Targeting Kupffer cells in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Why and how?

Mechanisms for non-alcoholic steatohepatitis(NASH)development are under investigation in an era of increased prevalence of obesity and metabolic syndrome. Previous findings have pointed to the role of adipose tissue, adipose tissue macrophages and their secretory products in the development of a chronic inflammatory status inducing insulin resistance and a higher risk of liver steatosis called non-alcoholic fatty liver disease. The activation of resident macrophages [Kupffer cells(KC)] and the recruitment of blood derived monocytes/macrophages into the diseased liver have now been identified as key elements for disease initiation and progression. Those cells could be activated through gut flora modifications and an altered gut barrier function but also through the internalization of toxic lipid compounds in adjacent hepatocytes or in KC themselves. Due to the role of activated KC in insulin resistance, fibrosis development and inflammation amplification, they became a target in clinical trials. A shift towards an anti-inflammatory KC phenotype through peroxisome proliferator activator-receptorδ agonists, an inhibition of macrophage recruitment through anti-C-C chemokine receptor 2 action and a specific blocking of internalization of toxic lipoxidation or glycation compounds into KC by galectin-3 receptor inhibitors are now under investigation in human NASH.

Commonly used animal models of non-alcoholic steatohepatitis

BACKGROUND: Animal models are an essential tool in non-alcoholic steatohepatitis (NASH) studies. Ideally, such models should reflect the etiology, disease progression, and the established pathology of human NASH. To date, no single animal model displays the range of histopathologic and pathophysiologic features associated with human NASH. The currently available models do not or only partially reflect the real picture of human NASH. In particular, insulin resistance and fibrosing steatohepatitis are rarely reproduced by the currently available models. Consequently, it is necessary to establish NASH models that can best mimic the real etiology, disease progression, and pathogenesis of human NASH. DATA SOURCES: We reviewed the major currently available animal models published in the literature (PubMed) and briefly commented on the pros and cons of these models. RESULT: Three major categories of animal models, genetic, dietary, and combination models, were reviewed and discussed. CONCLUSIONS: Animal models are not only useful in revealing the etiology of NASH, but also are important platforms for the assessment of therapeutic strategies. Currently available models do not reflect the full picture of NASH in patients. Better animal models are needed for a full understanding of human NASH and the development of efficient therapies for this condition. (Hepatobiliary Pancreat Dis Int 2009; 8:233-240)

Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome

AIM: To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis(NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH.METHODS: This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome(Met S) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients receivedlifestyle advice and were treated for a 12 mo period with rosuvastatin(10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid(SUA), high sensitivity C reactive protein(hs CRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values.RESULTS: The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20 th, which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3rd treatment month(ANOVA P < 0.001), while alkaline phosphatase activities by the 6th treatment month(ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced(P < 0.001). Lipid values were normalised by the 3rd treatment month. No patient had Met S by the 9th treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed solely to rosuvastatin treatment. A limitation of the study is the absence of a control group.CONCLUSION: These findings suggest that rosuvastatin monotherapy could ameliorate biopsy proven NASH and resolve Met S within 12 mo. These effects and the reduction of fasting plasma glucose and SUA levels may reduce the risk of vascular and liver morbidity and mortality in NASH patients. These findings need confirmation in larger studies.

Hepatocellular carcinoma and non-alcoholic steatohepatitis:The state of play

Hepatocellular carcinoma(HCC) is now the fifth cancer of greatest frequency and the second leading cause of cancer related deaths worldwide. Chief amongst the risks of HCC are hepatitis B and C infection, aflatoxin B1 ingestion, alcoholism and obesity. The latter can promote non-alcoholic fatty liver disease(NAFLD), that can lead to the inflammatory form non-alcoholic steatohepatitis(NASH), and can in turn promote HCC. The mechanisms by which NASH promotes HCC are only beginning to be characterized. Here in this review, we give a summary of the recent findings that describe and associate NAFLD and NASH with the subsequent HCC progression. We will focus our discussion on clinical and genomic associations that describe new risks for NAFLD and NASH promoted HCC. In addition, we will consider novel murine models that clarify some of the mechanisms that drive NASH HCC formation.

Pediatric non-alcoholic steatohepatitis:The first report on the ultrastructure of hepatocyte mitochondria

AIM: To investigate the ultrastructure of abnormal hepatocyte mitochondria, including their cellular and hepatic zonal distribution, in bioptates in pediatric non-alcoholic steatohepatitis (NASH).

Non-alcoholic steatohepatitis and influence of age and gender on histopathologic findings

AIM:To characterize the histopathologic specifications of non-alcoholic steatohepatitis(NASH)according to age and gender.METHODS:An analytical cross-sectional study was conducted in two private gastroenterology clinics on biopsy proven patients suffering from NASH.Biopsy histopathologic findings as well as demographic and laboratory data of the patients at the time of biopsy were gathered retrospectively from clinical records.The grading and staging of histopathologic findings were performed according to the Brunt method after reevaluation of the slides by a pathologist.Patients were divided into two groups according to age(belowand above 55 years).Mean quantitative grade of all pathologic findings were also calculated according to Brunt scoring values.RESULTS:A total number of 77 NASH patients,consisting of 58 males(75.3%)and 19(24.7%)females with a mean age of 41.99±11.80 years(range,18-70 years),were enrolled.The mean age(48.72±13.99 years vs 39.74±10.16 years,P=0.004)and aspartate aminotransferase level(75.11±29.68 U/L vs 52.78± 25.00 U/L,P=0.002)was significantly higher in female patients.Mean quantitative grade of hepatosteatosis was significantly higher in females(2.00±0.82 vs 1.59 ±0.68,P=0.031)compared to males.Fifty four percent(34/65)of young patients had mild hepatosteatosis (GradeⅠ)while only one patient(11.2%)in the older group had gradeⅠhepatosteatosis.Patients aged≥55 had significantly more severe hepatosteatosis(GradeⅢ) (44.4%vs 9.5%,P=0.007)and the mean quantitative grade of hepatosteatosis was significantly higher among them(2.33±0.71 vs 1.56±0.67,P=0.002).Multivariate analysis after omitting the confounding role of age revealed a higher grade of hepatosteatosis in female patients(P=0.010).CONCLUSION:These findings point toward the possible influence of age in the severity of steatohepatitis,portal and lobar inflammation in patients suffering from NASH while gender independently might contribute to the level of steatohepatitis.

CEUS and Fibroscan in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

AIM: To determine intra-hepatic blood flow and liver stiffness in patients with non-alcoholic fatty liver disease(NAFLD) and non-alcoholic steatohepatitis (NASH) using contrast-enhanced ultrasound and fibroscan.METHODS: This prospective study included 15 patients with NAFLD, 17 patients with NASH and 16 healthy controls.In each patient, real-time ultrasound was used to locate the portal vein (PV) and the right liver lobe, and 5 mL of SonoVue? was then injected intravenous in a peripheral vein of the left arm over a 4-s span. Digital recording was performed for 3 min thereafter. The recording was subsequently retrieved to identify an area of interest in the PV area and in the right liver parenchyma(LP) to assess the blood flow by processing the data using dedicated software (Qontrast?, Bracco, Italy).The following parameters were evaluated: percentage of maximal contrast activity (Peak%), time to peak (TTP, s), regional blood volume (RBV, cm3), regional blood flow (RBF, cm3/s) and mean transit time (MTT, s).At 24-48 h post-injection, liver stiffness was evaluated using Fibroscan and measured in kPa. The statistical evaluation was performed using Student’s t test.RESULTS: In the PV, the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patientscompared with the controls (Peak%: NAFLD 26.3 ± 6.6,NASH 28.1 ± 7.3 vs controls 55.8 ± 9.9, P < 0.001;RBV: NAFLD 4202.3 ± 3519.7, NASH 3929.8 ± 1941.3vs controls 7473 ± 3281, P < 0.01; RBF: NAFLD 32.5± 10.8, NASH 32.7 ± 12.1 vs controls 73.1 ± 13.9, P< 0.001). The TTP in the PV was longer in both patient groups but reached statistical significance only in the NASH patients compared with the controls (NASH 79.5± 37.8 vs controls 43.2 ± 30, P < 0.01). In the LP,the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patients compared with the controls (Peak%: NAFLD 43.2 ± 7.3, NASH 41.7 ± 7.7 vs controls 56.6 ± 6.3, P < 0.001; RBV: NAFLD 4851.5± 2009, NASH 5069.4 ± 2292.5 vs controls 6922.9 ±2461.5, P < 0.05; RBF: NAFLD 55.7 ± 10.1, NASH 54.5 ± 12.1 vs controls 75.9 ± 10.5, P < 0.001). The TTP was longer in both patient groups but did not reach statistical significance. The MTT in both the PV and LP in the NAFLD and NASH patients was not different from that in the controls. Liver stiffness was significantly increased relative to the controls only in the NASH patients(NASH: 6.4 ± 2.2 vs controls 4.6 ± 1.5, P < 0.05).CONCLUSION: Blood flow derangement within the liver present not only in NASH but also in NAFLD suggests that a vascular flow alteration precedes liver fibrosis development.

Towards a standard diet-induced and biopsy-confirmed mouse model of non-alcoholic steatohepatitis: Impact of dietary fat source

BACKGROUND The trans-fat containing AMLN(amylin liver non-alcoholic steatohepatitis,NASH)diet has been extensively validated in C57BL/6J mice with or without the Lep^ob/Lep^ob(ob/ob)mutation in the leptin gene for reliably inducing metabolic and liver histopathological changes recapitulating hallmarks of NASH.Due to a recent ban on trans-fats as food additive,there is a marked need for developing a new diet capable of promoting a compatible level of disease in ob/ob and C57BL/6J mice.AIM To develop a biopsy-confirmed mouse model of NASH based on an obesogenic diet with trans-fat substituted by saturated fat.METHODS Male ob/ob mice were fed AMLN diet or a modified AMLN diet with trans-fat(Primex shortening)substituted by equivalent amounts of palm oil[Gubra amylin NASH,(GAN)diet]for 8,12 and 16 wk.C57BL/6J mice were fed the same diets for 28 wk.AMLN and GAN diets had similar caloric content(40%fat kcal),fructose(22%)and cholesterol(2%)level.RESULTS The GAN diet was more obesogenic compared to the AMLN diet and impaired glucose tolerance.Biopsy-confirmed steatosis,lobular inflammation,hepatocyte ballooning,fibrotic liver lesions and hepatic transcriptome changes were similar in ob/ob mice fed the GAN or AMLN diet.C57BL/6J mice developed a mild to moderate fibrotic NASH phenotype when fed the same diets.CONCLUSION Substitution of Primex with palm oil promotes a similar phenotype of biopsyconfirmed NASH in ob/ob and C57BL/6J mice,making GAN diet-induced obese mouse models suitable for characterizing novel NASH treatments.

Cross talk of the immune system in the adipose tissue and the liver in non-alcoholic steatohepatitis: Pathology and beyond

Non-alcoholic steatohepatitis(NASH) is considered to be the hepatic manifestation of the metabolic syndrome, thus has a tight correlation with systemic metabolic impairment. The complex mechanisms underlying the pathogenesis of NASH involve different organs and systems that cross talk together contributing to the onset of NASH. A crucial role is played by inflammatory mediators, especially those deriving from the adipose tissue and the liver, which are involved in the cascade of inflammation, fibrosis and eventually tumorigenesis. In this setting cytokines and adipokines as well as immunity are emerging drivers of the key features of NASH. The immune system participates in this process with disturbances of the cells constituting both the innate and the adaptive immune systems that have been reported in different organs, such as in the liver and in the adipose tissue, in clinical and preclinical studies. The role of the immune system in NASH is increasingly studied, not only because of its contribution to the pathogenetic mechanisms of NASH but also because of the new potential therapeutic options it offers in this setting. Indeed, novel treatments acting on the immune system could offer new options in the management of NASH and the correlated clinical consequences.

Fibroblast growth factor signaling in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis:Paving the way to hepatocellular carcinoma

Metabolic disorders are increasingly leading to non-alcoholic fatty liver disease,subsequent steatohepatitis,cirrhosis and hepatocellular carcinoma.Fibroblast growth factors and their receptors play an important role in maintaining metabolic homeostasis also in the liver and disorders in signaling have been identified to contribute to those pathophysiologic conditions leading to hepatic lipid accumulation and chronic inflammation.While specific and well tolerated inhibitors of fibroblast growth factor receptor activity are currently developed for(non-liver)cancer therapy,treatment of non-alcoholic fatty liver disease and nonalcoholic steatohepatitis is still limited.Fibroblast growth factor-mimicking or restoring approaches have recently evolved as a novel therapeutic option and the impact of such interactions with the fibroblast growth factor receptor signaling network during non-alcoholic fatty liver disease/non-alcoholic steatohepatitis development is reviewed here.

Non-invasive prediction of non-alcoholic steatohepatitis in Japanese patients with morbid obesity by artificial intelligence using rule extraction technology

AIM To construct a non-invasive prediction algorithm for predicting non-alcoholic steatohepatitis(NASH), we investigated Japanese morbidly obese patients using artificial intelligence with rule extraction technology.METHODS Consecutive patients who required bariatric surgery underwent a liver biopsy during the operation. Standard clinical, anthropometric, biochemical measurements were used as parameters to predict NASH and were analyzed using rule extraction technology. One hundred and two patients, including 79 NASH and 23 non-NASH patients were analyzed in order to create the predictionmodel, another cohort with 77 patients including 65 NASH and 12 non-NASH patients were analyzed to validate the algorithm.RESULTS Alanine aminotransferase, C-reactive protein, homeostasis model assessment insulin resistance, albumin were extracted as predictors of NASH using a recursive-rule extraction algorithm. When we adopted the extracted rules for the validation cohort using a highly accurate rule extraction algorithm, the predictive accuracy was 79.2%. The positive predictive value, negative predictive value,sensitivity and specificity were 88.9%, 35.7%, 86.2% and 41.7%, respectively.CONCLUSION We successfully generated a useful model for predicting NASH in Japanese morbidly obese patients based on their biochemical profile using a rule extraction algorithm.

Investigation of genome instability in patients with non-alcoholic steatohepatitis

AIM:To evaluate the occurrence of micronucleus(MN),nucleoplasmic bridges(NPBs)and nuclear buds(NBUDs)in the mitogen-stimulated lymphocytes of patients with non-alcoholic steatohepatitis(NASH).METHODS:The study was performed in 25(9 females,16 males)patients newly diagnosed with NASH,and 25healthy subjects of similar ages and genders were used as a control group.None of the controls was known to be receiving any drugs for medical or other reasons or using alcohol.Hepatosteatosis was further excluded by abdominal ultrasound imaging in the control group.The numbers of MN,NPBs and NBUDs scored in binucleated(BN)cells were obtained from the mitogen-stimulated lymphocytes of patients and control subjects.Statistical comparisons of the numbers of BN cells with MN,NPBs and NBUDs and ages between the patients with NASH and control subjects were performed.RESULTS:The mean ages of the patients and the control group were 41.92±13.33 and 41.80±13.09 years(P>0.05),respectively.The values of the mean body mass index(BMI),HOMA-IR,hemoglobin,creatinin,aspartate aminotransferase,alanine aminotransferase,triglyceride,high density lipoprotein,and low density lipoprotein were 31.19±4.62 kg/m2vs 25.07±4.14 kg/m2,6.71±4.68 vs 1.40±0.53,14.73±1.49 g/dL vs 14.64±1.30 g/dL,0.74±0.15 mg/dL vs 0.80±0.13 mg/dL,56.08±29.11 U/L vs 16.88±3.33 U/L,92.2±41.43U/L vs 15.88±5.88 U/L,219.21±141.68 mg/dL vs102.56±57.98 mg/dL,16.37±9.65 mg/dL vs 48.72±15.31 mg/dL,and 136.75±30.14 mg/dL vs 114.63±34.13 mg/dL in the patients and control groups,respectively.The total numbers and frequencies of BN cells with MN,NPBs and NBUDs,which were scored using the CBMN cytome assay on PHA-stimulated lymphocytes,were evaluated in the patients with NASH and control group.We found significantly higher numbers of MN,NPBs and NBUDs in the BN cells of patients with NASH than in those of the control subjects(21.60±9.32vs 6.88±3.91;29.28±13.31 vs 7.84±3.96;15.60±5.55 vs 4.20±1.63,respectively,P<0.0001).CONCLUSION:The increased numbers of MN,NPBs and NBUDs observed in the lymphocytes obtained from patients with NASH may reflect genomic instability.

Effects of Aerobic Exercise on the Intramuscular Lipid and Glycogen Content of Fiber Types in Soleus Muscles of Non-Alcoholic Steatohepatitis Model Rats

We studied the effects of exercise on muscle mitochondria, and lipid and glycogen content in non-alcoholic steatohepatitis (NASH) model rats. Male Sprague-Dawley rats were randomly separated into 3 groups: the control group was fed standard chow;the NASH group was fed a methionine-choline-deficient high-fat diet (MCD);the NASH-exercise group was fed the MCD and exercised three times a week. Exercise training consisted of continuous running for thirty minutes at a 13 m/min, 6° slope on a motor-driven rodent treadmill for 6 weeks. Mitochondria content in NASH group decreased in the both fiber types compared with those of the control group. As compared between the NASH and NASH-exercise groups, however, exercise not only promoted significant improvements in liver fibrosis and cirrhosis and triglyceride (TG) content but also increased mitochondria content in type I muscle fiber in particular. These data suggest that exercise improved hepatic steatosis in NASH model rats and can prevent the progression of NASH.

Fermented papaya preparation halts the progression of non-alcoholic steatohepatitis in rats

Non-alcoholic steatohepatitis (NASH) can progress to cirrhosis or hepatocellular carcinoma. Oxidative stress is implicated in NASH progression. Fermented papaya preparation (FPP) has oxygen radical scavenging activity and is effective in oxidative stress-related diseases. We investigated the effects of FPP on NASH progression using a rat NASH model. Plasma biochemical parameters and lipid peroxidation in the liver were elevated in NASH rats. Histologically, the liver of NASH rats showed liver fibrosis, mitochondrial dysfunction and over-expression of microsomal CYP2E1. Myeloperoxidase activity and nuclear factor-kappaB activation were also markedly increased in NASH. Oral administration of FPP ameliorated these changes in NASH rats. These results suggest that FPP halts NASH progression through its anti-oxidative and antiinflammatory properties.

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.

Non-alcoholic fatty liver disease may not be a severe disease at presentation among Asian Indians

AIM： To evaluate the clinical and biochemical profile of patients with non alcoholic fatty liver disease （NAFLD） and to assess their histological severity at presentation.METHODS： Consecutive patients presenting to the liver clinic of All India Institute of Medical Sciences （AIIMS） with raised transaminases to at least 1.5 times upper limit of normal, and histologically confirmed non-alcoholic fatty liver disease were included. Patients who had significant alcohol intake or positive markers of other liver diseases or who were taking drugs known to produce fatty liver were excluded. The clinical, biochemical and histological profile of this group was studied. RESULTS： Fifty-one patients with NAFLD formed the study population. Their median age and BMI were 34（17-58） years and 26.7（21.3-32.5） kg/m^2 respectively and 46 （90.1%） were males. The majority of the patients had mild inflammation, either grade 1 [32 （63%）] or grade 2 [16 （31%）] and only 3 （6%） patients had severe （grade 3） inflammation. Twenty-three （45%）, 19 （37%）, 8（16%） and 1（2%） patient had stage 0, 1, 2 and 3 fibrosis respectively on index biopsy and none had cirrhosis. On univariate analysis, triglyceride levels more than 150 mg % （OR = 7.1; 95% CI： 1.6-31.5, P = 0.002） and AST ALT ratio 〉 1 （OR = 14.3; 95% CI： 1.4-678.5, P = 0.008） were associated with high grades of inflammation and none was associated with advanced fibrosis. On multivariate logistic regression analysis, hypertriglyceridemia 〉150 mg% was the only factor independently associated with presence of high grade of inflammation （OR = 1.6; 95% CI： 1.3-22.7, P =0.02）, while none was associated with advanced fibrosis. Triglyceride levels correlated positively with inflammatory grade （r = 0.412; P = 0.003）. CONCLUSION： NAFLD in North Indian patients is a disease of young over-weight males, most of whom are insulin resistant and they tend to have a mild histological disease at presentation.

Non invasive evaluation of liver fibrosis in paediatric patients with nonalcoholic steatohepatitis

AIM: To identify the independent predictors of hepatic fibrosis in 69 children with nonalcoholic steatohepatitis (NASH) due to nonalcoholic fatty liver disease (NAFLD). METHODS: All patients with clinically suspected NASH underwent liver biopsy as a confirmatory test. The following clinical and biochemical variables at baseline were examined as likely predictors of fibrosis at histology: age, body mass index (BMI), systolic blood pressure (SBP), dyastolic blood pressure (DBP), fasting glucose, fasting insulin, homeostatic model assessment for insulin resistence (HOMA-IR), cholesterol, tryglicerides, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AST/ALT ratio, gamma glutamil transferase (GT), platelet count, prothrombin time (PT). RESULTS: At histology 28 (40.6%) patients had no fibrosis and 41 (59.4%) had mild to bridging fibrosis. At multivariate analysis, BMI > 26.3 was the only independent predictor of fibrosis (OR = 5.85, 95% CI = 1.6-21). CONCLUSION: BMI helps identify children with NASH who might have fibrotic deposition in the liver.

Clinical approaches to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)ranges from simple steatosis to nonalcoholic steatohepatitis(NASH),leading to fibrosis and potentially cirrhosis,and it is one of the most common causes of liver disease worldwide.NAFLD is associated with other medical conditions such as metabolic syndrome,obesity,cardiovascular disease and diabetes.NASH can only be diagnosed through liver biopsy,but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis,reducing the need for liver biopsy and risk to patients.Disease progression varies between individuals and is linked to a number of risk factors.Mechanisms involved in the pathogenesis are associated with diet and lifestyle,influx of free fatty acids to the liver from adipose tissue due to insulin resistance,hepatic oxidative stress,cytokines production,reduced very low-density lipoprotein secretion and intestinal microbiome.Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD.Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial.Omega 3 polyunsaturated fatty acids and statins may offer additional benefits.Bariatric surgery should be considered in morbidly obese patients.More research is needed to assess the impact of these treatments on a long-term basis.The objective of this article is to briefly review the diagnosis,management and treatment of this disease in order to aid clinicians in managing these patients.

Vitamin D:A new player in non-alcoholic fatty liver disease?

Vitamin D through its active form 1a-25-dihydroxyvtamin D[1,25(OH)2D]is a secosteroid hormone that plays a key role in mineral metabolism.Recent years have witnessed a significant scientific interest on vitamin D and expanded its actions to include immune modulation,cell differentiation and proliferation and inflammation regulation.As our understanding of the many functions of vitamin D has grown,the presence of vitamin D deficiency has become one of the most prevalent micronutrient deficiencies worldwide.Concomitantly,non-alcoholic fatty liver disease(NAFLD)has become the most common form of chronic liver disease in western countries.NAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several cardiometabolic risk factors.In this article we provide an overview of the epidemiology and pathophysiology linking NAFLD and vitamin D deficiency,as well as the available evidence on the clinical utility of vitamin D supplementation in NAFLD.

Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”

Nonalcoholic fatty liver disease(NAFLD) has become the dominant form of chronic liver disease in children and adolescents with the increasing prevalence of obesity worldwide. NAFLD represents a wide spectrum of conditions, ranging from fatty liver-which generally follows a benign, non-progressive clinical course-to non-alcoholic steatohepatitis, a subset of NAFLD that may progress to cirrhosis and end-stage liver disease or liver carcinoma. The underlying pathophysiological mechanism of "pediatric" NAFLD remains unclear, although it is strongly associated with obesity and insulin resistance. In this review we provide a general overview on the current understanding of NAFLD in children and adolescents, which underpins practice, enabling early diagnosis and appropriate therapeutic intervention for this life-threatening liver disease.