Metabolic dysfunction-associated steatotic liver disease:A silent pandemic

The worldwide epidemiology of non-alcoholic fatty liver disease(NAFLD)is showing an upward trend,parallel to the rising trend of metabolic syndrome,owing to lifestyle changes.The pathogenesis of NAFLD has not been fully understood yet.Therefore,NAFLD has emerged as a public health concern in the field of hepatology and metabolisms worldwide.Recent changes in the nomenclature from NAFLD to metabolic dysfunction-associated steatotic liver disease have brought a positive outlook changes in the understanding of the disease process and doctor-patient communication.Lifestyle changes are the main treatment modality.Recently,clinical trial using drugs that target‘insulin resistance’which is the driving force behind NAFLD,have shown promising results.Further translational research is needed to better understand the underlying pathophysiological mechanism of NAFLD which may open newer avenues of therapeutic targets.The role of gut dysbiosis in etiopathogenesis and use of fecal microbiota modification in the treatment should be studied extensively.Prevention of this silent epidemic by spreading awareness and early intervention should be our priority.

Association of Cytokines with Clinical Indicators in Patients with Drug-Induced Liver Injury

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators.Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),antiinfective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed.Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group.Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-αand IL-6 may partake the inflammatory process of DILI.

A Single-Cell Landscape of Human Liver Transplantation Reveals a Pathogenic Immune Niche Associated with Early Allograft Dysfunction

Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical concern,exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients.Unfortunately,the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD.Herein,we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients,with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages.Comparison of the 75231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells,granzyme B^(+)(GZMB^(+))granzyme K^(+)(GZMK^(+))natural killer cells,and S100 calcium binding protein A12^(+)(S100A12^(+))neutrophils.Moreover,we verified this immune niche and its association with EAD occurrence in two independent cohorts.Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level,thus,offering valuable insights into EAD onset.

Interplay between metabolic dysfunction-associated fatty liver disease and renal function: An intriguing pediatric perspective

Over recent years,the nomenclature of non-alcoholic fatty liver disease has undergone significant changes.Indeed,in 2020,an expert consensus panel proposed the term“Metabolic(dysfunction)associated fatty liver disease”(MAFLD)to underscore the close association of fatty liver with metabolic abnormalities,thereby highlighting the cardiometabolic risks(such as metabolic syndrome,type 2 diabetes,insulin resistance,and cardiovascular disease)faced by these patients since childhood.More recently,this term has been further replaced with metabolic associated steatotic liver disease.It is worth noting that emerging evidence not only supports a close and independent association of MAFLD with chronic kidney disease in adults but also indicates its interplay with metabolic impairments.However,comparable pediatric data remain limited.Given the progressive and chronic nature of both diseases and their prognostic cardiometabolic implications,this editorial aims to provide a pediatric perspective on the intriguing relationship between MAFLD and renal function in childhood.

Metabolic dysfunction-associated fatty liver disease and low muscle strength: A comment

The diagnosis of non-alcoholic fatty liver disease(NAFLD)and metabolic dysfunction-associated fatty liver disease only on the basis of laboratory parameter score such as Hepatic Steatosis Index which includes liver enzymes,gender,basal metabolic index,and presence of diabetic mellitus is not sufficient to exclude other causes of deranged liver enzymes especially medications and autoimmune related liver diseases.As the guideline suggests ultrasound is the preferred first-line diagnostic procedure for imaging of NAFLD,as it provides additional diagnostic information and the combination of biomarkers/scores and transient elastography might confer additional diagnostic accuracy and evident from previous similar studies too.

Effects of Yigan Capsule on the expression of HMGB1,RAGE and NF-κB protein in rats with drug-induced liver injury

Objective:To study the effect of Yigan capsule on the expression of high mobility group protein B1(HMGB1),nuclear factor-B(NF-κB)and receptor for advanced glycation end products(RAGE)in anti-tuberculosis drug-induced liver injury(ATB-DILI),and to explore its protective effect and mechanism on ATB-DILI,so as to provide experimental basis for the clinical application of Yigan capsule.Methods:Twenty-four rats were divided into two groups.Except for the blank group(n=6),the other 18 rats were given isoniazid(INH)+rifampicin(RFP)(50 mg/kg.d)for 4 weeks.Then 18 rats were randomly divided into three groups(model group,low dose group of Yigan capsule and high dose group of Yigan capsule)according to 6 rats in each group.The blank group and the model group were given 0.9%sodium chloride solution by intragastric administration.The low dose group of Yigan capsule was 0.468 g/kg,and the high dose group of Yigan capsule was 1.872 g/kg[1].After 4 weeks,the pathological changes of liver were observed by HE staining.The contents of ALT,AST,ALP,γ-GT and TBIL were detected.The expression of HMGB1,NF-κBp65 and RAGE protein was detected by IHC.The expression levels of HMGB1,NF-κBp65,RAGE,TNF-αand IL-1βwere detected by WB.Result:HE staining showed that the structure of the liver in the model group was disordered,the liver cells showed swelling and fusion,the number of inflammatory cells increased and accompanied by punctate necrosis,while the above pathological changes in each treatment group of Yigan capsule were significantly improved.The contents of ALT,AST,ALP,γ-GT and TBIL in the model group were higher than those in the blank group(P<0.05).The contents of ALT,AST,ALP,γ-GT and TBIL in each treatment group were significantly lower than those in the model group(P<0.05).Compared with the blank group,the expression levels of TNF-αand IL-1βin the model group were increased(P<0.05),and the expression levels of HMGB1,NF-κBp65 and RAGE were increased(P<0.05).Compared with the model group,the expression levels of TNF-αand IL-1βin each treatment group of Yigan capsule decreased(P<0.05),and the expression of HMGB1,NF-κBp65 and RAGE decreased(P<0.05).Conclusion:Yigan capsule may inhibit the secretion of inflammatory factors through HMGB1/RAGE/NF-κBp65 signaling pathway,thus protecting ATB-DILI.

Metabolic dysfunction-associated steatotic liver disease-associated fibrosis and cardiac dysfunction in patients with type 2 diabetes

BACKGROUND Metabolic dysfunction-associated steatotic liver disease(MASLD),particularly in the presence of liver fibrosis,increases the risk of cardiovascular morbidity and mortality,but the nature of the cardio-hepatic interaction in the context type 2 diabetes mellitus(T2DM)is not fully understood.AIM To evaluate the changes in cardiac morphology and function in patients with T2DM and MASLD-associated liver fibrosis.METHODS T2DM patients with MASLD underwent a medical evaluation that included an assessment of lifestyle,anthropometric measurements,vital signs,an extensive laboratory panel,and a standard echocardiography.Liver fibrosis was evaluated using two scores[Fibrosis-4(FIB4)and Non-alcoholic fatty liver disease-Fibrosis Score(NFS)],and subjects were classified as having advanced fibrosis,no fibrosis,or an indeterminate risk.The correlations between structural and functional cardiac parameters and markers of liver fibrosis were evaluated through bivariate and multiple regression analyses.Statistical significance was set at P<0.05.RESULTS Data from 267 T2DM-MASLD subjects with complete assessment was analyzed.Patients with scores indicating advanced fibrosis exhibited higher interventricular septum and left ventricular(LV)posterior wall thickness,atrial diameters,LV end-systolic volume,LV mass index(LVMi),and epicardial adipose tissue thickness(EATT).Their mean ejection fraction(EF)was significantly lower(49.19%±5.62%vs 50.87%±5.14%vs 52.00%±3.25%;P=0.003),and a smaller proportion had an EF≥50%(49.40%vs 68.90%vs 84.21%;P=0.0017).Their total and mid LV wall motion score indexes were higher(P<0.05).Additionally,they had markers of diastolic dysfunction,with a higher E/e’ratio[9.64±4.10 vs 8.44(2.43-26.33)vs 7.35±2.62;P=0.026],and over 70%had lateral e’values<10 cm/second,though without significant differences between groups.In multiple regression analyses,FIB4 correlated with left atrium diameter(LAD;β=0.044;P<0.05),and NFS with both LAD(β=0.039;P<0.05)and right atrium diameter(β=0.041;P<0.01),Moreover,LVMi correlated positively with age and EATT(β=1.997;P=0.0008),and negatively with serum sex-hormone binding protein(SHBP)concentrations(β=-0.280;P=0.004).SHBP also correlated negatively with LAD(β=-0.036;P<0.05).CONCLUSION T2DM patients with markers of MASLD-related liver fibrosis exhibit lower EF and present indicators of diastolic dysfunction and cardiac hypertrophy.Additionally,LVMi and LAD correlated negatively with serum SHBP concentrations.

Sarcopenia and metabolic dysfunction associated steatotic liver disease:Time to address both

Sarcopenia and metabolic dysfunction associated steatotic liver disease(MASLD)are closely intertwined.Sarcopenia,traditionally a disease of the older adult and chronic disease population,has been closely studied as one of the pathophysiologic conditions at play in the development of MASLD.They share similar risk factors of insulin resistance and physical inactivity.Given similar pathophysiology along the liver-muscle axis,sarcopenia has been studied as a risk factor for MASLD,and vice versa.Current research suggests a bidirectional relationship.Given the chronicity of MASLD as a chronic inflammatory liver disease,it can break down muscle mass and lead to sarcopenia,while sarcopenia promotes intramuscular lipid accumulation that releases cytokines that can aggravate inflammation in the liver.However,for the longest time,a lack of consensus definition for MASLD and sarcopenia made it difficult to study their relationship and outcomes.A recent nomenclature update to diagnosing MASLD has made it easier for researchers to identify cohorts for study.However,no gold standard technique to measure muscle mass or consensus sarcopenia definition has been identified yet.Future studies are needed to reach a consensus and reduce diagnostic variation.With similar pathophysiology and shared risk factors between the two diseases,future research may also identify potential therapeutic targets along the liver-muscle axis that would benefit both sarcopenia and MASLD in order to maximize their outcomes.

Ethanol extract of cassia seed alleviates metabolic dysfunction-associated steatotic liver disease by acting on multiple lipid metabolism-related pathways

Background and objective:In northern China's cold regions,the prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)exceeds 50%,significantly higher than the national and global rates.MASLD is an important risk factor for cardiovascular and cerebrovascular diseases,including coronary heart disease,stroke,and tumors,with no specific therapeutic drugs currently available.The ethanol extract of cassia seed(CSEE)has shown promise in lowering blood lipids and improving hepatic steatosis,but its mechanism in treating MASLD remains underexplored.This study aims to investigate the therapeutic effects and mechanisms of CSEE.Methods:MASLD models were established in male Wistar rats and golden hamsters using a high fat diet(HFD).CSEE(10,50,250 mg/kg)was administered via gavage for six weeks.Serum levels of total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),high-density lipoprotein cholesterol(HDL-C),aspartate aminotransferase(AST),and alanine aminotransferase(ALT),as well as liver TC and TG,were measured using biochemical kits.Histopathological changes in the liver were evaluated using Oil Red O staining,Hematoxylin-eosin(H&E)staining,and transmission electron microscopy(TEM).HepG2 cell viability was assessed using the cell counting kit-8(CCK8)and Calcein-AM/PI staining.Network pharmacology was used to analyze drug-disease targets,and western blotting was used to confirm these predictions.Results:CSEE treatment significantly reduced serum levels of TC,TG,LDL-C,ALT,and AST,and improved liver weight,liver index,and hepatic lipid deposition in rats and golden hamsters.In addition,CSEE alleviated free fatty acid(FFA)-induced lipid deposition in HepG2 cells.Molecular biology experiments demonstrated that CSEE increased the protein levels of p-AMPK,p-ACC,PPARα,CPT1A,PI3K P110 and p-AKT,while decreasing the protein levels of SREBP1,FASN,C/EBPα,and PPARγ,thus improving hepatic lipid metabolism and reducing lipid deposition.The beneficial effects of CSEE were reversed by small molecule inhibitors of the signaling pathways in vitro.Conclusion:CSEE improves liver lipid metabolism and reduces lipid droplet deposition in Wistar rats and golden hamsters with MASLD by activating hepatic AMPK,PPARα,and PI3K/AKT signaling pathways.

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 elementbinding 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.

Contribution of gut microbiota to drug-induced liver injury

Drug-induced liver injury(DILI)is caused by various drugs with complex pathogenesis,and diverse clinical and pathological phenotypes.Drugs damage the liver directly through drug hepatotoxicity,or indirectly through drug-mediated oxidative stress,immune injury and inflammatory insult,which eventually lead to hepatocyte necrosis.Recent studies have found that the composition,relative content and distribution of gut microbiota in patients and animal models of DILI have changed significantly.It has been confirmed that gut microbial dysbiosis brings about intestinal barrier destruction and microorganisms translocation,and the alteration of microbial metabolites may cause or aggravate DILI.In addition,antibiotics,probiotics,and fecal microbiota transplantation are all emerging as prospective therapeutic methods for DILI by regulating the gut microbiota.In this review,we discussed how the altered gut microbiota participates in DILI.

Implications of metabolic dysfunction associated fatty liver disease in COVID-19

Metabolic associated fatty liver disorder(MAFLD)characterizes the contributing etiologies(i.e.,type 2 diabetes mellitus,metabolic syndrome,overweight)of individuals with fatty liver disease that affects 1/3rd of the world population.In 2020,the coronavirus disease 2019(COVID-19)crisis was unprecedented,and people with different comorbidities became more susceptible to the infection caused by severe acute respiratory syndrome coronavirus 2.MAFLD patients are frequently obese with added metabolic menace like diabetes,hypertension,and dyslipidemia leading to greater jeopardy of COVID-19.MAFLD patients are 4 to 6-fold more prone towards infections.COVID-19 induces liver injury with elevated levels of aspartate aminotransferase and alanine aminotransferase and insignificantly elevated bilirubin.Hence,MAFLD in COVID-19 patients worsens the condition significantly.The evidence highlighting the interaction between MAFLD and altered liver functioning in COVID-19 suggested that COVID-19 patients with pre-existing MAFLD are at greater risk of morbidity or intensive care unit admission.Direct hepatic injury,enhanced levels of inflammatory cytokines,declined hepatic mitochondrial activity,and compromised immunity are considered as some underlying mechanisms.The main focus of this review is to discuss the implications of metabolic dysfunction associated with fatty liver disease in COVID-19 patients.The review systematically analyzes the effect of striking two worldwide pandemics(MAFLD and COVID-19)together in the present era.

Fournier gangrene in an infant, complicated with severe sepsis and liver dysfunction: A case report

BACKGROUND Fournier gangrene is a rare,life-threatening infection characterized by necrotizing fasciitis in the perineal,genital and/or lower abdominal regions.Despite its rarity,the unfavorable prognosis associated with this disease is dependent on the timing of medical care.CASE SUMMARY A 3-month-old boy was admitted to our pediatric intensive care unit in critical condition after a 5-day history of fever and scrotal erythema with breaching skin lesions and swelling.Despite ambulatory antibiotic treatment,the child’s clinical condition deteriorated.At the time of admission,the child had necrotizing scrotal fasciitis that had spread to the abdomen.Following reanimation,the surgeon decided on an immediate intervention to rule out testicular torsion and to debride the affected area.Despite optimal antibiotic and supportive therapy,the patient developed severe sepsis with liver dysfunction,making treatment more challenging.CONCLUSION Recognizing Fournier gangrene,prompt referral to pediatric surgery,and appropriate antibiotic coverage are critical for avoiding sepsis and multiorgan dysfunction.

Liver dysfunction-related COVID-19:A narrative review

The coronavirus 2019 disease(COVID-19)is caused by a novel coronavirus,severe acute respiratory syndrome coronavirus 2.This disease was designated by the World Health Organization as a pandemic on March 11,2020,which is not seen before.There are no classical features among the cases of the disease owing to the involvement of nearly all body tissues by the virus.Hepatic involvement is one of the characteristics of the COVID-19 course.There are six possible mechanisms of such involvement:Direct virus injury,drug-induced effect,inflammatory cytokine storm,hypoxia-ischemic destruction,abnormalities in liver function tests,and pre-existing chronic liver diseases.Liver abnormalities are seen commonly in the severe or critical stage of COVID-19.Therefore,these abnormalities determine the COVID-19 severity and carry a high rate of morbidity and mortality.The elderly and patients with comorbidities like diabetes mellitus and hypertension are more vulnerable to liver involvement.Another issue that needs to be disclosed is the liver manifestations following the COVID-19 vaccination,such as autoimmune hepatitis.Of note,complete vaccination with third and fourth booster doses is necessary for patients with previous chronic liver diseases or those who have been subjected to liver transplantation.This review aims to explore the various aspects of liver dysfunction during the COVID-19 course regarding the epidemiological features,predisposing factors,pathophysiological mechanisms,hepatic manifestations due to COVID-19 or following vaccination,role of liver function tests in the assessment of COVID-19 severity,adverse effects of the therapeutic agents for the disease,and prognosis.

COVID-19-related liver injury:Focus on genetic and drug-induced perspectives

BACKGROUND Empirical use of potentially hepatotoxic drugs in the management of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection is considered as one of the major etiopathogenetic factors for liver injury.Recent evidence has shown that an underlying genetic factor may also occur.Hence,it is important to understand the host genetics and iatrogenic-based mechanisms for liver dysfunction to make timely remedial measures.AIM To investigate drug-induced and genetic perspectives for the development of coronavirus disease 2019(COVID-19)-related liver injury.METHODS Reference Citation Analysis,PubMed,Google Scholar and China National Knowledge Infrastructure were searched by employing the relevant MeSH keywords and pertaining data of the duration,site and type of study,sample size with any subgroups and drug-induced liver injury outcome.Genetic aspects were extracted from the most current pertinent publications.RESULTS In all studies,the hepatic specific aminotransferase and other biochemical indices were more than their prescribed upper normal limit in COVID-19 patients and were found to be significantly related with the gravity of disease,hospital stay,number of COVID-19 treatment drugs and worse clinical outcomes.In addition,membrane bound O-acyltransferase domain containing 7 rs641738,rs11385942 G>GA at chromosome 3 gene cluster and rs657152 C>A at ABO blood locus was significantly associated with severity of livery injury in admitted SARS-CoV-2 patients.CONCLUSION Hepatic dysfunction in SARS-CoV-2 infection could be the result of individual drugs or due to drug-drug interactions and may be in a subset of patients with a geneticpropensity. Thus, serial estimation of hepatic indices in hospitalized SARS-CoV-2 patients shouldbe done to make timely corrective actions for iatrogenic causes to avoid clinical deterioration.Additional molecular and translational research is warranted in this regard.

Risk factors, surgical complications and graft survival in liver transplant recipients with early allograft dysfunction

Background: Early allograft dysfunction (EAD) is a severe complication after liver transplantation. The associated risk factors and complications have re-gained recent interest. This study investigated risk factors, survival and complications associated with EAD in a large liver transplant center in Latin America. Methods: Retrospective, unicenter, cohort, based on data from adult patients undergoing first deceaseddonor liver transplant from January 2009 to December 2013. EAD was defined by one or more of the following:(i) bilirubin ≥10 mg/dL on postoperative day 7;(ii) international normalized ratio ≥1.6 on postoperative day 7, and (iii) alanine aminotransferase or aspartate aminotransferase > 2000 IU/L within the first seven days after transplant. Results: A total of 602 patients were included;of these 34.2% developed EAD. Donor risk factors were male ( P = 0.007), age between 50 and 59 years ( P = 0.034), overweight ( P = 0.028) or grade I obesity ( P = 0.012), sodium > 157 mmol/L ( P = 0.002) and grade IV ischemia/reperfusion injury ( P = 0.002). Cold ischemia time ≥10 h ( P = 0.008) and warm ischemia time ≥40 min ( P = 0.013) were the surgical factors. Male ( P < 0.001) was the only recipient protective factor. Compared with the non-EAD group, patients with EAD were submitted to more reoperations (24.3% vs. 13.4%, P = 0.001) and had higher graft loss rates (37.9% vs. 21.2%, P < 0.001), with similar patient survival rates ( P = 0.238). Conclusions: EAD risk factors are related to donor, surgical procedure and recipient. Donor risk factors for EAD were male, age between 50 and 59 years, donor overweight or grade Ⅰ obesity, sodium > 157 mmol/L and grade Ⅳ ischemia/reperfusion injury. Cold ischemia time ≥10 h and warm ischemia time ≥40 min were the surgical risk factors. Male was the only recipient protective factor. Patients with EAD had higher reoperations and graft loss rates.

Practical guidelines for diagnosis and early management of drug-induced liver injury

The spectrum of drug-induced liver injury （DILI） is both diverse and complex. The first step in diagnosis is a suspicion of DILl based on careful consideration of recent comprehensive reports on the disease. There are some situations in which the suspicion of DILI is particularly strong. Exclusion of other possible etiologies according to the pattern of liver injury is essential for the diagnosis. In patients with suspected DILl, diagnostic scales, such as the Councils for International Organizations of Medical Sciences/ Roussel Uclaf Causality Assessment Method （CIOMS/RUCAM） scale, may be helpful for the final diagnosis. Early management of DILl involves prompt withdrawal of the drug suspected of being responsible, according to serum levels of alanine aminotransferase （ALT）, alkaline phosphatase （ALP）, and total bilirubin （T-Bil）. However, as DILI patients may show resolution of liver injury without discontinuation of the drug, it should be carefully evaluated whether the suspected drug should be discontinued immediately with adequate consideration of the importance of the medication.

Non-alcoholic fatty liver disease and thyroid dysfunction:A systematic review

Thyroid hormones are totally involved in the regulation of body weight, lipid metabolism, and insulin resistance. Therefore it is anticipated that thyroid hormones may have a role in the pathogenesis of non alcoholic fatty liver disease(NAFLD) and non alcoholic steatohepatitis(NASH). In this study, we reviewed the current literature on the association between thyroid dysfunction and NAFLD/NASH. A search for English language medical literature reporting an association between thyroid dysfunction and NAFLD/NASH in humans was conducted across PubMed, ISI Web of Science, and Scopus in August, 2013. Out of 140 studies initially identified through the search, 11 relevant articles were included in the final review. Thyroid dysfunctions in the form of overt or subclinical hypothyroidism are prevalent among patients with NAFLD/NASH. Hypothyroidism appears to be an independent risk factor for NAFLD/NASH in some studies; however, other newly published studies failed to find such anassociation. The results of the studies on the role of thyroid abnormalities in NAFLD/NASH are inconsistent, and further research is recommended to determine the relationship between hypothyroidism and NAFLD/NASH and the underlying mechanisms.

drug-induced autoimmune liver disease:a diagnostic dilemma of an increasingly reported disease

The aetiology of autoimmune hepatitis(AIH) is uncer-tain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs.AIH usually develops in individuals with a genetic back-ground mainly consisting of some risk alleles of the major histocompatibility complex(HLA).Many drugs have been linked to AIH phenotypes,which sometimes persist after drug discontinuation,suggesting that they awaken latent autoimmunity.At least three clini-cal scenarios have been proposed that refers to drug- induced autoimmune liver disease(DIAILD):AIH with drug-induced liver injury(DILI); drug induced-AIH(DI-AIH); and immune mediated DILI(IM-DILI).In addi-tion,there are instances showing mixed features of DI-AIH and IM-DILI,as well as DILI cases with positive autoantibodies.Histologically distinguishing DILI from AIH remains a challenge.Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however,a detailed standard-ised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diag-nosis between both entities.Growing information on the relationship of drugs and AIH is being available,being drugs like statins and biologic agents more fre-quently involved in cases of DIAILD.In addition,there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepa-totoxicity.Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of

Drug-induced liver injury:Is it somehow foreseeable?

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.