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1.
Cells ; 11(7)2022 Mar 24.
Article in English | MEDLINE | ID: covidwho-1785535

ABSTRACT

Sarcopenia is a common complication affecting liver disease patients, yet the underlying mechanisms remain unclear. We aimed to elucidate the cellular mechanisms that drive sarcopenia progression using an in vitro model of liver disease. C2C12 myotubes were serum and amino acid starved for 1-h and subsequently conditioned with fasted ex vivo serum from four non-cirrhotic non-alcoholic fatty liver disease patients (NAFLD), four decompensated end-stage liver disease patients (ESLD) and four age-matched healthy controls (CON) for 4- or 24-h. After 4-h C2C12 myotubes were treated with an anabolic stimulus (5 mM leucine) for 30-min. Myotube diameter was reduced following treatment with serum from ESLD compared with CON (-45%) and NAFLD (-35%; p < 0.001 for both). A reduction in maximal mitochondrial respiration (24% and 29%, respectively), coupling efficiency (~12%) and mitophagy (~13%) was identified in myotubes conditioned with NAFLD and ESLD serum compared with CON (p < 0.05 for both). Myostatin (43%, p = 0.04) and MuRF-1 (41%, p = 0.03) protein content was elevated in myotubes treated with ESLD serum compared with CON. Here we highlight a novel, experimental platform to further probe changes in circulating markers associated with liver disease that may drive sarcopenia and develop targeted therapeutic interventions.


Subject(s)
End Stage Liver Disease , Non-alcoholic Fatty Liver Disease , Sarcopenia , Humans , Muscle Fibers, Skeletal , Non-alcoholic Fatty Liver Disease/complications , Protein Biosynthesis , Sarcopenia/complications
2.
Gene ; 820: 146235, 2022 Apr 30.
Article in English | MEDLINE | ID: covidwho-1778131

ABSTRACT

The relationship of single nucleotide polymorphisms (SNPs) in patatin-like phospholipase domain containing 3 (PNPLA3) rs738409, transmembrane 6 superfamily member 2 (TM6SF2) rs58542926, and membrane bound O-acyltransferase domain containing 7 (MBOAT7) rs641738 with outcomes in patients with hepatitis C infection (HCV) is unclear. This study aimed to evaluate the association of PNPLA3, TM6SF2, and MBOAT7 with the baseline fibrosis stage and progression of liver fibrosis after HCV eradication with direct antiviral agents (DAAs). A total of 171 patients who received the DAAs at the Peking University First Hospital between June 2015 and June 2020 were included in the retrospective cohort. Transient elastography was used to determine liver stiffness measurements (LSMs) at the baseline, the end of treatment (EOT), 24 weeks after treatment (W24), and the last follow-up (LFU) visit. We used the QIAamp Blood Mini Kit (Qiagen) for whole blood genomic DNA extraction and polymerase chain reaction for PNPLA3, TM6SF2, and MBOAT7 amplification of the target gene. The PNPLA3 rs738409 SNP was associated with the baseline fibrosis stage in multivariate logistic regression analysis adjusted for other factors, and the adjusted odds ratio (OR) for advanced fibrosis (≥F3) at baseline was 2.52 (95% confidence interval[CI] = 1.096-5.794, p = 0.03). The G and GG alleles were predictive of advanced fibrosis (OR = 1.98, 95% CI = 1.021-4.196, p = 0.015; OR = 3.12, 95% CI = 1.572-6.536, p = 0.005). Similarly, the OR of TM6SF2 rs58542926 at baseline was 2.608 (95% CI = 1.081-6.29, p = 0.033). T and TT alleles were predictive of advanced fibrosis (OR = 2.3, 95% CI = 1.005-5.98, p = 0.007; OR = 3.05, 95% CI = 1.32-6.87, p = 0.001). After adjustment, the MBOAT7 rs641738 T plus TT alleles were not independently associated with the baseline fibrosis stage (95% CI = 0.707-2.959, p = 0.312). At the EOT, there were 35 patients and 136 patients in the fibrosis improvement and fibrosis non-improvement group, respectively. Logistic regression analysis showed that the G allele in PNPLA3 rs738409 was associated with fibrosis progression (OR = 2.47, 95% CI = 1.125-5.89, p = 0.003). The GG alleles were predictive of fibrosis progression (OR = 2.95, 95% CI = 1.35-6.35, p = 0.005). Similarly, the ORs of the T and TT alleles in TM6SF2 rs58542926 for fibrosis progression were 1.82 and 2.21, respectively (95% CI = 1.006-5.373, p = 0.045; 95% CI = 1.18-5.75, p = 0.01). At the W24 visit, we found that there was an association between the G allele in PNPLA3 rs738409 and fibrosis progression (OR = 2.218, 95% CI = 1.095-5.631, p = 0.015). Moreover, GG alleles were also predictive for fibrosis progression (OR = 2.558, 95% CI = 1.252-5.15, p = 0.008). Similarly, the OR of T allele and TT alleles in TM6SF2 rs58542926 for fibrosis progression was 2.056 and 2.652 (95% CI = 1.013-5.592, p = 0.038; 95% CI = 1.25-5.956, p = 0.015). For additional affirmation, we surveyed fibrosis progression utilizing the Cox proportional hazards model. G and GG alleles in PNPLA3 rs738409 were associated with an increased risk of progression to advanced fibrosis in multivariate model (hazard ratio [HR]1.566, 95% CI = 1.02-2.575, p = 0.017; and HR2.109, 95% CI = 1.36-3.271, p = 0.001, respectively). Besides, T and TT alleles in TM6SF2 rs58542926 were associated with an increased risk of progression to advanced fibrosis in multivariate model (HR = 1.322, 95% CI = 1.003-1.857, p = 0.045; and HR = 1.855, 95% CI = 1.35-2.765, p = 0.006, respectively). In contrast, rs641738 in MBOAT7 did not show a significant trend in the univariate and multivariate models. The PNPLA3 CG/GG SNP at rs738409 and TM6SF2 CT/TT SNP at rs58542926 were associated with the baseline fibrosis stage and fibrosis progression after HCV eradication with DAAs.


Subject(s)
Acyltransferases/economics , Acyltransferases/genetics , Liver Cirrhosis/genetics , Membrane Proteins/economics , Membrane Proteins/genetics , Phospholipases A2, Calcium-Independent/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Alleles , Disease Progression , Female , Genetic Predisposition to Disease , Hepacivirus , Hepatitis C/complications , Hepatitis C/virology , Humans , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/genetics , Prognosis , Retrospective Studies
3.
Can J Gastroenterol Hepatol ; 2022: 7235860, 2022.
Article in English | MEDLINE | ID: covidwho-1770044

ABSTRACT

Methods: We identified relevant cohort studies that assessed the relationship between liver fibrosis scores (e.g., FIB-4, NAFLD fibrosis score (NFS), and aspartate aminotransferase to platelet ratio index (APRI)) and associated prognosis outcomes by searching the PubMed, EMBASE, and medRxiv databases. The potential dose-response effect was performed using a stage robust error meta-regression. Results: Sixteen studies with 8,736 hospitalized patients with COVID-19 were included. One-point score in FIB-4 increase was significantly associated with increased mechanical ventilation (RR: 2.23, 95% CI: 1.37-3.65, P=0.001), severe COVID-19 (RR: 1.82, 95% CI: 1.53-2.16, P < 0.001), and death (RR: 1.47, 95% CI: 1.31-1.65, P < 0.001), rather than hospitalization (RR: 1.35, 95% CI: 0.72-2.56, P=0.35). Furthermore, there is a significant positive linear relationship between FIB-4 and severe COVID-19 (P nonlinearity=0.12) and mortality (P nonlinearity=0.18). Regarding other liver scores, one unit elevation in APRI increased the risk of death by 178% (RR: 2.78, 95% CI: 1.10-6.99, P=0.03). Higher NFS (≥-1.5) and Forns index were associated with increased risk of severe COVID-19 and COVID-19-associated death. Conclusion: Our dose-response meta-analysis suggests high liver fibrosis scores are associated with worse prognosis in patients with COVID-19. For patients with COVID-19 at admission, especially for those with coexisting chronic liver diseases, assessment of liver fibrosis scores might be useful for identifying high risk of developing severe COVID-19 cases and worse outcomes.


Subject(s)
COVID-19 , Non-alcoholic Fatty Liver Disease , COVID-19/epidemiology , Hospitalization , Humans , Liver Cirrhosis/complications , Non-alcoholic Fatty Liver Disease/complications , Respiration, Artificial/adverse effects
4.
Lancet Diabetes Endocrinol ; 10(4): 284-296, 2022 04.
Article in English | MEDLINE | ID: covidwho-1692744

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) has become an epidemic, much like other non-communicable diseases (NCDs), such as cancer, obesity, diabetes, and cardiovascular disease. The pathophysiology of NAFLD, particularly involving insulin resistance and subclinical inflammation, is not only closely linked to that of those NCDs but also to a severe course of the communicable disease COVID-19. Genetics alone cannot explain the large increase in the prevalence of NAFLD during the past 2 decades and the increase that is projected for the next decades. Impairment of glucose and lipid metabolic pathways, which has been propelled by the worldwide increase in the prevalence of obesity and type 2 diabetes, is most likely behind the increase in people with NAFLD. As the prevalence of NAFLD varies among subgroups of patients with diabetes and prediabetes identified by cluster analyses, stratification of people with diabetes and prediabetes by major pathological mechanistic pathways might improve the diagnosis of NAFLD and prediction of its progression. In this Review, we aim to understand how diabetes can affect the development of hepatic steatosis and its progression to advanced liver damage. First, we emphasise the extent to which NAFLD and diabetes jointly occur worldwide. Second, we address the major mechanisms that are involved in the pathogenesis of NAFLD and type 2 diabetes, and we discuss whether these mechanisms place NAFLD in an important position to better understand the pathogenesis of NCDs and communicable diseases, such as COVID-19. Third, we address whether this knowledge can be used for personalised treatment of NAFLD in the future. Finally, we discuss the current treatment strategies for people with type 2 diabetes and their effectiveness in treating the spectrum of hepatic diseases from simple steatosis to non-alcoholic steatohepatitis and hepatic fibrosis.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Insulin Resistance , Non-alcoholic Fatty Liver Disease , Prediabetic State , COVID-19/complications , COVID-19/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Humans , Liver/metabolism , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Prediabetic State/metabolism
5.
Nutrients ; 14(3)2022 Jan 27.
Article in English | MEDLINE | ID: covidwho-1667256

ABSTRACT

The coronavirus disease 2019 (COVID-19) lockdown dramatically changed people's lifestyles. Diet, physical activity, and the PNPLA3 gene are known risk factors for non-alcoholic fatty liver disease (NAFLD). Aim: To evaluate changes in metabolic and hepatic disease in NAFLD patients after the COVID-19 lockdown. Three hundred and fifty seven NAFLD patients were enrolled, all previously instructed to follow a Mediterranean diet (MD). Anthropometric, metabolic, and laboratory data were collected before the COVID-19 lockdown in Italy and 6 months apart, along with ultrasound (US) steatosis grading and information about adherence to MD and physical activity (PA). In 188 patients, PNPLA3 genotyping was performed. After the lockdown, 48% of patients gained weight, while 16% had a worsened steatosis grade. Weight gain was associated with poor adherence to MD (p = 0.005), reduced PA (p = 0.03), and increased prevalence of PNPLA3 GG (p = 0.04). At multivariate analysis (corrected for age, sex, MD, PA, and PNPLA3 GG), only PNPLA3 remained independently associated with weight gain (p = 0.04), which was also associated with worsened glycemia (p = 0.002) and transaminases (p = 0.02). During lockdown, due to a dramatic change in lifestyles, half of our cohort of NAFLD patients gained weight, with a worsening of metabolic and hepatologic features. Interestingly, the PNPLA3 GG genotype nullified the effect of lifestyle and emerged as an independent risk factor for weight gain, opening new perspectives in NAFLD patient care.


Subject(s)
COVID-19 , Non-alcoholic Fatty Liver Disease , Communicable Disease Control , Genotype , Humans , Life Style , Lipase/genetics , Membrane Proteins/genetics , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/genetics , SARS-CoV-2/genetics
6.
Eur J Gastroenterol Hepatol ; 33(12): 1578-1581, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1595632

ABSTRACT

AIM: Coronavirus disease 2019 (COVID-19) is a recently encountered disease that was declared a pandemic by WHO in 2020. Obesity and other components of the metabolic syndrome may aggravate the severity of COVID-19. Nonalcoholic fatty liver disease (NAFLD) represents the hepatic manifestation of metabolic syndrome. The aim of this study was to investigate a possible association between MAFLD and COVID-19 severity. METHODS: We performed a retrospective, case-control study, enrolling 71 consecutive COVID-19 patients who were divided into two groups according to the presence or absence of fatty liver by computed tomography scan. All medical records of eligible patients were reviewed including demographic, clinical, laboratory parameters and data regarding the presence of NAFLD and COVID-19 severity. RESULTS: NAFLD was identified in 22/71 (31%) of the study group. Out of 71, thirteen suffered from severe COVID-19. NAFLD patients had more severe COVID-19 compared with non-NAFLD subjects, 8/22 (36.3%) vs. 5/49(10.2%), (P < 0.005), respectively. Multiple logistic regression analysis showed that NAFLD subjects were more likely to have severe COVID-19 disease (odds ratio 3.57, 95% confidence interval: 1.22, 14.48, P = 0.0031). CONCLUSION: NAFLD represents a high risk for severe COVID-19 irrespective to gender, and independent of metabolic syndrome specifically in male gender. Moreover, obesity, hypertension and metabolic syndrome were also significantly associated with severe COVID-19.


Subject(s)
COVID-19 , Metabolic Syndrome , Non-alcoholic Fatty Liver Disease , Case-Control Studies , Humans , Male , Metabolic Syndrome/diagnosis , Metabolic Syndrome/epidemiology , Non-alcoholic Fatty Liver Disease/diagnostic imaging , Non-alcoholic Fatty Liver Disease/epidemiology , Retrospective Studies , Risk Factors , SARS-CoV-2
7.
Lancet Diabetes Endocrinol ; 9(11): 786-798, 2021 11.
Article in English | MEDLINE | ID: covidwho-1586178

ABSTRACT

Up to 50% of the people who have died from COVID-19 had metabolic and vascular disorders. Notably, there are many direct links between COVID-19 and the metabolic and endocrine systems. Thus, not only are patients with metabolic dysfunction (eg, obesity, hypertension, non-alcoholic fatty liver disease, and diabetes) at an increased risk of developing severe COVID-19 but also infection with SARS-CoV-2 might lead to new-onset diabetes or aggravation of pre-existing metabolic disorders. In this Review, we provide an update on the mechanisms of how metabolic and endocrine disorders might predispose patients to develop severe COVID-19. Additionally, we update the practical recommendations and management of patients with COVID-19 and post-pandemic. Furthermore, we summarise new treatment options for patients with both COVID-19 and diabetes, and highlight current challenges in clinical management.


Subject(s)
COVID-19/epidemiology , COVID-19/metabolism , Disease Management , Metabolic Diseases/epidemiology , Metabolic Diseases/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/therapy , Diabetes Mellitus/epidemiology , Diabetes Mellitus/metabolism , Diabetes Mellitus/therapy , Humans , Hypertension/epidemiology , Hypertension/metabolism , Hypertension/therapy , Metabolic Diseases/therapy , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/therapy , Obesity/epidemiology , Obesity/metabolism , Obesity/therapy
8.
Skelet Muscle ; 11(1): 27, 2021 12 11.
Article in English | MEDLINE | ID: covidwho-1571932

ABSTRACT

BACKGROUND: Several chronic inflammatory diseases co-exist with and accelerate sarcopenia (reduction in muscle strength, function and mass) and negatively impact on both morbidity and mortality. There is currently limited research on the extent of sarcopenia in such conditions, how to accurately assess it and whether there are generic or disease-specific mechanisms driving sarcopenia. Therefore, this study aims to identify potential mechanisms driving sarcopenia within chronic inflammatory disease via a multi-modal approach; in an attempt to help define potential interventions for future use. METHODS: This prospective cohort study will consist of a multi-modal assessment of sarcopenia and its underlying mechanisms. Recruitment will target three chronic inflammatory diseases: chronic liver disease (CLD) (n=50), with a subset of NAFLD (n=20), inflammatory bowel disease (IBD) (n=50) and rheumatoid arthritis (RA) (n=50) both before and after therapeutic intervention. In addition, 20 age and sex matched healthy individuals will be recruited for comparison. Participants will undergo 4 assessment visits at weeks 0, 2, 12 and 24. Visits will consist of the following assessments: blood tests, anthropometrics, functional assessment, quadriceps muscle imaging, actigraphy, quality of life questionnaires, food diary collection and muscle biopsy of the vastus lateralis (at weeks 2 and 24 only). In addition, stool and urine samples will be collected for future microbiome and metabolomics analysis. DISCUSSION: This is the first study to use a multi-modal assessment model to phenotype sarcopenia in these chronic inflammatory diseases. We hope to identify generic as well as disease-specific mechanisms driving sarcopenia. We appreciate that these cohorts do require separate standards of care treatments which limit comparison between groups. ETHICS AND DISSEMINATION: The study is approved by the Health Research Authority - West Midlands Solihull Research Ethics Service Committee Authority (REC reference: 18/WM/0167). Recruitment commenced in January 2019 and will continue until July 2021. The study was halted in March 2020 and again in January 2021 with the COVID-19 pandemic. The findings will be disseminated through peer-reviewed publications and conference presentations. All data will be stored on a secure server. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734496.


Subject(s)
End Stage Liver Disease/complications , Sarcopenia/etiology , Adult , Arthritis, Rheumatoid/complications , Case-Control Studies , Female , Humans , Inflammatory Bowel Diseases/complications , Male , Non-alcoholic Fatty Liver Disease/complications , Prospective Studies
9.
Nat Med ; 27(7): 1262-1271, 2021 07.
Article in English | MEDLINE | ID: covidwho-1550325

ABSTRACT

Preclinical and clinical data suggest that fibroblast growth factor 21 (FGF21) is anti-fibrotic, improves metabolic status and has potential to treat non-alcoholic steatohepatitis (NASH). We assessed the safety and efficacy of efruxifermin, a long-acting Fc-FGF21 fusion protein, for the treatment of NASH. BALANCED was a randomized, placebo-controlled study in patients with NASH conducted at 27 centers in the United States (ClinicalTrials.gov NCT03976401 ). Eighty patients, stratified by hepatic fat fraction (HFF) and fibrosis stage, were randomized using a centrally administered minimization algorithm 1:1:1:1 to receive placebo (n = 21) or efruxifermin 28 mg (n = 19), efruxifermin 50 mg (n = 20) or efruxifermin 70 mg (n = 20) via weekly subcutaneous injection for 16 weeks. The primary endpoint-absolute change from baseline in HFF measured as magnetic resonance imaging-proton density fat fraction at week 12-was met. For the full analysis set, the least squares mean absolute changes (one-sided 97.5% confidence interval) from baseline in HFF were -12.3% (-infinity (-inf), -10.3), -13.4% (-inf, -11.4) and -14.1% (-inf, -12.1) in the 28-, 50- and 70-mg groups, respectively, versus 0.3% (-inf, 1.6) in the placebo group, with statistically significant differences between efruxifermin groups and placebo (P < 0.0001 each). Overall, 70 of 79 patients who received the study drug (89%) experienced at least one treatment-emergent adverse event (TEAE), with the majority grade 1-2 (64 (81%)), five (6%) grade 3 and one grade 4. The most commonly reported drug-related TEAEs were grade 1-2 gastrointestinal (36 (46%)). Treatment with efruxifermin significantly reduced HFF in patients with F1-F3 stage NASH, with an acceptable safety profile.


Subject(s)
Fibroblast Growth Factors/therapeutic use , Immunoglobulin Fc Fragments/therapeutic use , Non-alcoholic Fatty Liver Disease/drug therapy , Recombinant Fusion Proteins/therapeutic use , Body Mass Index , Double-Blind Method , Female , Humans , Liver/pathology , Liver Cirrhosis/drug therapy , Magnetic Resonance Imaging , Male , Middle Aged , Treatment Outcome
10.
Mol Metab ; 55: 101409, 2022 01.
Article in English | MEDLINE | ID: covidwho-1540868

ABSTRACT

BACKGROUND: Chronic disease appears connected to obesity. However, evidence suggests that chronic metabolic diseases are more specifically related to adipose dysfunction rather than to body weight itself. SCOPE OF REVIEW: Further study of the first generation "insulin sensitizer" pioglitazone and molecules based on its structure suggests that is possible to decouple body weight from the metabolic dysfunction that drives adverse outcomes. The growing understanding of the mechanism of action of these agents together with advances in the pathophysiology of chronic metabolic disease offers a new approach to treat chronic conditions, such as type 2 diabetes, fatty liver disease, and their common organ and vascular sequelae. MAJOR CONCLUSIONS: We hypothesize that treating adipocyte dysfunction with new insulin sensitizers might significantly impact the interface of infectious disease and chronic metabolic disease.


Subject(s)
Chronic Disease/drug therapy , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Thiazolidinediones/pharmacology , Adipose Tissue/metabolism , COVID-19 , Diabetes Mellitus, Type 2/metabolism , Humans , Inflammation , Insulin/metabolism , Insulin Resistance , Metabolic Diseases/metabolism , Mitochondria , Non-alcoholic Fatty Liver Disease , Pioglitazone/metabolism
11.
BMC Gastroenterol ; 21(1): 439, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1533247

ABSTRACT

BACKGROUND AND AIMS: Some, but not all, prior studies have suggested that patients with chronic liver disease are at increased risk of contracting COVID-19 and developing more severe disease. However, nationwide data are lacking from well-phenotyped cohorts with liver histology and comparisons to matched general population controls. METHODS: We conducted a nationwide cohort study of all Swedish adults with chronic liver disease (CLD) confirmed by liver biopsy between 1966 and 2017 (n = 42,320), who were alive on February 1, 2020. CLD cases were matched to ≤ 5 population comparators by age, sex, calendar year and county (n = 182,147). Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for COVID-19 hospitalization and severe COVID-19 (intensive care admission or death due to COVID-19). RESULTS: Between February 1 and July 31, 2020, 161 (0.38%) CLD patients and 435 (0.24%) general population controls were hospitalized with COVID-19 (aHR = 1.36, 95% CI = 1.11-1.66), while 65 (0.15%) CLD patients and 191 (0.10%) controls developed severe COVID-19 (aHR = 1.08, 95% CI = 0.79-1.48). Results were similar in patients with CLD due to alcohol use, nonalcoholic fatty liver disease, viral hepatitis, autoimmune hepatitis, and other etiologies. Among patients with cirrhosis (n = 2549), the aHRs for COVID-19 hospitalization and for severe COVID-19 were 1.08 (95% CI 0.48-2.40) and 1.23 (95% CI = 0.37-4.04), respectively, compared to controls. Moreover, among all patients diagnosed with COVID-19, the presence of underlying CLD was not associated with increased mortality (aHR = 0.85, 95% CI = 0.61-1.19). CONCLUSIONS: In this nationwide cohort, patients with CLD had a higher risk of hospitalization for COVID-19 compared to the general population, but they did not have an increased risk of developing severe COVID-19.


Subject(s)
COVID-19 , Non-alcoholic Fatty Liver Disease , Adult , Cohort Studies , Humans , Liver Cirrhosis/epidemiology , Risk Factors , SARS-CoV-2
13.
J Cell Mol Med ; 25(24): 11212-11220, 2021 12.
Article in English | MEDLINE | ID: covidwho-1511334

ABSTRACT

This study aims to evaluate the effect of non-alcoholic fatty liver disease (NAFLD) on the susceptibility and consequences of coronavirus disease 2019 (COVID-19). We retrospectively collected data from 218 adult COVID-19 patients who showed no evidence of excessive alcohol consumption and underwent abdominal ultrasound examinations. Of these patients, 39.4% patients had been diagnosed with NAFLD, which indicates a much higher prevalence of NAFLD than that reported in the general population. Significantly elevated white blood cell count (p = 0.008), alanine aminotransferase (p = 0.000), aspartate aminotransferase (p = 0.006) and C reactive protein (p = 0.012) were found in the patients with NAFLD. These patients also had significantly higher proportions of hypertension (p = 0.006) and diabetes (p = 0.049) than the non-NAFLD cases. No significant differences existed in the severity, mortality, viral shedding time and length of hospital stay between patients with or without NAFLD in the sample population. However, subgroup analyses found that in patients with normal body mass index (BMI), NAFLD sufferers were more likely to experience a severe event (30.0% vs 11.5%, p = 0.021). Kaplan-Meier curve (log-rank p = 0.017) and Cox regression (HR = 3.26, 95% CI: 1.17-9.04, p = 0.023) analyses confirmed that before and after adjusting for gender, age and comorbidities, NAFLD patients with normal BMI had a higher incidence of suffering severe events. People with NAFLD may have a higher proportion of COVID-19. NAFLD may be correlated with the severity of COVID-19 patients in the normal BMI group.


Subject(s)
COVID-19/etiology , Non-alcoholic Fatty Liver Disease/etiology , Adult , Aged , Aged, 80 and over , Blood Chemical Analysis , Body Mass Index , COVID-19/epidemiology , COVID-19/therapy , Comorbidity , Disease Susceptibility , Female , Humans , Incidence , Kaplan-Meier Estimate , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/epidemiology , Prevalence , Retrospective Studies , Virus Shedding , Young Adult
14.
Mol Syst Biol ; 17(10): e10459, 2021 10.
Article in English | MEDLINE | ID: covidwho-1498031

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.


Subject(s)
Non-alcoholic Fatty Liver Disease , Animals , Diet, High-Fat , Humans , Inflammation , Liver , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/drug therapy , Weight Loss
15.
Molecules ; 26(21)2021 Oct 31.
Article in English | MEDLINE | ID: covidwho-1488679

ABSTRACT

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.


Subject(s)
Liver/drug effects , Liver/injuries , Zinc/pharmacology , COVID-19/complications , COVID-19/drug therapy , Chelating Agents/metabolism , Copper/metabolism , Hepatolenticular Degeneration/complications , Hepatolenticular Degeneration/drug therapy , Hepatolenticular Degeneration/metabolism , Humans , Liver/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , SARS-CoV-2/pathogenicity , Zinc/deficiency , Zinc/metabolism
16.
J Korean Med Sci ; 36(41): e291, 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1485031

ABSTRACT

BACKGROUND: Evidence for the association between underlying non-alcoholic fatty liver disease (NAFLD), the risk of testing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive, and the clinical consequences of coronavirus disease 2019 (COVID-19) is controversial and scarce. We aimed to investigate the association between the presence of NAFLD and the risk of SARS-CoV-2 infectivity and COVID-19-related outcomes. METHODS: We used the population-based, nationwide cohort in South Korea linked with the general health examination records between January 1, 2018 and July 30, 2020. Data for 212,768 adults older than 20 years who underwent SARS-CoV-2 testing from January 1 to May 30, 2020, were obtained. The presence of NAFLDs was defined using three definitions, namely hepatic steatosis index (HSI), fatty liver index (FLI), and claims-based definition. The outcomes were SARS-CoV-2 test positive, COVID-19 severe illness, and related death. RESULTS: Among 74,244 adults who completed the general health examination, there were 2,251 (3.0%) who were SARS-CoV-2 positive, 438 (0.6%) with severe COVID-19 illness, and 45 (0.06%) COVID-19-related deaths. After exposure-driven propensity score matching, patients with pre-existing HSI-NAFLD, FLI-NAFLD, or claims-based NAFLD had an 11-23% increased risk of SARS-CoV-2 infection (HSI-NAFLD 95% confidence interval [CI], 1-28%; FLI-NAFLD 95% CI, 2-27%; and claims-based NAFLD 95% CI, 2-31%) and a 35-41% increased risk of severe COVID-19 illness (HSI-NAFLD 95% CI, 8-83%; FLI-NAFLD 95% CI, 5-71%; and claims-based NAFLD 95% CI, 1-92%). These associations are more evident as liver fibrosis advanced (based on the BARD scoring system). Similar patterns were observed in several sensitivity analyses including the full-unmatched cohort. CONCLUSION: Patients with pre-existing NAFLDs have a higher likelihood of testing SARS-CoV-2 positive and severe COVID-19 illness; this association was more evident in patients with NAFLD with advanced fibrosis. Our results suggest that extra attention should be given to the management of patients with NAFLD during the COVID-19 pandemic.


Subject(s)
COVID-19/etiology , Non-alcoholic Fatty Liver Disease/complications , SARS-CoV-2 , Adult , Aged , Cohort Studies , Disease Susceptibility , Female , Humans , Male , Middle Aged , Severity of Illness Index
18.
Expert Rev Clin Pharmacol ; 14(4): 457-464, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1467264

ABSTRACT

INTRODUCTION: Galectin-3 (Gal-3) is a ß-galactoside binding protein associated with many disease pathologies, including chronic inflammation and fibrogenesis. It has been implicated in the disease severity of NASH, although its precise role is unknown. Inhibition of Gal-3 has shown to improve and prevent fibrosis progression and has now reached phase III clinical trial in NASH patients. AREAS COVERED: This discusses the role of Gal-3 in NASH. It brings together the current findings of Gal-3 in NASH and hepatic fibrosis by analyzing recent data from animal model studies and clinical trials. EXPERT OPINION: Gal-3 inhibitors, in particular, Belapectin (GR-MD-02), have shown promising results for NASH with advanced fibrosis. In a phase 2 trial, Belapectin did not meet the primary endpoint. However, a sub-analysis of Belapectin among a separate group of patients without esophageal varices showed 2 mg/kg of GR-MD-02 reduced HVPG and the development of new varices. A subsequent study is under way, aiming to replicate the positive findings in phase 2 and demonstrate greater efficacy. If Belapectin is shown to be effective, it will be coupled with other drugs that target steatohepatitis to maximize efficacy and disease reversal.


Subject(s)
Blood Proteins/antagonists & inhibitors , Galectins/antagonists & inhibitors , Liver Cirrhosis/drug therapy , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , Disease Models, Animal , Disease Progression , Humans , Liver Cirrhosis/metabolism , Liver Cirrhosis/physiopathology , Non-alcoholic Fatty Liver Disease/physiopathology , Pectins/administration & dosage , Pectins/pharmacology , Severity of Illness Index
19.
Hepatology ; 74(6): 3316-3329, 2021 12.
Article in English | MEDLINE | ID: covidwho-1458999

ABSTRACT

BACKGROUND AND AIMS: The surge in unhealthy alcohol use during the COVID-19 pandemic may have detrimental effects on the rising burden of alcohol-associated liver disease (ALD) on liver transplantation (LT) in the USA. We evaluated the effect of the pandemic on temporal trends for LT including ALD. APPROACH AND RESULTS: Using data from United Network for Organ Sharing, we analyzed wait-list outcomes in the USA through March 1, 2021. In a short-period analysis, patients listed or transplanted between June 1, 2019, and February 29, 2020, were defined as the "pre-COVID" era, and after April 1, 2020, were defined as the "COVID" era. Interrupted time-series analyses using monthly count data from 2016-2020 were constructed to evaluate the rate change for listing and LT before and during the COVID-19 pandemic. Rates for listings (P = 0.19) and LT (P = 0.14) were unchanged during the pandemic despite a significant reduction in the monthly listing rates for HCV (-21.69%, P < 0.001) and NASH (-13.18%; P < 0.001). There was a significant increase in ALD listing (+7.26%; P < 0.001) and LT (10.67%; P < 0.001) during the pandemic. In the COVID era, ALD (40.1%) accounted for more listings than those due to HCV (12.4%) and NASH (23.4%) combined. The greatest increase in ALD occurred in young adults (+33%) and patients with severe alcohol-associated hepatitis (+50%). Patients with ALD presented with a higher acuity of illness, with 30.8% of listings and 44.8% of LT having a Model for End-Stage Liver Disease-Sodium score ≥30. CONCLUSIONS: Since the start of COVID-19 pandemic, ALD has become the most common indication for listing and the fastest increasing cause for LT. Collective efforts are urgently needed to stem the rising tide of ALD on health care resources.


Subject(s)
Alcohol Drinking/adverse effects , COVID-19/complications , Liver Diseases, Alcoholic/etiology , Liver Transplantation/statistics & numerical data , Adult , Aged , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Cost of Illness , End Stage Liver Disease/epidemiology , End Stage Liver Disease/etiology , Female , Health Care Rationing/statistics & numerical data , Health Care Rationing/trends , Hepatitis, Alcoholic/epidemiology , Hepatitis, Alcoholic/etiology , Humans , Interrupted Time Series Analysis/methods , Liver Diseases, Alcoholic/epidemiology , Liver Diseases, Alcoholic/surgery , Liver Transplantation/trends , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/etiology , Retrospective Studies , SARS-CoV-2/genetics , Severity of Illness Index , Time Factors , United States/epidemiology , Waiting Lists
20.
J Hepatol ; 75(2): 439-441, 2021 08.
Article in English | MEDLINE | ID: covidwho-1454288

ABSTRACT

BACKGROUND & AIMS: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD. METHODS: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination. RESULTS: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m2 (IQR 23.8-28.1 kg/m2). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained. CONCLUSIONS: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD. LAY SUMMARY: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 , Immunogenicity, Vaccine/immunology , Non-alcoholic Fatty Liver Disease , Vaccination , Vaccines, Inactivated , Adult , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , China/epidemiology , Female , Humans , Male , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/epidemiology , Outcome Assessment, Health Care , SARS-CoV-2/immunology , Vaccination/adverse effects , Vaccination/methods , Vaccination/statistics & numerical data , Vaccines, Inactivated/administration & dosage , Vaccines, Inactivated/adverse effects
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