Significant Hepatic Fibrosis Research Articles

Transient elastography for measurement of liver stiffness measurement can detect early significant hepatic fibrosis in Japanese patients with viral and nonviral liver diseases

Many studies have reported the efficiency of transient elastography, a noninvasive, reproducible, and reliable method for predicting liver fibrosis, in patients with chronic hepatitis C (CHC) and B (CHB), but there are few reports about nonviral chronic liver disease (CLD) such as primary biliary cirrhosis (PBC), nonalcoholic steatohepatitis (NAFLD), and autoimmune hepatitis (AIH). We therefore compared the efficiency of transient elastography between CHC and nonviral CLD. We assessed the accuracy of liver stiffness measurement (LSM) using Fibroscan, and compared these values with those of hyaluronic acid, type 4 collagen, platelet count, prothrombin index, and AST/platelet ratio index (APRI) as indices for the diagnosis of liver fibrosis in 114 patients with a variety of chronic liver diseases: CHC (n = 51), CHB (n = 11), NAFLD (n = 17), PBC (n = 20), and AIH (n = 15). The histology was assessed according to the METAVIR score by two pathologists. The number of fibrosis stage (F0/1/2/3/4) with CHC was 9/15/12/6/10, and that with nonviral CLD was 10/21/11/4/6, respectively. The ability, assessed by area under receiver operating characteristic (AUROC) curve, to predict liver fibrosis F >or= 2 for LSM, HA, type 4 collagen, platelet count, prothrombin index, and APRI, was 0.92, 0.81, 0.87, 0.85, 0.85, and 0.92 in CHC patients, respectively; and 0.88, 0.72, 0.81, 0.67, 0.81, and 0.77 in nonviral CLD patients, respectively. In patients with nonviral CLD, LSM was most helpful in predicting significant fibrosis (F >or= 2). Transient elastography is a reliable method for predicting significant liver fibrosis, not only in CHC patients but also in nonviral CLD patients.

Factors Predictive of Significant Hepatic Fibrosis in Adults With Chronic Hepatitis B and Normal Serum ALT

This study examines the prevalence and correlates of significant liver fibrosis among patients with immunotolerant hepatitis B. Adults with chronic hepatitis B infection acquired early in life often have normal serum alanine aminotransferase (ALT) activity and high serum hepatitis B virus deoxyribonucleic acid loads (HBV DNA), known as "immunotolerant" hepatitis B. We conducted a cross-sectional study of 28 hepatitis B patients with serum HBV DNA titer >10 copies/mL, positive hepatitis B envelope antigen, and persistently normal serum ALT in a tertiary care setting. Liver biopsies were reviewed by a single pathologist who was blinded to other data. The prevalence of significant hepatic fibrosis was determined using the hospital-defined upper limit of normal for ALT and 2 more stringent criteria proposed by recent studies. Statistical analyses were conducted to identify factors associated with hepatic fibrosis. The prevalence of stage 2 fibrosis using the hospital laboratory, more stringent, and most stringent definitions of normal serum ALT, was 32%, 32%, and 13%, respectively, corresponding to negative predictive values of 68%, 68%, and 88%, respectively. Age greater than 30 years (P=0.035), grade 2 liver inflammation (P=0.005), and lower serum HBV DNA level (mean 7.45 vs. 8.42 log10 copies/mL, P<0.001) were independently associated with stage 2 fibrosis on liver biopsy. These results highlight the need to use stringent definitions of normal serum ALT when making clinical decisions for patients with chronic hepatitis B. Older age and lower serum HBV DNA level predict significant hepatic fibrosis on biopsy. Our findings may guide decisions regarding liver biopsy among patients with immunotolerant hepatitis B.

Diagnosis and Quantitation of Fibrosis

Hepatic fibrosis is the final common pathway for many different liver insults. Originally considered to be irreversible, hepatic fibrosis is now known to be a dynamic process with a significant potential for resolution. The diagnosis and quantitation of fibrosis have traditionally relied on liver biopsy. However, there are a number of drawbacks including the invasive nature of the procedure, sampling error, and interobserver variability. This article reviews the current role of liver biopsy in the assessment of hepatic fibrosis and discusses the role of the newer noninvasive methods including serum markers and radiologic tests.

Simple Tests to Predict Hepatic Fibrosis in Nonalcoholic Chronic Liver Diseases

Several simple tests for hepatic fibrosis employ indirect markers. However, the efficacy of using direct and indirect serum markers to predict significant fibrosis in clinical practice is inconclusive. We analyzed the efficacy of a previously reported indirect marker of hepatic fibrosis - the aspartate aminotransferase to platelet ratio index (APRI) - in patients with nonalcoholic chronic liver diseases (CLDs). A total of 134 patients who underwent a percutaneous liver biopsy with a final diagnosis of chronic hepatitis B (n=93), chronic hepatitis C (n=18), or nonalcoholic fatty liver disease (n=23) were enrolled. A single-blinded pathologist staged fibrosis from F0 to F4 according to the METAVIR system, with significant hepatic fibrosis defined as a METAVIR fibrosis score of >/=2. The mean area under the receiver operating characteristic curve (AUROC) of APRI for predicting significant fibrosis in nonalcoholic CLDs was 0.84 [95% confidence interval (CI), 0.78-0.91]. APRI yielded the highest mean AUROC in the patients with chronic hepatitis B (0.85; 95% CI, 0.771-0.926). The positive predictive value of APRI >/=1.5 for predicting significant fibrosis was 89%. The negative predictive value of APRI <0.5 for excluding significant fibrosis was 80%. APRI might be a simple and noninvasive index for predicting significant fibrosis in nonalcoholic CLDs.

Aspartate aminotransferase to platelet ratio index (APRI) can predict liver fibrosis in chronic hepatitis B

Background There have been still few valuable markers that can be used as indirect markers of liver fibrosis in chronic hepatitis B. Aims This study aimed to evaluate efficacy of several indirect markers of liver fibrosis and to identify the most valuable test in chronic hepatitis B. Patients and methods A total of 264 patients with chronic hepatitis B were consecutively enrolled. Fibrosis was staged by a single blinded pathologist according to the METAVIR system. Significant fibrosis was defined as stage ≥2. We investigated diagnostic accuracy of four indirect markers including aspartate aminotransferase to platelet ratio index for predicting significant fibrosis. Results Mean age was 28 years. 53% (141/264) had significant hepatic fibrosis. Of indirect markers, aspartate aminotransferase to platelet ratio index yielded the best area under the receiver operating characteristic curve (0.86; 95% confidence interval, 0.82–0.91). Positive predictive value/negative predictive value at 0.5, 1.5 and 2.0 of aspartate aminotransferase to platelet ratio index score for predicting significant fibrosis were 63%/91%, 83%/74% and 86%/65%, respectively. The odds ratio for aspartate aminotransferase to platelet ratio index ≥1.4 relative to less than aspartate aminotransferase to platelet ratio index of 1.4 was 17.971 ( p < 0.0001; 95% confidence interval, 9.677–33.376). Conclusions Of simple markers already developed in chronic hepatitis C, aspartate aminotransferase to platelet ratio index may be the most accurate and simple marker for predicting significant fibrosis in chronic hepatitis B.

Noninvasive Diagnosis of Hepatic Fibrosis in Patients With Chronic Hepatitis C by Splenic Doppler Impedance Index

The value of Doppler ultrasonography to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C (CHC) remains controversial. Consecutive histologically proven patients with CHC over a 4-year period were divided into training (n = 335) and validation (n = 168) sets. Hepatic Doppler impedance index, splenic Doppler impedance index, and mean portal vein velocity were evaluated for all patients before liver biopsies. Multivariate logistic regression was performed to find the independent factors to predict patients with significant fibrosis (>/=F2) and cirrhosis (F4) in the training set. Receiver operating characteristic curves were constructed for these factors to evaluate the diagnostic accuracy of significant hepatic fibrosis and cirrhosis in the training set, and in the validation set to evaluate the reproducibility. Multivariate logistic regression revealed that the splenic arterial pulsatility index (SAPI) and the mean portal vein velocity were predictive of significant fibrosis (>/=F2) and cirrhosis (F4). Receiver operating characteristic analysis showed the areas under the curves of regression models and SAPI were comparable in predicting significant fibrosis (0.88 vs 0.87, P = .22) and cirrhosis (0.92 vs 0.90, P = .12) in the training set. Areas under the curves of SAPI were 0.89 and 0.92 in predicting significant hepatic fibrosis and cirrhosis in the validation set. By choosing optimized cut-off levels, 54% and 76% of the patients with significant hepatic fibrosis and cirrhosis could be predicted correctly. SAPI is accurate and reproducible for assessing the severity of hepatic fibrosis in patients with CHC. Applying this simple Doppler index can decrease the need for staging liver biopsy.

Noninvasive tests for the prediction of significant hepatic fibrosis in hepatitis C virus carriers with persistently normal alanine aminotransferases

The diagnostic value of Doppler and various noninvasive indices in predicting significant hepatic fibrosis in hepatitis C virus (HCV) carriers with persistently normal alanine aminotransferases (PNALT) is unknown. Seventy-nine treatment-naïve HCV carriers with PNALT, who received Doppler ultrasonography and percutaneous liver biopsies, were enrolled in the study. Doppler indices, including portal vein velocity (PVV), hepatic arterial resistive index (HARI), hepatic arterial pulsatility index (HAPI), splenic arterial resistive index (SARI), and splenic arterial pulsatility index (SAPI), were compared with known biochemical indices used in HCV carriers with elevated ALT levels, including aspartate aminotransferase (AST) to platelet ratio index (APRI), age-platelet index (API), and AST to ALT ratio (AAR), for the diagnostic accuracy of significant hepatic fibrosis. SAPI was the most discriminatory index among the Doppler indices (P<0.001). By comparing areas under the receiver-operating characteristic (AUROC) of SAPI with various biochemical indices, SAPI was superior to APRI, API, and AAR for predicting significant fibrosis (> or =F2) (0.862 vs. 0.673, 0.639, 0.504). SAPI set at 0.85 and 1.10 had a sensitivity of 96.7% and 66.7%, a specificity of 44.6% and 96.0%, a positive predictive value of 41.4% and 87.1%, and an negative predictive value of 97% and 87.7% in predicting significant fibrosis. This study indicates that SAPI is the most useful index among Doppler and biochemical indices for the detection of significant hepatic fibrosis in HCV carriers with PNALT levels.

Noninvasive Markers of Liver Fibrosis and Inflammation in Chronic Hepatitis B-Virus Related Liver Disease

Noninvasive markers for predicting significant fibrosis and inflammation have not yet been validated in an unselected group of chronic hepatitis B virus (HBV) carriers. The aim of this study was to create noninvasive models to predict significant fibrosis and inflammation in chronic HBV carriers. A total of 276 (229 HBeAg negative, 47 HBeAg positive) unselected consecutive treatment naïve patients chronically infected with HBV who attended our center over a 36-month period underwent liver biopsy. HBeAg negative patients were randomly divided into two cohorts: training group (N = 130) and validation group (N = 99). HBeAg positive patients were analyzed as a whole without separation. Thirteen parameters were analyzed separately in HBeAg negative and HBeAg positive patients to predict significant fibrosis (Ishak stage >or=3) and inflammation (Ishak grade >or=7). In HBeAg negative patients significant liver fibrosis was best predicted using the variables HBV DNA levels, alkaline phosphatase, albumin, and platelet counts with an area under ROC curve (AUC) of 0.91 for the training group and 0.85 for the validation group. Using the low cutoff probability of 4.72, significant fibrosis could be excluded with negative predictive value of 99% in the entire cohort, and liver biopsy would have been avoided in 52% of patients. The best model for predicting significant inflammation included the variables age, HBV DNA levels, AST, and albumin with an AUC of 0.93 in the training and 0.82 in the validation group. In HBeAg positive patients no factor could predict accurately stages of liver fibrosis, but the best factor for predicting significant inflammation was AST with an AUC of 0.87. Significant hepatic fibrosis and necroinflammation can reliably be predicted using routinely checked tests and HBV DNA levels.

Screening for Hemochromatosis in Asymptomatic Subjects With or Without a Family History

Hemochromatosis in white subjects is mostly due to homozygosity for the common C282Y substitution in HFE. Although clinical symptoms are preventable by early detection of the genetic predisposition and prophylactic treatment, population screening is not currently advocated because of the discrepancy between the common mutation prevalence and apparently lower frequency of clinical disease. This study compared screening for hemochromatosis in subjects with or without a family history. We assessed disease expression by clinical evaluation and liver biopsy in 672 essentially asymptomatic C282Y homozygous subjects identified by either family screening or health checks. We also observed a subgroup of untreated homozygotes with normal serum ferritin levels for up to 24 years. Prevalence of hepatic iron overload and fibrosis were comparable between the 2 groups. Disease-related conditions were more common in male subjects identified by health checks, but they were older. Hepatic iron overload (grades 2-4) was present in 56% and 34.5% of male and female subjects, respectively; hepatic fibrosis (stages 2-4) in 18.4% and 5.4%; and cirrhosis in 5.6% and 1.9%. Hepatic fibrosis and cirrhosis correlated significantly with the hepatic iron concentration, and except in cases of cirrhosis, there was a 7.5-fold reduction in the mean fibrosis score after phlebotomy. All subjects with cirrhosis were asymptomatic. Screening for hemochromatosis in apparently healthy subjects homozygous for the C282Y mutation with or without a family history reveals comparable levels of hepatic iron overload and disease. Significant hepatic fibrosis is frequently found in asymptomatic subjects with hemochromatosis and, except when cirrhosis is present, is reversed by iron removal.

Expanding the applicability of noninvasive fibrosis markers in HIV/HCV co-infected patients

HCV therapy in patients co-infected with HIV/HCV shows worse responses than in patients infected with HCV, and often exhibits higher discontinuation rates.1-3 Therefore, a careful patient selection before antiviral therapy is advisable, usually reserving treatment for those with significant hepatic fibrosis. Liver biopsy is considered the gold standard method to assess fibrosis in chronic liver disease. However, it is an invasive technique with associated morbidity.4 Accurate noninvasive tests to predict liver fibrosis would be particularly useful in HIV/HCV patients in whom a more advanced liver disease is commonly observed.5, 6 We read with interest the article by Sterling et al.7, in which they developed the FIB-4 index, a model that uses age and routine tests such as AST, ALT, and platelet count (PLT) for the prediction of significant liver fibrosis in HIV/HCV patients, giving an important contribution to our knowledge in this field. However, these authors used AST and ALT levels expressed as International Units per liter. Considering that reference ranges for these tests exhibit considerable interlaboratory variability, we believe that the proposed cutoff for FIB-4 may show different sensitivities, specificities, and accuracies among medical centers using distinct limits of normality. Hence, it is possible that this method of expressing aminotransferases activity can limit the applicability of this index. We sought to validate FIB-4 using data retrospectively collected from treatment-naive HIV/HCV patients. The original model was adapted in order to use AST and ALT levels expressed as times the upper limit of normality (×ULN), as follows: (age [yr] × AST [×ULN]) × 10/((PLT [109/l]) × (ALT [×ULN])1/2). We evaluated 111 patients (males, 73%; mean age, 40.2 ± 7.8 years). Mean CD4+ cell count was 431 ± 225 cells/ml and 58% of patients had undetectable HIV viral load under antiretroviral therapy. All patients showed HCV viremia and underwent liver biopsy, irrespective of ALT levels. A single pathologist analyzed all liver biopsy slides using the METAVIR group scoring system. Advanced liver fibrosis, defined by the presence of F3 or F4 METAVIR stages, was observed in 28 patients (25%). To discriminate these subjects, the area under the receiver operating characteristic curve (ROC) of FIB-4 was 0.846 ± 0.046. Based on the ROC, 2 cutoffs were chosen: <2.6 and ≥5.0. Among patients with scores <2.6 or ≥5.0, concordant results were found in 88% (65/74). If biopsy indication was based only on FIB-4 results and restricted to scores in the intermediate range (≥2.6 and <5.0), 67% of liver biopsies could have been avoided. Overall, our results are similar to the data presented by Sterling et al. (Table 1). In fact, even higher sensitivities and positive and negative predictive values were achieved. The use of different histological scoring systems (i.e., METAVIR versus Ishak score) and the evaluation of our cohort by a single pathologist could be responsible for these differences. Nevertheless, in both studies the FIB-4 index could reliably predict the severity of liver fibrosis in about 70% of patients with HIV/HCV co-infection, possibly avoiding the requirement for a liver biopsy in those patients. Finally, we would like to suggest the use of AST and ALT levels as times the upper limit of normality in the calculation of FIB-4, which can expand its applicability to populations with different reference ranges for aminotransferases. Leonardo L. Schiavon M.D.*, Roberto J. Carvalho Filho M.D.*, Janaína L. Narciso M.D.*, Juliana P. Sampaio*, Valéria P. Lanzoni M.D.*, Maria Lucia G. Ferraz M.D.*, Antonio Eduardo B. Silva M.D.*, * Division of Gastroenterology, Hepatitis Section, Federal University of São Paulo, São Paulo, Brazil.

Hepatitis C virus genotype 3 predominates in North and Central India and is associated with significant histopathologic liver disease

Hepatitis C virus (HCV) genotypes help to tailor the treatment response, but their influence on the disease severity and association with hepatic steatosis is not well understood. The prevalence of HCV genotypes and their correlation with the histopathological severity of liver disease and steatosis in Indian patients were studied. HCV-RNA and genotyping was carried out in 398 patients with chronic hepatitis C. Liver biopsy was available in 292 (73.4%) patients. The severity of liver disease was graded on the basis of the histological activity index and the stage of hepatic fibrosis. The patients were categorized as having mild (histological activity index < or =5 and/or fibrosis < or =2) or severe (histological activity index > or =6 and/or fibrosis > or =3) liver disease. Steatosis was graded in 106 patients as 0 (no steatosis), 1 (<33% of hepatocytes affected), 2 (33%-66% of hepatocytes affected), or 3 (>66% of hepatocytes affected). HCV genotype 3 was detected in 80.2% patients (3a:24.4%, 3b:3.3%, 3c:0.5%, 3a/3b:36.7%, and un-subtypable 3:15.3%), genotype 1 in 13.1% (1a:3%, 1b:5.5%, 1a/1b:0.3%, and un-subtypable 1:4.3%), genotype 4 in 3% patients (4a:1.5%, 4b:0.3%, 4a/4c:0.5%, and un-subtypable 4:0.8%), 2 in 2.5% and mixed genotypes (more than one genotype) in 1.3% of patients. The median histological activity index and fibrosis scores were: 5 and 2 in genotype 1; 4 and 2 in genotype 2; 5 and 2 in genotype 3; 7 and 3 in genotype 4; and 5 and 2 in mixed genotypes, respectively. Severe liver disease was present in 17 of 38 (45%) with genotype 1; in 1 of 3 (33%) with genotype 2; in 128 of 236 (54%) with genotype 3; 7 of 10 (70%) with genotype 4; and in 1 of 4 (25%) with mixed genotype. Hepatic steatosis grade > or =2 was found in 28.1% of genotype 3; 23.5% of genotype 1; 20% of genotype 4; and in none of genotype 2 and mixed genotypes. In conclusion, genotype 3 is the most prevalent genotype in patients with chronic hepatitis C in North and Central India and this is associated with significant hepatic steatosis and fibrosis.

Validation of a simple model for predicting liver fibrosis in HIV/hepatitis C virus‐coinfected patients

Recently, several models incorporating laboratory measurements have been validated for use as surrogate markers for liver fibrosis in hepatitis C virus (HCV) mono-infection, the simplest of these being the aspartate aminotransferase (AST) to platelet ratio index (APRI). We evaluated how well the APRI predicts significant hepatic fibrosis in patients with HIV/HCV coinfection. Forty-six HIV/HCV-coinfected patients who underwent liver biopsy and had concomitant laboratory measurements (+/-3 months) were included in the study. Significant fibrosis was defined as F2-F4 using Batt and Ludwig scoring (=3 Ishak). APRI=[(AST/upper limit of normal)/platelet count (10(9)/L)] x 100. We used sas proc logistic (SAS Institute, Cary, NC) to calculate the area under the receiver operating curve (ROC) (AUC). Sensitivities, specificities, positive predictive value (PPV) and negative predictive value (NPV) were compared using cut-offs previously identified in the literature. Thirty-three of 46 patients (72%) had significant fibrosis on biopsy. For significant fibrosis, the area under the ROC for the APRI was 0.847+/-0.057. APRI scores >1.5 (the higher cut-off) were 100% specific and 52% sensitive; PPV was 100% and NPV 45%. Scores <0.5 (the lower cut-off) were 82% sensitive and 46% specific in ruling out significant fibrosis (PPV 79%; NPV 50%). A simple model incorporating readily available laboratory data is highly predictive of significant fibrosis in HIV/HCV coinfection and could serve as a biopsy-sparing measure, thus making treatment more accessible for this population.

Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index.

We sought to develop a clinically useful index comprising standard and physiologically relevant variables to predict the probability of significant hepatic fibrosis in subjects with chronic hepatitis C virus (HCV) infection. Fibrosis was graded as mild (stages F0 or F1) or significant (stages F2-F4). Thirty-five clinical and laboratory parameters were analyzed initially in 176 patients with detectable HCV RNA to derive a fibrosis probability index (FPI) to predict significant fibrosis. This index then was validated in a second group of 126 subjects. Among 18 variables associated with severe fibrosis on univariate analysis, multiple logistic regression analysis identified age, aspartate aminotransferase (AST), total cholesterol level, insulin resistance (by homeostasis model), and past alcohol intake as independent predictors of significant fibrosis. The area under the receiver operating characteristic (ROC) curves was 0.84 for the initial cohort and 0.77 for the validation cohort. In the initial cohort, the sensitivity of the FPI based on these five predictors was 96%, and the negative predictive value was 93% at a score of >/=0.2. At scores >/=0.8, the FPI was 94% specific and had a positive predictive value of 87%. In conclusion, an FPI using routinely assessed markers and incorporating a measure of insulin resistance can reliably predict the probability of significant hepatic fibrosis in most patients with chronic HCV infection. Such an index should prove useful to guide decision making regarding the need for liver biopsy, and potentially for avoiding or deferring biopsy in a large proportion of patients with mild liver disease.

Historia natural de la infección por el VHC

The generally indolent, slow and protracted course of hepatitis C virus infection has limited the realisation of studies that evaluate its natural history. The aim of such studies has been the probability of death through hepatic disease, hepatic cirrhosis (compensated or decompensated), and/or hepatocarcinoma, or the development of a significant hepatic fibrosis (essential anatamopathological substrate for the development of the complications of hepatic cirrhosis). In spite of their possible limitations, the results of these studies show that chronic hepatitis C virus infection generally follows a benign evolutionary course, above all if this occurs in young patients (<50 years of age), without other aggravating factors of a possible hepatopathy (alcohol, coinfection by other viruses, immunosuppression) and if this is evaluated in the first 10-20 years of infection. At present, it is not possible to identify with precision those patients with HCV infection with a greater risk of developing a clinically relevant hepatic disease. However, it is likely that those subjects with high transaminases (> 2 times the normal value) and significant necroinflammatory activity (periportal necrosis) and fibrosis in the hepatic biopsy will show a more aggressive evolutionary course than those with normal transaminases and an almost normal hepatic biopsy.

Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model

Liver biopsy is required for staging hepatic fibrosis in patients with chronic hepatitis C, but it is an expensive procedure with occasional complications and poor patient acceptance. This cohort study was designed to assess the accuracy of a noninvasive method aimed to discriminate between patients with and without significant liver fibrosis (stages 2-4 versus 0-1). Clinically relevant variables were analyzed in a cohort of 476 consecutive untreated patients (estimation group, 351 patients; validation group, 125 patients) with chronic hepatitis C who underwent a liver biopsy. Multivariate analysis identified age, gamma glutamyl transpeptidase (GGT), cholesterol, platelet count, and prothrombin time as independent predictors of fibrosis. We constructed a model and a score system combining age, GGT, cholesterol, and platelet count that proved useful to identify patients without significant hepatic fibrosis. The area under the ROC curve was 0.86 for the estimation group and 0.81 for the validation group. Using the best cutoff score (less than 4.2), presence of significant fibrosis (F2 to F4) could be excluded with high accuracy (negative predictive value of 96%) in 125 (36%) of 351 patients. Similarly, it could be excluded with the same certainty in 49 (39%) of the 125 patients of the validation group. Only 2 patients with liver fibrosis stage 2 were incorrectly classified. In conclusion, a combination of easily accessible variables accurately predicts the absence of significant fibrosis and might render liver biopsy unnecessary in more than one third of patients with chronic hepatitis C. (H EPATOLOGY 2002;36:986-992.)

Hepatitis C in childhood

The approach of a pediatric hepatologist in managing children with hepatitis C virus (HCV) differs from adult practice, because the pediatric hepatologist is dealing with the beginning of a chronic illness in which long-term outcomes will not occur for 20 or 40 years, and it is not possible to predict in the early stages of the infection which patients have a more sinister prognosis. The prevalence of chronic HCV in children is low, but varies between different countries in the Asia-Pacific region. In most countries, screening of blood products for HCV has virtually eliminated the risk of post-transfusion HCV, so that in Australia children aged less than 11 years will not have acquired HCV from blood transfusion or extracorporeal membrane oxygenation. The risk of perinatal transmission of this virus is only about 6%, but this remains virtually the only source of HCV transmission for children in most countries. While available data are limited, mild histological changes are present in the majority of children with hepatitis C, and cirrhosis is rare. Unfortunately, long-term natural history studies of the course of HCV infection in children have not been reported. Individual decisions on antiviral treatment are more difficult in childhood, not because the treatment is any less effective or because of the severity of side-effects (which tend to be less severe than for adults), but because the long-term outcome of infection is unclear. At present, treatment should be confined to those with significant hepatic fibrosis and continued moderate to severe necroinflammatory change. Measures to prevent HCV infection in childhood center on whether, as recently suggested, elective cesarean section may reduce the risk of transmission. Despite the presence of HCV-RNA in some breast milk samples, there is no evidence that breast-feeding confers any risk of HCV infection.

Endothelin-1 modulates intrahepatic resistance in a rat model of noncirrhotic portal hypertension.

Factors that increase resistance to blood flow through the hepatic sinusoids when portal hypertension occurs in the absence of significant hepatic fibrosis are not completely understood. Experiments were designed to test the hypothesis that endothelin-1 (ET-1) is one of the humoral factors that increases sinusoidal vascular resistance in a bile duct- ligated noncirrhotic portal hypertensive (BDL) rat. The effect of ET-1 and nitric oxide (NO) on contractility of rings of portal vein taken from BDL rats was tested. The effect of ET-1 and NO on intrahepatic resistance in an isolated perfused liver was studied, and localization of ET-1 in the liver was identified by immunohistochemistry. Portal vein rings in BDL rats showed increased maximal tension in response to ET-1, as well as a shift of the dose-response curve to the left as compared with sham-operated animals. Removal of the endothelium further increased contractility. In isolated perfused liver studies, ET-1 increased portal resistance in both sham operated and BDL rats. The endothelin Type A receptor antagonist BQ 123 lowered the high portal resistance in BDL rats to levels comparable with sham operated animals. Infusion of L-arginine lowered resistance to a much smaller extent. In livers from BDL rats, ET-1 was localized in periportal and pericentral hepatocytes and hepatic sinusoidal cells. We conclude that in a BDL model of portal hypertension where distortion of hepatic architecture by fibrosis is minimal, increased resistance to portal blood flow may be mediated by ET-1.

IFN-γ, IL-12, and TNF-α Are Required to Maintain Reduced Liver Pathology in Mice Vaccinated withSchistosoma mansoniEggs and IL-12

AbstractThe development of hepatic fibrosis and portal hypertension is the principal cause of morbidity and mortality in schistosomiasis mansoni. Nevertheless, relatively little is known about the mechanisms that lead to excessive collagen deposition during infection with Schistosoma mansoni. In the murine model, infection leads to significant egg-induced granuloma formation, tissue eosinophilia, and hepatic fibrosis. The pathology has been linked to dominant type 2 cytokine expression, and our recent studies showed that sensitizing animals to egg Ags in combination with IL-12, before infection, led to a highly significant reduction in egg-induced immunopathology. In this study, we demonstrate that in contrast with egg/IL-12-sensitized animals that showed marked decreases in pathology, mice similarly sensitized but depleted of IFN-γ, IL-12, or TNF-α at the time of egg laying developed granulomas that were similar to the non-IL-12-treated control group. Although all three anti-cytokine-treated groups exhibited a dominant type 1 response in lymph node cells restimulated ex vivo, the expression of type 2 cytokine mRNA was markedly restored at the site of granuloma formation, which suggests that all three cytokines are required to maintain the suppressed type 2 pattern. Moreover, egg/IL-12-sensitized mice depleted of IFN-γ or IL-12 displayed a partial reduction in IFN-γ production, suggesting that multiple type 1 cytokines were required to maintain polarized type 1 responses to chronic type 2-inducing stimuli. Together, these data reveal key roles for IFN-γ, IL-12, and TNF-α in the protective effects mediated by this IL-12-based vaccine to prevent pathology.

CLINICAL MANAGEMENT OF IRON OVERLOAD

HHC is a common inherited disorder, characterized by iron accumulation in the liver, heart, pancreas, and other organs. The clinical consequences of systemic iron loading are diverse and not always improved with iron reduction therapy. The most important prognostic factor at the time of diagnosis is the presence or absence of hepatic fibrosis or cirrhosis. Those without significant hepatic fibrosis may be expected to have a normal life expectancy with phlebotomy therapy. The availability of genetic testing for HHC has significantly changed the diagnostic approach to this disorder. Although liver biopsy remains vital to determining prognosis, genetic testing is increasingly used in the diagnosis and family screening of patients with HHC.

Animal models for alcoholic liver disease.

The baboon is the only animal in which alcoholic fibrosis and cirrhosis of the liver has been produced with a nutritionally adequate diet. Zinc deficiency is associated with alcoholic liver disease and may contribute to liver damage. We have therefore investigated whether zinc supplementation would reduce liver damage in ten baboons receiving ethanol and an adequate diet. Eight received ethanol at up to 25 g/kg/day (70% of calories) for up to 60 months (four were supplemented with 50 mg zinc/day). All animals gained weight, and blood concentrations of ethanol were 63–342 mg/dl. Changes in liver blood tests were slight. Liver histology only showed fatty change in six animals, severe in two, and minor inflammatory changes but no significant fibrosis or cirrhosis. In one of the animals with severe fatty change there were also degenerative changes in parenchymal cells. There was thus no significant hepatic fibrosis or cirrhosis in baboons given large amounts of ethanol and an adequate diet for up to 5 years.