Sherbrook,, Canada

Diagnosis of Fatty Liver with Outpatient Ultrasound

All patients presenting to dedicated hepatology clinic with concern for fatty liver will be evaluated by ultrasound. This will be compared with standard imaging performed for this condition. The data will be compared for effectiveness of outpatient evaluation with dedicated imaging currently practiced

Fatty Liver Patient Registry

The NAFLD registry is a local database provided by the principal investigator, Dr. J. Allard, which will be stored on the Research Intranet at the University Health Network, Toronto. The database will be password protected. Only clinic personnel and members of Dr. Allard's research team involved in the study will have access to the database. A code and date of birth will be used to identify each patient. All patients entering the NAFLD clinic at Toronto General Hospital will be consented for the registry. Only data from their regular clinic visits will be used for entry into the registry. Data entered into the registry will include: 1) Patient demography: age, sex, ethnicity, medical history; 2) Anthropometry: weight, height, BMI, waist circumference; 3) Nutritional assessment: Food records and food frequency questionnaires are kept by the subjects and data will be analyzed to assess the intake of macro- and micronutrients. Amount of alcohol and number of cigarette smoked will also be recorded; 4) Physical Activity will be assessed using the Paffenbarger Physical Activity Questionnaire; 5) Medications: insulin, non-steroidal anti-inflammatory drugs, corticosteroids, statins, medications used to treat diabetes/obesity (e.g. metformin, thiazolidinediones, orlistat…), medication to treat liver disease (eg. urso, carnitine, choline…), antioxidant vitamin or fish oil supplementation; 6) Blood work, currently including: complete blood count, biochemistry including liver enzymes, total protein, albumin, glucose, insulin, and blood lipid profile; other diagnostic blood work done to exclude other causes of liver disease, e.g. ceruloplasmin, anti-smooth muscle antibodies,… One plasma sample will be stored for assessment of cytokeratin 18 (CK-18) fragments as a novel marker for NASH in patients with NAFLD; 7) Presence of metabolic syndrome; 8) Disease categorization: SS, NASH, cirrhosis; 9) Survival: alive, death: causes, NAFLD-related or not NAFLD-related; 10) Liver biopsy results, NAFLD fibrosis score, and elastography results. Data will be entered after every clinic visit. Case report forms will be used to collect the data from the patient charts and facilitate data input into the registry database All patients will be followed prospectively until withdrawal from the clinic or death. Descriptive statistics will be performed. For the entire NAFLD population, probability of survival, cirrhosis, as well as liver and non-liver related morbidity will be calculated using the Kaplan Meier method.

Fighting Fatty Liver in India

STUDY BACKGROUND INFORMATION AND RATIONALE Non-alcoholic fatty liver disease (NAFLD): With an estimated global prevalence of 25% among adults, NAFLD is now the commonest chronic liver disease; its progressive form, non-alcoholic steatohepatitis (NASH), has been estimated to affect 1.5%-6.5% of the population with associated increased risk of cirrhosis, hepatocellular carcinoma and liver-specific mortality. Considering the key association of fat accumulation within the liver, in particular diacyl glycerols, to the generation of whole body insulin resistance and development of type 2 diabetes, NAFLD has been considered a pre-diabetic state. NAFLD has been associated with excess risk of non-fatal and fatal cardiovascular events independently of established co-morbidities including type 2 diabetes, dyslipidemia and obesity. Individuals of South Asian ethnicity have significantly higher rates of NAFLD, abdominal obesity and cardiovascular disease than whites and ethnicity is a risk factor for NAFLD independent of diabetes, BMI, hypertension and hypercholesterolemia. NAFLD problem in India: Consistent with the global trend, the health and economic burdens of metabolic syndrome and NAFLD have risen in India. In 2011, India had 63 million individuals with type 2 diabetes and by 2030, that number is predicted to be a staggering 90 million. Insulin resistance (IR) has also been shown to be more prevalent in Indians compared with other ethnic groups and this has been correlated with NAFLD regardless of adiposity. Despite these links, there are a number of key differences between Indian NAFLD patients and those in the West: mean BMI is significantly lower in Indians and there is also a lower prevalence of hypertension, diabetes and metabolic syndrome in non-cirrhotic NAFLD patients. Dietary influences on NAFLD: Diet may be one of the key environmental factors that accounts for ethnic variation in susceptibility to NAFLD. However, there is currently a lack of research into specific dietary factors influencing susceptibility to NAFLD, in particular, with regards to macronutrients, and there are few evidence-based dietary interventions, beyond energy restriction to induce weight loss. Considering the effectiveness of a modest increase in protein content and a reduction in the glycaemic index (GI) in maintaining weight loss, we investigated the effects of a low GI diet on the liver and demonstrated that it did not increase liver fat content whereas an increase was seen with an isoenergetic high GI diet controlled for macronutrient content. Diet has been found to influence the gut microbiome variably across human societies. Fibre encompassing a range of characteristics, is one of the fundamental components linking diet, the gut microbiome and fatty acid metabolism. The benefits of dietary fibre include improved glucose homeostasis and insulin sensitivity. Dietary fibres are at least partly fermented in the caecum and large intestine by the colonic microbiota resulting in some cases an increased production of short chain fatty acids (SCFAs) which regulate the balance between fatty acid synthesis, fatty acid oxidation and lipolysis in the body. The net result is a reduction in free fatty acid concentrations in plasma and a decrease in body weight. Dietary fibre overall is associated with greater gut microbiome diversity and we have recently shown that it is also associated with lower long-term weight gain.

Gastric Bypass Stent Small-Sample-Size Study For Nonalcoholic Fatty Liver Disease

The Gastric Bypass Stent System is intended to be used in Patients with Diagnosis of nonalcoholic fatty liver disease， Proton density fat fraction measured by magnetic resonance imaging (MRI-PDFF) ≥8%. In this pivotal, prospective, single-arm clinical investigation the Sponsor seeks to demonstrate the safety and performance of the Gastric Bypass Stent System in Treatment of Patients with Nonalcoholic Fatty Liver Disease

Fatty Liver Disease in Nordic Countries

Copeptin and Nonalcoholic Fatty Liver Disease

Participants: As a pilot study, the investigators will recruit 30 obese adults with NAFLD based upon ultrasound echogenicity within 6 months of enrollment, and 30 obese adults without NAFLD based upon ultrasound (US) echogenicity for comparison. Screening Visit/Study Visit: Patients in the investigator's Obesity clinic will be approached about the study and consented if interested at the screening. Participants will have a chart review for their history and physical Exam and medication review for inclusion and exclusion criteria. Qualified participants will be invited for a screening visit to be scheduled in conjunction with the labs and procedures performed as Standard of Care (SOC) in the obesity clinic. At the screening visit, following consent, participants will have vitals (blood pressure, Body Mass Index (BMI), waist circumference) and a physical examination performed. Participants' Standard of Care (SOC) labs including fasting lipid panel, HbA1c (unless done within last 3 months), comprehensive metabolic panel, titers for hepatitis b and c, and complete blood count will be drawn, along with the following research labs: insulin, glucagon, free fatty acids, adiponectin and a 24-hour urine cortisol collection. Those who have not had an abdominal US will have a SOC US performed to delineate non-NAFLD or NAFLD status. US will not be performed if already done within 6 months of enrollment. All ultrasound studies will be interpreted by one University of Colorado Denver radiologist to categorize the patient as NAFLD or non-NAFLD to limit inter-reader variability. Those with NAFLD present on US will also have a SOC Fibroscan done to assess severity of steatosis (based upon Controlled Attenuation Parameter or CAP Score) and fibrosis (based upon elastography). Given limitations of ultrasound to accurately detect significant steatosis unless >30%, the investigators will in addition perform Fibroscan (all particpants regardless of US) to assess steatosis, so as to confirm if significant steatosis and compare copeptin levels on a continuum of level of steatosis as part of research procedure. Fibroscan can detect steatosis (based upon Controlled Attenuation Parameter or CAP Score) and fibrosis (based upon elastography). FIbroscan with M probe has been found to have AUROC 0.823 for a cutoff of value of 248 dB/m for no steatosis vs steatosis (with other cutoffs at 268 dB/m between S1 and S2-S3 and 280 dB/m between S1-S2 and S3 disease).

Lifestyle Intervention in Fatty Liver (NAFLD)

Background Non-Alcoholic Fatty Liver Disease (NAFLD), including its more pathologic consequence, non-alcoholic steatohepatitis (NASH), is believed to be the most common chronic liver disease worldwide, affecting between 6 to 37% of the population. NAFLD is a so called 'silent killer', as clinical symptoms only surface at late stages of the disease, when it is no longer treatable. Untreated, NAFLD/NASH can lead to cirrhosis and hepatocellular carcinoma, culminating in liver failure. Several factors may contribute to the pathogenesis of NAFLD, including genetic assessment and mitochondrial dysfunction. Genetic factors might affect the pathophysiological aspects of NAFLD and its natural history. The European population appears to host genetic variants which can play a role in this respect. Recently, the common variant p.I148M of the enzyme adiponutrin (PNPLA3) has emerged as a major genetic determinant of hepatic steatosis and non-alcoholic steatohepatitis as well as its pathobiological sequelae fibrosis, cirrhosis, and hepatocellular cancer. PNPLA3 encodes a lipid droplet-associated, carbohydrate-regulated lipogenic and/or lipolytic enzyme. Homozygous carriers of the PNPLA3 variant (i.e. the presence of the PNPLA3 allele [M]) are prone to develop cirrhosis in the absence of other risk factors such as alcohol or viral hepatitis. Moreover, PNPLA3 p.I148M variant is associated with greater reduction of liver fat content after bariatric surgery, in comparison to carriers of PNPLA3 wild-type alleles. Other variants might also play a role and include transmembrane 6 superfamily member 2 (TM6SF2) p.E167K, and membrane-bound O-acyltransferase domain containing 7 (MBOAT7) rs641738. Neither PNPLA3 nor TM6SF2 risk alleles impair the response to dietetic intervention in NAFLD. MBOAT7 polymorphism is associated with increased triglyceride, total cholesterol, low density lipoprotein, and serum glucose levels, all factors associated with metabolic syndrome and liver steatosis. Patients with NAFLD/NASH display disturbances of intestinal permeability, and gut microbiota. In most cases, NAFLD/NASH is strongly linked to other metabolic conditions, including visceral adiposity. Liver biopsy is the gold standard for the diagnosis and staging of NAFLD but is invasive in nature and not easily usable as screening tool. Other imaging techniques include ultrasonography which is non-invasive, can detect hepatic steatosis (>20%-30%) and can be easily used in follow-up studies. Computerized tomography, magnetic resonance imaging, and spectroscopy are alternative imaging techniques used for the detection of hepatic steatosis. However, they have failed to show better accuracy, are expensive and can bring adverse effects (e.g., radiation). Therefore they are not feasible as screening tools. Liver enzymes represent surrogate markers of liver disease but have limited accuracy. By ultrasound, NAFLD prevalence ranges from 11%-30%. In the United States, ultrasonographic NAFLD appears to range between 5%-33%. Liver fibrosis may be non-invasively assessed by acoustic radiation force impulse imaging (ARFI), an ultrasound-based approach for estimating liver stiffness, a surrogate marker of liver fibrosis. ARFI imaging is based on short-duration, high-intensity acoustic pulses to produce mechanical excitation in tissue. Localized tissue displacement and shear wave propagation follow the tissue excitation. The velocity of the waves correlates with the degree of fibrosis, implying that the shear wave velocity increases as the amount of fibrosis increases. Optimal cut-off values are provided by various studies. In the study by Crespo et al. (2012), the sensitivity of ARFI imaging in 88 patients for ≥F2 fibrosis was 85% using a cut-off of 1.44 m/s and for F4 fibrosis was 92 percent using a cut-off of 1.9 m/s. The corresponding specificities were 76 and 87 percent, respectively. In another study, ARFI was compared with ultrasound-based transient elastography in 321 patients undergoing liver biopsy for chronic liver disease. No difference was found between ARFI and ultrasound-based transient elastography for the diagnosis of cirrhosis or severe fibrosis and ARFI was better in lean patients. Among non-obese patients the area under the receiver operating characteristic (ROC) curves for cirrhosis and severe fibrosis were 0.92 and 0.91, respectively. For obese patients they were 0.63 and 0.63, respectively. Several serologic markers, either direct or indirect, have been elaborated but not invariably validated. Major limitations include the fact they are considered as surrogates, not biomarkers, none of the markers are liver-specific (concurrent sites of inflammation may contribute to serum levels) and because they typically reflect the rate of matrix turnover, not deposition, results tend to be more elevated when the inflammatory activity is high. On the other end, even in the presence of minimal inflammation, extensive matrix deposition can occur. Lastly, serum levels are influenced by clearance rates (i.e. not only sinusoidal endothelial cell dysfunction but also impaired biliary excretion) (Table 3). Overall, studies of the various panels suggest that serologic tests have good ability to differentiate patients with significant fibrosis (F2 to F4) from those without significant fibrosis (F0 to F1), although no standard test has emerged so far yielding definitive distinction between different types of F scores. Breath Tests (BT) represent novel indirect "dynamic" tools which provide additional insights in functional diagnosis and follow-up of patients with liver diseases. Principles of BTs in hepatology are based on both biochemical and pharmacological considerations. Mechanisms of liver damage often include dysfunction of subcellular organelles such as microsomal hypertrophy, mitochondrial abnormalities, activation of peroxisomal metabolism (i.e. long chain fatty acids). Thus, assessing specific functions of such organelles by BTs may provide useful information to clinicians. Also, BTs allow the study of specific time-dependent metabolic processes by assessing the hepatic clearance of metabolically active substances. In this context, for a given exogenous substrate: HEPATIC CLEARANCE = HEPATIC PERFUSION x HEPATIC EXTRACTION (where HEPATIC EXTRACTION is the ratio of the difference between inflow and outflow concentration ÷ by inflow concentration of the probe). Hepatic clearance is defined as flow-limited (range 0.7-1.0) or enzyme-limited (<0.3). The intrinsic complexity of liver metabolic pathways does not allow a single functional test to explore the whole liver function. Different substrates are therefore used to assess cytosolic, microsomal or mitochondrial function. Such substrates are marked with the natural stable isotope of carbon 13C (currently the most widely used isotope). After intestinal absorption, the given substrate undergoes liver metabolism at different levels which ultimately results in the production and appearance of 13CO2 in expired air, as a marker of specific liver metabolic functions. BTs for the study of liver microsomal function include the use of methacetin, a derivative of phenacetin which is metabolized rapidly by the hepatic microsomal enzyme systems CYP1A2 into acetaminophen and 13CO2 by a single O-dealkylation step. Since methacetin has a high extraction (E>0.8) and undergoes extensive first-pass clearance, its metabolism can be altered by hepatic blood flow alterations and by hepatic "first-pass" effect. The methacetin metabolizing capacity is lower in elderly than adults. Methacetin BT was shown to accurately assess the degree of liver damage in patients with histologically proven chronic liver diseases and to distinguish chronic aggressive hepatitis from liver cirrhosis and between early cirrhosis (Child A) from non-cirrhotic patients. Methacetin BT was a useful predictive markers of clinical outcomes in chronic HCV patients. Moreover, methacetin BT can better estimate the degree of fibrosis in patients with chronic HCV infection than biochemical parameters (i.e. aspartate aminotransferase to platelet ratio, aspartate aminotransferase to alanine aminotransferase ratio) or Fibroindex. Ketoisocaproate (KICA) is an intermediate in the metabolism of leucine. The decarboxylation of KICA and the generation of CO2 reflects the mitochondrial branched-chain amino acid decarboxylation function. This step is observed when the transamination to leucine (the major competing pathway for KICA elimination) is suppressed by the concomitant administration of fixed doses of leucine. This metabolic pathway of KICA has been tested in experimental models, in isolated mitochondria, in healthy subjects treated with acetylsalicylic acid or with low ethanol intake, and in patients with liver diseases. We found that the mitochondrial decarboxylation capacity of KICA was lower in patients with advanced non-alcoholic steatohepatitis (NASH) compared with healthy subjects and patients with simple liver steatosis. Notably, the 13CO2 cumulative recovery values following 13C-KICA was inversely related to the extent of fibrosis, to serum hyaluronate, and to body size in NASH patients. We extended the studies with 13C-KICA BT and found that KICA decarboxylation was significantly lower in cirrhotic patients with hepatocellular carcinoma (HCC) compared with cirrhotic patients without HCC and identical Child-Pugh score. Moreover, KICA decarboxylation was deranged following radiofrequency ablation but not after transarterial chemoembolization. Finally, the recurrence of HCC was associated with an early decrease of KICA decarboxylation. In a different context, we recently found that 13C-KICA BT was abnormal (and therefore suggesting mitochondrial malfunction) in a female patient suffering from massive liver echinococcosis. Of note, mitochondrial liver function improved following pericystectomy and limited hepatectomy. KICA BT is useful for the assessment of drug effects on liver mitochondrial function. Liver injury might occur following the use of such drugs which accumulate into mitochondria and interfere with respiratory complexes or electron transfer. KICA BT may be helpful to ascertain the integrity of these organelles before the administration of potentially toxic drugs and to detect drug-induced mitochondrial damage before the appearance of symptoms in order to timely manage patients and prevent adverse effects. Examples are tacrolimus, aspirin, and ergot alkaloids. Potential applications are also with amiodarone, valproate, and retroviral drugs. Aim of the study The objective of the mtFOIE GRAS Uniba H2020 Project is to conduct a randomized controlled trial of 3 year-long weight reduction in the management of NAFLD/NASH patients using a lifestyle-dietary intervention program. Overweight or obese individuals with biopsy or ultrasonography (US) -proven NAFLD/NASH will be randomized to receive either standard medical care and educational sessions related to NAFLD/NASH, healthy eating, weight loss, and exercise (control group); or to an intensive weight management with a goal of at least 7-10 % weight reduction (lifestyle intervention group). The weight loss intervention will be modelled on Mediterranean-intervention-diet. We hypothesize that a 7-10% weight reduction through intensive lifestyle intervention will lead to improvement of clinical, US, anthropometric, and biochemical features of NAFLD/NASH as well as of intestinal permeability and faecal microbiota.

Digital Therapy for Fatty Liver Disease

The Liver BIoBank Lombardia of Fatty Liver

The aims of the project will be: - To examine whether a comprehensive HFC-GRS coupled with evaluation of environmental triggers, imaging techniques and novel circulating biomarkers help in stratifying of the risk of NAFLD and associated complications in a cohort of asymptomatic individuals at high risk from the general population (the Liver-Bible cohort). The Liver-Bible cohort is made up of >2,500 individuals with multiple metabolic risk factors, who are undergoing a comprehensive evaluation of environmental exposure, HFC and liver stiffness measurement, liver histology in those at risk of advanced fibrosis, circulating biomarkers of hepatic damage, coagulation status and early cardiovascular damage; - To validate the causal role of HFC in the alterations of metabolism, coagulation, and early cardiovascular damage associated with NAFLD; - To identify new inherited risk variants and microbiota profiles associated with NAFLD; to investigate the mechanism linking genetic susceptibility with liver disease and coagulation balance in in vitro models of NAFLD in hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells. The investigators expect to demonstrate that the combined evaluation of genetic and novel circulating biomarkers with imaging improves the non-invasive prediction of both liver-related (leading to personalised and cost-effective surveillance of liver-related complications) and unrelated complications of NAFLD in at risk individuals, with a special focus on the role of the coagulation balance, and to pinpoint new genetic modifiers of disease progression that may be prioritized for future therapeutic approaches.

Intermittent Fasting in Nonalcoholic Fatty Liver Disease