Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF).

BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.

Low-to-moderate alcohol consumption is associated with increased fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND & AIMS: Both metabolic dysfunction and alcohol consumption cause steatotic liver disease (SLD). New nomenclature and distinction of metabolic dysfunction-associated SLD (MASLD) and MetALD categories is based on arbitrary thresholds of alcohol intake. We assessed the impact of different levels of alcohol consumption on SLD severity and its interaction with metabolic comorbidities. METHODS: Population-based study with transient elastography (FibroScan®) data from participants in Spain (derivation) and U.S. (validation) cohorts. Controlled attenuation parameter (CAP≥275 dB/m) identified SLD. At least one cardiometabolic risk factor was required to define MASLD. Among MASLD patients, low alcohol consumption was defined as an average of 5-9 drinks/week, moderate consumption as 10-13 drinks/week for females and 10-20 drinks/week for males, and increased alcohol intake (MetALD) as 14-35 drinks/week for females and 21-42 drinks/week for males. Significant fibrosis was defined as LSM≥8 kPa and at-risk MASH as FAST score≥0.35. RESULTS: The derivation cohort included 2,227 subjects with MASLD (9% reported low, 14% moderate alcohol consumption), and 76 cases with MetALD. Overall prevalence of significant fibrosis and at-risk MASH were 7.6% and 14.8%, respectively. In the multivariable analysis, alcohol consumption was independently associated with significant fibrosis and at-risk MASH. A dose-dependent increase in the prevalence of significant fibrosis and at-risk MASH was observed between the number of drinks/week and the number of cardiometabolic factors. The validation cohort included 1,732 participants with MASLD, of whom 17% had significant fibrosis and 13% at-risk MASH. This cohort validated the association between moderate intake and MASLD at risk of progression (OR=1.69 [95%CI 1.06-2.71]). CONCLUSIONS: Moderate alcohol intake is commonly seen in MASLD and increases the risk of advanced disease, in a similar magnitude to MetALD spectrum. IMPACT AND IMPLICATIONS: Metabolic risk factors such as overweight, diabetes or dyslipidemia, and alcohol consumption can cause liver disease. These factors frequently co-exist, but their joint effects on liver fibrosis remain uncertain. This study analyzes subjects form the general population with metabolic dysfunction-associated steatotic liver disease (MASLD) enrolled in Spain and U.S. We show that moderate alcohol consumption has a supra-additive effect with metabolic risk factors, exponentially increasing the risk of liver fibrosis. These results suggest that patients with unhealthy metabolic status and MASLD have no safe limits of daily alcohol intake.

Increased risk of MAFLD and Liver Fibrosis in Inflammatory Bowel Disease Independent of Classic Metabolic Risk Factors.

BACKGROUND & AIMS: There is conflicting evidence regarding the prevalence of and risk factors for metabolic-associated fatty liver disease (MAFLD) in patients with inflammatory bowel disease (IBD). We aimed to determine MAFLD prevalence and risk factors in IBD patients. METHODS: Cross-sectional, case-control study included all consecutive IBD patients treated at 2 different university hospitals. Controls were subjects randomly selected from the general population and matched by age, sex, type 2 diabetes status, and body mass index in a 1:2 ratio. MAFLD was confirmed by controlled attenuation parameter. Liver biopsies were collected when MAFLD with significant liver fibrosis was suspected. In addition, age- and fibrosis stage-paired non-IBD patients with biopsy-proven MAFLD served as a secondary control group. RESULTS: Eight hundred thirty-one IBD patients and 1718 controls were included. The prevalence of MAFLD and advanced liver fibrosis (transient elastography ≥9.7 kPa) was 42.00% and 9.50%, respectively, in IBD patients and 32.77% and 2.31%, respectively, in the general population (P < .001). A diagnosis of IBD was an independent predictor of MAFLD (adjusted odds ratio, 1.99; P < .001) and an independent risk factor for advanced liver fibrosis (adjusted odds ratio, 5.55; P < .001). Liver biopsies were obtained from 40 IBD patients; MAFLD was confirmed in all cases, and fibrosis of any degree was confirmed in 25 of 40 cases (62.5%). Body mass index and type 2 diabetes prevalence were significantly lower in IBD-MAFLD patients than in severity-paired patients with biopsy-proven MAFLD. CONCLUSIONS: MAFLD and liver fibrosis are particularly prevalent in IBD patients, regardless of the influence of classic metabolic risk factors.

Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles.

BACKGROUND AND AIMS: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. APPROACH AND RESULTS: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. CONCLUSIONS: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.

High accuracy of spleen stiffness measurement in diagnosing clinically significant portal hypertension in metabolic-associated fatty liver disease.

BACKGROUND AND AIMS: Spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) has been tested in a limited number of studies versus hepatic venous pressure gradient (HVPG), especially with the 100 Hz spleen-specific module. The current study aims to evaluate the diagnostic performance of this novel module for detecting clinically significant portal hypertension (CSPH) in a cohort of compensated patients with metabolic-associated fatty liver disease (MAFLD) as the main aetiology and to improve the performance of the Baveno VII criteria for CSPH diagnosis by including SSM. METHODS: This is a retrospective single-centre study including patients with available measurements of HVPG, Liver stiffness measurement (LSM) and SSM by VCTE with the 100 Hz module. Area under the receiver operating characteristic (AUROC) curve analysis was conducted to identify dual cut-offs (rule-out and rule-in) associated with the absence/presence of CSPH. The diagnostic algorithms were adequate if negative predictive value (NPV) and positive predictive values (PPV) were >90%. RESULTS: A total of 85 patients were included, 60 MAFLD and 25 non-MAFLD. SSM showed a good correlation with HVPG (MAFLD: r = .74; p < .0001; non-MAFLD: r = .62; p < .0011). In MAFLD patients, SSM had a high accuracy in discarding/diagnosing CSPH (cut-off values of <40.9 and >49.9 kPa, AUC 0.95). The addition of these cut-offs in a sequential or combined approach to the Baveno VII criteria significantly reduced the grey zone (60% vs. 15%-20%), while maintaining adequate NPV and PPV. CONCLUSIONS: Our findings support the utility of SSM for diagnosing CSPH in MAFLD patients and demonstrate that the addition of SSM to the Baveno VII criteria increases accuracy.

Innovative Therapeutic Approaches in Non-Alcoholic Fatty Liver Disease: When Knowing Your Patient Is Key.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic steatosis may result from the dysfunction of multiple pathways and thus multiple molecular triggers involved in the disease have been described. The development of NASH entails the activation of inflammatory and fibrotic processes. Furthermore, NAFLD is also strongly associated with several extra-hepatic comorbidities, i.e., metabolic syndrome, type 2 diabetes mellitus, obesity, hypertension, cardiovascular disease and chronic kidney disease. Due to the heterogeneity of NAFLD presentations and the multifactorial etiology of the disease, clinical trials for NAFLD treatment are testing a wide range of interventions and drugs, with little success. Here, we propose a narrative review of the different phenotypic characteristics of NAFLD patients, whose disease may be triggered by different agents and driven along different pathophysiological pathways. Thus, correct phenotyping of NAFLD patients and personalized treatment is an innovative therapeutic approach that may lead to better therapeutic outcomes.

Faecal Microbiota Transplantation, Paving the Way to Treat Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent cause of chronic liver disease (CLD). Currently, the only therapeutic recommendation available is a lifestyle change. However, adherence to this approach is often difficult to guarantee. Alteration of the microbiota and an increase in intestinal permeability seem to be key in the development and progression of NAFLD. Therefore, the manipulation of microbiota seems to provide a promising therapeutic strategy. One way to do so is through faecal microbiota transplantation (FMT). Here, we summarize the key aspects of FMT, detail its current indications and highlight the most recent advances in NAFLD.

Fatty Liver Disease, Metabolism and Alcohol Interplay: A Comprehensive Review.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide, and its incidence has been increasing in recent years because of the high prevalence of obesity and metabolic syndrome in the Western population. Alcohol-related liver disease (ArLD) is the most common cause of cirrhosis and constitutes the leading cause of cirrhosis-related deaths worldwide. Both NAFLD and ArLD constitute well-known causes of liver damage, with some similarities in their pathophysiology. For this reason, they can lead to the progression of liver disease, being responsible for a high proportion of liver-related events and liver-related deaths. Whether ArLD impacts the prognosis and progression of liver damage in patients with NAFLD is still a matter of debate. Nowadays, the synergistic deleterious effect of obesity and diabetes is clearly established in patients with ArLD and heavy alcohol consumption. However, it is still unknown whether low to moderate amounts of alcohol are good or bad for liver health. The measurement and identification of the possible synergistic deleterious effect of alcohol consumption in the assessment of patients with NAFLD is crucial for clinicians, since early intervention, advising abstinence and controlling cardiovascular risk factors would improve the prognosis of patients with both comorbidities. This article seeks to perform a comprehensive review of the pathophysiology of both disorders and measure the impact of alcohol consumption in patients with NAFLD.

NAFLD and type 2 diabetes: A practical guide for the joint management.

Non-alcoholic fatty liver disease (NAFLD) is becoming a major cause of liver disease-related morbidity, as well as mortality. Importantly, NAFLD is considered a mediator of systemic diseases including cardiovascular disease. Its prevalence is expected to increase, mainly due to its close association with obesity and type 2 diabetes mellitus (T2D). In addition, T2D and NAFLD share common pathophysiological mechanisms, and one can lead to or worsen the other. Therefore, a close collaboration between primary care physician, endocrinologists and hepatologists is essential to optimize the management of patients with NAFLD and T2D. Here, we summarize relevant aspects about NAFLD and T2D that all clinician managing these patients should know as well as current therapeutic options for the treatment of T2D associated with NAFLD.

Inhibition of carnitine palmitoyltransferase 1A in hepatic stellate cells protects against fibrosis.

BACKGROUND & AIMS: The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored. METHODS: CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were performed in human HSC cell lines and primary HCSs. Finally, we induced fibrosis in mice lacking CPT1A specifically in HSCs. RESULTS: Herein, we show that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor ß1 (TGFß1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFß1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis induced by a choline-deficient high-fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride. CONCLUSIONS: These results indicate that CPT1A plays a critical role in the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment. LAY SUMMARY: We show that the enzyme carnitine palmitoyltransferase 1A (CPT1A) is elevated in hepatic stellate cells (HSCs) in patients with fibrosis and mouse models of fibrosis, and that CPT1A induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis by preventing the activation of HSCs.

Inhibition of ATG3 ameliorates liver steatosis by increasing mitochondrial function.

BACKGROUND & AIMS: Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. METHODS: By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. RESULTS: ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. CONCLUSIONS: Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. LAY SUMMARY: We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis.

Prevalence estimation of significant fibrosis because of NASH in Spain combining transient elastography and histology.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has become a major public health problem, but the prevalence of fibrosis associated with non-alcoholic steatohepatitis (NASH) is largely unknown in the general population. This study aimed to provide an updated estimation of the prevalence of NASH fibrosis in Spain. METHODS: This was an observational, retrospective, cross-sectional, population-based study with merged data from two Spanish datasets: a large (N = 12 246) population-based cohort (ETHON), including transient elastography (TE) data, and a contemporary multi-centric biopsy-proven NASH cohort with paired TE data from tertiary centres (N = 501). Prevalence for each NASH fibrosis stage was estimated by crossing TE data from ETHON dataset with histology data from the biopsy-proven cohort. RESULTS: From the patients with valid TE in ETHON dataset (N = 11 440), 5.61% (95% confidence interval [95% CI]: 2.53-11.97) had a liver stiffness measurement (LSM) ≥ 8 kPa. The proportion attributable to NAFLD (using clinical variables and Controlled Attenuation Parameter) was 57.3% and thus, the estimated prevalence of population with LSM ≥ 8 kPa because of NAFLD was 3.21% (95% CI 1.13-8.75). In the biopsy-proven NASH cohort, 389 patients had LSM ≥ 8 kPa. Among these, 37% did not have significant fibrosis (F2-4). The estimated prevalence of NASH F2-3 and cirrhosis in Spain's adult population were 1.33% (95% CI 0.29-5.98) and 0.70% (95% CI 0.10-4.95) respectively. CONCLUSIONS: These estimations provide an accurate picture of the current prevalence of NASH-related fibrosis in Spain and can serve as reference point for dimensioning the therapeutic efforts that will be required as NASH therapies become available.

Can NAFLD overwhelm the Spanish healthcare system in the years to come?

Non-alcoholic fatty liver disease (NAFLD) is the leading driver of chronic liver disease globally and is likely to become the main cause of end-stage liver disease and liver transplantation in the next decades. In a 2021 global study of the preparedness of 102 countries to address NAFLD, Spain scored ninth overall and seventh in Europe. Although, no country scored over 50/100. Other countries in Europe, including neighboring ones such as Italy, France and Portugal scored 7.77, 6.21 and 0.5, respectively, in their readiness to address NAFLD. Although, Spain is better prepared to battle this pandemic, there is still much work to be done to be able to tackle this highly prevalent, costly and often mortal condition by further identifying NAFLD preparedness gaps and addressing those already known.

Metabolic-associated fatty liver disease: From simple steatosis toward liver cirrhosis and potential complications. Proceedings of the Third Translational Hepatology Meeting, organized by the Spanish Association for the Study of the Liver (AEEH).

This is a meeting report of the 3rd Translational Hepatology Meeting held in Alicante, Spain, in October 2021. The meeting, which was organized by the Spanish Association for the Study of the Liver (AEEH), provided an update on the recent advances in the field of basic and translational hepatology, with a particular focus on the molecular and cellular mechanisms and therapeutic targets involved in metabolic-associated fatty liver disease (MAFLD), metabolic-associated steatohepatitis (MASH), cirrhosis and end-stage hepatocellular carcinoma (HCC).

Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH.

BACKGROUND & AIMS: Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). METHODS: Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. RESULTS: Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. CONCLUSIONS: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. LAY SUMMARY: Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein.

National digestive disease specialists survey on cardiovascular risk management in non-alcoholic fatty liver disease in spanish hospitals.

BACKGROUND & AIMS: Cardiovascular disease (CVD) is the main cause of mortality among non-alcoholic fatty liver disease (NAFLD) patients. The aim was to explore the level of knowledge and clinical management of cardiovascular risk (CVR) in NAFLD patients by Digestive Disease specialists. METHODS: An anonymous web-based survey was designed with 44 close-ended questions, divided into five sections, that were based on current guidelines on CVD prevention. Between November 2019 and January 2020, Digestive Disease specialists from Spanish hospitals were invited to participate in this survey via email and Twitter. Student's t, chi-square and Fishers' exact tests, and logistic regression were used for data analysis. RESULTS: 208 clinicians completed the survey. Most respondents (83.2%) believe that NAFLD is an independent risk factor for CVD, especially in the presence of NASH and fibrosis. Personal history of CVDs and cardiovascular risk-related comorbidities are collected by more than 75% of respondents. However, less than 17% perform an elementary physical examination to address the CVR, except weight which is evaluated by 69.8%. Over 54% of respondents do not perform or request any supplementary tests for CVR assessment, and only 10.2% use specific calculators. Furthermore, 54.3% spend less than 5 minutes giving lifestyle advice, and more than 52% do not start drug treatment after a recent diagnosis of any cardiovascular comorbidity. Only 25.6% have a multidisciplinary Unit for metabolic comorbidities in their hospitals, although 89% of the respondents would support the implementation of this Unit. CONCLUSIONS: Cardiovascular risk management in daily clinical practice by Digestive Disease specialists in Spain remains suboptimal.

Massive impact of coronavirus disease 2019 pandemic on gastroenterology and hepatology departments and doctors in Spain.

BACKGROUND AND AIM: Significant human and material resources have been diverted to coronavirus disease 2019 (COVID-19). Healthcare workers are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We assess the impact of the COVID-19 pandemic on gastroenterology and hepatology departments and specialists in Spain. METHODS: This study involves a nationwide survey addressing the impact of COVID-19 on resources, procedures, and physicians of gastroenterology and hepatology departments in 81 hospitals representative of the Spanish National Health Service. RESULTS: Overall, 41.8% of hospital beds and 40.7% of gastroenterology and hepatology beds were allocated to COVID-19 patient care, as well as 24.8% of gastroenterologists and 58.3% of residents. Outpatient visits, abdominal ultrasounds, and endoscopies were reduced by 81.8-91.9%. Nine large university hospitals had 75% and 89% reductions in therapeutic endoscopies and hepatocellular carcinoma surgery, respectively, with cancelation of elective liver transplant and transjugular intrahepatic portosystemic shunt. Prevalence of infected physicians was 10.6% and was dependent on regional population incidence (r = 0.74, P = 0.001), with 11% hospitalized and one physician dying. Up to 63.4% of physicians may have been infected before or shortly after Spain entered lockdown, 57% of them having recently performed endoscopies. Adequate protection was acknowledged in > 80% hospitals, but only 2.9% performed regular SARS-CoV-2 testing. CONCLUSIONS: The impact of the COVID-19 pandemic on healthcare delivery has been massive. A wave of gastroenterology-related complications is expected because of resource diversion. Gastroenterologists have a high prevalence of infection, although they may have been infected during a first phase of lower awareness and protection. Regular SARS-CoV-2 screening, adequate protection, and quick reorganization of healthcare resources are still needed.

LOXL2-A New Target in Antifibrogenic Therapy?

The concept of liver fibrosis and cirrhosis being static and therefore irreversible is outdated. Indeed, both human and animal studies have shown that fibrogenesis is a dynamic and potentially reversible process that can be modulated either by stopping its progression and/or by promoting its resolution. Therefore, the study of the molecular mechanisms involved in the pathogenesis of liver fibrosis is critical for the development of future antifibrotic therapies. The fibrogenesis process, common to all forms of liver injury, is characterized by the increased deposition of extracellular matrix components (EMCs), including collagen, proteoglycans, and glycoproteins (laminin and fibronectin 2). These changes in the composition of the extracellular matrix components alter their interaction with cell adhesion molecules, influencing the modulation of cell functions (growth, migration, and gene expression). Hepatic stellate cells and Kupffer cells (liver macrophages) are the key fibrogenic effectors. The antifibrogenic mechanism starts with the activation of Ly6Chigh macrophages, which can differentiate into macrophages with antifibrogenic action. The research of biochemical changes affecting fibrosis irreversibility has identified lysyl oxidase-like 2 (LOXL2), an enzyme that promotes the network of collagen fibers of the extracellular matrix. LOXL2 inhibition can decrease cell numbers, proliferation, colony formations, and cell growth, and it can induce cell cycle arrest and increase apoptosis. The development of a new humanized IgG4 monoclonal antibody against LOXL2 could open the window of a new antifibrogenic treatment. The current therapeutic target in patients with liver cirrhosis should focus (after the eradication of the causal agent) on the development of new antifibrogenic drugs. The development of these drugs must meet three premises: Patient safety, in non-cirrhotic phases, down-staging or at least stabilization and slowing the progression to cirrhosis must be achieved; whereas in the cirrhotic stage, the objective should be to reduce fibrosis and portal pressure.