Knodell Histological Activity Index Research Articles

Chronic hepatitis C infection and sex hormone levels: effect of disease severity and recombinant interferon‐α therapy

We aimed to investigate the associations between androgen status and markers of liver disease severity and to determine the effect of interferon-alpha (IFN-alpha) treatment on sex hormone levels in the context of hepatitis C infection. We audited liver biopsy and sex hormone data from 35 men with chronic hepatitis C and a separate group of 11 men with hepatitis C who received IFN-alpha treatment at Fremantle Hospital. We found that men with low fibrosis scores (0-2) on the modified Knodell histological activity index were more likely to have lower sex hormone-binding globulin (SHBG) levels (38.2 +/- 13.2 vs 66.6 +/- 43.3 nmol/L, P < 0.001) and higher free testosterone levels (380.4 +/- 102.0 vs 255.9 +/-83.0 pmol/L, P = 0.01) than those with higher fibrosis scores (3-6). SHBG directly correlated with fibrosis scores (r = 0.37, P = 0.032). Free testosterone levels inversely correlated with liver fibrosis scores (r = -0.43, P = 0.011). A transient reduction in total testosterone of 5.7 +/- 4.2 nmol/L (P = 0.014) occurred within the first 6 months of IFN-alpha therapy although free testosterone was unaffected. More severe liver disease was associated with lower free testosterone and higher SHBG. IFN-alpha therapy reduced total testosterone but not to hypogonadal levels, with no decline in free testosterone. These data suggest that liver disease in hepatitis C infection modulates androgen status indirectly via increased SHBG. Screening for androgen deficiency in the context of hepatitis C infection should selectively target men with more severe liver disease or documented higher grade fibrosis.

The value of α‐SMA in the evaluation of hepatic fibrosis severity in hepatitis B infection and cirrhosis development: a histopathological and immunohistochemical study

To investigate the value of alpha-smooth muscle actin (alpha-SMA), an indicator of stellate cell activation, in predicting fibrosis in chronic hepatitis B (CHB) patients. The liver biopsy specimens of 30 patients with a clinical diagnosis of CHB were obtained before treatment and scored by Knodell's histological activity index. The specimens were then immunohistochemically stained with alpha-SMA and semiquantitatively evaluated. Fibrosis and the immunoreactivity of alpha-SMA in the periportal, perisinusoidal and pericentral areas were compared. Fibrosis and necroinflammatory activity in CHB patients were significantly correlated (P =0.022). Furthermore, the degree of alpha-SMA expression and the scores of fibrosis (in periportal, perisinusoidal and pericentral areas) were highly correlated (P =0.000, 0.001, 0.000, respectively). In liver biopsy samples, alpha-SMA may prove to be a valuable marker in the evaluation of stellate cell activation and fibrosis progression and an early indicator of the development of fibrosis.

Apparent diffusion coefficient measurements with diffusion‐weighted magnetic resonance imaging for evaluation of hepatic fibrosis

To evaluate the use of apparent diffusion coefficient (ADC) measurements based on diffusion-weighted MRI (DWI) to assess stage of liver disease. A total of 31 patients who underwent both a liver biopsy and DWI and 132 patients who only underwent DWI were enrolled. Biopsy specimens were scored for fibrosis and necroinflammation according to the Knodell histology activity index (HAI). The 31 patients consisted of 21 patients with chronic hepatitis and 10 with cirrhosis (Child-Pugh stage A in nine and stage B in one), and the 132 patients consisted of 56 patients with cirrhosis (Child-Pugh stage A in 41, stage B in 10, and stage C in five), 42 with chronic hepatitis, and 34 with normal liver function. The ADCs in the liver parenchyma were measured using DWI with relatively low b factors (b = 0.01 and 128.01 seconds/mm(2)) and were compared among the HAI scores and among patients with cirrhosis, chronic hepatitis, and normal liver function. The ADCs decreased as the fibrosis score in the HAI increased, and the correlation was statistically significant (P < 0.0001). No relationship between the ADCs and the necroinflammation scores in the HAI was found. The ADCs decreased as the stage of liver disease progressed or as the Child-Pugh stage progressed, and these relationships were statistically significant (P < 0.0001). ADC measurements are potentially useful for the evaluation of fibrosis staging in the liver.

Interferon-Alpha-Induced Changes in Metallothionein Expression in Liver Biopsies from Patients with Chronic Hepatitis C

An association between reactive oxygen species and liver damage has been postulated in the course of hepatitis C virus (HCV) infection. Metallothionein (MT), induced by HCV core protein and interferon (IFN), plays a role in scavenging free radicals. MT expression in liver biopsies obtained from 21 patients with chronic HCV infection before and after IFN-alpha therapy was investigated. Changes in Knodell histological activity index (HAI) scores, MT protein levels (immunohistochemistry), MT-I and MT-II messenger (m)RNA expression levels (in situ hybridization) and proliferating cell nuclear antigen (PCNA) labelling index were determined and compared in serial liver specimens. MT staining was clustered around the portal tracts with inflammatory cells and fibrosis. The pattern of MT protein before IFN-alpha therapy was similar in all patients, but was higher in IFN-sustained responders than in nonresponders after IFN-alpha therapy. HAI scores and PCNA labelling indexes were significantly reduced after IFN-alpha therapy. MT-II mRNA expression correlated positively with PCNA index before therapy and with HAI scores after therapy (P<0.05). No correlation was found between MT-I mRNA and HAI scores or PCNA index. The findings indicate that IFN-alpha-induced hepatic MT may participate in the therapeutic effects of IFN-alpha for HCV. In addition, MT-II mRNA expression may be involved in cell proliferation in the livers of patients with chronic HCV infection.

A Pilot Study of Interleukin-11 in Subjects with Chronic Hepatitis C and Advanced Liver Disease Nonresponsive to Antiviral Therapy

To evaluate the effects of recombinant human interleukin (rhIL)-11 on liver histology in patients with chronic hepatitis C virus (HCV) infection and advanced liver disease who had failed antiviral therapy. This was an open-label study of rhIL-11 (Neumega), Wyeth Laboratories, Collegeville, PA) at a dose of 5 microg/kg administered by subcutaneous injection daily for 12 wk. The primary efficacy endpoint was the change in the Knodell Histology Activity Index (HAI) between pre- and posttreatment liver biopsies. Secondary efficacy endpoints included changes in plasma alanine transaminase (ALT) concentrations and in the number of platelets. The Knodell HAI improved in 11 (55%) of the 20 subjects enrolled, with the mean score improving from 7.3 to 5.9 (p= 0.006). Eight subjects (40%) experienced significant improvement as defined by a decrease of at least two points in the HAI. IL-11 treatment was also associated with a decrease in ALT levels from a mean level of 113 IU/L at baseline to 65 IU/L at week 12 (p < 0.001). Platelet levels increased from a mean of 143 x 10(3)/microl at baseline to 198 x 10(3)/mul at week 12 of treatment (p < 0.001). Overall, rhIL-11 was well tolerated and no serious adverse events (AEs) were reported. The most common AE was edema of the lower extremities, which occurred in all subjects. The findings from this pilot study suggest that rhIL-11 may be beneficial for patients with hepatic inflammation and advanced liver disease associated with chronic HCV infection. Larger clinical trials are warranted to further evaluate the long-term antiinflammatory and antifibrotic effects of rhIL-11.

Racial differences in liver inflammation and fibrosis related to chronic hepatitis C

Background & Aims: Hepatitis C virus (HCV) infection is more prevalent in black compared with white Americans. However, the natural course of HCV in black patients has not been defined. Methods: We performed a retrospective comparison of initial liver tests, HCV genotype and viral load, and liver histology findings in 87 black and 136 white American chronic hepatitis C patients who were evaluated at the University of Maryland between 1995 and 1998. The liver biopsy examinations were interpreted by using the Knodell Histologic Activity Index (HAI) criteria. Results: Black HCV patients were older (46.3 vs. 43.3 yr; P = 0.004) and were more likely to be infected with HCV genotype 1 (95% vs. 75%). The modes of HCV transmission, estimated duration of HCV infection, and prevalence of alcohol abuse were similar in the 2 groups. Yet, black patients had lower mean total HAI scores (7.6 vs. 8.7; P = 0.021), periportal hepatocyte necrosis scores ( P = 0.021), and liver fibrosis scores ( P = 0.049). In keeping with less hepatic necroinflammatory activity, black patients had a lower mean serum alanine transaminase (ALT) level (85.5 vs. 122.7; P = 0.002). Black patients also had lower serum iron levels ( P = 0.009). There were no racial differences in the prevalence of increased iron studies and hepatic iron loading. Conclusions: Black chronic HCV patients have milder liver necroinflammation and fibrosis than white patients with similar HCV duration. These differences in liver histology were not explained by a variance in hepatic iron loading.

A comparison of the spectrum of chronic hepatitis C virus between Caucasians and African Americans

Background & Aims: Differences in hepatitis C virus (HCV)-related liver disease between Caucasians and African Americans remain controversial. Methods: We performed a retrospective analysis of 302 consecutive inmates in the Virginia Department of Corrections evaluated for HCV between October 1998 and July 2002. All subjects were anti-HCV positive, HCV treatment naive, human immunodeficiency virus and HBV negative, and had compensated liver disease. Results: The mean age of the cohort was 41 years; they were 91% male and 51% Caucasian. The mean ALT level was 94 U/L, 49% had a normal ALT level, and 80% were genotype 1. The mean Knodell histologic activity index (HAI) was 7.03, with bridging fibrosis in 18% and cirrhosis in 6%. When analyzed by race, the mean ALT level (106 vs. 79 U/L; P = 0.01), proportion with normal ALT level (46% vs. 57%; P = 0.06), and proportion with genotype 1 (67% vs. 94%; P < 0.001) were different between Caucasians and African Americans, respectively. Although the HAI and proportion with bridging fibrosis/cirrhosis were similar between groups, African Americans had lower piecemeal necrosis (1.41 vs. 1.72; P = 0.034) and fibrosis (1.12 vs. 1.40; P = 0.047) scores compared to Caucasians. Multivariate analysis demonstrated that age, ALT, and race were significant independent variables associated with total HAI, piecemeal necrosis, and fibrosis scores. Conclusions: Although the overall spectrum of liver disease is similar, African Americans have less piecemeal necrosis and lower fibrosis scores independent of age and ALT compared with Caucasians.

Impact of highly active antiretroviral therapy on the spectrum of liver disease in hcv-hiv coinfection

Background & Aims: Hepatitis C virus (HCV) coinfection is common in patients with human immunodeficiency virus (HIV) infection. The mortality associated with HIV has decreased dramatically with the introduction of highly active antiretroviral therapy (HAART). However, the impact of HAART, including protease inhibitors (PIs), nucleoside reverse-transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs), on the spectrum of HCV-related liver disease remains unclear. The purpose of this retrospective analysis is to determine the impact of PI and NNRTI use on liver histological characteristics in patients with stable HIV-HCV coinfection (n = 101) compared with HIV-uninfected controls with HCV infection (n = 302). Methods: The majority of coinfected patients were men (75%), African American (82%), and had genotype 1 HCV (91%). Mean HIV load was 1.52 log copies/mL, 48% had undetectable HIV RNA and a mean CD4 count of 528 cells/μL, and 11% had a CD4 count < 200 cells/μL. Both mean alanine aminotransferase (ALT) level (83 U/L; 54% had a normal ALT level) and Knodell Histological Activity Index score (7.04; 33% had advanced fibrosis) were similar to those of our control population. Ninety-three percent of patients were administered a mean of 3 antiretroviral medications: NRTIs in 98%, NNRTIs in 45%, and PIs in 54%. Results: There were no significant differences in biochemical or histological parameters between patients administered or not administered PIs or NNRTIs. Conclusions: In this uncontrolled retrospective analysis, we were unable to show a significant impact of either PI or NNRTI use on the spectrum of liver disease.

Values of high-resolution computed tomography and pulmonary function tests in managements of patients with chronic hepatitis C virus infection.

To investigate pulmonary involvement via pulmonary function tests (PFT) and high-resolution computed tomography (HRCT) in patients with chronic hepatitis C virus (HCV) infection. Thirty-four patients with chronic HCV infection without diagnosis of any pulmonary diseases and 10 healthy cases were enrolled in the study. PFT and HRCT were performed in all cases. A decrease lower than 80% of the predicted value was detected in vital capacity in 9/34 patients, in forced expiratory volume in one second in 8/34 patients, and in forced expiratory flow 25-75 in 15/34 patients, respectively. Carbon monoxide diffusing capacity (DLCO) was decreased in 26/34 patients. Findings of interstitial pulmonary involvement were detected in the HRCT of 16/34 patients. Significant difference was found between controls and patients with HCV infection in findings of HRCT (chi2=4.7, P=0.003). Knodell histological activity index (KHAI) of 28/34 patients in whom liver biopsy was applied was 9.0+/-4.7. HRCT findings, PFT values and DLCO were not affected by KHAI in patients with HCV infection. In these patients, all the parameters were related with age. We suggest that chronic hepatitis C virus infection may cause pulmonary interstitial involvement without evident respiratory symptoms.

Fas antigen (CD95) expression and apoptosis in hepatocytes of patients with chronic viral hepatitis.

Apoptosis may be defined as programmed cell death. It is involved in the normal development and homeostasis of tissues in multicellular organisms. An increased or decreased rate of apoptosis may lead to a range of diseases. Fas antigen is a cell-surface receptor that induces apoptotic pathways when treated with Fas ligand or anti-Fas antibody. There is increasing evidence that apoptosis plays an important role in the immunopathogenesis of chronic viral hepatitis, in which the Fas antigen-Fas ligand pathway is particularly involved. Fas antigen expression and apoptosis (apoptotic index) were assayed using flow cytometry in the hepatocytes of 27 patients with chronic viral hepatitis. Histopathological activity, scored by Knodell's histological activity index, other histopathological parameters, serum transaminase values and patient age were then compared with apoptotic index and Fas antigen expression. Apoptosis and Fas antigen expression in hepatocytes were correlated closely with histological activity (grade) of chronic viral hepatitis, but there were no correlations with histological stage, patient age or serum transaminase levels. Apoptosis and its triggering molecule, Fas antigen, induce mechanisms that appear to be associated with the pathogenesis of chronic viral hepatitis.

A multicenter study of recombinant human interleukin 12 for the treatment of chronic hepatitis C virus infection in patients nonresponsive to previous therapy

Recombinant human interleukin 12 (IL-12) is an immunomodulatory cytokine that is active against several viruses. Treatment options in patients with chronic hepatitis C with nonresponse to interferon (IFN)-based therapy are limited. Prior dose-ranging studies have indicated drug tolerability and transient suppression of hepatitis C virus (HCV) RNA by IL-12. The aim of this study was to determine the safety and efficacy of prolonged IL-12 therapy in patients who have failed treatment with IFN-α ± ribavirin. A total of 225 patients at 21 U.S. sites who had a history of nonresponse to IFN-α or combination IFN-α plus ribavirin for treatment of HCV were randomized to 500 ng/kg IL-12 or placebo subcutaneously twice weekly for 12 weeks. The groups were then unblinded; patients receiving IL-12 continued for another 36 weeks, and the placebo group received 48 weeks of treatment with IL-12 in an open-label fashion. HCV RNA, serum alanine aminotransferase (ALT) level, and a repeat liver biopsy were assessed at 24 weeks following therapy. Approximately 1% (2 of 160) of nonresponsive patients enrolled for treatment had a sustained virologic response to IL-12 therapy, but 3% (7 of 225) developed severe adverse events probably related to treatment, resulting in early termination of the trial. Common adverse effects reported by most patients included chills, fever, fatigue, headache, and arthralgia. At termination of the study, 160 patients had received at least 8 weeks of treatment with IL-12. Paired liver biopsy specimens were available for evaluation in 54 patients, but there were no significant changes in Knodell fibrosis or histologic activity index (HAI) scores. In conclusion, IL-12 as monotherapy at the doses used in this trial for chronic hepatitis C has low efficacy, was poorly tolerated, and is unlikely to provide an alternative to conventional IFN-based therapy. (H epatology 2003;37:1368-1374.)

Predictive role of serum procollagen III peptide and Knodell's index in survival prognosis of patients with hepatitis B virus liver cirrhosis.

The objective of the study was to improve the accuracy of survival prognosis in patients with liver cirrhosis using procollagen III peptide (PIIIP), as a marker of inflammation and fibrogenesis, and Knodell's histologic activity index (KI) in addition to previously used prognostic factors. Five-year survival was followed in a group of 75 patients with hepatitis B virus (HBV) liver cirrhosis (patients testing anti-HBe positive and HBV-DNA negative). There were 31 patients with compensated cirrhosis and 44 with decompensated cirrhosis. The diagnostic procedure included clinical, laboratory, ultrasound and pathohistologic examination. We combined PIIIP and KI with other significant variables to achieve the highest possible sensitivity, specificity and accuracy for survival prognosis in HBV liver cirrhosis. The models were compared using ROC analysis. At the end of the five-year period of survival follow-up, there were 39 survivors and 36 patients had died (only three died from an extrahepatic cause). In the quantitative model, the discriminant canonical function (DCF) identified PIIIP, bilirubin, prothrombin time, ascites and KI as statistically significant parameters in the prognosis of five-year survival. Calculation of the score based on DCF yielded an accuracy of 89.3%. In the semiquantitative model, the analysis of variance identified PIIIP, bilirubin, albumin, pro-thrombin time, alkaline phosphatase, ascites and KI as significant variables. When PIIIP was added to the clinicohistologic diagnosis, Child-Pugh score and KI, the level of accuracy improved by 12% (from 78% to 90%), 11% (from 79% to 90%) and 10.6% (from 80% to 90.6%), respectively. When calculated with the three biochemical parameters (alkaline phosphatase, PIIIP and bilirubin) and KI identified by DCF, the accuracy was 90.6%. Combining PIIIP and KI with other prognostic parameters is useful in achieving a better precision of survival prognosis in patients with HBV liver cirrhosis.

Sampling Variability on Percutaneous Liver Biopsy in Patients with Chronic Hepatitis C Virus Infection

Background: Sampling variability on liver biopsy has been demonstrated in a variety of liver diseases. The objective of this study was to determine whether sampling variability exists on percutaneous liver biopsy in patients with chronic HCV infection. Methods: Two separate tissue samples were obtained from the right lobe of the liver, through a single skin puncture, in 29 patients (22 M, mean age 43.4 ± 8.1 years) with chronic HCV infection. The biopsies were assessed using a descriptive histological reporting system and Knodell's Histological Activity Index (HAI) and compared for differences in necroinflammatory activity (grade) and fibrosis (stage). Results: Thirteen (44.8%) patients had a difference of ≥1 grade between the 2 biopsies on the descriptive system and 13 differed by ≥1 stage. On the HAI, 20 (69.0%) patients had a difference of ≥2 in the necroinflammatory activity score and 10 (34.5%) had a difference of ≥4; whereas, 11 (38.0%) patients had a difference of ≥1 in the fibrosis score and 6 (20.7%) had a difference of ≥2. The mean difference between the two sets of biopsies was 2.4 ±2.1 (range 0–7) for the necroinflammatory activity and 0.6 ±0.9 (range 0–3) for fibrosis. Spearman's correlation coefficient (r) was moderate for both necroinflammatory activity (r = 0.53, P < 0.01) and fibrosis (r = 0.62, P < 0.0001). Conclusions: Sampling variability exists on percutaneous liver biopsy in patients with chronic HCV infection and should be taken into consideration when decisions regarding prognosis and therapy are made based on biopsy, and when defining histological response to antiviral regimens.

Efficacy of interferon alfa and lamivudine combination therapy versus interferon alfa monotherapy in Turkish patients with chronic hepatitis B: A double-blind, randomized, comparative study

Background: Interferon (IFN) alfa and lamivudine are the most effective agents used in the treatment of chronic hepatitis B virus (HBV). Monotherapy with IFN alfa or lamivudine provides significant benefit, but the combination of these drugs is still under investigation. It has been suggested that combination therapy has some advantages over monotherapy. Objective: The purpose of this study was to evaluate the efficacy of concurrent combination therapy with lamivudine and IFN alfa versus IFN alfa monotherapy in previously untreated patients with chronic HBV. Method: Patients were randomly assigned to 6 months' therapy with IFN alfa 9 million units 3 times weekly alone or in combination with 100 mg/d oral lamivudine. Alanine aminotransferase (ALT) measurements and viral load assessments (HBV DNA level as measured by polymerase chain reaction) were performed at baseline and months 6 and 12. Levels of hepatitis B e antigen (HBeAg) and anti-HBeAg were determined at baseline and at the end of treatment (month 12). Knodell histologic activity index score was determined at baseline. Results: Fifty patients were enrolled in each group. ALT normalization rates in the monotherapy and combination therapy groups, respectively, were 56% and 86% ( P < 0.05 between groups) at month 6, and 48% and 64% at month 12 ( P < 0.05 between groups). In the monotherapy and combination groups, respectively, there were 21 (42%) and 24 (48%) complete responders ( P < 0.05); 5 (10%) and 10 (20%) partial responders ( P < 0.05); and 24 (48%) and 16 (32%) nonresponders ( P < 0.05). HBeAg seroconversion rates were 22% in the monotherapy group and 30% in the combination therapy group at the end of 12 months ( P = NS between groups). Conclusion: Concurrent combination therapy with IFN alfa and lamivudine has a more beneficial effect on biochemical parameters (ie, ALT levels) than on viral parameters (ie, HBV DNA, seroconversion to anti-HBeAg) and this effect is more pronounced after 1 year of treatment than after 6 months. Further studies are needed to determine the long-term effects of combination therapy with lamivudine and IFN alfa.

Measurement of serum hyaluronic acid in patients with chronic hepatitis C and its relationship to liver histology. Consensus Interferon Study Group.

Chronic hepatitis C is a slowly progressing inflammatory disease of the liver that can lead to cirrhosis and its complications. Assessment of liver damage in hepatitis C has been primarily via histological evaluation. Liver biopsy, while useful in determining the extent of liver damage, has associated costs and places patients at a small but finite risk of bleeding. Studies in small patient populations have identified serum markers shown to correlate with liver histology, including procollogen III peptide and hyaluronic acid (HA). To determine whether serum HA was a reliable predictor of cirrhosis and fibrosis, we examined serum HA concentrations from 486 chronic Hepatitis C virus (HCV) patients. Patients were anti-HCV and HCV RNA positive, with elevated alanine aminotransferase values and underwent a liver biopsy. Sera were obtained at the baseline for HA using radioimmunoassay methodology. Patients with cirrhosis had significantly higher serum HA concentrations compared with non-cirrhotic patients (382+/-31 vs 110+/-9 microg/L respectively, P< 0.001). Patients with fibrosis had significantly higher mean serum HA concentrations (179+/-11 microg/L) compared with patients without fibrosis (62+/-20 microg/L; P< 0.001). The correlation between HA concentration and the components of the Knodell histological activity index score revealed no strong associations with the exception of fibrosis, which showed moderate correlation (R=0.5421, P<0.001). The clinical value of HA measurement appears to be its ability to exclude cirrhosis. A HA value of < 60 microg/L excluded the presence of cirrhosis or significant fibrosis with a predictive value of 99 and 93%, respectively. Serum HA measurement may be clinically useful to non-invasively assess the degree of fibrosis and cirrhosis. Further prospective studies are warranted to determine the clinical utility of HA as a non-invasive marker of liver fibrosis.

Human leukocyte antigen DRB1 1302 protects against bile duct damage and portal lymphocyte infiltration in patients with chronic hepatitis C

Background/Aims: To confirm the immune reaction of hosts in chronic hepatitis C, we examined the association of human leukocyte antigen (HLA) DR with the histopathological outcome including bile duct damage and steatosis, which are characteristic of hepatitis C virus (HCV) infection. Methods: One hundred and fifty-five patients with chronic HCV infection were examined. The pathological appearance of liver biopsy specimens was evaluated by both Knodell's histological activity index and examination of bile duct damage and steatosis. HLA DRB1 was determined by the polymerase chain reaction sequence-specific oligonucleotide probe method. Results: HLA DRB1 1302 was found with significantly higher frequency in patients without than with bile duct damage (34.8% vs. 4.7%, p=0.0001, p corrected by Bonferroni's inequality method=0.002). It was also found more frequently in patients without marked portal lymphocyte infiltration (28.6% vs. 7.7%, p=0.0015, p corrected by Bonferroni's method=0.03). HLA DRB1 1101 was found more frequently in patients without than with piecemeal necrosis ( p=0.004). In contrast, the frequency of HLA DRB1 1502 tended to be higher in patients with than without piecemeal necrosis and marked portal lymphocyte infiltration ( p=0.015 and p=0.03, respectively). HLA DRB1 1201 and 0802 were seen more frequently in bile duct damage-negative ( p=0.02) and piecemeal necrosis-negative patients ( p=0.03), respectively. Interestingly, serum HCV levels of HLA DRB1 1302-positive patients were significantly higher than those of 1302-negative patients (mean: 7.7Meq/ml vs. 3.1Meq/ml, p=0.0007). Conclusion: These findings suggest that some histopathological changes in chronically HCV-infected livers could be caused by the host's immune reaction regulated by HLA DR.

Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond.

In the last half of the 20th century, use of the liver biopsy has grown to serve multiple purposes: (1) confirmation of clinical diagnosis, (2) assessment of severity of necroinflammation and fibrosis, (3) evaluation of possible concomitant disease processes, and (4) assessment of therapeutic intervention. The current practice for reporting histopathological evaluation of chronic hepatitis involves separate statements for the cause of disease, if known, for severity of necroinflammatory lesions, and for the extent of parenchymal fibrosis. The Knodell histology activity index (HAI), published in HEPATOLOGY in 1981,1 was the first system of its type and is widely regarded as the benchmark for objective, semiquantitative, reproducible description of the various morphological lesions of chronic hepatitis. The report has been cited more than 940 times since its publication. Other proposals for semiquantitative evaluation have followed.2-8 Among these was the consensus report of Desmet et al.,2 which appeared in 1994 in HEPATOLOGY and has been cited more than 440 times. It not only described a modified grading and staging system but also significantly updated the classification of chronic hepatitis to include etiology.

Liver disease?Significant improvement with lamivudine

The natural history of chronic hepatitis B virus (HBV) infection is highly variable, ranging from a benign course to one of shortened life expectancy. Liver histology represents an accurate tool for assessing progressive liver disease, and has been used in five recent Phase III clinical trials of the oral nucleoside analogue, lamivudine, 100 mg/day, in patients with chronic hepatitis B. Significant improvements in the Knodell histological activity index (HAI) score were reported with lamivudine, with greater decreases noted after 2 years of therapy, consistent with continued alanine transaminase (ALT) normalisation. Histological data showed that lamivudine therapy can resolve or lessen the progression of fibrosis, and reduce the progression to cirrhosis in patients with chronic hepatitis B. These trials also showed that lamivudine provoked significant enhancement of hepatitis B e antigen (HBeAg) seroconversion compared with placebo, and had a profound effect on serum HBV DNA, resulting in rapid suppression of viraemia. The emergence of variants with a mutation in the YMDD (tyrosine-methionine-aspartate-as-partate) motif did not cause significant worsening of the Knodell HAI score. In conclusion, lamivudine is the first oral antiviral therapy for the treatment of chronic hepatitis B. It reduces significantly the severity of liver disease and reduces progression to cirrhosis. In addition, because lamivudine is well tolerated it represents a viable therapeutic option that may improve the prognosis of patients with chronic hepatitis B.

Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation

OBJECTIVES: Hepatitis C virus (HCV) is common in patients with end stage renal disease (ESRD) awaiting renal transplantation (RT). However, few data are available on the liver histology and viral titer in these patients relative to patients with HCV and normal renal function. The aims of this study were to assess liver histology, quantitative HCV-RNA titer, and alanine aminotransferase (ALT) levels in patients with ESRD awaiting RT, and to identify clinical predictors of histological progression to advanced bridging fibrosis and/or cirrhosis. METHODS: A total of 50 consecutive patients (mean age 42 yr, 62% male) with ESRD and HCV, who were awaiting RT, underwent liver biopsy. Two HCV populations, one with persistently normal ALT and another with elevated ALT, both with normal renal function, served as controls. HCV-RNA titer was assessed by quantitative PCR. RESULTS: Of the patients with ESRD, 94% had normal ALT. Log HCV RNA titer was significantly higher in patients with ESRD (5.8 ± 0.3) than in either normal ALT (5.4 ± 0.1) or elevated ALT (5.3 ± 0.1) controls ( p < 0.05). Knodell Histological Activity Index (HAI) in patients with ESRD was similar to that observed in control patients with normal ALT (4.8 ± 0.4 vs 4.9 ± 0.4) but significantly less ( p < 0.05) than that observed in control patients with elevated ALT (8.4 ± 0.5). The percentage of patients with bridging fibrosis or cirrhosis was similar in patients with ESRD and controls with persistently normal ALT (22% vs 13%) but significantly less ( p < 0.001) than that observed in control patients with elevated ALT (48%). No significant differences in ALT, HCV-RNA titer, duration on hemodialysis, or time from first possible exposure was observed between ESRD patients with advance fibrosis (n = 11) and those with mild disease (n = 39). CONCLUSIONS: Our data suggest that liver biopsy is necessary to exclude significant liver pathology in patients with HCV and ESRD, and to help define those patients in whom interferon treatment might be helpful.

Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation.

Hepatitis C virus (HCV) is common in patients with end stage renal disease (ESRD) awaiting renal transplantation (RT). However, few data are available on the liver histology and viral titer in these patients relative to patients with HCV and normal renal function. The aims of this study were to assess liver histology, quantitative HCV-RNA titer, and alanine aminotransferase (ALT) levels in patients with ESRD awaiting RT, and to identify clinical predictors of histological progression to advanced bridging fibrosis and/or cirrhosis. A total of 50 consecutive patients (mean age 42 yr, 62% male) with ESRD and HCV, who were awaiting RT, underwent liver biopsy. Two HCV populations, one with persistently normal ALT and another with elevated ALT, both with normal renal function, served as controls. HCV-RNA titer was assessed by quantitative PCR. Of the patients with ESRD, 94% had normal ALT. Log HCV RNA titer was significantly higher in patients with ESRD (5.8+/-0.3) than in either normal ALT (5.4+/-0.1) or elevated ALT (5.3+/-0.1) controls (p < 0.05). Knodell Histological Activity Index (HAI) in patients with ESRD was similar to that observed in control patients with normal ALT (4.8+/-0.4 vs 4.9+/-0.4) but significantly less (p < 0.05) than that observed in control patients with elevated ALT (8.4+/-0.5). The percentage of patients with bridging fibrosis or cirrhosis was similar in patients with ESRD and controls with persistently normal ALT (22% vs 13%) but significantly less (p < 0.001) than that observed in control patients with elevated ALT (48%). No significant differences in ALT, HCV-RNA titer, duration on hemodialysis, or time from first possible exposure was observed between ESRD patients with advance fibrosis (n = 11) and those with mild disease (n = 39). Our data suggest that liver biopsy is necessary to exclude significant liver pathology in patients with HCV and ESRD, and to help define those patients in whom interferon treatment might be helpful.