Knodell Histological Activity Research Articles

Effects of gadolinium-based MRI contrast agents on liver tissue.

MRI with contrast is often used clinically. However, recent studies have reported a high accumulation of gadolinium-based contrast agents (GBCAs) in kidney, liver, and spleen tissues in several mouse models. To compare the effects on liver tissue of gadolinium-based MRI contrast agents in the light of biochemical and histopathological evaluation. Institutional Review Board (IRB)-approved controlled longitudinal study. In all, 32 male Sprague-Dawley rats were divided into a healthy control group subjected to no procedure (Group 1), a sham group (Group 2), a gadodiamide group (Group 3), and a gadoteric acid group (Group 4). Not applicable. Liver tissues removed at the end of the fifth week and evaluated pathologically (scored Knodell's histological activity index [HAI] method by two histopathologists) immunohistochemical (caspase-3 and biochemical tests (AST, ALT, TAS, TOS, and OSI method by Erel et al) were obtained. Differences between groups were analyzed using the nonparametric Kruskal-Wallis test followed by the Tamhane test, and one-way analysis of variance (ANOVA) followed by Turkey's HSD test. An increase was observed in histological activity scores in sections from rats administered gadodiamide and gadoteric acid, and in caspase-3, AST and ALT values (P < 0.05). In contrast, we determined no change in TOS (P = 0.568 and P = 0.094, respectively), TAS (P = 0.151 and P = 0.055, respectively), or OSI (P = 0.949 and P = 0.494, respectively) values. These data suggest that gadodiamide and gadoteric acid trigger hepatocellular necrosis and apoptosis by causing damage in hepatocytes, although no change occurs in total antioxidant and antioxidant capacity. 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1367-1374.

Portal Vein Thrombosis in Splenectomized Cirrhotic Patient: A Case Report

Purpose: Portal vein thrombosis (PVT) and systemic venous thromboembolism are significantly increased in cirrhotic patients even without hepatocellular carcinoma. The risk of developing such complications is usually associated with advanced cirrhosis. When cirrhosis is mild and compensated, other possible causes of PVT should also be considered. We present a case of PVT in chronic hepatitis C infection with focal cirrhosis and portal hypertension with history of splenectomy. A 47-year-old Caucasian woman presented with chronic hepatitis C, genotype 1. She was treated with pegylated interferon and ribavirin for 48 weeks, but developed viral relapse. She had splenectomy when she was young for unclear reason. Her findings on pathologic examination of the liver biopsy were consistent with focal cirrhosis in mild to moderate chronic hepatitis; the Knodell's histologic activity index (HAI) score was 7-9/22. Her MELD score was 6. An annual esophagogastroduodenoscopy revealed non-bleeding grade II esophageal varices and cardial gastric varices. A computerized tomography scan revealed the sub-occlusive thrombus at the bifurcation of the main portal vein. The workup for hypercoagulable state showed low protein C, protein S, and antithrombin III levels. The inferior vena caval venogram showed thrombotic occlusion in left, right, and common portal vein with a portal systemic pressure gradient of 11 mmHg. Collateralization was present at portal hiatus. The ultrasound guided thrombus removal with interventional thrombolysis was attempted in order to avoid systemic anticoagulation therapy. However, the guidewire failed to pass through the obstructed portal vein. She eventually was evaluated for liver transplantation. This is a case that demonstrates the presence of PVT in a patient with mild compensated cirrhosis (based on both histological and clinical evaluation) without hepatocellular carcinoma. The incidence of PVT in well-compensated cirrhosis is reported between 0.6-16%. An increased frequency is reported in decompensated cirrhosis and in up to 35% of cirrhotic patients with hepatocellular carcinoma. The origin of PVT is multifactorial in most cirrhotic patients. Low serum protein C, protein S, and antithrombin III level secondary to decreased protein synthesis in cirrhosis can contribute to a prothrombotic state. Splenectomy is another possible cause of PVT in this case, since PVT after splenectomy occurs in 6-8%. However, the late onset of presentation makes it a less likely cause since most PVT occurs in days to weeks after splenectomy.

Abstract 394: Close association between subsided inflammation and the development of histologically less malignant HCC in HCV-associated LC

Abstract Aim: We recently demonstrated that severe inflammation in the background cirrhotic tissue correlate with the development of histologically more malignant hepatocellular carcinoma (Edmondson III HCC) in HCV-associated liver cirrhosis (LC), and that histology activity index (HAI) was the only one significant contributor to the development of Edmondson III (Ed III) HCC in small nodular HCC. There is a possibility, in the contrary of this phenomenon, that subsided inflammation correlates with the development of histologically less malignant HCC (Ed I type HCC) and that long-term subsided inflammation correlates with the development of large Ed I HCC. We examined the possibility. Methods: Curative hepatic resection for HCC with LC was performed in 264 patients during the past 10 years in Kanagawa Cancer Center hospital. Of 264 patients 197 patients were anti-HCV-positive or HCV-RNA positive. Out of the 197 patients, 32 patients whose HCC revealed only one small HCC nodule (≤ 3 cm) were selected for this study. Furthermore, the cases whose HCC nodules were large (&amp;gt; 3 cm), but consisted of predominantly Ed I component, were also examined. For the evaluation of inflammation in the background LC, modified Knodell's histology activity index (HAI) was used. (for the evaluation of pure inflammation, items of fibrosis was omitted); piece meal necrosis (1-4), intra lobular cellular degeneration and focal necrosis (1-4), portal cellular inflammation (1-4), were estimated by two well experienced pathologist. In each case, the HAI score was estimated in five field and average HAI score was calculated. All the sections of resected HCC tissue was examined pathologically in all patients for determining the grade of malignancy according to Edmondson Steiner's classification; Ed I (well differentiated), Ed II (moderately diff.), Ed III (poorly diff.). Results: The average HAI score in 7 Ed I HCC patients was as low as 3.61 ± 0.70 (mean ± SD), and was significantly lower than that in 17 Ed III HCC patients (5.21 ± 1.15, P &amp;lt;0.001). Furthermore, the average HAI in the 5 cases whose HCC nodules were more than 3 cm and whose major component of HCC nodules were Ed I, was also as low as 3.55 ± 0.74. Conclusions: It is suggested that subsiding inflammation in the background non-cancerous cirrhotic portion might correlate with the development of histologically less malignant HCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 394. doi:1538-7445.AM2012-394

Hepatitis C Virus Clearance after Discontinuation of Pegylated Interferon Alpha-2a Monotherapy in a Child

The present patient was a 4-year-old boy. His hepatitis C virus genotype was 2a, and his viral load was high (1400,000 U/mL). The pretreatment liver biopsy revealed no fibrosis or malignancy and mild chronic hepatitis; his Knodell's histological activity (HAI) score was 4. Single nucleotide polymorphism of IL28B (rs8099917) was major type. The patient began antiviral treatment with pegylated interferon alpha 2a (90 μg/week). At week 9, serum HCV RNA became undetectable, with a sensitivity of 50 copies/mL. Antiviral treatment was discontinued at week 11 because the ALT level increased to 610 U/L. After discontinuation of therapy, the patient's serum HCV RNA status became positive again. The serum viral load increased to 100,000 U/mL. During this period, he had been observed without medication. Sixteen months after stopping treatment, serum HCV became undetectable. Over a 4-year period, HCV RNA became negative and his anti-HCV antibody titer gradually decreased. In conclusion, though antiviral therapy resulted in failure or incomplete therapy, a reduced viral load resulted in viral clearance in the present patient. Interleukin 28B genotype might have association with the clearance of hepatitis C virus after discontinuation of antiviral therapy.

Serum fibrosis markers (Procollagen-III-peptide, hyaluronic acid, transforming growth factor β-1), aspartate-aminotransferase to platelet ratio index (APRI), and transient elastography (FibroScan) in patients with chronic HCV infection

Background: Although liver biopsy (LB) is the gold standard for the morphological diagnosis of diseases of the liver, recent noninvasive tests may also help in the evaluation of liver fibrosis. We have studied blood fibrosis markers and liver stiffness (LS) measurement to assess fibrosis in different forms of chronic hepatitis C virus (HCV) infection. Patients and methods: Out of 119 HCV-infected patients, 75 had biopsy-proven chronic hepatitis C, 24 had HCV cirrhosis, 20 individuals were symptom-free HCV carriers with persistently normal alanine aminotransferase (PNA), and 30 healthy blood donors served as controls. Wai's aspartate-aminotransferase (AST) to platelet ratio index (APRI) was calculated from serum AST and blood platelet number. Serum HCV-RNA (hepatitis C virus ribonucleic acid), procollagen-III-peptide (P-III-P) and hyaluronic acid (HA), plasma transforming growth factor β-1 (TGFβ-1), Knodell's histological activity index (HAI), and METAVIR fibrosis score were determined, and for LS measurement transient elastography (TE) (FibroScan) was applied. Results: In chronic hepatitis C patients, all fibrosis markers were significantly elevated compared to normal controls. HA, APRI, and LS values were highest in HCV cirrhosis and nonresponders to PEG-IFN + ribavirin (P/R) therapy. High P-III-P values occurred only in advanced fibrosis. Serum HA correlated with the fibrosis stage. Plasma TGFβ-1 was significantly higher in patients with chronic hepatitis C than in symptom-free HCV carriers, and it correlated with HAI. After 3–6 months of P/R therapy, both HA and TGFβ-1 levels significantly decreased even in virological nonresponders. APRI was 0.21 ± 0.05 in normal controls, 0.20 ± 0.08 in symptom-free HCV carriers, 0.70 ± 0.40 in patients with chronic hepatitis C, and 3.21 ± 2.3 in HCV cirrhosis cases. LS values were 5.10 ± 1.19 kPa in controls, 5.38 ± 1.37 kPa in HCV carriers with PNA, 9.67 ± 4.11 kPa in chronic hepatitis C patients, 6.56 ± 2.61 kPa in patients with sustained virological response, 18.55 ± 11.65 kPa in nonresponders to P/R, and 37.40 ± 16.85 kPa in HCV cirrhosis cases. On the basis of a novel sequential algorithm that comprises APRI and LS for assessment of fibrosis, 47% of our HCV patients did not need biopsy for diagnosing significant (F ≥ 2) fibrosis. Conclusion: Both blood fibrosis markers and LS, particularly in combination, represent an advance in the noninvasive assessment of fibrosis in HCV infection. P/R treatment may inhibit fibrosis progression even independently of virological response.

A single arm phase II study of a Far-Eastern traditional herbal formulation (sho-sai-ko-to or xiao-chai-hu-tang) in chronic hepatitis C patients

Hepatitis C is a major public health problem internationally. Many patients cannot benefit from the current treatment regimen (interferon/ribavirin combinations) due to its side effects or ineffectiveness. Xiao-Chai-Hu-Tang or Sho-sai-ko-to (SST), a compound of seven botanical extracts used for liver diseases traditionally in East Asia, was shown to reduce transaminases and the incidence of hepatocellular carcinoma in hepatitis B patients. We conducted a phase II trial of SST in hepatitis C patients who were not candidates for interferon-based therapy to determine whether this agent is worthy of further study. Twenty four chronic hepatitis C patients received SST at 2.5 g per os (p.o.) three times daily (t.i.d.) for 12 months. Liver function, hepatitis C virus (HCV) viral load and liver biopsy histology were assessed before and after the intervention. Improvement of aspartate aminotransferase (AST) was observed in 16 (67%) of study participants. Improvement of alanine aminotransferase (ALT) was seen in 18 (75%) patients. Viral load response was mixed, with 7 patients showing reductions, 10 increases and 7 indeterminate due to assay limitations. Among the 9 (38%) subjects who showed improvement per Knodell's histology activity index (HAI) scores in paired comparison of pre- and post-treatment liver biopsy (the primary endpoints of the study), 5 (21%) showed an improvement of 2 points or greater, meeting the pre-defined criteria for "response. Sho-sai-ko-to (SST or Xiao Chai Hu Tang) may improve liver pathology in selected hepatitis C patients who are not candidates for interferon based treatment. Larger, controlled studies of this botanical formulation may be warranted.

Abstract 2712: Inflammation in the background cirrhotic tissue might accelerate the promotion in the HCC development from HCV-associated cirrhosis

Abstract Aim: Hamada et al. succeeded in converting ER-1, a weakly tumorigenic cloned cell line of a rat mammary carcinoma, into a highly tumorigenic and metastatic cell line by interaction with host cell reactive to a foreign body (plastic plates). They attributed these phenomenon to the cytokines such as LL-6 derived from host reactive inflammatory cells crowded around the foreign body. It is possible that the same mechanism is involved in the development of human HCC, and that inflammation in the background cirrhotic tissue might accelerate the process of promotion. Methods: Curative hepatic resection for HCC with LC was performed in 223 patients during the past 8 years in Kanagawa Cancer Center hospital. Of 223 patients 182 patients were anti-HCV-positive or HCV-RNA positive without habitual alcohol intake. Out of 182 patients, 32 patents whose HCC revealed only one small HCC nodule of less than 3 centimeter in diameter were selected for this study. For the evaluation of inflammation in the background LC, modified Knodell's histology activity index (HAI) was used. (for the evaluation of pure inflammation, items of fibrosis was omitted); piece meal necrosis (1-4), intra lobular cellular degeneration and focal necrosis (1-4), portal cellular inflammation (1-4), were estimated by two well experienced pathologist. In each case, the HAI score was estimated in five field and average HAI score was calculated. All the sections of resected HCC tissue was examined pathologically in all patients for determining the grade of malignancy according to Edmondson Steiner's classification; Ed I (well differentiated), Ed II (moderately diff.), Ed III (poorly diff.) Results: The average HAI score in the non-cancerous cirrhotic portion in HCC patients with Ed III was 5.50 ± 0.98 (mean ± SD), and was significantly larger than that in HCC patients without Ed III (4.18 ± 0.70, p &amp;lt; 0.001). Furthermore, the occurence rate of HCC containing Ed III component in the HCC patients whose HAI score was more than 5.0 was as high as 88.9% (16 out of 18), and was highly significant as compared with those in HCC patients whose HAI score was less than 5.0% (3 out of 14, 21.4%, p &amp;lt; 0.005).Conclusions: It is suggested that inflammation in the surrounding non-cancerous cirrhotic tissue would accelerate the process of promotion in the HCC development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2712. doi:10.1158/1538-7445.AM2011-2712

Lamivudine causes reduction of histological activity index and viral load in liver biopsies in patients with chronic hepatitis B infection

The aim of this study was to compare the histological activity index and viral load, which one response more with lamivudine, an anti-viral agent used for treating chronic hepatitis B infected patients. Materials and methods Following the defined case selection protocol a total of 39 CHB cases were enrolled in the study. After initial evaluation they received with lamivudine orally for 52 weeks. Repeat biopsy could be obtained in 16 cases. 16 patients were analysed in this study. All patients had a liver biopsy at the beginning of the study before starting the drug. Lamivudine was given orally at a dose of 100 mg once daily for 52 weeks. A second liver biopsy was taken for comparison at the end of week 52. Biopsy materials were stained with Haematoxylin and Eosin staining as a routine procedure. Immunohistochemical staining for both surface and core antigens by using antibodies against these antigens were done as special staining. In routine staining biopsies were scored according to Knodell's Histological Activity Index (HAI). Improvements in histological activity index were regarded in cases where Knodell's HAI improved by 2 points or more after treatment. Both Viral Load and staining intensity of each antigen were assessed by visual inspection of 300 hepatocytes randomly under light microscope. Results 68% (11/16) patients had a reduction of hepatic necroinflammatory HAI score (Components 1 through 3) by 2 points or more at the end of 52 weeks of lamivudine therapy compared to the pretreatment values. Improvement in viral load was found in 80% (12/15) cases. Staining intensity of both viral antibodies was also decreased following treatment. Discussion One of the key objectives of treatment of chronic hepatitis B remains to improve hepatic histology in addition to clearing the virus. The quest continues in this regard and antivirals are potential tools at hand in achieving this goal. Conclusion Lamivudine causes significant improvement in viral load in the majority of patients treated for CHB.

Chronic hepatitis in Nigerian patients: a study of 70 biopsy-proven cases

Liver cirrhosis and hepatocellular carcinoma are known sequelae of chronic hepatitis. Early diagnosis and treatment of chronic hepatitis could delay or even abort progression to terminal liver disease. Prospective study of 70 consecutive patients with features of early liver disease or discovered with HBsAg (or anti-HCV) during pre-employment and/ or pre-donation screening at Ile-Ife, Nigeria. All the patients had liver biopsy and the histology evaluated with the Knodell Histological Activity Index. Fifty-three patients had symptomatic disease (M: F ratio, 1.5:1) while 17 were asymptomatic (M: F ratio, 3:1). The mean ages were 49.04 (SD+/-16.78) and 29.82 (SD+/-6.13) for the symptomatic and the asymptomatic patients respectively (P< 0.005). Major symptoms were right upper abdominal pain (68%), weight loss (51%) and fatigue (41.5%). Alcohol consumption was significantly related to symptomatic chronic hepatitis (P< 0.01). Over 50 % of patients with asymptomatic chronic hepatitis had abnormal liver scan and liver function tests. All the asymptomatic cases and 77.4 % of the symptomatic group had HBsAg while only 1 patient (symptomatic) was anti-HCV positive. On liver histology, all the patients with asymptomatic chronic hepatitis had a Knodell score of< or = 8 and none had fibrosis. Over half of the symptomatic patients had a Knodell score of > or = 9 (56.6%) and stage 2 or 3 fibrosis (51 %). Asymptomatic chronic hepatitis patients tend to be younger and of the male sex. Symptomatic chronic hepatitis may signal the onset of significant fibrosis and alcohol abuse may accelerate this process. Serum ALT and liver scan are useful initial screening tests for asymptomatic patients with hepatitis B or C viral markers.

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.

Relationship between serum cytokine levels and histopathological changes of liver in patients with hepatitis B

To investigate whether there was a relationship between the liver functions and fibrosis scores of hepatitis B patients and their TNF-alpha, IFN-gamma, IL-4, and TGF-beta(1) serum levels based on the studies of liver biopsies. Thirty patients with chronic hepatitis B (CHB) receiving no treatment and 30 healthy individuals with negative hepatitis serology and normal values of liver biochemistry were studied. After serum samples of the patients were collected, liver needle biopsy was performed on each patient. Cytokine levels were studied by ELISA. The biopsy materials were scored based on Knodell's histological activity index. In comparison of cytokine levels between CHB patients and control group, TNF-alpha, IL-4, and TGF-beta(1) levels of the patients were higher in CHB patients than in the controls, while IFN-gamma level was lower in the patients than in the controls. There were significant differences between the groups in TNF-alpha, IL-4, TGF-beta(1), and IFN-gamma (P<0.005, 0.03, 0.002, 0.0001, respectively). There was a negative correlation between TGF-beta(1) and IL-4 and IFN-gamma (P<0.05), TNF-alpha and the other cytokines and IFN-gamma and IL-4 were not correlated (P>0.05). TGF-beta(1) was correlated with fibrosis (P<0.05). Liver necroinflammatory activity and fibrosis and TNF-alpha, IL-4, and IFN-gamma were not correlated (P>0.05). In the course of HBV infection and its chronic progress, cytokines play an important role. IL-4 and IFN-gamma are effective in the chronic progression, while TGF-beta(1) is effective in the development of fibrosis. Serum cytokine levels may be effective tools in the estimation of chronic progression and fibrosis development.

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.

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.

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

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. 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. 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: 7.7 Meq/ml vs. 3.1 Meq/ml, p=0.0007). 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.

Enhanced expression of interleukin-6 in chronic hepatitis C.

There is a possibility that proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the inflammatory process of chronic hepatitis C. This study was undertaken to investigate the possible role of IL-6 in the pathophysiology of chronic hepatitis C. Serum IL-6 levels in 63 patients with chronic hepatitis C and in 26 normal controls were measured. Light and electron immunostaining studies to localize IL-6 protein as well as in situ hybridization to localize IL-6 messenger RNA were performed on 10 liver biopsy specimens. Serum IL-6 levels were significantly (p<0.01) elevated in chronic hepatitis C compared to those in normal controls. Although no statistically significant correlation was found between serum IL-6 levels and hepatobiliary enzyme levels, a significant correlation (p<0.01) was found between serum IL-6 levels and category II of Knodell's histological activity index score. Non-parenchymal cells in hepatic sinusoids and the cells infiltrating enlarged fibrous portal tracts were definitely positive for IL-6 protein and mRNA by immunohistochemistry and in situ hybridization. In addition, immunoelectron microscopy revealed a weak and occasional positive reaction in the cytoplasm of hepatocytes. The majority of the positive cells in hepatic sinusoids showed CD68 immunoreactivity in consecutive sections indicating that these were Kupffer cells. Sinusoidal endothelial cells and hepatic stellate cells also exhibited a weak reaction. These results strongly suggest that Kupffer cells in liver parenchyma and macrophages infiltrating in portal tracts are the main producers of elevated IL-6 in serum. Moreover, there is a possibility that IL-6 produced by hepatocytes could also act as a regenerative stimulus to hepatocytes themselves in an autocrine fashion.

Histological changes in liver biopsies after one year of lamivudine treatment in patients with chronic hepatitis B infection

The aim of this study was to examine the histological changes in liver biopsies induced by 52 weeks of lamivudine therapy in patients with e-antigen positive and e-antigen negative chronic hepatitis B infection. Twenty patients were enrolled into this open-label study. All patients had a liver biopsy within the 4 weeks before starting lamivudine therapy. Lamivudine was given orally at a dose of 100 mg OD for 52 weeks. A second liver biopsy was taken for comparison at the end of week 52. Blinded biopsies were evaluated by a histopathologist and scored according to Knodell's histology activity index (HAI). Ninety-five percent (19/20) patients had a reduction of their hepatic necroinflammatory HAI score (components 1 through 3) by > or =2 points at the end of 52 weeks of lamivudine therapy compared to their pretreatment values. Not only were improvements in necroinflammatory activity observed, but 7/20 (35%) of patients had improvement in fibrosis. This histologic improvement was independent of the presence or absence of e-antigen. Significant improvements in liver histology can be obtained in the majority of patients when they are treated with lamivudine for 1 year.

Hepatitis C virus (HCV) hypervariable region 1 complexity does not correlate with severity of liver disease, HCV type, viral load or duration of infection

Several studies have suggested that infection with a highly heterogeneous population of hepatitis C virus correlates with a low response rate to interferon. It is still debated, however, whether or not this heterogeneity might be associated with liver disease severity. The aim of this study was to analyse hepatitis C virus genome complexity in patients with various stages of liver disease. We used polymerase chain reaction-single strand conformation polymorphism (SSCP) analysis to estimate the degree of complexity of the hypervariable region (HVR1) in 95 anti-HCV and serum HCV-RNA positive patients. They were divided into two groups according to Knodell's histological activity index (HAI) grading: 22 with HAI <4 and 73 with HAI> or =4, including 19 with cirrhosis. The number of visible SSCP bands ranged from 1 to 7. There was no significant difference in the number of SSCP bands between patients with HAI <4 and patients with HAI> or =4 (median number of bands was 4 in both groups). The number of SSCP bands was not correlated to the biochemical activity, the genotype, the HCV-RNA titre or the duration of hepatitis C virus infection. The HCV-HVR1 complexity profile alone does not correlate with the severity of liver disease, whatever the biological and virological profile of the viral infection.

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

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. 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 of lobular, portal and periportal necroinflammation. 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. 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.

Current anatomico-pathological classification of hepatitis: characteristics of HCV infection.

Better knowledge of the natural history and aetiology of chronic hepatitis and the introduction of effective treatments have lead to revising the histopathological classification of chronic hepatitis. The basic lesions observed in chronic hepatitis are intra-portal inflammatory infiltrate, piecemeal necrosis, lobular necrotico-inflammatory lesions, and fibrosis. The histological activity of chronic hepatitis is usually assessed by apply Knodell's score or histological activity index (HAI). This score includes inflammatory lesions and fibrosis. But fibrosis is in fact the consequence of portal and lobular inflammation. The current classifications, including that proposed at the 1994 world conference on gastroenterology, propose discriminating between activity, or grade, and fibrosis, or stage. The classification of chronic hepatitis has also been revised because it was ill-adapted to assessing the C virus-linked chronic hepatitis. Histologically, these are little active chronic hepatitis associated with intra-sinusoidal inflammatory infiltrates of the leukaemia type, intralobular microgranulomas, intraportal lymphoid aggregates, and lesions of the small biliary tracts. Although non-specific, these lesions are evocative enough to histologically back-up diagnosis. Liver biopsy confirms chronic hepatitis diagnosis, determines its grade and stage, sometimes its cause. Liver biopsy also permits assessing treatment response.