Serum alpha-fetoprotein levels in patients with chronic hepatitis C. Relationships with serum alanine aminotransferase values, histologic activity index, and hepatocyte MIB-1 scores.

Patients with chronic viral hepatitis and cirrhosis often have elevated serum alpha-fetoprotein (AFP) values, the causes of which are unclear. We studied 81 patients with chronic hepatitis C and the relationships of serum AFP and alanine aminotransferase (ALT) values, hepatic histologic features, and hepatocyte proliferation activity scores. Twenty-two patients had nil to mild fibrosis, 34 had moderate fibrosis, and 25 had marked fibrosis-cirrhosis. The mean serum AFP value was significantly greater in patients with more fibrosis. Serum ALT values were slightly greater in the marked fibrosis-cirrhosis patient group. The differences in the HAI and in hepatocyte MIB-1 scores were not significant. Among all patients, increasing serum AFP values significantly correlated with increasing ALT values. However, there were no significant correlations with serum ALT or HAI and serum AFP values. There was no association between serum AFP values and immunohistochemical staining for AFP within hepatocytes. These results suggest that elevated serum AFP values are the result of altered hepatocyte-hepatocyte interaction and loss of normal architectural arrangements. The presence of marked fibrosis or cirrhosis, a state of significant altered hepatocyte architecture, may be the underlying cause of increased serum AFP, rather than necrosis or active regeneration.     

HIV/hepatitis C virus-coinfected patients with normal alanine aminotransferase levels

BACKGROUND AND AIMS: The significance of normal alanine aminotransferase (ALT) levels in patients with HIV/hepatitis C virus (HCV) coinfection is not well understood. METHODS: We performed a cross-sectional retrospective analysis on consecutive HIV/HCV-coinfected patients (n = 89) who underwent a liver biopsy during a 2-year period. Similar data were also collected on HCV-monoinfected patients (n = 117). RESULTS: Mean ALT levels and the percentage of patients with normal ALT (< or =40 U/L) levels were similar in HIV/HCV-coinfected (mean +/- SD, 81.7 +/- 56.1 U/L; 21%) and HCV-monoinfected patients (97.3 +/- 100.7 U/L; 18%; P = 0.19 and 0.54, respectively). Coinfected patients, however, had significantly advanced necroinflammation (P= 0.001) and fibrosis (P = 0.02) compared with monoinfected patients. The percentage of patients with advanced necroinflammation (grades 3 or 4) was lower in HCV-monoinfected patients with normal ALT levels compared with those with elevated ALT (5% vs 20%, respectively). In contrast, the percentage of coinfected patients with advanced necroinflammation was similar whether the patient had normal or elevated ALT levels (32% vs 37%, respectively). CONCLUSIONS: In coinfected patients, normal ALT levels are not an indicator of mild necroinflammation and may not portend a more benign disease course.     

Clinical and virological characteristics of untreated patients with chronic hepatitis C who develop serum alanine aminotransferase flare-up

Among patients with chronic hepatitis C virus (HCV) infection, serum alanine aminotransferase (ALT) rarely increases above 500 IU/L. We examined the clinical and virological features of untreated patients with serum ALT > or = 500 IU/L. One thousand seven hundred and sixty adult patients with chronic HCV infection were followed-up. Among these patients, 22 developed ALT flare-up (M:F=13:9, median age, 50.5 years). We evaluated liver function tests, genotype, and viral titer in these patients and 44 randomly selected age- and sex-matched control without ALT flare-up. In four patients with ALT flare-up, we examined changes in viral loads and sequential changes in amino acid sequences of the core region, hypervariable region 1 (HVR1), and interferon sensitivity determining region (ISDR) before and after ALT flare-up. Multivariate analysis identified genotype 2 as the only significant determinant of ALT flare-up. ALT flare-up occurred in three of four patients without increase in viral load. Several alterations in amino acids were noted in HVR1 before and within 6 months of ALT flare-up. One or two alterations in the core region and many alterations in HVR1 were noted after ALT flare-up in some patients. Genotype 2 is an important factor for ALT flare-up. However, we could not directly relate ALT flare-up to these alterations in amino acids of the core region, HVR1, and ISDR.     

Liver fibrosis in HIV-positive patients with hepatitis C virus: role of persistently normal alanine aminotransferase levels

BACKGROUND: Liver fibrosis requiring treatment in HIV/hepatitis C virus (HCV)-coinfected patients with persistently normal alanine aminotransferase (ALT) values (PNAL) is currently not well defined; in this study clinical and histologic features of PNAL were compared with those of subjects with elevated ALT (EAL). METHODS: A total of 326 liver biopsies of HIV/HCV-coinfected patients, performed from 1997-2003, were retrospectively identified. Subjects with at least 3 consecutive normal ALT determinations during a prebiopsy follow-up of 12 months were grouped as PNAL (24 patients) and compared with EAL subjects (302 patients). Liver biopsy was classified with the modified Ishak score. RESULTS: Age, HCV viral load, and genotype, CD4 T-cell count, and antiretroviral drugs did not show a statistical difference between the 2 groups. Statistical significance was found when comparing mean grading (1.4 +/- 1.8 vs. 7.2 +/- 2.6, P < 0.0001) and staging (1.4 +/- 1.79 vs. 2.5 +/- 1.7, P < 0.0003) between PNAL and EAL subjects. The proportion of PNAL patients fulfilling histologic criteria for anti-HCV treatment (25% with stage 2-6) was also significantly different from EAL subjects (69%; P = 0.0001). At multivariate analysis, only age, CD4 count (>500 vs. < or =500 cells/mL), and patient's group (EAL vs. PNAL) were found to be independently associated with a fibrosis score of > or =2. CONCLUSION: Liver fibrosis requiring treatment was found in 25% of HIV/HCV-coinfected subjects with PNAL values.     

Therapy with interferon alfa and ribavirin in patients with chronic hepatitis C and normal levels of alanine aminotransferase

The aim of the study was to evaluate the efficacy of combination therapy with interferon-alpha (IFN-alpha) and ribavirin in patients with chronic hepatitis C and normal alanine aminotransferase (ALT) values. In this retrospective study, 12 HCV-RNA positive patients (7 males and 5 females, mean age 38.1 years), treated between 1998 and 2001, with normal or near normal ALT values on three consecutive occasions and histologically mild disease were identified. During the induction period of four weeks they received 56 MU IFN-alpha 2b and ribavirin 1000 mg daily. During the next 44 weeks they received 3 MU IFN-alpha 2b three times a week with ribavirin 1000 mg daily. Seven out of 12 (58%) patients were HCV-RNA negative at the end of the therapy (end-of-treatment-response) and 5 of 12 (42%) showed sustained virologic response at 6 months. No significant elevation of aminotransferase values was recorded during therapy. Patients with mild chronic hepatitis C and normal ALT levels respond well to combination therapy with interferon and ribavirin, similar to those with elevated ALT levels. As long as the natural history and long-term outcome of these patients are not completely known, this might be a beneficial treatment option.     

Long‐term follow‐up of patients with hepatitis C with a normal alanine aminotransferase

An attempt was made to identify factors influencing the cumulative probability of an increased alanine aminotransferase (ALT) level and hepatocarcinogenesis in hepatitis C patients with a normal ALT level initially. A total of 398 consecutive patients with a normal ALT level initially for 6 months or more and follow‐up period longer than 3 years during the period January 1995 to December 2004 were included. Patients were classified by ALT level into three groups: Group A (3–20 IU/L), Group B (21–30 IU/L), and Group C (31–35 IU/L). Factors associated with the cumulative probability of increased ALT level and hepotocarcinogenesis were evaluated. Women in groups B and C and men in Group C showed high cumulative probabilities of increased ALT levels. Factors associated with increased ALT were a high ALT level (Group B, relative risk; 1.758 [95% confidence interval: 1.290–2.392], P < 0.001, Group C, 3.328 [2.256–4.909], P < 0.001), high lactate dehydrogenase level (2.352 [1.445–3.829], P = 0.001), or low total cholesterol level (1.957 [1.330–2.882], P = 0.001). Factors associated with incidence of hepatocellular carcinoma were increased age (3.088 [1.025–9.308], P = 0.045), high ALT level (Group C, 5.803 [1.530–22.066], P = 0.010), and high total bilirubin level (8.309 [2.235–30.888], P = 0.002). In patients with hepatitis C with a normal ALT level initially, an ALT level of 21–35 IU/L is a risk factor for an increased ALT level and hepatocarcinogenesis. J. Med. Virol. 81:446–451, 2009. © 2009 Wiley‐Liss, Inc.     

Influence of stable, long-term treatment with phenobarbital on the activity of serum alanine aminotransferase and gamma-glutamyltransferase

Phenobarbital, a long-acting barbiturate, is generally considered to be a fairly safe and effective drug; however, hepatotoxicity is an infrequent but potentially fatal adverse effect and there is little information on the serum activity of liver enzymes in patients on stable, long-term monotherapy. The serum activity of alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) are measured along with phenobarbital as part of the routine biochemical measurement in 128 consecutive adult out-patients on stable, long-term phenobarbital treatment. The control population consists of 2468 consecutive outpatients matched for age and gender. The patients on long-term phenobarbital therapy had significantly higher serum activities of ALT (27 IU/L versus 23 IU/L, P < 0.001) and GGT (79 IU/L versus 24 IU /L, P < 0.001). The prevalence of subjects with abnormal GGT values, but not ALT, was significantly higher than that in the control population. No significant differences were observed in either the mean activity or the prevalence of abnormal values of ALT or GGT between patients with suboptimal and therapeutic concentrations of the drug. These results suggest that chronic phenobarbital therapy may be associated with a clinically significant elevation of serum GGT activity. If confirmed, a specific GGT reference range should be adopted. Moreover, in those patients presenting with high serum GGT activity, it would not be necessary to reduce the dosage, discontinue the drug or change to a different anti-epileptic medication.     

Effect of streptococcal preparation (picibanil) on the postoperative rise in serum alanine aminotransferase activity in patients with urogenital cancer

The effect of Picibanil, a streptococcal agent, on the development of liver injury after operations for urogenital cancer was studied retrospectively in the light of serum alanine aminotransferase (ALT) activity. The series comprised 32 cases receiving Picibanil and 33 controls with otherwise comparable clinical backgrounds. Picibanil reduced the incidence of postoperative ALT rise over 50 U/l within 6 weeks but increased it thereafter. The increase in ALT activity after 6 weeks was relatively small and was seen more often in patients given blood transfusions. It was interpreted as retardation and suppression of ALT rise and as being related to the induction of interferon or to immunopotentiation. Other antihepatotoxic effects of Picibanil, due to its antioxidant activity, for example, may also account for the prevention of the early postoperative rise in ALT activity.     

Relationship of TT virus infection with prevalence of hepatitis C virus infection and elevated alanine aminotransferase levels.

A novel DNA virus, TT virus (TTV), was identified in a Japanese patient with posttransfusion hepatitis. The epidemiology and etiological role of this virus have not been elucidated. We investigated the epidemiology of TTV infection in hepatitis C virus (HCV) high endemic and low endemic areas, R town and M town, respectively. The seroprevalence, potential risk factors, and laboratory features of TTV in relation to those of HCV were analyzed. TTV DNA was detected using a seminested polymerase chain reaction and the TTV genotypes were determined by a direct sequencing method. TTV DNA was detected in 16.1% of the subjects in R town and 17.5% of those in M town. The TTV DNA positivity rates of the 2 areas did not differ significantly. A history of blood transfusion was not a specific risk factor for TTV infection. The mean serum alanine aminotransferase (ALT) level of the anti-HCV-positive subjects was significantly higher than that of the TTV DNA-positive subjects, most of whom had normal ALT levels. The TTV genotype distributions of these 2 distinct areas differed. These results suggest that TTV infection is widespread with a geographical genotypic distribution independent of HCV infection and that the ALT abnormalities are not attributable to TTV but to HCV infection in the general population.     

阿德福韦治疗慢性乙型肝炎过程中HBV DNA及丙氨酸氨基转移酶水平的变化

目的 研究新药阿德福韦(ADV)治疗慢性乙型肝炎过程中HBV DNA及丙氨酸氨基转移酶(ALT)水平的变化情况,从而指导临床用药. 方法 采集16例慢性乙型肝炎(CHB)患者用ADV治疗前血清,即基线(BL)血清,以及持续服药12、16、28、40、48、52、68、80、92周共10个时段的系列血清.用荧光定量PCR法检测其HBV DNA的水平.用全自动生化仪检测其ALT的水平. 结果 从BL到48周时段,HBV DNA中位数显著下降;在52周,HBV DNA中位数出现反弹;从52至92周时段,HBVDNA中位数再次下降.16例不同时段血清ALIT中位数的变化与HBV DNA中位数变化一致.ADV治疗12周时,HBV DNA中位数较基线下降了2.34 lg拷贝/ml,无HBV DNA阴转、HBeAg血清学转换;治疗28周时,HBV DNA中位数较基线下降了2.91 lg拷贝/ml,有2例HBV DNA阴转、ALT恢复正常、HBeAg血清学转换;治疗40、48周时,HBV DNA中位数较基线分别显著下降了3.83、3.95 kg拷贝/ml,有4例HBV DNA阴转、ALT恢复正常、HBeAg血清学转换;治疗52周时,HBV DNA中位数较基线下降了2.90 lg拷贝/ml,出现反弹,但仍有4例HBV DNA阴转、ALT恢复正常、HBeAg血清学转换;治疗68、80、92周时,HBV DNA中位数较基线显著下降了3.51、3.81、4.01 lg拷贝/ml,分别有4、6、6例HBV DNA阴转、ALT恢复正常、HBeAg血清学转换.16例患者接受ADV治疗的两年中,有9例患者分别从16、28、40周开始HBV DNA的水平显著下降;7例患者HBV DNA的水平下降但不显著. 结论 阿德福韦治疗慢性乙型肝炎过程中,HBV DNA及ALT中位数的变化情况基本一致.52周时段HBV DNA水平出现反弹,提示52周可能是抗病毒的关键时段.     

Reduced antibody reactivity to hepatitis C virus antigens in hemodialysis patients coinfected with hepatitis B virus.

Antibody reactivities to hepatitis C virus (HCV) antigens and to synthetic peptides derived from different parts of the HCV genome (core, NS4, and NS5) were evaluated in HCV-infected hemodialysis patients. In the RIBA 3 assay, NS5 was significantly less recognizable by sera of hemodialysis patients compared to other HCV-infected subjects. Among hemodialysis patients, those coinfected with hepatitis B virus (HBV) (positive for hepatitis B surface antigen [HBsAg+]) showed a reduction in reactivity to C33 and C100. Sera of only 23% of the hemodialysis patients (37 of 161) reacted with more than three of eight peptides tested, significantly fewer than the 60% (12 of 20) of the sera of other HCV-infected patients tested (P = 0.001). This immunosuppression was also manifested by a reduced frequency of recognition of additional peptides on follow-up. An even more reduced reactivity was observed among the HBV-coinfected patients (HBsAg+). The low-responder hemodialysis patients were not infected with any particular genotype of HCV, and the same HCV genotypes observed in the whole group of hemodialysis patients (1a, 1b, 2a, and 3a) were found circulating in the low-responder group. Even in this low-responder population, the good performance of two peptides (peptide 716, corresponding to a portion of the core, and peptide 59, corresponding to a portion of NS4) corroborates the immunodominance of the conserved epitopes within these peptides.     

Evaluation of molecular parameters for routine assessment of viremia in patients with chronic hepatitis C who are undergoing antiviral therapy

OBJECTIVE: To define the usefulness of molecular parameters in patients with chronic hepatitis C who are undergoing antiviral therapy. Anti-hepatitis C virus (HCV) treatment was monitored by determination of serum HCV load and by presence of HCV RNA in peripheral blood mononuclear cells (PBMCs). STUDY DESIGN/METHODS: Fifty-one patients with chronic hepatitis C undergoing antiviral therapy with interferon-alpha plus ribavirin were studied. Serum HCV RNA load was tested with a quantitative assay (Amplicor HCV Monitor Test) before, during, and up to 12 months after end of treatment. If HCV RNA was not detectable, serum samples were subsequently tested with a qualitative assay (Cobas Amplicor HCV Test) and corresponding ethylenediaminetetraacetic acid (EDTA)-treated blood was checked for presence of HCV RNA in peripheral blood mononuclear cells (PBMCs). Sustained virologic response was defined by loss of HCV RNA 12 months after the end of treatment. RESULTS: Four patients (7.8%) were found to be sustained virologic responders, 17 (33.3%) were transient virologic responders, and 30 (58.8%) were virologic nonresponders. No significant difference was found in the median pretreatment serum HCV RNA load between sustained virologic responders, transient virologic responders, and virologic nonresponders. At 1 month after start of therapy, HCV RNA was not detectable with both the serum and the PBMC assay in 12 (23.5%) of 51 patients. Four remained HCV RNA-negative until 12 months after the end of treatment. In 14 of 17 transient virologic responders, reappearance of HCV RNA was detected earlier in PBMCs than in serum. CONCLUSIONS: Based on these results in 51 patients, quantitation of baseline serum HCV RNA does not appear to be a decisive factor to the management of the individual patient. Early assessment of serum HCV RNA level after start of anti-viral treatment seems to be of major importance to identify virologic nonresponders. Reappearance of HCV RNA may be demonstrated earlier in PBMCs than in serum.     

Rapid normalization of alanine aminotransferase predicts viral response during combined peginterferon and ribavirin treatment in chronic hepatitis C patients

Background/Aims

The treatment for chronic hepatitis C (CHC) is removal of the virus in order to prevent progression to liver cirrhosis and hepatocellular carcinoma (HCC). Few data have been presented regarding the clinical significance of changes in the alanine aminotransferase (ALT) level in this context. We analyzed the patterns of changes in ALT level and investigated the relationship between the rapid normalization of ALT and sustained virologic response (SVR) after combined treatment with peginterferon and ribavirin.

Methods

CHC patients (n=370) were classified into four groups according to the initial ALT level and subsequent changes: (1) initially abnormal ALT level and sustained abnormal ALT level during treatment, (2) initially abnormal ALT level but achievement of ALT normalization, (3) initially normal ALT level and variable ALT abnormality during treatment, and (4) initially normal ALT level and sustained normalization of ALT level during treatment. We subdivided groups 1 and 2 into those with patterns of decreased and normalization of ALT, with or without rapid normalization. We checked the end-treatment response (ETR) and SVR rates in each group and the factors associated with SVR, including patterns of changes in ALT level.

Results

A total of 168 patients completed the therapy (age=54.34±10.64 years [mean±SD], 95 males [56.5%], genotype 1:82 [48.8%]). SVR was achieved in 115 (68.45%) of the completely treated patients. The SVR rate was significantly lower in group 1 than in group 2 (37.8 vs. 81.6%, P<0.001), and significantly higher in the rapid normalization group than in the group without rapid normalization (78.5% vs. 41.2%, P<0.001). Multiple logistic regression analysis revealed that age (odds ratio [OR]=0.94, 95% confidence interval [CI]=0.91-0.98, P=0.005), viral genotype (OR=2.76, 95% CI=1.20-6.38, P=0.017), and initial hepatitis C virus RNA titer (OR=0.28, 95% CI=0.10-0.75, P=0.012) were identified as independent significant predictive factors for SVR.

Conclusions

The SVR rate is significantly associated with normalization, and especially rapid normalization of ALT. Rapid normalization of ALT by 4 weeks after treatment might be a useful response factor that is readily available in clinical practice, and especially for genotype 1 patients.     

Quantification and genotyping of serum HCV-RNA in patients with chronic hepatitis C undergoing interferon treatment

Summary.  Quantification of serum HCV-RNA and HCV genotyping was studied in 27 patients with chronic hepatitis C undergoing interferon treatment. Pretreatment serum HCV-RNA levels were quantified using competitive RT-PCR and compared to a quantitative RT-PCR assay based on co-amplification of HCV-RNA with a synthetic RNA standard. HCV genotyping was performed using a line probe reversed hybridisation assay or direct solid-phase sequencing. This study shows the feasibility of performing HCV-RNA quantification. RT-PCR based on co-amplification HCV-RNA titer less than 6× 10⁴ genome equivalents/ml serum did correlate with a complete sustained response to α interferon in chronic hepatitis C. HCV genotype 1b was α predominantly associated with a high non-responder rate. Future prospective trials will be required to evaluate quantitative HCV-RNA levels and HCV genotyping as response predicting parameters for interferon-treatment.     

抗-HCV阳性无病毒血症患者HCV特异性免疫反应研究

目的　研究抗HCV阳性无病毒血症患者特异的体液及细胞免疫状态。方法　对 15例抗HCV阳性无病毒血症患者 ,15例慢性HCV持续感染者及 15例正常对照者进行研究 ,通过MTT、LDH释放法、酶联免疫等方法观察患者外周T细胞反应、自然杀伤 (NK)细胞活性、细胞因子分泌及特异性体液免疫反应。结果　无病毒血症者T细胞增殖反应明显大于持续感染者及对照组 ,并且T细胞对核心区抗原增殖最大 ,NS3次之 ,对NS5则无明显增值。而NK细胞活性较持续感染者及对照组稍高 ,但无统计学差异。此外我们观察了患者抗HCV抗体产生 ,发现无病毒血症患者与持续感染者抗 -HCV抗体产生无明显统计学差异。还观察到在无病毒血症组抗原刺激后产生IFN明显高于持续感染组 ,两组在无抗原刺激下IFN产生水平均极低下。结论　抗HCV阳性无病毒血症患者 ,其T细胞免疫及抗体的产生均高于持续感染者 ,这可能在病毒的清除中起一定作用 ,而免疫反应在慢性HCV感染中的作用及机制 ,尚需进一步研究     

Elevated serum alanine aminotransferase (ALT) levels in patients with serologically verified Mycoplasma pneumoniae pneumonia

The possibility of liver involvement in Mycoplasma pneumoniae pneumonia is still controversial. This study investigated 33 adult patients with serologically confirmed M. pneumoniae community-acquired pneumonia (CAP) (median age 31 years) and 38 patients with bacteraemic Streptococcus pneumoniae CAP (median age 54 years), all without pre-existing liver disease. Serum alanine aminotransferase (ALT) levels were elevated in 12 (36.4%) patients with M. pneumoniae CAP (median 53.5 U/L), and in four (10.5%) patients with S. pneumoniae CAP (median 61 U/L) (p 0.025). In most patients with M. pneumoniae CAP, the elevated ALT levels decreased during macrolide therapy, although this decrease was not significant.