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1.
N Engl J Med ; 387(6): 514-524, 2022 08 11.
Article in English | MEDLINE | ID: covidwho-2031920

ABSTRACT

BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency. METHODS: We assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography-mass spectrometry. RESULTS: All the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved. CONCLUSIONS: In this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).


Subject(s)
Liver Cirrhosis , RNAi Therapeutics , alpha 1-Antitrypsin Deficiency , alpha 1-Antitrypsin , Adult , Genotype , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Injections, Subcutaneous , Liver/drug effects , Liver/enzymology , Liver/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/etiology , Liver Cirrhosis/genetics , Mutation , RNAi Therapeutics/adverse effects , RNAi Therapeutics/methods , alpha 1-Antitrypsin/analysis , alpha 1-Antitrypsin/blood , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/complications , alpha 1-Antitrypsin Deficiency/drug therapy , alpha 1-Antitrypsin Deficiency/genetics
2.
JAMA Surg ; 157(8): 742, 2022 08 01.
Article in English | MEDLINE | ID: covidwho-2030925
3.
Eur J Gastroenterol Hepatol ; 34(9): 933-939, 2022 09 01.
Article in English | MEDLINE | ID: covidwho-2029141

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants have become the dominant variants worldwide, and studies focused on liver injury in these patients are limited. MATERIALS AND METHODS: In this study, 157 SARS-CoV-2-infected patients were enrolled, including 77 Delta variant-infected patients and 80 Omicron variant-infected patients. Liver injury data and clinical data were summarized and compared between patients infected with the two variants, additionally, patients with or without liver injury were also compared and multivariate analysis was performed to explore the predictive factors related to liver injury in SARS-CoV-2-infected patients. RESULTS: Liver injury was found in 18 (23.4%)/15 (18.8%) in Delta/Omicron variant-infected patients on admission, and 4 (5.2%)/1 (1.3%) in Delta/Omicron variant-infected patients during hospitalization, respectively. The ratios of liver injury did not differ between the two groups ( χ2 = 1.571; P = 0.210). Among these patients, 17 (77.3%) and 12 (75.0%) Delta and Omicron variant-infected patients were considered to be related to SARS-CoV-2 infection, the biomarkers of liver function were mildly elevated, dominated by the parameter of cholangiocyte injury: 76.5% (13/17) and 83.3% (10/12) in Delta and Omicron variant-infected patients, and most of these patients recovered to normal during follow-up. Multivariate analysis showed that male sex [odds ratio (OR), 4.476; 95% confidence interval (CI), 1.235-16.222; P = 0.023] and high levels of peak viral load in the nasopharynx (OR, 3.022; 95% CI, 1.338-6.827; P = 0.008) were independent factors related to liver injury. CONCLUSION: Cholangiocyte injury biomarkers are dominated in Delta and Omicron variant-infected patients, male sex and high levels of peak viral load in the nasopharynx are predictive factors related to liver injury in SARS-CoV-2-infected patients.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/complications , COVID-19/diagnosis , Humans , Liver , Male , Viral Load
4.
Pan Afr Med J ; 41: 56, 2022.
Article in English | MEDLINE | ID: covidwho-2025479

ABSTRACT

Hepatic injuries have been reported in patients with Coronavirus disease 2019 infection, particularly in those with moderate to severe illness. To date, pathological changes caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in liver tissue are unclear. Moreover, the mechanisms involved in liver injury in Coronavirus disease 2019 infection are not yet established. In this paper, we summarize the spectrum of pathologic findings of liver injury in patients infected by SARS-CoV-2 and we discuss the clinicopathological correlation and the mechanisms of liver damage in Coronavirus disease 2019 infection.


Subject(s)
COVID-19 , COVID-19/complications , Humans , Liver , SARS-CoV-2
5.
Genes (Basel) ; 13(8)2022 07 26.
Article in English | MEDLINE | ID: covidwho-2023338

ABSTRACT

CD71+ erythroid cells (CECs) were only known as erythrocyte progenitors not so long ago. In present times, however, they have been shown to be active players in immune regulation, especially in immunosuppression by the means of ROS, arginase-1 and arginase-2 production. Here, we uncover organ-of-origin differences in cytokine gene expression using NanoString and protein production using Bio-Plex between CECs from healthy human adult bone marrow and from human fetal liver parenchyma. Namely, healthy human adult bone marrow CECs both expressed and produced IFN-a, IL-1b, IL-8, IL-18 and MIF mRNA and protein, while human fetal liver parenchymaCECs expressed and produced IFN-a, IL15, IL18 and TNF-b mRNA and protein. We also detected TLR2 and TLR9 gene expression in both varieties of CECs and TLR1 and NOD2 gene expression in human fetal liver parenchymaCECs only. These observations suggest that there might be undiscovered roles in immune response for CECs.


Subject(s)
Arginase , Bone Marrow , Adult , Erythroid Cells , Humans , Liver , RNA, Messenger , Secretome , Transcriptome
6.
Braz J Biol ; 82: e262008, 2022.
Article in English | MEDLINE | ID: covidwho-2022146

ABSTRACT

The coronavirus disease outbreak of 2019 (COVID-19) poses a serious threat to public health worldwide. Lung injury is the most common complication of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. However, other organs, including the liver, can also be affected. Currently, there is limited evidence that liver impairment is associated with severe SARS-CoV-2 infection. Clinicians will need to determine whether liver injury is caused by an underlying liver condition, COVID-19 therapy, the virus directly, or immune-mediated inflammation or represents a complicated disease course in the context of COVID-19. To address the scarcity of data on histopathological changes and immunological effects on the liver with COVID-19 positivity, we analyze and summarize recent findings. We searched PubMed, Medline, Google Scholar, Science Direct, Scopus, and Web of Science databases up to December 1, 2021, identifying published studies with the search terms "Histopathology in COVID-19," "COVID-19," "Pathological changes in liver in COVID-19," "Liver pathology in COVID-19," "immunological effects in liver in COVID-19," and "SARS-CoV-2." This concise review will aid clinicians and researchers in better understanding the tissue histopathology and immunological consequences of SARS-CoV-2 on the liver, enabling improved care planning and avoiding future dangers.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Liver
7.
Microb Biotechnol ; 15(9): 2464-2475, 2022 09.
Article in English | MEDLINE | ID: covidwho-2019054

ABSTRACT

Poultry meat production is one of the most important agri-food industries in the world. The selective pressure exerted by widespread prophylactic or therapeutic use of antibiotics in intensive chicken farming favours the development of drug resistance in bacterial populations. Chicken liver, closely connected with the intestinal tract, has been directly involved in food-borne infections and found to be contaminated with pathogenic bacteria, including Campylobacter and Salmonella. In this study, 74 chicken livers, divided into sterile and non-sterile groups, were analysed, not only for microbial indicators but also for the presence of phages and phage particles containing antibiotic resistance genes (ARGs). Both bacteria and phages were detected in liver tissues, including those dissected under sterile conditions. The phages were able to infect Escherichia coli and showed a Siphovirus morphology. The chicken livers contained from 103 to 106 phage particles per g, which carried a range of ARGs (blaTEM , blaCTx-M-1 , sul1, qnrA, armA and tetW) detected by qPCR. The presence of phages in chicken liver, mostly infecting E. coli, was confirmed by metagenomic analysis, although this technique was not sufficiently sensitive to identify ARGs. In addition, ARG-carrying phages were detected in chicken faeces by qPCR in a previous study of the group. Comparison of the viromes of faeces and liver showed a strong coincidence of species, which suggests that the phages found in the liver originate in faeces. These findings suggests that phages, like bacteria, can translocate from the gut to the liver, which may therefore constitute a potential reservoir of antibiotic resistance genes.


Subject(s)
Bacteriophages , Animals , Anti-Bacterial Agents/pharmacology , Bacteria/genetics , Bacteriophages/genetics , Chickens , Drug Resistance, Microbial/genetics , Escherichia coli , Genes, Bacterial , Liver
8.
Nat Rev Gastroenterol Hepatol ; 19(9): 556, 2022 09.
Article in English | MEDLINE | ID: covidwho-2016729
9.
Int J Mol Sci ; 23(17)2022 Sep 02.
Article in English | MEDLINE | ID: covidwho-2010108

ABSTRACT

Metabolic associated fatty liver disease (MAFLD) is one of the most common causes of chronic liver disease worldwide. To date, there is no FDA-approved treatment, so there is an urgent need to determine its pathophysiology and underlying molecular mechanisms. Autophagy is a lysosomal degradation pathway that removes damaged organelles and misfolded proteins after cell injury through endoplasmic reticulum stress or starvation, which inhibits apoptosis and promotes cell survival. Recent studies have shown that autophagy plays an important role in removing lipid droplets from hepatocytes. Autophagy has also been reported to inhibit the production of pro-inflammatory cytokines and provide energy for the hepatic stellate cells activation during liver fibrosis. Thyroid hormone, irisin, melatonin, hydrogen sulfide, sulforaphane, DA-1241, vacuole membrane protein 1, nuclear factor erythroid 2-related factor 2, sodium-glucose co-transporter type-2 inhibitors, immunity-related GTPase M, and autophagy-related gene 7 have been reported to ameliorate MAFLD via autophagic induction. Lipid receptor CD36, SARS-CoV-2 Spike protein and leucine aminopeptidase 3 play a negative role in the autophagic function. This review summarizes recent advances in the role of autophagy in MAFLD. Autophagy modulates major pathological changes, including hepatic lipid metabolism, inflammation, and fibrosis, suggesting the potential of modulating autophagy for the treatment of MAFLD.


Subject(s)
Autophagy , Liver Diseases , Non-alcoholic Fatty Liver Disease , Humans , Liver/metabolism , Liver Diseases/metabolism , Liver Diseases/physiopathology , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/physiopathology
10.
Nat Immunol ; 23(9): 1292, 2022 09.
Article in English | MEDLINE | ID: covidwho-2000913

Subject(s)
COVID-19 , Humans , Ketone Bodies , Liver
11.
Nutrients ; 14(17)2022 Aug 24.
Article in English | MEDLINE | ID: covidwho-1997734

ABSTRACT

BACKGROUND: COVID-19 lockdowns had a significant impact on people's health, triggering levels of anxiety, perceived stress, and changes in food and nutritional status. OBJECTIVES: To assess the changes in dietary habits, metabolic syndrome (MetS) and liver parameters before and after the COVID-19 lockdown according to changes in intrahepatic fat content in adults with non-alcoholic fatty liver disease (NAFLD) and MetS. DESIGN: Pre- and post-lockdown observation of the COVID-19 lockdown on fifty-nine 40-60-year-old participants with MetS and NAFLD, in a parallel group, randomised experiment intended to treat NAFLD. METHODS: Anthropometrics, liver and MetS biochemical parameters, intrahepatic fat content by abdominal magnetic resonance imaging, and dietary assessment using a validated 148-item Food Frequency Questionnaire were collected pre-COVID-19 lockdown and post-lockdown. RESULTS: COVID-19 lockdown led to negative changes in the liver of patients with NAFLD and MetS, with weight gain and increases in glycemia, ALT and intrahepatic fat content post lockdown. Participants with worsened liver status had low consumption of fibre, cheese, nuts and coffee, and high consumption of sweets and pastries. Participants who improved liver status ameliorated ALT values, waist circumference, and intrahepatic fat content, assessed by magnetic resonance imaging post-lockdown. CONCLUSIONS: The maintenance of healthy lifestyle habits is vital, especially for populations with NAFLD and MetS, to reduce unhealthy lifestyle patterns displayed during lockdown.


Subject(s)
Body Fat Distribution , COVID-19 , Liver , Metabolic Syndrome , Non-alcoholic Fatty Liver Disease , Adult , COVID-19/prevention & control , Communicable Disease Control , Feeding Behavior , Humans , Liver/diagnostic imaging , Liver/pathology , Magnetic Resonance Imaging , Metabolic Syndrome/complications , Metabolic Syndrome/diagnostic imaging , Middle Aged , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/diagnostic imaging
12.
Emerg Microbes Infect ; 11(1): 2222-2228, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1997030

ABSTRACT

ABSTRACTMulticenter case series has reported patients with hepatic injury following COVID-19 vaccination, which raised concern for the possibility of vaccine-induced liver dysfunction. We aimed to assess the impact of COVID-19 vaccination on liver function of pregnant women, who may be uniquely susceptible to vaccine-induced liver dysfunction. We conducted a retrospective cohort study at a tertiary hospital in Shanghai, China. Vaccine administration was obtained from the electronic vaccination record. Serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total bile acid (TBA) and total bilirubin (TBIL) in early pregnancy were determined by enzymatic methods. Among the 7745 included pregnant women, 3832 (49.5%) received at least two doses of an inactivated vaccine. COVID-19 vaccination was significantly associated with higher levels of maternal serum TBA. Compared with unvaccinated pregnant women, the mean TBA levels increased by 0.17 µmol/L (ß = 0.17, 95% CI, 0.04, 0.31) for women who had been vaccinated within 3 months before the date of conception. Moreover, COVID-19 vaccination was significantly associated with an increased risk of maternal hyperbileacidemia. The risk of hyperbileacidemia increased by 113% (RR = 2.13; 95% CI, 1.17-3.87) for pregnant women who had been vaccinated within 3 months before conception compared with unvaccinated pregnant women. However, when the interval from complete vaccination to conception was prolonged to more than 3 months, COVID-19 vaccination was not associated with serum TBA levels or maternal hyperbileacidemia. Our findings suggest that vaccination with inactivated COVID-19 vaccines more than 3 months before conception have no detrimental effects on maternal liver function in early pregnancy.


Subject(s)
COVID-19 Vaccines , COVID-19 , Pregnant Women , Alanine Transaminase , Aspartate Aminotransferases , Bile Acids and Salts , Bilirubin , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , China/epidemiology , Cohort Studies , Female , Humans , Liver , Liver Function Tests , Pregnancy , Retrospective Studies , Vaccines, Inactivated
13.
Am J Case Rep ; 23: e936250, 2022 Aug 18.
Article in English | MEDLINE | ID: covidwho-1994516

ABSTRACT

BACKGROUND The incidence of abnormal liver function, mainly aspartate aminotransferase and alanine aminotransferase elevations, in patients with COVID-19 is not uncommon, but persistent liver damage after the acute phase of the disease is uncommon and has been recently recognized as a new entity named post-COVID-19 cholangiopathy. CASE REPORT We report a clinical case with progressive cholestatic disease following severe COVID-19. AST and ALT peaked at hospital admission and while its serum concentration went down, bilirubin and cholestatic liver enzymes started to increase, reaching the maximum at day 122. Magnetic resonance imaging (MRI) revealed a diffuse irregularity of intra- and extrahepatic bile ducts, with multiple focal strictures alternating with mild focal dilations of the biliary tree, suggesting a sclerosing cholangiopathy. A transjugular liver biopsy showed a prominent bile ductular reaction, cholangiocyte injury, inflammatory infiltrate rich in neutrophils, biliary infarctions, marked cholestasis, and portal fibrosis, suggesting the diagnosis of post-Covid-19 secondary sclerosing cholangitis. The patient evolved with a continuous deterioration of liver functions, but liver transplantation was not performed due to his poor clinical condition. CONCLUSIONS Post-COVID-19 SSC is a severe disease with no effective clinical treatment and has liver transplantation as the only treatment for a few selected patients.


Subject(s)
Bile Ducts, Extrahepatic , COVID-19 , Cholangitis, Sclerosing , Liver Transplantation , Bile Ducts, Extrahepatic/pathology , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/diagnosis , Humans , Liver/pathology , Liver Transplantation/adverse effects
15.
Dtsch Arztebl Int ; 117(42): 717, 2020 10 16.
Article in English | MEDLINE | ID: covidwho-1383842
16.
17.
Clin Gastroenterol Hepatol ; 18(12): 2851-2852, 2020 11.
Article in English | MEDLINE | ID: covidwho-1382282

Subject(s)
COVID-19 , Humans , Liver , SARS-CoV-2
18.
J Obstet Gynaecol Res ; 48(11): 2713-2720, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1968160

ABSTRACT

AIM: The aim of the study was to evaluate the association between SARS-CoV-2 infection and serum hepatic biomarker levels among women with obstetric cholestasis. METHODS: In this prospective study, we recruited all pregnant women admitted in our hospital with obstetric cholestasis. Among those with a concurrent SARS-CoV-2 infection, we evaluated the following serum hepatic biomarkers: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and biliar acids (BA). RESULTS: Among the 88 women enrolled in the study, 20 presented with a SARS-CoV-2 infection while 68 were negative. SARS-CoV-2 infected women were younger (mean age 30.5 ± 5.7 vs. 34.3 ± 5.4; p < 0.01) and in a greater percentage of non-Caucasian ethnicity when compared to noninfected women (60.0% vs. 17.6%; p < 0.01). Regarding levels of hepatic biomarkers, they showed higher levels of AST (111.5 ± 134.1 vs. 37.3 ± 43.4 UI/L; p = 0.02), ALT (132.2 ± 115.7 vs. 50.5 ± 73.173.1 UI/L; p < 0.01), and BA (41.4 ± 46.8 vs. 18.4 ± 13.4 µmol/L; p = 0.04) compared to noninfected patients. No significant differences in maternal or fetal outcomes were found between infected and noninfected women. CONCLUSION: SARS-CoV-2 infection was associated with higher levels of liver enzymes in patients with obstetric cholestasis. This could be the result of a possible hepatic involvement in patients with SARS-CoV-2 infection.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , Female , Humans , Pregnancy , Young Adult , Adult , SARS-CoV-2 , Prospective Studies , Liver , Biomarkers
19.
Int J Mol Sci ; 23(14)2022 Jul 08.
Article in English | MEDLINE | ID: covidwho-1964000

ABSTRACT

Acetaminophen (APAP) is a widely used antipyretic analgesic which can lead to acute liver failure after overdoses. Chronic alcoholic fatty liver disease (AFLD) appears to enhance the risk and severity of APAP-induced liver injury, and the level of angiotensin II (Ang II) increased sharply at the same time. However, the underlying mechanisms remain unclear. Caveolin-1 (CAV1) has been proven to have a protective effect on AFLD. This study aimed to examine whether CAV1 can protect the APAP-induced hepatotoxicity of AFLD by affecting Ang II or its related targets. In vivo, the AFLD model was established according to the chronic-plus-binge ethanol model. Liver injury and hepatic lipid accumulation level were determined. The levels of Angiotensin converting enzyme 2 (ACE2), Ang II, CAV1, and other relevant proteins were evaluated by western blotting. In vitro, L02 cells were treated with alcohol and oleic acid mixture and APAP. CAV1 and ACE2 expression was downregulated in APAP-treated AFLD mice compared to APAP-treated mice. The overexpression of CAV1 in mice and L02 cells alleviated APAP-induced hepatotoxicity in AFLD and downregulated Ang II, p-EGFR/EGFR and P-ERK/ERK expression. Immunofluorescence experiments revealed interactions between CAV1, Ang II, and EGFR. The application of losartan (an Ang II receptor antagonist) and PD98059 (an ERK1/2 inhibitor) alleviated APAP-induced hepatotoxicity in AFLD. In conclusion, our findings verified that CAV1 alleviates APAP-aggravated hepatotoxicity in AFLD by downregulating the Ang II /EGFR/ERK axis, which could be a novel therapeutic target for its prevention or treatment.


Subject(s)
Caveolin 1 , Chemical and Drug Induced Liver Injury , Fatty Liver, Alcoholic , Acetaminophen/adverse effects , Angiotensin II/metabolism , Angiotensin-Converting Enzyme 2 , Animals , Caveolin 1/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/metabolism , ErbB Receptors/metabolism , Fatty Liver, Alcoholic/metabolism , Liver/metabolism , Mice , Mice, Inbred C57BL
20.
Nat Rev Gastroenterol Hepatol ; 19(9): 556, 2022 09.
Article in English | MEDLINE | ID: covidwho-1956405
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