关于血清丙氨酸氨基转移酶水平正常值上限标准的探讨

最近,美国肝病研究学会的Kim等~[1]总结了ALT的生理学特征以及在健康及疾病状态下的临床意义,强调ALT不仅是肝脏疾病敏感可靠的指标,而且对全身性疾病,特别是肥胖、代谢综合征和心血管疾病也有较高的预测价值.     

Upper limit of normal serum alanine and aspartate aminotransferase levels in Korea

Background and Aim: The widely accepted range of upper limits of normal (ULN) alanine aminotransferase (ALT) levels (ULN < 40 U/L) was recently challenged by several reports. Both ALT and aspartate aminotransferase (AST) are commonly used as surrogate markers of liver disease, but almost all studies of aminotransferase activity were conducted on ALT. We investigated not only ULN of ALT but also AST activity and to identify factors modulating them in healthy Korean. Methods: A cross‐sectional study of 411 240 registered blood donors in all nationwide blood banks belonging to the Korean Red Cross were conducted. ULN of ALT and AST was evaluated adjusting their age according to the national population census database. “Decision tree model” was used to identify the affecting factors of ALT and AST and optimal cut‐off points of affecting factors. Results: “ULN of ALT” was 34 U/L in men and 24 U/L in women and “ULN of AST” was 32 U/L in men and 26 U/L in women in the blood donor database. Decision tree analysis showed that ALT levels were mostly influenced by body mass index level and its critical two cut‐off points were 23.5 kg/m² and 25.8 kg/m², respectively. The most affecting factor of AST was gender. Conclusion: Upper limits of normal of ALT and AST in Koreans were lower than conventional accepted values (< 40 U/L) but higher than recently suggested values (male < 30 U/L and female < 19 U/L). Body mass index was the most determining factor for ALT and gender was the most influencing factor for AST activity.     

血清ALT与慢性乙型肝炎、肝硬化FibroScan 弹性值动态检测结果的相关性

目的探讨肝脏弹性值（LSM）在慢性乙型肝炎发作过程中的变化及ALT对LSM影响。方法 43名慢性乙型肝炎感染者,包括慢性乙型肝炎（CHB）23人、肝炎肝硬化（LC）20人;入院时行腹部B超检查,住院期间每7～10天、出院后每1～3月行Fibroscan（FS）检测,同时行常规血液指标化验。结果 CHB组中LSM与ALT有显著相关性（r=0.324,P=0.004）,偏相关分析提示LSM与ALT无统计学相关性（r=0.190,P=0.098）;随ALT下降,LSM逐渐降至诊断肝硬化界值14.6 kPa以下,呈现持续下降、先升后降或下降后波动等三种模式。LC组中,LSM与ALT无统计学相关性;在ALT好转的11例中,LSM较入院当天下降（P=0.003）,但仍高于肝硬化临界值。结论在非肝硬化CHB患者中,LSM受ALT水平影响较大。动态观察单一患者ALT与LSM变化,可能提高LSM预测肝纤维化准确性。     

Prevalence and etiology of elevated serum alanine aminotransferase level in an adult population in Taiwan

BACKGROUND: The prevalence and etiologies of elevated alanine aminotransferase (ALT) have geographic variations and they are rarely reported in Taiwan. Through a population-based screening study, the prevalence and etiologies of elevated ALT in an adult population of Taiwan were assessed. METHODS: A cross-sectional community study in a rural village of Taiwan was conducted in 3260 Chinese adults (age >or=18 years) undergoing ultrasonography (US), blood tests, and interviews with a structured questionnaire. The diagnostic criteria of non-alcoholic fatty liver disease (NAFLD) included alcohol intake <20 g/week for women or <30 g/week for men, negative hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, no known etiologies of liver disease, and US consistent with fatty liver. RESULTS: The prevalence of elevated ALT was 11.4% (372/3260). The probable cause of this elevation was excess alcohol consumption in 0.8%, HBV in 28.5%, HCV in 13.2%, both HBV and HCV in 2.2%, NAFLD in 33.6%, and unexplained cause in 21.8%. The etiologic distribution of elevated ALT was similar in both genders, although elevation was more common in men compared to women (17.3%vs 6.1%, P < 0.05). The prevalence of elevated ALT in NAFLD was 18.1% (125/691), and the positive predictive value was 33.6% (125/372). The development of NAFLD was related to increasing age (age between 40 years and 64 years, odds ratio [OR] 1.59, 95% confidence interval [CI]: 1.25-2.01; age >or= 65 years, OR 1.46, 95%CI: 1.08-1.96), fasting plasma glucose (FPG) >or= 126 mg/dL (OR 1.54, 95%CI: 1.11-2.14), body mass index (BMI) >or= 25 kg/m(2) (OR 5.01, 95%CI: 4.13-6.26), triglyceridemia >or= 150 mg/dL (OR 1.96, 95%CI: 1.58-2.42), and hyperuricemia (OR 1.50, 95%CI: 1.22-1.84). Elevated ALT was related to male gender, BMI >or= 25 kg/m(2), and triglyceridemia >or= 150 mg/dL in subjects without known etiologies of liver disease (all P < 0.05). CONCLUSIONS: Non-alcoholic fatty liver disease appears to be the commonest cause of elevated ALT and presumed liver injury in Taiwan. The development of NAFLD is closely associated with many metabolic disorders. Metabolic disorders are also related to elevated ALT in subjects without known etiologies of liver disease.     

Increased hepatic expression is a major determinant of serum alanine aminotransferase elevation in mice with nonalcoholic steatohepatitis

Background: Serum alanine aminotransferase (ALT) is a biomarker for hepatitis of various aetiologies including fatty liver disease. Increased serum ALT is thought to be related to its increased release from dying hepatocytes. Aim: We sought to understand the mechanisms by which serum ALT is elevated in a mouse model of experimental fatty liver disease where hepatocyte death is minimal. Methods: To induce fatty liver disease, female A/J mice were fed a methionine‐choline deficient (MCD) diet for up to 12 weeks. Serum and liver ALT expression and hepatic inflammation, necrosis and apoptosis were assessed and expressed relative to their expressions in control‐diet‐fed mice. Results: Feeding mice the MCD diet produced hepatic steatosis with minimal hepatic inflammation or necrosis. Liver cell apoptosis was not significantly increased by MCD diet treatment. Conversely, serum ALT activity was approximately four‐fold increased at 12 weeks of diet treatment, and ALT protein expressions in serum were correspondingly increased: ALT1 1.7‐fold and ALT2 1.9‐fold at 12 weeks. The expressions of ALT1 and ALT2 protein in liver increased over 2–12 weeks of MCD treatment. At 12 weeks, liver ALT1 protein was 2.27±0.31‐fold increased and ALT2 protein 4.72±0.48‐fold increased relative to their expressions in the mice fed a diet replete with methionine and choline. Liver ALT mRNA expressions were correspondingly increased: ALT1 mRNA 2.58‐fold and ALT2 mRNA 4.97‐fold at 12 weeks. Linear regression analysis showed a strong correlation between serum and liver tissue expressions for both ALT1 and ALT2. Conclusions: These findings suggest that induction of hepatic expression significantly contributes to increased serum ALT in this model of experimental fatty liver disease, whereas cell death appears not to.     

Metabolic syndrome and alanine aminotransferase: a global perspective from the NAVIGATOR screening population

Aims Non‐alcoholic fatty liver disease (NAFLD) is associated with features of the metabolic syndrome (MetS) and may be an expression of the syndrome within the liver. Using screening data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study (n = 42 149), we examined whether alanine aminotransferase (ALT), a biomarker for NAFLD, clustered with features of MetS and whether the clusters differed across global geographic regions. Methods Exploratory factor analysis using principle components analysis was applied to data drawn from the NAVIGATOR screening population (n = 41 111). Demographic data, anthropomorphic measurements and blood pressure (BP) collected during the screening visit, as well as blood samples analysed for ALT, total cholesterol, triglycerides, high‐density lipoprotein, low‐density lipoprotein, and fasting and 2‐h glucose measures after an oral glucose tolerance test were used for our analysis. Results Two factors, interpreted as lipid (Factor 1), and BP/obesity (Factor 2) were identified, explaining approximately 50% of the variance in the overall population. Similar patterns of aggregation were reproducible across all geographic regions except Asia, where fasting glucose loaded more consistently on Factor 1. ALT loaded with mean arterial pressure, fasting glucose and waist circumference except in Asia, where it loaded only with mean arterial pressure and waist circumference. Conclusions ALT aggregated with components of MetS, and the pattern of aggregation of ALT with other features of MetS was similar across regions except Asia, possibly indicating a different pathophysiology for NAFLD in Asia. Predictive models of NAFLD may need to be adjusted for regional and ethnic differences.     

Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin

Pegylated interferon (Peg‐IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg‐IFN alpha‐2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan–Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60–64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.     

A prospective study on the causes of notably raised alanine aminotransferase (ALT)

Objective High levels of alanine aminotransferase (ALT) can be a marker of severe liver disease with variable aetiologies and prognosis. Very few prospective studies have been undertaken on the aetiology and prognosis of patients with high ALT levels. No population-based prospective study has systematically evaluated drug-induced liver injury (DILI) among these patients. The objective was to determine the aetiology and prognosis of patients with high ALT. Materials and methods In a catchment area of 160,000 inhabitants, a population-based prospective study identified all adult patients with serum level of ALT?>500 U/L during a 12-month period. All underwent thorough diagnostic work-up and follow-up. In suspected DILI, causality was assessed with Roussel Uclaf Causality Assessment Method. Results A total of 155 patients were identified with ALT?>500 U/L, 12 children and one with ALT of non-liver-related origin, leaving 142 patients for the analysis: 73 (51%) males, median age 52 (IQR 36–68, range 19–89 years). The most common causes were choledocholithiasis 48/142 (34%), ischaemic hepatitis 26 (18%), viral hepatitis 16 (11%) and DILI 15 (11%), hepatobiliary malignancy (n?=?6), surgery/interventions (n?=?8) and other aetiologies (n?=?23). No specific aetiology was found in 6% of cases. In the total study cohort 99 (70%) required hospitalisation, 78 (55%) had jaundice and 22 (16%) died, liver-related death in 10%, 35% in IH and 7% in DILI. Conclusions The most common cause of notably high ALT was choledocholithiasis. Ischaemic hepatitis was a common aetiology with approximately 35% liver-related mortality. Viral hepatitis and DILI were important aetiologies among these patients.     

ALT正常的HBeAg阳性高病毒载量慢性HBV感染者明显肝组织学改变的独立预测因素

目的探索ALT正常的HBe Ag阳性高病毒载量慢性HBV感染者明显肝组织学改变(SLHC)的独立预测因素。方法回顾性分析2013年6月-2015年8月于复旦大学附属公共卫生临床中心住院的116例初治ALT正常的(50 U/L)HBe Ag阳性高病毒载量(HBV DNA≥105拷贝/ml)慢性HBV感染者临床资料。SLHC定义为炎症≥G2和(或)纤维化≥S2。计量资料组间比较采用t检验或Mann-Whitney U秩和检验,计数资料组间比较采用χ~2检验。采用单因素、多因素回归分析筛查SLHC的独立预测因素。结果 116例患者中47例(40.5%)伴SLHC。多因素分析发现年龄、ALT和GGT是ALT正常的HBe Ag阳性高病毒载量慢性HBV感染者伴SLHC的独立预测因素(比值比分别为2.828、1.011、1.089,P值均0.05)。年龄≤30岁患者SLHC发生率低于年龄30岁患者(21.6%vs 49.4%,χ~2=6.42,P=0.015);ALT≤30 U/L患者SLHC发生率低于30 U/LALT≤50 U/L组(17.6%vs 50.0%,χ~2=19.86,P0.001);GGT≤40 U/L患者SLHC发生率低于GGT40 U/L组(28.8%vs 66.7%,χ~2=28.63,P=0.002)。结论 ALT正常的高病毒载量HBe Ag阳性慢性HBV感染者中,年龄30岁、ALT30 U/L、GGT40 U/L的患者伴SLHC的可能性更大,更加迫切需要肝穿刺病理组织学评估。     

Persistently normal alanine aminotransferase levels in HIV/HCV-coinfected patients: the role of steatosis

Objective

The frequency and significance of, and liver biopsy findings associated with, a persistently normal alanine aminotransferase (ALT) level in HIV/hepatitis C virus (HCV)‐coinfected patients are poorly characterized. We analysed factors associated with persistently normal ALT levels, defined as at least three consecutive normal ALT values over a 6‐month period, in a group of 381 HIV/HCV‐coinfected patients.

Methods

Patients were categorized into two groups according to ALT values: group 1, patients with persistently normal ALT levels; and group 2, patients with elevated ALT values. Possible interactions with host factors, HIV and HCV viral factors, antiretroviral treatment and histological features were examined.

Results

Thirty‐six patients (9.4%) had persistently normal ALT levels. None of the 36 patients had cirrhosis. Seven patients (19.4%) had a METAVIR fibrosis score of F3. In multivariate analysis, a lower mean METAVIR inflammation score [odds ratio (OR) 0.50, 95% confidence interval (CI) 0.28–0.89; P=0.017], the absence of steatosis (OR 0.43, 95% CI 0.20–0.90; P=0.026) and HCV genotype 4 infection (OR 2.81, 95% CI 1.15–6.68; P=0.023) were associated with persistently normal ALT levels.

Conclusion

The slower progression of chronic hepatitis in patients with persistently normal ALT levels could be related, in part, to a lower frequency of steatosis

     

Determinants of alanine aminotransferase levels in a large population from Southern Italy: Relationship between alanine aminotransferase and age

Background

Determinants of alanine aminotransferase levels have never been investigated in real-life settings. The relationship between alanine aminotransferase and age remains controversial. We evaluated epidemiological, anthropometric, and metabolic factors associated with alanine aminotransferase, focusing on the relationship between alanine aminotransferase and age.

Methods

A 5-year retrospective analysis was performed on data recorded by 120 general practitioners from Naples (Italy), caring for 170,000 subjects. Exclusion criteria were age <18 years, diagnosis of chronic liver disease, positive markers for viral hepatitis, alcohol abuse, and alanine aminotransferase >100 UI/L.

Results

44,232 subjects were enrolled (42.7% males, mean age 56 ± 18 years). Alanine aminotransferase showed independent direct associations with body mass index, glycaemia, cholesterol, and triglycerides (p < 0.001), and inverse associations with high-density lipoprotein cholesterol (p < 0.001) and creatinine (p < 0.01). The relationship between alanine aminotransferase and age was better expressed by polynomial regression (r = 0.18, p < 0.001), creating an inverted parabola. Mean alanine aminotransferase increased until the third decade in males and the fifth in females, with a subsequent progressive decrease in both genders. The inverse association between alanine aminotransferase and age in older subjects was independent from metabolic factors.

Conclusions

This real-life setting study, supports the concept that dysmetabolism is a strong determinant of liver injury. Based on our data, a reduction of the standard upper limit of normal alanine aminotransferase should be considered for older subjects.     

Determination of the upper cut-off values of serum alanine aminotransferase and aspartate aminotransferase in Chinese

AIM:To determine the upper cut-off values of serumalanine aminotransferase(ALT)and aspartate aminotransferase(AST)in a Northern Chinese population.METHODS:A total of 3769 subjects in Jilin Province Northeast China were stratified to determine the potential factors affecting serum ALT and AST levels.The upper cut-off values of serum ALT and AST in these subjects were determined using receiver operating characteristic analysis and their sensitivity and specificity were evaluated.RESULTS:Stratification analysis revealed that serum ALT and AST levels were associated with gender,alcohol consumption,serum cholesterol and triglyceride levels,and body mass index.The upper cut-off values of serum ALT and AST were 22.15 U/L and 25.35 U/L for healthy men and 22.40 U/L and 24.25 U/L for healthy women,respectively.The new cut-off values had a higher sensitivity,but a slightly lower specificity than the current standards.CONCLUSION:Our results indicate that the new upper cut-off values of serum ALT and AST are markedly lower than current standards and may be valuable for the evaluation of liver function.     

慢性乙型肝炎丙氨酸转氨酶低于2倍正常上限者的肝组织学改变

目的 通过肝组织活检评价慢性乙型肝炎患者丙氨酸转氨酶(ALT)低于2倍正常上限(2×ULN)者的肝组织病理学特征,为临床抗病毒治疗提供客观依据。方法 2005年10月至2010年8月四川省人民医院感染科肝脏组织活检患者。肝脏组织活检纳入标准：①HBsAg阳性持续6个月以上;②HBeAg阳性者,HBV DNA≥103拷贝/ml,HBeAg阴性者,HBV DNA≥104拷贝/ml;③AIT＜2×UIN持续6个月以上,且未使用任何保肝降酶药;④既往未接受过任何抗病毒治疗,包括干扰素和核苷类似物;⑤愿意接受肝活检。肝脏组织活检前查血常规、凝血酶原时间、生化、乙型肝炎病毒标志物、HBV DNA定量,常规B型超声定位,肝组织活检评价炎症坏死分级范围和纤维化程度。比较各因素与肝脏炎症和纤维化之间的关系。结果 符合诊断标准病例共383例,其中男性240例,女性143例,年龄16～59岁,平均年龄28.0岁。肝脏炎症G0期2例(0.5％)、G1期165例(43.1％)、G2期191例(49.9％)、(3期25例(6.5％)、G4期0例(0.0％),≥G2期占56.4％。肝脏纤维化S0期103例(26.9％)、S1期265例(69.2％)、S2期13例(3.4％)、S3期2例(0.5％)、S4期0例(0.0％),肝脏纤维化≥S2期仅3.9％。不同年龄、AIT水平、HBV DNA水平和H BeAg状态与肝脏炎症严重程度发生率相关(P＜0.05)。肝纤维化程度仅与年龄、ALT水平及HBeAg状态相关(P＜0.05),HBV DNA水平与肝纤维化发生率无明显相关性(P＞0.05)。结论 ALT低于2×ULN患者大多数有明显的肝脏炎症和不同程度的肝纤维化,建议应通过肝活检了解肝损伤程度作为评价是否具有抗病毒治疗的指征。     

ALT小于2倍正常值上限的慢性乙型肝炎患者显著肝脏炎症的简易血清标志物探索

目的探索有效预测ALT2倍正常值上限(ULN)的慢性乙型肝炎(CHB)患者显著肝脏炎症的简易血清标志物。方法回顾性纳入278例ALT2×ULN(ULN=40 U/L)的CHB患者。显著肝脏炎症定义为炎症程度(G)≥2。计量资料满足正态分布的组间比较采用t检验;不满足正态分布的采用Kruskal-Wallis秩和检验,计数资料组间比较采用χ2检验。多因素回归分析筛查ALT2×ULN的CHB患者显著肝脏炎症的独立预测因素。受试者工作特征(ROC)曲线评估血清标志物对显著肝脏炎症的诊断价值。结果 278例患者中175例(62.9%)无显著肝脏炎症(G0~1组);103例(37.1%)伴显著肝脏炎症(G2~4组)。2组在ALT、AST、ALP、GGT、白蛋白(Alb)、球蛋白(Glb)、凝血酶原时间(PT)、血小板(PLT)、中性粒细胞绝对数(ANC)、透明质酸(HA)、甘胆酸(CG)、Ⅲ型前胶原(PCⅢ)和IV型胶原(ⅣC)等方面的差异均有统计学意义(P值均0.05)。单因素回归分析发现ALT、AST、ALP、GGT、Glb、PT、HA、CG、PCⅢ和ⅣC的水平越高,伴显著肝脏炎症的可能性越大[比值比(OR)均1,P值均0.05];PLT、Alb和ANC的水平越低,伴显著肝脏炎症的可能性越大(OR均1,P值均0.05)。多因素回归分析发现GGT、PT、IVC和HA是ALT2×ULN CHB患者显著肝脏炎症的独立预测因素(OR值分别为1.015、1.600、1.151、1.014,P值分别为0.008、0.021、0.003、0.018)。GGT、PT、IVC和HA诊断显著肝脏炎症的ROC曲线下面积依次为0.804、0.722、0.707和0.632。GGT≥48.5 U/L预测显著肝脏炎症的特异性为90.3%、阴性预测值为74.6%。结论 GGT、PT、IVC和HA是ALT正常或2倍以内升高CHB患者显著肝脏炎症的独立预测因素,其中以GGT的预测价值最大。     

Fish to meat intake ratio and cooking oils are associated with hepatitis C virus carriers with persistently normal alanine aminotransferase levels

Aim: Dietary habits are involved in the development of chronic inflammation; however, the impact of dietary profiles of hepatitis C virus carriers with persistently normal alanine transaminase levels (HCV‐PNALT) remains unclear. The decision‐tree algorithm is a data‐mining statistical technique, which uncovers meaningful profiles of factors from a data collection. We aimed to investigate dietary profiles associated with HCV‐PNALT using a decision‐tree algorithm. Methods: Twenty‐seven HCV‐PNALT and 41 patients with chronic hepatitis C were enrolled in this study. Dietary habit was assessed using a validated semiquantitative food frequency questionnaire. A decision‐tree algorithm was created by dietary variables, and was evaluated by area under the receiver operating characteristic curve analysis (AUROC). Results: In multivariate analysis, fish to meat ratio, dairy product and cooking oils were identified as independent variables associated with HCV‐PNALT. The decision‐tree algorithm was created with two variables: a fish to meat ratio and cooking oils/ideal bodyweight. When subjects showed a fish to meat ratio of 1.24 or more, 68.8% of the subjects were HCV‐PNALT. On the other hand, 11.5% of the subjects were HCV‐PNALT when subjects showed a fish to meat ratio of less than 1.24 and cooking oil/ideal bodyweight of less than 0.23 g/kg. The difference in the proportion of HCV‐PNALT between these groups are significant (odds ratio 16.87, 95% CI 3.40–83.67, P = 0.0005). Fivefold cross‐validation of the decision‐tree algorithm showed an AUROC of 0.6947 (95% CI 0.5656–0.8238, P = 0.0067). Conclusion: The decision‐tree algorithm disclosed that fish to meat ratio and cooking oil/ideal bodyweight were associated with HCV‐PNALT.     

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.