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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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Abstract
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 contribution of ascitic fluid to body weight in patients with liver cirrhosis, and its estimation using girth: a cross-sectional observational study.
Lamarti, E, Hickson, M
Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2020;(3):404-413
Abstract
BACKGROUND There is a high prevalence of malnutrition among people with decompensated liver disease. Standard nutritional screening tools use weight and body mass index (BMI) to identify risk, although these are difficult to measure for those with ascites, often secondary to liver cirrhosis. Dietetic guidance suggests adjusting for ascitic weight by 2.2-14 kg, although there is a lack of evidence to substantiate these values. The present study aimed to measure the contribution of ascitic fluid weight and compare this with the current guidance, as well as to examine whether girth circumference can be used to estimate ascitic weight. METHODS A cross-sectional, observational study was conducted over 13 weeks. Participants attending for paracentesis were weighed, their girths measured, and BMI was calculated pre- and post-paracentesis. Fluid removed via paracentesis was recorded. Ethical approval was received (IRAS project ID: 218747). RESULTS Eighteen participants underwent paracentesis. The range of ascitic fluid drained was 3.8-19 L [mean (SD) = 8.7 (3.7) L]. Weight difference between pre- and post-paracentesis was in the range 4.5-20 kg [mean (SD) = 8.7 (3.9) kg]. Ascitic fluid weight is shown to be higher in each category (minimal, moderate, severe ascites) than the current guidance values. Weight difference was greater than 14 kg in 11% (n = 2) of participants. A strong, statistically significant relationship (rho = 0.68, P ≤ 0.01) between ascitic weight and pre-paracentesis girth was found. An equation was formulated to enable the estimation of ascitic fluid from pre-paracentesis girth. CONCLUSIONS Current dietetic guidance should be re-evaluated to reflect the greater weight differences identified. Measuring girth pre-paracentesis may help to inform dry weight estimation. Further research is required to verify the accuracy of estimating ascitic weight from pre-paracentesis girth.
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Diastolic dysfunction in patients with liver cirrhosis: A short-term, observational study at a Malaysian hospital.
Abdul Aziz, KA, Draman, N, Wan Isa, WYH, Mustaffa, N
The Medical journal of Malaysia. 2020;(4):396-399
Abstract
Cirrhotic cardiomyopathy is a recognised complication of liver cirrhosis and predicts poor outcomes. Detection of diastolic dysfunction, an early indicator of left ventricular dysfunction can help identify those patients at risk of disease progression. In our study we showed that there was a high prevalence of diastolic dysfunction amongst patients with liver cirrhosis at our outpatient clinic, with the majority being Child-Pugh A/low MELD score. Multiple regression analysis indicated that age and sodium levels were significantly associated with the presence of diastolic dysfunction. This further reinforces the importance of dietary sodium restriction amongst patients with liver cirrhosis.
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Clinical implications with tolvaptan on monitored bioimpedance-defined fluid status in patients with cirrhotic ascites: an observational study.
Shiba, S, Chu, PS, Nakamoto, N, Yamataka, K, Taniki, N, Ojiro, K, Yamaguchi, A, Morikawa, R, Yoshida, A, Ikura, A, et al
BMC gastroenterology. 2020;(1):53
Abstract
BACKGROUND Prognostic value or clinical implications of fluid status monitoring in liver cirrhosis are not fully elucidated. Tolvaptan, an orally available, selective vasopressin V2-receptor antagonist approved for hyponatremia in the United States and European Union. It is also used for cirrhotic ascites at a relatively low dose (3.75 mg to 7.5 mg) in Japan, exerts its diuretic function by excreting electrolyte-free water. We hypothesized that bioimpedance-defined dynamic changes in fluid status allow prediction of response of V2 antagonism and survival in cirrhotic patients. METHODS In this prospective observational study, 30 patients with decompensated liver cirrhosis who were unresponsive to conventional diuretics were enrolled. Detailed serial changes of body composition that were assessed by using non-invasive bioimpedance analysis (BIA) devices, along with biochemical studies, were monitored at 5 time points. RESULTS Sixteen patients were classified as short-term responders (53%). Rapid and early decrease of BIA-defined intracellular water, as soon as 6 h after the first dose (ΔICWBIA%-6 h), significantly discriminated responders from non-responders (AUC = 0.97, P < 0.0001). ΔICWBIA%-6 h was highly correlated with the change of BIA-derived phase angle of trunk, e.g. reduced body reactance operated at 50 kHz after 24 h of the first dose of tolvaptan. Lower baseline blood urea nitrogen and lower serum aldosterone were predictive of a rapid and early decrease of ICWBIA. A rapid and early decrease of ICWBIA in response to tolvaptan was also predictive of a better transplant-free survival. CONCLUSIONS BIA-defined water compartment monitoring may help predict short-term efficacy and survival in decompensated cirrhotic patients treated with tolvaptan.
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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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Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.
Carrat, F, Fontaine, H, Dorival, C, Simony, M, Diallo, A, Hezode, C, De Ledinghen, V, Larrey, D, Haour, G, Bronowicki, JP, et al
Lancet (London, England). 2019;(10179):1453-1464
Abstract
BACKGROUND Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort. METHODS We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458. FINDINGS Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0-40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio [HR] 2·77, 95% CI 2·07-3·71) and decompensated cirrhosis (3·83, 2·29-6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33-0·70) and hepatocellular carcinoma (0·66, 0·46-0·93), and was not associated with decompensated cirrhosis (1·14, 0·57-2·27). INTERPRETATION Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection. FUNDING INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
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Outcomes of Bariatric Surgery in Patients with Cirrhosis.
Miñambres, I, Rubio, MA, de Hollanda, A, Breton, I, Vilarrasa, N, Pellitero, S, Bueno, M, Lecube, A, Marcuello, C, Goday, A, et al
Obesity surgery. 2019;(2):585-592
Abstract
CONTEXT Information concerning the risk-benefit profile of bariatric surgery in subjects with liver cirrhosis is scarce. Our aim was to describe the long-term outcomes of bariatric surgery in a cohort of patients with liver cirrhosis submitted to bariatric surgery. METHODS This was a multicenter, retrospective observational study performed by the Obesity Group of the Spanish Society of Endocrinology and Nutrition (GOSEEN), with a review of patients with cirrhosis who had undergone bariatric surgery during the period from April 2004 to March 2017 in ten public reference hospitals in Spain. RESULTS Data on 41 patients with cirrhosis submitted to obesity surgery were collected (mean age 53.8 ± 7.9 years, 46.3% women, presurgical BMI 45 ± 8.3 kg/m2). All but one patient belonged to Child-Pugh class A, and sleeve gastrectomy was conducted in 68.3% of cases. Percentage of total weight loss (%TWL) was 26.33 ± 8.3% and 21.16 ± 15.32% at 1 and 5 years after surgery, respectively. This was accompanied by a significant reduction of type 2 diabetes, high blood pressure, and dyslipidemia and by an improvement of liver enzymes over time. Model for End-Stage Liver Disease (MELD) index increased from 7.2 ± 1.9 to 9.8 ± 4.6 after 5 years. Seven patients (17%) developed early postsurgical complications. No postsurgical mortality was observed. During follow-up, only five patients developed liver decompensation. CONCLUSIONS Bariatric surgery in selected patients with liver cirrhosis has metabolic benefits that could have a positive impact on liver prognosis. TRIAL REGISTRATION Controlledtrials.com Identifier: 10.1186/ISRCTN15009106.
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Reduced Serum Sphingolipids Constitute a Molecular Signature of Malnutrition in Hospitalized Patients With Decompensated Cirrhosis.
Rachakonda, V, Argemi, J, Borhani, AA, Bataller, R, Tevar, A, Behari, J
Clinical and translational gastroenterology. 2019;(3):e00013
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Abstract
INTRODUCTION Malnutrition is a leading cause of morbidity and mortality in cirrhosis. Although multiple noninvasive measures of nutritional status have been studied, no consensus exists for early identification of malnutrition in cirrhosis. Serum metabolomics offers a novel approach for identifying biomarkers in multiple disease states. To characterize alterations in metabolic pathways associated with malnutrition in hospitalized cirrhotic patients and to identify biomarkers for disease prognosis. METHODS In this cross-sectional, observational cohort study, 51 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on low mid-arm muscle circumference and dominant handgrip strength. Anthropometric measurements and computed tomography body composition analysis were performed. Serum was collected after overnight fasting for unbiased metabolomics analysis. RESULTS Malnourished cirrhotic patients exhibited mild reductions in skeletal muscle index, with more marked reductions in visceral fat index. Seventy-one biochemicals were significantly altered in malnourished subjects. The serum metabolite profile was significantly different between nourished and malnourished cirrhotic patients. Pathway analysis demonstrated that only sphingolipid metabolic pathways were significantly enriched in altered metabolites. Hierarchical clustering revealed that sphingolipid metabolites clustered into nourished and malnourished cohorts. Spearman analysis demonstrated multiple statistically significant correlations between sphingolipid species and Model for End-Stage Liver Disease-Sodium. Using logistic regression, we identified 8 sphingolipids that were significantly associated with malnutrition after controlling for Model for End-Stage Liver Disease-Sodium, age, and gender. CONCLUSIONS Malnutrition in hospitalized cirrhotic patients is characterized by reductions in multiple sphingolipid species. Dysregulated sphingolipid metabolism may be involved in the pathophysiology of malnutrition in cirrhosis and potentially serve as a biomarker of nutritional status in this population.
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Prognosis of patients with ascites after PleurX insertion: an observational study.
Riedel, AN, Kimer, N, Hobolth, L, Gluud, LL
Scandinavian journal of gastroenterology. 2018;(3):340-344
Abstract
OBJECTIVE To evaluate the safety of PleurX in cirrhotic patients with refractory ascites. METHODS We prospectively registered patients who received a PleurX catheter cirrhosis-associated refractory ascites at our department from July 2015 to November 2016. Our control group consisted of matched cirrhotic patients with refractory ascites treated with large volume paracentesis (LVP) and patients with malignant ascites treated with PleurX during the same period. RESULTS We included 25 patients with cirrhosis-related ascites (7 in PleurX group) and 17 with malignant ascites (14 in PleurX group). Of these, six patients had hepatocellular carcinoma and cirrhosis (5 in PleurX group). None were eligible for insertion of a TIPS or liver transplantation. The maximum duration of follow-up was (480 days) in the PleurX group and 366 days in the LVP group (median 84 and 173 days, respectively). There was no difference in mortality when comparing PleurX with LVP treatment (hazard ratios: 3.0 and 1.0, p = .23 and .96, respectively). Mortality was higher in patients with malignant ascites (p= .01). We found no significant differences in adverse events (incl. spontaneous bacterial peritonitis) or in P-albumin, P-creatinine and P-sodium between the groups. CONCLUSION PleurX insertion for the treatment of refractory ascites in cirrhotic patients appears to be safe. Prospective randomized trials are necessary in order to confirm these findings.
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Pronounced Coronary Arteriosclerosis in Cirrhosis: Influence on Cardiac Function and Survival?
Danielsen, KV, Wiese, S, Hove, J, Bendtsen, F, Møller, S
Digestive diseases and sciences. 2018;(5):1355-1362
Abstract
BACKGROUND The relation between excessive alcohol consumption and coronary arteriosclerosis has remained controversial. The etiology of cirrhosis has been considered a substantial risk factor for development of arteriosclerotic lesions. The coronary artery calcium-score derived from coronary CT angiography is a robust marker of coronary arteriosclerosis. AIMS To study the burden of coronary arteriosclerosis in cirrhotic patients of various etiologies and association to cardiac dysfunction and survival. METHODS Fifty-seven patients with cirrhosis without cardiovascular disease underwent coronary CT angiography, tissue Doppler echocardiography, electrocardiogram and registration of clinical and biochemical characteristics. RESULTS In patients with cirrhosis the median coronary artery calcium-score was increased in comparison with age and race-adjusted healthy reference values (men: 328 vs. 9 HU and women: 136 vs. 0 HU; p < 0.001). Moreover, the coronary artery calcium-score in alcohol-related cirrhosis was significantly higher than in nonalcohol-related cirrhosis (362 vs. 46 HU, p < 0.001). Coronary artery calcium-score correlated with age (p = 0.002) but not with established cardiovascular risk factors including smoking, type 2 diabetes, hypertension, gender, or hypercholesterolemia. Coronary artery calcium-score was associated with diastolic dysfunction, lateral e´ (p = 0.025), but not with other markers of cardiac dysfunction. During a median follow-up of 25 months 12 patients (21%) died but coronary artery calcium-score was not associated with survival. CONCLUSIONS Coronary arteriosclerosis was particular extensive in patients with alcoholic cirrhosis. However, the current results suggest that coronary arteriosclerosis only have limited influence on cardiac function and survival. Surprisingly, no other established risk factors apart from age seemed to interfere with coronary arteriosclerosis in cirrhotic patients.