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Effect of traditional Chinese medicine formula Sinisan on chronic restraint stress-induced nonalcoholic fatty liver disease: a rat study
research-article
Author(s):
Fafeng Cheng ,
Chongyang Ma ,
Xueqian Wang
,
Changming Zhai ,
Guoli Wang ,
Xiaolin Xu ,
Jie Mu ,
Changxiang Li ,
Zisong Wang ,
Xiaoyu Zhang ,
Wenchao Yue ,
Xin Du ,
Yajun Lian ,
Wenxiang Zhu ,
Xiangjun Yin ,
Zhen Wei ,
Wenjie Song ,
Qingguo Wang
Publication date (Electronic):
7 April 2017
Publisher:
BioMed Central
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Abstract
Background
Nonalcoholic fatty liver disease (NAFLD) represents one of the most common forms of liver disease worldwide, and it is always regarded as a consequence of a sedentary, food-abundant lifestyle, sitting for an extended time, and a low physical activity level, which often coincide with chronic and long-lasting psychological stress. A Chinese medicine Sinisan (SNS) may be a potential formula for treating this kind of disease.
Methods
In this study, a long-term chronic restraint stress protocol was used to investigate the mechanism underlying stress-induced NALFD. To investigate the effect of SNS treatment on stress-induced NAFLD, we measured the liver and serum values of total cholesterol (TC), triglyceride (TG), liver free fatty acids (FFA), low-density lipoprotein, superoxide dismutase, tumor necrosis factor-α, malondialdehyde, interleukin (IL)-6, and serum values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase. Results are shown as a mean ± standard deviation. Significant differences between the groups were evaluated using the Student t-test. For multiple comparisons, one-way analysis of variance (ANOVA) was used. If the results of ANOVA indicated significant differences, post hoc analysis was performed with the Tukey test or Dunnett test, and p < 0.05 was considered statistically significant.
Results
Long-term chronic stress led to steatosis and non-alcoholic steatohepatitis. Additionally, SNS treatment significantly increased body weight gain ( p < 0.01) and sucrose preference ( p < 0.001), and it reduced the liver values of TC, TG, and FFA ( p < 0.05). SNS also reduced the serum values of AST and ALT ( p < 0.001), and the liver value of IL-6 ( p < 0.01).
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Most cited references35
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EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease
(2016)
Introduction The Clinical Practice Guidelines (CPG) propose recommendations for the diagnosis, treatment and follow-up of non-alcoholic fatty liver disease (NAFLD) patients and are the product of a joint effort by the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO). They update a position statement based on the 2009 EASL Special Conference [1]. The data have been retrieved by an extensive PubMed search up to April 2015. The final statements are graded according to the level of evidence and strength of recommendation, which are adjustable to local regulations and/or team capacities (table 1) [2]. In particular, screening for NAFLD in the population at risk should be in the context of the available resources, considering the burden for the national healthcare systems and the currently limited effective treatments. The document is intended both for practical use and for advancing the research and knowledge of NAFLD in adults, with specific reference to paediatric NAFLD, whenever necessary. The final purpose is to improve patient care and awareness of the importance of NAFLD, and to assist stakeholders in the decision-making process by providing evidence-based data, which also takes into consideration the burden of clinical management for the healthcare system. Definition NAFLD is characterised by excessive hepatic fat accumulation, associated with insulin resistance (IR), and defined by the presence of steatosis in >5% of hepatocytes according to histological analysis or by the proton density fat fraction (PDFF, providing a rough estimation of the volume fraction of fatty material in the liver) >5.6% assessed by proton magnetic resonance spectroscopy (1H-MRS) or quantitative fat/water selective magnetic resonance imaging (MRI). NAFLD includes two pathologically distinct conditions with different prognoses: non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); the latter covers a wide spectrum of disease severity, including fibrosis, cirrhosis and hepatocellular carcinoma (HCC) (table 2). The diagnosis of NAFLD requires exclusion of both secondary causes and a daily alcohol consumption ≥30 g for men and 20 g for women [1]. The relationship between alcohol and liver injury depends on several cofactors (type of alcoholic beverage, drinking patterns, duration of exposure, individual/genetic susceptibility), rendering simple quantitative thresholds at least partly arbitrary. Specifically, patients consuming moderate amounts of alcohol may be still predisposed to NAFLD if they have metabolic risk factors. Of note, the overall impact of metabolic risk factors on the occurrence of steatosis appears to be higher than that of alcohol in these patients [3]. The definitive diagnosis of NASH requires a liver biopsy. Recommendations Patients with IR and/or metabolic risk factors (i.e., obesity or metabolic syndrome (MetS)) should undergo diagnostic procedures for the diagnosis of NAFLD, which relies on the demonstration of excessive liver fat (A1) Individuals with steatosis should be screened for secondary causes of NAFLD, including a careful assessment of alcohol intake. The interaction between moderate amounts of alcohol and metabolic factors in fatty liver should always be considered (A1) Other chronic liver diseases, that may coexist with NAFLD, should be identified as this might result in more severe liver injury (B1) Prevalence and Incidence NAFLD is the most common liver disorder in Western countries, affecting 17-46% of adults, with differences according to the diagnostic method, age, sex and ethnicity [4]. It parallels the prevalence of MetS and its components, which also increases the risk of more advanced disease, both in adults and in children. NAFLD is also present in 7% of normal-weight (lean) persons [5], more frequently in females, at a younger age and with normal liver enzymes. Their liver disease may nonetheless be progressive [6]. NAFLD incidence has rarely been measured. It was 20-86/1,000 person-years based on elevated liver enzymes and/or on ultrasound (US), and 34/1,000 per year by 1H-MRS [7]. The need for NAFLD screening in the community has been questioned given the high direct and indirect costs of testing, the low predictive value of non-invasive tests, the risks of liver biopsy and the lack of effective treatments [8]. However, the progressive form of NAFLD (i.e. NASH), particularly when associated with advanced fibrosis, should be identified in patients at risk (age > 50 years, type 2 diabetes mellitus (T2DM) or MetS), because of its prognostic implications. Validated cost-utility studies on extensive screening programmes are eagerly awaited. Similarly, although familial clustering occurs, family screening is not generally advisable, with the exception of cases with defined inherited diseases (e.g. lysosomal acid lipase deficiency). Recommendations All individuals with steatosis should be screened for features of MetS, independent of liver enzymes. All individuals with persistently abnormal liver enzymes should be screened for NAFLD, because NAFLD is the main reason for unexpectedly elevated liver enzymes (A1) In subjects with features of MetS, screening for NAFLD by liver enzymes and/or ultrasound should be part of routine work-up. In high risk individuals (age > 50 years, T2DM, MetS) case finding of advanced disease (i.e. NASH with fibrosis) is advisable (A2) Pathogenesis: Lifestyle and Genes A high-calorie diet, excess (saturated) fats, refined carbohydrates, sugar-sweetened beverages, a high fructose intake and a Western diet [9] have all been associated with weight gain and obesity, and more recently with NAFLD. High fructose consumption may increase the risk of NASH and advanced fibrosis, although the association may be confounded by excess calorie intake or by unhealthy lifestyles and sedentary behaviour [10], which are more common in NAFLD [11]. Recommendations Unhealthy lifestyles play a role in the development and progression of NAFLD. The assessment of dietary and physical activity habits is part of a comprehensive NAFLD screening (A1) Several genetic modifiers of NAFLD have been identified [12], but a minority has been robustly validated (supplementary table 1; available at http://content.karger.com/ProdukteDB/produkte.asp?doi=443344 ). The best-characterised genetic association is with PNPLA3, initially identified from genome-wide association studies and confirmed in multiple cohorts and ethnicities as a modifier of NAFLD severity across the entire histological spectrum [13,14]. Recently, the TM6SF2 gene has been reported as another disease modifier [15,16] and may have clinical utility assisting risk stratification for liver-related vs. cardiovascular morbidity. The PNPLA3 rs738409 variant also confers susceptibility and affects the histological pattern of NAFLD and fibrosis in obese children and adolescents [17]. A NASH risk score based on four polymorphisms has been validated in obese children with increased liver enzymes [18]. Recommendations Carriers of the PNPLA3 I148M and the TM6SF2 E167K variants have a higher liver fat content and increased risk of NASH. NAFLD due to these variants is not systematically associated with features of insulin resistance. Genotyping may be considered in selected patients and clinical studies but is not recommended routinely (B2) Liver Biopsy Liver biopsy is essential for the diagnosis of NASH and is the only procedure that reliably differentiates NAFL from NASH, despite limitations due to sampling variability [19]. NAFL encompasses: a) steatosis alone, b) steatosis with lobular or portal inflammation, without ballooning, and c) steatosis with ballooning but without inflammation [20]. The diagnosis of NASH requires the joint presence of steatosis, ballooning and lobular inflammation [20,21,22]. Other histological features can be seen in NASH, but are not necessary for the diagnosis: portal inflammation, polymorphonuclear infiltrates, Mallory-Denk bodies, apoptotic bodies, clear vacuolated nuclei, microvacuolar steatosis and megamitochondria. Perisinusoidal fibrosis is also frequent, but not part of the diagnostic criteria; the term ‘borderline’ NASH is confusing, unnecessary and should be abandoned. The prospectively designed FLIP algorithm increases observer agreement and precisely defines the grading of ballooning [22]. ‘Burned-out NASH’ describes regression of advanced disease (steatosis, inflammation or ballooning) in patients exposed to metabolic risk factors. The NAFLD Activity Score (NAS) scoring system should not be used for the diagnosis of NASH but rather for the evaluation of disease severity, once the diagnosis has been established by the overall pathological assessment. Although NAS is correlated with aminotransferase and homeostasis model assessment of insulin resistance (HOMA-IR) [23], they have a low prognostic value [24]. The steatosis, activity and fibrosis (SAF) score [22] is an alternative with good reproducibility and provides a more accurate and comprehensive description. Fibrosis staging relies on the Kleiner classification [21] (used in a simplified pattern in SAF) [22]. In children, NASH displays many of the features observed in adults, even though the distribution of lesions may be different. Portal inflammation is a frequent feature, but can also be seen in adults with more severe disease [25]. Hepatocellular ballooning and Mallory-Denk bodies are only sporadically observed in paediatric NASH, and portal-based chronic inflammation is predominant [21]. Based on the distinctive histological pattern, a specific histological score (Paediatric NAFLD Histological Score - PNHS) has been validated for a better classification of children with/without NASH [26]. Non-Invasive Assessment Non-invasive markers should aim to: i) in primary care settings, identify the risk of NAFLD among individuals with increased metabolic risk; ii) in secondary and tertiary care settings, identify those with worse prognosis, e.g. severe NASH; iii) monitor disease progression; iv) predict response to therapeutic interventions. Achieving these objectives could reduce the need for liver biopsy. Steatosis Rationale: Steatosis should be documented whenever NAFLD is suspected as the primary disease or as a coexisting condition. It also predicts future diabetes mellitus, cardiovascular events and arterial hypertension. In clinical practice, quantification of fat content is not of interest, except as a surrogate of treatment efficacy, and is therefore not generally recommended. In individual patients, especially in tertiary care centres, steatosis should be identified by imaging, preferably US, because it is more widely available and cheaper than the gold standard, MRI (supplementary table 2; available at http://content.karger.com/ProdukteDB/produkte.asp?doi=443344 ). The best-validated steatosis scores are the fatty liver index (FLI), the SteatoTest® and the NAFLD liver fat score; they have all been externally validated in the general population or in grade 3 obese persons and variably predict metabolic, hepatic and cardiovascular outcomes/mortality. These scores are associated with IR and reliably predict the presence, not the severity, of steatosis [30]. Another imaging technique, the controlled attenuation parameter (CAP) can diagnose steatosis, but has a limited ability to discriminate histological grades and has never been compared with 1H-MRS-measured steatosis. Also, the data from studies comparing CAP with US are inconclusive. Thus more data are needed to define the role of CAP. Recommendations US is the preferred first-line diagnostic procedure for imaging of NAFLD, as it provides additional diagnostic information (A1) Whenever imaging tools are not available or feasible (e.g., large epidemiological studies), serum biomarkers and scores are an acceptable alternative for the diagnosis of steatosis (B2) A quantitative estimation of liver fat can only be obtained by 1H-MRS. This technique is of value in clinical trials and experimental studies, but is expensive and not recommended in the clinical setting (A1) Steatohepatitis, NASH Rationale: The diagnosis of NASH provides important prognostic information and indicates an increased risk of fibrosis progression, cirrhosis and possibly hepatic comorbidities (HCC). It may also prompt a closer follow-up and possibly a greater need for more intensive therapy. Clinical, biochemical or imaging measures cannot distinguish NASH from steatosis [31,32]. Cytokeratin-18 fragments (CK-18), which are generated during cell death (M65 fragments) or apoptosis (M30 fragments), have modest accuracy for the diagnosis of NASH (66% sensitivity, 82% specificity) [33,34]. CK-18 changes parallel histological improvement but do not perform better than alanine transaminase (ALT) in identifying histological responders [35]. To date, non-invasive tests are not validated for the diagnosis of NASH. Recommendations NASH has to be diagnosed by a liver biopsy showing steatosis, hepatocyte ballooning and lobular inflammation (A1) Fibrosis Rationale: Fibrosis is the most important prognostic factor in NAFLD and is correlated with liver-related outcomes and mortality [24]. The presence of advanced fibrosis identifies patients in need of in-depth hepatological investigation, including, on a case-by-case basis, confirmatory biopsy and intensive therapies. Monitoring of fibrosis progression is also necessary at variable time intervals. Many serum markers have shown acceptable diagnostic accuracy as defined by an area under the receiver operating characteristic curve (AUROC) >0.8 (supplementary table 3; available at http://content.karger.com/ProdukteDB/produkte.asp?doi=443344 ) [32]. NAFLD fibrosis score (NFS) and fibrosis 4 calculator (FIB-4) have been externally validated in ethnically different NAFLD populations, with consistent results. NFS, FIB-4, Enhanced Liver Fibrosis (ELF) and FibroTest® predict overall mortality, cardiovascular mortality and liver-related mortality. NFS predicts incident diabetes, and changes in NFS are associated with mortality. The tests perform best at distinguishing advanced (≥F3) vs. non-advanced fibrosis but not significant (≥F2) or any (≥F1) fibrosis vs. no fibrosis [36]. Importantly, the negative predictive values (NPVs) for excluding advanced fibrosis are higher than the corresponding positive predictive values (PPVs) [36,37]; therefore, non-invasive tests may be confidently used for first-line risk stratification to exclude severe disease. However, predictive values depend on prevalence rates and most of these studies have been conducted in tertiary centres where the pre-test probability of advanced fibrosis is higher than in the community. Among imaging techniques, transient elastography performs better for cirrhosis (F4) than for advanced fibrosis (F3). Elastography has a higher rate of false-positive than false-negative results and higher NPV than PPV [38], hence the ability to diagnose bridging fibrosis or cirrhosis is insufficient for clinical decision-making. The main shortcoming of transient elastography is unreliable results in the presence of high BMI and/or thoracic fold thickness. In a large, unselected, European series, up to 20% of examinations had unreliable results [39], mainly in obese NAFLD [38]. The XL probe should be used in these patients to reduce the failure rate, which remains high (35%) [40]. There is no consensus on thresholds or strategies for use in clinical practice when trying to avoid liver biopsy [32]. Some data suggest that the combination of elastography and serum markers performs better than either method alone [41]. Importantly, longitudinal data correlating changes in histological severity and in non-invasive measurements are urgently needed. Recommendations Biomarkers and scores of fibrosis, as well as transient elastography, are acceptable non-invasive procedures for the identification of cases at low risk of advanced fibrosis/cirrhosis (A2). The combination of biomarkers/scores and transient elastography might confer additional diagnostic accuracy and might save a number of diagnostic liver biopsies (B2) Monitoring of fibrosis progression in clinical practice may rely on a combination of biomarkers/scores and transient elastography, although this strategy requires validation (C2) The identification of advanced fibrosis or cirrhosis by serum biomarkers/scores and/or elastography is less accurate and needs to be confirmed by liver biopsy, according to the clinical context (B2) In selected patients at high risk of liver disease progression, monitoring should include a repeat liver biopsy after at least 5-year follow-up (C2) Non-Invasive Testing in Paediatric NAFLD The position paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Hepatology Committee has recently delineated diagnostic criteria for paediatric NAFLD [42]. In obese children, NAFLD should always be suspected; elevated aminotransferase levels and liver hyperechogenicity deserve further evaluation and the exclusion of other causes of liver disease. Due to the poor sensitivity of these tests in overweight/obese children, non-invasive markers and imaging techniques are the first diagnostic step [43]. Recommendations In children, predictors of fibrosis, including elastometry, acoustic radiation force impulse (ARFI) imaging and serum biomarkers might help reduce the number of biopsies (B2) Common Metabolic Disorders Related to NAFLD NAFLD is tightly associated with IR not only in the liver but also in muscle and adipose tissues [44], and also with MetS, defined as the cluster of any three of the following five features associated with IR: impaired fasting glucose (IFG) or T2DM, hypertriglyceridaemia, low high-density lipoprotein(HDL)-cholesterol (gender-adjusted), increased waist circumference (ethnicity adjusted) and high blood pressure [45]. As all components of MetS correlate with liver fat content, independently of BMI, the presence of MetS in any given patient should lead to an evaluation of the risk of NAFLD, and vice versa the presence of NAFLD should lead to an assessment of all components of MetS. Hepatic triacylglycerol accumulation is accompanied by abnormal hepatic energy metabolism [46] and impaired insulin-mediated suppression of hepatic glucose and very low-density lipoprotein production [47], leading to hyperglycaemia, hypertriglyceridaemia and hyperinsulinaemia. In non-diabetic persons, the product of fasting glucose (in mmol/l) and insulin (in mU/ml), divided by 22.5 (HOMA-IR) can serve as surrogate for IR [48], and is therefore an acceptable alternative to more expensive and time-consuming dynamic testing. Liver disease progression has been associated with persistence or worsening of metabolic abnormalities, including HOMA-IR [49,50]. However, the validity of HOMA-IR depends on the ability of insulin secretion to adapt to IR, questioning its suitability in overt diabetes. Moreover, the assays for insulin measurements vary widely, and there is no agreement on a threshold defining IR using HOMA-IR. Recommendations HOMA-IR provides a surrogate estimate of IR in persons without diabetes and can therefore be recommended provided proper reference values have been established (A1) HOMA-IR is of limited use for NAFLD diagnosis in patients with metabolic risk factors. It could confirm altered insulin sensitivity, thereby favouring a diagnosis of IR-associated NAFLD, in cases of diagnostic uncertainty (e.g. US-defined steatosis with normal body weight) (B2) During follow-up, HOMA-IR might help identify patients at risk of NASH or fibrosis progression in selected cases. Improvement of HOMA-IR during weight loss may indicate metabolic improvement that could be beneficial for NAFLD (C2) Obesity BMI and waist circumference, a measure of visceral adiposity, are positively related to the presence of NAFLD [51] and predict advanced disease, particularly in the elderly [52]. A large proportion of patients with cryptogenic cirrhosis have a high prevalence of metabolic risk factors [53], suggesting that in the majority of cases of cryptogenic cirrhosis are ‘burned-out’ NASH. Common comorbidities of obesity, such as T2DM, and sleep apnoea [54], polycystic ovary syndrome and other endocrine disorders (hypogonadism), further drive NAFLD prevalence and severity. Importantly, patients with BMI 10-fold higher in T2DM and obesity) varies according to study population (population-based, natural history vs. clinic-based cohorts with/without fibrosis or cirrhosis) from 7.6% at 5 years in persons with advanced fibrosis or cirrhosis to only 0.25% in a larger series, followed for 5.6 years [77]. At diagnosis, patients with NAFLD-associated HCC are older than those with non-NAFLD HCC, have more extrahepatic comorbidities, but a lower prevalence of cirrhosis (only two-thirds of cases) (supplementary table 5; available at http://content.karger.com/ProdukteDB/produkte.asp?doi=443344 ). NAFLD-related HCC may, however, be diagnosed at more advanced stages, due to less systematic surveillance, and receive less treatment. Conflicting data are reported on survival. At present, NAFLD is the second leading indication for HCC-related transplantation in the USA [78]. The large number of NAFLD cases at risk of HCC makes systematic surveillance largely impracticable. PNPLA3 rs738409: C>G gene polymorphism has been associated with an increased HCC risk and might provide patient-risk stratification for tailored HCC surveillance in NAFLD, but it is not yet considered cost-effective (supplementary table 1; available at http://content.karger.com/ProdukteDB/produkte.asp?doi=443344 ). Recommendations Although NAFLD is a risk factor for HCC, which may also develop in the pre-cirrhotic stage, and the risk is further increased by the presence of the PNPLA3 rs738409 C>G polymorphism, no recommendation can be currently made on the timing of surveillance and its cost-effectiveness (B1) Other Extrahepatic Disorders Chronic kidney disease (CKD) can be found in 20-50% of NAFLD patients, particularly in biopsy-proven NASH [79]. US-defined NAFLD carries a 1.5- to 2-fold adjusted risk of incident CKD in type 1 diabetes mellitus [80]. NAFLD is also associated with colorectal cancer [81], metabolic bone disease (vitamin D deficiency, osteoporosis) [62,82] and rare metabolic diseases (lipodystrophies, glycogen storage diseases). Treatment Rationale: Successful treatment of NASH should improve outcomes, i.e. decrease NASH-related mortality, reduce progression to cirrhosis or HCC. The resolution of the histological lesions defining NASH is now accepted as a surrogate endpoint, particularly in clinical trials. Only a few properly designed randomised controlled trials (RCTs) are available, with improvement/regression of hepatic necroinflammation and/or fibrosis as primary outcomes [83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105] (table 4). Diet and Lifestyle Changes Rationale: Epidemiological evidence suggests a tight relationship between unhealthy lifestyle and NAFLD [106], which makes lifestyle correction mandatory in all patients (table 5). Of note, daily alcohol consumption up to 30 g (men) or 20 g (women) is insufficient to induce alcoholic steatosis and might even be protective against NAFLD, NASH and fibrosis as compared with total abstinence. Relatively small amounts of weight loss reduce liver fat and improve hepatic IR [119]. In a pilot RCT of cognitive-behaviour therapy, lifestyle intervention resulted in more weight loss, more frequent resolution of NASH and a borderline higher (p = 0.05) reduction in the NAS score [93]. In a post hoc analysis, a weight loss ≥7% was associated with histological improvement. In an uncontrolled, 12-month study with 261 paired biopsies, a modest lifestyle-induced weight loss was associated with NASH regression (25% of total cases) without worsening of fibrosis [120]. Pragmatic approaches combining dietary restriction and a progressive increase in aerobic exercise/resistance training [121] are preferable and should be individually tailored. No data are available on their long-term effects on the natural history of NAFLD. Recommendations Structured programmes aimed at lifestyle changes towards healthy diet and habitual physical activity are advisable in NAFLD C2 Patients without NASH or fibrosis should only receive counselling for healthy diet and physical activity and no pharmacotherapy for their liver condition B2 In overweight/obese NAFLD, a 7-10% weight loss is the target of most lifestyle interventions, and results in improvement of liver enzymes and histology B1 Dietary recommendations should consider energy restriction and exclusion of NAFLD-promoting components (processed food, and foods and beverages high in added fructose). The macronutrient composition should be adjusted according to the Mediterranean diet B1 Both aerobic exercise and resistance training effectively reduce liver fat. The choice of training should be tailored based on patients' preferences to be maintained in the long-term B2 Drug Treatment Rationale: Drug therapy should be indicated for progressive NASH (bridging fibrosis and cirrhosis) but also for early-stage NASH with increased risk of fibrosis progression (age > 50 years; diabetes, MetS, increased ALT [122]) or active NASH with high necroinflammatory activity [123]. No drug has currently been tested in phase III trials and is approved for NASH by regulatory agencies. Therefore, no specific therapy can be firmly recommended and any drug treatment would be off-label (for reviews see [124,125,126], table 4). Safety and tolerability are essential prerequisites for drug treatment, because of NASH-associated comorbidities and polypharmacy, a potential source of drug-drug interactions. Insulin Sensitisers There is scarce evidence for a histological efficacy of metformin in NASH [84,90,92]. The effect of metformin on liver fat is weak, because of its inability to restore serum adiponectin levels in the short-term [127]. Some preclinical data support an anti-tumorigenic activity of metformin on liver cancer [128], while the demonstration of reduced rates of HCC in humans is limited to retrospective studies [129] and insufficient for evidence-based recommendations. Thiazolidinediones are peroxisome proliferator-activated receptor gamma (PPARγ) agonists with insulin-sensitising effects. The PIVENS trial compared low dose pioglitazone vs. vitamin E vs. placebo for 2 years in patients without overt diabetes. Pioglitazone improved all histological features (except for fibrosis) and achieved resolution of NASH more often than placebo [95]. The histological benefit occurred together with ALT improvement and partial correction of IR. Similar results were reported in two smaller and shorter RCTs [85,89]. Prolonged therapy with rosiglitazone, up to 2 years, did not result in further histological improvement [88,94], although this was not formally tested with pioglitazone. Side effects of glitazones are of concern: weight gain, bone fractures in women, and rarely congestive heart failure. Despite the safety and tolerability profile, pioglitazone can be used for selected patients with NASH, particularly in T2DM where the drug has a registered use. Incretin mimetics, acting on the glucose-insulin interplay have shown favourable results in pre-marketing studies on liver enzymes [130]. A small pilot trial of daily injections of liraglutide met the histological outcome of NASH remission without worsening of fibrosis [105]. Antioxidants, Cytoprotective and Lipid-Lowering Agents In the PIVENS trial, vitamin E (800 IU/day) improved steatosis, inflammation and ballooning and induced resolution of NASH in 36% of patients (21% in the placebo arm) [95]. Reduced ALT correlated with histological improvement, and histological non-responders did not reduce ALT [131]. In the paediatric TONIC trial [98], vitamin E failed to reduce aminotransferases, steatosis and inflammation but improved ballooning and doubled the rate of NASH clearance vs. placebo. These results contrast with previous trials, which were mostly negative in both adults and children. Concerns about long-term safety of vitamin E exist, mainly an increase in overall mortality [132], in haemorrhagic stroke [133] and prostate cancer in males older than 50 [134]. Vitamin E may be used in non-cirrhotic non-diabetic NASH patients but further studies are needed before firm recommendations can be made. Ursodeoxycholic acid (UDCA) has been investigated in several RCTs, at different doses and for up to 2 years, but only showed some biochemical but no histological improvements [83,87,96]. A synthetic farnesoid X receptor agonist, obeticholic acid, improved IR in T2DM [135]. In the phase IIb FLINT trial, a 72-week treatment with obeticholic acid in non-cirrhotic NASH patients improved all NASH lesions while improving fibrosis [99]. Main issues with safety and tolerability were increased low-density lipoprotein(LDL)-cholesterol and pruritus. Preliminary data from small or uncontrolled studies suggested that n-3 polyunsaturated fatty acids (PUFAs) might reduce liver fat [136], but two trials testing PUFAs on histological outcomes were negative [102,104]. Available data on pentoxifylline and orlistat are limited or inconclusive [86,91,97]. Also, data on lipid-lowering drugs are poor; recent trials with ezetimibe were negative [101,103], whereas statins have not been adequately tested. Their use in NAFLD is safe, with no increased risk of hepatotoxicity, and may even significantly reduce aminotransferases [137]. Promising novel agents with anti-inflammatory, antifibrotic or insulin sensitising properties (dual PPARα/δ agonists, dual chemokine receptor(CCR)2/CCR5 antagonists and fatty acid/bile acid conjugates) and antifibrotic agents (anti-lysyl oxidase-like (anti-LOXL2) monoclonal antibodies) are also being tested in late phase RCTs in NASH. Recommendations Pharmacotherapy should be reserved for patients with NASH, particularly for those with significant fibrosis (stage F2 and higher). Patients with less severe disease, but at high risk of disease progression (i.e., with diabetes, MetS, persistently increased ALT, high necroinflammation) could also be candidates to prevent disease progression B1 While no firm recommendations can be made, pioglitazone (most efficacy data, but off-label outside T2DM) or vitamin E (better safety and tolerability in the short term) or their combination could be used for NASH B2 The optimal duration of therapy is unknown; in patients with increased ALT at baseline, treatment should be stopped if there is no reduction in aminotransferases after 6 months of therapy; in patients with normal ALT at baseline, no recommendations can be made C2 Statins may be confidently used to reduce LDL-cholesterol and prevent cardiovascular risk, with no benefits or harm on liver disease. Similarly n-3 polyunsaturated fatty acids reduce both plasma and liver lipids, but there are no data to support their use specifically for NASH (B1) Iron Depletion Hepatic iron accumulation is associated with IR, and iron depletion improves IR [138]. In NAFLD, high ferritin levels are common, in the presence of variable transferrin saturation, independent of gene polymorphisms of familial hemochromatosis. In these patients, a phlebotomy programme to reduce iron stores to near iron deficiency improved the NAS score, without worsening fibrosis [100], but more data are needed. Paediatric NAFLD In children, diet and exercise training reduce steatosis, but do not affect ballooning, inflammation and fibrosis [139]. Although several drug-based therapies, such as vitamin E and metformin, and dietary supplementation, including probiotics and docosahexaenoic acid, have shown beneficial effects on ballooning, steatosis and inflammation, fibrotic lesions are refractory to treatment [140] and the long-term outcome of paediatric NASH remains poor [141]. Recommendations Diet and physical activity improve steatosis and hepatic inflammation in paediatric NAFLD, but no beneficial effects on fibrosis have ever been demonstrated. No safe drug treatment has proven effective on fibrosis in paediatric NAFLD B1 Bariatric (Metabolic) Surgery In patients unresponsive to lifestyle changes and pharmacotherapy, bariatric surgery is an option for reducing weight and metabolic complications, with stable results in the long term [142]. Surrogate markers indicate that bariatric surgery is effective on NAFLD-associated liver injury, and there is also initial evidence for improved necroinflammation and fibrosis [143]. A recent cohort study with 1-year follow-up confirmed that bariatric surgery-associated weight loss cleared NASH in 85% of patients and improved fibrosis in 34% [144], although the possible benefits should be balanced against peri-/post-operative complications. No solid data on the comparative effects of different bariatric procedures on liver fat are available. Recommendations By improving obesity and diabetes, bariatric (metabolic) surgery reduces liver fat and is likely to reduce NASH progression; prospective data have shown an improvement in all histological lesions of NASH, including fibrosis B1 Liver Transplantation NAFLD-associated cirrhosis is among the top three indications for liver transplantation. The 3- and 5-year survival is not different in NAFLD vs. no-NAFLD; NAFLD carries a higher risk of death from cardiovascular complications and sepsis, whereas the risk of graft failure is lower [145,146]. The overall mortality is associated with BMI and diabetes, with 50% of cases with BMI > 35 kg/m2 dying within 1 year of transplantation [147]. Transplant failure (10% and 45% at 10 and 20 years, respectively [148]) in obese patients is rarely associated with recurrent NASH cirrhosis (≈2%) [146]. Recommendations Liver transplantation is an accepted procedure in NASH patients with end-stage liver disease, with comparable overall survival to other indications, despite a higher cardiovascular mortality. NASH patients with liver failure and/or HCC are candidates for liver transplantation A1 Disclosure Statement Giulio Marchesini declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Christopher P. Day declares he has been a consultant/advisor for Abbott Laboratories and Genfit and completed sponsored lectures for Abbott Laboratories. Jean-François Dufour declares he has been a consultant/advisor for Intercept and Genfit. Ali Canbay declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Valerio Nobili declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Vlad Ratziu declares he has been a consultant/advisor for Genfit. In addition he has been on the advisory board for Gilead, Genfit, Roche and Galmed Pharmaceuticals. Herbert Tilg declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Michael Roden has received research support and been involved in clinical trials for Boehringer Ingelheim, Novartis Pharma and Sanofi-Aventis Germany. He has been a consultant/advisor for GI Dynamics, Sanofi-Aventis Germany and Merck & Co. Inc. He has completed sponsored lectures for Eli Lilly and Novo Nordisk. Amalia Gastaldelli has received research support from Amylin-BMS-AstraZeneca and has been a consultant/advisor for Roche, Eli-Lilly and Sanofi Aventis. Hannele Yki-Järvinen declares she does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Fritz Schick declares he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Roberto Vettor declares that he has been a consultant/advisor as well as received grants/research support from Sanofi. In addition he has completed sponsored lectures for Novo Nordisk, Sanofi and AstraZeneca. Gema Frühbeck declares that she is on the Novo Nordisk Obesity Scientific Communication Global Advisory Board. Lisbeth Mathus-Vliegen declares she does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
- Record: found
- Abstract: found
- Article: not found
Relationship of sitting time and physical activity with non-alcoholic fatty liver disease.
Seungho Ryu, Yoosoo Chang, Hyun-Suk Jung … (2015)
The goal of this study was to examine the association of sitting time and physical activity level with non-alcoholic fatty liver disease (NAFLD) in Korean men and women and to explore whether any observed associations were mediated by adiposity.
- Record: found
- Abstract: found
- Article: not found
Non alcoholic fatty liver: epidemiology and natural history.
Non Alcoholic Fatty Liver Disease (NAFLD), defined as the presence of a significant amount of lipid accumulation in the liver (at least in 5% of hepatocytes), represents a challenging issue for the Hepatologists. NAFLD is not represented by a single entity, but rather by two different entities that have different natural history and evolution that range from simple fat accumulation in the liver (without any consequence), to necroinflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The reason of these differences has to be found in the host characteristics and associated risk factors. Globally, its prevalence among liver diseases, and in the general population, is rising in the recent years along with its associated conditions: obesity, insulin resistance, metabolic syndrome and diabetes. This increment, together with the reported clinical conditions, may be accounted for changes in dietary habits and the increase of sedentary lifestyle. Its diffusion seems to be pandemic, given that it is beginning to affect the populations in the developing world due to the spread of Western lifestyle. This is particularly worrying in young adults and children in what seems to have become the main cause of liver disease. Even if the real rate of global incidence of NAFLD are not known, its worldwide prevalence in general population is estimated to be 20-30% in Western Countries and 5-18% in Asia and it is increasing over time. In this review we will report on the global and regional prevalence of NAFLD, the principal risk factors and the natural history of its different presentations.
Author and article information
Contributors
Fafeng Cheng: fafengcheng@gmail.com
Chongyang Ma: machongyang@live.com
Xueqian Wang: 86-13601183429
,
shirlyding@163.com
Changming Zhai: zhaichangming1989@163.com
Guoli Wang: 767375896@qq.com
Xiaolin Xu: xuxiaolin0502@163.com
Jie Mu: 1041415560@qq.com
Changxiang Li: 673872817@qq.com
Zisong Wang: phoenix_wzs@163.com
Xiaoyu Zhang: 1282015632@qq.com
Wenchao Yue: yuewenchao@bucm.edu.cn
Xin Du: 1558137524@qq.com
Yajun Lian: niangkuosir@bucm.edu.cn
Wenxiang Zhu: leon_zhu0619@163.com
Xiangjun Yin: yinxiangjun2016@163.com
Zhen Wei: weizhen901210@126.com
Wenjie Song: 411563495@qq.com
Qingguo Wang: 86-13601183429
,
wangqg8558@163.com
Journal
Journal ID (nlm-ta): BMC Complement Altern Med
Journal ID (iso-abbrev): BMC Complement Altern Med
Title:
BMC Complementary and Alternative Medicine
Publisher:
BioMed Central
(London
)
ISSN
(Electronic):
1472-6882
Publication date
(Electronic):
7
April
2017
Publication date PMC-release: 7
April
2017
Publication date Collection: 2017
Volume: 17
Electronic Location Identifier: 203
Affiliations
Article
Publisher ID: 1707DOI: 10.1186/s12906-017-1707-2
PMC ID: 5383977
PubMed ID: 28388904
SO-VID: eee62f75-7153-4d54-a60b-21c3956682f9
Copyright © © The Author(s). 2017
License:
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
History
Date
received
: 4
November
2016
Date
accepted
: 24
March
2017
Funding
Funded by: National Basic Research Program of China
Award ID: 2011CB505100
Categories
Subject:
Research Article
Custom metadata
issue-copyright-statement © The Author(s) 2017
ScienceOpen disciplines: Complementary & Alternative medicine