持续丙氨酸氨基转移酶正常乙型肝炎肝硬化的临床分析

目的探讨持续ALT正常乙型肝炎肝硬化患者的肝组织病理特征及其相关因素,为临床诊断及治疗提供参考。方法选取2005年1月-2012年12月住院的乙型肝炎肝硬化患者68例,对所有患者进行肝组织病理学检查,分析肝组织病理改变程度与患者年龄、HBV DNA载量、ALT水平的相关性。结果 30岁的肝组织病变以轻度为主,≥30岁且40岁者以中度病变为主,≥40岁者以重度病变为主(P0.05);当HBV DNA载量5×105拷贝/ml时,以重度改变为主(P0.05);ALT水平为0~20 U/L时肝组织以轻度病理改变为主,20~30 U/L以中度病理改变为主,30~40 U/L以重度病理改变为主(P0.05)。结论对ALT持续正常的肝硬化患者,应结合其年龄、HBV DNA载量及ALT水平综合评估,40岁以上、HBV DNA载量5×105拷贝/ml、ALT水平在30~40 U/L的患者,应行肝组织活检以明确疾病有无进展,即使不做肝组织活检,也应予以合理的抗病毒治疗。     

Fibrosis progression rates between chronic hepatitis B and C patients with elevated alanine aminotransferase levels

BACKGROUND: We evaluated the annual rate of fibrosis progression in chronic hepatitis B and C patients with elevated alanine aminotransferase (ALT) levels. METHODS: Forty-nine chronic hepatitis B patients and 21 chronic hepatitis C patients, each of whom had undergone two or more liver biopsies at an interval of more than 1 year, were enrolled in this retrospective clinical research protocol. The annual rate of fibrosis progression was calculated by dividing the change in fibrosis stage between the first and second liver biopsies by the interval in years between them. RESULTS: The median interval in chronic hepatitis B and C was 3.4 (first and third quartiles, 1.8-4.7) and 3.2 (2.1-6.5) years, respectively. Overall, the mean fibrosis progression rate was 0.21 +/- 0.31 (mean +/- SD) fibrosis units (FU) per year in 49 patients with chronic hepatitis B, and 0.13 +/- 0.18 FU/year in 21 patients with chronic hepatitis C. The ALT level was an independent variable correlating with fibrosis progression. In patients whose median ALT level was 70 IU/l or more, the mean fibrosis progression rate was 0.28 +/- 0.32 FU/year in 36 patients with chronic hepatitis B, and 0.22 +/- 0.23 FU/year in eight patients with chronic hepatitis C. CONCLUSION: This paired-biopsy study of untreated chronic hepatitis B or C demonstrated that fibrosis progression occurred largely in patients with continuously elevated ALT levels even over a relatively short period, and that liver fibrosis might progress by one stage within an average of 4-5 years of follow-up in patients with elevated ALT of 70 IU/l or more.     

A novel liver stiffness measurement‐based prediction model for cirrhosis in hepatitis B patients

Backgrounds/aims: While liver stiffness measurement (LSM) predicts histological cirrhosis accurately, complementary methods are needed for better performance. Furthermore, alanine aminotransferase (ALT) influences LSM, making it necessary to modify its use in patients with high ALT levels. We developed a new LSM‐based prediction model for cirrhosis and estimated the thresholds for different ALT levels. Methods: From 2008 to 2009, we prospectively enrolled 330 consecutive patients who were diagnosed with chronic hepatitis B (CHB) and underwent a liver biopsy and LSM on the same day. For detection of cirrhosis, we performed univariate and multivariate analyses, using the χ²‐test/t‐test and logistic regression respectively. Thereafter, a prediction model was derived from multivariate predictors. Results: In multivariate analyses of patients with and without cirrhosis, we found significant differences in the LSM, spleen diameter and platelet count. Then, we developed an LSM–spleen diameter to platelet ratio index (LSPI): (LSM × spleen diameter/platelet count) × 100. The area under the receiver operating curve was 0.956, significantly higher than LSM alone (0.919, P=0.032). We suggested different thresholds in patients with ALT≤upper limit of normal (ULN) (normal‐ALT group, 164 patients) and ALT>ULN (high‐ALT group, 166 patients). In the normal‐ALT group, LSPI thresholds of 38 and 62 provided 95.7% negative predictive value (NPV) and a 95.5% PPV (positive predictive value), while in the high‐ALT group, thresholds of 42 and 94 yielded 95.1% NPV and 96.4% PPV respectively. Therefore, liver biopsy could be avoided in 76.7% of the subjects. Conclusions: LSPI is a useful, non‐invasive tool that can replace liver biopsy in the assessment of liver fibrosis in the majority of CHB patients.     

Antiviral therapy for hepatitis B virus‐related decompensated cirrhosis

Antiviral therapy is important in patients with hepatitis B virus (HBV)‐related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child–Pugh or model for end‐stage liver disease (MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is the first‐line therapy for nucleos(t)ide analogue (NA)‐naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug‐resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma (HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug‐resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV‐related cirrhosis and a long‐term follow‐up in China, where a large number of such patients are found, are recommended.     

Usefulness of albumin‐bilirubin grade for evaluation of long‐term prognosis for hepatitis B‐related cirrhosis

Long‐term prognosis varies widely among patients with hepatitis B virus (HBV)‐related liver cirrhosis. Our study aimed to investigate the applicability of albumin‐bilirubin (ALBI), Child‐Pugh and model for end‐stage liver disease (MELD) scores to the long‐term prognosis prediction of HBV‐related cirrhosis. Patients diagnosed with HBV‐associated cirrhosis from the First Affiliated Hospital of Wenzhou Medical University between January 2010 and December 2015 were enrolled in this study. The patients were followed up every 3 months. The prognostic performance of ALBI in long‐term outcome prediction for HBV‐related cirrhosis was compared with Child‐Pugh and MELD scores using time‐dependent receiver operating characteristic curve (tdROC) and decision curve analysis. A total of 806 patients were included in our study with 275 (34.1%) deceased during the follow‐up. Multivariate Cox regression analysis showed that ALBI grade was an independent predictor associated with mortality. The tdROC analysis showed that ALBI score (0.787, 0.830 and 0.833) was superior to MELD (0.693, P=.003; 0.717, P<.001; 0.744, P<.001) and Child‐Pugh score (0.641, P<.001; 0.649, P<.001; 0.657, P<.001) for predicting 1‐year, 2‐year and 3‐year mortality. Additionally, decision curves also got the similar results. In addition, patients with lower ALBI score had a longer life expectancy, even among patients within the same Child‐Pugh class. Thus, ALBI score was effective in predicting the long‐term prognosis for patients with HBV‐related cirrhosis and more accurate than Child‐Pugh and MELD scores.     

Long‐term therapy for chronic hepatitis B: Hepatitis B virus DNA suppression leading to cirrhosis reversal

Since the licensing of the first treatment for chronic hepatitis B in the nucleoside/tide analog class almost 15 years ago, considerable progress has been made in improving drug efficacy and safety with highly potent nucleoside/tide analogs exhibiting a high barrier to resistance. Physicians are now able to treat patients safely for many years and to be able to see convincing improvements in histology, including regression of fibrosis and even reversal of cirrhosis. The robust data that have been generated help us build confidence that we can now offer patients with chronic hepatitis B long‐term, disease‐modifying therapy that can alter the natural course of disease and help prevent the morbidity and mortality associated with it.     

The gamma‐glutamyl transpeptidase‐to‐albumin ratio predicts significant fibrosis and cirrhosis in chronic hepatitis B patients

Background/Aim Simple, inexpensive and clinically available noninvasive liver fibrosis tests are highly needed. We aimed to develop a novel noninvasive index for predicting significant fibrosis and cirrhosis in chronic hepatitis B (CHB) patients. Methods Using liver histology as gold standard, we developed a novel index to predict significant fibrosis and cirrhosis in CHB patients and then compared the diagnostic accuracy of the novel index, aspartate transaminase‐to‐platelet ratio index (APRI), and fibrosis index based on four factors (FIB‐4) in a training set (606 patients) and a validation set (216 patients) from the same patient catchment area. Results Of 606 CHB patients in the training set, 33.2% had significant fibrosis and 11.4% had cirrhosis. In multivariable analysis, gamma‐glutamyl transpeptidase (GGT) (OR=1.032, p<0.001) and albumin (OR=0.953, p=0.048) were independent predictors of significant fibrosis. Consequently, a GGT‐to‐albumin ratio (GAR) was developed. In the training set, the area under the receiver operating characteristic curve (AUROC) of GAR was significantly higher than that of APRI and FIB‐4 to predict ≥F2 (0.82, 0.70, and 0.68, respectively), ≥F3 (0.86, 0.76, and 0.75, respectively), and F4 (0.88, 0.75, and 0.73, respectively), respectively. In the validation set, the AUROC of GAR was also better than APRI and FIB‐4 for predicting ≥F2 (0.81, 0.63 and 0.61, respectively), ≥F3 (0.88, 0.78, and 0.76, respectively) and F4 (0.92, 0.85, and 0.78, respectively), respectively. Conclusions GAR is a more accurate noninvasive index than APRI and FIB‐4 to stage significant fibrosis and cirrhosis in CHB patients and represents a novel noninvasive alternative to liver biopsy.     

Hepatitis B virus DNA in patients with hepatitis B‐related liver cirrhosis with or without hepatocellular carcinomas: a matched case‐control study

OBJECTIVE: The relationship between serum viremia and the development of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)‐related cirrhosis remains unclear. We aimed at calculating odds ratios (OR) for the presence of HCC over a range of HBV DNA levels in these patients. METHODS: Patients were identified retrospectively and 155 pairs of matched, treatment‐naive HBV‐related cirrhotic patients with and without HCC were recruited. Their serum HBV DNA levels were measured at HCC diagnosis, or at the equivalent age in non‐HCC patients, and correlations between the presence of HCC and different DNA levels were calculated using conditional logistic regression. RESULTS: The median HBV DNA level was significantly higher in HCC patients than in non‐HCC patients (5.15 vs 4.83 log₁₀ copies/mL, P = 0.024). The overall OR for HCC in patients with HBV DNA ≥ 3 log₁₀ copies/mL was 2.13, compared with patients with levels <3 log₁₀ copies/mL. Compared with patients with <3 log₁₀ copies/mL, the OR for HCC were 2.39 and 2.61 for patients with 4 to <5 and 5 to <6 log₁₀ copies/mL, respectively, while the OR for DNA levels of ≥6 log₁₀ copies/mL were not significantly different. CONCLUSION: In HBV‐related cirrhosis, a detectable serum HBV DNA was associated with the presence of HCC, but the likelihood of having HCC did not successively increase with increasing serum HBV DNA levels: patients with serum HBV DNA levels between 4 and <6 log₁₀ copies/mL were most likely to present with HCC.     

Seropositivity for delta hepatitis in patients with chronic hepatitis B and liver cirrhosis in Turkey: a meta‐analysis

Background: Recent reports suggest a decline of delta hepatitis (DH) in the West as well as in the Far East. Aim: To study the DH seroepidemiology in Turkey. Methods: Statistical power analysis was utilized based on data available in a recent article using prevalence figure estimates. Binominal distribution was applied in order to assess the number of samples required to estimate the prevalence with a given precision. Results: Out of 62 studies in the original study, 32 were eliminated because of insufficient power. A total of 6734 patients (5231 with chronic hepatitis and 1503 with cirrhosis) were analysed. Anti‐HDV seropositivity among patients with chronic hepatitis B (CHB) and hepatitis B‐induced cirrhosis was lowest in the west of the country and highest in the southeast (5 vs. 27%, P<0.0001 and 20 vs. 46%, P<0.0001) respectively. Compared with data obtained before 1995, after 1995, DH prevalence in patients with CHB and cirrhosis decreased from 29 to 12% (P<0.0001) and from 38 to 27% (P=0.03) in central and southeast Turkey and from 38 to 20% (P<0.0001) and from 66 to 46% (P<0.002) in west and southeast Turkey respectively. Conclusion: Despite the decrease of its prevalence in Turkey, DH remains a significant health problem in parts of the country with low socio‐economic level.     

A higher alanine aminotransferase level correlates with earlier hepatitis B e antigen seroconversion in lamivudine‐treated chronic hepatitis B patients

Background/Aims: A pretherapy serum alanine aminotransferase (ALT) level above five times the upper limit of normal (ULN) is known to predict hepatitis B e antigen (HBeAg) seroconversion during lamivudine therapy for chronic hepatitis B patients. However, whether an even higher pretherapy serum ALT value or other viral factors could affect treatment responses remains unclear. Patients and methods: A total of 253 HBeAg‐positive chronic hepatitis B patients who had a pretherapy serum ALT level over five times ULN and received lamivudine for 12–18 months were retrospectively collected. Among these patients, 38% had received prior lamivudine treatment. HBeAg seroconversion was the primary endpoint of treatment. Baseline clinical and viral features were compared between responders and non‐responders at the end of treatment and 6 months post‐treatment. Results: At the end of therapy, the overall HBeAg seroconversion rate was 33.6%. For lamivudine‐naïve patients, the HBeAg seroconversion rate was 37.8%. Subgroup analysis showed that patients with pretherapy ALT levels over 10 times ULN had a significantly higher HBeAg seroconversion rate than those with a pretherapy ALT level between five and 10 times ULN at 3 months (P=0.045) and 6 months (P=0.037) of lamivudine treatment. No significant difference was found in terms of pretherapy serum ALT values, viral load and genotypes between seroconverters and non‐seroconverters. Conclusions: For lamivudine‐treated HBeAg‐positive patients with pretherapy ALT levels over five times ULN, an even higher ALT level could predict earlier HBeAg seroconversion; however, neither ALT levels nor viral factors correlate with higher response rates after 12–18 months of treatment.     

Predictive value of aminotransferase and hepatitis B virus DNA levels on response to interferon therapy for chronic hepatitis B

In a previously reported randomized controlled trial of interferon-α (IFN-α) for chronic hepatitis B, we found a significant difference in response between Chinese adults with elevated vs normal pretreatment aminotransferase (ALT) levels. The aim of this study was to determine the correlation between serum hepatitis B virus (HBV) DNA levels and response to IFN therapy. HBV DNA levels in residual stored sera from patients who participated in the above trial were quantified by a branched DNA (bDNA) assay. Nominal logistic regression was used to estimate the probability of response to IFN treatment as a function of pretreatment ALT and/or HBV DNA levels. We found a significant ( P <0.01) correlation between the HBV DNA levels at midtreatment and response to IFN therapy. Response was achieved in 53% of patients who had undetectable HBV DNA levels at midtreatment but in only 17% of those who remained HBV DNA positive ( P <0.01). In contrast, the probabilities of response for patients with baseline HBV DNA levels over the range 10 to 10000 million equivalents (MEq)ml^–1 were almost identical. We also found a significant correlation between the pretreatment ALT levels and response to IFN therapy. The probabilities of response for patients with pretreatment ALT levels of 500 and 100IUl^–1 were higher than for patients with normal ALT levels by two and onefold, respectively. Our findings may help to improve the cost-effectiveness of IFN therapy for chronic hepatitis B by guiding the selection of patients for therapy and in optimizing the duration of treatment for the individual patient.     

Histological improvement of long‐term antiviral therapy in chronic hepatitis B patients with persistently normal alanine aminotransferase levels

The aim of this study was to evaluate the histological outcomes of chronic hepatitis B (CHB) patients with persistently normal alanine aminotransferase (ALT) levels after long‐term antiviral therapy. Paired liver biopsies before and after lamivudine (LAM) treatment in CHB patients with normal and elevated ALT levels were compared. Histological response was defined as a 1‐point decrease according to the Scheuer scoring system, without worsening of fibrosis between pretreatment and posttreatment biopsies. Among the 48 patients who underwent paired liver biopsies, 17 had persistently normal baseline ALT level and 31 had elevated ALT level. The median age of the patients was 44 years and 72.9% of the patients were male. The median duration of antiviral treatment was 44.5 months (range 14–104). Long‐term follow‐up of liver biopsies revealed that 82.4% of patients in the normal ALT group and 61.3% in the elevated ALT group had a baseline fibrosis score of 4, which was reduced to 17.6% and 38.7% after long‐term therapy, respectively, indicating reversal of cirrhosis in a large proportion of both groups, especially in patients with normal baseline ALT levels. Long‐term antiviral treatment could achieve significant histological improvement in CHB patients with fibrosis or cirrhosis, regardless of ALT level.