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名家視點丨超聲彈性成像方法及其在肝纖維化評估中的應用

黃麗虹(Grace LH Wong)

中國香港中文大學消化疾病研究所,內科和治療學系,消化疾病重點實驗室

肝纖維化是慢性肝病尤為重要的一個病理學變化,是指機體針對繼發於慢性肝病,如慢性乙型肝炎(CHB)和丙型肝炎(CHC)、非酒精性脂肪肝病(NAFLD)或酒精中毒等的肝實質損傷的反應性瘢痕組織累積。細胞外基質和纖維組織對肝細胞的持續和進行性替代最終導致肝硬化,後者是肝細胞癌(HCC)的關鍵風險因素。

肝纖維化也是各種慢性肝病的重要治療適應證。如CHB的各國際治療指南均指出,開始CHB抗病毒治療前應考慮肝纖維化的嚴重程度——無論血清丙氨酸轉氨酶(ALT)水準如何。目前有可靠的證據支持「肝纖維化可逆」這一可能。

因此,診斷和評估肝纖維化的嚴重程度,以提供適當的管理,從而防止進一步的肝損傷,有著重要的意義。在評估肝纖維化的各種方法中,基於超聲的彈性成像是非侵入性評估肝纖維化的最成熟方法之一。下文簡要介紹研究最多的幾種超聲彈性成像類型及應用。

幾種研究較多的超聲彈性成像

瞬時彈性成像

瞬時彈性成像(FibroScan?,EchoSens,法國巴黎)是將探頭置於肝實質表面的皮膚之上,通過超聲在肝內產生的剪切波測量肝硬度測量(LSM)。採用多普勒技術計算穿過肝實質的剪切波的速度,速度越高,說明肝實質越硬。根據廠家的介紹,得出一個可靠的檢查結果需要成功嘗試至少10次,且測量值的四分位間距與中位數的比值應小於0.3。

LSM反映了肝纖維化的程度,甚至還可以識別無纖維化或極輕微纖維化的患者,並將其與重度纖維化或肝硬化患者區分開來。已證明其在不同類型的肝臟疾病中(例如慢性乙型肝炎和丙型肝炎、自身免疫性肝炎)中均有用。

然而,在肥胖患者中,瞬時彈性成像檢測得到的LSM的可靠性較低。此外,在某些情況下LSM的結果可能會不夠準確,如嚴重的肝炎急性加重和CHB或CHC患者治療後的纖維化分期。

聲異塵餘生力脈衝(ARFI)成像

聲異塵餘生力脈衝(Acoustic Radiation Force Impulse,ARFI)成像是另一種評估肝纖維化的技術。使用現成的超聲掃描儀就可以進行該項檢測,無需其他的外部設備。 常規的超聲探頭自動產生一個聲「推動」脈衝,在通過組織時可形成剪切波。評估波的傳播速度,同樣,速度越快,肝硬度測量值越高。

ARFI有幾個優勢。由於這是超聲掃描儀的功能,因此無需額外費用。ARFI不僅可顯示纖維化程度,還可提供慢性肝病(例如CHC)疾病進展的外部信息。該工具的另一個優點是能夠提供實時結果並且易於操作。在超重和肥胖患者中,ARFI的測量結果似乎比瞬時彈性成像更準確。

然而,ARFI有一個顯著的缺點,是其測量範圍相當窄(僅從0.5 m/s到4.4 m/s)。此外,很難將纖維化程度與波傳播速度相匹配,即難以確定截斷值(cut-off值)。

剪切波彈性成像(SWE)

剪切波彈性成像(Shear wave elastography,SWE)是一種二維超聲技術,評估聚焦的超聲波束異塵餘生力的剪切波速度,可通過方程將測量值轉換為以kPa為部門的結果。該方法不需要額外的振動器或探測器,因為它可以集成到常規的超聲系統中。此外,肝組織的彈性可以以數值和顏色兩種方式顯示(即較高的硬度用紅色反映),這可以快速反映肝組織的相對硬度。數值可用kPa或m/s表示,與瞬時彈性成像或ARFI的結果匹配。

實際上,與瞬時彈性成像或AFRI相比,SWE在評估纖維化程度方面的準確性更高,尤其是在早期肝纖維化患者中。在最新的指南中,使用SWE評估脾臟硬度的方法已被推薦作為慢性丙型肝炎所致肝纖維化患者的一線評估。然而,只有少數研究驗證了其臨床應用。

基於超聲的彈性成像——從診斷到預後判斷

門靜脈高壓及相關併發症

所有上述無創檢查手段的作用已經從診斷進入到了預後判斷。它們有助於預測肝臟相關併發症的風險,從而預測慢性肝病患者的預後。例如,LSM為13.6 kPa可用於預測門靜脈高壓的存在。將LSM與APRI或纖維指數(fibroindex)結合,可增加預測門靜脈高壓的靈敏度。ARFI>2.34 m/s表明肝儲備功能較差。使用彈性核磁成像(MRE)評估脾丟失模量,是識別嚴重門靜脈高壓或食管靜脈曲張並有高出血傾向患者的良好方法。 結合LSM和脾硬度測量(SSM),可排除大食管靜脈曲張的存在,該方法靈敏度高,可用於風險分層和靜脈曲張篩查策略。

生存

無創檢測手段可用於預測慢性肝病患者的生存。LSM或FibroTest?對慢性病毒性肝炎患者的生存預後具有較高的預測價值。研究顯示,LSM和Hui指數能準確預測CHB患者的無肝臟相關事件生存。

肝細胞癌

有很好的證據表明非侵入性檢測對HCC具有很強的預測價值,甚至是診斷作用。

通過評估聲觸診組織成像(virtual touch tissue imaging,VTI)和聲觸診組織定量(virtual touch tissue quantification,VTQ),可利用ARFI來區分良性和惡性肝臟腫瘤,惡性病變與良性部位相比,VTI更硬,VTQ更高。

超聲彈性成像也是某些HCC風險評分的重要組成部分。例如,使用LSM對CU-HCC 評分進行優化而得到的LSM-HCC評分,對CHB患者3~5年的HCC發生率的陰性預測值進一步提高到接近100%。

LSM 結果還有助於預測病毒性肝炎患者肝細胞癌的發生。另外,在接受部分肝切除術或經動脈化療栓塞的HCC患者中,LSM 是一個獨立的預後因素。

結論

隨著肝纖維化非侵入性評估手段的廣泛應用,全球20億名慢性肝病患者的管理髮生了變革。肝活檢檢查仍在診斷過程中發揮重要作用,而基於超聲的彈性成像在診斷晚期纖維化和肝硬化方面具有較高的準確性。ARFI和SWE對肝纖維化的分期是有作用的,尤其是在把超聲作為評估瀰漫性肝病的首選成像工具時。

Ultrasound-based Elastography in Assessing Fibrosis

Grace Lai-Hung Wong1,2,3

1Institute of Digestive Disease, 2Department of Medicine and Therapeutics, and 3State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong

Liver fibrosis is such a key pathological change of chronic liver diseases. It is the accumulation of scar tissue in response to parenchymal injury secondary to chronic liver disease, e.g. chronic hepatitis B and C, non-alcoholic fatty liver disease (NAFLD) or alcoholism. The continuous and progressive replacement of hepatocytes by extracellular matrix and fibrous tissue leads to liver cirrhosis, which is a key risk factor for hepatocellular carcinoma (HCC).

Liver fibrosis also serves as an important treatment indication in various chronic liver diseases. Different international treatment guidelines mentioned that the severity of liver fibrosis should be considered, regardless of serum alanine aminotransferase (ALT) level, for starting antiviral treatment for chronic hepatitis B (CHB). There are now solid evidence supporting the fact that liver fibrosis is potentially reversible.

Therefore, it is important to diagnose and assess the severity of liver fibrosis in order to provide appropriate management in order to prevent further liver damage. Among various modalities, ultrasound-based elastography is one of the most well-established approaches of to assess liver fibrosis non-invasively. The following are the few most well-studied types of ultrasound-based elastography.

Transient elastography

Transient elastography (Fibroscan?, Echosens, Paris, France) assesses liver stiffness measurement (LSM) by transmitting shear wave followed by ultrasound wave through a probe putting on the skin overlying the liver parenchyma. The velocity of the shear wave passing through the liver parenchyma is calculated by Doppler technique. The higher the velocity, the stiffer the liver parenchyma is.

As mentioned by the manufacturer, for an examination to be considered as reliable, it requires at least 10 successful attempts and the ratio of interquartile range to median of those measurements should be less than 0.3.

LSM reflects the degree of liver fibrosis. It can even identify those with no or minimal fibrosis and differentiate them from those with severe fibrosis or cirrhosis. It has been proved useful across different liver disease entity (e.g. chronic hepatitis B and C, autoimmune hepatitis). However, LSM by transient elastography is found to be less reliable in obese patients. It can be less accurate in certain situation, e.g. severe acute exacerbation of hepatitis, post-treatment fibrosis stages in CHB or chronic hepatitis C (CHC) patients.

Acoustic Radiation Force Impulse (ARFI) imaging

ARFI is another technique for estimating liver fibrosis. It is implemented in current ultrasound scanner, without acquirement of external equipment. The conventional ultrasound probe automatically produces an acoustic 「push」 pulse for generating shear-wave which passes through the tissue. The wave propagation speed is assessed. Again, higher the speed, higher the liver stiffness measurement is.

There are several advantages for ARFI. As it is a function of the ultrasound scanner, no additional cost is required. The ARFI not only shows the degree of fibrosis, it also provides external information for disease progression for different chronic liver disease, for example HCV. Another advantage of this tool is that it can provide real-time results and easy to perform. The measurement results appear to be more accurate in overweight and obese patients, compared with transient elastography.

However, one prominent disadvantage for ARFI is that the range of its measurement is quite narrow (only from 0.5 m/s to 4.4 m/s). Furthermore, it is quite difficult to match the degree of fibrosis with the wave propagation speed, i.e. a cut-off, which is difficult to be defined.

Shear wave elastography (SWE)

Shear wave elastography (SWE) is a 2-dimensional ultrasound technique based on the estimation of shear wave velocity from the radiation force of a focused beam of ultrasound, and it can be converted results in terms of kPa by an equation.

No extra vibrator or detector is required as it is integrated into a conventional ultrasound system. Besides, elasticity of liver tissues can be shown in both numerical values and colour (i.e. higher stiffness is reflected in red colour), which can reflect the relative stiffness of the liver tissue quickly. The numerical values can be expressed in either kPa or m/s, which can be comparable with the results from transient elastography or ARFI.

Actually, its accuracy is higher compared to transient elastography or AFRI in assessing the degree of fibrosis, especially in those with early-stage liver fibrosis. SWE with spleen stiffness index is recommended as the first line assessment for patients with liver fibrosis due to chronic hepatitis C in the latest guidelines. However, only a few studies validate its clinical application.

Ultrasound-based elastography -- from diagnostic to prognostic

Portal hypertension and related complications

The role of all these non-invasive tests is moving from diagnostic to prognostic. They are useful to predict liver-related complications and hence the prognosis of patients with chronic liver diseases.

For example, a LSM with 13.6 kPa can be a predictive value the presence of portal hypertension. Combing LSM with APRI or Fibroindex increases the sensitivities for portal hypertension predication. Liver stiffness with ARFI greater than 2.34 m/s indicates a poor liver reserve function. Assessment of spleen loss modulus by MRE is a good method for recognizing patients with severe portal hypertension or oesophageal varices with high bleeding tendency. Combing LSM and spleen stiffness measurement (SSM) may exclude the presence of large oesophageal varices with high sensitivity and can be adopted in the risk stratification and variceal screening strategy.

Survival

Survival for chronic liver disease can be predicted using non-invasive test. LSM or FibroTest? has a high prognostic value for patients with chronic viral hepatitis. The usage of LSM and Hui index for predicting hepatic-event free survival in CHB patients is shown to be accurate.

Hepatocellular carcinoma (HCC)

There is good evidence show the strong predictive and even diagnostic role of the non-invasive tests for HCC.

ARFI is used for differentiating benign and malignant liver tumours by the assessment of virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ), as VTI appears to be stiffer and VTQ is higher in malignant lesion than its benign counterpart.

Ultrasound-based elastography is also an important part of some HCC risk score. For example, LSM-HCC score, which is optimized from CU-HCC score with LSM, further increases the negative predictive value to close to 100% for HCC prediction in 3 to 5 years in CHB patients. LSM results can help predict the occurrence of HCC in patients with viral hepatitis. In HCC patients receiving partial hepatectomy or transarterial chemoembolization, LSM is an independent prognostic factor.

CONCLUSION

With the wide applicability of non-invasive assessments of liver fibrosis, the management of two billion patients with chronic liver diseases worldwide has been revolutionized. While liver biopsy examination still has an important role in the diagnostic process, Ultrasound-based elastography has high accurate to diagnose advanced fibrosis and cirrhosis. ARFI and SWE are effective for staging liver fibrosis, especially when ultrasound is the first imaging tool for assessment of diffuse liver disease.


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