PNPLA3 GENE POLYMORPHISM AND RED MEAT CONSUMPTION INCREASED FIBROSIS RISK IN NASH BIOPSY-PROVEN PATIENTS UNDER MEDICAL FOLLOW-UP IN A TERTIARY CENTER IN SOUTHWEST BRAZIL.

BACKGROUND: Recent studies show an increase in nonalcoholic fatty liver disease (NAFLD) in populations with higher consumption of red meat, processed and cooked at high temperatures. On the other hand, the single nucleotide polymorphism rs738409 in the Patatin-like phospholipase domain containing 3 (PNPLA3) gene has been implicated in susceptibility to NAFLD and liver fibrosis. However, the synergistic effect between red meat consumption and the PNPLA3 gene polymorphism in NAFLD has not yet been evaluated. OBJECTIVE: To evaluate the association between the presence of the polymorphism in the PNPLA3 gene and the consumption of macronutrients, including meat consumption and its cooking method among NAFLD patients. METHODS: This was a cross-sectional study with 91 patients diagnosed with NAFLD by liver biopsy with genotyping for the polymorphism in the PNPLA3 gene were included. The consumption of calories and macronutrients was verified using the semi-quantitative food frequency questionnaire and the specific questionnaire on meat consumption. PNPLA3 gene polymorphism was analyzed by real-time polymerase chain reaction (RT-PCR) and anthropometric evaluation was realized. RESULTS: The mean BMI was 32.38±4.58 kg/m² and the waist circumference was 107±10 cm. On liver biopsy, 42% of patients had significant fibrosis (F≥2). The odds ratio of F≥2 was 2.12 for the GG group and 1.54 for the CG group, compared to the CC group. The mean caloric intake was 1170±463.20 kcal/d. The odds ratio in the CC group concerning high red meat consumption in comparison to low consumption was 1.33. For white meat, the odds ratio was 0.8 when comparing high and low intake, also in the CC group. CONCLUSION: High red meat intake and PNPLA3 gene polymorphism seem to synergistically affect NAFLD and liver fibrosis, requiring confirmation in a larger number of patients and in different populations.

Non-pharmacological management options for MAFLD: a practical guide.

Lifestyle changes should be the main basis for any treatment for metabolic dysfunction-associated fatty liver disease (MAFLD), aiming to increase energy expenditure, reduce energy intake and improve the quality of nutrients consumed. As it is a multifactorial disease, approaches such as physical exercise, a better dietary pattern, and possible pharmacological intervention are shown to be more efficient when used simultaneously to the detriment of their applications. The main treatment for MAFLD is a lifestyle change consisting of diet, activity, exercise, and weight loss. The variables for training prescription such as type of physical exercise (aerobic or strength training), the weekly frequency, and the intensity most indicated for the treatment of MAFLD remain uncertain, that is, the recommendations must be adapted to the clinical conditions comorbidities, and preferences of each subject in a way individual. This review addresses recent management options for MAFLD including diet, nutrients, gut microbiota, and physical exercise.

Polimorfismo no gene PNPLA3 e o consumo de carne vermelha aumentam o risco de fibrose em pacientes com DHGNA comprovado por biópsia em acompanhamento médico em um centro terciário no Sudoeste do Brasil / Pnpla3 gene polymorphism and red meat consumption increased fibrosis risk in nash biopsy-proven patients under medical follow-up in a tertiary center in southwest brazil

ABSTRACT Background: Recent studies show an increase in nonalcoholic fatty liver disease (NAFLD) in populations with higher consumption of red meat, processed and cooked at high temperatures. On the other hand, the single nucleotide polymorphism rs738409 in the Patatin-like phospholipase domain containing 3 (PNPLA3) gene has been implicated in susceptibility to NAFLD and liver fibrosis. However, the synergistic effect between red meat consumption and the PNPLA3 gene polymorphism in NAFLD has not yet been evaluated. Objective: To evaluate the association between the presence of the polymorphism in the PNPLA3 gene and the consumption of macronutrients, including meat consumption and its cooking method among NAFLD patients. Methods: This was a cross-sectional study with 91 patients diagnosed with NAFLD by liver biopsy with genotyping for the polymorphism in the PNPLA3 gene were included. The consumption of calories and macronutrients was verified using the semi-quantitative food frequency questionnaire and the specific questionnaire on meat consumption. PNPLA3 gene polymorphism was analyzed by real-time polymerase chain reaction (RT-PCR) and anthropometric evaluation was realized. Results: The mean BMI was 32.38±4.58 kg/m² and the waist circumference was 107±10 cm. On liver biopsy, 42% of patients had significant fibrosis (F≥2). The odds ratio of F≥2 was 2.12 for the GG group and 1.54 for the CG group, compared to the CC group. The mean caloric intake was 1170±463.20 kcal/d. The odds ratio in the CC group concerning high red meat consumption in comparison to low consumption was 1.33. For white meat, the odds ratio was 0.8 when comparing high and low intake, also in the CC group. Conclusion: High red meat intake and PNPLA3 gene polymorphism seem to synergistically affect NAFLD and liver fibrosis, requiring confirmation in a larger number of patients and in different populations.

RESUMO Contexto: Estudos recentes mostram um aumento da doença hepática gordurosa não alcoólica (DHGNA) em populações com maior consumo de carne vermelha, processada e cozida em altas temperaturas. Por outro lado, o polimorfismo rs738409 no gene Patatin-like fosfolipase contendo 3 (PNPLA3) tem sido implicado na suscetibilidade à DHGNA e fibrose hepática. No entanto, o efeito sinérgico entre o consumo de carne vermelha e o polimorfismo no gene PNPLA3 na DHGNA ainda não foi avaliado. Objetivo: Avaliar a associação entre a presença do polimorfismo no gene PNPLA3 e o consumo de macronutrientes, incluindo o consumo de carne e seu modo de cozimento em pacientes com DHGNA. Métodos: Realizamos um estudo transversal com 91 pacientes diagnosticados com DHGNA por biópsia hepática e genotipados para o polimorfismo no gene PNPLA3. O consumo de calorias e macronutrientes foi verificado por meio do questionário de frequência alimentar semi-quantitativo (QFA) e do questionário específico sobre consumo de carnes. O polimorfismo no gene PNPLA3 foi analisado por reação em cadeia da polimerase em tempo real (RT-PCR) e a avaliação antropométrica foi realizada. Resultados: O índice de massa corporal médio foi de 32,38±4,58 kg/m² e a circunferência da cintura foi de 107±10 cm. Na biópsia hepática, 42% dos pacientes apresentavam fibrose significativa (F≥2). O odds ratio de F≥2 foi de 2,12 para o grupo GG e 1,54 para o grupo GC, comparado ao grupo CC. A ingestão calórica média foi de 1.170±463,20 kcal/d. O odds ratio para alto consumo de carne vermelha no grupo CC em comparação ao baixo consumo foi de 1,33. Para a carne branca, este valor foi de 0,8 ao comparar o alto e o baixo consumo, também no grupo CC. Conclusão: A alta ingestão de carne vermelha e o polimorfismo no gene PNPLA3 parecem afetar sinergicamente a DHGNA e a fibrose hepática, necessitando de confirmação em maior número de pacientes e em diferentes populações.

IMPACT OF CURRENT DIET AT THE RISK OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD).

The nonalcoholic fatty liver disease (NAFLD) affects approximately 20%-30% of general population and is even more prevalent among obese individuals. The risk factors mainly associated with NAFLD are diseases related to the metabolic syndrome, genetics and environment. In this review, we provide a literature compilation evaluating the evidence behind dietary components, including calories intake, fat, protein, fibers and carbohydrate, especially fructose which could be a trigger to development and progression of the NAFLD. In fact, it has been demonstrated that diet is an important factor for the development of NAFLD and its association is complex and extends beyond total energy intake.

Impacto da dieta usual no risco de doença hepática gordurosa não alcoólica (DHGNA) / Impact of current diet at the risk of non-alcoholic fatty liver disease (nafld)

ABSTRACT The nonalcoholic fatty liver disease (NAFLD) affects approximately 20%-30% of general population and is even more prevalent among obese individuals. The risk factors mainly associated with NAFLD are diseases related to the metabolic syndrome, genetics and environment. In this review, we provide a literature compilation evaluating the evidence behind dietary components, including calories intake, fat, protein, fibers and carbohydrate, especially fructose which could be a trigger to development and progression of the NAFLD. In fact, it has been demonstrated that diet is an important factor for the development of NAFLD and its association is complex and extends beyond total energy intake.

RESUMO A doença hepática gordurosa não alcoólica (DHGNA) afeta aproximadamente de 20% a 30% da população geral sendo prevalente entre os indivíduos obesos. Os fatores de risco associados à DHGNA são: doenças relacionadas à síndrome metabólica, fatores genéticos e meio ambiente. Nesta revisão, fornecemos uma compilação bibliográfica avaliando como as evidências relacionadas aos componentes da dieta, incluindo ingestão calórica, de gorduras, de proteínas, de fibras e de carboidratos, especialmente a frutose, poderiam ser um estímulo para o desenvolvimento e progressão da DHGNA. Foi demonstrado que a dieta é um fator importante para o desenvolvimento da DHGNA e sua associação se estende além do consumo total de calorias.

Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis.

AIM: To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls. METHODS: This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed. RESULTS: No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 µU/mL vs 15.8 ± 8.33 µU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0.651), dyslipidaemia (P = 0.328), hypertension (P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0 (95%CI: 1.35-20; P = 0.017)]. CONCLUSION: The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.

Avaliação antropométrica e de composição corporal em mulheres sedentárias pós-menopausa com doença hepática gordurosa não alcoólica (DHGNA) submetidas à atividade física

A Doença hepática gordurosa não alcoólica (DHGNA) é uma das formas mais comuns de doença hepática, acometendo cerca de 20 a 30% da população adulta, sendo mais frequente em indivíduos obesos (70 a 80%). Os principais fatores de risco associados à doença são os componentes da Síndrome metabólica. Até o momento, não há um tratamento farmacológico específico para a DHGNA e modificações no estilo de vida com redução de peso e exercício físico são sempre preconizados. Existem poucos dados sobre o impacto da atividade física e uma estratégia nutricional ideal no tratamento da DHGNA. Visto a necessidade de elucidar o impacto da atividade física e a busca por uma estratégia nutricional ideal no tratamento da DHGNA, propusemos um estudo randomizado controlado avaliando os efeitos de uma dieta hipocalórica e hiperproteica e do exercício físico aeróbio associado a esta dieta nos parâmetros metabólicos e antropométricos de mulheres sedentárias pós-menopausa. Foram incluídas 40 mulheres sedentárias pós-menopausa com DHGNA, que possuíam biópsia hepática em um período igual ou menor que 2 (dois) anos. Essas pacientes foram randomizadas em 2 grupos: grupo TREINO: treinamento aeróbio associado à dieta hipocalórica e hiperproteica e grupo DIETA: somente dieta hipocalórica e hiperproteica e, acompanhadas por um período de 6 meses. Na análise intra-grupo das variáveis antropométricas nos períodos pré e pós-intervenção dietética ou exercício físico aeróbio não foram observadas diferenças significativas em ambos os grupos. Na análise intra-grupo das variáveis bioquímicas, o HDL mostrou-se estatisticamente diferente (p= 0,004) no grupo TREINO. Na análise inter-grupos das variáveis bioquímicas observamos um aumento significativo para HDL-C (p= 0,036) no grupo TREINO. Na análise intra-grupo das variáveis ergoespirométricas observamos diferença significativa para as variáveis VO2máx Relativo (p= 0,04), Tempo LA (p= 0,001), Tempo PCR (p= 0,003) e Tempo Pico (p= 0,001) no grupo TREINO...

The Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver diseases, affecting approximately 20-30% of the adult population and is more common in obese individuals (70-80%). The main risk factors associated with the disease are the components of the Metabolic syndrome. To date, there is no specific pharmacological treatment for NAFLD and changes in lifestyle with weight reduction and exercise are always recommended. Few datas exist on the impact of physical activity and optimal nutritional strategy for the treatment of NAFLD. Seen the need to elucidate the impact of physical activity and the search for an ideal nutritional strategy in the treatment of NAFLD, we proposed a randomized controlled trial evaluating the effects of a hypocaloric high-protein diet and aerobic exercise associated with this diet on metabolic and anthropometric parameters in sedentary postmenopausal women. 40 sedentary postmenopausal women with NAFLD who had liver biopsy for a period equal to or less than 2 (two) years were included. These patients were randomized into 2 groups: TRAINING group: aerobic training with hypocaloric high-protein diet and DIET group: only hypocaloric high-protein diet, and followed for a period of six months. In intra-group anthropometric variables pre and post dietary intervention or aerobic exercise analysis, no significant differences were observed in both groups. In intra-group analysis of biochemical variables, HDL was statistically different (p= 0.004) on the TRAINING group. In inter-group analysis of biochemical variables observed a significant increase in HDL-C (p= 0.036) on TRAINING group. In the analysis of intra-group ergospirometric variables significant differences were observed for the variables Relative VO2max (p= 0.04), Time at VAT (p= 0.001), Time at RCP (p= 0.003) and Time at peak (p= 0.001) in TRAINING group...

Hypocaloric high-protein diet improves clinical and biochemical markers in patients with nonalcoholic fatty liver disease (NAFLD) / La dieta hipocalórica rica en proteínas mejora los marcadores clínicos y bioquímicos en pacientes con hepatopatía grasa no alcohólica (HPGNA)

Objective: To investigate the role of hypocaloric high-protein diet, a prospective clinical study was conducted in NAFLD patients. Research methods and procedures: Pre-versus post-interventional data were analyzed in 48 stable NAFLD patients (submitted to a hypocaloric high-protein diet during 75 days. Variables included anthropometrics (body mass index/ BMI and waist circumference/WC), whole-body and segmental bioimpedance analysis and biochemical tests. Diet compliance was assessed by interviews every two weeks. Results: BMI, WC and body fat mass remained relatively stable (-1.3%, -1.8% and -2.5% respectively, no significance). HDL- cholesterol increased (P < 0.05) whereas total, LDL and VLDL cholesterol, triglycerides, aspartate aminotransferase/AST, gamma glutamyltransferase/GGT, alkaline phosphatase/AP, fasting blood glucose and glycated hemoglobin/ HbA1c decreased (P < 0.05). When patients were stratified according to increase (22/48, 45.8%) and decrease (21/48, 43.8%) of BMI, association between weight decrease and liver benefit could be elicited in such circumstances for ALT, AP and AST/ALT ratio. No change could be demonstrated in patients who gained weight. Multivariate assessment confirmed that waist circumference, ferritin, triacylglycerol, and markers of glucose homeostasis were the most relevant associated with liver enzymes. Discussion: Ours results are consistent with the literature of calorie restriction in the management of NAFLD. Changes in lifestyle and weight loss are recommended for NAFLD patients. European guidelines also support this recommendation. Conclusion: This is the first study that demonstrated that a high protein, hypocaloric diet were associated with improvement of lipid profile, glucose homeostasis and liver enzymes in NAFLD independent on BMI decrease or body fat mass reduction (AU)

Objetivo: Para investigar el papel de la dieta hipocalórica rica en proteínas, se realizó un estudio clínico prospectivo en pacientes con HPGNA. Métodos de investigación y procedimientos: Se analizaron los datos antes y después de la intervención en 48 pacientes con HPGNA estable, sometidos a una dieta hipocalórica y rica en proteínas durante 75 días. Las variables incluían medidas antropométricas (índice de masa corporal (IMC) y circunferencia de la cintura (CC)), análisis de bioimpedancia corporal completa y segmentaria y pruebas bioquímicas. El cumplimiento de la dieta se evaluó mediante entrevistas quincenales. Resultados: El IMC, la CC y la masa grasa corporal permanecieron relativamente estables (-1,3 %, -1,8 % y -2,5%, respectivamente, sin significación). Las HDL-colesterol aumentaron (P < 0,05) mientras que el colesterol total, las LDL y las VLDL, los triglicéridos, la aspartato aminotransferasa (AST), la gamma glutamiltransferasa (GGT), la fosfatasa alcalina (FA), la glucemia en ayunas y la hemoglobina glucosilada (HbA1c) disminuyeron (P < 0,05). Cuando se estratificó a los pacientes en función del aumento (22/48, 45,8 %) o descenso (21/48, 43,8 %) del IMC, se pudo observar una asociación entre la pérdida de peso y el beneficio hepático reflejado en la ALT, la FA y el cociente AST/ALT. No se pudo demostrar ningún cambio en los pacientes que ganaron peso. La evaluación multivariada confirmó que la circunferencia de la cintura, la ferritina, el triacilglicerol y los marcadores de la homeostasis de la glucosa eran los que más relevantemente se asociaban con las enzimas hepáticas. Discusión: Nuestros resultados son consistentes con la bibliografía relativa a la restricción calórica en el manejo de la HPGNA. Los cambios en el estilo de vida y la pérdida de peso se recomiendan en los pacientes con HPGNA. Las guías europeas también apoyan esta recomendación. Conclusión: Éste es el primer estudio que demuestra que una dieta rica en proteínas se asocia con la mejora del perfil lipídico, la homeostasis de la glucosa y las enzimas hepáticas en la HPGNA independientemente del descenso del IMC o la reducción de la masa grasa corporal (AU)