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BACKGROUND: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G. cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G. cambogia either alone (n=5) or in combination with green tea (n=16) or Ashwagandha (n=1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G. cambogia and 103 patients from other HDS. RESULTS: Patients who took G. cambogia were between 17 to 54 years, with liver injury arising 13 to 223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G. cambogia group (p

The 2020 Nobel Prize in Medicine or Physiology was awarded to Drs. Harvey Alter, Michael Houghton, and Charles Rice for their contributions to the discovery and characterization of the hepatitis C virus (HCV). Their achievements represent a remarkable triumph of biomedical science which allowed the development of curative therapy for HCV, that will save countless lives. This tribute provides a historical perspective of the laureates' seminal work leading to the discovery of the HCV and a synopsis of a forum hosted by the American Association for the Study of Liver Diseases to honor the laureates in which they offered their perspectives, advice for young investigators and what's left to accomplish in the field. Finally, others in the research community who have worked closely with one or more of the laureates, share some of their personal reflections and anecdotes.

BACKGROUND AND AIMS Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

As part of the United States Pharmacopeia’s ongoing review of dietary supplement safety data, a new comprehensive systematic review on green tea extracts (GTE) has been completed. GTEs may contain hepatotoxic solvent residues, pesticide residues, pyrrolizidine alkaloids and elemental impurities, but no evidence of their involvement in GTE-induced liver injury was found during this review. GTE catechin profiles vary significantly with manufacturing processes. Animal and human data indicate that repeated oral administration of bolus doses of GTE during fasting significantly increases bioavailability of catechins, specifically EGCG, possibly involving saturation of first-pass elimination mechanisms. Toxicological studies show a hepatocellular pattern of liver injury. Published adverse event case reports associate hepatotoxicity with EGCG intake amounts from 140 mg to ∼1000 mg/day and substantial inter-individual variability in susceptibility, possibly due to genetic factors. Based on these findings, USP included a cautionary labeling requirement in its Powdered Decaffeinated Green Tea Extract monograph that reads as follows: “Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes).”

The U.S. Drug Induced Liver Injury Network assayed the contents of herbal and dietary supplements collected from patients enrolled into its prospective study. The aim was to determine the accuracy of product labels, and to identify known hepatotoxins. Using high‐performance liquid chromatography coupled with mass spectrometry to assay 272 product, 51% were found to be mislabeled; that is, to have chemical contents that did not match the label. Appearance enhancement, sexual performance, and weight loss products were most commonly mislabeled. Whether the mislabeling contributed to liver injury is under study; however, the high mislabeling rate underscores the need for more stringent regulation of supplements., Herbal and dietary supplements can cause liver injury. The precise cause for injury due to supplements is difficult to determine, as this studies shows that labels are largely unreliable.

Background Bodybuilding supplements can cause a profound cholestatic syndrome. Aim To describe the drug-Induced liver injury network's experience with liver injury due to bodybuilding supplements. Methods Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were analysed in prospectively enrolled subjects with bodybuilding supplement-induced liver injury with causality scores of probable or higher. Results Forty-four males (mean age 33 years) developed liver injury with a median latency of 73 days. Forty-one per cent presented with hepatocellular pattern of liver injury as defined by the R > 5 ([Fold elevation of ALT] ÷ [Fold elevation of Alk Phos] (mean, range = 6.4, 0.5-31.4, n = 42) despite all presenting with clinical features of cholestatic liver injury (100% with jaundice and 84% with pruritus). Liver biopsy (59% of subjects) demonstrated a mild hepatitis and profound cholestasis in most without bile duct injury, loss or fibrosis. Seventy-one per cent were hospitalised, and none died or required liver transplantation. In some, chemical analysis revealed anabolic steroid controlled substances not listed on the label. No enrichment of genetic variants associated with cholestatic syndromes was found, although mutations in ABCB11 (present in up to 20%) were significantly different than in ethnically matched controls. Conclusions Patients with bodybuilding supplements liver injury uniformly presented with cholestatic injury, which slowly resolved. The ingested products often contained anabolic steroids not identified on the label, and no enrichment in genetic variants was found, indicating a need for additional studies.

Drug-induced liver injury (DILI), a relatively rare condition, is nevertheless a major reason for not approving a drug in development or for removing one already marketed. With a specific diagnostic biomarker lacking, finding elevated serum enzyme [alanine aminotransferase (ALT), aspartate aminotransferase and alkaline phosphatase] activities remains an initial signal for incipient liver injury. Enzyme elevations alone may not be harmful, but if caused by a drug and followed by jaundice (called ‘Hy's law') there is a high possibility of serious DILI. In 1997 several drugs were approved by the Food and Drug Administration (FDA) of the USA that were later withdrawn from the market for serious liver toxicity. New drugs in development are now required to be monitored for liver injury, and the data is to be considered in the approval decision. A program called e-DISH (evaluation of drug-induced serious hepatotoxicity) was introduced in 2004 to aid medical reviewers to select from all subjects studied those few who show nontrivial liver injury and estimate the most likely cause. The threshold of enzyme elevation comprising a warning for possibly serious DILI is uncertain, although generally accepted as 3-5 times the ‘upper limit of normal'. The new direct-acting antiviral agents for treating chronic hepatitis C virus, which often lead to a reduction of elevated ALTs, mandate that a later increase without viral breakthrough be compared to the new on-treatment level of values. The drug may be discontinued or interrupted for evaluation to exclude other possible causes of liver injury. The FDA has approved no drug since 1997 that has been withdrawn later because of serious hepatotoxicity.

Causality assessment is a critical step in establishing the diagnosis of drug induced liver injury (DILI) during drug development. DILI may resemble almost any type of liver disease, and often presents a serious challenge to clinical investigators and drug makers. The diagnosis of DILI is largely based upon a combination of a compatible clinical course, exclusion of all other reasonable causes, resemblance of clinical and pathological features to known features of liver injury due to the drug (i.e., “drug’s signature”), and incidence of liver injury among patients treated with the drug compared to placebo or comparator. Causality assessment for suspected DILI is currently performed using either evaluation by physicians with expertise in liver disorders (i.e., expert opinion) or standardized scoring instruments such as the Roussel Uclaf Causality Assessment Method (RUCAM). Both approaches are widely used in the post marketing setting. Causality assessment based on expert opinion is considered superior to standardized instruments such as RUCAM, in the setting of drug development, and is currently the preferred approach during clinical trials. There is a need for a systematic revision of RUCAM that will render it more suitable for the setting of clinical trials and drug development. Careful monitoring and meticulous data collection during clinical trials are essential in all cases with established liver injury to allow for a proper causality assessment. A workshop was convened to discuss best practices for the assessment of drug-induced liver injury (DILI) in clinical trials. This publication is based on the conclusions of this workshop.

Approximately half the US adult population consumes herbals and dietary supplements (HDS),(1,2) with recent reports showing their use to be increasing.(3,4) Supplement users are more commonly women, non-Hispanic whites, over age 40, and have higher levels of education than non-users.(4-7) NHANES III data indicate that multivitamins and minerals are the most common supplements used, followed by calcium and fish oils.(5) However, the range of HDS is far broader and includes numerous commercial products. Although dietary supplements are perceived as safe (8), the current regulatory framework established by the Dietary Supplement Health and Education Act of 1994 (9) requires less evidence of safety prior to marketing as assessed by the Food and Drug Administration (FDA) than is required for pharmaceuticals. The FDA and other regulatory bodies can take action against a manufacturer only if there is proven adulteration or injury from its supplement. Recent cases of life-threatening hepatotoxicity from the dietary supplement OxyElite Pro (10) underscore the potential adverse consequences of this oversight process. The Drug-Induced Liver Injury Network (DILIN), supported by the National Institutes of Diabetes and Digestive and Kidney Diseases, was established in 2003 to identify, enroll, and characterize cases of drug-induced liver injury attributable to medications (excluding acetaminophen) and HDS (ClinicalTrials.gov Identifier:NCT00345930).(11) The original DILIN report identified HDS as the second most common cause for liver injury. (12) Since that report, many more cases have been accrued by the DILIN. Thus, we examined the burden and characteristics of liver injury attributable to HDS in the DILIN, and compared this injury with that due to conventional medications.

Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typically induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supplements, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (Hepatology 2017;65:363-373).

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The standard of care (SOC) therapy for patients with chronic hepatitis C virus (HCV) infection has been the use of both peginterferon (PegIFN) and ribavirin (RBV). These drugs are administered for either 48 weeks (HCV genotypes 1, 4, 5, and 6) or for 24 weeks (HCV genotypes 2 and 3), inducing sustained virologic response (SVR) rates of 40%-50% in those with genotype 1 and of 80% or more in those with genotypes 2 and 3 infections.5-7 Once achieved, an SVR is associated with long-term clearance of HCV infection, which is regarded as a virologic “cure,” as well as with improved morbidity and mortality.8-10 Two major advances have occurred since the last update of treatment guidelines for chronic hepatitis C (CHC) that have changed the optimal treatment regimen of genotype 1 chronic HCV infection: the development of direct-acting antiviral (DAA) agents11-17 and the identification of several single-nucleotide polymorphisms associated with spontaneous and treatment-induced clearance of HCV infection.18,19 Although PegIFN and RBV remain vital components of therapy, the emergence of DAAs has led to a substantial improvement in SVR rates and the option of abbreviated therapy in many patients with genotype 1 chronic HCV infection. A revision of the prior treatment guidelines is therefore necessary, but is based on data that are presently limited. Accordingly, there may be need to reconsider some of the recommendations as additional data become available. These guidelines review what treatment for genotype 1 chronic HCV infection is now regarded as optimal, but they do not address the issue of prioritization of patient selection for treatment or of treatment of special patient populations.

The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years. Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. Six hundred seventy-nine clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5% per year) than subjects with fibrosis (3.3% per year) (P < 0.0001). Child-Turcotte-Pugh (CTP) score ≥7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a CTP score ≥7, the rate of subsequent events increased to 12.9% per year, including a death rate of 10% per year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis. Conclusion: Among patients with advanced hepatitis C who failed peginterferon and ribavirin therapy, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once the CTP score reaches at least 7. (HEPATOLOGY 2011)

Hepatitis C infection has evolved in the past quarter century from a newly recognized entity without a known pathogen (non-A, non-B hepatitis) to one of the world’s most prevalent causes of liver disease, an important source for hepatocellular carcinoma, and the major indication for liver transplantation. It is caused by a virus with a complex replication cycle that occurs in multiple genotypes, of which the four most prevalent (1, 2, 3, and 4) exhibit differences in clinical behavior and responses to therapy. Chronic hepatitis C virus (HCV) in particular has evolved from a disease with no known treatment to one with several primary treatment options, none of which is uniformly effective, and a growing list of secondary treatment options for those who have failed to respond to, or relapsed after initial therapy. As treatment is often associated with significant side effects, it is now a disease that presents clinicians with multiple important decisions: whom to treat, when and with what to treat them initially, and how to manage patients who have failed during initial therapy to achieve a sustained virological response, the gold standard of effective therapy. This review examines each of these important decisions, presenting evidence to help guide clinicians in their choices. The decisions are addressed sequentially as they arise during the initial evaluation and subsequent treatment of a typical, newly recognized patient with chronic HCV, and the considerations facing the clinician when the patient has failed to achieve an SVR.

A diagnosis of hepatotoxicity must be considered when liver injury is identified in a person taking a prescription drug, herbal, or over-the-counter product, even if there is already preexisting liver disease.1-5 Because there is currently no specific marker of drug-induced liver injury (DILI), the diagnosis rests on excluding other conditions that can mimic such injury. The diagnosis is especially difficult when affected persons are taking multiple products, any one of which might be responsible, and because of possible synergism between drugs.1,6-8 In the traditional diagnostic approach to suspected DILI, which involves clinical, biochemical, and histological evaluation, attempts are made to establish the latency between the start of the drug and the onset of injury, its clinical signature, the exclusion of alternate etiologies, evidence of improvement of the liver injury upon drug withdrawal (dechallenge), and the effect of deliberate or inadvertent rechallenge. When performed by an experienced clinician, the assessment is considered by expert opinion. However, even for experts, the diagnosis of DILI can be problematic because of the inherently subjective nature of this approach. Efforts have therefore turned toward developing more objective diagnostic strategies through the creation of specific instruments such as the Roussel-Uclaf Causality Assessment Method (RUCAM), the Maria and Victorino method, and the Naranjo scale, the last designed to assess all forms of adverse drug reactions.9-13 In a head-to-head comparison of these instruments, RUCAM has been found to perform best for diagnosing hepatotoxicity, but it is cumbersome and therefore is rarely used in clinical practice. The Drug-Induced Liver Injury Network (DILIN) is a multicenter study whose primary aims are to identify and collect information on bona fide cases of drug-induced liver disease and to obtain serum, DNA, and liver tissue to allow for mechanistic investigation. When the study was being planned, the decision was made to assess causality with both expert opinion and RUCAM. A highly structured expert opinion method was developed that was specifically designed to include standardized terminology and specific methodology, and it is hereafter called structured expert opinion. It was hypothesized that this approach may have certain advantages in comparison with RUCAM. This report describes how the expert opinion approach was developed and refined and compares its effectiveness to that of RUCAM.14

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States. The association between NAFLD and quality of life (QOL) remains unclear. These data are important to estimate the burden of illness in NAFLD. The aim was to report QOL scores of adults with NAFLD and examine the association between NAFLD severity and QOL. QOL data were collected from adults with NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network using the Short Form 36 (SF-36) survey, and scores were compared with normative U.S. population scores. Liver biopsy histology was reviewed by a central pathology committee. A total of 713 subjects with NAFLD (male = 269, female = 444) were included. Mean age of subjects was 48.3 years; 61% had definite nonalcoholic steatohepatitis (NASH), and 28% had bridging fibrosis or cirrhosis. Diabetes was present in 27% of subjects. Subjects with NAFLD had worse physical (mean, 45.2) and mental health scores (mean, 47.6) compared with the U.S. population with (mean, 50) and without (physical, 55.8; mental, 52.5) chronic illness. Subjects with NASH reported lower physical health compared with subjects with fatty liver disease without NASH (44.5 versus 47.1, P = 0.02). Subjects with cirrhosis had significantly (P < 0.001) poorer physical health scores (38.4) than subjects with no (47.6), mild (46.2), moderate (44.6), or bridging fibrosis (44.6). Cirrhosis was associated with poorer physical health after adjusting for potential confounders. Mental health scores did not differ between participants with and without NASH or by degree of fibrosis. Conclusion: Adults with NAFLD have a significant decrement in QOL. Treatment of NAFLD should incorporate strategies to improve QOL, especially physical health. (HEPATOLOGY 2009.)

In the late 1960's, only types A and B hepatitis were believed to exist, distinguished by circumstances of exposure and incubation periods. In the early 1970's, studies of transfusion recipients were begun with the belief that hepatitis B would be responsible should transfusion-associated hepatitis develop. After discovery of the viruses of hepatitis A and B, neither agent was found responsible, hence non-A, non-B (NANB) hepatitis. Initial follow-up of these cases showed that approximately 50% developed chronic hepatitis based on persistence of serum enzymes for at least 6 months. Approximately 15 years later, after the hepatitis C virus had been identified as the cause for NANB hepatitis, chronic hepatitis was found to develop more frequently as indicated by persistent viral infection in over 80% of infected adults but in only about 50% of infected children or young women. Follow-up over 2 to 4 decades indicated that many infected persons developed progressive hepatic fibrosis, sometimes culminating in cirrhosis and/or liver cancer. Long-term natural history studies have proved to be challenging because disease onset is often silent and progression extremely slow. Differing strategies have been used to determine the natural history, the descriptions and results of which are presented in this review.

The dramatic growth of the pharmaceutical industry over the past 50–60 years has resulted in the development and marketing of an ever-increasing number of drugs. In the United States, medical drugs, both overthe-counter and those dispensed by prescription, are widely advertised on television, in the popular press, and on the worldwide web. The result is that the general public, especially in western countries, are accustomed to hearing about drugs and have come to expect their availability for all ailments, regardless of their severities. While most conventional drugs are designed to be beneficial, they can also cause undesired adverse effects that may range from trivial to death-dealing injury. Numerous epidemiologic surveys indicate that adverse reactions from conventional drugs account for between 3% and over 8% of all hospital admissions [1–4], and are responsible for a significant number of deaths [1,5,6]. Adverse reactions can affect all organ systems including the liver, the focus of this editorial. Herbals and dietary supplements also now play an important role in the ‘‘therapeutic armamentarium.” Herbals have been utilized by indigenous peoples and certain cultures for centuries, but interest in their use among western populations is a relatively recent phenomenon, although their frequency of use is growing exponentially and is beginning to parallel and even exceed that of conventional medications. In early telephone surveys conducted in the United States, the use

Summary. 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.

There is appropriate concern about the potential risk for hepatotoxicity from herbal products because they are unregulated and therefore not standardized with regard to their contents. This is particularly the case for the crude herbals that are commonly formulated as a mixture, so that their ingredients may be ambiguous and even contain harmful contaminants. Presented here is an overview of the more commonly recognized herbal products that have been reported to be associated with liver injury. Although many of them are clearly implicated, there are some, particularly those identified solely through an occasional case report, for which the relationship is uncertain.

Complementary and alternative medicine (CAM) has been used for centuries in China and Japan to treat various illnesses, including viral hepatitis. Several therapeutic approaches constitute CAM, the most relevant for this review being the use of herbals. However, profound disagreements exist between conventional and alternative medicine practitioners regarding their value. Western medical advocates cite deep concerns about the purity of most herbals because of lack of standardized production, the paucity of pharmacokinetic data, the fact that few well-designed randomized, controlled trials of these products have been performed and the evidence that some herbals have been responsible for severe adverse effects. Nevertheless, many in the public, even in western countries, turn to the use of herbals, believing that they must be safe and effective because they are ‘natural’ and have been used for centuries, and because of dissatisfaction with conventional medicine. Accordingly, their use in western countries and the costs incurred have increased each year. While there is evidence that some herbals have physiological effects, there still is insufficient evidence to recommend their use. This paper reviews the classification, epidemiology and philosophy of CAM, and the reasons advanced for herbal use to treat viral hepatitis. The criteria necessary to develop a potential pharmacological agent are presented, as well as the requirements for conducting a scientifically valid treatment trial of herbals. Five herbals used in the past to treat viral hepatitis are reviewed and evaluated for the quality of their studies and mention is made of herbals known to have adverse effects.

Idiosyncratic drug induced liver injury (DILI) remains poorly understood. It is assumed that the affected individuals possess a rare combination of genetic and non genetic factors that, if identified, would greatly improve understanding of the underlying mechanisms. This single topic conference brought together basic scientists, translational investigators, and clinicians with an interest in DILI. The goal was to define high priority areas of investigation that will soon be made possible by The Drug-Induced Liver Injury Network (DILIN). Since 2004 DILIN has been collecting clinical data, genomic DNA and some tissues from patients who have experienced bone fide DILI. The presentations spanned many different areas of DILI, and included novel data concerning mechanisms of hepatotoxicity, new "omics" approaches, and the challenges of improving causation assessment.

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon RBV and had Ishak fibrosis scores > 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/ mm 3 (n 559); (B) bridging fibrosis with platelet counts 125,000/mm 3 (n 198); and (D) cirrhosis with platelet counts

Objective: Histologic liver injury is reported to be less severe in persons who acquire hepatitis C through injection drug use (IDU) than by blood transfusion. Because age correlates with histologic severity, it may be that differences between routes of acquisition reflect the younger age of most drug abuscrs. The early histopathologic changes of hepatitis C acquired through IDU are less defined, probably because of the lack of liver biopsy material from a cohort of patients not long after initial exposure. The availability of material from a cohort of patients who had liver biopsy for IDU-related hepatitis C in the 1970s enabled us to compare the histology with that of current patients. Methods: Liver biopsies of a group of injection drug users (n = 70, all males; mean age, 27.6 years, designated as Group 1) in the 1970s cohort were compared with biopsies of patients (n = 63, all males; mean age, 48 years, designated as Group 2, 23 who admitted past IDU) entering a treatment trial in 1999. All patients were positive for anti-HCV at the time of biopsy. Results: The histologic features of the 23 patients in Group 2 with a history of IDU did not differ significantly from the other 40 patients who denied past IDU. Using a modified Histologic Activity Index (HAI), there was no difference between Group 1 and Group 2 in portal inflammation or periportal injury. However, parenchymal (lobular) injury and inflammation was significantly (P < 0.0001) greater in Group 1 than Group 2. Fibrosis was significantly (P = 0.014) greater in Group 2. Conclusions: The degree of parenchymal injury was greater in Group 1 than Group 2, perhaps because they were closer to the time of exposure or possibly because of a stronger immunologic response in younger patients. The degree of hepatic fibrosis was greater in Group 2, suggesting that progression with age may be the natural history of chronic hepatitis C.

Recent studies have found hepatitis C virus (HCV) RNA in peripheral blood mononuclear cells (PBMCs) of the majority of presumed recovered subjects. We investigated this unexpected finding using samples from patients whose HCV RNA and anti-HCV status had been serially confirmed. HCV RNA was detected in PBMCs from 66/67 chronic HCV carriers. Subpopulation analysis revealed that the viral load (log copies/106 cells) in B cells (4.14 ± 0.71) was higher than in total PBMCs (3.62 ± 0.71, p

Hepatitis C virus (HCV) infection is transmitted by injection drug use and associated with psychiatric conditions. Patients with drug use or significant psychiatric illness have typically been excluded from HCV treatment trials noting the 1997 National Institutes of Health Consensus Statement on HCV that indicated active drug use and major depressive illness were contraindications to treatment of HCV infection. However, the 2002 NIH Consensus Statement recognized that these patients could be effectively treated for HCV infection and recommended that treatment be considered on a case-by-case basis. Treating HCV infection in these patients is challenging, with drug use relapse possibly leading to psychosocial instability, poor adherence, and HCV reinfection. Interferon therapy may exacerbate preexisting psychiatric symptoms. Co-occurring human immunodeficiency virus or hepatitis B virus provide additional challenges, and access to ancillary medical and psychiatric services may be limited. Patients with co-occurring HCV infection, substance use, and psychiatric illness can complete interferon treatment with careful monitoring and aggressive intervention. Clinicians must integrate early interventions for psychiatric conditions and drug use into their treatment algorithm. Few programs or treatment models are designed to manage co-occurring substance use, psychiatric illness, and HCV infection and therapy. The National Institute on Drug Abuse convened a panel of experts to address the current status and the long-range needs through a 2-day workshop, Co-occurring Hepatitis C, Substance Abuse, and Psychiatric Illness: Addressing the Issues and Developing Integrated Models of Care. This conference report summarizes current data, medical management issues, and strategies discussed.

Background & Aims: Studies on hepatitis C virus (HCV) quasispecies dynamics in the natural course of infection are rare owing to difficulties in obtaining samples from the early phase of infection. Methods: We studied 15 patients from the Transfusion-Transmitted Viruses Study who seroconverted to anti-HCV after receiving infected blood. Follow-up serum samples were collected every 2–3 weeks for 6 months, at 10 months, and at 11–16 years. Viral quasispecies in the second envelope hypervariable region 1 (E2/HVR1) and 5′ untranslated region (5′UTR) were analyzed with single-strand conformation polymorphism (SSCP) and heteroduplex mobility assay (HMA). Results: Seven patients cleared infection within 7–24 weeks (mean, 14.0 wk) and 3 patients eventually became anti-HCV negative. In 6 patients with resolving hepatitis the SSCP band pattern remained stable, whereas in one patient minor changes appeared before clearance. In contrast, in all 8 patients progressing to chronicity, major changes in the E2/HVR1 quasispecies developed at 8–22 weeks (mean, 13.1 wk). Shannon entropy and medium mobility shift values derived from HMA gels remained stable in patients with resolving hepatitis but changed in those who developed chronic infection. Only 2 patients showed minor changes in 5′UTR. A decrease in E2/HVR1 complexity at the time of transmission (bottleneck) was found in 5 patients altogether. Conclusions: Changes in E2/HVR1 quasispecies 8–22 weeks after infection, likely caused by mounting immune pressure, were predictive of ensuing chronic infection, whereas stability was associated with resolution. Our study also showed that composition of HCV quasispecies may be preserved during transmission from host to host.

Paraoxonase 1 (PON) may contribute to the cardioprotective action of high-density lipoprotein (HDL) because it inhibits low-density lipoprotein (LDL) oxidation, a prerequisite for the onset of atherosclerosis. Because light drinking and heavy drinking have diametrically opposite effects on cardioprotection, we have determined the effects of ethanol dosage on rat serum PON activity and its hepatic expression. Furthermore, we have investigated PON activity and polymorphism in human light and heavy drinkers. Our results confirm that HDL-PON inhibited LDL oxidation, destroyed oxidized LDL, and inhibited its uptake by macrophages. Light ethanol feeding caused a 20% to 25% (P

Hepatitis C is both a cause and a complication of chronic renal disease. Chronic infection with hepatitis C virus (HCV) can lead to the immune complex syndromes of cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN). The pathogenetic mechanisms for these conditions have not been defined, although they are clearly caused by the chronic viral infection. Management of HCV-related cryoglobulinemia and MPGN is difficult; antiviral therapy is effective in clearing HCV infection in a proportion of patients, but these conditions can be severe and resistant to antiviral therapy. Hepatitis C also is a complicating factor among patients with end-stage renal disease and renal transplants. The source of HCV infection in these patients can be nosocomial. Screening and careful attention to infection control precautions are mandatory for dialysis units to prevent the spread of hepatitis C. Prevention of spread is particularly important in these patients because HCV infection is associated with significant worsening of survival on dialysis therapy, as well as after kidney transplantation. Furthermore, therapy for hepatitis C is problematic, only partially effective, and associated with significant side effects in this population. There are significant needs in both basic and clinical research in the pathogenesis, natural history, prevention, and therapy for hepatitis C in patients with renal disease.

Background: Tests for hepatitis C antibodies (anti-HCV enzyme immunoassays) are usually described as positive or negative. Several studies, mainly in blood donors, have found that specimens with low signal/cutoff (S/C) ratios are commonly negative when tested with a recombinant immunoblot assay (RIBA) or for HCV RNA. Methods: We retrospectively reviewed 17 418 consecutive anti-HCV results from a screening program for high-risk veterans; 2986 (17.1%) samples were anti-HCV-positive, and 490 (16.4%) had S/C ratios ≤3.7 (low positive). Additional tests were performed in 1814 anti-HCV-positive individuals. Results: RIBA was performed in 263 patients with low-positive anti-HCV; results were negative in 86%, indeterminate in 12%, and positive in 2%. Only 16 of 140 individuals (11%) with low-positive anti-HCV values were HCV RNA-positive, whereas HCV RNA was positive in 90% of 1435 individuals with high-positive anti-HCV values (P Conclusions: The S/C ratio is important even in high-risk individuals; laboratories should report the S/C ratio along with anti-HCV EIA results and perform supplemental RIBA testing in those with low-positive values to avoid reporting false-positive results.

The incidence of newly acquired hepatitis C infection has diminished in the United States. This decline is largely because of a decrease in cases among IDUs for reasons that are unclear and, to a lesser extent, to testing of blood donors for HCV. The virus is transmitted by blood, and such transmission now occurs primarily through injection drug use, sex with an infected partner or multiple partners, and occupational exposure. Most infections become chronic, and therefore the prevalence of HCV infections is high, with about 3 million Americans estimated, to be chronically infected. HCV is a leading cause of cirrhosis, a common cause of HCC and the leading cause of liter transplantation in the United States. The disease spectrum associated with HCV infection varies greatly. Various studies have suggested that 3% to 10% of chronically infected patients will develop cirrhosis over a 20-year period, and these patients are at risk for HCC. Persons who are older at the time of infection, patients with continuous exposure to alcohol, and those coinfected with HIV or HBV demonstrate accelerated progression to more advanced liver disease. Conversely, individuals infected at a younger age have little or no disease progression over several decades. The diagnosis of chronic hepatitis C infection often is suggested by abnormalities in ALT levels and is established by EIA followed by confirmatory determination of HCV RNA. Several sensitive and specific assays are automated partly for the purposes of detecting HCV RNA and quantifying the viral level. Although there is little correlation between viral level and disease manifestations, these assays have proven useful in identifying those patients who are more likely to benefit from treatment and, particularly, in demonstrating successful response to treatment as defined by an SVR. Liver biopsy is useful in defining baseline abnormalities of liver disease and in enabling patients and healthcare providers to reach a decision regarding antiviral therapy. Noninvasive tests do not provide the information that can be obtained through liver biopsy. Information on the genotype of the virus is important to guide treatment decisions. Genotype 1, most commonly found in the United States, is less amenable to treatment than genotypes 2 or 3. Therefore, clinical trials of antiviral therapies require genotyping information for appropriate stratification of subjects. Recent therapeutic trials in defined, selected populations have shown clearly that combinations of interferons and ribavirin are more effective than monotherapy. Moreover, trials using pegylated interferons have yielded improved SVR rates with similar toxicity profiles. Results continue to show, however, that the SVR rate is less common in patients with genotype 1 infections, higher HCV RNA levels, or more advanced stages of fibrosis. Genotype 1 infections require therapy for 48 weeks, whereas shorter treatment is feasible in genotype 2 and 3 infections. In genotype 1, the lack of an early virologic response (< 2 log decrease in HCV RNA) is associated with failure to achieve an SVR. The SVR is lower in patients with advanced liver disease than in patients without cirrhosis. Ongoing trials are exploring the usefulness of combination therapy in various populations. Preliminary experience in IDUs, individuals coinfected with HIV, children, and other special groups suggests similar responses are achievable in these populations. Patients with acute hepatitis C may be treated, but specific recommendations for antiviral treatment must await further evaluation of the rate of spontaneous clearance of the virus and determination of the optimal time to initiate treatment. Preventive measures beyond blood-banking practices include prompt identification of infected individuals, awareness of the potential for perinatal transmission, implementation of safe injection practices, linkage of drug users to drug treatment programs. and implementation of community-based education and support programs to modify risk behavior. Some of these measures have been implemented successfully in the control of HIV infections, and it stands to reason that they would be valuable for reducing HCV transmission. Future advances in the diagnosis and management of hepatitis C require continued vigilance concerning the transmission of this infection, extending treatment to populations not evaluated previously in treatment trials, and the introduction of more effective therapies.

Much controversy surrounds the issue of the natural history of hepatitis C virus (HCV) infection. Many authorities view the disease as inexorably progressive with a high probability of advancing over time to cirrhosis and occasionally hepatocellular carcinoma (HCC) and, therefore, likely to be responsible for causing death. Others regard chronic hepatitis C as having a variable outcome, the majority of infected persons not dying from the disease, but more likely from the comorbid conditions that so often accompany infection by this agent, or from more common medical conditions. Disagreements probably derive from the manner of conduct of the study and the populations studied. Efforts to determine natural history are handicapped by the primary characteristics of the disease, namely that its onset rarely is recognized and its course is prolonged exceedingly. Thus, different outcomes have come from retrospective rather than from prospective studies, but both have concluded that at least 20% of chronically infected adults develop cirrhosis within 20 years. More recent studies that used a retrospective/prospective approach, focusing largely on young infected individuals, have produced different results. Among these young people, particularly young women, spontaneous resolution of the viral infection is more common than previously thought and cirrhosis has been identified in 5% or fewer of them. The major failing for all groups studied, young and old, is that natural history studies have rarely exceeded the first 2 decades, so that outcome beyond this time is not known, other than through modeling. Several host-related and extraneous factors probably affect the natural history.

Serial serum samples were obtained over a 27-year period from a hepatitis C virus (HCV)-infected patient and from a nurse who appeared to become infected by this patient. The hypervariable region 1 (HVR1) and 5'noncoding region (5'NCR) of the HCV genome were amplified from each serum sample by polymerase chain reaction (PCR) and cloned. In the first serum specimen from the patient and the first two serum specimens from the nurse, most of the 20 clones from each serum sample had one common sequence in the HVR1 gene. All later serum samples contained a heterogeneous mixture of HCV quasispecies. The uniformity of the HVR1 sequence in the early samples and the emergence of greater diversity in later serum samples is consistent with the apparent transmission of HCV between the patient and nurse and the eventual emergence of other quasispecies as the virus replicated in the new host. In addition, the immune globulin given to the nurse may have been responsible for some of the HCV quasispecies changes observed in her serum.

p.63. 42. Bacon BR, Li J, Britton RS, Wang B-e. Herbal Medicine 861 has direct antiproliferative effects on hepatic stellate cells. Complementary and Alternative Medicine in Chronic Liver Disease. Submitted abstract, p.56. 43. Batey RG, Bensousson A, Fan YY, Bollipo S, Hossain M. Preliminary report of a randomized, double-blind placebo-controlled trial of a Chinese herbal medicine preparation CH100 in the treatment of chronic hepatitis C. J Gastroenterol Hepatol 1998;13:244-247. 602 SEEFF ET AL. HEPATOLOGY September 2001

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.

Herbal and dietary supplement use is common. Most marketed products consist of complex mixtures. Although they are perceived as safe, instances of hepatotoxicity attributable to these products underscore their potential for injury, but the exact component that is responsible for injury is difficult to discern. The lenient regulatory environment in the United States, which opens the possibility of adulteration and contamination, adds to the challenge of disease attribution. Although many different herbal and dietary supplements have been reported to cause liver injury, in the United States, products used for bodybuilding and weight loss are the most commonly implicated.

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, γ-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

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.

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.

Over the past half-century, major strides have been made in the understanding of disease susceptibility, pathogenesis, and therapy. As a result, many new drugs have either replaced or been added to the vast array of existing medications available for the treatment of disease. Because the liver is the primary site of metabolism and biotransformation, it is not surprising that drug-induced hepatic injury is relatively common. Indeed, it has long been known that a number of widely used and generally well-tolerated drugs can cause acute liver injury. Chronic drug-induced liver disease (injury lasting more than 3 months), by contrast, was first described in the 1950s with the identification of a prolonged cholestatic illness related to chlorapromazine use. 70 Since that time, several other drugs have been implicated in the cause of chronic hepatic injury. Efforts to accurately define the frequency and spectrum of drug-induced chronic liver disease faces several obstacles. On the one hand, many drugs may cause clinically inapparent liver injury. As a consequence, estimates of the true incidence of drug-induced liver disease may be falsely low. On the other hand, case reports in the literature tend to focus on the most severe or fatal drug-related reactions, creating the impression of a falsely elevated drug-associated morbidity and mortality. Lastly, the potential for drugs to cause liver injury must take into account the intrinsic or predictable ability of the drug to produce injury (e.g., via toxins) as well as host susceptibility factors that may lead to unpredictable injury. Taking these factors into account, recent data suggest that drug-induced liver injury occurs in approximately 1 in 600 to 1 in 3500 hospital admissions. 28 Two percent to 5% of hospital admissions for jaundice in the United States are drug-induced, as are between 15% to 30% of instances of fulminant hepatic failure, and 20% to 50% of cases of nonviral chronic hepatitis. 26,28,41,55 At present, 500 to 1000 agents have been implicated in the cause of a broad spectrum of liver diseases. 32,103,120

Approximately 85% of persons with acute hepatitis C develop chronic hepatitis as determined by persistently abnormal serum enzymes and/or viremia (hepatitis C virus [HCV] RNA). Both the acute and chronic illnesses are predominantly asymptomatic. For this reason and because the chronic illness runs an extremely protracted course, it has been difficult to accurately define the frequency and rate of progression to symptomatic or end-stage liver disease, specifically cirrhosis and hepatocellular carcinoma (HCC). Three evaluation strategies have been used. The first, prospective studies beginning from disease onset, have identified over 8 to 14 year follow-up periods that morbidity (symptoms, cirrhosis) and mortality (hepatic failure, HCC) are modest in frequency. The second, prospective studies of subjects with already established chronic liver disease, have demonstrated high rates of development of cirrhosis, HCC, and mortality over relatively short follow-up periods. The third, retrospective/prospective (nonconcurrent prospective) studies, has consisted of follow-up of recipients of HCV-contaminated immunoglobulin and of transfusion recipients from five enzyme-monitored transfusion studies of the early 1970s. The former study identified no mortality, trivial morbidity, and minimal cirrhosis 17 years after infection. The latter, involving hepatitis cases and matched nonhepatitis controls studied over a 20-year period, demonstrated no increase in all-cause but a slight increase in liver-related mortality. Clinically evident chronic liver disease was noted to be minimal among those in follow-up with biochemically defined chronic hepatitis whose biopsy specimens showed no cirrhosis, but common among those with histologically detected cirrhosis. More than 90% of subjects with an original diagnosis of transfusion-related hepatitis C have remained positive for antibody to HCV (anti-HCV), most with persistent viremia. Two thirds of the anti-HCV-positive individuals have biochemically defined chronic hepatitis, whereas one third have persistently normal enzymes. Taken together, available data suggest that in the first two decades after infection, mortality and morbidity are modest in frequency. Both can be expected to increase as the disease advances to the third and fourth decades after acute infection, especially among those with established cirrhosis. The outcome among those with chronic hepatitis but without cirrhosis remains to be determined.

Within a short time of the recognition of acute non-A, non-B (NANB) hepatitis, identified in the course of enzyme-monitored transfusion studies conducted during the early 1970s, it became clear that, despite a paucity of symptoms, the illness failed to resolve in approximately half of those affected. The evidence for disease persistence was the fact that the serum enzymes, specifically alanine aminotransferase (ALT), continued to remain abnormal for periods in excess of 6 months. Now labeled chronic hepatitis by convention, liver biopsy examination confirmed this clinical diagnosis through the identification of histologically-defined chronic hepatitis of graded severity in about 50% to 60% of instances and of cirrhosis in another 20%. Despite these findings, most affected persons remained oblivious to these outcomes because of continued lack of symptoms. The detection almost a decade and a half later of the hepatitis C virus (HCV) provided a further tool for identifying chronicity. With the development of the highly sensitive polymerase chain reaction (PCR), it was possible to identify the persistence of HCV RNA in an additional group, even in the absence of raised ALT values. Currently, it is believed that approximately 85% of acutely infected individuals fail to recover fully following acute HCV infection. Short-term prospective, point-prevalence, and retrospective studies have since shown that, once chronically infected with HCV, such persons are at risk of progressing from histologically defined chronic hepatitis to cirrhosis and, in some instances, to hepatocellular carcinoma (HCC). More often than not, these events can continue to occur in the complete absence of symptoms which may emerge only when end-stage liver disease is reached. The true frequency and rate of these progressive changes have represented an area of uncertainty and have led to conflicting views on the subject. Some authorities have suggested that progression to severe end-stage liver disease is inevitable, provided the infected person does not succumb first to another lethal illness; others have concluded that disease progression is restricted to a limited few and that the challenge is to define factors that might account for wide differences in outcome. These opposing views can be accounted for, at least in part, by the extraordinarily insidious nature of the process and the almost snails' pace rate of its progression. Efforts to resolve this controversy are required for two obvious reasons: (1) the need to inform HCV carriers of what to anticipate in their future in the hope of reassuring them about potential sequelae; and (2) the need to make prudent decisions regarding therapy with drugs that are currently of only limited therapeutic benefit. The only means of resolving the conflict is to conduct appropriate long-term studies of the natural history of the disease.