74例肝硬化合并肝性脑病临床分析
摘要
肝性脑病（hepatic encephalopathy，HE）是严重的肝功能失调或障碍引起的、以代谢紊乱为基础的中枢神经系统失调的综合征。其主要临床表现包括神经和精神方面的异常，如意识障碍、行为失常和昏迷。HE分为A、B、C三型：A型是急性肝衰竭相关的肝性脑病（acute liver failure associated HE，ALFA-HE），B型是存在明显门体分流而无内在肝病的脑病。C型是与肝硬化及门脉高压和（或）门-体分流相关的肝性脑病。过去将无明显HE临床表现和生化异常，但精细的智力测验和/或电生理检测可发现异常的情况称为亚临床性肝性脑病（subclinical HE，SHE）或隐性HE（latent HE），现称轻微HE（minimalHE，MHE），以表是HE的一个阶段。HE是肝病患者常见的并发症和死亡原因。临床上以C型，尤其是肝硬化并发HE者最为多见，如果将亚临床HE计算在内，肝硬化患者发生HE的比例可达70%，HE是肝硬化最常见的死亡原因，其病死率约为20-30%。本文全面回顾分析了最常见的肝硬化HE的临床特点，重点阐述了影响患者预后的相关因素，指导治疗。
材料与方法：病例选自我院1999年1月-2004年1月收治的74例肝硬化合并肝性脑病患者。肝硬化合并HE诊断标准：（1）依据病史、典型的临床表现及肝功能、肝脏B超、CT检查，确诊为肝硬化；（2）出现神经、精神症状；（3）可有肝性脑病诱因；（4）扑翼样震颤、血氨升高和脑电图改变有重要价值；（5）除外代谢性脑病、中毒性脑病、颅内病变和精神病。HE分期标准：I期：轻度性格改变，行为异常，无扑翼样震颤；II期：精神错乱，睡眠障碍、行为反常，有扑翼样震颤；III期：错睡，能唤醒，有扑翼样震颤。IV期：昏迷，不能唤醒，引不出扑翼样震颤。观察项目：1、流行病学资料：发病年龄、性别、病因构成和病死率。2、诱因：常见诱因及发病、死亡情况；3、临床表现：常见症状、体征发病；血常规、肝功能、凝血象、肾功能、血离子的临床特征。4.预后：性别和年龄、诱因和治疗、症状和体征、child-pugh分级、实验室检查、并发症与预后的关系。实验数据用平均值±标准差表示，
配对的计量资料采用t检验进行分析，多组间均数比较用方差分析。率的比较、定性资料分析采用X2检验。P<0.05示差异有显著性，P<0.01示差异十分显著。
结果：1、患者发病年龄27.5-77.9岁，平均53.9±11.1岁，40-70岁高发，占81.08%（60例/74例），男女在发病年龄无明显差别。男女发病比例54：20，男性明显高于女性。病死率22.97%。2、病因构成如下：乙型肝炎后肝硬化60例（81.08%），酒精性肝硬化4例（5.41%），丙型肝炎后肝硬化3例（4.05%），乙型肝炎合并酒精性肝硬化者2例（2.71%），乙型肝炎合并丙型肝炎后肝硬化者1例（1.35%），原发性胆汁性肝硬化1例（1.35%），隐原性肝硬化3例（4.05%）。3、（1）引起肝性脑病的诱因依次如下（其中部分病例同时合并几种诱因）：①上消化道出血33例（44.6%）。②各种感染29例（39.2%），其中肺部感染18例，腹膜感染15例，尿路感染8例，胆道感染6例,肠道感染4例，不明3例，部分病人为多重感染。分别占全部感染例数的62.1%，51.7%，20.7%，13.8%，10.3%。③电解质紊乱26例（35.1%），低钠22例，低钾18例。④医源性因素16例（21.6%），其中手术13例、大量利尿、放腹水2例、镇静药物1例。⑤肾功能不全14例（18.9%）。⑥高蛋白饮食10例（13.6%）。⑦便秘8例（10.8%）。⑧腹泻4例（5.4%）。⑨其他4例（5.4%）。⑩不明诱因4例（5.4%）。（2）上消化道出血、肾功能不全、感染为死亡患者最常见诱因。占本统计死亡百分数分别为58.8%、52.9%和47.1%。（3）1种诱因组23例，2种诱因组26例，3种以上诱因组21例，各组死亡人数分别为2例、6例和9例，组间比较，差异十分显著。（4）及时驱除诱因者，预后好。4、半数以上患者存在黄疸（66.2%）、腹水（52.7%）、睡眠异常（56.8%）。死亡患者多有黄疸、腹水和昏迷。II、III期脑病患者常有扑翼样震颤。脑病各期病例为：I期8例（10.8%），II期36例（48.6%），III期13例（17.6%），IV期17例（23.0%），随着脑病加重，病死率升高。5、存活组和死亡组在凝血象、胆红素、胆碱酯酶、红细胞、血红蛋白、凝血酶原时间、血肌酐、血钠和血钾水平方面有差异。提示预后不良的化验指标有：
胆红素高于34.2umol/L，凝学酶原时间延长超过6秒，血钠低于125mmol/L，血肌酐高于177umol/L。伴有酶胆分离者，均死亡。6、年龄、性别与预后相关性不明显。诱因、黄疸、腹水、肝性脑病分期、 child-pugh 分级、并发症与预后相关性显著。
结论：1、肝硬化肝性脑病患者以男性多见，中、老年为发病高峰。肝硬化的病因以乙型肝炎为主。肝硬化肝性脑病的病死率为22.97%。2、肝硬化肝性脑病发病常有诱因。最常见诱因为：上消化道出血、各种感染、电解质紊乱。死亡患者最常见诱因为上消化道出血、肾功能不全、感染。诱因数量越多，预后越差。及时发现并祛除诱因，可改善预后。3、肝硬化肝性脑病突出的临床表现有黄疸、腹水和睡眠异常。死亡患者多出现黄疸、腹水和昏迷。脑病分期越高，预后越差。4、肝功能检查、血常规、凝血象、肾功能、血离子与预后密切相关。提示
Hepatic encephalopathy (HE) is a major complication of acute and chronic liver failure, defined as a disturbance in central nervous system function because of hepatic insufficiency. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. The most commom type of HE is the encephalopathy associated with cirrhosis and portal hypertension and/or portal-systemic shunts, alternative term: type C encephalopathy. Subtle signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis. Approximately 20-30% of patients die of end-stage liver disease experience significant encephalopathy, approaching coma. Therefore, HE continues to be a major clinical problem of hepatology.
Objective and methods: To study the clinical features and prognosis of patients with type C encephalopathy.74 cases with hepatic encephalopathy of cirrhosis between 1999. 1 and 2004.1, diagnosed by clinical, biochemical, histological and psychometric methods, were selected.Other metabolic disorders, infectious diseases, intracranial vascular events, and intracranial spaceoccupying lesions must be exclusived. The clinical stages of hepatic encephalopathy are as follows: Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or depression. Asterixis can be detected. Stage 2. Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. Stage 3. Gross disorientation. Bizarre behavior. Semistupor to stupor. Asterixis generally absent. Stage 4. Coma.
Results: Seventy-four patients with histologically proven cirrhosis (54 male, 20female; mean age 53.9 years; SD11.1; range 27.5-77.9 years) were entred the analysis. The etiology of cirrhosis was chronic viral hepatitis in 66 patients,
alcohol abuse in 6 patients. The overall hospital mortality was 22.97%. The factors that can precipitate hepatic encephalopathy of cirrhosis are well recognized, and include gastrointestinal bleeding (44.6%), infection (39.2%), electrolyte disturbances (35.1%), medications (21.6%), renal failure (18.9%), dietary protein overload (13.6%), constipation (10.8%), diarrhea (5.4%), and others (5.4%). The major causes of death were gastrointestinal bleeding, renal failure and infection. The patients with more precipitating factors had worse outcomes. jaundice, ascites and abnormal sleep were found in more than 50% of patients with HE. There were significant differences in the investigations between the survival and the dead. According to the Child classification, the patients with degree C had the most serious sympotom, the most complications and the worst prognosis.
Conclusions: The peak ages of hepatid encephalopathy of cirrhosis was 40-70 years old. The major etiology of cirrhosis was chronic viral hepatitis. The overall hospital mortality was 22.97%. Gastrointestinal bleeding, infection, and electrolyte disturbances were the three most commom precipitating factors in patients with type C encephalopathy. The patients with more precipitating factors had worse outcomes. The Child classification can help predict the prognosis. Prevention and removal of precipitating factors and complications are the key managements.
材料与方法：病例选自我院1999年1月-2004年1月收治的74例肝硬化合并肝性脑病患者。肝硬化合并HE诊断标准：（1）依据病史、典型的临床表现及肝功能、肝脏B超、CT检查，确诊为肝硬化；（2）出现神经、精神症状；（3）可有肝性脑病诱因；（4）扑翼样震颤、血氨升高和脑电图改变有重要价值；（5）除外代谢性脑病、中毒性脑病、颅内病变和精神病。HE分期标准：I期：轻度性格改变，行为异常，无扑翼样震颤；II期：精神错乱，睡眠障碍、行为反常，有扑翼样震颤；III期：错睡，能唤醒，有扑翼样震颤。IV期：昏迷，不能唤醒，引不出扑翼样震颤。观察项目：1、流行病学资料：发病年龄、性别、病因构成和病死率。2、诱因：常见诱因及发病、死亡情况；3、临床表现：常见症状、体征发病；血常规、肝功能、凝血象、肾功能、血离子的临床特征。4.预后：性别和年龄、诱因和治疗、症状和体征、child-pugh分级、实验室检查、并发症与预后的关系。实验数据用平均值±标准差表示，
配对的计量资料采用t检验进行分析，多组间均数比较用方差分析。率的比较、定性资料分析采用X2检验。P<0.05示差异有显著性，P<0.01示差异十分显著。
结果：1、患者发病年龄27.5-77.9岁，平均53.9±11.1岁，40-70岁高发，占81.08%（60例/74例），男女在发病年龄无明显差别。男女发病比例54：20，男性明显高于女性。病死率22.97%。2、病因构成如下：乙型肝炎后肝硬化60例（81.08%），酒精性肝硬化4例（5.41%），丙型肝炎后肝硬化3例（4.05%），乙型肝炎合并酒精性肝硬化者2例（2.71%），乙型肝炎合并丙型肝炎后肝硬化者1例（1.35%），原发性胆汁性肝硬化1例（1.35%），隐原性肝硬化3例（4.05%）。3、（1）引起肝性脑病的诱因依次如下（其中部分病例同时合并几种诱因）：①上消化道出血33例（44.6%）。②各种感染29例（39.2%），其中肺部感染18例，腹膜感染15例，尿路感染8例，胆道感染6例,肠道感染4例，不明3例，部分病人为多重感染。分别占全部感染例数的62.1%，51.7%，20.7%，13.8%，10.3%。③电解质紊乱26例（35.1%），低钠22例，低钾18例。④医源性因素16例（21.6%），其中手术13例、大量利尿、放腹水2例、镇静药物1例。⑤肾功能不全14例（18.9%）。⑥高蛋白饮食10例（13.6%）。⑦便秘8例（10.8%）。⑧腹泻4例（5.4%）。⑨其他4例（5.4%）。⑩不明诱因4例（5.4%）。（2）上消化道出血、肾功能不全、感染为死亡患者最常见诱因。占本统计死亡百分数分别为58.8%、52.9%和47.1%。（3）1种诱因组23例，2种诱因组26例，3种以上诱因组21例，各组死亡人数分别为2例、6例和9例，组间比较，差异十分显著。（4）及时驱除诱因者，预后好。4、半数以上患者存在黄疸（66.2%）、腹水（52.7%）、睡眠异常（56.8%）。死亡患者多有黄疸、腹水和昏迷。II、III期脑病患者常有扑翼样震颤。脑病各期病例为：I期8例（10.8%），II期36例（48.6%），III期13例（17.6%），IV期17例（23.0%），随着脑病加重，病死率升高。5、存活组和死亡组在凝血象、胆红素、胆碱酯酶、红细胞、血红蛋白、凝血酶原时间、血肌酐、血钠和血钾水平方面有差异。提示预后不良的化验指标有：
胆红素高于34.2umol/L，凝学酶原时间延长超过6秒，血钠低于125mmol/L，血肌酐高于177umol/L。伴有酶胆分离者，均死亡。6、年龄、性别与预后相关性不明显。诱因、黄疸、腹水、肝性脑病分期、 child-pugh 分级、并发症与预后相关性显著。
结论：1、肝硬化肝性脑病患者以男性多见，中、老年为发病高峰。肝硬化的病因以乙型肝炎为主。肝硬化肝性脑病的病死率为22.97%。2、肝硬化肝性脑病发病常有诱因。最常见诱因为：上消化道出血、各种感染、电解质紊乱。死亡患者最常见诱因为上消化道出血、肾功能不全、感染。诱因数量越多，预后越差。及时发现并祛除诱因，可改善预后。3、肝硬化肝性脑病突出的临床表现有黄疸、腹水和睡眠异常。死亡患者多出现黄疸、腹水和昏迷。脑病分期越高，预后越差。4、肝功能检查、血常规、凝血象、肾功能、血离子与预后密切相关。提示
Hepatic encephalopathy (HE) is a major complication of acute and chronic liver failure, defined as a disturbance in central nervous system function because of hepatic insufficiency. It is characterized by personality changes, intellectual impairment, and a depressed level of consciousness. The most commom type of HE is the encephalopathy associated with cirrhosis and portal hypertension and/or portal-systemic shunts, alternative term: type C encephalopathy. Subtle signs of hepatic encephalopathy are observed in nearly 70% of patients with cirrhosis. Approximately 20-30% of patients die of end-stage liver disease experience significant encephalopathy, approaching coma. Therefore, HE continues to be a major clinical problem of hepatology.
Objective and methods: To study the clinical features and prognosis of patients with type C encephalopathy.74 cases with hepatic encephalopathy of cirrhosis between 1999. 1 and 2004.1, diagnosed by clinical, biochemical, histological and psychometric methods, were selected.Other metabolic disorders, infectious diseases, intracranial vascular events, and intracranial spaceoccupying lesions must be exclusived. The clinical stages of hepatic encephalopathy are as follows: Stage 1. Trivial lack of awareness. Shortened attention span. Impaired addition or subtraction. Hypersomnia, insomnia, or inversion of sleep pattern. Euphoria or depression. Asterixis can be detected. Stage 2. Lethargy or apathy. Disorientation. Inappropriate behavior. Slurred speech. Obvious asterixis. Stage 3. Gross disorientation. Bizarre behavior. Semistupor to stupor. Asterixis generally absent. Stage 4. Coma.
Results: Seventy-four patients with histologically proven cirrhosis (54 male, 20female; mean age 53.9 years; SD11.1; range 27.5-77.9 years) were entred the analysis. The etiology of cirrhosis was chronic viral hepatitis in 66 patients,
alcohol abuse in 6 patients. The overall hospital mortality was 22.97%. The factors that can precipitate hepatic encephalopathy of cirrhosis are well recognized, and include gastrointestinal bleeding (44.6%), infection (39.2%), electrolyte disturbances (35.1%), medications (21.6%), renal failure (18.9%), dietary protein overload (13.6%), constipation (10.8%), diarrhea (5.4%), and others (5.4%). The major causes of death were gastrointestinal bleeding, renal failure and infection. The patients with more precipitating factors had worse outcomes. jaundice, ascites and abnormal sleep were found in more than 50% of patients with HE. There were significant differences in the investigations between the survival and the dead. According to the Child classification, the patients with degree C had the most serious sympotom, the most complications and the worst prognosis.
Conclusions: The peak ages of hepatid encephalopathy of cirrhosis was 40-70 years old. The major etiology of cirrhosis was chronic viral hepatitis. The overall hospital mortality was 22.97%. Gastrointestinal bleeding, infection, and electrolyte disturbances were the three most commom precipitating factors in patients with type C encephalopathy. The patients with more precipitating factors had worse outcomes. The Child classification can help predict the prognosis. Prevention and removal of precipitating factors and complications are the key managements.
引文
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朱畴文, 王吉耀, 刘天舒. 氟马西平治疗肝硬化并发肝性脑病的随机双盲研究. 中华消化杂志, 1998, 18:355
Babaro G, Di Lorenzo G, Soldini M, et al. Flumazennil for hepatic encephalopathygrade III and IVa in patients with cirrhosis:an Italian multicenter double-blind, placebo-controlled, cross-over study. Hepatology, 1998, 28:374-378
Basil AS, Jones EA. Ammonia and GABA-ergic neurotransmission
interralated factor in the pathogenesis of hepatic encephalopthy. Heptology, 1997,25:1303
Kramer L, Gendo A, Madl C, et al. A controlled studu of sorbent suspension dialysis in chronic liver disease and hepatic encepalopathy. Int Atif Organs, 2001,5:7 11.
Kawagishi N,Ohkohchi N,Fujimori K,et al .Experience with artificial liver support in 16 living related liver transplant recipients,Ther Apher,2001,5:7-11
Sechser A, Osorio J, Freise C, et al. Artificial liver support device for fuminant liver failure. Clin Liver Dis, 2001,5:415-430.
Kaptanoglu L, Blei AT, Current status of liver support systems. Clin Liver Dis, 2000, 4:711 729.
Stange J, Hassanein TI, Mehta R, et al. Tee molecular adsorbent recycling system as a liver support system based on alvumindialysis: a summary of preclinical investigatioms, prospective, randomized comtrolled clinical trial, and clinical experience from 19 centers. Atif Organs, 2002,26:103-110
De Silvestro G, Matson P, Marson P, Brandolese R, et al. A single insritution’s experience (1982-1999) with plasma-exchane therapy in patients with fulminant hepatic failure, 2000,23:454 461
Jasmund I, et al. Adv Biochem Eng Biotechnol, 2002;74(1):99-109
Cerlach JC, Lemmens P, Schon M, et al. Expenrimental evaluation of a hybrid liver support system. Transplant Proc, 1997,29:852
Blei AT. Medical therapy of brain edema in fuiminant heptic failure. Hepatology, 2000,32:666-669
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Maley GT, Fujimura M, Ma T, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med, 2000,6:159-163
Mas MR, Simsek I, Can C, et al. Fulminant hepatic failure as the intial manifestation of primary hepatocellular carcinoma. Eur J Gastroenterol Hepatol, 2000,12:575-578
Ytrebo LM, Ingebrigtsen T, Nedredal GI, et al. Protein S-100beta:a biochemical markerfor increased intracranial preddure in pigs with acute hepatic failure. Scand J Gastroenterol, 2000,35:546-551
Strauss GI, Knudsen GM, Christiansen M, et al. Neuronal and glial markers and their relation to cerebral herniation in fulminanthepatic hepatic failure. Liver Transplantation, 2000,6:C-37
Richardson D. Bellamy M.Intracranial hypertension in acute liver failure. Nephrol Dial Transplant, 2002,17:23-27
Velde AA, Bosman DK, Oldenburg J, et al. Three different hepatocyte transplantation techniques for enzyme deficiency disease and acute hepatic failure. Artif Organs, 1992,16(5):522
王吉耀. 原位肝移植的内科问题. 见:陈灏珠主编. 实用内科学. 第11版. 北京:人民卫生出版社, 2001:1890-1893
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Blei AT. Pathagenesis of hepatic encephalopathy. In:Arroyo V, Bosch J, Brugnera M. et al eds: Therapy in licer diseases. Barcelona: Masson SA, 1997,93
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Pomier–Layrargues G, Giguere JF, Lavaie GJ, et al. Flumazenil in cirrotic patients in hepatic coma:a randomized double blind placebo controlled crossover tial. Hepatology, 1994,19:32
Fabbri A, Magrini N, Bianchi G, et al. Overview of randomized clinical trials of oral branched-chain amino acid treatment in chronic hepatic encephalopathy. Jpen J Parenter Enteral Nutr, 1996, 20:159-164.
朱畴文, 王吉耀, 刘天舒. 氟马西平治疗肝硬化并发肝性脑病的随机双盲研究. 中华消化杂志, 1998, 18:355
Babaro G, Di Lorenzo G, Soldini M, et al. Flumazennil for hepatic encephalopathygrade III and IVa in patients with cirrhosis:an Italian multicenter double-blind, placebo-controlled, cross-over study. Hepatology, 1998, 28:374-378
Basil AS, Jones EA. Ammonia and GABA-ergic neurotransmission
interralated factor in the pathogenesis of hepatic encephalopthy. Heptology, 1997,25:1303
Kramer L, Gendo A, Madl C, et al. A controlled studu of sorbent suspension dialysis in chronic liver disease and hepatic encepalopathy. Int Atif Organs, 2001,5:7 11.
Kawagishi N,Ohkohchi N,Fujimori K,et al .Experience with artificial liver support in 16 living related liver transplant recipients,Ther Apher,2001,5:7-11
Sechser A, Osorio J, Freise C, et al. Artificial liver support device for fuminant liver failure. Clin Liver Dis, 2001,5:415-430.
Kaptanoglu L, Blei AT, Current status of liver support systems. Clin Liver Dis, 2000, 4:711 729.
Stange J, Hassanein TI, Mehta R, et al. Tee molecular adsorbent recycling system as a liver support system based on alvumindialysis: a summary of preclinical investigatioms, prospective, randomized comtrolled clinical trial, and clinical experience from 19 centers. Atif Organs, 2002,26:103-110
De Silvestro G, Matson P, Marson P, Brandolese R, et al. A single insritution’s experience (1982-1999) with plasma-exchane therapy in patients with fulminant hepatic failure, 2000,23:454 461
Jasmund I, et al. Adv Biochem Eng Biotechnol, 2002;74(1):99-109
Cerlach JC, Lemmens P, Schon M, et al. Expenrimental evaluation of a hybrid liver support system. Transplant Proc, 1997,29:852
Blei AT. Medical therapy of brain edema in fuiminant heptic failure. Hepatology, 2000,32:666-669
孟宪镛. 重症肝病并发脑水肿、脑疝. 见:孟宪镛主编. 实用消化病诊疗学. 第1版. 上海:世界图书出版社, 2001:361-364
Maley GT, Fujimura M, Ma T, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med, 2000,6:159-163
Mas MR, Simsek I, Can C, et al. Fulminant hepatic failure as the intial manifestation of primary hepatocellular carcinoma. Eur J Gastroenterol Hepatol, 2000,12:575-578
Ytrebo LM, Ingebrigtsen T, Nedredal GI, et al. Protein S-100beta:a biochemical markerfor increased intracranial preddure in pigs with acute hepatic failure. Scand J Gastroenterol, 2000,35:546-551
Strauss GI, Knudsen GM, Christiansen M, et al. Neuronal and glial markers and their relation to cerebral herniation in fulminanthepatic hepatic failure. Liver Transplantation, 2000,6:C-37
Richardson D. Bellamy M.Intracranial hypertension in acute liver failure. Nephrol Dial Transplant, 2002,17:23-27
Velde AA, Bosman DK, Oldenburg J, et al. Three different hepatocyte transplantation techniques for enzyme deficiency disease and acute hepatic failure. Artif Organs, 1992,16(5):522
王吉耀. 原位肝移植的内科问题. 见:陈灏珠主编. 实用内科学. 第11版. 北京:人民卫生出版社, 2001:1890-1893
Sakurabayashi S, Sezai S, Yamamoto Y, et al. Embolization of portal-systemic shunts in cirrhotic patients with chronic recurrent hepatic encephalopathy. Cardiovasc Intervent Radiol, 1997,20:102-104.
Blei AT. Pathagenesis of hepatic encephalopathy. In:Arroyo V, Bosch J, Brugnera M. et al eds: Therapy in licer diseases. Barcelona: Masson SA, 1997,93
Morgan MY. Noninvasive neuroinvestigation in liver Disease.Semin Liver Dis 1996,16:293
刘锦堂, 王培珍, 高峰, 等. 肝性脑病患者血浆B-内啡肽变化及纳络酮疗效观察. 临床荟萃, 2000, 15:747-748