Rare ATG7 genetic variants predispose patients to severe fatty liver disease

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants.Methods: We performed whole-exome sequencing in in-dividuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level.Results: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese in-dividuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Tran-scriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFa pathway, which was conversely upregulated in p.V471A carriers.Conclusions: We identified rare and low-frequency ATG7 loss-of -function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation.Lay summary: We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self -renewal of cellular content, leading to liver damage and inflammation.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/)

A multi-society Delphi consensus statement on new fatty liver disease nomenclature

Unlabelled: The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Methods: A modified Delphi process was led by three large pan-national liver associations. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Results: A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms 'non-alcoholic' and 'fatty' were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350 g/week and 210 to 420 g/week for females and males respectively). Conclusions: The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification

Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance

Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages.Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR.Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2-4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5-8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2-4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p.Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD.Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL)

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Acute hepatitis caused by a natural lipid-lowering product: When "alternative" medicine is no "alternative" at all

Background/Aims The general public's growing mistrust of the pharmaceutical industry and its perception of the lack of adverse effects of "natural" therapy have lead to the increasing use of "alternative drugs" for hypercholesterolemia. Methods A sixty-three year old woman presented with severe hypertransaminasemia that had developed progressively over a few weeks. For six months she had been taking Equisterol ® , an over-the-counter lipid-lowering product containing guggulsterol and red yeast rice extract. The product had been prescribed for hypercholesterolemia because the patient had developed hepatotoxicity while on lovastatin. Results Liver biopsy revealed severe lobular necroinflammatory changes with an eosinophilic infiltrate. The episode was regarded as an adverse drug reaction after exclusion of other possible causes of acute liver disease and the prompt normalization of liver function tests after Equisterol ® had been discontinued. Red yeast rice extract's cholesterol-lowering properties are largely due to fungal metabolites known as monacolins, one of which – monacolin K – is identical to lovastatin. Conclusions The choice of an alternative medicine approach in this case subjected the patient to "re-challenge" with the official medicine agent that had previously caused mild hepatotoxicity. Physicians should keep in mind that "alternative" medicine is not always the safest alternative and sometimes it is not even "alternative.

DEVIL'S HERB

We describe a case of Mandragora autumnalis poisoning which occurred in a 72-year-old female patient who had eaten the venenous M. Autumnalis, picked near her home, mistaking it for the edible Borago Officinalis. M. Autumnalis is a solanaceous plant, common in the Sicilian countryside, which contains a variable concentration of solanum alkaloids, causing gastrointestinal irritation, and tropane alkaloids, with anticholinergic properties. Unluckily, M. Autumnalis is often mistaken for the edible B. Officinalis, likewise widespread in Sicilian countryside. The diagnosis of Mandragora poisoning was made on the basis of clinical symptoms and signs of anticholinergic syndrome associated with a history of vegetable meal of uncontrolled origin, moreover analysing the vegetable obtained from gastric lavage. Decontamination and symptomatic treatment were useful in our patient to control acute poisoning

SiNAPS: An implantable active pixel sensor CMOS-probe for simultaneous large-scale neural recordings

Abstract Large-scale neural recordings with high spatial and temporal accuracy are instrumental to understand how the brain works. To this end, it is of key importance to develop probes that can be conveniently scaled up to a high number of recording channels. Despite recent achievements in complementary metal-oxide semiconductor (CMOS) multi-electrode arrays probes, in current circuit architectures an increase in the number of simultaneously recording channels would significantly increase the total chip area. A promising approach for overcoming this scaling issue consists in the use of the modular Active Pixel Sensor (APS) concept, in which a small front-end circuit is located beneath each electrode. However, this approach imposes challenging constraints on the area of the in-pixel circuit, power consumption and noise. Here, we present an APS CMOS-probe technology for Simultaneous Neural recording that successfully addresses all these issues for whole-array read-outs at 25 kHz/channel from up to 1024 electrode-pixels. To assess the circuit performances, we realized in a 0.18  μ m CMOS technology an implantable single-shaft probe with a regular array of 512 electrode-pixels with a pitch of 28  μ m. Extensive bench tests showed an in-pixel gain of 45.4 ± 0.4 dB (low pass, F-3 dB = 4 kHz), an input referred noise of 7.5 ± 0.67 μVRMS (300 Hz to 7.5 kHz) and a power consumptio

Consequences of simulated microgravity in neural stem cells: biological effects and metabolic response.

Objective: Microgravity was often shown to cause cell damage and impair cell cycle in a variety of biological systems. Since the effects on the neural system were poorly investigated, we aimed to gain insight into how biological processes such as cell cycle, cell damage, stemness features and metabolic status are involved in neural stem cells (NSC) when they experience simulated microgravity. We also wished to investigate whether these modulations were transient or permanent once cells were returned to normal gravity. Methods: NSC were isolated from mouse cerebella and cultured in the Rotary Cell Culture System (RCCS) to model microgravity. We analyzed cell cycle, stress and apoptotic response. We also performed a 1H NMR-based metabolomic analysis and evaluation of stemness features of NSC in simulated microgravity and once in the returned to normogravity cell culture. Results: Biological processes and metabolic status were modulated by simulated microgravity. Cells were arrested in S-phase together with enhanced apoptosis. Metabolic changes occurred in NSC after simulated microgravity. Interestingly, these modulations were transient. Indeed, stemness features and metabolic footprint returned to basal levels after few days of culture in normal conditions. Moreover NSC clonogenic ability was not impaired. Conclusions: Our data suggest that simulated microgravity impacts on NSC biological processes, including cell cycle and apoptosis. However, NSC does not suffer from permanent damage

A single course of lusutrombopag for multiple invasive procedures in cirrhosis-associated thrombocytopenia: A case series

Rationale: Lusutrombopag is a thrombopoietin receptor agonist which reduces the need for platelet transfusions before planned invasive procedures. A post hoc analysis of data from the registration trials observed that lusutrombopag-treated patients who achieved a platelet count > 50 x 10(9)/L (responder patients) did so in a median of 6 days and the effect on platelet count lasted for nearly 3 weeks in total. Since patients with cirrhosis often require repeat invasive procedures, this kind of response-time trend sheds light on the possibility of placing more than one invasive procedure within a single course of lusutrombopag treatment. Patient concerns: Platelet transfusion represents the gold standard in this setting, but is limited by the risk of adverse events and limited availability. Diagnoses: We describe our experience with lusutrombopag in three patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive procedures after a single course of treatment. Interventions: The treatment schedule is lusutrombopag orally 3 mg/daily for 7 days and then a time window of 6 days (day 9-14) for the elective invasive procedure. Outcomes: All three patients achieved good response to lusutrombopag treatment and were able to undergone more invasive procedures in the same course of treatment without need of platelet transfusion. Lessons: our preliminary experience supports the safety and the effectiveness of lusutrombopag in patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive elective procedures after a single course