Redefining non-alcoholic fatty liver disease to metabolic associated fatty liver disease: Is this plausible?

Recently, a single letter change has taken the world by storm. A group of experts have developed a consensus to upgrade the term non-alcoholic fatty liver disease (NAFLD) to metabolic associated fatty liver disease (MAFLD), suggesting that MAFLD would more accurately reflect not only the disease pathogenesis but would also help in patient stratification for management with NAFLD. However, the difference of opinion exists, which has made the NAFLD vs MAFLD debate the current talk of the town. This review will focus on the plausibility and implications of redefining NAFLD as MAFLD.     

Chronic kidney disease in patients with non-alcoholic fatty liver disease: What the Hepatologist should know?

The association of non-alcoholic fatty liver disease (NAFLD) with several other diseases has gained increased interest during the recent years. Among them, the association with chronic kidney disease (CKD) has emerged as an important one regarding both its prevalence and significance. The early recognition of this association is important for the prognosis of patients with NAFLD and CKD. Apart from early diagnosis, the accurate assessment of renal function is also crucial in the clinical practice of hepatologists. Several methods have been used in the literature for the evaluation of kidney function in patients with NAFLD up to now. In this respect, calculators (or formulas) for the estimation of Glomerular Filtration Rate (eGFR) and Albumin to Creatinine Ratio (ACR) are simple, practical and easily available methods for this purpose. The aim of this review is to report on the epidemiology and pathophysiology of the relationship between NAFLD and CKD and to describe the different methods of kidney function assessment in patients with NAFLD. The collection of all relevant data regarding this association will provide hepatologists with pertinent knowledge on this topic and allow them to use the most accurate methods for the assessment of kidney function in these patients in their clinical practice.     

Is there any progress in the treatment of non-alcoholic fatty liver disease?

Despite the fact that non-alcoholic fatty liver disease(NAFLD) and its severe clinical form,non-alcoholic steatohepatitis,are becoming increasingly prevalent in the industrialised countries,there are no licensed pharmacological treatments for them.Weight loss and life modifications,antioxidant therapies and insulin-sensitising agents are the current treatment strategies and have all been tested with inconclusive results.Low sample numbers,inadequate treatment duration and invalid surrogate markers for treatment response might all account for these results.As NAFLD is a systemic rather than a liver disease,future trials should address the patient as a whole and also address cardiovascular risk factors.     

Should nonalcoholic fatty liver disease be renamed?

BACKGROUND: None of the synonyms of nonalcoholic fatty liver disease (NAFLD) include clinical correlates nor do they mention insulin resistance, a recognized determinant of the etiopathogenesis and natural history of NAFLD. METHOD: The literature concerning the pathogenesis and definition of NAFLD is reviewed. RESULTS: The reasons why NAFLD should be renamed are: (a) clinically meaningful hepatic steatosis could be present at less than 5% triglyceride hepatic content; (b) steatosis is usually no longer observed in the most advanced forms of NAFLD ('cryptogenic cirrhosis'); (c) the concurrence of metabolic derangements could be more important than alcohol in the pathogenesis of alcoholic liver disease; (d) a concurrent metabolic etiology might worsen the course of chronic HCV and autoimmune hepatitis; (e) in NAFLD the liver is a target organ of the metabolic syndrome, a systemic subclinical inflammatory state. CONCLUSION: The introduction of a positive criterion also mentioned in its definition would benefit the diagnosis of NAFLD and of steatohepatitis observed in the setting of other liver diseases, help to estimate the risk of its progression and aid the treatment of metabolic (fatty) liver disorders. There is a compelling need for an experts' agreement on a new definition of insulin resistance/metabolic-related liver disease.     

Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link?

Non-alcoholic fatty liver disease (NAFLD) has emerged as a growing public health problem worldwide. Increasing recognition of the importance of NAFLD and its association with the features of the metabolic syndrome has stimulated an interest in its putative role in the development and progression of chronic kidney disease (CKD). Accumulating evidence suggests that NAFLD and CKD share many important cardio-metabolic risk factors and common pathogenetic mechanisms and that NAFLD is associated with an increased prevalence and incidence of CKD. This association appears to be independent of obesity, hypertension, and other potentially confounding factors, and it occurs both in patients without diabetes and in those with diabetes. Although further research is needed to establish a definitive conclusion, these observations raise the possibility that NAFLD is not only a marker of CKD but also might play a part in the pathogenesis of CKD, possibly through the systemic release of several pro-inflammatory/pro-coagulant mediators from the steatotic/inflamed liver or through the contribution of NAFLD itself to insulin resistance and atherogenic dyslipidemia. However, given the heterogeneity and small number of observational longitudinal studies, further research is urgently required to corroborate the prognostic significance of NAFLD for the incidence of CKD, and to further elucidate the complex and intertwined mechanisms that link NAFLD and CKD. If confirmed in future large-scale prospective studies, the potential adverse impact of NAFLD on kidney disease progression will deserve particular attention, especially with respect to the implications for screening and surveillance strategies in the growing number of patients with NAFLD.     

Hypothyroidism and non-alcoholic fatty liver disease: A coincidence or a causal relationship?

Non-alcoholic fatty liver disease (NAFLD) is a global problem. It may be caused by metabolic and hormonal disorders, including hypothyroidism. However, non-thyroid causes of NAFLD in people with hypothyroidism, including improper eating behavior and low physical activity, should be acknowledged. This study aimed to present the current literature on whether the development of NAFLD is related to hypothyroidism or a typical consequence of an unhealthy lifestyle in people with hypothyroidism. The results of previous studies do not allow for an unequivocal determination of the pathogenetic relationship between hypothyroidism and NAFLD. Important non-thyroid-initiating factors include providing too many calories in relation to requirements, consuming excessive amounts of monosaccharides and saturated fats, being overweight, and maintaining low physical activity levels. The recommended nutritional model for both hypothyroidism and NAFLD may be the Mediterranean diet, which is rich in fruits and vegetables, polyunsaturated fatty acids, and vitamin E.     

When should mitral valve prolapse be considered a real disease?

Mitral valve prolapse should be considered as a disease when superior displacement of the mitral leaflets during systole is more than 2 mm with a maximal leaflet thickness of at least 5 mm. Using these criteria, the prevalence of mitral valve prolapse is 1.3% in the general population, nearly the same in men and women. Serious complications may occur during follow-up with a 1 to 3% patient-year risk. The most important complication is mitral regurgitation, mainly due to rupture of the chordae tendineae, which must be quickly corrected by surgical repair. Second is infective endocarditis, a complication which may occur particularly in men older than 45 years of age with systolic murmur. Arrhythmias are not infrequent but ischemic neurologic events are unusual, especially in young patients. Cases of sudden death have occasionally been reported.     

Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon?

Non-alcoholic fatty liver disease (NAFLD), comprising a spectrum of conditions ranging from pure steatosis to steatohepatitis and cirrhosis, has reached epidemic proportions and represents the most common cause of chronic liver disease in the community. The prevalence of NAFLD has been estimated to be between 20% and 30% in the general population, but this value is much higher (∼70–80%) in type 2 diabetic patients, who are also at higher risk of developing advanced fibrosis and cirrhosis. Increasing recognition of the importance of NAFLD and its strong relationship with the metabolic syndrome has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Several epidemiological studies indicate that NAFLD, especially in its more severe forms, is linked to an increased risk of CVD, independently of underlying cardiometabolic risk factors. This suggests that NAFLD is not merely a marker of CVD, but may also be actively involved in its pathogenesis. The possible molecular mediators linking NAFLD and CVD include the release of pro-atherogenic factors from the liver (C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 and other inflammatory cytokines) as well as the contribution of NAFLD per se to whole-body insulin resistance and atherogenic dyslipidemia, in turn favouring CVD progression. The clinical impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Which metabolic syndrome criteria best predict the presence of non-alcoholic fatty liver disease?

Aims

To know which MS criteria best predict the presence of NAFLD and the prevalences of metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) diagnosed ultrasonographically among pre-diabetic and diabetic subjects based on three different MS criteria (IDF, ATP III, WHO).

Methods

Subjects were screened and those with a fasting serum glucose level ≥100 mg/dL were further tested with a 75 g oral glucose tolerance test. And those who were newly diagnosed as having pre-diabetes or diabetes were evaluated for MS and NAFLD. We compared the risk ratios of NAFLD among three MS criteria using multivariate and multiple logistic regression analyses.

Results

A total of 1365 subjects (977 males, mean age 48.4 ± 9.5 years) were analyzed. The WHO criteria produced the highest prevalence of MS in both the pre-diabetic (49.8%) and diabetic (58.9%) groups. The IDF criteria produced the highest odds ratio for NAFLD in both pre-diabetic (3.89 [95% CI 2.75-5.51]) and diabetic (5.53 [95% CI 3.21-9.52]) groups.

Conclusions

The prevalence of MS depends on the set of diagnostic criteria used. IDF criteria best predicts the presence of NAFLD. The presence of NAFLD should be considered as a component of the diagnostic criteria for MS.     

Risk of cardiovascular disease and chronic kidney disease in diabetic patients with non-alcoholic fatty liver disease: just a coincidence?

Non-alcoholic fatty liver disease (NAFLD) is estimated to afflict ~20-30% of the general population, and over 70% of the patients with Type 2 diabetes. Given the expected rise in the prevalence of obesity and diabetes, NAFLD will be, if not already there, an epidemic. The consequences of NAFLD are numerous, and range from progression to chronic liver disease with its associated morbidity and mortality, to worsening insulin resistance and Type 2 diabetes, to being a contributor to both cardiovascular disease (CVD) and chronic kidney disease (CKD). NAFLD is, therefore, a complex problem with implications far beyond the liver. This review focuses on the rapidly expanding body of clinical evidence suggesting that NAFLD is associated with an increased prevalence and incidence of both CVD and CKD in patients with diabetes. This association appears to be independent of obesity, hypertension, and other potential confounding factors. However, given the heterogeneity and small number of observational studies, further research is urgently required to corroborate the prognostic role of NAFLD in the development and progression of CVD and CKD among patients with diabetes, and to further elucidate the complex and intertwined mechanisms that link NAFLD with these adverse outcomes.     

A lipid to treat non-alcoholic fatty liver disease - the dawn of 'lipo-rehabilitation'?

Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unusual phosphatidylcholine species with two saturated 12 carbon fatty acid acyl sidechains (dilauroyl phosphatidylcholine (DLPC)) is an LRH-1 agonist ligand in vitro. DLPC treatment induces bile acid biosynthetic enzymes in mouse liver, increases bile acid levels, and lowers hepatictriglycerides and serum glucose. DLPC treatment also decreases hepatic steatosis and improves glucose homeostasis in two mouse models of insulin resistance. Both the antidiabetic and lipotropic effects are lost in liver-specific Lrh-1 knockouts. These findings identify an LRH-1 dependent phosphatidylcholine signalling pathway that regulates bile acid metabolism and glucose homeostasis.     

Therapeutic strategies for pediatric non-alcoholic fatty liver disease： A challenge for health care providers

Non-alcoholic steato-hepatitis (NASH) is related to insulin resistance and, thus, frequently occurs as part of the metabolic changes that accompany obesity, diabetes and hyperlipidemia. In childhood, the overwhelming boost of obesity and its co-morbidities have lead to the extraordinarily increased prevalence of NASH. Establishing effective therapeutic strategies to treat the disease represents the challenge for hepatologists and gastroenterologists in the next decade. Therapeutic approaches have aimed at treating associated conditions (obesity, insulin resistance, hyperlipemia, etc ) or reducing liver oxidative damage (vitamin E).     

What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome?

Non-alcoholic fatty liver disease (NAFLD) is currently not a component of the diagnostic criteria for metabolic syndrome (MetS); however, the development of NAFLD has some common mechanisms with the development of MetS, as they share the pathophysiologic basis of insulin resistance. It is also recognized that NAFLD is the hepatic manifestation of MetS. To define MetS, the presence of at least three of the proposed criteria is required, and sometimes it is sufficient to have only one laboratory value, modified by diet or drugs, for the classification of MetS. Ultrasonographically-detected NAFLD (US-NAFLD) is more stable, only changing during the middleto long-term. Although controversies over MetS continue, and considering that abdominal ultrasonography for diagnosing NAFLD has high specificity and guidelines to modify the natural course of NAFLD by diet composition or lifestyle have not yet been established, why should we not introduce US-NAFLD as a new criterion to define MetS?     

Vitamin D: A new player in non-alcoholic fatty liver disease?

Vitamin D through its active form 1a-25-dihydroxyvtamin D[1,25(OH)2D]is a secosteroid hormone that plays a key role in mineral metabolism.Recent years have witnessed a significant scientific interest on vitamin D and expanded its actions to include immune modulation,cell differentiation and proliferation and inflammation regulation.As our understanding of the many functions of vitamin D has grown,the presence of vitamin D deficiency has become one of the most prevalent micronutrient deficiencies worldwide.Concomitantly,non-alcoholic fatty liver disease(NAFLD)has become the most common form of chronic liver disease in western countries.NAFLD and vitamin D deficiency often coexist and epidemiologic evidence has shown that both of these conditions share several cardiometabolic risk factors.In this article we provide an overview of the epidemiology and pathophysiology linking NAFLD and vitamin D deficiency,as well as the available evidence on the clinical utility of vitamin D supplementation in NAFLD.     

What does irritable bowel syndrome share with non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease(NAFLD)and irritable bowel syndrome(IBS)are two very common diseases in the general population.To date,there are no studies that highlight a direct link between NAFLD and IBS,but some recent reports have found an interesting correlation between obesity and IBS.A systematic PubMed database search was conducted highlighting that common mechanisms are involved in many of the local and systemic manifestations of NAFLD,leading to an increased cardiovascular risk,and IBS,leading to microbial dysbiosis,impaired intestinal barrier and altered intestinal motility.It is not known when considering local and systemic inflammation/immune system activation,which one has greater importance in NAFLD and IBS pathogenesis.Also,the nervous system is implicated.In fact,inflammation participates in the development of mood disorders,such as anxiety and depression,characteristics of obesity and consequently of NAFLD and,on the other hand,in intestinal hypersensitivity and dysmotility.     

Could metabolic syndrome lead to hepatocarcinoma via non-alcoholic fatty liver disease?

It was estimated that from 2002 to 2008 the risk of developing cancer increased a quarter-fold in men and twofold in women due to excessive BMI.Obesity,metabolic syndrome and type 2 diabetes mellitus are strictly related and are key pathogenetic factors of non-alcoholic fatty liver disease(NAFLD),the most frequent liver disease worldwide.The most important consequence of the"metabolic epidemics"is the probable rise in the incidence of hepatocarcinoma(HCC),and NAFLD is the major causative factor.Adipose tissue is not merely a storage organ where lipids are preserved as an energy source.It is an active organ with important endocrine,paracrine,and autocrine actions in addition to immune functions.Adipocytes produce a wide range of hormones,cytokines,and growth factors that can act locally in the adipose tissue microenvironment and systemically.In this article,the main roles of insulin growth factor(IGF)-1 and IGF-2 are discussed.The role of IGF-2 is not only confined to HCC,but it may also act in early hepato-carcinogenesis,as preneoplastic lesions express IGF-2 mRNA.IGF-1 and IGF-2interact with specific receptors(IGF-1R and IGF-2R).IGF-1R is over-expressed in in vitro and in animal models of HCC and it was demonstrated that IGF ligands exerted their effects on HCC cells through IGF-1R and that it was involved in the degeneration of pre-neoplastic lesions via an increase in their mitotic activity.Both IGF-2R and TGFβ,a growth inhibitor,levels are reduced in human HCC compared with adjacent normal liver tissues.Another key mechanism involves peroxisome proliferator-activated receptor(PPAR)γ.In in vitro studies,PPARγinhibited various carcinomas including HCC,most probably by regulating apoptosis via the p21,p53 and p27 pathways.Finally,as a clinical consequence,to improve survival,efforts to achieve a"healthier diet"should be promoted by physicians and politicians.     

Sarcopenia and non-alcoholic fatty liver disease:Is there a relationship?A systematic review

AIM To perform a systematic review to evaluate the incidence and prevalence of non-alcoholic fatty liver disease(NAFLD) in adult patients with sarcopenia.METHODS Randomized clinical trials,cross-sectional or cohort studies including adult patients(over 18 years) with sarcopenia were selected.The primary outcomes of interest were the prevalence or incidence of NAFLD in sarcopenic patients.In the screening process,44 fulltext articles were included in the review and 41 studies were excluded.RESULTS Three cross-sectional studies were included.The authors attempted to perform a systematic review,but due to the differences between the studies,a qualitative synthesis was provided.The diagnosis of NAFLD was made by non-invasive methods(image methods or any surrogate markers) in all three evaluated studies.All the studies suggested that there was an independent association between sarcopenia and NAFLD.CONCLUSION Sarcopenia is independently associated with NAFLD and possibly to an advanced fibrosis.