Insulin resistance and adipose tissue interactions as the cornerstone of metabolic (dysfunction)-associated fatty liver disease pathogenesis.

The relationship between metabolic derangements and fatty liver development are undeniable, since more than 75% of patients with type 2 diabetes mellitus present with fatty liver. There is also significant epidemiological association between insulin resistance (IR) and metabolic (dysfunction)-associated fatty liver disease (MAFLD). For little more than 2 years, the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups. While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed, the bottom line relies on the role of IR as an initiator and perpetuator of this disease. There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations, where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory element-binding protein-1c induced lipogenic enzyme stimulation; therefore, increased endogenous production of triglycerides. The same effect is achieved through impaired suppression of adipose tissue (AT) lipolysis in insulin-resistant states, increasing fatty acid influx into the liver. The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion, modifying fatty acid metabolism as well as IR in a variety of tissues, including skeletal muscle, AT, and the liver. The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

Synergistic Effect of Biejia-Ruangan on Fibrosis Regression in Patients With Chronic Hepatitis B Treated With Entecavir: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Long-term nucleos(t)ide analogue (NA) treatment can reverse liver fibrosis in chronic hepatitis B (CHB), but its effect on fibrosis regression remains limited. Biejia-Ruangan (BR) has been approved in China as an antifibrotic traditional Chinese medicine drug in patients with chronic liver diseases. A multicenter randomized controlled trial aims to evaluate the effect of BR on fibrosis regression in CHB patients treated with NAs. METHODS: CHB patients with histologically confirmed advanced fibrosis or cirrhosis were randomly assigned to receive entecavir (ETV) (0.5 mg per day) plus BR (2 g 3 times a day) or placebo for 72 weeks. Liver fibrosis regression was defined as a reduction of ≥ 1 point by the Ishak fibrosis stage (IFS). RESULTS: Overall, 500 patients were enrolled in each group as the intention-to-treat population. The rate of fibrosis regression after 72 weeks of treatment was significantly higher in the ETV + BR group (40% vs 31.8%; P = .0069). Among 388 patients with cirrhosis (ie, IFS ≥ 5) at baseline, the rate of cirrhosis reversal (ie, IFS ≤ 4) was significantly higher in the ETV + BR group (41.5% vs 30.7%; P = .0103). CONCLUSIONS: Addition of BR to the current standard treatment with NAs in CHB patients with advanced fibrosis or cirrhosis can improve liver fibrosis regression. CLINICAL TRIALS REGISTRATION: NCT01965418.

Nutraceuticals and microbiota.

Nutraceuticals are defined as products isolated or purified from foods that are generally sold in medicinal or dosage forms not usually associated with food which is demonstrated to have a physiological benefit or provide protection against chronic disease. In this context, the products offered should be rigorously evaluated by international regulatory agencies. More recently, nutraceuticals have been proposed as a potential preventive and therapeutic option in the assessment of chronic diseases, mainly by altering the microbiome composition. However, the current lack of conclusive evidence supporting the "healthy" or "normal" microbiome, along with the dysbiosis concept paradigm, could be both contributing to the lack of homogeneous results. These issues may be solved in the next years with the use of emergent technologies in the individual's microbiome assessment and its fluctuations in time or related to many factors, such as nutraceuticals. Additionally, future research assessing the independent association between the dysbiosis modification and any "potential" nutraceutical product (including bioactive ingredient or chemical compound in food) is going to enlarge the currently reduced "established nutraceuticals" group. In this work we have assessed the nutraceutical's potential role as a microbiome-targeted manipulation therapy, and the gut-liver axis involved in the digestive diseases' pathogenesis and progression, including the chronic liver diseases. Moreover, microbiome targeted nutraceuticals that show consistent results might be further included in clinical research and trials in the therapeutic assessment of chronic diseases. Finally, the indication of these quality microbiome-targeted nutraceuticals will undoubtedly carry health benefits for individuals.

Drug-induced liver injury: A management position paper from the Latin American Association for Study of the liver.

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals and dietary supplements) is an uncommon cause of liver disease presenting with a wide range of phenotypes and disease severity, acute hepatitis mimicking viral hepatitis to autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes. Disease severity ranges from asymptomatic liver test abnormalities to acute liver failure. DILI has been traditionally classified in predictable or intrinsic (dose-related) or unpredictable (not dose-related) mechanisms. Few prospective studies are assessing the real prevalence and incidence of hepatotoxicity in the general population. DILI registries represent useful networks used for the study of liver toxicity, aimed at improving the understanding of causes, phenotypes, natural history, and standardized definitions of hepatotoxicity. Although most of the registries do not carry out population-based studies, they may provide important data related to the prevalence of DILI, and also may be useful to compare features from different countries. With the support of the Spanish Registry of Hepatotoxicity, our Latin American Registry (LATINDILI) was created in 2011, and more than 350 DILI patients have been recruited to date. This position paper describes the more frequent drugs and herbs-induced DILI in Latin America, mainly focusing on several features of responsible medicaments. Also, we highlighted the most critical points on the management of hepatotoxicity in general and those based on findings from our Latin American experience in particular.

Impact of Herbal and Dietary Supplements Causing Drug-Induced Liver Injury in Latin America.

Watch a video presentation of this article.

Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review.

BACKGROUNDS: Traditional Chinese medicine (TCM) is becoming increasingly popular and related adverse events are often ignored or underestimated. AIMS: This systematic review aimed to evaluate the clinical characteristics and outcomes of TCM-induced liver injury (TCM-ILI) and to estimate the proportion of TCM-ILI in all drug-induced liver injuries (DILI). METHODS: China National Knowledge Infrastructure, Wanfang, VIP, PubMed, and Embase databases were searched. Demographic, clinical, and survival data were extracted and pooled. Factors associated with worse outcomes were calculated. For the proportion meta-analyses, the data were pooled by using a random-effects model. RESULTS: Overall, 21,027 articles were retrieved, of which 625 were finally included. There was a predominance of female and older patients. The proportion of liver transplantation was 2.18% (7/321). The mortality was 4.67% (15/321). Male, higher aspartate aminotransferase and direct bilirubin, and lower albumin were significantly associated with an increased risk of death/liver transplantation in TCM-ILI patients. The proportion of TCM-ILI in all DILI was 25.71%. The proportion was gradually increased with year. CONCLUSIONS: Our work summarises current knowledge regarding clinical presentation, disease course, and prognosis of TCM-ILI. TCM can result in hepatotoxicity, even death or necessitate life-saving liver transplantation. Governmental regulation of TCM products should be strictly established.

Herbal Medicine in Mexico: A Cause of Hepatotoxicity. A Critical Review.

In Mexico, herbal products are commonly used as therapeutic tools. The analysis of several publications reveals that there are dozens of different herbs and herbal products used for different reasons, some of which have been implicated in causing toxic liver disease. However, methodological aspects limit the attribution of causality, and the precise incidence and clinical manifestations of herb-induced liver injury have not been well characterized. This review outlines the history of traditional herbal medicine in Mexico, critically summarizes the mechanisms and adverse effects of commonly used herbal plants, and examines the regulatory issues regarding the legal use of these products.

A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy.

BACKGROUND AND AIM: Because low serum zinc levels precipitate hepatic encephalopathy, zinc supplementation is considered a potential therapeutic option. The aim of this study was to assess the effects of oral zinc supplementation in the treatment of hepatic encephalopathy. METHODS: For this systematic review and meta-analysis, data sources included electronic databases (CENTRAL, MEDLINE, EMBASE) and manual searching. Randomized clinical trials of adult patients diagnosed with liver cirrhosis and hepatic encephalopathy were included. The types of interventions considered were any oral zinc supplementation versus no intervention, placebo, or other interventions for the management of hepatic encephalopathy. The data were analyzed by calculating the RR for each trial and expressing the uncertainty as 95% CI. Continuous data were analyzed by calculating the standard mean differences (SMD) between groups within each trial and their 95% CI. Statistical heterogeneity was defined as a P-value > 0.10 (χ2) or I2 > 25%. RESULTS: Four trials with a total of 233 patients were included. Oral zinc supplementation was associated with a significant improvement in performance on the number connection test (SMD -0.62; 95% CI -1.12 to -0.11) reported in three trials (n = 189), but not with encephalopathy recurrence reduction (RR 0.64; 95% CI 0.26 to 1.59) reported in two trials (n = 169). Other clinically significant outcomes (mortality, liver related morbidity, quality of life) were not reported. CONCLUSION: Oral zinc supplementation improved performance on the number connection test, but no evidence about other clinical or biochemical outcomes was available.

High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity.

BACKGROUND & AIMS: Some phytochemicals present in coffee have a potential antioxidant role which seems to protect the human body against cardiovascular diseases, liver disease and malignancies. Nonalcoholic fatty liver disease is a common disease with limited therapeutic options. This study investigated the antioxidant effect of coffee by measuring antioxidant enzymes and lipid peroxidation markers in patients with nonalcoholic fatty liver disease. MATERIAL AND METHODS: We performed a case-control study at the University Hospital, Mexico City. Anthropometric, metabolic, dietary and biochemical variables of all patients were determined and compared. The presence of nonalcoholic fatty liver disease was established by ultrasonography. All patients completed a dietary questionnaire in order to determine their of coffee consumption. Catalase, superoxide dismutase and thiobarbituric acid reactive substances were measured in all of the patients. RESULTS: Seventy-three subjects with and 57 without nonalcoholic fatty liver disease were included. Patients with nonalcoholic fatty liver disease had significantly higher body mass index, blood glucose, homeostasis model of assessment-insulin resistance and insulin values in comparison to patients without nonalcoholic fatty liver disease. On the one hand, there was a significant difference in coffee intake between the groups (p < 0.05, for all comparisons). There was no significant difference between groups in catalase (0.39 ± 0.74 vs. 0.28 ± 0.69 nM/min/mL), superoxide dismutase (5.4 ± 3.45 vs. 4.7 ± 2.1 U/mL) or thiobarbituric acid-reactive substances (4.05 ± 1.87 vs. 3.94 ± 1.59 µM/mL). CONCLUSIONS: A high intake of coffee has a protective effect against nonalcoholic fatty liver disease however there was no significant difference in the antioxidant variables analyzed.

Sorafenib, a systemic therapy for hepatocellular carcinoma.

Hepatocellular carcinoma is a lethal disease that requires a multidisciplinary approach and management. Surgical therapy offers long-term survival; however, few patients are candidates. There has been no accepted systemic therapy for this disease until recently. This article briefly discusses the role of RAS/RAF/MEK/ERK signaling pathway in the pathogenesis of the disease and the promising role of sorafenib for advanced disease.

[Ghrelin and the gastro-hypothalamic axis]. / La ghrelina y su importancia con el eje gastrohipotalámico.

Obesity is currently considered one of the most important diseases worldwide due to its high morbidity and mortality rates. The mechanisms involved in the control of satiation, body weight and energy expenditure has led to the discovery of new hormones that participate in the gastrichypothalamic axis in charge of regulating satiation and other obesity-related processes. Ghrelin a novel hormone secreted mainly by gastric tissue, has shed some light on this mechanism. It is a hormone that regulates satiation and body weight by centrally mediated mechanisms, involving neuropeptide Y and Agouti associated proteins. The present review focuses on some important physiological aspects of this hormone.

La ghrelina y su importancia con el eje gastrohipotalámico / Ghrelin and the gastro-hypothalamic axis

La obesidad se considera una de las enfermedades más importantes en la medida que acarrea gran morbilidad y mortalidad. El conocimiento de los mecanismos que intervienen en la saciedad, el peso corporal y el gasto de energía ha permitido el descubrimiento de hormonas relacionadas con el eje gastrohipotalámico, encargado de regular la saciedad y otros procesos que participan en la obesidad. La ghrelina, una hormona de secreción predominantemente gástrica, dio luz para comprender estos mecanismos, pues se trata de una hormona que regula la saciedad y el peso corporal por medio de mecanismos centrales mediados por el neuropéptido Y y la proteína relacionada con el agutí. En este artículo se revisan los aspectos fundamentales de esta hormona y de sus efectos en diversos órganos y sistemas.

Obesity is currently considered one of the most important diseases worldwide due to its high morbidity and mortality rates. The mechanisms involved in the control of satiation, body weight and energy expenditure has led to the discovery of new hormones that participate in the gastrichypothalamic axis in charge of regulating satiation and other obesity-related processes. Ghrelin a novel hormone secreted mainly by gastric tissue, has shed some light on this mechanism. It is a hormone that regulates satiation and body weight by centrally mediated mechanisms, involving neuropeptide Y and Agouti associated proteins. The present review focuses on some important physiological aspects of this hormone.