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FDA approves mAb combo for hepatocellular carcinoma
The approval was supported by results from the IMbrave150 trial (N Engl J Med. 2020;382:1894-1905). This phase 3 trial enrolled 501 patients with hepatocellular carcinoma who were randomized to receive either sorafenib or atezolizumab plus bevacizumab.
The median overall survival was not reached in patients who received atezolizumab plus bevacizumab, but it was 13.2 months in patients who received sorafenib (hazard ratio, 0.58; 95% confidence interval, 0.42-0.79; P = .0006). The median progression-free survival was 6.8 months in patients who received atezolizumab plus bevacizumab and 4.3 months for those who received sorafenib.
The most common adverse events seen in the atezolizumab-bevacizumab arm were hypertension, fatigue, and proteinuria.
The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks.
The FDA collaborated with regulatory agencies from Canada, Australia, and Singapore on the review of the atezolizumab application, as part of Project Orbis. The FDA approved the application ahead of schedule. It is still under review for the other agencies.
The approval was supported by results from the IMbrave150 trial (N Engl J Med. 2020;382:1894-1905). This phase 3 trial enrolled 501 patients with hepatocellular carcinoma who were randomized to receive either sorafenib or atezolizumab plus bevacizumab.
The median overall survival was not reached in patients who received atezolizumab plus bevacizumab, but it was 13.2 months in patients who received sorafenib (hazard ratio, 0.58; 95% confidence interval, 0.42-0.79; P = .0006). The median progression-free survival was 6.8 months in patients who received atezolizumab plus bevacizumab and 4.3 months for those who received sorafenib.
The most common adverse events seen in the atezolizumab-bevacizumab arm were hypertension, fatigue, and proteinuria.
The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks.
The FDA collaborated with regulatory agencies from Canada, Australia, and Singapore on the review of the atezolizumab application, as part of Project Orbis. The FDA approved the application ahead of schedule. It is still under review for the other agencies.
The approval was supported by results from the IMbrave150 trial (N Engl J Med. 2020;382:1894-1905). This phase 3 trial enrolled 501 patients with hepatocellular carcinoma who were randomized to receive either sorafenib or atezolizumab plus bevacizumab.
The median overall survival was not reached in patients who received atezolizumab plus bevacizumab, but it was 13.2 months in patients who received sorafenib (hazard ratio, 0.58; 95% confidence interval, 0.42-0.79; P = .0006). The median progression-free survival was 6.8 months in patients who received atezolizumab plus bevacizumab and 4.3 months for those who received sorafenib.
The most common adverse events seen in the atezolizumab-bevacizumab arm were hypertension, fatigue, and proteinuria.
The recommended atezolizumab dose is 1,200 mg, followed by 15 mg/kg bevacizumab on the same day every 3 weeks.
The FDA collaborated with regulatory agencies from Canada, Australia, and Singapore on the review of the atezolizumab application, as part of Project Orbis. The FDA approved the application ahead of schedule. It is still under review for the other agencies.
Nucleoside polymers show early promise in HBV
For patients with chronic hepatitis B virus (HBV) infection, triple-combination therapy with tenofovir disoproxil fumarate, pegylated interferon alfa-2a (TDF-pegIFN), and either of two investigational nucleic acid polymers was tolerable and led to long-term functional cures in an open-label phase 2 trial.
The addition of either REP 2139 or REP 2165 to backbone TDF-pegIFN therapy produced functional cures in 39% of patients without lessening HBV DNA control or exacerbating treatment-induced neutropenia or thrombocytopenia, said Michel Bazinet, MD, of Replicor in Montreal and his associates. “Increases in levels of transaminases were significantly more frequent (P < .001 vs. controls) and greater (P = .002 vs. controls) in the nucleic acid polymer groups but did not produce symptoms, correlated with [an] initial decrease in hepatitis B surface antigen [HBsAg], and normalized during therapy and follow-up,” the investigators wrote in Gastroenterology.
Nucleic acid polymers (NAPs) suppress the assembly and secretion of HBV subviral particles. NAP monotherapy is active against HBV but usually does not provide long-term virologic control. In a small study, adding pegIFN or thymosin alpha-1 to an investigational NAP achieved functional control (HBsAg positive, HBV DNA ≤ 2000 IU/mL, and normal alanine aminotransferase levels) in eight of nine patients.
Building on these findings, two triple-combination NAP regimens were evaluated in 40 noncirrhotic HB envelope antigen–negative adults with chronic HBV infection. After 24 weeks of TDF monotherapy, participants were randomly assigned to either 48 weeks of REP 2139 or REP 2165 plus backbone therapy with TDF and pegIFN, or 24 weeks of backbone therapy followed by 48 weeks of triple-combination treatment. Patients were then followed without treatment for 24-48 weeks.
Backbone TDF-pegIFN therapy produced no HBsAg seroconversions, and HBsAg levels dropped by more than 1 log10 IU/mL in only three patients. In contrast, triple-combination NAP therapy produced undetectable HBsAg and HBsAg seroconversions (up to 233,055 mIU/mL) for 60% of patients. Among 36 patients followed for 24-48 weeks after completing treatment, 78% maintained virologic control and 39% showed functional cures (HBsAg < 0.05 IU/mL, undetectable HBV DNA, and normal ALT). “Additional follow-up is planned to confirm the long-term stability of [these] outcomes,” the researchers said.
Both NAPs were formulated with chelated magnesium to improve their tolerability. Although 95% of patients experienced transaminase flares, these “self-resolved or declined during continuing NAP therapy and normalized in 32 of 34 (94%) of participants completing 48 weeks of follow-up,” the researchers said. In keeping with prior studies, transaminase flares were associated with early declines in HBsAg but not with altered liver function or liver disease symptoms.
The study was conducted at three sites in Maldova. Most participants were men with HBV genotype D infection. “During follow-up, viral rebound occurred in participants [in whom] HBsAg was still detectable at the end of 48 weeks of combination therapy (≥ 57.9 IU/mL), who did not complete therapy, or [for whom] HBsAg clearance occurred very late in therapy,” the researchers wrote. Thus, “persistent exposure to pegIFN while HBsAg is cleared may be important for the establishment of virologic control and functional cure.” They recommended evaluating NAP plus nucleos(t)ide analogue (NUC) therapy to assess response in the absence of pegIFN. Such studies should enroll “NUC-experienced participants with well-controlled HBV DNA.”
Replicor provided funding. Dr. Bazinet and the senior investigator reported that they are employees and shareholders of Replicor and have invented patents that Replicor holds. One coinvestigator reported compensation from Replicor to his institution. The remaining 11 coinvestigators reported having no relevant disclosures.
SOURCE: Bazinet M et al. Gastroenterology. 2020 Mar 5. doi: 0.1053/j.gastro.2020.02.058.
Manhal Izzy, MD, is assistant professor of medicine, Vanderbilt University Medical Center, division of gastroenterology, hepatology, and nutrition, and transplant hepatology at the Vanderbilt Clinic, Nashville, Tenn. He has no conflicts.
Manhal Izzy, MD, is assistant professor of medicine, Vanderbilt University Medical Center, division of gastroenterology, hepatology, and nutrition, and transplant hepatology at the Vanderbilt Clinic, Nashville, Tenn. He has no conflicts.
Manhal Izzy, MD, is assistant professor of medicine, Vanderbilt University Medical Center, division of gastroenterology, hepatology, and nutrition, and transplant hepatology at the Vanderbilt Clinic, Nashville, Tenn. He has no conflicts.
For patients with chronic hepatitis B virus (HBV) infection, triple-combination therapy with tenofovir disoproxil fumarate, pegylated interferon alfa-2a (TDF-pegIFN), and either of two investigational nucleic acid polymers was tolerable and led to long-term functional cures in an open-label phase 2 trial.
The addition of either REP 2139 or REP 2165 to backbone TDF-pegIFN therapy produced functional cures in 39% of patients without lessening HBV DNA control or exacerbating treatment-induced neutropenia or thrombocytopenia, said Michel Bazinet, MD, of Replicor in Montreal and his associates. “Increases in levels of transaminases were significantly more frequent (P < .001 vs. controls) and greater (P = .002 vs. controls) in the nucleic acid polymer groups but did not produce symptoms, correlated with [an] initial decrease in hepatitis B surface antigen [HBsAg], and normalized during therapy and follow-up,” the investigators wrote in Gastroenterology.
Nucleic acid polymers (NAPs) suppress the assembly and secretion of HBV subviral particles. NAP monotherapy is active against HBV but usually does not provide long-term virologic control. In a small study, adding pegIFN or thymosin alpha-1 to an investigational NAP achieved functional control (HBsAg positive, HBV DNA ≤ 2000 IU/mL, and normal alanine aminotransferase levels) in eight of nine patients.
Building on these findings, two triple-combination NAP regimens were evaluated in 40 noncirrhotic HB envelope antigen–negative adults with chronic HBV infection. After 24 weeks of TDF monotherapy, participants were randomly assigned to either 48 weeks of REP 2139 or REP 2165 plus backbone therapy with TDF and pegIFN, or 24 weeks of backbone therapy followed by 48 weeks of triple-combination treatment. Patients were then followed without treatment for 24-48 weeks.
Backbone TDF-pegIFN therapy produced no HBsAg seroconversions, and HBsAg levels dropped by more than 1 log10 IU/mL in only three patients. In contrast, triple-combination NAP therapy produced undetectable HBsAg and HBsAg seroconversions (up to 233,055 mIU/mL) for 60% of patients. Among 36 patients followed for 24-48 weeks after completing treatment, 78% maintained virologic control and 39% showed functional cures (HBsAg < 0.05 IU/mL, undetectable HBV DNA, and normal ALT). “Additional follow-up is planned to confirm the long-term stability of [these] outcomes,” the researchers said.
Both NAPs were formulated with chelated magnesium to improve their tolerability. Although 95% of patients experienced transaminase flares, these “self-resolved or declined during continuing NAP therapy and normalized in 32 of 34 (94%) of participants completing 48 weeks of follow-up,” the researchers said. In keeping with prior studies, transaminase flares were associated with early declines in HBsAg but not with altered liver function or liver disease symptoms.
The study was conducted at three sites in Maldova. Most participants were men with HBV genotype D infection. “During follow-up, viral rebound occurred in participants [in whom] HBsAg was still detectable at the end of 48 weeks of combination therapy (≥ 57.9 IU/mL), who did not complete therapy, or [for whom] HBsAg clearance occurred very late in therapy,” the researchers wrote. Thus, “persistent exposure to pegIFN while HBsAg is cleared may be important for the establishment of virologic control and functional cure.” They recommended evaluating NAP plus nucleos(t)ide analogue (NUC) therapy to assess response in the absence of pegIFN. Such studies should enroll “NUC-experienced participants with well-controlled HBV DNA.”
Replicor provided funding. Dr. Bazinet and the senior investigator reported that they are employees and shareholders of Replicor and have invented patents that Replicor holds. One coinvestigator reported compensation from Replicor to his institution. The remaining 11 coinvestigators reported having no relevant disclosures.
SOURCE: Bazinet M et al. Gastroenterology. 2020 Mar 5. doi: 0.1053/j.gastro.2020.02.058.
For patients with chronic hepatitis B virus (HBV) infection, triple-combination therapy with tenofovir disoproxil fumarate, pegylated interferon alfa-2a (TDF-pegIFN), and either of two investigational nucleic acid polymers was tolerable and led to long-term functional cures in an open-label phase 2 trial.
The addition of either REP 2139 or REP 2165 to backbone TDF-pegIFN therapy produced functional cures in 39% of patients without lessening HBV DNA control or exacerbating treatment-induced neutropenia or thrombocytopenia, said Michel Bazinet, MD, of Replicor in Montreal and his associates. “Increases in levels of transaminases were significantly more frequent (P < .001 vs. controls) and greater (P = .002 vs. controls) in the nucleic acid polymer groups but did not produce symptoms, correlated with [an] initial decrease in hepatitis B surface antigen [HBsAg], and normalized during therapy and follow-up,” the investigators wrote in Gastroenterology.
Nucleic acid polymers (NAPs) suppress the assembly and secretion of HBV subviral particles. NAP monotherapy is active against HBV but usually does not provide long-term virologic control. In a small study, adding pegIFN or thymosin alpha-1 to an investigational NAP achieved functional control (HBsAg positive, HBV DNA ≤ 2000 IU/mL, and normal alanine aminotransferase levels) in eight of nine patients.
Building on these findings, two triple-combination NAP regimens were evaluated in 40 noncirrhotic HB envelope antigen–negative adults with chronic HBV infection. After 24 weeks of TDF monotherapy, participants were randomly assigned to either 48 weeks of REP 2139 or REP 2165 plus backbone therapy with TDF and pegIFN, or 24 weeks of backbone therapy followed by 48 weeks of triple-combination treatment. Patients were then followed without treatment for 24-48 weeks.
Backbone TDF-pegIFN therapy produced no HBsAg seroconversions, and HBsAg levels dropped by more than 1 log10 IU/mL in only three patients. In contrast, triple-combination NAP therapy produced undetectable HBsAg and HBsAg seroconversions (up to 233,055 mIU/mL) for 60% of patients. Among 36 patients followed for 24-48 weeks after completing treatment, 78% maintained virologic control and 39% showed functional cures (HBsAg < 0.05 IU/mL, undetectable HBV DNA, and normal ALT). “Additional follow-up is planned to confirm the long-term stability of [these] outcomes,” the researchers said.
Both NAPs were formulated with chelated magnesium to improve their tolerability. Although 95% of patients experienced transaminase flares, these “self-resolved or declined during continuing NAP therapy and normalized in 32 of 34 (94%) of participants completing 48 weeks of follow-up,” the researchers said. In keeping with prior studies, transaminase flares were associated with early declines in HBsAg but not with altered liver function or liver disease symptoms.
The study was conducted at three sites in Maldova. Most participants were men with HBV genotype D infection. “During follow-up, viral rebound occurred in participants [in whom] HBsAg was still detectable at the end of 48 weeks of combination therapy (≥ 57.9 IU/mL), who did not complete therapy, or [for whom] HBsAg clearance occurred very late in therapy,” the researchers wrote. Thus, “persistent exposure to pegIFN while HBsAg is cleared may be important for the establishment of virologic control and functional cure.” They recommended evaluating NAP plus nucleos(t)ide analogue (NUC) therapy to assess response in the absence of pegIFN. Such studies should enroll “NUC-experienced participants with well-controlled HBV DNA.”
Replicor provided funding. Dr. Bazinet and the senior investigator reported that they are employees and shareholders of Replicor and have invented patents that Replicor holds. One coinvestigator reported compensation from Replicor to his institution. The remaining 11 coinvestigators reported having no relevant disclosures.
SOURCE: Bazinet M et al. Gastroenterology. 2020 Mar 5. doi: 0.1053/j.gastro.2020.02.058.
FROM GASTROENTEROLOGY
Health care costs nearly doubled for patients with NAFLD
The health care costs of patients with nonalcoholic fatty liver disease (NAFLD) were nearly twice that of matched population controls, according to the results of a longitudinal cohort study.
Patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) were hospitalized an average of 0.27 times per year versus 0.16 times for controls (P < .001), for an annual incremental cost of $635, reported Hannes Hagström, MD, PhD, of Karolinska University Hospital in Stockholm. Patients with NAFLD also made significantly more outpatient care visits than controls (P < .001), he said. “Patients with advanced fibrosis [had] the highest costs, suggesting that reducing fibrosis progression is important to reduce future health care costs” among patients with NASH, Dr. Hagström and his associates wrote in Clinical Gastroenterology and Hepatology.
The retrospective longitudinal cohort study included all 646 patients diagnosed with biopsy-confirmed NAFLD at two hospitals in Sweden between 1971 and 2019. Patients with other liver diseases were excluded, as were heavy drinkers: men who drank more than 30 g of alcohol (just under four units) daily and women who drank more than 20 g daily. Each patient with NAFLD was matched with 10 population controls matched by age, sex, and county of residence.
Over a mean of 19.9 years of follow-up (range, 0-40 years), patients with NASH were hospitalized a total of 3,478 times, an average of 5.4 hospitalizations per patient. Controls were hospitalized an average of 3.2 times during the same time period (P < .001 vs. NASH patients). “This corresponded to a higher incremental cost in NAFLD patients of $635 per year (95% confidence interval, $407-$864; P < .001),” the researchers reported.
Between 2001 and 2009, patients with NAFLD averaged 5.4 more outpatient visits than controls (P < .001), with annual averages of 1.46 versus 0.86 visits (P < .001). Consequently, patient with NASH incurred $255 more per year in annual outpatient care costs. Liver disease accounted for 6% of outpatient care costs among NASH patients versus 0.2% of costs among controls.
“Cumulative costs in the [fibrosis stage 3 and 4] subgroup were relatively matched with the control population until around year 4 after biopsy, when costs diverged,” the researchers said. “This could possibly be an effect of the larger F3 population developing cirrhosis and increasing costs due to decompensation events.”
They noted that the rising prevalence of NAFLD will further burden health care budgets. “Costs [among patients with NASH] were higher in conjunction with liver biopsy, which is why using noninvasive diagnostic methods (e.g., transient elastography) is likely to reduce total costs,” they added. Of note, although patients with NAFLD also incurred somewhat more per year in prescription costs, the difference was not statistically significant.
The study was supported by Stockholm City Council, the Bengt Ihre Foundation, the County Council of Östergötland, and Gilead. The researchers reported having no conflicts of interest.
SOURCE: Kim H et al. Clin Gastroenterol Hepatol. 2019 Sep 12. doi: 10.1016/j.cgh.2019.10.023.
The possibility of FDA approval of NASH-modifying drugs later this year brings the hope of improving outcomes for patients with NAFLD. Inevitably, the cost effectiveness of those drugs also will be scrutinized as we evaluate their impact in the coming years. To that end, Hagstrom et al. provide useful insight regarding the real-world costs of medical care among patients with histologically staged NAFLD in Sweden.
Their main finding is that medical costs for a patient with NAFLD over 20 years is double that for a random control patient from the general population.
It is worth taking a deeper dive into the factors that drove the cost differential. First, higher inpatient and outpatient specialty care costs accounted for the incremental cost of NAFLD care; drug costs were materially similar in the two groups, albeit examined over a very short time period in the study due to limited national registry data. Second, the cost differential was largest in the first year of diagnosis and attributed to the cost of liver biopsy and related expenses. Last, as one would expect, the cost differential was largest between patients who had stage 3-4 fibrosis, possibly explained by the costs of NASH-related complications.
While we hope that NASH-modifying drugs will reduce the risk of liver-specific complications, the cumulative financial impact of such therapies remains to be seen. On the one hand, short-term costs may increase because of the direct expense of the NASH-modifying drugs plus additional expenses related to management of side effects. In addition, it is likely patients treated with NASH-modifying drugs will need more frequent assessments of liver disease severity to evaluate whether the medication is working, which even if done noninvasively, is likely the add to medical costs. In the long term however, NASH-modifying treatments may reduce the risk of NAFLD complications over time, mitigating the cumulative cost of NAFLD care. The true net effect remains to be seen. In the meantime, we need further studies that quantify costs of NAFLD care - ideally by disease severity and that provide greater insight into the cost of caring for the complications of NASH progression, including liver disease clinical decompensations and transplant.
Maya Balakrishnan, MD, MPH, is an assistant professor, department of medicine, section of gastroenterology & hepatology, Baylor College of Medicine, Houston, and director of hepatology at Ben Taub General Hospital, Houston. She has no conflicts of interest.
The possibility of FDA approval of NASH-modifying drugs later this year brings the hope of improving outcomes for patients with NAFLD. Inevitably, the cost effectiveness of those drugs also will be scrutinized as we evaluate their impact in the coming years. To that end, Hagstrom et al. provide useful insight regarding the real-world costs of medical care among patients with histologically staged NAFLD in Sweden.
Their main finding is that medical costs for a patient with NAFLD over 20 years is double that for a random control patient from the general population.
It is worth taking a deeper dive into the factors that drove the cost differential. First, higher inpatient and outpatient specialty care costs accounted for the incremental cost of NAFLD care; drug costs were materially similar in the two groups, albeit examined over a very short time period in the study due to limited national registry data. Second, the cost differential was largest in the first year of diagnosis and attributed to the cost of liver biopsy and related expenses. Last, as one would expect, the cost differential was largest between patients who had stage 3-4 fibrosis, possibly explained by the costs of NASH-related complications.
While we hope that NASH-modifying drugs will reduce the risk of liver-specific complications, the cumulative financial impact of such therapies remains to be seen. On the one hand, short-term costs may increase because of the direct expense of the NASH-modifying drugs plus additional expenses related to management of side effects. In addition, it is likely patients treated with NASH-modifying drugs will need more frequent assessments of liver disease severity to evaluate whether the medication is working, which even if done noninvasively, is likely the add to medical costs. In the long term however, NASH-modifying treatments may reduce the risk of NAFLD complications over time, mitigating the cumulative cost of NAFLD care. The true net effect remains to be seen. In the meantime, we need further studies that quantify costs of NAFLD care - ideally by disease severity and that provide greater insight into the cost of caring for the complications of NASH progression, including liver disease clinical decompensations and transplant.
Maya Balakrishnan, MD, MPH, is an assistant professor, department of medicine, section of gastroenterology & hepatology, Baylor College of Medicine, Houston, and director of hepatology at Ben Taub General Hospital, Houston. She has no conflicts of interest.
The possibility of FDA approval of NASH-modifying drugs later this year brings the hope of improving outcomes for patients with NAFLD. Inevitably, the cost effectiveness of those drugs also will be scrutinized as we evaluate their impact in the coming years. To that end, Hagstrom et al. provide useful insight regarding the real-world costs of medical care among patients with histologically staged NAFLD in Sweden.
Their main finding is that medical costs for a patient with NAFLD over 20 years is double that for a random control patient from the general population.
It is worth taking a deeper dive into the factors that drove the cost differential. First, higher inpatient and outpatient specialty care costs accounted for the incremental cost of NAFLD care; drug costs were materially similar in the two groups, albeit examined over a very short time period in the study due to limited national registry data. Second, the cost differential was largest in the first year of diagnosis and attributed to the cost of liver biopsy and related expenses. Last, as one would expect, the cost differential was largest between patients who had stage 3-4 fibrosis, possibly explained by the costs of NASH-related complications.
While we hope that NASH-modifying drugs will reduce the risk of liver-specific complications, the cumulative financial impact of such therapies remains to be seen. On the one hand, short-term costs may increase because of the direct expense of the NASH-modifying drugs plus additional expenses related to management of side effects. In addition, it is likely patients treated with NASH-modifying drugs will need more frequent assessments of liver disease severity to evaluate whether the medication is working, which even if done noninvasively, is likely the add to medical costs. In the long term however, NASH-modifying treatments may reduce the risk of NAFLD complications over time, mitigating the cumulative cost of NAFLD care. The true net effect remains to be seen. In the meantime, we need further studies that quantify costs of NAFLD care - ideally by disease severity and that provide greater insight into the cost of caring for the complications of NASH progression, including liver disease clinical decompensations and transplant.
Maya Balakrishnan, MD, MPH, is an assistant professor, department of medicine, section of gastroenterology & hepatology, Baylor College of Medicine, Houston, and director of hepatology at Ben Taub General Hospital, Houston. She has no conflicts of interest.
The health care costs of patients with nonalcoholic fatty liver disease (NAFLD) were nearly twice that of matched population controls, according to the results of a longitudinal cohort study.
Patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) were hospitalized an average of 0.27 times per year versus 0.16 times for controls (P < .001), for an annual incremental cost of $635, reported Hannes Hagström, MD, PhD, of Karolinska University Hospital in Stockholm. Patients with NAFLD also made significantly more outpatient care visits than controls (P < .001), he said. “Patients with advanced fibrosis [had] the highest costs, suggesting that reducing fibrosis progression is important to reduce future health care costs” among patients with NASH, Dr. Hagström and his associates wrote in Clinical Gastroenterology and Hepatology.
The retrospective longitudinal cohort study included all 646 patients diagnosed with biopsy-confirmed NAFLD at two hospitals in Sweden between 1971 and 2019. Patients with other liver diseases were excluded, as were heavy drinkers: men who drank more than 30 g of alcohol (just under four units) daily and women who drank more than 20 g daily. Each patient with NAFLD was matched with 10 population controls matched by age, sex, and county of residence.
Over a mean of 19.9 years of follow-up (range, 0-40 years), patients with NASH were hospitalized a total of 3,478 times, an average of 5.4 hospitalizations per patient. Controls were hospitalized an average of 3.2 times during the same time period (P < .001 vs. NASH patients). “This corresponded to a higher incremental cost in NAFLD patients of $635 per year (95% confidence interval, $407-$864; P < .001),” the researchers reported.
Between 2001 and 2009, patients with NAFLD averaged 5.4 more outpatient visits than controls (P < .001), with annual averages of 1.46 versus 0.86 visits (P < .001). Consequently, patient with NASH incurred $255 more per year in annual outpatient care costs. Liver disease accounted for 6% of outpatient care costs among NASH patients versus 0.2% of costs among controls.
“Cumulative costs in the [fibrosis stage 3 and 4] subgroup were relatively matched with the control population until around year 4 after biopsy, when costs diverged,” the researchers said. “This could possibly be an effect of the larger F3 population developing cirrhosis and increasing costs due to decompensation events.”
They noted that the rising prevalence of NAFLD will further burden health care budgets. “Costs [among patients with NASH] were higher in conjunction with liver biopsy, which is why using noninvasive diagnostic methods (e.g., transient elastography) is likely to reduce total costs,” they added. Of note, although patients with NAFLD also incurred somewhat more per year in prescription costs, the difference was not statistically significant.
The study was supported by Stockholm City Council, the Bengt Ihre Foundation, the County Council of Östergötland, and Gilead. The researchers reported having no conflicts of interest.
SOURCE: Kim H et al. Clin Gastroenterol Hepatol. 2019 Sep 12. doi: 10.1016/j.cgh.2019.10.023.
The health care costs of patients with nonalcoholic fatty liver disease (NAFLD) were nearly twice that of matched population controls, according to the results of a longitudinal cohort study.
Patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) were hospitalized an average of 0.27 times per year versus 0.16 times for controls (P < .001), for an annual incremental cost of $635, reported Hannes Hagström, MD, PhD, of Karolinska University Hospital in Stockholm. Patients with NAFLD also made significantly more outpatient care visits than controls (P < .001), he said. “Patients with advanced fibrosis [had] the highest costs, suggesting that reducing fibrosis progression is important to reduce future health care costs” among patients with NASH, Dr. Hagström and his associates wrote in Clinical Gastroenterology and Hepatology.
The retrospective longitudinal cohort study included all 646 patients diagnosed with biopsy-confirmed NAFLD at two hospitals in Sweden between 1971 and 2019. Patients with other liver diseases were excluded, as were heavy drinkers: men who drank more than 30 g of alcohol (just under four units) daily and women who drank more than 20 g daily. Each patient with NAFLD was matched with 10 population controls matched by age, sex, and county of residence.
Over a mean of 19.9 years of follow-up (range, 0-40 years), patients with NASH were hospitalized a total of 3,478 times, an average of 5.4 hospitalizations per patient. Controls were hospitalized an average of 3.2 times during the same time period (P < .001 vs. NASH patients). “This corresponded to a higher incremental cost in NAFLD patients of $635 per year (95% confidence interval, $407-$864; P < .001),” the researchers reported.
Between 2001 and 2009, patients with NAFLD averaged 5.4 more outpatient visits than controls (P < .001), with annual averages of 1.46 versus 0.86 visits (P < .001). Consequently, patient with NASH incurred $255 more per year in annual outpatient care costs. Liver disease accounted for 6% of outpatient care costs among NASH patients versus 0.2% of costs among controls.
“Cumulative costs in the [fibrosis stage 3 and 4] subgroup were relatively matched with the control population until around year 4 after biopsy, when costs diverged,” the researchers said. “This could possibly be an effect of the larger F3 population developing cirrhosis and increasing costs due to decompensation events.”
They noted that the rising prevalence of NAFLD will further burden health care budgets. “Costs [among patients with NASH] were higher in conjunction with liver biopsy, which is why using noninvasive diagnostic methods (e.g., transient elastography) is likely to reduce total costs,” they added. Of note, although patients with NAFLD also incurred somewhat more per year in prescription costs, the difference was not statistically significant.
The study was supported by Stockholm City Council, the Bengt Ihre Foundation, the County Council of Östergötland, and Gilead. The researchers reported having no conflicts of interest.
SOURCE: Kim H et al. Clin Gastroenterol Hepatol. 2019 Sep 12. doi: 10.1016/j.cgh.2019.10.023.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Medicare claims review builds case for NAFLD/NASH screening
Nonalcoholic fatty liver disease isn’t being diagnosed early enough; by the time it’s caught, patients often have advanced complications such as decompensated cirrhosis or hepatocellular carcinoma, according a review of Medicare claims data from 2007-2015.
Among 10,826,456 enrollees – about 20% of the Medicare population – 621,253 had International Classification of Diseases codes for NAFLD/nonalcoholic steatohepatitis (NASH), yielding a prevalence of 5.7%. That’s substantially lower than modeling estimates of 30% in the general population, indicating that there is “considerable underdiagnosis of NAFLD in real-world clinical practice,” and that less severe disease, and the opportunity to treat it before it progresses, is being missed, said investigators led by Rohit Loomba, MD, director of the NAFLD Research Center at the University of California, San Diego, NAFLD Research Center (Aliment Pharmacol Ther. 2020 May 5. doi: 10.1111/apt.15679).
When the team excluded patients with other causes of liver disease such as alcohol abuse or viral hepatitis, they were left with a study population of 260,950 subjects; 71.1% had NAFLD/NASH alone, and 28.9% had NAFLD cirrhosis, almost all of them first diagnosed with decompensated cirrhosis. More than half of the 581 hepatocellular carcinoma patients had no previous diagnosis of cirrhosis.
The cumulative risk of progression of NAFLD to cirrhosis over the 8-year study period was 39%, and from compensated cirrhosis to decompensated cirrhosis, it was 45%. Among a subgroup of 258 patients with compensated cirrhosis, 19% progressed to decompensated cirrhosis or hepatocellular carcinoma, or died, over a median of a year and a half.
The findings “highlight the urgent need for an algorithm to identify individuals at higher risk of NAFLD/NASH,” so the disease is caught at a point when lifestyle and medical interventions might halt or delay progression, the team said.
Screening isn’t currently recommended in guidelines because of the limited efficacy of current treatments, but “with promising novel NAFLD/NASH interventions currently under development and review,” the team said it might be time to rethink the issue.
The majority of patients with early NAFLD/NASH have nonspecific symptoms, which makes screening difficult. However, the investigators identified several independent predictors of disease progression and death, including cardiovascular disease – present among 68.7% of subjects – dyslipidemia (84.1%), diabetes (55.5%), and renal impairment (24.3%).
The finding “supports the evaluation of certain variables” in a screening algorithm, “including advanced age and certain components of metabolic syndrome. Furthermore, important variables in previously developed noninvasive NAFLD/NASH staging algorithms including body mass index and biomarkers for liver function and insulin resistance may also warrant evaluation as components of an identification algorithm,” the team said.
It’s possible the study overestimated the risks of disease progression and mortality with NAFLD/NASH because patients with more severe disease were probably more likely to have been identified in Medicare data, the investigators said.
The mean age of the NAFLD/NASH subjects was 67.4 years, and 60% were women.
The work was funded by Gilead, which has several drugs under development for NAFLD/NASH. Two authors are Gilead employees, and the rest, including Dr. Loomba, reported funding and other ties to the company.
To help your patients better understand NASH, visit the AGA GI Patient Center at https://www.gastro.org/
SOURCE: Loomba R et al. Aliment Pharmacol Ther. 2020 May 5. doi: 10.1111/apt.15679.
Nonalcoholic fatty liver disease isn’t being diagnosed early enough; by the time it’s caught, patients often have advanced complications such as decompensated cirrhosis or hepatocellular carcinoma, according a review of Medicare claims data from 2007-2015.
Among 10,826,456 enrollees – about 20% of the Medicare population – 621,253 had International Classification of Diseases codes for NAFLD/nonalcoholic steatohepatitis (NASH), yielding a prevalence of 5.7%. That’s substantially lower than modeling estimates of 30% in the general population, indicating that there is “considerable underdiagnosis of NAFLD in real-world clinical practice,” and that less severe disease, and the opportunity to treat it before it progresses, is being missed, said investigators led by Rohit Loomba, MD, director of the NAFLD Research Center at the University of California, San Diego, NAFLD Research Center (Aliment Pharmacol Ther. 2020 May 5. doi: 10.1111/apt.15679).
When the team excluded patients with other causes of liver disease such as alcohol abuse or viral hepatitis, they were left with a study population of 260,950 subjects; 71.1% had NAFLD/NASH alone, and 28.9% had NAFLD cirrhosis, almost all of them first diagnosed with decompensated cirrhosis. More than half of the 581 hepatocellular carcinoma patients had no previous diagnosis of cirrhosis.
The cumulative risk of progression of NAFLD to cirrhosis over the 8-year study period was 39%, and from compensated cirrhosis to decompensated cirrhosis, it was 45%. Among a subgroup of 258 patients with compensated cirrhosis, 19% progressed to decompensated cirrhosis or hepatocellular carcinoma, or died, over a median of a year and a half.
The findings “highlight the urgent need for an algorithm to identify individuals at higher risk of NAFLD/NASH,” so the disease is caught at a point when lifestyle and medical interventions might halt or delay progression, the team said.
Screening isn’t currently recommended in guidelines because of the limited efficacy of current treatments, but “with promising novel NAFLD/NASH interventions currently under development and review,” the team said it might be time to rethink the issue.
The majority of patients with early NAFLD/NASH have nonspecific symptoms, which makes screening difficult. However, the investigators identified several independent predictors of disease progression and death, including cardiovascular disease – present among 68.7% of subjects – dyslipidemia (84.1%), diabetes (55.5%), and renal impairment (24.3%).
The finding “supports the evaluation of certain variables” in a screening algorithm, “including advanced age and certain components of metabolic syndrome. Furthermore, important variables in previously developed noninvasive NAFLD/NASH staging algorithms including body mass index and biomarkers for liver function and insulin resistance may also warrant evaluation as components of an identification algorithm,” the team said.
It’s possible the study overestimated the risks of disease progression and mortality with NAFLD/NASH because patients with more severe disease were probably more likely to have been identified in Medicare data, the investigators said.
The mean age of the NAFLD/NASH subjects was 67.4 years, and 60% were women.
The work was funded by Gilead, which has several drugs under development for NAFLD/NASH. Two authors are Gilead employees, and the rest, including Dr. Loomba, reported funding and other ties to the company.
To help your patients better understand NASH, visit the AGA GI Patient Center at https://www.gastro.org/
SOURCE: Loomba R et al. Aliment Pharmacol Ther. 2020 May 5. doi: 10.1111/apt.15679.
Nonalcoholic fatty liver disease isn’t being diagnosed early enough; by the time it’s caught, patients often have advanced complications such as decompensated cirrhosis or hepatocellular carcinoma, according a review of Medicare claims data from 2007-2015.
Among 10,826,456 enrollees – about 20% of the Medicare population – 621,253 had International Classification of Diseases codes for NAFLD/nonalcoholic steatohepatitis (NASH), yielding a prevalence of 5.7%. That’s substantially lower than modeling estimates of 30% in the general population, indicating that there is “considerable underdiagnosis of NAFLD in real-world clinical practice,” and that less severe disease, and the opportunity to treat it before it progresses, is being missed, said investigators led by Rohit Loomba, MD, director of the NAFLD Research Center at the University of California, San Diego, NAFLD Research Center (Aliment Pharmacol Ther. 2020 May 5. doi: 10.1111/apt.15679).
When the team excluded patients with other causes of liver disease such as alcohol abuse or viral hepatitis, they were left with a study population of 260,950 subjects; 71.1% had NAFLD/NASH alone, and 28.9% had NAFLD cirrhosis, almost all of them first diagnosed with decompensated cirrhosis. More than half of the 581 hepatocellular carcinoma patients had no previous diagnosis of cirrhosis.
The cumulative risk of progression of NAFLD to cirrhosis over the 8-year study period was 39%, and from compensated cirrhosis to decompensated cirrhosis, it was 45%. Among a subgroup of 258 patients with compensated cirrhosis, 19% progressed to decompensated cirrhosis or hepatocellular carcinoma, or died, over a median of a year and a half.
The findings “highlight the urgent need for an algorithm to identify individuals at higher risk of NAFLD/NASH,” so the disease is caught at a point when lifestyle and medical interventions might halt or delay progression, the team said.
Screening isn’t currently recommended in guidelines because of the limited efficacy of current treatments, but “with promising novel NAFLD/NASH interventions currently under development and review,” the team said it might be time to rethink the issue.
The majority of patients with early NAFLD/NASH have nonspecific symptoms, which makes screening difficult. However, the investigators identified several independent predictors of disease progression and death, including cardiovascular disease – present among 68.7% of subjects – dyslipidemia (84.1%), diabetes (55.5%), and renal impairment (24.3%).
The finding “supports the evaluation of certain variables” in a screening algorithm, “including advanced age and certain components of metabolic syndrome. Furthermore, important variables in previously developed noninvasive NAFLD/NASH staging algorithms including body mass index and biomarkers for liver function and insulin resistance may also warrant evaluation as components of an identification algorithm,” the team said.
It’s possible the study overestimated the risks of disease progression and mortality with NAFLD/NASH because patients with more severe disease were probably more likely to have been identified in Medicare data, the investigators said.
The mean age of the NAFLD/NASH subjects was 67.4 years, and 60% were women.
The work was funded by Gilead, which has several drugs under development for NAFLD/NASH. Two authors are Gilead employees, and the rest, including Dr. Loomba, reported funding and other ties to the company.
To help your patients better understand NASH, visit the AGA GI Patient Center at https://www.gastro.org/
SOURCE: Loomba R et al. Aliment Pharmacol Ther. 2020 May 5. doi: 10.1111/apt.15679.
FROM ALIMENTARY PHARMACOLOGY & THERAPEUTICS
High rate of fatty liver disease found among 9/11 first responders
First responders to the site of the 2001 World Trade Center attack may have an elevated risk of nonalcoholic fatty liver disease (NAFLD), according to investigators.
In a retrospective look at 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program, 195 (82.6%) had NAFLD, compared with 24%-45% of the general population, reported lead author Mishal Reja, MD, of Robert Wood Johnson University Hospital, New Brunswick, N.J.
The increased rate of NAFLD among first responders is likely because of toxin exposure at ground zero, which can cause a subtype of NAFLD known as toxin-associated fatty liver disease (TAFLD), Dr. Reja wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
“I was not surprised [by these findings],” Dr. Reja said during a virtual press conference. “In the prior literature that did examine TAFLD, it did show that populations exposed to these specific chemicals ... at the ground zero site had extremely high rates – consistent with the rates we found in our study – of fatty liver disease.”
Dr. Reja said that 9/11 first responders were exposed to “many common toxins that are consistently in occupational and environmental toxicant literature.” In particular, he named polycyclic aromatic hydrocarbons and vinyl chloride.
“A lot of these toxins are ... included in industrial solvents as well as building demolition,” Dr. Reja said. “So they’ve been around for so long, and they’ve been studied for so long, [that we have] literature that shows these toxins are associated with fatty liver disease, which is how we arrived at the hypothesis in the first place.”
The first responders were stratified by roles, which were associated with varying levels of exposure. About 40% of individuals in the study were involved in moving debris from the site, a small group (4%) were involved in clean-up and maintenance, while approximately 30%-40% worked in more protected, administrative roles.
Comparing individuals in the study with TAFLD versus those without TAFLD revealed additional risk factors. Multivariate logistical regression analysis showed that obese individuals had a significantly increased risk of fatty liver disease, suggesting a synergistic effect.
“If you were exposed to these toxins in the World Trade Center, and you were obese, [then] you are actually between two to three times more likely to get [TAFLD],” Dr. Reja said, noting that hypertension and diabetes were also identified as independent risk factors.
Dr. Reja and colleagues are planning a prospective trial to investigate further. The study will likely involve 100-200 first responders with TAFLD, a similar number of individuals with NAFLD, and another group without liver disease.
The investigators reported no outside funding or conflicts of interest.
SOURCE: Reja M et al. DDW 2020, Abstracts available online May 2.
First responders to the site of the 2001 World Trade Center attack may have an elevated risk of nonalcoholic fatty liver disease (NAFLD), according to investigators.
In a retrospective look at 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program, 195 (82.6%) had NAFLD, compared with 24%-45% of the general population, reported lead author Mishal Reja, MD, of Robert Wood Johnson University Hospital, New Brunswick, N.J.
The increased rate of NAFLD among first responders is likely because of toxin exposure at ground zero, which can cause a subtype of NAFLD known as toxin-associated fatty liver disease (TAFLD), Dr. Reja wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
“I was not surprised [by these findings],” Dr. Reja said during a virtual press conference. “In the prior literature that did examine TAFLD, it did show that populations exposed to these specific chemicals ... at the ground zero site had extremely high rates – consistent with the rates we found in our study – of fatty liver disease.”
Dr. Reja said that 9/11 first responders were exposed to “many common toxins that are consistently in occupational and environmental toxicant literature.” In particular, he named polycyclic aromatic hydrocarbons and vinyl chloride.
“A lot of these toxins are ... included in industrial solvents as well as building demolition,” Dr. Reja said. “So they’ve been around for so long, and they’ve been studied for so long, [that we have] literature that shows these toxins are associated with fatty liver disease, which is how we arrived at the hypothesis in the first place.”
The first responders were stratified by roles, which were associated with varying levels of exposure. About 40% of individuals in the study were involved in moving debris from the site, a small group (4%) were involved in clean-up and maintenance, while approximately 30%-40% worked in more protected, administrative roles.
Comparing individuals in the study with TAFLD versus those without TAFLD revealed additional risk factors. Multivariate logistical regression analysis showed that obese individuals had a significantly increased risk of fatty liver disease, suggesting a synergistic effect.
“If you were exposed to these toxins in the World Trade Center, and you were obese, [then] you are actually between two to three times more likely to get [TAFLD],” Dr. Reja said, noting that hypertension and diabetes were also identified as independent risk factors.
Dr. Reja and colleagues are planning a prospective trial to investigate further. The study will likely involve 100-200 first responders with TAFLD, a similar number of individuals with NAFLD, and another group without liver disease.
The investigators reported no outside funding or conflicts of interest.
SOURCE: Reja M et al. DDW 2020, Abstracts available online May 2.
First responders to the site of the 2001 World Trade Center attack may have an elevated risk of nonalcoholic fatty liver disease (NAFLD), according to investigators.
In a retrospective look at 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program, 195 (82.6%) had NAFLD, compared with 24%-45% of the general population, reported lead author Mishal Reja, MD, of Robert Wood Johnson University Hospital, New Brunswick, N.J.
The increased rate of NAFLD among first responders is likely because of toxin exposure at ground zero, which can cause a subtype of NAFLD known as toxin-associated fatty liver disease (TAFLD), Dr. Reja wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.
“I was not surprised [by these findings],” Dr. Reja said during a virtual press conference. “In the prior literature that did examine TAFLD, it did show that populations exposed to these specific chemicals ... at the ground zero site had extremely high rates – consistent with the rates we found in our study – of fatty liver disease.”
Dr. Reja said that 9/11 first responders were exposed to “many common toxins that are consistently in occupational and environmental toxicant literature.” In particular, he named polycyclic aromatic hydrocarbons and vinyl chloride.
“A lot of these toxins are ... included in industrial solvents as well as building demolition,” Dr. Reja said. “So they’ve been around for so long, and they’ve been studied for so long, [that we have] literature that shows these toxins are associated with fatty liver disease, which is how we arrived at the hypothesis in the first place.”
The first responders were stratified by roles, which were associated with varying levels of exposure. About 40% of individuals in the study were involved in moving debris from the site, a small group (4%) were involved in clean-up and maintenance, while approximately 30%-40% worked in more protected, administrative roles.
Comparing individuals in the study with TAFLD versus those without TAFLD revealed additional risk factors. Multivariate logistical regression analysis showed that obese individuals had a significantly increased risk of fatty liver disease, suggesting a synergistic effect.
“If you were exposed to these toxins in the World Trade Center, and you were obese, [then] you are actually between two to three times more likely to get [TAFLD],” Dr. Reja said, noting that hypertension and diabetes were also identified as independent risk factors.
Dr. Reja and colleagues are planning a prospective trial to investigate further. The study will likely involve 100-200 first responders with TAFLD, a similar number of individuals with NAFLD, and another group without liver disease.
The investigators reported no outside funding or conflicts of interest.
SOURCE: Reja M et al. DDW 2020, Abstracts available online May 2.
FROM DDW 2020
Key clinical point: First responders to the site of the 2001 World Trade Center attack may have a higher risk of fatty liver disease.
Major finding: Eighty-three percent of first responders presenting with gastrointestinal symptoms had toxin-associated fatty liver disease (TAFLD), a subtype of nonalcoholic fatty liver disease (NAFLD).
Study details: A retrospective study involving 236 first responders presenting with gastrointestinal symptoms to the World Trade Center Health Program between January 2014 and August 2019.
Disclosures: The investigators reported no outside funding or conflicts of interest.
Source: Reja M et al. DDW 2020, Abstracts available online May 2.
AGA CPU: Screening and surveillance for hepatocellular carcinoma in patients with NAFLD
Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.
Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.
Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.
Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.
Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.
The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”
They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.
It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.
The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.
SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.
Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.
Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.
Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.
Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.
Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.
The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”
They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.
It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.
The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.
SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.
Physicians should consider liver cancer screening for all patients with nonalcoholic fatty liver disease (NAFLD) and cirrhosis, according to a new clinical practice update from the American Gastroenterological Association.
Screening “should be offered for patients with cirrhosis of varying etiologies when the risk of hepatocellular carcinoma is approximately at least 1.5% per year, as has been noted with NAFLD cirrhosis,” wrote Rohit Loomba, MD, of the University of California, San Diego, and associates. Although patients with noncirrhotic NAFLD also can develop hepatocellular carcinoma, “[a]t this point, we believe that [the benefit of screening] is restricted to patients with compensated cirrhosis or those with decompensated cirrhosis listed for liver transplantation,” they wrote in Gastroenterology.
Liver cancer in NAFLD often goes undetected until it is advanced enough that patients are not candidates for curative therapy. Current guidelines provide limited recommendations on which patients with NAFLD to monitor for hepatocellular carcinoma, how best to do so, and how often. To fill this gap, Dr. Loomba and associates reviewed and cited 79 published papers and developed eight suggestions for clinical practice.
Patients with NAFLD and stage 0-2 fibrosis are at “extremely low” risk for hepatocellular carcinoma and should not be routinely screened, the practice update stated. Advanced fibrosis is a clear risk factor but can be challenging to detect in NAFLD – imaging is often insensitive, and screening biopsy tends to be infeasible. Hence, the experts suggest considering liver cancer screening if patients with NAFLD show evidence of advanced fibrosis or cirrhosis on at least two noninvasive tests of distinct modalities (that is, the two tests should not both be point-of-care, specialized blood tests or noninvasive imaging). To improve specificity, the recommended cut-point thresholds for cirrhosis are 16.1 kPa for vibration-controlled transient elastography and 5 kPa for magnetic resonance elastography.
Screening ultrasound accurately detects hepatocellular carcinoma in patients with cirrhosis who have a good acoustic window. However, ultrasound quality is operator dependent, and it can be difficult even for experienced users to detect mass lesions in overweight or obese patients. Thus, it is important always to document parenchymal heterogeneity, beam attenuation, and whether the entire liver was visualized. If ultrasound quality is inadequate, patients should be screened every 6 months with CT or MRI, with or without alpha-fetoprotein, according to the practice update.
The authors advised clinicians to counsel all patients with NAFLD and cirrhosis to avoid alcohol and tobacco. “Irrespective of NAFLD, the bulk of epidemiological data support alcohol drinking as a major risk for hepatocellular carcinoma,” they note. Likewise, pooled studies indicate that current smokers are at about 50%-85% greater risk of liver cancer than never smokers. The experts add that “[al]though specific data do not exist, we believe that e-cigarettes may turn out to be equally harmful and patients be counseled to abstain from those as well.”
They also recommended optimally managing dyslipidemia and diabetes among patients with NAFLD who are at risk for hepatocellular carcinoma. Statins are safe for patients with NAFLD and dyslipidemia and may lower hepatocellular carcinoma risk, although more research is needed, according to the experts. For now, they support “the notion that the benefits of statin therapy among patients with dyslipidemia and NAFLD significantly outweigh the risk and should be utilized routinely.” Type 2 diabetes mellitus clearly heightens the risk of hepatocellular carcinoma, which metformin appears to reduce among patients with NAFLD, cirrhosis, and type 2 diabetes. Glucagonlike peptide–1 receptor agonists and some thiazolidinediones also appear to attenuate liver steatosis, inflammation, degeneration, and fibrosis, but it remains unclear if these effects ultimately lower cancer risk.
It is unclear if obesity directly contributes to hepatocellular carcinoma among patients with NAFLD, but obesity is an “important risk factor” for NAFLD itself, and “weight-loss interventions are strongly recommended to improve NAFLD-related outcomes,” the experts wrote. Pending further studies on whether weight loss reduces liver cancer risk in patients with NAFLD, they called for lifestyle modifications, pharmacotherapy, or bariatric surgery or bariatric endoscopy procedures to optimally manage obesity in patients with NAFLD who are at risk for liver cancer.
The authors disclosed funding from the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the Cancer Prevention & Research Institute of Texas, and the Center for Gastrointestinal Development, Infection and Injury. Dr. Loomba disclosed ties to Intercept Pharmaceuticals, Bird Rock Bio, Celgene, Enanta Pharmaceuticals, and a number of other companies. Two coauthors disclosed ties to Allergan, AbbVie, Conatus Pharmaceuticals, Genfit, Gilead, and Intercept. The remaining coauthor reported having no conflicts of interest.
SOURCE: Loomba R et al. Gastroenterology. 2020 Jan 29. doi: 10.1053/j.gastro.2019.12.053.
FROM GASTROENTEROLOGY
CDC: Screen nearly all adults, including pregnant women, for HCV
In the latest issue of the Morbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention recommended hepatitis C virus screening for all adults and all pregnant women – during each of their pregnancies – in areas where prevalence of the infection is 0.1% or greater.
That’s essentially the entire United States; there’s no state with a statewide adult prevalence below 0.1%, and “few settings are known to exist” otherwise, the CDC noted (MMWR Recomm Rep. 2020 Apr 10;69(2):1-17).
The agency encouraged providers to consult state or local health departments or the CDC directly to determine local HCV prevalence. “As a general guide ... approximately 59% of anti-HCV positive persons are HCV RNA positive,” indicating active infection, the agency noted.
The advice was an expansion from the CDC’s last universal screening recommendation in 2012, which was limited to people born from 1945 to 1965; the incidence of acute infections has climbed since then and is highest now among younger people, so the guideline needed to be revisited, explained authors led by Sarah Schillie, MD, of the CDC’s Division of Viral Hepatitis, Atlanta.
The U.S. Preventive Services Task Force also recently recommended universal adult screening after previously limiting it to baby boomers.
As for pregnancy, the CDC’s past advice was to screen pregnant women with known risk factors, but that needed to be revisited as well. For one thing, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have since recommended testing all pregnant women.
But also, the CDC said, it’s an opportune time for screening because “many women only have access to health care during pregnancy and the immediate postpartum period,” when treatment, if needed, can be started. Plus, HCV status is important for management decisions, such as using amniocentesis in positive women instead of chorionic villus sampling.
The rest of CDC’s 2012 recommendations stand, including screening all people with risk factors and repeating screening while they persist. Also, “any person who requests hepatitis C testing should receive it, regardless of disclosure of risk,” because people might be reluctant to report things like IV drug use, the authors said.
Screening in the guidelines means an HCV antibody test, followed by a nucleic acid test to check for active infection. The CDC encouraged automatic reflex testing, meaning immediately checking antibody positive samples for HCV RNA. RNA in the blood indicates active, replicating virus.
The new recommendations penciled out in modeling, with an incremental cost-effectiveness ratio (ICER) for universal adult screening of approximately $36,000 per quality-adjusted life year (QALY) gained, and an ICER of approximately $15,000 per QALY gained for pregnancy screening, where HCV prevalence is 0.1%; the 0.1% cost/benefit cutpoint was one of the reasons it was chosen as the prevalence threshold. An ICER under $50,000 is the conservative benchmark for cost-effectiveness, the authors noted.
There was no external funding, and the authors had no disclosures.
SOURCE: Schillie S et al. MMWR Recomm Rep. 2020 Apr 10;69[2]:1-17).
In the latest issue of the Morbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention recommended hepatitis C virus screening for all adults and all pregnant women – during each of their pregnancies – in areas where prevalence of the infection is 0.1% or greater.
That’s essentially the entire United States; there’s no state with a statewide adult prevalence below 0.1%, and “few settings are known to exist” otherwise, the CDC noted (MMWR Recomm Rep. 2020 Apr 10;69(2):1-17).
The agency encouraged providers to consult state or local health departments or the CDC directly to determine local HCV prevalence. “As a general guide ... approximately 59% of anti-HCV positive persons are HCV RNA positive,” indicating active infection, the agency noted.
The advice was an expansion from the CDC’s last universal screening recommendation in 2012, which was limited to people born from 1945 to 1965; the incidence of acute infections has climbed since then and is highest now among younger people, so the guideline needed to be revisited, explained authors led by Sarah Schillie, MD, of the CDC’s Division of Viral Hepatitis, Atlanta.
The U.S. Preventive Services Task Force also recently recommended universal adult screening after previously limiting it to baby boomers.
As for pregnancy, the CDC’s past advice was to screen pregnant women with known risk factors, but that needed to be revisited as well. For one thing, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have since recommended testing all pregnant women.
But also, the CDC said, it’s an opportune time for screening because “many women only have access to health care during pregnancy and the immediate postpartum period,” when treatment, if needed, can be started. Plus, HCV status is important for management decisions, such as using amniocentesis in positive women instead of chorionic villus sampling.
The rest of CDC’s 2012 recommendations stand, including screening all people with risk factors and repeating screening while they persist. Also, “any person who requests hepatitis C testing should receive it, regardless of disclosure of risk,” because people might be reluctant to report things like IV drug use, the authors said.
Screening in the guidelines means an HCV antibody test, followed by a nucleic acid test to check for active infection. The CDC encouraged automatic reflex testing, meaning immediately checking antibody positive samples for HCV RNA. RNA in the blood indicates active, replicating virus.
The new recommendations penciled out in modeling, with an incremental cost-effectiveness ratio (ICER) for universal adult screening of approximately $36,000 per quality-adjusted life year (QALY) gained, and an ICER of approximately $15,000 per QALY gained for pregnancy screening, where HCV prevalence is 0.1%; the 0.1% cost/benefit cutpoint was one of the reasons it was chosen as the prevalence threshold. An ICER under $50,000 is the conservative benchmark for cost-effectiveness, the authors noted.
There was no external funding, and the authors had no disclosures.
SOURCE: Schillie S et al. MMWR Recomm Rep. 2020 Apr 10;69[2]:1-17).
In the latest issue of the Morbidity and Mortality Weekly Report, the Centers for Disease Control and Prevention recommended hepatitis C virus screening for all adults and all pregnant women – during each of their pregnancies – in areas where prevalence of the infection is 0.1% or greater.
That’s essentially the entire United States; there’s no state with a statewide adult prevalence below 0.1%, and “few settings are known to exist” otherwise, the CDC noted (MMWR Recomm Rep. 2020 Apr 10;69(2):1-17).
The agency encouraged providers to consult state or local health departments or the CDC directly to determine local HCV prevalence. “As a general guide ... approximately 59% of anti-HCV positive persons are HCV RNA positive,” indicating active infection, the agency noted.
The advice was an expansion from the CDC’s last universal screening recommendation in 2012, which was limited to people born from 1945 to 1965; the incidence of acute infections has climbed since then and is highest now among younger people, so the guideline needed to be revisited, explained authors led by Sarah Schillie, MD, of the CDC’s Division of Viral Hepatitis, Atlanta.
The U.S. Preventive Services Task Force also recently recommended universal adult screening after previously limiting it to baby boomers.
As for pregnancy, the CDC’s past advice was to screen pregnant women with known risk factors, but that needed to be revisited as well. For one thing, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America have since recommended testing all pregnant women.
But also, the CDC said, it’s an opportune time for screening because “many women only have access to health care during pregnancy and the immediate postpartum period,” when treatment, if needed, can be started. Plus, HCV status is important for management decisions, such as using amniocentesis in positive women instead of chorionic villus sampling.
The rest of CDC’s 2012 recommendations stand, including screening all people with risk factors and repeating screening while they persist. Also, “any person who requests hepatitis C testing should receive it, regardless of disclosure of risk,” because people might be reluctant to report things like IV drug use, the authors said.
Screening in the guidelines means an HCV antibody test, followed by a nucleic acid test to check for active infection. The CDC encouraged automatic reflex testing, meaning immediately checking antibody positive samples for HCV RNA. RNA in the blood indicates active, replicating virus.
The new recommendations penciled out in modeling, with an incremental cost-effectiveness ratio (ICER) for universal adult screening of approximately $36,000 per quality-adjusted life year (QALY) gained, and an ICER of approximately $15,000 per QALY gained for pregnancy screening, where HCV prevalence is 0.1%; the 0.1% cost/benefit cutpoint was one of the reasons it was chosen as the prevalence threshold. An ICER under $50,000 is the conservative benchmark for cost-effectiveness, the authors noted.
There was no external funding, and the authors had no disclosures.
SOURCE: Schillie S et al. MMWR Recomm Rep. 2020 Apr 10;69[2]:1-17).
Early liver transplantation for alcoholic hepatitis
Case
A 45-year-old male was admitted to the hospital with severe alcoholic hepatitis. After several days of supportive care and medical therapy, the patient continued to show clinical decline. The patient is now admitted to the intensive-care unit with a Maddrey’s Discriminant Function score of 45 and a Model for End-Stage Liver Disease score of 38. He has no other significant medical comorbidities. On rounds, the patient’s wife, who is at the bedside, asks the team whether her husband would be a candidate for liver transplantation.
Should this patient be offered liver transplantation? What medical and psychosocial factors should we consider? What ethical principles should we consider?
Medical considerations
With the advent of direct-acting antivirals (DAAs), there has been a decline in the number of liver transplants performed for hepatitis C virus–related cirrhosis.1 Instead, alcohol-related liver disease (ALD) has become the most common indication for liver transplant in the United States.2 The 6-month abstinence requirement was a widespread practice within the transplant community that would exclude any patients who were actively drinking from being considered for liver transplant. However, data are inconclusive whether the 6-month rule serves as a predictor of future drinking or poor outcomes after liver transplant.3,4 Unfortunately, many patients with severe alcoholic hepatitis will not survive long enough to fulfill the 6-month requirement.5
In 2011, Mathurin and colleagues led the pivotal European trial demonstrating the effectiveness of liver transplant as a rescue option for highly selected patients with severe alcoholic hepatitis.5 The selection criteria included patients with severe alcoholic hepatitis unresponsive to medical therapy, first liver-decompensating event, presence of close supportive family members, absence of severe psychiatric disorders, and agreement by patients to adhere to lifelong total alcohol abstinence. The study showed that the 6-month survival rate of patients who received early liver transplant was 77%, compared with 25% among those who did not. The positive outcomes were subsequently replicated at several centers in the United States, and this led to a wider adoption of early liver transplant for severe alcoholic hepatitis.6-8
Psychosocial considerations
At present, we do not have well-validated consensus selection criteria to identify patients with alcoholic hepatitis most suitable for liver transplant. Each transplant center employs its own set of selection criteria with slight variations from the original European trial which prompted a national expert consensus meeting in Dallas in 2019.9 The consortium published a set of guidelines for centers planning to or already performing alcoholic hepatitis transplants. The proposed criteria to determine liver transplant candidacy are the following: 1) patients presenting for the first time with decompensated liver disease who are nonresponders to medical therapy; 2) assessment by a multidisciplinary psychosocial team including a social worker and an additional specialist; 3) no repeated unsuccessful attempts at addiction rehabilitation; 4) lack of other substance use/dependence; 5) insight with a commitment to sobriety; 6) presence of close supportive family members. The goal was to select candidates with the least likelihood of relapse in the hope of preventing poor outcomes after liver transplant. A study by a Johns Hopkins group comparing patients with severe alcoholic hepatitis who underwent careful psychosocial evaluation versus alcoholic cirrhosis with at least 6 months abstinence found that the survival and alcohol relapse rates were similar between the two groups.7
Ethical considerations
Expanding liver transplant indications to include some patients with severe alcoholic hepatitis will uphold the principle of beneficence given clear evidence of a survival benefit. In addition, graft survival rates were comparable with those of patients who underwent liver transplant for other causes.10 However, in an era of persistent organ shortage, it is important to balance justice or fairness to the patient with utilitarian policies that optimize outcomes for all who are in need of liver transplantation.
Justice
Justice means fair and equal distribution of scarce health resources to patients without bias on account of sex, race, wealth, and the nature of a patient’s disease. Based on the principle of justice, a patient with alcoholic hepatitis should be afforded opportunities for liver transplant equal to patients with other etiologies of liver disease.
Opponents of adoption of liver transplant for alcoholic hepatitis often base their reluctance on the following: patients’ failure to gain control of their alcohol use disorder, fears of alcohol relapse, and ultimately perceptions that these patients may be less deserving, compared with patients with other etiologies of liver disease. But, is this fair to the patient?
Alcohol use disorder, in general, is stigmatized and is considered by some to be a self-inflicted condition. As a medical community, we do not withhold life-saving treatment from patients who had inflicted their own injuries. Nevertheless, the stigma against alcoholism is so entrenched in our society that some fear transplanting a patient who is actively drinking would negatively affect the public’s perception of the transplant community and thus diminish the organ donation rate and harm the common good. Interestingly, a public opinion survey actually showed that the majority of respondents were at least neutral about the idea of transplanting patients with alcoholic hepatitis.11
Utility
Utility means achieving the greatest good for the greatest number of patients. The absolute scarcity of available organs imposes a need for a strict allocation decision. A liver that is used for a patient with severe alcoholic hepatitis is an organ not used for another patient suffering chronic liver disease. It is worth noting that about 20% of patients with severe alcoholic hepatitis might recover without a transplant.5 That means about one out of five liver transplants performed for alcoholic hepatitis may have been done in a patient who would have recovered without a transplant. Does this policy optimize the greatest good for everyone who is on the wait list?
Moss and Siegler argued that it was not the alcoholism that made patients with alcoholic liver disease less deserving of liver transplant, but rather their failure to seek treatment for alcoholism that made their claim for liver transplant weaker, compared with those who developed cirrhosis through no fault of their own.12 This argument is problematic. For example, patients with nonalcoholic steatohepatitis (NASH) are often compared with patients with alcoholic liver disease when it comes to modifiable behaviors that affect their health, whether it is through weight loss or abstinence, respectively. Yet, there is very little argument for lower priority for NASH patients who failed to lose weight. Secondly, alcohol use disorder is a psychosocially complex disease that requires a multidisciplinary treatment approach. Substance abuse rehabilitation is not readily available to most patients and could single out vulnerable patients from lower socioeconomic classes who are at higher risk for developing alcohol use disorder. Imposing a strict abstinence period regardless of a patient’s medical need is punitive and does not treat the underlying disease. Instead of focusing on disease causality, we ought to advocate for medical treatment of the underlying disease.
Conclusions
Liver transplant effectively functions as a zero-sum game. Efforts to save individual patients with severe alcoholic hepatitis can result in trade-offs to other patients on the wait list. Balancing the ethical principles of utility and justice is challenging. A strict 6-month rule, while convenient, does not strike the balance. The decision to transplant a patient with alcoholic hepatitis should be made on a case-by-case basis. As stewards of donor organs, transplant centers have a duty to carefully evaluate a potential candidate based on medical needs and recipient outcome without the influence of bias. We feel that, when considering liver transplant in patients with severe alcoholic hepatitis, the principle of justice or fairness to the patient is the overriding ethical principle. Provided the patient meets medical and psychosocial criteria that available evidence suggests would result in long-term survival post transplantation, we would support listing for liver transplantation.
References
1. Goldberg D et al. Gastroenterology, 2017;152(5):1090-9.e1.
2. Cholankeril G, Ahmed A. Clin Gastroenterol Hepatol. 2018;16(8):1356-8.
3. Neuberger J et al. J Hepatol. 2002;36(1):130-7.
4. DiMartini A, et al. Clin Liver Dis. 2011;15(4):727-51.
5. Mathurin P et al. N Engl J Med, 2011;365(19):1790-800.
6. Im GY et al. Am J Transplant. 2016;16(3):841-9.
7. Lee BP et al. Ann Surg. 2017;265(1):20-9.
8. Lee BP et al. Gastroenterology. 2018. 155(2):422-30.e1.
9. Asrani SK et al. Liver Transpl. 2020;26(1):127-40.
10. Singal AK et al. Transplantation. 2013;95(5):755-60.
11. Stroh G et al. Am J Transplant. 2015;15(6):1598-604.
12. Moss AH, Siegler M. JAMA. 1991;265(10):1295-8.
Dr. Wang is a gastroenterology fellow in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine; Dr. Aronsohn is associate professor in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine.
Case
A 45-year-old male was admitted to the hospital with severe alcoholic hepatitis. After several days of supportive care and medical therapy, the patient continued to show clinical decline. The patient is now admitted to the intensive-care unit with a Maddrey’s Discriminant Function score of 45 and a Model for End-Stage Liver Disease score of 38. He has no other significant medical comorbidities. On rounds, the patient’s wife, who is at the bedside, asks the team whether her husband would be a candidate for liver transplantation.
Should this patient be offered liver transplantation? What medical and psychosocial factors should we consider? What ethical principles should we consider?
Medical considerations
With the advent of direct-acting antivirals (DAAs), there has been a decline in the number of liver transplants performed for hepatitis C virus–related cirrhosis.1 Instead, alcohol-related liver disease (ALD) has become the most common indication for liver transplant in the United States.2 The 6-month abstinence requirement was a widespread practice within the transplant community that would exclude any patients who were actively drinking from being considered for liver transplant. However, data are inconclusive whether the 6-month rule serves as a predictor of future drinking or poor outcomes after liver transplant.3,4 Unfortunately, many patients with severe alcoholic hepatitis will not survive long enough to fulfill the 6-month requirement.5
In 2011, Mathurin and colleagues led the pivotal European trial demonstrating the effectiveness of liver transplant as a rescue option for highly selected patients with severe alcoholic hepatitis.5 The selection criteria included patients with severe alcoholic hepatitis unresponsive to medical therapy, first liver-decompensating event, presence of close supportive family members, absence of severe psychiatric disorders, and agreement by patients to adhere to lifelong total alcohol abstinence. The study showed that the 6-month survival rate of patients who received early liver transplant was 77%, compared with 25% among those who did not. The positive outcomes were subsequently replicated at several centers in the United States, and this led to a wider adoption of early liver transplant for severe alcoholic hepatitis.6-8
Psychosocial considerations
At present, we do not have well-validated consensus selection criteria to identify patients with alcoholic hepatitis most suitable for liver transplant. Each transplant center employs its own set of selection criteria with slight variations from the original European trial which prompted a national expert consensus meeting in Dallas in 2019.9 The consortium published a set of guidelines for centers planning to or already performing alcoholic hepatitis transplants. The proposed criteria to determine liver transplant candidacy are the following: 1) patients presenting for the first time with decompensated liver disease who are nonresponders to medical therapy; 2) assessment by a multidisciplinary psychosocial team including a social worker and an additional specialist; 3) no repeated unsuccessful attempts at addiction rehabilitation; 4) lack of other substance use/dependence; 5) insight with a commitment to sobriety; 6) presence of close supportive family members. The goal was to select candidates with the least likelihood of relapse in the hope of preventing poor outcomes after liver transplant. A study by a Johns Hopkins group comparing patients with severe alcoholic hepatitis who underwent careful psychosocial evaluation versus alcoholic cirrhosis with at least 6 months abstinence found that the survival and alcohol relapse rates were similar between the two groups.7
Ethical considerations
Expanding liver transplant indications to include some patients with severe alcoholic hepatitis will uphold the principle of beneficence given clear evidence of a survival benefit. In addition, graft survival rates were comparable with those of patients who underwent liver transplant for other causes.10 However, in an era of persistent organ shortage, it is important to balance justice or fairness to the patient with utilitarian policies that optimize outcomes for all who are in need of liver transplantation.
Justice
Justice means fair and equal distribution of scarce health resources to patients without bias on account of sex, race, wealth, and the nature of a patient’s disease. Based on the principle of justice, a patient with alcoholic hepatitis should be afforded opportunities for liver transplant equal to patients with other etiologies of liver disease.
Opponents of adoption of liver transplant for alcoholic hepatitis often base their reluctance on the following: patients’ failure to gain control of their alcohol use disorder, fears of alcohol relapse, and ultimately perceptions that these patients may be less deserving, compared with patients with other etiologies of liver disease. But, is this fair to the patient?
Alcohol use disorder, in general, is stigmatized and is considered by some to be a self-inflicted condition. As a medical community, we do not withhold life-saving treatment from patients who had inflicted their own injuries. Nevertheless, the stigma against alcoholism is so entrenched in our society that some fear transplanting a patient who is actively drinking would negatively affect the public’s perception of the transplant community and thus diminish the organ donation rate and harm the common good. Interestingly, a public opinion survey actually showed that the majority of respondents were at least neutral about the idea of transplanting patients with alcoholic hepatitis.11
Utility
Utility means achieving the greatest good for the greatest number of patients. The absolute scarcity of available organs imposes a need for a strict allocation decision. A liver that is used for a patient with severe alcoholic hepatitis is an organ not used for another patient suffering chronic liver disease. It is worth noting that about 20% of patients with severe alcoholic hepatitis might recover without a transplant.5 That means about one out of five liver transplants performed for alcoholic hepatitis may have been done in a patient who would have recovered without a transplant. Does this policy optimize the greatest good for everyone who is on the wait list?
Moss and Siegler argued that it was not the alcoholism that made patients with alcoholic liver disease less deserving of liver transplant, but rather their failure to seek treatment for alcoholism that made their claim for liver transplant weaker, compared with those who developed cirrhosis through no fault of their own.12 This argument is problematic. For example, patients with nonalcoholic steatohepatitis (NASH) are often compared with patients with alcoholic liver disease when it comes to modifiable behaviors that affect their health, whether it is through weight loss or abstinence, respectively. Yet, there is very little argument for lower priority for NASH patients who failed to lose weight. Secondly, alcohol use disorder is a psychosocially complex disease that requires a multidisciplinary treatment approach. Substance abuse rehabilitation is not readily available to most patients and could single out vulnerable patients from lower socioeconomic classes who are at higher risk for developing alcohol use disorder. Imposing a strict abstinence period regardless of a patient’s medical need is punitive and does not treat the underlying disease. Instead of focusing on disease causality, we ought to advocate for medical treatment of the underlying disease.
Conclusions
Liver transplant effectively functions as a zero-sum game. Efforts to save individual patients with severe alcoholic hepatitis can result in trade-offs to other patients on the wait list. Balancing the ethical principles of utility and justice is challenging. A strict 6-month rule, while convenient, does not strike the balance. The decision to transplant a patient with alcoholic hepatitis should be made on a case-by-case basis. As stewards of donor organs, transplant centers have a duty to carefully evaluate a potential candidate based on medical needs and recipient outcome without the influence of bias. We feel that, when considering liver transplant in patients with severe alcoholic hepatitis, the principle of justice or fairness to the patient is the overriding ethical principle. Provided the patient meets medical and psychosocial criteria that available evidence suggests would result in long-term survival post transplantation, we would support listing for liver transplantation.
References
1. Goldberg D et al. Gastroenterology, 2017;152(5):1090-9.e1.
2. Cholankeril G, Ahmed A. Clin Gastroenterol Hepatol. 2018;16(8):1356-8.
3. Neuberger J et al. J Hepatol. 2002;36(1):130-7.
4. DiMartini A, et al. Clin Liver Dis. 2011;15(4):727-51.
5. Mathurin P et al. N Engl J Med, 2011;365(19):1790-800.
6. Im GY et al. Am J Transplant. 2016;16(3):841-9.
7. Lee BP et al. Ann Surg. 2017;265(1):20-9.
8. Lee BP et al. Gastroenterology. 2018. 155(2):422-30.e1.
9. Asrani SK et al. Liver Transpl. 2020;26(1):127-40.
10. Singal AK et al. Transplantation. 2013;95(5):755-60.
11. Stroh G et al. Am J Transplant. 2015;15(6):1598-604.
12. Moss AH, Siegler M. JAMA. 1991;265(10):1295-8.
Dr. Wang is a gastroenterology fellow in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine; Dr. Aronsohn is associate professor in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine.
Case
A 45-year-old male was admitted to the hospital with severe alcoholic hepatitis. After several days of supportive care and medical therapy, the patient continued to show clinical decline. The patient is now admitted to the intensive-care unit with a Maddrey’s Discriminant Function score of 45 and a Model for End-Stage Liver Disease score of 38. He has no other significant medical comorbidities. On rounds, the patient’s wife, who is at the bedside, asks the team whether her husband would be a candidate for liver transplantation.
Should this patient be offered liver transplantation? What medical and psychosocial factors should we consider? What ethical principles should we consider?
Medical considerations
With the advent of direct-acting antivirals (DAAs), there has been a decline in the number of liver transplants performed for hepatitis C virus–related cirrhosis.1 Instead, alcohol-related liver disease (ALD) has become the most common indication for liver transplant in the United States.2 The 6-month abstinence requirement was a widespread practice within the transplant community that would exclude any patients who were actively drinking from being considered for liver transplant. However, data are inconclusive whether the 6-month rule serves as a predictor of future drinking or poor outcomes after liver transplant.3,4 Unfortunately, many patients with severe alcoholic hepatitis will not survive long enough to fulfill the 6-month requirement.5
In 2011, Mathurin and colleagues led the pivotal European trial demonstrating the effectiveness of liver transplant as a rescue option for highly selected patients with severe alcoholic hepatitis.5 The selection criteria included patients with severe alcoholic hepatitis unresponsive to medical therapy, first liver-decompensating event, presence of close supportive family members, absence of severe psychiatric disorders, and agreement by patients to adhere to lifelong total alcohol abstinence. The study showed that the 6-month survival rate of patients who received early liver transplant was 77%, compared with 25% among those who did not. The positive outcomes were subsequently replicated at several centers in the United States, and this led to a wider adoption of early liver transplant for severe alcoholic hepatitis.6-8
Psychosocial considerations
At present, we do not have well-validated consensus selection criteria to identify patients with alcoholic hepatitis most suitable for liver transplant. Each transplant center employs its own set of selection criteria with slight variations from the original European trial which prompted a national expert consensus meeting in Dallas in 2019.9 The consortium published a set of guidelines for centers planning to or already performing alcoholic hepatitis transplants. The proposed criteria to determine liver transplant candidacy are the following: 1) patients presenting for the first time with decompensated liver disease who are nonresponders to medical therapy; 2) assessment by a multidisciplinary psychosocial team including a social worker and an additional specialist; 3) no repeated unsuccessful attempts at addiction rehabilitation; 4) lack of other substance use/dependence; 5) insight with a commitment to sobriety; 6) presence of close supportive family members. The goal was to select candidates with the least likelihood of relapse in the hope of preventing poor outcomes after liver transplant. A study by a Johns Hopkins group comparing patients with severe alcoholic hepatitis who underwent careful psychosocial evaluation versus alcoholic cirrhosis with at least 6 months abstinence found that the survival and alcohol relapse rates were similar between the two groups.7
Ethical considerations
Expanding liver transplant indications to include some patients with severe alcoholic hepatitis will uphold the principle of beneficence given clear evidence of a survival benefit. In addition, graft survival rates were comparable with those of patients who underwent liver transplant for other causes.10 However, in an era of persistent organ shortage, it is important to balance justice or fairness to the patient with utilitarian policies that optimize outcomes for all who are in need of liver transplantation.
Justice
Justice means fair and equal distribution of scarce health resources to patients without bias on account of sex, race, wealth, and the nature of a patient’s disease. Based on the principle of justice, a patient with alcoholic hepatitis should be afforded opportunities for liver transplant equal to patients with other etiologies of liver disease.
Opponents of adoption of liver transplant for alcoholic hepatitis often base their reluctance on the following: patients’ failure to gain control of their alcohol use disorder, fears of alcohol relapse, and ultimately perceptions that these patients may be less deserving, compared with patients with other etiologies of liver disease. But, is this fair to the patient?
Alcohol use disorder, in general, is stigmatized and is considered by some to be a self-inflicted condition. As a medical community, we do not withhold life-saving treatment from patients who had inflicted their own injuries. Nevertheless, the stigma against alcoholism is so entrenched in our society that some fear transplanting a patient who is actively drinking would negatively affect the public’s perception of the transplant community and thus diminish the organ donation rate and harm the common good. Interestingly, a public opinion survey actually showed that the majority of respondents were at least neutral about the idea of transplanting patients with alcoholic hepatitis.11
Utility
Utility means achieving the greatest good for the greatest number of patients. The absolute scarcity of available organs imposes a need for a strict allocation decision. A liver that is used for a patient with severe alcoholic hepatitis is an organ not used for another patient suffering chronic liver disease. It is worth noting that about 20% of patients with severe alcoholic hepatitis might recover without a transplant.5 That means about one out of five liver transplants performed for alcoholic hepatitis may have been done in a patient who would have recovered without a transplant. Does this policy optimize the greatest good for everyone who is on the wait list?
Moss and Siegler argued that it was not the alcoholism that made patients with alcoholic liver disease less deserving of liver transplant, but rather their failure to seek treatment for alcoholism that made their claim for liver transplant weaker, compared with those who developed cirrhosis through no fault of their own.12 This argument is problematic. For example, patients with nonalcoholic steatohepatitis (NASH) are often compared with patients with alcoholic liver disease when it comes to modifiable behaviors that affect their health, whether it is through weight loss or abstinence, respectively. Yet, there is very little argument for lower priority for NASH patients who failed to lose weight. Secondly, alcohol use disorder is a psychosocially complex disease that requires a multidisciplinary treatment approach. Substance abuse rehabilitation is not readily available to most patients and could single out vulnerable patients from lower socioeconomic classes who are at higher risk for developing alcohol use disorder. Imposing a strict abstinence period regardless of a patient’s medical need is punitive and does not treat the underlying disease. Instead of focusing on disease causality, we ought to advocate for medical treatment of the underlying disease.
Conclusions
Liver transplant effectively functions as a zero-sum game. Efforts to save individual patients with severe alcoholic hepatitis can result in trade-offs to other patients on the wait list. Balancing the ethical principles of utility and justice is challenging. A strict 6-month rule, while convenient, does not strike the balance. The decision to transplant a patient with alcoholic hepatitis should be made on a case-by-case basis. As stewards of donor organs, transplant centers have a duty to carefully evaluate a potential candidate based on medical needs and recipient outcome without the influence of bias. We feel that, when considering liver transplant in patients with severe alcoholic hepatitis, the principle of justice or fairness to the patient is the overriding ethical principle. Provided the patient meets medical and psychosocial criteria that available evidence suggests would result in long-term survival post transplantation, we would support listing for liver transplantation.
References
1. Goldberg D et al. Gastroenterology, 2017;152(5):1090-9.e1.
2. Cholankeril G, Ahmed A. Clin Gastroenterol Hepatol. 2018;16(8):1356-8.
3. Neuberger J et al. J Hepatol. 2002;36(1):130-7.
4. DiMartini A, et al. Clin Liver Dis. 2011;15(4):727-51.
5. Mathurin P et al. N Engl J Med, 2011;365(19):1790-800.
6. Im GY et al. Am J Transplant. 2016;16(3):841-9.
7. Lee BP et al. Ann Surg. 2017;265(1):20-9.
8. Lee BP et al. Gastroenterology. 2018. 155(2):422-30.e1.
9. Asrani SK et al. Liver Transpl. 2020;26(1):127-40.
10. Singal AK et al. Transplantation. 2013;95(5):755-60.
11. Stroh G et al. Am J Transplant. 2015;15(6):1598-604.
12. Moss AH, Siegler M. JAMA. 1991;265(10):1295-8.
Dr. Wang is a gastroenterology fellow in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine; Dr. Aronsohn is associate professor in the division of gastroenterology, hepatology, and nutrition, department of internal medicine, University of Chicago Medicine.
See acute hepatitis? Consider COVID-19, N.Y. case suggests
A woman presented to the emergency department with high liver enzyme levels and dark urine. She developed fever on day 2 of care, and then tested positive for the new coronavirus, researchers at Northwell Health, in Hempstead, New York, report.
The authors say the case, published online in the American Journal of Gastroenterology, is the first documented instance of a patient with COVID-19 presenting with acute hepatitis as the primary symptom before developing respiratory symptoms.
Prior data show that the most common early indications of COVID-19 are respiratory symptoms with fever, shortness of breath, sore throat, and cough, and with imaging results consistent with pneumonia. However, liver enzyme abnormalities are not uncommon in the disease course.
“In patients who are now presenting with acute hepatitis, people need to think of COVID,” senior author David Bernstein, MD, chief of the Division of Hepatology at Northwell Health, told Medscape Medical News.
In addition to Bernstein, Praneet Wander, MD, also in Northwell’s hepatology division, and Marcia Epstein, MD, with Northwell’s Department of Infectious Disease, authored the case report.
Bernstein said Northwell currently has the largest number of COVID-19 cases in the nation and that many patients are presenting with abnormal liver test results and COVID-19 symptoms.
He said that anecdotally, colleagues elsewhere in the United States are also reporting the connection.
“It seems to be that the liver enzyme elevations are part and parcel of this disease,” he said.
Case Details
According to the case report, the 59-year-old woman, who lives alone, came to the emergency department with a chief complaint of dark urine. She was given a face mask and was isolated, per protocol.
“She denied cough, sore throat, shortness of breath, diarrhea, nausea, vomiting or abdominal pain,” the authors wrote. She denied having been in contact with someone who was sick.
She had well-controlled HIV, and recent outpatient liver test results were normal. Eighteen hours after she came to the ED, she was admitted, owing to concern regarding rising liver enzyme levels in conjunction with her being HIV positive.
On presentation, her temperature was 98.9° F. There were no skin indications, lungs were normal, and “there was no jaundice, right upper quadrant tenderness, hepatomegaly or splenomegaly.”
Liver enzyme levels were as follows: aspartate aminotransferase (AST), 1230 (IU/L); alanine aminotransferase (ALT), 697 IU/L (normal for both is < 50 IU/L); alkaline phosphatase, 141 IU/L (normal, < 125 IU/L).
The patient tested negative for hepatitis A, B, C, E, cytomegalovirus, and Epstein-Barr virus. A respiratory viral panel and autoimmune markers were normal.
Fever Appeared on Day 2
She was admitted, and 18 hours after she came to the ED, she developed a fever of 102.2° F. A chest x-ray showed interstitial opacities in both lungs.
Nasopharyngeal samples were taken, and polymerase chain reaction test results were positive for the novel coronavirus. The patient was placed on 3 L of oxygen.
On post admission day 4, a 5-day course of hydroxychloroquine (200 mg twice a day) was initiated.
The patient was discharged to home on hospital day 8. The serum bilirubin level was 0.6 mg/dL; AST, 114 IU/L; ALT, 227 IU/L; and alkaline phosphatase, 259 IU/L.
According to Bernstein, it’s hard to tell in what order COVID-19 symptoms occur because people are staying home with other complaints. They may only present to the emergency department after they develop more typical COVID-19 symptoms, such as shortness of breath.
In this case, the patient noticed a darkening of her urine, “but if she had come the next day, she would have had fever. I think we just happened to catch it early,” Bernstein said.
He added that he saw no connection between the underlying HIV and her liver abnormalities or COVID-19 diagnosis.
Bernstein notes that most COVID-19 patients are not admitted, and he said he worries that a COVID-19 test might not be on the radar of providers in the outpatient setting when a patient presents with elevated liver enzymes levels.
If elevated liver enzyme levels can predict disease course, the information could alter how and where the disease is treated, Bernstein said.
“This is a first report. We’re really right now in the beginning of learning,” he said.
This article first appeared on Medscape.com.
A woman presented to the emergency department with high liver enzyme levels and dark urine. She developed fever on day 2 of care, and then tested positive for the new coronavirus, researchers at Northwell Health, in Hempstead, New York, report.
The authors say the case, published online in the American Journal of Gastroenterology, is the first documented instance of a patient with COVID-19 presenting with acute hepatitis as the primary symptom before developing respiratory symptoms.
Prior data show that the most common early indications of COVID-19 are respiratory symptoms with fever, shortness of breath, sore throat, and cough, and with imaging results consistent with pneumonia. However, liver enzyme abnormalities are not uncommon in the disease course.
“In patients who are now presenting with acute hepatitis, people need to think of COVID,” senior author David Bernstein, MD, chief of the Division of Hepatology at Northwell Health, told Medscape Medical News.
In addition to Bernstein, Praneet Wander, MD, also in Northwell’s hepatology division, and Marcia Epstein, MD, with Northwell’s Department of Infectious Disease, authored the case report.
Bernstein said Northwell currently has the largest number of COVID-19 cases in the nation and that many patients are presenting with abnormal liver test results and COVID-19 symptoms.
He said that anecdotally, colleagues elsewhere in the United States are also reporting the connection.
“It seems to be that the liver enzyme elevations are part and parcel of this disease,” he said.
Case Details
According to the case report, the 59-year-old woman, who lives alone, came to the emergency department with a chief complaint of dark urine. She was given a face mask and was isolated, per protocol.
“She denied cough, sore throat, shortness of breath, diarrhea, nausea, vomiting or abdominal pain,” the authors wrote. She denied having been in contact with someone who was sick.
She had well-controlled HIV, and recent outpatient liver test results were normal. Eighteen hours after she came to the ED, she was admitted, owing to concern regarding rising liver enzyme levels in conjunction with her being HIV positive.
On presentation, her temperature was 98.9° F. There were no skin indications, lungs were normal, and “there was no jaundice, right upper quadrant tenderness, hepatomegaly or splenomegaly.”
Liver enzyme levels were as follows: aspartate aminotransferase (AST), 1230 (IU/L); alanine aminotransferase (ALT), 697 IU/L (normal for both is < 50 IU/L); alkaline phosphatase, 141 IU/L (normal, < 125 IU/L).
The patient tested negative for hepatitis A, B, C, E, cytomegalovirus, and Epstein-Barr virus. A respiratory viral panel and autoimmune markers were normal.
Fever Appeared on Day 2
She was admitted, and 18 hours after she came to the ED, she developed a fever of 102.2° F. A chest x-ray showed interstitial opacities in both lungs.
Nasopharyngeal samples were taken, and polymerase chain reaction test results were positive for the novel coronavirus. The patient was placed on 3 L of oxygen.
On post admission day 4, a 5-day course of hydroxychloroquine (200 mg twice a day) was initiated.
The patient was discharged to home on hospital day 8. The serum bilirubin level was 0.6 mg/dL; AST, 114 IU/L; ALT, 227 IU/L; and alkaline phosphatase, 259 IU/L.
According to Bernstein, it’s hard to tell in what order COVID-19 symptoms occur because people are staying home with other complaints. They may only present to the emergency department after they develop more typical COVID-19 symptoms, such as shortness of breath.
In this case, the patient noticed a darkening of her urine, “but if she had come the next day, she would have had fever. I think we just happened to catch it early,” Bernstein said.
He added that he saw no connection between the underlying HIV and her liver abnormalities or COVID-19 diagnosis.
Bernstein notes that most COVID-19 patients are not admitted, and he said he worries that a COVID-19 test might not be on the radar of providers in the outpatient setting when a patient presents with elevated liver enzymes levels.
If elevated liver enzyme levels can predict disease course, the information could alter how and where the disease is treated, Bernstein said.
“This is a first report. We’re really right now in the beginning of learning,” he said.
This article first appeared on Medscape.com.
A woman presented to the emergency department with high liver enzyme levels and dark urine. She developed fever on day 2 of care, and then tested positive for the new coronavirus, researchers at Northwell Health, in Hempstead, New York, report.
The authors say the case, published online in the American Journal of Gastroenterology, is the first documented instance of a patient with COVID-19 presenting with acute hepatitis as the primary symptom before developing respiratory symptoms.
Prior data show that the most common early indications of COVID-19 are respiratory symptoms with fever, shortness of breath, sore throat, and cough, and with imaging results consistent with pneumonia. However, liver enzyme abnormalities are not uncommon in the disease course.
“In patients who are now presenting with acute hepatitis, people need to think of COVID,” senior author David Bernstein, MD, chief of the Division of Hepatology at Northwell Health, told Medscape Medical News.
In addition to Bernstein, Praneet Wander, MD, also in Northwell’s hepatology division, and Marcia Epstein, MD, with Northwell’s Department of Infectious Disease, authored the case report.
Bernstein said Northwell currently has the largest number of COVID-19 cases in the nation and that many patients are presenting with abnormal liver test results and COVID-19 symptoms.
He said that anecdotally, colleagues elsewhere in the United States are also reporting the connection.
“It seems to be that the liver enzyme elevations are part and parcel of this disease,” he said.
Case Details
According to the case report, the 59-year-old woman, who lives alone, came to the emergency department with a chief complaint of dark urine. She was given a face mask and was isolated, per protocol.
“She denied cough, sore throat, shortness of breath, diarrhea, nausea, vomiting or abdominal pain,” the authors wrote. She denied having been in contact with someone who was sick.
She had well-controlled HIV, and recent outpatient liver test results were normal. Eighteen hours after she came to the ED, she was admitted, owing to concern regarding rising liver enzyme levels in conjunction with her being HIV positive.
On presentation, her temperature was 98.9° F. There were no skin indications, lungs were normal, and “there was no jaundice, right upper quadrant tenderness, hepatomegaly or splenomegaly.”
Liver enzyme levels were as follows: aspartate aminotransferase (AST), 1230 (IU/L); alanine aminotransferase (ALT), 697 IU/L (normal for both is < 50 IU/L); alkaline phosphatase, 141 IU/L (normal, < 125 IU/L).
The patient tested negative for hepatitis A, B, C, E, cytomegalovirus, and Epstein-Barr virus. A respiratory viral panel and autoimmune markers were normal.
Fever Appeared on Day 2
She was admitted, and 18 hours after she came to the ED, she developed a fever of 102.2° F. A chest x-ray showed interstitial opacities in both lungs.
Nasopharyngeal samples were taken, and polymerase chain reaction test results were positive for the novel coronavirus. The patient was placed on 3 L of oxygen.
On post admission day 4, a 5-day course of hydroxychloroquine (200 mg twice a day) was initiated.
The patient was discharged to home on hospital day 8. The serum bilirubin level was 0.6 mg/dL; AST, 114 IU/L; ALT, 227 IU/L; and alkaline phosphatase, 259 IU/L.
According to Bernstein, it’s hard to tell in what order COVID-19 symptoms occur because people are staying home with other complaints. They may only present to the emergency department after they develop more typical COVID-19 symptoms, such as shortness of breath.
In this case, the patient noticed a darkening of her urine, “but if she had come the next day, she would have had fever. I think we just happened to catch it early,” Bernstein said.
He added that he saw no connection between the underlying HIV and her liver abnormalities or COVID-19 diagnosis.
Bernstein notes that most COVID-19 patients are not admitted, and he said he worries that a COVID-19 test might not be on the radar of providers in the outpatient setting when a patient presents with elevated liver enzymes levels.
If elevated liver enzyme levels can predict disease course, the information could alter how and where the disease is treated, Bernstein said.
“This is a first report. We’re really right now in the beginning of learning,” he said.
This article first appeared on Medscape.com.
Year-long synbiotic regimen fails to improve NAFLD
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
Synbiotics can alter gut microbiota in patients with nonalcoholic fatty liver disease (NAFLD), but associated liver benefits remain unseen, according to a recent phase II study.
NAFLD patients who received a year-long regimen of fructo-oligosaccharides and Bifidobacterium animalis had no significant changes in liver fat content or fibrosis, compared with those who received placebo, reported lead author Eleonora Scorletti, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
“There is recent growing interest in the role of gut microbiota in NAFLD pathogenesis, and there are several metaorganismal pathways linking altered gut microbiota ... and NAFLD,” the investigators wrote in Gastroenterology.According to the investigators, previous studies have shown that patients with NAFLD may have some characteristic alterations to their microbiota, such as increased Gram-negative bacteria or more abundant Ruminococcus species, the latter of which were associated with worse fibrosis.
“However, there is currently a lack of consistency in these findings due to the marked variance in the population studied, with differing ages, diets, and geographic locations,” the investigators wrote. “Nonetheless, despite these inconsistencies, there is the possibility that manipulation of the gut microbiota to a more favorable profile could provide a beneficial effect on liver disease in patients with NAFLD.”
To evaluate this possibility, the investigators enrolled 104 patients with NAFLD in the United Kingdom. Patients were randomly divided into a placebo (n = 49) and synbiotic group (n = 55), with the latter receiving 4 grams of fructo-oligosaccharides twice per day plus 10 billion colony-forming units of Bifidobacterium animalis subspecies lactis BB-12 on a daily basis. Treatments were given for 10-14 months.
Diagnostics were conducted across all participants at the beginning and end of the study. These included fecal microbiota analysis by 16s ribosomal DNA sequencing, liver fat measurement by proton magnetic resonance spectroscopy, biomarker-based liver fibrosis scoring, and liver stiffness assessment by vibration-controlled transient elastography.
At the end of the study, patients in the synbiotic group had increased abundance of Bifidobacterium and Faecalibacterium species and reduced proportions of Oscillibacter and Alistipes species, compared with baseline. These changes were not observed in the placebo group.
But changes in microbiota had no apparent impact on liver pathology. Although mean liver fat percentages dropped from 32.3% to 28.5% in the synbiotic group (approximately 4%), they also dropped in the placebo group, from 31.3% to 25.2% (approximately 6%), with differences between groups lacking statistical significance. Using multivariate analysis, the investigators linked these liver fat improvements, which occurred in 65% of participants, with weight loss.
“The fact that most patients had an improvement in ... liver fat, regardless of treatment allocation, is consistent with the so-called clinical trial effect, whereby participants benefit from participating in clinical trials,” the investigators wrote.
Similarly to liver fat content, no significant intergroup differences were found for liver fibrosis or stiffness, whereas, again, weight loss was linked with improvements in both disease parameters.
“Our randomized clinical trial suggests that changing the gut microbiota with this synbiotic may occur without clinically significant effects on the liver in NAFLD,” the investigators concluded.
Still, they noted that the failure of one synbiotic regimen does not discount the possibility of microbiota-based NAFLD interventions as a whole.
“Previous studies that have tested the effects of synbiotic treatment in NAFLD have also used a combination of multiple strains of probiotics as a component of the synbiotic treatment,” the investigators wrote. “Therefore, it might be possible that, because the intestine harbors trillions of bacteria, adding 1 single type of bacterium in a synbiotic may not be as effective as adding 3 or 6 different types of bacteria with the potential to influence many more bacterial species.”
The study was supported by the National Institute of Health Research, the Parnell Diabetes Trust, and Chr. Hansen Holding. One author reported funding from Chr. Hansen unrelated to this trial.
SOURCE: Scorletti E et al. Gastro. 2020 Jan 24. doi: 10.1053/j.gastro.2020.01.031.
FROM GASTROENTEROLOGY