瞬时肝弹性测定在慢性乙型肝炎中的应用

在亚洲,慢性乙型肝炎病毒（HBV）感染是肝硬化与肝癌常见的病因。随抗病毒治疗进展,肝癌已成为一种潜在可预防的疾病,一项荟萃分析证实干扰素与核苷（酸）类似物能够减少慢性乙型肝炎中肝癌的发病风险,定期肝癌监测能够检查到早期和潜在可切除的肝癌,改善患者生存率。肝纤维化是炎症坏死的自然创面愈合过程,是导致肝硬化基本的致病过程。既往肝纤维化评估在很大程度上受阻于肝活检的局限性,引入瞬时肝弹性测定这一可靠及非侵入性肝纤维化检测方法,在病毒性肝炎难以研究的领域洒下了新的曙光。     

瞬时弹性成像技术在慢性乙型肝炎中的应用进展

肝活检是诊断肝脏疾病的金标准,胃镜是诊断食管胃静脉曲张的金标准;但二者均为有创检查,因此应用受限。近年来瞬时弹性成像技术作为无创检测,临床已经广泛采用。介绍了瞬时弹性成像技术在慢性乙型肝炎患者肝纤维化、肝脂肪变、肝硬化及肝癌等方面的最新进展。未来可在乙型肝炎肝硬化和肝癌早期联合诊疗方面进行更多研究。     

Increased liver stiffness measurement by transient elastography in severe acute exacerbation of chronic hepatitis B

Background and Aims:  The proposed cut-off values for the degree of fibrosis as assessed by liver stiffness measurement (LSM) might not be applicable in severe acute exacerbation of chronic hepatitis B (CHB). We aimed to assess the effect of necroinflammatory activity on LSM in this condition.
Methods:  We prospectively recruited consecutive patients with severe acute exacerbation of CHB (alanine aminotransferase or ALT > 10× upper limit of normal). The relationship of ALT levels and LSM were serially assessed and liver biopsy was carried out after ALT normalization.
Results:  Eleven patients (10 male, median age 43 years) were followed up for 25 weeks; nine patients received antiviral therapy. Overall, LSM was positively correlated with ALT levels ( r  = 0.67, P  < 0.001). At initial presentation, the median serum ALT and LSM was 1136 (581–2210) IU/L and 26.3 (11.1–33.3) kPa. A progressive reduction in LSM was observed during subsequent visits in parallel with the reduction of ALT levels. At the last visit, the median ALT was 27 (11–52) IU/L and LSM was 7.7 (4.7–10.8) kPa. Among the five patients who had liver biopsy carried out at week 25, four patients had F2 fibrosis (LSM 5.7–8.1 kPa) and one patient had F3 fibrosis (LSM 8.6 kPa).
Conclusions:  LSM using transient elastography with the current proposed cut-off values might misdiagnose liver cirrhosis in patients suffering from severe acute exacerbation of CHB. LSM should be assessed after normalization of ALT levels in order to accurately assess the degree of fibrosis.     

Improving transient elastography performance for detecting hepatitis B cirrhosis

Background

Transient elastography is a well-established method for detecting cirrhosis.

Aim

To improve the performance of transient elastography in detecting hepatitis B cirrhosis by alanine aminotransferase (ALT)-stratified cutoffs, bilirubin normalization and transient elastography-based algorithms.

Methods

A total of 315 compensated patients were analysed following liver biopsies, transient elastography, ultrasonography and blood tests.

Results

The area under the receiver operating characteristics (ROC) curve of transient elastography for predicting cirrhosis was 0.88 (95% confidence interval 0.84-0.92). The cutoffs to exclude and confirm cirrhosis were 10.4 kPa and 17.3 kPa in patients with ALT <5 × upper limit of normal range, 13.7 kPa and 25.0 kPa in ALT ≥5 × upper limit of normal range, respectively. With ALT-stratified cutoffs, 68.6% of patients did not require liver biopsies. Areas under the ROC curve in patients with normal or abnormal bilirubin was 0.90(0.85-0.95) and 0.84(0.77-0.92), respectively. In patients with normal bilirubin, the cutoffs for excluding and confirming cirrhosis were 10.6 kPa and 16.9 kPa, respectively. By transient elastography screening, 78.3% of patients with normal bilirubin would not need a liver biopsy. Areas under the ROC curves between transient elastography and transient elastography-based algorithm including transient elastography-splenomegaly-platelet index [0.90(0.86-0.94)] and ultrasonic score-transient elastography index [0.91(0.86-0.96)] were not significantly different.

Conclusions

Amongst ALT-stratified cutoffs, bilirubin normalization and transient elastography-based algorithm, bilirubin normalization was especially important for improving performance of transient elastography for compensated hepatitis B cirrhosis detection.     

两种超声弹性成像技术诊断慢性乙型肝炎患者肝纤维化价值比较*

目的 探讨瞬时弹性成像和二维剪切波弹性成像用于CHB患者肝纤维化诊断的临床价值。方法 2016年3月～2018年12月我院收治的CHB患者164例,均行瞬时弹性成像和二维剪切波弹性成像检查及肝穿刺活检,采用受试者工作特性(ROC)曲线下面积比较两种超声弹性成像检查诊断不同肝纤维化分期的效能。结果 经肝穿刺活检,在164例CHB患者中,诊断肝组织S₁期50例,S₂期42例,S₃期39例,S₄期33例;瞬时弹性成像检查S₁～S₄期肝纤维化分期的弹性值分别为(6.5±1.1)kPa、(8.6±1.4)kPa、(11.7±1.8)kPa和(16.3±1.8)kPa,二维剪切波弹性成像检查弹性值分别为(5.9±0.8) kPa、(8.1±1.2)kPa、(10.9±1.5)kPa和(16.7±1.9) kPa,两种超声弹性成像检查不同肝纤维化分期弹性值差异无统计学意义(P >0.05);二维剪切波弹性成像检查诊断肝纤维化S₂、S₃和S₄期的ROC曲线下面积(AUC)分别为0.971、0.979和0.973,显著高于瞬时弹性成像检查的0.902、0.906和0.904(P <0.05),其诊断的敏感性分别为90.3%、90.6%和100.0%,特异性分别为95.8%、90.6%和84.5%,而瞬时弹性成像检查诊断则分别为78. 5%、81.3%和73.1%,和93.3%、87.9%和91.0%。结论 二维剪切波弹性成像和瞬时弹性成像检查均可用于慢性乙型肝炎患者的肝纤维化诊断,其临床价值均需要进一步探讨。     

Performance of liver stiffness measurements by transient elastography in chronic hepatitis

AIM:To compare results of liver stiffness measurements by transient elastography(TE) obtained in our patients population with that used in a recently published meta-analysis.METHODS:This was a single center cross-sectional study.Consecutive patients with chronic viral hepatitis scheduled for liver biopsy at the outpatient ward of our Infectious Diseases Department were enrolled.TE was carried out by using FibroScan(Echosens,Paris,France).Liver biopsy was performed on the same day as TE,as day case procedure.Fibrosis was staged according to the Metavir scoring system.The diagnostic performance of TE was assessed by using receiver operating characteristic(ROC) curves and the area under the ROC curve analysis.RESULTS:Two hundred and fifty-two patients met the inclusion criteria.Six(2%) patients were excluded due to unreliable TE measurements.Thus,246(171 men and 75 women) patients were analyzed.One hundred and ninety-five(79.3%) patients had chronic hepatitis C,41(16.7%) had chronic hepatitis B,and 10(4.0%) were coinfected with human immunodeficiency virus.ROC curve analysis identified optimal cut-off value of TE as high as 6.9 kPa forF ≥ 2;7.9 kPa forF ≥ 3;9.6 kPa for F = 4 in all patients(n = 246),and as high as 6.9 kPa for F ≥ 2;7.3 kPa for F ≥ 3;9.3 kPa for F = 4 in patients with hepatitis C(n = 195).Cut-off values of TE obtained by maximizing only the specificity were as high as 6.9 kPa for F ≥ 2;9.6 kPa for F ≥ 3;12.2 kPa for F = 4 in all patients(n = 246),and as high as 7.0 kPa forF ≥ 2;9.3 kPa forF ≥ 3;12.3 kPa forF = 4 in patients with hepatitis C(n = 195).CONCLUSION:The cut-off values of TE obtained in this single center study are comparable to that obtained in a recently published meta-analysis that included up to 40 studies.     

The usefulness of transient elastography in the assessment of patients with HBeAg‐negative chronic hepatitis B virus infection

Histological severity is often mandatory for the management of HBeAg‐negative chronic HBV patients. We evaluated the performance of transient elastography (TE) in this setting. We included 357 untreated HBeAg‐negative patients with ≥1 reliable liver stiffness measurement (LSM‐kPa) by TE: 182 inactive carriers with HBV‐DNA < 2000 (n = 139) or 2000–19 999 IU/mL (n = 43) and 175 patients with chronic hepatitis B (CHB). In carriers, HBV‐DNA > 2000 and/or LSM > 6.5 were considered as biopsy indications. LSMs did not differ between carriers with low and high viremia, but were lower in carriers than in patients with CHB (5.8 ± 1.7 vs 9.0 ± 5.6, P < 0.001) offering moderate differentiation between these two groups (AUROC: 0.705). LSMs did not change significantly in carriers after 16 (12–24) months. In carriers with a liver biopsy, Ishak's staging scores were similar between cased with low and high viremia but higher in cases with LSM > 6.5 than ≤6.5 kPa. Moderate fibrosis (stages: 2–3) was detected in 0/10 carriers with only HBV‐DNA > 2000 IU/mL, 2/10 (20%) carriers with only LSM > 6.5 and 5/10 (50%) carriers with both HBV‐DNA > 2000 and LSM > 6.5 (P = 0.009). In patients with CHB, LSMs correlated significantly with grading and staging scores and offered excellent accuracy for ≥moderate, ≥severe fibrosis or cirrhosis (AUROC ≥ 0.919–0.950). TE can be helpful for the noninvasive assessment of HBeAg‐negative chronic HBV patients. In conclusion, LSMs offer excellent accuracy for fibrosis severity in HBeAg‐negative patients with CHB and can identify carriers with high risk of moderate fibrosis, which may be present in up to 35% of carriers with LSM > 6.5 kPa and 50% of carriers with LSM > 6.5 kPa and HBV‐DNA > 2000 IU/mL.     

Larger biopsies evaluation of transient elastography for detecting advanced fibrosis in patients with compensated chronic hepatitis B

Background and Aim: Although larger biopsies sample had been recommended for the study of non‐invasive liver fibrosis assessment, few studies with larger biopsies for transient elastography (TE) detecting liver fibrosis had been reported. The present study tries to re‐evaluate the performance of TE for detecting advanced fibrosis (≥F3) with larger biopsies in patients with compensated chronic hepatitis B. Methods: A total of 375 compensated patients were analyzed, who had undergone liver biopsy, reliable TE and routine blood tests. Results: The area under the receiver operating characteristic curve (AUC) was influenced by liver biopsy sample: 0.873 (95% confidence interval 0.838–0.909) in total patients, 0.880 (0.844–0.917) in length ≥ 15 mm, 0.897 (0.863–0.932) in length ≥ 20 mm and 0.911 (0.874–0.949) in length ≥ 25 mm. In patients with sample length ≥ 20 mm, the cutoffs to exclude and confirm advanced fibrosis were 7.1 kPa and 12.7 kPa, respectively. Stratified by alanine aminotransferase of two times the upper limit of normal (ALT 2 × ULN), transient elastography detecting advanced fibrosis with the most efficiency by 72.5% of patients obviated from liver biopsy. In patients with normal bilirubin and ALT < 2 × ULN, the area was 0.921 (0.860–0.982), and cutoffs for excluding and confirming diagnosis were 7.4 kPa and 10.6 kPa, respectively; 80% of patients could be classified with or without advanced fibrosis (AF). In patients with normal bilirubin and ALT ≥ 2 × ULN, the corresponding numbers were 0.885 (0.824–0.947), 7.5 kPa, 12.7 kPa and 79.2%, respectively. Conclusions: Inadequate sample study would underestimate the efficiency of TE on detecting advanced fibrosis. With ALT 2 × ULN stratified cutoffs, TE determined nearly 80% of patients with normal bilirubin as AF or non‐AF and obviated them from liver biopsies.     

Australian Liver Association (ALA) expert consensus recommendations for the use of transient elastography in chronic viral hepatitis

Since the introduction of Transient Elastography (TE) into Australia in 2008, non‐invasive liver fibrosis assessments have integrated themselves into clinical hepatology. The Australian Liver Association (ALA) recognizes these technologies perform an important role in the assessment of chronic viral hepatitis B and C. However, in the setting of viral hepatitis and many other chronic liver diseases, there remains no consensus or guidelines regarding the performance, utility or reporting of TE. Accordingly, the ALA sought to produce an expert consensus statement for the use of TE in chronic viral hepatitis. The recommendations incorporated in this document are based upon a thorough literature review and draw on extensive clinical experience using TE. The initial draft was presented at Australian Gastroenterology Week (AGW) 2013. Through a collaborative process and expert external review a finalized document was presented at AGW 2014.     

The management of chronic hepatitis B infection

Chronic hepatitis B infection is frequently diagnosed within the genitourinary clinic setting with sexual transmission the commonest route of acquisition in the United Kingdom. Only 3--5% of adults who contract acute hepatitis B will progress to chronic infection, and these individuals can be identified by the presence of hepatitis B surface antigen (HBsAg) in the bloodstream 6 months after infection. Individuals at highest risk of long-term complications such as cirrhosis and hepatocellular carcinoma, carry HBeAg and have high levels of circulating hepatitis B virus (HBV) deoxyribonucleic acid (DNA). Therapy should be targeted towards this group of patients. Two forms of therapy are now licensed for use in chronic hepatitis B infection: interferon-alpha and lamivudine. Seroconversion occurs in 30--40% of patients treated with interferon and treatment is often limited by toxicity. Lamivudine is well tolerated with seroconversion rates of 15--20% at one year, rising with increasing duration of therapy. Long-term monotherapy is limited however by the development of resistance mutations and combination nucleoside therapy is likely to become the treatment of choice in the future. Patients with chronic hepatitis B should be counselled regarding transmission, partner vaccination and alcohol intake and co-infection with other hepatitis viruses should be excluded.     

瞬时弹性成像联合门静脉血流动力学指标诊断慢性乙型肝炎患者肝纤维化意义探讨*

目的 探讨瞬时弹性成像联合门静脉血流动力学指标诊断慢性乙型肝炎(CHB)患者肝纤维化的临床价值。方法 2016年2月～2019年9月我院收治的经肝组织活检诊断的CHB患者98例,使用FibroScan 502型诊断仪行肝脏硬度测定(LSM),使用超声检测门静脉主干内径(PVD)、平静呼吸时门静脉最大流速(Vmax)和平静呼吸时门静脉平均流速(Vmean)。采用多因素分析影响肝纤维化的因素,应用受试者工作特征(ROC)曲线评价诊断效能。结果 98例CHB患者经肝穿组织病理学检查,诊断为肝纤维化F0期6例,F1期22例,F2期34例,F3期28,F4期8例;F4期患者LSM、PVD、Vmax和Vmean分别为(28.6±7.8)kPa、(1.4±0.4)cm、(27.4±2.5)cm/s和(22.8±3.1)cm/s,与F1期比,差异显著[分别为(6.1±0.4)kPa、(1.0±0.2)cm、(33.8±1.4)cm/s和(28.5±1.4)cm/s,P<0.05];以F0和F1期划归为非显著性肝纤维化,将>F2期划归为显著肝纤维化。70例显著肝纤维化患者LSM、PVD、Vmax和Vmean分别为(14.2±3.8)kPa、(1.4±0.4)cm、(29.1±2.1)cm/s和(24.1±2.1)cm/s,与28例非显著肝纤维化患者比,差异显著[分别为(5.9±0.4)kPa、(1.0±0.2)cm、(36.8±1.5)cm/s和(30.5±1.4)cm/s,P<0.05];二分类Logistic回归分析结果提示LSM和PVD是肝纤维化发生的独立预测指标(P<0.05),以LSM等于8.4 kPa为截断点,其诊断显著肝纤维化的AUC为0.84(95%CI :0.80～0.89),敏感性为82%(95%CI:76%～85%),特异性为89%(95%CI:81%～93%),而PVD诊断的截断点为1.4 cm,其AUC为0.83(95%CI :0.78～0.89),敏感性为81%(95%CI:75%～86%),特异性为90%(95%CI:85%～94%)。结论 采用LSM和超声检测的PVD诊断CHB患者显著肝纤维化具有很高的诊断效能,值得临床扩大验证。     

Longitudinal assessment of liver stiffness by transient elastography for chronic hepatitis B patients treated with nucleoside analog

Aim: To evaluate the association between liver stiffness measured by transient elastography (FibroScan) and the efficacy of long‐term nucleoside analog (NA) treatment for patients with chronic hepatitis B. Methods: Study 1: Forty‐four chronic HBV patients had liver stiffness measured by FibroScan and underwent liver biopsy. Study 2: Group A: 22 patients started NA treatment at entry and FibroScan was done annually for 3 years. Group B: 23 patients started NA treatment prior to pretreatment FibroScan measurement, and FibroScan was done for from 3 to 5 years after the start of NA treatment. Results: Study 1: The FibroScan values were significantly correlated with fibrosis stage (r = 0.672, P < 0.0001). Optimal cutoff of FibroScan values were 6.1 kPa for ≥ F1, 6.3 kPa for ≥ F2, 8.9 kPa for ≥ F3 and 12.0 kPa for F4. Study 2: For Group A, the baseline median FibroScan value was 8.2 kPa. FibroScan values significantly decreased annually for 3 years after the start of NA treatment (6.4 kPa, 5.8 kPa and 5.3 kPa at years 1, 2 and 3, respectively). For Group B, the FibroScan values did not significantly improve over the 3 years after the start of NA treatment. Conclusions: Liver stiffness, measured by transient elastography, of chronic hepatitis B patients treated with NA showed a rapid decline in the first 3 years followed by a more steady transition for from 3 to 5 years irrespective of long term virological effect.     

Transient elastography in chronic hepatitis B: an Asian perspective

Transient elastography (TE) is a new non-invasive tool for assessing liver stiffness, which is correlated with the histologic stage of liver fibrosis. Many studies have reported a good accuracy of TE in predicting signif icant fibrosis and an optimal accuracy in predicting cirrhosis. Furthermore, the potential role of TE in screening the general population has also been proven. TE thus helps physicians to decide treatment strategies, predict prog-nosis, and monitor disease progression in patients with chron...