Type 2 Diabetes Subtypes and Their Role in Metabolic Liver Disease and Fibrosis Progression.

BACKGROUND The relationship between different subgroups of type 2 diabetes (T2D) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis has not been thoroughly studied. This study aims to determine the association between T2D subgroups and the risk of developing advanced liver fibrosis using the Fibrosis-4 (FIB-4) index, a non-invasive marker for assessing liver fibrosis risk. MATERIAL AND METHODS A total of 1205 patients with T2D were categorized into 4 distinct subgroups: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The FIB-4 index was calculated for each patient to estimate the degree of liver fibrosis, with the following cutoff points: <1.3 indicating no or mild fibrosis, 1.3-2.67 suggesting moderate fibrosis, and >2.67 indicating advanced fibrosis (F3-F4). Logistic regression was used to compare the odds of advanced fibrosis across these subgroups. RESULTS The SIRD subgroup exhibited significantly higher odds of advanced liver fibrosis (F3-F4), compared with the other subgroups, as indicated by elevated FIB-4 scores (P<0.05). In contrast, the SIDD and MOD subgroups had lower odds of advanced fibrosis, while the MARD subgroup showed an intermediate association. CONCLUSIONS The findings suggest that the FIB-4 index, as a noninvasive assessment tool, effectively stratifies liver fibrosis risk among different T2D subgroups. This stratification can inform more personalized management strategies for patients with MASLD, underscoring the importance of accounting for the heterogeneity within T2D in clinical assessments of liver fibrosis risk.

From Liver to Brain: How MAFLD/MASLD Impacts Cognitive Function.

Metabolic dysfunction-associated fatty liver disease or metabolic dysfunction-associated steatotic liver disease (MAFLD/MASLD), is a common chronic liver condition affecting a substantial global population. Beyond its primary impact on liver function, MAFLD/MASLD is associated with a myriad of extrahepatic manifestations, including cognitive impairment. The scope of cognitive impairment within the realm of MAFLD/MASLD is a matter of escalating concern. Positioned as an intermediate stage between the normal aging process and the onset of dementia, cognitive impairment manifests as a substantial challenge associated with this liver condition. Insights from studies underscore the presence of compromised executive function and a global decline in cognitive capabilities among individuals identified as being at risk of progressing to liver fibrosis. Importantly, this cognitive impairment transcends mere association with metabolic factors, delving deep into the intricate pathophysiology characterizing MAFLD/MASLD. The multifaceted nature of cognitive impairment in the context of MAFLD/MASLD is underlined by a spectrum of factors, prominently featuring insulin resistance, lipotoxicity, and systemic inflammation as pivotal contributors. These factors interplay within the intricate landscape of MAFLD/MASLD, fostering a nuanced understanding of the links between hepatic health and cognitive function. By synthesizing the available evidence, exploring potential mechanisms, and assessing clinical implications, the overarching aim of this review is to contribute to a more complete understanding of the impact of MAFLD/MASLD on cognitive function.

Bilirubin Molecular Species Play an Important Role in the Pathophysiology of Acute-on-Chronic Liver Failure.

Bilirubin plays a key role in early diagnosis, prognosis, and prevention of liver diseases. Unconjugated bilirubin (UCB) requires conversion to a water-soluble form through liver glucuronidation, producing monoglucuronide (BMG) or diglucuronide bilirubin (BDG) for bile excretion. This study aimed to assess the roles of bilirubin's molecular species-UCB, BMG, and BDG-in diagnosing and understanding the pathogenesis of liver cirrhosis in patients with acute-on-chronic liver failure (ACLF), compensated liver cirrhosis (LC) patients, and healthy individuals. The study included patients with ACLF and compensated LC of diverse etiologies, along with healthy controls. We collected laboratory and clinical data to determine the severity and assess mortality. We extracted bilirubin from serum samples to measure UCB, BMG, and BDG using liquid chromatography-mass spectrometry (LC-MS). The quantification of bilirubin was performed by monitoring the mass charge (m/z) ratio. Of the 74 patients assessed, 45 had ACLF, 11 had LC, and 18 were healthy individuals. Among ACLF patients, the levels of molecular species of bilirubin were UCB 19.69 µmol/L, BMG 47.71 µmol/L, and BDG 2.120 µmol/L. For compensated cirrhosis patients, the levels were UCB 11.29 µmol/L, BMG 1.49 µmol/L, and BDG 0.055 µmol/L, and in healthy individuals, the levels were UCB 6.42 µmol/L, BMG 0.52 µmol/L, and BDG 0.028 µmol/L. The study revealed marked elevations in the bilirubin species in individuals with ACLF compared to those with compensated cirrhosis and healthy controls, underscoring the progression of liver dysfunction. The correlation of BMG and BDG levels with commonly used inflammatory markers suggests a relationship between bilirubin metabolism and systemic inflammation in ACLF.

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.

Hepamet Fibrosis Score in Nonalcoholic Fatty Liver Disease Patients in Mexico: Lower than Expected Positive Predictive Value.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has been associated with different negative outcomes in the presence of advanced fibrosis. The Hepamet Fibrosis Score (HFS), a recently described noninvasive score, has shown excellent performance for the detection of advanced fibrosis. The aim of this study was to assess its performance in a Mexican population with NAFLD. METHODS: This was a retrospective cross-sectional study performed in 222 patients with biopsy-proven NAFLD, of whom 33(14%) had advanced fibrosis. We retrieved clinical data from each patient's medical record to compute the HFS, the NAFLD Fibrosis Score (NFS), and the Fibrosis-4 (FIB-4), and assess their performance. RESULTS: When considering the models as continuous variables, the area under the receiving operating characteristics curve of the HFS(0.758) was not different from that of the NFS(0.669, p = 0.09) or FIB-4(0.796, p = 0.1). The HFS had a sensitivity, specificity, positive and negative predictive values of 76.7% (95% CI 57.7-90.1), 90.1% (95% CI 85-93.9), 36.7% (95% CI 19.9-56.1), and 94.3% (95% CI 88.5-97.7), respectively. Indeterminate results (i.e., gray area) were more common with FIB-4 and HFS when compared with NFS [139(63%) and 122(55%) vs 80(36%), p < 0.001]. The variables that were associated with misclassification using the HFS were diabetes [OR 3.40 (95% CI 1.42-8.10), p = 0.006] and age [OR 1.06 (95% CI 1.01-1.11), p = 0.01]. CONCLUSION: The HFS showed sensitivity and specificity similar to that reported in the original publication; however, the positive predictive value was 36.7% at a pretest probability of 14%. The role of the HFS in prospective studies and in combination with other methods should be further explored.

[Tratamiento de infección crónica por virus de hepatitis C en niños, ¿perspectiva hacia la curación o lejos de la meta?]

La infección por el virus de hepatitis C es un problema global de salud pública; en México aproximadamente 2 % de la población se encuentra infectada. En niños, los datos de prevalencia son variables según la edad, pero se estima que 0.1 a 2 % de los niños presenta infección crónica por virus de hepatitis C, cuya principal vía de transmisión es la perinatal. Actualmente existen antivirales de acción directa aprobados en adultos con una tasa de respuesta viral sostenida superior a 95 %; sin embargo, en niños aún son pocos los estudios que confirman su seguridad y efectividad. Aunque todavía estamos lejos de la meta, avanzamos rápidamente hacia un tratamiento óptimo de curación también para pacientes pediátricos.

Infection with hepatitis C virus is a global health problem; in Mexico, approximately 2% of the population is infected. In children, data on prevalence are variable according to the age group, but 0.1-2% of children are estimated to have chronic infection with hepatitis C virus, the main way of transmission of which is perinatal. Currently, there are direct-acting antiviral agents approved in adults that offer a sustained viral response rate higher than 95%; however, in children there are still only few studies confirming their safety and effectiveness. Although we are still far from the goal, we are rapidly advancing towards an optimal curative treatment also for pediatric patients.

A Rare Association: Hereditary Hemorrhagic Telangiectasia with Liver Cirrhosis Causing Portal Hypertension.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a vascular disorder of autosomal dominant etiology. The hallmark clinical feature is the presence of recurrent episodes of epistaxis in patients with vascular malformations and a tendency to bleed. We present the case of a 71-year-old woman who presented to the emergency department with upper gastrointestinal bleeding caused by esophageal varices, in conjunction with gastric angiodysplasias. The presence of oronasopharyngeal telangiectasias and hepatomegaly raised suspicion of HHT. The diagnostic workup confirmed the presence of angiodysplasia in the gastric region, portal arteriovenous malformation, and a pulmonary shunt.

Helicobacter pylori infection is associated with liver fibrosis in patients with obesity undergoing bariatric surgery.

Background: Obesity is a significant risk factor for metabolic-associated steatotic liver disease (MASLD). The association between Helicobacter pylori (HP) infection and liver fibrosis has not been fully elucidated in patients with obesity and MASLD. Methods: This observational retrospective study included clinical and biochemical parameters of patients with obesity undergoing bariatric surgery. HP infection was confirmed by gastric endoscopy, and liver biopsies were performed during surgery. Bivariate and logistic regression analyses were employed to evaluate independent associations with liver fibrosis and steatosis by biopsy. Results: The mean age of the subjects was 42 ± 10 years, with 84.7% being women, and they had a mean BMI of 42.97 ± 7.56 kg/m2. Overall, 41.7% of patients had an HP infection. Multiple logistic regression models were conducted to assess the association between HP infection, liver steatosis, and fibrosis by biopsy. HP infection was independently associated with liver fibrosis [OR = 3.164 (95% CI 1.011-9.900)]. Conclusion: Biopsy findings associated HP infection with increased liver fibrosis.

Pirfenidone use in fibrotic diseases: What do we know so far?

BACKGROUND: Pirfenidone has demonstrated significant anti-inflammatory and antifibrotic effects in both animal models and some clinical trials. Its potential for antifibrotic activity positions it as a promising candidate for the treatment of various fibrotic diseases. Pirfenidone exerts several pleiotropic and anti-inflammatory effects through different molecular pathways, attenuating multiple inflammatory processes, including the secretion of pro-inflammatory cytokines, apoptosis, and fibroblast activation. OBJECTIVE: To present the current evidence of pirfenidone's effects on several fibrotic diseases, with a focus on its potential as a therapeutic option for managing chronic fibrotic conditions. FINDINGS: Pirfenidone has been extensively studied for idiopathic pulmonary fibrosis, showing a favorable impact and forming part of the current treatment regimen for this disease. Additionally, pirfenidone appears to have beneficial effects on similar fibrotic diseases such as interstitial lung disease, myocardial fibrosis, glomerulopathies, aberrant skin scarring, chronic liver disease, and other fibrotic disorders. CONCLUSION: Given the increasing incidence of chronic fibrotic conditions, pirfenidone emerges as a potential therapeutic option for these patients. However, further clinical trials are necessary to confirm its therapeutic efficacy in various fibrotic diseases. This review aims to highlight the current evidence of pirfenidone's effects in multiple fibrotic conditions.

How far are we from an approved drug for nonalcoholic steatohepatitis?

INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) previously known but still debatable, as nonalcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease and subsequent cirrhosis worldwide, accounting for around 30% of liver diseases. The change in its nomenclature has been brought about by the novel discoveries regarding its pathogenesis, in which metabolic dysfunction plays the most important role. It is widely known that for every disease, the treatment should always be targeted toward the underlying etiology and pathogenesis. AREAS COVERED: MAFLD/NAFLD pathogenesis is heterogeneous, and includes multiple gene polymorphisms, presence of insulin resistance, as well as concomitant diseases that contribute to the disease onset and progression. As a result of this, even though lifestyle modification (owing to metabolic abnormalities) is the first line of treatment, multiple drugs have been tested to target each of the known pathways leading to MAFLD/NAFLD and progression of steatohepatitis. We aim to review the most relevant information regarding previous and ongoing research and recommendations regarding treatment of MAFLD/NAFLD. EXPERT OPINION: Combination therapies associated to weight loss and exercise will be the optimal approach for these patients. It is important to evaluate each patient to select the specific combination according to patient characteristics.

Rifaximin Alfa and Liver Diseases: More Than a Treatment for Encephalopathy, a Disease Modifier.

RFX, a rifamycin-based antibacterial agent obtained by the culture of the actinomycete Streptomyces mediterranei, has a broad antibacterial spectrum covering gram- positive, gram-negative, aerobic, and anaerobic bacteria. RFX is an antibiotic that elicits its effect by inhibiting bacterial RNA synthesis. When administered orally, its intestinal absorption is extremely low (<0.4%), restricting antibacterial activity mainly in the intestinal tract, with few systemic side effects. RFX has been recommended by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver guidelines for the treatment of HE. RFX may contribute to restore hepatic function and to decrease the development of liver fibrosis. Its efficacy has been shown in patients with previous hepatic encephalopathy and several complications, such as infections, including spontaneous bacterial peritonitis, ascites and oesophageal variceal bleeding. Thus, RFX has an outstanding role in the therapeutic arsenal in hepatic cirrhosis, under the concept of disease modifier.

Antibiotics in Chronic Liver Disease and Their Effects on Gut Microbiota.

Impairments in liver function lead to different complications. As chronic liver disease progresses (CLD), hypoalbuminemia and alterations in bile acid compositions lead to changes in gut microbiota and, therefore, in the host-microbiome interaction, leading to a proinflammatory state. Alterations in gut microbiota composition and permeability, known as gut dysbiosis, have important implications in CLD; alterations in the gut-liver axis are a consequence of liver disease, but also a cause of CLD. Furthermore, gut dysbiosis plays an important role in the progression of liver cirrhosis and decompensation, particularly with complications such as hepatic encephalopathy and spontaneous bacterial peritonitis. In relation to this, antibiotics play an important role in treating CLD. While certain antibiotics have specific indications, others have been subjected to continued study to determine whether or not they have a modulatory effect on gut microbiota. In contrast, the rational use of antibiotics is important, not only because of their disrupting effects on gut microbiota, but also in the context of multidrug-resistant organisms. The aim of this review is to illustrate the role of gut microbiota alterations in CLD, the use and impact of antibiotics in liver cirrhosis, and their harmful and beneficial effects.

Cirrhosis etiology trends in developing countries: Transition from infectious to metabolic conditions. Report from a multicentric cohort in central Mexico.

Background: Cirrhosis is a public health threat associated with high mortality. Alcoholic Liver Disease (ALD) is the leading cause in Latin America and Metabolic Associated Fatty Liver Disease (MAFLD) in western countries. In Mexico, ALD and chronic Hepatitis C Virus infection (HCV) were the most frequent aetiologies during the past decades. We aimed to describe the trends in the aetiologies of cirrhosis in a middle-income country. Methods: We performed a retrospective cohort study including patients diagnosed with cirrhosis between 2000 and 2019 from six different tertiary care hospitals in central Mexico. We collected information regarding cirrhosis etiology, year of diagnosis, hepatocellular carcinoma development, liver transplantation, and death. We illustrated the change in the tendencies of cirrhosis aetiologies by displaying the proportional incidence of each etiology over time stratified by age and gender, and we compared these proportions over time using chi square tests. Findings: Overall, 4,584 patients were included. In 2019, MAFLD was the most frequent cirrhosis etiology (30%), followed by ALD (24%) and HCV (23%). During the study period, MAFLD became the leading etiology, ALD remained second, and HCV passed from first to fourth. When analysed by gender, ALD was the leading etiology for men and MAFLD for women. The annual incidence of HCC was 3·84 cases/100 persons-year, the median survival after diagnosis was 12·1 years, and seven percent underwent LT. Interpretation: Increased alcohol consumption and the obesity epidemic have caused a transition in the aetiologies of cirrhosis in Mexico. Public health policies must be tailored accordingly to mitigate the burden of alcohol and metabolic conditions in developing countries. Funding: None.

Hepatic Dendritic Cells in the Development and Progression of Metabolic Steatohepatitis.

Metabolic Associated Fatty liver disease (MAFLD) is a global health problem and represents the most common cause of chronic liver disease in the world. MAFLD spectrum goes from simple steatosis to cirrhosis, in between metabolic steatohepatitis with progressive fibrosis, which pathogenesis is not completely understood. Hence, the role of the immune system has become an important fact in the trigger of inflammatory cascades in metabolic steatohepatitis and in the activation of hepatic stellate cells (HSCs). Among, the more studied immune cells in the pathogenesis of MAFLD are macrophages, T cells, natural killer and dendritic cells. In particular, hepatic dendritic cells had recently attracted a special attention, with a dual role in the pathogenesis of MAFLD. These cells have the capacity to switch from a tolerant state to active state inducing an inflammatory cascade. Furthermore, these cells play a role in the lipid storage within the liver, having, thus providing a crucial nexus between inflammation and lipid metabolism. In this review, we will discuss the current knowledge on the dual role of dendritic cells in lipid accumulation, as wells as in the triggering of hepatic inflammation and hepatocytes cell death in metabolic steatohepatitis.

Gut Microbiota in Metabolic-associated Fatty Liver Disease and in Other Chronic Metabolic Diseases.

The gut microbiome plays a key role in the health-disease balance in the human body. Although its composition is unique for each person and tends to remain stable throughout lifetime, it has been shown that certain bacterial patterns may be determining factors in the onset of certain chronic metabolic diseases, such as type 2 diabetes mellitus (T2DM), obesity, metabolic-associated fatty liver disease (MAFLD), and metabolic syndrome. The gut-liver axis embodies the close relationship between the gut and the liver; disturbance of the normal gut microbiota, also known as dysbiosis, may lead to a cascade of mechanisms that modify the epithelial properties and facilitate bacterial translocation. Regulation of gut microbiota is fundamental to maintaining gut integrity, as well as the bile acids composition. In the present review, we summarize the current knowledge regarding the microbiota, bile acids composition and their association with MAFLD, obesity, T2DM and metabolic syndrome.

Obesity and Gallstones.

BACKGROUND: The prevalence of obesity has been increasing globally and represents the main risk factor for the development of gallstone disease (GD). SUMMARY: Excess body weight represents the main cause for the development of GD; nevertheless, there have been described multiple risk factors for its development, among them modifiable risk factors as diet, lifestyle, physical inactivity, and non-modifiable risk factors as ethnicity, female sex, advanced age, parity, and genetic mutations. Body mass index, abdominal perimeter, and waist-hip index have been used to determine the degree of adiposity of a person. Hence, central abdominal fat has been mostly associated with insulin resistance with the consequent increase in the hepatic cholesterol secretion; contributing as one of the multiple mechanisms associated with the development of gallstones. This disease has a low mortality; however, it has been associated with multiple diseases such as cardiovascular diseases, carotid atherosclerosis, metabolic associated fatty liver disease, and gallbladder cancer, probably because they share many of the risk factors. KEY MESSAGES: GD continues to be considered a disease with a high medical burden, in which it is sought to intervene in modifiable risk factors to reduce its development.

Metabolic associated fatty liver disease and acute-on-chronic liver failure: common themes for common problems.

Metabolic associated fatty liver disease (MAFLD) affects 20-30% of the worldwide population and is becoming the most common cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). MAFLD is the hepatic expression of metabolic dysfunction correlated with a variety of metabolic comorbidities including obesity, dyslipidemia, hypertension and type 2 diabetes (T2DM). Obesity, altered gut permeability, chronic inflammation and dysbiosis related to MAFLD might predispose patients with cirrhosis to the development of acute-on-chronic liver failure (ACLF); however, this relationship remains unclear. ACLF is a syndrome with high short-term mortality, presenting with acute hepatic decompensation associated with organ failures in patients with underlying chronic liver disease with or without an identifiable precipitating event. While this syndrome can occur in any patient with cirrhosis, the increasing prevalence of cirrhosis due to MAFLD is of great concern because, in a recent analysis, MAFLD was the fastest rising cause of cirrhosis associated with ACLF among patients listed for LT in the US. In this review, we will discuss the current knowledge on MAFLD and the development of ACLF.

Prevalence and clinical characteristics of alpha-1 antitrypsin deficiency in liver explants in a Mexican cohort.

INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a risk factor for liver disease. PASD-positive inclusions have been found unexpectedly in approximately 10% of liver explants in patients with no previous diagnosis of AATD, particularly, in patients with non-alcoholic steatohepatitis (NASH), supporting a synergistic mechanism of liver injury between AATD and environmental factors. We aimed to determine the clinical characteristics of mestizo patients in which AATD was diagnosed before or after liver transplantation. METHODS: Liver explants of patients with cryptogenic, alcoholic, and NAFLD/NASH cirrhosis undergoing orthotopic liver transplantation (OLT) were included. Liver histopathology was assessed by two expert pathologists. Hematoxylin and eosin staining, PASD staining, and confirmatory AAT immunohistochemistry were performed. In explants with positive histopathology, genotyping for SERPINA1 was performed. RESULTS: A total of 180 liver transplants were performed during the study period. Of these, 44 patients with cryptogenic cirrhosis, NASH, and alcoholic cirrhosis were included. Of these patients, two liver explants (4.5%) had PASD-positive inclusions stain and confirmatory immunochemistry. During the period evaluated, another two patients with a diagnosis of AATD before the OLT were also included. The four patients had overweight or obesity, three had type 2 diabetes mellitus, and two developed liver steatosis after the OLT. CONCLUSION: AATD was found to be an infrequent finding in patients with cryptogenic, NASH/NAFLD, and alcoholic cirrhosis in our population. However, it is important to consider this entity as it may represent an additional factor in the appearance and progression of liver fibrosis in patients with metabolic syndrome.

Tratamiento de infección crónica por virus de hepatitis C en niños, ¿perspectiva hacia la curación o lejos de la meta? / Treatment of chronic hepatitis C virus infection in children, prospect towards cure or far from the goal?

Resumen La infección por el virus de hepatitis C es un problema global de salud pública; en México aproximadamente 2 % de la población se encuentra infectada. En niños, los datos de prevalencia son variables según la edad, pero se estima que 0.1 a 2 % de los niños presenta infección crónica por virus de hepatitis C, cuya principal vía de transmisión es la perinatal. Actualmente existen antivirales de acción directa aprobados en adultos con una tasa de respuesta viral sostenida superior a 95 %; sin embargo, en niños aún son pocos los estudios que confirman su seguridad y efectividad. Aunque todavía estamos lejos de la meta, avanzamos rápidamente hacia un tratamiento óptimo de curación también para pacientes pediátricos.

Abstract Infection with hepatitis C virus is a global health problem; in Mexico, approximately 2% of the population is infected. In children, data on prevalence are variable according to the age group, but 0.1-2% of children are estimated to have chronic infection with hepatitis C virus, the main way of transmission of which is perinatal. Currently, there are direct-acting antiviral agents approved in adults that offer a sustained viral response rate higher than 95%; however, in children there are still only few studies confirming their safety and effectiveness. Although we are still far from the goal, we are rapidly advancing towards an optimal curative treatment also for pediatric patients.