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Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis.
Shen, W, Middleton, MS, Cunha, GM, Delgado, TI, Wolfson, T, Gamst, A, Fowler, KJ, Alazraki, A, Trout, AT, Ohliger, MA, et al
Journal of hepatology. 2023;(2):238-246
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Abstract
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH) is prevalent in adults with obesity and can progress to cirrhosis. In a secondary analysis of prospectively acquired data from the multicenter, randomized, placebo-controlled FLINT trial, we investigated the relationship between reduction in adipose tissue compartment volumes and hepatic histologic improvement. METHODS Adult participants in the FLINT trial with paired liver biopsies and abdominal MRI exams at baseline and end-of-treatment (72 weeks) were included (n = 76). Adipose tissue compartment volumes were obtained using MRI. RESULTS Treatment and placebo groups did not differ in baseline adipose tissue volumes, or in change in adipose tissue volumes longitudinally (p = 0.107 to 0.745). Deep subcutaneous adipose tissue (dSAT) and visceral adipose tissue volume reductions were associated with histologic improvement in NASH (i.e., NAS [non-alcoholic fatty liver disease activity score] reductions of ≥2 points, at least 1 point from lobular inflammation and hepatocellular ballooning, and no worsening of fibrosis) (p = 0.031, and 0.030, respectively). In a stepwise logistic regression procedure, which included demographics, treatment group, baseline histology, baseline and changes in adipose tissue volumes, MRI hepatic proton density fat fraction (PDFF), and serum aminotransferases as potential predictors, reductions in dSAT and PDFF were associated with histologic improvement in NASH (regression coefficient = -2.001 and -0.083, p = 0.044 and 0.033, respectively). CONCLUSIONS In adults with NASH in the FLINT trial, those with greater longitudinal reductions in dSAT and potentially visceral adipose tissue volumes showed greater hepatic histologic improvements, independent of reductions in hepatic PDFF. CLINICAL TRIAL NUMBER NCT01265498. IMPACT AND IMPLICATIONS Although central obesity has been identified as a risk factor for obesity-related disorders including insulin resistance and cardiovascular disease, the role of central obesity in non-alcoholic steatohepatitis (NASH) warrants further clarification. Our results highlight that a reduction in central obesity, specifically deep subcutaneous adipose tissue and visceral adipose tissue, may be related to histologic improvement in NASH. The findings from this analysis should increase awareness of the importance of lifestyle intervention in NASH for clinical researchers and clinicians. Future studies and clinical practice may design interventions that assess the reduction of deep subcutaneous adipose tissue and visceral adipose tissue as outcome measures, rather than simply weight reduction.
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Efficacy of a 2-Month Very Low-Calorie Ketogenic Diet (VLCKD) Compared to a Standard Low-Calorie Diet in Reducing Visceral and Liver Fat Accumulation in Patients With Obesity.
Cunha, GM, Guzman, G, Correa De Mello, LL, Trein, B, Spina, L, Bussade, I, Marques Prata, J, Sajoux, I, Countinho, W
Frontiers in endocrinology. 2020;11:607
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Plain language summary
Excess fat in the liver, known as non-alcoholic fatty liver disease (NAFLD), has been shown to increase the risk of chronic diseases such as type 2 diabetes. Standard treatment regimens consist of low-calorie (LC) diets and exercise, however these may be ineffective at reversing fat accumulation in the liver. A very low-calorie ketogenic diet (VLCKD) has been proposed as an alternative treatment for NAFLD. This randomised control pilot study of 39 individuals with obesity aimed to compare LC diet and VLCKD on fat accumulation and indicators for NAFLD for two months. The results showed greater weight loss, abdominal fat reduction, liver fat reduction and improvements in liver function with VLCKD compared to the LC diet. Cholesterol was significantly reduced by both diets. However liver stiffness remained unchanged. The authors concluded that VLCKD was more successful at reducing liver fat and abdominal fat accumulation than current standard therapy and has the potential to improve NAFLD. Health care professionals could use this study to improve liver and abdominal fat loss in patients with obesity to improve NAFLD, when standard therapy has been inadequate.
Abstract
Background: Currently the treatment of non-alcoholic fatty liver disease (NAFLD) is based on weight loss through lifestyle changes, such as exercise combined with calorie-restricted dieting. Objectives: To assess the effects of a commercially available weight loss program based on a very low-calorie ketogenic diet (VLCKD) on visceral adipose tissue (VAT) and liver fat content compared to a standard low-calorie (LC) diet. As a secondary aim, we evaluated the effect on liver stiffness measurements. Methods: Open, randomized controlled, prospective pilot study. Patients were randomized and treated either with an LC or a VLCKD and received orientation and encouragement to physical activity equally for both groups. VAT, liver fat fraction, and liver stiffness were measured at baseline and after 2 months of treatment using magnetic resonance imaging. Paired t-tests were used for comparison of continuous variables between visits and unpaired test between groups. Categorical variables were compared using the χ2-test. Pearson correlation was used to assess the association between VAT, anthropometric measures, and hepatic fat fraction. A significance level of the results was established at p < 0.05. Results: Thirty-nine patients (20 with VLCKD and 19 with LC) were evaluated at baseline and 2 months of intervention. Relative weight loss at 2 months was -9.59 ± 2.87% in the VLCKD group and -1.87 ± 2.4% in the LC group (p < 0.001). Mean reductions in VAT were -32.0 cm2 for VLCKD group and -12.58 cm2 for LC group (p < 0.05). Reductions in liver fat fraction were significantly more pronounced in the VLCKD group than in the LC group (4.77 vs. 0.79%; p < 0.005). Conclusion: Patients undergoing a VLCKD achieved superior weight loss, with significant VAT and liver fat fraction reductions when compared to the standard LC diet. The weight loss and rapid mobilization of liver fat demonstrated with VLCKD could serve as an effective alternative for the treatment of NAFLD. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04322110.
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MRI estimated changes in visceral adipose tissue and liver fat fraction in patients with obesity during a very low-calorie-ketogenic diet compared to a standard low-calorie diet.
Cunha, GM, Correa de Mello, LL, Hasenstab, KA, Spina, L, Bussade, I, Prata Mesiano, JM, Coutinho, W, Guzman, G, Sajoux, I
Clinical radiology. 2020;(7):526-532
Abstract
AIM: To compare the changes in visceral adipose tissue (VAT), liver fat fraction, and liver stiffness using quantitative magnetic resonance imaging (MRI) during a very-low-calorie ketogenic (VLCK) diet and a standard low-calorie diet (LC). MATERIALS AND METHODS The study involved secondary analysis of prospective collected clinical data. Patients undergoing weight loss interventions were randomised to either a LC or a VLCK diet. VAT, liver fat fraction, and stiffness were measured at baseline and after 2 months. RESULTS Forty-six patients were included; 39 patients were evaluated at baseline and at 2 months follow-up. Mean weight loss was -9.7±3.8 kg (interquartile range [IQR]: -12.3; -7 kg) in the VLCK group and -1.67±2.2 kg (IQR: -3.3, -0.1 kg) in the LC group (p<0.0001). Mean VAT reductions were -39.3±40 cm2 (IQR: -52, -10 cm2) and -12.5±38.3 cm2 (IQR: -29, 5 cm2; p=0.0398), and mean liver proton density fat fraction (PDFF) reductions were -4.77±4.2% (IQR: -7.3, -1.7%) and -0.79±1.7%, (IQR: -1.8, -0.4%; p<0.005) in the VLCK group and in the LC group, respectively. No significant changes in liver stiffness occurred from baseline to follow-up. CONCLUSION A VLCK diet resulted in greater weight loss than a standard low-calorie diet and in significantly greater reduction in liver PDFF. As anthropometric measurements may not correlate with liver fat changes, it may be advantageous to include quantitative MRI to the monitoring strategies of patients undergoing weight-loss programmes.
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Early use of alcohol associated with sociodemographic, nutritional and lifestyle factors: survival analysis with Brazilian students.
Pinto, TJP, Mendonça, EP, Bloch, KV, Cunha, GM, Coutinho, ESF
Journal of public health (Oxford, England). 2020;(3):579-587
Abstract
BACKGROUND To evaluate the early age of onset (AOO) of alcohol consumption and its association with sociodemographic, nutritional and lifestyle characteristics. METHODS A national cross-sectional multi-centered study assessed 12-17-year old adolescents from 1247 public and private schools in 124 Brazilian municipalities with more than 100 000 habitants. Our variable of interest was the AOO of alcohol consumption. Covariates comprised sociodemographic status, lifestyle habits and nutritional parameters. We used adapted survival models to investigate the association between covariates and the AOO of alcohol consumption. RESULTS From a sample of 67 672 adolescents, 50% were females. The mean AOO of alcohol consumption was 12.9 years. Male adolescents had a lower mean age of alcohol experimentation when compared to females in Northeast and South regions. The difference between private and public school for AOO was observed only for the Northeast Region (12.6 versus 13.1, respectively). Adolescents who reported smoking or mental health problems or from the Southern Region presented earlier alcohol use. Physical activity and overweight were positively associated with earlier use of alcohol. CONCLUSIONS There is no homogeneity in the AOO of alcohol consumption among adolescents, which should be considered when formulating public policies and government campaigns directed toward reducing alcohol consumption.
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Right and left ventricular function and myocardial scarring in adult patients with sickle cell disease: a comprehensive magnetic resonance assessment of hepatic and myocardial iron overload.
Junqueira, FP, Fernandes, JL, Cunha, GM, T A Kubo, T, M A O Lima, C, B P Lima, D, Uellendhal, M, Sales, SR, A S Cunha, C, L R de Pessoa, V, et al
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance. 2013;(1):83
Abstract
BACKGROUND Patients with Sickle cell disease (SCD) who receive regular transfusions are at risk for developing cardiac toxicity from iron overload. The aim of this study was to assess right and left cardiac volumes and function, late gadolinium enhancement (LGE) and iron deposits in patients with SCD using CMR, correlating these values with transfusion burden, ferritin and hemoglobin levels. METHODS Thirty patients with SCD older than 20 years of age were studied in a 1.5 T scanner and compared to age- and sex-matched normal controls. Patients underwent analysis of biventricular volumes and function, LGE and T2* assessment of the liver and heart. RESULTS When compared to controls, patients with SCD presented higher left ventricular (LV) volumes with decreased ejection fraction (EF) with an increase in stroke volume (SV) and LV hypertrophy. The right ventricle (RV) also presented with a decreased EF and hypertrophy, with an increased end-systolic volume. Although twenty-six patients had increased liver iron concentrations (median liver iron concentration value was 11.83 ± 9.66 mg/g), only one patient demonstrated an abnormal heart T2* < 20 msec. Only four patients (13%) LGE, with only one patient with an ischemic pattern. CONCLUSIONS Abnormal heart iron levels and myocardial scars are not a common finding in SCD despite increased liver iron overload. The significantly different ventricular function seen in SCD compared to normal suggests the changes in RV and LV function may not be due to the anemia alone. Future studies are necessary to confirm this association.
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Melatonin improves sleep and reduces nitrite in the exhaled breath condensate in cystic fibrosis--a randomized, double-blind placebo-controlled study.
de Castro-Silva, C, de Bruin, VM, Cunha, GM, Nunes, DM, Medeiros, CA, de Bruin, PF
Journal of pineal research. 2010;(1):65-71
Abstract
Cystic fibrosis (CF) is a chronic progressive disorder characterized by repeated episodes of respiratory infection. Impaired sleep is common in CF leading to reduced quality of life. Melatonin, a secretory product of the pineal gland, has an important function in the synchronization of circadian rhythms, including the sleep-wake cycle, and has been shown to possess significant anti-oxidant properties. To evaluate the effects of exogenous melatonin on sleep and inflammation and oxidative stress markers in CF, a randomized double-blind, placebo-controlled study initially involving 20 patients with CF was conducted. One individual failed to conclude the study. All subjects were clinically stable when studied and without recent infectious exacerbation or hospitalization in the last 30 days. Groups were randomized for placebo (n = 10; mean age 12.1 +/- 6.0) or 3 mg melatonin (n = 9; mean age 16.6 +/- 8.26) for 21 days. Actigraphy was performed for 6 days before the start of medication and in the third week (days 14-20) of treatment. Isoprostane and nitrite levels were determined in exhaled breath condensate (EBC) at baseline (day 0) and after treatment (day 21). Melatonin improved sleep efficiency (P = 0.01) and tended to improve sleep latency (P = 0.08). Melatonin reduced EBC nitrite (P = 0.01) but not isoprostane. In summary, melatonin administration reduces nitrite levels in EBC and improves sleep measures in clinically stable CF patients. The failure of melatonin to reduce isoprostane levels may have been a result of the low dose of melatonin used as a treatment.