Esteatose hepática - uma doença crônica que pode vir do intestinoɁ
O fígado gordo [não alcoólico]: sua construção por endotoxinas intestinais
[Imagem: hepatolog.spb.ru]
Invariavelmente, quando o tema do fígado gordo [esteatose hepática não alcoólica ou NAFLD] aparece na pauta médica dominante, busca-se a causa na genética ou na frutose. Há décadas essa é uma fala mainstream: foi o consumo de frutose que construiu o fígado gordo, frutose é tóxica ao ponto de ser causa eventual de fígado esteatótico. Genética ou frutose: ficam girando em torno desse círculo. No caso da frutose, o equívoco é grosseiro.
R. Peat teve o mérito de levantar as endotoxinas como uma provável causa da esteatose hepática. G Dinkov em nota do ano passado [2023] mostrou material científico recente [2022] que tem tudo para jogar por terra um dos mitos de estimação da medicina oficial que é o de culpar a frutose pelo fígado esteatotico.
Bem construído, o trabalho científico [A] mostra que, em vez do açúcar, o que estaria por trás da esteatose hepática [non alcohoolic fatty liver disease] tem a ver com as bactérias intestinais, com endotoxinas [LPS, lipopolissacarideos] produzidos a partir do mibrobioma intestinal.
A esteatose hepática é uma das doenças hepáticas mais comuns em todo o mundo. E “desde os anos 1990, a frequência da esteatose não-alcoólica do fígado mais do que dobrou em adultos e adolescentes” [C]. Aparentemente, sua incidência se dá em um terço da população.
E, sim, aquilo que consumimos na alimentação – no caso, determinadas fibras vegetais e amidos – termina sendo o fator importante na gênese do fígado gordo [excluído o álcool].
As endotoxinas produzidas por tais fibras que alimentam bactérias, promove, “a partir do cólon, uma reação tipo inflamação crônica de baixa intensidade na parede intestinal, a qual, ao longo do tempo compromete a assim chamada ´barreira intestinal´ e causa uma condição chamada de ´intestino que vaza´. Uma vez que tal hiperpermeabilidade intestinal [leaky gut] é estabelecida, um monte de endotoxinas liberadas, potencialmente depois de cada refeição, alcança a veia porta que as drena para o fígado.
A endotoxina por si mesma é uma molécula altamente inflamatória e é notória por causar degeneração de tecidos, incluindo fibrose e mesmo câncer. A maioria desses efeitos das endotoxinas são levados adiante através da ativação do receptor TLR4, que dispara uma cascata, ladeira abaixo, de óxido nítrico, histamina, IL-6, NF-kB, serotonina e outros mediadores inflamatórios” [D].
Ele acrescenta que os níveis sanguíneos dessas endotoxinas estão diretamente correlacionados com o estágio e severidade da doença [D].
Ou seja, quanto mais a pessoa consome aquelas fibras vegetais que alimentam bactérias [presentes em grãos, cereais, hortaliças e legumes, além dos incensados pró-bióticos] maior presença de endotoxinas, mais chance de construir ou agravar, por exemplo, a esteatose hepática e outras formas de doença hepática, além de doenças crônico-degenerativas.
Corrigir o problema pela raiz significa reformatar a alimentação para diminuir seu impacto sobre o crescimento bacteriano [levando em conta, por exemplo, a grande quantidade de argumentação contra as endotoxinas, papel a que se propôs o livro intitulado Por que (quase) toda doença começa pelo intestino, que pode ser obtido aqui], sendo que há indícios de que a suplementação com a [verdadeira] vitamina E ajude nesse objetivo [C].
A pesquisa científica acima citada [A] – e que examinou vários trabalhos científicos - comparou pessoas com fígado saudável com grupo que apresentava esteatose hepática e esteatohepatite e descobriu que o sangue dos pacientes com fígado enfermo apresentavam níveis muito altos de endotoxinas. E constatou que quanto mais grave o problema do fígado gordo, quanto mais avançados os achados histológicos da doença, maiores os níveis de endotoxinas no sangue. A análise também revelou “aumento significativo” de marcadores bioquímicos de inflamação sistêmica [proteína C reativa, PCR], e de síndrome metabólica [A].
Os cientistas concluem [A] que, uma vez que níveis de endotoxinas altos são encontrados mesmo em pacientes com esteatose hepática leve [comparados com pessoas com fígados saudáveis] os níveis plasmáticos de endotoxinas podem constituir um potencial biomarcador para a esteatose hepática não alcoólica [A], que, aliás vem a ser o titulo do seu trabalho.
Valendo lembrar que a esteatose hepática é uma doença de evolução silenciosa, até que essa degeneração hepática alcance graus mais profundos [fibrose, cirrose].
Estamos diante de uma doença muito comum no conjunto da população, doença potencialmente capaz de levar a cirrose e câncer de fígado. Infelizmente, é muito comum e plenamente legitimado pela medicina/nutrição oficial o hábito de alimentar a flora bacteriana intestinal com alimentos portadores de fibras vegetais pró-bactérias.
De tal forma que deixar de promover essa microbiota pode se constituir na medida preventiva mais poderosa que a pessoa pode assumir na linha de proteção do fígado [não apenas de esteatose, mas da capacidade hepática de eliminar estrogênio dos sistemas] e da prevenção de várias das doenças crônico-degenerativas cuja origem está no intestino.
GM Fontes, Brasília 19-4-24
As informações aqui presentes não pretendem servir para uso diagnóstico, prescrição médica, tratamento, prevenção ou mitigação de qualquer doença humana. Não pretendem substituir a consulta ao profissional médico ou servir como recomendação para qualquer plano de tratamento. Trata-se de informações com fins estritamente educativos. Nenhuma das notas aqui presentes, neste blog, conseguirá atingir o contexto específico do paciente singular, nem doses, modo de usar etc. Este trabalho compete ao paciente com seu médico. Isso significa que nenhuma dessas notas - necessariamente parciais - substitui essa relação.
Referências ___________________
[A] SOPPERT J BRANDT E F HEUSSEN N M, 2022. Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2023 Oct;21(11):2746-2758. doi: 10.1016/j.cgh.2022.11.030. Epub 2022 Dec 5 - DOI: 10.1016/j.cgh.2022.11.030
Free article “Background & aims: Growing evidence supports a role of gut-derived metabolites in nonalcoholic fatty liver disease (NAFLD), but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. This systematic review with meta-analysis aims to provide further insights. Methods: PubMed, Embase, and Cochrane Library were searched for studies published until January 2022 assessing blood endotoxins in patients with NAFLD. Meta-analyses and univariate/multivariate meta-regression, as well as correlation analyses, were performed for endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, and metabolic syndrome, as well as liver function and histology. Results: Forty-three studies were included, of which 34 were used for meta-analyses. Blood endotoxin levels were higher in patients with simple steatosis vs liver-healthy controls (standardized mean difference, 0.86; 95% confidence interval, 0.62-1.11) as well as in patients with nonalcoholic steatohepatitis vs patients with nonalcoholic fatty liver/non-nonalcoholic steatohepatitis (standardized mean difference, 0.81; 95% confidence interval, 0.27-1.35; P = .0078). Consistently, higher endotoxin levels were observed in patients with more advanced histopathological gradings of liver steatosis and fibrosis. An increase of blood endotoxin levels was partially attributed to a body mass index rise in patients with NAFLD compared with controls. Nevertheless, significant increases of blood endotoxin levels in NAFLD retained after compensation for differences in body mass index, metabolic condition, or liver enzymes. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations, and in most cases, paralleled a rise in markers for intestinal permeability. Conclusion: Our results support blood endotoxin levels as relevant diagnostic biomarker for NAFLD, both for disease detection as well as staging during disease progression, and might serve as surrogate marker of enhanced intestinal permeability in NAFLD. Registration number in Prospero: CRD42022311166.
[B COLLAPSE, 2022. December 22, 2022 Blood endotoxins may aid disease detection, staging in NAFLD “Blood endotoxin levels were increased among patients with nonalcoholic fatty liver disease compared with healthy controls and may serve as a relevant diagnostic biomarker, according to research in Clinical Gastroenterology and Hepatology.
“NAFLD is asymptomatic during early development, thus hindering early disease detection. Moreover, even during progression of the disease, noninvasive diagnostic tools for a reliable diagnosis and disease staging are lacking,” Josefin Soppert, MS, a PhD candidate at the Institute for Molecular Cardiovascular Research at University Hospital RWTH Aachen in Germany, and colleagues wrote. “Increasing evidence suggests the importance of gut-derived microbial constituents in NAFLD progression. ... Previous studies have reported increased levels of endotoxins in blood and liver of patients with biopsy-proven NAFLD. However, a high variability of the reported blood endotoxin concentrations is noted among studies.”
“NAFLD is asymptomatic during early development, thus hindering early disease detection. Moreover, even during progression of the disease, noninvasive diagnostic tools for a reliable diagnosis and disease staging are lacking,” Josefin Soppert, MS, and colleagues wrote.
In a systematic review and meta-analysis, Soppert and colleagues evaluated 43 studies to determine endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, metabolic syndrome, liver function and histology.
They reported higher blood endotoxin levels among patients with simple steatohepatitis compared with healthy controls (standardized mean difference [SMD] = 0.86; 95% CI, 0.62-1.11) as well as among patients with nonalcoholic steatohepatitis compared with nonalcoholic fatty liver and non-NASH patients (SMD = 0.81; 95% CI, 0.27-1.35). Further, patients with more advanced histopathological gradings of liver steatosis and fibrosis had “consistently higher” endotoxin levels.
A rise in BMI among patients with NAFLD also correlated with increased blood endotoxin levels ( = 0.2217; 95% CI, 0.0391-0.4043), and meta-analysis revealed a “significant increase” in biochemical parameters of systemic inflammation (C-reactive protein), metabolic syndrome and liver dysfunction.
“Our meta-analysis revealed that blood endotoxin levels are increased in NAFLD patients compared to liver-healthy controls, also after compensation for differences in BMI,” Soppert and colleagues concluded. “Increased blood endotoxin levels were already detected in simple steatosis patients vs. liver-healthy controls as well as in NASH vs. NAFL/non-NASH patients, overall suggesting blood endotoxin levels as potential biomarker for NAFLD. “For a future clinical application of blood endotoxins as noninvasive diagnostic tool, additional clinical trials addressing the diagnostic accuracy of systemic endotoxin levels, alone or in combination with other parameters, as noninvasive biomarker for NAFLD onset and progression as well as intestinal permeability are required.” Published by: Sources/Disclosures Collapse
Source: Soppert J, et al. Clin Gastroenterol Hepatol. 2022;doi:10.1016/j.cgh.2022.11.030.
[C] KAREDATH J JAVED H TALPUR F A, 2022. Effect of Vitamin E on Clinical Outcomes in Patients With Non-alcoholic Fatty Liver Disease: A Meta-Analysis. Published: December 21, 2022 DOI: 10.7759/cureus.32764 Peer-Reviewed - Cureus 14(12): e32764. Cite this article as: Karedath J, Javed H, Ahsan Talpur F, et al. (December 21, 2022) Effect of Vitamin E on Clinical Outcomes in Patients With Non-alcoholic Fatty Liver Disease: A Meta-Analysis. doi:10.7759/cureus.32764 “The aim of the current meta-analysis was to assess the effects of vitamin E on clinical outcomes in individuals with non‐alcoholic fatty liver disease (NAFLD). The current meta-analysis was planned, reported, and conducted per the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Two authors systematically searched for all papers using PubMed, Cochrane Central Register, and Embase from inception to October 15, 2022. Outcomes assessed in the current meta-analysis included changes in alanine transaminase (ALT) and aspartate transaminase (AST) from baseline in IU/L. Other outcomes included a change in BMI (kg/cm2), a change in total cholesterol level from baseline (mg/l), and a fibrosis score. Total articles were included in the current meta-analysis, enrolling 569 patients (274 patients in the vitamin E group and 295 in the placebo group). The study found that reduction in ALT levels, AST levels, and BMI was significantly greater in patients in the vitamin E group compared to the placebo group. However, no significant differences were reported in terms of change in fibrosis score and total cholesterol.
Introduction & Background - Non‐alcoholic fatty liver disease (NAFLD) is characterized by fatty deposition in the liver cells in individuals without excessive intake of alcohol. It includes a variety of illnesses, from cirrhosis to steatohepatitis to fatty liver [1]. It is one of the most common forms of chronic liver disease worldwide. Since the 1990s, the frequency of NAFLD has more than doubled in adolescents and adults. This chronic liver disease is a substantial cause of morbidity [2]. A meta-analysis conducted by Younossi ZM et al. found that the global prevalence of NAFLD was around 25.24% between 1989 and 2015 [3]. In addition, NAFLD is linked to a significant clinical, financial, and health-related quality of life burden [3].
As the pathogenesis of NAFLD remains poorly understood, NAFLD treatment is far from optimum. The recommended treatment options for NAFLD include weight reduction, regular physical activity, and a healthy diet. Vitamin E is one of the major types of chain-breaking, lipid-soluble antioxidants found in the human body. It occurs naturally in certain foods like seeds, leafy green vegetables, and nuts [4]. Vitamin E is considered a cytoprotective factor. It helps to prevent the liver's degenerative and inflammatory processes during exposure to various dietary factors, environmental pollutants, and xenobiotics [5]. In combination with lifestyle changes, vitamin E may have a potential function in the treatment of NAFLD, according to the literature. However, the limitations of the currently available research prevent us from drawing definitive conclusions on the impact of vitamin E on different clinical outcomes in NAFLD patients [6].
Vitamin E is also known as tocopherol. It is a chain-breaking antioxidant in free radical reactions that is particularly significant in lipid peroxidation and membrane stability. Vitamin E enhances the histology features and biochemistry of NAFLD. A study reported that vitamin E reduced intrahepatic triglycerides through the inhibition of hepatic de novo lipogenesis via its antioxidant activity [7]. Other studies showed that vitamin E lessened NAFLD via multiple other mechanisms, such as protection of cellular structures against upregulation of superoxide dismutase activity, damage from oxygen free radicals, fibrosis, adiponectin, and leptin expression [8-9]. In addition, vitamin E limits membrane injury precipitated by reactive oxygen species (ROS) and is considered a promising antioxidant entity for treating NAFLD [7].
One of the most crucial global public health concerns is the rising prevalence of NAFLD. One of the leading causes of the beginning and progression of NAFLD is oxidative stress [10]. Antioxidant therapy has thus been thought to be potentially helpful in treating NAFLD. In particular, vitamin E helps those with NAFLD's histological alterations and liver function [10]. Despite several studies on this topic, there is a dearth of meta-analyses drawing robust conclusions from these studies. Amanullah I et al. carried out a systematic review and reported that vitamin E had beneficial impacts on NAFLD [11]. Since then, certain new studies have been conducted related to the beneficial impacts of vitamin E on NAFLD. In the current meta-analysis, a quantitative synthesis of all these studies has been done to quantify the magnitude of treatment response associated with vitamin E. Current meta-analysis aims to assess the effects of vitamin E in individuals with NAFLD.
Discussion - Our current meta-analysis aimed to assess the efficacy of vitamin E treatment compared to other treatments in patients affected by NAFLD. The study found that the use of vitamin E in life modification programs adds a significant impact in terms of decreasing ALT levels, AST levels, and BMI. However, no significant differences were reported in terms of total cholesterol and fibrosis score.
NAFLD and metabolic syndrome are closely connected. It may be more severe, and the condition may progress and cause cirrhosis [21]. The core of treatment for individuals with NAFLD includes dietary changes and weight loss [22]. Patients, however, rarely succeed in their lifestyle objectives, and pharmaceutical treatment is typically thought to have the best results [23]. Even though data related to the pathogenesis of NAFLD is rate, oxidative stress can be a major factor in the progression and evolution of NAFLD among patients [6]. With regards to free radical processes like lipid peroxidation, vitamin E is regarded as a chain-breaking antioxidant. It protects against lipid peroxidation by creating complexes with the free radicals' electrons. In this context, vitamin E is regarded as an efficient agent against reactive oxygen species (ROS) and offers defense against liver fibrosis caused by the cytokine "transforming growth factor-beta 1 (TGF-1)" [24].
Among all the included studies that assessed the effect of vitamin E on ALT levels, four studies supported the point that change in ALT is significantly greater in patients receiving vitamin E compared to patients in the control group. Similarly, three RCTs also reported that the change in AST levels is significantly greater in patients receiving vitamin E. Several case-control and cohort studies have been done to assess the impact of vitamin E on NAFLD, but the findings are inconclusive [25]. Erhardt A et al. compared the antioxidant levels of patients with NAFLD with the control. The study concluded reduced levels of tocopherols in NAFLD [6]. A past meta-analysis conducted by Amanullah I et al. showed that the impact of vitamin E is significantly greater in reducing ALT and AST. One of the limitations of this meta-analysis was that the pooled analysis was conducted on just post values of ALT and AST and ignored baseline values [11]. In contrast, the current meta-analysis has focused on changes in ALT and AST values from baseline.
The current meta-analysis did not find a significant difference between patients who received vitamin E and the control group in terms of reducing fibrosis scores. However, only 3 three assessed this outcome and their findings need to be cautiously interpreted as limited by the low sample size.
A study conducted by Hoofnagle JH et al. found that weight loss needs to be the most important priority as obesity can cause worsening of fibrosis [26]. One RCT concluded that vitamin E enhanced ALT and those histological responses were more apparent in individuals with NAFLD who lost weight [26]. The current meta-analysis has also found that the reduction in BMI was significantly greater in patients receiving vitamin E compared to the patients in the control group. The meta-analysis conducted by Amanullah I et al. also found similar results [11].
The current meta-analysis is associated with certain limitations. Firstly, the sample size of the studies was limited. In addition, heterogeneity among the study results in each outcome was high due to variations in vitamin E dosage, formulation, study population, and comparison groups. Despite all these limitations, all included studies were RCTs and covered both children and adults, giving ideas about vitamin E therapy's benefits in both age groups. Considering that the sample size of all studies was very small, it is important that future trials that cover a large population need to be conducted. In addition, future trials should consider the aptness of dosage regimens to develop more recommendations. Secondly, the safety aspect should also be assessed in future studies in children and adults to determine the tolerability of the desired doses of vitamin E.
Conclusions - The current meta-analysis was conducted to determine the efficiency of vitamin E in enhancing clinical outcomes in patients with NAFLD. The study found that the reduction of ALT, AST, and BMI was significantly greater in patients receiving vitamin E compared to the control group. However, no significant differences were reported between the two groups in relation to fibrosis score and total cholesterol levels. Most included studies were limited, with a low sample size and follow-up duration. However, the current meta-analysis may help to review the guidelines of NAFLD by providing high evidence levels.
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[D] DINKOV G, 2023. Serum endotoxin leve lis a reliable biomarker of liver disease. Fonte:
http://haidut.me/?p=2162
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Muito obrigado pelo esclarecimentos!
Bom dia! Qual seria essa “verdadeira” vitamina E e a sua Dose Recomendada Diária?