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An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases...
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An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease

A special issue of Medicina (ISSN 1648-9144). This special issue belongs to the section "Gastroenterology & Hepatology".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 13861

Special Issue Editor

Dr. Galileo Escobedo

E-Mail Website
Guest Editor
Head of the Immunometabolism Lab, Research Division, General Hospital of Mexico, Mexico City 06720, Mexico
Interests: inflammatory immune; obesity; type 2 diabetes; non-alcoholic fatty liver disease

Special Issue Information

Dear Colleagues, 

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic hepatic illness today. NAFLD results from the abnormal accumulation of lipids in the liver, causing a disease spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). The prevalence of NAFLD has increased worldwide in recent decades; however, we still do not know how emerging threats such as the coronavirus disease 2019 (COVID-19) pandemic and lockdown could have impacted the epidemiology of NAFLD. Furthermore, our conception of the molecular basis behind NAFLD has evolved from a single relationship with obesity to a complex network where de novo lipogenesis, fatty acid beta-oxidation, insulin resistance, and systemic inflammation interact to worsen NAFLD, even in non-obese patients. Finally, there is still a deep urgency to design a better disease risk score where circulating biomarkers combined with modern imaging techniques can help to diagnose NAFLD in a timely manner to prevent the onset of NASH, cirrhosis, and HCC.

For these reasons, Medicina is launching a Special Issue which will publish original research and review articles, clinical trials, and case reports covering the most recent aspects of NAFLD’s epidemiology, diagnostic challenges, and molecular bases. The Special Issue is focused on but not limited to:

  • Impact of COVID-19 on NAFLD incidence in different age groups of patients;
  • Unbalance between de novo lipogenesis and fatty acid beta-oxidation in NAFLD development;
  • Contribution of insulin resistance, glucose intolerance, and metabolic syndrome to NAFLD and NASH in non-obese or obese patients;
  • Characterization of immune cell profiles and cytokine networks mediating NASH, cirrhosis, and HCC;
  • Therapeutic targets to prevent NAFLD progression;
  • Design of noninvasive or minimally invasive NAFLD scores and diagnostic tools.

Dr. Galileo Escobedo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Medicina is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • fatty liver disease
  • steatohepatitis
  • fibrosis
  • COVID-19 lockdown
  • insulin resistance
  • metabolic syndrome
  • T cell
  • macrophage
  • computed tomography
  • magnetic resonance imaging

Published Papers (8 papers)

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Research

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14 pages, 16519 KiB  
Article
Insulin-like Growth Factor Binding Proteins and Cellular Senescence Are Involved in the Progression of Non-Alcoholic Fatty Liver Disease and Fibrosis in a Mouse Model
by Carolina Guzmán, Miriam G. Bautista-Ubaldo, Adriana Campos-Espinosa, Ivette I. Romero-Bello, Ángel Daniel Santana-Vargas and Gabriela Gutierrez-Reyes
Medicina 2024, 60(3), 429; https://doi.org/10.3390/medicina60030429 - 02 Mar 2024
Viewed by 922
Abstract
Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor [...] Read more.
Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor binding proteins (IGFBPs) are a family of secreted proteins involved in senescence and scarring, mainly synthetized in the liver. Here, we aimed to study the association of IGFBPs and their induced senescence with the progression of NAFLD and liver fibrosis. Materials and Methods: A total of 16-week-old male C57BL/6 mice weighing 23 ± 3 g were fed either methionine/choline-deficient (MCD) or control diet for 2, 8, or 12 weeks. Blood and liver samples were collected, and a histological assessment of NAFLD and fibrosis was performed. Fat contents were measured. Cellular senescence was evaluated in the liver. IGFBP levels were assessed in the liver and serum. Data were expressed as mean ± SD and analyzed by a one-way ANOVA followed by Tukey’s test. Lineal regression models were applied for NAFLD and fibrosis progression. p < 0.05 was considered significant. Results: IGFBP-1 and -2 were increased in serum during NAFLD. IGFBP-7 was significantly increased in the serum in NASH compared with the controls. Senescence increased in NAFLD. Serum and liver IGFBP-7 as well as SA-β-gal activity increased as fibrosis progressed. Both IGFBP-7 and cellular senescence were significantly higher during NAFLD and fibrosis in MCD-fed mice. Conclusions: IGFBP-1, -2, and -7, through their consequent senescence, have a role in the progression of NAFLD and its associated fibrosis, being a plausible determinant in the progression from steatosis to NASH. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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15 pages, 2200 KiB  
Article
Metabolomic Phenotype of Hepatic Steatosis and Fibrosis in Mexican Children Living with Obesity
by Nayely Garibay-Nieto, Karen Pedraza-Escudero, Isabel Omaña-Guzmán, María José Garcés-Hernández, Eréndira Villanueva-Ortega, Mariana Flores-Torres, José Luis Pérez-Hernández, Mireya León-Hernández, Estibalitz Laresgoiti-Servitje, Berenice Palacios-González, Juan Carlos López-Alvarenga, Mauricio Lisker-Melman and Felipe Vadillo-Ortega
Medicina 2023, 59(10), 1785; https://doi.org/10.3390/medicina59101785 - 07 Oct 2023
Viewed by 1629
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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12 pages, 2425 KiB  
Article
Effect of Roselle Flower Extract (Hibiscus sabdariffa Linn.) on Reducing Steatosis and Steatohepatitis in Vitamin B12 Deficiency Rat Model
by Irena Ujianti, Imelda Rosalyn Sianipar, Ani Retno Prijanti, Irsan Hasan, Wawaimuli Arozal, Ahmad Aulia Jusuf, Heri Wibowo, Joedo Prihartono, Patwa Amani and Dewi Irawati Soeria Santoso
Medicina 2023, 59(6), 1044; https://doi.org/10.3390/medicina59061044 - 28 May 2023
Cited by 2 | Viewed by 2220
Abstract
Background and Objectives: Non-alcoholic Fatty Liver Disease (NAFLD) can occur as a result of micronutrient deficiencies. Hibiscus sabdarifa, a plant used in traditional medicine, contains ingredients that can help prevent this process. This study looked at the potency of Hibiscus sabdariffa Ethanol [...] Read more.
Background and Objectives: Non-alcoholic Fatty Liver Disease (NAFLD) can occur as a result of micronutrient deficiencies. Hibiscus sabdarifa, a plant used in traditional medicine, contains ingredients that can help prevent this process. This study looked at the potency of Hibiscus sabdariffa Ethanol Extract (HSE) to prevent homocysteine-induced liver damage in animals that were deficient in vitamin B12. Materials and Methods: A comparative study of the effects of roselle extract is presented in an experimental design. Thirty Sprague–Dawley rats were divided into six groups using randomization. To demonstrate the absence of liver damage in the experimental animals under normal conditions, a control group was fed a normal diet without HSE. For the induction of liver damage in the experimental animals, the vitamin B12-restricted group was administered a vitamin B12-restricted diet. To test the effect of HSE on liver damage, the treatment group was given HSE along with a vitamin B12-restricted diet. Each group was given two treatment periods of eight and sixteen weeks. These results were compared with the results of the parameter examination between the vitamin B12 restriction group, with and without HSE, using an ANOVA statistic. The data were analyzed with licensed SPSS 20.0 software. Results: HSE significantly increased the blood levels of vitamin B12 while lowering homocysteine levels. The administration of HSE reduced liver damage based on the activity of liver function enzymes in the plasma due to a limitation of vitamin B12. HSE decreased Sterol Regulatory Element-Binding Protein-1c (SREBP1c) and Nuclear Factor Kappa B (NFkB) protein expressions in the liver tissue, but did not decrease Glucose-Regulated Protein 78 (GRP78) protein expression. Significantly, the levels of Tumor Necrosis Factor alpha (TNF-a) and IL-6 in the liver tissue were lower, while the levels of IL-10 and Nuclear factor-erythroid-2 Related Factor 2 (NRF2) were higher with HSE administration. HSE produced a better histopathological profile of the Hematoxylin and Eosin (H&E)–Masson tricrome for inflammation, fat and fibrosis in the liver. Conclusions: In this study, HSE was found to slow the development of liver damage in experimental animals that were given a vitamin B12-deficient diet. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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11 pages, 2329 KiB  
Article
Alleviation of Hepatic Steatosis by Alpha-Defensin Is Associated with Enhanced Lipolysis
by Emad Maraga, Rifaat Safadi, Johnny Amer, Abd Al-roof Higazi and Rami Abu Fanne
Medicina 2023, 59(5), 983; https://doi.org/10.3390/medicina59050983 - 19 May 2023
Cited by 3 | Viewed by 1555
Abstract
Background and Objectives: The neutrophilic peptide, alpha-defensin, is considered an evolving risk factor intimately linked with lipid mobilization. It was previously linked to augmented liver fibrosis. Here, we assess a potential association between alpha-defensin and fatty liver. Materials and Methods: A [...] Read more.
Background and Objectives: The neutrophilic peptide, alpha-defensin, is considered an evolving risk factor intimately linked with lipid mobilization. It was previously linked to augmented liver fibrosis. Here, we assess a potential association between alpha-defensin and fatty liver. Materials and Methods: A cohort of transgenic C57BL/6JDef+/+ male mice that overexpress the human neutrophil-derived alpha-defensin in their polymorphonuclear neutrophils (PMNs) were assessed for liver steatosis and fibrosis development. Wild type (C57BL/6JDef.Wt) and transgenic (C57BL/6JDef+/+) mice were maintained on a standard rodent chow diet for 8.5 months. At the termination of the experiment, systemic metabolic indices and hepatic immunological cell profiling were assessed. Results: The Def+/+ transgenic mice exhibited lower body and liver weights, lower serum fasting glucose and cholesterol, and significantly lower liver fat content. These results were associated with impaired liver lymphocytes count and function (lower CD8, NK cells, and killing marker CD107a). The metabolic cage demonstrated dominant fat utilization with a comparable food intake in the Def+/+ mice. Conclusions: Chronic physiological expression of alpha-defensin induces favorable blood metabolic profile, increased systemic lipolysis, and decreased hepatic fat accumulation. Further studies are needed to characterize the defensin net liver effect. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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14 pages, 2346 KiB  
Article
Correlation between CT Abdominal Anthropometric Measurements and Liver Density in Individuals with Non-Alcoholic Fatty Liver Disease
by Dragoș Constantin Cucoranu, Marian Pop, Raluca Niculescu, Vlad Vunvulea, Irina-Bianca Kosovski, Radu-Ovidiu Togănel, Eliza Russu, Adrian Vasile Mureșan, Răzvan-Andrei Licu and Anca Bacârea
Medicina 2023, 59(3), 500; https://doi.org/10.3390/medicina59030500 - 03 Mar 2023
Cited by 2 | Viewed by 2065
Abstract
Background: With a growing frequency, nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. NAFLD has a strong correlation with other metabolic disorders, such as obesity, particularly abdominal obesity, even though the underlying causes or risk factors are [...] Read more.
Background: With a growing frequency, nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. NAFLD has a strong correlation with other metabolic disorders, such as obesity, particularly abdominal obesity, even though the underlying causes or risk factors are not entirely understood. This study aims to investigate correlations between abdominal anthropometric measurements and the presence and intensity of liver steatosis as assessed by unenhanced computed tomography (CT). Methods: One hundred and nineteen patients (male/female, 66/53; mean age 54.54 +/− 12.90 years) underwent abdominal non–contrast-enhanced CT. CT images were examined to determine the attenuation of liver parenchyma, subcutaneous fat depth, and waist circumference (WC). Results: Among all patients, WC (r = −0.78, p < 0.0001), infraumbilical subcutaneous fat thicknesses (r = −0.51, p < 0.0001), right paraumbilical subcutaneous fat thicknesses (r = −0.62, p < 0.0001), and left paraumbilical subcutaneous fat thicknesses (r = −0.53, p < 0.0001) had a high inverse correlation with the liver attenuation values. The presence of T2D (OR: 2.40, p = 0.04), WC (OR: 11.45, p < 0.001), right paraumbilical (OR: 10.09, p < 0.001), left paraumbilical (OR: 2.81, p = 0.01), and infraumbilical (OR: 3.06, p = 0.007) were strongly independent predictors of NAFLD risk. Moreover, regarding the laboratory parameters, only the higher value of GGT (OR: 2.84, p = 0.009) is a predictor of NAFLD risk. Conclusions: Our data show that higher baseline values of all abdominal anthropometric measurements are correlated with liver attenuation and act as predictors of NAFLD risk. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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8 pages, 1325 KiB  
Article
Human Neutrophil α-Defensins 1–3 Are Upregulated in the Microenvironment of Fibrotic Liver
by Rami Abu Fanne, Emad Maraga, Eiass Kassem, Gabriel Groisman, Naama Amsalem, Abdel-Rauf Zeina, Moran Abu Mouch, Randa Taher and Saif Abu-Mouch
Medicina 2023, 59(3), 496; https://doi.org/10.3390/medicina59030496 - 02 Mar 2023
Cited by 1 | Viewed by 1198
Abstract
Background and Objectives: Neutrophil infiltration is an established signature of Non-Alcoholic Fatty Liver Disease (NAFLD) and Steatohepatitis (NASH). The most abundant neutrophilic peptide, alpha-defensin, is considered a new evolving risk factor in the inflammatory milieu, intimately involved in lipid mobilization. Our objective [...] Read more.
Background and Objectives: Neutrophil infiltration is an established signature of Non-Alcoholic Fatty Liver Disease (NAFLD) and Steatohepatitis (NASH). The most abundant neutrophilic peptide, alpha-defensin, is considered a new evolving risk factor in the inflammatory milieu, intimately involved in lipid mobilization. Our objective is to assess for potential association between alpha-defensin immunostains and NAFLD severity. Materials and Methods: We retrospectively investigated the liver biopsies of NAFLD/NASH patients, obtained at Hillel Yaffe Medical center between the years 2012 and 2016. Patients’ characteristics were recorded, including relevant blood tests at the time of biopsy. Each biopsy was semi-quantitatively scored using NAFLD Activity Score (NAS) and NASH fibrosis stage. The biopsies were immunostained for alpha-defensin. The precipitation of alpha-defensin was correlated to NAS and fibrosis. Results: A total of 80 biopsies were evaluated: male ratio 53.2%, mean age 44.9 ± 13.2 years, 54 had fibrosis grades 0–2, and 26 were grade 3–4. Conventional metabolic risk factors were more frequent in the high-grade fibrosis group. Immunostaining for alpha-defensin disclosed higher intensity (a.u.) in grade 3–4 fibrosis relative to grades 0–2, 25% vs. 6.5%, p < 0.05, respectively. Moreover, alpha-defensin staining was nicely co-localized with fibrosis. Conclusions: In our group of NASH/NAFLD patients, higher metabolic risk profile was associated with higher fibrosis grade. Immunostaining for alpha-defensin showed patchy intense staining concordant with high fibrosis, nicely co-localized with histological fibrosis. Whether alpha-defensin is a profibrotic risk factor or merely risk marker for fibrosis must be clarified in future studies. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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11 pages, 772 KiB  
Article
Clinical Implications of Cardiac Symptoms and Electrocardiographic Abnormalities for Advanced Liver Fibrosis in Patients with Nonalcoholic Fatty Liver Disease
by Min-Kyu Kang and Min-Cheol Kim
Medicina 2023, 59(2), 375; https://doi.org/10.3390/medicina59020375 - 15 Feb 2023
Cited by 1 | Viewed by 1307
Abstract
Background and Objectives: Advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) can be a major predictor of cardiovascular disease (CVD) events and cardiac complications. However, the clinical significance of cardiac symptoms and abnormal electrocardiography (ECG) findings in patients with [...] Read more.
Background and Objectives: Advanced liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) can be a major predictor of cardiovascular disease (CVD) events and cardiac complications. However, the clinical significance of cardiac symptoms and abnormal electrocardiography (ECG) findings in patients with NAFLD associated with advanced liver fibrosis is unclear. Therefore, our study was aimed to evaluate the clinical implications based on the association between cardiac symptoms with ECG abnormalities for advanced liver fibrosis in patients with NAFLD. Materials and Methods: Of 31,795 participants who underwent health checkups, 6293 were diagnosed with NAFLD using ultrasound and inclusion criteria in a retrospective cross-sectional study. Advanced liver fibrosis was assessed based on a low NAFLD fibrosis score (NFS) and fibrosis-4 index (Fib-4) cut-off values (COVs). Cardiac data were assessed using a cardiac symptom questionnaire and 12-lead electrocardiography (ECG). Results: Among 6293 NAFLD patients with NAFLD, 304 (4.8%) experienced cardiac symptoms. NFS and Fib-4 indicated higher rates of advanced fibrosis in the cardiac-symptomatic group than in the non-symptomatic group (NFS: 7.3 vs. 4.1%; Fib-4: 7.8 vs. 3.7%; both p < 0.001). Cardiac symptoms were independently associated with advanced liver fibrosis using a step-wise-adjusted model and NFS and Fib-4 (final adjusted odds ratio (aOR), 1.40; 95% CI, 1.06–1.85; p = 0.018 for NFS; aOR, 1.67; 95%, 1.30–2.15; p < 0.001 for Fib-4). Cardiac symptoms with abnormal ECG findings independently predicted advanced liver fibrosis (aOR, 2.43; 95% CI, 1.72–3.39; p < 0.001 for NFS; aOR, 3.02; 95% CI, 2.19–4.15; p < 0.001 for Fib-4). Conclusions: Patients who have had cardiac symptoms and some ECG abnormalities may have a higher association with advanced liver fibrosis. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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Review

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38 pages, 1390 KiB  
Review
Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease
by Aleksandra Bołdys, Łukasz Bułdak, Mateusz Maligłówka, Stanisław Surma and Bogusław Okopień
Medicina 2023, 59(10), 1789; https://doi.org/10.3390/medicina59101789 - 08 Oct 2023
Viewed by 2303
Abstract
Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require [...] Read more.
Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require an active approach to prompt diagnosis and treatment. Therapeutic lifestyle changes should be introduced in a great majority of patients; but, in many cases, the adherence is not satisfactory. There is a great need for an effective pharmacological therapy for Metabolic-Associated Fatty Liver Disease, especially before the onset of steatohepatitis. Currently, there are no specific recommendations on the selection of drugs to treat liver steatosis and prevent patients from progression toward more advanced stages (steatohepatitis, cirrhosis, and cancer). Therefore, in this Review, we provide data on the clinical efficacy of therapeutic interventions that might improve the course of Metabolic-Associated Fatty Liver Disease. These include the drugs used in the treatment of obesity and hyperlipidemias, as well as affecting the gut microbiota and endocrine system, and other experimental approaches, including functional foods. Finally, we provide advice on the selection of drugs for patients with concomitant Metabolic-Associated Fatty Liver Disease. Full article
(This article belongs to the Special Issue An Update to the Epidemiology, Diagnostic Challenges, and Molecular Bases of Nonalcoholic Fatty Liver Disease)
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