65例慢加急性酒精性肝衰竭患者临床特征、预后评估及中医辨证论治初探
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摘要
研究目的：
酒精性肝衰竭是酒精性肝病最为严重的临床类型,发生在有酒精依赖史的酒精性肝炎、酒精性肝硬化基础上的慢加急性肝衰竭临床较为常见,其并发症多,死亡率高,国内关于这方面的报道尚不多见。本研究通过回顾性调查首都医科大学附属北京地坛医院收治的65例慢加急性酒精性肝衰竭患者的临床资料,初步认识慢加急性酒精性肝衰竭的临床特征、疾病的转归及其相关的预测因素,并探讨慢加急性酒精性肝衰竭的中医病因病机及辨证论治，
研究方法：
1、检索我院2002年1月至2012年1月期间收治的诊断“酒精性肝病&重型肝炎”、“酒精性肝衰竭”的住院病例,根据制定的慢加急性酒精性肝衰竭纳入和排除标准进行筛选,共收集到符合条件的病例65例。
2、记录患者一般情况、合并症和并发症、疾病转归和随访情况；详细记录患者实验室检查和辅助检查结果；使用中药治疗的患者记录其舌脉、中医辨证和方药。
3、根据调查资料,重点分析(1)慢加急性酒精性肝衰竭的临床特征(2)疾病的转归及相关的预测(3)慢加急性酒精性肝衰竭患者中医证候特点和辨证论治。
4统计学方法：使用SPSS19.0软件,用描述性分析、独立样本t检验、one-way ANOVA检验、x2检验等多种方法进行统计学分析,以双侧P≤0.05作为差异有统计学意义。
研究结果：
1、患者临床特征：
(1)男性多于女性,男女比例高达64：1；年龄40-60岁间发病率最高；饮酒10-30年的患者、日均饮酒量在80-400g的患者分别占患者总数80%以上
(2)93.8%(61/65)的患者在发生肝衰竭前有肝病就诊史,其中70.5%(43/61)的患者在初次就诊时即诊断酒精性肝硬化,入组前最常见的并发症为腹水(72.3%)、消化道出血(26.2%)和肝性脑病(23.1%)。
3)感染、近期大量饮酒、上消化道出血是慢加急性酒精性肝衰竭最常见的诱因。
(4)住院期间常见的并发症和合并症为腹水和低蛋白血症(100%)、中重度贫血(86.2%)、电解质紊乱(中重度的低钠、低钾,75.4%)、脾功能亢进(72.3%)、肝性脑病(70.8%)、上消化道出血(56.9%)、肺部感染(46.2%)、肝肾综合征(41.5%)等,多脏器功能衰竭和酒精戒断综合征的发生率各为20%。
(5)慢加急性肝衰竭患者符合酒精性肝病特征,如AST>ALT,AST/ALT比值>2的例数约占总数的70%,GGT升高和MCV升高等。本组患者基线TBIL为342.5±171umol/1,PTA为29.1±9.6%,DBIL/TBIL比例为0.55±0.12。
(6)基线时30%患者出现血清肌酐的升高,85.7%患者出现低钙,70.8%低钠、46.8%低镁,血钾异常的发生率接近50%,以低钾为主
(7)36例患者T细胞亚群结果显示,基线CD3、CD8、CD4计数以下降为主,而CD4/CD8比值升高为主,提示CD8下降的幅度更为明显。20例患者结果显示,基线补体C3、C4较正常值下降,其中补体C3100%低于正常,下降更为明显。
(8)腹部超声结果显示：86.2%患者进入肝硬化阶段,有肝硬化典型表现或同时伴有门脉高压血流改变、脾大、胸水、腹水等并发症；25例患者胃镜结果显示约有92%的患者合并有食管静脉曲张,47.8%患者有胃底静脉曲张；胸片或胸部CT检查结果显示,52.4%患者(33/63)住院期间发现一侧或双侧的炎症。
2、疾病转归
65例患者在院死亡30例,死亡率46.2%,多脏器功能衰竭和失血性休克为最主要的死亡原因,各占30%,肝肾综合征和肝性脑病各占13.3%。出院时判定好转的21例患者中,出院后死亡3例,5例失访,13例存活(随访时间10月-6年)。出院时判定为未愈的14例患者中,失访3例,10例出院后陆续死亡,仅1例肝移植患者术后存活(随访2年)。
结合出院后随访期死亡的患者,第4周、8周、12周、24周、48周、96周累计死亡率为27.7%,40%,41.5%,55.4%,61.5%,63.1%。因有8例患者失访,提示实际死亡率可能更高。
3、预后评估
(1)死亡组和非死亡组患者的比较
以患者是否在院期间死亡分为两组,结果显示：死亡组患者较非死亡组肝硬化病史更长、PT更长、INR更高,PTA、CHE、TCHO.血Na水平更低,两组间有显著差异。两组患者在TBIL和DBIL水平上无明显差异；死亡组ALT、AST.LDH均值较非死亡组为高,ALB、GGT、TBA均值较非死亡组低,但以上指标两组间无显著差异；
用MELD.MELD-Na.MDF.CTP四种评分方法对在院期间死亡组和非死亡组患者进行比较发现,在基线时死亡组和非死亡组四种评分均有显著差异,P值分别为0.027、0.002、0.034、0.037,提示MELD-Na评分优于另外三种评分动态的评分结果显示,在第0、1、2、3、4、6周,MELD评分死亡组明显大于非死亡组,两组间有显著差异,而MELD-Na评分两组间在0、3、4周有显著差异,MDF评分两组间在0、3、5周有显著差异,CTP评分两组间在0、8周有显著差异。提示四种评分方法均可用于慢加急性酒精性肝衰竭患者的预后评估。
(2)患者入组时不同肝衰竭分期对疾病转归的影响
入组时不同的肝衰竭分期对病情的转归有非常明显的影响。入组时处于肝衰竭早期的患者共6例,无死亡病例,1例病情好转出院后在第12周后失访；入组时处于肝衰竭中期的患者共33例,4周、12周、24周、48周死亡率与生存率分别为15.2%vs81.8%、24.2%vs60.6%、36.4%vs48.5%、39.4%vs42.4%,至96周死亡率超过生存率(48.5%vs33.3%)；入组时处于肝衰竭晚期的患者26例,4周的死亡率即高于生存率(53.8%vs46.2%),随时间延长,死亡率和生存率差距逐渐拉大,至96周死亡率和生存率为84.6%vs11.5%。
(3)患者年龄、饮酒情况对疾病转归的影响
患者年龄>45岁与年龄≤45岁组比较,在第12、24、48、96周死亡风险增加,两组有显著差异；
饮酒持续时间>20年与≤20年组比较,在第48、96周时死亡风险增加,两组有显著差异,提示饮酒持续时间>20年患者其远期死亡风险增高；
患者日均饮酒量>200g和≤200g比较,两组对疾病转归无显著影响；患者入组前是否戒酒对疾病转归无显著影响。
(4)不同的评分方法对慢加急性酒精性肝衰竭患者疾病转归的评价
根据基线MELD评分是否>18分(中位数)将患者分为两组,显示基线MELD评分>18分,其4周时死亡率较<18分组明显上升,分别为40.5%和14.3%,两组有显著差异；
第1周MELD评分和基线MELD评分的差值≥2组在第4、8、12周较差值<2组死亡率更高,两组间有显著差异,提示第1周MELD评分比基线时增加2分及以上的患者近期死亡风险明显增加。
患者基线时MELD-Na评分>26分(中位数)与<26分组相比,其死亡风险在第4、8、12、24、48、96周时均明显加大,两组间有显著性差异；
以基线MDF评分<55分(中位数)和>55分组,显示两组间疾病转归无显著差异。
4、慢加急性酒精性肝衰竭患者中医病因病机及辨证论治
酒精性肝衰竭属中医“急黄”范畴,多发生在“酒癖”和“酒臌”的基础上,可兼有“神昏”和“出血”等证。嗜酒过度、复感外邪、饮食劳倦为发生急黄的常见诱因。酒毒是酒精性肝衰竭最主要的病因,病性属本虚标实,脾胃虚弱是发病的基础,湿热、血分瘀热是重要病机。
症状可见：周身面目皆黄,身色如金,烦渴壮热,胸腹胀满,尿少腹大神昏谵语,甚或惊厥,吐血、衄血、便血,或肌肤瘀斑,胁下癥积,多舌质红绛,苔白或黄,厚腻苔多见,恢复期患者可见少苔,脉弦、滑或细数。
中医证型：可分为湿热内蕴、毒热瘀结、脾虚湿困、气阴两伤四型。
治法：急则治标,清热化湿、解毒凉血是基本治法,治疗过程中,应始终顾护脾胃,扶助正气。
结论
慢加急性酒精性肝衰竭是酒精性肝病最为严重的类型,并发症多,死亡率高,男性发病多于女性,发病年龄以40-60岁最多,饮酒持续时间10-30年的占80%,常见诱因为感染、上消化道出血、近期大量饮酒,常见并发症和合并症依次为腹水、低蛋白血症、电解质紊乱、脾功能亢进、肝性脑病、肺部感染、上消化道出血等。截止患者出院时为止,65例患者中,好转21例(32.3%),未愈14例(21.5%),死亡30例(46.2%),结合出院后随访,第4、8、12、24、48、96周累计死亡率分别为27.7%、40%、41.5%,55.4%,61.5%,63.1%。在院期间死亡的患者其PT更长,INR更高,PTA、CHE、TCHO、血Na水平更低。入组时不同的肝衰竭分期对病情的转归有非常明显的影响,死亡风险晚期>中期>早期；年龄>45岁患者12周以后的死亡风险增高,饮酒持续时间>20年患者其远期(48、96周)死亡风险增高。MELD评分>18分、MELD-Na评分>26分、第1周MELD和基线MELD评分的差值≥2分可预测患者死亡风险增加。对于病情稳定期的患者,可尝试使用中药进行辨证论治,中药疗效的判断需要进一步研究。
Objective
Alcoholic liver failure is the most severe clinical type of alcoholic liver disease. Acute-on-chronic alcoholic liver failure occurred in alcoholic hepatitis, alcohol ic cirrhosis which had a history of alcohol dependence is the most common. This disease has many complications and high mortality rate. The report on this aspect is still rare. Through the retrospective investigation of65cases of patients with acute-on-chronic alcoholic liver failure from Beijing Ditan Hospital, we tried to do a preliminary study about the clinical features, disease outcomes and their associated predictors. And this study will preliminary discussed the Traditional Chinese Medicine (TCM) syndrome differentiation of acute-on-chronic alcoholic liver failure.
Methods:
1、Retrieved cases admitted from January2002to January2012and diagnosed "alcoholic liver disease and severe hepatitis","alcoholic liver failure"。Based on acute-on-chronic alcoholic liver failure as defined by the filtered into and out of standard,65eligible cases were collected.
2、Recorded patients general conditions, complications, the disease outcome and follow-up; Keep detailed records of laboratory results and other examination results; Recorded tongue and pulse, syndrome differentiation of patients which accepted TCM.
3、 According to survey data, focus on analysis (1) The clinical features of acute-on-chronic alcoholic liver failure (2) The disease outcome and forecast (3) TCM symptoms characteristics and syndrome differentiation
4、 Statistical methods:using SPSS19.0soft ware, applied descriptive statistics, independent sample t test, one-way ANOVA, chi-square test methods, etc. Bilateral P<0.05as the standard showing that difference was statistically significant.
Result:
1.clinical features:
(1)Men more than women, men and women proportion was as high as64:1; Age between40-60incidence was the highest; Patients of drinking10to30years and average daily drink in80-400g accounted for over80%of the total number of patients.
(2)93.8%(61/65) of the patients had seen doctors for liver disease before liver failure happened.70.5%of the patients (43/61) was diagnosed alcoholic liver cirrhosis when first visit. Ascites was the most common complication, accounting for72.3%, followed by upper gastrointestinal hemorrhage (26.2%) and hepatic encephalopathy (23.1%) before liver failure happened.
(3)Infections, drinking too much recently, upper gastrointestinal bleeding was the most common cause of acute-on-chronic alcoholic liver fa ilure.
(4)Common complications during hospitalization were ascites and hypoalbuminemia (100%), moderate and severe anemia (86.2%), electrolyte disorder (75.4%), hypersplenism (72.3%), hepatic encephalopathy (70.8%), upper gastrointestinal hemorrhage (56.9%), pulmonary infection (46.2%), hepatorenal syndrome (41.5%), multiple organ failure and alcohol withdrawl syndrome incidence was20%.
(5)Patients with acute-on-chronic alcoholic liver failure have characteristics of alcoholic liver disease, such as AST> ALT and AST/ALT ratio>2cases accounted for about70%of the total, elevated GGT and the MCV, etc. The baseline TBIL was342.5±171umol/1, PTA was29.1±9.6%, direct bilirubin/total bilirubin levels was0.55±0.12.
(6)30%of patients were found baseline serum creatininc increase, and85.7%of patients hypocalcemi a,70.8%hypona t rem ia,46.8%hypomagnesemia. Potassium abnormality rate was close to50%, mainly low potassium.
(7)According to the results of36cases of patients with liver failure, baseline CD3, CD8, CD4were ruduced, and the CD4/CD8ratio was rised, show CD8decreased more obviously. Baseline complement C3, C4decreased. C3100%below normal, dropped more obviously.
(8)Abdominal ultrasound results showed that86.2%patients had entered liver cirrhosis period, with typical cirrhosis manifestation or with blood flow changes in portal hypertension, splenomegaly, hydrothorax, ascites, etc; Endoscopy results from25patients showed about92%of the patients with esophageal varices,47.8%with gastric variccs; according to Chest X-ray or chest CT examination of63cases,33cases were found inflammation on one side or both.
2, Disease outcomes
30cases with acute acute-on-chronic alcoholic liver failure died in hospital. Mortality in hospital was46.2%. Multiple organ failure and hemorrhagic shock were the main cause of death, both were30%; Moreover, hepatic encephalopathy, hepatorenal syndrome each accounted for13.3%.21patients judged to be improved according to the assessment of therapeutic effects,3cases were died,5cases were lost,13cases were survived after they were discharged from the hospital (follow-up time from10months to6years).14cases of patients judged to be not improved when discharged,3cases were lost to fol low-up,10patients died after discharged, only1case of liver transplantation survival (follow-up time2years)
Alcoholic liver failure cases show high mortality,4,8,12,24,48,96weeks cumulative mortality rates were27.7%,40%,41.5%,55.4%,61.5%,63.1%. Because there're a total of8cases of the patients lost to follow-up, the mortality rate may be higher.
3. Disease outcome prediction
(1)Compare of the death group and not death group results showed that history of1iver cirrhosis of death group was longer than not death group. PT and INR were higher, and the levels of PTA, CHE, TCHO, blood Na were lower in death group. Two groups of patients have no significant differences in TBIL and DBIL levels;ALT, AST, LDH levels of the death group were higher, and ALB, GGT, TBA lower than the not death group, but no significant difference between the two groups;
Using MELD, MELD-Na, MDF, CTP score four methods to measure the difference between death group and not death group, the results show that the scores by four methods at baseline were significantly different, P values were0.027,0.002,0.034,0.037, and the score of MELD-Na better than the other three. Dynamic scoring, at0,1,2,3,4,6weeks, MELD scores significantly greater in death group, there were significant differences between the two groups, and MELD-Na scores at0,3,4weeks had significant differences between the two groups, MDF scores at0,3,5weeks has significant differences, CTP scores at0,8weeks saw a significant difference. Four score methods are available to assess the prognosis of patients with alcoholic liver failure.
(2) Liver failure stage has a significant effect on the disease outcome, nearly stage patients include6cases, no deaths,1case was lost after12weeks; Middle stage include33cases, the mortality and survival rate at4,12,24,48weeks were15.2%vs81.8%,24.2%vs60.6%,36.4%vs48.5%,39.4%vs42.4%, at96weeks, mortality was more than survival rate (48.5%vs33.3%); Late stage in elude26cases, mortalitywas higher than survival at4weeks (53.8%vs46.2%), this gap was widening with the prolongation time, mortality and survival rate was84.6%and11.5%at 96weeks
(3)Patient age, drinking impact on disease outcome
Patients with age>45compared with age≤45years old, the disease outcome at12,24,48,96weeks had significantdifference.Patients with age>45years old showed the increased risk of death after12weeks.
Drinking duration>20years compared with the group of≤20years, disease outcome at48,96weeks had significant differences, patients of drinking duration>20years increased risk of death;According to patients with average daily consumption of> or≤200g compared, results show two groups of disease outcome no significant difference; According to whether stop drinking, the patients were divided into two groups, the results show disease outcome no significant difference;
(4)Different grading method to measure the disease outcome
According to whether the baseline MELD score>18points (median) divided the patients into two groups, MELD score>18points, its mortality at4week was increased significantly than<18group(40.5%vs14.3%). According to whether the difference value of MELD score Week1and baseline≥2divided the patients into two groups, the mortality of group≥2was higher than group<2at4,8,12weeks, there were significant differences. Show patients with first week MELD score≥2more than the baseline significantly increased risk of death in the near future.Patients with baseline MELD score-Na>26and<26group compared, the risk of death at4,8,12,24,48,96weeks were significantly increased;With MDF baseline score<55and>55grouping, showed the disease outcome there was no significant difference between the two groups.
4. TCM symptoms characteristics and syndrome differentiation
Alcoholic liver failure belonged to the "acute and severe jaundice" category of traditional Chinesemedicine. It t ended to occur in patients with "Alcoholic Pi" and "Alcoholic Tympanites". We could see common complications such as "hepatic coma" and "bleeding", etc. Drinking too much, attack of external evil, improper diet and over tiredness were the common causes of acute and severe jaundice. The main cause of alcoholic liver failure is "Alcoholic Toxin". The nature of the disease was deficiency in origin and excess in superficiality. The spleen-stomach deficiency was the basis of disease attack, and damp-heat> blood heat and stasis was the important pathogenesis.
Alcoholic liver failure patients mainly show red, dark red,purple tongue. Patients during recovery period may show red tongue few fluid. White thick, yellow thick, greasy tongue coatings were more common, and thin white, thin yellow, gray, black, less coatings were visible.Taut pulse, taut and slippery pulse more common, thready and rapid pulse vis ible.
According to the clinical manifestations, the patients were divided into four types:damp-heat accumulation, toxic heat and blood stasis, spleen deficiency and dampness obstruction, qi and Yin deficiency, treatment:symptomatic treatment in acute condition.The patients were treated with clearing heat, eliminating dampness, cooling blood as the basic treatment. In the process of treatment, we should always be on protecting spleen and stomach, supports vital energy.
Conclusion
Acute-on-chronic alcoholic liver failure is the most severe type of alcoholic liver disease, and has high mortality rate. Clinical features included:men more than women, age40-60years old, drinking10to30years, average daily drink in80-400g more common. The common cause was infection, upper gastrointestinal bleeding, drinking too much recently. Common compl ications were in order:ascites, hypoalbuminemia, moderate and severe anemia, electrolyte disorder, hypersplenism, hepatic encephalopathy, upper gastrointestinal hemorrhage, pulmonary infection, hepatorenal syndrome, etc. Out of65patients,21cases improved when discharged from hospital (32.3%),14cases were not improved (21.5%),30cases died (46.2%). Alcoholic liver fai lure cases show high mortality,12,24,48,96weeks cumulative mortality rates were41.5%,55.4%,61.5%,63.1%. The group of pa t ient s died in hospital, PT and INR higher, the PTA, CHE, TCHO levels lower. Different stage of liver failure has a very obvious effect on disease outcome, risk of death the late stage>the middle stage>the early stage. Patients with age>45increased risk of death after12weeks, drinking duration>20years patients increased risk of death after48,96week. MELD score>18points, MILD-Na score>26points, week1MELD and baseline MELD score difference≥2points predictable increased risk of death. We can try to use Chinese traditional medicine for patients in relatively stable period, its curative effect evaluation needs further research.
酒精性肝衰竭是酒精性肝病最为严重的临床类型,发生在有酒精依赖史的酒精性肝炎、酒精性肝硬化基础上的慢加急性肝衰竭临床较为常见,其并发症多,死亡率高,国内关于这方面的报道尚不多见。本研究通过回顾性调查首都医科大学附属北京地坛医院收治的65例慢加急性酒精性肝衰竭患者的临床资料,初步认识慢加急性酒精性肝衰竭的临床特征、疾病的转归及其相关的预测因素,并探讨慢加急性酒精性肝衰竭的中医病因病机及辨证论治，
研究方法：
1、检索我院2002年1月至2012年1月期间收治的诊断“酒精性肝病&重型肝炎”、“酒精性肝衰竭”的住院病例,根据制定的慢加急性酒精性肝衰竭纳入和排除标准进行筛选,共收集到符合条件的病例65例。
2、记录患者一般情况、合并症和并发症、疾病转归和随访情况；详细记录患者实验室检查和辅助检查结果；使用中药治疗的患者记录其舌脉、中医辨证和方药。
3、根据调查资料,重点分析(1)慢加急性酒精性肝衰竭的临床特征(2)疾病的转归及相关的预测(3)慢加急性酒精性肝衰竭患者中医证候特点和辨证论治。
4统计学方法：使用SPSS19.0软件,用描述性分析、独立样本t检验、one-way ANOVA检验、x2检验等多种方法进行统计学分析,以双侧P≤0.05作为差异有统计学意义。
研究结果：
1、患者临床特征：
(1)男性多于女性,男女比例高达64：1；年龄40-60岁间发病率最高；饮酒10-30年的患者、日均饮酒量在80-400g的患者分别占患者总数80%以上
(2)93.8%(61/65)的患者在发生肝衰竭前有肝病就诊史,其中70.5%(43/61)的患者在初次就诊时即诊断酒精性肝硬化,入组前最常见的并发症为腹水(72.3%)、消化道出血(26.2%)和肝性脑病(23.1%)。
3)感染、近期大量饮酒、上消化道出血是慢加急性酒精性肝衰竭最常见的诱因。
(4)住院期间常见的并发症和合并症为腹水和低蛋白血症(100%)、中重度贫血(86.2%)、电解质紊乱(中重度的低钠、低钾,75.4%)、脾功能亢进(72.3%)、肝性脑病(70.8%)、上消化道出血(56.9%)、肺部感染(46.2%)、肝肾综合征(41.5%)等,多脏器功能衰竭和酒精戒断综合征的发生率各为20%。
(5)慢加急性肝衰竭患者符合酒精性肝病特征,如AST>ALT,AST/ALT比值>2的例数约占总数的70%,GGT升高和MCV升高等。本组患者基线TBIL为342.5±171umol/1,PTA为29.1±9.6%,DBIL/TBIL比例为0.55±0.12。
(6)基线时30%患者出现血清肌酐的升高,85.7%患者出现低钙,70.8%低钠、46.8%低镁,血钾异常的发生率接近50%,以低钾为主
(7)36例患者T细胞亚群结果显示,基线CD3、CD8、CD4计数以下降为主,而CD4/CD8比值升高为主,提示CD8下降的幅度更为明显。20例患者结果显示,基线补体C3、C4较正常值下降,其中补体C3100%低于正常,下降更为明显。
(8)腹部超声结果显示：86.2%患者进入肝硬化阶段,有肝硬化典型表现或同时伴有门脉高压血流改变、脾大、胸水、腹水等并发症；25例患者胃镜结果显示约有92%的患者合并有食管静脉曲张,47.8%患者有胃底静脉曲张；胸片或胸部CT检查结果显示,52.4%患者(33/63)住院期间发现一侧或双侧的炎症。
2、疾病转归
65例患者在院死亡30例,死亡率46.2%,多脏器功能衰竭和失血性休克为最主要的死亡原因,各占30%,肝肾综合征和肝性脑病各占13.3%。出院时判定好转的21例患者中,出院后死亡3例,5例失访,13例存活(随访时间10月-6年)。出院时判定为未愈的14例患者中,失访3例,10例出院后陆续死亡,仅1例肝移植患者术后存活(随访2年)。
结合出院后随访期死亡的患者,第4周、8周、12周、24周、48周、96周累计死亡率为27.7%,40%,41.5%,55.4%,61.5%,63.1%。因有8例患者失访,提示实际死亡率可能更高。
3、预后评估
(1)死亡组和非死亡组患者的比较
以患者是否在院期间死亡分为两组,结果显示：死亡组患者较非死亡组肝硬化病史更长、PT更长、INR更高,PTA、CHE、TCHO.血Na水平更低,两组间有显著差异。两组患者在TBIL和DBIL水平上无明显差异；死亡组ALT、AST.LDH均值较非死亡组为高,ALB、GGT、TBA均值较非死亡组低,但以上指标两组间无显著差异；
用MELD.MELD-Na.MDF.CTP四种评分方法对在院期间死亡组和非死亡组患者进行比较发现,在基线时死亡组和非死亡组四种评分均有显著差异,P值分别为0.027、0.002、0.034、0.037,提示MELD-Na评分优于另外三种评分动态的评分结果显示,在第0、1、2、3、4、6周,MELD评分死亡组明显大于非死亡组,两组间有显著差异,而MELD-Na评分两组间在0、3、4周有显著差异,MDF评分两组间在0、3、5周有显著差异,CTP评分两组间在0、8周有显著差异。提示四种评分方法均可用于慢加急性酒精性肝衰竭患者的预后评估。
(2)患者入组时不同肝衰竭分期对疾病转归的影响
入组时不同的肝衰竭分期对病情的转归有非常明显的影响。入组时处于肝衰竭早期的患者共6例,无死亡病例,1例病情好转出院后在第12周后失访；入组时处于肝衰竭中期的患者共33例,4周、12周、24周、48周死亡率与生存率分别为15.2%vs81.8%、24.2%vs60.6%、36.4%vs48.5%、39.4%vs42.4%,至96周死亡率超过生存率(48.5%vs33.3%)；入组时处于肝衰竭晚期的患者26例,4周的死亡率即高于生存率(53.8%vs46.2%),随时间延长,死亡率和生存率差距逐渐拉大,至96周死亡率和生存率为84.6%vs11.5%。
(3)患者年龄、饮酒情况对疾病转归的影响
患者年龄>45岁与年龄≤45岁组比较,在第12、24、48、96周死亡风险增加,两组有显著差异；
饮酒持续时间>20年与≤20年组比较,在第48、96周时死亡风险增加,两组有显著差异,提示饮酒持续时间>20年患者其远期死亡风险增高；
患者日均饮酒量>200g和≤200g比较,两组对疾病转归无显著影响；患者入组前是否戒酒对疾病转归无显著影响。
(4)不同的评分方法对慢加急性酒精性肝衰竭患者疾病转归的评价
根据基线MELD评分是否>18分(中位数)将患者分为两组,显示基线MELD评分>18分,其4周时死亡率较<18分组明显上升,分别为40.5%和14.3%,两组有显著差异；
第1周MELD评分和基线MELD评分的差值≥2组在第4、8、12周较差值<2组死亡率更高,两组间有显著差异,提示第1周MELD评分比基线时增加2分及以上的患者近期死亡风险明显增加。
患者基线时MELD-Na评分>26分(中位数)与<26分组相比,其死亡风险在第4、8、12、24、48、96周时均明显加大,两组间有显著性差异；
以基线MDF评分<55分(中位数)和>55分组,显示两组间疾病转归无显著差异。
4、慢加急性酒精性肝衰竭患者中医病因病机及辨证论治
酒精性肝衰竭属中医“急黄”范畴,多发生在“酒癖”和“酒臌”的基础上,可兼有“神昏”和“出血”等证。嗜酒过度、复感外邪、饮食劳倦为发生急黄的常见诱因。酒毒是酒精性肝衰竭最主要的病因,病性属本虚标实,脾胃虚弱是发病的基础,湿热、血分瘀热是重要病机。
症状可见：周身面目皆黄,身色如金,烦渴壮热,胸腹胀满,尿少腹大神昏谵语,甚或惊厥,吐血、衄血、便血,或肌肤瘀斑,胁下癥积,多舌质红绛,苔白或黄,厚腻苔多见,恢复期患者可见少苔,脉弦、滑或细数。
中医证型：可分为湿热内蕴、毒热瘀结、脾虚湿困、气阴两伤四型。
治法：急则治标,清热化湿、解毒凉血是基本治法,治疗过程中,应始终顾护脾胃,扶助正气。
结论
慢加急性酒精性肝衰竭是酒精性肝病最为严重的类型,并发症多,死亡率高,男性发病多于女性,发病年龄以40-60岁最多,饮酒持续时间10-30年的占80%,常见诱因为感染、上消化道出血、近期大量饮酒,常见并发症和合并症依次为腹水、低蛋白血症、电解质紊乱、脾功能亢进、肝性脑病、肺部感染、上消化道出血等。截止患者出院时为止,65例患者中,好转21例(32.3%),未愈14例(21.5%),死亡30例(46.2%),结合出院后随访,第4、8、12、24、48、96周累计死亡率分别为27.7%、40%、41.5%,55.4%,61.5%,63.1%。在院期间死亡的患者其PT更长,INR更高,PTA、CHE、TCHO、血Na水平更低。入组时不同的肝衰竭分期对病情的转归有非常明显的影响,死亡风险晚期>中期>早期；年龄>45岁患者12周以后的死亡风险增高,饮酒持续时间>20年患者其远期(48、96周)死亡风险增高。MELD评分>18分、MELD-Na评分>26分、第1周MELD和基线MELD评分的差值≥2分可预测患者死亡风险增加。对于病情稳定期的患者,可尝试使用中药进行辨证论治,中药疗效的判断需要进一步研究。
Objective
Alcoholic liver failure is the most severe clinical type of alcoholic liver disease. Acute-on-chronic alcoholic liver failure occurred in alcoholic hepatitis, alcohol ic cirrhosis which had a history of alcohol dependence is the most common. This disease has many complications and high mortality rate. The report on this aspect is still rare. Through the retrospective investigation of65cases of patients with acute-on-chronic alcoholic liver failure from Beijing Ditan Hospital, we tried to do a preliminary study about the clinical features, disease outcomes and their associated predictors. And this study will preliminary discussed the Traditional Chinese Medicine (TCM) syndrome differentiation of acute-on-chronic alcoholic liver failure.
Methods:
1、Retrieved cases admitted from January2002to January2012and diagnosed "alcoholic liver disease and severe hepatitis","alcoholic liver failure"。Based on acute-on-chronic alcoholic liver failure as defined by the filtered into and out of standard,65eligible cases were collected.
2、Recorded patients general conditions, complications, the disease outcome and follow-up; Keep detailed records of laboratory results and other examination results; Recorded tongue and pulse, syndrome differentiation of patients which accepted TCM.
3、 According to survey data, focus on analysis (1) The clinical features of acute-on-chronic alcoholic liver failure (2) The disease outcome and forecast (3) TCM symptoms characteristics and syndrome differentiation
4、 Statistical methods:using SPSS19.0soft ware, applied descriptive statistics, independent sample t test, one-way ANOVA, chi-square test methods, etc. Bilateral P<0.05as the standard showing that difference was statistically significant.
Result:
1.clinical features:
(1)Men more than women, men and women proportion was as high as64:1; Age between40-60incidence was the highest; Patients of drinking10to30years and average daily drink in80-400g accounted for over80%of the total number of patients.
(2)93.8%(61/65) of the patients had seen doctors for liver disease before liver failure happened.70.5%of the patients (43/61) was diagnosed alcoholic liver cirrhosis when first visit. Ascites was the most common complication, accounting for72.3%, followed by upper gastrointestinal hemorrhage (26.2%) and hepatic encephalopathy (23.1%) before liver failure happened.
(3)Infections, drinking too much recently, upper gastrointestinal bleeding was the most common cause of acute-on-chronic alcoholic liver fa ilure.
(4)Common complications during hospitalization were ascites and hypoalbuminemia (100%), moderate and severe anemia (86.2%), electrolyte disorder (75.4%), hypersplenism (72.3%), hepatic encephalopathy (70.8%), upper gastrointestinal hemorrhage (56.9%), pulmonary infection (46.2%), hepatorenal syndrome (41.5%), multiple organ failure and alcohol withdrawl syndrome incidence was20%.
(5)Patients with acute-on-chronic alcoholic liver failure have characteristics of alcoholic liver disease, such as AST> ALT and AST/ALT ratio>2cases accounted for about70%of the total, elevated GGT and the MCV, etc. The baseline TBIL was342.5±171umol/1, PTA was29.1±9.6%, direct bilirubin/total bilirubin levels was0.55±0.12.
(6)30%of patients were found baseline serum creatininc increase, and85.7%of patients hypocalcemi a,70.8%hypona t rem ia,46.8%hypomagnesemia. Potassium abnormality rate was close to50%, mainly low potassium.
(7)According to the results of36cases of patients with liver failure, baseline CD3, CD8, CD4were ruduced, and the CD4/CD8ratio was rised, show CD8decreased more obviously. Baseline complement C3, C4decreased. C3100%below normal, dropped more obviously.
(8)Abdominal ultrasound results showed that86.2%patients had entered liver cirrhosis period, with typical cirrhosis manifestation or with blood flow changes in portal hypertension, splenomegaly, hydrothorax, ascites, etc; Endoscopy results from25patients showed about92%of the patients with esophageal varices,47.8%with gastric variccs; according to Chest X-ray or chest CT examination of63cases,33cases were found inflammation on one side or both.
2, Disease outcomes
30cases with acute acute-on-chronic alcoholic liver failure died in hospital. Mortality in hospital was46.2%. Multiple organ failure and hemorrhagic shock were the main cause of death, both were30%; Moreover, hepatic encephalopathy, hepatorenal syndrome each accounted for13.3%.21patients judged to be improved according to the assessment of therapeutic effects,3cases were died,5cases were lost,13cases were survived after they were discharged from the hospital (follow-up time from10months to6years).14cases of patients judged to be not improved when discharged,3cases were lost to fol low-up,10patients died after discharged, only1case of liver transplantation survival (follow-up time2years)
Alcoholic liver failure cases show high mortality,4,8,12,24,48,96weeks cumulative mortality rates were27.7%,40%,41.5%,55.4%,61.5%,63.1%. Because there're a total of8cases of the patients lost to follow-up, the mortality rate may be higher.
3. Disease outcome prediction
(1)Compare of the death group and not death group results showed that history of1iver cirrhosis of death group was longer than not death group. PT and INR were higher, and the levels of PTA, CHE, TCHO, blood Na were lower in death group. Two groups of patients have no significant differences in TBIL and DBIL levels;ALT, AST, LDH levels of the death group were higher, and ALB, GGT, TBA lower than the not death group, but no significant difference between the two groups;
Using MELD, MELD-Na, MDF, CTP score four methods to measure the difference between death group and not death group, the results show that the scores by four methods at baseline were significantly different, P values were0.027,0.002,0.034,0.037, and the score of MELD-Na better than the other three. Dynamic scoring, at0,1,2,3,4,6weeks, MELD scores significantly greater in death group, there were significant differences between the two groups, and MELD-Na scores at0,3,4weeks had significant differences between the two groups, MDF scores at0,3,5weeks has significant differences, CTP scores at0,8weeks saw a significant difference. Four score methods are available to assess the prognosis of patients with alcoholic liver failure.
(2) Liver failure stage has a significant effect on the disease outcome, nearly stage patients include6cases, no deaths,1case was lost after12weeks; Middle stage include33cases, the mortality and survival rate at4,12,24,48weeks were15.2%vs81.8%,24.2%vs60.6%,36.4%vs48.5%,39.4%vs42.4%, at96weeks, mortality was more than survival rate (48.5%vs33.3%); Late stage in elude26cases, mortalitywas higher than survival at4weeks (53.8%vs46.2%), this gap was widening with the prolongation time, mortality and survival rate was84.6%and11.5%at 96weeks
(3)Patient age, drinking impact on disease outcome
Patients with age>45compared with age≤45years old, the disease outcome at12,24,48,96weeks had significantdifference.Patients with age>45years old showed the increased risk of death after12weeks.
Drinking duration>20years compared with the group of≤20years, disease outcome at48,96weeks had significant differences, patients of drinking duration>20years increased risk of death;According to patients with average daily consumption of> or≤200g compared, results show two groups of disease outcome no significant difference; According to whether stop drinking, the patients were divided into two groups, the results show disease outcome no significant difference;
(4)Different grading method to measure the disease outcome
According to whether the baseline MELD score>18points (median) divided the patients into two groups, MELD score>18points, its mortality at4week was increased significantly than<18group(40.5%vs14.3%). According to whether the difference value of MELD score Week1and baseline≥2divided the patients into two groups, the mortality of group≥2was higher than group<2at4,8,12weeks, there were significant differences. Show patients with first week MELD score≥2more than the baseline significantly increased risk of death in the near future.Patients with baseline MELD score-Na>26and<26group compared, the risk of death at4,8,12,24,48,96weeks were significantly increased;With MDF baseline score<55and>55grouping, showed the disease outcome there was no significant difference between the two groups.
4. TCM symptoms characteristics and syndrome differentiation
Alcoholic liver failure belonged to the "acute and severe jaundice" category of traditional Chinesemedicine. It t ended to occur in patients with "Alcoholic Pi" and "Alcoholic Tympanites". We could see common complications such as "hepatic coma" and "bleeding", etc. Drinking too much, attack of external evil, improper diet and over tiredness were the common causes of acute and severe jaundice. The main cause of alcoholic liver failure is "Alcoholic Toxin". The nature of the disease was deficiency in origin and excess in superficiality. The spleen-stomach deficiency was the basis of disease attack, and damp-heat> blood heat and stasis was the important pathogenesis.
Alcoholic liver failure patients mainly show red, dark red,purple tongue. Patients during recovery period may show red tongue few fluid. White thick, yellow thick, greasy tongue coatings were more common, and thin white, thin yellow, gray, black, less coatings were visible.Taut pulse, taut and slippery pulse more common, thready and rapid pulse vis ible.
According to the clinical manifestations, the patients were divided into four types:damp-heat accumulation, toxic heat and blood stasis, spleen deficiency and dampness obstruction, qi and Yin deficiency, treatment:symptomatic treatment in acute condition.The patients were treated with clearing heat, eliminating dampness, cooling blood as the basic treatment. In the process of treatment, we should always be on protecting spleen and stomach, supports vital energy.
Conclusion
Acute-on-chronic alcoholic liver failure is the most severe type of alcoholic liver disease, and has high mortality rate. Clinical features included:men more than women, age40-60years old, drinking10to30years, average daily drink in80-400g more common. The common cause was infection, upper gastrointestinal bleeding, drinking too much recently. Common compl ications were in order:ascites, hypoalbuminemia, moderate and severe anemia, electrolyte disorder, hypersplenism, hepatic encephalopathy, upper gastrointestinal hemorrhage, pulmonary infection, hepatorenal syndrome, etc. Out of65patients,21cases improved when discharged from hospital (32.3%),14cases were not improved (21.5%),30cases died (46.2%). Alcoholic liver fai lure cases show high mortality,12,24,48,96weeks cumulative mortality rates were41.5%,55.4%,61.5%,63.1%. The group of pa t ient s died in hospital, PT and INR higher, the PTA, CHE, TCHO levels lower. Different stage of liver failure has a very obvious effect on disease outcome, risk of death the late stage>the middle stage>the early stage. Patients with age>45increased risk of death after12weeks, drinking duration>20years patients increased risk of death after48,96week. MELD score>18points, MILD-Na score>26points, week1MELD and baseline MELD score difference≥2points predictable increased risk of death. We can try to use Chinese traditional medicine for patients in relatively stable period, its curative effect evaluation needs further research.
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[42]贠建蔚,苌新明.酒精性肝病研究进展.国际消化病杂志,2012,32(1)：41-47
[1]郭桂华,刘鹏,张成博.中医古籍中“酒癖”的病因病机探讨.山东中医学院学报,2006,7(4)：8-g
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[1]中华医学会感染病学分会肝衰竭与人工肝学组,中华医学会肝病学分会重型肝病与人工肝学组.肝衰竭诊疗指南.中华肝脏病杂志,2006,14(9)：643-646
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[2]范建高,朱军,李建新,等.上海市成人脂肪肝患病率及其危险因素流行病学调查. 中华肝脏病杂志,2005,1 3(2)：83-88
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[14]Gordon H. Detection of alcoholic liver disease.World J Castroenterol,2001;7 (3):297
[15]中华医学会肝病学分会脂肪肝和酒精性肝病学组. 酒精性肝病诊疗指南. 中华内科杂志,2010,49(4)：357-359
[16]Shen Z, Li YM, Yu CH, et al. Risk factors for alcohol-related liver injury in the island population of China:a population-based case-control study. World J Gastroenterol,2008,14 (14):2255-2261
[17]鲁晓岚,罗金燕,陶明,等.酒精性肝病的危险因素分析. 中华肝脏病杂志,2004；12(7)：442-443
[18]Becker U, Gronbaek M, Johansen D, et al. Lower risk for alcohol-induced cirrhosis in wine drinkers. Hepatology,2002,35(14):868-875
[19]Lu XL, Luo JY, Tao M, et al. Risk factors for alcoholic liver disease in China. World J Gastroenterol,2004,10 (16):2423-2426
[20]杨瑞巧,张新华,田雪梅,等.新疆少数民族饮酒与酒精性脂肪肝关系的调查. 中华肝脏病杂志,2005,13(11)：849-851
[21]Yu C, Li Y, Chen W, et al. Genotype of ethanolmetabolizing enzyme genes by ol igonucleotide microarray in alcoholic liver diseasein Chinese people. Chin Med J (Engl),2002,115 (7):1085-1087
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[23]鲁晓岚,罗金燕,陶明,等.酒精性肝病的危险因素分析. 胃肠病学和肝病学杂志,2004；13(2)：172-174
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[28]厉有名,陈卫星, 虞朝辉,等.浙江省酒精性肝病流行病学调查概况.中华肝脏病杂志,2003,11(11)：647-649
[29]陆伦根.酒精性肝病与乙型和丙型病毒性肝炎.现代医药卫生,2004；20(6)：393
[30]Cohen JI. Nagy LE. Pathogenesis of alcoholic liver disease: interactions between parenchymal and nonparenchymal cells. J Dig Dis, 2011,12(1):3-9
[31]马力,郑聘聘,王炳元. 酒精性肝炎的诊断与治疗策略.传染病信息,2011,24(5)：267-269
[32]周永莉,段志军,肝炎后肝硬化与酒精性肝硬化患者临床特征的比较及防治.世界华人消化杂志2010年11月8日；18(31)：3313-3319
[33]田丽艳,陆伦根.2012欧洲肝病学会临床实践指南：酒精性肝病的治疗.中国医学前沿杂志(电子版)2012,4(9)：64-71
[34]徐有青,翟庆玲,张倩,等.酒精性肝硬化的常用实验室指标分析.实用肝脏病杂志,2008，11(4)：253-254
[35]陈仲平.酒精性肝炎患者血清铁蛋白测定的临床意义.实用医技杂志2006,13(5)：757-758
[36]张月萍,孙绍武.酒精性肝病患者T细胞亚群的变化.实用肝脏病杂志.2003,6(1)：40-41
[37]历有名.国内外酒精性肝病诊断标准的比较分析.临床肝胆病杂志2010,26(3)：249-251
[38]Louvet A,Naveau S, Abdelnour M, et al. The Lille model:a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology,2007,45(6):1348-1354.
[39]Forrest EH, Morris AJ, Stewart S,et al. The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.Gut,2007,56(12):1743-1746.
[40]丁雯瑾范建高2010年美国肝病学会酒精性肝病内容介绍.肝脏,2011,16(2)：150-151
[41]范建高,张舒宜.加强重症酒精性肝炎治疗的临床研究.实用肝脏病杂志,2012,15(3)：183-185
[42]贠建蔚,苌新明.酒精性肝病研究进展.国际消化病杂志,2012,32(1)：41-47
[1]郭桂华,刘鹏,张成博.中医古籍中“酒癖”的病因病机探讨.山东中医学院学报,2006,7(4)：8-g
[2]李丰衣,孙劲晖,田德禄.田德禄教授治疗酒精性肝纤维化经验浅探.吉林中医药,2006,26(8)：10-11
[3]马卫国,张良,叶永安.田德禄教授治疗酒精性肝病的经验探讨.中西医结合肝病杂志.2007,17(2)：111-112
[4]孙劲晖,赵鲲鹏,孙岸搜.酒精性肝病治疗思路阐要.中医药学报,2012,40(1)：1-3
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