A model of alcoholic liver disease based on different hepatotoxics leading to liver cancer.

The worst-case scenario related to alcoholic liver disease (ALD) arises after a long period of exposure to the harmful effect of alcohol consumption along with other hepatotoxics. ALD encompasses a broad spectrum of liver-associated disorders, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Based on the chronic administration of different hepatotoxics, including ethanol, sucrose, lipopolysaccharide, and low doses of diethylnitrosamine over a short period, here we aimed to develop a multiple hepatotoxic (MHT)-ALD model in the mouse that recapitulates the human ALD-associated disorders. We demonstrated that the MHT-ALD model induces ADH1A and NXN, an ethanol metabolizer and a redox-sensor enzyme, respectively; promotes steatosis associated with the induction of the lipid droplet forming FSP27, inflammation identified by the infiltration of hepatic neutrophils-positive to LY-6G marker, and the increase of MYD88 level, a protein involved in inflammatory response; and stimulates the early appearance of cellular senescence identified by the senescence markers SA-ß-gal activity and p-H2A.XSer139. It also induces fibrosis associated with increased desmin, a marker of hepatic stellate cells whose activation leads to the deposition of collagen fibers, accompanied by cell death and compensatory proliferation revealed by increased CASP3-mediated apoptosis, and KI67- and PCNA-proliferation markers, respectively. It also induces histopathological traits of malignancy and the level of the HCC marker, GSTP1. In conclusion, we provide a useful model for exploring the chronological ALD-associated alterations and stages, and addressing therapeutic approaches.

Nucleoredoxin Redox Interactions Are Sensitized by Aging and Potentiated by Chronic Alcohol Consumption in the Mouse Liver.

Aging is characterized by increased reactive species, leading to redox imbalance, oxidative damage, and senescence. The adverse effects of alcohol consumption potentiate aging-associated alterations, promoting several diseases, including liver diseases. Nucleoredoxin (NXN) is a redox-sensitive enzyme that targets reactive oxygen species and regulates key cellular processes through redox protein-protein interactions. Here, we determine the effect of chronic alcohol consumption on NXN-dependent redox interactions in the liver of aged mice. We found that chronic alcohol consumption preferentially promotes the localization of NXN either into or alongside senescent cells, declines its interacting capability, and worsens the altered interaction ratio of NXN with FLII, MYD88, CAMK2A, and PFK1 proteins induced by aging. In addition, carbonylated protein and cell proliferation increased, and the ratios of collagen I and collagen III were inverted. Thus, we demonstrate an emerging phenomenon associated with altered redox homeostasis during aging, as shown by the declining capability of NXN to interact with partner proteins, which is enhanced by chronic alcohol consumption in the mouse liver. This evidence opens an attractive window to elucidate the consequences of both aging and chronic alcohol consumption on the downstream signaling pathways regulated by NXN-dependent redox-sensitive interactions.

Identification of ABCC3 and its isoforms as potential biomarker in hepatocellular carcinoma.

Liver diseases preceding the occurrence of hepatocellular carcinoma (HCC) play a crucial role in the progression and establishment of HCC, a malignancy ranked as the third deadliest cancer worldwide. Late diagnosis, alongside ineffective treatment, leads patients to a poor survival rate. This scenario argues for seeking novel alternatives for detecting liver alterations preceding the early occurrence of HCC. Experimental studies have reported that ABCC3 protein increases within HCC tumors but not in adjacent tissue. Therefore, we analyzed ABCC3 expression in public databases and investigated the presence of ABCC3 and its isoforms in plasma, urine and its release in extracellular vesicles (EVs) cargo from patients bearing cirrhosis and HCC. The UALCAN and GEPIA databases were used to analyze the expression of ABCC3 in HCC. The results were validated in a case-control study including 41 individuals bearing cirrhosis and HCC, and the levels of ABCC3 in plasma and urine samples, as well as EVs, were analyzed by ELISA and western blot. Our data showed that ABCC3 expression was higher in HCC tissues than in normal tissues and correlated with HCC grade and stage. ABCC3 protein levels were highly increased in both plasma and urine and correlated with liver disease progression and severity. The isoforms MRP3A and MRP3B of ABCC3 were significantly increased in both EVs and plasma/urine of patients bearing HCC. ABCC3 expression gradually increases in HCC tissues, and its protein levels are increased in both plasma and urine of patients with cirrhosis and HCC. MRP3A and MRP3B isoforms have the potential to be prognostic biomarkers of HCC.

Metabolomic Phenotype of Hepatic Steatosis and Fibrosis in Mexican Children Living with Obesity.

Background and Objectives: Metabolic-dysfunction-associated steatotic liver disease or MASLD is the main cause of chronic liver diseases in children, and it is estimated to affect 35% of children living with obesity. This study aimed to identify metabolic phenotypes associated with two advanced stages of MASLD (hepatic steatosis and hepatic steatosis plus fibrosis) in Mexican children with obesity. Materials and Methods: This is a cross-sectional analysis derived from a randomized clinical trial conducted in children and adolescents with obesity aged 8 to 16 years. Anthropometric and biochemical data were measured, and targeted metabolomic analyses were carried out using mass spectrometry. Liver steatosis and fibrosis were estimated using transient elastography (Fibroscan® Echosens, Paris, France). Three groups were studied: a non-MASLD group, an MASLD group, and a group for MASLD + fibrosis. A partial least squares discriminant analysis (PLS-DA) was performed to identify the discrimination between the study groups and to visualize the differences between their heatmaps; also, Variable Importance Projection (VIP) plots were graphed. A VIP score of >1.5 was considered to establish the importance of metabolites and biochemical parameters that characterized each group. Logistic regression models were constructed considering VIP scores of >1.5, and the receiver operating characteristic (ROC) curves were estimated to evaluate different combinations of variables. Results: The metabolic MASLD phenotype was associated with increased concentrations of ALT and decreased arginine, glycine, and acylcarnitine (AC) AC5:1, while MASLD + fibrosis, an advanced stage of MASLD, was associated with a phenotype characterized by increased concentrations of ALT, proline, and alanine and a decreased Matsuda Index. Conclusions: The metabolic MASLD phenotype changes as this metabolic dysfunction progresses. Understanding metabolic disturbances in MASLD would allow for early identification and the development of intervention strategies focused on limiting the progression of liver damage in children and adolescents.

Consensus document on acute-on-chronic liver failure (ACLF) established by the Mexican Association of Hepatology.

Acute-on chronic liver failure (ACLF) has been an intensively debated topic mainly due to the lack of a unified definition and diagnostic criteria. The growing number of publications describing the mechanisms of ACLF development, the progression of the disease, outcomes and treatment has contributed to a better understanding of the disease, however, it has also sparked the debate about this condition. As an attempt to provide medical professionals with a more uniform definition that could be applied to our population, the first Mexican consensus was performed by a panel of experts in the area of hepatology in Mexico. We used the most relevant and impactful publications along with the clinical and research experience of the consensus participants. The consensus was led by 4 coordinators who provided the most relevant bibliography by doing an exhaustive search on the topic. The entire bibliography was made available to the members of the consensus for consultation at any time during the process and six working groups were formed to develop the following sections: 1.- Generalities, definitions, and criteria, 2.- Pathophysiology of cirrhosis, 3.- Genetics in ACLF, 4.- Clinical manifestations, 5.- Liver transplantation in ACLF, 6.- Other treatments.

The CCR2+ Monocyte Subsets Increase in Obese Boys but Not Girls with Abnormally High Carotid Intima-Media Thickness: A Pilot Study.

The differential contribution of monocyte subsets expressing the C-C chemokine receptor 2 (CCR2) to subclinical atherosclerosis in girls and boys is unclear. In this pilot study, we compared classical, intermediate, and nonclassical monocyte subsets expressing CCR2 in 33 obese children of both sexes aged 8 to 16 divided by carotid intima-media thickness (IMT), considering values above the 75th percentile (p75) as abnormally high IMT. Obesity was defined as body mass index above the 95th percentile according to age and sex. Flow cytometry analyses revealed that boys but not girls with IMT ≥ p75 displayed increased CCR2+ cell percentage and CCR2 expression in the three monocyte subsets, compared to boys with IMT < p75. The CCR2+ cell percentage and CCR2 expression in the three monocyte subsets significantly correlated with increased IMT and insulin resistance in boys but not girls, where the CCR2+ nonclassical monocyte percentage had the strongest associations (r = 0.73 and r = 0.72, respectively). The role of CCR2+ monocyte subpopulations in identifying an abnormally high IMT shows a marked sexual dimorphism, where boys seem to be at higher subclinical atherosclerosis risk than girls.

Lesión hepática inducida por fármacos anestésicos / Liver injury induced by anesthetic drugs

Resumen: El daño hepático por medicamentos no es tan raro, su diagnóstico es por exclusión, en algunos casos puede inducir falla hepática aguda. Se realizó una revisión de la bibliografía de los medicamentos más utilizados en los procedimientos anestésicos y el riesgo que existe en estos medicamentos de desarrollar daño hepático por fármacos; los únicos medicamentos que tienen mayor riesgo de hepatotoxicidad son los inhalados halogenados, particularmente el halotano, ahora en desuso, el resto de los medicamentos son seguros.

Abstract: Liver damage by drugs is not so rare, its diagnosis is by exclusion, in some cases can induce acute liver failure. A review of the literature of the drugs most used in anesthetic procedures and the risk that exists of these drugs in the development of liver damage by drugs was carried out; the only drugs that have a higher risk of hepatotoxicity are halogenated inhaled ones, particularly halothane now in disuse, the rest of the drugs are safe.

Alcoholic Liver Disease.

Content available: Author Interview and Audio Recording.

Auditory and visual P300 event-related potentials to detect minimal hepatic encephalopathy.

INTRODUCTION: the diagnosis of minimal hepatic encephalopathy (MHE) requires psychometric tests, although new methods are needed since their sensitivity, specificity, and accuracy are low. The P300 event-related potential (ERP) is obtained by auditory and visual stimuli, although only the auditory P300 has been used to detect MHE. This study aimed to compare the diagnostic features of auditory and visual P300 to detect MHE. MATERIALS AND METHODS: sixty patients with liver cirrhosis and thirty-five healthy controls completed the Psychometric Hepatic Encephalopathy Score (PHES), the critical flicker frequency (CFF), and auditory and visual P300 tests. MHE was diagnosed if PHES and CFF scores were abnormal. RESULTS: fifty-three cirrhotic patients (aged 54.5 ± 8.6 years) completed all tests. Abnormal scores were obtained for PHES (49.1 %) and CFF (67.9 %). The proportion of MHE was 21.4 %. The area under the receiver operating (ROC) curves (AUROC) for auditory P300 was better than for visual P300 for distinguishing MHE from controls (AUROC: 0.792 vs 0.725; p < 0.005 for both; accuracy: 73.8 % vs 70.2 %; sensitivity: 72.2 % for both; specificity: 74.2 vs 69.7, respectively). Among cirrhotic patients, only auditory P300 was useful to detect MHE (AUROC: 0.723; p < 0.05; 77.4 % accuracy; 61.1 % sensitivity, and 81.8 % specificity). CONCLUSIONS: auditory P300 sensitivity, specificity, and accuracy were similar to those of CFF. Our results showed that only auditory P300 is useful to differentiate patients with MHE, although both modalities, auditory and visual, differentiated patients with cirrhosis from controls. Thus, we consider that visual P300 is not suitable for detecting MHE.

Perioperative Morbidity in Acute Appendicitis: Is Delayed Appendectomy Still an Option?

Background: Acute appendicitis is one of the most common causes of acute abdominal pain worldwide. Although several studies have tried to investigate effects of delayed appendectomy, robust recommendations on this topic are still lacking. The aim of this retrospective study was to evaluate the correlation between delayed surgical treatment in acute appendicitis and postoperative complications. Materials and Methods: A 5-year retrospective study was conducted including all patients aged >15 years who underwent laparoscopic appendectomy. Groups were categorized according to the time of in-hospital delay (IHD) (time from hospital admission to surgical incision) as Group A: Early appendectomy (IHD <8 hours) and Group B: Delayed appendectomy (IHD ≥8 hours). Demographics and clinical characteristics, operative time, appendicitis grading score according to disease severity score, and clinical outcomes were considered for analyses. Results: A total of 290 patients were included for statistical analysis: 145 patients (50%) in Group A and 145 patients (50%) in Group B. Patients' baseline characteristics were similar between groups. There were no statistically significant differences between groups A and B in terms of operative time (72.60 minutes versus 72.47 minutes, P = .061), use of drain (53.8% versus 46.2%, P = .731), postoperative complications (47.4% versus 52.6%, P = .812), and length of hospital stay (2.39 [1-24] versus 2.79 [1-12], P = .645). There were no 30-day readmissions in both groups. Overall mortality was 0.3%. Conclusion: Our results suggest that an IHD of ≥8 hours does not significantly increase the risk of complicated appendicitis, the incidence of perioperative complications, postoperative length of stay, or mortality.

Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients.

BACKGROUND: Matrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans. AIM: To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC). METHODS: A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest ® and/or FibroScan ® . Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays. RESULTS: Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 (P < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; P < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 (P < 0.001). CONCLUSION: High concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.

Chronic viral hepatitis C micro-elimination program using telemedicine. The Mexican experience.

In response to the kind letter from Joaquín Cabezas et al., we agree that medical care in the COVID era has radically changed and using new mechanisms in the care of different diseases is undoubtedly now a priority to avoid contagion of both the patient and the medical staff. Although a vaccine could protect the population, there are still many questions to answer. The model we use for the care of patients with a diagnosis of hepatitis C virus (HCV) in Mexico showed great benefits, as in other studies.

Chronic viral hepatitis C micro-elimination program using telemedicine. The Mexican experience.

BACKGROUND: hepatitis C virus (HCV) infection is a global health problem. Chronic infection induces the development of fibrosis and cirrhosis together with all the related complications. The use of direct-acting antiviral (DAA) drugs has proven highly effective. Telemedicine is a present-day resource that brings treatment closer to distant areas and may result in cost savings. OBJECTIVE: to implement a microelimination program for HCV using DAAs with the support of a telemedicine program to minimize expenses. PATIENTS AND METHODS: the program was developed at the Medical Services department of Petróleos Mexicanos (SMPM) with a national coverage; patients diagnosed with chronic hepatitis C were included. These were classified into locals and outsiders. Treatment for foreign patients was indicated, monitored and completed via telemedicine. Thus, avoiding their travel to the country's capital city, in order to save on transportation costs and travel allowances. RESULTS: a total of 136 patients, 74 locals and 62 outsiders, participated in the study. Transfer was avoided for 62 patients (45.5 %), which meant that telemedicine resulted in savings of 3,176.20 USD per patient, with overall savings of 196,924.40 USD from cost minimization. A total of 30 patients remained untreated due to lack of medication, hence the coverage amounted to 86 %. Sustained virological response (SVR) was achieved in 99 % of cases. Only two patients had treatment failure. Adverse events included headache and fatigue in 5 % of the cohort. CONCLUSIONS: with the aid of a telemedicine approach, significant savings were achieved by minimizing costs, since nearly half of patients were outsiders. Coverage reached 86 % and treatment with DAAs was successful for 99 % of our cases.

Differential production of insulin-like growth factor-binding proteins in liver fibrosis progression.

Noninvasive methods for liver disease diagnoses offer great advantages over biopsy, but they cannot be utilized in all cases. Therefore, specific indicators for chronic liver disease management are necessary. The aim was to assess the production of insulin-like growth factor-binding proteins (IGFBPs) 1-7 and their correlation with the different stages of fibrosis in chronic hepatitis C (CHC). A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized by FibroTest® and/or FibroScan®. Serum concentrations of IGFBPs 1-7 were determined through multiple suspension arrangement array technology. Significant differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. Logistic regression models were performed to assess the association between the IGFBPs and fibrosis stages. The association was determined utilizing odds ratios (ORs), and receiver operating characteristic (ROC) curves were constructed to distinguish the IGFBPs in relation to the diagnosis of fibrosis. IGFBP-1 and IGFBP-7 concentrations were higher in CHC than in the healthy individuals, whereas IGFBP-3, IGFBP-5, and IGFBP-6 were downregulated in the patients. An apparent increase of all the IGFBPs was found at fibrosis stage F4, but with different regulations. IGFBP-2, -4, -6, and -7 had the best OR, showing the relation to fibrosis progression. The ROC curves showed that IGFBP-7 was the only protein that distinguished F1 from F3 and F2 from F3. IGFBPs participate in liver fibrosis progression and could be employed as circulating novel protein panels for diagnosis and as possible therapeutic targets in liver fibrosis progression.

Chronic administration of diethylnitrosamine to induce hepatocarcinogenesis and to evaluate its synergistic effect with other hepatotoxins in mice.

Hepatocellular carcinoma (HCC) arises after a long period of exposition to etiological factors that might be either independent or collectively contributing. Several rodent models resemble human HCC; however, the major limitation of these models is the lack of chronic injury that reproducibly mimics the molecular alterations as it occurs in humans. Thus, we hypothesized that chronic administration of different DEN treatments identifies the best-fit dose to induce the HCC and/or to determine whether small DEN doses act synergistically with other known hepatotoxins to induce HCC in mice. C57BL/6 J male mice were intraperitoneally injected twice a week for 6 weeks with different DEN doses ranging from 2.5 to 40 mg/kg body weight; then, selected doses (2.5, 5 and 20 mg/kg) for 6, 10, 14, and 18 weeks. We demonstrated that DEN at 20 mg/kg promoted reactive oxygen species and 4-hydroxynonenal production, cell proliferation inflammatory infiltrate, and fibrosis, which in turn induced liver cancer by week 18. These parameters were established by evaluating histopathological changes, HCC markers such as glutathione S-transferase placental-1 (Gstp1), Cytokeratin-19 (Ck19) and prostaglandin reductase-1 (Ptgr1); that of Cyp2e1, a DEN metabolizing enzyme; and the expression of the proliferation marker Ki67. While DEN at 2.5 and 5 mg/kg increased Gstp1 and Ck19, DEN at 20 mg/kg decreased them and Cyp2e1 expression and activity. In summary, our results demonstrate that DEN chronically administrated at 20 mg/kg induces the HCC, while DEN at 2.5 and 5 mg/kg could be useful in elucidating its synergistic effect with other hepatotoxic agents in mice.

Current trends of liver cirrhosis in Mexico: Similitudes and differences with other world regions.

AIM: To investigate the main current etiologies of cirrhosis in Mexico. METHODS: We performed a cross-sectional retrospective multicenter study that included eight hospitals in different areas of Mexico. These hospitals provide health care to people of diverse social classes. The inclusion criteria were a histological, clinical, biochemical, endoscopic, or imaging diagnosis of liver cirrhosis. Data were obtained during a 5-year period (January 2012-December 2017). RESULTS: A total of 1210 patients were included. The mean age was 62.5 years (SD = 12.1), and the percentages of men and women were similar (52.0% vs 48.0%). The most frequent causes of liver cirrhosis were hepatitis C virus (HCV) (36.2%), alcoholic liver disease (ALD) (31.2%), and nonalcoholic steatohepatitis (23.2%), and the least frequent were hepatitis B virus (1.1%), autoimmune disorders (7.3%), and other conditions (1.0%). CONCLUSION: HCV and ALD are the most frequent causes of cirrhosis in Mexico. However, we note that non-alcoholic fatty liver disease (NAFLD) as an etiology of cirrhosis increased by 100% compared with the rate noted previously. We conclude that NAFLD will soon become one of the most frequent etiologies of liver cirrhosis in Mexico.

Malnutrition is a key prognostic factor related to high mortality-rate in patients with severe alcoholic hepatitis.

BACKGROUND AND AIM: comparatively with European or North-American populations, severe alcoholic hepatitis has a high mortality rate in Mexican population, becoming as high as 50 to 81% in those classified as ABIC B or C; this is true even when they receive specific therapy with steroids or pentoxifylline. The aim of this study was to know which clinical factors are related to early mortality (first 30 days) in Mexican patients with severe alcoholic hepatitis. SUBJECTS AND METHODS: this was a retrospective cohort study that included patients with severe alcoholic hepatitis, defined by a Maddrey's discriminant function ≥ 32, treated at a tertiary care center in a period of five years (2010 to 2015). RESULTS: seventy-six patients were included, 72 (94.7%) were males, mean age was 43 ± 9.1 year-old, and 58 (76.3%) had also cirrhosis. According to the subjective global assessment (SGA), 38 (50%) had severe malnutrition, 22 (28.9%) were at risk of malnutrition, and 16 (21.1%) were well-nourished. At 30 days, 46 patients (60.5%) died. In the multivariate analysis, only the presence of severe malnutrition was associated with 30-day mortality: OR = 6.4; 95% CI: 1.9-22.1; p = 0.003. CONCLUSIONS: the nutritional status seems to be a cardinal prognostic factor associated with early mortality (first 30 days). Malnutrition can explain the high mortality rate observed in Mexican patients with severe alcoholic hepatitis.

Behavior of Oxidative Stress Markers in Alcoholic Liver Cirrhosis Patients.

Alcohol is the most socially accepted addictive substance worldwide, and its metabolism is related with oxidative stress generation. The aim of this work was to evaluate the role of oxidative stress in alcoholic liver cirrhosis (ALC). This study included 187 patients divided into two groups: ALC, classified according to Child-Pugh score, and a control group. We determined the levels of reduced and oxidized glutathione (GSH and GSSG) and the GSH/GSSG ratio by an enzymatic method in blood. Also, protein carbonyl and malondialdehyde (MDA) content were estimated in serum. MDA levels increased in proportion to the severity of damage, whereas the GSH and GSSG levels decreased and increased, respectively, at different stages of cirrhosis. There were no differences in the GSH/GSSG ratio and carbonylated protein content between groups. We also evaluated whether the active consumption of or abstinence from alcoholic beverages affected the behavior of these oxidative markers and only found differences in the MDA, GSH, and GSSG determination and the GSH/GSSG ratio. Our results suggest that alcoholic cirrhotic subjects have an increase in oxidative stress in the early stages of disease severity and that abstinence from alcohol consumption favors the major antioxidant endogen: GSH in patients with advanced disease severity.