Efeito da suplementação com probióticos em pacientes com esteato-hepatite não alcoólica : ensaio clínico randomizado

Introdução: A Doença hepática gordurosa não alcoólica (DHGNA) compreende desde a esteatose hepática simples até esteato-hepatite não alcoólica (EHNA), que pode progredir para cirrose ou hepatocarcinoma. Atinge um quarto da população mundial e está associada com a epidemia da obesidade. Considerando o aumento da prevelância de EHNA e a existência de lacunas no seu tratamento, esse estudo objetivou avaliar o efeito da suplementação com probióticos em marcadores de função hepática e parâmetros clínicos em pacientes com EHNA. Métodos: Trata-se de um ensaio clínico randomizado duplo-cego que incluiu pacientes adutos com EHNA diagnosticados por biópsia hepática. A intervenção consistiu de 24 semanas de suplementação com um mix de probióticos (Lactobacillus acidophillus + Bifidobacterium lactis + Lactobacillus rhamnosus + Lactobacillus paracasei, 1x109 CFU) ou placebo, duas vezes ao dia. No período basal e após as 24 semanas de tratamento, foram avaliados os seguintes parâmetros: dados clínicos e demográficos, elastografia transitória (FibroScan), enzimas hepáticas, NAFLD Fibrosis Score, Fatty Liver Index, avaliação laboratorial, concentração sérica de Toll-Like receptor -4 (TLR-4) e biomarcador Citokeratin 18 (CK-18). Foi também realizada avaliação antropométrica, atividade física e do consumo alimentar, além de análises da microbiota intestinal através da região hipervariável V4 do gene 16S rRNA. Resultados: Foram 85 pacientes elegíveis, desses, 46 pacientes confirmaram o diagnóstico de EHNA por biópsia hepática e, Quarenta e quatro pacientes completaram o estudo, sendo 59% mulheres, com média de idade de 51,4 ±11,6 anos. No período basal, 87% dos pacientes tinham baixo grau de fibrose (26% F0; 61% F1 através de biopsia), valores de enzimas hepáticas [AST 32 (24-46) U/L, ALT 42 (28-63) U/L, GGT 46 (28-84) U/L], circunferência de cintura aumentada (104,7±12 cm) e IMC com classificação de obesidade 30,97 (28,36-33,75) kg/m2, 76% em Síndrome Metabólica (SM). Após 24 semanas de intervenção, não foram observadas diferenças entre os grupos probiotico e placebo nos componentes da SM, circunferência da cintura, IMC, escores e enzimas hepáticas. (p> 0.05 para todos). CK-18 reduziu em ambos os grupos após a intervenção: no grupo probiótico de 981.09 (738.34-1134.73) para 639.46 (509.50-817.23) mIU / ml (p ≤0.01) e no grupo placebo de 789.74 (540.80-985.65) para 605.45 (472.13-837.22) mIU / ml (p = 0.013), entretanto sem diferença significativa entre os grupos (p = 0.109). Da mesma forma, TLR-4 reduziu em ambos os grupos após a intervenção, mas sem diferença entre os grupos (p = 0.885). Em relação à microbiota intestinal, não foram observadas diferenças na diversidade e abundância de filos e gêneros no grupo probiótico. Nenhuma outra mudança clinicamente significativa foi 10 observada nos grupos. Conclusão: A intervenção com probióticos por 24 semanas em pacientes com EHNA com baixo grau de fibrose demonstrou ser incapaz de promover alterações significativas na redução de biomarcadores de lesão e inflamação hepática, nas variáveis clínicas e nutricionais, e também na diversidade da microbiota intestinal.Introduction: Nonalcoholic fatty liver disease (NAFLD) embraces from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis or hepatocarcinoma. It affects a quarter of the world population and is associated with the obesity epidemic. Considering the increasing prevalence of NASH, and the existing gaps in its treatment, this study aimed to evaluate the effect of probiotic supplementation on liver function markers, and clinical parameters, in NASH patients. Methods: This double-blind, randomized clinical trial included adult outpatients with biopsy-proven NASH. The intervention consisted of 24 weeks of supplementation with probiotic mix (Lactobacillus acidophillus + Bifidobacterium lactis + Lactobacillus rhamnosus + Lactobacillus paracasei, 1x109 CFU for each) or placebo, twice a day. At baseline and 24-weeks after treatment, the following parameters were evaluated: demographic and clinical data, transient elastography (FibroScan), hepatic enzymes, NAFLD fibrosis score, Fatty Liver Index, laboratory assessment, serum concentration of toll-like receptor-4 (TLR-4) and cytokeratin 18 (CK-18) biomarker. An anthropometric data assessment, dietary intake and physical activity were also carried out, as well as an analysis of the intestinal microbiota through the hypervariable V4 region of the 16S rRNA gene. Results: From the 85 patients eligible, 46 were diagnosed with NASH through hepatic biopsy, and forty-four patients completed the trial (51,4 ±11,6 years, 59% women). At baseline, 87% had low hepatic fibrosis degree (26% F0; 61% F1 at biopsy), values of hepatic enzymes close to normal [AST 32 (24-46) U/L, ALT 42 (28-63) U/L, GGT 46 (28-84) U/L], increased waist circumference (104,7±12 cm), and BMI with obesity classification 30,97 (28,36-33,75) kg/m2, and 76% with Metabolic Syndrome (MetS). After 24 weeks of intervention, no differences were observed between the Probiotic and Placebo groups in the components of the MetS, waist circumference, BMI, scores or liver enzymes (p> 0.05 for all). CK-18 was reduced in both groups after the intervention: in the probiotic group from 981.09 (738.34-1134.73) to 639.46 (509.50-817.23) mIU / ml (p ≤ <0.01) and in the placebo group from 789.74 (540.80-985.65) to 605.45 (472.13-837.22) mIU / ml; p = 0.013, however with no significant difference between groups (p = 0.109). Likewise, TLR-4 was reduced in both groups after the intervention, also with no difference between groups (p = 0.885). In terms of gut microbiota (GM) no differences were observed in the diversity or abundance of philum and genus in probiotic group. No other clinically significant changes were observed in the groups. Conclusion: The intervention with probiotics for 24 weeks in 12 patients with EHNA with low degree of fibrosis demonstrated to be unable to promote significant changes in the reduction of liver injury and inflammation biomarkers, nutritional and clinical parameters, and also in the diversity GM

Effect of probiotic supplementation in nonalcoholic steatohepatitis patients : PROBILIVER TRIAL protocol

Background: Recently factors in the relationship between gut microbiota, obesity, diabetes and the metabolic syndrome have been suggested in the development and progression of nonalcoholic steatohepatitis (NASH). In this sense, this work aims to evaluate the effects of probiotic supplementation on intestinal microbiota modulation, degree of hepatic steatosis and fibrosis, inflammation, gut permeability, and body composition. Methods: This double-blind, randomized clinical trial will include adult outpatients with a diagnosis of NASH confirmed by biopsy with or without transient elastography. All patients will undergo a complete anamnesis to investigate their alcohol consumption, previous history, medications, nutritional assessment (dietary intake and body composition), sarcopenia, physical activity level and physical and functional capacity, cardiovascular risk, biochemical parameters for assessment of inflammatory status, lipid profile, hepatic function, gut permeability, and assessment of microbiota. These procedures will be performed at baseline and repeated after 24 weeks (at the end of the study). Through the process of randomization, patients will be allocated to receive treatment A or treatment B. Both patients and researchers involved will be blinded (double-blind study). The intervention consists of treatment with a probiotic mix (Lactobacillus acidophillus + Bifidobacterium lactis + Lactobacillus rhamnosus + Lactobacillus paracasei, 1 x 109 CFU for each) and the placebo which is identical in all its characteristics and packaging. Patients will be instructed to consume two sachets/day during 24 weeks and to report any symptoms or side effects related to the use of the sachets. Adherence control will be carried out through the patient’s notes on a form provided, and also by checking the number of sachets used. Discussion: The final results of study will be analyzed and disseminated in 2020

Alimentação escolar saudável : orientações para manipuladores de alimentos do PNAE

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Probiotic supplementation for 24 weeks in patients with non-alcoholic steatohepatitis: the PROBILIVER randomized clinical trial

Background and aimConsidering the increasing prevalence of non-alcoholic steatohepatitis (NASH) and treatment gaps, this study aimed to evaluate the effect of probiotic supplementation on liver function markers, nutritional status, and clinical parameters.MethodsThis double-blind, randomized clinical trial (ClinicalTrials.gov ID: NCT0346782) included adult outpatients with biopsy-proven NASH. The intervention consisted of 24 weeks of supplementation with the probiotic mix Lactobacillus acidophilus (1 × 109 CFU) + Lactobacillus rhamnosus (1 × 109 CFU) + Lactobacillus paracasei (1 × 109 CFU) + Bifidobacterium lactis (1 × 109 CFU), or placebo, twice a day. The following parameters were evaluated: demographic and clinical data, transient elastography (FibroScan), liver enzymes, NAFLD fibrosis score, fatty liver index, laboratory assessment, serum concentration of toll-like receptor-4 (sTLR-4) and cytokeratin 18 (CK-18), anthropometric data, dietary intake, and physical activity. Regarding data analysis, the comparison between the groups was based on the delta of the difference of each variable analyzed (value at the end of treatment minus the baseline value) using the t-test for independent samples or the Mann–Whitney U-test.ResultsForty-four patients with NASH completed the trial (51.4 ± 11.6 years). At baseline, 87% of participants had a mild liver fibrosis degree on biopsy, normal values of liver enzymes, transient elastography values consistent with grade 1 fibrosis in both groups, increased waist circumference (WC), a BMI of 30.97 kg/m2, and 76% presented with metabolic syndrome (MetS). After the intervention, no differences were observed between the probiotic and placebo groups in terms of MetS, WC, BMI scores, or liver enzyme levels (p &gt; 0.05 for all). The elastography values remained consistent with grade 1 fibrosis in both groups. Although CK-18 was reduced in both groups, a larger effect size was noted in the probiotic group (D = 1.336). sTLR-4 was also reduced in both groups, with no difference between groups (p = 0.885).ConclusionIntervention with probiotics in the early stages of NASH demonstrated no significant change in hepatic and clinical parameters.Clinical trial registrationClinicalTrials.gov, identifier NCT0346782

Comparação dos métodos de avaliação do estado nutricional em pacientes com retocolite ulcerativa

Introdução: A desnutrição é uma característica frequente em pacientes com Retocolite Ulcerativa (RCU) em atividade, porém poucos estudos têm mostrado esse status nutricional em pacientes em remissão. Devido à falta de informações com relação ao estado nutricional dos pacientes com RCU fez-se necessário o desenvolvimento desse estudo para avaliar essa população e prevenir possíveis deficiências que venham a afetar negativamente o curso da doença. Metodologia: Neste estudo transversal foram incluídos 80 pacientes portadores de RCU do Ambulatório de Doenças Inflamatórias Intestinais do Hospital de Clínicas de Porto Alegre, atendidos no período de 2014 a 2015, maiores de 18 anos. Foram excluídos pacientes portadores de doença maligna atual, transplantados de órgãos, gestantes e nutrizes, portadores de deficiência física que limitassem a execução dos procedimentos do estudo, portadores de doenças crônicas clinicamente relevantes, e pacientes que já tenham realizado procedimento cirúrgico relacionado à RCU. Os participantes de pesquisa realizaram bioimpedância (BIA), antropometria (índice de massa corporal, dobra cutânea triciptal, circunferência do braço e circunferência muscular do braço), coleta de sangue de hemograma, albumina, transferrina, cálcio, vitamina B12, ferro, Aspartatoaminotransferase (AST) e Alanina Aminotransferase (ALT), Velocidade de Sedimentação Globular (VSG), gama GT, creatinina e Proteína C-reativa (PCR), ), além de realizar o preenchimento de um registro alimentar de 3 dias, Avaliação Subjetiva Global (ASG) e medida força do aperto de mão não dominante (FAM). Resultados: A amostra compôs-se de mulheres, 62,5% (N: 50), média de idade de 45,6 ± 11,7 anos, 96% dos indivíduos eram caucasianos. Cinquenta e cinco por cento da população apresentava pancolite. Os medicamentos, mais utilizados foram os aminossalicilatos (mezalazina) com 30% da amostra. O tempo de diagnóstico dos pacientes foi de 11 ± 7,36 anos. A associação do tempo de doença com desnutrição não apresentou significância estatística, assim como a associação da extensão da doença com desnutrição para cada método utilizado, considerando a extensão máxima (pancolite). Comparando os diferentes métodos de avaliação nutricional 2,5% indivíduos foram classificados como desnutridos pelo Índice de Massa Corporal (IMC), na dobra cutânea triceptal (DCT), circunferência do braço (CB), circunferência muscular do braço (CMB) os pacientes apresentaram valores abaixo dos padrões de normalidade, 72,5%, 55% e 27,5% respectivamente. O FAM demonstrou que 79% dos pacientes apresentavam risco nutricional. Quanto à ASG, 3,8% dos pacientes foram classificados como moderadamente ou suspeita de serem desnutridos. Quanto à avaliação bioquímica os seguintes valores se mostraram abaixo da normalidade: albumina (1 paciente),transferrina, 35%, ferro sérico, 19%, cálcio, 10% , vitamina B12 2,5% ; ácido fólico nenhum dos pacientes apresentou deficiência. Quanto aos níveis de hemoglobina, 16% e hematócrito 25% dos sujeitos de pesquisa apresentaram-se com valor abaixo da normalidade. Os seguintes valores se mostraram acima da normalidade: VSG, 30% e PCR 21%, creatinina 8%, AST 6%, ALT 3% e Gama GT, 14%. Na avaliação nutricional, 35% dos pacientes apresentaram-se desnutridos em 3 métodos, 23% para 2 e 24% para 1 método utilizado; nenhum apresentou desnutrição para as 6 metodologias empregadas. IMC e ASG apresentaram a maior taxa de concordância (TC) entre os métodos (94% de concordância), enquanto FAM e ASG apresentaram a pior TC (19%). Quanto à TC dos métodos de avaliação clínica com marcadores séricos do estado nutricional, IMC e ASG também apresentaram as maiores TC com todos os marcadores séricos (62% a 95%), enquanto FAM apresentou as piores TC (18% a 48%), quando combinado com qualquer das outras variáveis utilizadas. Conclusões: A desnutrição classificada por todos os métodos utilizados não mostrou associação significativa com tempo de doença, bem como com a extensão máxima, mas demonstrou relação com todos os exames bioquímicos quando avaliada por IMC e ASG. Os pacientes apresentaram uma tendência de sobrepeso quando avaliados por IMC, assim como uma parcela dos sujeitos apresentaram um percentual de gordura acima da normalidade. Os sujeitos revelaram um possível risco da força muscular diminuída quando avaliados pela FAM, que não concordou com os outros métodos, assim, nosso estudo sugere que este método não tem utilidade na nossa população. Quando avaliados pelo registro alimentar, apresentaram déficits na ingestão de cálcio e ácido fólico. Os métodos de avaliação nutricional devem ser utilizados respeitando individualidades e disponibilidade de uso, buscando concordância na conclusão da avaliação, sendo que nosso estudo sugere por melhor anuência o uso de IMC em associação com a ASG.Malnutrition is a frequent feature in active UC patients, however, there are few published studies regarding nutritional status in patients that are in remission. Due to the lack of information related to the nutritional status of UC patients, the aim of this study was to evaluate this population and to prevent possible deficiencies that could negatively affect the disease course. This cross-sectional study included eighty UC patients over eighteen years old from the Inflammatory Bowel Disease Unit of the Hospital de Clínicas de Porto Alegre (HCPA), attended from 2014 to 2015, were included in this study. There were excluded from the study patients with current malignant disease, with transplanted organs, pregnant and lactating women, the physically disabled who would limit the performance of the procedures, carriers of clinically relevant chronic diseases, and the ones who have already performed surgical procedure related to UC. Participants of this study underwent bioimpedance analysis (BIA), anthropometric evaluation, body mass index (BMI), triceps skinfold thickness (TSF), mid-arm circumference (MAC) and mid-arm muscle circumference (MAMC), to determine complete blood count (CBC), serum albumin, transferrin, calcium, vitamin B12, iron, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), erythrocyte sedimentation rate (ESR), gamma-glutamyltransferase (GGT), creatinine and C-reactive protein (CRP), completion of a food record of three days for dietary assessment, SGA and HGS. Patients were composed by women, 62.5% (N:50), the average age was of 45.6 ± 11.7 years old, and 96% of the individuals were caucasian. Regarding the disease extent, 55% of the population presented pancolitis. The predominant treatment used was aminosalicylates (mesalazine), with 30% of the patients; while the time of diagnosis was 11 ± 7.36 years. The association of the disease duration and extent to malnutrition didn’t result in statistical significance regarding every method employed, when considering the maximum extent (pancolitis). When anthropometric parameters were evaluated, 2,5% individuals were classified as malnourished through body mass index (BMI). Analysis of triceps skinfold thickness (TSF), mid-arm circumference (MAC) and mid-arm muscle circumference (MAMC) resulted in subnormal values, 72.5%, 55% and 27.5%, respectively. HGS demonstrated that 79% of patients (N:61) presented nutritional risk. Regarding SGA, three individuals were classified as mildly or suspected of being malnourished. Biochemical evaluation of blood samples resulted in subnormal values: albumin (1 patient), transferrin 35% (N=28), iron 19% (N=15), calcium 10% (N=8), vitamin B12 2.5% (N=2); there was no deficiency in folic acid levels. Hemoglobin and hematocrit levels were subnormal in 16% (N:13) and 25% (N:20) of patients. The following parameters presented higher values than normal: ESR 30% (N:24) and CRP 21% (N:17), creatinine 8% (N:7), AST 6% (N:5), ALT 3% (3) and GGT 14% (N:11). In nutritional assessment, 35% of the patients presented positive results for three analyzes, 23% for two analyzes and 24% for one analysis; none of the patients presented malnutrition for all 6 analyzes. BMI and SGA demonstrated the highest concordance rate (CR) between the methods (94% of concordance), while HGS and SGA demonstrated the worst CR (19%). Considering the CR between the clinical methods of evaluation and the serum markers of the nutritional status, BMI and SGA presented the highest CR to all serum markers (62% to 95%), while HGS presented the worst CR (18% to 48%). Conclusions: Malnutrition classified by all methods here used didn’t result in any significant association with duration of the disease, as well as with the maximum extent; however, it demonstrated relation to all of the biochemical exams when evaluated through BMI and SGA. Patients showed a tendency to overweight when evaluated by BMI, as well as a share of the subjects presented a fat percentage above normal. The subjects revealed a possible risk of decreased muscle strength as assessed by HGS, which didn’t agree to the other methods, therefore, our study suggests that this method has no use in our population. When evaluated through food recall, patients presented deficits in calcium and folic acid intake. The nutritional assessment methods should be employed respecting the individualities and availability of use, seeking for concordance when concluding the evaluation, whereas our study suggests a better concordance in the use of BMI in association with SGA

Oral 24-week probiotics supplementation did not decrease cardiovascular risk markers in patients with biopsy proven NASH: A double-blind placebo-controlled randomized study

Introduction and Objectives: Cardiovascular disease (CVD) is the major cause of death in non-alcoholic fatty liver disease (NAFLD), a clinical condition without any approved pharmacological therapy. Probiotics are often indicated for the disease, but their results are controversial in part due to the poor quality of studies. Thus, we investigated the impact of 24-week probiotics supplementation on cardiovascular risk (CVR) in biopsy-proven non-alcoholic steatohepatitis (NASH) patients. Patients and Methods: Double-blind, placebo-controlled, single-center study (NCT03467282), adult NASH, randomized for 24 weeks daily sachets of probiotic mix (109CFU of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus paracasei and Bifidobacterium lactis) or placebo. Clinical scores (atherogenic indexes, atherosclerotic cardiovascular disease-ASCVD and systematic coronary risk evaluation-SCORE), biochemistry, miR-122, miR-33a, plasminogen activator inhibitor-1 (PAI-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), were determined before and after the intervention. Results: Forty-six patients were enrolled (23 received probiotics and 23 placebo), with a mean age of 51.7 years, most of them females and whites. Clinical and demographic features were similar between the groups at the baseline. The Median NAFLD activity score was 4.13 in both groups. Fibrosis was mild in most patients (15.2% and 65.2% F0 and F1, respectively). Treatment did not promote any clinically significant changes in body mass index or laboratory, including lipid and glucose profile. High CVR patients through atherogenic indexes decreased from baseline in both groups, as well as PAI-1 and miR-122 levels, although there was no difference between probiotics and placebo. Conclusions: A 24-week probiotic mix administration was not superior to placebo in reducing CVR markers in patients with NASH