Staging Liver Fibrosis: Time to Abandon Liver Biopsy?
Nezam H. Afdhal, MD
Chief of Hepatology
Beth Israel Deaconess Medical Center
Associate Professor of Medicine
Harvard Medical School
传统认为经皮肝活检是评价肝病的公认得金标准。肝活检被用来对肝病作出诊断，对预后进行推断、和进行肝病的分期。尽管对于肝病的血清学诊断试验的进步，肝活检仍然被用来对证实肝病的类型。活检也被用来决定肝病的预后，通常是通过肝硬化的存在与否来作出判断的。进来，肝活检被用于病毒性肝炎肝纤维化的分期，进而来为是否需要治疗提供决策依据。更多的专家推荐对于合并间隔纤维化或更严重的患者（METAVIR分期大于等于2期）给予治疗。随着治疗耐受性或有效性的不断提高改变了这一治疗决策，增加了医师和患者接收治疗比率和降低肝活检需要。
超声波引导或标记的肝活检轿发生一些严重的并发症是罕见的，出血的几率罕见（1：10000肝活检）。肝活检的主要问题是费用（大约为2200美金）和病人的接收性和焦虑。此外进来的研究还发现肝活检仅能对80％的患者作出正确的肝纤维化分期，其可能会遗漏30％患者的一些严重的肝纤维化或肝硬化结节。肝活检所伴有的不准确性与肝病本身的多态性，穿刺标本较小和病理学家的经验有关。这就导致这样一个感念的形成既肝活检至少需要获得25mm长的组织标本以降低标本误差。尽管这是一个病理学目标，但具有临床的难以实现性，仅有约20％的肝活检标本能够达到这一长度。
肝活检的局限性导致临床研究者不断地寻找替代方法来为肝病进行分期。非浸入性的血清学生化标记物是最广泛的用来代替肝活检的指标，进来被进行了详细的回顾。有两个重要的生化学试验，他们分别是采用临床变量进行肝纤维化的分期，一些细胞外基质标记物来进行分期。有一些特异性的试验，但从总体上讲这些试验的特点均是相对相似的。
试验的准确性通常是通过曲线下面值来界定的。一个理想的试验应该具有100％的敏感性和特异性，那其曲线下面积为1.0。多数已提出的生化试验――特别是那些临床上较易获得试验，其曲线下面值多在0.80-0.85之间，不能用于疾病分期，但可以将分期为F0/F1的患者从那些纤维化分期为F2-F4的患者中区分出来。因为血清学标记物具有根肝活检相似的准确性，肝活检的准确性约为80％；因此从统计学上讲，生化标记物可能对于肝纤维化的分期效果更佳。有趣的是生化学指标对于疾病的极端情况效果更优，不确定的结果可能发生于分期为F1/F2的患者身上，这并不令人吃惊，因为这些疾病的分期本来就是人为根据疾病进展来进行划分的。
肝病分期的一个替代方法是通过纤维化扫描（FibroScan）测定肝脏的坚硬性和弹性。其原理是相对简单的，即通过50mHZ的切变速度传送来对2－5cm的肝脏片断进行测量，然后将其转化为坚硬度的值（单位为千帕，kPA）这一诊断试验的准确性在总体上与那些生化标记物试验是相似的，但其对肝硬化的诊断可能作用更大，曲线下面值达到了0.95。这一试验具有简单，结果的可读性，但这设备仍然处于美国的研究阶段，且是相对昂贵的。联合FibroScan和生化学标记物将增加二者的准确性。
现阶段我们能作出什么推荐呢？当诊断是可疑的时候，肝活检仍然是金标准（一定要进行充分的肝活检）。然而，当问题是关于纤维化的分期或治疗决定和排除肝硬化时，生化学标记物和非浸入性检测是合理的首先措施。如果生化指标提示处于疾病的早期或者晚期阶段，就不需进行进一步的评估。当结果是含糊的时候，则需要进行肝活检。最后，我们可以预期之后患者根据每年的生化学和坚硬度扫描就可以预测疾病的进展或好转。在目前这个简单还不是抛弃肝活检用于疾病分期的时候，因为生命之舟随时会结束，而鲨鱼仍环伺在我们周围。
The established gold standard for the evaluation of liver disease has traditionally been a percutaneous liver biopsy. Liver biopsy is used predominantly for the diagnosis, prognosis, and staging of liver disease. Despite improvements in serologic diagnostic tests for liver disease, a biopsy is often still indicated to make the diagnosis of many forms of liver disease. Biopsy is also useful for determining prognosis, usually by confirming the presence or absence of cirrhosis. More recently, biopsy has been used for staging fibrosis in viral hepatitis and for decision analysis as to the need for treatment. Many treatment algorithms recommend treatment for patients with septal fibrosis or greater (≥ METAVIR stage 2). Improvement in either tolerability or efficacy of therapy could easily alter this current treatment paradigm, increasing physician and patient acceptability of therapy and reducing the need for liver biopsy.
Liver biopsy is rarely associated with severe complications in this era of ultrasound guidance or marking, and bleeding is rare (1:10,000 biopsies).[1] The major issues with biopsy are cost (approximately $2200) and patient acceptability and anxiety. In addition, recent studies have suggested that biopsy is only about 80% accurate in the staging of liver fibrosis and may even miss advanced fibrosis or cirrhosis in 30% of patients. The factors associated with the inaccuracy of biopsy include the heterogeneous nature of liver disease, the relatively small size of a biopsy compared to the size of the liver, and the experience of the pathologist. This has led to the concept that a liver biopsy should be at least 25 mm in length to reduce the sampling error.[2] Although this is a noble aim pathologically, it remains a clinical rarity, with only 20% of liver biopsies even approaching this length.
These limitations of biopsy have led clinical investigators to study alternative methods to stage liver disease. Noninvasive serum biomarkers are the most widely used alternative to liver biopsy and have recently been reviewed.[3] There are 2 major types of biomarker tests, those that use clinical variables to stage fibrosis and those that use extracellular matrix (ECM) markers.[4,5] There are advocates of specific tests, but overall the performance characteristics of all these tests are relatively similar.
The accuracy of a test is often given as the area under the curve (AUC) of the receiver operator characteristic (ROC). A perfect test with a 100% sensitivity and specificity would have an AUC of 1.0. The majority of proposed biomarker tests—and in particular, those available for use in clinical practice—have an AUC of between 0.80-0.85, not for staging disease, but for differentiating mild from (F0/F1) from significant fibrosis (F2-F4). Since the biomarker is validated against the biopsy, and the accuracy of the biopsy is only 80%, it is probably statistically impossible for a biomarker to perform any better for staging fibrosis. Interestingly, the performance of biomarkers is superior at the extremes of disease; the indeterminate results occur when patients have F1/2 disease. This is not surprising, since these stages are relatively artificial separations of a spectrum of a dynamic disease process.
An alternative method for staging liver disease is to measure liver stiffness or elasticity using a FibroScan.[6] The principle is relatively simple and involves measuring the shear velocity of a 50 mHZ wave propagated through a 2-5 cm segment of the liver, and converting this into a stiffness value in kilopascals (kPA). The diagnostic accuracy of the test is similar overall to that reported for biomarkers, but it is probably better in diagnosing cirrhosis, with an AUC of 0.95. The test is simple and the results readily available, but the machine is still investigational in the United States and relatively expensive. Combining a FibroScan measurement with biomarkers may increase the accuracy of both tests.[7]
What can we recommend at the present time? Certainly, when the diagnosis is in doubt, a liver biopsy remains the gold standard (just make sure it is an adequate biopsy!) However, when the issue is staging of fibrosis for either treatment decision or exclusion of cirrhosis, biomarkers and noninvasive tests represent a valid initial alternative. If the biomarkers are clearly indicative of mild or advanced disease, no further evaluation is necessary, and where they are equivocal, a biopsy can subsequently be performed. Eventually one could even anticipate following patients on an annual basis with biomarkers and stiffness scans to follow the progression or regression of disease. It is not yet time to abandon liver biopsy for disease staging, but the lifeboats are out and the sharks are circling.
References
1. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med. 2001;344:495-500.
2. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449-1457.
3. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol. 2004;99:1160-1174.
4. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069-1075.
5. Patel K, Gordon SC, Jacobson I, Hezode C, Oh E, Smith KM, Pawlotsky JM, McHutchison JG. Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients. J Hepatol. 2004;41:935-942.
6. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, Christidis C, Ziol M, Poulet B, Kazemi F, Beaugrand M, Palau R. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003;29:1705-1713.
7. Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, De Ledinghen V. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343-350.
|
