[Liver disease during the pandemic of COVID-19 infection: prediction of the course and tactics of management: A review].

The hepatic consequences of SARS-CoV-2 infection are now recognized as an important component of CoronaVIrus Disease 2019 (COVID-19). This aspect is most clinically relevant in patients with pre-existing chronic liver disease (CKD), who are at extremely high risk of severe COVID-19 and death. Risk factors for severe CKD, especially in people with liver cirrhosis and non-alcoholic fatty liver disease, are the direct and indirect cytotoxic effects of coronavirus against the background of systemic inflammation, blood clotting disorders and immune dysfunction. The severe negative impact of the pandemic in the presence of CKD and the difficulties of patient relationships contribute to the progressive increase in the global burden of liver disease on the health system.

Nonalcoholic fatty liver disease and non-liver comorbidities.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by excess fat accumulation in the liver. It is closely associated with metabolic syndrome, and patients with NAFLD often have comorbidities such as obesity, type 2 diabetes mellitus, and dyslipidemia. In addition to liver-related complications, NAFLD has been associated with a range of non-liver comorbidities, including cardiovascular disease, chronic kidney disease, and sleep apnea. Cardiovascular disease is the most common cause of mortality in patients with NAFLD, and patients with NAFLD have a higher risk of developing cardiovascular disease than the general population. Chronic kidney disease is also more common in patients with NAFLD, and the severity of NAFLD is associated with a higher risk of developing chronic kidney disease. Sleep apnea, a disorder characterized by breathing interruptions during sleep, is also more common in patients with NAFLD and is associated with the severity of NAFLD. The presence of non-liver comorbidities in patients with NAFLD has important implications for the management of this disease. Treatment of comorbidities such as obesity, type 2 diabetes mellitus, and dyslipidemia may improve liver-related outcomes in patients with NAFLD. Moreover, treatment of non-liver comorbidities may also improve overall health outcomes in patients with NAFLD. Therefore, clinicians should be aware of the potential for non-liver comorbidities in patients with NAFLD and should consider the management of these comorbidities as part of the overall management of this disease.

Effects of COVID-19 Pandemic on Metabolic Status and Psychological Correlates of a Cohort of Italian NAFLD Outpatients.

Non-alcoholic fatty liver disease (NAFLD) is a potentially progressive condition characterized by the presence of fat in more than 5% of hepatocytes, representing the hepatic expression of metabolic syndrome (MetS). A reduction of at least 5-7% in initial body weight improves the metabolic profile underlying NAFLD. The aim of our study was to evaluate the effects of the COVID-19 lockdown on a cohort of non-advanced NAFLD Italian outpatients. We identified 43 patients with 3 available time point visits in our center: first visit (T0) when behavioral indications aimed at controlling MetS were provided, a pre-COVID visit (T1) and a post-COVID visit (T2). During the lockdown, an online compilation of validated psychological tests (SRQ-20, EQ5D, SF-12 and STAI) and a specifically formulated questionnaire for NAFLD was presented to our cohort and completed by 14 consenting patients. Patients who had lost more than 5% of the initial weight at T1 (9 subjects, 21%) maintained the results even at T2, with an overall reduction in BMI and liver stiffness; patients who had not lost the desired weight at T1 (34 subjects, 79%) displayed a further increase in BMI and visceral adiposity at T2. Of interest is that patients in the latter group reported signs of psychological suffering. Our data demonstrated that the setting of good counseling was effective in controlling the metabolic disorder underlying NAFLD in our cohort of outpatients. Given the need for patients to play an active role in the behavioral therapy for NAFLD, we advocate that a multidisciplinary approach be adopted, including a psychological support to obtain the best results over time.

Digital Therapeutics: Emerging New Therapy for Nonalcoholic Fatty Liver Disease.

The increased prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide is particularly worrisome, as no medication has been approved to treat the disease. Lifestyle modifications aimed at promoting weight loss and weight maintenance remain the current first-line treatment for NAFLD. However, due to the lack of standard and scientific guidance and out-of-hospital supervision, long-term outcomes of lifestyle interventions for patients with NAFLD are often unsatisfactory. In addition, the COVID-19 pandemic aggravated this dilemma. At the same time, digital therapeutics (DTx) are expected to be a new method for the convenient management and treatment of patients with NAFLD and are attracting a great deal of attention. DTx, which provide evidence-based medicine through software programs for remote intervention in preventing, treating, or managing diseases, overcome the drawbacks of traditional treatment. The efficacy of the approach has already been demonstrated for some chronic diseases, but DTx have not been fully developed for NAFLD. This study reviews the concepts, clinical value, and practical applications related to DTx, with an emphasis on recommendations based on unmet needs for NAFLD. A better understanding of the current state will help clinicians and researchers develop high-quality, standardized, and efficient DTx products, with the aim of optimizing the prognosis of patients with NAFLD.

Changes in the Prevalences of Obesity, Abdominal Obesity, and Non-Alcoholic Fatty Liver Disease among Korean Children during the COVID-19 Outbreak.

PURPOSE: We aimed to investigate the prevalences of obesity, abdominal obesity, and non-alcoholic fatty liver disease (NAFLD) among children and adolescents during the coronavirus disease 2019 (COVID-19) outbreak. MATERIALS AND METHODS: This population-based study investigated the prevalences of obesity, abdominal obesity, and NAFLD among 1428 children and adolescents between 2018-2019 and 2020. We assessed the prevalences of obesity, abdominal obesity, and NAFLD according to body mass index, age, sex, and residential district. Logistic regression analyses were performed to determine the relationships among obesity, abdominal obesity, and NAFLD. RESULTS: In the obese group, the prevalence of abdominal obesity increased from 75.55% to 92.68%, and that of NAFLD increased from 40.68% to 57.82%. In age-specific analysis, the prevalence of abdominal obesity increased from 8.25% to 14.11% among participants aged 10-12 years and from 11.70% to 19.88% among children aged 13-15 years. In residential district-specific analysis, the prevalence of both abdominal obesity and NAFLD increased from 6.96% to 15.74% in rural areas. In logistic regression analysis, the odds ratio of abdominal obesity for NAFLD was 11.82. CONCLUSION: Our results demonstrated that the prevalences of abdominal obesity and NAFLD increased among obese Korean children and adolescents and in rural areas during the COVID-19 outbreak. Additionally, the prevalence of abdominal obesity increased among young children. These findings suggest the importance of closely monitoring abdominal obesity and NAFLD among children during COVID-19, focusing particularly on obese young children and individuals in rural areas.

Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints.

Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints.

Vaccination dilemma in the thermodynamic limit.

The vaccination game is a social dilemma that refers to the conundrum individuals face (to get immunized or not) when the population is exposed to an infectious disease. The model has recently gained much traction due to the COVID-19 pandemic since the public perception of vaccines plays a significant role in disease dynamics. This paper studies the vaccination game in the thermodynamic limit with an analytical method derived from the 1D Ising model called Nash equilibrium mapping. The individual dilemma regarding vaccination comes from an internal conflict wherein one tries to balance the perceived advantages of immunizing with the apparent risks associated with vaccination, which they hear through different news media. We compare the results of Nash equilibrium (NE) mapping from other 1D Ising-based models, namely, Darwinian evolution (DE) and agent-based simulation. This study aims to analyze the behavior of an infinite population regarding what fraction of people choose to vaccinate or not vaccinate. While Nash equilibrium mapping and agent-based simulation agree mostly, DE strays far from the two models. DE fails to predict the equilibrium behavior of players in the population reasonably. We apply the results of our study to analyze the AstraZeneca (AZ) COVID-19 vaccine risk vs disease deaths debate, both via NE mapping and the agent-based method. Both predict nearly 100% AZ vaccine coverage for people aged above 40, notwithstanding the risk. At the same time, younger people show a slight reluctance. We predict that while government intervention via vaccination mandates and/or advertisement campaigns are unnecessary for the older population, for the younger population (ages: 20-39), some encouragement from the government via media campaigns and/or vaccine mandates may be necessary.

Nanodrug delivery systems for metabolic chronic liver diseases: advances and perspectives.

Nanomedicines are revolutionizing healthcare as recently demonstrated by the Pfizer/BioNTech and Moderna COVID-2019 vaccines, with billions of doses administered worldwide in a safe manner. Nonalcoholic fatty liver disease is the most common noncommunicable chronic liver disease, posing a major growing challenge to global public health. However, due to unmet diagnostic and therapeutic needs, there is great interest in the development of novel translational approaches. Nanoparticle-based approaches offer novel opportunities for efficient and specific drug delivery to liver cells, as a step toward precision medicines. In this review, the authors highlight recent advances in nanomedicines for the generation of novel diagnostic and therapeutic tools for nonalcoholic fatty liver disease and related liver diseases.

Chronic liver diseases are a growing concern for global public health since they can affect up to 25% of the global adult population. Currently, there is no effective treatment or cure for these diseases. Nanometer-sized capsules can be loaded with drugs and more accurately deliver these drugs to their sites of action. They help improve the availability of medicines to the liver and have the potential to reduce their side effects. Here, the authors discuss recent advances to explain how nanotechnology can help improve the benefits of existing medicines for liver disease therapy.

COVID-19 and liver injury in individuals with obesity.

Coronavirus disease 2019 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 that manifests as a variety of clinical manifestations, including liver damage commonly detected by a hepatocellular pattern from liver function tests. Liver injury is associated with a worse prognosis overall. Conditions associated with the severity of the disease include obesity and cardiometabolic comorbidities, which are also associated with nonalcoholic fatty liver disease (NAFLD). The presence of NAFLD, similarly to obesity, is associated with an unfavourable impact on the coronavirus disease 2019 outcome. Individuals with these conditions could present with liver damage and elevated liver function tests due to direct viral cytotoxicity, systemic inflammation, ischemic or hypoxic liver damage or drug side effects. However, liver damage in the setting of NAFLD could also be attributed to a pre-existing chronic low-grade inflammation associated with surplus and dysfunctional adipose tissue in these individuals. Here we investigate the hypothesis that a pre-existing inflammatory status is exacerbated after severe acute respiratory syndrome coronavirus 2 infection, which embodies a second hit to the underestimated liver damage.

Independent Predictors of Mortality Among Patients With NAFLD Hospitalized With COVID-19 Infection.

The impact of the coronavirus disease 2019 (COVID-19) pandemic among patients with chronic liver disease is unknown. Given the high prevalence of nonalcoholic fatty liver disease (NAFLD), we determined the predictors of mortality and hospital resource use among patients with NAFLD admitted with COVID-19 by using electronic medical records data for adult patients with COVID-19 hospitalized in a multihospital health system who were discharged between March and December 2020. NAFLD was diagnosed by imaging or liver biopsy without other liver diseases. Charlson's comorbidity index (CCI) and Elixhauser comorbidity index (ECI) scores were calculated. In the study sample, among the 4,835 patients hospitalized for COVID-19, 553 had NAFLD (age: 55 ± 16 years, 51% male, 17% White, 11% Black, 58% Hispanic, 8% Asian, 5% from congregated living, 58% obese, 15% morbid obesity [body mass index ≥ 40], 51% type 2 diabetes, 63% hypertension, mean [SD] baseline CCI of 3.9 [3.2], and baseline ECI of 13.4 [11.3]). On admission, patients with NAFLD had more respiratory symptoms, higher body temperature and heart rate, higher alanine aminotransferase and aspartate aminotransferase than non-NAFLD controls (n = 2,736; P < 0.05). Of the patients with NAFLD infected with COVID-19, 3.9% experienced acute liver injury. The NAFLD group had significantly longer length of stay, intensive care unit use, and mechanical ventilation, with a crude inpatient mortality rate of 11%. In multivariate analysis, independent predictors of inpatient mortality among patients with NAFLD infected with COVID-19 were older age, morbid obesity, ECI score ≥ 11, higher Fibrosis-4 Index (FIB-4) score, and oxygen saturation <90% (all P < 0.05), but not sex, race/ethnicity, or any individual comorbidity (all P > 0.05). Conclusion: Patients with NAFLD infected with COVID-19 tend to be sicker on admission and require more hospital resource use. Independent predictors of mortality included higher FIB-4 and multimorbidity scores, morbid obesity, older age, and hypoxemia on admission.

Impact of nonalcoholic fatty liver disease on clinical outcomes in patients with COVID-19 among persons living with HIV: A multicenter research network study.

BACKGROUND: People living with human immunodeficiency virus (PLWH) are at an increased risk of nonalcoholic fatty liver disease (NAFLD) but how these patients react to COVID-19 infection is unclear. We examined the clinical characteristics and outcomes of patients with and without nonalcoholic fatty liver disease (NAFLD) among people living with human immunodeficiency virus (PLWH) diagnosed with COVID-19. METHODS: A multicenter, retrospective cohort study was conducted using TriNetX. Participants diagnosed with COVID-19 between January 20, 2020, and October 31, 2021, in PLWH were identified and divided into cohorts based on preexisting NAFLD. The primary outcome was all-cause mortality, and secondary outcomes were hospitalization, severe disease, critical care, need for mechanical ventilation, and acute kidney injury(AKI). Propensity score matching (PSM) mitigated the imbalance among group covariates. Risk ratios (RR) with 95 % confidence intervals (CI) were calculated. RESULTS: Of the 5012 PLWH identified with confirmed COVID-19 during the study period, 563 had a diagnosis of NAFLD. After PSM, both groups were well-matched with 561 patients. The primary outcome did not differ between the cohorts at 30-days, even after a fully adjusted analysis, and the risk of all-cause mortality did not differ at 60 and 90 days. NAFLD had a significantly higher risk for hospitalization rates (RR 1.32; 95 % CI, 1.06-1.63) and AKI (RR 2.55; 95 % CI 1.42-4.57) than the non-NAFLD group at 30 days. No other differences were detected in other secondary outcome measures. CONCLUSIONS: Preexisting NAFLD is associated with an increased risk for hospitalization and AKI among PLWH infected with COVID-19. The potential role of NAFLD in developing severe COVID-19 among PLWH remains to be elucidated in future studies. Still, this study indicates the need for careful monitoring of this at-risk population.

COVID-19 and the liver: Are footprints still there?

The coronavirus disease 2019 (COVID-19) hit the entire world as a global pandemic and soon became the most important concern for all patients with chronic diseases. An early trend in higher mortality in patients with acute respiratory distress attracted all researchers to closely monitor patients for the involvement of other systems. It soon became apparent that patients with chronic liver diseases are at increased risk of mortality given their cirrhosis-associated immune dysfunction. Additionally, liver function abnormalities were noted in patients with severe COVID-19. Profound cytokine storm, direct viral infection, drugs and reactivation of viral infections were causes of deranged liver functions. Here, we discuss the relation between COVID-19 and chronic liver disease, specifically cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease (NAFLD), as well as the liver manifestations of COVID-19. The metabolic syndrome, obesity, diabetes mellitus and NAFLD were found to worsen outcome in different studies reported worldwide. Decompensated cirrhosis should be considered a risk factor for death and severe COVID-19. Recently, COVID-19 related cholangiopathy has also been reported with changes of secondary sclerosing cholangitis. The long-term persistence of viral antigens in gut epithelia raises concern regarding the future risk of autoimmune liver diseases.

Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study.

BACKGROUND: Management strategies for non-alcoholic steatohepatitis (NASH) are based predominantly on lifestyle modification, with no approved disease-modifying drugs yet available. We aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of pegozafermin (BIO89-100), a glycoPEGylated FGF21 analogue, in participants with NASH. METHODS: This randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study enrolled adults (aged 21-75 years) who had NASH with stage F1-F3 fibrosis, or non-alcoholic fatty liver disease and a high risk of NASH (referred to in this study as phenotypic NASH) due to central obesity with type 2 diabetes, or central obesity with increased alanine aminotransferase (ALT) or a Fibroscan score of 7 kPa or greater, across 12 specialist centres and clinics in the USA. Patients were centrally randomised by use of an interactive web response system to receive subcutaneously administered pegozafermin (3, 9, 18, or 27 mg once weekly; 18 or 36 mg once every 2 weeks) or placebo for 12 weeks. The primary endpoints were the safety, tolerability, and pharmacokinetics of pegozafermin. This trial is registered with ClinicalTrials.gov (NCT04048135). FINDINGS: Between July 29, 2019, and Aug 3, 2020, 275 participants were screened and 81 (15 [19%] with biopsy-confirmed NASH) were randomly assigned: 62 to pegozafermin (six to 3 mg once weekly, 12 to 9 mg once weekly, 11 to 18 mg once weekly, ten to 27 mg once weekly, 14 to 18 mg once every 2 weeks, and nine to 36 mg once every 2 weeks) and 19 to placebo; 63 received pegozafermin and 18 received placebo, as one participant in the placebo group inadvertently received 3 mg pegozafermin once weekly. Adverse events were reported in eight (44%) of 18 participants in the pooled placebo group, six (86%) of seven in the 3 mg once weekly pegozafermin group, four (33%) of 12 in the 9 mg once weekly group, seven (64%) of 11 in the 18 mg once weekly group, seven (70%) of ten in the 27 mg once weekly group, eight (57%) of 14 in the 18 mg once every 2 weeks group, and eight (89%) of nine in the 36 mg once every 2 weeks group. The most common treatment-related adverse event was mild increased appetite (in ten [16%] of 63 participants in the pooled pegozafermin group vs none of 18 in the pooled placebo group), which was not associated with bodyweight gain. Two patients discontinued treatment due to an adverse event (one each in the 27 mg once weekly and 18 mg once every 2 weeks groups). No treatment-related serious adverse events or deaths occurred. Dose-proportional pharmacokinetics were observed. Anti-drug antibodies were detected in 41 (65%) of 63 participants treated with pegozafermin. By week 13, pegozafermin significantly reduced the least squares mean (LSM) absolute differences in hepatic fat fraction versus pooled placebo (-8·9% [95% CI -14·8 to -3·1; p=0·0032] for 3 mg once weekly, -11·5% [-16·1 to -6·9; p<0·0001] for 9 mg once weekly, -8·9% [-13·7 to -4·2; p=0·0004] for 18 mg once weekly, -14·9% [-20·1 to -9·7; p<0·0001] for 27 mg once weekly, -10·4% [-14·7 to -6·1; p<0·0001] for 18 mg once every 2 weeks, and -11·1% [-16·2 to -6·0; p<0·0001] for 36 mg once every 2 weeks). At week 13, significant LSM relative reductions versus pooled placebo in ALT were observed for pegozafermin 9 mg once weekly, 18 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. At week 13, significant LSM relative reductions versus pooled placebo in aspartate aminotransferase were observed for pegozafermin 3 mg once weekly, 27 mg once weekly, and 36 mg once every 2 weeks. Significant improvements were also observed with pegozafermin treatment for triglycerides (9 mg once weekly, 27 mg once weekly, and 18 mg once every 2 weeks), LDL-C (9 mg once weekly and 27 mg once weekly), HDL-C (3 mg once weekly and 18 mg once every 2 weeks), non-HDL-C (9 mg once weekly and 27 mg once weekly), adiponectin (all doses except for 36 mg once every 2 weeks), PRO-C3 (27 mg once weekly), and bodyweight (27 mg once weekly). Changes in insulin resistance and HbA1c were not significant. INTERPRETATION: Pegozafermin was generally well tolerated and associated with clinically meaningful reductions in liver fat, measures of liver function, and circulating lipids. Further evaluation of pegozafermin in individuals with NASH is warranted. FUNDING: 89bio.

Clinical implications of COVID-19 in patients with metabolic-associated fatty liver disease.

People across the world are affected by the "coronavirus disease 2019 (COVID-19)", brought on by the "SARS-CoV type-2 coronavirus". Due to its high incidence in individuals with diabetes, metabolic syndrome, and metabolic-associated fatty liver disease (MAFLD), COVID-19 has gained much attention. The metabolic syndrome's hepatic manifestation, MAFLD, carries a significant risk of type-2-diabetes. The link between the above two conditions has also drawn increasing consideration since MAFLD is intricately linked to the obesity epidemic. Independent of the metabolic syndrome, MAFLD may impact the severity of the viral infections, including COVID-19 or may even be a risk factor. An important question is whether the present COVID-19 pandemic has been fueled by the obesity and MAFLD epidemics. Many liver markers are seen elevated in COVID-19. MAFLD patients with associated comorbid conditions like obesity, cardiovascular disease, renal disease, malignancy, hypertension, and old age are prone to develop severe disease. There is an urgent need for more studies to determine the link between the two conditions and whether it might account for racial differences in the mortality and morbidity rates linked to COVID-19. The role of innate and adaptive immunity alterations in MAFLD patients may influence the severity of COVID-19. This review investigates the implications of COVID-19 on liver injury and disease severity and vice-versa. We also addressed the severity of COVID-19 in patients with prior MAFLD and its potential implications and therapeutic administration in the clinical setting.