The Effect of Caffeine and Alcohol Consumption on Liver Fibrosis

StephenW

http://www.medscape.com/viewarticle/756665
From Liver InternationalThe Effect of Caffeine and Alcohol Consumption on Liver FibrosisA Study of 1045 Asian Hepatitis B Patients Using Transient Elastography

Arlinking Ong; Vincent Wai-SunWong; Grace Lai-Hung Wong; Henry Lik-Yuen Chan

[url=]Authors and Disclosures[/url]

Posted: 01/25/2012; Liver International. 2011;31(7):1047-1053. © 2011 Blackwell Publishing

Abstract and Introduction
Abstract
Background: Role of caffeine consumption in chronic hepatitis B virus (HBV)-infected patients and the interaction with alcohol consumption is unclear.
Aim: This study aimed to investigate the relationship between caffeine and alcohol consumption and liver stiffness in chronic HBV-infected patients.
Methods: Chronic HBV-infected patients who underwent transient elastography examination in 2006–2008 were studied. Advanced fibrosis was defined as liver stiffness >9 kPa for patients with normal alanine aminotransferase (ALT) or >12 kPa for those with elevated ALT according to previous validation study. Caffeine and alcohol consumption was recorded using a standardized questionnaire. Excessive alcohol intake was defined as 30 g/day in men and 20 g/day in women.
Results: The liver stiffness of 1045 patients who completed the questionnaire was 8.3 ± 6.2 kPa. Two hundred and sixteen (20.7%) patients had advanced fibrosis. Ninety-five (19.0%) patients who drank ≥1 cup of coffee had advanced fibrosis, compared with 121 (22.2%) patients who drank <1 cup (P=0.21). The amount of caffeine intake had positive correlation with the amount of alcohol intake (r s=0.167, P<0.001). Although 231 (22.1%) patients reported alcohol consumption, only 11 (1%) had excessive alcohol intake. The prevalence of advanced fibrosis among patients with mild to moderate alcohol intake (26, 18.8%) was comparable to that among non-drinkers (190, 21.0%) (P=0.57).
Conclusion: Caffeine intake does not affect liver stiffness in chronic HBV-infected patients. Patients who drink coffee regularly tend to drink alcohol. Most chronic HBV-infected patients do not have excessive alcohol consumption. The prevalence of advanced fibrosis among mild to moderate alcohol drinkers was low in this population.

Introduction
Chronic hepatitis B virus (HBV) infection is a global health problem affecting over 350 million people. Persistent hepatic inflammation because of chronic HBV infection will result in progressive liver fibrosis, which will eventually result in cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC).[1]                        
Alcoholism[2] is a primary chronic disease with genetic, psychosocial and environmental factors influencing its development and manifestations. Heavy alcohol consumption commonly causes alcoholic liver disease, cirrhosis and even HCC.[3] However, it is unclear whether consumption of a smaller amount of alcohol is safe in chronic hepatitis B patients.
On the other hand, consumption of coffee or caffeine may reduce liver injury. Greater coffee, and especially caffeine, intake was associated with a lower prevalence of abnormal alanine aminotransferase (ALT) activity in USA[4] and Japan.[5] Plasma glutathione was increased by 16% on coffee consumption in an Italian population.[6] In a prospective study among advanced Hepatitis C-related liver disease, regular coffee consumption was associated with lower rates of disease progression.[7] In human hepatoma cell lines, coffee and its major components (caffeine, cafestol and kahweol) alter expression and activity of enzymes involved in xenobiotic mechanisms.[8] Mice pretreated with cafestol and kahweol were protected from carbon tetrachloride toxicity by inhibiting cytochrome CYP 2E1,[9] an enzyme responsible for carbon tetrachloride bioactivation while caffeine specifically inhibited expression of connective tissue growth factor by interfering with transforming growth factor-β signaling through the SMAD pathway and upregulate peroxisome proliferator activated receptor γ levels. These in vitro and in vivo data suggested that caffeine has antifibrotic effects.[10]                     
A recent case control study among chronic hepatitis B carriers showed that coffee consumption reduced the risk of HCC by half with a significant dose-response effect.[11] It is uncertain if the beneficial effect is mediated through prevention of liver fibrosis and cirrhosis. In the past, large-scaled studies on risk factors of liver fibrosis and cirrhosis were difficult to conduct because the assessment required liver biopsy, which was invasive and not acceptable by all patients. In this study, we aimed to determine the effect of alcohol and caffeine consumption on the prevalence of advanced liver fibrosis among chronic HBV-infected patients using transient elastography.




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StephenW

摘要

背景：咖啡因消费在慢性乙型肝炎病毒（HBV）的感染的病人，并与饮酒的互动的作用尚不清楚。
目的：本研究旨在探讨咖啡因和酒精消费和慢性乙肝病毒感染患者的肝脏硬度之间的关系。
方法：在2006-2008年经历了瞬时弹性检查的慢性乙型肝炎病毒感染的患者进行了研究。晚期肝纤维化是指肝脏硬度> 9千帕患者与正常的谷丙转氨酶（ALT）或ALT升高，根据以往的验证研究> 12千帕。咖啡因和酒精消费量录得使用一个标准化的问卷。过量饮酒被定义为男性每天30克/ 20克/天的妇女。
结果：完成问卷1045例肝脏硬度为8.3 ± 6.2千帕。两日的行动中，116名（20.7％）患者晚期肝纤维化。九十五例（19.0％），喝一杯咖啡≥1晚期肝纤维化，谁喝1杯（P = 0.21）的患者，其中121（22.2％）相比。咖啡因摄入量呈正相关，与酒精摄入量（RS = 0.167，P <0.001）。虽然231例（22.1％），报饮酒，只有11人（1％）有过量饮酒。轻度患者中晚期肝纤维化的发病率，适度饮酒，18.8％（26）相媲美，不饮酒，21.0％（190）（P = 0.57）之间。
结论：咖啡因摄入量不影响肝慢性HBV感染患者的刚度。经常喝咖啡的患者往往喝酒。大多数慢性乙肝病毒感染的患者不必过度饮酒。晚期肝纤维化之间的轻度至中度饮酒者的患病率在这一人群低。
简介

慢性乙型肝炎病毒（HBV）感染是一个全球性的健康问题，影响超过350万人。持久性肝炎，因为慢性乙肝病毒感染会导致渐进性肝纤维化，最终会导致肝硬化，肝功能失代偿和肝细胞癌（HCC）[1]。

[2]酒精中毒是一个主要的慢性疾病与遗传，心理和环境因素影响其发展和表现。酗酒通常会导致酒精性肝病，肝硬化，甚至肝癌。[3]然而，目前还不清楚是否在慢性乙型肝炎患者是安全的酒精消费量较小。

另一方面，咖啡或咖啡因的消费量可能减少肝损伤。更大的咖啡，尤其是咖啡因摄入量与发病率较低的异常谷丙转氨酶（ALT）的活动在美国[4]和日本。[5]血浆谷胱甘肽的咖啡消费量增加了16％，在意大利的人口。[6在先进的C型肝炎相关肝病之间的前瞻性研究，普通咖啡消费率较低的疾病进展相关。[7]在人肝癌细胞株，咖啡和其主要成分（咖啡因，cafestol和kahweol）中的表达改变和异生机制所涉及的酶的活性[8] cafestol和kahweol预处理的小鼠四氯化碳毒性的保护，抑制细胞色素CYP 2E1 [9]一种酶负责四氯化碳bioactivati​​on而咖啡因专门抑制结缔组织生长因子的表达干扰，转化生长因子-β信号通过Smad通路和上调过氧化物酶体增殖物激活受体γ水平。 [10]在体外和体内的数据，这些建议，咖啡因具有抗肝纤维化的影响。

最近的一个案例，慢性乙肝病毒携带者之间的对照研究显示，咖啡消费量减少了一半，一个显著的剂量 - 反应的影响肝癌的风险。[11]它的有益效果是不确定的，如果是通过介导预防肝纤维化和肝硬化。在过去，大型风险研究肝纤维化和肝硬化的因素难以进行，因为评估需要肝活检，这是入侵，所有患者不能接受的。在这项研究中，我们的目的是确定上先进的肝纤维化慢性乙型肝炎病毒感染的患者使用瞬时弹性之间患病率的酒精和咖啡因消费的作用。

StephenW

Discussion
In this large territory-wide observational study with prospective recruitment, we assessed the relationship between caffeine and alcohol consumption and the risk of advanced liver fibrosis in chronic hepatitis B patients with different disease severity. Caffeine intake was not associated with advanced fibrosis. Patients who drank coffee regularly were more likely to consume alcohol. On the other hand, few chronic hepatitis B patients in Hong Kong had excessive alcohol consumption. Mild to moderate alcohol consumption did not increase the risk of advanced fibrosis.
Coffee is a rich source of a number of phenol compounds with antioxidant effects in vitro, with main polyphenols are phenolic acids such as chlorogenic and caffeic acid.[27] Caffeine and its metabolites, 1-methylxanthine and 1-methyluric acid, have also been shown to have antioxidant properties.[28] Caffeine has also been reported to inhibit chemical carcinogenesis and ultraviolet B light induced carcinogenesis in mice.[29,30] Coffee is also found to decrease the progression of liver disease among those with advanced hepatic fibrosis[7] and even reduce the risk of HCC[31,32] One study[33] concluded that approximately 2 coffee cup equivalents/day was associated with less severe hepatic fibrosis, but the beneficial effect was only shown in patients with chronic hepatitis C rather than patients with other liver diseases. A case control study in Italy showed that the protective effect of coffee on HCC was mainly in people who are not chronically infected with HBV.[31] Overall, previous studies included mostly chronic hepatitis C patients and HBV patients were underrepresented. Based on our results, it appears that liver fibrosis in chronic hepatitis B patients is determined mainly by virological and genetic factors and less affected by caffeine intake.
In previous reports, men who have daily alcohol intake of 30–39 g and women who consumed 20–29 g of alcohol daily would have an increased risk of all cause mortality among the general population.[34] Seventy-eight percent of our cohort did not drink alcohol at all while only 1% of patient had history of excessive alcohol consumption. Nonetheless, we could not find any deleterious effect of mild to moderate alcohol consumption to liver fibrosis. As alcohol drinkers were mostly coffee drinkers as well, the concomitant caffeine intake might but one of the confounders leading to the absence of increased risk of advanced fibrosis in alcohol drinkers. Nonetheless only a minority (1% of the study population has excessive alcohol intake, we believe that the major reason of the absence of increased risk of advanced fibrosis in alcohol drinkers was the modest instead of excess amount of alcohol use. Because most of our patients had no advanced liver disease as compared with other studies (33, 35–38), our results could not be extrapolated to cirrhotic patients. Less than 20 g of alcohol intake tends not to increase risk of advanced fibrosis in our present study. Controlled prospective studies may be done in the future to verify this.
One of the limitations of our study was the lack of liver biopsy. As liver biopsy is an invasive procedure, studies using histological fibrosis as an endpoint might suffer from the problem of small sample size and selection bias towards patients with active or advanced liver disease.[39] On the other hand, a non-invasive test such as transient elastography could be applied to a large number of patients with different disease severity. In fact, transient elastography has been shown to be highly accurate in detecting histological advanced fibrosis and cirrhosis in chronic hepatitis B patients,[16,23] though the accuracy might be limited in settings of grossly elevated transaminase levels,[16] but not in the presence of steatosis.[18] Secondly, recall bias might occur during the questionnaire survey and affect the accuracy of the measurement of the caffeine intake measured. We have tried to minimize this bias by using a quantity-frequency questionnaire, which has been previously adapted in a study demonstrating the protective effect of coffee consumption from HCC.[11] There were 159 (15.2%) participants drinking >2–3 coffee-cup equivalents/day and 103 (9.9%) drinking >3 coffee-cup equivalents/day. Because the above numbers for these groups were low and previous finding showing 2 coffee-cup equivalents/day was associated to less severe liver fibrosis, we combined these groups for analysis. Because this is a cross sectional study, possible unmeasured as well as poorly measured confounding factors that may affect the interpretation of our data such as changes in the drinking habit of the patients, variability of caffeine intake over time, socioeconomic status, educational level were not considered in our analysis.
In conclusion, cross-sectional caffeine intake does not affect liver stiffness in chronic HBV-infected patients. The protective effect of caffeine on HCC demonstrated in previous studies is probably via the pathway other than reducing liver fibrosis. The prevalence of advanced liver fibrosis is low (20%) in chronic hepatitis B patients with daily alcohol consumption below 20 g.

StephenW

讨论

我们在这个大全港有意招聘的观察研究，评估咖啡因和酒精消费和先进的肝纤维化疾病的严重程度不同的慢性乙型肝炎患者的风险之间的关系。咖啡因的摄入量是不相关的晚期纤维化。经常喝咖啡的患者更可能饮酒。另一方面，香港的一些慢性肝炎B组患者有过量饮酒。轻度至中度饮酒不增加晚期肝纤维化的风险。

咖啡是一种酚化合物的体外抗氧化作用，主要多酚类物质，丰富的来源是酚酸，绿和咖啡酸等。[27]咖啡因及其代谢物，1 - 甲基1 - methyluric酸，也被证明具有抗氧化性能。[28]咖啡因也有报道抑制化学致癌和紫外线B光诱导小鼠致癌。[29,30]咖啡还发现，以减少在先进的肝纤维化的肝脏疾病的进展[ 7]，甚至降低风险HCC [31,32] [33]的研究结论伴有较严重的肝纤维化，约2杯咖啡当量/天，但有利的影响只有在慢性C型肝炎，而患者中比与其他肝脏疾病患者。在意大利的病例对照研究表明，咖啡对肝癌的保护作用主要是在那些没有慢性乙型肝炎病毒感染的人。[31]总体而言，以往的研究主要包括慢性丙型肝炎患者和乙肝患者人数偏低。根据我们的研究结果，它出现在慢性乙型肝炎患者的肝纤维化，主要由病毒学和遗传因素决定，咖啡因摄入量的影响较小。

在以前的报告中，男性每日酒精摄入量30-39克，女性酒精每天消耗20-29克，在普通人群中的所有原因的死亡率风险增加。[34] 78％，我们的队列不喝酒在所有的酒精，而只有1％的患者有过量饮酒史。尽管如此，我们仍无法找到任何有害影响，适量饮酒对肝脏纤维化轻度。由于饮酒者大多是喝咖啡的人以及随之而来的咖啡因摄入量可能会导致晚期肝纤维化饮酒者的风险增加的情况下混杂因素之一。然而，只有少数（1％的研究人口过量饮酒，我们相信，晚期肝纤维化饮酒者的风险增加的情况下，主要的原因是温和的，而不是使用酒精过量。，因为大多数的患者没有先进的肝脏疾病，与其他研究（33，35-38）比较，我们的结果不能外推到肝硬化患者小于20克酒精的摄入量在我国目前的研究往往不增加晚期肝纤维化的风险控制的前瞻性可能在未来的研究来验证这个。

我们研究的局限性之一是缺乏肝活检。由于肝活检是一种侵入性的过程，作为终点的病理纤维化的研究可能遭受。[39]另一方面，非侵入性测试等主动或晚期肝病患者对小样本的大小和选择偏差的问题瞬时弹性可以适用于大量的患者，不同疾病的严重程度。事实上，瞬时弹性已被证明是高度准确检测组织学晚期肝纤维化和肝硬化的慢性乙肝患者[16,23]，虽然精度可能是严重的转氨酶水平设置的限制，[16]，但不脂肪变性的存在。[18]其次，回忆偏差，可能会发生在问卷调查和影响的咖啡因摄入量测测量的准确性。我们曾尝试使用量频率调查问卷，先前已在一项研究中适应，展示从肝癌的咖啡消费量的保护作用，最大限度地减少这种偏差。[11]有159（15.2％）的参与者> 2-3咖啡饮用杯当量/日和103（9.9％）饮用3杯咖啡当量/天。由于这些群体上面的数字低，和以前的发现显示2杯咖啡/天，相关的不太严重的肝纤维化的等值，我们结合这些群体进行分析。因为这是一个横断面研究，可能不可测以及测量不善的混杂因素可能会影响我们的数据，如病人的饮酒习惯的变化，咖啡因摄入量的变化，随着时间的推移，社会经济地位的解释，受教育程度不在我们的分析认为。

总之，横断面的咖啡因摄入量不影响肝慢性HBV感染患者的刚度。咖啡因对肝癌的保护作用，在以往的研究表明可能是通过其他途径比减少肝纤维化。先进的肝纤维化的发生率较低（20％），慢性乙型肝炎患者每日饮酒量低于20克。

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