Serum hyaluronic acid reflects the effect of interferon treatment on hepatic fibrosis in patients with chronic hepatitis C

Changes in serum hyaluronic acid (HA) in 35 patients treated with interferon (IFN) were studied and the histological change in fibrosis was analysed. Serum HA levels and hepatitis C virus (HCV) RNA were followed from the start of therapy to 12 months after completion of treatment. Histological changes in pre- and post-treatment liver biopsies were assessed using a modified Knodell's scoring system. The serum levels of HA (r = 0.79; P<0.0001) correlated with the degree of fibrosis more closely than with that of amino terminal peptides of type III procollagen (PIIIP; r = 0.45; P<0.05) or type IV collagen (IV-C; r = 0.42; P<0.05). Only complete responders (CR) had a significant decrease in serum levels of HA and IV-C (P<0.05), in parallel with histological improvement (P<0.01). Neither partial responders (PR) nor non-responders (NR) had significant changes in histological scores and in serum levels of fibrotic markers. Significant differences were observed between CR and NR, both in HA levels (P<0.01) and PIIIP levels (P<0.05) 12 months after the cessation of treatment. These results suggest that serum HA is an indicator of the extent of fibrosis in chronic hepatitis C. Serial determinations of serum HA levels may be of use for monitoring the histological response of hepatic fibrosis to IFN treatment in chronic hepatitis C.     

Prediction of response to interferon therapy by serum levels of type IV collagen and prolyl hydroxylase in chronic hepatitis C

We evaluated histological activity index (HAI) score and serum markers of liver fibrosis, type IV collagen (IV-C) and prolyl hydroxylase (PH), to analyze whether they are predictors of response to interferon (IFN) treatment for chronic hepatitis C. Efficacy of IFN therapy was evaluated in 16 patients. Mean serum levels of IV-C and PH before treatment in five responders were lower than those in 11 non-responders (not significant). Among seven patients whose IV-C values were less than 200 ng/ml and PH less than 80 ng/ml, five patients (71.4%) were responders. The response rate of these seven patients was significantly (P < 0.005) higher than that (0%) in the other nine patients. When patients were histologically divided by the total HAI scores, the response rate to IFN in patients with low HAI score (10 or less) was 71.4% (five of seven patients), while that in patients with high HAI score (more than 10) was 0%. The result that the response rate to IFN in patients with low serum IV-C and PH levels equaled that in patients with low HAI score suggests that the efficacy of IFN treatment may be predictable by measuring serum levels of IV-C and PH in patients with chronic hepatitis C.     

Long-term monitoring of platelet count, as a non-invasive marker of hepatic fibrosis progression and/or regression in patients with chronic hepatitis C after interferon therapy

Background: Platelet count has been shown to correlate with the hepatic fibrosis stage in chronic hepatitis C (CHC). The aim of the present study was to assess hepatic fibrosis progression or regression of CHC patients by long‐term monitoring of the platelet count. Methods: A total of 429 interferon (IFN)‐treated CHC patients were studied. Follow‐up data on the platelet count were collected every 6 months after IFN therapy. The IFN response was defined as follows: complete responders (CR, n = 121) demonstrating persistent clearance of serum hepatitis C virus (HCV) RNA; biochemical responders (BR, n = 94) demonstrating alanine aminotransferase (ALT) normalization for ≥6 months without eradication of HCV‐RNA; and non‐responder (NR, n = 214) demonstrating all other patterns. Results: In comparison with the baseline level, mean platelet count increased in the CR group from 0.5 years after IFN therapy (for each point, P < 0.01), but significantly decreased in the NR group from 1 year after IFN therapy (for each point, P < 0.01). In the BR group, an increase in mean platelet count was observed from 0.5 to 3.5 years following IFN therapy (for each point, P < 0.01), followed by a gradual decrease. Conclusion: An increase from baseline values in platelet count was observed, regardless of the presence of HCV‐RNA, in both the CR and BR groups, suggesting the importance of ALT normalization in preventing hepatic fibrosis progression in IFN‐treated CHC patients.     

Alpha-interferon improves liver fibrosis in chronic hepatitis C: clinical significance of the serum N-terminal propeptide of procollagen type III

Our objective was to estimate the effect of interferon (IFN) on the evolution of fibrosis in chronic hepatitis C and the significance of the N-terminal propeptide of procollagen type III (PIIIP) as a marker of fibrogenesis. One hundred seventeen patients, 72 male (61%) and 45 female (39%), with a mean age of 40.7 ± 11.9 years were treated with 2b-IFN, 3 to 5 MU, for 12 months: sustained responders (SR = 44), relapsers (RR = 35), and nonresponders (NR = 38). Liver biopsies were performed before treatment and 1 year after cessation of IFN for evaluation of the histological activity index (HAI). Serum PIIIP was obtained at the time of liver biopsy, at the beginning, during, and end of therapy and during the follow-up. The normal value in 29 healthy individuals was 0.37 ± 0.18 U/L. Staging was reduced in 58% of SR, 12.5% of RR, and 11.5% of NR. There was a correlation between PIIIP and the HAI before (n = 71, r _s = 0.41, P < 0.0004) and after IFN (n = 71, r _s = 0.58, P < 0.0001). The SR had a better improvement in grading (90.3%; P < 0.05) and staging (58%; P < 0.001). The correlation of the HAI parameters with the variation of PIIIP showed significance only for fibrosis (r _s = 0.36, P < 0.002) and portal inflammation (r _s = 0.35, P < 0.01). PIIIP normalized only in patients whose fibrosis improved (P < 0.01). At the end of therapy, PIIIP had a predictive value in the distinction of SR from RR (PPV, 64; PNV, 55.6). During the follow-up, PIIIP remained lower in SR compared with RR and NR (P < 0.002). The response to -IFN improved liver inflammation and fibrosis. Serum PIIIP is a useful noninvasive method to evaluate serially fibrogenesis in chronic hepatitis C treated with IFN.     

Fibrogenesis serum markers in patients with chronic hepatitis C treated with α-IFN

The correlation between therapeutic response and liver fibrogenesis was studied in serum and liver specimens taken from 31 patients treated with α-interferon (IFN) (14 sustained responders and 17 non-responders) for chronic hepatitis C. Serum samples, collected before therapy, and at further 6-month intervals over 2 years, were tested for markers of liver neofibrogenesis. Serum N-terminal procollagen III peptide (PIIINP) displayed a significant and persistent decrease (P < 0.05) in sustained responders but not in non-responders; significantly lowered (P < 0.05) mean levels of C-terminal procollagen I peptide (PICP) were transiently observed in both patient groups, apparently as a result of IFN administration. Serum laminin (Lam) levels remained unchanged. One year after the cessation of treatment, liver biopsy re-testing showed an improvement in necro-inflammatory scores only in sustained responders, with the histological fibrosis scores remaining unaltered in both groups. IFN treatment seemed to exert an influence on serum levels of markers of hepatic connective tissue turnover even in patients that did not respond to therapy, while no effect was observed on preexistent liver fibrosis. Received: June 15, 1998/Accepted: November 27, 1998     

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

Background: We aimed to investigate the associations between androgen status and markers of liver disease severity and to determine the effect of interferon‐α (IFN‐α) treatment on sex hormone levels in the context of hepatitis C infection. Methods: 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‐α treatment at Fremantle Hospital. Results: 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‐α therapy although free testosterone was unaffected. Conclusion: More severe liver disease was associated with lower free testosterone and higher SHBG. IFN‐α 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.     

Hepatic expression of type I interferon receptor for predicting response to interferon therapy in chronic hepatitis C patients: a comparison of immunohistochemical method vs. competitive polymerase chain reaction assay

The focus of this study is to determine both mRNA and protein expression levels of the type I interferon (IFN) receptor subunits, IFNα receptor (IFNAR1) and IFNα/β receptor (IFNAR2), in the liver, and to assess which quantification method is most useful in predicting response to IFN in chronic hepatitis C patients. Liver biopsy specimens from 41 chronic hepatitis C patients subsequently treated with IFN were immunostained with IFNAR1 and IFNAR2 antibodies, and also analyzed for both receptor subunit mRNA levels, using competitive polymerase chain reaction. Immunostaining of IFNAR1 and IFNAR2 was observed in the cell membrane and cytoplasm of hepatocytes in all liver specimens. Hepatic expression of IFNAR1 (r=0.45, P=0.012) or IFNAR2 mRNA (r=0.46, P=0.009) was weakly correlated with their protein expression in hepatocytes. The labeling indexes of IFNAR1 (136.7±94.1 vs. 77.4±76.8, P=0.032) and IFNAR2 (153.1±80.2 vs. 87.2±75.5, P=0.011) in liver specimens were significantly higher in sustained virologic responders (n=17) than in non-sustained virologic responders (n=24), while mRNA levels of either receptor subunit did not differ between response groups. These results suggest that protein expression of the type I IFN receptor in liver is a more useful measure than its mRNA expression in predicting response to IFN in chronic hepatitis C patients.     

Eradication of hepatitis C virus by interferon improves whole‐body insulin resistance and hyperinsulinaemia in patients with chronic hepatitis C

Background/Aims: To investigate whether eradication of hepatitis C virus (HCV) by interferon (IFN) therapy influences systemic glucose metabolism. Methods: Seventy‐two patients with chronic hepatitis C were enrolled in this study. Patients received IFN therapy and were classified into two groups: sustained responders (n=48) and nonsustained responders (n=24). We analysed systemic glucose metabolism in terms of the following indices: homeostasis model assessment for insulin resistance (HOMA‐IR) and β‐cell function (HOMA‐β), insulinogenic index (II), composite insulin sensitivity index (ISI composite) and the area under the curve of plasma glucose (PG‐AUC) and serum insulin (SI‐AUC) in oral glucose tolerance tests. In 28 sustained responders and 16 nonsustained responders, serum levels of soluble tumour necrosis factor receptor 2 (sTNFR2) were measured. Indices were determined before and 6 months after therapy. Results: In the sustained responders, HOMA‐β (P=0.0004) and SI‐AUC (P=0.002) were significantly decreased and the ISI composite was increased (P=0.009), although there were no significant changes in HOMA‐IR, II or PG‐AUC. Serum sTNFR2 levels decreased significantly after therapy in sustained responders (P=0.001). In the nonsustained responders, there were no changes in any index. Conclusions: Eradication of HCV by IFN therapy could improve whole‐body insulin resistance and insulin hypersecretion with reduced serum TNF‐α levels.     

Relationships between serum aminotransferase levels, liver histologies and virological status in patients with chronic hepatitis C in Taiwan

In patients with chronic hepatitis C, the relationships between serum alanine aminotransferase (ALT) levels, histological liver injury and serum hepatitis C virus (HCV) RNA titres remain controversial. To evaluate these relationships, 93 Chinese patients with histological diagnosis of chronic hepatitis C were enrolled for this study. Serum ALT levels, HCV-RNA titres and HCV genotypes were examined. The histology was evaluated according to a modified histological activity score based on the degree of periportal necro-inflammation, intralobular necro-inflammation, portal inflammation, total necro-inflammation and fibrosis. The mean serum ALT level was significantly higher in patients with severe intralobular necro-inflammation activity than in patients with mild or no activity (P= 0.013). However, scores of intralobular activity were only weakly correlated with serum ALT levels (r= 0.27) and could not be used to adequately predict ALT values. Serum ALT levels showed no significant correlation with the scores of portal inflammation, periportal necro-inflammation, total necro-inflammation and fibrosis. Also, there was no significant difference in the mean serum ALT level among different serum HCV-RNA levels and HCV genotypes. Serum HCV-RNA titres and genotypes showed no significant correlation with liver histology and serum HCV-RNA titres were only weakly correlated with the total necro-inflammatory score (r= 0.27). In conclusion, although serum ALT levels were higher in patients with more severe intralobular necro-inflammatory activity, the correlation was not strong enough to adequately predict ALT values. Serum HCV-RNA titres and genotypes also showed no significant correlation with serum ALT levels and liver histologies.     

Serum immunoglobulins in patients with chronic hepatitis C: a surrogate marker of disease severity and treatment outcome

BACKGROUND/AIMS: Moderate polyclonal hypergammaglobulinemia is a common finding in chronic viral liver disease; however, its clinical significance has not been completely elucidated. We attempted to determine whether serum immunoglobulin levels were correlated with the disease severity and the treatment outcome in patients with chronic hepatitis C. METHODOLOGY: In a total of 102 patients with chronic hepatitis C, we performed serum tests on immunoglobulins and determined the histology activity index (HAI) score by liver biopsy. In 97 patients, immunoglobulin levels were followed prior to and 6 months after interferon (IFN) therapy. RESULTS: Serum gamma (y)-globulin and immunoglobulin (IgG) were well correlated with HAI score (both; p < 0.0001), grading score (both; p < 0.01), and staging score (both; p < 0.0001). Among the 97 patients who received 6 months of IFN monotherapy, 31, 29, and 37 patients were complete, transient and non-responders, respectively. In the three subgroups, a significant difference was found in histological HAI, grading, and staging scores (p < 0.01, p < 0.05 and p < 0.0001, respectively), and in serum levels of gamma-globulin and IgG (both; p < 0.0001). Following IFN treatment, serum gamma-globulin and IgG were significantly decreased in the complete responders (both; p < 0.0001). Furthermore, serum levels of gamma-globulin and IgG of 1.5 g/dL were useful for predicting the treatment outcome of IFN monotherapy. CONCLUSIONS: The measurement of serum gamma-globulin and IgG is a valuable non-invasive tool for assessing the disease severity and treatment outcome in patients with chronic hepatitis C.     

The importance of cofactors in the histologic progression of minimal and mild chronic hepatitis C

Abstract: A follow-up liver biopsy was done 9–16 years (mean 12 years) after initial biopsy in 20 untreated Swedish patients infected with hepatitis C (8 men, 12 women; mean age 30 years at initial biopsy) in whom first biopsy had been classified as chronic persistent hepatitis. A significant progression of liver damage was found when using Histology Activity Index (HAI) scoring according to Knodell (p=0.006 for total HAI score; p=0.03 for grading, i.e., sum of HAI components 1, 2, and 3; p=0.01 for staging, i.e., HAI component 4, fibrosis). Fourteen of 20 (70%) patients had increased while 6 had decreased or unchanged HAI scores on follow-up biopsy. Occasional heavy alcohol drinkers (n=6) had an increased follow-up HAI score as compared with nondrinkers (p<0.05). Eight of 14 who deteriorated on follow-up versus 0 of 6 with improved or unchanged liver histology were anti-HBc positive (p=0.04). There was no significant correlation between HCV genotype and prognosis; however, the only two patients with liver cirrhosis on follow-up had genotype lb. In conclusion, most patients with minimal or mild chronic hepatitis C in the present study had histologic progression on the latest biopsy. Cofactors such as alcohol abuse and exposure to hepatitis B may have a greater influence than HCV alone in determining the rate of deterioration of liver disease.     

Clinical significance of serum hyaluronan in patients with chronic viral liver disease

In order to elucidate the clinical significance of serum hyaluronan in chronic viral hepatitis, serum hyaluronan concentrations were measured using a sandwich enzyme binding assay in 115 patients with chronic viral hepatitis. These findings were examined in relation to the results of laboratory liver tests, levels of serum markers for fibrosis and liver histological findings. Serum hyaluronan levels increased with the progress of liver disease, particularly in liver cirrhosis. There were no significant differences in serum hyaluronan levels among the cirrhotic patients according to Child's grade. Multivariate analysis showed that the significant independent predictors of serum hyaluronan were serum aspartate aminotransferase (P= 0.020), serum alanine aminotransferase (P= 0.008), serum cholinesterase (P< 0.001), particularly serum type IV collagen 7S domain (P< 0.0001), and the histological degree of liver fibrosis (P< 0.0001). These findings suggest that elevated serum hyaluronan levels are closely related to the severity of liver fibrosis. We assessed the predictive value of serum hyaluronan in differentiating cirrhosis from chronic hepatitis, constructing receiver operating curves; we found that serum hyaluronan was a better test for diagnosing cirrhosis than serum type IV collagen 7S domain and laboratory liver tests.     

Hepatitis B infection and changes in interferon-α and -γ production in patients with systemic lupus erythematosus in Taiwan

According to previous reports, the prevalence of hepatitis B virus (HBV) infection in patients with systemic lupus erythematosus (SLE) is varied. There has been no report on Taiwan, a hyperendemic area for HBV infection. Furthermore, impaired production of interferon (IFN) in peripheral blood mononuclear cells (PBMC) has been reported to be potentially pathogenic to both chronic HBV infection and SLE. However, the production of IFN in patients with both diseases coexisting is unknown. The aims of this study were to evaluate the prevalence of HBV infection in lupus patients in Taiwan and to measure the production of IFN in patients with both diseases coexisting. One hundred and seventy-three consecutive lupus patients and a control group of 692 ageand sex-matched healthy subjects were included for evaluation of the prevalence of HBsAg. Four groups of subjects (patients with SLE and HbsAg, SLE, chronic hepatitis B and normal controls) were selected for evaluation of the in vitro production of IFN-α and -γ. Six (3.5%) of the 173 SLE patients were positive for HBsAg, which was significantly lower than that of controls (14.7%; P< 0.0001). Patients with coexistent SLE and chronic HBV infection had less lupus activity, including less proteinuria (P= 0.02) and a lower serum titre of anti-double stranded DNA antibodies (anti-dsDNA; P= 0.04), than HBsAg-negative lupus patients. The in vitro production of IFN-α in patients with chronic hepatitis B was significantly lower than in those patients with SLE or in the normal control group (P<0.01). The yields of IFN-α and -γ in patients with coexistent SLE and chronic HBV infection were significantly different from those patients with SLE alone (P<0.05), but close to those of patients with chronic HBV infection. In conclusion, the prevalence of HBsAg carriers is significantly lower in lupus patients in Taiwan. Patients with coexistent SLE and chronic HBV infection had less lupus activity. Interferon-α and -γ may play a role in the above phenomenon.     

Viral and host factors in the prediction of response to interferon-α therapy in chronic hepatitis C after long-term follow-up

Acute infection with hepatitis C virus (HCV) develops into a chronic hepatitis in about 50–70% of patients. Treatment of these patients with interferon-α (IFN-α) results in a sustained long-term response in only 15–20% but causes numerous unwanted side-effects in a higher percentage of patients. The aim of our study was to define host or viral parameters that would allow identification of responders and non-responders to IFN-α prior to the onset of treatment. We studied a group of 87 patients suffering from chronic hepatitis C who were treated with IFN-α. After long-term follow-up, 18 patients (21%) showed a sustained response to IFN-α therapy (normalization of serum transaminases and loss of viral RNA from serum) for up to 7 years after therapy had ceased. By univariate and multivariate analyses, no host factors were found to be predictive of response to therapy. Neither the degree of inflammation or fibrosis in liver biopsy samples obtained before treatment nor immunogenetic factors (major histocompatibility complex II haplotype and tumour necrosis factor-α promoter polymorphism) were associated with response to therapy. In contrast, viral parameters showed a strong association with response to therapy. HCV genotype 3 was found significantly more frequently in responders (P = 0.034), and mean HCV RNA concentration was lower in responders (3.1 × 10⁴) than in non-responders (2.5 × 10⁵) (P = 0.01). By multivariate analysis, both HCV genotype and HCV RNA concentration were independent predictors of response to therapy. However, exact prediction of response to treatment for an individual patient was not possible on the basis of pretreatment viral RNA concentration or viral genotype. The best association with response to therapy was found to be clearance of HCV RNA from serum 3 months after the start of treatment (32 of 34 partial and sustained responders vs 0 of 53 non-responders; P = 0.001). In conclusion, determination of pretreatment viral factors, but not host factors, was significantly correlated with treatment response but did not give an accurate prediction for patients, whereas clearance of HCV RNA from serum after 3 months of therapy was predictive of response to therapy.     

How much does alcohol contribute to the variability of hepatic fibrosis in chronic hepatitis C?

In order to determine the contribution of alcohol intake to the severity of hepatic fibrosis in patients with chronic hepatitis C, we studied associations between various levels of alcohol intake, other demographic variables and semiquantitative liver histology in 434 cases of chronic hepatitis C. Clinical, demographic and disease-related data were entered into a relational database. Liver histology was scored according to Scheuer. The average daily alcohol intake for the year preceding liver biopsy (recent exposure) and for earlier periods (past exposure) was categorized into five levels of intake. One-third of patients gave a history of alcohol intake that had exceeded 40g/day for at least 5 years. By univariate analysis, age, but not recent or past alcohol intake or other baseline variables, was associated with portal score (r=0.14, P= 0.004), fibrosis score (r= 0.46, P < 0.001), total Scheuer score (r= 0.35, P < 0.001), However, by multivariate analysis, age (P < 0.001), past (but not present) alcohol intake (P < 0.001) and birth in Egypt (P= 0.006) were independently associated with fibrosis score. Age, past alcohol and birth place in Egypt contributed 27% to total variance of the hepatic fibrosis score, while age alone accounted for 23%. Age also independently predicted portal activity (P=0.02) and total Scheuer score (P < 0.001), whereas past alcohol intake correlated with total Scheuer score (P= 0.002) but not with other histological indices. A separate multivariate analysis was performed on a more homogeneous subgroup of 196 patients who acquired hepatitis C by injection drug use. In this subgroup, age (P < 0.05) and past alcohol (P < 0.05) were independently associated with fibrosis score. In both the overall and subgroup analyses, there was a threshold level of past alcohol intake (>80g/day) beyond which the risk of fibrosis increased significantly. It is concluded that toxic levels of alcohol exposure for at least 5 years accentuate hepatic fibrosis in hepatitis C but the influence of alcohol appears to be minor compared with age and other variables and is exerted only at toxic levels of intake.     

Noninvasive estimation of liver fibrosis and response to interferon therapy by a serum fibrogenesis marker， YKL-40, in patients with HCV-associated liver disease

AIM: To evaluate the clinical utility of serum fibrosis markers, including YKL-40, in patients with HCV-associated liver disease. METHODS: A total of 109 patients with HCV-associated liver disease were enrolled. We measured serum type IV collagen, amino-terminal peptide of type III procollagen (PIIIP), hyaluronic acid (HA), YKL-40 levels and biochemical. Parameters by RIA or ELISA. Eighty-eight patients underwent liver biopsy, and 67 of 109 patients received interferon (IFN) therapy. We also investigated the relationship between the concentrations of serum fibrosis markers and histological fibrosis scores (METAVIR), and evaluated the changes of the levels of fibrosis markers before and after the IFN therapy. RESULTS: The increase in serum levels of all markers, particularly HA, was correlated with the progression of liver fibrosis (for type IV collagen, F= 9.076, P<0.0001; for PIIIP, F= 9.636, P<0.0001; for HA, F=13.128, P<0.0001; and for YKL-40, F= 8.016, P<0.0001). YKL-40 had strong correlation with HA (r= 0.536, P<0.0001). Based on the receiver operating curve (ROC), the ability of serum HA exceeded the abilities of other serum markers to determine fibrosis score 4 from fibrosis score 0-3 (AUC = 0.854). While YKL-40 was superior to other fibrosis markers for predicting severe fibrosis (F2-F4) from mild fibrosis (FO-F1) (YKL-40, AUC = 0.809; HA, AUC = 0.805). After IFN therapy, only YKL-40 values significantly decreased not only in the responder group, but also in the nonresponder group (P = 0.03). CONCLUSION: YKL-40 may be a useful non-invasive serum marker to estimate the degree of liver fibrosis and to evaluate the efficacy of IFN therapies in patients with HCV-associated liver disease.     

Quantitative versus morphological assessment of liver fibrosis: semi‐quantitative scores are more robust than digital image fibrosis area estimation

Abstract: Background/Aim: Digital image analysis (DIA) allows quantitative assessment of fibrosis on liver biopsy. Accurate determination of a threshold greyscale level representing fibrous tissue is critical. This method has not been fully evaluated in clinical practice. Methods: Digital images of stained liver biopsy sections were captured by microscopy and converted to greyscale. A novel method of determining the threshold greyscale value at which to measure fibrosis area was developed (peak proportion area change (PPAC)). Reproducibility was tested in comparison with standard interactive thresholding and with semi‐quantitative scoring using the Histological activity index (HAI) system by a histopathologist. Fibrosis areas for different sections from the same biopsy core were also compared by each method. Results: Comparison between PPAC and interactive thresholding method demonstrated superior reproducibility of the PPAC method: r > 0.7, P < 0.001 compared with r = 0.19–0.64 (not all reaching significance). On a single section, reproducibility was similar for PPAC and the modified HAI system. When different sections from the same core were compared, the HAI system was more robust. Conclusions: The PPAC method is superior to standard interactive thresholding. However, variability in DIA scores between sections invalidates the technique for clinical use and semi‐quantitative scoring systems remain the gold standard for fibrosis assessment.     

The effect of interferon on the liver in chronic hepatitis C: a quantitative evaluation of histology by meta-analysis

Background/Aims: Several randomized clinical trials of interferon in chronic hepatitis C have examined the histological changes in paired biopsy specimens. We have attempted a quantitative evaluation by meta-analysis.Methods: Randomized Clinical Trials found by MEDLINE search were included if: a) they compared different IFN regimens with non-active treatment or with each other, b) they obtained biopsies before starting and at the time of stopping IFN in a sizable proportion of the treated and control patients, and c) they assessed the biopsy-specimens semi-quantitatively according to Scheuer's numerical scoring, system or Knodell's Histological Activity Index, with quantitation of fibrosis and Iobular, portal and periportal necroinflammation.Results: Seventeen trials were identified, in which 1223 adult patients had been studied. All trials homogeneously pointed towards a favorable interferon effect. The pooled data show a statistically significant histological improvement in treated patients as compared with controls for each of the four Histological Activity Index components and for the total Histological Activity Index score (overall improvement was −0.82 in favor of interferon, p<0.0001, 95% Confidence Interval −1.25 to −0.40). In the ten trials reporting histological changes separately in biochemical responders (primary and sustained responders) and non-responders, histological improvement was confined to the subset of biochemical responders. No change or very little change occurred in non-responders.Conclusions: Interferon treatment in chronic hepatitis C significantly improves liver histology. The effect of interferon is closely related to biochemical response. Studies assessing histological outcome 1 year or more after interferon treatment in long-term responders and comparatively in non-responders or relapsers would be important to confirm the regression of the necroinflammatory process in the former, as suggested by the normal serum alanine aminotransferase levels.