Liver Disease

BOSTON – Terlipressin, an investigational vasopressin analogue, improved renal function and reversed hepatorenal syndrome type 1 (HRS-1) among patients with progressive advanced liver disease in a randomized trial, according to investigators.

Compared with albumin alone, terlipressin plus albumin significantly reversed worsening of renal function in cirrhotic patients, including those meeting systemic inflammatory response syndrome (SIRS) criteria, said investigators, led by Florence Wong, MD, from the University of Toronto.

“This response was durable and associated with less need for early renal replacement therapy,” said Dr. Wong and coauthors of an abstract describing the study, which will be presented in a late-breaking study session here at the annual meeting of the American Association for the Study of Liver Diseases.

The North American randomized, controlled trial, known as CONFIRM, was designed to confirm the safety and efficacy of terlipressin/albumin as a treatment for HRS-1, a serious but potentially reversible type of acute kidney injury seen in patients with cirrhosis and ascites, investigators said in their communication.

Patients in CONFIRM had “well-defined” HRS-1, based on diagnostic criteria as outlined by the International Club of Ascites, investigators said.

A total of 300 participants were randomized, 199 to terlipressin 1 mg IV every 6 hours and 101 to placebo, with both groups also receiving albumin, for up to 14 days of treatment. According to the report, 132 subjects (44%) met SIRS criteria.

Verified HRS reversal was documented in 29.1% of terlipressin-treated patients versus just 15.8% of the placebo group (P less than .012), investigators reported in their abstract. Among the SIRS patients, verified HRS reversal was seen in 33.3% and 6.3% of the terlipressin- and placebo-treated groups, respectively (P less than .001).

As the primary endpoint of the study, verified HRS reversal is an outcome that combines improvement in renal function, short-term survival following improvement, and avoidance of renal replacement therapy, investigators explained in their report.

Liver transplantation occurred in 23.1% of the terlipressin group and 28.7% of the placebo group, investigators also reported in their abstract.

Ischemia-associated adverse events were seen in 4.5% of the terlipressin arm and 0% for placebo, though in general the rate of adverse events were similar for the treatment and control arms, Dr. Wong and colleagues noted in their report.

The CONFIRM study is supported by Mallinckrodt. Dr. Wong provided disclosures related to Mallinckrodt, Ferring, and Sequana.

BOSTON – Terlipressin, an investigational vasopressin analogue, improved renal function and reversed hepatorenal syndrome type 1 (HRS-1) among patients with progressive advanced liver disease in a randomized trial, according to investigators.

Compared with albumin alone, terlipressin plus albumin significantly reversed worsening of renal function in cirrhotic patients, including those meeting systemic inflammatory response syndrome (SIRS) criteria, said investigators, led by Florence Wong, MD, from the University of Toronto.

“This response was durable and associated with less need for early renal replacement therapy,” said Dr. Wong and coauthors of an abstract describing the study, which will be presented in a late-breaking study session here at the annual meeting of the American Association for the Study of Liver Diseases.

The North American randomized, controlled trial, known as CONFIRM, was designed to confirm the safety and efficacy of terlipressin/albumin as a treatment for HRS-1, a serious but potentially reversible type of acute kidney injury seen in patients with cirrhosis and ascites, investigators said in their communication.

Patients in CONFIRM had “well-defined” HRS-1, based on diagnostic criteria as outlined by the International Club of Ascites, investigators said.

A total of 300 participants were randomized, 199 to terlipressin 1 mg IV every 6 hours and 101 to placebo, with both groups also receiving albumin, for up to 14 days of treatment. According to the report, 132 subjects (44%) met SIRS criteria.

Verified HRS reversal was documented in 29.1% of terlipressin-treated patients versus just 15.8% of the placebo group (P less than .012), investigators reported in their abstract. Among the SIRS patients, verified HRS reversal was seen in 33.3% and 6.3% of the terlipressin- and placebo-treated groups, respectively (P less than .001).

As the primary endpoint of the study, verified HRS reversal is an outcome that combines improvement in renal function, short-term survival following improvement, and avoidance of renal replacement therapy, investigators explained in their report.

Liver transplantation occurred in 23.1% of the terlipressin group and 28.7% of the placebo group, investigators also reported in their abstract.

Ischemia-associated adverse events were seen in 4.5% of the terlipressin arm and 0% for placebo, though in general the rate of adverse events were similar for the treatment and control arms, Dr. Wong and colleagues noted in their report.

The CONFIRM study is supported by Mallinckrodt. Dr. Wong provided disclosures related to Mallinckrodt, Ferring, and Sequana.

BOSTON – Terlipressin, an investigational vasopressin analogue, improved renal function and reversed hepatorenal syndrome type 1 (HRS-1) among patients with progressive advanced liver disease in a randomized trial, according to investigators.

Compared with albumin alone, terlipressin plus albumin significantly reversed worsening of renal function in cirrhotic patients, including those meeting systemic inflammatory response syndrome (SIRS) criteria, said investigators, led by Florence Wong, MD, from the University of Toronto.

“This response was durable and associated with less need for early renal replacement therapy,” said Dr. Wong and coauthors of an abstract describing the study, which will be presented in a late-breaking study session here at the annual meeting of the American Association for the Study of Liver Diseases.

The North American randomized, controlled trial, known as CONFIRM, was designed to confirm the safety and efficacy of terlipressin/albumin as a treatment for HRS-1, a serious but potentially reversible type of acute kidney injury seen in patients with cirrhosis and ascites, investigators said in their communication.

Patients in CONFIRM had “well-defined” HRS-1, based on diagnostic criteria as outlined by the International Club of Ascites, investigators said.

A total of 300 participants were randomized, 199 to terlipressin 1 mg IV every 6 hours and 101 to placebo, with both groups also receiving albumin, for up to 14 days of treatment. According to the report, 132 subjects (44%) met SIRS criteria.

Verified HRS reversal was documented in 29.1% of terlipressin-treated patients versus just 15.8% of the placebo group (P less than .012), investigators reported in their abstract. Among the SIRS patients, verified HRS reversal was seen in 33.3% and 6.3% of the terlipressin- and placebo-treated groups, respectively (P less than .001).

As the primary endpoint of the study, verified HRS reversal is an outcome that combines improvement in renal function, short-term survival following improvement, and avoidance of renal replacement therapy, investigators explained in their report.

Liver transplantation occurred in 23.1% of the terlipressin group and 28.7% of the placebo group, investigators also reported in their abstract.

Ischemia-associated adverse events were seen in 4.5% of the terlipressin arm and 0% for placebo, though in general the rate of adverse events were similar for the treatment and control arms, Dr. Wong and colleagues noted in their report.

The CONFIRM study is supported by Mallinckrodt. Dr. Wong provided disclosures related to Mallinckrodt, Ferring, and Sequana.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

A toll-like receptor 9 (TLR9) antagonist may eventually be used to combat brain edema in acute liver failure, according to investigators.

This prediction is based on results of a recent study involving mouse models, which showed that ODN2088, a TLR9 antagonist, could stop ammonia-induced colocalization of DNA with TLR9 in innate immune cells, thereby blocking cytokine production and ensuant brain edema, reported lead author Godhev Kumar Manakkat Vijay of King’s College London and colleagues.

“Ammonia plays a pivotal role in the development of hepatic encephalopathy and brain edema in acute liver failure,” the investigators explained in Cellular and Molecular Gastroenterology and Hepatology. “A robust systemic inflammatory response and susceptibility to developing infection are common in acute liver failure, exacerbate the development of ammonia-induced brain edema and are major prognosticators. Experimental models have unequivocally associated ammonia exposure with astrocyte swelling and brain edema, potentiated by proinflammatory cytokines.”

The investigators added that, “although the evidence base supporting the relationship between ammonia, inflammation, and brain edema is robust in acute liver failure, there is a paucity of data characterizing the specific pathogenic mechanisms entailed.” Previous research suggested that TLR9 plays a key role in acetaminophen-induced liver inflammation, they noted, and that ammonia, in combination with DNA, triggers TLR9 expression in neutrophils, which brought TLR9 into focus for the present study.

Along with wild-type mice, the investigators relied upon two knockout models: TLR9–/– mice, in which TLR9 is entirely absent, and LysM-Cre TLR9fl/fl mice, in which TLR9 is absent from lysozyme-expressing cells (predominantly neutrophils and macrophages). Comparing against controls, the investigators assessed cytokine production and brain edema in each type of mouse when intraperitoneally injected with ammonium acetate (4 mmol/kg). Specifically, 6 hours after injection, they measured intracellular cytokines in splenic macrophages, CD8+ T cells, and CD4+ T cells. In addition, they recorded total plasma DNA and brain water, a measure of brain edema.

Following ammonium acetate injection, wild-type mice developed brain edema and liver enlargement, while TLR9–/– mice and control-injected mice did not. After injection, total plasma DNA levels rose by comparable magnitudes in both wild-type mice and TLR9–/– mice, but did not change in control-injected mice, suggesting that ammonium-acetate injection was causing a release of DNA, which was binding with TLR9, resulting in activation of the innate immune system.

This hypothesis was supported by measurements of cytokines in T cells and splenic macrophages, which showed that wild-type mice had elevations of cytokines, whereas knockout mice did not. Further experiments showed that LysM-Cre TLR9fl/fl mice had similar outcomes as TLR9–/– mice, highlighting that macrophages and neutrophils are the key immune cells linking TLR9 activation with cytokine release, and therefore brain edema.

To ensure that brain edema was not directly caused by the acetate component of ammonium acetate, or acetate’s potential to increase pH, a different set of wild-type mice were injected with sodium acetate adjusted to the same pH as ammonium acetate. This had no impact on cytokine production, brain-water content, or liver-to-body weight ratio, confirming that acetate was not responsible for brain edema while providing further support for the role of TLR9.

Finally, the investigators treated wild-type mice immediately after ammonium acetate injection with the TLR9 antagonist ODN2088 (50 mcg/mouse). This treatment halted cytokine production, inflammation, and brain edema, strongly supporting the link between these ammonia-induced processes and TLR9 activation.

“These data are well supported by the findings of Imaeda et al. (J Clin Invest. 2009 Feb 2. doi: 10.1172/JCI35958), who in an acetaminophen-induced hepatotoxicity model established that inhibition of TLR9 using ODN2088 and IRS954, a TLR7/9 antagonist, down-regulated proinflammatory cytokine release and reduced mortality,” the investigators wrote. “The amelioration of brain edema and cytokine production by ODN2088 supports exploration of TLR9 antagonism as a therapeutic modality in early acute liver failure to prevent the development of brain edema and intracranial hypertension.”

The study was funded by the U.K. Institute of Liver Studies Charitable Fund and the National Institutes of Health. The investigators reported no conflicts of interest.

SOURCE: Vijay GKM et al. Cell Mol Gastroenterol Hepatol. 2019 Aug 8. doi: 10.1016/j.jcmgh.2019.08.002.

Liver abnormalities in patients with psoriatic arthritis are common and are associated with higher body mass index, more severe disease, and certain therapies, new research suggests.

Wavebreakmedia Ltd/ThinkStockPhotos.com

Patients with psoriatic arthritis (PsA) often have comorbidities such as cardiovascular disease, metabolic syndrome, inflammatory bowel disease, osteoporosis, malignancy, and ophthalmic disease, and liver disease is no exception, wrote Rattapol Pakchotanon, MD, of the department of internal medicine at Phramongkutlao Hospital and College of Medicine, Bangkok, and associates. Their report is in the Journal of Rheumatology.

In psoriasis patients, the prevalence of liver abnormalities has been 24%-36% in previous research, but research regarding liver disease in PsA has been limited.

Of 1,061 patients from the University of Toronto Psoriatic Arthritis Clinic who were included in the study, 343 (32%) had liver abnormalities, including 256 who developed a liver abnormality or disease after their first evaluation at the clinic. Liver abnormality was defined as having aspartate transaminase, alanine transaminase, or alkaline phosphatase levels 1.5 times the upper limit of normal or greater, and liver diseases included drug-induced liver injury, fatty liver, viral hepatitis, autoimmune liver disease, alcoholic liver disease, liver fibrosis, and cirrhosis.

Among the patients with PsA who developed liver abnormalities or disease after their first visit, liver abnormalities occurred after an average of 8.3 years of follow-up and at a mean age of 50.5 years. The average BMI in this group was 29.7 kg/m², and 11% of patients consumed alcohol daily. A total of 105 patients had recurrent liver abnormalities, and the rest had only one visit with an abnormality; those with transient abnormalities were significantly less likely to have evidence of liver disease (P less than .001).

The most common cause of liver disease was drug-induced hepatitis (14%) and fatty liver (13%). Alcohol-induced hepatitis occurred in 10 patients, and cirrhosis was reported in 2 patients.

In a multivariable analysis, factors found to be independently associated with liver abnormalities in PsA included BMI (odds ratio, 1.07; 95% confidence interval, 1.02-1.12; P = .007), daily alcohol intake (OR, 4.46; 95% CI, 1.30-15.28; P = .02), damaged joint count (OR, 1.04; 95% CI, 1.01-1.08; P = .01), elevated C-reactive protein (OR, 2.00; 95% CI, 1.04-3.85; P = .04), use of methotrexate or leflunomide (OR, 4.39; 95% CI, 1.67-11.54; P = .003), and use of tumor necrosis factor inhibitors (OR, 10.56; 95% CI, 3.63-30.69; P less than .0001).

“We recommend monitoring liver function tests in these high risk PsA patients,” the researchers concluded. “This is important in the management of patients with PsA as many of the therapeutic options may aggravate or even lead to liver abnormalities in this patient population.”

The study was funded in part by the Arthritis Society, the Canadian Institutes of Health Research, and the Krembil Foundation. The investigators reported that they had no conflicts of interest. Dr. Pakchotanon conducted the research while he was at the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Hospital.

lfranki@mdedge.com

SOURCE: Gladman DD et al. J Rheumatol. 2019 Oct 15. doi: 10.3899/jrheum.181312

Liver abnormalities in patients with psoriatic arthritis are common and are associated with higher body mass index, more severe disease, and certain therapies, new research suggests.

Wavebreakmedia Ltd/ThinkStockPhotos.com

Patients with psoriatic arthritis (PsA) often have comorbidities such as cardiovascular disease, metabolic syndrome, inflammatory bowel disease, osteoporosis, malignancy, and ophthalmic disease, and liver disease is no exception, wrote Rattapol Pakchotanon, MD, of the department of internal medicine at Phramongkutlao Hospital and College of Medicine, Bangkok, and associates. Their report is in the Journal of Rheumatology.

In psoriasis patients, the prevalence of liver abnormalities has been 24%-36% in previous research, but research regarding liver disease in PsA has been limited.

Of 1,061 patients from the University of Toronto Psoriatic Arthritis Clinic who were included in the study, 343 (32%) had liver abnormalities, including 256 who developed a liver abnormality or disease after their first evaluation at the clinic. Liver abnormality was defined as having aspartate transaminase, alanine transaminase, or alkaline phosphatase levels 1.5 times the upper limit of normal or greater, and liver diseases included drug-induced liver injury, fatty liver, viral hepatitis, autoimmune liver disease, alcoholic liver disease, liver fibrosis, and cirrhosis.

Among the patients with PsA who developed liver abnormalities or disease after their first visit, liver abnormalities occurred after an average of 8.3 years of follow-up and at a mean age of 50.5 years. The average BMI in this group was 29.7 kg/m², and 11% of patients consumed alcohol daily. A total of 105 patients had recurrent liver abnormalities, and the rest had only one visit with an abnormality; those with transient abnormalities were significantly less likely to have evidence of liver disease (P less than .001).

The most common cause of liver disease was drug-induced hepatitis (14%) and fatty liver (13%). Alcohol-induced hepatitis occurred in 10 patients, and cirrhosis was reported in 2 patients.

In a multivariable analysis, factors found to be independently associated with liver abnormalities in PsA included BMI (odds ratio, 1.07; 95% confidence interval, 1.02-1.12; P = .007), daily alcohol intake (OR, 4.46; 95% CI, 1.30-15.28; P = .02), damaged joint count (OR, 1.04; 95% CI, 1.01-1.08; P = .01), elevated C-reactive protein (OR, 2.00; 95% CI, 1.04-3.85; P = .04), use of methotrexate or leflunomide (OR, 4.39; 95% CI, 1.67-11.54; P = .003), and use of tumor necrosis factor inhibitors (OR, 10.56; 95% CI, 3.63-30.69; P less than .0001).

“We recommend monitoring liver function tests in these high risk PsA patients,” the researchers concluded. “This is important in the management of patients with PsA as many of the therapeutic options may aggravate or even lead to liver abnormalities in this patient population.”

The study was funded in part by the Arthritis Society, the Canadian Institutes of Health Research, and the Krembil Foundation. The investigators reported that they had no conflicts of interest. Dr. Pakchotanon conducted the research while he was at the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Hospital.

lfranki@mdedge.com

SOURCE: Gladman DD et al. J Rheumatol. 2019 Oct 15. doi: 10.3899/jrheum.181312

Liver abnormalities in patients with psoriatic arthritis are common and are associated with higher body mass index, more severe disease, and certain therapies, new research suggests.

Wavebreakmedia Ltd/ThinkStockPhotos.com

Patients with psoriatic arthritis (PsA) often have comorbidities such as cardiovascular disease, metabolic syndrome, inflammatory bowel disease, osteoporosis, malignancy, and ophthalmic disease, and liver disease is no exception, wrote Rattapol Pakchotanon, MD, of the department of internal medicine at Phramongkutlao Hospital and College of Medicine, Bangkok, and associates. Their report is in the Journal of Rheumatology.

In psoriasis patients, the prevalence of liver abnormalities has been 24%-36% in previous research, but research regarding liver disease in PsA has been limited.

Of 1,061 patients from the University of Toronto Psoriatic Arthritis Clinic who were included in the study, 343 (32%) had liver abnormalities, including 256 who developed a liver abnormality or disease after their first evaluation at the clinic. Liver abnormality was defined as having aspartate transaminase, alanine transaminase, or alkaline phosphatase levels 1.5 times the upper limit of normal or greater, and liver diseases included drug-induced liver injury, fatty liver, viral hepatitis, autoimmune liver disease, alcoholic liver disease, liver fibrosis, and cirrhosis.

Among the patients with PsA who developed liver abnormalities or disease after their first visit, liver abnormalities occurred after an average of 8.3 years of follow-up and at a mean age of 50.5 years. The average BMI in this group was 29.7 kg/m², and 11% of patients consumed alcohol daily. A total of 105 patients had recurrent liver abnormalities, and the rest had only one visit with an abnormality; those with transient abnormalities were significantly less likely to have evidence of liver disease (P less than .001).

The most common cause of liver disease was drug-induced hepatitis (14%) and fatty liver (13%). Alcohol-induced hepatitis occurred in 10 patients, and cirrhosis was reported in 2 patients.

In a multivariable analysis, factors found to be independently associated with liver abnormalities in PsA included BMI (odds ratio, 1.07; 95% confidence interval, 1.02-1.12; P = .007), daily alcohol intake (OR, 4.46; 95% CI, 1.30-15.28; P = .02), damaged joint count (OR, 1.04; 95% CI, 1.01-1.08; P = .01), elevated C-reactive protein (OR, 2.00; 95% CI, 1.04-3.85; P = .04), use of methotrexate or leflunomide (OR, 4.39; 95% CI, 1.67-11.54; P = .003), and use of tumor necrosis factor inhibitors (OR, 10.56; 95% CI, 3.63-30.69; P less than .0001).

“We recommend monitoring liver function tests in these high risk PsA patients,” the researchers concluded. “This is important in the management of patients with PsA as many of the therapeutic options may aggravate or even lead to liver abnormalities in this patient population.”

The study was funded in part by the Arthritis Society, the Canadian Institutes of Health Research, and the Krembil Foundation. The investigators reported that they had no conflicts of interest. Dr. Pakchotanon conducted the research while he was at the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Hospital.

lfranki@mdedge.com

SOURCE: Gladman DD et al. J Rheumatol. 2019 Oct 15. doi: 10.3899/jrheum.181312

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

All adult patients with primary sclerosing cholangitis should be screened at least annually for cholangiocarcinoma and gallbladder cancer, particularly in the first year after their diagnosis, according to a clinical practice update published in Clinical Gastroenterology and Hepatology.

Individuals with primary sclerosing cholangitis have a 400-fold higher risk of cholangiocarcinoma, compared with the general population, and around one-third of cancers are detected within 1 year of the cholangitis diagnosis, Christopher L. Bowlus, MD, of the University of California, Davis, and coauthors wrote.

The clinical practice update from the American Gastroenterological Association was in response to the observation that, while there is significant evidence for an increasing incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplant listing among patients with primary sclerosing cholangitis, there is a lack of good evidence to guide cholangiocarcinoma surveillance in these patients.

“The low prevalence and long duration of PSC [primary sclerosing cholangitis] present substantial barriers to better understanding risk stratification, developing biomarkers, and measuring the impact surveillance has on clinical outcomes,” they wrote.

The first recommendation was that surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with primary sclerosing cholangitis, regardless of their disease stage. The authors especially emphasized the importance of surveillance in the first year after a diagnosis of primary sclerosing cholangitis, in patients who also have ulcerative colitis, and in those diagnosed at an older age.

They cited one study that found regular surveillance of patients with primary sclerosing cholangitis was associated with significantly higher 5-year survival rates, compared with those no regular screening (68% vs. 20%; P less than .0061).

In terms of surveillance modalities, the update suggested 6- to 12-monthly imaging of the biliary tree with ultrasound computed tomography, computed tomography, or magnetic resonance imaging – with or without serum carbohydrate antigen 19-9. However the authors wrote that MRI was often preferred to CT because of its superior sensitivity.

They advised against endoscopic retrograde cholangiopancreatography with brush cytology for routine surveillance because of procedural risks. On the other hand, they suggested this procedure, with or without fluorescence in situ hybridization analysis and/or cholangioscopy, could be used for investigation.

“In addition to ERCP [endoscopic retrograde cholangiopancreatography] with brushings, endoscopic ultrasound, intraductal ultrasonography, and cholangioscopy may be used to direct biopsy sampling,” they wrote. Symptoms such as increasing cholestatic biochemistry values, jaundice, fever, right upper quadrant pain, or pruritus should trigger evaluation for cholangiocarcinoma.

However the authors advised “great caution” with the use of fine-needle aspiration of perihilar biliary strictures in liver transplant candidates because of the risk of tumor seeding if the lesion turned out to be cholangiocarcinoma.

On the question of cholangiocarcinoma surveillance in pediatric patients and those with small-duct primary sclerosing cholangitis, the authors wrote that cholangiocarcinoma was so rare in these patients that routine cholangiocarcinoma surveillance was not required.

The clinical update also looked at the prevalence and risk factors for gallbladder cancer, which affects around 2% of individuals with primary sclerosing cholangitis. Two studies found gallbladder polyps in 10%-17% of patients, but the authors noted that “the optimal modality for diagnosis of gallbladder polyps in PSC remains unknown”.

“Because of the high risk of malignancy in gallbladder mass lesions and a 5-year survival rate of 5% to 10% for gallbladder cancer, patients should undergo annual US [ultrasound] screening,” they wrote.

They said the question of whether to perform a cholecystectomy in patients with gallbladder polyps should be guided by the size and growth of the polyps because there is an increased risk of gallbladder cancer in polyps larger than 8 mm and by the clinical status of the patient.

Finally, the update examined the issue of hepatocellular carcinoma in patients with primary sclerosing cholangitis, which – while rare – may increase with the presence of cirrhosis.

The authors advised that patients with primary sclerosing cholangitis and cirrhosis should undergo surveillance for hepatocellular carcinoma every 6 months with ultrasound, CT, or MRI.

“We anticipate that with the development of large patient cohorts, advances in uncovering genetic and other risk factors for cholangiocarcinoma, and development of effective treatments for PSC, further refinement of this practice update will be required.”

Two authors declared consultancies, grants and research contracts with the pharmaceutical sector. No other conflicts of interest were declared.

SOURCE: Bowlus C et al. Clin Gastroenterol Hepatol. 2019 Jul 12. doi 10.1016/j.cgh.2019.07.011.

Patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis reported lower quality of life that is worsened in those who develop cirrhosis, based on data from 1,667 individuals.

NASH is becoming an increasingly common cause of liver disease, cirrhosis, and hepatocellular carcinoma and can have a negative effect on patients’ quality of life and other patient-reported outcomes (PROs), but studies of the impact on PROs in these patients are limited, wrote Zobair M. Younossi, MD, of the Inova Health System, Falls Church, Va., and colleagues.

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed data from 870 adults with NASH cirrhosis and 797 with NASH and bridging fibrosis. The average age of the patients was 58 years, 73% were white, 40% were male, 52% had cirrhosis, and 74% had diabetes.

The researchers used four tools to assess quality of life: the SF-36 (36-Item Short Form Health Survey), the EQ-5D (Euroqol, a generic health questionnaire), the CLDQ-NASH (Chronic Liver Disease Questionnaire-NASH), and the WPAI:SHP (Work Productivity and Activity Impairment: Specific Health Problem).

The SF-36 score is based on eight domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health.

Overall, patients with NASH and cirrhosis had significantly lower scores on domains of the SF-36 that related to physical function, compared with bridging fibrosis patients (70.3 vs. 73.6), as well as role physical (71.6 vs. 75.4) and bodily pain (65.0 vs. 68.6). The other areas of significant impairment in NASH patients with cirrhosis, compared with NASH patients with fibrosis, appeared in four domains of the disease-specific CLDQ-NASH: activity, emotional, fatigue, and worry. In addition, the EQ-5D utility score was significantly lower in cirrhosis patients, compared with fibrosis patients.

Older age, male sex, Asian race, and U.S. location of study enrollment were independent predictors of higher PRO scores in a multivariate analysis, while black race, history of smoking, history of diabetes, higher body mass index, cirrhosis, and history of comorbidities that were gastrointestinal, musculoskeletal, psychiatric, or neurologic were independent predictors of lower PRO scores in patients with advanced fibrosis and NASH.

WPAI:SHP scores, which focused on work productivity impairment and absenteeism, were not significantly different between the groups.

The study findings were limited by several factors including the specific nature of the study population and absence of non-NASH controls, the potential of false positives because of the use of self-reports, and the lack of longitudinal data, the researchers said. The results should be verified in a larger, diverse patient population, the researchers noted, but the data highlight the impairment in quality of life and productivity among patients with NASH and “can inform patients, clinicians, payers, and policymakers about the total burden of the disease and also the comprehensive benefit of treatment,” they concluded.

The study was supported by Gilead Sciences. Dr. Younossi disclosed relationships with Gilead Sciences, as well as Intercept, NovoNordisk, BMS, Allergan/Tobira, Terns, Viking, AbbVie, Novartis, and Quest Diagnostics.

SOURCE: Younossi ZM et al. Clin Gastroenterol Hepatol. 2019. doi: 10.1016/j.cgh.2019.02.024.

Patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis reported lower quality of life that is worsened in those who develop cirrhosis, based on data from 1,667 individuals.

NASH is becoming an increasingly common cause of liver disease, cirrhosis, and hepatocellular carcinoma and can have a negative effect on patients’ quality of life and other patient-reported outcomes (PROs), but studies of the impact on PROs in these patients are limited, wrote Zobair M. Younossi, MD, of the Inova Health System, Falls Church, Va., and colleagues.

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed data from 870 adults with NASH cirrhosis and 797 with NASH and bridging fibrosis. The average age of the patients was 58 years, 73% were white, 40% were male, 52% had cirrhosis, and 74% had diabetes.

The researchers used four tools to assess quality of life: the SF-36 (36-Item Short Form Health Survey), the EQ-5D (Euroqol, a generic health questionnaire), the CLDQ-NASH (Chronic Liver Disease Questionnaire-NASH), and the WPAI:SHP (Work Productivity and Activity Impairment: Specific Health Problem).

The SF-36 score is based on eight domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health.

Overall, patients with NASH and cirrhosis had significantly lower scores on domains of the SF-36 that related to physical function, compared with bridging fibrosis patients (70.3 vs. 73.6), as well as role physical (71.6 vs. 75.4) and bodily pain (65.0 vs. 68.6). The other areas of significant impairment in NASH patients with cirrhosis, compared with NASH patients with fibrosis, appeared in four domains of the disease-specific CLDQ-NASH: activity, emotional, fatigue, and worry. In addition, the EQ-5D utility score was significantly lower in cirrhosis patients, compared with fibrosis patients.

Older age, male sex, Asian race, and U.S. location of study enrollment were independent predictors of higher PRO scores in a multivariate analysis, while black race, history of smoking, history of diabetes, higher body mass index, cirrhosis, and history of comorbidities that were gastrointestinal, musculoskeletal, psychiatric, or neurologic were independent predictors of lower PRO scores in patients with advanced fibrosis and NASH.

WPAI:SHP scores, which focused on work productivity impairment and absenteeism, were not significantly different between the groups.

The study findings were limited by several factors including the specific nature of the study population and absence of non-NASH controls, the potential of false positives because of the use of self-reports, and the lack of longitudinal data, the researchers said. The results should be verified in a larger, diverse patient population, the researchers noted, but the data highlight the impairment in quality of life and productivity among patients with NASH and “can inform patients, clinicians, payers, and policymakers about the total burden of the disease and also the comprehensive benefit of treatment,” they concluded.

The study was supported by Gilead Sciences. Dr. Younossi disclosed relationships with Gilead Sciences, as well as Intercept, NovoNordisk, BMS, Allergan/Tobira, Terns, Viking, AbbVie, Novartis, and Quest Diagnostics.

SOURCE: Younossi ZM et al. Clin Gastroenterol Hepatol. 2019. doi: 10.1016/j.cgh.2019.02.024.

Patients with nonalcoholic steatohepatitis (NASH) and advanced fibrosis reported lower quality of life that is worsened in those who develop cirrhosis, based on data from 1,667 individuals.

NASH is becoming an increasingly common cause of liver disease, cirrhosis, and hepatocellular carcinoma and can have a negative effect on patients’ quality of life and other patient-reported outcomes (PROs), but studies of the impact on PROs in these patients are limited, wrote Zobair M. Younossi, MD, of the Inova Health System, Falls Church, Va., and colleagues.

In a study published in Clinical Gastroenterology and Hepatology, the researchers reviewed data from 870 adults with NASH cirrhosis and 797 with NASH and bridging fibrosis. The average age of the patients was 58 years, 73% were white, 40% were male, 52% had cirrhosis, and 74% had diabetes.

The researchers used four tools to assess quality of life: the SF-36 (36-Item Short Form Health Survey), the EQ-5D (Euroqol, a generic health questionnaire), the CLDQ-NASH (Chronic Liver Disease Questionnaire-NASH), and the WPAI:SHP (Work Productivity and Activity Impairment: Specific Health Problem).

The SF-36 score is based on eight domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health.

Overall, patients with NASH and cirrhosis had significantly lower scores on domains of the SF-36 that related to physical function, compared with bridging fibrosis patients (70.3 vs. 73.6), as well as role physical (71.6 vs. 75.4) and bodily pain (65.0 vs. 68.6). The other areas of significant impairment in NASH patients with cirrhosis, compared with NASH patients with fibrosis, appeared in four domains of the disease-specific CLDQ-NASH: activity, emotional, fatigue, and worry. In addition, the EQ-5D utility score was significantly lower in cirrhosis patients, compared with fibrosis patients.

Older age, male sex, Asian race, and U.S. location of study enrollment were independent predictors of higher PRO scores in a multivariate analysis, while black race, history of smoking, history of diabetes, higher body mass index, cirrhosis, and history of comorbidities that were gastrointestinal, musculoskeletal, psychiatric, or neurologic were independent predictors of lower PRO scores in patients with advanced fibrosis and NASH.

WPAI:SHP scores, which focused on work productivity impairment and absenteeism, were not significantly different between the groups.

The study findings were limited by several factors including the specific nature of the study population and absence of non-NASH controls, the potential of false positives because of the use of self-reports, and the lack of longitudinal data, the researchers said. The results should be verified in a larger, diverse patient population, the researchers noted, but the data highlight the impairment in quality of life and productivity among patients with NASH and “can inform patients, clinicians, payers, and policymakers about the total burden of the disease and also the comprehensive benefit of treatment,” they concluded.

The study was supported by Gilead Sciences. Dr. Younossi disclosed relationships with Gilead Sciences, as well as Intercept, NovoNordisk, BMS, Allergan/Tobira, Terns, Viking, AbbVie, Novartis, and Quest Diagnostics.

SOURCE: Younossi ZM et al. Clin Gastroenterol Hepatol. 2019. doi: 10.1016/j.cgh.2019.02.024.

Direct-acting antiviral (DAA) therapy significantly reduced the risk of death in patients with hepatitis C infections and a history of hepatocellular carcinoma, based on data from 797 individuals.

Previous studies have reported a benefit of direct-acting antiviral (DAA) therapy for reducing mortality in patients with hepatocellular carcinoma (HCC), but data on its impact in patients with complete responses to HCC therapy are limited, wrote Amit G. Singal, MD, of the University of Texas, Dallas, and colleagues.

In a study published in Gastroenterology, the researchers identified adult HCC patients who achieved complete treatment response between January 2013 and December 2017. The study included patients from 31 locations in the United States and Canada. Complete response to treatment was defined as “disappearance of arterial enhancement from all HCC lesions on contrast-enhanced cross-sectional imaging.”

A total of 383 (48.1%) of patients were randomized to DAA therapy, and 414 (51.9%) did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy.

A total of 43 deaths occurred among DAA patients over 941 person-years of follow-up, compared with 103 deaths over 527 person-years of follow-up for the untreated controls. Overall, DAA therapy was associated with a significantly reduced risk of death (hazard ratio, 0.54), compared with no therapy. Of note, patients with a sustained virologic response showed a reduced risk of death (HR, 0.29), but those without a sustained virologic response to DAA therapy did not (HR, 1.13).

The findings support those from previous studies suggesting that DAA therapy may reduce mortality in patients with a history of HCC, the researchers said.

The study findings were limited by several factors, including potential confounding if DAA was given to patients with better prognoses, the researchers noted. Other limitations include the use of imaging in routine clinical care rather than centralized review, the loss of approximately 9% of the patients to follow-up, and the lack of data on hepatic decompensation during follow-up, the researchers said. However, the results were strengthened by the multicenter design, large cohort, and inclusion of untreated controls, and support the use of DAA therapies as “likely beneficial in HCV-infected patients with a history of HCC,” they concluded.

The study was funded in part by the National Cancer Institute and AbbVie. Dr. Singal disclosed relationships with companies including AbbVie, Gilead, Bayer, Eisai, Wako Diagnostics, Exact Sciences, Exelixis, Roche, Glycotest, and Bristol-Myers Squibb.

SOURCE: Singal AG et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.07.040.

Direct-acting antiviral (DAA) therapy significantly reduced the risk of death in patients with hepatitis C infections and a history of hepatocellular carcinoma, based on data from 797 individuals.

Previous studies have reported a benefit of direct-acting antiviral (DAA) therapy for reducing mortality in patients with hepatocellular carcinoma (HCC), but data on its impact in patients with complete responses to HCC therapy are limited, wrote Amit G. Singal, MD, of the University of Texas, Dallas, and colleagues.

In a study published in Gastroenterology, the researchers identified adult HCC patients who achieved complete treatment response between January 2013 and December 2017. The study included patients from 31 locations in the United States and Canada. Complete response to treatment was defined as “disappearance of arterial enhancement from all HCC lesions on contrast-enhanced cross-sectional imaging.”

A total of 383 (48.1%) of patients were randomized to DAA therapy, and 414 (51.9%) did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy.

A total of 43 deaths occurred among DAA patients over 941 person-years of follow-up, compared with 103 deaths over 527 person-years of follow-up for the untreated controls. Overall, DAA therapy was associated with a significantly reduced risk of death (hazard ratio, 0.54), compared with no therapy. Of note, patients with a sustained virologic response showed a reduced risk of death (HR, 0.29), but those without a sustained virologic response to DAA therapy did not (HR, 1.13).

The findings support those from previous studies suggesting that DAA therapy may reduce mortality in patients with a history of HCC, the researchers said.

The study findings were limited by several factors, including potential confounding if DAA was given to patients with better prognoses, the researchers noted. Other limitations include the use of imaging in routine clinical care rather than centralized review, the loss of approximately 9% of the patients to follow-up, and the lack of data on hepatic decompensation during follow-up, the researchers said. However, the results were strengthened by the multicenter design, large cohort, and inclusion of untreated controls, and support the use of DAA therapies as “likely beneficial in HCV-infected patients with a history of HCC,” they concluded.

The study was funded in part by the National Cancer Institute and AbbVie. Dr. Singal disclosed relationships with companies including AbbVie, Gilead, Bayer, Eisai, Wako Diagnostics, Exact Sciences, Exelixis, Roche, Glycotest, and Bristol-Myers Squibb.

SOURCE: Singal AG et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.07.040.

Direct-acting antiviral (DAA) therapy significantly reduced the risk of death in patients with hepatitis C infections and a history of hepatocellular carcinoma, based on data from 797 individuals.

Previous studies have reported a benefit of direct-acting antiviral (DAA) therapy for reducing mortality in patients with hepatocellular carcinoma (HCC), but data on its impact in patients with complete responses to HCC therapy are limited, wrote Amit G. Singal, MD, of the University of Texas, Dallas, and colleagues.

In a study published in Gastroenterology, the researchers identified adult HCC patients who achieved complete treatment response between January 2013 and December 2017. The study included patients from 31 locations in the United States and Canada. Complete response to treatment was defined as “disappearance of arterial enhancement from all HCC lesions on contrast-enhanced cross-sectional imaging.”

A total of 383 (48.1%) of patients were randomized to DAA therapy, and 414 (51.9%) did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy.

A total of 43 deaths occurred among DAA patients over 941 person-years of follow-up, compared with 103 deaths over 527 person-years of follow-up for the untreated controls. Overall, DAA therapy was associated with a significantly reduced risk of death (hazard ratio, 0.54), compared with no therapy. Of note, patients with a sustained virologic response showed a reduced risk of death (HR, 0.29), but those without a sustained virologic response to DAA therapy did not (HR, 1.13).

The findings support those from previous studies suggesting that DAA therapy may reduce mortality in patients with a history of HCC, the researchers said.

The study findings were limited by several factors, including potential confounding if DAA was given to patients with better prognoses, the researchers noted. Other limitations include the use of imaging in routine clinical care rather than centralized review, the loss of approximately 9% of the patients to follow-up, and the lack of data on hepatic decompensation during follow-up, the researchers said. However, the results were strengthened by the multicenter design, large cohort, and inclusion of untreated controls, and support the use of DAA therapies as “likely beneficial in HCV-infected patients with a history of HCC,” they concluded.

The study was funded in part by the National Cancer Institute and AbbVie. Dr. Singal disclosed relationships with companies including AbbVie, Gilead, Bayer, Eisai, Wako Diagnostics, Exact Sciences, Exelixis, Roche, Glycotest, and Bristol-Myers Squibb.

SOURCE: Singal AG et al. Gastroenterology. 2019. doi: 10.1053/j.gastro.2019.07.040.

A new study involving both human patients and mice has confirmed a long-believed association between nonalcoholic fatty liver disease (NAFLD) and an alteration in the gut microbiome that produces high levels of alcohol.

NIAID

The study was initiated after the treatment of a rare case: a patient who presented with severe nonalcoholic steatohepatitis (NASH) plus auto-brewery syndrome. The patient had a very high blood alcohol concentration but an alcohol-free, high-carbohydrate diet. It was determined that strains of high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) rather than a fungal infection were the catalyst for the high blood alcohol level. As such, Jing Yuan of the Capital Institute of Pediatrics in Beijing and coauthors attempted to “connect these commensal HiAlc Kpn to the pathogenesis of hepatic damage” through this study, which was published in Cell Metabolism.

The researchers began by examining 43 patients with NAFLD and 48 healthy controls. Among the patients with NAFLD, 11 had nonalcoholic fatty liver and 32 had NASH. Specifically, they analyzed the presence and effects of HiAlc Kpn, determining that the abundance of Klebsiella pneumoniae was slightly higher in the feces of NAFLD patients, compared with healthy patients, but that their alcohol-producing ability in NAFLD patients was significantly stronger. Of the patients with NAFLD, 61% carried HiAlc and medium-alcohol-producing Kpn, compared with 6.25% of the controls.

Another phase of their study involved feeding specific pathogen-free mice either HiAlc Kpn, ethanol, or yeast extract peptone dextrose medium (pair-fed) for 4, 6, and 8 weeks. The mice that were fed HiAlc Kpn or ethanol showed clear microsteatosis and macrosteatosis in their livers at 4 and 8 weeks, compared with the pair-fed mice. In addition, the HiAlc-Kpn-fed and ethanol-fed mice had increased levels of aspartate transaminase and alanine transaminase in their serum and increased levels of triglycerides and thiobarbituric acid reactive substances in their liver. The results overall indicated that the HiAlc-Kpn-fed mice had developed hepatic steatosis.

An additional phase included the intestinal flora from a NASH patient with a specific Kpn strain being fed to germ-free mice. At the same time, two types of intestinal flora from mice with NAFLD were transplanted into healthy mice: one induced by two other specific Kpn strains and one in which those strains had been selectively eliminated. The results saw obvious steatosis in the mice who received the flora from either mice with NAFLD induced by Kpn or the NASH patient at 4 weeks and 8 weeks, respectively. The mice who received the flora win which Kpn had been eliminated saw no fat-related changes in the liver. “These results further suggest that HiAlc Kpn might be one of the major causes of NAFLD development,” the researchers wrote.

The authors acknowledged the study’s limitations, chiefly including the lack of a clinical cohort of individuals with auto brewery syndrome but without NAFLD that could be used as a control. However, they also noted a belief that “causality was shown by the transfer experiments of HiAlc Kpn” while adding that “the further analysis of the impact of ethanol in ABS [auto brewery syndrome] patients should be investigated.”

The study was funded by grants from the National Natural Science Foundation for Key Programs of China, the National Natural Science Foundation of China, Megaprojects of Science and Technology Research of China, and CAMS Innovation Fund for Medical Sciences. The authors reported no conflicts of interest.
 

SOURCE: Yuan J et al. Cell Metab. 2019 Sep 19. doi: 10.1016/j.cmet.2019.08.018.

A new study involving both human patients and mice has confirmed a long-believed association between nonalcoholic fatty liver disease (NAFLD) and an alteration in the gut microbiome that produces high levels of alcohol.

NIAID

The study was initiated after the treatment of a rare case: a patient who presented with severe nonalcoholic steatohepatitis (NASH) plus auto-brewery syndrome. The patient had a very high blood alcohol concentration but an alcohol-free, high-carbohydrate diet. It was determined that strains of high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) rather than a fungal infection were the catalyst for the high blood alcohol level. As such, Jing Yuan of the Capital Institute of Pediatrics in Beijing and coauthors attempted to “connect these commensal HiAlc Kpn to the pathogenesis of hepatic damage” through this study, which was published in Cell Metabolism.

The researchers began by examining 43 patients with NAFLD and 48 healthy controls. Among the patients with NAFLD, 11 had nonalcoholic fatty liver and 32 had NASH. Specifically, they analyzed the presence and effects of HiAlc Kpn, determining that the abundance of Klebsiella pneumoniae was slightly higher in the feces of NAFLD patients, compared with healthy patients, but that their alcohol-producing ability in NAFLD patients was significantly stronger. Of the patients with NAFLD, 61% carried HiAlc and medium-alcohol-producing Kpn, compared with 6.25% of the controls.

Another phase of their study involved feeding specific pathogen-free mice either HiAlc Kpn, ethanol, or yeast extract peptone dextrose medium (pair-fed) for 4, 6, and 8 weeks. The mice that were fed HiAlc Kpn or ethanol showed clear microsteatosis and macrosteatosis in their livers at 4 and 8 weeks, compared with the pair-fed mice. In addition, the HiAlc-Kpn-fed and ethanol-fed mice had increased levels of aspartate transaminase and alanine transaminase in their serum and increased levels of triglycerides and thiobarbituric acid reactive substances in their liver. The results overall indicated that the HiAlc-Kpn-fed mice had developed hepatic steatosis.

An additional phase included the intestinal flora from a NASH patient with a specific Kpn strain being fed to germ-free mice. At the same time, two types of intestinal flora from mice with NAFLD were transplanted into healthy mice: one induced by two other specific Kpn strains and one in which those strains had been selectively eliminated. The results saw obvious steatosis in the mice who received the flora from either mice with NAFLD induced by Kpn or the NASH patient at 4 weeks and 8 weeks, respectively. The mice who received the flora win which Kpn had been eliminated saw no fat-related changes in the liver. “These results further suggest that HiAlc Kpn might be one of the major causes of NAFLD development,” the researchers wrote.

The authors acknowledged the study’s limitations, chiefly including the lack of a clinical cohort of individuals with auto brewery syndrome but without NAFLD that could be used as a control. However, they also noted a belief that “causality was shown by the transfer experiments of HiAlc Kpn” while adding that “the further analysis of the impact of ethanol in ABS [auto brewery syndrome] patients should be investigated.”

The study was funded by grants from the National Natural Science Foundation for Key Programs of China, the National Natural Science Foundation of China, Megaprojects of Science and Technology Research of China, and CAMS Innovation Fund for Medical Sciences. The authors reported no conflicts of interest.
 

SOURCE: Yuan J et al. Cell Metab. 2019 Sep 19. doi: 10.1016/j.cmet.2019.08.018.

A new study involving both human patients and mice has confirmed a long-believed association between nonalcoholic fatty liver disease (NAFLD) and an alteration in the gut microbiome that produces high levels of alcohol.

NIAID

The study was initiated after the treatment of a rare case: a patient who presented with severe nonalcoholic steatohepatitis (NASH) plus auto-brewery syndrome. The patient had a very high blood alcohol concentration but an alcohol-free, high-carbohydrate diet. It was determined that strains of high alcohol-producing Klebsiella pneumoniae (HiAlc Kpn) rather than a fungal infection were the catalyst for the high blood alcohol level. As such, Jing Yuan of the Capital Institute of Pediatrics in Beijing and coauthors attempted to “connect these commensal HiAlc Kpn to the pathogenesis of hepatic damage” through this study, which was published in Cell Metabolism.

The researchers began by examining 43 patients with NAFLD and 48 healthy controls. Among the patients with NAFLD, 11 had nonalcoholic fatty liver and 32 had NASH. Specifically, they analyzed the presence and effects of HiAlc Kpn, determining that the abundance of Klebsiella pneumoniae was slightly higher in the feces of NAFLD patients, compared with healthy patients, but that their alcohol-producing ability in NAFLD patients was significantly stronger. Of the patients with NAFLD, 61% carried HiAlc and medium-alcohol-producing Kpn, compared with 6.25% of the controls.

Another phase of their study involved feeding specific pathogen-free mice either HiAlc Kpn, ethanol, or yeast extract peptone dextrose medium (pair-fed) for 4, 6, and 8 weeks. The mice that were fed HiAlc Kpn or ethanol showed clear microsteatosis and macrosteatosis in their livers at 4 and 8 weeks, compared with the pair-fed mice. In addition, the HiAlc-Kpn-fed and ethanol-fed mice had increased levels of aspartate transaminase and alanine transaminase in their serum and increased levels of triglycerides and thiobarbituric acid reactive substances in their liver. The results overall indicated that the HiAlc-Kpn-fed mice had developed hepatic steatosis.

An additional phase included the intestinal flora from a NASH patient with a specific Kpn strain being fed to germ-free mice. At the same time, two types of intestinal flora from mice with NAFLD were transplanted into healthy mice: one induced by two other specific Kpn strains and one in which those strains had been selectively eliminated. The results saw obvious steatosis in the mice who received the flora from either mice with NAFLD induced by Kpn or the NASH patient at 4 weeks and 8 weeks, respectively. The mice who received the flora win which Kpn had been eliminated saw no fat-related changes in the liver. “These results further suggest that HiAlc Kpn might be one of the major causes of NAFLD development,” the researchers wrote.

The authors acknowledged the study’s limitations, chiefly including the lack of a clinical cohort of individuals with auto brewery syndrome but without NAFLD that could be used as a control. However, they also noted a belief that “causality was shown by the transfer experiments of HiAlc Kpn” while adding that “the further analysis of the impact of ethanol in ABS [auto brewery syndrome] patients should be investigated.”

The study was funded by grants from the National Natural Science Foundation for Key Programs of China, the National Natural Science Foundation of China, Megaprojects of Science and Technology Research of China, and CAMS Innovation Fund for Medical Sciences. The authors reported no conflicts of interest.
 

SOURCE: Yuan J et al. Cell Metab. 2019 Sep 19. doi: 10.1016/j.cmet.2019.08.018.

Medical comorbidity burden is significantly associated with 6-month and overall mortality in individuals with suspected drug-induced liver injury (DILI). In addition, a model consisting of Charlson Comorbidity Index, model for end-stage liver disease score, and serum albumin strongly predicts 6-month mortality in patients with suspected DILI.

Those are key findings from a study which set out to investigate the association between comorbidity burden and outcomes of patients with DILI and to develop a model to calculate risk of death within 6 months.

“Drug-induced liver injury is an important cause of liver-related morbidity and mortality that is likely under-recognized,” investigators led by Marwan S. Ghabril, MD, of the division of gastroenterology and hepatology at Indiana University, Indianapolis, wrote in a study published in Gastroenterology. “Its diagnosis depends on high index of suspicion, compatible temporal relationship, and thorough exclusion of competing etiologies. DILI by an implicated drug commonly occurs in patients with one or several comorbid conditions such as hypertension, diabetes mellitus, cardiovascular disease, renal disease, and malignancy. However, the impact of comorbidity burden on mortality in patients with suspected DILI has not been previously investigated.”

For the current analysis and model development, the researchers drew from 306 patients enrolled in the multicenter Drug-Induced Liver Injury Network Prospective Study at Indiana University between 2003 and 2017 (discovery cohort; Drug Saf. 2009;32:55-68). To validate their model, they used data from 247 patients who were enrolled in the same study at the University of North Carolina (validation cohort). The primary outcome of interest was mortality within 6 months of onset of liver injury.

The mean ages of the discovery and validation cohorts were 49 years and 51 years, respectively. Dr. Ghabril and colleagues found that 6-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. “The most common class of implicated agent was antimicrobials with no significant differences between groups,” they wrote. “However, herbal and dietary supplements were predominantly implicated in patients with none to mild comorbidity, while cardiovascular agents were predominantly implicated in patients with significant comorbidity.”

Among patients in the discovery cohort, the presence of significant comorbidities, defined as a Charlson Comorbidity Index score greater than 2, was independently associated with 6-month mortality (odds ratio, 5.22), as was model for end-stage liver disease score (OR, 1.11) and serum level of albumin at presentation (OR, 0.39). When the researchers created a morbidity risk model based on those three clinical variables, it performed well, identifying patients who died within 6 months with a C statistic value of 0.89 in the discovery cohort and 0.91 in the validation cohort. This spurred the development of a web-based risk calculator, which clinicians can access at http://gihep.com/calculators/hepatology/dili-cam/.

“Since DILI is not a unique cause of liver injury, it is conceivable that models incorporating comorbidity burden and severity of liver injury could prove useful in improving the prediction of mortality in a variety of liver injuries and diseases, and as such warrants further studies,” the researchers wrote.

The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Ghabril reported having no financial disclosures, but two coauthors reported having numerous financial ties to industry.

dbrunk@mdedge.com

SOURCE: Ghabril M et al. Gastroenterology. 2019 Jul 11. doi: 10/1053/j.gastro.2019.07.006.

Medical comorbidity burden is significantly associated with 6-month and overall mortality in individuals with suspected drug-induced liver injury (DILI). In addition, a model consisting of Charlson Comorbidity Index, model for end-stage liver disease score, and serum albumin strongly predicts 6-month mortality in patients with suspected DILI.

Those are key findings from a study which set out to investigate the association between comorbidity burden and outcomes of patients with DILI and to develop a model to calculate risk of death within 6 months.

“Drug-induced liver injury is an important cause of liver-related morbidity and mortality that is likely under-recognized,” investigators led by Marwan S. Ghabril, MD, of the division of gastroenterology and hepatology at Indiana University, Indianapolis, wrote in a study published in Gastroenterology. “Its diagnosis depends on high index of suspicion, compatible temporal relationship, and thorough exclusion of competing etiologies. DILI by an implicated drug commonly occurs in patients with one or several comorbid conditions such as hypertension, diabetes mellitus, cardiovascular disease, renal disease, and malignancy. However, the impact of comorbidity burden on mortality in patients with suspected DILI has not been previously investigated.”

For the current analysis and model development, the researchers drew from 306 patients enrolled in the multicenter Drug-Induced Liver Injury Network Prospective Study at Indiana University between 2003 and 2017 (discovery cohort; Drug Saf. 2009;32:55-68). To validate their model, they used data from 247 patients who were enrolled in the same study at the University of North Carolina (validation cohort). The primary outcome of interest was mortality within 6 months of onset of liver injury.

The mean ages of the discovery and validation cohorts were 49 years and 51 years, respectively. Dr. Ghabril and colleagues found that 6-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. “The most common class of implicated agent was antimicrobials with no significant differences between groups,” they wrote. “However, herbal and dietary supplements were predominantly implicated in patients with none to mild comorbidity, while cardiovascular agents were predominantly implicated in patients with significant comorbidity.”

Among patients in the discovery cohort, the presence of significant comorbidities, defined as a Charlson Comorbidity Index score greater than 2, was independently associated with 6-month mortality (odds ratio, 5.22), as was model for end-stage liver disease score (OR, 1.11) and serum level of albumin at presentation (OR, 0.39). When the researchers created a morbidity risk model based on those three clinical variables, it performed well, identifying patients who died within 6 months with a C statistic value of 0.89 in the discovery cohort and 0.91 in the validation cohort. This spurred the development of a web-based risk calculator, which clinicians can access at http://gihep.com/calculators/hepatology/dili-cam/.

“Since DILI is not a unique cause of liver injury, it is conceivable that models incorporating comorbidity burden and severity of liver injury could prove useful in improving the prediction of mortality in a variety of liver injuries and diseases, and as such warrants further studies,” the researchers wrote.

The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Ghabril reported having no financial disclosures, but two coauthors reported having numerous financial ties to industry.

dbrunk@mdedge.com

SOURCE: Ghabril M et al. Gastroenterology. 2019 Jul 11. doi: 10/1053/j.gastro.2019.07.006.

Medical comorbidity burden is significantly associated with 6-month and overall mortality in individuals with suspected drug-induced liver injury (DILI). In addition, a model consisting of Charlson Comorbidity Index, model for end-stage liver disease score, and serum albumin strongly predicts 6-month mortality in patients with suspected DILI.

Those are key findings from a study which set out to investigate the association between comorbidity burden and outcomes of patients with DILI and to develop a model to calculate risk of death within 6 months.

“Drug-induced liver injury is an important cause of liver-related morbidity and mortality that is likely under-recognized,” investigators led by Marwan S. Ghabril, MD, of the division of gastroenterology and hepatology at Indiana University, Indianapolis, wrote in a study published in Gastroenterology. “Its diagnosis depends on high index of suspicion, compatible temporal relationship, and thorough exclusion of competing etiologies. DILI by an implicated drug commonly occurs in patients with one or several comorbid conditions such as hypertension, diabetes mellitus, cardiovascular disease, renal disease, and malignancy. However, the impact of comorbidity burden on mortality in patients with suspected DILI has not been previously investigated.”

For the current analysis and model development, the researchers drew from 306 patients enrolled in the multicenter Drug-Induced Liver Injury Network Prospective Study at Indiana University between 2003 and 2017 (discovery cohort; Drug Saf. 2009;32:55-68). To validate their model, they used data from 247 patients who were enrolled in the same study at the University of North Carolina (validation cohort). The primary outcome of interest was mortality within 6 months of onset of liver injury.

The mean ages of the discovery and validation cohorts were 49 years and 51 years, respectively. Dr. Ghabril and colleagues found that 6-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. “The most common class of implicated agent was antimicrobials with no significant differences between groups,” they wrote. “However, herbal and dietary supplements were predominantly implicated in patients with none to mild comorbidity, while cardiovascular agents were predominantly implicated in patients with significant comorbidity.”

Among patients in the discovery cohort, the presence of significant comorbidities, defined as a Charlson Comorbidity Index score greater than 2, was independently associated with 6-month mortality (odds ratio, 5.22), as was model for end-stage liver disease score (OR, 1.11) and serum level of albumin at presentation (OR, 0.39). When the researchers created a morbidity risk model based on those three clinical variables, it performed well, identifying patients who died within 6 months with a C statistic value of 0.89 in the discovery cohort and 0.91 in the validation cohort. This spurred the development of a web-based risk calculator, which clinicians can access at http://gihep.com/calculators/hepatology/dili-cam/.

“Since DILI is not a unique cause of liver injury, it is conceivable that models incorporating comorbidity burden and severity of liver injury could prove useful in improving the prediction of mortality in a variety of liver injuries and diseases, and as such warrants further studies,” the researchers wrote.

The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Ghabril reported having no financial disclosures, but two coauthors reported having numerous financial ties to industry.

dbrunk@mdedge.com

SOURCE: Ghabril M et al. Gastroenterology. 2019 Jul 11. doi: 10/1053/j.gastro.2019.07.006.

A new supercooling process could extend ex vivo liver viability by more than a day, potentially expanding transplant availability, according to investigators.

Massachusetts General Hospital

Standard cooling to 4°C provides just 12 hours of organ preservation, but laboratory testing showed that supercooling to –4°C added 27 hours of viability, reported lead author Reinier J. de Vries, MD, of Harvard Medical School and Massachusetts General Hospital in Boston, and colleagues.

“The absence of technology to preserve organs for more than a few hours is one of the fundamental causes of the donor organ–shortage crisis,” the investigators wrote in Nature Biotechnology.

Supercooling organs to high-subzero temperatures has been shown to prolong organ life while avoiding ice-mediated injury, but techniques that are successful for rat livers have been difficult to translate to human livers because of their larger size, which increases the risk of ice formation, the investigators explained.

Three strategies were employed to overcome this problem: minimization of air-liquid interfaces, development of a new supercooling-preservation solution, and hypothermic machine perfusion to more evenly distribute preservation solution throughout the liver tissue. For recovery of organs after supercooling, the investigators used subnormothermic machine perfusion, which has been used effectively in rat transplants.

In order to measure the impact of this process on organ viability, the investigators first measured adenylate energy content, both before supercooling and after recovery.

“Adenylate energy content, and, particularly, the organ’s ability to recover it during (re)perfusion, is considered the most representative metric for liver viability,” they wrote.

The difference between pre- and postsupercooling energy charge was less than 20%; in comparison, failed liver transplants in large animals and clinical trials have typically involved an energy-charge loss of 40% or more.

To further test organ viability, the investigators measured pre- and postsupercooling levels of bile production, oxygen uptake, and vascular resistance. All of these parameters have been shown to predict transplant success in rats, and bile production has additional precedent from human studies.

On average, bile production, portal resistance, and arterial resistance were not significantly affected by supercooling. Although portal vein resistance was 20% higher after supercooling, this compared favorably with increases of 100%-150% that have been measured in nonviable livers. Similarly, oxygen uptake increased by a mean of 17%, but this was three times lower than changes that have been observed in livers with impaired viability, at 51%.

Additional measures of hepatocellular injury, including AST and ALT, were also supportive of viability after supercooling. Histopathology confirmed these findings by showing preserved tissue architecture.

“In summary, we find that the human livers tested displayed no substantial difference in viability before and after extended subzero supercooling preservation,” the investigators wrote.

To simulate transplantation, the investigators reperfused the organs with blood at a normal temperature, including platelets, complement, and white blood cells, which are drivers of ischemia reperfusion injury. During this process, energy charge remained stable, which indicates preserved mitochondrial function. While energy charge held steady, lactate metabolism increased with bile and urea production, suggesting increased liver function. Bile pH and HCO_3– levels fell within range for viability. Although bile glucose exceeded proposed criteria, the investigators pointed out that levels still fell within parameters for research-quality livers. Lactate levels also rose within the first hour of reperfusion, but the investigators suggested that this finding should be interpreted with appropriate context.

“It should be considered that the livers in this study were initially rejected for transplantation,” they wrote, “and the confidence intervals of the lactate concentration at the end of reperfusion largely overlap with time-matched values reported by others during [normothermic machine perfusion] of rejected human livers.”

Hepatocellular injury and histology also were evaluated during and after simulated transplantation, respectively, with favorable results. Although sites of preexisting hepatic injury were aggravated by the process, and rates of apoptosis increased, the investigators considered these changes were clinically insignificant.

Looking to the future, the investigators suggested that further refinement of the process could facilitate even-lower storage temperatures while better preserving liver viability.

“The use of human livers makes this study clinically relevant and promotes the translation of subzero organ preservation to the clinic,” the investigators concluded. “However, long-term survival experiments of transplanted supercooled livers in swine or an alternative large animal model will be needed before clinical translation.”

The study was funded by the National Institutes of Health and the Department of Defense. Dr. de Vries and four other coauthors have provisional patent applications related to the study, and one coauthor disclosed a financial relationship with Organ Solutions.

SOURCE: de Vries RJ et al. Nature Biotechnol. 2019 Sep 9. doi: 10.1038/s41587-019-0223-y.

A new supercooling process could extend ex vivo liver viability by more than a day, potentially expanding transplant availability, according to investigators.

Massachusetts General Hospital

Standard cooling to 4°C provides just 12 hours of organ preservation, but laboratory testing showed that supercooling to –4°C added 27 hours of viability, reported lead author Reinier J. de Vries, MD, of Harvard Medical School and Massachusetts General Hospital in Boston, and colleagues.

“The absence of technology to preserve organs for more than a few hours is one of the fundamental causes of the donor organ–shortage crisis,” the investigators wrote in Nature Biotechnology.

Supercooling organs to high-subzero temperatures has been shown to prolong organ life while avoiding ice-mediated injury, but techniques that are successful for rat livers have been difficult to translate to human livers because of their larger size, which increases the risk of ice formation, the investigators explained.

Three strategies were employed to overcome this problem: minimization of air-liquid interfaces, development of a new supercooling-preservation solution, and hypothermic machine perfusion to more evenly distribute preservation solution throughout the liver tissue. For recovery of organs after supercooling, the investigators used subnormothermic machine perfusion, which has been used effectively in rat transplants.

In order to measure the impact of this process on organ viability, the investigators first measured adenylate energy content, both before supercooling and after recovery.

“Adenylate energy content, and, particularly, the organ’s ability to recover it during (re)perfusion, is considered the most representative metric for liver viability,” they wrote.

The difference between pre- and postsupercooling energy charge was less than 20%; in comparison, failed liver transplants in large animals and clinical trials have typically involved an energy-charge loss of 40% or more.

To further test organ viability, the investigators measured pre- and postsupercooling levels of bile production, oxygen uptake, and vascular resistance. All of these parameters have been shown to predict transplant success in rats, and bile production has additional precedent from human studies.

On average, bile production, portal resistance, and arterial resistance were not significantly affected by supercooling. Although portal vein resistance was 20% higher after supercooling, this compared favorably with increases of 100%-150% that have been measured in nonviable livers. Similarly, oxygen uptake increased by a mean of 17%, but this was three times lower than changes that have been observed in livers with impaired viability, at 51%.

Additional measures of hepatocellular injury, including AST and ALT, were also supportive of viability after supercooling. Histopathology confirmed these findings by showing preserved tissue architecture.

“In summary, we find that the human livers tested displayed no substantial difference in viability before and after extended subzero supercooling preservation,” the investigators wrote.

To simulate transplantation, the investigators reperfused the organs with blood at a normal temperature, including platelets, complement, and white blood cells, which are drivers of ischemia reperfusion injury. During this process, energy charge remained stable, which indicates preserved mitochondrial function. While energy charge held steady, lactate metabolism increased with bile and urea production, suggesting increased liver function. Bile pH and HCO_3– levels fell within range for viability. Although bile glucose exceeded proposed criteria, the investigators pointed out that levels still fell within parameters for research-quality livers. Lactate levels also rose within the first hour of reperfusion, but the investigators suggested that this finding should be interpreted with appropriate context.

“It should be considered that the livers in this study were initially rejected for transplantation,” they wrote, “and the confidence intervals of the lactate concentration at the end of reperfusion largely overlap with time-matched values reported by others during [normothermic machine perfusion] of rejected human livers.”

Hepatocellular injury and histology also were evaluated during and after simulated transplantation, respectively, with favorable results. Although sites of preexisting hepatic injury were aggravated by the process, and rates of apoptosis increased, the investigators considered these changes were clinically insignificant.

Looking to the future, the investigators suggested that further refinement of the process could facilitate even-lower storage temperatures while better preserving liver viability.

“The use of human livers makes this study clinically relevant and promotes the translation of subzero organ preservation to the clinic,” the investigators concluded. “However, long-term survival experiments of transplanted supercooled livers in swine or an alternative large animal model will be needed before clinical translation.”

The study was funded by the National Institutes of Health and the Department of Defense. Dr. de Vries and four other coauthors have provisional patent applications related to the study, and one coauthor disclosed a financial relationship with Organ Solutions.

SOURCE: de Vries RJ et al. Nature Biotechnol. 2019 Sep 9. doi: 10.1038/s41587-019-0223-y.

A new supercooling process could extend ex vivo liver viability by more than a day, potentially expanding transplant availability, according to investigators.

Massachusetts General Hospital

Standard cooling to 4°C provides just 12 hours of organ preservation, but laboratory testing showed that supercooling to –4°C added 27 hours of viability, reported lead author Reinier J. de Vries, MD, of Harvard Medical School and Massachusetts General Hospital in Boston, and colleagues.

“The absence of technology to preserve organs for more than a few hours is one of the fundamental causes of the donor organ–shortage crisis,” the investigators wrote in Nature Biotechnology.

Supercooling organs to high-subzero temperatures has been shown to prolong organ life while avoiding ice-mediated injury, but techniques that are successful for rat livers have been difficult to translate to human livers because of their larger size, which increases the risk of ice formation, the investigators explained.

Three strategies were employed to overcome this problem: minimization of air-liquid interfaces, development of a new supercooling-preservation solution, and hypothermic machine perfusion to more evenly distribute preservation solution throughout the liver tissue. For recovery of organs after supercooling, the investigators used subnormothermic machine perfusion, which has been used effectively in rat transplants.

In order to measure the impact of this process on organ viability, the investigators first measured adenylate energy content, both before supercooling and after recovery.

“Adenylate energy content, and, particularly, the organ’s ability to recover it during (re)perfusion, is considered the most representative metric for liver viability,” they wrote.

The difference between pre- and postsupercooling energy charge was less than 20%; in comparison, failed liver transplants in large animals and clinical trials have typically involved an energy-charge loss of 40% or more.

To further test organ viability, the investigators measured pre- and postsupercooling levels of bile production, oxygen uptake, and vascular resistance. All of these parameters have been shown to predict transplant success in rats, and bile production has additional precedent from human studies.

On average, bile production, portal resistance, and arterial resistance were not significantly affected by supercooling. Although portal vein resistance was 20% higher after supercooling, this compared favorably with increases of 100%-150% that have been measured in nonviable livers. Similarly, oxygen uptake increased by a mean of 17%, but this was three times lower than changes that have been observed in livers with impaired viability, at 51%.

Additional measures of hepatocellular injury, including AST and ALT, were also supportive of viability after supercooling. Histopathology confirmed these findings by showing preserved tissue architecture.

“In summary, we find that the human livers tested displayed no substantial difference in viability before and after extended subzero supercooling preservation,” the investigators wrote.

To simulate transplantation, the investigators reperfused the organs with blood at a normal temperature, including platelets, complement, and white blood cells, which are drivers of ischemia reperfusion injury. During this process, energy charge remained stable, which indicates preserved mitochondrial function. While energy charge held steady, lactate metabolism increased with bile and urea production, suggesting increased liver function. Bile pH and HCO_3– levels fell within range for viability. Although bile glucose exceeded proposed criteria, the investigators pointed out that levels still fell within parameters for research-quality livers. Lactate levels also rose within the first hour of reperfusion, but the investigators suggested that this finding should be interpreted with appropriate context.

“It should be considered that the livers in this study were initially rejected for transplantation,” they wrote, “and the confidence intervals of the lactate concentration at the end of reperfusion largely overlap with time-matched values reported by others during [normothermic machine perfusion] of rejected human livers.”

Hepatocellular injury and histology also were evaluated during and after simulated transplantation, respectively, with favorable results. Although sites of preexisting hepatic injury were aggravated by the process, and rates of apoptosis increased, the investigators considered these changes were clinically insignificant.

Looking to the future, the investigators suggested that further refinement of the process could facilitate even-lower storage temperatures while better preserving liver viability.

“The use of human livers makes this study clinically relevant and promotes the translation of subzero organ preservation to the clinic,” the investigators concluded. “However, long-term survival experiments of transplanted supercooled livers in swine or an alternative large animal model will be needed before clinical translation.”

The study was funded by the National Institutes of Health and the Department of Defense. Dr. de Vries and four other coauthors have provisional patent applications related to the study, and one coauthor disclosed a financial relationship with Organ Solutions.

SOURCE: de Vries RJ et al. Nature Biotechnol. 2019 Sep 9. doi: 10.1038/s41587-019-0223-y.

Patients with viral hepatitis may live longer after treatment with direct-acting antiviral agents (DAAs), but their risk of extrahepatic causes of death may rise as a result, according to investigators.

Importantly, this increasing rate of extrahepatic mortality shouldn’t be seen as a causal link with DAA use, cautioned lead author Donghee Kim, MD, PhD, of Stanford (Calif.) University, and colleagues. Instead, the upward trend is more likely because of successful treatment with DAAs, which can increase lifespan, and with it, time for susceptibility to extrahepatic conditions.

This was just one finding from a retrospective study that used U.S. Census and National Center for Health Statistics mortality records to evaluate almost 28 million deaths that occurred between 2007 and 2017. The investigators looked for mortality trends among patients with common chronic liver diseases, including viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD), noting that each of these conditions is associated with extrahepatic complications. The study included deaths due to extrahepatic cancer, cardiovascular disease, and diabetes.

While the efficacy of therapy for viral hepatitis has improved markedly since 2014, treatments for ALD and NAFLD have remained static, the investigators noted.

“Unfortunately, there have been no significant breakthroughs in the treatment of [ALD] over the last 2 decades, resulting in an increase in estimated global mortality to 3.8%,” the investigators wrote in Gastroenterology.

“[NAFLD] is the most common chronic liver disease in the world,” they added. “The leading cause of death in individuals with NAFLD is cardiovascular disease, followed by extrahepatic malignancies, and then liver-related mortality. However, recent trends in ALD and NAFLD-related extrahepatic complications in comparison to viral hepatitis have not been studied.”

The results of the current study supported the positive impact of DAAs, which began to see widespread use in 2014. Age-standardized mortality among patients with hepatitis C virus rose until 2014 (2.2% per year) and dropped thereafter (–6.5% per year). Mortality among those with hepatitis B virus steadily decreased over the study period (–1.2% per year).

Of note, while deaths because of HCV-related liver disease dropped from 2014 to 2017, extrahepatic causes of death didn’t follow suit. Age-standardized mortality for cardiovascular disease and diabetes increased at average annual rates of 1.9% and 3.3%, respectively, while the rate of extrahepatic cancer-related deaths held steady.

“The widespread use, higher efficacy and durable response to DAA agents in individuals with HCV infection may have resulted in a paradigm shift in the clinical progression of coexisting disease entities following response to DAA agents in the virus-free environment,” the investigators wrote. “These findings suggest assessment and identification of risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals who have been successfully treated and cured of HCV infection.”

In sharp contrast with the viral hepatitis findings, mortality rates among patients with ALD and NAFLD increased at an accelerating rate over the 11-year study period.

Among patients with ALD, all-cause mortality increased by an average of 3.4% per year, at a higher rate in the second half of the study than the first (4.6% vs 2.1%). Liver disease–related mortality rose at a similar, accelerating rate. In the same group, deaths due to cardiovascular disease increased at an average annual rate of 2.1%, which was accelerating, while extrahepatic cancer-related deaths increased at a more constant rate of 3.6%.

For patients with NAFLD, all-cause mortality increased by 8.1% per year, accelerating from 6.1% in the first half of the study to 11.2% in the second. Deaths from liver disease increased at an average rate of 12.6% per year, while extrahepatic deaths increased significantly for all three included types: cardiovascular disease (2.0%), extrahepatic cancer (15.1%), and diabetes (9.7%).

Concerning the worsening rates of mortality among patients with ALD and NAFLD, the investigators cited a lack of progress in treatments, and suggested that “the quest for newer therapies must remain the cornerstone in our efforts.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Kim D et al. Gastroenterology. 2019 Jun 25. doi: 10.1053/j.gastro.2019.06.026.

Patients with viral hepatitis may live longer after treatment with direct-acting antiviral agents (DAAs), but their risk of extrahepatic causes of death may rise as a result, according to investigators.

Importantly, this increasing rate of extrahepatic mortality shouldn’t be seen as a causal link with DAA use, cautioned lead author Donghee Kim, MD, PhD, of Stanford (Calif.) University, and colleagues. Instead, the upward trend is more likely because of successful treatment with DAAs, which can increase lifespan, and with it, time for susceptibility to extrahepatic conditions.

This was just one finding from a retrospective study that used U.S. Census and National Center for Health Statistics mortality records to evaluate almost 28 million deaths that occurred between 2007 and 2017. The investigators looked for mortality trends among patients with common chronic liver diseases, including viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD), noting that each of these conditions is associated with extrahepatic complications. The study included deaths due to extrahepatic cancer, cardiovascular disease, and diabetes.

While the efficacy of therapy for viral hepatitis has improved markedly since 2014, treatments for ALD and NAFLD have remained static, the investigators noted.

“Unfortunately, there have been no significant breakthroughs in the treatment of [ALD] over the last 2 decades, resulting in an increase in estimated global mortality to 3.8%,” the investigators wrote in Gastroenterology.

“[NAFLD] is the most common chronic liver disease in the world,” they added. “The leading cause of death in individuals with NAFLD is cardiovascular disease, followed by extrahepatic malignancies, and then liver-related mortality. However, recent trends in ALD and NAFLD-related extrahepatic complications in comparison to viral hepatitis have not been studied.”

The results of the current study supported the positive impact of DAAs, which began to see widespread use in 2014. Age-standardized mortality among patients with hepatitis C virus rose until 2014 (2.2% per year) and dropped thereafter (–6.5% per year). Mortality among those with hepatitis B virus steadily decreased over the study period (–1.2% per year).

Of note, while deaths because of HCV-related liver disease dropped from 2014 to 2017, extrahepatic causes of death didn’t follow suit. Age-standardized mortality for cardiovascular disease and diabetes increased at average annual rates of 1.9% and 3.3%, respectively, while the rate of extrahepatic cancer-related deaths held steady.

“The widespread use, higher efficacy and durable response to DAA agents in individuals with HCV infection may have resulted in a paradigm shift in the clinical progression of coexisting disease entities following response to DAA agents in the virus-free environment,” the investigators wrote. “These findings suggest assessment and identification of risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals who have been successfully treated and cured of HCV infection.”

In sharp contrast with the viral hepatitis findings, mortality rates among patients with ALD and NAFLD increased at an accelerating rate over the 11-year study period.

Among patients with ALD, all-cause mortality increased by an average of 3.4% per year, at a higher rate in the second half of the study than the first (4.6% vs 2.1%). Liver disease–related mortality rose at a similar, accelerating rate. In the same group, deaths due to cardiovascular disease increased at an average annual rate of 2.1%, which was accelerating, while extrahepatic cancer-related deaths increased at a more constant rate of 3.6%.

For patients with NAFLD, all-cause mortality increased by 8.1% per year, accelerating from 6.1% in the first half of the study to 11.2% in the second. Deaths from liver disease increased at an average rate of 12.6% per year, while extrahepatic deaths increased significantly for all three included types: cardiovascular disease (2.0%), extrahepatic cancer (15.1%), and diabetes (9.7%).

Concerning the worsening rates of mortality among patients with ALD and NAFLD, the investigators cited a lack of progress in treatments, and suggested that “the quest for newer therapies must remain the cornerstone in our efforts.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Kim D et al. Gastroenterology. 2019 Jun 25. doi: 10.1053/j.gastro.2019.06.026.

Patients with viral hepatitis may live longer after treatment with direct-acting antiviral agents (DAAs), but their risk of extrahepatic causes of death may rise as a result, according to investigators.

Importantly, this increasing rate of extrahepatic mortality shouldn’t be seen as a causal link with DAA use, cautioned lead author Donghee Kim, MD, PhD, of Stanford (Calif.) University, and colleagues. Instead, the upward trend is more likely because of successful treatment with DAAs, which can increase lifespan, and with it, time for susceptibility to extrahepatic conditions.

This was just one finding from a retrospective study that used U.S. Census and National Center for Health Statistics mortality records to evaluate almost 28 million deaths that occurred between 2007 and 2017. The investigators looked for mortality trends among patients with common chronic liver diseases, including viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD), noting that each of these conditions is associated with extrahepatic complications. The study included deaths due to extrahepatic cancer, cardiovascular disease, and diabetes.

While the efficacy of therapy for viral hepatitis has improved markedly since 2014, treatments for ALD and NAFLD have remained static, the investigators noted.

“Unfortunately, there have been no significant breakthroughs in the treatment of [ALD] over the last 2 decades, resulting in an increase in estimated global mortality to 3.8%,” the investigators wrote in Gastroenterology.

“[NAFLD] is the most common chronic liver disease in the world,” they added. “The leading cause of death in individuals with NAFLD is cardiovascular disease, followed by extrahepatic malignancies, and then liver-related mortality. However, recent trends in ALD and NAFLD-related extrahepatic complications in comparison to viral hepatitis have not been studied.”

The results of the current study supported the positive impact of DAAs, which began to see widespread use in 2014. Age-standardized mortality among patients with hepatitis C virus rose until 2014 (2.2% per year) and dropped thereafter (–6.5% per year). Mortality among those with hepatitis B virus steadily decreased over the study period (–1.2% per year).

Of note, while deaths because of HCV-related liver disease dropped from 2014 to 2017, extrahepatic causes of death didn’t follow suit. Age-standardized mortality for cardiovascular disease and diabetes increased at average annual rates of 1.9% and 3.3%, respectively, while the rate of extrahepatic cancer-related deaths held steady.

“The widespread use, higher efficacy and durable response to DAA agents in individuals with HCV infection may have resulted in a paradigm shift in the clinical progression of coexisting disease entities following response to DAA agents in the virus-free environment,” the investigators wrote. “These findings suggest assessment and identification of risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals who have been successfully treated and cured of HCV infection.”

In sharp contrast with the viral hepatitis findings, mortality rates among patients with ALD and NAFLD increased at an accelerating rate over the 11-year study period.

Among patients with ALD, all-cause mortality increased by an average of 3.4% per year, at a higher rate in the second half of the study than the first (4.6% vs 2.1%). Liver disease–related mortality rose at a similar, accelerating rate. In the same group, deaths due to cardiovascular disease increased at an average annual rate of 2.1%, which was accelerating, while extrahepatic cancer-related deaths increased at a more constant rate of 3.6%.

For patients with NAFLD, all-cause mortality increased by 8.1% per year, accelerating from 6.1% in the first half of the study to 11.2% in the second. Deaths from liver disease increased at an average rate of 12.6% per year, while extrahepatic deaths increased significantly for all three included types: cardiovascular disease (2.0%), extrahepatic cancer (15.1%), and diabetes (9.7%).

Concerning the worsening rates of mortality among patients with ALD and NAFLD, the investigators cited a lack of progress in treatments, and suggested that “the quest for newer therapies must remain the cornerstone in our efforts.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Kim D et al. Gastroenterology. 2019 Jun 25. doi: 10.1053/j.gastro.2019.06.026.