Effects of Tomato Consumption on Steatosis, Intestinal Function and Glucose and Lipid Metabolism in Subjects With NAFLD
Chronic liver diseases are among the leading causes of morbidity, mortality. The increase in mortality from liver disease has been associated with the greater prevalence of NAFLD, which is, the most frequent chronic liver disease observed in clinical practice in Western countries. The term "hepatic steatosis" is the hallmark of NAFLD and refers to a fat deposit in the liver cells greater than 5% and which is not related to alcohol intake or viral infections or the use of drugs. It is possible to distinguish between hepatic steatosis and non-alcoholic steatohepatitis (NASH), a subtype of NAFLD in which fat deposition is associated with lobular inflammation, with or without fibrosis, characterized by the risk of possible progression to liver cirrhosis and, possibly, to hepatocellular carcinoma. Hepatic steatosis is an independent risk factor for all liver alterations that characterize NAFLD, particularly inflammation and fibrosis. Globally, the prevalence of NAFLD, assessed by liver ultrasound, is on average 30.69%. In the last 10-15 years its prevalence, always assessed by liver ultrasound, has increased by +38.7%, going from 25.16% in the period 1990-2006 to 34.59% in the period 2016 -2019. If the highest prevalence of NAFLD is in Latin America (44.37%), it is 31.2% in North America and 25.1% in Western Europe. Studies conducted in Italy indicate a prevalence of NAFLD of 22.5 -27.0% in the general population, with a 2 % prevalence of fibrosis, diagnosed by non-invasive means. In patients with NAFLD, the mortality rate for all causes is equal to 12.60 per 1000 person-years, while that from cardiovascular causes, extra-hepatic tumors and liver-related causes is, respectively, equal to 4.20 per 1000 people/year,2.83 per 1000 person-years and 0.92 per 1000 person-years. In the onset and progression of NAFLD, alongside the role of insulin resistance and generalized inflammation, pathways of relationship between the intestine and the liver are also involved, in turn influenced by the type of intestinal microbiota. Age also influences the evolution of these liver diseases and, as they advance, the prevalence of NAFLD and related fibrosis increases. Furthermore, the prevalence of NAFLD increases in parallel with the increase in the presence of metabolic alterations such as dyslipidemia and type 2 diabetes mellitus. Al though the main causes of death in people affected by NAFLD are cardiovascular diseases and extrahepatic malignancies, fibrosis hepatic advanced appears to be "in itself" an unfavorable prognostic marker for the outcomes of liver diseases. In the absence of officially approved pharmacological therapies for the treatment of NAFLD, European clinical guidelines and systematic reviews with meta-analyses recommend lifestyle-based interventions. These mainly involve quantitative and qualitative changes in diet and an increase in regular physical exercise, considered together as the best therapeutic strategy for the management of patients with NAFLD. Diet can improve NAFLD by reducing the amount of liver fat and insulin resistance, while exercise promotes weight loss and improves liver function. The diet therefore acts as an effective prevention tool in combating metabolic-related diseases, such as NAFLD. In particular, fruit with its high content of polyphenols has been shown to exert a high anti-inflammatory, antithrombotic and antiproliferative action. Recently, it has been demonstrated in vitro on human colorectal carcinoma cell lines that table grape polyphenolic extracts can inhibit cell proliferation and growth as well as influence the morphology of the cell, inhibiting its migration capacity. These data support the idea that grapes, as a nutraceutical, can have health effects and prevent the mechanisms of oxidation, cellular inflammation and metastasis. Furthermore, a clinical trial on healthy volunteers demonstrated that the daily intake of grapes can down-regulate the expression of small single-stranded non-coding RNA molecules, called miRNAs, metabolically associated with the "metabolism of cancer of the gastrointestinal tract". Therefore, their inhibition would lead to preventing the transformation of the cell in a neoplastic sense. Recently, among food antioxidants, particular attention has been paid to lycopene, a phytochemical belonging to the carotenoid family. Lycopene is found abundantly in vegetables and is responsible for their characteristic color. Its bioactive properties are influenced by many factors, such as bioavailability, metabolism and interaction with other carotenoids. In nature, lycopene occurs in its trans isoform, which is responsible for its bioavailability in the presence of elevated temperatures (trans to cis). It is assumed that due to the cis form, lycopene is more highly bioavailable. Since it is a fat-soluble substance, the associated consumption of dietary fats amplifies its bioavailability. The main sources of lycopene in the Mediterranean diet are tomatoes and tomato products. In the European population, lycopene consumption varies between 5 and 7 mg/day and over 80% of its daily intake comes from tomato-based products. Several studies have demonstrated the beneficial effects of lycopene on health resulting from its structure and lipophilic nature, which determines its anti-inflammatory and antioxidant effects. Recent studies suggest that changes in the intestinal microbiota may represent a new strategy to prevent or treat NAFLD and it is now known that a specific diet and regular physical exercise can induce changes in the composition of the intestinal microbiota, which in turn contribute to an increase of insulin. sensitivity and hepatic lipid metabolism. Furthermore, a recent prospective study observed that NAFLD is associated with an increase in 20% risk of developing irritable bowel syndrome (IBS), a disease not due to organic lesions and characterized by abdominal pain and abdominal swelling, associated with frequent diarrhea or prolonged constipation, often in periodic alternation, relief of symptoms after defecation, modification of the frequency of bowel movements and/or consistency of the stool. IBS affects 4.1% to 10.1% of the general population and is responsible for a reduction in the quality of life and an increase in healthcare costs and, therefore, it is a priority to identify lifestyle factors that can improve the IBS symptoms.Since NAFLD and IBS share variations in circulating levels of proinflammatory cytokines(increased tumor necrosis factor (TNF)-α, interleukin (IL)-6, etc and reduction in IL-10),cross-talk between the liver- brain-gut and gut-liver axis, dysfunction of the intestinal microbiota, alterations of the intestinal barrier and alterations of intestinal motility, it cannot be excluded that the improvement or worsening of NAFLD may favor the improvement or worsening of IBS. Furthermore, it has been seen that the mechanisms that regulate intestinal barrier function are altered in NAFLD and this situation represents an aggravating factor. Inflammation associated with liver disease may in turn play a significant role in the development of gastrointestinal (GI) disorders. It is a chronic low intensity state that involves the entire organism. Inflammation is related to an increase in inflammatory cytokines in tissues which,by activating immune responses, alter cellular metabolic pathways. In general, chronic low-level inflammation and the variation in the concentration of metabolic hormones, together with the distribution of adipose tissue in the abdominal cavity and alterations in the bacterial populations of the intestinal microbiota, represent the main factors involved in the development of gastrointestinal pathologies that they develop precisely through alterations of the intestinal barrier. The intestinal barrier can be considered a dynamic system that also responds to humoral signals and to a series of different molecules which, in various ways, are called into question. Among these, it is important to consider zonulin, a GI peptide capable of modulating the functionality of tight junctions (TJs). Serum zonulin levels have been shown to correlate with the extent of mucosal barrier impairment. Cellular and/or TJ damage can have a significant impact on the correct function of intestinal permeability (PI). The I-FABPs (intestinal fatty acid binding proteins) are cytosolic proteins present in epithelial cells responsible for the transport of fatty acids. They can be released into the circulation following the loss of membrane integrity and are rapidly eliminated in the urine; therefore, they represent non-invasive markers of early damage at the cellular level of the intestinal epithelium. Likewise the heck oxidase (DAO), an intracellular enzyme with a high level of activity in the upper layer of the intestinal villi, is considered a serum marker of intestinal epithelial integrity. Alterations in the barrier function can favor the entry of bacteria and their products. Lipopolysaccharide (LPS), a predominant component in the cell wall of Gram-negative bacteria, has been found to influence barrier function. Under physiological conditions, LPS is unable to cross intact epithelium, but in the presence of reduced epithelial integrity, it can cross the GI barrier. Tryptophan is an essential amino acid for humans since it is not synthesized in humans; commensal bacteria catabolize tryptophan into various derivatives, which are absorbed by the intestine and eliminated in the urine. Two of these compounds, indoxyl sulfate and 3-methyl-indole (skatole), are currently used to diagnose small intestinal and colon dysbiosis. The study will be a randomized and controlled study with nutritional intervention: 60 subjects, suffering from NAFLD, will be enrolled and randomly assigned to the two groups of the study: Group A (Treatment): the subjects enrolled in this group will have to consume 200g of fresh raw tomatoes and 50g of sauce per day Group B (Control): the subjects enrolled in this group must comply with one diet free of tomatoes All groups will be provided with instructions on the diet to follow, depending on the arm to which they will be assigned. The treatment will last 6 weeks and, in addition to the V0 (Screening Visit), 2 other visits (V1-V2) are planned. At V0, will be subjected to: Medical history; Fibroscan, to evaluate the degree of NAFLD; - Detection of anthropometric characteristics; BIA Test. Enrolled patients will be invited to return for V1, after 7 days to receive the personalized diet. In V1, they will be subjected to blood sampling and body composition assessment using DEXA. Whole blood and serum samples will be used for the measurement of routine blood chemistry parameters and nutritional, metabolic and cardiovascular risk parameters. The HOMA index and the degree of hepatic steatosis FLI and FIB-4 will be calculated. The main adipokines (leptin, RBP-4, visfatin), the main hepatic growth factors (HGF, Fetuin-A, FGF21, FGF19, PAI-1) and the main proinflammatory cytokines (highly sensitive C-reactive protein, IL-6 , IL-8, TNF-α) and anti-inflammatory (IL-4); other aliquots will be used for lipidomics and biochemical analyses. On the serum samples taken from the subjects at times V1 and V2, the antioxidant activity and the inflammatory state and the serum levels of the deglycant enzymes will be evaluated, through the study of the SOD1 and SOD2 enzymes, IL-6, TNF-alpha and the Fructosamine 3-Kinase and glyoxalase. The study subjects will also be asked to bring two stool samples for the evaluation of the intestinal microbiota and for the measurement of fecal Zonulin and the fecal metabolome, as well as two urine samples. Optional visits Patients enrolled in the study will be asked, on an optional and voluntary basis, to undergo two outpatient sigmoidoscopies with cold biopsies if they wish to undergo. A sigmoidoscopy after the screening visit, the second would be performed at the end of 6 weeks.
Phase
N/ASpan
53 weeksSponsor
Azienda Ospedaliera Specializzata in Gastroenterologia Saverio de BellisRecruiting
Healthy Volunteers
Effect of VLCD on the Reduction of Liver Steatosis and Fibrosis in Subjects With Obesity and NAFLD
Study design: The investigators plan to perform a controlled, non-randomized, open-label, pilot clinical trial to evaluate the effect of an 8-week VLCD intervention on NAFLD. The main variable of this study is the magnitude of liver steatosis and fibrosis assessed non-invasively by elastography. The investigators will compare these variables before and after the VLCD intervention. Hereby, it is hypothesized that VLCD reduces liver steatosis and fibrosis. Study Subjects: Potential adult participants with obesity [age ≥ 18 years old; body mass index (BMI) ≥ 30 kg/m2 and ≤ 50 kg/m2] will be recruited at the Weight Management Clinic, at the Diabetes Center and at the Digestive Health Center, all at University of Iowa Health Care (UIHC). The investigators will invite potential participants with negative tests for viral hepatitis C and autoimmune hepatitis, and elastography results positive for fibrosis grade F0 through F4 and/or steatosis grade S1 through S3 within the last 6 months. The above tests, along with complete blood count (CBC), basic metabolic profile (BMP), thyroid stimulating hormone (TSH) with reflex free thyroxine (free T4) and hemoglobin A1c are routinely obtained as part of the standard of care at the recruitment clinics. Oral health status of these patients will be obtained from the available dental charts, if not, a dental examination will be performed. With Institutional Board Review (IRB) authorization, the investigators will interrogate the charts to verify whether subjects meet criteria for participation. Case managers will contact potential participants by telephone, electronic mail or letter. Detailed sessions: Week 0 Visit (enrolment visit): Subjects who meet the above criteria will be invited for week 0 visit at UIHC Preventive Intervention Center. Subjects will fast for 12 hours for week 0 visit. After signing informed consent, the inclusion/exclusion criteria will be reviewed again. Clinical history and physical exam will be charted from the last clinical note. Subjects will fill the AUDIT C, a screening questionnaire for alcohol consumption. Vitals signs (that is, seated and standing blood pressure and heart rate, ambient air pulse saturation of O2, weight, height, and neck and waist circumferences). Blood samples for sodium, potassium, creatinine, CBC, AST, ALT, triglycerides, glucose, insulin, A1c (table 1), miR, and platelets will also be drawn during week 0 visit. Female participants at reproductive age will be asked to provide urine sample for pregnancy test. Unstimulated saliva will be collected from the participants by asking them to spit into a collection tube. Supplies for stool collection with instructions for sample return will be provided for assessment of baseline fecal microbiome testing. Stools samples should be returned to the research center before VLCD initiation. The participant will also meet the research manager for education about the VLCD and lower calorie diet during week 0 visit. The research manager will dispense 2-week worth of Optifast® replacement meals. Week 2 Visit: At the end of week 2, the participant who consumes VLCD, but not a lower calorie diet, will return to the UIHC Preventive Intervention Center, when vital signs will be assessed and blood samples for laboratory tests will be drawn (table 1). On week 2 visit, sodium, potassium and creatinine will be assessed. Participants will complete of an adverse event questionnaire. Very low-calorie diets will be dispensed at week 2 visit. Week 4 Visit: At the end of week 4, the participant who consumes VLCD, but not a lower calorie diet, will return to the UIHC Preventive Intervention Center, when vital signs will be assessed and blood samples for laboratory tests will be drawn (table 1). On week 4 visit, sodium, potassium, creatinine, ALT, AST, and uric acid will be assessed. Participants will complete of an adverse event questionnaire. Very low-calorie diets will be dispensed at week 4 visit. Week 8 Visit (closing visit): At the end of week 8, the participant who consumes VLCD or a lower calorie diet will return to the UIHC Preventive Intervention Center for week 8 visit. Subjects will fast 12 hours for week 8 visit when saliva and blood samples for sodium, potassium, creatinine, CBC, ALT, AST, triglycerides, glucose, insulin, A1c (table 1) and miR will be collected. The participant will be instructed to bring a stool sample for microbiome analysis using collection supplies dispensed beforehand. The post-VLCD elastography will be performed during the final visit. Participants will complete of an adverse event questionnaire. The participant will also meet the research manager and receive education about transitioning from VLCD to a low calorie, low fat diet during the closure visit. The participants will be recommended to weight themselves weekly after the VLCD intervention. The research manager will contact the participant by telephone or video-call to assess adherence to low calorie, low fat diet and to review the weight trajectory 1 month after termination of the study. Telephone and/or video-call contacts: Between week 0 and 8 visits, the research manager will contact the participant by telephone or video-call on a weekly basis for diet compliance, and assessment of adherence, response and adverse events of VLCD or lower calorie diet for 8 weeks, and then for 4 weeks after termination of the diet. Therefore, the total time of participation in the study is 12 weeks. Very low-calorie diet treatment: The VLCD program will last 8 weeks and then will be followed by a gradual re-introduction of food through the next 1 month. The only sources of nutrition during this phase are the Optifast® products providing up to 800 kcal per day. Two liters (67.63 fl oz) of water should also be consumed each day. Participants will receive Optifast® replacement meals at no cost. The replacement meals will be dispensed at the UIHC Preventive Intervention Center on weeks 0, 2, and 4. Participants will be instructed to use 5 replacement meals per day (800 kcal total) with 40% of calories as protein, 40% as carbohydrate, and 20% as fat (Ard, Lewis et al. 2019).
Phase
N/ASpan
170 weeksSponsor
University of IowaRecruiting
The Role of Immune Semaphorins in Steatotic Liver Disease and Sepsis
The liver, with its ability to produce acute phase proteins, complement and cytokines, plays a central role in regulating inflammation. A balanced pro- and anti-inflammatory liver response results in bacterial clearance and resolution of inflammation. Steatotic liver disease (SLD) is the most common chronic liver disease associated with systemic changes in immune response. Although there are numerous immunological links between sepsis and SLD, there is a significant gap in knowledge regarding the role of SLD in sepsis. Semaphorins were recently recognized as one of the key regulators of immune responses; while some suppress immune cells activation, proliferation and production of inflammatory cytokines, others stimulate immune responses. Semaphorins were recently shown to be associated with pathogenesis of viral hepatitis, SLD and progression of fibrosis. However, their role in sepsis is unknown. The hypothesis of this project is that semaphorins are regulators of inflammation in patients with SLD that have impact on sepsis outcome.
Phase
N/ASpan
113 weeksSponsor
University Hospital for Infectious Diseases, CroatiaRecruiting
Comparison of iLivTouch and FibroScan for the Assessment of Liver Fibrosis and Steatosis in Adult Patients in the US
Clinical phase: Phase IV investigator-initiated study Study centers planned: Approximately 4 centers in different regions of the USA Objectives: 1. Primary Objectives To evaluate the consistency of Liver Stiffness Measurement (LSM) and Ultrasound/Controlled Attenuation Parameters (UAP/CAP) between iLivTouch-FT9000 and FibroScan 530 devices. 2. Secondary Objectives 1. To compare the operational features of the two devices, reflected in the success rate of examination and number of effective examinations. 2. To compare LSM obtained from each device with liver stiffness estimated by APRI, FIB-4, and SAFE scores. 3. The number of adverse events, serious events, and percentage of subjects with events will be calculated for AE, SAE, AE of special interest, and AE leading to study withdrawal.
Phase
N/ASpan
80 weeksSponsor
New Discovery LLCRecruiting
Multi-parametric Magnetic Resonance Imaging for the Precise Diagnosis and Quantitative Study of Liver Steatosis, Inflammation, and Fibrosis in Chronic Liver Disease.
Patients with chronic hepatitis have increased risks of liver damage, including fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma and end-stage liver disease requiring liver transplantation. These diseases are/will be the source of enormous health care costs and morbidity/mortality in the China. Most hepatologists still rely on liver biopsy findings in patients newly diagnosed with chronic hepatitis, which enables the assessment of liver damage (fibrosis and inflammation). Liver biopsy has limitations, including cost, invasiveness, poor patient acceptance, limited sampling, inter-observer variability and is difficult to repeat. Non invasive tests to capture the extent of liver damage at a larger scale are urgently needed. These will gain more acceptance among patients and hepatologists. In this proposal, the investigators would like to test and validate non invasive MRI methods based on advanced MR elastography and MRI-PDFF techniques for the detection of fibrosis, cirrhosis and liver fat content in patients with chronic hepatitis. In order to improve the diagnostic performance of MRI, the investigators would like to build and validate a predictive model based on advanced functional MRI metrics (storage modulus, loss modulus and damping ratio [DR]) by follow up every 6 month. If validated, this novel non invasive algorithm will not only decreases the number of liver biopsies, but also enable earlier diagnosis of liver fibrosis when antiviral treatment is more effective, and enable a comprehensive evaluation of the liver (to assess for cirrhosis, portal hypertension and hepatocellular cancer). This study is aimed to evaluate whether the change of liver stiffness assessed by MRE can predict treatment effectiveness in chronic liver disease treatment by follow up every 6 month.
Phase
N/ASpan
168 weeksSponsor
Shengjing HospitalRecruiting