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1.
Nonalcoholic Steatohepatitis: A Review.
Sheka, AC, Adeyi, O, Thompson, J, Hameed, B, Crawford, PA, Ikramuddin, S
JAMA. 2020;(12):1175-1183
Abstract
IMPORTANCE Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) and is associated with disease progression, development of cirrhosis, and need for liver transplant. Despite its importance, NASH is underrecognized in clinical practice. OBSERVATIONS NASH affects an estimated 3% to 6% of the US population and the prevalence is increasing. NASH is strongly associated with obesity, dyslipidemia, type 2 diabetes, and metabolic syndrome. Although a number of noninvasive tests and scoring systems exist to characterize NAFLD and NASH, liver biopsy is the only accepted method for diagnosis of NASH. Currently, no NASH-specific therapies are approved by the US Food and Drug Administration. Lifestyle modification is the mainstay of treatment, including dietary changes and exercise, with the primary goal being weight loss. Substantial improvement in histologic outcomes, including fibrosis, is directly correlated with increasing weight loss. In some cases, bariatric surgery may be indicated to achieve and maintain the necessary degree of weight loss required for therapeutic effect. An estimated 20% of patients with NASH will develop cirrhosis, and NASH is predicted to become the leading indication for liver transplants in the US. The mortality rate among patients with NASH is substantially higher than the general population or patients without this inflammatory subtype of NAFLD, with annual all-cause mortality rate of 25.56 per 1000 person-years and a liver-specific mortality rate of 11.77 per 1000 person-years. CONCLUSIONS AND RELEVANCE Nonalcoholic steatohepatitis affects 3% to 6% of the US population, is more prevalent in patients with metabolic disease and obesity, progresses to cirrhosis in approximately 20% of cases, and is associated with increased rates of liver-specific and overall mortality. Early identification and targeted treatment of patients with nonalcoholic steatohepatitis are needed to improve patient outcomes, including directing patients toward intensive lifestyle modification to promote weight loss and referral for bariatric surgery as indicated for management of obesity and metabolic disease.
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Beyond Body Weight-Loss: Dietary Strategies Targeting Intrahepatic Fat in NAFLD.
Worm, N
Nutrients. 2020;(5)
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease in industrialized countries. It is regarded as the hepatic manifestation of the metabolic syndrome (MetS) resulting from insulin resistance. Moreover, insulin resistance impairs glycogen synthesis, postprandially diverting a substantial amount of carbohydrates to the liver and storing them there as fat. NAFLD has far-reaching metabolic consequences involving glucose and lipoprotein metabolism disorders and risk of cardiovascular disease, the leading cause of death worldwide. No pharmaceutical options are currently approved for the treatment of NAFLD. Exercise training and dietary interventions remain the cornerstone of NAFLD treatment. Current international guidelines state that the primary goal of nutritional therapy is to reduce energy intake to achieve a 7%-10% reduction in body weight. Meal replacement therapy (formula diets) results in more pronounced weight loss compared to conventional calorie-restricted diets. However, studies have shown that body mass index (BMI) or weight reduction is not obligatory for decreasing hepatic fat content or to restore normal liver function. Recent studies have achieved significant reductions in liver fat with eucaloric diets and without weight loss through macronutrient modifications. Based on this evidence, an integrative nutritional therapeutic concept was formulated that combines the most effective nutrition approaches termed "liver-fasting." It involves the temporary use of a low calorie diet (total meal replacement with a specific high-protein, high-soluble fiber, lower-carbohydrate formula), followed by stepwise food reintroduction that implements a Mediterranean style low-carb diet as basic nutrition.
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Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases.
Campisano, S, La Colla, A, Echarte, SM, Chisari, AN
Nutrition research reviews. 2019;(1):128-145
Abstract
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.
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4.
Ghrelin forms in the modulation of energy balance and metabolism.
Gortan Cappellari, G, Barazzoni, R
Eating and weight disorders : EWD. 2019;(6):997-1013
Abstract
Ghrelin is a gastric hormone circulating in acylated (AG) and unacylated (UnAG) forms. This narrative review aims at presenting current emerging knowledge on the impact of ghrelin forms on energy balance and metabolism. AG represents ~ 10% of total plasma ghrelin, has an appetite-stimulating effect and is the only form for which a receptor has been identified. Moreover, other metabolic AG-induced effects have been reported, including the modulation of glucose homeostasis with stimulation of liver gluconeogenesis, the increase of fat mass and the improvement of skeletal muscle mitochondrial function. On the other hand, UnAG has no orexigenic effects, however recent reports have shown that it is directly involved in the modulation of skeletal muscle energy metabolism by improving a cluster of interlinked functions including mitochondrial redox activities, tissue inflammation and insulin signalling and action. These findings are in agreement with human studies which show that UnAG circulating levels are positively associated with insulin sensitivity both in metabolic syndrome patients and in a large cohort from the general population. Moreover, ghrelin acylation is regulated by a nutrient sensor mechanism, specifically set on fatty acids availability. These recent findings consistently point towards a novel independent role of UnAG as a regulator of muscle metabolic pathways maintaining energy status and tissue anabolism. While a specific receptor for UnAG still needs to be identified, recent evidence strongly supports the hypothesis that the modulation of ghrelin-related molecular pathways, including those involved in its acylation, may be a potential novel target in the treatment of metabolic derangements in disease states characterized by metabolic and nutritional complications.Level of evidence Level V, narrative review.
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5.
The Role of Autophagy in Liver Epithelial Cells and Its Impact on Systemic Homeostasis.
Tomaipitinca, L, Mandatori, S, Mancinelli, R, Giulitti, F, Petrungaro, S, Moresi, V, Facchiano, A, Ziparo, E, Gaudio, E, Giampietri, C
Nutrients. 2019;(4)
Abstract
: Autophagy plays a role in several physiological and pathological processes as it controls the turnover rate of cellular components and influences cellular homeostasis. The liver plays a central role in controlling organisms' metabolism, regulating glucose storage, plasma proteins and bile synthesis and the removal of toxic substances. Liver functions are particularly sensitive to autophagy modulation. In this review we summarize studies investigating how autophagy influences the hepatic metabolism, focusing on fat accumulation and lipids turnover. We also describe how autophagy affects bile production and the scavenger function within the complex homeostasis of the liver. We underline the role of hepatic autophagy in counteracting the metabolic syndrome and the associated cardiovascular risk. Finally, we highlight recent reports demonstrating how the autophagy occurring within the liver may affect skeletal muscle homeostasis as well as different extrahepatic solid tumors, such as melanoma.
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Fructose metabolism, cardiometabolic risk, and the epidemic of coronary artery disease.
Mirtschink, P, Jang, C, Arany, Z, Krek, W
European heart journal. 2018;(26):2497-2505
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Abstract
Despite strong indications that increased consumption of added sugars correlates with greater risks of developing cardiometabolic syndrome (CMS) and cardiovascular disease (CVD), independent of the caloric intake, the worldwide sugar consumption remains high. In considering the negative health impact of overconsumption of dietary sugars, increased attention is recently being given to the role of the fructose component of high-sugar foods in driving CMS. The primary organs capable of metabolizing fructose include liver, small intestine, and kidneys. In these organs, fructose metabolism is initiated by ketohexokinase (KHK) isoform C of the central fructose-metabolizing enzyme KHK. Emerging data suggest that this tissue restriction of fructose metabolism can be rescinded in oxygen-deprived environments. In this review, we highlight recent progress in understanding how fructose metabolism contributes to the development of major systemic pathologies that cooperatively promote CMS and CVD, reference recent insights into microenvironmental control of fructose metabolism under stress conditions and discuss how this understanding is shaping preventive actions and therapeutic approaches.
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7.
The effects of vitamin D supplementation on metabolic profiles and liver function in patients with non-alcoholic fatty liver disease: A systematic review and meta-analysis of randomized controlled trials.
Tabrizi, R, Moosazadeh, M, Lankarani, KB, Akbari, M, Heydari, ST, Kolahdooz, F, Samimi, M, Asemi, Z
Diabetes & metabolic syndrome. 2017;:S975-S982
Abstract
BACKGROUND A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to summarize the evidence on the effect of vitamin D supplementation on metabolic profiles in patients with non-alcoholic fatty liver disease (NAFLD). METHODS We systematically searched PubMed, EMBASE and five other databases to identify all RCTs investigating the association between vitamin D and NAFLD up until 5 October 2016. Seven RCTs with 452 participants (227 patients and 225 controls) were included in the meta-analysis. RESULTS The results showed that vitamin D administration had no beneficial effect on fasting plasma glucose (FPG) (standardized mean difference [SMD]-0.23; 95% confidence interval [CI], -0.88, 0.42), insulin (SMD -1.09; 95% CI, -2.70,0.52) and homeostasis model assessment of insulin resistance (HOMA-IR) (SMD -1.89; 95% CI, -3.88,0.09). Vitamin D supplementation also had no effect on lipid profiles including triglycerides (SMD -0.36; 95% CI, -1.77, 1.04), and total-cholesterol (SMD -0.46; 95% CI: -1.3, 0.39), as well as on aspartate transaminase (AST) (SMD -0.53; 95% CI, -1.11, 0.05), alanine aminotransferase (ALT) (SMD -0.66; 95% CI, -1.43,0.11), and body mass index (BMI) (SMD -0.25; 95% CI, -0.76,0.27). CONCLUSIONS Vitamin D supplementation had no effect on FPG, insulin, HOMA-IR, triglycerides, total-, LDL-cholesterol, AST, ALT, and BMI.
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Diabetic hepatosclerosis: True clinical entity or ghost disease?
Vallianou, NG, Kazazis, C, Ioannidis, G
Diabetes & metabolic syndrome. 2017;:S775-S776
Abstract
Diabetic hepatosclerosis is a novel entity that has recently been introduced by reviewing archived liver biopsies as a non-cirrhotic form of peri-sinusoidal fibrosis with basement membrane formation. Diabetic hepatosclerosis is usually characterized by an indolent clinical course. Serum aminotransferase levels are normal or minimally elevated, but elevated alkaline phosphatase levels is usually present. Clinically relevant to DH is the co-existence of other diabetic microvascular complications in the same patient, such as ESRD on long-term dialysis or renal transplantation, retinopathy, or neuropathy. Although it seems that DH occurs in patients with type 1 more often than type 2 diabetes mellitus, the true prevalence of this entity still remains unknown. Future prospective studies should include long-term follow-up to examine the natural history and to explore treatment options for this form of hepatic micro-angiopathy disease.
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Influence of dietary macronutrients on liver fat accumulation and metabolism.
Parry, SA, Hodson, L
Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2017;(8):1102-1115
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Abstract
The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the available observational and intervention studies that have investigated the influence of dietary macronutrients on liver fat content. Findings from observational studies are conflicting with some reporting that relative to healthy controls, patients with NAFLD consume diets higher in total fat/saturated fatty acids, whilst others find they consume diets higher in carbohydrates/sugars. From the limited number of intervention studies that have been undertaken, a consistent finding is a hypercaloric diet, regardless of whether the excess calories have been provided either as fat, sugar, or both, increases liver fat content. In contrast, a hypocaloric diet decreases liver fat content. Findings from both hyper- and hypo-caloric feeding studies provide some suggestion that macronutrient composition may also play a role in regulating liver fat content and this is supported by data from isocaloric feeding studies; fatty acid composition and/or carbohydrate content/type appear to influence whether there is accrual of liver fat or not. The mechanisms by which specific macronutrients, when consumed as part of an isocaloric diet, cause a change in liver fat remain to be fully elucidated.
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Iron and the liver.
Pietrangelo, A
Liver international : official journal of the International Association for the Study of the Liver. 2016;:116-23
Abstract
Humans have evolved to retain iron in the body and are exposed to a high risk of iron overload and iron-related toxicity. Excess iron in the blood, in the absence of increased erythropoietic needs, can saturate the buffering capacity of serum transferrin and result in non-transferrin-bound highly reactive forms of iron that can cause damage, as well as promote fibrogenesis and carcinogenesis in the parenchymatous organs. A number of hereditary or acquired diseases are associated with systemic or local iron deposition or iron misdistribution in organs or cells. Two of these, the HFE- and non-HFE hemochromatosis syndromes represent the paradigms of genetic iron overload. They share common clinical features and the same pathogenic basis, in particular, a lack of synthesis or activity of hepcidin, the iron hormone. Before hepcidin was discovered, the liver was simply regarded as the main site of iron storage and, as such, the main target of iron toxicity. Now, as the main source of hepcidin, it appears that the loss of the hepcidin-producing liver mass or genetic and acquired factors that repress hepcidin synthesis in the liver may also lead to iron overload. Usually, there is low-grade excess iron which, through oxidative stress, is sufficient to worsen the course of the underlying liver disease or other chronic diseases that are apparently unrelated to iron, such as chronic metabolic and cardiovascular diseases. In the future, modulation of hepcidin synthesis and activity or hepcidin hormone-replacing strategies may become therapeutic options to cure iron-related disorders.