COVID-19 and MAFLD/NAFLD: An updated review.

The COVID-19 pandemic is ongoing and places a substantial burden on healthcare systems worldwide. As we further shed light on different disease characteristics, we identify more and more groups of people at higher risk of poor COVID-19 outcomes. Metabolic-associated fatty liver disease (MAFLD) (previously non-alcoholic fatty liver disease or NAFLD) is a common metabolic disorder characterized by fat accumulation and liver fibrosis. Given its close correlation with metabolic syndrome, an established risk factor for severe COVID-19, it is necessary to investigate its interplay with the novel coronavirus. In this study, we review the available data on COVID-19 prognosis, treatment and prevention options in patients with MAFLD, and the effect that the disease and the pandemic have on MAFLD care. Furthermore, we point out the gaps in the current literature to accentuate the work that needs to be done to improve MAFLD care during the pandemic and beyond.

Infection prevention and control programme and COVID-19 measures: Effects on hospital-acquired infections in patients with cirrhosis.

Background & Aims: Bacterial infections affect survival of patients with cirrhosis. Hospital-acquired bacterial infections present a growing healthcare problem because of the increasing prevalence of multidrug-resistant organisms. This study aimed to investigate the impact of an infection prevention and control programme and coronavirus disease 2019 (COVID-19) measures on the incidence of hospital-acquired infections and a set of secondary outcomes, including the prevalence of multidrug-resistant organisms, empiric antibiotic treatment failure, and development of septic states in patients with cirrhosis. Methods: The infection prevention and control programme was a complex strategy based on antimicrobial stewardship and the reduction of patient's exposure to risk factors. The COVID-19 measures presented further behavioural and hygiene restrictions imposed by the Hospital and Health Italian Sanitary System recommendations. We performed a combined retrospective and prospective study in which we compared the impact of extra measures against the hospital standard. Results: We analysed data from 941 patients. The infection prevention and control programme was associated with a reduction in the incidence of hospital-acquired infections (17 vs. 8.9%, p <0.01). No further reduction was present after the COVID-19 measures had been imposed. The impact of the infection prevention and control programme remained significant even after controlling for the effects of confounding variables (odds ratio 0.44, 95% CI 0.26-0.73, p = 0.002). Furthermore, the adoption of the programme reduced the prevalence of multidrug-resistant organisms and decreased rates of empiric antibiotic treatment failure and the development of septic states. Conclusions: The infection prevention and control programme decreased the incidence of hospital-acquired infections by nearly 50%. Furthermore, the programme also reduced the prevalence of most of the secondary outcomes. Based on the results of this study, we encourage other liver centres to adopt infection prevention and control programmes. Impact and implications: Infections are a life-threatening problem for patients with liver cirrhosis. Moreover, hospital-acquired infections are even more alarming owing to the high prevalence of multidrug-resistant bacteria. This study analysed a large cohort of hospitalised patients with cirrhosis from three different periods. Unlike in the first period, an infection prevention programme was applied in the second period, reducing the number of hospital-acquired infections and containing multidrug-resistant bacteria. In the third period, we imposed even more stringent measures to minimise the impact of the COVID-19 outbreak. However, these measures did not result in a further reduction in hospital-acquired infections.

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.

Non-alcoholic fatty liver disease and COVID-19: Harmless companions or disease intensifier?

The pandemics of coronavirus disease 2019 (COVID-19) and non-alcoholic fatty liver disease (NAFLD) coexist. Elevated liver function tests are frequent in COVID-19 and may influence liver damage in NAFLD, while preexisting liver damage from NAFLD may influence the course of COVID-19. However, the prognostic relevance of this interaction, though, is unclear. Obesity is a risk factor for the presence of NAFLD as well as a severe course of COVID-19. Cohort studies reveal conflicting results regarding the influence of NAFLD presence on COVID-19 illness severity. Striking molecular similarities of cytokine pathways in both diseases, including postacute sequelae of COVID-19, suggest common pathways for chronic low-activity inflammation. This review will summarize existing data regarding the interaction of both diseases and discuss possible mechanisms of the influence of one disease on the other.

Diet-Induced Obesity and NASH Impair Disease Recovery in SARS-CoV-2-Infected Golden Hamsters.

Obese patients with non-alcoholic steatohepatitis (NASH) are prone to severe forms of COVID-19. There is an urgent need for new treatments that lower the severity of COVID-19 in this vulnerable population. To better replicate the human context, we set up a diet-induced model of obesity associated with dyslipidemia and NASH in the golden hamster (known to be a relevant preclinical model of COVID-19). A 20-week, free-choice diet induces obesity, dyslipidemia, and NASH (liver inflammation and fibrosis) in golden hamsters. Obese NASH hamsters have higher blood and pulmonary levels of inflammatory cytokines. In the early stages of a SARS-CoV-2 infection, the lung viral load and inflammation levels were similar in lean hamsters and obese NASH hamsters. However, obese NASH hamsters showed worse recovery (i.e., less resolution of lung inflammation 10 days post-infection (dpi) and lower body weight recovery on dpi 25). Obese NASH hamsters also exhibited higher levels of pulmonary fibrosis on dpi 25. Unlike lean animals, obese NASH hamsters infected with SARS-CoV-2 presented long-lasting dyslipidemia and systemic inflammation. Relative to lean controls, obese NASH hamsters had lower serum levels of angiotensin-converting enzyme 2 activity and higher serum levels of angiotensin II-a component known to favor inflammation and fibrosis. Even though the SARS-CoV-2 infection resulted in early weight loss and incomplete body weight recovery, obese NASH hamsters showed sustained liver steatosis, inflammation, hepatocyte ballooning, and marked liver fibrosis on dpi 25. We conclude that diet-induced obesity and NASH impair disease recovery in SARS-CoV-2-infected hamsters. This model might be of value for characterizing the pathophysiologic mechanisms of COVID-19 and evaluating the efficacy of treatments for the severe forms of COVID-19 observed in obese patients with NASH.

Liver Fibrosis Indices Predict the Severity of SARS-CoV-2 Infection.

Discovering novel risk and prognostic factors for COVID-19 may help not only in reducing severity and mortality but also in creating targeted therapies considering patients' individual features. Liver fibrosis is considered a complication in Non-alcoholic Fatty Liver Disease (NAFLD), it is a feature of steatohepatitis (NASH), and it has already been related to an increased risk for a wide range of diseases. Here, we aimed to define if any parameter assessing metabolic status has predictive power in identifying inpatients at risk for poorer prognosis and an increased mortality from COVID-19. This retrospective study was conducted at the Sub-Intensive Medicine Care Unit of the Presidio Maxi-Emergenze Fiera del Levante, Azienda Ospedaliero-Universitaria Policlinico di Bari, Italy. We evaluated 271 inpatients with moderate-to-severe SARS-CoV-2-related respiratory failure by comparing biochemical features and non-invasive liver fibrosis scores among discharged, transferred to Intensive Care Units (ICU) and non-survivor patients. Moreover, by performing ROC curves, we defined cut-off values to predict mortality and disease severity for each score. We found that non-invasive scores of liver fibrosis, obtained at day of admission, such as AAR (p < 0.001), FIB-4 and mFIB-4, FORNS, and AARPRI (p < 0.05) strongly predict not only in-hospital mortality but also the length of hospitalization and eventual admission to ICU. FIB-4 was the best score to identify non-survivor patients (sensitivity of 80% and specificity of 63%) and predict the need for ICU or mortality (71% of sensitivity and 65% of specificity), with a cut-off value of 1.94. Therefore, we present the predictive power and the cut-off values of several liver fibrosis scores here for disease severity and mortality in SARS-CoV-2 in-patients and we proposed the use of the present scores to identify ab initio the clinical therapeutic and diagnostic protocols for high-risk patients.

Clinical Interest of Serum Alpha-2 Macroglobulin, Apolipoprotein A1, and Haptoglobin in Patients with Non-Alcoholic Fatty Liver Disease, with and without Type 2 Diabetes, before or during COVID-19.

In patients with non-alcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM), alpha-2 macroglobulin (A2M), apolipoprotein A1 (ApoA1), and haptoglobin are associated with the risk of liver fibrosis, inflammation (NASH), and COVID-19. We assessed if these associations were worsened by T2DM after adjustment by age, sex, obesity, and COVID-19. Three datasets were used: the "Control Population", which enabled standardization of protein serum levels according to age and sex (N = 27,382); the "NAFLD-Biopsy" cohort for associations with liver features (N = 926); and the USA "NAFLD-Serum" cohort for protein kinetics before and during COVID-19 (N = 421,021). The impact of T2DM was assessed by comparing regression curves adjusted by age, sex, and obesity for the liver features in "NAFLD-Biopsy", and before and during COVID-19 pandemic peaks in "NAFLD-Serum". Patients with NAFLD without T2DM, compared with the values of controls, had increased A2M, decreased ApoA1, and increased haptoglobin serum levels. In patients with both NAFLD and T2DM, these significant mean differences were magnified, and even more during the COVID-19 pandemic in comparison with the year 2019 (all p < 0.001), with a maximum ApoA1 decrease of 0.21 g/L in women, and a maximum haptoglobin increase of 0.17 g/L in men. In conclusion, T2DM is associated with abnormal levels of A2M, ApoA1, and haptoglobin independently of NAFLD, age, sex, obesity, and COVID-19.

Outcomes of COVID-19 in Patients with Cirrhosis or Liver Transplantation.

Coronavirus disease 2019 (COVID-19) is associated with a significant morbidity and mortality in patients with cirrhosis. There is a significantly higher morbidity and mortality due to COVID-19 in patients with decompensated cirrhosis as compared to compensated cirrhosis, and in patients with cirrhosis as compared to noncirrhotic chronic liver disease. The fear of COVID-19 before or after liver transplantation has lead to a significant reduction in liver transplantation numbers, and patients with decompensated cirrhosis remain at risk of wait list mortality. The studies in liver transplantation recipients show that risk of mortality due to COVID-19 is generally driven by higher age and comorbidities. The current review discusses available literature regarding outcomes of COVID-19 in patients with cirrhosis and outcomes in liver transplant recipients.

Incidence, characteristics, and outcome of COVID-19 in patients on liver transplant program: a retrospective study in the north of Iran.

The risk of severe coronavirus disease-2019 (COVID-19) disease seems to be higher in individuals with solid organ transplantation. Therefore, the purpose of the present research is to investigate the incidence of COVID-19 and laboratory data and epidemiologic factors in liver transplant recipients and the patients on the waiting list for liver transplantation. In this study, we evaluated the records of patients on the waiting list for liver transplantation and of recipients of a liver transplant. Demographic data, underlying disease, history of drug use and participants' outcomes were collected. The diagnosis of SARS-CoV-2 infection for all patients was confirmed using a nasopharyngeal swab specimen with real-time RT-PCR. During the study period, 172 patients were enrolled, among whom 85 patients (49.4%) were on the waiting list for liver transplantation, and 87 patients (50.6%) were recipients of a liver transplant. Out of them, 10 (5.8%) had a positive result for SARS-CoV-2. Of these patients, 7.05% (6/85) and 4.6% (4/87) of patients on the waiting list and recipients of liver transplants were positive for SARS-CoV-2, respectively. Patients on the waiting list with COVID-19 infection had a higher median of albumin, ALT, AST, TBIL, DBIL, HDL and LDL value. In summary, the incidence of COVID-19 in liver transplant patients was slightly higher. The existence of underlying liver diseases should be well known as one of the poor predictive factors for worse outcomes in patients with COVID-19. So, comparative studies are recommended to identify risk factors for COVID-19 in patients with liver injury.

FibroScan-AST Score Predicts 30-Day Mortality or Need for Mechanical Ventilation among Patients Hospitalized with COVID-19.

BACKGROUND: Liver involvement in Coronavirus disease 2019 (COVID-19) has been recognised. We aimed to investigate the correlation of non-invasive surrogates of liver steatosis, fibrosis and inflammation using transient elastography (TE) and FibroScan-AST (FAST) score with (a) clinical severity and (b) 30-day composite outcome of mechanical ventilation (MV) or death among patients hospitalized due to COVID-19. METHOD: Patients with non-critical COVID-19 at admission were included. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed by TE. Clinical severity of COVID-19 was assessed by 4C Mortality Score (4CMS) and need for high-flow nasal cannula (HFNC) oxygen supplementation. RESULTS: 217 patients were included (66.5% males, median age 65 years, 4.6% with history of chronic liver disease). Twenty-four (11.1%) patients met the 30-day composite outcome. Median LSM, CAP and FAST score were 5.2 kPa, 274 dB/m and 0.31, respectively, and neither was associated with clinical severity of COVID-19 at admission. In multivariate analysis FAST > 0.36 (OR 3.19, p = 0.036), 4CMS (OR 1.68, p = 0.002) and HFNC (OR 7.03, p = 0.001) were independent predictors of adverse composite outcome. CONCLUSION: Whereas LSM and CAP failed to show correlation with COVID-19 severity and outcomes, FAST score was an independent risk factor for 30-day mortality or need for MV.

Impact of Fibrosis-4 Index Prior to COVID-19 on Outcomes in Patients at Risk of Non-alcoholic Fatty Liver Disease.

BACKGROUND: Severity of disease and outcomes in patient with COVID-19 has been associated with several risk factors tied to the metabolic syndrome. AIMS: We conducted a study with the objective of describing the association between the baseline Fibrosis-4 (FIB-4) index prior to SARS-CoV-2 infection and the severity of COVID-19 among patients at risk of non-alcoholic fatty liver disease (NAFLD). METHODS: This was a retrospective cohort study of patients with at least two risk factors for metabolic syndrome diagnosed with COVID-19. The main exposure of interest was FIB-4 index prior to infection, categorized into three previously validated age-specific levels. The main outcomes of interest were disease requiring hospitalization and in-hospital mortality. RESULTS: We included 373 patients [median age, 62 years; 194 male (52%); median number of metabolic syndrome risk factors, 3]. The median FIB-4 index was 1.10 (interquartile range 0.78-1.61). In models adjusting for diabetes mellitus and chronic kidney disease, patients with intermediate FIB-4 index had 67% higher odds of hospitalization compared to those in the low category {odds ratio (OR) 1.67 [(95% CI 1.06-2.64); p = 0.03]} and patients with high FIB-4 index had higher odds of mortality compared to intermediate and low category with an OR 2.22 (95% CI 1.20-4.12; p = 0.01). However, when we evaluated components of FIB-4 (age and AST/ALT ratio), we found that age alone was the best predictor of hospitalization and mortality. CONCLUSIONS: Among patients at risk of NAFLD with COVID-19 infection, elevated pre-infection FIB-4 index was associated with worsened clinical outcomes, but age was the strongest predictor.

Infections at the nexus of metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) is a chronic liver disease that affects about a quarter of the world population. MAFLD encompasses different disease stadia ranging from isolated liver steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma. Although MAFLD is considered as the hepatic manifestation of the metabolic syndrome, multiple concomitant disease-potentiating factors can accelerate disease progression. Among these risk factors are diet, lifestyle, genetic traits, intake of steatogenic drugs, male gender and particular infections. Although infections often outweigh the development of fatty liver disease, pre-existing MAFLD could be triggered to progress towards more severe disease stadia. These combined disease cases might be underreported because of the high prevalence of both MAFLD and infectious diseases that can promote or exacerbate fatty liver disease development. In this review, we portray the molecular and cellular mechanisms by which the most relevant viral, bacterial and parasitic infections influence the progression of fatty liver disease and steatohepatitis. We focus in particular on how infectious diseases, including coronavirus disease-19, hepatitis C, acquired immunodeficiency syndrome, peptic ulcer and periodontitis, exacerbate MAFLD. We specifically underscore the synergistic effects of these infections with other MAFLD-promoting factors.

Impact of COVID-19 on the management of hepatocellular carcinoma in a high-prevalence area.

BACKGROUND & AIMS: Patients affected by hepatocellular carcinoma (HCC) represent a vulnerable population during the COVID-19 pandemic and may suffer from altered allocation of healthcare resources. The aim of this study was to determine the impact of the COVID-19 pandemic on the management of patients with HCC within 6 referral centres in the metropolitan area of Paris, France. METHODS: We performed a multicentre, retrospective, cross-sectional study on the management of patients with HCC during the first 6 weeks of the COVID-19 pandemic (exposed group), compared with the same period in 2019 (unexposed group). We included all patients discussed in multidisciplinary tumour board (MTB) meetings and/or patients undergoing a radiological or surgical programmed procedure during the study period, with curative or palliative intent. Endpoints were the number of patients with a modification in the treatment strategy, or a delay in decision-to-treat. RESULTS: After screening, n = 670 patients were included (n = 293 exposed to COVID, n = 377 unexposed to COVID). Fewer patients with HCC presented to the MTB in 2020 (p = 0.034) and fewer had a first diagnosis of HCC (n = 104 exposed to COVID, n = 143 unexposed to COVID, p = 0.083). Treatment strategy was modified in 13.1% of patients, with no differences between the 2 periods. Nevertheless, 21.5% vs. 9.5% of patients experienced a treatment delay longer than 1 month in 2020 compared with 2019 (p <0.001). In 2020, 7.1% (21/293) of patients had a diagnosis of an active COVID-19 infection: 11 (52.4%) patients were hospitalised and 4 (19.1%) patients died. CONCLUSIONS: In a metropolitan area highly impacted by the COVID-19 pandemic, we observed fewer patients with HCC, and similar rates of treatment modification, but with a significantly longer treatment delay in 2020 vs. 2019. LAY SUMMARY: During the coronavirus disease 2019 (COVID-19) pandemic era, fewer patients with hepatocellular carcinoma (HCC) presented to the multidisciplinary tumour board, especially with a first diagnosis of HCC. Patients with HCC had a treatment delay that was longer in the COVID-19 period than in 2019.

The incidence of COVID-19 in patients with metabolic syndrome and non-alcoholic steatohepatitis: A population-based study.

BACKGROUND: The novel coronavirus disease (COVID-19) emerged from China in 2019 and rapidly spread worldwide. Patients with metabolic comorbid conditions are more susceptible to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Metabolic syndrome is a constellation of interlinked metabolic risk factors that predispose patients to increased risk of complications. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and non-alcoholic steatohepatitis (NASH) is the aggressive form of NAFLD. OBJECTIVE: The aim of this study is to determine the relationship between metabolic syndrome components and the risk of COVID-19. METHODS: We reviewed data from a large commercial database (Explorys IBM) that aggregates electronic health records from 26 large nationwide healthcare systems. Using systemized nomenclature of clinical medical terms (SNOMED-CT), we identified adults with the diagnosis of metabolic syndrome and its individual components from 1999 to 2019. We included patients with the diagnosis of COVID-19 from December 2019 to May 2020. Comorbidities known to be associated with COVID-19 and metabolic syndrome such as obesity, diabetes mellitus, dyslipidemia, smoking, male gender, African American, and hypertension were collected. Univariable and multivariable analyses were performed to investigate whether metabolic syndrome or its individual components are independently associated with the risk of COVID-19. RESULTS: Out of 61.4 million active adult patients in the database, 8885 (0.01%) had documented COVID-19. The cumulative incidence of COVID-19 was higher if metabolic syndrome was the primary diagnosis (0.10% vs 0.01%, OR 7.00 [6.11-8.01]). The adjusted odds (aOR) of having COVID-19 was higher in patients if they were African Americans (aOR 7.45 [7.14-7.77]), hypertensive (aOR 2.53 [2.40-2.68]), obese (aOR 2.20 [2.10-2.32]), diabetic (aOR 1.41 [1.33-1.48]), hyperlipidemic (aOR 1.70 [1.56-1.74]), or diagnosed with NASH (aOR 4.93 [4.06-6.00]). There was a slight decrease in the adjusted odds of having COVID-19 in males as compared to females (aOR 0.88 [0.84-0.92]). CONCLUSION: The incidence of COVID-19 in patients with metabolic syndrome is high. Among all comorbid metabolic conditions, NASH had the strongest association with COVID-19.

Impact of COVID-19 on the care of patients with liver disease: EASL-ESCMID position paper after 6 months of the pandemic.

During the early stages of the coronavirus disease 2019 (COVID-19) pandemic, EASL and ESCMID published a position paper to provide guidance for physicians involved in the care of patients with chronic liver disease. While some healthcare systems are returning to a more normal routine, many countries and healthcare systems have been, or still are, overwhelmed by the pandemic, which is significantly impacting on the care of these patients. In addition, many studies have been published focusing on how COVID-19 may affect the liver and how pre-existing liver diseases might influence the clinical course of COVID-19. While many aspects remain poorly understood, it has become increasingly evident that pre-existing liver diseases and liver injury during the disease course must be kept in mind when caring for patients with COVID-19. This review should serve as an update on the previous position paper, summarising the evidence for liver disease involvement during COVID-19 and providing recommendations on how to return to routine care wherever possible.

Care of patients with liver disease during the COVID-19 pandemic: EASL-ESCMID position paper.

The coronavirus disease 2019 (COVID-19) pandemic poses an enormous challenge to healthcare systems in affected communities. Older patients and those with pre-existing medical conditions have been identified as populations at risk of a severe disease course. It remains unclear at this point to what extent chronic liver diseases should be considered as risk factors, due to a shortage of appropriate studies. However, patients with advanced liver disease and those after liver transplantation represent vulnerable patient cohorts with an increased risk of infection and/or a severe course of COVID-19. In addition, the current pandemic requires unusual allocation of healthcare resources which may negatively impact the care of patients with chronic liver disease that continue to require medical attention. Thus, the challenge hepatologists are facing is to promote telemedicine in the outpatient setting, prioritise outpatient contacts, avoid nosocomial dissemination of the virus to patients and healthcare providers, and at the same time maintain standard care for patients who require immediate medical attention.