Rising NAFLD and metabolic severity during the Sars-CoV-2 pandemic among children with obesity in the United States.

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD), the most common liver disease among youth with obesity, precedes more severe metabolic and liver diseases. However, the impact of the Sars-CoV-2 global pandemic on the prevalence and severity of NAFLD and the associated metabolic phenotype among youth with obesity is unknown. METHODS: Participants were recruited from the Yale Pediatric Obesity Clinic during the Sars-CoV-2 global pandemic (August 2020 to May 2022) and were compared with a frequency-matched control group of youth with obesity studied before the Sars-CoV-2 global pandemic (January 2017 to November 2019). Glucose metabolism differences were assessed during an extended 180-minute oral glucose tolerance test. Magnetic resonance imaging-derived proton density fat fraction (PDFF) was used to determine intrahepatic fat content in those with NAFLD (PDFF ≥ 5.5). RESULTS: NAFLD prevalence increased in participants prior to (36.2%) versus during the Sars-CoV-2 pandemic (60.9%), with higher PDFF values observed in participants with NAFLD (PDFF ≥ 5.5%) during versus before the pandemic. An increase in visceral adipose tissue and a hyperresponsiveness in insulin secretion during the oral glucose tolerance test were also observed. CONCLUSIONS: Hepatic health differences were likely exacerbated by environmental and behavioral changes associated with the pandemic, which are critically important for clinicians to consider when engaging in patient care to help minimize the future risk for metabolic perturbations.

Metabolic dysfunction associated fatty liver disease and coronavirus disease 2019: clinical relationship and current management.

The coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). At present, the COVID-19 has been prevalent worldwide for more than a year and caused more than four million deaths. Liver injury was frequently observed in patients with COVID-19. Recently, a new definition of metabolic dysfunction associated fatty liver disease (MAFLD) was proposed by a panel of international experts, and the relationship between MAFLD and COVID-19 has been actively investigated. Several previous studies indicated that the patients with MAFLD had a higher prevalence of COVID-19 and a tendency to develop severe type of respiratory infection, and others indicated that liver injury would be exacerbated in the patients with MAFLD once infected with COVID-19. The mechanism underlying the relationship between MAFLD and COVID-19 infection has not been thoroughly investigated, and recent studies indicated that multifactorial mechanisms, such as altered host angiotensin converting enzyme 2 (ACE2) receptor expression, direct viral attack, disruption of cholangiocyte function, systemic inflammatory reaction, drug-induced liver injury, hepatic ischemic and hypoxic injury, and MAFLD-related glucose and lipid metabolic disorders, might jointly contribute to both of the adverse hepatic and respiratory outcomes. In this review, we discussed the relationship between MAFLD and COVID-19 based on current available literature, and summarized the recommendations for clinical management of MAFLD patients during the pandemic of COVID-19.

Pathologic Diagnosis of Nonalcoholic Fatty Liver Disease.

CONTEXT.­: Nonalcoholic fatty liver disease (NAFLD) encompasses steatosis and steatohepatitis. The cause may be multifactorial, and diagnosis requires correlation with clinical information and laboratory results. OBJECTIVE.­: To provide an overview of the status of histology diagnosis of steatosis, steatohepatitis, and associated conditions. DATA SOURCES.­: A literature search was performed using the PubMed search engine. The terms ''steatosis,'' ''steatohepatitis,'' ''nonalcoholic fatty liver disease (NAFLD),'' ''nonalcoholic steatohepatitis (NASH),'' "alcoholic steatohepatitis (ASH)," ''type 2 diabetes (T2DM),'' "cryptogenic cirrhosis," "drug-induced liver injury (DILI)," "immune checkpoint inhibitor therapy," and "COVID-19 and liver" were used. CONCLUSIONS.­: Nonalcoholic fatty liver disease has become the most common chronic liver disease in the United States. NASH is the progressive form of nonalcoholic fatty liver disease. The hallmarks of steatohepatitis are steatosis, ballooned hepatocytes, and lobular inflammation. NASH and alcoholic steatohepatitis share similar histologic features, but some subtle differences may help their distinction. NASH is commonly seen in patients with metabolic dysfunction but can also be caused by other etiologies. Examples are medications including newly developed immune checkpoint inhibitors and viral infections such as coronavirus disease 2019 (COVID-19). NASH is also a common cause of cryptogenic cirrhosis but can be reversed. The results from recent clinical trials for NASH treatment are promising in reducing the severity of steatosis, ballooning, and fibrosis.

Functional Characterization of Organoids Derived From Irreversibly Damaged Liver of Patients With NASH.

BACKGROUND AND AIMS: NASH will soon become the leading cause of liver transplantation in the United States and is also associated with increased COVID-19 mortality. Currently, there are no Food and Drug Administration-approved drugs available that slow NASH progression or address NASH liver involvement in COVID-19. Because animal models cannot fully recapitulate human NASH, we hypothesized that stem cells isolated directly from end-stage liver from patients with NASH may address current knowledge gaps in human NASH pathology. APPROACH AND RESULTS: We devised methods that allow the derivation, proliferation, hepatic differentiation, and extensive characterization of bipotent ductal organoids from irreversibly damaged liver from patients with NASH. The transcriptomes of organoids derived from NASH liver, but not healthy liver, show significant up-regulation of proinflammatory and cytochrome p450-related pathways, as well as of known liver fibrosis and tumor markers, with the degree of up-regulation being patient-specific. Functionally, NASH liver organoids exhibit reduced passaging/growth capacity and hallmarks of NASH liver, including decreased albumin production, increased free fatty acid-induced lipid accumulation, increased sensitivity to apoptotic stimuli, and increased cytochrome P450 metabolism. After hepatic differentiation, NASH liver organoids exhibit reduced ability to dedifferentiate back to the biliary state, consistent with the known reduced regenerative ability of NASH livers. Intriguingly, NASH liver organoids also show strongly increased permissiveness to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vesicular stomatitis pseudovirus as well as up-regulation of ubiquitin D, a known inhibitor of the antiviral interferon host response. CONCLUSION: Expansion of primary liver stem cells/organoids derived directly from irreversibly damaged liver from patients with NASH opens up experimental avenues for personalized disease modeling and drug development that has the potential to slow human NASH progression and to counteract NASH-related SARS-CoV-2 effects.

The role of fibrosis index FIB-4 in predicting liver fibrosis stage and clinical prognosis: A diagnostic or screening tool?

This review evaluates the ability of the fibrosis index based on four factors (FIB-4) identifying fibrosis stages, long-time prognosis in chronic liver disease, and short-time outcomes in acute liver injury. FIB-4 was accurate in predicting the absence or presence of advanced fibrosis with cut-offs of 1.0 and 2.65 for viral hepatitis B, 1.45 and 3.25 for viral hepatitis C, 1.30 (<65 years), 2.0 (≥65 years), and 2.67 for non-alcoholic fatty liver disease (NAFLD), respectively, but had a low-to-moderate accuracy in alcoholic liver disease (ALD) and autoimmune hepatitis. It performed better in excluding fibrosis, so we built an algorithm for identifying advanced fibrosis by combined methods and giving work-up and follow-up suggestions. High FIB-4 in viral hepatitis, NAFLD, and ALD was associated with significantly high hepatocellular carcinoma incidence and mortality. Additionally, FIB-4 showed the ability to predict high-risk varices with cut-offs of 2.87 and 3.91 in cirrhosis patients and predict long-term survival in hepatocellular carcinoma patients after hepatectomy. In acute liver injury caused by COVID-19, FIB-4 had a predictive value for mechanical ventilation and 30-day mortality. Finally, FIB-4 may act as a screening tool in the secondary prevention of NAFLD in the high-risk population.

Risk of severe illness of COVID-19 patients with NAFLD and increased NAFLD fibrosis scores.

BACKGROUND: There is still little knowledge about the association of liver fibrosis with the clinical outcomes of COVID-19 patients with non-alcoholic fatty liver disease (NAFLD). The aim of the study was to determine the association of NAFLD fibrosis score (NFS)-determined liver fibrosis with clinical outcomes of COVID-19 patients with NAFLD. METHODS: The NAFLD was diagnosed by the Hepatic Steatosis Index (HSI) in the absence of other causes of chronic liver diseases. NFS was used to evaluate the severity of liver fibrosis. RESULTS: A total of 86 COVID-19 patients with NAFLD were included. The median age was 43.5 years, and 58.1% of patients were male. Thirty-eight (44.2%) patients had advanced liver fibrosis according to the NFS. Multivariate analysis indicated that concurrent diabetes (odds ratio [OR] 8.264, 95% confidence interval [CI] 1.202-56.830, p = 0.032) and advanced liver fibrosis (OR 11.057, 95% CI 1.193-102.439, p = 0.034) were independent risk factors of severe illness in COVID-19 patients with NAFLD. CONCLUSION: NAFLD patients with NFS-determined advanced liver fibrosis are at higher risk of severe COVID-19.

COVID-19 and the liver - Lessons learned.

Liver involvement, indicated by elevated liver function test results, is common in hospitalized patients with coronavirus disease 2019 (COVID-19) and has been linked to disease severity and outcome. A dual pattern of elevated liver function tests can be observed especially in patients with severe or critical COVID-19, characterized by an increase in aminotransferases early in the course of this disease, followed by an increase in cholestasis-associated biochemistry markers at later stages. This dual pattern is associated with inflammatory response markers and poor outcome. Current notions on the mechanisms of liver injury in COVID-19 include direct cytopathic effects of the virus on hepatocytes and cholangiocytes, ischemic and hypoxic liver damage, drug-induced liver injury, activation of hepatic immune cells by excess cytokine production and exacerbation of pre-existing liver disease. Patients with obesity-related non-alcoholic fatty liver disease and, in particular, patients with cirrhosis are at high risk of liver injury and a fatal outcome from COVID-19. In contrast, individuals receiving stable immunosuppressive medication for autoimmune liver diseases or during long-term follow-up after liver transplantation do not have a higher case-to-infection ratio and have a fairly favourable outcome. The present review describes the epidemiology, characteristics and potential pathological mechanisms of COVID-19-related liver injury. Moreover, the influence of pre-existing liver disease on the susceptibility and severity of liver injury in COVID-19 are discussed.

Potential effects of SARS-CoV-2 on the gastrointestinal tract and liver.

COVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early reported symptoms include fever, cough, and respiratory symptoms. There were few reports of digestive symptoms. However, with COVID-19 spreading worldwide, symptoms such as vomiting, diarrhoea, and abdominal pain have gained increasing attention. Research has found that angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, is strongly expressed in the gastrointestinal tract and liver. Whether theoretically or clinically, many studies have suggested a close connection between COVID-19 and the digestive system. In this review, we summarize the digestive symptoms reported in existing research, discuss the impact of SARS-CoV-2 on the gastrointestinal tract and liver, and determine the possible mechanisms and aetiology, such as cytokine storm. In-depth exploration of the relationship between COVID-19 and the digestive system is urgently needed.

In-hospital mortality is associated with inflammatory response in NAFLD patients admitted for COVID-19.

BACKGROUND & AIMS: Although metabolic risk factors are associated with more severe COVID-19, there is little evidence on outcomes in patients with non-alcoholic fatty liver disease (NAFLD). We here describe the clinical characteristics and outcomes of NAFLD patients in a cohort hospitalised for COVID-19. METHODS: This study included all consecutive patients admitted for COVID-19 between February and April 2020 at Imperial College Healthcare NHS Trust, with either imaging of the liver available dated within one year from the admission or a known diagnosis of NAFLD. Clinical data and early weaning score (EWS) were recorded. NAFLD diagnosis was based on imaging or past medical history and patients were stratified for Fibrosis-4 (FIB-4) index. Clinical endpoints were admission to intensive care unit (ICU)and in-hospital mortality. RESULTS: 561 patients were admitted. Overall, 193 patients were included in the study. Fifty nine patients (30%) died, 9 (5%) were still in hospital, and 125 (65%) were discharged. The NAFLD cohort (n = 61) was significantly younger (60 vs 70.5 years, p = 0.046) at presentation compared to the non-NAFLD (n = 132). NAFLD diagnosis was not associated with adverse outcomes. However, the NAFLD group had higher C reactive protein (CRP) (107 vs 91.2 mg/L, p = 0.05) compared to non-NAFLD(n = 132). Among NAFLD patients, male gender (p = 0.01), ferritin (p = 0.003) and EWS (p = 0.047) were associated with in-hospital mortality, while the presence of intermediate/high risk FIB-4 or liver cirrhosis was not. CONCLUSION: The presence of NAFLD per se was not associated with worse outcomes in patients hospitalised for COVID-19. Though NAFLD patients were younger on admission, disease stage was not associated with clinical outcomes. Yet, mortality was associated with gender and a pronounced inflammatory response in the NAFLD group.