肝癌和生活方式 - 酒，咖啡，饮食，运动，吸烟

StephenW

www.natap.org
"Epidemiological studies have indicated that physical activity lowers the risk of various carcinomas (esophagus, colon, breast, bladder, lung, kidney, prostate, pancreas, endometrium and ovary)"

Hepatocellular Carcinoma and Lifestyles - alcohol, coffee, diet, exercise, smoking

Journal of Hepatology Sept 1 2015



Uttara Saran1,2, Bostjan Humar3, Philippe Kolly1,2 and Jean-François Dufour1,2
1Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland
2University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland
3Department of Visceral & Transplantation Surgery, University Hospital Zürich, Zürich,
Switzerland







AbstractThe majority of hepatocellular carcinoma occurs over pre-existing chronic liver diseases that share cirrhosis as an endpoint. In the last decade, a strong association between lifestyle and hepatocellular carcinoma has become evident. Abundance of energy-rich food and sedentary lifestyles have caused metabolic conditions such as obesity and diabetes mellitus to become global epidemics. Obesity and diabetes mellitus are both tightly linked to nonalcoholic fatty liver disease and also increase hepatocellular carcinoma risk independent of cirrhosis. Emerging data suggest that physical activity not only counteracts obesity, diabetes mellitus and nonalcoholic fatty liver disease, but also reduces cancer risk. Physical activity exerts significant anticancer effects in the absence of metabolic disorders. Here, we present a systematic review on lifestyles and hepatocellular carcinoma.


Cancers result from the interactions of host features with environment factors. Lifestyles, which comprise the habits by which a person chooses to live, define these interactions. Therefore, lifestyles such as dietary choices, smoking, alcohol consumption and physical activity have a profound influence on cancer development, including hepatocellular carcinoma (HCC). The capacity to survive famine was one of the strongest selection traits during evolution. This changed drastically about 50 years ago with generalization of a lifestyle characterized by abundance of food and lack of exercise. Human physiology has not changed in such a short period of time. As a consequence, we are maladapted to our new environment and this maladaptation leads to the epidemics of obesity and diabetes mellitus (DM). Obesity has been consistently associated with a 1.5–4.5 times increase of HCC risk [[url=][1][/url], [url=][2][/url], [url=][3][/url], [url=][4][/url], [url=][5][/url], [url=][6][/url], [url=][7][/url]]. Even an increase in body mass index (BMI) during childhood was associated with an elevated risk of HCC during adulthood [[url=]8[/url]]. DM was also linked to a 2–3-fold increase of HCC risk [[url=][9][/url], [url=][10][/url], [url=][11][/url]], independently of the underlying liver disease [[url=]11[/url]] and even in lean individuals [[url=]12[/url]]. Moreover, treating diabetic patients with insulin and/or insulin sensitizers may further increase the risk to develop HCC. This highlights how strongly lifestyles influence the risk of developing HCC.

SmokingSmoking is associated with the development of several types of cancers, particularly those arising in organs directly exposed to smoke. Smoking also increases the risk of developing HCC (Table 1). Tobacco smoke contains chemicals that become activated as carcinogens when metabolized in the liver [[url=]13[/url]]. A linear relation between 4-aminobiphenyl-DNA adduct levels in liver tissue and HCC risk was reported, which was also significant after adjustment for covariates, including hepatitis B surface antigen status [[url=]14[/url]]. In a large Chinese retrospective study, smokers had a higher risk ratio for HCC than nonsmokers; this concerned males as well as females and the risk correlated with the degree of cigarette consumption [[url=]15[/url]]. This was confirmed in two Asian prospective studies which adjusted for alcohol consumption [[url=]16[/url]], [[url=]17[/url]]. Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) suggested that, in Europe, smoking contributes to nearly half the cases of HCC, which is actually more than hepatitis B and C viruses [[url=]18[/url]]. Moreover, smokers who underwent HCC resection had a higher rate of recurrence and liver-specific mortality [[url=]19[/url]].
AlcoholAlcohol is linked to HCC via the development of cirrhosis. The published evidence does not support a role for alcohol as a direct carcinogen for HCC. Alcohol-induced liver disease is one of the most prevalent causes of cirrhosis and alcohol-induced cirrhosis is associated with a 5-year cumulative risk for HCC of 8% [[url=]20[/url]]. The odds ratios for HCC increase linearly with alcohol intake and are higher in cases of DM or infection with hepatitis B or C virus[[url=]21[/url]], [[url=]22[/url]].

CoffeeSince 2002, when a protective effect of coffee against HCC was first reported [[url=]23[/url]], epidemiological studies, covering different geographical areas and different HCC etiologies and with different designs, have substantiated this observation. Three meta-analyses comprising studies from Europe and Asia found a statistically significant association between coffee consumption and an approximately 40% reduced liver cancer risk[[url=]24[/url]], [[url=]25[/url]], [[url=]26[/url]]. Prospective studies confirmed the benefit of coffee consumption. A prospective cohort that enrolled Finnish male smokers reported that coffee intake (boiled or filtered) was inversely associated with incident liver cancer [[url=]27[/url]]. Comparing high coffee consumers with low coffee consumers in the EPIC study, Bamia et al. found a decreased risk for HCC with a hazard ratio of 0.28 [[url=]28[/url]]. Finally, a large, multiethnic, population-based prospective cohort found a dose-dependent protective effect of coffee intake [[url=]29[/url]].

DietMore than specific nutrients, it is the promotion of obesity and DM by overnutrition and energy-rich diets which increases the risk of HCC. Two case–control studies from southern Europe found a positive association between high dietary glycemic load and HCC among patients with chronic HBV or HCV infections [[url=]30[/url]], [[url=]31[/url]]. Although the latter study found that this positive association was present in patients without chronic hepatitis infection, this link was weaker and not statistically significant [[url=]31[/url]]. There is growing evidence that adherence to a healthy diet plays a role in delaying HCC development in at-risk populations. Epidemiological studies have suggested that increased consumption of fruits decreases the risk of HCC [[url=]32[/url]] and low vegetable intake was significantly associated with an increased risk of HCC [[url=]33[/url]]. An Italian case–control study reported an inverse relation between intakes of fruits, milk/yoghurt, white meats, eggs and HCC risk [[url=]34[/url]]. Higher intake of total dietary fiber and a lower intake of dietary sugar were associated with decreased risk of HCC [[url=]7[/url]]. Finally, the degree of adherence to a “Mediterranean” diet was significantly inversely related to HCC risk. Turati et al. scored adherence to a “Mediterranean” diet in 518 cases of HCC and 712 controls from Italy and Greece [[url=]35[/url]]. They found that good adherence is associated with a 50% reduction in HCC incidence and that this effect is particularly striking in patients with a chronic viral hepatitis B or C.

Physical activityRegular exercise reduces the negative consequences associated with overconsumption of an energy-dense diet, including insulin resistance, weight gain, and obesity [[url=][12][/url], [url=][36][/url], [url=][37][/url]]. The recognition that physical activity can also prevent cancer has motivated growing interest in this area of research.

Preventive benefits of exercise (primary prevention)Epidemiological studies have indicated that physical activity lowers the risk of various carcinomas (esophagus, colon, breast, bladder, lung, kidney, prostate, pancreas, endometrium and ovary). While risk reductions seem to be small for endometrial [[url=]38[/url]] and prostate cancer [[url=]39[/url]], a pronounced benefit was shown for breast [[url=]40[/url]], colon [[url=]41[/url]], and lung cancer [[url=]42[/url]]. Physical activity may even reduce lung cancer incidence in smokers [[url=]43[/url]], and breast cancer risk in BRCA1/2 mutation carriers who are genetically predisposed to the disease [[url=]44[/url]], illustrating the powerful impact of exercise. In a recent prospective study of a large Taiwanese cohort, Wen et al. observed a gradual correlation between decline in HCC risk and degree of physical activity [[url=]45[/url]], an observation which has been duplicated in an NIH study by Behrens et al. [[url=]46[/url]]. In terms of primary prophylaxis, HCC associated mortality appears to be reduced (relative risk [RR] 0.71; 95% confidence interval [CI] 0.52–0.98) in patients on moderate-to vigorous-intensity physical activity regimes (>7 h/week) before the diagnosis of cancer relative to inactive subjects [[url=]47[/url]].

Benefits of exercise post cancer diagnosisIn addition to its preventive effects, physical activity also favorably impacts on outcomes following cancer diagnosis. Mounting evidence indicates an improved quality of life, a decreased risk of recurrence, and up to 50% reduced risk of cancer-related mortality in physically active breast, prostate or colorectal cancer survivors compared with their less active peers. In men diagnosed with early prostate cancer, regular vigorous-intensity exercise (⩾3 h/week) was associated with a 61% and 57% decreased risk of cancer-specific mortality and progression, respectively [[url=]48[/url]], [[url=]49[/url]]. As for liver cancer, one can consider the beneficial effects of lifestyle changes in patients with cirrhosis as secondary prevention. At the level of tertiary prevention, there is presently no evidence that exercise decreases HCC recurrence.

Hepatic effects of exerciseThe benefits of physical activity have been consistently observed in a number of studies that are summarized in Table 2. Regular physical activity reduces steatosis and improves insulin sensitivity even in the absence of weight loss [[url=][50][/url], [url=][51][/url], [url=][52][/url], [url=][53][/url], [url=][54][/url], [url=][55][/url], [url=][56][/url], [url=][57][/url], [url=][58][/url]]. Exercise improves adipocytic insulin sensitivity, reducing the flow of fatty acids (FAs) to the liver irrespective of BMI [[url=][59][/url], [url=][60][/url], [url=][61][/url]]. Correspondingly, elevated physical activity is inversely associated with the onset of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [[url=]53[/url]], [[url=]56[/url]], [[url=]57[/url]], [[url=]62[/url]], [[url=]63[/url]], [[url=]64[/url]], [[url=]65[/url]], [[url=]66[/url]], [[url=]67[/url]], [[url=]68[/url]], [[url=]69[/url]], [[url=]70[/url]]. Although currently speculative, the increased energy expenditure should further mitigate the procarcinogenic features of lipotoxicity and excess lipids, while improved insulin sensitivity should counteract the glucose-addicted phenotype of cancer cells. Kaibori et al. observed greater loss of body fat through exercise compared with dietary modification in a cohort of HCC patients, with insulin sensitivity improving only in the group with the highest exercise intensity [[url=]71[/url]].




Experimental data regarding the impact of exercise on the livers of diet-induced animal models predisposed to NAFLD, NASH, and HCC are summarized in Table 3. Despite the heterogeneity of the experimental set-ups (particularly the composition of diets), the sum of evidence confirms the beneficial effects of exercising. Exercise programs improved adipose mass, steatosis, insulin resistance, inflammation or other parameters associated with the metabolic syndromes, which may also be improved when exercise is introduced midway through a high-fat diet regimen [[url=][72][/url], [url=][73][/url], [url=][74][/url], [url=][75][/url]], [[url=]76[/url]]. When comparing exercise with calorie restriction, Rector et al. noted elevated mitochondrial ?-oxidation, oxidative enzyme function, improved glucose tolerance, and suppression of hepatic de novo lipogenesis in the exercise group, providing support to the claim that exercise has effects superior to those of dietary modification [[url=]77[/url]]. Interestingly, halting exercise for short periods (7 days) does not appear to hamper its benefits, although longer interruptions (4 weeks) caused deterioration of the overall metabolic phenotype in hyperphagic rats [[url=]78[/url]]. In a genetic mouse model of NASH-induced HCC, regular exercise had a positive effect in delaying the onset of HCC [[url=]79[/url]].

Molecular mechanismsLifestyles, in particular exercise, affect several aspects of hepatocarcinogenesis. They modify the metabolism, influence the immune system and affect inflammation (Figure ure1).


Metabolic programmingExercise reduces the cellular ATP:AMP ratio and hereby activates AMP-activated protein kinase (AMPK). AMPK inhibits mammalian target of rapamycin complex 1 (mTORC1) and activates peroxisome proliferator-activated receptor-α (PPARα) [[url=][80][/url], [url=][81][/url]] (Figure ure2). mTORC1 is a key metabolic growth promoter, which in situations of nutrient and insulin availability activates sterol regulatory element-binding protein (SREBP), a transcription factor which controls the expression of lipogenic genes such as fatty acid synthase (FAS) [[url=]82[/url]]. In contrast, PPARα induces genes required for ?-oxidation including carnitine palmitoyltransferase I (CPT1) [[url=][39][/url], [url=][83][/url], [url=][84][/url], [url=][85][/url]]. mTORC1 stimulates glutamate dehydrogenase (GDH), possibly via the downregulation of sirtuin 4 (SIRT4) [[url=][86][/url], [url=][87][/url]]. GDH converts glutamine to α-ketoglutarate, which enters the tricarboxylic acid (TCA) cycle for ATP generation [[url=]88[/url]]. In muscle, exercise downregulates SIRT4; this releases its inhibitory effects on malonyl-CoA decarboxylase (MCD) resulting in reduced levels of malonyl-CoA, an inhibitor of ?-oxidation [[url=][89][/url], [url=][90][/url], [url=][91][/url]]. It remains to be investigated whether exercise has similar effects in the liver and to what extent they occur in HCC. Wang et al. reported reduced expression of SIRT4 in HCC samples [[url=]92[/url]]. In HCC, decreased AMPK activity has been associated with poor outcome and AMPK activation-induced apoptosis [[url=]93[/url]]. Likewise, mTORC1 activity has been suggested to regulate lipogenesis in hepatocarcinogenesis, with the lipogenic phenotype of HCC cells correlating to clinical aggressiveness [[url=]94[/url]]. Hence exercise could counteract HCC risk/progression in part by upregulating AMPK and downregulating mTORC1.

Interestingly, the exercise-induced changes in AMPK/Akt-mTORC1 do not require the presence of obesity/DM, indicating an independent effect of exercise on HCC inhibition [[url=]80[/url]]. Both calorie restriction and exercise have been shown to independently lower circulating insulin and insulin growth factor 1 (IGF-1) levels [[url=]95[/url]] which, apart from generally dampening PI3K-Akt-mTOR activities [[url=][81][/url], [url=][96][/url]] may also play a role in preventing the initiation and propagation of malignant tumors in the liver [[url=]97[/url]].

Immune systemExercise is known to have immunostimulatory effects in cancer patients; however, no study has yet addressed this in HCC patients. In breast cancer survivors, regular exercise increased the percentage of CD4(+)CD69(+) cells and increased DNA synthesis after stimulation of these cells [[url=]98[/url]]. Circulating natural killer (NK) cells have key functions in the immunological defense against cancer. Brief bouts of exercise seem to be sufficient to increase the number of circulating NK cells by 4–5-fold, at least in young healthy adults [[url=]99[/url]]. Experimentally, exercise may induce relatively long-lasting changes in NK cells, with elevations sustained for up to 3 weeks following cessation of exercise in mice. Furthermore, these exercised animals developed resistance to lung tumor formation compared with sedentary controls [[url=]100[/url]]. Significant differences in T-cell proliferation between sedentary and exercised tumor-bearing rats have been reported, with the latter demonstrating higher macrophage cytotoxic antitumor action [[url=]101[/url]].




InflammationExperimental models of diet-induced and genetic-induced obesity promote low-grade hepatic inflammation, which leads to the development of HCCs [[url=]102[/url]]. HCC progression was reversed when the hepatic inflammation was reduced by deletion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Clinically,modification of diet has been shown to reduce inflammation. A study with obese individuals reported an association between caloric-restricted weight reduction and decreased plasma C-reactive protein (CRP) levels [[url=]103[/url]]. Different diets were able to decrease IL-6 levels as long as weight loss was achieved [[url=]104[/url]]. Physical activity also reduces systemic inflammation, either directly or in combination with weight loss [[url=]105[/url]]. Even in low-intensity exercise groups of cancer patients, decreased levels of oxidative DNA damage have been observed [[url=]106[/url]]. The nuclear factor erythroid 2-related factor (NRF2) system is likely to provide an important contribution to the antioxidative properties of exercising; the increased production of reactive oxygen species (ROS) during exercise leads to NRF2 activation, which in turn activates a number of antioxidant enzymes [[url=]107[/url]]. Exercise primed against exercise-unrelated oxidative stress and significantly blunted carcinogenic stimuli [[url=][80][/url], [url=][106][/url], [url=][107][/url], [url=][108][/url], [url=][109][/url], [url=][110][/url], [url=][111][/url], [url=][112][/url], [url=][113][/url], [url=][114][/url]]. Physical intervention programs can reduce serum IL-6 levels independently of BMI and DM in men [[url=][115][/url], [url=][116][/url]]. In healthy adults, high-intensity training reduces responses of blood cells to TNF-α [[url=]111[/url]], while moderate exercise in cancer patients alters inflammatory cytokine responses [[url=]113[/url]].
Physical activity may dampen inflammatory states by decreasing the circulating levels of proinflammatory cytokines such as leptin and IGF-1 levels [[url=][95][/url], [url=][117][/url]]. In rats bearing mammary tumors, both calorie restriction and/or voluntary exercise decreased serum insulin, IGF-1, and tumor burden, along with Akt pathway downregulation and increased AMPK activity in tumors as well as in other tissues such as liver [[url=][80][/url], [url=][81][/url]]. Exercise reduces circulating leptin levels independent of metabolic conditions [[url=][109][/url], [url=][118][/url]]. Leptin opposes the beneficial effects of adiponectin and AMPK in cancer patients, extending its role beyond proinflammatory signaling [[url=][118][/url], [url=][119][/url]]. Experimental studies observed that impairment of leptin signal transduction mediated by Janus-activated kinase-2 (JAK-2) and the mitogen-activated protein kinase (MAPK) pathway occurs specifically in fructose-fed rats but not in glucose-fed rats [[url=][120][/url], [url=][121][/url]].
Diet and/or genetic obesity also induces alterations of gut microbiota, resulting in increased levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. Enterohepatic circulation of DCA provokes senescence-associated secretory phenotype (SASP) in hepatic stellate cells (HSC), which in turn secrete various inflammatory and tumor-promoting factors. Yoshimoto et al. reported that SASP promoted obesity-associated HCC development in mice [[url=]122[/url]]. Subsequent blocking of DCA production or decreasing gut bacteria efficiently prevented HCC development in obese mice. Mice lacking SASP inducers or depleted of senescent HSCs also showed similar results, indicating that the DCA-SASP axis in HSCs plays a key role in obesity-associated HCC development [[url=]122[/url]].


ConclusionThe preventive and therapeutic impact of lifestyle on cancer is remarkable and its exploitation should be further promoted. HCC is a cancer tightly linked to lifestyle. We need multicenter, prospective studies on large patient cohorts with different levels of intervention. We further need more detailed experimental studies on signaling pathways involved in liver carcinogenesis that may be negatively or positively modified by lifestyles. The implementation of policies favoring the adoption of healthier lifestyles should be an integral part of our efforts against HCC.

StephenW

www.natap.org

“流行病学研究已经表明，身体活动降低各种癌（食道癌，结肠癌，乳腺癌，膀胱癌，肺癌，肾癌，前列腺癌，胰腺癌，子宫内膜和卵巢）的风险”

肝癌和生活方式 - 酒，咖啡，饮食，运动，吸烟

中华肝脏病杂志2015年9月1日

郁多罗Saran1,2，波斯蒂安Humar3，菲利普Kolly1,2和让 - 弗朗索瓦Dufour1,2
1Hepatology，临床研究部，伯尔尼大学，瑞士伯尔尼
内脏手术的2University临床和医学，伯尔尼小岛医院伯尔尼，瑞士伯尔尼
3Department内脏移植手术，大学医院苏黎世，苏黎世，
瑞士


抽象的

大多数肝细胞癌发生在共享肝硬化作为终点预先存在的慢性肝病。在过去十年中，生活方式和肝细胞癌之间有很强的关联已变得明显。能源丰富的食物和久坐的生活方式富足引起代谢性疾病如肥胖，糖尿病，成为全球性流行病。肥胖和糖尿病都紧密相连的非酒精性脂肪肝疾病，并增加肝癌风险的独立肝硬化。新兴的数据表明，体力活动不仅抵消肥胖，糖尿病和非酒精性脂肪性肝病，而且还降低了患癌症的风险。身体活动施加在缺乏代谢紊乱的显著抗癌作用。在这里，我们提出的生活方式和肝癌的系统评价。

癌症导致的主机功能与环境因素的相互作用。生活方式，其中包括由一个人选择住习惯，定义这些相互作​​用。因此，生活方式，如饮食选择，吸烟，饮酒和体力活动对癌症的发展产生深远的影响，其中包括肝细胞癌（HCC）。生存饥荒的能力是进化过程中的最强性状选择之一。这大大改变大约50年前，特点是丰富的食物和缺乏锻炼的生活方式的推广。人体生理学还没有在这么短的时间内改变。其结果是，我们是不适应的，以我们的新的环境，这适应不良导致肥胖和糖尿病（DM）的流行病。肥胖一贯用1.5-4.5倍增加肝癌风险相关[[1]，[2]，[3]，[4]，[5]，[6]，[7]。甚至在儿童期的增加身体质量指数（BMI）是在成年期与肝癌风险升高相关联的[8]。 DM也被链接到2-3倍的增加的肝细胞癌的风险[[9]，[10]，[11]，独立地底层肝病[11]，甚至在瘦的个体[12]。此外，治疗糖尿病患者的胰岛素和/或胰岛素增敏剂可进一步增加发展肝癌的风险。这突出的生活方式如何强烈地影响开发肝癌的风险。

冒烟

吸烟与几种类型的癌症，在直接暴露于烟雾所产生的器官特别是那些的发展有关。吸烟还会增加患肝癌（表1）的风险。烟草烟雾中含有时，在肝脏[13]的代谢被激活致癌物质的化学物质。之间肝组织和HCC风险中4-氨基联苯加合物的DNA水平的线性关系进行了报道，这也是显著调整为协变量之后，包括乙型肝炎表面抗原状态[14]。在中国大型回顾性研究中，吸烟者有较高的风险比为HCC比不吸烟者;这种关心男性以及女性和与香烟消耗量[15]的程度相关的风险。这两个亚前瞻性研究哪个调整饮酒[16]，[17]证实。来自欧洲前瞻性研究癌症和营养（EPIC）的数据显示，在欧洲，吸烟有助于肝癌的近一半的情况下，这实际上是超过乙肝和丙肝病毒的[18]。此外，吸烟者谁接受肝癌切除术后有较高的复发率和肝脏特异性死亡率[19]。
酒精

酒精是通过肝硬化的发展联系在一起肝癌。从已公布的证据并不支持作为直接致癌物肝癌作用的酒精。酒精性肝病是肝硬化和酒精性肝硬化的最普遍的原因之一与用于8％[20]肝癌一个5年累积风险相关。肝癌的比值比与酒精摄入线性增加并在DM或感染的乙型或丙型肝炎病毒[21]例更高，[22]。
咖啡

自2002年以来，当首次报道的咖啡对肝癌有保护作用[23]，流行病学研究，覆盖不同地理区域和不同的肝癌的病因和不同的设计，已证实这一观察。三荟萃分析包括：从欧洲和亚洲的研究发现饮用咖啡和大约40％的降低肝癌风险[24]之间，[25]，[26]具有统计学显著关联。前瞻性研究证实饮用咖啡的好处。一项前瞻性队列的入选芬兰男性吸烟者报告说，咖啡摄入量（煮沸或过滤）呈负事故肝癌[27]有关。在EPIC研究，比较高的咖啡消费者提供较低的咖啡消费者，BAMIA等。发现风险降低肝癌为0.28 [28]危险比。最后，一​​个大的，多种族，基于人口的前瞻性队列发现咖啡摄取[29]的剂量依赖性保护作用。

节食

以上特殊的营养物质，它是促进肥胖及DM由营养过剩和能源丰富的饮食这增加肝癌的风险。来自欧洲南部的两个病例对照研究发现，高膳食血糖负荷和肝癌之间的正相关之间的慢性HBV或HCV感染[30]，[31]。虽然后者的研究发现，这种正相关性存在于患者无慢性肝炎的感染，这种联系是弱，没有统计学显著[31]。有越来越多的证据表明，坚持健康的饮食习惯起着延缓肝癌发展的高危人群的作用。流行病学研究已经表明，水果的消费量增加降低肝癌[32]和低蔬菜摄入的危险患有HCC的风险增加[33]被显著相关联。意大利的病例对照研究报告水果，牛奶/酸奶，白肉类，鸡蛋和肝癌的风险[34]的摄入量呈反比关系。更高摄入的总膳食纤维和下摄取的饮食中糖均与肝癌[7]的风险降低。最后，坚持到了“地中海”饮食程度显著负相关肝癌的风险。图拉蒂等。打进坚持一个“地中海”饮食518例肝癌和来自意大利和希腊[35] 712控制。他们发现，良好的粘附性与肝癌的发病率降低50％相关联，并且，这种效果尤其显着的患者慢性病毒性肝炎B或C
体力活动

规律的运动减少了与一个高能量的饮食过度相关的负面后果，包括胰岛素抵抗，体重增加和肥胖[[12]，[36]，[37]。在认识到体育锻炼也可以防癌抗癌已促使在这一领域的研究越来越感兴趣。
锻炼预防好处（一级预防）

流行病学研究已经表明，身体活动降低各种癌（食道癌，结肠癌，乳腺癌，膀胱癌，肺癌，肾癌，前列腺癌，胰腺癌，子宫内膜和卵巢）的风险。而风险降低似乎是小子宫内膜[38]和前列腺癌的[39]，一个显着的好处是示出对乳腺癌[40]，结肠[41]，和肺癌[42]。体育锻炼甚至可能降低肺癌发病率吸烟者[43]，并在谁是遗传倾向的疾病[44] BRCA1 / 2突变携带者患乳腺癌的风险，说明运动的强大的冲击力。在一个大的队列台湾最近的一个前瞻性研究中，温家宝等人。观察到下降在HCC风险和身体活动的[45]，它已被复制在美国国立卫生研究院研究Behrens等人的观察的程度之间的逐渐的相关性。 [46]。在一级预防方面，肝癌相关的死亡率出现下降（相对危险度[RR] 0.71; 95％可信区间为0.52-0.98）患者的中度至剧烈的体力活动制度（> 7小时/周），相对于非活动对象[47]癌症的诊断之前。
运动后癌症诊断的好处

除了其预防效果，身体活动也毫不逊色下面对结果的影响癌症诊断。越来越多的证据表明生活质量的改善，复发的风险降低，以及高达50％减少体力活动乳腺癌，前列腺癌或具有其活性较低同行相比肠癌幸存者癌症相关的死亡的风险。在男性中诊断出患有早期前列腺癌，经常剧烈的运动（⩾3H /周）与61％相关联的57％降低癌症的死亡率和进展的风险分别为[48]，[49]。而对于肝癌，可以考虑改变生活方式肝硬化作为二级预防的有益作用的患者。在三级预防水平，目前并没有证据表明，运动减少肝癌复发。
行使肝效应

身体活动的益处已在许多研究，归纳于表2中普通身体活动减少脂肪变性和甚至在没有体重减轻[[50]的改善胰岛素敏感性，[51]一贯观察，[52]， [53]，[54]，[55]，[56]，[57]，[58]]。运动能改善脂肪细胞对胰岛素的敏感性，降低到不论体重指数肝脏脂肪酸（FAS）的流动[[59]，[60]，[61]]。相应地，提高的身体活动成反比与发病非酒精性脂肪肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）的[53]相关联，[56]，[57]，[62]，[63]，[64]，[ 65]，[66]，[67]，[68]，[69]，[70]。虽然目前推测，增加的能量消耗应当进一步减轻脂毒性和过量脂质的procarcinogenic功能，同时提高了胰岛素敏感性应抵消癌细胞的葡萄糖嗜表型。 Kaibori等。通过运动与肝癌患者的队列饮食调整相比，观察到更大的损失体脂，胰岛素敏感性改善只有在组内具有最高运动强度[71]。
是关于运动对的易患NAFLD，NASH，和HCC饮食诱导的动物模型的肝脏中产生的影响的实验数据总结于表3尽管实验设置窗口的异质性（饲料的特别的组合物），的总和证据证实行使的有利影响。锻炼计划改善脂肪量，脂肪变性，胰岛素抵抗，炎症或与代谢综合征相关的其它参数，其中，当运动的中途引入通过高脂肪的饮食方案可也将得到改善[[72]，[73]，[74] ，[75]]，[76]。当比较运动与限制热量摄入，校长等。悉高架线粒体？氧化作用，氧化酶的功能，改善糖耐量，以及抑制肝脏从头脂肪生成的运动组的，该运动有效果优于饮食调整[77]的要求提供支持。有趣的是，停止运动短时间（7天）未出现妨碍它的好处，尽管更长的中断（4周）引起餮大鼠[78]的总的代谢表型的恶化。在NASH引起的肝癌的遗传小鼠模型中，有规律的运动产生了积极的效果在延缓肝癌[79]的发生。

的分子机制

生活方式，特别是运动，影响肝癌的几个方面。他们修改代谢，影响免疫系统和炎症影响（图ure1）。
代谢编程

锻炼降低细胞ATP：AMP比率，并在此激活AMP活化蛋白激酶（AMPK）。 AMPK抑制雷帕霉素络合物1（mTORC1的）哺乳动物靶标，并激活过氧化物酶体增殖物激活受体α（PPARα）[[80]，[81]（图ure2）。的mTORC1是一个关键代谢生长启动子，其在营养和胰岛素的可用性的情况下激活固醇调节元件结合蛋白（SREBP），它控制生脂基因如脂肪酸合酶（FAS）的[82]的表达的转录因子。与此相反，PPARα诱导所需？氧化作用的基因，包括肉碱棕榈我（CPT1）[[39]，[83]，[84]，[85]]。的mTORC1刺激谷氨酸脱氢酶（GDH），通过沉默调节蛋白的下调4（SIRT4）可能[[86]，[87]]。 GDH转换谷氨酰胺为α-酮戊二酸，即进入三羧酸（TCA）循环产生ATP [88]。在肌肉，锻炼下调SIRT4;此释放其上丙二酰-CoA脱羧酶（MCD）抑制作用导致丙二酰-CoA，α-氧化作用的抑制剂的水平降低[[89]，[90]，[91]]。它还有待调查锻炼是否具有在肝脏和它们发生在HCC什么程度类似的效果。 Wang等人。 SIRT4的肝癌样本中报道表达降低[92]。在肝癌，降低AMPK活性已与预后差和AMPK的活化诱导的凋亡[93]有关。同样，mTORC1的活动已建议在肝癌调节脂肪生成，与肝癌细胞的脂肪合成表型相关临床攻击性[94]。因此，运动可以抵消肝癌的风险/进展，部分通过上调AMPK和下调mTORC1的。

有趣的是，在AMPK / Akt信号-的mTORC1的运动引起的变化不要求肥胖病/糖尿病的存在，说明运动对肝癌抑制[80]一个独立的效果。既热量限制和锻炼已显示独立的低级循环的胰岛素和胰岛素样生长因子-1（IGF-1）的水平[95]其中，除了通常润湿的PI3K-AKT-mTOR的活性[[81]，[96]]也可在预防的启动和恶性肿瘤的传播在肝脏[97]的作用。
免疫系统

锻炼已知具有在癌症患者免疫刺激作用;然而，没有研究尚未解决了这一HCC患者。在乳腺癌幸存者，经常锻炼这些细胞[98]的刺激后增加的CD4（+）CD69的细胞增加DNA合成的百分比（+）和。循环自然杀伤（NK）细胞在对抗癌症的免疫防御的关键功能。简要较量行使似乎足以通过4-5倍，以增加循环NK细胞的数量，至少是在年轻健康成人[99]。实验上，运动可诱导NK细胞相对持久的变化，随着海拔持续长达3周运动后的小鼠停止。此外，这些动物实行开发性肺肿瘤的形成与久坐不动的控制[100]相比较。久坐和行使荷瘤大鼠之间显著差异在T细胞增殖的报道，与后者示范更高的巨噬细胞的细胞毒性抗肿瘤作用[101]。
炎症

饮食诱导的和遗传性肥胖的实验模型促进低档肝脏炎症，其导致肝细胞癌[102]的发展。当肝脏炎症减少了缺失白细胞介素-6（IL-6）和肿瘤坏死因子α（TNF-α）肝癌进展被逆转。在临床上，饮食的修改已经显示减少炎症。一项研究与肥胖个体报道热量限制的重量减少之间的关联和降低血浆C-反应蛋白（CRP）水平[103]。不同的饮食能降低IL-6水平，只要减重达到[104]。身体活动也减少全身性炎症，无论是直接或与体重减轻[105]组合。甚至在癌症患者的低强度运动组，降低氧​​化性DNA损伤的水平已经观察到[106]。核因子红细胞2相关因子（NRF2）系统是可能提供给行使抗氧化性质有重要贡献;活性氧的产量增加（ROS）的运动过程中导致NRF2激活，从而激活一个数抗氧化酶[107]的。运动引发的抗运动无关的氧化应激和显著减弱致癌刺激[[80]，[106]，[107]，[108]，[109]，[110]，[111]，[112]，[113]， [114]。物理干预方案可降低血清IL-6水平的单独的BMI和DM在男性[[115]，[116]。在健康成人，高强度的训练降低血液细胞对TNF-α[111]反应，而温和的运动对肿瘤患者改变炎性细胞因子的反应[113]。

身体活动可以通过降低促炎性细胞因子如瘦素和IGF-1水平[[95]，[117]]的循环水平抑制炎症状态。在大鼠轴承乳腺肿瘤，既热量限制和/或自愿锻炼降低血清胰岛素，IGF-1，和肿瘤负荷，连同Akt途径的下调和增加的AMPK活性在肿瘤中，以及在其它组织，如肝[[80] ，[81]]。运动可以降低循环瘦素水平无关的代谢疾病[109]，[118]。瘦素反对脂联素和AMPK在癌症患者的有益作用，延长其作用以外促炎症信号传导[[118]，[119]。实验研究发现，瘦素信号转导介导的障碍的Janus激活激酶-2（JAK​​-2）和丝裂原活化蛋白激酶（MAPK）途径特别发生在果糖喂养大鼠，但不是在葡萄糖喂养大鼠[[120 ]，[121]。

饮食和/或遗传性肥胖也诱导肠道菌群的改变，导致脱氧胆酸（DCA），肠细菌代谢物已知会导致DNA损伤的增加的水平。 DCA的肠肝循环挑起衰老相关表现型分泌（SASP）肝星状细胞（HSC），这反过来又分泌多种炎症和肿瘤促进因素。吉等人。报道称，SASP促进肥胖相关的肝癌发展的小鼠[122]。随后DCA生产或减少肠道细菌的阻挡有效地防止肝癌发展的肥胖小鼠。小鼠缺乏SASP诱导剂或贫衰老HSC的也显示类似的结果，表明对DCA-SASP轴在造血干细胞起着肥胖相关肝癌发展[122]的关键作用。
结论

生活方式对癌症的预防和治疗作用是显着的，它的开发利用应当进一步发扬。肝癌是癌症紧密相连的生活方式。我们需要与不同层面的干预较大患者群的多中心，前瞻性研究。我们进一步对信号参与肝癌发生的途径可能是通过生活方式的消极或积极的修改需要更详细的实验研究。对有利于采取更健康的生活方式政策的实施应该是我们对肝癌的努力的一个组成部分。