This Web Site is committed to the memory of Janis Morrow.
Learning About Liver Fibrosis
2004
|
Progression of hepatic fibrosis in patients with
hepatitis C: a prospective repeat liver biopsy study; 33% showed
progression of at least 1 fibrosis point |
||
|
Gut 2004;53:451-455 S D Ryder on behalf of the Trent Hepatitis C Study Group Queen's Medical Centre, University Hospital, Nottingham NG7 2UH, UK "...This large prospective liver biopsy based study of fibrosis progression in chronic HCV infection demonstrates that even in patients with apparently mild liver disease at presentation, progression of fibrosis does occur in a significant proportion (70/214, 33%) in less than three years... ...The overall rate of fibrosis progression is low but increased in patients who are older or have fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years as the population infected with HCV ages". ABSTRACT Background: The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment. Patients: We studied 214 HCV infected patients (126 male; median age 36 years (range 5--8)) with predominantly mild liver disease who were prospectively followed without treatment and assessed for risk factors for progression of liver disease. Interbiopsy interval was a median of 2.5 years. Paired biopsies from the same patient were scored by the same pathologist. Results: Seventy of 219 (33%) patients showed progression of at least 1 fibrosis point in the Ishak score; 23 progressed at least 2 points. Independent predictors of progression were age at first biopsy and any fibrosis on first biopsy. Factors not associated with progression were: necroinflammation, duration of infection, alcohol consumption, alanine aminotransferase levels, current or past hepatitis B virus infection, ferritin, HCV genotype, and steatosis or iron deposition in the initial biopsy. The results of multivariate analysis are show the most significant independent risk factors for severe progression of fibrosis by 2 points or more were age at biopsy and the presence of any fibrosis on the index biopsy. No other variable reached independent statistical significance. Identical results were obtained if significant progression in fibrosis was defined as 1 point in the Ishak score. Immunoglobulin G levels were elevated in 16 patients but unrelated to fibrosis progression (p = 0.81). Five patients had low titre (<1/50) positive antinuclear antibody levels and three had low titre (<1/100) antismooth muscle antibodies; again, neither was associated with fibrosis progression. Mode of transmission (IVDU v other) had no association with progression. No significant differences were obtained relating to risk of progression of fibrosis if Knodell scores for fibrosis were used rather than the Ishak fibrosis score. A very strong correlation existed between the two scoring systems (p = 0.0001, data not shown). Forty six patients had persistently normal ALT values. Overall, fibrosis progression was seen in 10 (22%) of these patients (five by 1 Ishak stage, five (12%) by more than 1). While indicating a trend for disease progression to be less in this subgroup, these values were not significantly different from those for patients with abnormal ALT values where 59/162 (36%) patients progressed (41 by 1 stage, 18 (12%) by more than 1). Conclusions: One third of patients with predominantly mild hepatitis C showed significant fibrosis progression over a median period of 30 months. Histologically, mild hepatitis C is a progressive disease. The overall rate of fibrosis progression in patients with hepatitis C was low but increased in patients who were older or had fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years. DISCUSSION This large prospective liver biopsy based study of fibrosis progression in chronic HCV infection demonstrates that even in patients with apparently mild liver disease at presentation, progression of fibrosis does occur in a significant proportion (70/214, 33%) in less than three years. Most previous studies of the natural history of hepatitis C infection have been retrospective.2,8,9 The largest study2 used a single liver biopsy with an estimated duration of infection to calculate a fibrosis progression rate. This approach has inherent error, infection duration relying predominantly on date of first use of injectable drugs. In addition, 17% of patients in that study had cirrhosis on initial biopsy and fibrosis cannot be graded further than cirrhosis. It is well known that asymptomatic cirrhosis can be present for many years, thus inclusion of such patients will underestimate fibrosis progression. Use of a single biopsy and calculation of progression rates also assumes linear progression through all stages of infection, an assumption which has no clear evidence base. There are other prospective series of patients in the literature.10--12 The largest of these studied 123 patients12 with a mean interval between biopsies of 44 months. None of these studies has details of the total patient population and how they were selected, which limits the significance of their conclusions. The major factor identified as increasing fibrosis risk in these studies was necroinflammation, a factor not significant in studies of single biopsies with an estimated date of infection.13 In univariate analysis, our data showed that necroinflammatory grade score in the index biopsy predicted fibrosis progression but this was not an independent factor when entered into the multivariate analysis. The necroinflammatory grade in this cohort of patients was modest (>5 in only 26 patients) on the index biopsy but showed a significant rise in the second biopsy. This is the first study to show that necroinflammation increases over time. There was no suggestion in our study that higher ALT values carry an increased risk of fibrosis progression, a finding contrary to another twin biopsy study.12 In this cohort, ALT values varied over time in most individuals, and a single, even marked, elevation in ALT value carries little value in that individual as a predictor of fibrosis. Our study avoided the pitfall of estimated duration of infection by prospectively following a relatively large group of patients selected to have mild or moderate liver disease. In addition, serial data were collected on factors such as alcohol intake and transaminase values, which have not been available previously. The Trent Hepatitis C cohort is likely to be representative of the UK population, as there is no tertiary referral bias in this group and all patients included and excluded from the study were known. The rate of progression of hepatic fibrosis in this cohort was variable, the most rapid progression being from a fibrosis score of 0 to cirrhosis in less than two years, but the majority of patients showed no progression. If a linear rate of progression is assumed from the time of infection to the development of cirrhosis, the rate of progression overall was 0.17 Ishak fibrosis points per year. This is similar to previous data2,12,13 which suggest progression rates from 0.12 to 0.19 units per year. This study however provides strong evidence that progression of hepatic fibrosis in hepatitis C is non-linear. The most significant risk factors were age at biopsy, rather than duration of infection, and the presence of fibrosis on the index biopsy. This suggests that hepatitis C infection may somehow become more fibrogenic with advancing host age. This may be one explanation for the apparent lack of fibrotic liver disease progression in young women infected with hepatitis C via immunoglobulin anti-D.14 There are emerging data from the post-transplant setting which suggest that this may be a general effect of the aging liver. Increasing donor age is a significant risk factor for severe post-transplant recurrence of hepatitis C.15,16 The potential mechanisms for this accelerated organ damage are not known. All paired liver biopsies in this study were assessed by a single histopathologist, and three experienced liver histopathologists were involved in this study. Intraobserver variation between assessments of the same sample is less for fibrosis stage than for necroinflammatory grade,17 and in this study was low. Regression of fibrosis was seen in 10% of patients in this study, presumably due to a combination of observer error in interpretation and sampling variation. Fibrosis progressed in 33%. Previous studies have emphasised the role of male sex and high alcohol consumption, a combination of these factors doubling the rate of fibrosis.2 This was not seen here. Overall alcohol consumption in the study group was however very low, as most patients willing to attend regularly and to have repeat liver biopsies take notice of medical advice and consume little alcohol. It is of note that in patients who present with significant liver disease in our cohort, alcohol consumption is much higher that that seen in this follow up study of patients presenting with mild disease.4 This suggests that alcohol is an important cofactor at presentation, but if alcohol consumption is reduced, prior fibrosis and age become the most important predictors of severe disease. Several recent studies have suggested that the presence of steatosis in liver biopsies in hepatitis C may predict progression.18 Fibrosis has been correlated with steatosis and body mass index,19 and steatosis has been linked with increased hepatitis C core protein expression.20 A recent small study in patients with HCV infection showed weight loss reduced both steatosis and fibrosis.21 Our data showed that steatosis did not increase the risk of fibrosis progression. There is evidence of viral interference in livers containing replicating HBV and HCV.22,23 There is evidence that HBsAg carriage alone may enhance fibrosis in HCV positive patients.24,25 The presence of occult HBV infection in patients with HCV infection has been correlated with increased histological severity scores.26--28 This study showed no significant association of anti-HBc with increased fibrosis progression although the increased proportion of anti-HBc positive patients in the progressor group is worthy of further study. Genotypes 1 and 3 predominated in our cohort, a distribution very similar to those previously reported in the UK.29 There was no significant relationship between genotype and risk of development of fibrosis. There are conflicting reports in the literature with regard to this issue.30--33 Our data do not suggest that genotype 1 has a significant role in progression of fibrosis although it clearly is an important factor in the prediction of response to therapy.34 Iron loading has been the subject of intense study in hepatic fibrosis. Hepatic iron concentrations are elevated in hepatitis C35 and correlate with necroinflammatory change and increased stellate cell numbers.36 Iron loading has been suggested to be a factor in fibrosis progression in hepatitis C.37 Our data showed a non-significant increase in serum ferritin (77 v 105) in patients with progression of hepatic fibrosis but histological iron stores assessed on a Perl's stained section did not correlate with increased fibrosis. We conclude that histologically mild hepatitis C is a progressive disease. The overall rate of fibrosis progression is low but increased in patients who are older or have fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years as the population infected with HCV ages. INTRODUCTION Hepatitis C virus (HCV) was described in 1989 and is a significant cause of chronic liver disease. A number of factors have been suggested to influence progression of liver disease towards cirrhosis. Data are from studies which are predominantly retrospective or have uncertain inclusion criteria; many are from tertiary referral centres which may have a bias towards more severe liver disease. The largest study of the natural history of liver fibrosis in HCV infection relies on a single liver biopsy fibrosis score and an estimated duration of infection, thus making assumptions that the date of infection was reliable and that liver fibrosis progresses at a linear rate. Treatment for HCV infection remains complex, is costly, has substantial side effects, and even with improved regimens only a 55% prospect of success. The majority of patients with HCV have mild liver disease on biopsy. Hence reliable data on the rates and risk factors for progression of liver fibrosis are essential for the development of a rational treatment strategy. This study aimed to determine the factors leading to histological progression of fibrosis in a cohort of patients with HCV infection with paired liver biopsy samples taken after a time interval, with no intervening therapy. RESULTS Patient details Of the 214 patients studied, 126 were male (59%). Median age at the time of initial biopsy was 36 years (range 5--78). A total of 114 (52%) patients admitted to having used injectable drugs and a further 49 (23%) had received blood components prior to 1991 (when blood donor screening for HCV was introduced in the UK). Where known, viral genotypes were 1 in 73 patients, 2 in 21, 3 in 60, and one each of types 4 and 5. Three patients were HBsAg positive and a further 53 had evidence of previous exposure to HBV (anti-HBc positive). Median duration of infection among patients with a probable date of infection (using the first date of exposure to risk) was 18.9 years (range 4--41). Median interbiopsy interval was 2.5 years (range 1.9--9.4). Seven per cent of all biopsies in this study were scored twice, producing an intraobserver variability of 0.07 for fibrosis and 0.13 for necroinflammation, and an interobserver variability of 0.1 for fibrosis stage and 0.2 for necroinflammatory grade. Assessment of initial liver biopsy The median total Ishak score on the initial biopsy was 3 (range 0--19). The majority of patients (188) had total scores of 6 or less, with fibrosis stage scores of 0 or 1 (183 patients). Progression of disease evident on second liver biopsy Median necroinflammatory grade and fibrosis stage scores progressed between biopsies from 2 to 3 and from 0 to 1, respectively (p = 0.025 and p<0.001). Changes in these scores are shown in table 1. Seventy of 214 (33%) patients had an increase in fibrosis stage score of 1 or more point in Ishak stage. Twenty three of 210 patients (11%) (excluding five patients with fibrosis stage 5 or more on the index biopsy who therefore could not progress by more than a single point) showed progression of 2 points or more. Twenty two patients had a reduction in fibrosis score on the second biopsy (10%), 20 by 1 point, one by 2 points, and one by 3 points. Factors related to fibrosis progression between biopsies 1 and 2 For the purposes of analysis of fibrosis progression, patients were considered to have any progression if the score increased by 1 point or more and serious progression if the score increased by 2 points. The comparator groups for the analysis were a combination of patients with any fibrosis regression and those with no change in fibrosis for analysis of 1 point progression. For the severe (2 point) progressors, the comparator group was patients with fibrosis regression, stable fibrosis, and 1 point progression. The results of univariate analysis of factors influencing severe fibrosis progression (2 points in Ishak stage) are shown in table 2. Age at biopsy (45.6 v 36.2 years; p<0.001), estimated age at infection (27.4 v 18.7 years; p = 0.04), necroinflammatory score on biopsy 1 (median 4 v 2; p = .007), and fibrosis score on biopsy 1 (16/23 progressors v 64/187 non-progressors; p = o.001) all predicted progression while sex, alcohol consumption, steatosis and siderosis on biopsy 1, ALT, and HCV genotype did not. Markers of HBV infection were not statistically significant as a risk factor for progression although there was an excess of anticore antibody positive patients in the progressor group. Interval between biopsy (taken as 0--2 years, 2--4 years and >4 years) was also not a significant factor predicting fibrosis, probably because 88% of all second biopsies occurred between 2.5 and 3.5 years after the index biopsy. Fatty Liver Accelerates Fibrosis: diabetes, mitochondrial dyfunction, obesity associated Natural history of nonalcoholic steatohepatitis: A longitudinal study of repeat liver biopsies" Hepatology Volume 40, Issue 4, October 2004 Eduardo Fassio 1 *, Estela Álvarez 2, Nora Domínguez 1, Graciela Landeira 1, Cristina Longo 1 1Hepatology Unit, Gastroenterology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires, Argentina 2Pathology Service, Hospital Nacional Profesor Alejandro Posadas, El Palomar, Buenos Aires, Argentina "...Our study shows that 31.8% of 22 patients with NASH had a progression of liver fibrosis over a median follow-up of 4.3 years. These findings confirmed the progressive potential of NASH. However, most of the patients (68.2%) had no fibrosis progression... ... A two-hit hypothesis has been proposed to explain the mechanisms of liver damage in NASH... The first hit has been associated with insulin resistance... in only a proportion of patients with insulin resistance and NASH will an advanced liver disease develop, and other factors, or hits (like oxidative stress, mitochondrial dysfunction, and abnormal cytokine production), should be present to produce severe cellular injury or fibrosis... ... Among 12 variables studied at baseline, we found that the prevalence of obesity and BMI were the only variables [associated with fibrosis]... Presence of diabetes has been shown to be an independent predictor of severe fibrosis in a retrospective study that analyzed a large number of patients. Among our patients, four of seven (57%) from group P and 4 of 15 (27%) from group NP had diabetes... ... Some very recent, noncontrolled studies have shown that insulin-sensitizing agents (rosiglitazone and pioglitazone) can lead to improvement in histological features in NASH patients after 48 weeks of treatment. If these results were confirmed in larger, controlled studies, this kind of therapy would be accepted as being able to modify the natural evolution of NASH and would be recommended promptly for clinical practice..." ABSTRACT/SUMMARY Nonalcoholic steatohepatitis may cause severe fibrosis, cirrhosis, and hepatocellular carcinoma, but supporting evidence is based on indirect data. Few publications have examined the results of repeat liver biopsies to evaluate progression of fibrosis. The aims of this study were to assess rate of fibrosis progression in untreated patients with nonalcoholic steatohepatitis and to identify associated variables. Among 106 patients, a second liver biopsy was proposed to those who had undergone their first liver biopsy at least 3 years before. None of them had been given pharmacological therapy. Liver biopsy samples were evaluated blindly. Variables were compared between patients with (group P) and without (group NP) fibrosis progression, using a Wilcoxon rank-sum test for numerical variables and a difference of two binomial proportions for categorical ones. Twenty-two patients (median age, 45 years; age range, 20-69 years; 13 women; diabetes in 8 patients, obesity in 10 patients) underwent a second liver biopsy 4.3 years (range, 3.0-14.3 years) after the first. Fibrosis progression was found in 7 patients in group P (31.8%), no progression was found in 15 patients in group NP. There were no differences between both groups regarding age, gender, diabetes, hyperlipidemia, ALT levels, AST-to-ALT ratio levels, albumin levels, prothrombin activity, steatosis, or inflammation. Obesity was significantly more prevalent in group P (86%) than in group NP (27%; P = .01). Basal body mass index was higher in group P (median, 33.2; range, 29.1-38.2) than in group NP (median, 29.0; range, 24.0-38.1; P = .024). Time between biopsies was not different between groups. In conclusion, progression of liver fibrosis was found in a third of nonalcoholic steatohepatitis patients 4.3 years after the first liver biopsy, and obesity and body mass index were the only associated factors with such progression. Article Text Nonalcoholic fatty liver disease is probably the main cause of chronic liver disease in the West. The histological spectrum of nonalcoholic fatty liver disease includes simple steatosis (type 1), steatosis plus lobular inflammation (type 2), steatosis plus ballooning degeneration (type 3), and steatosis plus ballooning degeneration plus Mallory bodies or fibrosis (type 4). This classification is clinically important. Whereas simple steatosis seems to be a benign and nonprogressive condition, nonalcoholic steatohepatitis (NASH) that includes the types 3 and 4 of nonalcoholic fatty liver disease is recognized as a potentially progressive disease that may cause cirrhosis and liver-related death. However, our knowledge of the natural history of NASH is still very limited and is largely based on indirect evidence. Cross-sectional series have shown that 30% to 40% of patients have advanced liver fibrosis at the time of presentation, whereas 10% to 15% of them may have established cirrhosis. Three studies have found that patients with cryptogenic cirrhosis have a greater rate of diabetes, obesity, or both than those with cirrhosis resulting from other causes, suggesting that cryptogenic cirrhosis may represent burned out NASH. In patients who underwent liver transplantation for cryptogenic cirrhosis, steatosis, and NASH have been shown in the graft during follow-up. Finally, the appearance of hepatocellular carcinoma has been reported in NASH patients, and in two large series of patients with hepatocellular carcinoma evaluated retrospectively, it has been found that cryptogenic cirrhosis (with the clinical phenotype of NASH) was the underlying liver disease in 7% to 13% of the cohort. Therefore, indirect data suggest that NASH may cause the entire spectrum of complications of chronic liver disease: progressive fibrosis, cirrhosis, end-stage liver disease, and hepatocellular carcinoma. However, longitudinal studies showing what percentage of patients with NASH will have a progressive course are lacking. To our knowledge, the published results of repeat liver biopsies come from only 56 patients without cirrhosis but with NASH (included in six different studies). The second biopsies were performed 1.2 to 15.7 years after the first and showed fibrosis progression in 39.3% of patients. The first four studies were clinical series examining NASH in which only a minority of patients underwent a repeat biopsy, whereas the last two studies were specially designed to evaluate histological changes. Furthermore, none of the previous studies addressed whether basal variables could differentiate patients with and without progression. These previous results are very interesting, but the number of patients studied is still very limited, and further prospective studies should be conducted to expand the knowledge of the natural history of NASH. Thus, the aims of this prospective, longitudinal study were to assess the progression rate of liver fibrosis in nontreated NASH patients and to identify clinical, biochemical, and histological variables associated with fibrosis progression. AUTHOR DISCUSSION Our study shows that 31.8% of 22 patients with NASH had a progression of liver fibrosis over a median follow-up of 4.3 years. These findings confirmed the progressive potential of NASH. However, most of the patients (68.2%) had no fibrosis progression. The different evolution can not be explained by a smaller time span between biopsies in the NP group. These patients underwent their second liver biopsy at a median time of 4.3 years after the first (range, 3.2-7.9 years), not significantly different from those in the P group. It is important to emphasize that both the pathogenesis and the natural history of nonalcoholic fatty liver disease and NASH are still incompletely understood, but they may be closely related. It has been postulated that most of the patients with nonalcoholic fatty liver disease have a fatty liver alone, a smaller proportion has steatohepatitis, and a percentage has advanced fibrosis. A two-hit hypothesis has been proposed to explain the mechanisms of liver damage in NASH. The first hit has been associated with insulin resistance, which has been demonstrated in almost all NASH patients studied and would cause the accumulation of excess fat in the hepatocytes. However, in only a proportion of patients with insulin resistance and NASH will an advanced liver disease develop, and other factors, or hits (like oxidative stress, mitochondrial dysfunction, and abnormal cytokine production), should be present to produce severe cellular injury or fibrosis. Considering that only approximately one third of NASH patients will have increasing liver fibrosis in the midterm, it would be useful to know the factors associated with that evolution, and our study sought to identify clinical, biochemical, and histological variables able to predict progression. Among 12 variables studied at baseline, we found that the prevalence of obesity and BMI were the only variables that were significantly different between the groups (with 86% and 27% of patients being obese in the groups P and NP, respectively). Interestingly, the changes in BMI during the follow-up were not different between the groups. In fact, the gradients (final vs. basal values) of BMI were very close to 0 in both groups. Thus, among NASH patients, those with obesity would be very prone to fibrosis progression. Furthermore, in this subgroup of patients, the dietary recommendations seem to be insufficient to prevent progression, and they should be included in trials of experimental pharmacological therapy (or immediately treated when a drug is accepted as being efficacious). Presence of diabetes has been shown to be an independent predictor of severe fibrosis in a retrospective study that analyzed a large number of patients. Among our patients, four of seven (57%) from group P and 4 of 15 (27%) from group NP had diabetes. The P value (.2267) was far from being significant, but we can not exclude a type II error because of the small sample size of patients having both NASH and diabetes. All the patients were referred to the Nutrition Department and encouraged to follow a low-calorie and low-fat diet. However, it is known that it is difficult for these patients to adhere to dietary therapy in the long term. During the follow-up, 27% of patients (6 of 22) achieved a 5% or more reduction in their body weight, and that percentage was not different between groups P and NP. Thus, we believe that it is unlikely that the dietary treatment could have played an important role in modifying the evolution of our patients' courses, but we can not exclude a mild beneficial effect. Among the four patients showing a decrease in the final fibrosis score, only one had had that kind of weight reduction. Comparing our results with those of 59 patients without cirrhosis but with NASH and repeat liver biopsies previously published in the literature, we found in our study a lower rate of fibrosis progression (32%) during a longer follow-up (median, 4.3 years; mean, 5.3 years) than those observed in the first four studies that were clinical series and included 30 patients. It is difficult to determine the reasons for that difference, because the demographical or analytical data are not fully available in the papers. However, among 24 patients whose clinical data are known, 22 (91.7%) were obese (the only predictor of progression, according to our results), and this could be the main explanation for a faster progression. The last two studies, like ours, were designed to analyze changes in histological findings, and Harrison et al. reported results impressively similar: 7 of their 22 patients showed fibrosis progression in a mean time of 5.7 years between biopsies. The clinical data of their patients also were similar to ours, but the obesity prevalence was slightly higher (77%). Other findings of our study worth noting are as follows. First, the inflammatory activity in the basal liver biopsy was not different between patients with or without fibrosis progression, in contrast to what was expected. However, it should be noted that the grade of inflammation was mild in most of the patients (19 of 22). Second, changes in grade of steatosis run an independent course from those in fibrosis, being found in the final liver biopsy a decrease in steatosis and an increase in fibrosis, either in the entire population or in group P patients. This observation is consistent with the suggestion that NASH patients may lose the fatty infiltration when they reach the stage of cirrhosis, which becomes a cryptogenic cirrhosis. Third, the evolution of ALT values was not different between both groups and, especially in group P, a normalization of ALT values was observed in six of seven patients. It is important to emphasize that a normalization of ALT levels does not guarantee fibrosis stabilization or improvement, because many pilot studies evaluating pharmacological treatments in NASH have claimed different drugs to be efficacious based only on the decreasing ALT values. The rate of progression of liver fibrosis has not been studied previously in NASH. Considering the entire population, the rate of liver fibrosis progression was estimated in 0.059 units of fibrosis per year. In a recent study, in patients with chronic hepatitis C, Ghany et al. found progression of liver fibrosis in 39% over a mean interval of 44 months (range, 2-211 mo) between both biopsies. The rate of liver fibrosis progression was estimated in 0.12 fibrosis units per year. Thus, our figure of fibrosis progression in NASH patients is approximately half of that found in hepatitis C patients. However, in patients from group P, the rate of progression was estimated to be 0.280 units of fibrosis per year. Some very recent, noncontrolled studies have shown that insulin-sensitizing agents (rosiglitazone and pioglitazone) can lead to improvement in histological features in NASH patients after 48 weeks of treatment. If these results were confirmed in larger, controlled studies, this kind of therapy would be accepted as being able to modify the natural evolution of NASH and would be recommended promptly for clinical practice. In that eventuality, studies like ours, aimed at understanding natural history, no longer would be carried out because they would be considered unethical, and the knowledge of the natural history of NASH would remain rather limited. In summary, the results of this longitudinal study have shown progression of liver fibrosis in approximately one third of patients with NASH in a median follow-up of 4.3 years, the presence of obesity being the only factor associated with the progression. Patients with NASH who are obese should be included in controlled trials of experimental pharmacological therapy or should be treated promptly when some agreement exists regarding the efficacy of any drug in retarding the progression of fibrosis. Patients and Methods From October 1986 through December 2002, 106 patients were diagnosed with NASH in the Liver Unit at the Professor Alejandro Posadas Hospital. The diagnosis of NASH was based on the following four criteria. Persistently abnormal alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, or both was the first criterion. A daily alcohol intake of less than 40 g in men and less than 20 g in women, as confirmed by patient anamnesis and interview of close family members, was the second criterion. These cutoff levels of ethanol intake were chosen because they were the usual ones when we designed the study. Surrogate biochemical markers of alcohol consumption were not used. Appropriate exclusion of other causes of chronic liver disease, such as hepatitis B and C, autoimmune hepatitis, drug-induced hepatitis, primary biliary cirrhosis, hemochromatosis, Wilson disease, was the third criterion. The fourth criterion was characteristic features in the liver biopsy, including macrovesicular steatosis (>10% of hepatocytes) and lobular inflammation plus ballooning degeneration, Mallory hyaline fibrosis, sinusoidal fibrosis, or a combination thereof. Patients demonstrating only steatosis and lobular inflammation in their biopsy results were not considered to have NASH. Either ballooning degeneration or sinusoidal fibrosis had to be present to confirm the diagnosis of NASH. This population included 55 males and 51 females with a median age of 45 years (range, 17-78 years). Patients were considered to have diabetes mellitus either if they were receiving insulin or oral hypoglycemic treatment or if a fasting plasma glucose test result was 126 mg/dL or more, according to the American Diabetes Association definition. Hyperlipidemia was diagnosed when fasting levels of cholesterol were more than 200 mg/dL, fasting levels of triglycerides were more than 200 mg/dL in two occasions, or both. Obesity was defined as a body mass index (BMI) of more than 30, both in men and women. BMI was calculated using the following formula: kg(weight)/m2(height). Waist circumference or waist-to-hip ratio measurements were not obtained in these patients. All the patients were referred to the Nutrition Department for the treatment of their metabolic disorders (hyperlipidemia, obesity, glucose intolerance, or diabetes), but no experimental pharmacological treatment for NASH (e.g. ursodeoxycholic acid, vitamin E, glitazones) was given to any patient. No patient was taking drugs associated with secondary NASH, such as corticosteroids, perhexiline, tamoxifen, and amiodarone. All the patients were scheduled to undergo a repeat liver biopsy at least 3 years after the previous biopsy. Patients lost to follow-up were contacted by phone calls or conventional mailing. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics and research committees of our hospital. Informed consent was obtained from each enrolled patient. Liver biopsy samples were obtained by the percutaneous route using the Menghini method. One or two passes were performed to assure samples at least 25 mm in length. Formalin-fixed, paraffin-embedded liver sections were stained routinely with hematoxylin and eosin, silver reticulin, Masson trichrome, Perls' Prussian blue, and diastase-resistant periodic acid-Schiff. After determining patient inclusion, all the liver biopsy specimens (basal and final samples) were reexamined in a blind and nonpaired manner by an experienced pathologist (E.A.) who was unaware of the clinical and biochemical data of the patients or the order of the biopsies. Studies on the liver specimens included a semiquantitative assessment of the grades of steatosis (mild or grade 1, >10% but <33% of hepatocytes affected; moderate or grade 2, 33%-66% of hepatocytes affected; severe or grade 3, >66% of hepatocytes affected); of inflammatory activity (according to Brunt classification); and of fibrosis (according to Brunt classification and to Ishak classification). Brunt classification of fibrosis assessment includes five stages: stage 0, no fibrosis; stage 1, zone 3 perisinusoidal or pericellular fibrosis, focally or extensively present; stage 2, zone 3 perisinusoidal or pericellular fibrosis with focal or extensive periportal fibrosis; stage 3, zone 3 perisinusoidal or pericellular fibrosis and portal fibrosis with focal or extensive bridging fibrosis; stage 4, cirrhosis. Ishak classification ranges from zero to six stages: stage 0, no fibrosis; stage 1, fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, fibrous expansion of most portal areas with occasional portal to portal bridging; stage 4, fibrous expansion of portal areas with marked bridging (portal to portal) as well as portal to central; stage 5, marked bridging with occasional nodules (incomplete cirrhosis); stage 6, cirrhosis, probable or definite. Progression of liver fibrosis was defined as an increase 1 grade or more in the final stage with respect to the basal biopsy, in any of the two classifications. Although Brunt classification was designed especially for NASH patients, we decided to analyze changes in fibrosis according to Ishak classification as well, because of its greater flexibility in evaluating septal fibrosis (score 3 for occasional bridging, score 4 for marked bridging), incomplete cirrhosis (score 5), and definite cirrhosis (score 6). http://www.natap.org/ |
||
|
Digestive and Liver Disease
Volume 36, Issue 10 , October 2004, Pages 646-654
doi:10.1016/j.dld.2004.06.011
Copyright © 2004 Editrice Gastroenterologica Italiana S.r.l. Published
by
Elsevier Ltd.
Clinical Review
A. Alberti, , a, b, L. Benvegnùa, S. Boccatoa, A. Ferraria and G.
Sebastiania
a Department of Clinical and Experimental Medicine, University of Padova,
Via Giustiniani, 2, 35128, Padua, Italy
b Venetian Institute of Molecular Medicine, Padua, Italy
Available online 4 August 2004.
Abstract
The hepatitis C virus is a leading cause of chronic liver disease,
cirrhosis
and hepatocellular carcinoma in western countries. Chronic hepatitis C
is
highly heterogeneous and many patients present with a mild form of liver
disease. Population-based studies have indeed demonstrated that around
50%
of hepatitis C virus carriers have persistently normal ALT and two-third
have mild histological liver lesions. Studies on the natural history of
initially mild chronic disease indicate that the short-term outcome is
always benign. However, progression of liver fibrosis can be observed at
long-term (>5–7 years) follow-up, particularly in those cases who have
elevated and/or fluctuating transaminase levels. Observational
prospective
studies and outcome modelling projections indicate that the risk of
liver
disease progression towards severe fibrosis/cirrhosis is minimal at
10–15
years in hepatitis C virus carriers with persistently normal ALT, around
5–10% in patients with elevated ALT and F0 (no fibrosis) in the initial
biopsy but >30–40% in chronic carriers with elevated ALT and F1 (portal
fibrosis) in the initial biopsy. Cofactors like age at infection,
alcohol,
coinfections and liver steatosis accelerate disease progression. On the
basis of these findings, patients with initially mild chronic hepatitis
C
and elevated ALT should be proposed for antiviral therapy in the absence
of
contraindications.
Author Keywords: Hepatitis C; HCV; Natural history
Corresponding author. Tel.: +39 049 821 2294; fax: +39 049 821 1826.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Serum
Immunoglobulins Predict the Extent of Hepatic Fibrosis in HCV Patients Recently, the authors of the current study documented that immunoglobulins stimulate the proliferative activity of rat hepatic stellate cells in vitro. The aim of the present study was to determine whether there is any association between serum immunoglobulin levels and hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection. Charts from 116 patients with biochemical, serologic, virologic and histologic evidence of chronic hepatitis C infection and serum immunoglobulin levels (IgA, IgG, IgM and total) were reviewed. The mean (+/-SD) age of the study population was 46 +/- 11 years and 67 (58%) were male. There were significant correlations between serum IgA (r = 0.39, P = 0.00001), IgG (r = 0.49, P = 0.000002) and total (r = 0.51, P = 0.000003) immunoglobulin levels and the stage of hepatic fibrosis. When serum immunoglobulin levels were included into logistic regression analysis with variables known to be associated with advanced disease (male gender, age >40 years at onset of infection, duration of infection beyond 20 years and concurrent alcohol abuse) only IgA, IgG and total immunoglobulin levels (P < 0.05, <0.05 and <0.005, respectively) emerged as independent predictors of hepatic fibrosis. The authors conclude, "Our data indicate a strong association between serum immunoglobulin levels (IgA, IgG and total) and hepatic fibrosis in patients with HCV infection. This finding supports the need to further investigate whether immunoglobulins independently promote disease progression in patients with chronic HCV infection." Department of Medicine, Section of Hepatology, University of Manitoba, Winnipeg, Canada. 08/11/04 Reference K Watt and others. Serum immunoglobulins predict the extent of hepatic fibrosis in patients with chronic hepatitis C virus infection. Journal of Viral Hepatitis 11(3): 251-256. May 2004 http://www.hivandhepatitis.com/hep_c/news/2004/081104_a.html
Common Heterozygous Hemochromatosis Gene Mutations Are
Risk Factors for Inflammation and Fibrosis in Chronic Hepatitis C Liver biopsies from 166 patients were scored for inflammatory activity (A0-4) and hepatic fibrosis (F0-4). Gene mutations were determined by LightCycler, restriction fragment length polymorphism analysis, or direct sequencing. Results The frequencies of common HFE mutations C282Y and H63D are 4.2% and 21.3%, whereas the recently described S65C substitution and the Y250X mutation in the transferrin receptor 2 gene are very rare. In regression analysis, heterozygous carriers of C282Y or H63D mutations display significantly (P<0.05) higher inflammatory activities and more advanced fibrosis than patients without mutations. For C282Y heterozygous patients, the odds ratios for marked inflammatory activity (A2-4) and advanced liver fibrosis or cirrhosis (F2-4) are 4.9 and 4.6, respectively, compared with patients carrying homozygous wild-type alleles. C282Y mutations are associated with significantly (P<0.05) increased serum iron and aminotransferase levels, whereas H63D heterozygotes display higher transferrin saturation, serum iron, and ferritin concentrations compared to wild-type (P<0.01). Conclusions In conclusion, the authors write, "Common heterozygous hemochromatosis mutations are associated with higher grades of inflammation and more severe hepatic fibrosis. Our findings support a role of HFE mutations as primary risk factors for fibrogenesis and disease progression in chronic hepatitis C." Department of
Medicine III, University Hospital Aachen, Aachen University (RWTH), Aachen,
Germany.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Intercept Pharmaceuticals Announces Publication of Study Demonstrating Its Lead Compound Can Reverse Liver Fibrosis
- Proof-of-Principle Study Published in Gastroenterology -
NEW YORK, Aug. 12 /PRNewswire/ -- Intercept Pharmaceuticals, Inc., an
emerging specialty pharmaceutical company focused on developing small molecule
drugs for the treatment of chronic liver and metabolic diseases, today
announced publication in Gastroenterology of a major set of studies led by its
scientific co-founder, Stefano Fiorucci, M.D., demonstrating that Intercept's
lead FXR agonist, INT-747, can stop development of, and perhaps even reverse,
liver fibrosis in animal models.
Liver fibrosis is the process of chronic scarring that leads eventually to
cirrhosis and liver failure. It affects individuals with alcoholic liver
disease, chronic viral infections like hepatitis B and C, and obesity
associated non-alcoholic fatty liver disease (NAFLD), making it a major cause
of disability and death for tens of millions of people worldwide. There
currently are no approved treatments for liver fibrosis, leaving liver
transplant as the only option available for those few patients with end-stage
disease able to receive a donor organ.
"Publication of this landmark study which confirms the therapeutic
rationale underlying our lead compound for liver fibrosis is an important
milestone for our company," said Mark Pruzanski, M.D., President and CEO of
Intercept Pharmaceuticals. "Until recently, liver fibrosis and cirrhosis have
not been considered treatable, yet Dr. Fiorucci and his team have now
demonstrated in validated animal models that liver fibrosis may be slowed and
perhaps even reversed by Intercept's lead compound. Based on these
encouraging results, we plan to advance INT-747 into human clinical trials in
early 2005."
Prior work by Intercept's founders and other researchers elucidated the
role of FXR, a member of the nuclear hormone receptor family, in the
regulation of bile flow and rate of bile synthesis from dietary cholesterol.
These studies suggested that FXR agonists may have utility in the treatment of
a variety of cholestatic liver diseases which impair enterohepatic bile flow,
resulting in progressive damage to the liver. More recently, as reported in
the Gastroenterology paper, Intercept has uncovered the potential of FXR
agonists to directly repress the degenerative processes underlying liver
fibrosis.
"On behalf of the many researchers, clinicians and patients who have been
frustrated by our inability to treat liver fibrosis, I am encouraged to report
the positive results of our initial work with INT-747," said Stefano Fiorucci,
M.D., Professor of Gastroenterology at the University of Perugia in Italy and
a well known liver disease researcher and clinician. "Agents like INT-747 for
the first time give us the possibility of treating this often fatal condition
to preserve adequate liver function and perhaps even restore lost function. I
look forward to working with the Intercept team to rapidly advance INT-747 and
associated compounds towards human clinical testing."
Intercept's lead compound, a potent, orally bioavailable FXR agonist
formerly known as 6ECDCA, was discovered in 2001 through a collaboration
between GlaxoSmithKline and University of Perugia scientists. Worldwide
intellectual property rights to the compound and to a number of other FXR
agonists, antagonists and modulators have been assigned to Intercept. FXR is
known to be expressed in the liver, intestine and kidney, and Intercept
intends to continue to lead research efforts to fully elucidate the
therapeutic potential of this target.
About Intercept Pharmaceuticals
New York City-based Intercept Pharmaceuticals, Inc. is an emerging
specialty pharmaceutical company focused on developing small molecule drugs
for the treatment of chronic liver and metabolic diseases. The company is
currently advancing its lead drug candidate, INT-747(6ECDCA), for the
treatment of a group of life threatening fibrotic and cholestatic liver
diseases for which there are virtually no effective marketed drugs. The
company intends to lead in the advancement of drug candidates acting on FXR in
multiple indications through clinical proof-of-concept. As a ligand-regulated
nuclear hormone receptor, FXR is a member of a target class that has
consistently yielded successful marketed pharmaceuticals in a variety of
indications.
Contacts: Media:
Intercept Pharmaceuticals GendeLLindheim BioCom Partners
Mark Pruzanski, M.D. Barbara Lindheim
(917) 744-4043 (212) 918-4650
mark@interceptpharma.com
SOURCE Intercept Pharmaceuticals
Hepatic Fibrosis Influences Early Virological Response
Rates in Chronic Hepatitis C
Early virological response (EVR), during HCV therapy is defined as undetectable HCV RNA or at least a 2-log decrease in HCV RNA at week 12. Failure to achieve this has been shown to accurately predict non-response.
The aim of the current study was to determine the influence of hepatic fibrosis on EVR rates.
138 genotype 1 CHC patients who had received either combination peginterferon alfa-2b (Peg-Intron) 1.5mcg/kg weekly or standard interferon alfa (3MU TIW) and ribavirin (1000-1200 mg/d) were retrospectively identified from the databases of 2 hospitals.
Serum HCV RNA was measured at baseline, week 12, and at 24 weeks after completion of therapy using a quantitative PCR assay with a lower limit of detection of 100 copies/ml (NGI, Los Angeles, CA).
Pre-treatment liver biopsies were scored for fibrosis by the METAVIR system.
Results
Of 138 patients, 95 (69%) were male, 81 (59%) were Caucasian, 47 (34%) were African American. 61 (44%) had Metavir stage F0-F1 and 77 (56%) had Metavir stage F2-F4.
Overall 67/138 (49%) patients achieved EVR and 33/138 (24%) achieved SVR.
Patients most likely to achieve an EVR were those with fibrosis stage F0-F1 compared with F2-F4 (62% vs 38%; p=0.006), male patients with lower grades of fibrosis (66% vs 40%; p=0.02) and Caucasian patients with fibrosis scores 0-1 (74% vs 42%; p=0.004).
Only 15/47 (32%) of African American patients achieved EVR and 9/47(19%) achieved SVR.
There was no difference in EVR between African American high and low-grade fibrosis groups.
In the low-grade fibrosis group, Caucasians were more likely to achieve EVR than African Americans (74% vs 32%; p=0.012).
The authors conclude, “In difficult to treat HCV genotype 1 infection, the negative predictive value of EVR still holds true irrespective of fibrosis score. Male and Caucasian patients with lower grades of fibrosis were more likely to achieve EVR compared to patients with higher grades of fibrosis. This study also confirms previously observed poor rates of response in African Americans.”
06/07/04
Reference
A T Dev and
others. Hepatic Fibrosis Influences Early Virological Response Rates in
Chronic Hepatitis C (CHC). Abstract 1159 (poster). Digestive Disease Week.
May 15-20, 2004. New Orleans, LA.
http://www.hivandhepatitis.com/2004icr/ddw2004/docs/0607/060904_b.html
Viscum Album and Solanum
Lycopersicum Inhibit Fibrosis in Chronic Hepatitis C
Untreated HCV leads to liver cirrhosis and hepatocellular carcinoma in 20-30% of cases after 25 years of infection. No successful treatment is known following failure or contraindications to standard therapy (pegylated interferon and ribavirin).
German researchers investigated the effect on fibrosis in a pilot study using a complementary concept with mistletoe and herbal extracts of Solanum lycopersicum, Fragaria vesca/Vitis vinifera (Hepatodoron).
8 patients with HCV (genotype 1) were treated with Viscum album (Abnobaviscum aceris or Helixor M) 3 x weekly 1 Amp. sc., Solanum lyc. D4-D6 2-6 Tbl. and Hepatodoron 2-6 Tbl. daily.
A liver biopsy was conducted before and 6-10 months after treatment and the HAI score was calculated.
Results
In 8 patients (5 female, 3 male; mean age 43, mean duration of HCV 20.5 years) the HAI score before treatment was 7.75; after 18 - 23 months (12 months of treatment and 6-11 months follow-up) the score was 5.25 (p=0.05).
The fibrosis stage decreased from 2.5 to 1.375 (p=0.05). In 5 patients, fibrosis decreased by 1-3 score points, 1 patient increased by 1 scored point and 2 were stable.
Discussion
Viscum album and the herbal extract were able to inhibit and reduce fibrosis in liver biopsies scored by HAI, according to the authors. They conclude, “This therapy concept might be beneficial to non-responders and patients not compliant with standard HCV therapy. Further studies are necessary to confirm this preliminary data.”
05/24/04
Reference
Friedemann
Schad and others. Viscum Album L and Solanum Lycopersicum Inhibit Fibrosis
in Chronic Hepatitis C (HCV): A Pilot Study. Abstract 1154 (poster).
Digestive Disease Week. May 15-20, 2004. New Orleans, LA.
Internet Conference Report
Digestive Disease Week (DDW 2004)
May 15 - 20, 2004, New
Orleans, Louisiana
Treatment with
Peginterferon Alfa-2b (PEG-Intron) Plus Ribavirin Is Cost-effective for
Hepatitis C Patients with F1 Fibrosis
Although not all patients with histologically mild chronic hepatitis C progress, prior studies suggest that antiviral treatment should be cost-effective, but those studies were based on mild inflammation and involved interferon alone or with ribavirin.
The objective of this study was to determine the cost-effectiveness of peginterferon alfa-2b (PEG-Intron) + ribavirin for histologically mild F1 fibrosis.
Using data from Manns (Lancet 2001), researchers compared no antiviral therapy to peginterferon alfa-2b + >10.6 mg/kg ribavirin. Lifelong clinical and economic outcomes were based on Cox proportional hazard models estimating the likelihood of developing Metavir fibrosis stages F1-F4 over time (using 2313 liver biopsies), and on recent UNOS, SEER and NIH data (Wong, AASLD 2003).
Drug costs applied the 12-week stopping rule. Cost-effectiveness results are presented as incremental cost per discounted (3%) quality-adjusted life year gained.
Cost-effectiveness ratios below $50,000 per discounted quality-adjusted life year gained were considered to be cost-effective.
Results
Observed sustained viral response rates for peginterferon alfa-2b + ribavirin treatment of F1 were 63% overall, 52% for genotype 1 and 91% for genotype 2/3.
Antiviral treatment reduced the 20-year incidence of cirrhosis from 20% to 7.6% overall, to 9.7% for genotype 1 and to 1.8% for genotype 2/3.
Antiviral treatment extended life expectancy by 2.3 years overall, 1.9 years for genotype 1 and 3.4 years for genotype 2/3.
Quality-adjusted life expectancy benefits of treatment were 4.7 years overall, 3.9 years for genotype 1 and 6.8 years for genotype 2/3.
Antiviral treatment reduced the future cost of hepatitis C complications by $27,500 overall, $22,900 for genotype 1 and $40,100 for genotype 2/3.
Compared to no antiviral treatment, cost-effectiveness ratios for treatment were $5100 per discounted quality-adjusted life year gained overall, $9000 per discounted quality-adjusted life year gained for genotype 1 and $400 per discounted quality-adjusted life year gained for genotype 2/3.
The authors conclude, “Weight-based peginterferon alfa-2b + ribavirin should be cost-effective for patients with F1 fibrosis.”
05/21/04
Reference
J B Wong and
others. Cost-Effectiveness of Peginterferon á-2b plus Ribavirin Treatment of
Chronic Hepatitis C with F1 Fibrosis. Abstract 1215 (poster). Digestive
Disease Week 2004. May 15-20, 2004. New Orleans, LA.
Update on Cirrhosis -- The Role of Fibrosis Markers
New Orleans, Wednesday, May 19, 2004 -- Important new data presented at this year's Digestive Disease Week (DDW) meeting emphasized and reviewed the current state of noninvasive (serum) markers as surrogates for measuring fibrosis by liver biopsy. This report highlights some of the more key information from these proceedings and places it in relevant and appropriate context for the clinician.
Background and Context
The natural history of cirrhosis is such that chronic liver injury (and usually inflammation) leads first to fibrosis, and, if present over long periods of time, to cirrhosis. It would thus be ideal to be able to assess where in the disease progression each patient may be found. Currently, the primary method to assess the degree of fibrosis is liver biopsy. However, liver biopsy is known to be associated with morbidity and even mortality. Furthermore, physicians and patients alike often have a preference to avoid liver biopsy. Thus, there is considerable interest in the development of noninvasive markers of liver fibrosis (and liver function, for that matter).
During this year's DDW meeting, considerable interest was displayed in the area of fibrosis assessment. Reflective of this focus, a symposium entitled "Prognostic Markers of Liver Disease" was convened, as sponsored by the Liver and Biliary section, and a number of study abstracts were presented.
Serum Markers to Assess Fibrosis
A number of serum markers are currently available that can be used to assess liver fibrosis. The rationale for these tests is that they offer the advantage of measures of liver function or use mathematical formulas that take into account liver function, often in combination with markers that are fibrosis-specific. Examples of these types of tests are the APRI (a novel index, AST [aspartate aminotransferase]-to-platelet ratio index)[1] and the Fibrotest.[2] It is emphasized that in general, these tests are effective at excluding advanced fibrosis (cirrhosis) and minimal or no fibrosis. However, they typically do not accurately differentiate intermediate grades of fibrosis (ie, Metavir grades F1-F3), and thus indeterminate values become problematic in clinical practice. The more fibrosis-specific tests include definitive serum markers such as YKL-40, hyaluronic acid, collagens, fibronectins, and combinations of serum markers. Included in the "combination" category is the FibroSpect II, a unique noninvasive diagnostic panel to assist in the detection of liver fibrosis. This panel uses a combination of components in the fibrogenic cascade, such as hyaluronic acid, TIMP-1 (tissue inhibitor of metalloproteinase), and alpha-2-macroglobulin.
Patel and colleagues[3] presented the results of a study assessing the utility of this serum panel in a cohort of 244 patients with hepatitis C-related liver disease. They found that this test had a 71% to 87% positive predictive value for differentiating mild fibrosis (Metavir F0-F1) from more severe (Metavir F2-F4) disease. Again, these findings are consistent with the general tenet that these tests are able to differentiate advanced liver disease from minimal disease, but highlight the concept that they lack the ability to discriminate among intermediate degrees of fibrosis.
The Future of Prognostic Markers
Scott L. Friedman[4] emphasized the evolution of proteomics in this field, suggesting that fingerprints of the protein composition in the blood may be able to accurately reflect the fibrogenic activity of the liver. Recent work in this area has suggested the feasibility of this approach. This point was considerably strengthened by Hui and coworkers[5] who assessed the utility of a novel non-electrophoresis-based proteomic technology, SELDI-TOF MS (surface-enhanced laser desorption/ionization time-of-flight mass spectrometry), in predicting different degrees of liver fibrosis in chronic hepatitis B. They used SELDI-TOF MS to perform protein profiling, followed by implementation of artificial neural networks to generate models for prediction of fibrosis. The results were striking in that they were able to identify 30 proteomic profiles that were significantly associated with fibrosis in patients with hepatitis B. When these investigators divided subjects into those with moderate/severe fibrosis (Ishak stage 3-4) and those with cirrhosis (Ishak stage 5-6), they were able to demonstrate that the method had a sensitivity and specificity of greater than 90% for prediction of either moderate/severe fibrosis or cirrhosis. These data suggest that this methodology may be extremely useful in the future for more precise assessment of fibrosis risk.
Concluding Remarks
At present, methods to accurately assess fibrosis noninvasively are in evolution, and although controversy about their usefulness exists, it is anticipated that as the methods become more refined, such noninvasive measurement of fibrosis will be readily feasible
http://www.medscape.com/viewarticle/478434
Internet
Conference Report
Digestive Disease
Week (DDW 2004)
May 15 - 20, 2004, New Orleans,
Louisiana
Fibrosis Progression Is Dependent upon Hepatic Inflammation in Chronic Hepatitis C
Many patients (pts) with chronic HCV develop progressive fibrosis while others remain stable for 5-10 yrs or longer. Liver biopsy (LBX) is utilized to stage fibrosis. However, the role of hepatic inflammation (INFL) and the effect of this on fibrosis remains undefined.
Pts with chronic HCV who were either non-responders (NR) to prior IFN/RBV or who deferred treatment (tx) were enrolled in a prospective study to monitor fibrosis progression.
All pts underwent baseline LBX (prior to IFN tx, if administered), were followed prospectively and had repeat LBX after a mean of 6 years (>5 yrs after stopping IFN). LBX were scored according to Knodell HAI without knowledge of clinical or previous histologic data. HCV RNA was determined by Amplicor and genotype by InnoLippa.
Results
To date, 142 pts have undergone paired LBX. Mean age at first LBX was 43 yrs, 61% were male, 63% Caucasian and 89% genotype 1. 85% received IFN/RBV after the initial LBX.
At baseline 22% had no fibrosis (NF), 37% portal fibrosis (PF), 30% bridging (BF) and 11% cirrhosis (CX). Mean INFL score increased significantly (p=0.02) with increasing fibrosis. This was solely the result of an increase in piecemeal necrosis (PMN) and was associated with increased ALT (108 vs 125 IU/ml; p=0.02).
No relationship existed between fibrosis stage and either age, sex, race, genotype or serum HCV RNA.
On repeat LBX, fibrosis progression was observed in 56/142 pts: 70% in those with NF, 74% PF and 21% with BF. Pts with progression had a significant increase in INFL and PMN scores compared to those with no progression; this was unrelated to ALT, age, sex, race, GT, and HCV RNA.
Progression was significantly (p<0.001) slower in pts with BF than NF or PF. After a mean follow-up of 6 yrs, no difference in fibrosis progression was observed between NR and those who deferred therapy (57 vs 42%).
Conclusions
Fibrosis progression in NR with chronic HCV is directly related to INFL, specifically PMN, but not serum HCV RNA or demographic factors. This is unaffected by a single course of IFN in those with non-response.
These data suggest that NR with mild INFL are at low risk for fibrosis progression and unlikely to benefit from maintenance IFN therapy regardless of histologic stage.
Pts with significant INFL are at higher risk to progress and may benefit from agents which reduce INFL.
These data underscore the importance of LBX in the management of chronic HCV.
05/26/04
Reference
J M
Myung and
others. Fibrosis Progression Is Dependent upon Hepatic Inflammation in
Patients with Chronic HCV. Abstract 2018 (poster). Digestive Disease Week.
May 15-20, 2004. New Orleans, LA.
Internet Conference Report
Digestive Disease
Week (DDW 2004)
May 15 - 20, 2004, New Orleans,
Louisiana
Factors Associated with HCV Stage 3/4 Fibrosis
Most previous studies on hepatitis C virus (HCV) related cirrhosis included a small cohort of patients and assessed limited variables. Thus, studies including a large cohort of patients with systematic analyses are required to further define factors associated with HCV-stage 3/4 fibrosis.
The present study aimed to determine the risk factors for and the clinical presentation of HCV-stage 3/4 fibrosis in a large cohort of US patients.
The study subjects were collected consecutively from the Liver Clinics at Loma Linda University and the VA Medical Centers between July 1, 1999 and March 30, 2003. The inclusion criteria were positive HCV RNA PCR, liver biopsy-proven chronic hepatitis, negative HBsAg and anti-HIV, and absence of previous HCV treatment. The data were obtained through a retrospective chart review.
Results
Of the 460 patients, 331were males and 129 were females with mean age of 48.4+8.0 years, and 191 (41.7%) had stage 3/4 (III = 25.3%, IV = 16.4 %).
After adjusting for a history of alcohol use > 30 g/day, age > 60 years at entry (p=0.03), estimated duration of HCV infection > 25 years (p=0.04), being obese (p=0.017) and a history of diabetes mellitus (DM, p=0.03) were independently associated with stage 3/4 fibrosis.
Univariate analysis revealed a significant association of 2 X upper limits of normal ALT and AST (i.e. > 80 U/L), AST/ALT ratio > 1, alpha fetoprotein (AFP) > 15 ng/ml, transferrin saturation > 50%, histological activity index (HAI) > 7, and grade II/III hepatic steatosis were significantly associated with stage 3/4 fibrosis.
After adjusting for elevated ALT, AST/ALT ratio, and transferrin saturation, HAI > 7, and HCV genotype 1 infection, 2 X upper limit of normal AST (p=0.009), grade 2/3 hepatic steatosis (p=0.04), and serum AFP > 15 ng/ml (p=0.04) were independently associated with stage 3/4 fibrosis.
In addition, significantly higher frequencies of hypoalbuminemia (< 3.5 g/L, 70.37%, p < 0.001), thrombocytopenia (< 130 X 109/L, 80.72%, p < 0.001), and splenomegaly (66.34%, p < 0.001) were seen in patients with stage 3/4 fibrosis.
Conclusions
Elderly, longer duration of HCV infection, being obese, and a history of DM serve as independent risk factors for HCV-stage 3/4 fibrosis. Clinically, elevated AST and AFP, grade 2/3 hepatic steatosis, hypoalbuminemia, thrombocytopenia, and splenomegaly are associated with HCV-stage 3/4 fibrosis.
04/26/04
Reference
K-Q Hu and
others. Factors Associated with HCV-Stage III/IV Fibrosis: A Retrospective
Study of a Large Cohort of US Patients. Abstract 2036 (poster).
Digestive Disease Week. May 15-20, 2004. New Orleans, LA.