我的看法：為什麼和如何評估乙肝患者的纖維化

StephenW

My Take: Why and How We Should Assess Fibrosis in Patients With HBV
         

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Paul Y. Kwo, MD
Professor of Medicine
Director of Hepatology
Stanford University School of Medicine
Palo Alto, California
       
       

When evaluating a patient for HBV treatment candidacy, most healthcare practitioners are aware that you need HBV DNA and ALT levels. However, in many cases, you also need to determine the presence and degree of fibrosis and inflammation.

Why Perform Fibrosis Assessments?
Many patients with HBV infection will have elevated DNA levels with normal ALT levels or ALT levels above the upper limit of normal (ULN) but < 2 x ULN, below the treatment threshold per the AASLD guidance. However, recent studies from Asia and the United States suggest that > 20% of the individuals who do not meet these cutoffs for treatment may have at least moderate inflammation and/or moderate fibrosis (≥ A2/F2) on liver biopsy. Therefore, if we relied solely on DNA and ALT levels, some patients who would greatly benefit from treatment would be missed.

The AASLD guidance from 2018 also recognizes the importance of assessing disease severity and activity, and they now emphasize that individuals with high HBV DNA but ALT levels < 2 x ULN should be assessed for fibrosis and/or inflammation, especially individuals older than 40 years of age. Fibrosis and inflammation have classically been assessed by liver biopsy, but practically speaking, not everyone with HBV infection is willing or able to have a liver biopsy—hence, we rely on noninvasive markers.

Elastography
One common way to assess fibrosis noninvasively is via elastography. Transient elastography, such as a FibroScan, is a point-of-care test that determines the level of liver scarring and can rule in or rule out advanced fibrosis. Transient elastography also simultaneously provides an indication of the level of steatosis via controlled attenuation parameter.

There are also other types of elastography, including ultrasonographic exam with shear wave elastography. Because this type of elastography uses ultrasound, it also has the advantage of providing information on morphologic characteristics of the liver. For example, you may be able to identify the presence of nodular liver, splenomegaly, or a dilated portal vein—all of which would suggest advanced fibrosis. However, remember that if a patient has an intermediate level of scarring, the liver is likely going to look morphologically normal, and only the shear wave elastography score would indicate fibrosis.

Finally, magnetic resonance elastography is the most accurate of the liver imaging modalities. However, these tests require a radiology referral and are more expensive.

Biomarker Tests
Biomarker tests that can be derived from very simple blood measurements are also available. If you are in an area that has limited resources, the FIB-4 index, which incorporates age, AST, ALT, and platelet levels, and the AST to platelet ratio index (APRI) may be more available and affordable than imaging assessments. These tests can accurately predict advanced fibrosis and cirrhosis.

In addition, there are combinations of serum markers that can be assessed. One example is the commercially available FibroTest, which uses gamma glutamyl transpeptidase, haptoglobin, bilirubin, A1 apolipoprotein, and α-2 macroglobulin levels. I recommend using these with caution—some individuals will have abnormal levels of these markers for other reasons, which renders the test inaccurate in those cases. However, they also can be a useful tool to help guide you in the right direction.

I also recommend looking at the platelet count as a simple first step in the assessment of fibrosis: If the platelet count is < 150,000/mm3, this may be an indicator of more advanced fibrosis. Another useful indicator is the AST to ALT ratio because a higher AST level vs ALT level is also a very important marker that may indicate advanced fibrosis in the absence of alcohol use.

Interpreting Results
As you assess patients with HBV, ensure that all measurements point in the same direction. For example, if a patient has a FibroScan or a transient elastography score suggestive of elevated liver stiffness or cirrhosis, then you would expect the FIB-4 and APRI to indicate more advanced fibrosis. If a patient has a high FIB-4, you would expect higher liver stiffness on elastography.

In some cases, it is challenging to determine the level of fibrosis noninvasively and you need a liver biopsy. However, as we further refine and evolve noninvasive markers, I think that for most patients, you can determine a level of fibrosis accurate enough to decide if you should move forward with treatment or continue monitoring.

Patients With Cirrhosis
One of the important changes in the 2018 AASLD guidance regarded the recommendations for patients with cirrhosis. The guidelines now recommend that patients with compensated cirrhosis and detectable HBV DNA should be treated with nucleot(s)ide analogue therapy. Previous guidance documents did not recommend treatment in those with compensated cirrhosis and low-level viremia, and now it does not matter if the ALT is normal or if the HBV DNA is low—treatment is recommended. Note that the AASLD guidance and the US 2015 treatment algorithm both suggest that persons with undetectable HBV DNA and compensated cirrhosis are not recommended for treatment. However, in my opinion, these individuals, although rare, must either be followed closely or treatment should be initiated.

Similarly, all patients with decompensated cirrhosis, regardless of HBV DNA and ALT levels, should be treated. This is recommended to prevent reactivation, which can lead to a significant episode of worsening cirrhosis, and flares in patients with decompensated cirrhosis are tolerated very poorly, unfortunately. As we improve our screening efforts for hepatitis B, my hope is that we will see fewer and fewer patients presenting with decompensated cirrhosis. Nonetheless, we continue to encounter these patients, and once identified, they should be counseled that they will require lifelong therapy while they have decompensated cirrhosis.

Your Thoughts?
How do you incorporate noninvasive methods to assess fibrosis into your practice? Please share your thoughts in the comments section.

StephenW

我的看法：為什麼和如何評估乙肝患者的纖維化
  

Kwo_Paul_100x100_Circle



醫學博士Paul Y.Kwo
醫學教授
肝病學主任
斯坦福大學醫學院
加利福尼亞帕洛阿爾托



在評估患者的HBV治療候選資格時，大多數醫療從業人員都知道您需要HBV DNA和ALT水平。但是，在許多情況下，您還需要確定纖維化和炎症的存在和程度。

為什麼要進行纖維化評估？
許多HBV感染患者的DNA水平會升高，而正常ALT水平或ALT水平高於正常上限（ULN），但<2 x ULN，低於AASLD指南規定的治療閾值。但是，來自亞洲和美國的最新研究表明，超過20％的未達到上述臨界值進行治療的個體在肝活檢中可能至少具有中度炎症和/或中度纖維化（≥A2 / F2）。因此，如果僅依靠DNA和ALT水平，就會錯過一些將從治療中受益匪淺的患者。

2018年的AASLD指南也認識到評估疾病嚴重程度和活動的重要性，他們現在強調，應評估HBV DNA高但ALT水平<2 x ULN的個體的纖維化和/或炎症，尤其是40歲以上的個體年齡。肝組織活檢通常對纖維化和炎症進行了評估，但實際上，並不是每個感染HBV的人都願意或能夠進行肝活檢-因此，我們依靠非侵入性標記物。

彈性成像
一種無創評估纖維化的常見方法是通過彈性成像。瞬態彈性成像（例如FibroScan）是一種現場檢查，可以確定肝臟瘢痕形成的水平，並可以排除或排除晚期纖維化。瞬態彈性成像還可通過控制衰減參數同時提供脂肪變性水平的指示。

還有其他類型的彈性成像，包括具有剪切波彈性成像的超聲檢查。因為這種類型的彈性成像使用超聲，所以它還具有提供肝臟形態特徵信息的優勢。例如，您可能能夠識別出結節性肝，脾腫大或門靜脈擴張-所有這些都表明晚期纖維化。但是，請記住，如果患者有中等程度的瘢痕形成，則肝臟在形態上可能看起來正常，並且只有剪切波彈性成像評分才能表明纖維化。

最後，磁共振彈性成像是最精確的肝臟成像方式。但是，這些檢查需要放射科轉診，而且價格昂貴。

生物標誌物測試
也可以使用可以從非常簡單的血液測量得出的生物標誌物測試。如果您位於資源有限的地區，則FIB-4指數（包括年齡，AST，ALT和血小板水平）以及AST與血小板比率指數（APRI）可能比影像學評估更容易獲得和負擔得起。這些測試可以準確預測晚期纖維化和肝硬化。

此外，還有可以評估的血清標誌物組合。一個例子是可商購的FibroTest，其使用γ-谷氨酰轉肽酶，觸珠蛋白，膽紅素，A1載脂蛋白和α-2巨球蛋白水平。我建議謹慎使用這些標記-有些人由於其他原因會導致這些標記的水平異常，這會使這些情況下的測試不准確。但是，它們也是有用的工具，可以幫助您正確地引導您。

我還建議將血小板計數視為評估纖維化的一個簡單的第一步：如果血小板計數<150,000 / mm3，則可能是更嚴重的纖維化的指標。另一個有用的指標是AST與ALT的比率，因為較高的AST水平相對於ALT水平也是非常重要的標誌，可表明在不飲酒的情況下晚期纖維化。

解釋結果
在評估HBV患者時，請確保所有測量都指向同一方向。例如，如果患者的FibroScan或瞬時彈性成像評分提示肝勁度增加或肝硬化，那麼您會期望FIB-4和APRI指示更晚期的纖維化。如果患者的FIB-4較高，則在彈性成像上您會期望更高的肝硬度。

在某些情況下，非侵入性地確定纖維化水平具有挑戰性，您需要進行肝活檢。但是，隨著我們進一步完善和發展非侵入性標記物，我認為對於大多數患者而言，您可以確定足夠準確的纖維化水平，以決定是否應該繼續治療或繼續監測。
肝硬化患者
2018年AASLD指南中的重要變化之一是針對肝硬化患者的建議。現在，指南建議肝硬化代償性和可檢測的HBV DNA患者應接受核苷酸類似物治療。以前的指南文件不建議對代償性肝硬化和低水平病毒血症的患者進行治療，現在，ALT正常或HBV DNA較低都無所謂，建議進行治療。請注意，AASLD指南和US 2015治療算法均建議不建議檢測不到HBV DNA和代償性肝硬化的患者進行治療。但是，我認為，這些人雖然很少見，但必須密切關注或應開始治療。

同樣，所有代償期肝硬化患者，無論HBV DNA和ALT水平如何，均應接受治療。推薦這樣做以防止重新激活，這可能導致嚴重的肝硬化發作，並且對代償性肝硬化患者的耀斑耐受性很差，很不幸。隨著我們改善對乙型肝炎的篩查工作，我希望能夠看到越來越多的失代償性肝硬化患者。儘管如此，我們仍會繼續遇到這些患者，一旦被確認，應勸告他們在失代償性肝硬化期間需要終生治療。

你的想法？
您如何將非侵入性方法評估纖維化納入您的實踐中？請在評論部分分享您的想法。

StephenW

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