William F. Balistreri, MD

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

This spring, global health advisories have been issued regarding an alarming – and as-yet unexplained – uptick of hepatitis in children. Currently, over 200 cases have been reported worldwide, a relatively small amount that nonetheless belies a considerable toll, including several deaths and the need for liver transplantation in a number of patients. The long-term implications are not yet known. Global health officials are working hard to determine a cause, with many focusing on the underlying cases of adenovirus that several patients have presented with.

To understand more, this news organization reached out to frequent contributor William F. Balistreri, MD, a specialist in pediatric gastroenterology and hepatology at Cincinnati Children’s Hospital Medical Center, where to date they have treated at least six cases of hepatitis in otherwise healthy young children, with one requiring a liver transplant. Dr. Balistreri discussed how the outbreak has developed to date, his advice to hepatologists and pediatricians, and where we stand now in this fast-evolving crisis.
 

Tracing the outbreak in the United States

How has this outbreak played out thus far in the United States, and what have we learned from that?

Sporadic reports of cases in multiple states are appearing. On April 21, 2022, a health alert was issued by the Centers for Disease Control and Prevention, recommending testing for adenovirus in children with acute hepatitis of an unknown etiology.

Baker and colleagues recently described five children with severe hepatitis and adenovirus viremia who were admitted to a children’s hospital in Birmingham, Ala., between October and November 2021. In collaboration with local and state officials, the CDC reviewed clinical records in order to identify patients with hepatitis and concomitant adenovirus infection, confirmed by polymerase chain reaction (PCR).

By February 2022, a total of nine children were identified. There was no epidemiologic linkage among these nine patients; all were well and immunocompetent. The prodromal features were somewhat similar: upper respiratory infection, vomiting, diarrhea, and jaundice. All children had markedly elevated aminotransferase levels and variably elevated total bilirubin levels. Extensive workup for other causes of acute liver injury (for example, other viruses, toxins/drugs, metabolic and autoimmune diseases) was unrevealing.

Specifically, none had documented SARS-CoV-2 infection. However, in all nine children, adenovirus was detected in whole blood samples. In the six children who underwent liver biopsy, there was nonspecific hepatitis, without inclusions or immunohistochemical detection of viral agents, including adenovirus. In three patients, the liver injury progressed, and despite the administration of antiviral agents, two underwent liver transplantation.

Baker and colleagues also suggested that measurement of adenovirus titers in whole blood (rather than plasma) may be more sensitive.

The CDC has recommended monitoring and surveillance in order to more fully understand the nature of the illness.
 

European and global cases

What has been the experience with this in Europe and elsewhere globally?

In mid-to-late 2021, several cases of acute hepatitis of unknown nature in children were identified in Europe. Public health officials in the United Kingdom investigated the high number of cases seen in children from England, Scotland, and Wales. They noted approximately 60 cases in England, mostly in children aged 2-5 years.

Marsh and colleagues reported a cluster of cases of severe hepatitis of unknown origin in Scotland affecting children aged 3-5 years. In Scotland, admitted cases were routinely tested for SARS-CoV-2. Of the 13 cases, five had a recent positive test. They discussed the possibility of increased severity of disease following infection with Omicron BA.2 (the dominant SARS-CoV-2 virus circulating in Scotland at that time) or infection by an uncharacterized SARS-CoV-2 variant. None of the children had been vaccinated for SARS-CoV-2.

On April 15, 2022, the World Health Organization Disease Outbreak News published a report of acute hepatitis of unknown etiology occurring in Great Britain and Northern Ireland. By April 21, 2022, 169 cases of acute hepatitis of unknown origin in children younger than 16 years had been reported from 11 countries in the WHO European region and 1 country in the WHO region of the Americas. Approximately 10% required a liver transplantation and at least one death was reported.

What has been established about the possible connection to the SARS-CoV-2 virus, particularly as it relates to coinfection with adenovirus?

In that WHO report of 169 cases, adenovirus was detected in 74 and SARS-CoV-2 in 20. Of note, 19 cases had a SARS-CoV-2 and adenovirus coinfection.

The report’s authors emphasized that, “while adenovirus is a possible hypothesis, investigations are ongoing for the causative agent.” The authors questioned whether this represents a continuing increase in cases of hepatitis or reflects an increased awareness.

The stated priority of the WHO is to determine the cause and to further refine control and prevention actions.

Given the worldwide nature of this outbreak, have connections between any of the cases been made yet?

Not to my knowledge.
 

What clinicians need to know

What makes this outbreak of hepatitis cases particularly concerning to the health care community, in comparison to other childhood diseases that occur globally? Is it because the cause is unknown or is it for other reasons?

It may be a collective heightened concern following the emergence of COVID.

Whether it represents a new form of acute hepatitis, a continuing increase in cases of hepatitis, or an increased awareness because of the well-publicized alerts remains to be determined. We certainly saw “viral-induced hepatitis” in the past.

Young patients may first be brought to pediatricians. What, if anything, should pediatricians be on the lookout for? Do they need a heightened index of suspicion or are the cases too rare at this point?

An awareness of the “outbreak” may allow the clinician to extend the typical workup of a child presenting with an undefined, presumably viral illness.

In the cases reported, the prodromal and/or presenting symptoms were respiratory and gastrointestinal in nature. They include nausea, vomiting, diarrhea, and abdominal pain.

Specifically, if jaundice and/or scleral icterus is noted, then hepatitis should be suspected.

Should pediatricians consider early referral to a pediatric gastroenterologist or hepatologist?

Yes, because there is the potential for finding a treatable cause (for example, autoimmune hepatitis or a specific metabolic disease) in a patient presenting in this fashion.

In addition, the potential for progression to acute liver failure (with coagulopathy and encephalopathy), albeit rare, exists.

What do hepatologists need to be doing when presented with suspected cases?

The typical clinical picture holds and the workup is standard. The one new key, given the recent data, is to test for adenovirus, using whole blood versus plasma, as the former may be more sensitive.

In addition, it is prudent to check for SARS-CoV-2 by PCR.

What are the major questions that remain and that you’d like to see elucidated going forward?

There are many. Is this a new disease? A new variant of adenovirus? A synergy or susceptibility related to SARS-CoV-2? Is it related to a variant of SARS-CoV-2? Is it triggering an adverse immune response? Are there other epigenetic factors involved? And finally, is this an increase, or is it related to a collective heightened concern following the pandemic?

Dr. Balistreri is the Dorothy M.M. Kersten Professor of Pediatrics, director emeritus of the Pediatric Liver Care Center, medical director emeritus of liver transplantation, and professor at the University of Cincinnati; he is also with the department of pediatrics at Cincinnati Children’s Hospital Medical Center.

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

While evaluating an adolescent who had endured a several-day history of vomiting and diarrhea, I mentioned the likelihood of a viral causation, including SARS-CoV-2 infection. His well-informed mother responded, “He has no respiratory symptoms. Does COVID cause GI disease?”

Indeed, not only is the gastrointestinal tract a potential portal of entry of the virus but it may well be the site of mediation of both local and remote injury and thus a harbinger of more severe clinical phenotypes.

As we learn more about the clinical spectrum of COVID, it is becoming increasingly clear that certain features of GI tract involvement may allow us to establish a timeline of the clinical course and perhaps predict the outcome.
 

The GI tract’s involvement isn’t surprising

The ways in which the GI tract serves as a target organ of SARS-CoV-2 have been postulated in the literature. In part, this is related to the presence of abundant receptors for SARS-CoV-2 cell binding and internalization. The virus uses angiotensin-converting enzyme 2 receptors to enter various cells. These receptors are highly expressed on not only lung cells but also enterocytes. Binding of SARS-CoV-2 to ACE2 receptors allows GI involvement, leading to microscopic mucosal inflammation, increased permeability, and altered intestinal absorption.

The clinical GI manifestations of this include anorexia, nausea, vomiting, diarrhea, and abdominal pain, which may be the earliest, or sole, symptoms of COVID-19, often noted before the onset of fever or respiratory symptoms. In fact, John Ong, MBBS, and colleagues, in a discussion about patients with primary GI SARS-CoV-2 infection and symptoms, use the term “GI-COVID.”
 

Clinical course of GI manifestations

After SARS-CoV-2 exposure, adults most commonly present with respiratory symptoms, with GI symptoms reported in 10%-15% of cases. However, the overall incidence of GI involvement during SARS-CoV-2 infection varies according to age, with children more likely than adults to manifest intestinal symptoms.

There are also differences in incidence reported when comparing hospitalized with nonhospitalized individuals. In early reports from the onset of the COVID-19 pandemic, 11%-43% of hospitalized adult patients manifested GI symptoms. Of note, the presence of GI symptoms was associated with more severe disease and thus predictive of outcomes in those admitted to hospitals.

In a multicenter study that assessed pediatric inpatients with COVID-19, GI manifestations were present in 57% of patients and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had a higher risk for pediatric intensive care unit admission. Patients admitted to the PICU also had higher serum C-reactive protein and aspartate aminotransferase values.
 

Emerging data on MIS-C

In previously healthy children and adolescents, the severe, life-threatening complication of multisystem inflammatory syndrome in children (MIS-C) may present 2-6 weeks after acute infection with SARS-CoV-2. MIS-C appears to be an immune activation syndrome and is presumed to be the delayed immunologic sequelae of mild/asymptomatic SARS-CoV-2 infection. This response manifests as hyperinflammation in conjunction with a peak in antibody production a few weeks later.

One report of 186 children with MIS-C in the United States noted that the involved organ system included the GI tract in 92%, followed by cardiovascular in 80%, hematologic in 76%, mucocutaneous in 74%, and respiratory in 70%. Affected children were hospitalized for a median of 7 days, with 80% requiring intensive care, 20% receiving mechanical ventilation, and 48% receiving vasoactive support; 2% died. In a similar study of patients hospitalized in New York, 88% had GI symptoms (abdominal pain, vomiting, and/or diarrhea). A retrospective chart review of patients with MIS-C found that the majority had GI symptoms with any portion of the GI tract potentially involved, but ileal and colonic inflammation predominated.

Elizabeth Whittaker, MD, and colleagues described the clinical characteristics of children in eight hospitals in England who met criteria for MIS-C that were temporally associated with SARS-CoV-2. At presentation, all of the patients manifested fever and nonspecific GI symptoms, including vomiting (45%), abdominal pain (53%), and diarrhea (52%). During hospitalization, 50% developed shock with evidence of myocardial dysfunction.

Ermias D. Belay, MD, and colleagues described the clinical characteristics of a large cohort of patients with MIS-C that were reported to the U.S. Centers for Disease Control and Prevention. Of 1,733 patients identified, GI symptoms were reported in 53%-67%. Over half developed hypotension or shock and were admitted for intensive care. Younger children more frequently presented with abdominal pain in contrast with adolescents, who more frequently manifest respiratory symptoms.

In a multicenter retrospective study of Italian children with COVID-19 that was conducted from the onset of the pandemic to early 2021, GI symptoms were noted in 38%. These manifestations were mild and self-limiting, comparable to other viral intestinal infections. However, a subset of children (9.5%) had severe GI manifestations of MIS-C, defined as a medical and/or radiologic diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, abdominal fluid collection, or diffuse adenomesenteritis requiring surgical consultation. Overall, 42% of this group underwent surgery. The authors noted that the clinical presentation of abdominal pain, lymphopenia, and increased C-reactive protein and ferritin levels were associated with a 9- to 30-fold increased probability of these severe sequelae. In addition, the severity of the GI manifestations was correlated with age (5-10 years: overall response, 8.33; >10 years: OR, 6.37). Again, the presence of GI symptoms was a harbinger of hospitalization and PICU admission.

Given that GI symptoms are a common presentation of MIS-C, its diagnosis may be delayed as clinicians first consider other GI/viral infections, inflammatory bowel disease, or Kawasaki disease. Prompt identification of GI involvement and awareness of the potential outcomes may guide the management and improve the outcome.

These studies provide a clear picture of the differential presenting features of COVID-19 and MIS-C. Although there may be other environmental/genetic factors that govern the incidence, impact, and manifestations, COVID’s status as an ongoing pandemic gives these observations worldwide relevance. This is evident in a recent report documenting pronounced GI symptoms in African children with COVID-19.

It should be noted, however, that the published data cited here reflect the impact of the initial variants of SARS-CoV-2. The GI binding, effects, and aftermath of infection with the Delta and Omicron variants is not yet known.
 

Cause and effect, or simply coincidental?

Some insight into MIS-C pathogenesis was provided by Lael M. Yonker, MD, and colleagues in their analysis of biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. They demonstrated that in children with MIS-C the prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. They were then able to decrease plasma SARS-CoV-2 spike antigen levels and inflammatory markers, with resulting clinical improvement after administration of larazotide, a zonulin antagonist.

These observations regarding the potential mechanism and triggers of MIS-C may offer biomarkers for early detection and/or strategies for prevention and treatment of MIS-C.
 

Bottom line

The GI tract is the target of an immune-mediated inflammatory response that is triggered by SARS-CoV-2, with MIS-C being the major manifestation of the resultant high degree of inflammation. These observations will allow an increased awareness of nonrespiratory symptoms of SARS-CoV-2 infection by clinicians working in emergency departments and primary care settings.

Clues that may enhance the ability of pediatric clinicians to recognize the potential for severe GI involvement include the occurrence of abdominal pain, leukopenia, and elevated inflammatory markers. Their presence should raise suspicion of MIS-C and lead to early evaluation.

Of note, COVID-19 mRNA vaccination is associated with a lower incidence of MIS-C in adolescents. This underscores the importance of COVID vaccination for all eligible children. Yet, we clearly have our work cut out for us. Of 107 children with MIS-C who were hospitalized in France, 31% were adolescents eligible for vaccination; however, none had been fully vaccinated. At the end of 2021, CDC data noted that less than 1% of vaccine-eligible children (12-17 years) were fully vaccinated.

The Pfizer-BioNTech vaccine is now authorized for receipt by children aged 5-11 years, the age group that is at highest risk for MIS-C. However, despite the approval of vaccines for these younger children, there is limited access in some parts of the United States at a time of rising incidence.

We look forward to broad availability of pediatric vaccination strategies. In addition, with the intense focus on safe and effective therapeutics for SARS-CoV-2 infection, we hope to soon have strategies to prevent and/or treat the life-threatening manifestations and long-term consequences of MIS-C. For example, the recently reported central role of the gut microbiota in immunity against SARS-CoV-2 infection offer the possibility that “microbiota modulation” may both reduce GI injury and enhance vaccine efficacy.

Dr. Balistreri has disclosed no relevant financial relationships.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, Pediatric Liver Care Center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology, and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

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

While evaluating an adolescent who had endured a several-day history of vomiting and diarrhea, I mentioned the likelihood of a viral causation, including SARS-CoV-2 infection. His well-informed mother responded, “He has no respiratory symptoms. Does COVID cause GI disease?”

Indeed, not only is the gastrointestinal tract a potential portal of entry of the virus but it may well be the site of mediation of both local and remote injury and thus a harbinger of more severe clinical phenotypes.

As we learn more about the clinical spectrum of COVID, it is becoming increasingly clear that certain features of GI tract involvement may allow us to establish a timeline of the clinical course and perhaps predict the outcome.
 

The GI tract’s involvement isn’t surprising

The ways in which the GI tract serves as a target organ of SARS-CoV-2 have been postulated in the literature. In part, this is related to the presence of abundant receptors for SARS-CoV-2 cell binding and internalization. The virus uses angiotensin-converting enzyme 2 receptors to enter various cells. These receptors are highly expressed on not only lung cells but also enterocytes. Binding of SARS-CoV-2 to ACE2 receptors allows GI involvement, leading to microscopic mucosal inflammation, increased permeability, and altered intestinal absorption.

The clinical GI manifestations of this include anorexia, nausea, vomiting, diarrhea, and abdominal pain, which may be the earliest, or sole, symptoms of COVID-19, often noted before the onset of fever or respiratory symptoms. In fact, John Ong, MBBS, and colleagues, in a discussion about patients with primary GI SARS-CoV-2 infection and symptoms, use the term “GI-COVID.”
 

Clinical course of GI manifestations

After SARS-CoV-2 exposure, adults most commonly present with respiratory symptoms, with GI symptoms reported in 10%-15% of cases. However, the overall incidence of GI involvement during SARS-CoV-2 infection varies according to age, with children more likely than adults to manifest intestinal symptoms.

There are also differences in incidence reported when comparing hospitalized with nonhospitalized individuals. In early reports from the onset of the COVID-19 pandemic, 11%-43% of hospitalized adult patients manifested GI symptoms. Of note, the presence of GI symptoms was associated with more severe disease and thus predictive of outcomes in those admitted to hospitals.

In a multicenter study that assessed pediatric inpatients with COVID-19, GI manifestations were present in 57% of patients and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had a higher risk for pediatric intensive care unit admission. Patients admitted to the PICU also had higher serum C-reactive protein and aspartate aminotransferase values.
 

Emerging data on MIS-C

In previously healthy children and adolescents, the severe, life-threatening complication of multisystem inflammatory syndrome in children (MIS-C) may present 2-6 weeks after acute infection with SARS-CoV-2. MIS-C appears to be an immune activation syndrome and is presumed to be the delayed immunologic sequelae of mild/asymptomatic SARS-CoV-2 infection. This response manifests as hyperinflammation in conjunction with a peak in antibody production a few weeks later.

One report of 186 children with MIS-C in the United States noted that the involved organ system included the GI tract in 92%, followed by cardiovascular in 80%, hematologic in 76%, mucocutaneous in 74%, and respiratory in 70%. Affected children were hospitalized for a median of 7 days, with 80% requiring intensive care, 20% receiving mechanical ventilation, and 48% receiving vasoactive support; 2% died. In a similar study of patients hospitalized in New York, 88% had GI symptoms (abdominal pain, vomiting, and/or diarrhea). A retrospective chart review of patients with MIS-C found that the majority had GI symptoms with any portion of the GI tract potentially involved, but ileal and colonic inflammation predominated.

Elizabeth Whittaker, MD, and colleagues described the clinical characteristics of children in eight hospitals in England who met criteria for MIS-C that were temporally associated with SARS-CoV-2. At presentation, all of the patients manifested fever and nonspecific GI symptoms, including vomiting (45%), abdominal pain (53%), and diarrhea (52%). During hospitalization, 50% developed shock with evidence of myocardial dysfunction.

Ermias D. Belay, MD, and colleagues described the clinical characteristics of a large cohort of patients with MIS-C that were reported to the U.S. Centers for Disease Control and Prevention. Of 1,733 patients identified, GI symptoms were reported in 53%-67%. Over half developed hypotension or shock and were admitted for intensive care. Younger children more frequently presented with abdominal pain in contrast with adolescents, who more frequently manifest respiratory symptoms.

In a multicenter retrospective study of Italian children with COVID-19 that was conducted from the onset of the pandemic to early 2021, GI symptoms were noted in 38%. These manifestations were mild and self-limiting, comparable to other viral intestinal infections. However, a subset of children (9.5%) had severe GI manifestations of MIS-C, defined as a medical and/or radiologic diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, abdominal fluid collection, or diffuse adenomesenteritis requiring surgical consultation. Overall, 42% of this group underwent surgery. The authors noted that the clinical presentation of abdominal pain, lymphopenia, and increased C-reactive protein and ferritin levels were associated with a 9- to 30-fold increased probability of these severe sequelae. In addition, the severity of the GI manifestations was correlated with age (5-10 years: overall response, 8.33; >10 years: OR, 6.37). Again, the presence of GI symptoms was a harbinger of hospitalization and PICU admission.

Given that GI symptoms are a common presentation of MIS-C, its diagnosis may be delayed as clinicians first consider other GI/viral infections, inflammatory bowel disease, or Kawasaki disease. Prompt identification of GI involvement and awareness of the potential outcomes may guide the management and improve the outcome.

These studies provide a clear picture of the differential presenting features of COVID-19 and MIS-C. Although there may be other environmental/genetic factors that govern the incidence, impact, and manifestations, COVID’s status as an ongoing pandemic gives these observations worldwide relevance. This is evident in a recent report documenting pronounced GI symptoms in African children with COVID-19.

It should be noted, however, that the published data cited here reflect the impact of the initial variants of SARS-CoV-2. The GI binding, effects, and aftermath of infection with the Delta and Omicron variants is not yet known.
 

Cause and effect, or simply coincidental?

Some insight into MIS-C pathogenesis was provided by Lael M. Yonker, MD, and colleagues in their analysis of biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. They demonstrated that in children with MIS-C the prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. They were then able to decrease plasma SARS-CoV-2 spike antigen levels and inflammatory markers, with resulting clinical improvement after administration of larazotide, a zonulin antagonist.

These observations regarding the potential mechanism and triggers of MIS-C may offer biomarkers for early detection and/or strategies for prevention and treatment of MIS-C.
 

Bottom line

The GI tract is the target of an immune-mediated inflammatory response that is triggered by SARS-CoV-2, with MIS-C being the major manifestation of the resultant high degree of inflammation. These observations will allow an increased awareness of nonrespiratory symptoms of SARS-CoV-2 infection by clinicians working in emergency departments and primary care settings.

Clues that may enhance the ability of pediatric clinicians to recognize the potential for severe GI involvement include the occurrence of abdominal pain, leukopenia, and elevated inflammatory markers. Their presence should raise suspicion of MIS-C and lead to early evaluation.

Of note, COVID-19 mRNA vaccination is associated with a lower incidence of MIS-C in adolescents. This underscores the importance of COVID vaccination for all eligible children. Yet, we clearly have our work cut out for us. Of 107 children with MIS-C who were hospitalized in France, 31% were adolescents eligible for vaccination; however, none had been fully vaccinated. At the end of 2021, CDC data noted that less than 1% of vaccine-eligible children (12-17 years) were fully vaccinated.

The Pfizer-BioNTech vaccine is now authorized for receipt by children aged 5-11 years, the age group that is at highest risk for MIS-C. However, despite the approval of vaccines for these younger children, there is limited access in some parts of the United States at a time of rising incidence.

We look forward to broad availability of pediatric vaccination strategies. In addition, with the intense focus on safe and effective therapeutics for SARS-CoV-2 infection, we hope to soon have strategies to prevent and/or treat the life-threatening manifestations and long-term consequences of MIS-C. For example, the recently reported central role of the gut microbiota in immunity against SARS-CoV-2 infection offer the possibility that “microbiota modulation” may both reduce GI injury and enhance vaccine efficacy.

Dr. Balistreri has disclosed no relevant financial relationships.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, Pediatric Liver Care Center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology, and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

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

While evaluating an adolescent who had endured a several-day history of vomiting and diarrhea, I mentioned the likelihood of a viral causation, including SARS-CoV-2 infection. His well-informed mother responded, “He has no respiratory symptoms. Does COVID cause GI disease?”

Indeed, not only is the gastrointestinal tract a potential portal of entry of the virus but it may well be the site of mediation of both local and remote injury and thus a harbinger of more severe clinical phenotypes.

As we learn more about the clinical spectrum of COVID, it is becoming increasingly clear that certain features of GI tract involvement may allow us to establish a timeline of the clinical course and perhaps predict the outcome.
 

The GI tract’s involvement isn’t surprising

The ways in which the GI tract serves as a target organ of SARS-CoV-2 have been postulated in the literature. In part, this is related to the presence of abundant receptors for SARS-CoV-2 cell binding and internalization. The virus uses angiotensin-converting enzyme 2 receptors to enter various cells. These receptors are highly expressed on not only lung cells but also enterocytes. Binding of SARS-CoV-2 to ACE2 receptors allows GI involvement, leading to microscopic mucosal inflammation, increased permeability, and altered intestinal absorption.

The clinical GI manifestations of this include anorexia, nausea, vomiting, diarrhea, and abdominal pain, which may be the earliest, or sole, symptoms of COVID-19, often noted before the onset of fever or respiratory symptoms. In fact, John Ong, MBBS, and colleagues, in a discussion about patients with primary GI SARS-CoV-2 infection and symptoms, use the term “GI-COVID.”
 

Clinical course of GI manifestations

After SARS-CoV-2 exposure, adults most commonly present with respiratory symptoms, with GI symptoms reported in 10%-15% of cases. However, the overall incidence of GI involvement during SARS-CoV-2 infection varies according to age, with children more likely than adults to manifest intestinal symptoms.

There are also differences in incidence reported when comparing hospitalized with nonhospitalized individuals. In early reports from the onset of the COVID-19 pandemic, 11%-43% of hospitalized adult patients manifested GI symptoms. Of note, the presence of GI symptoms was associated with more severe disease and thus predictive of outcomes in those admitted to hospitals.

In a multicenter study that assessed pediatric inpatients with COVID-19, GI manifestations were present in 57% of patients and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had a higher risk for pediatric intensive care unit admission. Patients admitted to the PICU also had higher serum C-reactive protein and aspartate aminotransferase values.
 

Emerging data on MIS-C

In previously healthy children and adolescents, the severe, life-threatening complication of multisystem inflammatory syndrome in children (MIS-C) may present 2-6 weeks after acute infection with SARS-CoV-2. MIS-C appears to be an immune activation syndrome and is presumed to be the delayed immunologic sequelae of mild/asymptomatic SARS-CoV-2 infection. This response manifests as hyperinflammation in conjunction with a peak in antibody production a few weeks later.

One report of 186 children with MIS-C in the United States noted that the involved organ system included the GI tract in 92%, followed by cardiovascular in 80%, hematologic in 76%, mucocutaneous in 74%, and respiratory in 70%. Affected children were hospitalized for a median of 7 days, with 80% requiring intensive care, 20% receiving mechanical ventilation, and 48% receiving vasoactive support; 2% died. In a similar study of patients hospitalized in New York, 88% had GI symptoms (abdominal pain, vomiting, and/or diarrhea). A retrospective chart review of patients with MIS-C found that the majority had GI symptoms with any portion of the GI tract potentially involved, but ileal and colonic inflammation predominated.

Elizabeth Whittaker, MD, and colleagues described the clinical characteristics of children in eight hospitals in England who met criteria for MIS-C that were temporally associated with SARS-CoV-2. At presentation, all of the patients manifested fever and nonspecific GI symptoms, including vomiting (45%), abdominal pain (53%), and diarrhea (52%). During hospitalization, 50% developed shock with evidence of myocardial dysfunction.

Ermias D. Belay, MD, and colleagues described the clinical characteristics of a large cohort of patients with MIS-C that were reported to the U.S. Centers for Disease Control and Prevention. Of 1,733 patients identified, GI symptoms were reported in 53%-67%. Over half developed hypotension or shock and were admitted for intensive care. Younger children more frequently presented with abdominal pain in contrast with adolescents, who more frequently manifest respiratory symptoms.

In a multicenter retrospective study of Italian children with COVID-19 that was conducted from the onset of the pandemic to early 2021, GI symptoms were noted in 38%. These manifestations were mild and self-limiting, comparable to other viral intestinal infections. However, a subset of children (9.5%) had severe GI manifestations of MIS-C, defined as a medical and/or radiologic diagnosis of acute abdomen, appendicitis, intussusception, pancreatitis, abdominal fluid collection, or diffuse adenomesenteritis requiring surgical consultation. Overall, 42% of this group underwent surgery. The authors noted that the clinical presentation of abdominal pain, lymphopenia, and increased C-reactive protein and ferritin levels were associated with a 9- to 30-fold increased probability of these severe sequelae. In addition, the severity of the GI manifestations was correlated with age (5-10 years: overall response, 8.33; >10 years: OR, 6.37). Again, the presence of GI symptoms was a harbinger of hospitalization and PICU admission.

Given that GI symptoms are a common presentation of MIS-C, its diagnosis may be delayed as clinicians first consider other GI/viral infections, inflammatory bowel disease, or Kawasaki disease. Prompt identification of GI involvement and awareness of the potential outcomes may guide the management and improve the outcome.

These studies provide a clear picture of the differential presenting features of COVID-19 and MIS-C. Although there may be other environmental/genetic factors that govern the incidence, impact, and manifestations, COVID’s status as an ongoing pandemic gives these observations worldwide relevance. This is evident in a recent report documenting pronounced GI symptoms in African children with COVID-19.

It should be noted, however, that the published data cited here reflect the impact of the initial variants of SARS-CoV-2. The GI binding, effects, and aftermath of infection with the Delta and Omicron variants is not yet known.
 

Cause and effect, or simply coincidental?

Some insight into MIS-C pathogenesis was provided by Lael M. Yonker, MD, and colleagues in their analysis of biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. They demonstrated that in children with MIS-C the prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. They were then able to decrease plasma SARS-CoV-2 spike antigen levels and inflammatory markers, with resulting clinical improvement after administration of larazotide, a zonulin antagonist.

These observations regarding the potential mechanism and triggers of MIS-C may offer biomarkers for early detection and/or strategies for prevention and treatment of MIS-C.
 

Bottom line

The GI tract is the target of an immune-mediated inflammatory response that is triggered by SARS-CoV-2, with MIS-C being the major manifestation of the resultant high degree of inflammation. These observations will allow an increased awareness of nonrespiratory symptoms of SARS-CoV-2 infection by clinicians working in emergency departments and primary care settings.

Clues that may enhance the ability of pediatric clinicians to recognize the potential for severe GI involvement include the occurrence of abdominal pain, leukopenia, and elevated inflammatory markers. Their presence should raise suspicion of MIS-C and lead to early evaluation.

Of note, COVID-19 mRNA vaccination is associated with a lower incidence of MIS-C in adolescents. This underscores the importance of COVID vaccination for all eligible children. Yet, we clearly have our work cut out for us. Of 107 children with MIS-C who were hospitalized in France, 31% were adolescents eligible for vaccination; however, none had been fully vaccinated. At the end of 2021, CDC data noted that less than 1% of vaccine-eligible children (12-17 years) were fully vaccinated.

The Pfizer-BioNTech vaccine is now authorized for receipt by children aged 5-11 years, the age group that is at highest risk for MIS-C. However, despite the approval of vaccines for these younger children, there is limited access in some parts of the United States at a time of rising incidence.

We look forward to broad availability of pediatric vaccination strategies. In addition, with the intense focus on safe and effective therapeutics for SARS-CoV-2 infection, we hope to soon have strategies to prevent and/or treat the life-threatening manifestations and long-term consequences of MIS-C. For example, the recently reported central role of the gut microbiota in immunity against SARS-CoV-2 infection offer the possibility that “microbiota modulation” may both reduce GI injury and enhance vaccine efficacy.

Dr. Balistreri has disclosed no relevant financial relationships.

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, Pediatric Liver Care Center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology, and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. In his spare time, he coaches youth lacrosse.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

Those of us treating nonalcoholic fatty liver disease (NAFLD) often find ourselves having similar conversations with our patients. After diagnosis, our next step is usually describing to them how they can improve their outcomes through a healthy diet and exercise.

Westend61/Getty Images

We can point to the latest data espousing the benefits of moderate weight reduction. The recently released American Gastroenterological Association (AGA) Clinical Practice Update gives us compelling evidence of what can be achieved with specific thresholds of total body weight loss: >5% can decrease hepatic steatosis, >7% potentially leads to resolution of nonalcoholic steatohepatitis, and >10% possibly allows for regression or stability of fibrosis.

More often than not, our patients then ask us, “What diet do you recommend?”

The AGA’s Clinical Practice Update recommends that people with NAFLD follow the Mediterranean diet, minimize saturated fatty acid intake (specifically red and processed meat), and limit or eliminate consumption of commercially produced fructose.

It’s a tried-and-true, evidence-based recommendation. Yet, recent data suggest that modifying the Mediterranean diet so that it’s further enriched with specific green polyphenols may yield even more benefits to at-risk patients.
 

The upside of a greener Mediterranean diet

In a recently published study, investigators behind the DIRECT-PLUS clinical trial randomly assigned 294 participants with abdominal obesity/dyslipidemia into three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean, and the so-called green Mediterranean diet.

Both Mediterranean diet groups were calorie restricted and called for 28 g/day of walnuts (+440 mg/day polyphenols provided). However, the green Mediterranean diet was further supplemented with 3-4 cups/day of green tea and 100 g/day of Mankai (a Wolffia globosa aquatic plant strain) in the form of frozen cubes turned into a green shake that replaced dinner (+1,240 mg/day total polyphenols provided). The percent change in intrahepatic fat content was quantified continuously by proton magnetic resonance spectroscopy. NAFLD was defined as an intrahepatic fat content of >5%.

After 18 months, the prevalence of NAFLD declined to 54.8% in the HDG group, 47.9% in the standard Mediterranean group, and 31.5% in the green Mediterranean group. Both Mediterranean groups achieved similar moderate weight loss and had significantly higher total plasma polyphenol levels versus the HDG group. However, the green Mediterranean group achieved significantly greater proportional intrahepatic fat content loss (-38.9%) than both the standard Mediterranean (-19.6; P = .023) and HDG (-12.2%; P < .001) groups.

In isolating the individual components of the diets, researchers determined that the degree of intrahepatic fat content loss was significantly associated with increased Mankai and walnut intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, and changes in microbiome composition and specific bacteria.

The authors suggest that the mechanisms by which polyphenols reduced steatosis and prevented liver injury may include reduced de novo lipogenesis, increased fatty acid oxidation, and reduced oxidative stress.

In an additional analysis, DIRECT-PLUS investigators also revealed the beneficial effects of the green Mediterranean diet on cardiometabolic health. Although both Mediterranean diets achieved similar weight loss (-6.2 kg for green Mediterranean and -5.4 kg for standard Mediterranean), which was superior to that observed in the HDG group (-1.5 kg; P < .001), the green Mediterranean group had a greater reduction in waist circumference than the standard Mediterranean group (-8.6 vs. -6.8 cm, respectively; P = .033). Within 6 months, the green Mediterranean group also achieved a greater decrease in low-density lipoprotein cholesterol levels, diastolic blood pressure, and insulin resistance.
 

A new dietary tool for combating obesity

The rising global incidence of NAFLD has made it even more urgent to identify new and improved ways of preventing the onset of obesity-related complications. To aid those efforts, we’ve been equipped with useful tools for educating our patients and their families, such as the 2020-2025 Dietary Guidelines for Americans from the U.S. Department of Agriculture (USDA), which makes a clear case for the disease-combating effects of healthy eating patterns.

This message does not appear to be making the impact it should, however, particularly among teens and young adults. It was recently reported that in 2017, only 7% of U.S. high school students consumed recommended amounts of fruits and only 2% consumed enough vegetables to meet USDA recommendations.

Novel approaches, including enhanced school and community programs, will be required to address this issue, but so will presenting patients with satisfactory dietary alternatives. Compellingly, DIRECT-PLUS investigators reported an 89.8% retention rate at 18 months among volunteers, who were able to comply with the dietary regimen with no significant complaints regarding taste. This signals that even though the “green” modification is more stringent than the typical Mediterranean regimen, it is one to which participants can adhere.

Although the real-world applicability of this diet remains to be seen, DIRECT-PLUS gives us encouraging evidence that a Mediterranean diet amplified with green plant-based proteins/polyphenols can lead to twice the intrahepatic fat loss, as compared to other nutritional strategies, and reduce the rate of NAFLD.

And as we know, having another dietary option to offer our patients is always a welcome addition to the menu.

Dr. Balistreri is with the department of hepatology & nutrition at Cincinnati Children’s Hospital Medical Center. He has disclosed no relevant financial relationships.

Iris Shai, PhD, one of the authors of the study, “Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial,” is an adviser to Hinoman, which markets Mankai. Ilan Youngster, MD, another author of that study, is medical adviser for MyBiotics.

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

This article was updated May 21, 2021.

Those of us treating nonalcoholic fatty liver disease (NAFLD) often find ourselves having similar conversations with our patients. After diagnosis, our next step is usually describing to them how they can improve their outcomes through a healthy diet and exercise.

Westend61/Getty Images

We can point to the latest data espousing the benefits of moderate weight reduction. The recently released American Gastroenterological Association (AGA) Clinical Practice Update gives us compelling evidence of what can be achieved with specific thresholds of total body weight loss: >5% can decrease hepatic steatosis, >7% potentially leads to resolution of nonalcoholic steatohepatitis, and >10% possibly allows for regression or stability of fibrosis.

More often than not, our patients then ask us, “What diet do you recommend?”

The AGA’s Clinical Practice Update recommends that people with NAFLD follow the Mediterranean diet, minimize saturated fatty acid intake (specifically red and processed meat), and limit or eliminate consumption of commercially produced fructose.

It’s a tried-and-true, evidence-based recommendation. Yet, recent data suggest that modifying the Mediterranean diet so that it’s further enriched with specific green polyphenols may yield even more benefits to at-risk patients.
 

The upside of a greener Mediterranean diet

In a recently published study, investigators behind the DIRECT-PLUS clinical trial randomly assigned 294 participants with abdominal obesity/dyslipidemia into three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean, and the so-called green Mediterranean diet.

Both Mediterranean diet groups were calorie restricted and called for 28 g/day of walnuts (+440 mg/day polyphenols provided). However, the green Mediterranean diet was further supplemented with 3-4 cups/day of green tea and 100 g/day of Mankai (a Wolffia globosa aquatic plant strain) in the form of frozen cubes turned into a green shake that replaced dinner (+1,240 mg/day total polyphenols provided). The percent change in intrahepatic fat content was quantified continuously by proton magnetic resonance spectroscopy. NAFLD was defined as an intrahepatic fat content of >5%.

After 18 months, the prevalence of NAFLD declined to 54.8% in the HDG group, 47.9% in the standard Mediterranean group, and 31.5% in the green Mediterranean group. Both Mediterranean groups achieved similar moderate weight loss and had significantly higher total plasma polyphenol levels versus the HDG group. However, the green Mediterranean group achieved significantly greater proportional intrahepatic fat content loss (-38.9%) than both the standard Mediterranean (-19.6; P = .023) and HDG (-12.2%; P < .001) groups.

In isolating the individual components of the diets, researchers determined that the degree of intrahepatic fat content loss was significantly associated with increased Mankai and walnut intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, and changes in microbiome composition and specific bacteria.

The authors suggest that the mechanisms by which polyphenols reduced steatosis and prevented liver injury may include reduced de novo lipogenesis, increased fatty acid oxidation, and reduced oxidative stress.

In an additional analysis, DIRECT-PLUS investigators also revealed the beneficial effects of the green Mediterranean diet on cardiometabolic health. Although both Mediterranean diets achieved similar weight loss (-6.2 kg for green Mediterranean and -5.4 kg for standard Mediterranean), which was superior to that observed in the HDG group (-1.5 kg; P < .001), the green Mediterranean group had a greater reduction in waist circumference than the standard Mediterranean group (-8.6 vs. -6.8 cm, respectively; P = .033). Within 6 months, the green Mediterranean group also achieved a greater decrease in low-density lipoprotein cholesterol levels, diastolic blood pressure, and insulin resistance.
 

A new dietary tool for combating obesity

The rising global incidence of NAFLD has made it even more urgent to identify new and improved ways of preventing the onset of obesity-related complications. To aid those efforts, we’ve been equipped with useful tools for educating our patients and their families, such as the 2020-2025 Dietary Guidelines for Americans from the U.S. Department of Agriculture (USDA), which makes a clear case for the disease-combating effects of healthy eating patterns.

This message does not appear to be making the impact it should, however, particularly among teens and young adults. It was recently reported that in 2017, only 7% of U.S. high school students consumed recommended amounts of fruits and only 2% consumed enough vegetables to meet USDA recommendations.

Novel approaches, including enhanced school and community programs, will be required to address this issue, but so will presenting patients with satisfactory dietary alternatives. Compellingly, DIRECT-PLUS investigators reported an 89.8% retention rate at 18 months among volunteers, who were able to comply with the dietary regimen with no significant complaints regarding taste. This signals that even though the “green” modification is more stringent than the typical Mediterranean regimen, it is one to which participants can adhere.

Although the real-world applicability of this diet remains to be seen, DIRECT-PLUS gives us encouraging evidence that a Mediterranean diet amplified with green plant-based proteins/polyphenols can lead to twice the intrahepatic fat loss, as compared to other nutritional strategies, and reduce the rate of NAFLD.

And as we know, having another dietary option to offer our patients is always a welcome addition to the menu.

Dr. Balistreri is with the department of hepatology & nutrition at Cincinnati Children’s Hospital Medical Center. He has disclosed no relevant financial relationships.

Iris Shai, PhD, one of the authors of the study, “Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial,” is an adviser to Hinoman, which markets Mankai. Ilan Youngster, MD, another author of that study, is medical adviser for MyBiotics.

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

This article was updated May 21, 2021.

Those of us treating nonalcoholic fatty liver disease (NAFLD) often find ourselves having similar conversations with our patients. After diagnosis, our next step is usually describing to them how they can improve their outcomes through a healthy diet and exercise.

Westend61/Getty Images

We can point to the latest data espousing the benefits of moderate weight reduction. The recently released American Gastroenterological Association (AGA) Clinical Practice Update gives us compelling evidence of what can be achieved with specific thresholds of total body weight loss: >5% can decrease hepatic steatosis, >7% potentially leads to resolution of nonalcoholic steatohepatitis, and >10% possibly allows for regression or stability of fibrosis.

More often than not, our patients then ask us, “What diet do you recommend?”

The AGA’s Clinical Practice Update recommends that people with NAFLD follow the Mediterranean diet, minimize saturated fatty acid intake (specifically red and processed meat), and limit or eliminate consumption of commercially produced fructose.

It’s a tried-and-true, evidence-based recommendation. Yet, recent data suggest that modifying the Mediterranean diet so that it’s further enriched with specific green polyphenols may yield even more benefits to at-risk patients.
 

The upside of a greener Mediterranean diet

In a recently published study, investigators behind the DIRECT-PLUS clinical trial randomly assigned 294 participants with abdominal obesity/dyslipidemia into three diet groups (all accompanied by physical activity): standard healthy dietary guidelines (HDG), standard Mediterranean, and the so-called green Mediterranean diet.

Both Mediterranean diet groups were calorie restricted and called for 28 g/day of walnuts (+440 mg/day polyphenols provided). However, the green Mediterranean diet was further supplemented with 3-4 cups/day of green tea and 100 g/day of Mankai (a Wolffia globosa aquatic plant strain) in the form of frozen cubes turned into a green shake that replaced dinner (+1,240 mg/day total polyphenols provided). The percent change in intrahepatic fat content was quantified continuously by proton magnetic resonance spectroscopy. NAFLD was defined as an intrahepatic fat content of >5%.

After 18 months, the prevalence of NAFLD declined to 54.8% in the HDG group, 47.9% in the standard Mediterranean group, and 31.5% in the green Mediterranean group. Both Mediterranean groups achieved similar moderate weight loss and had significantly higher total plasma polyphenol levels versus the HDG group. However, the green Mediterranean group achieved significantly greater proportional intrahepatic fat content loss (-38.9%) than both the standard Mediterranean (-19.6; P = .023) and HDG (-12.2%; P < .001) groups.

In isolating the individual components of the diets, researchers determined that the degree of intrahepatic fat content loss was significantly associated with increased Mankai and walnut intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, and changes in microbiome composition and specific bacteria.

The authors suggest that the mechanisms by which polyphenols reduced steatosis and prevented liver injury may include reduced de novo lipogenesis, increased fatty acid oxidation, and reduced oxidative stress.

In an additional analysis, DIRECT-PLUS investigators also revealed the beneficial effects of the green Mediterranean diet on cardiometabolic health. Although both Mediterranean diets achieved similar weight loss (-6.2 kg for green Mediterranean and -5.4 kg for standard Mediterranean), which was superior to that observed in the HDG group (-1.5 kg; P < .001), the green Mediterranean group had a greater reduction in waist circumference than the standard Mediterranean group (-8.6 vs. -6.8 cm, respectively; P = .033). Within 6 months, the green Mediterranean group also achieved a greater decrease in low-density lipoprotein cholesterol levels, diastolic blood pressure, and insulin resistance.
 

A new dietary tool for combating obesity

The rising global incidence of NAFLD has made it even more urgent to identify new and improved ways of preventing the onset of obesity-related complications. To aid those efforts, we’ve been equipped with useful tools for educating our patients and their families, such as the 2020-2025 Dietary Guidelines for Americans from the U.S. Department of Agriculture (USDA), which makes a clear case for the disease-combating effects of healthy eating patterns.

This message does not appear to be making the impact it should, however, particularly among teens and young adults. It was recently reported that in 2017, only 7% of U.S. high school students consumed recommended amounts of fruits and only 2% consumed enough vegetables to meet USDA recommendations.

Novel approaches, including enhanced school and community programs, will be required to address this issue, but so will presenting patients with satisfactory dietary alternatives. Compellingly, DIRECT-PLUS investigators reported an 89.8% retention rate at 18 months among volunteers, who were able to comply with the dietary regimen with no significant complaints regarding taste. This signals that even though the “green” modification is more stringent than the typical Mediterranean regimen, it is one to which participants can adhere.

Although the real-world applicability of this diet remains to be seen, DIRECT-PLUS gives us encouraging evidence that a Mediterranean diet amplified with green plant-based proteins/polyphenols can lead to twice the intrahepatic fat loss, as compared to other nutritional strategies, and reduce the rate of NAFLD.

And as we know, having another dietary option to offer our patients is always a welcome addition to the menu.

Dr. Balistreri is with the department of hepatology & nutrition at Cincinnati Children’s Hospital Medical Center. He has disclosed no relevant financial relationships.

Iris Shai, PhD, one of the authors of the study, “Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial,” is an adviser to Hinoman, which markets Mankai. Ilan Youngster, MD, another author of that study, is medical adviser for MyBiotics.

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

This article was updated May 21, 2021.