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标题: 谷丙转氨酶:检测肝损伤的临床和调节工具—过去,现在 [打印本页]

作者: 肝胆速递    时间: 2012-9-2 07:28     标题: 谷丙转氨酶:检测肝损伤的临床和调节工具—过去,现在

本帖最后由 肝胆速递 于 2012-9-16 00:20 编辑

Alanine Aminotransferase: A Clinical and Regulatory Tool for Detecting Liver Injury–Past,Present, and Future
谷丙转氨酶:检测肝损伤的临床和调节工具—过去,现在和将来

JR Senior
Office of Pharmacovigilance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Federal Research Center at White Oak,
Silver Spring, Maryland, USA. Correspondence: JR Senior ([email protected])
Received 8 May 2012; accepted 8 June 2012; advance online publication 1 August 2012. doi:10.1038/clpt.2012.108
Clinical pharmacology & Therapeutics

Assay of the serum activity of the enzyme alanine aminotransferase (ALT) has become the primary screening tool for detecting acute liver injury. But what does an elevated value mean? Not what it is too often mistakenly believed to indicate. It is not a test of liver function. It does not necessarily predict worse effects to come (in a given person). It is not
a valid measure of severity of liver injury or dysfunction. It is too unspecific to be reliable in screening for relatively rare effects on the liver. Although these are substantial limitations, ALT is a very useful biomarker if understood and used properly. It is important to consider how and why these erroneous concepts came to have such wide acceptance, and how
elevations of ALT activity for evaluating patients and subjects under study might be interpreted better.

[extracts]
A small set of serum chemical tests for liver injury or dysfunction is now considered “classic,” namely: the serum concentration of total bilirubin (TBL) and the serum activities of alkaline phosphatase (ALP), aspartate aminotransferase (AST),and ALT.
Of these tests, the elevated serum enzyme activities may indicate injury to hepatocytes or biliary cells, but only the bilirubin elevation indicates any loss of liver function. These tests have been “validated” and “qualified,” not by opinions of an expert committee, but by clinical use for more than six decades of successful application in millions of cases.

What Does All This Add Up To?
Since the 1978 Fogarty Conference and 1982 NCI toxicity criteria
proposal, vast amounts of data have been accumulated.
It is now obvious that elevations in serum enzyme levels alone
are not necessarily measures of clinical severity. Elevated levels
of ALT do not predict what will happen; they only indicate
what has happened up to the time of measurement. Serum
ALT enzyme activity levels are not measures of liver function.
It is not a function of the liver to regulate the levels of activity
of serum enzymes that have no function in the plasma but
represent leakage or release from damaged cells in which they
previously did have functions. In plasma, the levels of activity
are determined by the rates of release from cells and by their
rates of inactivation or degradation by nonspecific proteases.
To a greater extent the TBL or prothrombin time (or derived
international normalized ratio) are better measures of the
ability of the whole liver to perform its true functions, such
as clearing the plasma of bilirubin or synthesizing important
coagulation proteins.
I now propose that the gradings of severity (Table 1) published
since 1982 by the NCI as the Common Toxicity Criteria
for Adverse Events be considered instead as measures of urgency.
To do what?—(i) to repeat the tests immediately (in local laboratories
to avoid the delay involved in obtaining results when
specimens are sent to distant central laboratories); (ii) to confirm
the findings, and establish the direction and rapidity of
change; (iii) to initiate additional studies to clarify the probable
cause (Table 2) of the findings if they become worrisome; (iv)
to preserve serum samples for possible retrospective tests to be
done later as needed.
Elevations in the concentration levels of serum TBL, or of the
direct-reacting, conjugated bilirubin, are highly specific to liver
problems but are not very sensitive as markers; also, the elevation
often occurs only late in a disease process. The search for
new biomarkers should accept the combined biomarker of (ALT
and TBL) as the standard to surpass, rather than ALT alone.
Under the new regulations of 2010,45,46 it is the responsibility of
the sponsors of drug trials to supervise local investigators and
guide them on the procedure to follow when abnormal liver test
results are found; all data are required to be recorded in the case
report forms, both in local and central laboratories.
Despite the limitations on the predictive value of ALT elevations
in individual subjects, it has been found repeatedly that the
increased occurrence of such elevations in groups that are being
studied is highly predictive of what is later likely to be found
in other groups. This is an important point, the significance of
which is often misunderstood.47–49
Recommendations
Proposed here are some new interpretations relating to elevated
levels of ALT activity, and suggestions for how they might lend
themselves to better general use, to trigger discussions, objections,
or corrections, to stimulate debate, and to aim at consensus
and more consistent application:
1. The measurements of serum ALT (as well as AST and ALP)
are not tests of liver function, but of liver cell injury.
2. Whole-liver dysfunction is what really determines the severity
of the injury.
3. Serum bilirubin concentration does measure at least one
function of the liver, namely, to clear plasma of bilirubin,
and depends on whole-liver functional capacity.
4. The combined biomarker (ALT and TBL) has the high sensitivity
of ALT and the very great specificity of TBL, and is the
current standard to surpass for proposed new biomarkers.
5. Urgency (to repeat the test and initiate special study) should
replace severity in the NCI CTC guideline relating to serum
enzyme activity levels.
6. Elevated ALT activity does not necessarily predict what will
happen to the liver for an individual but is of predictive value
when found in groups.
7. There is need for standardization, both of the methods used
to measure ALT activity and of what should be adopted as
the truly “normal” range.50,51
8. Suitable revisions in guidances, teaching approaches, and
clinical practice will need to reflect these points.


作者: 肝胆速递    时间: 2012-9-2 07:30

谷丙转氨酶的临床和管理工具检测肝损伤的过去,现在和未来
JR高级
办公室的警戒和流行病学,药物评价和研究中心,美国食品和药物管理局,联邦研究中心的白橡木,
,美国马里兰州银泉市。通讯地址:JR高级(john.senior @ fda.hhs.gov)
2012年5月8日2012年6月8日网上提前出版的2012年8月1日。 DOI:10.1038/clpt.2012.108
临床药理学与治疗
血清活性的酶丙氨酸转氨酶(ALT)的含量已经成为主要的筛选工具,用于
检测急性肝损伤。但到底是什么升高值是什么意思?没有什么太经常被误认为到
表示。这不是一个测试的肝功能。这并不一定预测效果越差,在一个特定的人来()。这是不
严重的肝损伤或功能障碍的一个有效措施。这是比较少见的非特异性筛查是可靠的
对肝脏的影响。虽然这些都是很大的限制,ALT是一个非常有用的生物标志物,如果理解和使用
正确。重要的是要考虑如何以及为什么这些错误的概念来有广泛的接受,以及如何
评估病人的活动和研究课题ALT的升高可能会被解释更好。

[摘录]
一个小组的血清肝损伤或功能障碍的化学测试,现在被认为是“经典”,即:总胆红素(TBL)的血药浓度,血清碱性磷酸酶(ALP),谷草转氨酶(AST),ALT活动。
这些测试中,升高的血清酶活动可能表示肝细胞或胆道细胞的伤害,但只有胆红素升高表示肝功能的任何损失。这些测试已经被“验证”和“合格”,而不是由一个专家委员会的意见,但超过六十年的成功应用,数百万例的临床使用。

所有的这一切要添加吗?
自从1978年的的福格蒂会议和1982年美国国立癌症研究所毒性标准
建议,已经积累了大量的数据。
现在很明显,升高血清酶浓度的单独
不一定是临床严重程度的措施。水平升高
ALT不预测将会发生什么,他们只表示
发生了什么事的时​​间的测量。血清
肝功能ALT酶活性水平的措施。
它不是一个肝脏功能调节活性水平
有没有在血浆中的功能,但血清酶
代表从受损细胞的泄漏或释放在他们
以前具备的功能。在血浆中,活动水平
是由从细胞中释放率,并通过他们的
率的非特异性蛋白酶的失活或降解。
为了在更大程度上TBL或凝血酶原时间(或派生
国际标准化比值)是更好的措施,
整个肝脏的能力履行其真正的功能,如
,清除胆红素血浆或合成的重要
凝血蛋白。
我现在提出的严重程度(表1),评级发表
自1982年以来,由美国国立癌症研究所通用毒性标准
不良事件被认为是紧急措施。
做什么? - (一)立即重复的测试(在当地实验室
取得的结果时,以避免延迟
标本被送到遥远的中心实验室),(ii)确认
的调查结果,并确立方向和速度
改变;(三)开展更多的研究,以澄清可能
使(表2)的结果,如果他们成为令人担忧(ⅳ);
保存血清样本可能的回顾性测试
完成后根据需要。
浓度,血清TBL升高,或
直接反应,结合胆红素,是非常具体的,以肝脏
的问题,但都不是很敏感的标记;,海拔
在疾病过程中经常发生才。搜索
应该接受新的生物标志物的组合生物标志物(ALT
TBL)为标准,超越,而不是ALT孤独。
,2010,45,46根据新的规定,它的责任是
药物临床试验的赞助商,以监督当地调查和
指导他们遵循的程序时,肝功能异常测试
结果发现,要被记录的情况下,所有的数据都需要
报告形式,无论是在地方和中央的实验室。
尽管ALT升高的预测值上的限制
在个别科目,它已被发现多次,
在组正在发生这样的海拔高度增加
研究高度预测的是什么后可能会发现
其他各组。这是一个重要的点的意义
这往往是misunderstood.47-49
建议
在这里建议了一些新的诠释有关升高
ALT活性水平,并建议他们可能会借
自己更好的通用性使用,引发讨论,反对,
或更正,刺激辩论,并力求以协商一致方式
和更一致的应用程序:
1。血清ALT(以及作为AST和ALP)的测量
不是肝功能的测试,但是,肝细胞损伤。
2。全肝功能障碍是什么真正决定的严重程度
的伤害。
3。血清胆红素浓度确实措施中的至少一个
肝脏的功能,即,以清除血浆中胆红素,
并且依赖于整个肝脏功能的能力。
4。合并后的生物标志物(ALT和TBL)具有较高的灵敏度
ALT和TBL很大的特异性的,并且是
超过现行标准提出了新的生物标志物。
5。紧迫性(重复的测试,并开始专门研究)
NCI CTC指引,有关血清取代的严重程度
酶的活性水平。
6。谷丙转氨酶活性升高并不一定预测
发生肝的一个人,但预测值
当发现组。
7。有必要进行标准化,无论所使用的方法
衡量ALT活性和应采取什么作为
真正的“正常”range.50,51
8。适用修订的指导原则,教学方法,
临床实践的需要,以反映这点。




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