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1.
Statin Therapy Does Not Reduce Liver Fat Scores in Patients Receiving Antiretroviral Therapy for HIV Infection.
El Kamari, V, Hileman, CO, Gholam, PM, Kulkarni, M, Funderburg, N, McComsey, GA
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019;(3):536-542.e1
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Abstract
BACKGROUND & AIMS Therapies are needed to limit progression of fatty liver diseases in patients with human immunodeficiency virus (HIV) infection. We analyzed data from a prospective study of the effects of rosuvastatin (a statin) on hepatic steatosis in HIV-positive adults. METHODS We performed a secondary analysis of data from a double-blind trial of adult patients with HIV infection (78% male; 68% African American; mean age, 46 y; body mass index, 29 kg/m2; HIV1 RNA < 1000 copies/mL; low-density lipoprotein cholesterol, <130 mg/dL) receiving antiretroviral therapy. The patients were randomly assigned to groups given 10 mg daily rosuvastatin (n = 72) or placebo (n = 75). Demographic and clinical data were collected, and blood samples were analyzed. Changes in liver fat score (LFS, a composite score calculated from metabolic and liver function parameters) and markers of systemic inflammation and immune activation were assessed through 96 weeks of drug or placebo administration. We performed multivariable linear and logistic regressions to study relationships among variables. RESULTS The placebo and rosuvastatin groups each had significant increases in LFS, compared with baseline, at 96 weeks (P = .01 and P < .01; P = .49 for difference increase between groups). Baseline LFS was independently associated with blood level of C-X-C motif chemokine ligand 10 (P = .04) and the soluble CD163 molecule (P = .01). After we adjusted for baseline characteristics, an increase in LFS over time was significantly associated with the blood level of C-X-C motif chemokine ligand 10 (P = .04), insulin resistance (P < .01), and viral load (P = .02), but not rosuvastatin use (P = .06). CONCLUSIONS In a secondary analysis of data from a trial of patients receiving treatment for HIV infection, hepatic steatosis increased over time, regardless of statin treatment, and was independently associated with markers of immune activation. Patients who received rosuvastatin appeared to have a nonsignificant increase in hepatic steatosis over 96 weeks. Despite their ability to reduce the risk of cardiovascular disease, statins do not appear to reduce hepatic steatosis. Clinicaltrials.gov no: NCT01218802.
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Macronutrients and the Adipose-Liver Axis in Obesity and Fatty Liver.
Duwaerts, CC, Maher, JJ
Cellular and molecular gastroenterology and hepatology. 2019;(4):749-761
Abstract
Macronutrient metabolism is a highly orchestrated process, with adipose tissue and liver each playing central roles in nutrient uptake, processing, transport, and storage. These 2 tissues form an important metabolic circuit, particularly as it relates to lipids as the primary storage form of excess energy. The function of the circuit is influenced by many factors, including the quantity and type of nutrients consumed and their impact on the overall health of the tissues. In this review we begin with a brief summary of the homeostatic disposition of lipids between adipose tissue and liver and how these processes can become dysregulated in obesity. We then explore how specific dietary nutrients and nutrient combinations can exert unique influences on the liver-adipose tissue axis.
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Improvement in liver steatosis after the switch from a ritonavir-boosted protease inhibitor to raltegravir in HIV-infected patients with non-alcoholic fatty liver disease.
Calza, L, Colangeli, V, Borderi, M, Coladonato, S, Tazza, B, Fornaro, G, Badia, L, Guardigni, V, Verucchi, G, Viale, P
Infectious diseases (London, England). 2019;(8):593-601
Abstract
Background: The ritonavir-boosted protease inhibitor (PI/r) use has been associated with several metabolic abnormalities, and the non-alcoholic fatty liver disease (NAFLD) is becoming a very frequent comorbidity among HIV-infected patients. Methods: We performed an observational, prospective study of HIV-infected patients with NAFLD, receiving one PI/r plus two nucleoside analogues, who switched from the PI/r to raltegravir or were treated only with lifestyle modification, maintaining antiretroviral therapy unchanged. Changes in liver steatosis after 12 months were evaluated by transient elastography and measurement of controlled attenuation parameter (CAP). Results: As a whole, 61 patients (46 males; median age, 55.4 years) were enrolled, and 32 of them have been switched from PI/r to raltegravir. At baseline, median CAP was 259 dB/m, 28 (45.9%) subjects had a moderate-to-severe hepatic steatosis (CAP ≥260 dB/m), and 19 patients (31.1%) had elevated aminotransferases. Type-2 diabetes mellitus was present in 5 persons, and chronic HCV coinfection in 4. At month 12, the median decrease in CAP values was -27 dB/m in patients switched to raltegravir and -11 dB/m in those with unchanged cART (p = .021). The number of patients with CAP ≥260 dB/m decreased from 16 to 6 (-62.5%) in patients switched to raltegravir and from 12 to 8 (-33.3%) in the other group (p = .037). Conclusion: After 12 months, HIV-infected patients with NAFLD switching from a PI/r to raltegravir showed a significantly greater decrease in the hepatic steatosis degreee in comparison with those with unchanged cART and treated only with lifestyle modification.
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Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: Think out of the box!
Ranjbar, G, Mikhailidis, DP, Sahebkar, A
Metabolism: clinical and experimental. 2019;:154001
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.
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Probiotic supplementation increases obesity with no detectable effects on liver fat or gut microbiota in obese Hispanic adolescents: a 16-week, randomized, placebo-controlled trial.
Jones, RB, Alderete, TL, Martin, AA, Geary, BA, Hwang, DH, Palmer, SL, Goran, MI
Pediatric obesity. 2018;(11):705-714
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Abstract
BACKGROUND Numerous studies have shown that there are links between obesity, liver fat and the gut microbiome. However, there are mixed results on whether probiotics could impact the gut microbiome and/or help to decrease liver fat and obesity outcomes. OBJECTIVE This study aimed to determine whether a probiotic supplement (VSL#3® ) intervention altered gut microbiota and/or gut hormones associated with appetite regulation. The secondary aim of this study was to determine whether VSL#3® altered body composition and liver fat and fibrosis. METHODS We conducted a double-blind, randomized placebo-controlled trial in 19 obese Latino adolescents. The intervention consisted of three packets per day of VSL#3® or a matched placebo for 16 weeks. Pre-intervention and post-intervention measures included gut microbial abundance, gut appetite regulating hormones, anthropometrics, body composition, liver fat and liver fibrosis. We conducted linear models to determine whether there were any significant differences in the changes in these outcomes following VSL#3® intervention. RESULTS Compared with placebo, adolescents that received VSL#3 had significant increases in total adiposity (%) (+1.7 ± 0.6 vs. -1.3 ± 0.5, p < 0.01) and trunk adiposity (%) (+3.3 ± 0.8 vs. -1.8 ± 0.8, p < 0.01) with no significant effects on liver fat/fibrosis, insulin/glucose, gut microbial abundances or gut hormones. CONCLUSION VSL#3 supplementation may lead to increased adiposity in obese Latino adolescents with no significant detectable changes in gut microbiota, gut appetite-regulating hormones, liver fat and fibrosis and dietary intake. However, it is important to note that recruitment efforts were terminated early and the sample size fell short of what was planned for this trial.
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Effects of Delta-tocotrienol Supplementation on Liver Enzymes, Inflammation, Oxidative stress and Hepatic Steatosis in Patients with Nonalcoholic Fatty Liver Disease.
Pervez, MA, Khan, DA, Ijaz, A, Khan, S
The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology. 2018;(2):170-176
Abstract
BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and is associated with increased morbidity and mortality. Currently, there is no definitive treatment for this disease. δ-Tocotrienol has potent anti-inflammatory and antioxidant properties and may reduce liver injury in NAFLD. The present study aims to evaluate the efficacy and safety of δ-tocotrienol in the treatment of NAFLD. MATERIALS AND METHODS The present study was a randomized, double-blind, placebo-controlled pilot study conducted in patients aged > 20 years, belonging to both sexes, having ultrasound-proven fatty liver disease, having a fatty liver index (FLI) of ≥ 60, and persistent elevation of alanine transaminase. A total of 71 patients were assigned to receive either oral δ-tocotrienol (n=35, 300 mg twice daily) or placebo (n=36) for 12 weeks. At the baseline and at the end of the study, clinical and biochemical parameters, including lipid profile, liver function tests, high-sensitivity C-reactive protein (hs-CRP), and malondialdehyde (MDA) were measured. Body mass index and FLI were calculated, and ultrasound grading of hepatic steatosis was performed. RESULTS Out of 71 enrolled patients, 64 patients, 31 in the δ-tocotrienol group and 33 in the placebo group, completed the study. After 12 weeks of supplementation, δ-tocotrienol showed greater efficacy than placebo by decreasing serum aminotransferases, hs-CRP, MDA, and FLI score (p<0.001). However, it did not improve hepatic steatosis on ultrasound examination. No adverse effects were reported. CONCLUSION δ-Tocotrienol was safe, and it effectively improved aminotransferase levels and inflammatory and oxidative stress markers in patients with NAFLD. Large-scale randomized clinical trials are warranted to further support these findings.
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Noninvasive Tests Do Not Accurately Differentiate Nonalcoholic Steatohepatitis From Simple Steatosis: A Systematic Review and Meta-analysis.
Verhaegh, P, Bavalia, R, Winkens, B, Masclee, A, Jonkers, D, Koek, G
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;(6):837-861
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease is a rapidly increasing health problem. Liver biopsy analysis is the most sensitive test to differentiate between nonalcoholic steatohepatitis (NASH) and simple steatosis (SS), but noninvasive methods are needed. We performed a systematic review and meta-analysis of noninvasive tests for differentiating NASH from SS, focusing on blood markers. METHODS We performed a systematic search of the PubMed, Medline and Embase (1990-2016) databases using defined keywords, limited to full-text papers in English and human adults, and identified 2608 articles. Two independent reviewers screened the articles and identified 122 eligible articles that used liver biopsy as reference standard. If at least 2 studies were available, pooled sensitivity (sensp) and specificity (specp) values were determined using the Meta-Analysis Package for R (metafor). RESULTS In the 122 studies analyzed, 219 different blood markers (107 single markers and 112 scoring systems) were identified to differentiate NASH from simple steatosis, and 22 other diagnostic tests were studied. Markers identified related to several pathophysiological mechanisms. The markers analyzed in the largest proportions of studies were alanine aminotransferase (sensp, 63.5% and specp, 74.4%) within routine biochemical tests, adiponectin (sensp, 72.0% and specp, 75.7%) within inflammatory markers, CK18-M30 (sensp, 68.4% and specp, 74.2%) within markers of cell death or proliferation and homeostatic model assessment of insulin resistance (sensp, 69.0% and specp, 72.7%) within the metabolic markers. Two scoring systems could also be pooled: the NASH test (differentiated NASH from borderline NASH plus simple steatosis with 22.9% sensp and 95.3% specp) and the GlycoNASH test (67.1% sensp and 63.8% specp). CONCLUSION In the meta-analysis, we found no test to differentiate NASH from SS with a high level of pooled sensitivity and specificity (≥80%). However, some blood markers, when included in scoring systems in single studies, identified patients with NASH with ≥80% sensitivity and specificity. Replication studies and more standardized study designs are urgently needed. At present, no marker or scoring system can be recommended for use in clinical practice to differentiate NASH from simple steatosis.
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Metformin for Rapidly Maturing Girls with Central Adiposity: Less Liver Fat and Slower Bone Maturation.
de Zegher, F, García Beltrán, C, López-Bermejo, A, Ibáñez, L
Hormone research in paediatrics. 2018;(2):136-140
Abstract
BACKGROUND/AIMS: Girls with low-birth weight (LBW) and postnatal weight catch-up tend to develop visceral and hepatic fat excess, which may be accompanied by an upregulated adrenarche with precocious pubarche (PP) and by a rapidly progressive puberty with early menarche and shorter stature. A pilot study suggested that metformin treatment for 4 years reduces central adiposity in LBW-PP girls and normalizes puberty and adult height. In this cohort, we studied the relationship between metformin treatment, bone maturation, and body composition. METHODS Longitudinal hand X-rays (0-4 years, analyzed by BoneXpert) were available from 34 LBW-PP girls (89% of the original cohort; n = 17 untreated, n = 17 metformin-treated; age at the start of treatment 8 years) along with body composition (0-4 years, by DXA), hepatic fat, and abdominally subcutaneous and visceral fat (posttreatment, by MRI). RESULTS The tempo of bone aging was accelerated in untreated girls (≈16% faster vs. chronological aging) and normal in metformin-treated girls (≈20% slower vs. untreated girls). Metformin-treated girls gained more height per bone-age year and had less visceral and hepatic fat. The tempo of bone maturation was associated (R = 0.55; p < 0.001) with hepatic fat. CONCLUSION Metformin treatment in rapidly maturing girls with central adiposity normalized bone maturation. This normalization was accompanied by less central fat and was related closely to hepatic fat.
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Proton pump inhibitors as risk factor for metabolic syndrome and hepatic steatosis in coeliac disease patients on gluten-free diet.
Imperatore, N, Tortora, R, Testa, A, Gerbino, N, Caporaso, N, Rispo, A
Journal of gastroenterology. 2018;(4):507-516
Abstract
BACKGROUND Recent research has shown that patients with coeliac disease (CD) are at risk of developing metabolic syndrome (MS) and hepatic steatosis (HS) after commencing a gluten-free diet (GFD). This study aimed to evaluate the predictive factors for MS and HS in CD after 1 year of GFD. METHODS All consecutive newly diagnosed CD patients were enrolled. We prospectively collected data about BMI; waist circumference; blood pressure; cholesterol; triglycerides, glucose and insulin blood levels; insulin resistance (through the homeostatic model assessment HOMA-IR) and treatment with proton pump inhibitors (PPI). Diagnosis of MS was made in accordance with current guidelines and HS was diagnosed by ultrasonography. The prevalence of MS and HS was re-assessed after 1 year of GFD. A logistic regression analysis was performed to identify risk factors for MS and HS occurrence after 1 year of GFD. RESULTS Of 301 patients with newly diagnosed CD, 4.3% met criteria for diagnosis of MS and 25.9% presented with HS at the time of CD diagnosis; 99 subjects (32.8%) had long-term exposure to PPI during the study period. After 1 year, 72 (23.9%) patients had developed MS (4.3 vs 23.9%; p < 0.001, OR 6.9) and 112 (37.2%) had developed HS (25.9 vs 37.2%; p < 0.01, OR 1.69). At multivariate analysis, high BMI at diagnosis (OR 10.8; p < 0.001) and PPI exposure (OR 22.9; p < 0.001) were the only factors associated with the occurrence of MS; HOMA-IR (OR 9.7; p < 0.001) and PPI exposure (OR 9.2; p < 0.001) were the only factors associated with the occurrence of HS. CONCLUSIONS PPI exposure adds further risk of occurrence of MS and HS for patients with CD on GFD. The use of PPI in patients with CD on GFD should be limited to strict indications.
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Dyslipidemia and Fatty Liver Disease in Overweight and Obese Children.
Deeb, A, Attia, S, Mahmoud, S, Elhaj, G, Elfatih, A
Journal of obesity. 2018;:8626818
Abstract
INTRODUCTION Obesity is a worldwide concern. It is associated with morbidity such as dyslipidemia and liver disease. Childhood obesity has dramatically increased, particularly in the Gulf region. We aim to assess the prevalence of dyslipidemia and fatty liver disease (FLD) in overweight and obese children and analyze the association between different anthropometric measures with dyslipidemia and fatty liver disease. METHODS A descriptive, cross-sectional study conducted on children referred with obesity. BMI percentiles were plotted and standardized waist circumference (WC) was generated. Family history of metabolic syndrome was recorded. Fasting lipid, liver transaminases, and ultrasound scans (US) for those with elevated enzymes were performed. Descriptive statistics were used for quantitative parameters. RESULTS 216 participants were recruited. Mean ± SD age was 10.58 ± 2.996 years. 55.3% had dyslipidemia; 11.7% had high cholesterol, 28.6% high triglyceride, 32.7% high LDL, and 18.0% low HDL. 51 (84%) had either elevated transaminases. All had liver US, and 43 had FLD. WC was strongly associated with dyslipidemia and FLD (P=0.04 and 0.003). CONCLUSION Dyslipidemia is common in overweight, obese children. FLD is prevalent in those with elevated liver transaminases. WC is an easy tool that can be utilized to screen for dyslipidemia and FLD in overweight and obese children.