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。     

Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study

Summary. For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty‐six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e‐antigen (HBeAg)‐positive, 293 (69%) were HBeAg‐negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow‐up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow‐up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow‐up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow‐up ALT levels were independent significant factors associated with a decline in LSM.     

Dynamics of liver stiffness by transient elastography in patients with chronic hepatitis C virus infection receiving direct‐acting antiviral therapy—Results from the German Hepatitis C‐Registry

The impact of direct‐acting antiviral (DAA) therapies on fibrosis regression remains uncertain. In the current study, we prospectively evaluated dynamics of liver stiffness by transient elastography (TE) in patients with chronic HCV infection receiving DAA‐based treatment. Patients (260) were enrolled in the German Hepatitis C‐Registry (DHC‐R), a national multicentre real‐world cohort. Liver stiffness (LS) was assessed at baseline, end of treatment (EOT) and 24 weeks after EOT (FU24) by TE. Biochemical, virological and clinical data were obtained in parallel. In patients with SVR, there was a significant improvement of LS between baseline (median [range], 8.6 [1.7‐73.5] kPa) and FU24 (7.9 [1.7‐75 kPa]; P < .0001) as well as between EOT (8.4 [1.7‐73.5 kPa]) and FU24 [P < .0001]. Stratified by fibrosis stage, patients classified into F4 had higher magnitude of LS reduction between BL (median [range], 25.1 [13.5‐73.5] kPa) and FU24 (21.5 [3.1‐75] kPa; P = .002) compared to those with F2‐F3 (8.9 [7.1‐12.4] kPa and 8.8 [4.2‐29.1]; P = .060) or F0‐F1 (5.3 [1.7‐7] kPa and 5.2 [1.7‐7.7]; P = .064). In cirrhotic patients, low platelets were significantly associated with lack of liver stiffness improvement, both at EOT (P = .018) and at FU24 (P = .012). LS significantly correlated with ALT (r = .371), AST (r = .552), platelets (r = ?.499), GGT (r = .250), bilirubin (r = .230), APRI score (r = .512), FIB‐4 score (r = .517) and FORNS index (r = .562); P < .0001. Liver elastography improved significantly in our real‐world cohort after DAA‐based therapy. As LS correlates similarly with transaminase levels and serum fibrosis markers, it might reflect both reduction of necroinflammation and fibrosis regression.     

Estimation of liver fibrosis by noncommercial serum markers in comparison with transient elastography in patients with chronic hepatitis C virus infection receiving direct‐acting antiviral treatment

Treatment decisions are based on extent of fibrosis in patients with chronic hepatitis C (HCV) infection. Noninvasive diagnostic tools may help to avoid liver biopsy. We investigated the diagnostic accuracy of noncommercial serum scores in comparison with transient elastography (TE). Data analysis was undertaken based on 2458 patients enrolled in the German Hepatitis C Registry, in a prospective, observational study. Aspartate aminotransferase‐to‐platelet ratio index (APRI), FORNS index and FIB‐4 score were calculated and the diagnostic accuracy was compared to TE. As estimated by TE, 955 (38.9%) patients had absence of significant fibrosis (SF), 736 (29.9%) patients had SF, and 767 (31.2%) patients were shown to have cirrhosis. Patients with absence of SF had a sustained virological response (SVR) rate of 97.9%, whereas SVR was attained in 96.2% and 92.2% in those with SF and cirrhosis, respectively (P < 0.0001). The area under the receiver operator characteristic curve (AUROC), sensitivity and specificity in discriminating of SF were 0.789, 0.596 and 0.939 by APRI; 0.838, 0.852 and 0.748 by FORNS index; and 0.828, 0.658 and 0.946 by FIB‐4 score. AUROCs for the prediction of cirrhosis, sensitivity and specificity were 0.881, 0.851 and 0.854 by APRI; 0.846, 0.948 and 0.628 by FORNS index; and 0.907, 0.907 and 0.848 by FIB‐4 score. In conclusion, in the present multicentre real‐world cohort, SF and cirrhosis were predicted with high accuracy with noncommercial serum markers using TE as reference. Further prospective long‐term follow‐up is necessary to compare biomarkers with TE concerning liver‐related outcome and overall mortality.     

Usefulness of transient elastography for assessment of liver fibrosis in chronic hepatitis B: Regression of liver stiffness during entecavir therapy

Aim: The usefulness of transient elastography remains to be validated in chronic hepatitis B, particularly as a tool for monitoring the degree of liver fibrosis during treatment. Methods: The subjects were 50 patients with chronic hepatitis B virus infection. Liver biopsy was performed in 38 patients, and in 12 patients with platelet counts of 50 × 10⁹/L or less, cirrhosis was clinically diagnosed on the basis of specific signs of portal hypertension. Liver stiffness was measured by transient elastography at baseline and after 12 months of treatment in 20 nucleos(t)ide‐naïve patients who started entecavir within 3 months after study entry. Results: Twenty (40%) patients were classified as F1, 10 (20%) as F2, 5 (10%) as F3, and 15 (30%) as F4 (cirrhosis). Median liver stiffness (interquartile range) was 7.0 kPa (5.6–9.4), 9.8 kPa (5.6–14.7), 9.8 kPa (7.6–12.9), and 17.3 kPa (8.2–27.6) in fibrosis stages F1 to F4, respectively. Liver stiffness significantly correlated with fibrosis stage (r = 0.46; P = 0.0014). Of the patients who started entecavir, median liver stiffness significantly decreased from 11.2 kPa (7.0–15.2) to 7.8 kPa (5.1–11.9; P = 0.0090) during 12 months of treatment. Median levels of amino‐terminal peptide of type III procollagen and type IV collagen 7S domain in serum significantly decreased from 0.9 (0.6–1.3) to 0.6 (0.5–0.7) U/mL (P = 0.0010) and from 5.0 (4.4–6.7) to 3.9 (3.2–4.4) ng/mL (P = 0.015), respectively. Conclusion: Liver stiffness measurement can be useful for monitoring regression of liver fibrosis during entecavir treatment in patients with chronic hepatitis B virus infection.     

An evaluation of transient elastography in the discrimination of HBeAg-negative disease from inactive hepatitis B carriers

Summary.  Liver biopsy is frequently required in HBeAg-negative disease to determine the stage of fibrosis. It can be difficult to distinguish cohorts with undetectable HBeAg who may have varying degrees of fibrosis due to different stages of disease. We have assessed the utility of transient elastography (TE) to evaluate differences in HBeAg-negative patients. A total of 220 HBsAg-positive individuals were studied: 125 (group 1) had an inactive HBsAg carrier state and 95 (group 2) were HBeAg-negative, anti-HBe-positive patients with persistently or intermittent elevation of alanine aminotransferase (ALT) and/or HBV DNA >10⁵ copies/mL. Mean stiffness was 4.83 ± 1.2 kPa in group 1 vs 8.53 ± 6 kPa in group 2 ( P  <   0.001); statistically significant differences were also found between AST/ULN ALT/ULN ratios, HBV DNA in group 1 vs group 2, respectively ( P  <   0.001). In the multivariate analysis, the only variable independently associated with the stage of fibrosis was the stiffness. This study shows that mean hepatic stiffness by elastography is significantly lower in patients with inactive hepatitis B compared to those with HBeAg-negative disease. The procedure is a useful adjunct to diagnosis to confirm a clinical pattern of disease, and for more selective use of liver biopsy before considering antiviral therapy.     

Transient elastography for patients with chronic hepatitis B and C virus infection: Non-invasive, quantitative assessment of liver fibrosis

Aim/Methods: The aim of the present study was to compare the diagnostic performance of transient elastography (FibroScan) with that of serum fibrosis markers and stages of hepatic fibrosis by biopsy in 68 patients with chronic hepatitis B virus (HBV) and in 161 patients with hepatitis C virus (HCV) infection. Results: The serum levels of hyaluronic acid (r = 0.601) and type IV collagen (r = 0.663) significantly positively associated with the FibroScan values (all P < 0.05). Classified by fibrosis stages, the median values of FibroScan were 3.5 kPa for F0, 6.4 kPa for F1, 9.5 kPa for F2, 11.4 kPa for F3, and 15.4 kPa forF4 in patients with chronic HBV infection, and were 6.3 kPa for F0, 6.7 kPa for F1, 9.1 kPa for F2, 13.7 kPa for F3, and 26.4 kPa for F4 in those with chronic HCV infection. The values were significantly correlated with fibrosis stage for both (HBV, r = 0.559, P = 0.0093, and HCV, r = 0.686, P < 0.0001). Conclusion: These results suggest that FibroScan is an efficient and simple method for evaluating liver fibrosis in patients with chronic infection, both for HBV and HCV.     

The effect of caffeine and alcohol consumption on liver fibrosis – a study of 1045 Asian hepatitis B patients using transient elastography

Background: Role of caffeine consumption in chronic hepatitis B virus (HBV)‐infected patients and the interaction with alcohol consumption is unclear. Aim: This study aimed to investigate the relationship between caffeine and alcohol consumption and liver stiffness in chronic HBV‐infected patients. Methods: Chronic HBV‐infected patients who underwent transient elastography examination in 2006–2008 were studied. Advanced fibrosis was defined as liver stiffness >9 kPa for patients with normal alanine aminotransferase (ALT) or >12 kPa for those with elevated ALT according to previous validation study. Caffeine and alcohol consumption was recorded using a standardized questionnaire. Excessive alcohol intake was defined as 30 g/day in men and 20 g/day in women. Results: The liver stiffness of 1045 patients who completed the questionnaire was 8.3 ± 6.2 kPa. Two hundred and sixteen (20.7%) patients had advanced fibrosis. Ninety‐five (19.0%) patients who drank ≥1 cup of coffee had advanced fibrosis, compared with 121 (22.2%) patients who drank <1 cup (P=0.21). The amount of caffeine intake had positive correlation with the amount of alcohol intake (r_s=0.167, P<0.001). Although 231 (22.1%) patients reported alcohol consumption, only 11 (1%) had excessive alcohol intake. The prevalence of advanced fibrosis among patients with mild to moderate alcohol intake (26, 18.8%) was comparable to that among non‐drinkers (190, 21.0%) (P=0.57). Conclusion: Caffeine intake does not affect liver stiffness in chronic HBV‐infected patients. Patients who drink coffee regularly tend to drink alcohol. Most chronic HBV‐infected patients do not have excessive alcohol consumption. The prevalence of advanced fibrosis among mild to moderate alcohol drinkers was low in this population.     

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.     

The usefulness of liver stiffness measurement using FibroScan in chronic hepatitis C in South Korea: a multicenter, prospective study

Aim: We investigated the accuracy of liver stiffness measurement (LSM) in chronic hepatitis C (CHC) in a multicenter, prospective study in South Korea. Methods: Between June 2005 and July 2009, 91 CHC patients without a previous history of antiviral treatment, clinical evidences of cirrhosis, coinfection with other viruses, and heavy alcohol consumption and with alanine aminotransferase (ALT) ≤ 5x upper limit of normal, total bilirubin ≤ 1.5 mg/dL, sufficient liver biopsy quality (≥ 15 mm and more than six portal tracts), interquartile range to median liver stiffness (LS) value ratio ≤ 0.21, and more than 10 valid measurements, were recruited. The Batts and Ludwig scoring system was used for histologic assessment. Age–platelet index (API), aspartate aminotransferase (AST)–to–platelet ratio index (APRI), and age–spleen–platelet ratio index (ASPRI) were calculated. Area under the receiver operating characteristic curve (AUROC) was used to evaluate the performance of LSM and other noninvasive models. Results: The mean age was 47.9 years, and the mean LS value was 7.7 kPa (44 men and 47 women). LS value was highly correlated to the fibrosis stages (r = 0.835, P < 0.001). The AUROCs of LSM were 0.909 for ≥ F2, 0.993 for ≥ F3, and 0.970 for F = 4 and were superior to those of API (0.72, 0.858, and 0.948, respectively), APRI (0.780, 0.887, and 0.904, respectively), and ASPRI (0.713, 0.862, and 0.957, respectively). The optimal cutoff LS values were 6.2 kPa for ≥ F2, 7.7 kPa for ≥ F3, and 11.0 kPa for F = 4. Conclusions: Our data suggest that LSM can accurately assess liver fibrosis in patients with CHC and be applied in South Korea.     

Non‐invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B

Background: The need for new non‐invasive tools to assess liver fibrosis in chronic liver diseases has been largely advocated. Liver stiffness measurement (LSM) using transient elastography (FibroScan^®, Echosens^?) has been shown to be correlated to liver fibrosis in various chronic liver diseases. This study aims to assess its diagnosis accuracy in patients with chronic hepatitis B. Patients and methods: We prospectively enrolled 202 patients with chronic hepatitis B in a multicentre study. Patients underwent liver biopsy (LB) and LSM. METAVIR and Ishak liver fibrosis stages were assessed by two pathologists. Results: LSM or LB was considered unreliable in 29 patients. Statistical analysis was conducted in 173 patients. LSM was significantly (P<0.001) correlated with METAVIR (r=0.65) and Ishak fibrosis stage (0.65). The area under receiver‐operating characteristic curves were 0.81 (95% confidence intervals, 0.73–0.86) for F≥2, 0.93 (0.88–0.96) for F≥3 and 0.93 (0.82–0.98) for F=4. Optimal LSM cut‐off values were 7.2 and 11.0 kPa for F≥2 and F=4, respectively, by maximizing the sum D of sensitivity and specificity, and 7.2 and 18.2 kPa by maximizing the diagnosis accuracy. Conclusion: In conclusion, LSM appears to be reliable for detection of significant fibrosis or cirrhosis in HBV patients and cut‐off values are only slightly different from those observed in HCV patients.     

HBV DNA阳性慢性重型乙型肝炎的抗病毒疗效分析

目的：探讨核苷类抗病毒药治疗对HBV DNA阳性慢性重型乙型肝炎患者短期生存率的影响及不同药物的疗效差异。方法：将入院时432例HBV DNA阳性的慢性重型乙型肝炎患者分为两组：230例为抗病毒组（根据服用不同抗病毒药又分为3组）,202例为对照组。比较两组患者治疗12周的生存率及总胆红素（TBil）、凝血酶原活动度（PTA）、HBV DNA转阴率的差异,同时比较不同抗病毒药物治疗12周的生存率差异和生化指标及HBV DNA阴转的差异。结果：①治疗12周生存率抗病毒组为70.70%,对照组为58.50%,两组比较差异有显著性意义（P〈0.05）。②治疗12周HBV DNA阴转率,抗病毒组为69.06%（96/139）,对照组为32.29%（31/96）,两组比较差异有显著性意义（P〈0.01）。③不同抗病毒药物中12周生存率,恩替卡韦组为73.30%,拉米夫定组70.50%,替比夫定组67.70%,3种药物比较差异无显著性意义（P〉0.05）。④治疗12周时患者TBil、PTA、HBV DNA转阴率拉米夫定组分别为（83.63±99.47）μmol/L、（58.57±16.69）%、65.08%,替比夫定组分别为（102.33±113.58）μmol/L、（55.61±15.98）%、69.23%,恩替卡韦组分别为（70.66±108.86）μmol/L、（57.46±17.12）%、74.00%。3组比较差异均无显著性意义（P〉0.05）。结论：抗病毒治疗可以改善慢性重型乙型肝炎的预后及肝功能,常用的3种核苷类药物疗效的差异无统计学意义。     

Impact of liver steatosis on the antiviral response in the hepatitis C virus-associated chronic hepatitis.

BACKGROUND/AIM: Liver steatosis (LS) has been variably associated with chronic hepatitis C (CHC) but whether it affects sustained virological response to antiviral treatment and by what mechanisms is a question still under debate, at least for some genotypes. The aim of this work was to assess the frequency of LS, its relationship with host and viral factors and to what extent it can influence the response to antiviral combination therapy with pegylated interferon (INF)+ribavirin in a group of patients with CHC from a single center. PATIENTS: One hundred and twelve patients with histologically proven CHC were treated with Peg INF-alpha 2a 180 microg a week subcutaneously for 48 weeks plus ribavirin 1000 or 1200 mg/day, according to the patient's body weight. Steatosis was graded according to Brunt et al. RESULTS: Forty-six out of 112 patients (41.1%) were sustained virological responders (SVR). Seventy-two out of 112 (64.3%) presented with LS at histology; in this group, there were 24 patients (33.3%) with SVR compared with 22 (55%) of the non-steatosis group (chi(2)=6.5, P<0.02). Variables associated with the steatosis group were: higher serum levels of AST (P<0.04), alanine aminotransferase (P<0.02), gamma-GT (P<0.004), genotype 3a (P<0.03) and severity of histology (staging P<0.05) but at multiple linear regression analysis only genotype 3a and staging were significantly associated with LS. In the SVR group, age and body mass index (BMI) were significantly lower (P<0001 and P<0.03, respectively) compared with non-responders; moreover, genotype 1 was more frequent in the NR group, while genotype 3 was more frequent in the SVR group. At histology, grading and staging were also lower in the SVR group. Multiple logistic regression showed that only the grade of steatosis and genotype 3a were the variables independently associated with SVR. CONCLUSIONS: This study showed a frequency of LS on the higher side of the range so far reported in the literature and confirmed that it negatively influences response to therapy. Genotype1 was confirmed to be the most frequent type in our area. It is more frequent in patients with mild-moderate steatosis and seems to condition therapeutic response negatively, together with BMI and age. In contrast, genotype 3a is more frequent in patients with severe steatosis, but is a favorable predictor of successful therapy.