Factors For Chronic Liver Disease Research Articles

Effect of senolytic treatment on expression of senescence‐associated miR‐126 expression in young and old female mice.

Cellular senescence represents one of the major risk factors for chronic liver disease and contributes to morbidity, mortality, and increased healthcare spending. A relevant strategy for understanding the role of senescent cells in liver pathogenesis is to use genetic or pharmacological strategies to eliminate senescent cells. The combination of the senolytic drugs, Dasatinib and Quercetin (D+Q), effectively reduces senescent cell burden in multiple tissues, extending both healthspan and lifespan in mice, and alliviating obesity and age‐associated hepatic steatosis. The aim of this study was to investigate effects of D+Q treatment on livers of young and old female mice. A total of 40 mice, 20 young females (3‐months) and 20 old females (18‐months), was divided into 4 groups: Young (Y) mice treated with either D+Q or placebo and old (O) mice treated with D+Q or placebo. The treatment was performed for 3 consecutive days every 2 weeks over 10 weeks. Comparative analysis of hepatic miRNAs indicated that D+Q treatment significantly decreased levels of senescence‐specific miR‐126 expression in livers of old mice treated with D+Q compared to vehicle‐treated old mice (p=0.025), As expected, there was no effect of D+Q treatment in young animals. Analysis of miR‐126 target genes indicated that PI3K gene expression was significantly increased in response to D+Q treatment (p=0.003). Additionally, Akt1 and mTOR mRNA levels were increased in D+Q‐treated mice (p=0.008 and p=0.02, respectively). In summary, our data suggest that the mechanism of PI3K signaling pathway activation upon elimination of senescent cells by treatment with D+Q is mediated through downregulation of senescence‐specific miR‐126.Support or Funding InformationThis work is supported by National Institutes of Health (NIH) (R56AG061414, R15AG059190 and R03AG059846)

Case 275.

HistoryA 61-year-old woman presented to the cardiology service with sinus tachycardia. As part of her work-up, she underwent routine echocardiography that showed a normal heart but incidentally revealed multiple lesions in the liver (Fig 1). An outpatient CT scan was performed to characterize the liver lesions (Figs 2-5). The patient had emigrated to Canada from the Middle East several years earlier and had no medical history of note; in particular, there was no history of cancer or predisposing factors for chronic liver disease. The patient's clinical examination findings; laboratory test results, including complete blood count; and liver function test results were normal.[Figure: see text][Figure: see text][Figure: see text][Figure: see text][Figure: see text].

Obesity Is the Most Common Risk Factor for Chronic Liver Disease: Results From a Risk Stratification Pathway Using Transient Elastography.

Obesity has been associated with liver fibrosis, yet guidelines do not emphasize it as an independent risk factor in which to have a high index of suspicion of advanced disease. We aimed to elucidate the effect of a raised body mass index on the risk of liver disease using data from a community risk stratification pathway. We prospectively recruited patients from a primary care practice with hazardous alcohol use and/or type 2 diabetes and/or obesity. Subjects were invited for a transient elastography reading. A threshold of ≥8.0 kPa defined an elevated reading consistent with clinically significant liver disease. Five hundred seventy-six patients participated in the pathway; of which, 533 patients had a reliable reading and 66 (12.4%) had an elevated reading. Thirty-one percent of patients with an elevated reading had obesity as their only risk factor. The proportion of patients with an elevated reading was similar among those with obesity (8.9%) to patients with more recognized solitary risk factors (type 2 diabetes 10.8%; hazardous alcohol use 4.8%). Obesity in combination with other risk factors further increased the proportion of patients with an elevated reading. In multivariate logistic regression, increasing body mass index and type 2 diabetes were significantly associated with an elevated reading. Obesity as a single or additive risk factor for chronic liver disease is significant. Future case-finding strategies using a risk factor approach should incorporate obesity within proposed algorithms.

Development and implementation of a commissioned pathway for the identification and stratification of liver disease in the community

ObjectiveTo describe the development of the Nottingham liver disease stratification pathway, present a 12-month evaluation of uptake and stratification results, and compare the pathway with current British Society of Gastroenterology...

Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction.

Hepatocellular cancer (HCC) is the fourth leading cause of cancer-related deaths worldwide and the fastest growing cause of cancer deaths in the United States. The overall prognosis of HCC remains dismal, except for the subset of patients who are diagnosed at early stage and receive potentially curative therapies, such as surgical resection and liver transplantation. Given this, expert society guidelines recommend HCC surveillance every 6 months in at-risk individuals. Despite these recommendations, the effectiveness of HCC surveillance remains a subject of debate. We discuss current best practices for HCC surveillance and the evidence that support these recommendations. We also describe several initiatives that are underway to improve HCC surveillance and outline areas that may serve as high-yield targets for future research. Overall, we believe these efforts will help the field move toward precision surveillance, where surveillance tests and intervals are tailored to individual HCC risk. Doing so can maximize surveillance benefits, minimize surveillance harms, and optimize overall value for all patients.

Cetylpyridinium chloride interaction with the hepatitis B virus core protein inhibits capsid assembly

Hepatitis B virus (HBV) infection is a major risk factor for chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) worldwide. While multiple hepatitis B drugs have been developed, build up of drug resistance during treatment or weak efficacies observed in some cases have limited their application. Therefore, there is an urgent need to develop substitutional pharmacological agents for HBV-infected individuals. Here, we identified cetylpyridinium chloride (CPC) as a novel inhibitor of HBV. Using computational docking of CPC to core protein, microscale thermophoresis analysis of CPC binding to viral nucleocapsids, and in vitro nucleocapsid formation assays, we found that CPC interacts with dimeric viral nucleocapsid protein (known as core protein or HBcAg) specifically. Compared with other HBV inhibitors, such as benzenesulfonamide (BS) and sulfanilamide (SA), CPC achieved significantly better reduction of HBV particle number in HepG2.2.15 cell line, a derivative of human HCC cells that stably expresses HBV. CPC also inhibited HBV replication in mouse hydrodynamic model system. Taken together, our results show that CPC inhibits capsid assembly and leads to reduced HBV biogenesis. Thus, CPC is an effective pharmacological agent that can reduce HBV particles.

Fulminant hepatitis with negative viral serological markers: A possible case of occult hepatitis B virus infection

Infection with hepatitis B virus (HBV) shows variable clinical manifestations ranging from asymptomatic carrier state, acute, chronic, fulminant, and occult HBV infection (OBI). OBI is defined as the presence of HBV viral DNA in the liver (with or without detectable HBV DNA in serum) of hepatitis B surface antigen-negative individuals tested with the currently available assays. A cutoff of HBV DNA if present is expected to be <200 IU/ml. As high as 20% of individuals with OBI carriage evidenced by HBV DNA detection could be nonreactive for anti-hepatitis B core or any other serological evidence of exposure to HBV. With a reported prevalence of 5.4% among blood donors in Ile Ife, Nigeria, OBI is a risk factor for chronic liver disease and hepatocellular carcinoma. Given the sensitivity of our diagnostic tools in this environment, it is likely that most cases of OBI are going undiagnosed among many blood donors. We present a case of fulminant hepatitis with negative serological markers for viral hepatitis in a 25-year-old male.

Endothelial fatty liver binding protein 4: a new targetable mediator in hepatocellular carcinoma related to metabolic syndrome

Metabolic syndrome (MS) is becoming the leading risk factor for hepatocellular carcinoma (HCC). HCC development related to MS may occur in advanced or non-advanced liver fibrosis, suggesting specific molecular pathways. Among these pathways, basal inflammatory state and adipokines production are involved. The aim of this study was to evaluate the role of fatty acid-binding protein 4 (FABP4). In this study, we demonstrate the specific overexpression of FABP4 in human HCC samples from patients with MS compared to other risk factors for chronic liver disease with FABP4 expression restricted to peritumoral endothelial cells. In vitro, glucose, insulin, VEGFA and hypoxia upregulated endothelial FABP4, which was reversed by metformin through mTOR pathway inhibition. FABP4 exerts oncogenic effects on hepatoma cell lines by upregulating the angiogenesis gene signature and pathways involved in the cell cycle, leading to increased cell proliferation and migration, and downregulating HIF1 pathway; effects were reversed in the presence of a specific FABP4 inhibitor (BMS309403). We showed the role of microvesicles as FABP4 vectors between endothelial and tumor cells. In vivo, BMS309403 significantly reduces tumor growth in heterotopic and orthotopic xenografted mice model. In conclusion, this study demonstrates the emerging oncogenic role of liver endothelial cells through FABP4 in HCC related to MS, and highlights new anti-neoplastic mechanism of metformin.

The XL probe: A luxury or a necessity? Risk stratification in an obese community cohort using transient elastography.

Transient elastography is a non-invasive tool which can stratify patients at risk of chronic liver disease. However, a raised body mass index has been independently associated with a failed or unreliable examination. The purpose of this study was to analyse the performance of two probes (M/XL) on a portable transient elastography device within an obese community population. The method involved a prospective study with recruitment from a primary care practice. Patients identified with a risk factor for chronic liver disease were invited to a community-based risk stratification pathway for transient elastography readings with both probes. A threshold of ≥8.0 kPa defined elevated liver stiffness. A total of 477 patients attended the pathway. Of the patients, 21% had no valid measurements with the M probe. There was a significant difference between the probes in the proportion achieving ≥10 valid readings (M versus XL probe: 66.2% versus 90.2%; p ≤ 0.001) and in their reliability (M versus XL probe: 77.4% versus 98.5%; p = 0.028). Unreliable readings with the M probe increased as the body mass index increased. The XL probe re-stratified 5.2% of patients to have a normal reading. The XL probe on a portable device significantly improves the applicability of transient elastography within a community-based risk stratification pathway.

Periodontitis is associated with incident chronic liver disease-A population-based cohort study.

Chronic liver disease is a major health concern worldwide and the identification of novel modifiable risk factors may benefit subjects at risk. Few studies have analyzed periodontitis as a risk factor for liver complications. We studied whether periodontitis is associated with incident severe liver disease. The study comprised 6165 individuals without baseline liver disease who participated in the Finnish population-based Health 2000 Survey (BRIF8901) during 2000-2001, a nationally representative cohort. Follow-up was until 2013 for liver-related admissions, liver cancer and mortality from National Hospital Discharge, Finnish Cancer Registry and Causes of Death Register, Statistics Finland. Mild to moderate periodontitis was defined as ≥1 tooth with periodontal pocket ≥4mm deep, and advanced periodontitis as ≥5 teeth with such pockets. Multiple confounders were considered. A total of 79 subjects experienced a severe liver event during follow-up. When adjusted for age, sex and number of teeth, hazards ratios by Cox regression regarding incident severe liver disease were, for mild to moderate periodontitis, 2.12 (95% CI 0.98-4.58), and, for advanced periodontitis, 3.69 (95% CI 1.79-7.60). These risk estimates remained stable after additionally adjusting for alcohol use, smoking, metabolic risk, serum gamma-glutamyltransferase, dental-care habits, lifestyle and socioeconomic status. Periodontal disease-associated liver risk was accentuated among subjects with non-alcoholic fatty liver disease or heavy alcohol use at baseline. Periodontitis was associated with incident liver disease in the general population independently of various confounders. As a preventable disease, periodontal disease might present a modifiable risk factor for chronic liver disease.

A middle-aged man with progressive jaundice

Vanishing bile duct syndrome is the group of acquired cholestatic liver disease associated with progressive destruction and disappearance of the intrahepatic bile ducts. We report a case ofa 55-years old man with end-stage renal disease and diabetic mellitus who presented with progressive cholestatic jaundice. He had no risk factors for chronic liver disease and hepatotoxic medications.The liver function tests were cholestasis pattern. The liver biopsy showed severe ductopenia compatible with vanishing bile duct syndrome.&#x0D; Figure 3 (H&amp;E, 400x) The liver histology shows biliary cirrhosis with “jigsaw-pattern” regenerative nodules (*), lobular, and cholangiolar cholestasis (arrow) (PT = portal tract)&#x0D;

The elevated prevalence of risk factors for chronic liver disease among ageing people with hemophilia and implications for treatment.

Chronic liver disease (CLD) is frequently seen in the hemophilia population. The ADVANCE Working Group conducted a cross-sectional study in which people with hemophilia (PWH) aged ≥40 years were included. This study aimed to assess the associations between CLD and its risk factors using data from the H3 study, and to suggest implications for optimal care.Data from 13 European countries were collected at a single time-point (2011–2013). Univariate and multivariate logistic regression (MLR) analyses were performed.A total of 532 PWH were included with either hemophilia A (n = 467) or hemophilia B (n = 65). A total of 127 (24%) were diagnosed with CLD. Hepatitis C virus (HCV), human immunodeficiency virus (HIV), total cholesterol, and severe hemophilia were significant risk factors in univariate logistic regressions. In MLR, HCV Ab+/PCR+ (OR = 17.6, P < .001), diabetes (OR = 3.0, P = .02), and HIV (OR = 1.9, P = .049) were positively associated with CLD. Total cholesterol (OR = 0.6, P = .002) was negatively associated with CLD. We found no evidence of interaction effects among the explanatory variables. No significant associations with age and type of or severity of hemophilia were observed in MLR.The main risk factors for CLD in this European cohort also apply to the general population, but the prevalence of HCV and HIV is considerably larger in this cohort. With new and improved treatment options, intensified eradication therapy for HCV seems justified to prevent CLD. Similarly, intensified monitoring and treatment of diabetes seem warranted.

Management of hepatocellular carcinoma: a study on 240 patients in a single referral center

Epidemiology of hepatocellular carcinoma (HCC) is changing globally and trends show an increasing morbidity rates in Northern, Cen­tral and Eastern Europe and North America but a slow decline in Japan, Korea and China. The bur­den of this important complication of chronic advanced liver disease will further increase in the next 10 years. Several reviews focus on a broad spectrum of HCC clinical manage­ment worldwide, including surveillance of patients with cirrhosis thus establishing proper HCC diagnostic and therapeutic options. The study of I. Ivanova et al . involves patient data from a single referral center in St. Marina University Hospital of Varna. It is the first report of the results of a project enti­tled ‘Hepatocellular Carcinoma - a Current Diagnos­tic and Therapeutic Approach`. The study achieves its goal to present the results from this multidisciplinary HCC treatment. This is one of the three largest cohort studies in Bulgaria so far. The paper reports 240 HCC patients during an 11-year period (from 2006 to 2016) in the Clinic of Gastroenterology, St. Marina University Hospital of Varna. These results aim at evaluating the risk factors for HCC and etiology of chron­ic liver disease, the characteristics and severity of underlying liver disease, the methods for HCC diagnosis and tumor burden as well as staging and treatment methods. The analysis of the risk factors for HCC and etiology of chron­ic liver disease shows that chronic hepatitis-B virus (HBV) infection has been registered in 40.4% and chronic hepatitis-C virus (HCV) infection - in 25.8% of HCC patients. There are two cases with HBV/HCV co-infection and four had HBV/hepatitis-D virus (HDV) co-infection. The other rare etiologic factors for chronic liver disease in our cohort are the following: Wilson`s disease in three, autoimmune hepatitis - in two and non-alco­holic fatty liver disease (NAFLD) - in one patient. Unknown etiology has been registered in 28 patients, as 10 of them (36%) have presented with a marker for exposure to HBV (anti-HBc positive antibodies). Despite the common understanding of the link between liver cirrhosis and HCC, only 82% of HCC patients have developed this pathology. HCC is the first complication of chronic liver dis­ease in 2/3 of cases (n=156). One limitation of the study when comparing laboratory results is the lack of similar cohort of patients without malignant transformation. The diagnostic algorithm includes various imaging and biopsy modalities. The primary diagnosis of HCC is based on at least two imaging methods in 133 cases. In any other patients, the imaging method is combined with at least one ultasonography- or computed-tomography-guided biopsy of the he­patic lesions. The pa­tients with very early and early HCC stage account­ for 13% of all HCCs. The treatment modalities encompass every current modality available such as surgical resection (in 23%), radiofrequency ablation (in 5%) and transarterial chemoembolization (TACE) (in 2% of the cases). System­ic therapy, predominantly with Sorafenib, has been intro­duced to 17% of the patients. The significance of ultrasound surveillance in liver cirrhosis patients is confirmed with the large percentage of diagnosed tumors - 51%. In contrast, most HCCs are detected at stage D, mainly due to advance baseline liver cirrhosis. In summary, findings from this study confirm that surveillance with ultrasound and tumor markers like alpha-fetoprotein (AFP) among pa­tients with advanced liver disease may increase HCC detection rate and achieve longer patient survival rate.

Nutritional issues in patients with obesity and cirrhosis.

Obesity and metabolic syndrome are considered as responsible for a condition known as the non-alcoholic fatty liver disease that goes from simple accumulation of triglycerides to hepatic inflammation and may progress to cirrhosis. Patients with obesity also have an increased risk of primary liver malignancies and increased body mass index is a predictor of decompensation of liver cirrhosis. Sarcopenic obesity confers a risk of physical impairment and disability that is significantly higher than the risk induced by each of the two conditions alone as it has been shown to be an independent risk factor for chronic liver disease in patients with obesity and a prognostic negative marker for the evolution of liver cirrhosis and the results of liver transplantation. Cirrhotic patients with obesity are at high risk for depletion of various fat-soluble, water-soluble vitamins and trace elements and should be supplemented appropriately. Diet, physical activity and protein intake should be carefully monitored in these fragile patients according to recent recommendations. Bariatric surgery is sporadically used in patients with morbid obesity and cirrhosis also in the setting of liver transplantation. The risk of sarcopenia, micronutrient status, and the recommended supplementation in patients with obesity and cirrhosis are discussed in this review. Furthermore, the indications and contraindications of bariatric surgery-induced weight loss in the cirrhotic patient with obesity are discussed.

Abstract A34: Risk factors for liver disease/cancer among adults of Mexican descent in the United States and Mexico

Abstract A34: Risk factors for liver disease/cancer among adults of Mexican descent in the United States and Mexico

Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography.

Rising cirrhosis incidence and mortality in the United Kingdom has been attributed predominantly to excess alcohol consumption. However, metabolic risk factors such as Type 2 diabetes and obesity may also be important. To screen at-risk individuals in general practice for undetected cirrhosis using transient elastography and study the risk factors underlying these cases. The study was undertaken in 4 general practices (adult patient population 20 868) between February 2012 and September 2014. Patients with defined risk factors for chronic liver disease (hazardous alcohol use and/or Type 2 diabetes) were identified from the General Practice electronic records and invited for transient elastography. Elevated liver stiffness was defined as ≥8 kPa. Cirrhosis was confirmed by established histological, radiological and biochemical methods. Two thousand three hundred and sixty eight patients were invited for transient elastography and 899/919 who attended (97.8%) had valid measurements. Of these 230 patients had elevated liver stiffness (25.6%) and 27 had cirrhosis (2.9%). Risk factors for new cirrhosis diagnoses were obesity and/or Type 2 diabetes in 16 patients (59.3%), alcohol alone in 3 (11.1%) and both alcohol and obesity and/or diabetes in eight (29.6%). Presence of cirrhosis was significantly increased in obese patients with Type 2 diabetes or hazardous alcohol use compared to non-obese (odds ratio 9.4 [95% CI 2.2-40.9] and 5.6 [95% CI 1.6-19.7] respectively). The number of new cases of cirrhosis diagnosed clearly demonstrates that existing estimates of prevalence are likely to be gross underestimates. Obesity was an important risk factor for cirrhosis within both alcohol users and diabetics.

Risk of chronic liver disease in post-menopausal women due to body mass index, alcohol and their interaction: a prospective nested cohort study within the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

BackgroundWe investigated the risk of chronic liver disease (CLD) due to alcohol consumption and body mass index (BMI) and the effects of their interaction in a prospective cohort study of women recruited to the UKCTOCS trial.Methods95,126 post-menopausal women without documented CLD were stratified into 12 groups defined by combinations of BMI (normal, overweight, obese) and alcohol consumption (none, <1–15, 16–20 and ≥21 units/week), and followed for an average of 5.1 years. Hazard ratios (HR) were calculated for incident liver-related events (LRE).ResultsFirst LREs were reported in 325 (0.34%) participants. Compared to women with normal BMI, HR = 1.44 (95% CI; 1.10–1.87) in the overweight group and HR = 2.25 (95% CI; 1.70–2.97) in the obese group, adjusted for alcohol and potential confounders. Compared to those abstinent from alcohol, HR = 0.70 (95% CI; 0.55–0.88) for <1–15 units/week, 0.93 (95% CI; 0.50–1.73) for 16–20 units/week and 1.82 (95% CI; 0.97–3.39) for ≥21 units/week adjusted for BMI and potential confounders. Compared to women with normal BMI drinking no alcohol, HR for LRE in obese women consuming ≥21 units/week was 2.86 (95% CI; 0.67–12.42), 1.58 (95% CI; 0.96–2.61) for obese women drinking <1–15 units/week and 1.93 (95% CI; 0.66–5.62) in those with normal BMI consuming ≥21 units/week after adjustment for potential confounders. We found no significant interaction between BMI and alcohol.ConclusionHigh BMI and alcohol consumption and abstinence are risk factors for CLD in post-menopausal women. However, BMI and alcohol do not demonstrate significant interaction in this group.Trial registrationUKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.

Nonalcoholic Steatohepatitis Challenges Hepatitis B Virus as the Leading Cause of Chronic Hepatitis in Bangladesh

Background: Chronic hepatitis is inflammation of the liver that lasts at least 6 months. Knowledge of aetiology and pattern of development of complications of chronic liver disease will help in designing optimal and cost effective control measures of the disease. Methods: The present study was performed to find out the aetiological factors in patients of chronic liver disease. This was a retrospective, cross-sectional study. Patients attending Hepatology Green Unit, Bangabandhu Sheikh Mujib Medical University, Dhaka in 2014 with chronic hepatitis were included. Results: Total 3250 patients were studied, 2310(71.08%) males and 940(28.92 %) females. Most of the patients 1547 (47.6%) belong to age group of 18 to 30 years followed by 922 (28.37%) who were between the age group of 31-40 years. Majority of patients 2012(61.91%) had HBV infection, 1095(33.69%) had nonalcoholic steatohepatitis ( NASH), 81(2.49%) had HCV infection, 7(0.22%) had alcohol abuse, 28(0.86%) had Wilson’s disease, 19(0.58%) had autoimmune hepatitis and no aetiological factors were recorded in 8(0.25%) patients. However in case of females 52.55 % (494/940) due to NASH, while 40.21 % (378/940) due to HBV. Conclusion: HBV infection is the major risk factor for chronic liver disease and NASH challenges HBV in our patients.Bangladesh J Medicine Jan 2017; 28(1) : 24-27

P417 Non-invasive assessment of liver fibrosis by transient elastography and AST to ALT ratio in patients with Crohn's disease treated with methotrexate

Background: One of the most feared concerns about the use of methotrexate (MTX) is the risk of developing chronic liver injury. Transient elastography is a simple, non-invasive method for estimating liver fibrosis. AST to ALT ratio (AST/ALT ratio) is also a good easy-to-use indicator of the risk of fibrosis in chronic liver diseases. The aim was to assess the risk of chronic liver injury induced by MTX in a cohort of patients with Crohn's disease (CD) at a high-volume tertiary center. Methods: Cross-sectional study including CD patients treated with methotrexate. Clinical and laboratorial data, duration of treatment, and cumulative dose of methotrexate were obtained. Liver stiffness was assessed by FibroScan®, and the cutoff values for significant liver fibrosis (according to METAVIR) was F ≥2: 7.1 kPa. AST/ALT ratio was considered significant for risk of fibrosis if >1. Patients with chronic hepatitis B or C, excessive daily consumption of alcoholic, non-alcoholic steatohepatitis, or other known causes of chronic liver disease were excluded. Estimates of the presence and severity of steatosis according to the parameter of controlled attenuation (CAP) were also evaluated, considering the absence of significant steatosis (S0) if less than 200 dB/m, mild (S1) if 200–249 dB/m, moderate (S2) if 250–299 dB/m, and severe (S3) if 300 dB/m or greater. Results: 62 patients were included, 35 female (56.5%), with a mean age of 37.5±11.3 years. MTX was the first-line immunosuppressant in 9 patients (14.5%). Indications for initiating MTX included: adjuvant to anti-TNF agent (43.5%), intolerance to azathioprine (27.4%), corticodependence (19.4%) and corticoresistance (9.7%). Mean treatment duration was 88±86 weeks. Mean cumulative MTX dose was 998±871 mg. All patients received MTX subcutaneously. In sixteen patients MTX was discontinued due to changes in liver function tests. The mean value of Fibroscan was 5.3±1.5 kPa, and in 11.1% of cases the value was considered significant for fibrosis (≥7.1 kPa). In none of the cases was a value compatible with METAVIR F4 (>11 kPa). The mean CAP value was 198±58 dB/m, distributed as follows: S0 63.3%, S1 16.7%, S2 13.3% and S3 6.7%. The mean AST/ALT ratio was 1.12±0.43 and was considered significant (>1) in 58.7% of the cases. Fibroscan values correlated directly with ALT (0.44, p=0.026) and bilirubin (0.426, p=0.038), but not with duration of treatment or cumulative dose. Likewise, these variables did not correlate with the AST/ALT ratio. Conclusions: Excluding patients with other risk factors for chronic liver disease, the use of methotrexate regardless of the cumulative dose appears to be safe in the medium to long term in CD patients according to non-invasive methods.

Effects of Moderate and Vigorous Exercise on Nonalcoholic Fatty Liver Disease: A Randomized Clinical Trial.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent risk factor for chronic liver disease and cardiovascular disease. To compare the effects of moderate and vigorous exercise on intrahepatic triglyceride content and metabolic risk factors among patients with NAFLD. In this randomized clinical trial, participants with central obesity and NAFLD were recruited from community-based screening in Xiamen, China, from December 1, 2011, through December 25, 2013. Data analysis was performed from August 28, 2015, through December 15, 2015. Participants were randomly assigned to vigorous-moderate exercise (jogging 150 minutes per week at 65%-80% of maximum heart rate for 6 months and brisk walking 150 minutes per week at 45%-55% of maximum heart rate for another 6 months), moderate exercise (brisk walking 150 minutes per week for 12 months), or no exercise. Primary outcome, change in intrahepatic triglyceride content measured by proton magnetic resonance spectroscopy at 6 and 12 months; secondary outcomes, changes in body weight, waist circumference, body fat, and metabolic risk factors. A total of 220 individuals (mean [SD] age, 53.9 [7.1] years; 149 woman [67.7%]) were randomly assigned to control (n = 74), moderate exercise (n = 73), and vigorous-moderate exercise (n = 73) groups. Of them, 211 (95.9%) completed the 6-month follow-up visit; 208 (94.5%) completed the 12-month follow-up visit. Intrahepatic triglyceride content was reduced by 5.0% (95% CI, -7.2% to 2.8%; P < .001) in the vigorous-moderate exercise group and 4.2% (95% CI, -6.3% to -2.0%; P < .001) in the moderate exercise group compared with the control group at the 6-month assessment. It was reduced by 3.9% (95% CI, -6.0% to -1.7%; P < .001) in the vigorous-moderate exercise group and 3.5% (95% CI, -5.6% to -1.3%; P = .002) in the moderate exercise group compared with the control group at the 12-month assessment. Changes in intrahepatic triglyceride content were not significantly different between vigorous-moderate and moderate exercise at the 6- or 12-month assessment. Body weight, waist circumference, and blood pressure were significantly reduced in the vigorous-moderate exercise group compared with the moderate exercise and control groups at the 6-month assessment and in the vigorous-moderate and moderate exercise groups compared with the control group at the 12-month assessment. In addition, body fat was significantly reduced in the vigorous-moderate exercise group compared with the moderate exercise and control groups at the 12-month assessment. After adjusting for weight loss, the net changes in intrahepatic triglyceride content were diminished and became nonsignificant between the exercise and control groups (except for the moderate exercise group at the 6-month assessment). Vigorous and moderate exercise were equally effective in reducing intrahepatic triglyceride content; the effect appeared to be largely mediated by weight loss. clinicaltrials.gov Identifier: NCT01418027.