Resmetirom, the long-awaited first treatment for metabolic dysfunction-associated steatohepatitis and liver fibrosis?

The most important factor associated with liver-related mortality in NAFLD is liver fibrosis. There is no approved treatment for metabolic dysfunction-associated steatohepatitis (MASH) or liver fibrosis. In the MAESTRO-NASH trial, Harrison et al.1 demonstrated the efficacy of resmetirom, a selective THR-ß agonist, for the treatment of MASH and liver fibrosis at 52 weeks.

The Relationship between Pathogenesis and Possible Treatments for the MASLD-Cirrhosis Spectrum.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a term that entails a broad spectrum of conditions that vary in severity. Its development is influenced by multiple factors such as environment, microbiome, comorbidities, and genetic factors. MASLD is closely related to metabolic syndrome as it is caused by an alteration in the metabolism of fatty acids due to the accumulation of lipids because of an imbalance between its absorption and elimination in the liver. Its progression to fibrosis is due to a constant flow of fatty acids through the mitochondria and the inability of the liver to slow down this metabolic load, which generates oxidative stress and lipid peroxidation, triggering cell death. The development and progression of MASLD are closely related to unhealthy lifestyle habits, and nutritional epigenetic and genetic mechanisms have also been implicated. Currently, lifestyle modification is the first-line treatment for MASLD and nonalcoholic steatohepatitis; weight loss of ≥10% produces resolution of steatohepatitis and fibrosis regression. In many patients, body weight reduction cannot be achieved; therefore, pharmacological treatment should be offered in particular populations.

Occult liver disease: A multinational perspective.

Occult liver disease refers to the presence of unrecognized chronic liver disease and cirrhosis. Liver disease is currently the eleventh cause of death globally, representing 4% of all deaths in the world. Alcohol consumption is the leading cause of cirrhosis globally, accounting for approximately 60% of cases. The estimated global prevalence of non-alcoholic fatty liver disease (NAFLD) is 32.4% and has been steadily increasing over the last years. Viral hepatitis B and C accounted for 1.3 million deaths in 2020. Several studies in populations at high risk of chronic liver disease (elevated liver enzymes, type 2 diabetes, excessive alcohol consumption) have found an elevated prevalence of occult liver disease. Attempts should be made to assess the prevalence of occult liver disease in Latin America, a region with one of the highest rates of metabolic diseases and excessive alcohol consumption. Screening for NAFLD in high-risk subjects and screening for excessive drinking and alcohol use disorders at every level of medical care is relevant. Efforts should also focus on the early treatment of occult liver disease to try to reduce liver disease burden and, in the case of occult viral hepatitis infection, prevent further spreading.

Understanding the Relationship between Nonalcoholic Fatty Liver Disease and Thyroid Disease.

The prevalence of hypothyroidism in patients with nonalcoholic fatty liver disease (NAFLD) is high (22.4%). Thyroid hormones (THs) regulate many metabolic activities in the liver by promoting the export and oxidation of lipids, as well as de novo lipogenesis. They also control hepatic insulin sensitivity and suppress hepatic gluconeogenesis. Because of its importance in lipid and carbohydrate metabolism, the involvement of thyroid dysfunction in the pathogenesis of NAFLD seems plausible. The mechanisms implicated in this relationship include high thyroid-stimulating hormone (TSH) levels, low TH levels, and chronic inflammation. The activity of the TH receptor (THR)-ß in response to THs is essential in the pathogenesis of hypothyroidism-induced NAFLD. Therefore, an orally active selective liver THR-ß agonist, Resmetirom (MGL-3196), was developed, and has been shown to reduce liver fat content, and as a secondary end point, to improve nonalcoholic steatohepatitis. The treatment of NAFLD with THR-ß agonists seems quite promising, and other agonists are currently under development and investigation. This review aims to shine a light on the pathophysiological and epidemiological evidence regarding this relationship and the effect that treatment with THs and selective liver THR-ß agonists have on hepatic lipid metabolism.

Prebiotics and Probiotics: Therapeutic Tools for Nonalcoholic Fatty Liver Disease.

Alterations in the gut-liver axis and changes in the gut microbiome are among the risk factors for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). These patients show increased bacterial overgrowth in the small intestine and impaired intestinal permeability. Therefore, therapeutic options such as probiotics or prebiotics have been investigated to modulate intestinal microbiota composition to improve NAFLD. Most in vivo and in vitro probiotic studies have focused on reducing hepatic fat accumulation. The beneficial effects of probiotics on NAFLD have been demonstrated in animal models, and the most widely used microorganisms are those of the Lactobacillus and Bifidobacterium genera. In animal models, probiotics help restore the intestinal microbiota and improve the integrity of the intestinal barrier. This narrative review summarizes published evidence and the likely benefits of probiotics and prebiotics as a therapeutic option for patients with NAFLD.

The Interlink Between Metabolic-Associated Fatty Liver Disease and Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) affects around 10% of women in the reproductive age group and is characterized by ovulatory dysfunction, hyperandrogenism, and/or polycystic ovarian morphology. PCOS is highly associated with metabolic-associated fatty liver disease (MAFLD) as both diseases share common risk factors. At the time of diagnosis of PCOS, screening for MAFLD is necessary because most patients with MAFLD are asymptomatic. The importance of early detection of MAFLD in patients with PCOS is that a timely intervention in patients with steatosis or steatohepatitis can reduce the probability of liver disease progression.

Current approaches to hepatic encephalopathy.

Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portosystemic shunts. Between 30%-40% of patients with cirrhosis will present overt HE during their lifetime. While the pathophysiology of HE is not entirely understood, three critical factors have been identified: hyperammonaemia, systemic inflammation and oxidative stress by glutaminase gene alterations. Minimal HE is defined by the presence of signs of cognitive abnormalities in a patient without asterixis or disorientation; it can only be diagnosed with neuropsychological or psychometric tests. The diagnosis of overt HE is based on clinical examination with clinical scales. Currently, only overt HE should be routinely treated. The aims of treatment in an acute episode should be to improve the mental status, identify and treat the precipitating factor, reduce duration and limit consequences. Treatment strategies are targeted at reducing ammonia production and/or increasing its elimination. Even though minimal HE has negative effects on the patient's quality of life and effects on prognosis, indications for treatment are still controversial. There are still many unanswered questions regarding the pathophysiology and management of HE. We should also endeavor to develop more accurate and objective diagnostic methods for overt HE that would permit early detection and help improve outcomes on quality of life and economic burden.

Understanding the Role of Metabolic Syndrome as a Risk Factor for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) and metabolic syndrome (MetS) have a rising prevalence worldwide. The relationship between these two entities has long been studied and understanding it has become a public health and clinical priority. This association follows, in most patients, the path through non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis and finally HCC. Nonetheless, increasing evidence has been found, that shows MetS as an independent risk factor for the development of HCC. This review brings together the clinical evidence of the relationship between these highly prevalent diseases, with a particular interest in the impact of each component of MetS on HCC; It aims to summarize the complex physiopathological pathways that explain this relationship, and to shed light on the different clinical scenarios of this association, the impact of treating the different components of MetS on the risk of HCC and what is known about screening for HCC in patients with MetS. By doing so, it hopes to improve awareness on this topic.

Epidemiological and Genetic Aspects of NAFLD and NASH in Mexico.

Content available: Author Interview and Audio Recording.

Cross-sectional pilot study to assess primary healthcare workers' knowledge of nonalcoholic fatty liver disease in a marginalized community in Mexico.

The registered incidence of nonalcoholic fatty liver disease (NAFLD) in primary healthcare centers is lower than expected, suggesting a lack of awareness by primary care healthcare professionals. The implementation of educational tools for healthcare workers has been found to increase timely referral and treatment of patients. We aimed to determine healthcare workers' knowledge of NAFLD to identify their educational needs in one marginalized region. We performed a cross-sectional survey of 261 healthcare professionals in Tlapa de Comonfort, Guerrero, Mexico from October 2019 to December 2019. We created a questionnaire that assessed domains most relevant to NAFLD knowledge. Two hundred and forty-six questionnaires were completed. Of the respondents, 38.3% were nurses and 63.4% were women. Most nurses identified NAFLD as a prevalent (89%) and preventable (93%) disease. Hypertension (33%) and obesity (84%) were recognized as risk factors. The associations between NAFLD and cancer, cirrhosis and cardiovascular disease were identified by 53%, 67% and 72% of respondents, respectively. The largest gaps were found in diagnostic workup, therapeutic approach and the current treatments. We identify modifiable knowledge gaps in NAFLD. Educational strategies for primary care workers could enhance the identification of patients with NAFLD and prevent complications.

Lactate-dehydrogenase associated with mortality in hospitalized patients with COVID-19 in Mexico: a multi-centre retrospective cohort study.

INTRODUCTION AND OBJECTIVES: As of January 2021, over 88 million people have been infected with COVID-19. Almost two million people have died of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A high SOFA score and a D-Dimer >1 µg/mL identifies patients with high risk of mortality. High lactate dehydrogenase (LDH) levels on admission are associated with severity and mortality. Different degrees of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) abnormalities have been reported in these patients, its association with a mortality risk remains controversial. The aim of this study was to explore the correlation between LDH and in-hospital mortality in Mexican patients admitted with COVID-19. MATERIALS & METHODS: We performed a retrospective multi-centre cohort study with 377 hospitalized patients with confirmed SARS-CoV-2 in three centres in Mexico City, Mexico, who were ≥18 years old and died or were discharged between April 1 and May 31, 2020. RESULTS: A total of 377 patients were evaluated, 298 (79.1%) patients were discharged, and 79 (20.9%) patients died during hospitalization. Non-survivors were older, with a median age of 46.7 ± 25.7 years old, most patients were male. An ALT > 61 U/l (OR 3.45, 95% CI 1.27-9.37; p = 0.015), C-reactive protein (CRP) > 231 mg/l (OR 4.71, 95% CI 2.35-9.46; p = 0.000), LDH > 561 U/l (OR 3.03, 95% CI 1.40-6.55; p = 0.005) were associated with higher odds for in-hospital death. CONCLUSIONS: Our results indicate that higher levels of LDH, CRP, and ALT are associated with higher in-hospital mortality risk in Mexican patients admitted with COVID-19.