Interplay of gut microbiota,glucagon-like peptide receptor agonists,and nutrition:New frontiers in metabolic dysfunction-associated steatotic liver disease therapy

The gut-liver axis plays a crucial role in the development and progression of metabolic dysfunction-associated steatotic liver disease(MASLD).Key metabolites,including lipopolysaccharides,short-chain fatty acids(SCFAs),bile acids,and beneficial gut bacteria such as Bifidobacterium and Lactobacillus,are pivotal in this process.Glucagon-like peptide-1 receptor agonists(GLP-1 RAs)show promise in managing MASLD by promoting weight loss,enhancing insulin secretion,and improving liver health.They restore gut-liver axis functionality,and their effects are amplified through dietary modifications and gut microbiometargeted therapies.Emerging research highlights the interplay between GLP-1 RAs and gut microbiota,indicating that the gut microbiome significantly influences therapeutic outcomes.Metabolites produced by gut bacteria,can stimulate glucagon-like peptide-1(GLP-1)secretion,further improving metabolic health.Integrating dietary interventions with GLP-1 RA treatment may enhance liver health by modulating the gut microbiota-SCFAs-GLP-1 pathway.Future research is needed to understand personalized effects,with prebiotics and probiotics offering treatment avenues for MASLD.

Molecular Therapy and Prevention of Liver Diseases

Molecular analyses have become an integral part of biomedical research as well as clinical medicine. The definition of the genetic basis of many human diseases has led to a better understanding of their pathogenesis and has in addition offered new perspectives for their diagnosis, therapy and prevention. Genetically, human diseases can be classified as hereditary monogenic, acquired monogenic and polygenic diseases. Based on this classification, gene therapy is based on six concepts: (1) gene repair, (2) gene substitution, (3) cell therapy, (4) block of gene expression or function, (5) DNA vaccination and (6) gene augmentation. While major advances have been made in all areas of gene therapy during the last years, various delivery, targeting and safety issues need to be addressed before these strategies will enter clinical practice. Nevertheless, gene therapy will eventually become part of the management of patients with various liver diseases, complementing or replacing existing therapeutic and preventive strategies.

Antioxidant and anti-inflammatory agents in chronic liver diseases:Molecular mechanisms and therapy

Chronic liver disease(CLD)is a continuous process that causes a reduction of liver function lasting more than six months.CLD includes alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD),chronic viral infection,and autoimmune hepatitis,which can lead to liver fibrosis,cirrhosis,and cancer.Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD.Molecular signaling pathways such as AMPactivated protein kinase(AMPK),C-Jun N-terminal kinase,and peroxisome proliferator-activated receptors(PPARs)are implicated in the pathogenesis of CLD.Therefore,antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD,NAFLD,and hepatocellular carcinoma(HCC).In this review,we summarize some powerful products that can be potential applied in all the stages of CLD,from ALD/NAFLD to HCC.The selected agents such asβ-sitosterol,curcumin,genistein,and silymarin can regulate the activation of several important molecules,including AMPK,Farnesoid X receptor,nuclear factor erythroid 2-related factor-2,PPARs,phosphatidylinositol-3-kinase,and lysyl oxidase-like proteins.In addition,clinical trials are undergoing to evaluate their efficacy and safety.

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.

Gene therapy: Regulations, ethics and its practicalities in liver disease

Gene therapy is a new and promising approach which opens a new door to the treatment of human diseases. By direct transfer of genetic materials to the target cells, it could exert functions on the level of genes and molecules. It is hoped to be widely used in the treatment of liver disease, especially hepatic tumors by using different vectors encoding the aim gene for anti-tumor activity by activating primary and adaptive immunity, inhibiting oncogene and angiogenesis. Despite the huge curative potential shown in animal models and some pilot clinical trials, gene therapy has been under fierce discussion since its birth in academia and the public domain because of its unexpected side effects and ethical problems. There are other challenges arising from the technique itself like vector design, administration route test and standard protocol exploration. How well we respond will decide the fate of gene therapy clinical medical practice.

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.

Safety and efficacy of dual antiplatelet therapy after percutaneous coronary interventions in patients with end-stage liver disease

The prevalence of coronary artery disease(CAD)increases in patients with endstage liver disease,with part of them receiving the percutaneous coronary intervention(PCI)as a treatment option.Dual antiplatelet therapy(DAPT),a standard of care after PCI,could result in catastrophic consequences in this population.Before PCI and the start of DAPT,it is recommended to assess patient bleeding risk.Based on novel findings,liver cirrhosis does not necessarily lead to a significant increase in bleeding complications.Furthermore,conventional methods,such as the international normalized ratio,might not be appropriate in assessing individual bleeding risk.The highest bleeding risk among cirrhotic patients has a subgroup with severe thrombocytopenia(<50×10^(9)/L)and elevated portal pressure.Therefore,every effort should be made to maintain thrombocyte count above>50×10^(9)/L and prevent variceal bleeding.There is no solid evidence for DAPT in patients with cirrhosis.However,randomized trials investigating short(one month)DAPT duration after PCI with new drug-eluting stents(DES)in a high bleeding risk patient population can be implemented in patients with cirrhosis.Based on retrospective studies(with older stents and protocols),PCI and DAPT appear to be safe but with a higher risk of bleeding complications with longer DAPT usage.Finally,novel methods in assessing CAD severity should be performed to avoid unnecessary PCI and potential risks associated with DAPT.When indicated,PCI should be performed over radial artery using contemporary DES.Complementary medical therapy,such as proton pump inhibitors and beta-blockers,should be prescribed for lower bleeding risk patients.Novel approaches,such as thromboelastography and“preventive”upper endoscopies in PCI circumstances,warn clinical confirmation.

Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease

Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts.Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients.The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments.Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence,the number of new infections.Antiviral treatments have decreased the rates of liver decompensation and as a result,lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection.The quality of life of chronically infected patients has also been improved significantly by modern treatment.Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis.Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation.This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.

Traditional Chinese herbal extracts inducing autophagy as a novel approach in therapy of nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is one of the leading causes of chronic liver diseases around the world due to the modern sedentary and food-abundant lifestyle, which is characterized by excessive fat accumulation in the liver related with causes other than alcohol abuse. It is widely acknowledged that insulin resistance, dysfunctional lipid metabolism, endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis/necrosis may all contribute to NAFLD. Autophagy is a protective self-digestion of intracellular organelles, including lipid droplets(lipophagy), in response to stress to maintain homeostasis. Lipophagy is another pathway for lipid degradation besides lipolysis. It is reported that impaired autophagy also contributes to NAFLD. Some studies have suggested that the histological characteristics of NAFLD(steatosis, lobular inflammation, and peri-sinusoid fibrosis) might be improved by treatment with traditional Chinese herbal extracts, while autophagy may be induced. This review will provide insights into the characteristics of autophagy in NAFLD and the related role/mechanisms of autophagy induced by traditional Chinese herbal extracts such as resveratrol, Lycium barbarum polysaccharides, dioscin, bergamot polyphenol fraction, capsaicin, and garlic-derived S-allylmercaptocysteine, which may inhibit the progression of NAFLD. Regulation of autophagy/lipophagy with traditional Chinese herbal extracts may be a novel approach for treating NAFLD, and the molecular mechanisms should be elucidated further in the near future.

Periodontal treatment and microbiome-targeted therapy in management of periodontitis-related nonalcoholic fatty liver disease with oral and gut dysbiosis

A growing body of evidence from multiple areas proposes that periodontal disease,accompanied by oral inflammation and pathological changes in the microbiome,induces gut dysbiosis and is involved in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).A subgroup of NAFLD patients have a severely progressive form,namely nonalcoholic steatohepatitis(NASH),which is characterized by histological findings that include inflammatory cell infiltration and fibrosis.NASH has a high risk of further progression to cirrhosis and hepatocellular carcinoma.The oral microbiota may serve as an endogenous reservoir for gut microbiota,and transport of oral bacteria through the gastro-intestinal tract can set up a gut microbiome dysbiosis.Gut dysbiosis increases the production of potential hepatotoxins,including lipopolysaccharide,ethanol,and other volatile organic compounds such as acetone,phenol and cyclopentane.Moreover,gut dysbiosis increases intestinal permeability by disrupting tight junctions in the intestinal wall,leading to enhanced translocation of these hepatotoxins and enteric bacteria into the liver through the portal circulation.In particular,many animal studies support that oral administration of Porphyromonas gingivalis,a typical periodontopathic bacterium,induces disturbances in glycolipid metabolism and inflammation in the liver with gut dysbiosis.NAFLD,also known as the hepatic phenotype of metabolic syndrome,is strongly associated with metabolic complications,such as obesity and diabetes.Periodontal disease also has a bidirectional relationship with metabolic syndrome,and both diseases may induce oral and gut microbiome dysbiosis with insulin resistance and systemic chronic inflammation cooperatively.In this review,we will describe the link between periodontal disease and NAFLD with a focus on basic,epidemiological,and clinical studies,and discuss potential mechanisms linking the two diseases and possible therapeutic approaches focused on the microbiome.In conclusion,it is presumed that the pathogenesis of NAFLD involves a complex crosstalk between periodontal disease,gut microbiota,and metabolic syndrome.Thus,the conventional periodontal treatment and novel microbiome-targeted therapies that include probiotics,prebiotics and bacteriocins would hold great promise for preventing the onset and progression of NAFLD and subsequent complications in patients with periodontal disease.

Evaluation of a protocol for rifaximin discontinuation in critically ill patients with liver disease receiving broad-spectrum antibiotic therapy

BACKGROUND Rifaximin is frequently administered to critically ill patients with liver disease and hepatic encephalopathy,but patients currently or recently treated with antibiotics were frequently excluded from studies of rifaximin efficacy.Due to overlapping spectrums of activity,combination therapy with broad-spectrum antibiotics and rifaximin may be unnecessary.A pharmacist-driven protocol was piloted to reduce potentially overlapping therapy in critically ill patients with liver disease.It was hypothesized that withholding rifaximin during broad-spectrum antibiotic therapy would be safe and reduce healthcare costs.AIM To determine the clinical,safety,and financial impact of discontinuing rifaximin during broad-spectrum antibiotic therapy in critically ill liver patients.METHODS This was a single-center,quasi-experimental,pre-post study based on a pilot pharmacist-driven protocol.Patients in the protocol group were prospectively identified via the medical intensive care unit(ICU)(MICU)protocol to have rifaximin withheld during broad-spectrum antibiotic treatment.These were compared to a historical cohort who received combination therapy with broadspectrum antibiotics and rifaximin.All data were collected retrospectively.The primary outcome was days alive and free of delirium and coma(DAFD)to 14 d.Safety outcomes included MICU length of stay,48-h change in vasopressor dose,and ICU mortality.Secondary outcomes characterized rifaximin cost savings and protocol adherence.Multivariable analysis was utilized to evaluate the association between group assignment and the primary outcome while controlling for potential confounding factors.RESULTS Each group included 32 patients.The median number of delirium-and coma-free days was similar in the control and protocol groups[3 interquartile range(IQR 0,8)vs 2(IQR 0,9.5),P=0.93].In multivariable analysis,group assignment was not associated with a reduced ratio of days alive and free of delirium or coma at 14 d.The protocol resulted in a reduced median duration of rifaximin use during broad-spectrum antibiotic therapy[6 d control(IQR 3,9.5)vs 1 d protocol(IQR 0,1);P<0.001].Rates of other secondary clinical and safety outcomes were similar including ICU mortality and 48-h change in vasopressor requirements.Overall adherence to the protocol was 91.4%.The median estimated total cost of rifaximin therapy per patient was reduced from$758.40(IQR$379.20,$1200.80)to$126.40(IQR$0,$126.40),P<0.01.CONCLUSION The novel pharmacist-driven protocol for rifaximin discontinuation was associated with significant cost savings and no differences in safety outcomes including DAFD.

Impact of continuous positive airway pressure therapy for nonalcoholic fatty liver disease in patients with obstructive sleep apnea

BACKGROUND Obstructive sleep apnea(OSA)has been suggested as an independent risk factor for nonalcoholic fatty liver disease(NAFLD),and continuous positive airway pressure(CPAP)is the first-line therapy for OSA.AIM To clarify the efficacy of effective CPAP therapy on NAFLD of OSA patients by serum markers and transient elastography(TE)using FibroScan®(Echosens,Paris,France).METHODS We prospectively enrolled 123 consecutive patients with OSA who met the indications for CPAP.Liver fibrosis and steatosis were assessed using TE.Before and after 6 mo of CPAP therapy,serum markers and TE were assessed for all patients.The mean usage rate of CPAP therapy for 6 mo was arbitrarily calculated in each patient and expressed as“mean compliance index”(m-CI).RESULTS In 50 OSA patients with NAFLD,both aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels were significantly decreased after 6 mo of CPAP therapy.Univariate analysis showed that decreased body weight(BW),decreased body mass index(BMI),decreased AST level,decreased hemoglobin A1c,and high m-CI were significantly related with improved ALT level.In multivariate regression model adjusted for quantities of BW change during 6 mo of CPAP therapy,high m-CI tended to improve ALT level(P=0.051).All 17 OSA patients with NAFLD,high m-CI and no BMI changes showed significant improvements in AST and ALT levels.Meanwhile,no significant changes in TE data or serum fibrosis markers were seen.CONCLUSION Some NAFLD could be associated with chronic intermittent hypoxia due to OSA independent of BW changes.In those cases,adequate reoxygenation from effective CPAP therapy may improve NAFLD.

Advances in traditional Chinese medicine for liver disease therapy in 2020

Liver diseases are gradually becoming a serious threat to human health worldwide.Although a number of medications have been introduced for the prophylaxis,diagnosis,and treatment of liver diseases,several limitations and challenges remain.Traditional Chinese medicine is frequently used to treat liver diseases and well known to protect hepatocytes and inhibit inflammation,oxidative stress,and fibrosis.However,given the complex composition of traditional Chinese medicine,clarifying the mechanisms behind its curative and protective effects is difficult.In this review,research progress on traditional Chinese medicine for the treatment of liver diseases in 2020 is summarized on the basis of the literature available in the PubMed database.Herbal extracts derived from traditional Chinese medicine,including flavonoids,polysaccharides,saponins,and alkaloids,and Chinese medicinal formulas,such as the classic decoctions Chaihu Shugan powder,Linggui Zhugan decoction,and Huanglian Jiedu decoction,have shown promising therapeutic efficacy in liver disease treatment.We summarized the findings of several studies on the active ingredients of traditional Chinese herbs used for liver disease treatment in 2020,focusing mainly on their ability to confer antiviral effects to treat hepatitis,regulate antioxidant levels and apoptosis to treat liver injury,inhibit inflammation and improve dysfunctions in amino acids and energy metabolism to treat alcoholic liver disease,reduce hepatic lipid deposition to treat nonalcoholic fatty liver disease,promote activated hepatic stellate cells to treat liver fibrosis,inhibit the proliferation or promote the apoptosis of liver cancer cells to treat hepatocellular carcinoma,and improve bile acid metabolism to treat cholestasis.

Advances in traditional Chinese medicine for liver disease therapy in 2021

Liver diseases and their co-morbidities represent a major public health problem.Owing to its progressive pathogenesis and lack of effective treatment,liver disease has become one of the most important causes of death worldwide.Traditional Chinese medicine(TCM)has potential advantages in the prevention and treatment of liver diseases,including high safety,remarkable curative effects,and low toxicity and side effects.In 2021,TCM extracts and their derivatives,TCM compounds,and ethnic medicines showed good efficacy in the treatment of liver diseases.The main mechanisms and representative drugs of TCM can be summarized by the use of amygdalin,dicoumarol,quercetin,and ancient ephedrine decoction to treat hepatitis by inhibiting viral replication,as well as the use of Gentianae Radix,lupeol,Zornia diphylla(L.)Pers.,and Chinese patent medicine Liuwei Wuling tablet to alleviate acute liver injury by improving oxidative stress and inflammatory responses in the body.In the treatment of alcoholic liver disease and metabolic-associated fatty liver disease,the mechanism of TCM is the inhibition of oxidative stress,improving metabolism,regulating intestinal microflora,and enhancing intestinal barrier function.The representative TCM for alcoholic liver disease includes astragaloside,puerarin,patchouli alcohol,and Mori Fructus polysaccharide,while those for metabolic-associated fatty liver disease include saikosaponin,dehydroabietic acid,hesperetin,berberine,and Panax Notoginseng saponins.Additionally,germacrone,forsythin,geniposide,and protocatechuic acid can inhibit the activation or migration of stellate cells and improve liver fibrosis.Toosendanin,paeoniflorin,chrysin,and the classical prescription Huanglian decoction can significantly inhibit the proliferation of liver cancer cells and promote their apoptosis for the treatment of hepatocellular carcinoma.The activation of the farnesol X receptor pathway can improve bile metabolism in the liver,thus,significantly alleviating cholestatic liver disease.Its representative drugs include the TCM extracts pterostilbene and arbutin.In this review,we summarize the advances made in research on TCM used in the treatment of liver diseases in 2021,providing a reference for further development of TCM for the prevention and treatment of liver diseases.

Predicting colorectal adenomatous polyps in patients with chronic liver disease: A novel nomogram

BACKGROUND Colorectal polyps are commonly observed in patients with chronic liver disease(CLD)and pose a significant clinical concern because of their potential for malignancy.AIM To explore the clinical characteristics of colorectal polyps in patients with CLD,a nomogram was established to predict the presence of adenomatous polyps(AP).METHODS Patients with CLD who underwent colonoscopy at Tianjin Second People’s Hospital from January 2020 to May 2023 were evaluated.Clinical data including laboratory results,colonoscopy findings,and pathology reports were collected.Key variables for the nomogram were identified through least absolute shrinkage and selection operator regression,followed by multivariate logistic regression.The performance of the model was evaluated using the area under the receiver area under curve,as well as calibration curves and decision curve analysis.RESULTS The study enrolled 870 participants who underwent colonoscopy,and the detection rate of AP in patients with CLD was 28.6%.Compared to individuals without polyps,six risk factors were identified as predictors for AP occurrence:Age,male sex,body mass index,alcohol consumption,overlapping metabolic dysfunction-associated steatotic liver disease,and serum ferritin levels.The novel nomogram(AP model)demonstrated an area under curve of 0.801(95%confidence interval:0.756-0.845)and 0.785(95%confidence interval:0.712-0.858)in the training and validation groups.Calibration curves indicated good agreement among predicted and actual probabilities(training:χ^(2)=11.860,P=0.157;validation:χ^(2)=7.055,P=0.530).The decision curve analysis underscored the clinical utility of the nomogram for predicting the risk of AP.CONCLUSION The AP model showed reasonable accuracy and provided a clinical foundation for predicting the occurrence of AP in patients with CLD,which has a certain predictive value.

Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination?

Alcohol consumption is the principal factor in thepathogenesis of chronic liver diseases.Alcoholic liver disease(ALD)is defined by histological lesions on the liver that can range from simple hepatic steatosis to more advanced stages such as alcoholic steatohepatitis,cirrhosis,hepatocellular carcinoma and liver failure.As one of the oldest forms of liver injury known to humans,ALD is still a leading cause of liver-related morbidity and mortality and the burden is exerting on medical systems with hospitalization and management costs rising constantly worldwide.Although the biological mechanisms,including increasing of acetaldehyde,oxidative stress with induction of cytochrome p4502E1,inflammatory cytokine release,abnormal lipid metabolism and induction of hepatocyte apoptosis,by which chronic alcohol consumption triggers serious complex progression of ALD is well established,there is no universally accepted therapy to prevent or reverse.In this article,we have briefly reviewed the pathogenesis of ALD and the molecular targets for development of novel therapies.This review is focused on current therapeutic strategies for ALD,including lifestyle modification with nutrition supplements,available pharmacological drugs and new agents that are under development,liver transplantation,application of complementary medicines,and their combination.The relevant molecular mechanisms of each conventional medication and natural agent have been reviewed according to current available knowledge in the literature.We also summarized efficacy vs safety on conventional and herbal medicines which are specifically used for the prevention and treatment of ALD.Through a system review,this article highlighted that the combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for ALD and its complications.It is worthwhile to conduct large-scale,multiple centre clinical trials to further prove the safety and benefits for the integrative therapy on ALD.

High intensity focused ultrasound,liver disease and bridging therapy

High-intensity focused ultrasound(HIFU)is a noninvasive modality that uses an extracorporeal source of focused ultrasound energy.This technique was introduced by Lynn et al and is able to induce coagulative necrosis in selected tissues without damaging adjacent structures.Although HIFU has been studied for 50years,recent technological developments now allow its use for tumours of the liver,prostate and other sites.In liver disease,HIFU has been used to treat unresectable,advanced stages of hepatocellular carcinoma(HCC)and liver metastases.Hepatocellular carcinoma is a serious health problem worldwide and is endemic in some areas because of its association with hepatitis B and C viruses(in 20%of cases).Liver transplantation(LT)has become one of the best treatments available because it removes both the tumour and the underlying liver disease such as cirrhosis(which is present in approximately 80%of cases).The prerequisite for longterm transplant success depends on tumour load and strict selection criteria regarding the size and number of tumour nodules.The need to obtain the optimal benefit from the limited number of organs available has prompted strict selection criteria limited to only those patients with early HCC who have a better long-term outcome after LT.The so-called"bridging therapy"has the aim of controlling disease burden for patients who are on the organ transplant waiting list.Amongst various treatment options,transarterial chemoembolisation and radiofrequency ablation are the most popular treatment choices.Recently,Cheung et al demonstrated that HIFU ablation is a safe and effective method for the treatment of HCC patients with advanced cirrhosis as a bridging therapy and that it reduced the dropout rate from the liver transplant waiting list.In this commentary,we discuss the current value of HIFU in the treatment of liver disease,including its value as a bridging therapy,and examine the potential advantages of other therapeutic strategies.

Management of restless legs syndrome in chronic liver disease:A challenge for the correct diagnosis and therapy

AIM To investigate the association between restless legs syndrome(RLS) and well-defined chronic liver disease, and the possible therapeutic options. METHODS Two hundred and eleven patients with chronic liver disease, complaining of sleep disturbances, painful leg sensation and daily sleepiness, were included. Patients with persistent alcohol intake, recent worsening of clinical conditions, or hepatitis C virus were excluded. Diagnosis of RLS was suggested by the Johns Hopkins questionnaire and verified by fulfilling the diagnostic criteria by Allen. All patients were tested, both at baseline and during follow-up, with the Hamilton rating scale for depression, sleep quality assessment(PSQI), Epworth sleepiness scale(ESS), International Restless Legs Syndrome Study Group evaluation, and international RLS severity(IRLS) scoring system. Ironfree level, ferritin, folate, vitamin B12 and D-OH25 were detected. Neurological examinations and blood testoccurred at the beginning of the therapy, after 2 wk, and at the 28^(th), 75 th, 105 th, 135 th, 165 th and 205 th day. Regarding therapy, pramipexole or gabapentin were used.RESULTS Patients were moderately depressed, with evident nocturnal sleep problems and concomitant daily sleepiness. Sleep problems and involuntary leg movements had been underestimated, and RLS s yndrome had not be e n c ons ide re d be fore t he neurological visit. All(211/211) patients fulfilled the RLS diagnostic criteria. Twenty-two patients considered their symptoms as mild, according to IRSL, but 189 found them moderate to very severe. No correlation was found between ammonium level and ESS or PSQI. Augmentation was rather precocious in our patients(135 th day), and more frequent(35%) than previous data(8.3%-9.1%). The dosage of dopamine agonists was found to be associated with augmentation and appears in range with the literature. Previous intake of alcohol and lower levels of vitamins have been related to the phenomenon in our study.CONCLUSION RLS is a common disorder, requiring rapid diagnosis and treatment. Further research is therefore fundamental.

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.

Efficacy of Sea Buckthorn Therapy in Patients with Nonalcoholic Fatty Liver Disease

Aim: To evaluate the clinical efficacy of the traditional Chinese medicine sea buckthorn (SBT) in the treatment of patients with nonalcoholic fatty liver disease (NAFLD). Method: 94 patients with NAFLD were randomly divided into two groups: 48 cases of patients received oral sea buckthorn 1.5 g (3 times a day) for three months as the treated group, and 46 cases received only the vehicle for three months as the control group. Serum lipids, transaminase and serum liver fibrosis indices were assessed at baseline and after SBT treatment. All patients underwent liver CT and Fibroscan examination at baseline and after treatment. Results: SBT treatment resulted in a significant decrease in the serum levels of alanine aminotransferase (ALT), LDL-C, hyaluronic acid and collagen type IV. The liver stiffness measurement (LSM) of the treated patients was significantly lower than that in the control or baseline. The CT liver/spleen ratio of the treated patients was also significantly increased. Conclusion: The results of our study demonstrated the beneficial effects of SBT on serum lipids, transaminase, and liver/spleen ratio and liver stiffness in patients with NAFLD, which may be further developed as a promising therapy for the treatment of NAFLD.