Article

The Effect of a Low-Carbohydrate, Ketogenic Diet on Nonalcoholic Fatty Liver Disease: A Pilot Study

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Abstract

Nonalcoholic fatty liver disease is an increasingly common condition that may progress to hepatic cirrhosis. This pilot study evaluated the effects of a low-carbohydrate, ketogenic diet on obesity-associated fatty liver disease. Five patients with a mean body mass index of 36.4 kg/m(2) and biopsy evidence of fatty liver disease were instructed to follow the diet (<20 g/d of carbohydrate) with nutritional supplementation for 6 months. Patients returned for group meetings biweekly for 3 months, then monthly for the second 3 months. The mean weight change was -12.8 kg (range 0 to -25.9 kg). Four of 5 posttreatment liver biopsies showed histologic improvements in steatosis (P=.02) inflammatory grade (P=.02), and fibrosis (P=.07). Six months of a low-carbohydrate, ketogenic diet led to significant weight loss and histologic improvement of fatty liver disease. Further research is into this approach is warranted.

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... A laparoscopic cholecystostomy is even less invasive. Several reports have shown that a low-carbohydrate diet is effective in obese patients [3][4][5], and weight loss by diet and exercise are both effective in patients with nonalcoholic steatohepatitis (NASH) [6][7][8][9]. We present an obese patient with acute cholecystitis and liver cirrhosis caused by NASH, who was successfully managed with laparoscopic cholecystostomy and low-carbohydrate diet with exercise, followed by open cholecystectomy. ...
... Several studies show that a low-carbohydrate diet is effective for weight loss in obese patients [3][4][5]. Weight loss including diet and exercise are effective in patients with NASH [6][7][8][9]. NASH is exacerbated by sugar intake because glucose is converted to triglyceride and stored as lipids in the liver. Based on this metabolic mechanism, a low-carbohydrate diet is thought to be a reasonable treatment for patients with NASH. ...
... After therapy, liver fibrosis improved in the repeat liver biopsy specimen. Although fibrosis is often considered to be irreversible, this result shows that fibrosis in patients with NASH cirrhosis is reversible and improved by limitation of sugar intake [7]. Improvement in the pathological findings of steatosis after therapy can be expected to result in improved liver function in patients with NASH cirrhosis. ...
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Introduction: Laparoscopic cholecystectomy for patients with acute cholecystitis and liver cirrhosis is associated with increased risk. We present an obese patient with acute cholecystitis and liver cirrhosis caused by nonalcoholic steatohepatitis (NASH), who was successfully managed with laparoscopic cholecystostomy and a low-carbohydrate diet with exercise. Presentation of case: A 61-year-old woman presented with right upper quadrant abdominal pain. Ultrasonography and computed tomography were consistent with acute cholecystitis with multiple stones and cirrhosis. The patient had no history of alcohol intake, and serologic tests were negative. The patient's body mass index was 39 kg/m2 (154 cm, 93 kg) and NASH was suspected. Percutaneous transhepatic drainage was impossible because of the anatomic position of the gallbladder. Emergency laparoscopic cholecystostomy was performed initially for drainage. A low-carbohydrate diet and exercise were started for weight loss and her weight reduced by 19 kg over three months. Open cholecystectomy was performed uneventfully, and liver biopsy suggested NASH. Discussion: Laparoscopic cholecystostomy is a reasonable temporary alternative to cholecystectomy in patients with acute cholecystitis and increased surgical risk. Weight loss with diet and exercise can be effective in patients with NASH. A low-carbohydrate diet is a reasonable treatment for NASH, because glucose is converted to triglycerides and stored as lipid in the liver. Conclusion: Laparoscopic cholecystostomy was effective in this obese patient with acute cholecystitis and NASH cirrhosis. Using a low-carbohydrate diet with exercise, her weight decreased, and subsequent open cholecystectomy was uneventful.
... A total of 25 publications were excluded, due to the following reasons: no data on measures of interest (n = 6), BMI < 30 (n = 1), article not available (n = 2), caloric restriction (n = 8), other diet or carbohydrate intake > 50 g per day (n = 5) and same cohort from another article (n = 4). Finally, the systematic research resulted in 20 studies that met the inclusion criteria [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Of these, 19 focused on weight loss, 8 on BMI, 8 on systolic and diastolic blood pressure, 14 on fasting glucose levels, 10 on fasting insulin levels, 5 on HOMA-IR, 7 on HbA1c level, 9 on total cholesterol, 15 on HDL and LDL levels, 16 on TG levels, 4 on AST levels, 5 on ALT levels, 1 on left hepatic lobe volume and 1 on liver biopsy histopathological characteristics ( Table 1). ...
... Weight loss is the main recommendation of health-care guidelines to reduce the risk of complication development [69,70] in the context of MetS. Interestingly, the majority of the studies have demonstrated a significant weight loss induced by KD [50][51][52][54][55][56][57][58][59][60][61][62][63][64][65][66]68]. In the eight studies which also investigated the effects of KD on the BMI, the significant weight loss was systematically associated with a significant decrease of the BMI [50,56,58,60,61,63,65]. ...
... Eight studies are interested in KD effects on cardiac function, measuring especially systolic and diastolic pressure. Five of them showed a significant decrease in systolic BP [49,58,64,65,68] and four in diastolic BP [49,58,65,68]. Thirteen studies demonstrated that KD is significantly efficient to decrease TG blood levels (Table 3) [49,51,52,[54][55][56]58,[61][62][63]65,66,68] and only three showed no significant effects [57,59,60]. ...
Article
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Metabolic syndrome (MetS) is a major societal concern due to its increasing prevalence and its high risk of cardiovascular complications. The ketogenic diet (KD), a high fat, low carbohydrate, and non-caloric restrictive diet, is a new popular weight loss intervention but its beneficial effects are controversial. This study aims to gather all of the relevant studies using KD for metabolic disease treatment to determine its beneficial effects and evaluate its safety and efficacy for patients. Following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 20 articles in the final review. Overall, most of the studies showed a significant effect of KD on weight loss (17/19 articles), BMI (7/7), glucose levels (9/13), insulin levels (7/9), HOMA-IR (4/5), HbA1c (7/7), total cholesterol (6/9), TG (13/15), AST (3/4), and ALT (3/5), and no major side effects. The results heterogeneity seems to be explained by a difference of diet composition and duration. In conclusion, KD is a safety diet which seems to be a promising approach for obesity and MetS treatment, even if the optimal carbohydrate proportion and diet duration must be explored to enhance the beneficial effects of KD.
... Tendler et al. [14] conducted a prospective single-arm clinical pilot trial of five obese patients (mean BMI = 36.8 kg/m2) with NAFLD (diagnosed by liver biopsy) to investigate the effects of an LC diet on hepatic steatosis, inflammation, fibrosis, and body weight. ...
... A pre-study liver biopsy was conducted to establish baseline hepatic steatosis, fibrosis, and inflammation. All patients either abstained from alcohol or had a maximum of five alcoholic beverages annually [14]. Patients adhered to an LC diet for six months. ...
... In addition, consumption of excessive carbohydrates results in increased hepatic de-novo lipogenesis as evident by Sevastinova et al. [12] study where the participants were overfed with simple carbohydrates resulting in accelerated hepatic de-novo lipogenesis. On the contrary, Tendler et al. [14], Browning et al. [7], Martens et al. [10], and Amy et al [13], all found that an LC diet lowered hepatic triglyceride content more than a low-calorie diet. Browning et al. [7] found that the LC diet decreased intrahepatic triglyceride content by 12%, compared with 5% in the lowcalorie HC diet. ...
Article
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Non-alcoholic fatty liver disease is the accumulation of excessive fat in the liver. Various treatment options are available to manage the condition, among which carbohydrate restriction has been shown to reduce liver fat accumulation, liver inflammation, serum liver enzyme levels, and hepatic de-novo lipogenesis in people with non-alcoholic fatty liver disease. Here, we present a case report of a 25-year-old South Asian patient presenting with right upper quadrant pain, fatigue, and headaches. After confirmation of non-Alcoholic fatty liver disease (NAFLD) diagnosis by biopsy, the patient initiated a low-carbohydrate diet. Four months after which significant improvement was noticed in clinical and laboratory parameters. Peer-reviewed publications were then sourced from online databases to explore the efficacy of low-carbohydrate diets for NAFLD. Our results were compared with the existing data. However, limited literature existed for such an intervention in the South Asian population therefore, the case report is novel. Combined with findings from the literature, our results from the case report supported our hypothesis that carbohydrate restriction might promote a reduction in hepatic fat accumulation and inflammation in patients with NAFLD and diabetes in various ethnicities including South Asians.
... A comprehensive review of the literature published in 2020 by Watanabe et al. [89] confirmed these doubts and indicated important aspects of the KD that require further research. On the other hand, there are studies thatreported the beneficial influence of KD ketone bodies on inflammation and fibrosis in patients with NAFLD; however, it is unknown if the effects werecaused by a very low carbohydrate intake (and ketosis) or by natural calorie restriction during KD (independently from ketosis and the macronutrient ratio [90]. ...
... The pilot study of a low-carbohydrate ketogenic diet (<20 g/d of carbohydrate) on obesity-associated biopsy-proven fatty liver disease showed that 6months of KD was associated with weight loss [90]. In another study, concerned the "Spanish Ketogenic Mediterranean Diet"(SKMD)(unrestricted calorie intake, high omega-3 PUFA), significant improvements in the body mass, BMI, waist circumference (WC), LDL, TG, HDL, ALT, AST, fasting plasma glucose (FPG), and steatosis degree wereobserved [91]. ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is a significant clinical and epidemiological problem that affects around 25% of the adult global population. A large body of clinical evidence highlights that NAFLD is associated with increased liver-related morbidity and mortality and an increased risk of cardiovascular disease, extrahepatic cancers, type 2 diabetes, and chronic kidney disease. Recently, a series of studies revealed the pivotal role of gut microbiota (GM) dysbiosis in NAFLD’s pathogenesis. The GM plays an essential role in different metabolic pathways, including the fermentation of diet polysaccharides, energy harvest, choline regulation, and bile acid metabolism. One of the most critical factors in GM stabilization is the diet; therefore, nutritional therapyappearsto be a promising tool in NAFLD therapy. This paper aims to review the current knowledge regardingthe nutritional approach and its implications with GM and NAFLD treatment. We discuss the positive impact of probiotics, prebiotics, and symbiotics in a reverse dysbiosis state in NAFLD and show the potential beneficial effects of bioactive substances from the diet. The full description of the mechanism of action and comprehensive examination of the impact of nutritional interventions on GM modulation may, in the future, be a simple but essential tool supporting NAFLD therapy.
... The intervention framework designed by us combines the aspect of diet, as well as physical activity, along with a behavioural modification to treat NAFLD. Many interventions done on NAFLD patients include either the diet [15][16] or exercise component [17][18] only. Also, many studies done on NAFLD patients are based on specific diets, such as the Mediterranean diet [19] and the ketogenic diet [15,20]. ...
... Many interventions done on NAFLD patients include either the diet [15][16] or exercise component [17][18] only. Also, many studies done on NAFLD patients are based on specific diets, such as the Mediterranean diet [19] and the ketogenic diet [15,20]. Our intervention framework is based on the balanced diet approach with individualized calorie reduction goals (500 -1,000 kcal/day) targeted towards gradual weight loss, similar to a six-month exclusive nutrition intervention used by Elias et al. on NAFLD patients [21]. ...
Article
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Purpose Non-alcoholic fatty liver disease (NAFLD), is recognized as a health care burden worldwide. Lifestyle modification remains the first line of treatment. However, the real challenge is ensuring the patient's adherence to lifestyle modification measures, especially in hospitals with resource-limited settings. Methods We developed a six-month-long, dietitian-led, hospital-based, lifestyle intervention framework for obese NAFLD patients and evaluated its content. Literature review, interviews, and discussions with 10 health experts (general physicians, dietitians/nutritionists, gastroenterologists, and a clinical psychologist) and 45 NAFLD patients (35 in Phase I and 10 in Phase II) in a tertiary hospital of India were carried out. Results The lifestyle intervention framework has unique features, such as an intensive nature to ensure adherence, a comprehensive educational format with clear guidelines, the customization of a prescription as per individual patient requirements, and a holistic approach to inculcate self-monitoring and behavioral change in NAFLD patients. Conclusion Health professionals worldwide can use this lifestyle intervention framework to develop counseling interventions for better adherence among obese NAFLD patients.
... Some factors such as type of disease, age, gender, changes in blood glucose, and obesity may affect the adipokine levels (13). Tendler et al. (2007) studied patients with fatty liver and found that after 24 weeks of intervention; low-fat diet and physical activity improve weight, body mass index, waist, and amounts of AST and ALT significantly (14). The results of many studies show that physical activities can improve lipid profile, insulin resistance, and RBP4 (15,16). ...
... Some factors such as type of disease, age, gender, changes in blood glucose, and obesity may affect the adipokine levels (13). Tendler et al. (2007) studied patients with fatty liver and found that after 24 weeks of intervention; low-fat diet and physical activity improve weight, body mass index, waist, and amounts of AST and ALT significantly (14). The results of many studies show that physical activities can improve lipid profile, insulin resistance, and RBP4 (15,16). ...
Article
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Background & Aims: Retinol-binding protein 4 (RBP4) as an adipokine is involved in regulating insulin function and glucose
... Vale ressaltar que a maioria dos trabalhos utilizou um protocolo hipocalórico com redução calórica moderada de 500-1000kcal/dia.41,48,49 Um estudo utilizou um protocolo cetogênico,50 e apenas um comparou protocolos de baixo carboidrato e baixo lipídeo, 43 em que ambas as dietas hipocalóricas diminuíram o peso corporal, a gordura corporal total, a gordura visceral e o conteúdo lipídico intra-hepático. No entanto, nenhum dos estudos avaliou os indivíduos após a finalização do protocolo, verificando se os efeitos perduram.Independentemente do tipo de dieta utilizado, o foco é que a regressão da DHGNA deve ser iniciada pela perda de peso. ...
... A perda rápida de peso, apesar de reduzir a gordura hepática, piora a inflamação e a fibrose do órgão, melhorando um lado da doença e prejudicando outro.43 Ademais, dietas de difícil aderência costumam acabar em compensação alimentar e superalimentação, as quais culminam na recuperação do peso anterior ou até aumento do mesmo, muitas vezes levando à piora do quadro, quando comparado ao estado anterior ao início da dieta.50 Em indivíduos com DHGNA, um ganho de peso modesto, de 3 a 5kg, já leva ao aumento da gordura hepática, 51 sendo necessário atentar para a individualidade de cada um para utilizar a dietoterapia mais adequada.CONCLUSÃOA DHGNA tem mecanismos de desenvolvimento complexos, multifatoriais e, na grande maioria das vezes, está associada à obesidade. ...
Article
Introdução: A doença hepática gordurosa não alcoólica (DHGNA) é a condição na qual há acúmulo excessivo de gordura no tecido hepático, não causada pelo consumo excessivo de etanol. A etiologia desse acúmulo é multifatorial, mas parece ocorrer por mecanismos que envolvem a síntese excessiva de lipídios e/ou a redução da excreção dos mesmos em indivíduos geneticamente predispostos. Objetivo: este artigo tem como objetivo descrever os principais mecanismos de desenvolvimento da DHGNA, assim como sua prevenção e tratamento com foco nutricional. Metodologia: revisão de literatura. Resultados: de maneira geral, apesar de ser uma doença que envolve o acúmulo de gorduras no fígado, ela parece não estar relacionada ao consumo excessivo de gorduras em si, mas ao sobrepeso causado pelo sedentarismo e ao balanço calórico positivo. Conclusão: o principal tratamento da DHGNA envolve, portanto, perda de peso, objetivando redução lenta e gradual de cerca de 10% do peso corporal, a qual deve ser feita por readequação da dieta e prática de atividades físicas. Nesse sentido, também foram descritos e comparados estudos com dietas hipercalóricas, normocalóricas, hipocalóricas, low carb/high fat, low fat/high carb, dieta mediterrânea, entre outras, visando à melhor estratégia para a regressão da doença e melhora da qualidade de vida do paciente.
... Although Okita et al. intervened in their research, with restriction of energy in taking from Carbohydrates, they increased the intake of vitamin A, vitamin C, and vegetables. Tendler et al. (2007) after six months of a low-carbohydrate, ketogenic diet observed significant weight loss and histological improvement of fatty liver disease (24). ...
... Although Okita et al. intervened in their research, with restriction of energy in taking from Carbohydrates, they increased the intake of vitamin A, vitamin C, and vegetables. Tendler et al. (2007) after six months of a low-carbohydrate, ketogenic diet observed significant weight loss and histological improvement of fatty liver disease (24). ...
Article
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Background: Nonalcoholic fatty liver (NAFLD) is a worldwide, leading cause of chronic liver disease, not yet approved medical treatment standards. The aim is to assess the effects of aerobic exercise sand calorie-restricted (CR) diet on many clinical and laboratory findings in patients with Nonalcoholic Steatohepatatis (NASH). Methods: In Randomized controlled trial study, in Mashhad, between February 2010-August 2011, Twenty-five patients with NASH, in ranging ages of 18-55, were randomly selected to be divided in to two groups, who received CR-diet and aerobic exercise (n = 12) and CR-diet alone (n = 13). We measured Anthropometric indices, cardio-respiratory fitness, and biochemical profiles in three steps, in baseline, and after 8-12 weeks of intervention. We measured hepatic steatosis and patient's quality of life by ultra-sonography and short form (questionnaire) 36 in three steps. Data was then analyzed by paired and independent samples T Test. Results: We observed a significant improvement in BP, FBS, TG, HOMA-IR, ultra-sonography grading of steatosis and quality of life, only in patients who received aerobic exercises. (P value 0.021, 0.005, 0.006, 0.042, 0.010 and 0.012). Waist circumference, waist-to-height ratio, serum ALT and peak oxygen consumption improved in both groups; however, improvement was significantly, higher in patients who received aerobic exercises (P value 0.027, 0.011, 0.020 and 0.020). Body weight, BMI, body fat percentage and AST improved in both groups but they were not significantly different. No significant changes noted in total cholesterol, LDL and HDL in groups. Conclusions: Add of aerobic exercises to CR diets can, not only enhance the therapeutic effects of calorie-restricted diet, but also bring more benefits in patients with NASH.
... Although exercise has broader benefits on metabolic health, excessive consumption of carbohydrates-especially the refined one-can likely outrun the benefits of exercising, argues Pathare (2021) [25] . Interestingly, as this review will discuss now onwards, the Low-Carbohydrate High-Fat [26,36,39] . LCHF diets achieve this by number of-but not limited to-benefits, such as reducing insulin levels, addressing insulin resistance, normalising appetite, improving heart health markers, and promoting abdominal-and overall-fat loss. ...
Article
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This study aims to equip health professionals with essential directions for their practice and research in fatty liver disease. In fatty liver disease, excess fat is accumulated in the liver cells, and it mainly has two types: Alcoholic Fatty Liver Disease (AFLD) and Non-Alcoholic Fatty Liver Disease (NAFLD). AFLD is widely accepted to be associated with excessive alcohol consumption. However, in NAFLD's case, although the name acknowledges that it is not associated with excessive alcohol consumption, the exact cause of NAFLD remains ambiguous. Furthermore, for almost four decades, without specialised treatments and prevention strategies, NAFLD has constantly increased, affecting more than a quarter of the world's population. Meanwhile, although the current dietary recommendations for NAFLD patients orbit around the conventional High-Carbohydrate Low-Fat diets, mounting evidence advocates the broader benefits of Low-Carbohydrate High-Fat (LCHF) diets in this regard. Therefore, focusing on the databases such as PubMed, Cochrane Library, and Google Scholar, the authors have carried out an advanced literature search reporting on the efficacy of LCHF diets on NAFLD. After a comprehensive search—using appropriate "keywords and Boolean operators" and "inclusion & exclusion criteria"—the authors selected a potentially relevant set of existing peer-reviewed articles for this narrative review. After critically investigating the LCHF-NAFLD theme, the authors found that LCHF diets may significantly decrease liver fat and may even reverse the disease by targeting the key causes of hepatic fat storage, i.e., high insulin levels, excessive calorie consumption (mainly from carbohydrates), and excessive consumption of refined carbohydrates. Additionally, LCHF diets may provide a comprehensive health benefit beyond liver health. The authors conclude that the LCHF- NAFLD theme represents a rich vein of research opportunities. The authors encourage and call researchers, doctors, nutritionists, dieticians, and related-health professionals to engage more with the LCHF-NAFLD theme.
... However, though ketogenic diets have largely been analyzed in rodents, only a few studies have been performed in humans. A pilot study in obesity-associated fatty liver disease showed that patients on a 6-month ketogenic diet lost weight and presented with histological improvements in steatosis, inflammation, and fibrosis [157]. Recently, a short-term ketogenic diet was shown to decrease hepatic lipids in obese patients in only 6 days, despite increased plasma FFA levels. ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
... While little is known about the natural history of fibrosis in LI, it has been shown that anti-inflammatory KDs are associated with decreased fibrosis in non-alcoholic fatty liver disease (NAFLD). A small pilot study (n = 5) in 2007 demonstrated a reduction in inflammation and fibrosis in NAFLD patients who undertook a 6-month KD [143]. Peng et al. [144] and Glass et al. [145] also observed reductions in hepatic fibrosis using a KD to treat NAFLD. ...
Article
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Lipedema (LI) is a common yet misdiagnosed condition, often misconstrued with obesity. LI affects women almost exclusively, and its painful and life-changing symptoms have long been thought to be resistant to the lifestyle interventions such as diet and exercise. In this paper, we discuss possible mechanisms by which patients adopting a ketogenic diet (KD) can alleviate many of the unwanted clinical features of LI. This paper is also an effort to provide evidence for the hypothesis of the potency of this dietary intervention for addressing the symptoms of LI. Specifically, we examine the scientific evidence of effectiveness of adopting a KD by patients to alleviate clinical features associated with LI, including excessive and disproportionate lower body adipose tissue (AT) deposition, pain, and reduction in quality of life (QoL). We also explore several clinical features of LI currently under debate, including the potential existence and nature of edema, metabolic and hormonal dysfunction, inflammation, and fibrosis. The effectiveness of a KD on addressing clinical features of LI has been demonstrated in human studies, and shows promise as an intervention for LI. We hope this paper leads to an improved understanding of optimal nutritional management for patients with LI and stimulates future research in this area of study.
... To date, lifestyle modifications including diet and exercise are the first line and cornerstone of NAFLD/NASH treatment. Most studies have demonstrated a reduction of steatosis or/and steatohepatitis without improvement in liver fibrosis [137][138][139][140][141][142][143] , nevertheless some have shown fibrosis regression, especially when a WL of 10% or more is achieved or when exercise therapy is included [144,145] . ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan's nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.
... Two of the trials evaluated a ketogenic diet (8% CHO in one, <20 g CHO per day in the other) over 2 and 24 weeks, respectively. 86,87 Despite weight loss in both, there was no significant reduction in ALT, however the 2 weeks study did show reduction in liver fat content. When low (<60 g/day) and high CHO (>180 g/day) diets were compared over an 11 weeks calorie restriction intervention, reduction in IHLC was comparable between both groups after 7% weight loss. ...
Article
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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and affects approximately one third of adults in the United States. The disease is becoming a global epidemic as a result of the rising rates of obesity and metabolic disease. Emerging data suggest weight loss of ≥10% overall body weight is beneficial in resolving steatosis and reversing fibrosis. Prospective trials comparing various diets are limited by lack of sufficient power as well as pre- and post-treatment histopathology, and therefore no specific diet is recommended at this time. In this narrative review we examine the pathophysiology behind specific macronutrient components that can either promote or reverse NAFLD to help inform more specific dietary recommendations. Overall, the data supports reducing saturated fat, refined carbohydrates, and red and processed meats in the diet, and increasing the consumption of plant-based foods. Diets that incorporate these recommendations include plant-based diets such as the Dietary Approaches to Stop Hypertension, Mediterranean, vegetarian, and vegan diets.
... Individuals with NAFLD have an excess of intrahepatic triglycerides. A ketogenic diet significantly reduced hepatic triglycerides in subjects with NAFLD compared to calorie restriction 61 , and another report demonstrated an improvement of NAFLD in patients who adopted a ketogenic diet 62,63 . ...
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Aging is a universal process that renders individuals vulnerable to many diseases. Although this process is irreversible, dietary modulation and caloric restriction are often considered to have antiaging effects. Dietary modulation can increase and maintain circulating ketone bodies, especially β-hydroxybutyrate (β-HB), which is one of the most abundant ketone bodies in human circulation. Increased β-HB has been reported to prevent or improve the symptoms of various age-associated diseases. Indeed, numerous studies have reported that a ketogenic diet or ketone ester administration alleviates symptoms of neurodegenerative diseases, cardiovascular diseases, and cancers. Considering the potential of β-HB and the intriguing data emerging from in vivo and in vitro experiments as well as clinical trials, this therapeutic area is worthy of attention. In this review, we highlight studies that focus on the identified targets of β-HB and the cellular signals regulated by β-HB with respect to alleviation of age-associated ailments.
... [4,[17][18][19][20][21][22] Several authors have demonstrated that a "simple ketogenic diet" may result in a significant improvement in hepatic steatosis. [23,24] Similarly, relatively high protein content may exert beneficial effects in fatty liver disease. [25,26] However, we are skeptical of whether a meaningful improvement in hepatic inflammation and fibrosis can be achieved without calorie depletion in the majority of patients with NASH. ...
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Background and objectives: Nonalcoholic steatohepatitis (NASH) is strongly associated with obesity. A weight loss of ≥10% is necessary to improve NASH severity, but this goal has rarely been achieved in published studies using different diet protocols. The effect of a ketogenic, hypocaloric, commercial diet ("Ideal Protein," IP) on body weight, metabolic markers, and liver tests in a group of NASH patients is evaluated in this study. Daily calorie intake was tailored to achieve a weight loss of ≥10%. Methods: We analyzed 38 patients with NASH who were placed on the IP diet between 2014 and 2018 and compared their outcomes with 6 control patients who declined the diet. All patients were evaluated by a trained health coach in weekly intervals throughout the study period. Clinical and laboratory data obtained before and at 6.5 months after intervention were compared using paired t-testing. Results: The patients on the IP diet experienced a significant weight reduction (217 ± 8 lb vs. 194 ± 7 lb; mean ± S.E.M.), corresponding to an average weight loss of 9.7% ± 1.6%. Significant changes in systolic blood pressure (133 ± 3 mmHg vs. 123 ± 3 mmHg), triglycerides (200 ± 21 mmol/L vs. 132 ± 11 mmol/L), hemoglobin A1c (6.71% ± 0.29% vs. 5.74% ± 0.19%), SGPT (97.3 ± 11.1 IU/L vs. 44.2 ± 5.9 IU/L), SGOT (82.4 ± 10.5 IU/L vs. 32.8 ± 5.2 IU/L), and Fib-4 scores (2.25 ± 0.23 vs. 1.40 ± 0.13) were also observed (P<0.05 in all cases). In the IP group, 50.5% of patients lost ≥10% body weight. In contrast, no significant changes were observed in the control group. The IP diet was well tolerated, and no safety signals were noticed. Conclusions: A ketogenic, hypocaloric resulted in striking weight loss and significant improvements in metabolic parameters and liver tests, suggesting that this approach carries promise for the dietary management of patients with NASH.
... In the same study, KD was more effective at reducing hepatic triglycerides than a low-energy diet (−28%), despite similar effects on body weight loss [30]. Furthermore, a six-month KD (<20 g/day carbohydrate intake) resulted in liver histology improvements including steatosis, and inflammation, with a tendency to ameliorate fibrosis in five biopsy-proven NAFLD patients with obesity, which also achieved weight reduction (−12.8 kg) [37]. ...
Article
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Nonalcoholic fatty liver disease (NAFLD) is on the rise worldwide representing a public health issue. Its coexistence with obesity and other metabolic alterations is highly frequent. Therefore, current therapy interventions for NAFLD are mainly focused on progressive weight loss through modulation of overall calorie intake with or without specific macronutrient adjustments. Furthermore, other relevant nutritional interventions are built on food selection and time-restricted eating. Since every strategy might bring different results, choosing the optimal diet therapy for a patient is a complicated task, because NAFLD is a multifactorial complex disease. Importantly, some factors need to be considered, such as nutrition-based evidence in terms of hepatic morphophysiological improvements as well as adherence of the patient to the meal plan and adaptability in their cultural context. Thus, the purpose of this review is to explore and compare the subtleties and nuances of the most relevant clinical practice guidelines and the nutritional approaches for the management of NAFLD with a special attention to tangible outcomes and long-term adherence.
... Also, among patients with NAFLD, regular coffee drinkers had lesser fibrosis (RR = 0.70) [25]. Fad diets in the form of intermittent fasting and the lowcalorie ketogenic diet have been shown to improve hepatic steatosis but whether the reduction in steatosis results from the calorie restriction or the induced ketosis remains to be explored [26]. ...
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Therapeutics aimed at treating non-alcoholic fatty liver disease (NAFLD) target the pathogenic process from deranged metabolism leading to steatosis to cell stress and death, leading to a cascade of inflammation and fibrosis, ultimately culminating into cirrhosis. The development of drugs for management of NAFLD has bloomed over the past decade, although at present there is no approved pharmacological agent for its management. Not all patients with the disease progress to cirrhosis and decompensation; hence, treatment specifically is provided for those with a high risk of progression such as those with biopsy-proven steatohepatitis or fibrosis. Along with disease-specific management, all patients must receive therapies directed at risk factors such as dyslipidemia, insulin resistance, type 2 diabetes mellitus and obesity. Comorbidities such as cardiovascular disease, sleep apnoea and chronic kidney disease need management. A current perspective on the therapeutic options is detailed in this review.
... It was recently demonstrated that reducing the portion of CHO lowers the intrahepatic lipid accumulation in a few weeks, independently from the weight loss [87,88]. Adoption of this low CHO diet reduces liver inflammation and fibrosis on the long term [89]. On top of that, CHO reduction has been shown to have beneficial effect on glycemic control in T2DM patients regardless from the presence or absence of polyunsaturated fatty acid (ω-3) [90,91]. ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation within the liver affecting 1 in 4 people worldwide. As the new silent killer of the twenty-first century, NAFLD impacts on both the request and the availability of new liver donors. The liver is the first line of defense against endogenous and exogenous metabolites and toxins. It also retains the ability to switch between different metabolic pathways according to food type and availability. This ability becomes a disadvantage in obesogenic societies where most people choose a diet based on fats and carbohydrates while ignoring vitamins and fiber. The chronic exposure to fats and carbohydrates induces dramatic changes in the liver zonation and triggers the development of insulin resistance. Common believes on NAFLD and different diets are based either on epidemiological studies, or meta-analysis, which are not controlled evidences; in most of the cases, they are biased on test-subject type and their lifestyles. The highest success in reverting NAFLD can be attributed to diets based on high protein instead of carbohydrates. In this review, we discuss the impact of NAFLD on body metabolic plasticity. We also present a detailed analysis of the most recent studies that evaluate high-protein diets in NAFLD with a special focus on the liver and the skeletal muscle protein metabolisms.
... However, this weight loss was not sustained, and the patient showed difficulty in maintaining his weight in the long term (20) . More evidence suggests that limiting carbohydrate intake to less than 20 g/day as well as maintaining a caloric deficit of 30%, both were beneficial in achieving improvements in NAFLD Activity Score (21) , hepatic lipids (22) and serum hepatic enzymes (23) . Therefore, a caloric deficit of 500-750 kcal/day is an appropriate therapeutic intervention for NAFLD. ...
Article
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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.
... In fact, restricting CHO as opposed to restricting fat produces the greatest reduction in blood glucose, be it postprandially or with other measures of glucose overload, including HbA1c. Refined CHO, in particular, can produce more harmful metabolic effects than do equivalent calories from saturated fats [10,11,13,30,38,[44][45][46][47][48][49][50][51][52][53][54]. Such is the case in Nile rats. ...
Article
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Objective: The Nile rat (Arvicanthis niloticus) is a superior model for Type-II Diabetes Mellitus (T2DM) induced by diets with a high glycemic index (GI) and glycemic load (GLoad). To better define the age and gender attributes of diabetes in early stages of progression, weanling rats were fed a high carbohydrate (hiCHO) diet for between 2 to 10 weeks. Methods. Data from four experiments compared two diabetogenic semipurified diets (Diet 133 (60:20:20, as % energy from CHO, fat, protein with a high glycemic load (GLoad) of 224 per 2000 kcal) versus Diets 73MBS or 73MB (70:10:20 with or without sucrose and higher GLoads of 259 or 295, respectively). An epidemiological technique was used to stratify the diabetes into quintiles of blood glucose (Q1 to Q5), after 2-10 weeks of dietary induction in 654 rats. The related metagenetic physiological growth and metabolic outcomes were related to the degree of diabetes based on fasting blood glucose (FBG), random blood glucose (RBG), and oral glucose tolerance test (OGTT) at 30 minutes and 60 minutes. Results. Experiment 1 (Diet 73MBS) demonstrated that the diabetes begins aggressively in weanlings during the first 2 weeks of a hiCHO challenge, linking genetic permissiveness to diabetes susceptibility or resistance from an early age. In Experiment 2, ninety male Nile rats fed Diet 133 (60:20:20) for 10 weeks identified two quintiles of resistant rats (Q1,Q2) that lowered their RBG between 6 weeks and 10 weeks on diet, whereas Q3-Q5 became progressively more diabetic, suggesting an ongoing struggle for control over glucose metabolism, which either stabilized or not, depending on genetic permissiveness. Experiment 3 (32 males fed 70:10:20) and Experiment 4 (30 females fed 60:20:20) lasted 8 weeks and 3 weeks respectively, for gender and time comparisons. The most telling link between a quintile rank and diabetes risk was telegraphed by energy intake (kcal/day) that established the cumulative GLoad per rat for the entire trial, which was apparent from the first week of feeding. This genetic permissiveness associated with hyperphagia across quintiles was maintained throughout the study and was mirrored in body weight gain without appreciable differences in feed efficiency. This suggests that appetite and greater growth rate linked to a fiber-free high GLoad diet were the dominant factors driving the diabetes. Male rats fed the highest GLoad diet (Diet 73MB 70:10:20, GLoad 295 per 2000 kcal for 8 weeks in Experiment 3], ate more calories and developed diabetes even more aggressively, again emphasizing the Cumulative GLoad as a primary stressor for expressing the genetic permissiveness underlying the diabetes. Conclusion: Thus, the Nile rat model, unlike other rodents but similar to humans, represents a superior model for high GLoad, low-fiber diets that induce diabetes from an early age in a manner similar to the dietary paradigm underlying T2DM in humans, most likely originating in childhood.
... While little is known about the natural history of fibrosis in LI, it has been shown that anti-inflammatory KDs are associated with decreased fibrosis in non-alcoholic fatty liver disease (NAFLD). A small pilot study (n = 5) in 2007 demonstrated a reduction in inflammation and fibrosis in NAFLD patients who undertook a 6-month KD [143]. Peng et al. [144] and Glass et al. [145] also observed reductions in hepatic fibrosis using a KD to treat NAFLD. ...
... 3,8,12 In general 500 Kcal of deficit per week leads to 1 pound reduction12 of weight each week and energy restriction of 25-30 Kcal/Kg/day leads to a weight loss of up to 10 after 6 months. [16][17][18] However, reports involving more intensive weight reduction up to 1.6 Kg/week in morbidly obese patients has led to increased risk of portal fibrosis, so caution has to be exercised at tempo of weight reduction. ...
Article
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The fatty change and the inflammation spectrum are similar to the alcoholic fatty liver disease. While primary or idiopathic NAFLD forms the major part of this disease spectrum, we should always address secondary causes leading to fatty changes in liver. Management consists of general measures of risk reduction like: instituting weight loss program, diet control, exercise, weight loss drugs, use of insulin sensitizers like metformin and thiozolidinediones, use of cytoprotective agents like vitamin E, betaine and hypolipidemics like statins.
... Two such views are that ketosis can increase the risk of complications in the liver [27], and the kidneys [28]. However, in human studies, it was demonstrated that the ketogenic diet may improve clinical outcomes of nonalcoholic fatty liver disease [29,31]. In the present study, we found that markers of liver health; total protein, albumin, globulin, ALB:GLOB ratio, bilirubin, alkaline phosphate, AST, and ALT; were unaffected and no different from placebo with exogenous ketone supplementation in a healthy population over 90 days. ...
Article
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The ketogenic diet is a high-fat, very low-carbohydrate, moderate-protein diet that will induce a state of ketosis. Ketosis is a metabolic state characterized by elevated ketone body production in response to the absence of carbohydrates. Some drawbacks of the ketogenic diet are that it can be difficult to adhere to due to its restrictive nature, and it can also cause some undesirable side effects like gastrointestinal distress and increases in apoB-lipoproteins. In order to maximize the benefit of ketosis and to minimize side effects, supplementing with exogenous beta-hydroxybutyrate may induce a state of temporary ketosis without undesirable side effects. In the present study, 22 healthy male and female adults consumed 12.75 grams of beta-hydroxybutyrate salts or maltodextrin placebo twice daily for 90 days. Comprehensive blood safety analysis, body composition, bone densitometry, psychological and immune surveys, and blood pressure were administered at baseline, 30, 60, and 90 days. There were no significant differences in any measures collected, indicating that exogenous beta-hydroxybutyrate had no detrimental impact on fasting blood values such as electrolyte levels, glucose, hemoglobin A1c, complete blood count, body composition, bone density, psychological well-being, immune status, or blood pressure. We conclude that supplementing with exogenous beta-hydroxybutyrate is safe and well-tolerated by healthy adults.
... Among other studies with varied carbohydrate intake, some reported a significant reduction of aminotransferases [37], with a recent meta-analysis from 10 clinical trials showing that a LCD in this patient cohort led to a significant reduction in IHF [38] with further paper suggesting that a plant-based Mediterranean style diet -supplemented with green tea, walnuts and polyphenols -reduced NAFLD by 50% [39]. ...
Article
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Purpose of review: This review outlines recent research in the application of low carbohydrate diets (LCD) for insulin resistance (IR) and metabolic syndrome (MetS). Recent findings: Studies included in this review explore how a LCD can be used in the management of patients with IR and MetS. LCDs have been shown to result in Type 2 Diabetes Mellitus (T2DM) remission, improve lipid profiles and dramatically reduce intrahepatic fat. Summary: The field of nutritional science is notoriously complex. The LCD has a simple narrative, which can easily and safely be applied in clinical practice. Current guidelines recognise and encourage the use of LCD as a valid option for patients with T2DM and obesity. Structured, evidence-based education should be available for all clinicians to increase confidence and ensure consistency and quality control. Further real-world evidence into the application and scalability of a LCD are required. The use of digital health solutions and improved health technology should see significant advances in this field, with dietary habit being driven by patient-derived health data in response to food, and not population-based food guidelines. The narrative around MetS and IR needs to change from progression to remission, with a LCD being a valid option for this.
... From these, there were 64 studies reporting neurological 335 outcomes of which 83% showed improvement, and 63 studies reporting inflammatory 336 biomarkers of which 71% improved. Both nervous system sensitisation and inflammation 337 occur in chronic pain and as such may be improved by low-carbohydrate nutritional therapy. 338 More clinical trials within this population are required to build on the few human trials that 339 have been done. ...
Article
Dietary restriction of carbohydrate has been demonstrated to be beneficial for nervous system dysfunction in animal models and may be beneficial for human chronic pain. The purpose of this review is to assess the impact of a low-carbohydrate/ketogenic diet on the adult nervous system function and inflammatory biomarkers to inform nutritional research for chronic pain. An electronic data base search was carried out in May 2021. Publications were screened for prospective research with dietary carbohydrate intake <130g/day and duration of ≥2 weeks. Studies were categorised into those reporting adult neurological outcomes to be extracted for analysis and those reporting other adult research outcomes Both groups were screened again for reported inflammatory biomarkers. From 1548 studies there were 847 studies included. Sixty-four reported neurological outcomes with 83% showing improvement. Five hundred and twenty-three studies had a different research focus (metabolic n=394, sport/performance n=51, cancer n=33, general n=30, neurological with non-neuro outcomes n=12, or gastrointestinal n=4). The second screen identified 63 studies reporting on inflammatory biomarkers with 71% reporting a reduction in inflammation. The overall results suggest a favourable outcome on the nervous system and inflammatory biomarkers from a reduction in dietary carbohydrates. Both nervous system sensitisation and inflammation occur in chronic pain and the results from this review indicate it may be improved by low-carbohydrate nutritional therapy. More clinical trials within this population are required to build on the few human trials that have been done.
... Аналогичные результаты получены в пилотном исследовании у лиц с НАЖБП при изучении влияния кетогенной диеты и уменьшения потребления фруктозы. Через 6 мес достигнуто улучшение печеночных функциональных тестов, гистологической картины НАСГ и уменьшение выраженности фиброза [105]. ...
Article
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The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM. The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described. The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus, obesity, dyslipidemia, etc.), chronic kidney disease and the risk of developing hepatocellular cancer were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented. The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered. The ability of ursodeoxycholic acid to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
... Other potential disease progression mechanisms (vitamin D insufficiency, hyperuricemia, industrial fructose intake, menopausal status, etc.) have been hypothesized, and they are typically shared by NAFLD, obesity, and IR, further complicating the complicated interplay between NAFLD and metabolic dysfunction [51]. Tendler et al. [52] found that a low-carbohydrate, KD reduced mean weight by −12.8 kg and improved histologic fatty liver disease after six months in research on the effect of low-carbohydrate, KD on NAFLD. Watanabe et al. [31,53] recently published a study that found that a low-carbohydrate diet (LCD) improves liver fat metabolism in obese NAFLD patients. ...
Article
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This review aims to define the effectiveness of the ketogenic diet (KD) for the management of sarcopenic obesity. As the combination of sarcopenia and obesity appears to have multiple negative metabolic effects, this narrative review discusses the effects of the ketogenic diet as a possible synergic intervention to decrease visceral adipose tissue (VAT) and fatty infiltration of the liver as well as modulate and improve the gut microbiota, inflammation and body composition. The results of this review support the evidence that the KD improves metabolic health and expands adipose tissue γδ T cells that are important for glycaemia control during obesity. The KD is also a therapeutic option for individuals with sarcopenic obesity due to its positive effect on VAT, adipose tissue, cytokines such as blood biochemistry, gut microbiota, and body composition. However, the long-term effect of a KD on these outcomes requires further investigations before general recommendations can be made.
... Previous studies have shown that 4-12 wk of ADF administration can effectively decrease body weight and visceral fat mass (50)(51)(52). The beneficial findings for blood lipids (decrease in LDL cholesterol and triglycerides, increase in size particle of LDL) have been reported in addition to these favorable effects of ADF and Ramadan Fasting (RF) on body composition (53)(54)(55)(56). ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is considered as one of the most common causes of chronic liver disease. It includes a group of conditions associated with fat deposition in liver cells. Also, NAFLD is strongly associated with obesity and insulin resistance (IR). Until now, there is no pharmacological treatment validated for this disease. Fasting, nutritional intervention, and weight loss can be considered the first line in treating hepatic steatosis. This review is based on the scientific evidence showing the results of these interventions in the past years. The results include fasting and nutritional support for NAFLD treatment in humans. In clinical trials and cohort studies, an increase in hepatic fat content was correlated with a weight loss of at least 7% and a diet resembling the Mediterranean diet (MD) improving hepatic biomarkers and histological regression of NAFLD. Fasting is a dietary approach known to improve the lipid profile in healthy and obese populations by decreasing overall cholesterol, triglycerides, LDL, and increasing HDL. Bariatric surgery helps improve liver fat content in patients with serious health problems due to overweight.
... It is very possible that the transport of excess glucose to the adipose tissue via lipoproteins creates the particles that cause the atherosclerotic damage (small LDL) (Figure 1) (30)(31)(32). This entire process of dietary carbohydrate leading to fatty liver, leading to small LDL, is reversed by a diet without carbohydrate (26,33,34). ...
Article
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Type 2 Diabetes Mellitus (T2DM) is characterized by chronically elevated blood glucose (hyperglycemia) and elevated blood insulin (hyperinsulinemia). When the blood glucose concentration is 100 milligrams/deciliter the bloodstream of an average adult contains about 5–10 grams of glucose. Carbohydrate-restricted diets have been used effectively to treat obesity and T2DM for over 100 years, and their effectiveness may simply be due to lowering the dietary contribution to glucose and insulin levels, which then leads to improvements in hyperglycemia and hyperinsulinemia. Treatments for T2DM that lead to improvements in glycemic control and reductions in blood insulin levels are sensible based on this pathophysiologic perspective. In this article, a pathophysiological argument for using carbohydrate restriction to treat T2DM will be made.
... Furthermore, the low-carbohydrate diet was associated with a greater improvement in HDL-cholesterol and triglyceride concentrations. Moreover, five biopsy-proven NAFLD patients went through a sixmonth low-CHO ketogenic diet (<20 g/day) that significantly improved histologic steatosis, inflammation and fibrosis [122]. However, these results are inconclusive due to the possibility that this improvement may be due to weight loss. ...
Article
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Non-alcoholic fatty liver disease (NAFLD) is a major global health threat due to its growing incidence and prevalence. It is becoming the leading cause of liver disease in addition to its strong association with cardio-metabolic disease. Therefore, its prevention and treatment are of strong public interest. Therapeutic approaches emphasize lifestyle modifications including physical activity and the adoption of healthy eating habits that intend to mainly control body weight and cardio-metabolic risk factors associated with the metabolic syndrome. Lifestyle interventions may be reinforced by pharmacological treatment in advanced stages, though there is still no registered drug for the specific treatment of NAFLD. The purpose of this review is to assess the evidence available regarding the impact of dietary recommendations against NAFLD, highlighting the effect of macronutrient diet composition and dietary patterns in the management of NAFLD.
... In contrast, low-carbohydrate/high-fat KD induce significantly increased rates of whole-body fatty acid oxidation and hepatic ketogenesis [14][15][16]. Thus, both LFD and KD have been demonstrated to reduce liver fat [17][18][19][20][21], but whether one approach is superior to the other in terms of effectiveness, when matched for energy, is less understood. Hypocaloric KDs have been shown to rapidly decrease liver fat [14,16], and in the shortterm (3-14 days) outperform LFDs despite being matched for energy content and weight loss [22,23]. ...
Article
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Ketogenic diets (KDs) often contain high levels of saturated fat, which may increase liver fat, but the lower carbohydrate intake may have the opposite effect. Using a controlled feeding design, we compared liver fat responses to a hypocaloric KD with a placebo (PL) versus an energy-matched low-fat diet (LFD) in overweight adults. We also examined the added effect of a ketone supplement (KS). Overweight adults were randomized to a 6-week KD (KD + PL) or a KD with KS (KD + KS); an LFD group was recruited separately. All diets were estimated to provide 75% of energy expenditure. Weight loss was similar between groups (p > 0.05). Liver fat assessed by magnetic resonance imaging decreased after 6 week (p = 0.004) with no group differences (p > 0.05). A subset with nonalcoholic fatty liver disease (NAFLD) (liver fat > 5%, n = 12) showed a greater reduction in liver fat, but no group differences. In KD participants with NAFLD, 92% of the variability in change in liver fat was explained by baseline liver fat (p < 0.001). A short-term hypocaloric KD high in saturated fat does not adversely impact liver health and is not impacted by exogenous ketones. Hypocaloric low-fat and KDs can both be used in the short-term to significantly reduce liver fat in individuals with NAFLD.
... A 10-15 % of energy can be gained from protein which is needed to decrease the associated insulin resistance in such patients. 13 All diabetic patients should have their calories spread over the day and with intermittent healthy snacks and this idea should synchronize with the dietary prescription of NAFLD. A lot of vitamin supplementation like vitamin E, C have been studied with varied results. ...
... The ketogenic diet has also been reported to extend lifespan and healthspan in adult and aging mice [554][555][556], at least in part by upregulating PPARα target genes [555]. Besides weight loss, the ketogenic diet was also found to result in a histologic improvement of NAFLD patients [557]. While the effectiveness and safety of the ketogenic diet for the treatment of obesity is well documented (e.g. ...
Article
The epidemic of obesity is a major challenge for health policymakers due to its far-reaching effects on population health and potentially overwhelming financial burden on healthcare systems. Obesity is associated with an increased risk of developing acute and chronic diseases, including hypertension, stroke, myocardial infarction, cardiovascular disease, diabetes, and cancer. Interestingly, the metabolic dysregulation associated with obesity is similar to that observed in normal aging, and substantial evidence suggests the potential of obesity to accelerate aging. Therefore, understanding the mechanism of fat tissue dysfunction in obesity could provide insights into the processes that contribute to the metabolic dysfunction associated with the aging process. Here, we review the molecular and cellular mechanisms underlying both obesity and aging, and how obesity and aging can predispose individuals to chronic health complications. The potential of lifestyle and pharmacological interventions to counter obesity and obesity-related pathologies, as well as aging, is also addressed.
... At the end of the study period, 4 of 5 posttreatment liver biopsies showed histologic improvements in steatosis, inflammatory grade, and fibrosis. 42 More recently, a study by Gepner and colleagues 43 showed that a Mediterranean low-carbohydrate diet reduced the hepatic fat content more effectively than the low-fat diet. A total of 278 patients were included in the study with diet intervention for 18 months. ...
Article
Nonalcoholic fatty liver disease (NAFLD) has become one of the most common causes of chronic liver disease worldwide. The prevalence of NAFLD has grown proportionally with the rise in obesity, sedentary lifestyle, unhealthy dietary patterns, and metabolic syndrome. Currently, in the absence of approved pharmacologic treatment, the keystone of treatment is lifestyle modification focused on achieving a weight loss of 7%-10%, cardiovascular exercise, and improving insulin sensitivity. The primary aim of this review is to outline the effect of different dietetic approaches against NAFLD and highlight the important micronutrient components in the management of NAFLD.
Article
Nonalcoholic fatty liver disease (NAFLD) is a major health problem, and its prevalence has increased in recent years, concurrent with rising rates of obesity and other metabolic diseases. Currently, there are no FDA-approved pharmacological therapies for NAFLD, and lifestyle interventions, including weight loss and exercise, remain the cornerstones for treatment. Manipulating diet composition and eating patterns may be a sustainable approach to NAFLD treatment. Dietary strategies including Paleolithic, ketogenic, Mediterranean, high-protein, plant-based, low-carbohydrate, and intermittent fasting diets have become increasingly popular because of their purported benefits on metabolic disease. This review highlights what is currently known about these popular dietary approaches in the management of NAFLD in clinical populations with mechanistic insight from animal studies. It also identifies key knowledge gaps to better inform future preclinical and clinical studies aimed at the treatment of NAFLD.
Article
Introduction: Dietary carbohydrate restriction or ketogenic diets are known to be beneficial in preventing liver fat accumulation. However, the effect of ketonemia on the risk of nonalcoholic fatty liver disease (NAFLD) in nondiabetic population is largely unknown. We investigated the association between fasting ketonuria and the risk of incident NAFLD in healthy adults. Methods: A cohort of 153,076 nondiabetic Koreans with no hepatic steatosis and low probability of fibrosis at baseline was followed for a median of 4.1 years. The outcome was incident hepatic steatosis with or without liver fibrosis, and it was assessed by liver ultrasound and noninvasive fibrosis indices, including fibrosis-4 and the NAFLD fibrosis score (NFS). Parametric proportional hazard models were used to estimate hazard ratios (HRs) for outcome according to ketonuria status. Results: Within 677,702.1 person-years of follow-up, 31,079 subjects developed hepatic steatosis. Compared with no ketonuria (reference), fasting ketonuria was significantly associated with a decreased risk of incident hepatic steatosis, with multivariable-adjusted HRs (95% confidence interval) of 0.81 (0.78-0.84). The corresponding HRs for incident hepatic steatosis with intermediate-to-high NFS were 0.79 (0.69-0.90). Similar associations were observed replacing NFS with fibrosis-4. In addition, the presence of persistent ketonuria at both baseline and subsequent visit was associated with the greatest decrease in the adjusted HR for incident NAFLD. Discussion: Ketonuria was associated with a reduced risk of developing incident hepatic steatosis with and without intermediate-to-high probability of advanced fibrosis in a large cohort of nondiabetic healthy individuals. The role of hyperketonemia in the prevention of NAFLD requires further exploration.
Article
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Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.
Chapter
The liver is the largest and most complex metabolic organ of the body. It performs critical functions for anabolism, detoxification, immune regulation/tolerance, and protection from gut-derived toxins. Advanced liver disease is strongly associated with malnutrition, and the severity of malnutrition correlates with the development of complications of liver disease, as well as mortality and poor outcome following liver transplantation. Optimal nutritional support can improve malnutrition in patients with liver disease and may decrease infectious complications, improve cognitive function, and in some instances, even decrease mortality. Obesity with “insulin resistance” is also a wide-spread problem and frequently leads to nonalcoholic fatty liver disease (NAFLD), and in some instances, nonalcoholic steatohepatitis (NASH) and cirrhosis. Dietary modification and vitamin E supplementation, lifestyle modification, and bariatric surgery have all been shown to improve the hepatic steatosis/liver histology in NASH. In this chapter, we review important interactions between nutrition and various types/stages of liver disease.
Article
Background: the Practical Guideline is based on the current scientific ESPEN guide on Clinical Nutrition in Liver Disease. Methods: it has been shortened and transformed into flow charts for easier use in clinical practice. The guideline is dedicated to all professionals including physicians, dieticians, nutritionists and nurses working with patients with chronic liver disease. Results: a total of 103 statements and recommendations are presented with short commentaries for the nutritional and metabolic management of patients with (i) acute liver failure, (ii) alcoholic steatohepatitis, (iii) non-alcoholic fatty liver disease, (iv) liver cirrhosis, and (v) liver surgery/transplantation. Disease-related recommendations are preceded by general recommendations on the diagnosis of nutritional status in liver patients and on liver complications associated with medical nutrition. Conclusion: this Practical Guideline gives guidance to health care providers involved in the management of liver disease on how to offer optimal nutritional care.
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Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, characterized by hepatic fat accumulation and possible development of inflammation, fibrosis, and cancer. The ketogenic diet (KD), with its drastic carbohydrate reduction, is a now popular weight loss intervention, despite safety concerns on a possible association with fatty liver. However, KDs were also reported to be beneficial on hepatic pathology, with ketone bodies recently proposed as effective modulators of inflammation and fibrosis. If the beneficial impact of weight loss on NAFLD is established, less is known on the effect of macronutrient distribution on such outcome. In a hypocaloric regimen, the latter seems not to be crucial, whereas at higher calorie intake, macronutrient ratio and, theoretically, ketosis, may become important. KDs could positively impact NAFLD for their very low carbohydrate content, and whether ketosis plays an additional role is unknown. Indeed, several mechanisms may directly link ketosis and NAFLD improvement, and elucidating these aspects would pave the way for new therapeutic strategies. We herein aimed at providing an accurate revision of current literature on KDs and NAFLD, focusing on clinical evidence, metabolic pathways involved, and strict categorization of dietary interventions.
Purpose of review: This study will provide a narrative review of the history of the clinical use of low-carbohydrate diets and give a practical example of how to implement a low-carbohydrate diet, with an emphasis on deprescribing medications. Recent findings: Low-carbohydrate diets have been used since the late 19th century to treat obesity and type 2 diabetes mellitus (T2DM). Recently, clinical research has validated the use of low-carbohydrate diets for individuals affected by obesity and T2DM, and these diets are included in several national clinical guidelines. Because medications are commonly used to treat hypertension and T2DM, special consideration must be made to monitor and reduce these medications to avoid overmedication. Clinic visits and home monitoring of blood pressure and glucose levels are important tools to alert clinicians that a reduction in medication levels may be indicated. Summary: Low-carbohydrate diets have been utilized clinically for many years to treat obesity and T2DM and can be used alongside effective monitoring to safely deprescribe dispensable medications for these diseases.
Article
Nonalcoholic fatty liver disease has been recognized as a major health burden. The efficacy and safety profile of pharmacotherapy in the treatment of nonalcoholic fatty liver disease remains uncertain; therefore, lifestyle modification is the first line of treatment. Based on available data, patients should optimally achieve at least a 5% to 10% weight reduction for histologic improvement. There is no clear consensus on the optimal diet or exercise regimen. Sustainability of any intervention is key to success; however, compliance has been a major issue in clinical trials. This finding underscores the importance of multidisciplinary strategies to achieve targeted weigh loss.
Article
Background and aims Increased levels of ketone bodies, an alternative fuel when glucose availability is low, may exert beneficial effects on cardiovascular disease (CVD) risk factors. Whether increased ketone bodies are associated with coronary artery calcium (CAC), a recognized and strong cardiovascular risk factor, remains unknown. We investigated the association of fasting ketonuria with CAC and its progression. Methods Cross-sectional and longitudinal studies were conducted in adults without diabetes or CVD. Subjects underwent routine health examinations including cardiac computed tomography estimations of CAC scores. Logistic regression models were performed to compute the odds ratios (ORs), 95% confidence intervals (CIs), for prevalent CAC scores >0 according to fasting ketonuria categories (0, 1, and ≥2). Linear mixed models with random intercepts and random slopes were used to estimate CAC progression. Results Of 144,346 subjects, 12.3% had CAC scores >0 at baseline. Overall, higher fasting ketonuria was associated with decreased prevalence of coronary calcification than no ketonuria. Multivariable-adjusted ORs (95% CIs) for prevalent CAC by comparing ketonuria categories 1 and ≥2 with no ketonuria, were 0.94 (0.84–1.06) and 0.82 (0.71–0.95), respectively. The associations did not differ according to clinically relevant subgroups. Ketonuria was associated with lower CAC progression over time; the multivariable adjusted ratio of progression rates comparing ketonuria ≥2 versus no ketonuria was 0.976 (0.965–0.995). Conclusions We found an inverse association between fasting ketonuria and subclinical coronary atherosclerosis, in both prevalence and progression. The potentially protective role of increased ketone body formation in CVD requires further investigation.
Article
Obesity is an emerging non-communicable disease associated with chronic low-grade inflammation and oxidative stress, compounded by the development of many obesity-related diseases, such as cardiovascular disease, type 2 diabetes mellitus, and a range of cancers. Originally developed for the treatment of epilepsy in drug non-responder children, the ketogenic diet (KD) is being increasingly used in the treatment of many diseases, including obesity and obesity-related conditions. The KD is a dietary pattern characterized by high fat intake, moderate to low protein consumption, and very low carbohydrate intake (<50 g) that has proved to be an effective and weight-loss tool. In addition, it also appears to be a dietary intervention capable of improving the inflammatory state and oxidative stress in individuals with obesity by means of several mechanisms. The main activity of the KD has been linked to improving mitochondrial function and decreasing oxidative stress. β-hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species, improving mitochondrial respiration. In addition, KDs exert anti-inflammatory activity through several mechanisms, e.g., by inhibiting activation of the nuclear factor kappa-light-chain-enhancer of activated B cells, and the inflammatory nucleotide-binding, leucine-rich-containing family, pyrin domain-containing-3, and inhibiting histone deacetylases. Given the rising interest in the topic, this review looks at the underlying anti-inflammatory and antioxidant mechanisms of KDs and their possible recruitment in the treatment of obesity and obesity-related disorders.
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Objective Aberrant ketogenesis is correlated with the degree of steatosis in NAFLD patients, and an inborn error of ketogenesis (mitochondrial HMG-CoA synthase deficiency) is commonly associated with the development of the fatty liver. Here we aimed to determine the impact of Hmgcs2-mediated ketogenesis and its modulations on the development and treatment of fatty liver disease. Methods Loss- and gain-of-ketogenic function through in vivo and in vitro models, achieved by Hmgcs2 knockout and overexpression, respectively, were examined to investigate the role of ketogenesis in the hepatic lipid accumulation during neonatal development and the diet-induced NAFLD mouse model. Results Ketogenic function was decreased in NAFLD mice with a reduction in Hmgcs2 expression. Mice lacking Hmgcs2 developed spontaneous fatty liver phenotype during postnatal development, which was rescued by a shift to a low-fat dietary composition via early weaning. Hmgcs2 heterozygous mice, which exhibited reduced ketogenic activity, were more susceptible to diet-induced NAFLD development, whereas HMGCS2 overexpression in NAFLD mice improved hepatosteatosis and glucose homeostasis. Conclusions Our study adds new knowledge to the field of ketone body metabolism and shows that Hmgcs2-mediated ketogenesis modulates hepatic lipid regulation under a fat-enriched nutritional environment. The regulation of hepatic ketogenesis may be a viable therapeutic strategy in the prevention and treatment of hepatosteatosis.
Article
Background The Practical guideline is based on the current scientific ESPEN guideline on Clinical Nutrition in Liver Disease. Methods It has been shortened and transformed into flow charts for easier use in clinical practice. The guideline is dedicated to all professionals including physicians, dieticians, nutritionists and nurses working with patients with chronic liver disease. Results A total of 103 statements and recommendations are presented with short commentaries for the nutritional and metabolic management of patients with (i) acute liver failure, (ii) alcoholic steatohepatitis, (iii) non-alcoholic fatty liver disease, (iv) liver cirrhosis, and (v) liver surgery/transplantation. The disease-related recommendations are preceded by general recommendations on the diagnostics of nutritional status in liver patients and on liver complications associated with medical nutrition. Conclusion This practical guideline gives guidance to health care providers involved in the management of liver disease to offer optimal nutritional care.
Chapter
Malnutrition is a manifestation of both acute and chronic pancreatitis (CP) and liver disease and can play a prognostic role, while nutritional interventions can play a therapeutic role. In these conditions, malnutrition is related to disease progression (Lautz et al., Clin Investig 70(6):478–86, 1992; Arvanitakis et al., Clin Nutr 39(3):612–31, 2020). There is overlap in deficiencies seen such as fat-soluble vitamins, which may be seen in pancreatic disorders and cholestatic liver disease; however, management varies between the conditions. Nutritional interventions such as optimal protein intake in liver disease and diet strategies post-cholecystectomy are important. In this chapter, the diagnosis of acute and chronic pancreatitis will be discussed along with an overview of the management of malnutrition for these and the post-cholecystectomy situations. In the liver disease section, the role of nutrition in liver disease will be discussed followed by it the nutritional management of various manifestations of acute and chronic liver disease (Figs. 7.1 and 7.2).
Chapter
Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading liver disease globally. NAFLD patients can have a progressive phenotype, non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis, liver failure and cancer. There is a close bi-directional relationship between NAFLD and type 2 diabetes mellitus (T2DM); NAFLD increases the risk for T2DM and its complications whereas T2DM increases the severity of NAFLD and its complications. The large global impact of NAFLD and T2DM on healthcare systems requires a paradigm shift from specialty care to early identification and risk stratification of NAFLD in primary care and diabetes clinics. Approach to diagnosis, risk stratification and management of NAFLD is discussed. In addition to optimizing the control of coexisting cardiometabolic comorbidities, early referral of NAFLD patients at high risk of having NASH or significant fibrosis to hepatology specialist care may improve management and allow access for clinical trials. Lifestyle modifications, vitamin E, pioglitazone and metformin are currently available options that may benefit patients with T2DM and NAFLD. The burst of clinical trials investigating newer therapeutic agents for NAFLD and NASH offer hope for new, effective and safe therapies in the near future.
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Context The prevalence of obesity and overweight increased in the United States between 1978 and 1991. More recent reports have suggested continued increases but are based on self-reported data.Objective To examine trends and prevalences of overweight (body mass index [BMI] ≥25) and obesity (BMI ≥30), using measured height and weight data.Design, Setting, and Participants Survey of 4115 adult men and women conducted in 1999 and 2000 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population.Main Outcome Measure Age-adjusted prevalence of overweight, obesity, and extreme obesity compared with prior surveys, and sex-, age-, and race/ethnicity–specific estimates.Results The age-adjusted prevalence of obesity was 30.5% in 1999-2000 compared with 22.9% in NHANES III (1988-1994; P<.001). The prevalence of overweight also increased during this period from 55.9% to 64.5% (P<.001). Extreme obesity (BMI ≥40) also increased significantly in the population, from 2.9% to 4.7% (P = .002). Although not all changes were statistically significant, increases occurred for both men and women in all age groups and for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. Racial/ethnic groups did not differ significantly in the prevalence of obesity or overweight for men. Among women, obesity and overweight prevalences were highest among non-Hispanic black women. More than half of non-Hispanic black women aged 40 years or older were obese and more than 80% were overweight.Conclusions The increases in the prevalences of obesity and overweight previously observed continued in 1999-2000. The potential health benefits from reduction in overweight and obesity are of considerable public health importance.
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The spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up and have not carefully delineated different histological types when determining clinical outcomes. The aim of this study was to compare clinical characteristics and outcomes of patients with different types of nonalcoholic fatty liver. All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related mortality. Of 772 liver biopsy specimens, complete data were available in 132 patients. Fatty liver (type 1) did not differ from the other three types combined with respect to gender, race, age, or obesity. Cirrhosis was more common in the other types combined (22%) than fatty liver alone (4%; P </= 0.001). Overall mortality, histological iron, and hepatitis C did not differ between groups. Most of the liver-related deaths were in type 4. The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver. These poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.
Article
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The prevalence of obesity and overweight increased in the United States between 1978 and 1991. More recent reports have suggested continued increases but are based on self-reported data. To examine trends and prevalences of overweight (body mass index [BMI] > or = 25) and obesity (BMI > or = 30), using measured height and weight data. Survey of 4115 adult men and women conducted in 1999 and 2000 as part of the National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. Age-adjusted prevalence of overweight, obesity, and extreme obesity compared with prior surveys, and sex-, age-, and race/ethnicity-specific estimates. The age-adjusted prevalence of obesity was 30.5% in 1999-2000 compared with 22.9% in NHANES III (1988-1994; P<.001). The prevalence of overweight also increased during this period from 55.9% to 64.5% (P<.001). Extreme obesity (BMI > or = 40) also increased significantly in the population, from 2.9% to 4.7% (P =.002). Although not all changes were statistically significant, increases occurred for both men and women in all age groups and for non-Hispanic whites, non-Hispanic blacks, and Mexican Americans. Racial/ethnic groups did not differ significantly in the prevalence of obesity or overweight for men. Among women, obesity and overweight prevalences were highest among non-Hispanic black women. More than half of non-Hispanic black women aged 40 years or older were obese and more than 80% were overweight. The increases in the prevalences of obesity and overweight previously observed continued in 1999-2000. The potential health benefits from reduction in overweight and obesity are of considerable public health importance.
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Despite the popularity of the low-carbohydrate, high-protein, high-fat (Atkins) diet, no randomized, controlled trials have evaluated its efficacy. We conducted a one-year, multicenter, controlled trial involving 63 obese men and women who were randomly assigned to either a low-carbohydrate, high-protein, high-fat diet or a low-calorie, high-carbohydrate, low-fat (conventional) diet. Professional contact was minimal to replicate the approach used by most dieters. Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months (mean [+/-SD], -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight; P=0.001) and 6 months (-7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight, P=0.02), but the difference at 12 months was not significant (-4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight, P=0.26). After three months, no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations. The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study. Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load. The low-carbohydrate diet produced a greater weight loss (absolute difference, approximately 4 percent) than did the conventional diet for the first six months, but the differences were not significant at one year. The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease. Adherence was poor and attrition was high in both groups. Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate, high-protein, high-fat diets.
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High-fructose diet stimulates hepatic de novo lipogenesis (DNL) and causes hypertriglyceridemia and insulin resistance in rodents. Fructose-induced insulin resistance may be secondary to alterations of lipid metabolism. In contrast, fish oil supplementation decreases triglycerides and may improve insulin resistance. Therefore, we studied the effect of high-fructose diet and fish oil on DNL and VLDL triglycerides and their impact on insulin resistance. Seven normal men were studied on four occasions: after fish oil (7.2 g/day) for 28 days; a 6-day high-fructose diet (corresponding to an extra 25% of total calories); fish oil plus high-fructose diet; and control conditions. Following each condition, fasting fractional DNL and endogenous glucose production (EGP) were evaluated using [1-13C]sodium acetate and 6,6-2H2 glucose and a two-step hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity. High-fructose diet significantly increased fasting glycemia (7 +/- 2%), triglycerides (79 +/- 22%), fractional DNL (sixfold), and EGP (14 +/- 3%, all P < 0.05). It also impaired insulin-induced suppression of adipose tissue lipolysis and EGP (P < 0.05) but had no effect on whole- body insulin-mediated glucose disposal. Fish oil significantly decreased triglycerides (37%, P < 0.05) after high-fructose diet compared with high-fructose diet without fish oil and tended to reduce DNL but had no other significant effect. In conclusion, high-fructose diet induced dyslipidemia and hepatic and adipose tissue insulin resistance. Fish oil reversed dyslipidemia but not insulin resistance.
Article
Background: Low-carbohydrate diets remain popular despite a paucity of scientific evidence on their effectiveness. Objective: To compare the effects of a low-carbohydrate, ketogenic diet program with those of a low-fat, low-cholesterol, reduced-calorie diet. Design: Randomized, controlled trial. Setting: Outpatient research clinic. Participants: 120 overweight, hyperlipidemic volunteers from the community. Intervention: Low-carbohydrate diet (initially, <20 g of carbohydrate daily) plus nutritional supplementation, exercise recommendation, and group meetings, or low-fat diet (<30% energy from fat, <300 mg of cholesterol daily, and deficit of 500 to 1000 kcal/d) plus exercise recommendation and group meetings. Measurements: Body weight, body composition, fasting serum lipid levels, and tolerability. Results: A greater proportion of the low-carbohydrate diet group than the low-fat diet group completed the study (76% vs. 57%; P = 0.02). At 24 weeks, weight loss was greater in the low-carbohydrate diet group than in the low-fat diet group (mean change, -12.9% vs. -6.7%; P < 0.001). Patients in both groups lost substantially more fat mass (change, -9.4 kg with the low-carbohydrate diet vs. -4.8 kg with the low-fat diet) than fat-free mass (change, -3.3 kg vs. -2.4 kg, respectively). Compared with recipients of the low-fat diet, recipients of the low-carbohydrate diet had greater decreases in serum triglyceride levels (change, -0.84 mmol/L vs. -0.31 mmol/L [-74.2 mg/dL vs. -27.9 mg/dL]; P = 0.004) and greater increases in high-density lipoprotein cholesterol levels (0.14 mmol/L vs. -0.04 mmol/L [5.5 mg/dL vs. -1.6 mg/dL]; P < 0.001). Changes in low-density lipoprotein cholesterol level did not differ statistically (0.04 mmol/L [1.6 mg/dL] with the low-carbohydrate diet and -0.19 mmol/L [-7.4 mg/dL] with the low-fat diet; P = 0.2). Minor adverse effects were more frequent in the low-carbohydrate diet group. Limitations: We could not definitively distinguish effects of the low-carbohydrate diet and those of the nutritional supplements provided only to that group. In addition, participants were healthy and were followed for only 24 weeks. These factors limit the generalizability of the study results. Conclusions: Compared with a low-fat diet, a low-carbohydrate diet program had better participant retention and greater weight loss. During active weight loss, serum triglyceride levels decreased more and high-density lipoprotein cholesterol level increased more with the low-carbohydrate diet than with the low-fat diet.
Article
Patients receiving long-term total parenteral nutrition (TPN) develop hepatic steatosis as a complication. Our previous studies have shown this to be caused, at least in part, by choline deficiency. We studied four patients (1 man, 3 women) aged 50 ± 13 years who had low plasma-free choline concentrations 4.8 ± 1.7 (normal, 11.4 ± 3.7 nmol/mL). The patients had received TPN for 9.7 ± 4.7 years. They received parenteral nutrition solutions containing choline chloride (1 to 4 g/d) for 6 weeks. Abdominal computed tomography (CT) was performed at baseline, biweekly during the choline supplementation, and 4 weeks after discontinuation of choline. During choline administration, the plasma-free choline concentration increased into the normal range within 1 week in all four patients and remained at or above the normal range for all 6 weeks, but decreased back to baseline when choline supplementation was discontinued. Hepatic steatosis resolved completely, as estimated by CT. Liver density increased from −14.2 ± 22.3 Hounsfield units (HU) to 8.4 ± 10.3 HU at week 2 (P = .002); 9.6 ± 10.7 HU at week 4 and 13.1 ± 7.3 HU at week 6, as determined by the liver-spleen CT number difference obtained by the subtraction of the average spleen CT number (in HU) from the average liver CT number. This improvement continued up to 4 weeks after choline supplementation (13.8 ± 2.8 HU). Hepatic steatosis was shown to have recurred in one patient after 10 weeks of return to choline-free parenteral nutrition. The hepatic steatosis associated with parenteral nutrition can be ameliorated, and possibly prevented, with choline supplementation. Therefore, choline may be an essential nutrient for patients who require long-term parenteral nutrition. (Hepatology 1995; 22:1399–1403).
Article
The liver histology of 503 consecutive victims of fatal (within 24 hours) traffic accidents submitted to medico-legal autopsy are used as a standard of reference. In 370 persons (74%) no pathological changes in the liver biopsies were observed. Fatty liver was found in 120 persons (24%), non-specific portal inflammation in 7 persons, alcoholic hepatitis in 6, and portal fibrosis in 5. No cases of cirrhosis, chronic aggressive hepatitis, changes compatible with chronic persistent hepatitis, viral hepatitis, or other internationally accepted morphological diagnoses were found. A significant positive correlation between the frequency of steatosis and age groups was demonstrable. Fatty liver was found in 1% of persons below 20 years, in 18% between 20--40 years, and in 39% of persons more than 60 years in this normal material. The persons with fatty liver had a higher body weight, but the overweight was not correlated to age. It is concluded that fatty infiltration in the liver is a normal observation in aged persons.
Article
Steatohepatitis (fatty liver hepatitis), histologically identical to alcoholic disease, occurs in some obese patients after jejunoileal bypass. A similar lesion occurs rarely in obese patients without bypass surgery, but the risk factors are poorly understood. Hepatic steatosis, steatohepatitis and fibrosis were sought in 351 apparently nonalcoholic patients at autopsy and various risk factors were evaluated. Incidence of steatosis and steatohepatitis correlated with the degree of obesity. Steatohepatitis was found in 18.5% of markedly obese patients and 2.7% of lean patients. Additional risk factors for steatohepatitis were type II diabetes, weight loss in the preterminal period shortly before death and intravenous glucose therapy in the last week of life. Severe fibrosis was found in 13.8% of markedly obese patients and in 6.6% of lean patients; this difference was largely explained by the higher prevalence of diabetes in obese groups. The risk factors defined in this study are known to be associated with abnormalities of free fatty acid metabolism. Obesity, type II diabetes and intravenous glucose therapy are associated with hyperinsulinemia, which may inhibit fatty acid oxidation. Obesity and weight loss increase the presentation of fatty acids to the liver. Similar metabolic changes may occur in obese patients after jejunoileal bypass surgery. Thus this study supports the hypothesis that fatty acids have a role in the hepatocellular necrosis found in some obese individuals.
Article
To study the metabolic effects of ketosis without weight loss, nine lean men were fed a eucaloric balanced diet (EBD) for one week providing 35-50 kcal/kg/d, 1.75 g of protein per kilogram per day and the remaining kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD)--isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented with minerals and vitamins. Weight and whole-body potassium estimated by potassium-40 counting (40K) did not vary significantly during the five-week study. Nitrogen balance (N-Bal) was regained after one week of the EKD. The fasting blood glucose remained lower during the EKD than during the control diet (4.4 mmol/L at EBD, 4.1 mmol/L at EKD-4, P less than 0.01). The fasting whole-body glucose oxidation rate determined by a 13C-glucose primed constant infusion technique fell from 0.71 mg/kg/min during the control diet to 0.50 mg/kg/min (P less than 0.01) during the fourth week of the EKD. The mean serum cholesterol level rose (from 159 to 208 mg/dL) during the EKD, while triglycerides fell from 107 to 79 mg/dL. No disturbance of hepatic or renal function was noted at EKD-4. These findings indicate that the ketotic state induced by the EKD was well tolerated in lean subjects; nitrogen balance was regained after brief adaptation, serum lipids were not pathologically elevated, and blood glucose oxidation at rest was measurably reduced while the subjects remained euglycemic.
Article
Patients receiving long-term total parenteral nutrition (TPN) develop hepatic steatosis as a complication. Our previous studies have shown this to be caused, at least in part, by choline deficiency. We studied four patients (1 man, 3 women) aged 50 +/- 13 years who had low plasma-free choline concentrations 4.8 +/- 1.7 (normal, 11.4 +/- 3.7 nmol/mL). The patients had received TPN for 9.7 +/- 4.7 years. They received parenteral nutrition solutions containing choline chloride (1 to 4 g/d) for 6 weeks. Abdominal computed tomography (CT) was performed at baseline, biweekly during the choline supplementation, and 4 weeks after discontinuation of choline. During choline administration, the plasma-free choline concentration increased into the normal range within 1 week in all four patients and remained at or above the normal range for all 6 weeks, but decreased back to baseline when choline supplementation was discontinued. Hepatic steatosis resolved completely, as estimated by CT. Liver density increased from -14.2 +/- 22.3 Hounsfield units (HU) to 8.4 +/- 10.3 HU at week 2 (P = .002); 9.6 +/- 10.7 HU at week 4 and 13.1 +/- 7.3 HU at week 6, as determined by the liver-spleen CT number difference obtained by the subtraction of the average spleen CT number (in HU) from the average liver CT number. This improvement continued up to 4 weeks after choline supplementation (13.8 +/- 2.8 HU). Hepatic steatosis was shown to have recurred in one patient after 10 weeks of return to choline-free parenteral nutrition. The hepatic steatosis associated with parenteral nutrition can be ameliorated, and possibly prevented, with choline supplementation. Therefore, choline may be an essential nutrient for patients who require long-term parenteral nutrition.
Article
To determine the clinical relevance of nonalcoholic steatohepatitis (NASH) and to review the available literature on the epidemiology, clinical features, histology, pathogenesis, clinical course, and management of this condition. Pertinent articles in English identified through a MEDLINE search (1966 to the present) and the bibliographies of relevant articles. All studies, including case reports, evaluating the salient features and clinical profile of NASH. Data were selected from all articles that fit the study selection criteria. Nonalcoholic steatohepatitis is a distinct clinical entity characterized by elevated plasma liver enzyme levels and liver biopsy findings that are identical to those seen in alcoholic hepatitis; patients with NASH, however, do not consume alcohol in quantities known to cause liver injury. Patients with NASH are typically obese, middle-aged women with asymptomatic hepatomegaly who are diabetic or hyperlipidemic and present with an unrelated medical problem. Analysis of liver biopsy specimens is the cornerstone of diagnosis; hepatic morphologic findings range from mild fatty degeneration and inflammation to cell degeneration, fibrosis, and cirrhosis with or without the presence of Mallory hyaline bodies. Elevated levels of free fatty acids in the liver are thought to be responsible for the development of steatohepatitis. Although NASH is most often a benign disease with an indolent course, patients with this condition occasionally develop cirrhosis, portal hypertension, and hepatic failure. In some cases, NASH may be reversed with weight reduction. Nonalcoholic steatohepatitis is an important differential diagnosis for asymptomatic patients with chronically elevated plasma liver enzyme levels, especially if obesity, diabetes, or hyperlipidemia are present. Analysis of liver biopsy specimens is necessary for diagnosis and must be done in all patients with unexplained abnormal liver function and negative results on a noninvasive workup. Prognosis is good in most patients. The precise role of weight reduction and ursodeoxycholic acid therapy in the favorable alteration of the natural history of this disorder needs to be addressed in large, well-controlled studies.
Article
Nonalcoholic steatohepatitis (NASH) is an hepatic disorder with histologic features of alcohol-induced liver disease that occurs in individuals who do not consume significant alcohol. NASH is believed to be one of the most common explanations for abnormal liver chemistries in American adults. Risk factors for NASH include obesity, type II diabetes, hyperlipidemia, total parenteral nutrition, jejuno-ileal bypass surgery, and the use of certain drugs. However, some patients with NASH have no identifiable risk factors for the disease. Clinically, NASH is a diagnosis of exclusion that should be suspected as a cause of chronic hepatitis in patients who deny significant alcohol consumption and have negative serologic tests for congenital and other acquired causes of liver disease. The identification of fatty liver on imaging studies supports the diagnosis of NASH, which can be established definitively by liver biopsy. The latter also provides useful prognostic information since most patients with simple steatosis follow an indolent clinical course, whereas those with steatohepatitis, fibrosis, or cirrhosis are more likely to develop clinically significant complications of liver disease. Weight reduction and treatment of confounding medical conditions are the mainstays of therapy for NASH. However, there is little evidence that any of the current treatments prevent progression to more histologically advanced stages of NASH. Several experimental therapies, including treatment with bile acids, antibiotics, nutritional supplements, and antioxidants, have had anecdotal success in selected patients, but improved understanding of the pathogenesis and natural history of NASH will be required to develop generally effective therapy for the disorder.
Article
The rising prevalence of obesity in children has been linked in part to the consumption of sugar-sweetened drinks. Our aim was to examine this relation. We enrolled 548 ethnically diverse schoolchildren (age 11.7 years, SD 0.8) from public schools in four Massachusetts communities, and studied them prospectively for 19 months from October, 1995, to May, 1997. We examined the association between baseline and change in consumption of sugar-sweetened drinks (the independent variables), and difference in measures of obesity, with linear and logistic regression analyses adjusted for potentially confounding variables and clustering of results within schools. For each additional serving of sugar-sweetened drink consumed, both body mass index (BMI) (mean 0.24 kg/m2; 95% CI 0.10-0.39; p=0.03) and frequency of obesity (odds ratio 1.60; 95% CI 1.14-2.24; p=0.02) increased after adjustment for anthropometric, demographic, dietary, and lifestyle variables. Baseline consumption of sugar-sweetened drinks was also independently associated with change in BMI (mean 0.18 kg/m2 for each daily serving; 95% CI 0.09-0.27; p=0.02). Consumption of sugar-sweetened drinks is associated with obesity in children.
Article
Troglitazone is a thiazolidinedione and peroxisome proliferator-activated receptor gamma (PPARgamma) ligand used to treat diabetes mellitus type II. Because hyperinsulinemia may be a factor in nonalcoholic steatohepatitis (NASH), we postulated that troglitazone could have beneficial effects in this disorder. Our study was initiated before reports of idiosyncratic hepatitis induced by this agent and was completed before its recent withdrawal from the market. We studied 10 female patients (age 44 +/- 16) with histological NASH. All but two were obese (mean body mass index, BMI = 38 +/- 6). One had type 2 diabetes, and three had well-compensated cirrhosis with NASH. Troglitazone was given at a dose of 400 mg/day for < or = 6 months. Responders (defined as normal ALT at the end of treatment) were rebiopsied. Paired specimens were compared in blinded fashion. Mitochondria were quantitated using ultrathin electron microscopy. Seven of ten patients responded with normal ALT at the end of treatment. One of three nonresponders initially normalized ALT but returned to pretreatment level at 3 months. In this patient, therapy was stopped, and the ALT has remained at the baseline level with no other clinical or laboratory findings. In the responders, ALT fell from 87 +/- 38 before to 39 +/- 9 at the end of treatment (p = 0.01), and AST decreased from 77 +/- 23 to 30 +/- 8 (p = 0.002). Biopsy comparisons before and after therapy showed persistent steatohepatitis in all cases, although four of seven showed a one-point improvement in the necroinflammatory grade. Electron microscopy revealed elongation of the mitochondria after therapy. Normal ALT was seen in 70% of NASH patients at the end of treatment, but this biochemical response was associated with only mild histological improvement, and all follow-up biopsies had evidence of NASH. Normalization of the liver enzymes in patients with NASH who are treated with thiazolidinediones should be viewed with reservation. Follow-up biopsy is essential to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest.
Article
Nonalcoholic steatohepatitis (NASH) is a significant form of chronic liver disease in adults and children. The natural history of NASH ranges from indolent to end-stage liver disease. Current studies are focusing on identification of histologic and/or clinical markers of progression. NASH may be an underlying cause of cryptogenic cirrhosis, and the lesions of NASH may recur in allograft livers. An expanding array of clinical conditions and pathogenetic mechanisms have been identified, but many cases remain "idiopathic"; lack of significant alcohol use is, by definition, common to all cases. Neither clinical evaluation nor laboratory values can ensure either the diagnosis or the exclusion of NASH, and liver biopsy interpretation continues to be considered the "gold standard" for diagnosis. The lesions in NASH are similar but not identical to those of alcoholic steatohepatitis; exact, specific histologic criteria for the diagnosis are currently under discussion. The lesions most commonly accepted for NASH include steatosis, hepatocyte ballooning degeneration, mild diffuse lobular mixed acute and chronic inflammation, and perivenular, perisinusoidal collagen deposition. Zone 3 accentuation may be detected. Mallory's hyaline, vacuolated nuclei in periportal hepatocytes, lobular lipogranulomas, and PAS-diastase-resistant Kupffer cells are common. In biopsy specimens from children, portal inflammation may be more prominent than in adults. Progression of fibrosis may result in bridging septa and cirrhosis. The lesions of steatohepatitis may be noted concurrently with other forms of chronic liver disease. A histological "grading and staging" system has been developed to reflect the unique features of steatohepatitis, gradations of severity and fibrosis, and to promote uniform reporting of the histopathology.
Article
Non-alcoholic steatohepatitis (NASH) is a clinicopathological entity characterized by the presence of steatosis and lobular and/or portal inflammation with or without fibrosis. Patients with non-alcoholic fatty liver and fibrosis on liver biopsy have increased liver-related deaths. 181 wedge liver biopsies, taken at the time of bariatric surgery from patients with a mean body mass index (BMI) of 47, were studied. In all cases, the liver biopsy was performed without knowledge of the patient's clinical and biochemical data, which were then examined with univariate and multivariate analysis. Diagnosis of NASH was established in 105 patients (91%); 74 patients (70%) showed mild steatosis, 20 (19%) had moderate inflammation and fibrosis, and 11 (10%) had steatosis with severe fibrosis. None of the liver biopsies showed cirrhosis. Age was the only independent predictor of moderate and severe fibrosis (p = 0.001). Since only age was a predictor of moderate or severe fibrosis, and no clinical or biochemical abnormalities detected slowly progressive hepatic fibrosis, liver biopsy is the only means of detecting progression to more advanced liver disease in a NASH patient.
Article
There is no established treatment for steatohepatitis in patients who are not alcoholics. This disease is a potentially progressive liver disease associated with hepatic insulin resistance. Only a weight-reducing diet in overweight patients has proved effective. We treated 20 patients who had steatohepatitis but were not alcoholics with metformin (500 mg three times a day for 4 months), an agent that improves hepatic insulin sensitivity. When compared with the six individuals not complying with treatment, long-term metformin significantly reduced mean transaminase concentrations, which returned to normal in 50% of actively-treated patients. Also, insulin sensitivity improved significantly and liver volume decreased by 20%. Similar data have been reported in insulin-resistant ob/ob mice with fatty liver. A randomised-controlled study is needed.
Article
The results of previous studies suggest that de novo lipogenesis may play an important role in the etiology of obesity, particularly during overconsumption of different carbohydrates. We hypothesized that de novo lipogenesis would increase during overfeeding, would vary depending on the type of carbohydrate consumed, and would be greater in obese than in lean women. De novo lipogenesis was measured during 96 h of overfeeding by 50% with either sucrose or glucose and during an energy balance treatment (control) in 8 lean and 5 obese women. De novo lipogenesis was determined by measuring the amount of deuterium incorporation into plasma triacylglycerols. Fat and carbohydrate balance were measured simultaneously by continuous whole-body calorimetry. De novo lipogenesis did not differ significantly between lean and obese subjects, except with the control treatment, for which de novo lipogenesis was greater in the obese subjects. De novo lipogenesis was 2- to 3-fold higher after overfeeding by 50% than after the control treatment in all subjects. The type of carbohydrate overfeeding (sucrose or glucose) had no significant effect on de novo lipogenesis in either subject group. Estimated amounts of absolute VLDL production ranged from a minimum of 2 g/d (control) to a maximum of 10 g/d after overfeeding. This compares with a mean fat balance of approximately 275 g after 96 h of overfeeding. Individual subjects showed characteristic amounts of de novo lipogenesis, suggesting constitutive (possibly genetic) differences. De novo lipogenesis increases after overfeeding with glucose and sucrose to the same extent in lean and obese women but does not contribute greatly to total fat balance.
Article
Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age- and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. In conclusion, most patients with NASH have IRS, and there is a near-universal association between NASH and IR irrespective of obesity. IR is present in mild as well as advanced cases of NASH but is unusual in chronic HCV of similar fibrotic severity.
Article
This study aims to determine the presence of the components of the metabolic syndrome in primary nonalcoholic steatohepatitis (NASH) and to assess the role of liver disease in the genesis of peripheral hyperinsulinemia. Nineteen patients (18 men and 1 woman; mean age, +/- SD, 38 +/- 10 years; body mass index [BMI], 26 +/- 2 kg/m(2)) with histologic evidence of NASH were enrolled; 19 age- and sex-matched normal subjects were investigated as controls. Plasma glucose, insulin, and C-peptide levels were measured during an oral glucose tolerance test, and a frequently sampled intravenous glucose tolerance test (FSIGT), analyzed by minimal modeling technique, was performed. Compared with controls, the NASH group had lower insulin sensitivity (3.84 +/- 2.44 vs. 7.48 +/- 3.01 10(-4) x min(-1)/microU/mL; P =.0003) and higher total insulin secretion (21 +/- 13 vs. 10 +/- 3 nmol/L in 240 minutes; P =.001). Hepatic insulin extraction was similar in both groups (69.8% +/- 16.1% vs. 70.2% +/- 18.3%; P =.854). According to the results of the oral glucose tolerance test, no patient was classified as diabetic, 5 were classified as glucose intolerant, and 1 was classified as having impaired fasting glycemia. Nine patients (47%) had at least the 2 minimum criteria required to define the metabolic syndrome according to the European Group for the Study of Insulin Resistance (EGIR). In conclusion, hyperinsulinemia and insulin resistance occur frequently in patients with NASH; these conditions do not stem from a reduced hepatic insulin extraction but from an enhanced pancreatic insulin secretion compensatory to reduced insulin sensitivity. The derangement of insulin regulation, often associated with the metabolic syndrome, may play a causal role in the pathogenesis of NASH.
Article
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease that occurs in nondrinkers but which cannot be distinguished from alcohol-induced liver disease histologically. There are no diagnostic blood tests for NAFLD but the disease is associated with several insulin-resistant states, including obesity, type 2 diabetes mellitus and dyslipidemia. Most of the liver-related morbidity and mortality that accompany NAFLD occur in patients who develop cirrhosis. The latter is most likely to occur in individuals who have progressed from simple steatosis (fatty liver) to steatohepatitis, a chronic inflammatory liver lesion. The mechanisms that promote the transition from steatosis to nonalcoholic steatohepatitis appear to involve multiple cellular adaptations to the oxidative stress that occurs when fatty acid metabolism is deranged during insulin resistance. A better understanding of these mechanisms is desired to target treatments to prevent and/or reverse nonalcoholic steatohepatitis, thereby aborting the evolution of cirrhosis.
Article
Increased insulin resistance is the major pathogenic mechanism in the development of non-alcoholic steatohepatitis. To investigate the therapeutic effect of metformin, a well-known insulin-sensitizing agent, in the treatment of non-alcoholic steatohepatitis. Thirty-six patients with non-alcoholic steatohepatitis were randomized into two groups. The first group was given lipid and calorie-restricted dietary treatment alone, and the second group was given metformin 850 mg b.d. plus dietary treatment, for 6 months. The changes in biochemical, sonographic and histological parameters were compared. The mean serum alanine/aspartate aminotransferase, insulin and C-peptide levels decreased and the index of insulin resistance improved significantly from baseline in the group given metformin. The mean changes in these parameters in the metformin group were significantly greater than those in the group given dietary treatment alone. Although more patients in the metformin group showed improvement in the necro-inflammatory activity, compared with the group given dietary treatment alone, no significant differences in necro-inflammatory activity or fibrosis were seen between the groups. The data suggest that improvement of the insulin sensitivity with metformin may improve the liver disease in patients with non-alcoholic steatohepatitis.
Article
Low-carbohydrate diets remain popular despite a paucity of scientific evidence on their effectiveness. To compare the effects of a low-carbohydrate, ketogenic diet program with those of a low-fat, low-cholesterol, reduced-calorie diet. Randomized, controlled trial. Outpatient research clinic. 120 overweight, hyperlipidemic volunteers from the community. Low-carbohydrate diet (initially, <20 g of carbohydrate daily) plus nutritional supplementation, exercise recommendation, and group meetings, or low-fat diet (<30% energy from fat, <300 mg of cholesterol daily, and deficit of 500 to 1000 kcal/d) plus exercise recommendation and group meetings. Body weight, body composition, fasting serum lipid levels, and tolerability. A greater proportion of the low-carbohydrate diet group than the low-fat diet group completed the study (76% vs. 57%; P = 0.02). At 24 weeks, weight loss was greater in the low-carbohydrate diet group than in the low-fat diet group (mean change, -12.9% vs. -6.7%; P < 0.001). Patients in both groups lost substantially more fat mass (change, -9.4 kg with the low-carbohydrate diet vs. -4.8 kg with the low-fat diet) than fat-free mass (change, -3.3 kg vs. -2.4 kg, respectively). Compared with recipients of the low-fat diet, recipients of the low-carbohydrate diet had greater decreases in serum triglyceride levels (change, -0.84 mmol/L vs. -0.31 mmol/L [-74.2 mg/dL vs. -27.9 mg/dL]; P = 0.004) and greater increases in high-density lipoprotein cholesterol levels (0.14 mmol/L vs. -0.04 mmol/L [5.5 mg/dL vs. -1.6 mg/dL]; P < 0.001). Changes in low-density lipoprotein cholesterol level did not differ statistically (0.04 mmol/L [1.6 mg/dL] with the low-carbohydrate diet and -0.19 mmol/L [-7.4 mg/dL] with the low-fat diet; P = 0.2). Minor adverse effects were more frequent in the low-carbohydrate diet group. We could not definitively distinguish effects of the low-carbohydrate diet and those of the nutritional supplements provided only to that group. In addition, participants were healthy and were followed for only 24 weeks. These factors limit the generalizability of the study results. Compared with a low-fat diet, a low-carbohydrate diet program had better participant retention and greater weight loss. During active weight loss, serum triglyceride levels decreased more and high-density lipoprotein cholesterol level increased more with the low-carbohydrate diet than with the low-fat diet.
Article
To examine American beverage consumption trends and causes. Nationally representative data from the 1977-1978 Nationwide Food Consumption Survey, the 1989-1991 and 1994-1996 (also for children aged 2 to 9 years in 1998) Continuing Surveys of Food Intake by Individuals (CSFII), and 1999-2001 National Health and Nutrition Examination Survey were used in this study. The sample consisted of 73,345 individuals, aged >or=2 years. For each survey year, the percentage of total energy intake from meals and snacks was calculated separately for respondents aged 2 to 18 years, 19 to 39, 40 to 59, and >or=60. The percentage of energy intake by location (at home consumption or preparation, vending, store eaten out, restaurant/fast food, and school), as well as for specific beverages was computed separately for all age groups. The proportion consumed, mean portion size, and number of servings were calculated. For all age groups, sweetened beverage consumption increased and milk consumption decreased. Overall, energy intake from sweetened beverages increased 135% and was reduced by 38% from milk, with a 278 total calorie increase. These trends were associated with increased proportions of Americans consuming larger portions, more servings per day of sweetened beverage, and reductions in these same measures for milk. There is little research that has focused on the beneficial impacts of reduced soft drink and fruit drink intake. This would seem to be one of the simpler ways to reduce obesity in the United States.
Article
Nonalcoholic fatty liver disease (NAFLD) is a common and potentially serious form of chronic liver disease that occurs in patients who do not abuse alcohol. Present dietary recommendations for all Americans, including those with NAFLD, endorse a low-calorie, low-fat diet. However, little is known about the effect of diet composition on liver histopathology in patients with NAFLD. The aim of this study was to determine whether overall calorie intake and diet composition are associated with the severity of NAFLD histopathology. Seventy-four consecutive morbidly obese patients presenting for bariatric surgery from January 2001 to March 2002 were retrospectively reviewed. In addition to a standard surgical and psychological evaluation, all patients underwent a preoperative dietary evaluation using a standardized 24-hr food recall. Food intake was evaluated for total calories and macronutrients and compared to liver histopathology from biopsies routinely obtained during surgery. Associations with the severity of steatosis and the presence of inflammation or fibrosis were assessed separately using chi-square for categorical variables and ANOVA for continuous variables. Further, we conducted multiple logistic regression analyses for each histological outcome. There were no significant associations between either total caloric intake or protein intake and either steatosis, fibrosis, or inflammation. However, higher CHO intake was associated with significantly higher odds of inflammation, while higher fat intake was associated with significantly lower odds of inflammation. In conclusion, present dietary recommendations may worsen NAFLD histopathology.
Article
It is not known how a low-carbohydrate, high-protein, high-fat diet causes weight loss or how it affects blood glucose levels in patients with type 2 diabetes. To determine effects of a strict low-carbohydrate diet on body weight, body water, energy intake and expenditure, glycemic control, insulin sensitivity, and lipid levels in obese patients with type 2 diabetes. Inpatient comparison of 2 diets. General clinical research center of a university hospital. 10 obese patients with type 2 diabetes. Usual diets for 7 days followed by a low-carbohydrate diet for 14 days. Body weight, water, and composition; energy intake and expenditure; diet satisfaction; hemoglobin A1c; insulin sensitivity; 24-hour urinary ketone excretion; and plasma profiles of glucose, insulin, leptin, and ghrelin. On the low-carbohydrate diet, mean energy intake decreased from 3111 kcal/d to 2164 kcal/d. The mean energy deficit of 1027 kcal/d (median, 737 kcal/d) completely accounted for the weight loss of 1.65 kg in 14 days (median, 1.34 kg in 14 days). Mean 24-hour plasma profiles of glucose levels normalized, mean hemoglobin A1c decreased from 7.3% to 6.8%, and insulin sensitivity improved by approximately 75%. Mean plasma triglyceride and cholesterol levels decreased (change, -35% and -10%, respectively). The study was limited by the short duration, small number of participants, and lack of a strict control group. In a small group of obese patients with type 2 diabetes, a low-carbohydrate diet followed for 2 weeks resulted in spontaneous reduction in energy intake to a level appropriate to their height; weight loss that was completely accounted for by reduced caloric intake; much improved 24-hour blood glucose profiles, insulin sensitivity, and hemoglobin A1c; and decreased plasma triglyceride and cholesterol levels. The long-term effects of this diet, however, remain uncertain.
Article
In individuals with biopsy-proven non-alcoholic steatohepatitis (NASH), short-term weight loss has been shown to improve biochemical abnormalities; however, its effect on liver histology is largely unknown. The aim of the article is to determine if dietary intervention is effective in improving histological features of steatohepatitis in patients with biopsy-proven NASH. Twenty-three patients (11M/12F) with BMI >25 kg/m(2) and biopsy-proven NASH received standardized nutritional counseling aimed at reducing insulin resistance (IR) and weight. Blood tests were checked at baseline and every 1-4 months, and liver biopsy was repeated at month 12. IR was assessed by the homeostasis model assessment (HOMA). Liver biopsies were scored according to modified Brunt criteria for NASH. "Histologic response" was defined as a reduction in total NASH score of >/=2 points with at least one point being in the non-steatosis component. Sixteen patients (8M/8F) completed 12 months of dietary intervention, and 15 underwent repeat liver biopsies. At month 12, mean weight decreased from 98.3 to 95.4 kg. Mean waist circumference, visceral fat, fasting glucose, IR, triglycerides, AST, ALT, and histologic score were all reduced but the difference was not significant. Nine patients had a histologic response, six had stable scores, and none had a worsened score. Compared to patients with unchanged histologic scores, patients with improved scores had significantly greater reduction in weight, waist circumference, AST, ALT, steatosis grade, and total NASH score. Among patients who successfully completed 1 yr of intense dietary intervention, nine of 15 patients with NASH displayed histologic improvement. This pilot study suggests that dietary intervention can be effective in improving histology in patients with biopsy-proven NASH.
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