Non-alcoholic fatty liver disease in type 2 diabetes:Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies

Nonalcoholic fatty liver disease(NAFLD)is a global epidemic,affecting more than half of the people living with type 2 diabetes(T2D).The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other,which significantly increases the hepatic as well as extrahepatic complications.Until recently,there was no approved pharmacological treatment for NAFLD/nonalcoholic steatohepatitits(NASH).However,there is evidence that drugs used for diabetes may have beneficial effects on NAFLD.Insulin sensitizers acting through peroxisome proliferator-activated receptor(PPAR)modulation act on multiple levels of NAFLD pathogenesis.Pioglitazone(PPARγ agonist)and saroglitazar(PPARα/γagonist)are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D,although data on biopsyproven NASH are lacking with the latter.Initial data on elafibanor(PPARα/δ agonist)and Lanifibranor(pan PPAR agonist)are promising.On the other hand,incretin therapies based on glucagon-like peptide-1(GLP-1)receptor agonists(GLP-1RA)and dual-and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties.GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual-and triple-agonists are required.Furthermore,the long-term safety of these therapies in NAFLD needs to be established.Collaborative efforts among healthcare providers such as primary care doctors,hepatologists,and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease

Heart failure with reduced ejection fraction(HFrEF)and nonalcoholic fatty liver disease(NAFLD)are two common comorbidities that share similar pathophysiological mechanisms.There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD.This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD.Pharmacological therapies,including angiotensinconverting enzyme inhibitors/angiotensin receptor blockers,mineralocorticoids receptor antagonist,and sodium-glucose cotransporter-2 inhibitors,have been shown to reduce fibrosis and fat deposits in the liver.However,there are currently no data showing the beneficial effects of sacubitril/valsartan,ivabradine,hydralazine,isosorbide nitrates,digoxin,or beta blockers on NAFLD in patients with HFrEF.This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities.Further research is needed in patients with coexisting HFrEF and NAFLD,with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.

Global trends and hotspots of treatment for nonalcoholic fatty liver disease:A bibliometric and visualization analysis(2010-2023)

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is chronic,with its progression leading to liver fibrosis and end-stage cirrhosis.Although NAFLD is increasingly common,no treatment guideline has been established.Many mechanistic studies and drug trials have been conducted for new drug development to treat NAFLD.An up-to-date overview on the knowledge structure of NAFLD through bibliometrics,focusing on research hotspots,is necessary to reveal the rational and timely directions of development in this field.AIM To research the latest literature and determine the current trends in treatment for NAFLD.METHODS Publications related to treatment for NAFLD were searched on the Web of Science Core Collection database,from 2010 to 2023.VOSviewers,CiteSpace,and R package“bibliometrix”were used to conduct this bibliometric analysis.The key information was extracted,and the results of the cluster analysis were based on network data for generating and investigating maps for country,institution,journal,and author.Historiography analysis,bursts and cluster analysis,cooccurrence analysis,and trend topic revealed the knowledge structure and research hotspots in this field.GraphPad Prism 9.5.1.733 and Microsoft Office Excel 2019 were used for data analysis and visualization.RESULTS In total,10829 articles from 120 countries(led by China and the United States)and 8785 institutions were included.The number of publications related to treatment for NAFLD increased annually.While China produced the most publications,the United States was the most cited country,and the United Kingdom collaborated the most from an international standpoint.The University of California-San Diego,Shanghai Jiao Tong University,and Shanghai University of Traditional Chinese Medicine produced the most publications of all the research institutions.The International Journal of Molecular Sciences was the most frequent journal out of the 1523 total journals,and Hepatology was the most cited and co-cited journal.Sanyal AJ was the most cited author,the most co-cited author was Younossi ZM,and the most influential author was Loomba R.The most studied topics included the epidemiology and mechanism of NAFLD,the development of accurate diagnosis,the precise management of patients with NAFLD,and the associated metabolic comorbidities.The major cluster topics were“emerging drug,”“glucagon-like peptide-1 receptor agonist,”“metabolic dysfunction-associated fatty liver disease,”“gut microbiota,”and“glucose metabolism.”CONCLUSION The bibliometric study identified recent research frontiers and hot directions,which can provide a valuable reference for scholars researching treatments for NAFLD.

Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD)/nonalcoholic steatohepatitis(NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers(thiazolidinediones) and antioxidants(vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.

Effects of plasma exchange combined with continuous renal replacement therapy on acute fatty liver of pregnancy

BACKGROUND: Acute fatty liver of pregnancy (AFLP) in the third trimester or early postpartum period can lead to fatal liver damage. Its traditional therapy is not very effective in facilitating hepatic recovery. The safety and effect of plasma exchange (PE)in combination with continuous renal replacement therapy(CRRT) (PE+CRRT) for AFLP still needs evaluation.METHODS: Five AFLP patients with hepatic encephalopathy and renal failure were subjected to PE+CRRT in our department from 2007 to 2012. Their symptoms, physical signs and results were observed, and all relevant laboratory tests were compared before and after PE+CRRT.RESULTS: All the 5 patients were well tolerated to the therapy. Four of them responded to the treatment and showed improvement in clinical symptoms/signs and laboratory results and they were cured and discharged home after the treatment One patient succeeded in bridging to transplantation for slowing down hepatic failure and its complications process after2 treatment sessions. Intensive care unit stay and hospital stay were 9.4 (range 5-18) and 25.0 days (range 11-42), respectively.CONCLUSION: PE+CRRT is safe and effective and should be used immediately at the onset of hepatic encephalopathy and/or renal failure in patients with AFLP.

Current and emerging pharmacological therapy for nonalcoholic fatty liver disease

The main treatment of patients with non-alcoholic fatty liver disease(NAFLD) is life style modification including weight reduction and dietary regimen.Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis(NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients. Several medications, mainly targeting baseline mechanism of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as insulin sensitizing agent and vitamin E as an antioxidant have been recommended for treatment of NASH by international guidelines. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet. Several emerging medications are in development for treatment of NASH. Obeticholic acid, liraglutide, elafibranor, cenicriviroc and aramchol have been tested in clinical trials or are completing trials. Here in, current and upcoming medications with promising results in clinical trial for treatment of NAFLD were reviewed.

Emerging role of engineered exosomes in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is the most common chronic liver dis-ease worldwide.NAFLD comprises a continuum of liver abnormalities from non-alcoholic fatty liver to nonalcoholic steatohepatitis,and can even lead to cirrhosis and liver cancer.However,a well-established treatment for NAFLD has yet to be identified.Exosomes have become an ideal drug delivery tool because of their high transmissibility,low immunogenicity,easy accessibility and targeting.Exosomes with specific modifications,known as engineered exosomes,have the potential to treat a variety of diseases.Here,we review the treatment of NAFLD with engineered exosomes and the potential use of exosomes as biomarkers and therapeutic targets for NAFLD.

Prevalence of hypothyroidism and effect of thyroid hormone replacement therapy in patients with non-alcoholic fatty liver disease:A population-based study

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)is currently considered as the most common cause of chronic liver disease worldwide.Risk factors for NAFLD have been well-described,including obesity,type 2 diabetes mellites(T2DM),dyslipidemia(DLP)and metabolic syndrome.Hypothyroidism has been identified as an independent risk factor for the development of NAFLD,although the literature is inconsistent AIM To evaluate the prevalence of hypothyroidism in patients with NAFLD,assess if it is an independent risk factor and explore the effect of thyroxine replacement therapy.METHODS Our cohort’s data was obtained using a validated,large,multicenter database(Explorys Inc,Cleveland,OH,United States)aggregated from pooled outpatient and inpatient records of 26 different healthcare systems,consisting of a total of 360 hospitals in the United States,and utilizing Systematized Nomenclature of Medicine-Clinical Terms for coding.We evaluated a cohort of patients with hypothyroidism and NAFLD.Multivariate analysis was performed to adjust for confounding risk factors including hypertension(HTN),T2DM,DLP,obesity and metabolic syndrome.SPSS version 25,IBM Corp was used for statistical analysis,and for all analyses,a 2-sided P value of<0.05 was considered statistically significant.Exclusion criteria were limited to age<18 years.RESULTS Among the 37648180 included individuals in this database who are above the age of 18 years,there were a total of 2320 patients with NAFLD(6.16 per 100000)in the last five years(2015-2020),amongst which 520 patients(22.4%)had hypothyroidism.Baseline characteristics of patients in this database are described in Table 1.Patients with NAFLD were also more likely to have obesity,T2DM,DLP,HTN,and metabolic syndrome(Table 2).While males and females were equally affected,patients in the age group 18-65 years as well as Caucasians seem to be at a higher risk.There was an increased risk of NAFLD among patients with hypothyroidism(OR=1.587).Furthermore,thyroid hormone replacement was not associated with a decreased risk for developing NAFLD(OR=1.106,C=0.952-1.285,P=0.303).CONCLUSION Hypothyroidism seems to be an independent risk factor for the development of NAFLD.Thyroid hormone replacement did not provide a statistically significant risk reduction.Further studies are needed to evaluate the effect of thyroid hormone replacement and assess if being euthyroid while on thyroid replacement therapy affects development and/or progression of NAFLD.

Vitamin E Therapy in Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is closely related to oxidative stress. Vitamin E (VE) is an effective antioxidant, which could relieve NAFLD symptoms by improving the balance of oxidation and anti-oxidation. However, recent researches indicate that the functional mechanisms of VE are not only limited to anti-oxidation, but also include adjusting the metabolism disorders of glucose and lipid. Furthermore, the efficacy of VE remains controversial in the treatment of NAFLD by far, and the suitable condition of patient, drug dosage, drug safety and course of treatment during clinical application still need to be discussed. Therefore, this paper reviewed the recent study progresses of clinical application of VE alone and VE and other drugs.

Research progress of external therapies of traditional Chinese medicine in the treatment of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is a common chronic liver disease characterized by diffuse hepatic steatosis.With the improvement of people's living standard,the incidence rate of NAFLD has been increasing,which has become one of the global health problems in 21st Century.However,there is no specific drug or standard treatment for NAFLD,which brings challenges to treatment.Acupuncture,moxibustion,massage and other external therapies based on the characteristics of traditional Chinese medicine have obvious curative effect in the clinical treatment of NAFLD,but the mechanism has not been systematically explained,which makes the clinical promotion evidence insufficient.This paper aims to summarize the researches on the treatment of NAFLD by external therapies of traditional Chinese medicine in recent years,and analyze its possible mechanism,so as to provide a scientific theoretical basis for future basic experiments and clinical research,and form a set of standardized clinical diagnosis and treatment scheme with the characteristics of traditional Chinese medicine.

Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma

Non-alcoholic fatty liver disease(NAFLD) associated hepatocellular carcinoma(HCC) incidence is increasing worldwide, paralleling the obesity epidemic. Although most cases are associated with cirrhosis, HCC can occur without cirrhosis in NAFLD. Diabetes and obesity are associated risk factors for HCC in patients. Given the sheer magnitude of the underlying risk factors(diabetes, obesity, non-cirrhotic NAFLD) screening for HCC in the non-cirrhotic population is not recommended. Optimal screening strategies in NAFLD cirrhosis are not completely elucidated with Ultrasound having significant limitations in detection of liver lesions in the presence of obesity and steatosis. Consequently NAFLD-HCC is more often diagnosed at a later stage with larger tumors and reduced opportunities for curative treatments as opposed to HCC in other causes of cirrhosis. When HCC is found at a curative stage treatments including liver transplantation, resection and loco-regional therapies are associated with good results similar to that seen in HCV-HCC. Future strategies under study include the use of chemopreventive and antioxidant agents to reduce development of cirrhosis and non-alcoholic steatohepatitis(NASH). Strategies to reverse NASH via weight loss, control of associated conditions like diabetes are key strategies in reducing the increasing incidence of NASH-HCC. Novel therapeutic agents for NASH are in trials and if successful in achieving reversal of NASH will be an important strategy in reducing NAFLD-HCC.

Non-alcoholic fatty liver disease and psoriasis: So far, so near

Psoriasis is a chronic inflammatory immune-mediated skin diseases which is frequently associated to comorbidities. Non-alcoholic fatty liver disease(NAFLD) is defined as an excessive accumulation of triglycerides in hepatocytes and includes a wide spectrum of liver conditions ranging from relatively benign steatosis to non-alcoholic steatohepatitis with fatty infiltration and lobular inflammation and to cirrhosis and endstage liver disease. Actually, psoriasis is considered a systemic diseases associated to comorbidities, as metabolic syndrome and NAFLD is seen the hepatic manifestation of the metabolic syndrome. The possible link between psoriasis, obesity and metabolic syndrome, which are known risk factors for NAFLD has beenrecently documented focusing in the crucial role of the adipose tissue in the development of the inflammatory background sharing by the above entities. According to recent data, patients with psoriasis show a greater prevalence of NAFLD and metabolic syndrome than the general population. Moreover, patients with NAFLD and psoriasis are at higher risk of severe liver fibrosis than those with NAFLD and without psoriasis. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple aspects linking NAFLD and psoriasis, only apparently far diseases.

Therapeutic approaches to non-alcoholic fatty liver disease: past achievements and future challenges

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver injury and mortality in Western countries and China. However, as to date, there is no direct and effective therapy for this disease. The aim of this review is to analyze the key progress and challenges of main current therapeutic approaches in NAFLD. DATA SOURCE: We carried out a PubMed search of English-language articles relevant to NAFLD therapy. RESULTS: There are two major therapeutic strategies for NAFLD treatment: (1) lifestyle interventions (including weight reduction, dietary modification and physical exercise) and (2) pharmaceutical therapies. Lifestyle interventions, particularly chronic and moderate intensity exercise, are the most effective and recognized clinical therapies for NAFLD. For pharmaceutical therapies, although their effects and mechanisms have been extensively investigated in laboratory studies, they still need further tests and investigations in clinical human trials. CONCLUSION: Future advancement of NAFLD therapy should focus on the mechanistic studies on cell based and animal models and human clinical trials of exercise, as well as the combination of lifestyle intervention and pharmaceutical therapy specifically targeting main signaling pathways related to lipid metabolism, oxidative stress and inflammation.

Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia

AIM: To investigate the efficacy and safety of n-3 polyunsaturated fatty acids (PUFA) from seal oils for patients with nonalcoholic fatty liver disease (NAFLD) associated with hyperlipidemia. METHODS: One hundred and forty-four patients with NAFLD associated with hyperlipidemia were included in the 24-wk, randomized, controlled trial. The patients were randomized into two groups. Group A (n = 72) received recommended diet and 2 g n-3 PUFA from seal oils, three times a day. Group B (n = 72) received recommended diet and 2 g placebo, three times a day. Primary endpoints were fatty liver assessed by symptom scores, liver alanine aminotransferase (ALT) and serum lipid levels after 8, 12, 16, and 24 wk. Hepatic fat inf iltration was detected by ultrasonography at weeks 12 and 24 after treatment. RESULTS: A total of 134 patients (66 in group A, 68 in group B) were included in the study except for 10 patients who were excluded from the study. After 24 wk of treatment, no change was observed in body weight, fasting blood glucose (FBG), renal function and blood cells of these patients. Total symptom scores, ALT and triglyceride (TG) levels decreased more significantly in group A than in group B (P < 0.05). As expected, there was a tendency toward improvement in aspartate aminotransferase (AST), γ-glutamyltranspeptidase (GGT), and total cholesterol (TCHO) and high- density lipoprotein (HDL) cholesterol levels (P < 0.05) after administration in the two groups. However, no significant differences were found between the two groups. The values of low-density lipoprotein (LDL) were significantly improved in group A (P < 0.05), but no significant change was found in group B at different time points and after a 24-wk treatment. After treatment, complete fatty liver regression was observed in 19.70% (13/66) of the patients, and an overall reduction was found in 53.03% (35/66) of the patients in group A. In contrast, in group B, only f ive patients (7.35%, 5/68) achieved complete fatty liver regression (P = 0.04), whereas 24 patients (35.29%, 24/68) had a certain improvement in fatty liver (P = 0.04). No serious adverse events occurred in all the patients who completed the treatment. CONCLUSION: Our results indicate that n-3 PUFA from seal oils is safe and effi cacious for patients with NAFLD associated with hyperlipidemia and can improve their total symptom scores, ALT, serum lipid levels and normalization of ultrasonographic evidence. Further study is needed to confi rm these results.

Dietary habits and behaviors associated with nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is one of the most frequent causes of health problems in Western(industrialized)countries.Moreover,the incidence of infantile NAFLD is increasing,with some of these patients progressing to nonalcoholic steatohepatitis.These trends depend on dietary habits and life-style.In particular,overeating and its associated obesity affect the development of NAFLD.Nutritional problems in patients with NAFLD include excess intake of energy,carbohydrates,and lipids,and shortages of polyunsaturated fatty acids,vitamins,and minerals.Although nutritional therapeutic approaches are required for prophylaxis and treatment of NAFLD,continuous nutrition therapy is difficult for many patients because of their dietary habits and lifestyle,and because the motivation for treatment differs among patients.Thus,it is necessary to assess the nutritional background and to identify nutritional problems in each patient with NAFLD.When assessing dietary habits,it is important to individually evaluate those that are consumed excessively or insufficiently,as well as inappropriate eating behaviors.Successful nutrition therapy requires patient education,based on assessments of individual nutrients,and continuing the treatment.In this article,we update knowledge about NAFLD,review the important aspects of nutritional assessment targeting treatment success,and present some concrete nutritional care plans which can be applied generally.

Heterogeneity of non-alcoholic fatty liver disease: Implications for clinical practice and research activity

Non-alcoholic fatty liver disease(NAFLD)is a heterogeneous condition with a wide spectrum of clinical presentations and natural history and disease severity.There is also substantial inter-individual variation and variable response to a different therapy.This heterogeneity of NAFLD is in turn influenced by various factors primarily demographic/dietary factors,metabolic status,gut microbiome,genetic predisposition together with epigenetic factors.The differential impact of these factors over a variable period of time influences the clinical phenotype and natural history.Failure to address heterogeneity partly explains the sub-optimal response to current and emerging therapies for fatty liver disease.Consequently,leading experts across the globe have recently suggested a change in nomenclature of NAFLD to metabolic-associated fatty liver disease(MAFLD)which can better reflect current knowledge of heterogeneity and does not exclude concomitant factors for fatty liver disease(e.g.alcohol,viral hepatitis,etc.).Precise identification of disease phenotypes is likely to facilitate clinical trial recruitment and expedite translational research for the development of novel and effective therapies for NAFLD/MAFLD.

Recent insights into farnesoid X receptor in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is the hepatic manifestation of metabolic syndrome and is one of the most prevalent liver disorders worldwide. NAFLD can gradually progress to liver inflammation, fibrosis, cirrhosis and even hepatocellular carcinoma. However, the pathogenesis of NAFLD is complex, and no efficient pharmaceutic treatments have yet been established for NAFLD. Accumulating data have shown that the farnesoid X receptor(FXR) plays important roles not only in bile acid metabolism, but also in lipid and carbohydrate homeostasis, inflammatory responses, among others. In this review, we aim to highlight the role of FXR in the pathogenesis and treatment of NAFLD.

Non-alcoholic fatty liver disease and type 2 diabetes mellitus: The liver disease of our age?

Non-alcoholic fatty liver disease(NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different nonalcoholic entities; fatty liver(NAFL, steatosis hepatis)and steatohepatitis(NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer.NAFL increasingly affects children(paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus(T2DM),insulin resistance(IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2 DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.

Intestinal microbiota in the treatment of metabolically associated fatty liver disease

Metabolically associated fatty liver disease (MAFLD) is a common cause ofchronic liver disease, the hepatic manifestation of metabolic syndrome. Despitethe increasing incidence of MAFLD, no effective treatment is available. Recentresearch indicates a link between the intestinal microbiota and liver diseases suchas MAFLD. The composition and characteristics of the intestinal microbiota andtherapeutic perspectives of MAFLD are reviewed in the current study. Animbalance in the intestinal microbiota increases intestinal permeability andexposure of the liver to adipokines. Furthermore, we focused on reviewing thelatest "gut-liver axis" targeted therapy.