary antitumoral effect along with an immune-modulatory effect rescuing cases with an immune excluded phenotype.
In this review, the authors discuss the applicability of precision oncology in HCC targeting the WNT/B-catenin pathway by inhibiting the interaction with transcriptional coactivators of B-catenin such as CBP and TCF or by enhancing the proteasomal degradation of B-catenin, reducing pathway activation, with drugs like Tankyrase inhibitors and casein kinase 1a activators. These approaches are challenging due to its associated off-target toxicity and its complexity. To overcome these caveats, the author propose to utilization of nanotechnology to deliver Wnt inhibitors, an approach that currently requires further research to refine the most promising strategies and drugs suitable for clinical implementation.
Josep M. Llovet, MD, PhD, FAASLD, director, Mount Sinai Liver Cancer Program in New York, and head of translational research in the Liver Cancer Group, Liver Unit, IDIBAPS, Hospital Clínic Barcelona. Dr. Llovet receives research support from Bayer Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen.
leading to safer treatment and better outcomes, according to a recent review.
Nanomedicines homing in on the Wnt/beta-catenin signaling pathway could be particularly impactful, Mamatha Bhat, MD, PhD, a hepatologist and clinician-scientist at Toronto General Hospital Research Institute, and colleagues reported, as this is one of the most up-regulated pathways in HCC.
To date, however, agents addressing this pathway have been hindered by off-target toxicity, suggesting that more work is needed to develop the right payload for nanoparticle delivery, the investigators wrote in Gastro Hep Advances.
“Although nanotherapeutics offers an unmatched improvement in drug delivery, due to the limited impact and treatment-resistance demonstrated by the current systemic therapies, there is currently no approved nanomedicine for the treatment of HCC,” the investigators wrote. “Therefore, it is of utmost importance to dig deeper into understanding the signaling pathways that govern hepatocarcinogenesis and identify novel targets that can be used to develop more specific and targeted nanotherapies.”
Their review focused on the Wnt/beta-catenin signaling pathway, but first, Dr. Bhat and colleagues discussed the characteristics of inorganic versus lipid nanoparticles, as these differences can determine liver uptake.
Inorganic nanoparticles have a high surface-to-volume ratio, leading to increased surface charges that enhance cellular uptake. However, they are prone to oxidation, requiring surface modifications or short circulation times to prevent degradation. These nanoparticles are limited in delivering chemotherapeutic drugs and peptides, and are not suitable for encapsulating nucleic acids.
In contrast, lipid nanoparticles are preferred for targeted delivery in HCC, according to the investigators. They have a natural affinity for apolipoprotein E (apo E), resembling lipoproteins, which aids in specific liver cell targeting. When lipid nanoparticles enter the bloodstream, they interact with apo E–rich lipoproteins like HDL cholesterol and LDL cholesterol, leading to formation of complexes recognized by LDL cholesterol receptors on liver cells. This triggers receptor-mediated endocytosis, internalizing apo E–lipid nanoparticle complexes into HCC cells.
The other major variable is the selected treatment target. Dr. Bhat and colleagues made the case for the Wnt/beta-catenin signaling pathway based on alterations found in approximately two-thirds of patients with HCC.
“Aberrant activation of this pathway and mutations in genes encoding key components are characteristic to hepatocarcinogenesis and promote tumor growth and dedifferentiation,” they wrote.
Although beta-catenin itself makes for an obvious molecular target, especially considering known associations with drug resistance, its flat structure lacks deep binding pockets that would be suitable for small-molecule inhibitors, and any available pockets may be altered by numerous posttranscriptional modifications. Instead, beta-catenin could be indirectly modulated by nanoparticle-mediated siRNA therapy, as this would allow for precise delivery of siRNA to cancer cells, minimizing off-target toxicity.
Alternative approaches could involve targeting proteasomal degradation of beta-catenin, transcriptional coactivators of beta-catenin, or different oncogenes in HCC, all of which are described in further detail in the review, along with promising preclinical findings.
“With ongoing advancements in nanotechnology, there is optimism that it will continue to play a vital role in overcoming the challenges associated with HCC management and contribute to further advancements in therapeutic outcomes for patients,” the authors concluded.
One coauthor disclosed external funding by a Mitacs Elevate postdoctoral fellowship in collaboration with Highland Therapeutics. The remaining authors disclosed no conflicts of interest.
leading to safer treatment and better outcomes, according to a recent review.
Nanomedicines homing in on the Wnt/beta-catenin signaling pathway could be particularly impactful, Mamatha Bhat, MD, PhD, a hepatologist and clinician-scientist at Toronto General Hospital Research Institute, and colleagues reported, as this is one of the most up-regulated pathways in HCC.
To date, however, agents addressing this pathway have been hindered by off-target toxicity, suggesting that more work is needed to develop the right payload for nanoparticle delivery, the investigators wrote in Gastro Hep Advances.
“Although nanotherapeutics offers an unmatched improvement in drug delivery, due to the limited impact and treatment-resistance demonstrated by the current systemic therapies, there is currently no approved nanomedicine for the treatment of HCC,” the investigators wrote. “Therefore, it is of utmost importance to dig deeper into understanding the signaling pathways that govern hepatocarcinogenesis and identify novel targets that can be used to develop more specific and targeted nanotherapies.”
Their review focused on the Wnt/beta-catenin signaling pathway, but first, Dr. Bhat and colleagues discussed the characteristics of inorganic versus lipid nanoparticles, as these differences can determine liver uptake.
Inorganic nanoparticles have a high surface-to-volume ratio, leading to increased surface charges that enhance cellular uptake. However, they are prone to oxidation, requiring surface modifications or short circulation times to prevent degradation. These nanoparticles are limited in delivering chemotherapeutic drugs and peptides, and are not suitable for encapsulating nucleic acids.
In contrast, lipid nanoparticles are preferred for targeted delivery in HCC, according to the investigators. They have a natural affinity for apolipoprotein E (apo E), resembling lipoproteins, which aids in specific liver cell targeting. When lipid nanoparticles enter the bloodstream, they interact with apo E–rich lipoproteins like HDL cholesterol and LDL cholesterol, leading to formation of complexes recognized by LDL cholesterol receptors on liver cells. This triggers receptor-mediated endocytosis, internalizing apo E–lipid nanoparticle complexes into HCC cells.
The other major variable is the selected treatment target. Dr. Bhat and colleagues made the case for the Wnt/beta-catenin signaling pathway based on alterations found in approximately two-thirds of patients with HCC.
“Aberrant activation of this pathway and mutations in genes encoding key components are characteristic to hepatocarcinogenesis and promote tumor growth and dedifferentiation,” they wrote.
Although beta-catenin itself makes for an obvious molecular target, especially considering known associations with drug resistance, its flat structure lacks deep binding pockets that would be suitable for small-molecule inhibitors, and any available pockets may be altered by numerous posttranscriptional modifications. Instead, beta-catenin could be indirectly modulated by nanoparticle-mediated siRNA therapy, as this would allow for precise delivery of siRNA to cancer cells, minimizing off-target toxicity.
Alternative approaches could involve targeting proteasomal degradation of beta-catenin, transcriptional coactivators of beta-catenin, or different oncogenes in HCC, all of which are described in further detail in the review, along with promising preclinical findings.
“With ongoing advancements in nanotechnology, there is optimism that it will continue to play a vital role in overcoming the challenges associated with HCC management and contribute to further advancements in therapeutic outcomes for patients,” the authors concluded.
One coauthor disclosed external funding by a Mitacs Elevate postdoctoral fellowship in collaboration with Highland Therapeutics. The remaining authors disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES