肝硬化患者消化道状态与血氨的关系研究

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贺勇, 高宝秀, 杨正兵, 聂鑫, 李贵星, 余霆, 胥劲, 宋昊岚. 肝硬化患者消化道状态与血氨的关系研究. 2012, 27(1): 44-47
HE Yong, GAO Baoxiu, YANG Zhengbing, NIE Xin, LI Guixing, YU Ting, XU Jing, SONG Haolan. The relationship of gastrointestinal state and plasma ammonia in cirrhosis patients. Labratory Medicine, 2012, 27(1): 44-47 复制到剪切板

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《检验医学》编辑部

肝硬化患者消化道状态与血氨的关系研究

贺勇¹, 高宝秀¹, 杨正兵², 聂鑫¹, 李贵星¹, 余霆¹, 胥劲¹, 宋昊岚¹

1.四川大学华西医院实验医学科,四川成都 610041

2.四川大学华西医院消化内科,四川成都 610041

通讯作者：李贵星,联系电话：028-85422615。

作者简介：贺勇,女,1982年生,硕士,主要从事疾病发生发展的生化机理与诊断方法的研究。

摘要

目的

研究肝硬化伴消化道功能障碍患者酸化肠道治疗前、后的血氨水平变化,探讨肝硬化患者消化道状态与血氨水平的关系,寻找减少肠道氨吸收的有效方法,达到降低血氨的目的。

方法

测定195例肝硬化患者(包括单纯性肝硬化患者100例、肝硬化伴消化道出血患者52例、肝硬化伴便秘患者43例)、50例单纯性肠梗阻患者、113例单纯性消化道出血患者及80名正常对照者的空腹血氨水平。比较各组血氨水平,研究肝硬化伴消化道出血或(和)便秘患者酸化肠道治疗前、后的血氨水平变化。

结果

肝硬化伴消化道出血组血氨水平为(67.71±30.31) μmol/L,高于单纯性肝硬化组[(45.81±28.78) μmol/L]、单纯性消化道出血组 [(24.85±10.79) μmol/L]和正常对照组[(22.42±7.93) μmol/L](P<0.05)。肝硬化伴便秘组血氨水平为(95.53±42.61) μmol/L,高于单纯性肝硬化组、肝硬化伴消化道出血组和单纯性肠梗阻组[(24.90±11.02) μmol/L](P<0.05)。单纯性肝硬化组血氨水平高于单纯性消化道出血、单纯性肠梗阻组及正常对照组(P<0.05);而单纯性消化道出血、单纯性肠梗阻组与正常对照组比较差异无统计学意义(P>0.05)。肝硬化伴消化道出血或(和)便秘组治疗前血氨水平为(83.28±37.93) μmol/L,明显高于经酸化肠道治疗后的血氨水平[(50.89±19.58) μmol/L](P<0.05)。

结论

肝硬化患者消化道状态与血氨水平关系密切;阻止消化道出血、酸化肠道及使用抗生素可抑制肠道中氨的产生和吸收,从而降低血氨水平,预防和治疗肝性脑病。

关键词: 血氨; 肝硬化; 消化道出血; 便秘

中图分类号:R446.1 文献标志码:A 文章编号:1673-8640(2012)01-44-04

The relationship of gastrointestinal state and plasma ammonia in cirrhosis patients

HE Yong¹, GAO Baoxiu¹, YANG Zhengbing², NIE Xin¹, LI Guixing¹, YU Ting¹, XU Jing¹, SONG Haolan¹

1.Department of Laboratory Medicine, West China Hospital , Sichuan University, Sichuan Chengdu 610041,China

2.Department of Digestion Medicine, West China Hospital, Sichuan University, Sichuan Chengdu 610041,China

Abstract

Objective

To study the changes on plasma ammonia among cirrhosis patients who had gastrointestinal symptoms before and after acidification intestinal treatment, investigate the relationship of gastrointestinal state and plasma ammonia among cirrhosis patients, and find an effective method to reduce plasma ammonia.

Methods

The fast plasma ammonia levels were detected among 195 cirrhosis patients (including 100 patients with just cirrhosis, 52 cirrhosis patients with gastrointestinal hemorrhage and 43 cirrhosis patients with constipation), 50 patients with just intestinal obstruction, 113 patients with just gastrointestinal hemorrhage and 80 healthy subjects. The plasma ammonia levels were compared, and the changes on plasma ammonia levels before and after acidification intestinal treatment were analyzed in cirrhosis patients with gastrointestinal hemorrhage and (or) constipation.

Results

Plasma ammonia level among cirrhosis patients with gastrointestinal hemorrhage was (67.71±30.31) μmol/L, which was higher than those of patients with just cirrhosis [(45.81±28.78) μmol/L], patients with just gastrointestinal hemorrhage [(24.85±10.79) μmol/L] and the healthy controls [(22.42±7.93) μmol/L] (P<0.05). The plasma ammonia level of cirrhosis patients with constipation was (95.53±42.61) μmol/L, which was higher than those of patients with just cirrhosis, cirrhosis patients with gastrointestinal hemorrhage and patients with just intestinal obstruction [(24.90±11.02) μmol/L] (P<0.05). The plasma ammonia level of patients with just cirrhosis were higher than those of patients with just gastrointestinal hemorrhage, patients with just intestinal obstruction and healthy subjects (P<0.05), while the plasma ammonia levels among patients with just intestinal gastrointestinal hemorrhage, patients with just obstruction and the healthy subjects showed no significant difference (P>0.05). The plasma ammonia levels of cirrhosis patients with gastrointestinal hemorrhage and (or) constipation before the treatment was (83.28±37.93) μmol/L, which was higher than the level after the treatment [(50.89±19.58) μmol/L] (P<0.05).

Conclusions

Gastrointestinal state is closely related with plasma ammonia levels in cirrhosis patients. Stopping gastrointestinal hemorrhage, acidizing gut and using antibiotic drugs could inhibit the production and absorption of ammonia, and those are effective ways to reduce plasma ammonia levels and to prevent and treat hepatic encephalopathy.

Keyword: Plasma ammonia; Cirrhosis; Gastrointestinal hemorrhage; Constipation

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引言

肝硬化是一种常见的慢性肝脏疾病,由于某些原因长期反复作用于肝脏,导致肝组织正常结构破坏,纤维增生使肝脏变形、变硬的一种综合征。肝硬化患者容易发生肝性脑病,血氨在肝硬化患者发生脑病过程中发挥了重要作用。氨中毒学说^{[ 1, 2]}是目前用于诊断和治疗肝性脑病的重要理论依据。血氨主要来源于肠道,经肝脏转化成尿素和谷氨酰胺,并通过肾脏排出尿素和氨。因此,血氨水平取决于肠(来源)-肝(转化)-肾(排泄)3个器官的功能状态。肝硬化时肝脏氨转化能力降低,血氨水平主要受肠道和肾脏功能状态的影响。我们通过分析肝硬化患者不同消化道状态下的血氨水平以及酸化肠道治疗的血氨水平变化,探讨消化道状态对肝硬化患者血氨水平的影响,寻找有效减少氨吸收的方法,达到降低血氨的目的。

材料和方法

一、研究对象

纳入2008年1月至2010年5月在四川大学华西医院消化科、传染内科及感染科确诊的肝硬化住院患者195例,男113例,女82例,平均年龄为52.7±11.4岁。其中肝炎性肝硬化117例(60.0%)、酒精性肝硬化24例(12.3%)、胆汁淤积性肝硬化17例(8.7%)、血吸虫性肝硬化1例(0.05%)、原因不明肝硬化36例(18.5%)。肝功能Child-Pugh分级结果:A级49例(25.1%),B级69例(35.4%),C级77例(39.5%)。195例肝硬化患者中单纯性肝硬化100例(51.3%),其中肝硬化伴消化道出血 52例(26.7%)、肝硬化伴便秘43例(22.0%)。

肝硬化诊断依据中华医学会肝脏病学分会脂肪肝和酒精性肝病学组推荐的诊断标准^{[ 3, 4]},根据病史和实验室检查排除有原发性肾病、肝肾综合征、糖尿病、高血压的患者。酸化肠道治疗组为肝硬化伴消化道出血或(和)便秘患者45例,排除治疗期间肝、肾、肠功能明显变化者。50例单纯性肠梗阻患者来自四川大学华西医院肛肠外科,113例单纯性消化道出血患者来自四川大学华西医院消化内科,80名正常对照者来自四川大学华西医院门诊健康体检者。

二、血氨检测

所有受试者隔夜禁食8 h, 次日晨抽取3 mL空腹肘静脉血,用肝素钠抗凝,2 000× g离心10 min,取血浆及时分析。血氨分析采用美国强生公司VITROS-250干化学分析仪及配套试剂,严格按标准化操作程序进行操作。样本在每日质控在控后进行测定,保证实验数据准确可靠。

三、酸化肠道治疗研究方案

酸化肠道治疗组纳入肝硬化伴消化道出血或(和)便秘的患者50例,其中5例在治疗过程中肝、肾、肠功能发生明显变化被排除,最终治疗组为45例。酸化肠道的方法包括口服乳果糖、口服白醋及白醋灌肠,使用剂量为临床常规剂量。乳果糖每天3次,每次15 mL;白醋灌肠方法为每天1次;口服白醋为每天250 mL。治疗前采集空腹肘静脉血3 mL,酸化肠道2 d后采集空腹肘静脉血3 mL,分析治疗前、后2次血氨水平。

四、统计学方法

应用SPSS15.0软件进行数据分析,计量资料采用( $\begin{matrix} \bar{x} \end{matrix}$ ±s)表示。临床资料及实验室检查分类资料比较采用χ²检验,血氨水平2组间比较采用成组 t检验,治疗前、后比较采用配对 t检验, P<0.05表示差异有统计学意义。

结果

一、肝硬化、单纯性消化道出血、单纯性肠梗组及正常对照组血氨水平比较

单纯性肝硬化组、肝硬化伴消化道出血组、单纯性消化道出血组、肝硬化伴便秘组、单纯性肠梗阻组及正常对照组血氨水平见表1。各组血氨水平由高到低依次为肝硬化伴便秘组>肝硬化伴消化道出血组>单纯性肝硬化组>单纯性消化道出血组、单纯性肠梗阻组和正常对照组,各组间差异均有统计学意义( P<0.05);而单纯性消化道出血组、单纯性肠梗阻组和正常对照组血氨水平比较差异无统计学意义( P>0.05)。

表1 各组血氨水平比较

\begin{matrix} \bar{x} \end{matrix}

±s,μmol/L

组别	例数	血氨
单纯性肝硬化组	100	45.81±28.78^*#
肝硬化伴消化道出血组	52	67.71±30.31^*
肝硬化伴便秘组	43	95.53±42.61
单纯性消化道出血组	113	24.85±10.79^*#Δ
单纯性肠梗阻组	50	24.90±11.02^*#Δ
正常对照组	80	22.42±7.93^*#Δ

注:与肝硬化伴便秘组比较,* P<0.05;与肝硬化伴消化道出血组比较,# P<0.05;与单纯性肝硬化组比较,Δ P<0.05

表1 各组血氨水平比较

\begin{matrix} \bar{x} \end{matrix}

±s,μmol/L

二、肝硬化伴肠道功能障碍患者酸化肠道治疗疗前、后血氨水平比较

肝硬化伴消化道功能障碍患者治疗前血氨水平为(83.28±37.93)μmol/L,经酸化肠道治疗后血氨水平为 (50.89±19.58)μmol/L,血氨平均降低率为32.34%,治疗前、后2组间血氨水平差异有统计学意义( P<0.05)。45例患者酸化肠道治疗前、后的血氨水平变化见图1。

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	图1 肝硬化伴消化道障碍患者酸化肠道治疗前、后血氨水平变化

讨论

肝性脑病的发病机制至今尚未阐明,目前存在的学说有氨中毒学说、氨基酸失衡与假性神经递质学说、γ-氨基丁酸学说、氧化应激学说、锰中毒学说、星形胶质细胞病学说等。大量的研究^{[ 5, 6, 7]}证实血氨水平与肝性脑病的严重程度密切相关,氨中毒学说是目前用于诊断和治疗肝性脑病的主要理论依据。氨代谢的器官包括肠、肝、肾。肠道是氨的来源,肝脏为氨的主要转化场所,而肾脏为氨及其代谢产物尿素的排泄器官。肠道作为氨的主要来源,其不同功能状态将直接影响氨的产生和吸收。本研究就肝硬化患者各种消化道状态对血氨的影响进行研究,探讨消化道状态与血氨的关系。

本研究肝硬化伴消化道出血组血氨水平高于单纯性肝硬化组和单纯性消化道出血组( P<0.05),而单纯性消化道出血组和正常对照组血氨水平差异无统计学意义( P>0.05)。这表明在肝脏功能正常时,消化道出血生成并吸收入血的氨被肝脏代偿转化,其血氨水平不升高;而肝硬化患者因门静脉高压,造成食道静脉曲张破裂出血,血红蛋白在肠道内分解而导致氨生成增加,NH₃分子弥散入血;另外,由于肝细胞数量减少和肝细胞功能减退,肝脏的鸟氨酸循环能力降低,肠道吸收的氨不能转化成尿素而导致血氨升高。

本研究肝硬化伴便秘组血氨水平高于单纯性肝硬化组和单纯性肠梗阻组( P<0.05),而单纯性肠梗阻组和正常对照组之间差异无统计学意义( P>0.05)。表明肠道梗阻时,肠内容物停留时间延长,蛋白质被肠菌酶分解产生氨增多,肠道吸收氨也随之增加。此时肝脏功能若正常,血氨被代偿转化,血液中氨水平不升高;而肝硬化患者因门静脉高压导致胃肠粘膜出现水肿,胃肠蠕动减弱,氨生成和吸收均增加,同时由于肝脏氨转化能力降低,吸收入血的氨不能被转化导致血氨升高。

本研究肝硬化伴便秘组血氨水平高于肝硬化伴消化道出血组( P<0.05),且肝硬化伴便秘组、肝硬化伴消化道出血组血氨水平均高于单纯性肝硬化组和正常对照组( P<0.05)。表明肝硬化患者肠道便秘比消化道出血更易引发血氨升高。目前,关于肝硬化患者是否控制饮食一直有争论。传统认为氨来源于蛋白质在肠道的分解,高蛋白易诱发或加重肝性脑病。因此,肝性脑病患者需要控制饮食中蛋白质的摄入量。有研究认为治疗慢性肝病限制蛋白食物的摄入可降低血氨升高的风险^{[ 8]}。而Heorghe等^{[ 9]}证实限制蛋白对于改善肝性脑病并非必须,每日摄入适当蛋白质有助于肝性脑病的恢复。本研究发现肝硬化患者消化道出血和便秘都会导致血氨水平升高。而这2个因素中,便秘是血氨升高的主要原因。结合国内外的研究,可以认为肝硬化患者是否限制蛋白摄取决于肠道的功能状态,如果肠道功能正常,可通过饮食摄入补充蛋白;如果肠道功能不正常,特别是有便秘的患者,饮食摄入补充蛋白的方式并不提倡。另外,通过分析45例肝硬化伴肠道功能障碍患者酸化肠道治疗前、后的血氨水平,可发现肠道酸化后血氨水平明显降低,血氨水平平均降低32.34%。结果说明肠道酸碱度对血氨水平有明显影响。

本研究证实肝硬化患者消化道出血、肠道便秘以及肠道的酸碱度与氨的产生和吸收密切相关。肠道状态对氨的产生和吸收有重要的影响。因此,改善肠道功能状态对于降低血氨有重要的作用。目前改善肠道功能状态的方法包括酸化肠道和使用抗生素。酸化肠道是肝性脑病患者常用的治疗手段。酸化肠道治疗一方面可增加肠蠕动,促使肠道的病原体和各种肠源性有毒物质及机体代谢产物迅速排出体外,从而有效地减少氨的生成;另一方面酸化肠道治疗可使结肠内pH值降低,肠道中NH₃转变成N $\begin{matrix} H_{4}^{+} \end{matrix}$ ,N $\begin{matrix} H_{4}^{+} \end{matrix}$ 不被吸收而被排出体外。酸化肠道的结果是减少氨的生成和吸收,从源头上发挥降血氨的作用。

综上所述,肝硬化患者消化道出血、肠道的酸碱度、便秘及肠道感染和血氨水平关系密切,采用经颈静脉肝内门体支架分流术(TIPS)治疗消化道出血、使用乳果糖等酸化肠道及促进肠蠕动是目前有效的降血氨的方法。由于本研究未评价所有治疗方案的效果,因此,现有的治疗方案有待于进一步评价,同时更需要寻找一些有价值的治疗手段。

The authors have declared that no competing interests exist.

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2004

2.659

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. 2004, 44(4):185-198 DOI:10.1016/S0197-0186(03)00153-0

Blood-brain barrier permeability to ammonia in liver failure:a critical reappraisal

Abstract In patients with acute liver failure (ALF), hyperammonemia is related to development of cerebral edema and herniation. The present review discusses the mechanisms for the cerebral uptake of ammonia. A mathematical framework is provided to allow a quantitative examination of whether published studies can be explained by the conventional view that cerebral uptake of ammonia is restricted to diffusion of the unprotonated form (NH 3 ) (the diffusion hypothesis). An increase in cerebral blood flow (CBF) enhanced ammonia uptake more than expected, possibly due to recruitment or heterogeneity of brain capillaries. Reported effects of pH on ammonia uptake were in the direction predicted by the diffusion hypothesis, but often less pronounced than expected. The published effects of mannitol, cooling, and indomethacin in experimental animals and patients were difficult to explain by the diffusion hypothesis alone, unless dramatic changes of capillary surface area or permeability for ammonia were induced. Therefore we considered the possible role of membrane protein mediated transport of NH 4 + across the blood–brain barrier (BBB). Early tracer studies in Rhesus monkeys suggested that NH 4 + is responsible for 20% or even more of the transport of ammonia from plasma to brain. In other locations, such as in the thick ascending limb of Hendle’s loop and in isolated astrocytes, transport protein mediated translocation of NH 4 + is predominant. Many of the ion-transporters involved in renal NH 4 + reabsorbtion are also present in brain capillary membranes and could mediate uptake of NH 4 + . Astrocytic uptake of NH 4 + is associated with increased extracellular K + , which is a potent cerebral vasodilator. Such interference between transport of NH 4 + and other cations could be clinically important because increased cerebral blood flow often precedes cerebral herniation in acute liver failure. We suggest that protein mediated transport of NH 4 + through the brain capillary wall is a realistic possibility that should be more intensely studied.

... 氨中毒学说^[1,2]是目前用于诊断和治疗肝性脑病的重要理论依据 ...

2007

9.858

0.0

. 2007, 47(2):168-171 DOI:10.1016/j.jhep.2007.05.003

Induction of cerebral hyperemia by ammonia plus endotoxin: does hyperammonemia unlock the blood-brain barrier

... 氨中毒学说^[1,2]是目前用于诊断和治疗肝性脑病的重要理论依据 ...

2006

0.0

... 肝硬化诊断依据中华医学会肝脏病学分会脂肪肝和酒精性肝病学组推荐的诊断标准^[3,4],根据病史和实验室检查排除有原发性肾病、肝肾综合征、糖尿病、高血压的患者 ...

2003

0.0

2003

4.768

0.0

... 大量的研究^[5,6,7]证实血氨水平与肝性脑病的严重程度密切相关,氨中毒学说是目前用于诊断和治疗肝性脑病的主要理论依据 ...

2003

9.858

0.0

. 2003, 38(4):441-446 DOI:10.1016/S0168-8278(02)00436-1

Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy

Abstract Background/Aims : To compare venous, arterial and partial pressure of ammonia (pNH 3 ) in 27 consecutive cirrhotics with hepatic encephalopathy, 15 cirrhotics without hepatic encephalopathy and nine controls; to reevaluate all parameters after the improvement of encephalopathy. Methods : Patients were studied by clinical examination and psychometric testing. pNH 3 was calculated from arterial ammonia and pH. Results : In patients with encephalopathy, each form of ammonia was higher than in both controls and patients without encephalopathy. The correlation with the severity of hepatic encephalopathy was similar for venous ( r =0.72), arterial ammonia ( r =0.76) and pNH 3 ( r =0.75). The sensitivity and specificity of each variable in correctly classifying the patients as having or not having hepatic encephalopathy was also similar. Each form of ammonia decreased after the resolution or amelioration of symptoms. However, even in the 17 patients with complete resolution of hepatic encephalopathy, all three ammonia determinations resulted unchanged or increased in some patients. Conclusions : Despite the significant correlation between pNH 3 and hepatic encephalopathy, our study suggests that neither pNH 3 nor arterial ammonia are, from a clinical point of view, more useful than venous ammonia: all three determinations being limited both for the diagnosis of hepatic encephalopathy and for the clinical management of the patients.

... 大量的研究^[5,6,7]证实血氨水平与肝性脑病的严重程度密切相关,氨中毒学说是目前用于诊断和治疗肝性脑病的主要理论依据 ...

2006

10.732

0.0

... 大量的研究^[5,6,7]证实血氨水平与肝性脑病的严重程度密切相关,氨中毒学说是目前用于诊断和治疗肝性脑病的主要理论依据 ...

2003

0.0

... 有研究认为治疗慢性肝病限制蛋白食物的摄入可降低血氨升高的风险^[8] ...

2005

0.0

... 而Heorghe等^[9]证实限制蛋白对于改善肝性脑病并非必须,每日摄入适当蛋白质有助于肝性脑病的恢复 ...