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Combined cranberry supplementation and weight loss diet in non-alcoholic fatty liver disease: a double-blind placebo-controlled randomized clinical trial.
Hormoznejad, R, Mohammad Shahi, M, Rahim, F, Helli, B, Alavinejad, P, Sharhani, A
International journal of food sciences and nutrition. 2020;(8):991-1000
Abstract
A double-blind placebo-controlled randomised clinical trial was conducted on 41 patients with non-alcoholic fatty liver disease (NAFLD). Participants were randomly allocated to receive either a cranberry supplement or a placebo for 12 weeks. Both groups were assigned to follow a weight loss diet. At the end of the study, alanine aminotransferase and insulin decreased significantly in both groups (p < .05); however, this reduction was significantly greater in the cranberry group than in the placebo group (p < .05). Significant improvements in insulin resistance were observed in the cranberry group and between the two groups (p < .001 and p = .020, respectively). Also, there was an improvement in steatosis grade and anthropometric measurements in both groups (p < .05), and there was no significant difference between the two groups in regard to these factors (p > .05). It seems that 288 mg of cranberry extract might improve managing NAFLD, which is equivalent to 26 g of dried cranberry.
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Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.
Younossi, ZM, Ratziu, V, Loomba, R, Rinella, M, Anstee, QM, Goodman, Z, Bedossa, P, Geier, A, Beckebaum, S, Newsome, PN, et al
Lancet (London, England). 2019;(10215):2184-2196
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Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING Intercept Pharmaceuticals.
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Liver Iron Load Influences Hepatic Fat Fraction in End-Stage Renal Disease Patients on Dialysis: A Proof of Concept Study.
Rostoker, G, Loridon, C, Griuncelli, M, Rabaté, C, Lepeytre, F, Ureña-Torres, P, Issad, B, Ghali, N, Cohen, Y
EBioMedicine. 2019;:461-471
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a spectrum of diseases including steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and end-stage liver failure. Hepatic iron accumulation has been linked to hepatic fibrosis severity in NASH and NAFLD. Iron overload induced by parenteral (IV) iron therapy is a potential clinical problem in dialysis patients. We analyzed the hypothetical triggering and aggravating role of iron on NAFLD in patients on dialysis. METHODS Liver iron concentration (LIC) and hepatic proton density fat fraction (PDFF) were analyzed prospectively in 68 dialysis patients by magnetic resonance imaging (MRI). Follow up of LIC and PDFF was performed in 17 dialysis patients during iron therapy. FINDINGS PDFF differed significantly among dialysis patients classified according to LIC: patients with moderate or severe iron overload had increased fat fraction (PDFF: 7.9% (0.5-14.8%)) when compared to those with normal LIC (PDFF: 5% (0.27-11%)) or mild iron overload (PDFF: 5% (0.30-11.6%); P = 0.0049). PDFF correlated with LIC, and ferritin and body mass index. In seven patients monitored during IV iron therapy, LIC and PDFF increased concomitantly (PDFF: initial 2.5%, final 8%, P = 0.0156; LIC: initial 20 μmol/g, final 160 μmol/g: P = 0.0156), whereas in ten patients with iron overload, PDFF decreased after IV iron withdrawal or major dose reduction (initial: 8%, final: 4%; P = 0.0098) in parallel with LIC (initial: 195 μmol/g, final: 45 μmol/g; P = 0.002). INTERPRETATION Liver iron load influences hepatic fat fraction in dialysis patients. Iron overload induced by iron therapy may aggravate or trigger NAFLD in dialysis patients. TRIAL REGISTRATION NUMBER (ISRCTN): 80100088.
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Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease.
Inoue, M, Hayashi, A, Taguchi, T, Arai, R, Sasaki, S, Takano, K, Inoue, Y, Shichiri, M
Journal of diabetes investigation. 2019;(4):1004-1011
Abstract
AIMS/INTRODUCTION Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor. METHODS AND MATERIALS In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease. RESULTS Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01). CONCLUSIONS Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.
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Multi-domain analysis of microvascular flow motion dynamics in NAFLD.
Chipperfield, AJ, Thanaj, M, Scorletti, E, Byrne, CD, Clough, GF
Microcirculation (New York, N.Y. : 1994). 2019;(5):e12538
Abstract
OBJECTIVE To determine whether analysis of microvascular network perfusion using complexity-based methods can discriminate between groups of individuals at an increased risk of developing CVD. METHODS Data were obtained from laser Doppler recordings of skin blood flux at the forearm in 50 participants with non-alcoholic fatty liver disease grouped for absence (n = 28) or presence (n = 14) of type 2 diabetes and use of calcium channel blocker medication (n = 8). Power spectral density was evaluated and Lempel-Ziv complexity determined to quantify signal information content at single and multiple time-scales to account for the different processes modulating network perfusion. RESULTS Complexity was associated with dilatory capacity and respiration and negatively with baseline blood flux and cardiac band power. The relationship between the modulators of flowmotion and complexity of blood flux is shown to change with time-scale improving discrimination between groups. Multiscale Lempel-Ziv achieved best classification accuracy of 86.1%. CONCLUSIONS Time and frequency domain measures alone are insufficient to discriminate between groups. As cardiovascular disease risk increases, the degree of complexity of the blood flux signal reduces, indicative of a reduced temporal activity and heterogeneous distribution of blood flow within the microvascular network sampled. Complexity-based methods, particularly multiscale variants, are shown to have good discriminatory capabilities.
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Nigella sativa and inflammatory biomarkers in patients with non-alcoholic fatty liver disease: Results from a randomized, double-blind, placebo-controlled, clinical trial.
Darand, M, Darabi, Z, Yari, Z, Saadati, S, Hedayati, M, Khoncheh, A, Hosseini-Ahangar, B, Alavian, SM, Hekmatdoost, A
Complementary therapies in medicine. 2019;:204-209
Abstract
OBJECTIVE The aim of this study was to assess the effects of Nigella sativa consumption on inflammatory biomarkers in patients with Non-alcoholic fatty liver disease (NAFLD). METHODS This is a randomized, double-blind, placebo-controlled clinical trial. Fifty NAFLD patients were assigned to receive either two gram/day Nigella sativa seed as Nigella sativa group (NSG), or two gram/day starch as placebo group (PG) for 12 weeks. RESULTS At the end of the study, the serum levels of tumor necrosis factor-α (TNF-α) decreased significantly compared with the beginning of the study in both groups, while the levels of high sensitive C reactive protein (hs-CRP) and nuclear factor kappa-B (NF-κB) only decreased significantly in the NSG (P 0 < 0.05). Only reduction in the serum levels of TNF-α was significantly more in NSG compared to the PG (P = 0.001). After adjusting the effects of confounding factors, the results remained unchanged. According to Fibroscan exam, hepatic steatosis and its percentage decreased significantly only in the NSG (P 0 < 0.005); however, the changes were not significantly different between two groups. After adjusting for confounding factors, only steatosis percentage reduction was significantly more in the NSG compared to PG (P = 0.005). CONCLUSION Our results have shown that two gram/day consumption of Nigella sativa can reduce inflammatory biomarkers in patients with NAFLD. Further studies with different doses are highly recommended to find the optimal dosage.
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Safety, tolerability and pharmacodynamics of apical sodium-dependent bile acid transporter inhibition with volixibat in healthy adults and patients with type 2 diabetes mellitus: a randomised placebo-controlled trial.
Tiessen, RG, Kennedy, CA, Keller, BT, Levin, N, Acevedo, L, Gedulin, B, van Vliet, AA, Dorenbaum, A, Palmer, M
BMC gastroenterology. 2018;(1):3
Abstract
BACKGROUND Pathogenesis in non-alcoholic steatohepatitis (NASH) involves abnormal cholesterol metabolism and hepatic accumulation of toxic free cholesterol. Apical sodium-dependent bile acid transporter (ASBT) inhibition in the terminal ileum may facilitate removal of free cholesterol from the liver by reducing recirculation of bile acids (BAs) to the liver, thereby stimulating new BA synthesis from cholesterol. The aim of this phase 1 study in adult healthy volunteers (HVs) and patients with type 2 diabetes mellitus (T2DM) was to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of ASBT inhibition with volixibat (SHP626; formerly LUM002). METHODS Participants were randomised 3:1 to receive once-daily oral volixibat (0.5 mg, 1 mg, 5 mg or 10 mg) or placebo for 28 days in two cohorts (HV and T2DM). Assessments included safety, faecal BA and serum 7α-hydroxy-4-cholesten-3-one (C4; BA synthesis biomarker). RESULTS Sixty-one individuals were randomised (HVs: placebo, n = 12; volixibat, n = 38; T2DM: placebo, n = 3; volixibat, n = 8). No deaths or treatment-related serious adverse events were reported. Mild or moderate gastrointestinal adverse events were those most frequently reported with volixibat. With volixibat, mean total faecal BA excretion on day 28 was ~1.6-3.2 times higher in HVs (643.73-1239.3 μmol/24 h) and ~8 times higher in T2DM (1786.0 μmol/24 h) than with placebo (HVs: 386.93 μmol/24 h; T2DM: 220.00 μmol/24 h). With volixibat, mean C4 concentrations increased by ~1.3-5.3-fold from baseline to day 28 in HVs and by twofold in T2DM. CONCLUSIONS Volixibat was generally well tolerated. Increased faecal BA excretion and serum C4 levels support the mechanistic rationale for exploring ASBT inhibition in NASH. The study was registered with the Dutch clinical trial authority (Centrale Commissie Mensgebonden Onderzoek; trial registration number NL44732.056.13; registered 24 May 2013).
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Vitamin D supplementation for the treatment of non-alcoholic fatty liver disease: A randomized double blind placebo controlled trial.
Dabbaghmanesh, MH, Danafar, F, Eshraghian, A, Omrani, GR
Diabetes & metabolic syndrome. 2018;(4):513-517
Abstract
BACKGROUND Low serum vitamin D has been associated with metabolic syndrome and Non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the impact of vitamin D supplementation in treatment of patients with NAFLD. METHODS In a double blind, randomized, placebo controlled trial patients with NAFLD were randomized to receive one weekly pearl of placebo, 50,000 U vitamin D3 (cholecalciferol) pearl per week and 0.25 mg calcitriol (1,25 dihydroxycholecalciferol) pearl per day for 3 months. RESULTS 106 NAFLD patients were randomized to receive calcitriol, vitamin D3 and placebo pearls for 12 weeks and data for 91 patients were analyzed. After 12 weeks of treatment, serum alkaline phosphatase levels was significantly decreased from baseline levels in vitamin D and calcitriol treated groups (P < 0.05). Serum and gamma glutamyl transferase (GGT) level was also significantly decreased compared to the baseline levels after 12 weeks of treatment with vitamin D. There was no statistically significant difference between placebo, calcitriol, vitamin D groups in terms of serum aminotransferase, alkaline phosphatase, serum GGT and lipid profile (P > 0.05). CONCLUSION While significant reduction of serum alkaline phosphatase and GGT were seen with vitamin D and calcitriol supplementation from baseline levels, no beneficial effects was seen when comparing vitamin D, calcitriol and placebo groups at the end of trial.
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A Customized Online Nutrition Guidance System Is Effective for Treating Patients with Nonalcoholic Fatty Liver Disease by Supporting Continuity of Diet Therapy at Home: A Pilot Study.
Aoyama, T, Takada, H, Uchiyama, A, Kon, K, Yamashina, S, Ikejima, K, Ban, H, Watanabe, S
Internal medicine (Tokyo, Japan). 2017;(13):1651-1656
Abstract
Continuity is required for diet therapy, but it depends on patients. We examined the utility of a new tool, the customized online nutrition guidance system, in patients with nonalcoholic fatty liver disease (NAFLD). Seven patients plotted their body weight (BW) and marked a customized task card on completion for 90 days on a website. The instructors encouraged them by e-mail. BW, serum transaminase levels, and system usage were evaluated. The results showed that BW and serum alanine aminotransferase levels were significantly lower than at baseline. BW and task visualization as well as encouragement by e-mails were effective in ensuring continuity. Thus, this system is effective in keeping NAFLD patients motivated to continue their diet therapy.
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High-risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial.
Puchner, SB, Lu, MT, Mayrhofer, T, Liu, T, Pursnani, A, Ghoshhajra, BB, Truong, QA, Wiviott, SD, Fleg, JL, Hoffmann, U, et al
Radiology. 2015;(3):693-701
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Abstract
PURPOSE To determine the association between nonalcoholic fatty liver disease (NAFLD) and the presence of high-risk coronary atherosclerotic plaque as assessed with coronary computed tomographic (CT) angiography. MATERIALS AND METHODS This study was approved by the local ethics committees; informed consent was obtained. Patients randomized to the coronary CT angiography arm of the Rule Out Myocardial Infarction using Computer Assisted Tomography, or ROMICAT, II trial who underwent both nonenhanced CT to assess calcium score and contrast material-enhanced coronary CT angiography were included. Readers assessed coronary CT angiography images for the presence of coronary plaque, significant stenosis (≥50%), and high-risk plaque features (positive remodeling, CT attenuation < 30 HU, napkin-ring sign, spotty calcium). NAFLD was defined as hepatic steatosis at nonenhanced CT (liver minus spleen CT attenuation < 1 HU) without evidence of clinical liver disease, liver cirrhosis, or alcohol abuse. To determine the association between high-risk plaque and NAFLD, univariable and multivariable logistic regression analyses were performed, with high-risk plaque as a dependent variable and NAFLD, traditional risk factors, and extent of coronary atherosclerosis as independent variables. RESULTS Overall, 182 (40.9%) of 445 patients had CT evidence of NAFLD. High-risk plaque was more frequent in patients with NAFLD than in patients without NAFLD (59.3% vs 19.0%, respectively; P < .001). The association between NAFLD and high-risk plaque (odds ratio, 2.13; 95% confidence interval: 1.18, 3.85) persisted after adjusting for the extent and severity of coronary atherosclerosis and traditional risk factors. CONCLUSION NAFLD is associated with advanced high-risk coronary plaque, independent of traditional cardiovascular risk factors and the extent and severity of coronary artery disease.