Silymarin use and liver disease progression in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis trial.

BACKGROUND: Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear. AIM: To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment. METHODS: Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes. RESULTS: At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33-1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes. CONCLUSIONS: Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164).

The course of hepatitis C viraemia in transfusion recipients prior to availability of antiviral therapy.

Knowing the likely distribution of intervals from hepatitis C infection to first RNA-negativity is important in deciding about therapeutic intervention. Prospectively collected sera and data from the Transfusion-transmitted Viruses Study (1974-1980) provide specific dates of infection and pattern of alanine aminotransferase (ALT) elevations. We examined frequency, timing and correlates of spontaneous resolution for 94 acutely infected transfusion recipients followed for a median of 9.5 months. Later, follow-up sera (>10 years) were available for 27 of the 94 cases from a Veterans Administration (VA) Study (1989-1990). Twenty-five (27%) of the 94 cases were classified as probably resolved during the episode itself. First RNA negativity occurred at 6-50 weeks (median, 19.5 weeks) after infection, and 5-43 weeks (median, 11 weeks) after ALT elevation. Thirteen of the 25 cases remained RNA-negative subsequently; 12 others had 1-6 RNA-positive sera intercalated between first and last RNA-negative results. RNA negativity, therefore, began variably and was interrupted in 12 cases of 25 (48%) by transient RNA-positive sera. Five of these 25 patients who were RNA-negative in the last study specimen had late, Veterans Administration Study follow-up; none showed viraemia. Of the remaining 69 transfusion transmitted virus study recipients, whose last serum was RNA-positive, two cleared viraemia after the last study serum but before late follow-up. Eleven (16%) had 23 intercalated RNA-negative sera before last positivity. RNA status, therefore, needs monitoring for many months before judging the spontaneous outcome as transient negativity may occur. Resolution was significantly more common in women and symptomatic cases; it was not associated with viral load in the infectious donation, HCV genotype, or the recipient's age.

Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity.

Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. It evolves from several chronic liver diseases, most of which culminate in cirrhosis. As the most common causes, other than alcoholic cirrhosis, are chronic hepatitis B and C infections, its prevalence worldwide is linked to the prevalence of these two viruses. Thus, the highest rates are in southeast Asia and sub-Saharan Africa, the world's most populous nations, where hepatitis B virus infection is endemic. In most western countries, hepatitis C virus infection is the predominant cause, and hepatitis B-related liver cancer occurs largely among immigrants from countries of high hepatitis B endemicity. In most western countries, the incidence and mortality from HCC is increasing as a consequence of the chronic sequelae of the 'epidemic' of hepatitis C of the 1960-1980s. In the US, modeling of this infection predicts a continued rise in liver cancer over the next decade. Surveillance by the National Cancer Institute and the Centers for Disease Control confirms the increasing incidence of and mortality from HCC to the year 2000, although subsequent analyses suggest a slowing or possibly decline in the rate of increase. Whether this trend will continue requires further evaluation.

Occurrence of identical hypervariable region 1 sequences of hepatitis C virus in transfusion recipients and their respective blood donors: divergence over time.

A total of 240 stored serum specimens from 30 transfusion recipients and 120 blood donors from the Transfusion-Transmitted Viruses Study (TTVS) were evaluated with the objective of establishing transmission of hepatitis C virus (HCV) by specific blood donors. Phylogenetic analysis of hypervariable region 1 (HVR1) and HCV genotyping were performed on the genomic region encoding amino acids 329 to 410. Amino acid distances between HVR1 sequences were calculated by the Kimura formula. Bootstrap analysis of HVR1 sequences provided support for linking recipients to specific donors. Linear regression analysis showed no differences between donor and recipient HVR1 sequences 7.9 weeks posttransfusion, but donor and recipient sequences diverged thereafter (r = 0.690). The initial lag phase in the evolution of HVR1 in the infected recipient was attributed to the time required to mount host immunologic defenses against the virus. Within-recipient divergence in HVR1 was determined from analyses of serial specimens collected within 2 weeks after the alanine transaminase peak, at the end of the original study (1974-1979), and in the follow-up study (1987-present). HVR1 remained invariant over a period of 6.7 to 9.5 days (95% CI) during acute infection. Within-patient divergence in HVR1 increased over a period of 11 to 15 years (r = 0.771), reaching the degree of divergence observed between unlinked subjects. In cases in which transfusion involved more than one HCV subtype, only one of the HCV subtypes established infection in the recipient. Subtype-specific differences in HVR1 were shown.

Hepatitis C: a brief clinical overview.

Hepatitis C has emerged as an important public health problem that has affected 3.9 million Americans and 170 million people worldwide and is currently the most common indication for orthotopic liver transplantation. The disease, characterized by asymptomatic onset, is often discovered incidentally through blood tests obtained during routine physical examination or before blood donation. Spontaneous recovery occurs in about 20% of patients. Among those who remain chronically infected, an equal percentage progress to cirrhosis within 20 yr, have stable nonprogressive disease, or progress more slowly over 40 to 60 yr. At present, combination therapy with interferon plus ribavirin is the treatment of choice for hepatitis C-infected patients identified as appropriate candidates for therapy. Unfortunately, sustained response rates are only modest, with a lesser response among African Americans, and treatment is associated with a number of side effects. Research studies attempting to improve the response to current therapy, to identify alternative treatments or treatment strategies, and to develop an effective vaccine are ongoing and will hopefully provide us with the ability to better understand and manage hepatitis C.

Prevalence and incidence of hepatitis C virus infection in the US military: a seroepidemiologic survey of 21,000 troops.

Because of a high prevalence of hepatitis C virus (HCV) infection (10-20%) among veterans seeking care in Department of Veterans Affairs (VA) hospitals, current US military forces were evaluated for HCV infection. Banked serum samples were randomly selected from military personnel serving in 1997 and were tested for antibody to HCV (anti-HCV). Overall prevalence of anti-HCV among 10,000 active-duty personnel was 0.48% (5/1,000 troops); prevalence increased with age from 0.1% among military recruits and active-duty personnel aged <30 years to 3.0% among troops aged >/=40 years. Prevalence among 2,000 Reservists and active-duty troops was similar. Based on sequential serum samples from 7,368 active-duty personnel (34,020 person-years of observation), annual incidence of infection was 2/10,000. Of 81 HCV RNA-positive troops for whom genotype was determined, genotypes 1a (63%) and 1b (22%) predominated, as in the civilian population. These data indicate that HCV infection risk among current military forces is lower than in VA studies and the general civilian population aged <40 years. The low level of HCV infection may be attributed to infrequent injection drug use in the military due to mandatory testing for illicit drugs prior to induction and throughout military service.

The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse.

BACKGROUND: Although concomitant alcoholism is widely believed to enhance liver disease progression in persons with hepatitis C virus (HCV) infection, this relationship has not been well quantified. OBJECTIVE: To quantify the relationship of transfusion-associated HCV infection and history of heavy alcohol abuse to development of cirrhosis. DESIGN: Retrospective cohort study. SETTING: Liver clinics in university and government hospitals. PATIENTS: Extended follow-up of 1030 patients in prospective investigations of transfusion-associated viral hepatitis conducted in the United States between 1968 and 1980. MEASUREMENTS: Development of cirrhosis and history of heavy alcohol abuse were determined from review of interviews with patients or their proxies, medical records, death certificates, and autopsy and biopsy reports. Logistic regression was used to estimate the risk for cirrhosis associated with transfusion-associated HCV infection and history of heavy alcohol abuse. RESULTS: The absolute risk for cirrhosis was 17% among patients with transfusion-associated HCV; 3.2% among patients with transfusion-associated non-A, non-B, non-C hepatitis; and 2.8% among controls. Patients with transfusion-associated HCV were more likely than controls to develop cirrhosis (odds ratio, 7.8 [95% CI, 4.0 to 15.1]). A history of heavy alcohol abuse was associated with a fourfold increased risk for cirrhosis. Hepatitis C virus infection plus a history of heavy alcohol abuse led to a substantial increase in risk for cirrhosis (odds ratio, 31.1 [CI, 11.4 to 84.5]) compared with controls without such a history. CONCLUSIONS: Heavy alcohol abuse greatly exacerbates the risk for cirrhosis among patients with HCV infection. This finding emphasizes the need to counsel such patients about their drinking habits.

Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study.

Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of follow-up, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P =.05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA.

Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests.

PURPOSE: To review information on performance characteristics for tests that are commonly used to identify acute and chronic hepatic injury. DATA SOURCES AND STUDY SELECTION: A MEDLINE search was performed for key words related to hepatic tests, including quality specifications, aminotransferases, alkaline phosphatase, gamma-glutamyltransferase, bilirubin, albumin, ammonia, and viral markers. Abstracts were reviewed, and articles discussing performance of laboratory tests were selected for review. Additional articles were selected from the references. Guideline Preparation and Review: Drafts of the guidelines were posted on the Internet, presented at the AACC Annual Meeting in 1999, and reviewed by experts. Areas requiring further amplification or literature review were identified for further analysis. Specific recommendations were made based on analysis of published data and evaluated for strength of evidence and clinical impact. The drafts were also reviewed by the Practice Guidelines Committee of the American Association for the Study of Liver Diseases and approved by the committee and the Association's Council. RECOMMENDATIONS: Although many specific recommendations are made in the guidelines, some summary recommendations are discussed here. Alanine aminotransferase is the most important test for recognition of acute and chronic hepatic injury. Performance goals should aim for total error of <10% at the upper reference limit to meet clinical needs in monitoring patients with chronic hepatic injury. Laboratories should have age-adjusted reference limits for enzymes in children, and gender-adjusted reference limits for aminotransferases, gamma-glutamyltransferase, and total bilirubin in adults. The international normalized ratio should not be the sole method for reporting results of prothrombin time in liver disease; additional research is needed to determine the reporting mechanism that best correlates with functional impairment. Harmonization is needed for alanine aminotransferase activity, and improved standardization for hepatitis C viral RNA measurements.

Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring.

PURPOSE: To review information on the use of laboratory tests in screening, diagnosis, and monitoring of acute and chronic hepatic injury. DATA SOURCES AND STUDY SELECTION: A MEDLINE search was performed for key words related to hepatic diseases, including acute hepatitis, chronic hepatitis, alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, and etiologic causes. Abstracts were reviewed, and articles discussing use of laboratory tests selected for review. Additional articles were selected from the references. Guideline Preparation and Review: Drafts of the guidelines were posted on the Internet, presented at the AACC Annual Meeting in 1999, and reviewed by experts. Areas requiring further amplification or literature review were identified for further analysis. Specific recommendations were made based on analysis of published data and evaluated for strength of evidence and clinical impact. RECOMMENDATIONS: Although many specific recommendations are made in the guidelines, only some summary recommendations are listed here. In acute hepatic injury, prothrombin time and, to a lesser extent, total bilirubin are the best indicators of severity of disease. Although ALT is useful for detecting acute and chronic hepatic injury, it is not related to severity of acute hepatic injury and only weakly related to severity of chronic hepatic injury. Specific tests of viral markers should be the initial differential tests in both acute and chronic hepatic injury; when positive, they are also useful for monitoring recovery from hepatitis B and C.

High-density lipoproteins from human alcoholics exhibit impaired reverse cholesterol transport function.

We have previously shown that chronic alcohol consumption leads to inhibition of sialylation of apolipoprotein E (apo E) that results in its impaired binding to high-density lipoprotein (HDL) molecule. Because apo E plays a major role in reverse cholesterol transport (RCT), we speculated that ethanol-mediated formation of HDL molecules without apo E may affect the RCT process. Therefore, we have investigated whether the RCT function of HDL is affected in chronic alcoholics with or without liver disease compared with nondrinkers. HDL was isolated from fasting plasma of normal subjects, n = 9 (nondrinkers), chronic alcoholics, n = 8 (ALC), and chronic alcoholics with liver disease, n = 6 (ALD). A portion of HDL sample from each subject was evaluated for its cholesterol efflux capacity from [3H]cholesterol oleate preloaded mouse macrophages. The remaining portion of each HDL sample was labeled with [3H]cholesterol oleate and evaluated for its ability to deliver cholesterol to the liver using HepG2 cells in culture. Cholesterol efflux capacity of HDLs was decreased by 83% (P < .0002) in alcoholics without liver disease and by 84% (P < .0006) in alcoholics with liver disease compared with the HDLs from nondrinkers. The capacities of HDLs to deliver cholesterol to the liver were decreased by 54% (P < .005) in alcoholics without liver disease and by 64% (P < .005) in alcoholics with liver disease compared with the HDLs from nondrinkers. The fact that further complications by liver disease in alcoholic subjects did not significantly exacerbate the extent of impairment in RCT function of HDL suggest that alcohol per se is responsible for its deleterious effects on RCT. Significantly, plasma HDL apo E concentration relative to that of apo A1 (apo E/apo A1 ratio) was also decreased by 31% to 32% (P < .0005) in alcoholics without or with liver disease compared with nondrinkers. It is therefore concluded that chronic alcohol consumption adversely affects the RCT function of HDL by altering its association with apo E due to ethanol-induced desialylation of apo E.

Recovery, persistence, and sequelae in hepatitis C virus infection: a perspective on long-term outcome.

Hepatitis C has emerged in recent years as the most common basis for liver disease in the United States, having infected an estimated 3.9 million people in this country and an estimated 170 million worldwide. Currently, it is the predominant reason for undergoing liver transplantation. The disease it causes is characterized by silent onset in most infected individuals, a high rate of viral persistence, and the potential for development of ever-worsening chronic liver disease, ranging from chronic hepatitis to cirrhosis and occasionally to hepatocellular carcinoma. Such progression, when it occurs, is also most commonly a silent process that may take 20-40, and occasionally even more, years to reach its end point. Because of these characteristics, it has been exceedingly difficult to accurately assess the natural history. Efforts to accomplish this have consisted of retrospective, prospective, and cohort studies. The most concerning data have derived from the retrospective study approach, generally performed at tertiary referral centers. Because these centers commonly attract persons with existing chronic liver disease, they have tended to describe a high rate of progression to cirrhosis and cancer. This "referral bias" is avoided in the prospective and cohort study approach, and data derived from these studies indicate a lower rate of progression and a correspondingly higher rate of either recovery or minimal liver disease. In this review, we briefly describe potential mechanisms of viral persistence; present detailed information on outcomes that have derived from retrospective, prospective, and cohort studies, involving both adults and children; examine the data regarding progression of fibrosis and of progression to hepatocellular carcinoma; consider cofactors that might enhance liver disease progression; and report the emerging data that suggest that spontaneous viral clearance may be higher than is currently believed. We conclude with the view that severe, life-threatening, progressive liver disease clearly occurs in a sizable minority (perhaps 30%) of chronically infected persons but speculate that fibrosis progression is neither linear or inevitable and hence that most hepatitis C virus carriers will have either a stable nonprogressive course or such indolent progression that they will die from an unrelated disease before the severe sequelae of hepatitis C become manifest or will have a sustained "curative" response to therapy. Although this view provides reasonable hope to the hepatitis C virus-infected individual, it does not deny the enormous burden this infection presents as the result of its high prevalence and global distribution. The sheer magnitude of the infected population will result in a large number with severe life-threatening liver disease even if the proportion of infected individuals that develop progressive disease is relatively small.

Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus.

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Owing to shared routes of transmission, HCV and human immunodeficiency virus (HIV) coinfection are common, affecting approximately one-third of all HIV-infected persons in the United States. In addition, HIV coinfection is associated with higher HCV RNA level and a more rapid progression of HCV-related liver disease, which leads to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons, because the incidence of infection is increased and the natural history of HCV infection is accelerated in coinfected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed for HIV-HCV-coinfected individuals.

Pathogenesis, natural history, treatment, and prevention of hepatitis C.

Approximately 4 million persons in the United States and probably more than 100 million persons worldwide are infected with hepatitis C virus. The virus has the unique ability to cause persistent infection in susceptible hosts after parenteral or percutaneous transmission, and its underlying mechanisms are not well understood. The immunologic correlates of protection and viral clearance and the pathogenesis of liver injury are yet to be defined, but recent studies suggest the importance of cell-mediated immune responses. Although 70% to 80% of infected persons become chronic carriers, most have relatively mild disease with slow progression. However, chronic and progressive hepatitis C carries significant morbidity and mortality and is a major cause of cirrhosis, end-stage liver disease, and liver cancer. Development of an effective hepatitis C virus vaccine is not imminent, but recent advances in technology and basic knowledge of molecular virology and immunology have engendered novel approaches to the fundamental problems encountered in vaccine development. Current therapy for hepatitis C, although effective in some patients, is problematic and still evolving. Advances in modern biology and immunology promise new therapies for this important disease.

Increased hepatic iron deposition resulting from treatment of chronic hepatitis C with ribavirin.

Increased levels of hepatic iron may impair the response of patients with chronic hepatitis C to treatment with interferon-alfa, but combination therapy with ribavirin has demonstrated efficacy in the treatment of hepatitis C. When used alone or with interferon-alfa, ribavirin may cause a dose-dependent reversible hemolytic anemia. We compared the extent and cellular localization of iron deposition in liver tissue from biopsy specimens obtained before and after 36 weeks of therapy with ribavirin or placebo for 59 patients with chronic hepatitis C. Paired slides were available for review from 26 ribavirin and 27 placebo recipients. Iron deposition was assessed using coded slides stained with Perls Prussian blue and was semi-quantitated in hepatocytes, Kupffer cells, and areas of fibrosis. The overall iron score fell by 0.96 in the placebo group and increased 1.69 in the ribavirin recipients. Iron was deposited mainly in hepatocytes; the hepatocyte iron score increased from 2.19 to 3.81 in the ribavirin group. The amount of iron staining in Kupffer cells declined in the placebo group and increased slightly in the ribavirin group. Iron changes in areas of fibrosis were minor and did not differ between groups. Increased total hepatic iron deposition occurred during a 9-month course of ribavirin. Ribavirin-associated hemolysis deposits iron preferentially in hepatocytes. This increased deposition of hepatic iron does not seem to affect the biochemical or histologic response to ribavirin therapy but may have implications for hepatocyte susceptibility to future injury.

45-year follow-up of hepatitis C virus infection in healthy young adults.

BACKGROUND: The sequelae during the first two decades after acute hepatitis C virus (HCV) infection have been well studied, but the outcome thereafter is unknown. OBJECTIVE: To conduct an extended study of the natural history of HCV infection by using archived serum specimens originally collected between 1948 and 1954. DESIGN: Retrospective cohort study. SETTING: A university, a Veterans Affairs medical center, and a medical follow-up agency that had access to the serum specimens and accompanying demographic and medical records. PARTICIPANTS: 8568 military recruits who were evaluated for group A streptococcal infection and acute rheumatic fever between 1948 and 1954. Blood samples were taken from the recruits and, after testing, were stored frozen for almost 45 years. MEASUREMENTS: The presence of antibodies to HCV was determined by enzyme-linked immunoassay, supplementary recombinant immunoblot assay, and polymerase chain reaction for HCV RNA. Morbidity and mortality were also assessed. RESULTS: Of 8568 persons, 17 (0.2%) had positive results on enzyme-linked immunosorbent assay and recombinant immunoblot assay. The rate was 1.8% among the African-American persons and 0.1% among the white persons in the total sample (relative risk, 25.9 [95% CI, 8.4 to 80.0]). During the 45-year follow-up, liver disease occurred in 2 of the 17 HCV-positive persons (11.8%) and 205 of the 8551 HCV-negative persons (2.4%) (ethnicity-adjusted relative risk, 3.56 [CI, 0.94 to 13.52]). Seven of the 17 HCV-positive persons (41 %) and 2226 of the 8551 HCV-negative persons (26%) had died by December 1996 (ethnicity-adjusted relative risk, 1.48 [CI, 0.8 to 2.6]). Of persons who were HCV-positive, 1 (5.9%) died of liver disease 42 years after the original phlebotomy, 5 (29%) died of non-liver-related disease a median of 37 years after the original phlebotomy, and 1 (5.9%) died of unknown causes. One hundred nineteen HCV-negative persons (1.4%) died of liver disease. CONCLUSIONS: The rate of HCV infection from 1948 to 1954 among a sample of military recruits parallels that among present-day military recruits and volunteer blood donors. During 45 years of follow-up, HCV-positive persons had low liver-related morbidity and mortality rates. This suggests that healthy HCV-positive persons may be at less risk for progressive liver disease than is currently thought.