Liver Disease

Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a two-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.

“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.

During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.

Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.

Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.

The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.

In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.

A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.

While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.

The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”

Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.

After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).

For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.

Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.

In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.

The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.

Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a two-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.

“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.

During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.

Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.

Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.

The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.

In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.

A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.

While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.

The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”

Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.

After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).

For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.

Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.

In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.

The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.

Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a two-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.

“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.

During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.

Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.

Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.

The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.

In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.

A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.

While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.

The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”

Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.

After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).

For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.

Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.

In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.

The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.

Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.

According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).

Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.

To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.

Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.

The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.

In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.

Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.

The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.

The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.

This article was updated on Sep. 20, 2022.

A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.

The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.

“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.

The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.

The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.

Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.

The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.

While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.

The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.

He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.

Dr. Liu and Dr. Brahmania have no relevant financial disclosures.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.

The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.

“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.

The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.

The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.

Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.

The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.

While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.

The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.

He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.

Dr. Liu and Dr. Brahmania have no relevant financial disclosures.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.

The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.

“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.

“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.

The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.

The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.

Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.

The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.

While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.

The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.

He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.

Dr. Liu and Dr. Brahmania have no relevant financial disclosures.

AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.

Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.

In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.

“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
 

Liver stiffness measured

Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.

The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.

The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.

The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.

They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.

The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
 

Uncovering a high prevalence of ALD and NAFLD

The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.

The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.

Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.

Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.

Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.

Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
 

Is drinking underreported?

In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.

Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.

“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.

“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.

Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”

Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.

No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.

In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.

“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
 

Liver stiffness measured

Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.

The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.

The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.

The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.

They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.

The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
 

Uncovering a high prevalence of ALD and NAFLD

The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.

The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.

Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.

Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.

Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.

Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
 

Is drinking underreported?

In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.

Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.

“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.

“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.

Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”

Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.

No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.

In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.

“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
 

Liver stiffness measured

Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.

The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.

The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.

The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.

They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.

The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
 

Uncovering a high prevalence of ALD and NAFLD

The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.

The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.

Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.

Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.

Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.

Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
 

Is drinking underreported?

In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.

Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.

“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.

“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.

Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”

Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.

No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

More than half of chronic hepatitis B e antigen–negative patients who withdraw from nucleoside or nucleotide analogue therapy experienced relapse within 4 years, according to a new study that looked at patients from 11 centers in Europe, North America, and Asia.

“We wanted to see if the patients stabilize after that year. Are they just having relapses within the first year, and then they’re inactive carriers? Especially patients who don’t achieve [hepatitis B surface antigen; HBsAg] loss. Is that mildly active disease? Would they have been better off being retreated, or are they better off [staying off] therapy? It is important to look at what happens among these patients who stop and if there is a way to tell which way they’re going to go,” said Grishma Hirode, who is a PhD candidate at the University of Toronto. Ms. Hirode presented the multinational study at the annual meeting of the American Association for the Study of Liver Diseases.

The study provided a clear picture: “They do not stabilize after 1 year. They have relapses, and these relapses aren’t mild fluctuations,” said Ms. Hirode. Another study, which was presented during the same session and investigated a national cohort in Taiwan, also found a high rate of flareups and retreatment out to 4 years.

The RETRACT-B study presented by Ms. Hirode collected data on 945 patients from 11 centers in North America, Europe, and Asia. Overall, 66% had at least one relapse within 1 year of drug withdrawal. At 2 years, 40% had a sustained remission without HBsAg loss, as had 20% at 4 years; 44% had sustained remission or HBsAg loss at 2 years, as did 30% at 4 years.

Subgroup analyses found differences between some populations: 48% of Whites and 28% of Asians had sustained remission or HBsAg loss, and 30% of Whites and 20% of Asians had sustained remission without HBsAg loss. Patients who were HBsAg positive at start of therapy were more likely to have a sustained remission or HBsAg loss (36% vs. 28%; P < .05) and to have a sustained remission without HBsAg loss (31% vs. 19%; P < .05). HBsAg levels below 100 IU/mL at cessation was also associated with a greater chance of sustained remission or HBsAg loss (58% vs. 24%; P < .05) and sustained remission without HBsAg loss (24% vs. 20%; P < .05). Not having a relapse within the first year after cessation was also associated with greater chance of sustained remission or HBsAg loss (50% versus 19%; P < .05) and sustained remission without HBsAg loss (37% vs. 13%; P < .05).

sarathsasidharan/Thinkstock

The Taiwan cohort study examined the repercussions of a government policy that limited reimbursement of nucleotide/nucleoside analogues to a fixed duration of time. Among 10,192 eligible patients, researchers at I-SHOU University found a 6.58% 4-year cumulative incidence of severe flare-ups after discontinuation (95% confidence interval, 5.91%-7.30%), defined as serum ALT levels higher than five times the upper limit of normal plus serum bilirubin levels above 2 mg/dL.

The overall incidence of flare-ups was 30.66% over 4 years (95% CI, 29.37%-31.96%). Higher risk of flareup was associated with older age (hazard ratio for each 10 years, 1.19; P<.0001), male sex (HR, 1.76; P < .0001), a diagnosis of cirrhosis (HR, 1.84; P < .0001), and a history of hepatic decompensation (HR, 1.45; P = .044).

The 4-year incidence of retreatment was 48.74% (95% CI, 46.55-50.90%)

The mortality rate was 0.63% at 4 years after a flareup (95% CI, 0.44-0.87%), and the combined rate of mortality or liver transplant was 0.79% (95% CI, 0.58-1.05%). Risk factors for higher mortality included older age (per 10 years; HR, 1.70; P < .0001), a diagnosis of cirrhosis (HR, 6.12; P < .0001), and hypertension (HR, 2.29; P = .029).
 

Selecting patients safely?

The results of both studies suggest that withdrawal from medication should be done cautiously, and patients monitored for relapse and retreatment, according to Anna Lok, MD, who was asked for comment. Dr. Lok is a professor of internal medicine, director of clinical hematology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.

Between the two studies, “the message is that this approach can benefit some patients, but if the goal of treatment withdrawal is to increase the rate of hepatitis B surface antigen loss, only a small percentage of patients would benefit. Contrary to studies in Europe, the rates of HBsAg loss in studies with predominantly Asian patients are much lower,” said Dr. Lok.

The new studies provide guidance as for which patients might safely stop treatment; specifically, she suggested, young White patients who have a low HBsAg level when treatment is stopped. “But you probably shouldn’t be trying it in older Asian patients who still have high HBsAg titer, because the chance of them relapsing is very high and the chance of benefit is very low,” she said.

“One has to be very careful in selecting which patients you’re going to try this on. And if you do want to try, you’ve got to make sure that you monitor patients very carefully so treatment can be promptly resumed if necessary because some of the patients can have a severe flare and they can even develop liver failure, and this should never be tried in patients with cirrhosis” said Dr. Lok.

Ms. Hirode and Dr. Lok have no relevant financial disclosures.

More than half of chronic hepatitis B e antigen–negative patients who withdraw from nucleoside or nucleotide analogue therapy experienced relapse within 4 years, according to a new study that looked at patients from 11 centers in Europe, North America, and Asia.

“We wanted to see if the patients stabilize after that year. Are they just having relapses within the first year, and then they’re inactive carriers? Especially patients who don’t achieve [hepatitis B surface antigen; HBsAg] loss. Is that mildly active disease? Would they have been better off being retreated, or are they better off [staying off] therapy? It is important to look at what happens among these patients who stop and if there is a way to tell which way they’re going to go,” said Grishma Hirode, who is a PhD candidate at the University of Toronto. Ms. Hirode presented the multinational study at the annual meeting of the American Association for the Study of Liver Diseases.

The study provided a clear picture: “They do not stabilize after 1 year. They have relapses, and these relapses aren’t mild fluctuations,” said Ms. Hirode. Another study, which was presented during the same session and investigated a national cohort in Taiwan, also found a high rate of flareups and retreatment out to 4 years.

The RETRACT-B study presented by Ms. Hirode collected data on 945 patients from 11 centers in North America, Europe, and Asia. Overall, 66% had at least one relapse within 1 year of drug withdrawal. At 2 years, 40% had a sustained remission without HBsAg loss, as had 20% at 4 years; 44% had sustained remission or HBsAg loss at 2 years, as did 30% at 4 years.

Subgroup analyses found differences between some populations: 48% of Whites and 28% of Asians had sustained remission or HBsAg loss, and 30% of Whites and 20% of Asians had sustained remission without HBsAg loss. Patients who were HBsAg positive at start of therapy were more likely to have a sustained remission or HBsAg loss (36% vs. 28%; P < .05) and to have a sustained remission without HBsAg loss (31% vs. 19%; P < .05). HBsAg levels below 100 IU/mL at cessation was also associated with a greater chance of sustained remission or HBsAg loss (58% vs. 24%; P < .05) and sustained remission without HBsAg loss (24% vs. 20%; P < .05). Not having a relapse within the first year after cessation was also associated with greater chance of sustained remission or HBsAg loss (50% versus 19%; P < .05) and sustained remission without HBsAg loss (37% vs. 13%; P < .05).

sarathsasidharan/Thinkstock

The Taiwan cohort study examined the repercussions of a government policy that limited reimbursement of nucleotide/nucleoside analogues to a fixed duration of time. Among 10,192 eligible patients, researchers at I-SHOU University found a 6.58% 4-year cumulative incidence of severe flare-ups after discontinuation (95% confidence interval, 5.91%-7.30%), defined as serum ALT levels higher than five times the upper limit of normal plus serum bilirubin levels above 2 mg/dL.

The overall incidence of flare-ups was 30.66% over 4 years (95% CI, 29.37%-31.96%). Higher risk of flareup was associated with older age (hazard ratio for each 10 years, 1.19; P<.0001), male sex (HR, 1.76; P < .0001), a diagnosis of cirrhosis (HR, 1.84; P < .0001), and a history of hepatic decompensation (HR, 1.45; P = .044).

The 4-year incidence of retreatment was 48.74% (95% CI, 46.55-50.90%)

The mortality rate was 0.63% at 4 years after a flareup (95% CI, 0.44-0.87%), and the combined rate of mortality or liver transplant was 0.79% (95% CI, 0.58-1.05%). Risk factors for higher mortality included older age (per 10 years; HR, 1.70; P < .0001), a diagnosis of cirrhosis (HR, 6.12; P < .0001), and hypertension (HR, 2.29; P = .029).
 

Selecting patients safely?

The results of both studies suggest that withdrawal from medication should be done cautiously, and patients monitored for relapse and retreatment, according to Anna Lok, MD, who was asked for comment. Dr. Lok is a professor of internal medicine, director of clinical hematology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.

Between the two studies, “the message is that this approach can benefit some patients, but if the goal of treatment withdrawal is to increase the rate of hepatitis B surface antigen loss, only a small percentage of patients would benefit. Contrary to studies in Europe, the rates of HBsAg loss in studies with predominantly Asian patients are much lower,” said Dr. Lok.

The new studies provide guidance as for which patients might safely stop treatment; specifically, she suggested, young White patients who have a low HBsAg level when treatment is stopped. “But you probably shouldn’t be trying it in older Asian patients who still have high HBsAg titer, because the chance of them relapsing is very high and the chance of benefit is very low,” she said.

“One has to be very careful in selecting which patients you’re going to try this on. And if you do want to try, you’ve got to make sure that you monitor patients very carefully so treatment can be promptly resumed if necessary because some of the patients can have a severe flare and they can even develop liver failure, and this should never be tried in patients with cirrhosis” said Dr. Lok.

Ms. Hirode and Dr. Lok have no relevant financial disclosures.

More than half of chronic hepatitis B e antigen–negative patients who withdraw from nucleoside or nucleotide analogue therapy experienced relapse within 4 years, according to a new study that looked at patients from 11 centers in Europe, North America, and Asia.

“We wanted to see if the patients stabilize after that year. Are they just having relapses within the first year, and then they’re inactive carriers? Especially patients who don’t achieve [hepatitis B surface antigen; HBsAg] loss. Is that mildly active disease? Would they have been better off being retreated, or are they better off [staying off] therapy? It is important to look at what happens among these patients who stop and if there is a way to tell which way they’re going to go,” said Grishma Hirode, who is a PhD candidate at the University of Toronto. Ms. Hirode presented the multinational study at the annual meeting of the American Association for the Study of Liver Diseases.

The study provided a clear picture: “They do not stabilize after 1 year. They have relapses, and these relapses aren’t mild fluctuations,” said Ms. Hirode. Another study, which was presented during the same session and investigated a national cohort in Taiwan, also found a high rate of flareups and retreatment out to 4 years.

The RETRACT-B study presented by Ms. Hirode collected data on 945 patients from 11 centers in North America, Europe, and Asia. Overall, 66% had at least one relapse within 1 year of drug withdrawal. At 2 years, 40% had a sustained remission without HBsAg loss, as had 20% at 4 years; 44% had sustained remission or HBsAg loss at 2 years, as did 30% at 4 years.

Subgroup analyses found differences between some populations: 48% of Whites and 28% of Asians had sustained remission or HBsAg loss, and 30% of Whites and 20% of Asians had sustained remission without HBsAg loss. Patients who were HBsAg positive at start of therapy were more likely to have a sustained remission or HBsAg loss (36% vs. 28%; P < .05) and to have a sustained remission without HBsAg loss (31% vs. 19%; P < .05). HBsAg levels below 100 IU/mL at cessation was also associated with a greater chance of sustained remission or HBsAg loss (58% vs. 24%; P < .05) and sustained remission without HBsAg loss (24% vs. 20%; P < .05). Not having a relapse within the first year after cessation was also associated with greater chance of sustained remission or HBsAg loss (50% versus 19%; P < .05) and sustained remission without HBsAg loss (37% vs. 13%; P < .05).

sarathsasidharan/Thinkstock

The Taiwan cohort study examined the repercussions of a government policy that limited reimbursement of nucleotide/nucleoside analogues to a fixed duration of time. Among 10,192 eligible patients, researchers at I-SHOU University found a 6.58% 4-year cumulative incidence of severe flare-ups after discontinuation (95% confidence interval, 5.91%-7.30%), defined as serum ALT levels higher than five times the upper limit of normal plus serum bilirubin levels above 2 mg/dL.

The overall incidence of flare-ups was 30.66% over 4 years (95% CI, 29.37%-31.96%). Higher risk of flareup was associated with older age (hazard ratio for each 10 years, 1.19; P<.0001), male sex (HR, 1.76; P < .0001), a diagnosis of cirrhosis (HR, 1.84; P < .0001), and a history of hepatic decompensation (HR, 1.45; P = .044).

The 4-year incidence of retreatment was 48.74% (95% CI, 46.55-50.90%)

The mortality rate was 0.63% at 4 years after a flareup (95% CI, 0.44-0.87%), and the combined rate of mortality or liver transplant was 0.79% (95% CI, 0.58-1.05%). Risk factors for higher mortality included older age (per 10 years; HR, 1.70; P < .0001), a diagnosis of cirrhosis (HR, 6.12; P < .0001), and hypertension (HR, 2.29; P = .029).
 

Selecting patients safely?

The results of both studies suggest that withdrawal from medication should be done cautiously, and patients monitored for relapse and retreatment, according to Anna Lok, MD, who was asked for comment. Dr. Lok is a professor of internal medicine, director of clinical hematology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.

Between the two studies, “the message is that this approach can benefit some patients, but if the goal of treatment withdrawal is to increase the rate of hepatitis B surface antigen loss, only a small percentage of patients would benefit. Contrary to studies in Europe, the rates of HBsAg loss in studies with predominantly Asian patients are much lower,” said Dr. Lok.

The new studies provide guidance as for which patients might safely stop treatment; specifically, she suggested, young White patients who have a low HBsAg level when treatment is stopped. “But you probably shouldn’t be trying it in older Asian patients who still have high HBsAg titer, because the chance of them relapsing is very high and the chance of benefit is very low,” she said.

“One has to be very careful in selecting which patients you’re going to try this on. And if you do want to try, you’ve got to make sure that you monitor patients very carefully so treatment can be promptly resumed if necessary because some of the patients can have a severe flare and they can even develop liver failure, and this should never be tried in patients with cirrhosis” said Dr. Lok.

Ms. Hirode and Dr. Lok have no relevant financial disclosures.

Multiple comorbidities appear to worsen mortality outcomes in patients with cirrhosis: Those with compensated cirrhosis and three comorbid conditions have a mortality rate similar to patients with decompensated cirrhosis, according to a new analysis of a population-based cohort in the Dallas-Fort Worth metroplex.

“I think it’s a pretty strong message that just the presence of these chronic diseases has such a strong effect in the long run. They at least contribute to mortality to some extent. It’s really important to focus on these chronic diseases as targets early during the care that we provide to these to cirrhotic patients to make sure that we control them so that, in the long run, we can decrease the premature death and mortality in these patients,” said Mohammad Amin Fallahzadeh, MD, MPH, who presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

The study included 35,361 patients with cirrhosis. The mean age of participants was 59.5 years, 41.8% were female, 29.7% were non-White, and 17.5% were Hispanic. Comorbidities were common, occurring in about 25% of patients. Forty-five percent of comorbidities were cardiovascular diseases (CVD); 28.9% of subjects had one comorbidity, 17.5% had two comorbidities, and 12.6% had three comorbidities.

A Kaplan-Meier curve showed that patients with compensated cirrhosis and no comorbidities had the highest survival over time, while decompensated patients with comorbidities had the lowest survival (P = .01). The curve showed similar survival between patients with compensated cirrhosis and three comorbidities and decompensated patients with no comorbidities.

The risk of death increased with one comorbidity (hazard ratio, 2.5; 95% confidence interval, 2.23-2.8), two comorbidities (HR, 3.27; 95% CI, 2.9-3.69), and three comorbidities (HR, 4.52; 95% CI, 3.99-5.12).

Mortality increased with the number of comorbidities in both compensated and decompensated patients; patients with hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease; by race (White, Black, and other); and in different age groups. A stronger effect of comorbidities was seen in compensated patients (HR, 6.4 vs. 4.1), female patients (HR, 5.2 vs. 4.1), and in patients older than age 65 years (HR, 7.2 vs. 3.7 in those aged 45-64 years and 5.0 in those younger than age 45 years).

The researchers also found an apparent synergistic effect of chronic kidney disease (CKD) and CVD. Both conditions were associated with increased risk on their own, but when a patient had both CVD and CKD, mortality was higher than just the added risk of the two conditions.

The findings confirm that patients with cirrhosis and comorbidities seem to have worse quality of life and higher mortality. “I didn’t expect that it would have such a major effect, to make a compensated patient as if they are decompensated, but we definitely see that in our daily practice,” said Dr. Fallahzadeh, who is a 2nd-year internal medicine resident at Baylor University Medical Center, Dallas.

“When a hepatologist or an internist has a visit with a patient who is diagnosed with cirrhosis, they need to screen them for the other chronic diseases like diabetes, CKD, and cardiovascular disease to make sure that if they have any of these conditions, they’ll be under control, or if they need any referral for better management. For example, if they need a nephrology referral, it [should] be done as early as possible so that we can minimize the burden of these diseases in the long run for these patients. And we need to educate the patients as well about controlling these chronic problems,” said Dr. Fallahzadeh.

The findings might make researchers reconsider how to classify compensated and decompensated cirrhosis. “When we talk about decompensated liver disease, we’re talking about variceal hemorrhage, ascites, and encephalopathy. In this case, they’re saying that if you’re compensated and you [have] three of these associated medical conditions, that you could be worse off than decompensated cirrhosis. It’s really challenging the status quo and how we think about these two disease entities. They’re thought of a lot differently in terms of the mortality. That needs to be further elucidated,” said Mayur Brahmania, MD, assistant professor of medicine at Western University, London, Ont., who moderated the session.

A key limitation to the study was that the researchers did not have access to data about medication use, so it could not be determined if comorbidities were being controlled. Body mass index and most lifestyle factors were also uncontrolled.

Dr. Fallahzadeh and Dr. Brahmania have no relevant financial disclosures.

Multiple comorbidities appear to worsen mortality outcomes in patients with cirrhosis: Those with compensated cirrhosis and three comorbid conditions have a mortality rate similar to patients with decompensated cirrhosis, according to a new analysis of a population-based cohort in the Dallas-Fort Worth metroplex.

“I think it’s a pretty strong message that just the presence of these chronic diseases has such a strong effect in the long run. They at least contribute to mortality to some extent. It’s really important to focus on these chronic diseases as targets early during the care that we provide to these to cirrhotic patients to make sure that we control them so that, in the long run, we can decrease the premature death and mortality in these patients,” said Mohammad Amin Fallahzadeh, MD, MPH, who presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

The study included 35,361 patients with cirrhosis. The mean age of participants was 59.5 years, 41.8% were female, 29.7% were non-White, and 17.5% were Hispanic. Comorbidities were common, occurring in about 25% of patients. Forty-five percent of comorbidities were cardiovascular diseases (CVD); 28.9% of subjects had one comorbidity, 17.5% had two comorbidities, and 12.6% had three comorbidities.

A Kaplan-Meier curve showed that patients with compensated cirrhosis and no comorbidities had the highest survival over time, while decompensated patients with comorbidities had the lowest survival (P = .01). The curve showed similar survival between patients with compensated cirrhosis and three comorbidities and decompensated patients with no comorbidities.

The risk of death increased with one comorbidity (hazard ratio, 2.5; 95% confidence interval, 2.23-2.8), two comorbidities (HR, 3.27; 95% CI, 2.9-3.69), and three comorbidities (HR, 4.52; 95% CI, 3.99-5.12).

Mortality increased with the number of comorbidities in both compensated and decompensated patients; patients with hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease; by race (White, Black, and other); and in different age groups. A stronger effect of comorbidities was seen in compensated patients (HR, 6.4 vs. 4.1), female patients (HR, 5.2 vs. 4.1), and in patients older than age 65 years (HR, 7.2 vs. 3.7 in those aged 45-64 years and 5.0 in those younger than age 45 years).

The researchers also found an apparent synergistic effect of chronic kidney disease (CKD) and CVD. Both conditions were associated with increased risk on their own, but when a patient had both CVD and CKD, mortality was higher than just the added risk of the two conditions.

The findings confirm that patients with cirrhosis and comorbidities seem to have worse quality of life and higher mortality. “I didn’t expect that it would have such a major effect, to make a compensated patient as if they are decompensated, but we definitely see that in our daily practice,” said Dr. Fallahzadeh, who is a 2nd-year internal medicine resident at Baylor University Medical Center, Dallas.

“When a hepatologist or an internist has a visit with a patient who is diagnosed with cirrhosis, they need to screen them for the other chronic diseases like diabetes, CKD, and cardiovascular disease to make sure that if they have any of these conditions, they’ll be under control, or if they need any referral for better management. For example, if they need a nephrology referral, it [should] be done as early as possible so that we can minimize the burden of these diseases in the long run for these patients. And we need to educate the patients as well about controlling these chronic problems,” said Dr. Fallahzadeh.

The findings might make researchers reconsider how to classify compensated and decompensated cirrhosis. “When we talk about decompensated liver disease, we’re talking about variceal hemorrhage, ascites, and encephalopathy. In this case, they’re saying that if you’re compensated and you [have] three of these associated medical conditions, that you could be worse off than decompensated cirrhosis. It’s really challenging the status quo and how we think about these two disease entities. They’re thought of a lot differently in terms of the mortality. That needs to be further elucidated,” said Mayur Brahmania, MD, assistant professor of medicine at Western University, London, Ont., who moderated the session.

A key limitation to the study was that the researchers did not have access to data about medication use, so it could not be determined if comorbidities were being controlled. Body mass index and most lifestyle factors were also uncontrolled.

Dr. Fallahzadeh and Dr. Brahmania have no relevant financial disclosures.

Multiple comorbidities appear to worsen mortality outcomes in patients with cirrhosis: Those with compensated cirrhosis and three comorbid conditions have a mortality rate similar to patients with decompensated cirrhosis, according to a new analysis of a population-based cohort in the Dallas-Fort Worth metroplex.

“I think it’s a pretty strong message that just the presence of these chronic diseases has such a strong effect in the long run. They at least contribute to mortality to some extent. It’s really important to focus on these chronic diseases as targets early during the care that we provide to these to cirrhotic patients to make sure that we control them so that, in the long run, we can decrease the premature death and mortality in these patients,” said Mohammad Amin Fallahzadeh, MD, MPH, who presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

The study included 35,361 patients with cirrhosis. The mean age of participants was 59.5 years, 41.8% were female, 29.7% were non-White, and 17.5% were Hispanic. Comorbidities were common, occurring in about 25% of patients. Forty-five percent of comorbidities were cardiovascular diseases (CVD); 28.9% of subjects had one comorbidity, 17.5% had two comorbidities, and 12.6% had three comorbidities.

A Kaplan-Meier curve showed that patients with compensated cirrhosis and no comorbidities had the highest survival over time, while decompensated patients with comorbidities had the lowest survival (P = .01). The curve showed similar survival between patients with compensated cirrhosis and three comorbidities and decompensated patients with no comorbidities.

The risk of death increased with one comorbidity (hazard ratio, 2.5; 95% confidence interval, 2.23-2.8), two comorbidities (HR, 3.27; 95% CI, 2.9-3.69), and three comorbidities (HR, 4.52; 95% CI, 3.99-5.12).

Mortality increased with the number of comorbidities in both compensated and decompensated patients; patients with hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease; by race (White, Black, and other); and in different age groups. A stronger effect of comorbidities was seen in compensated patients (HR, 6.4 vs. 4.1), female patients (HR, 5.2 vs. 4.1), and in patients older than age 65 years (HR, 7.2 vs. 3.7 in those aged 45-64 years and 5.0 in those younger than age 45 years).

The researchers also found an apparent synergistic effect of chronic kidney disease (CKD) and CVD. Both conditions were associated with increased risk on their own, but when a patient had both CVD and CKD, mortality was higher than just the added risk of the two conditions.

The findings confirm that patients with cirrhosis and comorbidities seem to have worse quality of life and higher mortality. “I didn’t expect that it would have such a major effect, to make a compensated patient as if they are decompensated, but we definitely see that in our daily practice,” said Dr. Fallahzadeh, who is a 2nd-year internal medicine resident at Baylor University Medical Center, Dallas.

“When a hepatologist or an internist has a visit with a patient who is diagnosed with cirrhosis, they need to screen them for the other chronic diseases like diabetes, CKD, and cardiovascular disease to make sure that if they have any of these conditions, they’ll be under control, or if they need any referral for better management. For example, if they need a nephrology referral, it [should] be done as early as possible so that we can minimize the burden of these diseases in the long run for these patients. And we need to educate the patients as well about controlling these chronic problems,” said Dr. Fallahzadeh.

The findings might make researchers reconsider how to classify compensated and decompensated cirrhosis. “When we talk about decompensated liver disease, we’re talking about variceal hemorrhage, ascites, and encephalopathy. In this case, they’re saying that if you’re compensated and you [have] three of these associated medical conditions, that you could be worse off than decompensated cirrhosis. It’s really challenging the status quo and how we think about these two disease entities. They’re thought of a lot differently in terms of the mortality. That needs to be further elucidated,” said Mayur Brahmania, MD, assistant professor of medicine at Western University, London, Ont., who moderated the session.

A key limitation to the study was that the researchers did not have access to data about medication use, so it could not be determined if comorbidities were being controlled. Body mass index and most lifestyle factors were also uncontrolled.

Dr. Fallahzadeh and Dr. Brahmania have no relevant financial disclosures.

The American Gastroenterological Association recently published a Clinical Care Pathway for screening, diagnosis, and treatment of patients with nonalcoholic fatty liver disease (NAFLD).

Recommendations are intended for a spectrum of clinical settings, including primary care, obesity medicine, gastroenterology, hepatology, and endocrinology practices, reported lead author Fasiha Kanwal, MD, of Baylor College of Medicine, Houston, and colleagues.

“Most patients with NAFLD and NASH [nonalcoholic steatohepatitis] are seen in primary care or endocrine clinics,” the authors wrote in Gastroenterology. “Although not all patients with NAFLD/NASH require secondary (i.e., hepatology) care, not knowing which patients might benefit from such care and when to refer them results in inconsistent care processes and possibly poor outcomes. Clinical Care Pathways, with careful explication of each step in screening, diagnosis, and treatment, have been shown to improve the quality of health care delivery in other areas of medicine, [and] are crucial to addressing the often inconsistent care processes characterizing current approaches to NAFLD/NASH.”

The guidance was drafted by a group of 15 multidisciplinary experts from around the world representing the AGA, the American Diabetes Association, the American Osteopathic Association, the Obesity Society, and the Endocrine Society. Recommendations were based on available literature and clinical experience.

The authors recommended a four-step screening process for NAFLD/NASH: Check for risk factors predicting clinically relevant fibrosis (stage F2 or higher), review history and perform relevant laboratory tests, conduct noninvasive liver fibrosis testing, and measure liver stiffness.

Patients at greatest risk for clinically significant fibrosis include those with two or more metabolic risk factors, those with type 2 diabetes, and those with incidentally detected steatosis and/or elevated aminotransferases.

“A recent retrospective cohort study found that patients with hepatic steatosis and elevated alanine aminotransferase had a significantly higher risk of progression to cirrhosis or hepatocellular carcinoma than patients with hepatic steatosis and persistently normal alanine aminotransferase,” the authors noted.

When any of the above risk factors are present, the authors recommended checking the patient’s history for excessive alcohol intake, conducting a complete blood count and liver function tests, and screening for other hepatic and biliary diseases, such as chronic hepatitis C virus infection and liver mass lesions.

If other liver diseases have been ruled out, the first step in liver fibrosis risk stratification involves noninvasive testing, with the authors favoring the Fibrosis-4 (FIB-4) score “because it has been shown to have the best diagnostic accuracy for advanced fibrosis, compared with other noninvasive markers of fibrosis in patients with NAFLD.”

The next step in risk stratification involves liver stiffness measurement (LSM) with FibroScan (vibration controlled transient elastography [VCTE]), or newer modalities, such as bidimensional shear wave elastography or point shear wave elastography, which offer “diagnostic performances at least as good as VCTE.”

According to the publication, patients with NAFLD at low risk of advanced fibrosis (FIB-4 less than 1.3 or LSM less than 8 kPa or liver biopsy F0-F1) can be managed by one provider, such as a primary care provider or endocrinologist, whereas indeterminate-risk patients (FIB-4 of 1.3-2.67 and/or LSM 8-12 kPa and liver biopsy unavailable) and high-risk patients (FIB-4 greater than 2.67 or LSM greater than 12 kPa or liver biopsy F2-F4) should be managed by a multidisciplinary team led by a hepatologist.

Lifestyle intervention, weight loss (if overweight or obese), and cardiovascular disease risk reduction are advised for patients of all risk categories.

“There are no large, long-term behavioral modification or pharmacotherapy studies regarding weight loss in individuals with NAFLD,” the authors wrote. “However, weight loss of any magnitude should be encouraged as beneficial.”

For patients with indeterminate and high risk, NASH pharmacotherapy is recommended, and if needed, diabetes care should involve medications with efficacy in NASH, such as pioglitazone.

“Although we recognize that knowledge is continuing to evolve and that recommendations may change accordingly over time, we believe this Pathway provides accessible, standardized, evidence-based, timely, and testable recommendations that will allow clinicians to care for a rapidly growing population of patients, most of whom are managed in primary care or endocrine clinics,” the authors concluded.

The article was supported by the American Gastroenterological Association, Intercept Pharmaceuticals, Pfizer, and others. The authors disclosed relationships with Novo Nordisk, Eli Lilly, Sanofi, and others.

The American Gastroenterological Association recently published a Clinical Care Pathway for screening, diagnosis, and treatment of patients with nonalcoholic fatty liver disease (NAFLD).

Recommendations are intended for a spectrum of clinical settings, including primary care, obesity medicine, gastroenterology, hepatology, and endocrinology practices, reported lead author Fasiha Kanwal, MD, of Baylor College of Medicine, Houston, and colleagues.

“Most patients with NAFLD and NASH [nonalcoholic steatohepatitis] are seen in primary care or endocrine clinics,” the authors wrote in Gastroenterology. “Although not all patients with NAFLD/NASH require secondary (i.e., hepatology) care, not knowing which patients might benefit from such care and when to refer them results in inconsistent care processes and possibly poor outcomes. Clinical Care Pathways, with careful explication of each step in screening, diagnosis, and treatment, have been shown to improve the quality of health care delivery in other areas of medicine, [and] are crucial to addressing the often inconsistent care processes characterizing current approaches to NAFLD/NASH.”

The guidance was drafted by a group of 15 multidisciplinary experts from around the world representing the AGA, the American Diabetes Association, the American Osteopathic Association, the Obesity Society, and the Endocrine Society. Recommendations were based on available literature and clinical experience.

The authors recommended a four-step screening process for NAFLD/NASH: Check for risk factors predicting clinically relevant fibrosis (stage F2 or higher), review history and perform relevant laboratory tests, conduct noninvasive liver fibrosis testing, and measure liver stiffness.

Patients at greatest risk for clinically significant fibrosis include those with two or more metabolic risk factors, those with type 2 diabetes, and those with incidentally detected steatosis and/or elevated aminotransferases.

“A recent retrospective cohort study found that patients with hepatic steatosis and elevated alanine aminotransferase had a significantly higher risk of progression to cirrhosis or hepatocellular carcinoma than patients with hepatic steatosis and persistently normal alanine aminotransferase,” the authors noted.

When any of the above risk factors are present, the authors recommended checking the patient’s history for excessive alcohol intake, conducting a complete blood count and liver function tests, and screening for other hepatic and biliary diseases, such as chronic hepatitis C virus infection and liver mass lesions.

If other liver diseases have been ruled out, the first step in liver fibrosis risk stratification involves noninvasive testing, with the authors favoring the Fibrosis-4 (FIB-4) score “because it has been shown to have the best diagnostic accuracy for advanced fibrosis, compared with other noninvasive markers of fibrosis in patients with NAFLD.”

The next step in risk stratification involves liver stiffness measurement (LSM) with FibroScan (vibration controlled transient elastography [VCTE]), or newer modalities, such as bidimensional shear wave elastography or point shear wave elastography, which offer “diagnostic performances at least as good as VCTE.”

According to the publication, patients with NAFLD at low risk of advanced fibrosis (FIB-4 less than 1.3 or LSM less than 8 kPa or liver biopsy F0-F1) can be managed by one provider, such as a primary care provider or endocrinologist, whereas indeterminate-risk patients (FIB-4 of 1.3-2.67 and/or LSM 8-12 kPa and liver biopsy unavailable) and high-risk patients (FIB-4 greater than 2.67 or LSM greater than 12 kPa or liver biopsy F2-F4) should be managed by a multidisciplinary team led by a hepatologist.

Lifestyle intervention, weight loss (if overweight or obese), and cardiovascular disease risk reduction are advised for patients of all risk categories.

“There are no large, long-term behavioral modification or pharmacotherapy studies regarding weight loss in individuals with NAFLD,” the authors wrote. “However, weight loss of any magnitude should be encouraged as beneficial.”

For patients with indeterminate and high risk, NASH pharmacotherapy is recommended, and if needed, diabetes care should involve medications with efficacy in NASH, such as pioglitazone.

“Although we recognize that knowledge is continuing to evolve and that recommendations may change accordingly over time, we believe this Pathway provides accessible, standardized, evidence-based, timely, and testable recommendations that will allow clinicians to care for a rapidly growing population of patients, most of whom are managed in primary care or endocrine clinics,” the authors concluded.

The article was supported by the American Gastroenterological Association, Intercept Pharmaceuticals, Pfizer, and others. The authors disclosed relationships with Novo Nordisk, Eli Lilly, Sanofi, and others.

The American Gastroenterological Association recently published a Clinical Care Pathway for screening, diagnosis, and treatment of patients with nonalcoholic fatty liver disease (NAFLD).

Recommendations are intended for a spectrum of clinical settings, including primary care, obesity medicine, gastroenterology, hepatology, and endocrinology practices, reported lead author Fasiha Kanwal, MD, of Baylor College of Medicine, Houston, and colleagues.

“Most patients with NAFLD and NASH [nonalcoholic steatohepatitis] are seen in primary care or endocrine clinics,” the authors wrote in Gastroenterology. “Although not all patients with NAFLD/NASH require secondary (i.e., hepatology) care, not knowing which patients might benefit from such care and when to refer them results in inconsistent care processes and possibly poor outcomes. Clinical Care Pathways, with careful explication of each step in screening, diagnosis, and treatment, have been shown to improve the quality of health care delivery in other areas of medicine, [and] are crucial to addressing the often inconsistent care processes characterizing current approaches to NAFLD/NASH.”

The guidance was drafted by a group of 15 multidisciplinary experts from around the world representing the AGA, the American Diabetes Association, the American Osteopathic Association, the Obesity Society, and the Endocrine Society. Recommendations were based on available literature and clinical experience.

The authors recommended a four-step screening process for NAFLD/NASH: Check for risk factors predicting clinically relevant fibrosis (stage F2 or higher), review history and perform relevant laboratory tests, conduct noninvasive liver fibrosis testing, and measure liver stiffness.

Patients at greatest risk for clinically significant fibrosis include those with two or more metabolic risk factors, those with type 2 diabetes, and those with incidentally detected steatosis and/or elevated aminotransferases.

“A recent retrospective cohort study found that patients with hepatic steatosis and elevated alanine aminotransferase had a significantly higher risk of progression to cirrhosis or hepatocellular carcinoma than patients with hepatic steatosis and persistently normal alanine aminotransferase,” the authors noted.

When any of the above risk factors are present, the authors recommended checking the patient’s history for excessive alcohol intake, conducting a complete blood count and liver function tests, and screening for other hepatic and biliary diseases, such as chronic hepatitis C virus infection and liver mass lesions.

If other liver diseases have been ruled out, the first step in liver fibrosis risk stratification involves noninvasive testing, with the authors favoring the Fibrosis-4 (FIB-4) score “because it has been shown to have the best diagnostic accuracy for advanced fibrosis, compared with other noninvasive markers of fibrosis in patients with NAFLD.”

The next step in risk stratification involves liver stiffness measurement (LSM) with FibroScan (vibration controlled transient elastography [VCTE]), or newer modalities, such as bidimensional shear wave elastography or point shear wave elastography, which offer “diagnostic performances at least as good as VCTE.”

According to the publication, patients with NAFLD at low risk of advanced fibrosis (FIB-4 less than 1.3 or LSM less than 8 kPa or liver biopsy F0-F1) can be managed by one provider, such as a primary care provider or endocrinologist, whereas indeterminate-risk patients (FIB-4 of 1.3-2.67 and/or LSM 8-12 kPa and liver biopsy unavailable) and high-risk patients (FIB-4 greater than 2.67 or LSM greater than 12 kPa or liver biopsy F2-F4) should be managed by a multidisciplinary team led by a hepatologist.

Lifestyle intervention, weight loss (if overweight or obese), and cardiovascular disease risk reduction are advised for patients of all risk categories.

“There are no large, long-term behavioral modification or pharmacotherapy studies regarding weight loss in individuals with NAFLD,” the authors wrote. “However, weight loss of any magnitude should be encouraged as beneficial.”

For patients with indeterminate and high risk, NASH pharmacotherapy is recommended, and if needed, diabetes care should involve medications with efficacy in NASH, such as pioglitazone.

“Although we recognize that knowledge is continuing to evolve and that recommendations may change accordingly over time, we believe this Pathway provides accessible, standardized, evidence-based, timely, and testable recommendations that will allow clinicians to care for a rapidly growing population of patients, most of whom are managed in primary care or endocrine clinics,” the authors concluded.

The article was supported by the American Gastroenterological Association, Intercept Pharmaceuticals, Pfizer, and others. The authors disclosed relationships with Novo Nordisk, Eli Lilly, Sanofi, and others.

LAS VEGAS – Over the course of the COVID-19 pandemic, alcohol-related liver disease has increased in severity, a finding that is likely related to higher consumption of alcohol and reduced care. The difference was notable in higher Model for End-Stage Liver Disease–sodium (MELD-Na) scores, more signs of hepatic decompensation, and higher mortality rates.

“Alcohol consumption during the COVID-19 pandemic led to increased morbidity and mortality, specifically in patients that already had underlying liver disease. The importance of alcohol cessation, counseling, and close physician monitoring is emphasized, given continued or relapsed alcohol consumption can significantly affect quality of life, life expectancy, and liver transplantation candidacy,” research team member Lindsay A. Sobotka, DO, said in an interview. Dr. Sobotka is an assistant professor of gastroenterology, hepatology, and nutrition at the Ohio State University Wexner Medical Center, Columbus.

The research was presented by Ayushi Jain, MD, at the annual meeting of the American College of Gastroenterology. Dr. Jain is a resident at the Ohio State University Wexner Medical Center.

Dr. Jain noted that alcohol sales have gone up during the pandemic, with monthly sales up 14%-44% between February and September 2020, compared with the same months in previous years.
 

Decompensation rates rose

The researchers analyzed data from patients with alcoholic cirrhosis or alcoholic hepatitis who were seen at the Ohio State University Medical Center between March and August 2019, and between March and August 2020.

alenkadr/Thinkstock

During the pandemic, the number of hospital admissions nearly doubled among alcoholic hepatitis patients (86 to 162), but declined slightly among patients with alcoholic cirrhosis (613 to 528), possibly because of efforts to manage decompensation and avoid hospitalizations during the pandemic, according to Dr. Jain. In total, 4 of 162 patients with alcoholic hepatitis and 14 of 528 patients with alcoholic cirrhosis had COVID-19 at the time of admission.

Higher mortality rates were seen during the pandemic, although this was only significant for alcoholic cirrhosis: 14.8% versus 7% for alcoholic hepatitis (P = .06) and 13.5% versus 7.4% for alcoholic cirrhosis (P = .001).

Among those with alcoholic hepatitis, there was no significant change in median Maddrey’s Discriminant Function during the pandemic (P = .51), but the researchers noted a significant decrease in steroid use, from 27 patients to 23 (P = .001). “This may be due to a statistically significant increase in GI bleeds and renal dysfunction that we noted during the pandemic,” said Dr. Jain.

Hepatic decompensation and critical care needs increased among patients admitted with alcoholic hepatitis, including hepatic encephalopathy (P = .037), gastrointestinal bleeding (P = .01), a need for increased oxygen (P = .024), vasopressor support (P = .005), and initiation of hemodialysis (P = .007). The median highest MELD-Na score during admission was also higher during the pandemic (24 vs. 23, P = .04).

Patients with alcoholic cirrhosis had greater decompensation as measured by ascites (P = .01), therapeutic paracentesis (P = .04), titration of diuretics (P = .005), acute kidney injury (P = .005), hepatorenal syndrome (P = .002), and spontaneous bacterial peritonitis (P = .04). They also had greater need for vasopressor support (9% to 14%; P = .006), were more likely to initiate hemodialysis (7% to 11%; P = .015), and had greater mortality (7% to 14%; P = .001).

In all, 212 patients reported increased alcohol intake, 161 reported little change over the past year, and 253 said they were abstinent. MELD-Na scores were highest in the increased group (27), compared with the unchanged group (24) and abstinent group (23) (P = .001).
 

More robust support needed

“This highlights that the increase in alcohol use seems to be associated with higher rates of more severe alcoholic hepatitis, and we are going to need to all be aware of and intervene in these individuals, and try to not only make health care more accessible, but help those with alcohol use disorder to reengage in some support systems [and] harm-reduction measures, to try to reduce the number of these episodes of admissions with severe alcoholic hepatitis,” said Paul Kwo, MD, who comoderated the session. Dr. Kwo is a professor of medicine at Stanford (Calif.) University.

Dr. Kwo suggested that the pandemic has presented dual challenges to patients with alcohol-related liver disease. One is that hospitals have filled up because of an influx of COVID-19 cases, which makes it hard for them to compete for limited resources. The other is that lockdowns and social interruptions may have interfered with the support systems that normally help them to keep sober and maintain health care. “The pandemic really disrupted everybody’s ecosystem substantially, and some of these individuals, as their ecosystems crumble, they don’t have other resources to engage in care, and then they present with far more advanced comorbidities than we might have seen prior to the pandemic,” said Dr. Kwo.

The findings underscore at least one lesson that can be drawn from the pandemic. “We now know that we have to develop more robust systems to provide support for all of these individuals,” said Dr. Kwo.

Comoderator Patricia D. Jones, MD, agreed, and expressed optimism. “We were forced develop more remote or virtual networks, so I think there are a lot of people that are taking advantage maybe of virtual [Alcoholics Anonymous], and that wasn’t something that they necessarily did [before the pandemic]. And so at least we’ve developed some parallel systems that hopefully people will benefit from,” said Dr. Jones, who is an assistant professor of medicine at the University of Miami.

She suggested that physicians should make inquiries about patients with alcohol-related liver disease and their social situations, and might consider trying to connect them to a social worker if called for. “I think that really speaking to the person about where they are would be beneficial,” said Dr. Jones.

Dr. Sobotka, Dr. Jain, Dr. Kwo, and Dr. Jones have no relevant financial disclosures.

LAS VEGAS – Over the course of the COVID-19 pandemic, alcohol-related liver disease has increased in severity, a finding that is likely related to higher consumption of alcohol and reduced care. The difference was notable in higher Model for End-Stage Liver Disease–sodium (MELD-Na) scores, more signs of hepatic decompensation, and higher mortality rates.

“Alcohol consumption during the COVID-19 pandemic led to increased morbidity and mortality, specifically in patients that already had underlying liver disease. The importance of alcohol cessation, counseling, and close physician monitoring is emphasized, given continued or relapsed alcohol consumption can significantly affect quality of life, life expectancy, and liver transplantation candidacy,” research team member Lindsay A. Sobotka, DO, said in an interview. Dr. Sobotka is an assistant professor of gastroenterology, hepatology, and nutrition at the Ohio State University Wexner Medical Center, Columbus.

The research was presented by Ayushi Jain, MD, at the annual meeting of the American College of Gastroenterology. Dr. Jain is a resident at the Ohio State University Wexner Medical Center.

Dr. Jain noted that alcohol sales have gone up during the pandemic, with monthly sales up 14%-44% between February and September 2020, compared with the same months in previous years.
 

Decompensation rates rose

The researchers analyzed data from patients with alcoholic cirrhosis or alcoholic hepatitis who were seen at the Ohio State University Medical Center between March and August 2019, and between March and August 2020.

alenkadr/Thinkstock

During the pandemic, the number of hospital admissions nearly doubled among alcoholic hepatitis patients (86 to 162), but declined slightly among patients with alcoholic cirrhosis (613 to 528), possibly because of efforts to manage decompensation and avoid hospitalizations during the pandemic, according to Dr. Jain. In total, 4 of 162 patients with alcoholic hepatitis and 14 of 528 patients with alcoholic cirrhosis had COVID-19 at the time of admission.

Higher mortality rates were seen during the pandemic, although this was only significant for alcoholic cirrhosis: 14.8% versus 7% for alcoholic hepatitis (P = .06) and 13.5% versus 7.4% for alcoholic cirrhosis (P = .001).

Among those with alcoholic hepatitis, there was no significant change in median Maddrey’s Discriminant Function during the pandemic (P = .51), but the researchers noted a significant decrease in steroid use, from 27 patients to 23 (P = .001). “This may be due to a statistically significant increase in GI bleeds and renal dysfunction that we noted during the pandemic,” said Dr. Jain.

Hepatic decompensation and critical care needs increased among patients admitted with alcoholic hepatitis, including hepatic encephalopathy (P = .037), gastrointestinal bleeding (P = .01), a need for increased oxygen (P = .024), vasopressor support (P = .005), and initiation of hemodialysis (P = .007). The median highest MELD-Na score during admission was also higher during the pandemic (24 vs. 23, P = .04).

Patients with alcoholic cirrhosis had greater decompensation as measured by ascites (P = .01), therapeutic paracentesis (P = .04), titration of diuretics (P = .005), acute kidney injury (P = .005), hepatorenal syndrome (P = .002), and spontaneous bacterial peritonitis (P = .04). They also had greater need for vasopressor support (9% to 14%; P = .006), were more likely to initiate hemodialysis (7% to 11%; P = .015), and had greater mortality (7% to 14%; P = .001).

In all, 212 patients reported increased alcohol intake, 161 reported little change over the past year, and 253 said they were abstinent. MELD-Na scores were highest in the increased group (27), compared with the unchanged group (24) and abstinent group (23) (P = .001).
 

More robust support needed

“This highlights that the increase in alcohol use seems to be associated with higher rates of more severe alcoholic hepatitis, and we are going to need to all be aware of and intervene in these individuals, and try to not only make health care more accessible, but help those with alcohol use disorder to reengage in some support systems [and] harm-reduction measures, to try to reduce the number of these episodes of admissions with severe alcoholic hepatitis,” said Paul Kwo, MD, who comoderated the session. Dr. Kwo is a professor of medicine at Stanford (Calif.) University.

Dr. Kwo suggested that the pandemic has presented dual challenges to patients with alcohol-related liver disease. One is that hospitals have filled up because of an influx of COVID-19 cases, which makes it hard for them to compete for limited resources. The other is that lockdowns and social interruptions may have interfered with the support systems that normally help them to keep sober and maintain health care. “The pandemic really disrupted everybody’s ecosystem substantially, and some of these individuals, as their ecosystems crumble, they don’t have other resources to engage in care, and then they present with far more advanced comorbidities than we might have seen prior to the pandemic,” said Dr. Kwo.

The findings underscore at least one lesson that can be drawn from the pandemic. “We now know that we have to develop more robust systems to provide support for all of these individuals,” said Dr. Kwo.

Comoderator Patricia D. Jones, MD, agreed, and expressed optimism. “We were forced develop more remote or virtual networks, so I think there are a lot of people that are taking advantage maybe of virtual [Alcoholics Anonymous], and that wasn’t something that they necessarily did [before the pandemic]. And so at least we’ve developed some parallel systems that hopefully people will benefit from,” said Dr. Jones, who is an assistant professor of medicine at the University of Miami.

She suggested that physicians should make inquiries about patients with alcohol-related liver disease and their social situations, and might consider trying to connect them to a social worker if called for. “I think that really speaking to the person about where they are would be beneficial,” said Dr. Jones.

Dr. Sobotka, Dr. Jain, Dr. Kwo, and Dr. Jones have no relevant financial disclosures.

LAS VEGAS – Over the course of the COVID-19 pandemic, alcohol-related liver disease has increased in severity, a finding that is likely related to higher consumption of alcohol and reduced care. The difference was notable in higher Model for End-Stage Liver Disease–sodium (MELD-Na) scores, more signs of hepatic decompensation, and higher mortality rates.

“Alcohol consumption during the COVID-19 pandemic led to increased morbidity and mortality, specifically in patients that already had underlying liver disease. The importance of alcohol cessation, counseling, and close physician monitoring is emphasized, given continued or relapsed alcohol consumption can significantly affect quality of life, life expectancy, and liver transplantation candidacy,” research team member Lindsay A. Sobotka, DO, said in an interview. Dr. Sobotka is an assistant professor of gastroenterology, hepatology, and nutrition at the Ohio State University Wexner Medical Center, Columbus.

The research was presented by Ayushi Jain, MD, at the annual meeting of the American College of Gastroenterology. Dr. Jain is a resident at the Ohio State University Wexner Medical Center.

Dr. Jain noted that alcohol sales have gone up during the pandemic, with monthly sales up 14%-44% between February and September 2020, compared with the same months in previous years.
 

Decompensation rates rose

The researchers analyzed data from patients with alcoholic cirrhosis or alcoholic hepatitis who were seen at the Ohio State University Medical Center between March and August 2019, and between March and August 2020.

alenkadr/Thinkstock

During the pandemic, the number of hospital admissions nearly doubled among alcoholic hepatitis patients (86 to 162), but declined slightly among patients with alcoholic cirrhosis (613 to 528), possibly because of efforts to manage decompensation and avoid hospitalizations during the pandemic, according to Dr. Jain. In total, 4 of 162 patients with alcoholic hepatitis and 14 of 528 patients with alcoholic cirrhosis had COVID-19 at the time of admission.

Higher mortality rates were seen during the pandemic, although this was only significant for alcoholic cirrhosis: 14.8% versus 7% for alcoholic hepatitis (P = .06) and 13.5% versus 7.4% for alcoholic cirrhosis (P = .001).

Among those with alcoholic hepatitis, there was no significant change in median Maddrey’s Discriminant Function during the pandemic (P = .51), but the researchers noted a significant decrease in steroid use, from 27 patients to 23 (P = .001). “This may be due to a statistically significant increase in GI bleeds and renal dysfunction that we noted during the pandemic,” said Dr. Jain.

Hepatic decompensation and critical care needs increased among patients admitted with alcoholic hepatitis, including hepatic encephalopathy (P = .037), gastrointestinal bleeding (P = .01), a need for increased oxygen (P = .024), vasopressor support (P = .005), and initiation of hemodialysis (P = .007). The median highest MELD-Na score during admission was also higher during the pandemic (24 vs. 23, P = .04).

Patients with alcoholic cirrhosis had greater decompensation as measured by ascites (P = .01), therapeutic paracentesis (P = .04), titration of diuretics (P = .005), acute kidney injury (P = .005), hepatorenal syndrome (P = .002), and spontaneous bacterial peritonitis (P = .04). They also had greater need for vasopressor support (9% to 14%; P = .006), were more likely to initiate hemodialysis (7% to 11%; P = .015), and had greater mortality (7% to 14%; P = .001).

In all, 212 patients reported increased alcohol intake, 161 reported little change over the past year, and 253 said they were abstinent. MELD-Na scores were highest in the increased group (27), compared with the unchanged group (24) and abstinent group (23) (P = .001).
 

More robust support needed

“This highlights that the increase in alcohol use seems to be associated with higher rates of more severe alcoholic hepatitis, and we are going to need to all be aware of and intervene in these individuals, and try to not only make health care more accessible, but help those with alcohol use disorder to reengage in some support systems [and] harm-reduction measures, to try to reduce the number of these episodes of admissions with severe alcoholic hepatitis,” said Paul Kwo, MD, who comoderated the session. Dr. Kwo is a professor of medicine at Stanford (Calif.) University.

Dr. Kwo suggested that the pandemic has presented dual challenges to patients with alcohol-related liver disease. One is that hospitals have filled up because of an influx of COVID-19 cases, which makes it hard for them to compete for limited resources. The other is that lockdowns and social interruptions may have interfered with the support systems that normally help them to keep sober and maintain health care. “The pandemic really disrupted everybody’s ecosystem substantially, and some of these individuals, as their ecosystems crumble, they don’t have other resources to engage in care, and then they present with far more advanced comorbidities than we might have seen prior to the pandemic,” said Dr. Kwo.

The findings underscore at least one lesson that can be drawn from the pandemic. “We now know that we have to develop more robust systems to provide support for all of these individuals,” said Dr. Kwo.

Comoderator Patricia D. Jones, MD, agreed, and expressed optimism. “We were forced develop more remote or virtual networks, so I think there are a lot of people that are taking advantage maybe of virtual [Alcoholics Anonymous], and that wasn’t something that they necessarily did [before the pandemic]. And so at least we’ve developed some parallel systems that hopefully people will benefit from,” said Dr. Jones, who is an assistant professor of medicine at the University of Miami.

She suggested that physicians should make inquiries about patients with alcohol-related liver disease and their social situations, and might consider trying to connect them to a social worker if called for. “I think that really speaking to the person about where they are would be beneficial,” said Dr. Jones.

Dr. Sobotka, Dr. Jain, Dr. Kwo, and Dr. Jones have no relevant financial disclosures.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

The MAVMET study, the first randomized controlled trial of maraviroc (Selzentry) with or without metformin, failed to reduce liver fat in people living with HIV and nonalcoholic fatty liver disease compared with placebo – and in some cases, prolonged use actually increased liver fat.

And that means clinicians like Yvonne Gilleece, MB BCh, who was not involved in the study but does run a liver clinic in England for people living with HIV, are returning to the one intervention proven to work. “As yet, the only thing that is proven to have a very positive effect that is published is weight loss,” said Dr. Gilleece, who runs the clinic at Brighton and Sussex University Hospital. “You don’t put someone on these particular drugs, particularly this combination, easily. MAVMET has really demonstrated that, actually, it’s not effective, and it’s not particularly beneficial to patients.”

The MAVMET trial data was presented at the 18th European AIDS Conference,

There was good reason to think maraviroc might work. A 2018 study in the journal Hepatology found that one of maraviroc’s molecular cousins, cenicriviroc, significantly reduced fibrosis in people with NAFLD. Dr. Gilleece is co-investigator of another study of maraviroc in NAFLD, the HEPMARC trial, which is wrapping up now. In addition to those studies, there are other potential treatments in ongoing trials, including semaglutide, which is being studied in the United States under the study name SLIM LIVER.

MAVMET enrolled 90 people living with HIV from six clinical sites in London who were 35 or older and who had at least one marker for NAFLD, such as abnormal liver lab results. But 70% qualified via imaging- and/or biopsy-confirmed NAFLD. Almost all participants (93%) were men and 81% were White. The trial excluded people who were pregnant or breastfeeding. The median age was 52, and the participants met the criteria for overweight but not obesity, with a median BMI of 28.

In other words, participants generally had fatty livers without the inflammation that characterizes the more aggressive nonalcoholic steatohepatitis (NASH). Clinicians can’t yet differentiate between those who will continue to have asymptomatic fatty liver and those who will progress to NASH and potentially need a liver transplant.

All people living with HIV in the trial had undetectable viral loads and were on HIV treatment. Nearly 1 in 5 (19%) were using a treatment regimen containing tenofovir alafenamide (TAF), which has been associated with weight gain. Nearly half were on integrase strand inhibitors.

Investigators divided the participants up into four groups: 24 people stayed on their HIV treatment and added nothing else; 23 people took maraviroc only; 21 took metformin only; and the final group took both maraviroc and metformin. Across groups, liver fat at baseline was 8.9%, and 78% had mild hepatic steatosis.

After taking the medications for 48 weeks, participants returned to clinic to be scanned via MRI proton density fat fraction (MRI-PDFF), which has been found to successfully measure liver fat. However, because of the COVID-19 pandemic, 20 of the 83 people who returned to the clinic came later than 48 weeks after the trial began.

When investigators looked at the results, they didn’t see what they hypothesized, said Sarah Pett, professor of infectious diseases at University College, London: The scatter plot graph of change in weight looked, well, scattershot: People who didn’t take any additional treatment sometimes lost more liver fat than those on treatment. In fact, the mean liver fat percentage rose by 2.2% in the maraviroc group, 1.3% in the metformin group, and 0.8% in the combination group. The control group saw an increase of 1.4% – meaning that there was no difference between the change in fat between those on treatment and those not.

What’s more, those who had delayed scans – and stayed on their treatment for a median of an additional 16 weeks – saw their liver fat increase even more.

In an interview, Dr. Pett called the results “disappointing.” “The numbers are quite small, but we still didn’t expect this,” she said. “It’s not explained by lockdown weight gain, although we still have to look in detail at how alcohol consumption could have contributed.”

There were also some limits to what the design of this particular trial could tell the researchers. For instance, nearly half of the participants in the maraviroc group, a third of the people in the metformin group, and 36% of those in the combination group had hepatic steatosis grades of 0, meaning that their livers were healthy. And MRI-PDFF becomes less reliable at that level.

“One of the regrets is that perhaps we should have done FibroScan [ultrasound], as well,” Dr. Pett said. The consequence is that the study may have undercounted the fat level by using MRI-PFDD.

“This suggests that the surrogate markers of NAFLD used in MAVMET were not very sensitive to those with a higher percentage of fat,” Dr. Pett said during her presentation. “We were really trying to be pragmatic and not require an MRI at screening.”

Whatever the case, she said that the failure of this particular treatment just highlights the growing need to look more seriously, and more collaboratively, at fat and liver health in people living with HIV.

“We need to really focus on setting up large cohorts of people living with HIV to look in a rigorous way at weight gain, changes in waist circumference, ectopic fat, capture fatty liver disease index scores, and cardiovascular risk, to acquire some longitudinal data,” she said. “And [we need to] join with our fellow researchers in overweight and obesity medicine and hepatology to make sure that people living with HIV are included in new treatments for NASH, as several large RCTs have excluded [people living with HIV].”

From Dr. Gilleece’s perspective, it also just speaks to how far the field has to go in identifying those with asymptomatic fatty livers from those who will progress to fibrosis and potentially need liver transplants.

“MAVMET shows the difficulty in managing NAFLD,” she said. “It seems quite an innocuous disease, because for the majority of people it’s not going to cause a problem in their lifetime. But the reality is, for some it will, and we don’t really know how to treat it.”

Dr. Gilleece has disclosed no relevant financial relationships. Dr. Pett reported receiving funding for trials from Gilead Sciences and Janssen-Cilag. ViiV Healthcare funded the MAVMET trial.

A version of this article first appeared on Medscape.com.

The MAVMET study, the first randomized controlled trial of maraviroc (Selzentry) with or without metformin, failed to reduce liver fat in people living with HIV and nonalcoholic fatty liver disease compared with placebo – and in some cases, prolonged use actually increased liver fat.

And that means clinicians like Yvonne Gilleece, MB BCh, who was not involved in the study but does run a liver clinic in England for people living with HIV, are returning to the one intervention proven to work. “As yet, the only thing that is proven to have a very positive effect that is published is weight loss,” said Dr. Gilleece, who runs the clinic at Brighton and Sussex University Hospital. “You don’t put someone on these particular drugs, particularly this combination, easily. MAVMET has really demonstrated that, actually, it’s not effective, and it’s not particularly beneficial to patients.”

The MAVMET trial data was presented at the 18th European AIDS Conference,

There was good reason to think maraviroc might work. A 2018 study in the journal Hepatology found that one of maraviroc’s molecular cousins, cenicriviroc, significantly reduced fibrosis in people with NAFLD. Dr. Gilleece is co-investigator of another study of maraviroc in NAFLD, the HEPMARC trial, which is wrapping up now. In addition to those studies, there are other potential treatments in ongoing trials, including semaglutide, which is being studied in the United States under the study name SLIM LIVER.

MAVMET enrolled 90 people living with HIV from six clinical sites in London who were 35 or older and who had at least one marker for NAFLD, such as abnormal liver lab results. But 70% qualified via imaging- and/or biopsy-confirmed NAFLD. Almost all participants (93%) were men and 81% were White. The trial excluded people who were pregnant or breastfeeding. The median age was 52, and the participants met the criteria for overweight but not obesity, with a median BMI of 28.

In other words, participants generally had fatty livers without the inflammation that characterizes the more aggressive nonalcoholic steatohepatitis (NASH). Clinicians can’t yet differentiate between those who will continue to have asymptomatic fatty liver and those who will progress to NASH and potentially need a liver transplant.

All people living with HIV in the trial had undetectable viral loads and were on HIV treatment. Nearly 1 in 5 (19%) were using a treatment regimen containing tenofovir alafenamide (TAF), which has been associated with weight gain. Nearly half were on integrase strand inhibitors.

Investigators divided the participants up into four groups: 24 people stayed on their HIV treatment and added nothing else; 23 people took maraviroc only; 21 took metformin only; and the final group took both maraviroc and metformin. Across groups, liver fat at baseline was 8.9%, and 78% had mild hepatic steatosis.

After taking the medications for 48 weeks, participants returned to clinic to be scanned via MRI proton density fat fraction (MRI-PDFF), which has been found to successfully measure liver fat. However, because of the COVID-19 pandemic, 20 of the 83 people who returned to the clinic came later than 48 weeks after the trial began.

When investigators looked at the results, they didn’t see what they hypothesized, said Sarah Pett, professor of infectious diseases at University College, London: The scatter plot graph of change in weight looked, well, scattershot: People who didn’t take any additional treatment sometimes lost more liver fat than those on treatment. In fact, the mean liver fat percentage rose by 2.2% in the maraviroc group, 1.3% in the metformin group, and 0.8% in the combination group. The control group saw an increase of 1.4% – meaning that there was no difference between the change in fat between those on treatment and those not.

What’s more, those who had delayed scans – and stayed on their treatment for a median of an additional 16 weeks – saw their liver fat increase even more.

In an interview, Dr. Pett called the results “disappointing.” “The numbers are quite small, but we still didn’t expect this,” she said. “It’s not explained by lockdown weight gain, although we still have to look in detail at how alcohol consumption could have contributed.”

There were also some limits to what the design of this particular trial could tell the researchers. For instance, nearly half of the participants in the maraviroc group, a third of the people in the metformin group, and 36% of those in the combination group had hepatic steatosis grades of 0, meaning that their livers were healthy. And MRI-PDFF becomes less reliable at that level.

“One of the regrets is that perhaps we should have done FibroScan [ultrasound], as well,” Dr. Pett said. The consequence is that the study may have undercounted the fat level by using MRI-PFDD.

“This suggests that the surrogate markers of NAFLD used in MAVMET were not very sensitive to those with a higher percentage of fat,” Dr. Pett said during her presentation. “We were really trying to be pragmatic and not require an MRI at screening.”

Whatever the case, she said that the failure of this particular treatment just highlights the growing need to look more seriously, and more collaboratively, at fat and liver health in people living with HIV.

“We need to really focus on setting up large cohorts of people living with HIV to look in a rigorous way at weight gain, changes in waist circumference, ectopic fat, capture fatty liver disease index scores, and cardiovascular risk, to acquire some longitudinal data,” she said. “And [we need to] join with our fellow researchers in overweight and obesity medicine and hepatology to make sure that people living with HIV are included in new treatments for NASH, as several large RCTs have excluded [people living with HIV].”

From Dr. Gilleece’s perspective, it also just speaks to how far the field has to go in identifying those with asymptomatic fatty livers from those who will progress to fibrosis and potentially need liver transplants.

“MAVMET shows the difficulty in managing NAFLD,” she said. “It seems quite an innocuous disease, because for the majority of people it’s not going to cause a problem in their lifetime. But the reality is, for some it will, and we don’t really know how to treat it.”

Dr. Gilleece has disclosed no relevant financial relationships. Dr. Pett reported receiving funding for trials from Gilead Sciences and Janssen-Cilag. ViiV Healthcare funded the MAVMET trial.

A version of this article first appeared on Medscape.com.

The MAVMET study, the first randomized controlled trial of maraviroc (Selzentry) with or without metformin, failed to reduce liver fat in people living with HIV and nonalcoholic fatty liver disease compared with placebo – and in some cases, prolonged use actually increased liver fat.

And that means clinicians like Yvonne Gilleece, MB BCh, who was not involved in the study but does run a liver clinic in England for people living with HIV, are returning to the one intervention proven to work. “As yet, the only thing that is proven to have a very positive effect that is published is weight loss,” said Dr. Gilleece, who runs the clinic at Brighton and Sussex University Hospital. “You don’t put someone on these particular drugs, particularly this combination, easily. MAVMET has really demonstrated that, actually, it’s not effective, and it’s not particularly beneficial to patients.”

The MAVMET trial data was presented at the 18th European AIDS Conference,

There was good reason to think maraviroc might work. A 2018 study in the journal Hepatology found that one of maraviroc’s molecular cousins, cenicriviroc, significantly reduced fibrosis in people with NAFLD. Dr. Gilleece is co-investigator of another study of maraviroc in NAFLD, the HEPMARC trial, which is wrapping up now. In addition to those studies, there are other potential treatments in ongoing trials, including semaglutide, which is being studied in the United States under the study name SLIM LIVER.

MAVMET enrolled 90 people living with HIV from six clinical sites in London who were 35 or older and who had at least one marker for NAFLD, such as abnormal liver lab results. But 70% qualified via imaging- and/or biopsy-confirmed NAFLD. Almost all participants (93%) were men and 81% were White. The trial excluded people who were pregnant or breastfeeding. The median age was 52, and the participants met the criteria for overweight but not obesity, with a median BMI of 28.

In other words, participants generally had fatty livers without the inflammation that characterizes the more aggressive nonalcoholic steatohepatitis (NASH). Clinicians can’t yet differentiate between those who will continue to have asymptomatic fatty liver and those who will progress to NASH and potentially need a liver transplant.

All people living with HIV in the trial had undetectable viral loads and were on HIV treatment. Nearly 1 in 5 (19%) were using a treatment regimen containing tenofovir alafenamide (TAF), which has been associated with weight gain. Nearly half were on integrase strand inhibitors.

Investigators divided the participants up into four groups: 24 people stayed on their HIV treatment and added nothing else; 23 people took maraviroc only; 21 took metformin only; and the final group took both maraviroc and metformin. Across groups, liver fat at baseline was 8.9%, and 78% had mild hepatic steatosis.

After taking the medications for 48 weeks, participants returned to clinic to be scanned via MRI proton density fat fraction (MRI-PDFF), which has been found to successfully measure liver fat. However, because of the COVID-19 pandemic, 20 of the 83 people who returned to the clinic came later than 48 weeks after the trial began.

When investigators looked at the results, they didn’t see what they hypothesized, said Sarah Pett, professor of infectious diseases at University College, London: The scatter plot graph of change in weight looked, well, scattershot: People who didn’t take any additional treatment sometimes lost more liver fat than those on treatment. In fact, the mean liver fat percentage rose by 2.2% in the maraviroc group, 1.3% in the metformin group, and 0.8% in the combination group. The control group saw an increase of 1.4% – meaning that there was no difference between the change in fat between those on treatment and those not.

What’s more, those who had delayed scans – and stayed on their treatment for a median of an additional 16 weeks – saw their liver fat increase even more.

In an interview, Dr. Pett called the results “disappointing.” “The numbers are quite small, but we still didn’t expect this,” she said. “It’s not explained by lockdown weight gain, although we still have to look in detail at how alcohol consumption could have contributed.”

There were also some limits to what the design of this particular trial could tell the researchers. For instance, nearly half of the participants in the maraviroc group, a third of the people in the metformin group, and 36% of those in the combination group had hepatic steatosis grades of 0, meaning that their livers were healthy. And MRI-PDFF becomes less reliable at that level.

“One of the regrets is that perhaps we should have done FibroScan [ultrasound], as well,” Dr. Pett said. The consequence is that the study may have undercounted the fat level by using MRI-PFDD.

“This suggests that the surrogate markers of NAFLD used in MAVMET were not very sensitive to those with a higher percentage of fat,” Dr. Pett said during her presentation. “We were really trying to be pragmatic and not require an MRI at screening.”

Whatever the case, she said that the failure of this particular treatment just highlights the growing need to look more seriously, and more collaboratively, at fat and liver health in people living with HIV.

“We need to really focus on setting up large cohorts of people living with HIV to look in a rigorous way at weight gain, changes in waist circumference, ectopic fat, capture fatty liver disease index scores, and cardiovascular risk, to acquire some longitudinal data,” she said. “And [we need to] join with our fellow researchers in overweight and obesity medicine and hepatology to make sure that people living with HIV are included in new treatments for NASH, as several large RCTs have excluded [people living with HIV].”

From Dr. Gilleece’s perspective, it also just speaks to how far the field has to go in identifying those with asymptomatic fatty livers from those who will progress to fibrosis and potentially need liver transplants.

“MAVMET shows the difficulty in managing NAFLD,” she said. “It seems quite an innocuous disease, because for the majority of people it’s not going to cause a problem in their lifetime. But the reality is, for some it will, and we don’t really know how to treat it.”

Dr. Gilleece has disclosed no relevant financial relationships. Dr. Pett reported receiving funding for trials from Gilead Sciences and Janssen-Cilag. ViiV Healthcare funded the MAVMET trial.

A version of this article first appeared on Medscape.com.