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Subclinical Liver Disease Is Associated with Subclinical Atherosclerosis in Psoriasis: Results from Two Observational Studies.
Gonzalez-Cantero, A, Teklu, M, Sorokin, AV, Prussick, R, González-Cantero, J, Martin-Rodriguez, JL, Patel, N, Parel, PM, Manyak, GA, Teague, HL, et al
The Journal of investigative dermatology. 2022;(1):88-96
Abstract
Psoriasis is associated with a higher risk of liver diseases. We investigated the impact of hepatic steatosis (European cohort) and hepatic inflammation (United States cohort) on subclinical atherosclerosis. In the European cohort (n = 76 psoriasis participants and 76 controls), nonalcoholic fatty liver disease, assessed by the sonographic hepatorenal index, was more prevalent in psoriasis than in controls (61% vs. 45%; P = 0.04). Participants with psoriasis with nonalcoholic fatty liver disease had a higher prevalence of subclinical atherosclerosis (ultrasonographic presence of plaque in femoral or carotid arteries) than participants with psoriasis without nonalcoholic fatty liver disease (61% vs. 23%; P = 0.006) and controls with nonalcoholic fatty liver disease (61% vs. 32%; P < 0.05). Sonographic hepatorenal index was a determinant of subclinical atherosclerosis in psoriasis (OR = 3.5; P = 0.01). In the United States cohort (n = 162 participants with psoriasis who underwent positron emission tomography and coronary computed tomography angiography), those with high hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake had higher noncalcified (1.3 [0.49 mm2] vs. 1.0 [0.40 mm2]), fibrofatty (0.23 [0.15 mm2] vs. 0.11 [0.087 mm2]), and lipid-rich necrotic core (4.3 [2.3 mm2] vs. 3.0 [1.7 mm2]) coronary burden (all P < 0.001). Hepatic 2-[fluorine-18]fluoro-2-deoxy-D-glucose uptake associated with noncalcified (β = 0.28; P < 0.001), fibrofatty (β = 0.49; P < 0.001), and lipid-rich necrotic core (β = 0.28; P = 0.003) burden. These results show the downstream cardiovascular effects of subclinical liver disease in psoriasis.
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Antioxidant activity of Hydroxytyrosol and Vitamin E reduces systemic inflammation in children with paediatric NAFLD.
Mosca, A, Crudele, A, Smeriglio, A, Braghini, MR, Panera, N, Comparcola, D, Alterio, A, Sartorelli, MR, Tozzi, G, Raponi, M, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2021;(9):1154-1158
Abstract
BACKGROUND The rise in paediatric non-alcoholic fatty liver disease (NAFLD) is particularly alarming. We recently reported that Hydroxytyrosol (HXT) and Vitamin E (VitE) may improve oxidative stress, insulin resistance, and steatosis in children with biopsy-proven NAFLD. AIM: Here, we investigated if HXT+VitE may reduce systemic inflammation in the above-mentioned patients. METHODS This study analysed the plasma levels of IL (interleukin)-6, IL-1β, IL-10, tumour necrosis factor (TNF)-α, 4‑hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2'deoxyguanosine (8-OHdG) in children enrolled in the HXT+VitE trial (ClinicalTrials.gov, NCT02842567). RESULTS Changes in markers of systemic inflammation were found in both placebo (Pla) and HXT+VitE. In particular, after four months, the levels of IL-1β and TNF-α were reduced in both groups, while IL-6 decreased, and IL-10 increased significantly only in the group treated with HXT+VitE. Children treated with HXT+VitE showed a significant decrease of 4-HNE and 8-OHdG that correlated with the improvement of triglyceride levels. Noticeably, only the 8-OHdG decrease correlated with steatosis amelioration and with the increase of IL-10 levels. CONCLUSION The treatment with HXT and VitE reduced the NAFLD-related systemic inflammation in children, mainly by an increase of IL-10 circulating levels that occurred in response to DNA damage recovery, ultimately improving steatosis and hypertriglyceridemia.
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A nomogram incorporated lifestyle indicators for predicting nonalcoholic fatty liver disease.
Peng, K, Wang, S, Gao, L, You, H
Medicine. 2021;(26):e26415
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Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its pathogenesis is complicated and triggered by unbalanced diet, sedentary lifestyle, and genetic background. The aim of this study was to construct and validate a nomogram incorporated lifestyle habits for predicting NAFLD incidence.The overall cohort was divided into training set and test set as using computer-generated random numbers. We constructed the nomogram by multivariate logistic regression analysis in the training set. Thereafter, we validated this model by concordance index, the area under the receiver operating characteristic curve (ROC), net reclassification index, and a calibration curve in the test set. Additionally, we also evaluated the clinical usefulness of the nomogram by decision curve analysis.There were no statistically significant differences about characteristics between training cohort (n = 748) and test cohort (n = 320). Eleven features (age, sex, body mass index, drinking tea, physical exercise, energy, monounsaturated fatty acids, polyunsaturated fatty acids, hypertension, hyperlipidemia, diabetes) were incorporated to construct the nomogram, concordance index, the area under the ROC curve, net reclassification index were 0.801, 0.801, and 0.084, respectively, indicating the nomogram have good discrimination of predicting NAFLD incidence. Also, the calibration curve showed good consistency between nomogram prediction and actual probability. Moreover, the decision curve showed that when the threshold probability of an individual is within a range from approximately 0.5 to 0.8, this model provided more net benefit to predict NAFLD incidence risk than the current strategies.This nomogram can be regarded as a user-friendly tool for assessing the risk of NAFLD incidence, and thus help to facilitate management of NAFLD including lifestyle and medical interventions.
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Impact of the Association Between PNPLA3 Genetic Variation and Dietary Intake on the Risk of Significant Fibrosis in Patients With NAFLD.
Vilar-Gomez, E, Pirola, CJ, Sookoian, S, Wilson, LA, Belt, P, Liang, T, Liu, W, Chalasani, N
The American journal of gastroenterology. 2021;(5):994-1006
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INTRODUCTION This study explored the relationship between patatin-like phospholipase domain-containing 3 gene (PNPLA3 rs738409), nutrient intake, and liver histology severity in patients with nonalcoholic fatty liver disease (NAFLD). METHODS PNPLA3-rs738409 variant was genotyped in 452 non-Hispanic whites with histologically confirmed NAFLD who completed Food Frequency Questionnaire within 6 months of their liver biopsy. The fibrosis severity on liver histology was the outcome of interest. RESULTS The distribution of PNPLA3 genotypes was CC: 28%, CG: 46%, and GG: 25%. High-carbohydrate (% of energy/d) intake was positively associated (adjusted [Adj] odds ratio [OR]: 1.03, P < 0.01), whereas higher n-3 polyunsaturated fatty acids (n-3 PUFAs) (g/d) (Adj. OR: 0.17, P < 0.01), isoflavones (mg/d) (Adj. OR: 0.74, P = 0.049), methionine (mg/d) (Adj. OR: 0.32, P < 0.01), and choline (mg/d) (Adj. OR: 0.32, P < 0.01) intakes were inversely associated with increased risk of significant fibrosis (stage of fibrosis ≥2). By using an additive model of inheritance, our moderation analysis showed that PNPLA3 rs738409 significantly modulates the relationship between carbohydrate (%), n-3 PUFAs, total isoflavones, methionine, and choline intakes and fibrosis severity in a dose-dependent, genotype manner. These dietary factors tended to have a larger and significant effect on fibrosis severity among rs738409 G-allele carriers. Associations between significant fibrosis and carbohydrates (Adj. OR: 1.04, P = 0.019), n-3 PUFAs (Adj. OR: 0.16, P < 0.01), isoflavones (Adj. OR: 0.65, P = 0.025), methionine (Adj. OR: 0.30, P < 0.01), and total choline (Adj. OR: 0.29, P < 0.01) intakes remained significant only among rs738409 G-allele carriers. DISCUSSION This gene-diet interaction study suggests that PNPLA3 rs738409 G-allele might modulate the effect of specific dietary nutrients on risk of fibrosis in patients with NAFLD.
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The association between Helicobacter pylori with nonalcoholic fatty liver disease assessed by controlled attenuation parameter and other metabolic factors.
Han, YM, Lee, J, Choi, JM, Kwak, MS, Yang, JI, Chung, SJ, Yim, JY, Chung, GE
PloS one. 2021;(12):e0260994
Abstract
AIM: Existing studies have suggested an association between Helicobacter pylori (Hp) infection and nonalcoholic fatty liver disease (NAFLD). We investigated the relationship between Hp infection and NAFLD using controlled attenuation parameter (CAP) and other metabolic factors. METHOD We conducted a retrospective cohort study of apparently healthy individuals who underwent liver Fibroscan during health screening tests between January 2018 and December 2018. Diagnosis of Hp infection was based on a serum anti-Hp IgG antibody test and CAP values were used to diagnose NAFLD. RESULTS Among the 1,784 subjects (mean age 55.3 years, 83.1% male), 708 (39.7%) subjects showed positive results of Hp serology. In the multivariate analysis, obesity (body mass index ≥25) (odds ratio [OR] 3.44, 95% confidence interval [CI] 2.75-4.29), triglyceride (OR 2.31, 95% CI 1.80-2.97), and the highest tertile of liver stiffness measurement (OR 2.08, 95% CI 1.59-2.71) were found to be associated with NAFLD, defined by CAP ≥248 dB/m, while Hp-seropositivity showed no association with NAFLD. Serum levels of HDL cholesterol significantly decreased in subjects with Hp-seropositivity compared to HP-seronegativity in both groups with and without NAFLD (P<0.001). CONCLUSION While Hp seropositivity was not associated with CAP-defined NAFLD, serum HDL cholesterol level were negatively associated with Hp-seropositivity in both groups with and without NAFLD. Further clinical and experimental studies are necessary to determine the association between Hp infection and NAFLD.
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Thiazolidinediones and Glucagon-Like Peptide-1 Receptor Agonists and the Risk of Nonalcoholic Fatty Liver Disease: A Cohort Study.
van Dalem, J, Driessen, JHM, Burden, AM, Stehouwer, CDA, Klungel, OH, de Vries, F, Brouwers, MCGJ
Hepatology (Baltimore, Md.). 2021;(5):2467-2477
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BACKGROUND AND AIMS Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists. APPROACH AND RESULTS We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63). CONCLUSIONS Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings.
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Long-term empagliflozin therapy improves levels of hepatic fibrosis marker in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus.
Shinozaki, S, Tahara, T, Lefor, AK, Ogura, M
The journal of medical investigation : JMI. 2020;(3.4):280-284
Abstract
The long-term outcomes of patients with non-alcoholic fatty liver disease (NAFLD) treated with sodium-glucose cotransporter-2 inhibitors remain indeterminate. Empagliflozin improves hyperglycemia by increasing glucose excretion in the urine, and it reduces fat volume and insulin resistance. The aim of this study is to assess the effect of long-term empagliflozin therapy on hepatic inflammation, function and fibrosis in patients with NAFLD. This is a two-center retrospective observational study including patients with NAFLD complicated by type 2 diabetes mellitus. We retrospectively reviewed the medical records. Changes in parameters were investigated over one-year empagliflozin treatment. Twenty-four patients treated with empagliflozin were evaluated. Weight, body mass index, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, fasting plasma glucose, hemoglobin A1c, serum insulin and homeostasis model assessment insulin resistance significantly decreased during treatment (p < 0.05). Albumin-bilirubin (ALBI) score, a marker of hepatic function, was significantly improved (p < 0.01). The FIB-4 index and Mac-2 Binding Protein Glucosylation Isomer, markers of hepatic fibrosis, significantly improved (p < 0.01). One-year empagliflozin treatment of patients with NAFLD complicated by type 2 diabetes mellitus significantly improves markers of hepatic inflammation, function and fibrosis. J. Med. Invest. 67 : 280-284, August, 2020.
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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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A newly noninvasive model for prediction of non-alcoholic fatty liver disease: utility of serum prolactin levels.
Zhang, P, Feng, W, Chu, X, Sun, X, Zhu, D, Bi, Y
BMC gastroenterology. 2019;(1):202
Abstract
BACKGROUNDS To investigate the value of prolactin (PRL) in diagnosing non-alcoholic fatty liver disease (NAFLD). METHODS Metabolic parameters and serum PRL levels were measured in 452 males and 421 females, who were randomized to the estimation or the validation group as a 1:1 ratio. Hepatic steatosis was diagnosed via abdominal ultrasound. Variables that significantly associated with NAFLD in univariate analysis were included in multiple logistic regression. We used the receiver operator characteristic (ROC) curves to test the model performance. Besides, 147 patients underwent metabolic and liver biopsy were analyzed to validate the diagnostic value of this model. RESULTS Body mass index, alanine aminotransferase, prolactin, high density lipoprotein cholesterol and HbA1c were included into models. In males, the area under ROC curve (AUC) was 0.86 (95%CI: 0.82-0.91) for the validation group. With two cut-off points (- 0.79 and 1.71), the sensitivity and specificity for predicting NALFD was 95.2 and 91.1% in the validation group, respectively. In females, the AUC was 0.82 (95%CI: 0.76-0.88) for the validation group. With two cut-off points (- 0.68 and 2.16), the sensitivity and specificity for predicting NALFD was 97.1 and 91.4% in the validation group, respectively. In subjects with liver pathology, the AUC was higher than that of fatty liver index. A positive correlation between the scores of the model and the severities of NAFLD was observed. Importantly, we demonstrated a potential value of this model in predicting nonalcoholic steatohepatitis. CONCLUSION We established a mathematic model that can conveniently and effectively diagnose the existence and severities of NAFLD.
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Presence of diabetic retinopathy is lower in type 2 diabetic patients with non-alcoholic fatty liver disease.
Zhang, M, Li, L, Chen, J, Li, B, Zhan, Y, Zhang, C
Medicine. 2019;(18):e15362
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To analyze the association between non-alcoholic fatty liver disease (NAFLD) and the presence of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM).Total 411 T2DM patients were divided into NAFLD and control groups. NAFLD was diagnosed by ultrasound. Retinopathy was diagnosed by fundus photography. All patients were screened based on medical history, physical examinations, and laboratory measurements.The prevalence of NAFLD and DR in T2DM patients was 60.8% and 40.9%, respectively. The presence of DR was associated with diabetes duration, systolic blood pressure (SBP), glycated hemoglobin (HbA1c), and proteinuria (all P < .001) using univariate and multivariate regression analyses. The prevalence of DR was lower in patients with NAFLD than those without NAFLD (37.2% vs 46.6%, P = .065), and significantly lower in patients with moderate and severe NAFLD (30.2% vs 46.6%, P = .012; 14.3% vs 46.6%, P = .024). The presence of DR in NAFLD patients was associated with diabetes duration (P = .032) in Chi-squared analysis.NAFLD and DR were highly prevalent in T2DM patients. Diabetes duration, SBP, HbA1c, and proteinuria were risk factors for DR in T2DM patients. The presence of DR was lower in T2DM patients with NAFLD, which was mainly due to their shorter diabetes duration.