Showing posts with label The natural history of hepatitis C. Show all posts
Showing posts with label The natural history of hepatitis C. Show all posts

Saturday, February 4, 2017

Weekend Reading - Natural History And Conditions Related To HCV

Greetings to all, welcome to this edition of Weekend Reading. Thanks to Henry E. Chang, a quick overview of HCV and related conditions is the focus on the blog today. The good doctor often tweets PDF full text HCV articles on twitter, follow him here.

The Stats
Today, approximately 2.7 million Americans are infected with hepatitis C, with an estimated 130–200 million people worldwide. Of persons infected with hepatitis C, 15-25 percent will recover (spontaneous clearance) and 75-85 percent will become chronically infected.

A Review of the Natural History of Chronic Hepatitis C Infection
The natural history of hepatitis C remains controversial. Among HCV-infected individuals progression to advanced liver disease generally requires decades but is influenced by several host factors. For instance studies have shown factors such as; (age, sex, race, genetics), viral characteristics (genotype), behavioral (smoking, alcohol), metabolic factors (insulin resistance, obesity), and co-infection (Hepatitis B and HIV) may impact the degree of fibrosis and progression to cirrhosis as well as the potential for development of liver cancer. These factors are discussed in a review of the natural history of hepatitis C, published in the 2014 issue of  North American Journal Of  Medicine And Science.

Does Alcohol  Influence Spontaneous Clearance?
The effects of alcohol on spontaneous clearance of acute hepatitis C virus infection in females versus males; Results indicate that abstaining from drinking alcohol may increase the likelihood of spontaneous clearance among women.

Although, chronic infection can be cured about 90% of the time with FDA approved treatments, host factors still determine disease progression in people without viral eradication. As an example, persons with HCV-related cirrhosis, who consume light-to-moderate alcohol, compared to people who do not drink - increase the risk for liver cancer.

But can host factors influence mortality risk in people who successfully clear the virus with HCV therapy?
In an article reviewing a study published in the Journal of Hepatology (2016), Michael Carter writes about the mortality rates among people with HCV who achieve SVR. Again, host factors/health risk behaviors were an important factor for mortality. He writes; Most of the excess mortality was due to drug use or liver cancer. Several modifiable characteristics were associated with subsequent mortality risk, including drug use and heavy alcohol consumption. People without these risk factors – approximately a third of the study population – had survival that matched that of the general population. Here is the article; People with HCV attaining SVR continue to have increased mortality risk but this is due to alcohol and drug use.

Disease Progression
Researchers often reference a unique cohort of HCV patients when describing the natural history of hepatitis C. Never has there been a more perfect natural history study, in that - the known dates of infection were clear and precise. This for the most part is difficult to achieve since the time of acute HCV infection is often impossible to establish.

The somewhat famous and tragic cohort include 704 Irish women (1977-1978) and 917 German women (1978-1979) who were exposed to hepatitis C from contaminated Anti-D immunoglobulin, all from a single source. Researchers have studied the aging population of women at 17, 20, 25 and 35 years after infection.

In the German cohort previous studies suggest low rates of liver disease progression at 20 and 25 years after infection, showing only 0.5% end-stage liver cirrhosis at 25 years after infection, according to an article published in Hepatology 2014;58:49–57.

In the article investigators extended the study to 35 years after infection comprising of 718 patients of the original anti-D cohort.

Mortality at 35 Years After Infection
Figure 4 summarizes the overall mortality of the German HCV cohort at 35 years after infection in relation to the HCV infection status.

In total, 30 patients (4.2%) of the actual study cohort died since 1979. In the group of HCV RNA-negative patients, 10 (3.0%) died, among them 2 who were classified as inoculated patients without hepatitis, 7 with spontaneous recovery from HCV infection, and 1 with SVR after treatment who died of a malignant disease other than HCC.

In the group of HCV RNA-positive patients, 20 (5.3%) died, among them 9 (1.3%) who succumbed to definite HCV-related end-stage liver complications, such as esophageal variceal bleeding or hepatic coma. The remaining 11 HCV RNA-positive patients (1.5%) died from additional non-liver-related causes, such as cardiac failure, nonliver malignancy, apoplectic insult, or accident.

Click on image to enlarge

Conclusion: The present study provides further evidence for a mild, but significant, disease progression at 35 years after infection in the German HCV (1b)-contaminated anti-D cohort. Patients with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best clinical long-term outcome.
Review the article; Evaluation of liver disease progression in the German HCV (1b)-contaminated anti-D cohort at 35 years after infection.

Of Interest
New study launched to discover how “super” immune system can prevent hepatitis C
Scientists from Trinity College Dublin are seeking volunteers who were exposed to anti-D contaminated with hepatitis C virus (HCV) between 1977 and 1979 as they attempt to discover why some people are naturally protected from HCV infection, while others are not.

Extrahepatic Manifestations
Review this series of great articles on the extrahepatic manifestations of HCV.
Published in Journal of Advanced Research
Volume 8, Issue 2, March 2017, Pages 85–87

Index Of Articles
HCV - Fatty liver disease and genotype 3
In this post a collection of journal articles and videos reviewing HCV and fatty liver disease is offered; with a focus on individuals afflicted with both conditions. In addition given the development of steatosis (abnormal levels of fat in your liver) is higher in people with HCV and genotype 3, links are provided to current therapies in this difficult to cure genotype. Finishing off with several tips to help keep your liver healthy.

An Overview Of Hepatitis C Medications
Treatment Options in Hepatitis C — The Current State of the Art
By Stefan Zeuzem published in the January 2017 issue of Deutsches Ärzteblatt International
This review is based on relevant publications retrieved by a selective literature search, and particularly on studies and reviews concerning the course and treatment of hepatitis C.
Begin here...

Clinical Care Options
How Data From the 2016 Boston Hepatology Meeting Will Influence Future HCV Patient Management
Mark S. Sulkowski MD - 1/31/2017
I am really enjoying treating patients with HCV infection in this era of highly effective direct-acting antivirals (DAAs). Think about it: Our patients present with life-threatening, chronic infections, and we cure more than 95% of them with few adverse events. Other than insurance challenges, what’s not to love?
Despite the relatively easy road to cure with modern therapy in most of my HCV-infected patients, I can think of 2 recent patients who presented challenges: a patient with relapse and resistance associated substitutions (RASs) after treatment with a DAA and a patient with genotype 3 HCV infection and severely reduced renal function...
*Free registration required to view article

Achieving A Cure
Liver- and Non-Liver Related Critical Events Down in HCV and Cirrhosis
For patients with hepatitis C virus (HCV) infection and biopsy-proven cirrhosis, sustained viral response (SVR) is associated with a reduction in critical events, both liver and non-liver related, according to research recently published in Gastroenterology.

Helpful Links

HCV Advocate
Clinical Trials Reference Guide
Users can search for a hepatitis C clinical trial by category (genotype), or learn how to evaluate a clinical trial and become familiar with commonly used terms. HCV Advocate offers an easy to navigate HCV Medications Blog as well, organized by HCV genotype.

2017-HCV Genotypes/Treatment
Offered on this page of the blog is research updates with a focus on treating HCV according to genotype using FDA approved and investigational medicines. Information is extracted from news articles, peer-reviewed journals, as well as liver meetings/conferences, research manuscripts and interactive learning activities. 

Hopefully, this small summary will leave you with a better understanding of the natural history of  hepatitis C, conditions outside the liver (Extrahepatic Manifestations) and medications used to treat the virus.   

May you all enjoy the rest of your weekend.

Monday, May 9, 2016

Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection

Metabolic Manifestations and Complications Associated With Chronic Hepatitis C Virus Infection

Download the PDF

Gastroenterology & HepatologyVolume 12, Issue 5, May 2016
Robert J. Wong, MD, MS, and Robert G. Gish, MD
Dr Wong is an assistant clinical professor of medicine at the University of California, San Francisco in San Francisco, California, and the director of research and education in the Division of Gastroenterology and Hepatology at Highland Hospital in Oakland, California. Dr Gish is a professor consultant in the Department of Medicine in the Division of Gastroenterology and Hepatology at Stanford University in Stanford, California; principal of Robert G. Gish Consultants, LLC, in San Diego, California; and senior medical director at St Joseph’s Hospital and Medical Center in Phoenix, Arizona.
Address correspondence to:Dr Robert J. WongHighland HospitalHighland Care Pavilion, 5th FloorEndoscopy Unit1411 East 31st StreetOakland, CA 94602Tel: 510-437-6531E-mail:
Chronic hepatitis C virus (HCV) infection is associated with many extrahepatic manifestations that contribute to morbidity and mortality. It is especially important to be aware of metabolic manifestations and serious complications that affect other organs and cancer risks. Chronic HCV infection itself contributes to de novo development of insulin resistance and hepatic steatosis, both of which increase the risk of cardiovascular diseases. Through these metabolic pathways (as well as through other hypothesized mechanisms that involve lipid metabolism, systemic inflammatory signals, and endothelial dysfunction), chronic HCV infection also contributes to significant systemic cardiovascular morbidity and mortality. While chronic HCV infection contributes to incident development of metabolic complications, the presence of concurrent metabolic diseases also contributes to disease progression, such as higher risks of hepatocellular carcinoma and progression to advanced fibrosis, among patients with chronic HCV infection. The implications of these observations are particularly important given the rising prevalence of obesity and metabolic syndrome in the United States and worldwide. Furthermore, concurrent nonalcoholic fatty liver disease, either as a result of underlying metabolic syndrome or as a direct result of HCV-induced fatty liver disease, further complicates the management of chronic HCV-infected patients. Greater awareness is needed toward the systemic manifestations of chronic HCV infection, with focused attention on the associated metabolic manifestations and complications. Successful treatment and cure of chronic HCV infection with the currently available, highly effective antiviral therapies will significantly improve long-term outcomes among these patients. It is also important to recognize and address the associated metabolic manifestations and complications to reduce cardiovascular-related morbidity and mortality.
Chronic hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality, with studies estimating a prevalence of 3 to 7 million persons affected in the United States.1-4 There have been major recent advances in antiviral therapy for the management of chronic HCV infection, with the majority of current therapies achieving sustained virologic response (SVR) in over 95% of chronic HCV-infected patients. Despite these improvements, the long-term impact of these therapies on viral clearance and prevention of disease progression to cirrhosis and cirrhosis-related complications (eg, hepatocellular carcinoma [HCC], liver failure) will take time to determine. Currently, chronic HCV infection remains the leading cause of HCC and decompensated cirrhosis requiring liver transplantation in the United States (Figure).5-7 While the impact of chronic HCV infection on liver-related complications and outcomes has been well studied, extrahepatic sequelae and complications of chronic HCV infection that result from the systemic effects of persistent viral infection are less well emphasized.8 The early recognition of systemic effects of chronic HCV infection provides an opportunity to advocate for early initiation of antiviral therapy in which SVR may be achieved, as well as to treat all patients, thereby preventing further, and potentially permanent, hepatic and extrahepatic consequences of chronic HCV infection. This review highlights the metabolic manifestations and complications associated with chronic HCV infection.
Insulin Resistance
The association between chronic HCV infection and metabolic manifestations primarily involves the potential diabetogenic effect of persistent viral infection. Several studies have investigated and demonstrated the association between chronic HCV infection and insulin resistance.9-14 Using data from the third National Health and Nutrition Examination Survey (1988-1994), Mehta and colleagues performed a cross-sectional study of adults in the United States.14 Among a study cohort of 9841 individuals, there was an 8.4% prevalence of diabetes mellitus and a 2.1% prevalence of individuals who were anti-HCV antibody–positive. After adjusting for multiple factors (including age, body mass index, and socioeconomic status), the authors demonstrated that adults age 40 years or older with HCV infection were nearly 4 times more likely to have concurrent diabetes than those without HCV infection.14 However, as the authors acknowledged, while this study and previous cross-sectional studies have demonstrated the association of chronic HCV infection with insulin resistance, it remains unclear whether chronic HCV infection preceded the development of diabetes or whether HCV infection itself contributed to incident diabetes.
To better address this question, Mehta and colleagues performed a follow-up study using data from the Atherosclerosis Risk in Communities Study.15 In this prospective case-control study of men and women between the ages of 44 and 65 years, 1084 adults without diabetes at baseline were evaluated to determine the association between antecedent chronic HCV infection and the development of diabetes. After risk stratification adjustments based on factors such as age and body mass index, the authors demonstrated that among individuals at high risk for developing diabetes, the presence of chronic HCV infection was associated with a greater than 11-fold higher risk of developing diabetes over 9 years of follow-up (hazard ratio [HR], 11.58; 95% CI, 1.39-96.6).15 Further supporting the increased risk of chronic HCV infection on insulin resistance, additional studies have demonstrated that successful clearance of HCV infection with antiviral therapy can lead to improved insulin resistance.16-24 In a study by Romero-Gomez and colleagues, 1059 patients with chronic HCV infection were evaluated to determine the impact of achieving SVR on insulin resistance as measured by the homeostasis model assessment of insulin resistance.24 The authors demonstrated that achieving SVR was an independent predictor of impaired fasting glucose or diabetes.24
However, another study by Giordanino and colleagues evaluated 202 chronic HCV-infected patients without pretreatment glucose abnormalities to determine whether antiviral treatment response affected the incidence of developing glucose abnormalities.25 After a median follow-up period of 8 years, the authors found no significant difference between patients who achieved long-term virologic response and those who were nonresponders with respect to their incidence of developing glucose abnormalities.25 Another study of 2842 chronic HCV-infected patients treated with interferon monotherapy or in combination with ribavirin evaluated the impact of antiviral treatment on incident diabetes.23 The investigators demonstrated a two-thirds reduction in the risk of developing incident diabetes associated with interferon treatment. Despite this seemingly conflicting study, the majority of studies continue to demonstrate the association of chronic HCV infection and insulin resistance, further emphasizing the potential metabolic benefit of achieving and maintaining viral clearance.
Cardiovascular Diseases
The association between chronic HCV infection and cardiovascular diseases has been well studied, and while potential mechanisms have been hypothesized, the current literature demonstrates variations in the degree of this association.26-34 Mechanistically, the potential increased risk of cardiovascular diseases among patients with chronic HCV infection may stem from insulin resistance, hepatic steatosis contributing to increased systemic inflammatory markers, and/or endothelial dysfunction.31,35-39 In addition, insulin resistance and hepatic steatosis are tightly linked and may further contribute to the development of other metabolic syndrome components such as hypertension and dyslipidemia.39-41 However, a recent systematic review that evaluated published studies from 1995 to 2013 included a total of 5 studies that met inclusion and exclusion criteria.26 The authors found 1 cohort study of US veterans that demonstrated a significantly increased risk of cardiovascular disease among patients with chronic HCV infection (HR, 1.27; 95% CI, 1.22-1.31); however, additional studies that also used US Veterans Affairs data, although from an earlier period, demonstrated a protective effect of chronic HCV infection on the development of cardiovascular disease.30,32 The remaining studies included in this systematic review did not demonstrate a clear clinical association between chronic HCV infection and cardiovascular disease, leading the authors to conclude that more prospective studies are needed to better evaluate this association before more definitive statements regarding chronic HCV infection and its impact on cardiovascular disease can be made.26
The difficulties in evaluating cardiovascular associations of chronic HCV infection are multifold. Different studies utilize varying definitions, categorizations, and surrogates of cardiovascular disease (eg, carotid artery intima-media thickness, subclinical atherosclerosis, congestive heart failure) and span large periods of time, during which antiviral treatment regimens have significantly improved with better efficacy and fewer side effects.26 Furthermore, while several hypotheses have been discussed, it is likely that chronic HCV infection and clearance of HCV infection with treatment impart a multitude of systemic metabolic changes that may affect cardiovascular disease risk in multidirectional ways. For example, as previously discussed, clearance of HCV infection improves insulin resistance, which may contribute to reducing cardiovascular disease risk.16-24 However, studies have also postulated that chronic HCV infection itself may be associated with lower serum lipid levels, and patients who achieve SVR may develop a significant rebound rise in lipid levels in the blood that may contribute to increased cardiovascular disease risks.39-41 Thus, the cumulative impact of persistent viral infection and subsequent viral clearance with antiviral therapy is a complex interplay of different mechanistic pathways, and while not all studies demonstrate clear and convincing evidence supporting the association between chronic HCV infection and cardiovascular diseases, it cannot be argued that viral clearance has an overall beneficial effect. Large prospective studies that include -multivariate -analysis and sensitivity testing would permit a more refined understanding of this issue.
Nonalcoholic Fatty Liver Disease
The interplay between chronic HCV infection and nonalcoholic fatty liver disease (NAFLD) is complex. As discussed above, chronic HCV infection can contribute to metabolic derangements (including insulin resistance and dyslipidemia) that subsequently increase the risk of developing concurrent NAFLD. In addition, several studies have reported that chronic HCV infection itself may contribute to the development of hepatic steatosis, the presence of which feeds into the cycle of metabolic diseases contributing to disease progression and complications among patients with chronic HCV infection.31,35,37,42 The strong association between chronic HCV infection and de novo hepatic steatosis is seen most prominently in patients with HCV genotype 3 infection.35,42-45 In a large meta-analysis, Leandro and colleagues evaluated 3068 patients with histologically confirmed chronic HCV infection from 10 centers in Italy, Switzerland, France, Australia, and the United States, among whom 50.9% had histologic evidence of hepatic steatosis.43 Hepatic steatosis was more commonly found, and was more severe, in patients with HCV genotype 3 infection. Interestingly, subsequent studies demonstrated that hepatic steatosis was significantly improved, and in some cases completely resolved, after antiviral therapy in patients with HCV genotype 3 infection.42,45-47 However, patients with non–genotype 3 infection did not demonstrate the same improvement in hepatic steatosis, even among those who achieved SVR with antiviral therapy.45-47 While the exact etiologies underlying these observations are not clear, several hypotheses have been raised. Studies have described the potential de novo lipogenic role of chronic HCV infection through activation of in vitro sterol regulatory element-binding proteins 1c and 2, both of which are transcription factors involved in lipogenesis.48 Further studies observed an inhibition of fatty acid oxidation by HCV infection, contributing to triglyceride accumulation.49-51 Other hypotheses have implicated impaired assembly and secretion of very low–density lipoprotein.52,53 Although the exact mechanisms of HCV-induced fatty liver disease are likely multifactorial and involve multiple systemic pathways, the implications of HCV-induced fatty liver are paramount to fully appreciating the systemic metabolic effects of chronic HCV infection. While clearance of chronic HCV infection with antiviral treatment will be important not only to address the hepatic and extrahepatic manifestations associated with persistent viral replication, increased awareness of associated metabolic derangements is also critical to prevent complications such as diabetes and cardiovascular diseases.
Impact of Metabolic Diseases on the Natural History of Chronic Hepatitis C Virus Infection
Understanding whether chronic HCV infection increases the risk of developing metabolic complications deserves greater attention. However, it is also important to understand the impact of underlying metabolic diseases on the natural history of chronic HCV infection. Recognizing the impact of obesity and insulin resistance on disease progression among patients with chronic HCV infection is especially important given the rising prevalence of obesity and metabolic syndrome observed in the United States.54,55
In a recent systematic review evaluating the impact of metabolic diseases on disease progression among patients with chronic HCV infection, Dyal and colleagues looked at literature from 2001 to 2014 and identified 20 cohort studies that met inclusion criteria.56 Focusing primarily on obesity, diabetes mellitus, and hepatic steatosis, the authors evaluated the association of these concurrent risk factors with the development of advanced fibrosis in patients with chronic HCV infection.56 The authors demonstrated that the presence of concurrent diabetes among patients with chronic HCV infection was associated with a significantly higher risk of developing advanced fibrosis, with effect measures ranging from odds ratios (ORs) of 2.25 to 9.24. The presence of hepatic steatosis was also significantly associated with an increased risk of developing advanced fibrosis, with effect measures ranging from ORs of 1.80 to 14.3.56 While the authors found 7 studies showing an increased risk of advanced fibrosis associated with obesity, 4 additional studies in the systematic review failed to show a significant association between the 2 conditions.
Disease progression to advanced fibrosis and cirrhosis is an important outcome among chronic HCV-infected patients. The development of HCC is another feared complication of chronic HCV infection. In a follow-up study, Dyal and colleagues performed a systematic review to evaluate the impact of obesity, diabetes mellitus, and hepatic steatosis on the risk of HCC among patients with chronic HCV infection.57 A total of 9 studies from 2001 to 2014 met inclusion criteria and were included in the analysis. The authors demonstrated that concurrent diabetes was significantly associated with higher risk of HCC among chronic HCV-infected patients, with effect measures ranging from a HR of 1.73 to a risk ratio of 3.52.57 The study also demonstrated an increased risk of HCC associated with obesity and hepatic steatosis, although the evidence supporting these associations were less robust, and larger studies with longer-term follow-up are needed to further explore these associations.
Both of the aforementioned systematic reviews attempted to better clarify the impact of concurrent metabolic diseases on disease progression and the -natural history of chronic HCV infection; however, several limitations must be acknowledged when interpreting these results. The ideal method for exploring the impact of metabolic diseases on disease progression would be to identify patients with antecedent metabolic diseases who subsequently acquired HCV infection. However, many of these studies were observational in nature and either utilized a case-control or retrospective cohort study design, which inherently limit the true ability to understand causation.56,57 Furthermore, the study period of the included studies spanned a period during which significant advancements in HCV therapies were introduced. Thus, improved therapies may have been a potential confounder or effect modifier that affected disease progression in chronic HCV-infected patients. Despite the general agreement that increasing rates of metabolic diseases undoubtedly contribute to worse outcomes such as cardiovascular diseases, the current studies suffer from heterogeneity in definitions of obesity and insulin resistance, and often do not take into account more accurate measures of metabolic risk such as waist circumference as a measure of visceral adiposity, which may be especially important when evaluating for metabolic diseases in ethnically diverse populations.6,26,54,58 Nevertheless, greater awareness of underlying metabolic diseases among patients with chronic HCV infection is paramount in that targeted treatment of these diseases can translate not only into improved management of liver disease but into overall health, including cardiovascular diseases.
In the current era of highly effective direct-acting antiviral therapies for chronic HCV infection, the ability to eradicate HCV will not only improve HCV-related liver disease, but will likely impact the incidence and prevalence of HCV-related metabolic diseases, given the association between the 2 conditions. However, greater awareness is also needed for metabolic diseases unrelated to chronic HCV infection, including NAFLD and NAFLD-related complications.
Despite the improvements in diagnosis, linkage to care, treatment, and eradication of chronic HCV infection, this condition will continue to pose a major disease burden for the near future. Chronic HCV infection contributes to significant hepatic disease and complications; however, it is important to understand and appreciate the systemic effects of chronic HCV infection as it relates to metabolic manifestations and complications. The associations between chronic HCV infection and metabolic disease and between chronic HCV infection and cardiovascular diseases are especially important in light of the increasing prevalence of obesity and metabolic syndrome and their costs to patients, the health care system, and society.
Dr Wong has received research grants from and is on the advisory board for Gilead. Dr Gish has received grants/research support from AbbVie, Benitec Biopharma, Gilead, and Merck. He has served as a consultant and/or advisor to AbbVie, Akshaya Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Genentech, Gilead, F Hoffmann-La Roche, Ionis Pharmaceuticals, Janssen, Merck, Nanogen Biopharmaceutical, and Presidio Pharmaceuticals, and is currently on the scientific or clinical advisory board of AbbVie, AstraZeneca, Genentech, Gilead, Janssen, Merck, and Nanogen Biopharmaceutical. Additionally, he is a member of the speakers bureau for AbbVie, Bristol-Myers Squibb, Gilead, and Merck and is a minor stock shareholder of Cocrystal Pharma.
1. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhnert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144(10):705-714.
2. Chak E, Talal AH, Sherman KE, Schiff ER, Saab S. Hepatitis C virus infection in USA: an estimate of true prevalence. Liver Int. 2011;31(8):1090-1101.
3. Ditah I, Ditah F, Devaki P, et al. The changing epidemiology of hepatitis C virus infection in the United States: National Health and Nutrition Examination Survey 2001 through 2010. J Hepatol. 2014;60(4):691-698.
4. Dominitz JA, Boyko EJ, Koepsell TD, et al. Elevated prevalence of hepatitis C infection in users of United States veterans medical centers. Hepatology. 2005;41(1):88-96.
5. Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547-555.
6. Wong RJ, Chou C, Sinha SR, Kamal A, Ahmed A. Ethnic disparities in the association of body mass index with the risk of hypertension and diabetes. J Community Health. 2014;39(3):437-445.
7. Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology. 2011;141(4):1249-1253.
8. Gill K, Ghazinian H, Manch R, Gish R. Hepatitis C virus as a systemic disease: reaching beyond the liver. Hepatol Int. 2016;10(3):415-423.
9. Stepanova M, Lam B, Younossi Y, Srishord MK, Younossi ZM. Association of hepatitis C with insulin resistance and type 2 diabetes in US general population: the impact of the epidemic of obesity. J Viral Hepat. 2012;19(5):341-345.
10. Mangia A, Ripoli M. Insulin resistance, steatosis and hepatitis C virus. Hepatol Int. 2013;7(suppl 2):782-789.
11. Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther. 2013;37(6):647-652.
12. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Hepatology. 2001;33(6):1554.
13. Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol. 2007;166(2):196-203.
14. Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med. 2000;133(8):592-599.
15. Mehta SH, Brancati FL, Strathdee SA, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatology. 2003;38(1):50-56.
16. Romero-Gómez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128(3):636-641.
17. Pearlman BL, Traub N. Sustained virologic response to antiviral therapy for chronic hepatitis C virus infection: a cure and so much more. Clin Infect Dis. 2011;52(7):889-900.
18. Thompson AJ, Patel K, Chuang WL, et al; ACHIEVE-1 and ACHIEVE-2/3 Study Teams. Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3. Gut. 2012;61(1):128-134.
19. Chien CH, Lin CL, Hu CC, Chang JJ, Chien RN. Clearance of hepatitis C virus improves insulin resistance during and after peginterferon and ribavirin therapy. J Interferon Cytokine Res. 2015;35(12):981-989.
20. Cua IH, Hui JM, Kench JG, George J. Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology. 2008;48(3):723-731.
21. White DL, Ratziu V, El-Serag HB. Hepatitis C infection and risk of diabetes: a systematic review and meta-analysis. J Hepatol. 2008;49(5):831-844.
22. Delgado-Borrego A, Jordan SH, Negre B, et al; Halt-C Trial Group. Reduction of insulin resistance with effective clearance of hepatitis C infection: results from the HALT-C trial. Clin Gastroenterol Hepatol. 2010;8(5):458-462.
23. Arase Y, Suzuki F, Suzuki Y, et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49(3):739-744.
24. Romero-Gómez M, Fernández-Rodríguez CM, Andrade RJ, et al. Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C. J Hepatol. 2008;48(5):721-727.
25. Giordanino C, Bugianesi E, Smedile A, et al. Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study. Am J Gastroenterol. 2008;103(10):2481-2487.
26. Wong RJ, Kanwal F, Younossi ZM, Ahmed A. Hepatitis C virus infection and coronary artery disease risk: a systematic review of the literature. Dig Dis Sci. 2014;59(7):1586-1593.
27. Roed T, Lebech AM, Kjaer A, Weis N. Hepatitis C virus infection and risk of coronary artery disease: a systematic review of the literature. Clin Physiol Funct Imaging. 2012;32(6):421-430.
28. Völzke H, Schwahn C, Wolff B, et al. Hepatitis B and C virus infection and the risk of atherosclerosis in a general population. Atherosclerosis. 2004;174(1):99-103.
29. Ishizaka N, Ishizaka Y, Takahashi E, et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima-media thickening. Lancet. 2002;359(9301):133-135.
30. Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis. 2009;49(2):225-232.
31. Adinolfi LE, Restivo L, Zampino R, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis. 2012;221(2):496-502.
32. Butt AA, Khan UA, McGinnis KA, Skanderson M, Kent Kwoh C. Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans. J Viral Hepat. 2007;14(12):890-896.
33. Forde KA, Haynes K, Troxel AB, et al. Risk of myocardial infarction associated with chronic hepatitis C virus infection: a population-based cohort study. J Viral Hepat. 2012;19(4):271-277.
34. Arcari CM, Nelson KE, Netski DM, Nieto FJ, Gaydos CA. No association between hepatitis C virus seropositivity and acute myocardial infarction. Clin Infect Dis. 2006;43(6):e53-e56.
35. Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33(6):1358-1364.
36. Gastaldelli A, Kozakova M, Højlund K, et al; RISC Investigators. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology. 2009;49(5):1537-1544.
37. Volzke H, Robinson DM, Kleine V, et al. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol. 2005;11(12):1848-1853.
38. Sanyal AJ, Contos MJ, Sterling RK, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol. 2003;98(9):2064-2071.
39. Marzouk D, Sass J, Bakr I, et al. Metabolic and cardiovascular risk profiles and hepatitis C virus infection in rural Egypt. Gut. 2007;56(8):1105-1110.
40. Bilora F, Rinaldi R, Boccioletti V, Petrobelli F, Girolami A. Chronic viral hepatitis: a prospective factor against atherosclerosis. A study with echo-color Doppler of the carotid and femoral arteries and the abdominal aorta. Gastroenterol Clin Biol. 2002;26(11):1001-1004.
41. Corey KE, Kane E, Munroe C, Barlow LL, Zheng H, Chung RT. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology. 2009;50(4):1030-1037.
42. Goossens N, Negro F. Is genotype 3 of the hepatitis C virus the new villain? Hepatology. 2014;59(6):2403-2412.
43. Leandro G, Mangia A, Hui J, et al; HCV Meta-Analysis (on) Individual Patients’ Data Study Group. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130(6):1636-1642.
44. Fartoux L, Poujol-Robert A, Guéchot J, Wendum D, Poupon R, Serfaty L. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54(7):1003-1008.
45. Rubbia-Brandt L, Quadri R, Abid K, et al. Hepatocyte steatosis is a cytopathic effect of hepatitis C virus genotype 3. J Hepatol. 2000;33(1):106-115.
46. Kumar D, Farrell GC, Fung C, George J. Hepatitis C virus genotype 3 is cytopathic to hepatocytes: reversal of hepatic steatosis after sustained therapeutic response. Hepatology. 2002;36(5):1266-1272.
47. Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003;38(1):75-85.
48. Waris G, Felmlee DJ, Negro F, Siddiqui A. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol. 2007;81(15):8122-8130.
49. Dharancy S, Malapel M, Perlemuter G, et al. Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology. 2005;128(2):334-342.
50. de Gottardi A, Pazienza V, Pugnale P, et al. Peroxisome proliferator-activated receptor-alpha and -gamma mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection. Aliment Pharmacol Ther. 2006;23(1):107-114.
51. Yamaguchi A, Tazuma S, Nishioka T, et al. Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci. 2005;50(7):1361-1371.
52. Mirandola S, Realdon S, Iqbal J, et al. Liver microsomal triglyceride transfer protein is involved in hepatitis C liver steatosis. Gastroenterology. 2006;130(6):1661-1669.
53. Perlemuter G, Sabile A, Letteron P, et al. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J. 2002;16(2):185-194.
54. Aguilar M, Bhuket T, Torres S, Liu B, Wong RJ. Prevalence of the metabolic syndrome in the United States, 2003-2012. JAMA. 2015;313(19):1973-1974.
55. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806-814.
56. Dyal HK, Aguilar M, Bhuket T, et al. Concurrent obesity, diabetes, and steatosis increase risk of advanced fibrosis among HCV patients: a systematic review. Dig Dis Sci. 2015;60(9):2813-2824.
57. Dyal HK, Aguilar M, Bartos G, et al. Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis C virus patients: a systematic review. Dig Dis Sci. 2016;61(2):636-645.
58. Ahmed A, Wong RJ, Harrison SA. Nonalcoholic fatty liver disease review: diagnosis, treatment, and outcomes. Clin Gastroenterol Hepatol. 2015;13(12):2062-2070.

Sunday, June 28, 2015

Weekend Reading - Natural history of hepatitis C: An Updated Look at the Rate of Progression to Cirrhosis and the Incidence of Decompensation

Weekend Reading: Natural history of hepatitis C

On most weekends this blog offers up a bit of easy "Weekend Reading" on the topic of HCV.

After receiving a hepatitis C diagnosis, the first task at hand is understanding how the virus damages the liver. A good place to start is with the Natural History Of Hepatitis C. 

To date the natural history of hepatitis C remains controversial. Among HCV-infected individuals progression to advanced liver disease generally requires decades but is influenced by several host factors, the following offers an update on the natural history of hepatitis C using information found online at MedscapeNATAP, and the interactive website Hepatitis C Online.

The Natural History of Chronic Hepatitis C. An Updated Look at the Rate of Progression to Cirrhosis and the Incidence of Decompensation in a Large U.S. Health Maintenance Organization

We begin with a commentary  titled, "Hepatitis C: 25 Years Old, and Fading," written by William F. Balistreri, MD., recently published over at Medscape. The good doctor writes about a study presented last month at "Digestive Disease Week," which suggested the rate of developing cirrhosis and decompensation in people with HCV is higher than previously thought. An excerpt follows with a link to corresponding slides provided this week by Jules Levin @ NATAP.  In addition stroll over to "Hepatitis C Online" or download "Natural History of Hepatitis C Infection" for a quick review of related studies including; spontaneous clearance versus chronic infection and factors that may impact the rate of fibrosis,


Cirrhosis and the Incidence of Decompensation

The projected public health burden of HCV is based on old natural history studies. One presentation[6] suggested a need to reexamine the natural history of HCV because the current patient cohort is older and confounded by a higher prevalence of obesity, and other comorbid conditions that may affect the outcome of the disease. Therefore, investigators conducted a retrospective cohort study at Kaiser Permanente Southern California.

From 2002-2013, 60,338 adults had an HCV diagnosis code or a positive HCV RNA lab test. Of these, 33,124 HCV cases met inclusion criteria and were matched with 164,221 controls. Mean age of the HCV cases and non-HCV controls was 54 years. Among case-patients, 41% were white and 27% were Hispanic; among controls, the respective proportions were 46% and 28%.

Prevalent cirrhosis was found in 19% of the HCV-infected cohort and 1.4% of the non-HCV controls. The incident decompensation rate among previously compensated HCV patients with cirrhosis was 47%, which was almost twice the incident decompensation rate among non-HCV cirrhotic controls. Of note, 23% of HCV cases were diagnosed with cirrhosis after a median follow-up of 2 years, which indicates that the rates of development of HCV-related cirrhosis and decompensation are higher than previously reported. The authors attributed this to aging of the HCV cohort and associated comorbidities, such as obesity. Multivariable analyses to explore the relationship between baseline comorbid conditions and the incidence of cirrhosis and decompensation are ongoing.

  1. Nyberg LM, Li X, Chiang K, et al. The natural history of chronic hepatitis C. An updated look at the rate of progression to cirrhosis and the incidence of decompensation in a large U.S. health maintenance organization. Program and abstracts of Digestive Disease Week; May 16-19, 2015; Washington, DC. Abstract 809.

View All Slides@ NATAP

The Natural History of Chronic Hepatitis C. An Updated Look at the Rate of Progression to Cirrhosis and the Incidence of Decompensation in a Large U.S. Health Maintenance Organization

Begin here....

About Hepatitis C Online
Hepatitis C Online is a free educational web site from the University of Washington.

The site is a comprehensive resource that addresses the diagnosis, monitoring, and management of hepatitis C virus infection. 

Hepatitis C Online

Website Site:

Spontaneous Clearance versus Chronic Infection 
Variable Outcomes of Chronic Infection 
Factors Impacting Rate of Progression of Fibrosis 
Summary Points 

Thursday, July 18, 2013

CDC- Hepatitis C Online Course

Hepatitis C Online Course

When a new learning activity pertaining to HCV is released online this blog provides readers with background information and links to the new video, article or CME.

Recently a "Hepatitis C Online Course" funded by the CDC and brought to you by a collaboration between the University of Washington and the International Antiviral Society-USA (IAS-USA) was launched online.

Hepatitis C patients taking part in the activity are given an opportunity to learn more about the progression of HCV, the evaluation and prognosis of patients with cirrhosis and noninvasive tests for diagnosing and assessing liver fibrosis. Other topics in the online course include a video presentation explaining "Extrahepatic Conditions Related to Hepatitis C Virus (HCV)" which may affect small vessels, skin, kidneys, salivary gland, eyes, thyroid, and immunologic system. This interactive course is offered in a text, video and slide presentation format.

Thursday, November 15, 2012

Chronic HCV infection: epidemiological and clinical relevance

Chronic HCV infection: epidemiological and clinical relevance

S Zaltron, A Spinetti, L Biasi, C Baiguera and F Castelli*

* Corresponding author: F Castelli Author Affiliations University Division of Infectious and Tropical Diseases, University of Brescia and Spedali Civili General Hospital, 25123, Brescia, Italy 

BMC Infectious Diseases 2012, 12(Suppl 2):S2 doi:10.1186/1471-2334-12-S2-S2

The electronic version of this article is the complete one and can be found online at:
Published: 12 November 2012

© 2012 Zaltron et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Hepatitis C virus (HCV), first recognized as a cause of transfusion-associated acute and chronic hepatitis in 1989, plays a major role as a cause of chronic liver injury, with potential for neoplastic degeneration. It is mainly transmitted by the parenteral route. However, although with lower efficiency, it may be also transmitted by sexual intercourses and by the mother-to-child route. Epidemiological evidence shows that a wave of infection occurred in the 1945-65 period (baby boomers) in western countries. After acute infection, as many as 50-85% of the patients fail to clear the virus resulting in chronic liver infection and/or disease. It is estimated that, on a global scale, about 170 million people are chronically infected with HCV, leading to about 350.000 deaths yearly. Among western countries southern Europe, and particularly Italy, is among the most affected areas. The impact on the public health systems is noteworthy, with high number of hospitalizations due to chronic liver disease, cirrhosis or hepatocellular carcinoma. While waiting for a safe and effective vaccine to be made available, new promising direct-acting antiviral (DAA) drugs offer a better therapeutic scenario than in the past even for the poor responder genotypes 1 and 4, provided that effective screening and care is offered. However, the long and aspecific prodromic period before clinical symptoms develop is a major obstacle to early detection and treatment. Effective screening strategies may target at-risk groups or age specific groups, as recently recommended by the CDC.

The hepatitis C virus (HCV) is a RNA virus belonging to the Flaviviridae family. It has been first recognized as a cause of transfusion-associated acute and chronic hepatitis (formerly known as non-A, non-B hepatitis) in 1989 [1]. Six different genotypes (HCV-1 to HCV-6) and several subtypes have subsequently been identified, with different geographical and virulence patterns and different response to conventional therapy. Its epidemiological relevance as a cause of chronic liver injury, with potential for neoplastic degeneration, has since been fully appreciated. At present, it is estimated that about 170 million people, roughly 3% of the world population, are chronically infected with HCV leading to about 350.000 deaths yearly, related to complications such as cirrhosis and liver cancer [2].

During the last 2 decades, an increasing body of knowledge has accumulated as to its virological properties, modes of transmission, epidemiological characteristics, pathogenesis, clinical features and public health impact. While waiting for a safe and effective vaccine to be made available, new promising direct-acting antiviral (DAA) drugs offer a better therapeutic scenario than in the past even for the poor responder genotypes 1 and 4.

Transmission routes and epidemiology
Similarly to other parenterally-transmitted infections such as HIV and HBV, other various modalities of HCV transmission have been documented:

- Intravenous drug use.
Since the most efficient transmission route of hepatitis C virus is percutaneous exposure, it is not surprising that intravenous needle sharing drug users show high infection rates, that may be as high as 90% when HIV co-infected drug addicts are considered [3].

- Non-intravenous recreational drug exposure.
Increasing evidence is accumulating that HCV may also cross the nasal mucosa and infect subjects chronically using inhalatory recreational drugs, such as cocaine, by the sharing of inhalatory instrumentation, favored by the frequent bleeding of the nasal mucosa occurring in these individuals [4].

- Accidental exposure.
The risk of HCV infection after accidental needle stick exposure has been reported to range between 0.2% to 10%, depending on various factors including hollow-bore needles, percutaneous exposure, high HCV viral load or HIV co-infection of the index case [5].

- Healthcare procedures.
Exposure to unsafe healthcare practice, including hemodyalisis, has been reported to be one of the most important risk factors associated with HCV infection, even in western countries [6,7].

- Mother to child vertical transmission.
Mother-to-child vertical transmission of HCV is reported to occur in 3-10% of cases, mostly in the late intrauterine period, at delivery or in the peri-natal period. Many factors have been reported to influence the transmission rate, including maternal high viral load, labour duration, newborn gender, premature membrane rupture and genotype [8]. The role of elective cesarean section to reduce mother-to-child transmission rates is debated and controversial [8,9] and the guidelines of the European Association for the Study of the Liver (EASL) does not recommend cesarean section to prevent HCV vertical transmission [10].

- Sexual exposure.
The efficiency of the sexual transmission of HCV has been the subject of extensive debate and it is generally considered to be very low [11]. However, among male intravenous drug users, the rate of HCV infection was found to be one third higher in those who had sex with men (MSM) than in heterosexuals [12]. Recent evidence points to the increasing incidence of HCV infections in MSM, probably facilitated by rectal mucosa traumatisms, especially when HIV-infection co-exists. Paradoxically, it has been noted that the increased incidence of the sexual transmission of HCV has paralleled the increased availability of Highly Active Anti-retroviral Therapy (HAART), suggesting that a false-security feeling may have played a role [13].

However, for a large share of cases, estimated at around 30%, no definite exposure source may be identified. Studies of age-specific prevalence rates of anti-HCV in the population show that HCV infection is rare among children while it increases with age, suggesting a possible cohort effect in anti-HCV positive elderly individuals who acquired the infection several years ago, before the introduction of effective preventive measures such as screening of donors and use of disposable needles and syringes in medical practice. During the last 10 years, the rate of transfusion-associated hepatitis C has significantly dropped as a consequence of the introduction of increasing restrictions on donor eligibility and the implementation of effective anti-HCV or HCV-RNA screening. Consequently, most of the millions who are chronically infected with HCV are now in the fourth or fifth decade of life (“baby boomers”). As they move into their 60s and 70s, these individuals constitute a wave of asymptomatic HCV infection that may move toward clinical disease. Whatever the transmission route, it is estimated that approximately 170 million individuals, i.e. 3% of the world population, are chronically infected with HCV [14]. HCV is the primary cause of death of 350,000 individuals every year, also representing the primary reason for liver transplantation.

The prevalence varies markedly from low (< 2.5%) in North America, Europe, Australia and Far East, to intermediate (2.5% to 10%) in some Mediterranean countries, South America, Africa and Middle East to high (>10%) prevalence areas in Egypt, Burundi, Gabon, Cameroon, Rwanda, Guinea, Bolivia, Mongolia with an steady North-South increasing trend. It has been estimated that in Southern Europe 9 million persons are anti-HCV positive, 1,600,000 of whom in Italy, and that HCV accounts for approximately 20% of reported cases of acute hepatitis. Six genotypes, numbered 1-6, and a large number of subtypes have been described. Genotype 1 (subtype 1a and 1b) is by far the most prevalent genotype worldwide. A number of studies have reported that subtypes 1a and 1b predominates in America and Europe, and that subtype 1b is the predominant genotype in Asia. Both types 2 and 3 are found with significant prevalence in many countries in North and South America, Europe and Asia. Others studies have found type 4 to be predominant in Africa. However, HCV type 4 and 5 can also be found sporadically outside of Africa.

Natural history and clinical impact
After HCV acute infection an average 50-85% of patients will not clear the virus, with higher rates in HIV-co-infected subjects, and will therefore remain chronically infected with plateau or fluctuating viremia detectable in the blood. The remaining 15-50% will gradually show a decrease and final disappearance of the virus from the blood, usually within 3 months from infection [15,16]. The complex mechanisms regulating virus clearance and persistence are still not completed understood, but probably imply both host and virus factors. The role of ethnicity has not been proved. On the contrary, sexual transmission of HCV and HBV co-infection might favor viral clearance, probably due to limited inoculum and viral interference, respectively [17]. From the virological perspective, the higher the genetic diversity of the infecting virus, the higher the probability that the immune response will not be able to control its replication, resulting in chronic infection, while a narrow quasispecies spectrum is more likely associated to viral clearance [18]. Of note, similar to hepatitis B infection but without genomic integration, it has been recently demonstrated that HCV may replicate in the liver in the absence of detectable viral level in the blood , a condition sometimes referred to as “occult C hepatitis”, with lower potential for progressive disease [19].

In the setting of persistent hepatitis C viremia, liver fibrosis is the consequence of chronic inflammation leading to the final distortion of hepatic architecture and impairment of liver microcirculation and cell functions. The main consequence of chronic HCV infection is the progression to cirrhosis, often clinically silent apart from non-specific symptoms such as fatigue, upper right quadrant pain or, sometimes, arthralgia and myalgia, until severe complications develop.

In most cases, abnormal ALT values are the only clinical aspecific findings of the disease, only representing a marker of hepatocellular dysfunction. In particular, a direct correlation between the degree of ALT elevation and stage of the HCV-related disease is often lacking as a significant cytolytic activity is not a surrogate marker of disease severity [20] as well as normal ALT does not always mean an healthy liver. Population-based studies indicate that up to 30%-40% of individuals with chronic HCV have persistently normal ALT values when serially tested. However, significant liver disease, with active inflammation and/or at least significant fibrosis, is biopsy-proven in about 20% of HCV carriers with normal ALT [21].

Chronic hepatitis C is the most common cause of cirrhosis and the most common indication for liver transplantation in Europe, North and South America, Australia and Japan. The risk of developing cirrhosis ranges from 5% to 25% over periods of 25-30 years [22].

Environmental and host factors can increase the risk and/or accelerate the natural course of HCV-related disease. Multiple studies have shown that alcohol consumption, in particular a daily intake greater than 40-50 g, is one of the most influential factor driving fibrosis progression in patients with HCV. Age at time of infection also plays a role: the estimated probability of progression is significantly higher in patients that were infected at an older age (> 40 years) [23]. Also, a recent and large analysis of published studies suggests that early acquisition of HCV in childhood is rarely associated to a severe future course of the disease [24]. Other factors that affect the progression of hepatic fibrosis include male gender, the degree of inflammation and fibrosis on the liver biopsy, co-morbidities such as immunosoppression or metabolic condition such as non-alcholic steatohepatitis, obesity and insulin resistance [20].

In addition, co-infection with HBV or HIV are significant risk factors for liver fibrosis. Approximately 4 to 5 million subjects with chronic hepatitis C are co-infected with HIV. Highest co-infection rates are observed among injection drug users (IDU): in the USA and in Europe, among HIV-infected IDU, HCV prevalence may be as high as 70-90 %. Paradoxically, the longer life-expectancy offered to HIV-infected patients by HAART permits slow-acting HCV-related liver injury to emerge as a significant cause of morbidity and mortality in HIV-HCV co-infected patients. Furthermore, the progression rate to cirrhosis and end-stage liver disease is accelerated in HIV co-infected patients: they have a twofold increased rate of cirrhosis compared to HCV mono-infected individuals [25], particularly when HIV associated immune-depression progresses.

The mechanisms underlying accelerated liver disease in HIV-HCV co-infected patients are not completely understood, possibly including direct HCV effects on hepatocytes and hepatic stellate cells as well as immunological alterations such as immune activation, apoptosis and impaired HCV specific T-cell response [26]. Furthermore, liver toxicity of anti-retroviral drugs and the burden of metabolic diseases may contribute to a faster progression of liver fibrosis in HIV-HCV co-infected patients.

Conversely, the role of HCV on the natural history of HIV infection continue to be debated and contrasting evidence exist [27,28].

HCV replication has been observed in extra-hepatic tissues, such as bone marrow, the central nervous system, endocrine glands, lymph nodes, spleen, monocytes, macrophages and skin cells. HCV is also often associated with profound alterations in the host immune system, resulting in immunological abnormalities and even autoimmune disease such as mixed cryoglobulemia (MC), rheumatoid factor (RF) production, B cell lymphoproliferative disorders that may progress to non–Hodgkin lymphoma, and others. Cryoglobulins are immunoglobulins that precipitate in the cold and are classified into three groups, based on Ig clonality. Type I cryoglobulins are usually associated with lymphoproliferative disorders, including myeloma and Waldenstrom macroglobulinemia, and usually consist of monoclonal IgM or IgG, rarely IgA. Type II cryoglobulins are composed of polyclonal IgG and monoclonal IgM, usually characterizing the condition known as essential MC that is often associated with HCV. Type III MC is also characterized by RF activity, although polyclonal IgG and polyclonal IgM exist. The incidence of HCV infection in MC ranges from 40% to 90%, with geographical variations [29]. The high incidence of disease among Mediterranean people and the association of certain human leukocyte antigen (HLA) supports that genetic factors play a role in the disease. The clinical picture is characterized by the skin manifestations ranging from purpura of lower limbs to chronic torpid skin ulcers, more frequent in the sovramalleolar regions. Skin reactions include Raynaud’s phenomenon, livedo reticularis, urticaria, and edema. Arthralgias more frequently involve the hands and the knees symmetrically. Renal injury may complicate MC in almost 30% of cases and involvement of the nervous system from 17% to 60%. Peripheral sensory-motor neuropathy can represent the first clinical sign of cryoglobulinemia.

Cirrhosis and hepatocellular carcinoma (HCC)
An important clinical feature of HCV infection is the high rate of chronic and slowly progressive lifelong infection, which may lead to cirrhosis and end-stage liver disease in about 10-40% of people with chronic hepatitis C, depending on the presence of co-factors.

Cirrhosis is defined as the progressive development of regenerative nodules embedded in fibrous bands in response to chronic liver injury that leads to portal hypertension and end-stage liver disease [30]. Globally, 57% of cirrhosis is attributable to either HBV (30%) or HCV (27%), while alcohol consumption is another important cause, accounting for about 20% of the cases [2]. Alcoholic liver disease and hepatitis C prevail in western countries, whereas hepatitis B is the prevailing cause in most parts of Asia and sub-Saharan Africa [30]. Liver cirrhosis is a widespread chronic disease in Italy, where it was listed between the top-ten main causes of death in 2001. Survival of patients with cirrhosis is heavily influenced by the onset of complications (i.e., ascites, encephalopathy, jaundice, oesophageal varices bleeding), that occur at a yearly rate of about 5-7% patients.

Ascites occurs in at least 50% of the patients during their life, heralding a negative prognosis in the short-medium term. Elimination of the causal factor delays progression and could even reverse cirrhosis, even if data about reversibility are contrasting.

Liver cirrhosis is a major risk factor for the development of hepatocellular carcinoma (HCC). Indeed HCC is the most severe complication of chronic inflammatory liver diseases and it is the most frequent primary liver cancer. As an example, in Italy HCC accounts for as many as 79% of liver cancers [31]. The incidence of HCC increases progressively with advancing age in all populations, reaching a peak at 70 years, with a strong male preponderance [32]. The prevalence of HCC in Italy is 53/100000 and 22/100000 inhabitants in males and in females respectively (risk ratio 2:1). It is the fifth cause of death in men (third cause in the age group 50-69 years) and the seventh cause of death in women [31]. Recently, the mortality rate has shown a decrease of 34% in men and 41% in women in the period 2000-2009 in Italy [33], probably due to an overall improvement of management of HCC both in terms of early diagnosis and therapy. On a global scale, the most frequent causes of HCC are HBV (54%), HCV (31%) and alcoholic abuse (15%) [34]. In Africa and Asia an important role of co-factor in the HBV carcinogenesis is played by dietary exposure to aflatoxin B.

As 90% of HCC are associated with a known underlying risk factor it is possible to identify patients at high risk for developing HCC and enter them into surveillance programs aimed at early detection of neoplastic lesions in order to reduce disease-related mortality. Periodic ultrasound (US) scan is probably the most appropriate surveillance test, even if the outcome is highly dependent on the expertise of the examiner and on the physical typology of the patient [35]. Six-monthly surveillance appears to offer the best cost-benefit ratio [36].

If histology remains the gold-standard, diagnosis may also be reached with high degree of specificity through non-invasive techniques (contrast TC or MRI), performing a 4-phase assessment of the lesion (pre-contrast, arterial, venous and delayed-contrast phase). Also contrast-US may efficiently lead to the diagnosis of HCC, provided that it is performed by highly skilled examiners (Figure. 1). HCC staging is based on CT or MRI images, but MRI is to be preferred when small lesions (Ø < 2 cm) are present [37]. In the absence of a universally accepted staging system, the current AASLD and EASL guidelines endorse the 5-stage Barcelona-Clinic Liver Cancer (BCLC) classification systems [38] because it links tumor stage with treatment strategy and includes prognostic variables related to tumor status, liver function and health performance status along with treatment-dependant variables.

Figure 1.. Left: Ultrasound (US) image of HCC. Right: contrast-US image of HCC with arterial enhancement (Courtesy Dr L. Biasi).

Public health impact of hepatitis C and its complications
The burden of HCV-related cirrhosis and HCC on the health systems of western countries is expected to increase in the coming years due to the diseases progression wave of HCV baby boomers, posing an increasing high burden on hepatologists and infectious diseases specialists.

In Europe, nine million people are affected by chronic hepatitis C and 86,000 people die each year because of HCV infection. In this continent, about 60-70% of HCC cases are caused by HCV and data from several european countries suggest that the mortality from liver cancer is rising [39].

In particular, Italy is the European country with the largest number of people chronically infected by hepatitis C virus [40], which is the leading cause of hepatic disease in this country. In Italy, chronic liver diseases impact on National Health System with about 160,000 hospital discharge diagnosis and account overall for 5% reimbursement due by the Regions to the Hospitals [41].

The Liver Match, an observational cohort study that prospectively enrolled liver transplantations performed at 20 Italian transplant Centers between 2007 and 2009, reported that hepatitis virus-related end stage liver disease (with and without HCC) accounts for 64.2% of indications to transplantation and HCV is the most frequent etiologic factor; in addition, 54% of the cases of HCV-related cirrhosis is associated with HCC [42].

Screening strategies
As most HCV-infected individuals are unaware of their infection status, they are therefore not monitored nor offered expert advice or treatment, when needed. The knowledge of the basic drivers of HCV infection (risk factors, geographical origin, age groups, etc.) may provide the rationale for screening strategies aimed at detecting those individuals who might benefit from the new therapeutic advances. Most health authorities have recommended HCV screening in those individuals more likely to be infected [43]. When individuals at high-risk for HCV infection have been screened, high HCV prevalence have been indeed detected, as expected. However, the efficacy of this risk-based strategies has proved far from optimal and many patients, even those with recognized high risk of exposure, remain unscreened and undetected even in western countries. Furthermore, it has been estimated that as many as 30-45% of HCV-infected patients in western countries do not have significant risk factors nor elevated transaminase levels, so that they are missed by targeted screening. When blind screening to the general population attending large Emergency Departments in Germany have been carried out, a higher HCV seroprevalence than expected has been documented [44]. Recently, the cost-benefit to enlarge the criteria for HCV screening in order to detect a larger number of HCV-infected individuals has been addressed and found favorable in the medium term provided that referral, treatment and cure were made available. In this model simulation, the incremental cost, compared to risk-based guidelines, for every quality-adjusted life year (QALY) gained was 7,900 $ and 4,200 $ if once-time HCV screening was to be proposed to the 20-69 yrs old or to the baby-boomers (birth date from 1945 to 1965) US population, respectively [45].

On the basis of the growing epidemiological evidences, the US Department of Health and Human Services has recently issued the 2012 “Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965” [46] recommending HCV screening testing for adults born in the period 1945-65 (one-time testing) in addition to testing adults of all ages reporting risk factors for HCV infection.

Competing interests
The Authors declare that they have no conflict of interest related to the content of the specific article.

Publication of this supplement was partly supported by an unrestricted grant provided by Roche. The articles were independently prepared by the authors with no input from Roche. Roche were not involved in selecting the articles for the supplement.

Dr Silvia Amadasi provided input to the article, with particular regard to the discussion of the clinical aspects of hepatocellular carcinoma. Her help is gratefully acknowledged.

This article has been published as part of BMC Infectious Diseases Volume 12 Supplement 2, 2012: Proceedings of the Second Workshop of the Regional Study Group on HCV in the Calabria Region (Southern Italy). The virus-host-therapy pathway in HCV disease management: from bench to bedside in the era of Directly Acting Antivirals. The full contents of the supplement are available online at

  1. Choo QL, Kou G, Weiner AJ, Overby LR, Bradley DW, Houghton M: Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989, 244:359-362. PubMed Abstract | Publisher Full Text OpenURL

  2. Perz JF, Armstrong GL, Farrington LA, Hutin Y, Bell B: The contributions of hepatitis B virus and hepatitis C virus to cirrhosis and primary liver cancer worldwide. J Hepatol 2006, 45:529-538. PubMed Abstract | Publisher Full Text OpenURL

  3. Taylor LE, Swan T, Mayer KH: HIV co-infection with hepatitis C virus: evolving epidemiology and treatment paradigms. Clin Infect Dis 2012, 55(S1):S33-S42. PubMed Abstract | Publisher Full Text OpenURL

  4. Allison RD, Conry-Cantilena C, Kozion D, Schechterly C, Ness P, Gibble J, Kleiner DE, Ghany MG, Alter HJ: A 25-year study of the clinical and histologic outcomes of hepatitis C virus infection and its modes of transmission in a cohort of initially asymptomatic blood donors. J Infect Dis 2012, 206:654-661. PubMed Abstract | Publisher Full Text OpenURL

  5. Corey KE, Servoss JC, Casson DR, Kim AY, Robbins GK, Franzini J, Twitchell K, Loomis SC, Abraczinskas DR, Terella AM, Dienstag JL, Chung RT: Pilot Study of Postexposure Prophylaxis for Hepatitis C Virus in Healthcare Workers. Infect Control Hosp Epidemiol 2009, 30:1000-1005. PubMed Abstract | Publisher Full Text OpenURL

  6. Perz JF, Grytdal S, Beck S, Fireteanu AM, Poissant T, Rizzo E, Bornschlegel K, Thomas A, Balter S, Miller J, Klevens M, Finelli L: Case-control study of hepatitis B and hepatitis C in older adults: do healthcare exposures contribute to burden of new infections? Hepatology 2012. DOI 10.1002/hep.25688 [Epub ahead of print]
    PubMed Abstract | Publisher Full Text OpenURL

  7. Martínez-Bauer E, Forns X, Armelles M, Planas R, Solà R, Vergara M, Fàbregas S, Vega R, Salmerón J, Diago M, Sánchez-Tapias JM, Bruguera M, Spanish Acute HCV Study Group: Hospital admission is a relevant source of hepatitis C virus acquisition in Spain. J Hepatol 2008, 48:20-27. PubMed Abstract | Publisher Full Text OpenURL

  8. Murakami J, Nagata I, Iitsuka T, Okamoto M, Kaji S, Hoshika T, Matsuda R, Kanzaki S, Shiraki K, Suyama A, Hino S: Risk factors for mother-to-child transmission of hepatitis C virus: maternal high viral load and fetal exposure in the birth canal. Hepatol Res 2012, 42:648-657. PubMed Abstract | Publisher Full Text OpenURL

  9. European Pediatric Hepatitis C Virus Network: A significant sex – but not elective cesarean section – effect on mother-to-child transmission of hepatitis C virus infection. J Infect Dis 2005, 192:1872-1879. PubMed Abstract | Publisher Full Text OpenURL

  10. European Association for the Study of the Liver: EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2011, 55:245-264. PubMed Abstract | Publisher Full Text OpenURL

  11. Tohme RA, Holmberg SD: Is sexual contact a major mode of hepatitis C virus transmission? Hepatology 2010, 52(4):1497-505. PubMed Abstract | Publisher Full Text OpenURL

  12. Marongiu A, Hope VD, Parry JV, Ncube F: Male IDUs who have sex with men in England, Wales and Northern Ireland: are they at greater risk of bloodborne virus infection and harm than those who only have sex with women? Sex Transm Infect 2012. [Epub ahead of print]
    PubMed Abstract | Publisher Full Text OpenURL

  13. Stolte IG, Dukers NH, Geskus RB, Coutinho RA, de Wit JB: Homosexual men change to risky sex when perceiving less threat of HIV/AIDS since availability of highly active anti-retroviral therapy: a longitudinal study. AIDS 2004, 18:303-309. PubMed Abstract | Publisher Full Text OpenURL

  14. Shepard CW, Finelli L, Alter MJ: Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005, 5:558-567. PubMed Abstract | Publisher Full Text OpenURL

  15. Thomson EC, Fleming VM, Main J, Klenerman P, Weber J, Eliahoo J, Smith J, McClure MO, Karayiannis P: Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011, 60:837-845. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  16. Santantonio T, Wiegand J, Gerlach JT: Acute hepatitis C: current status and remaining challenges. J Hepatol 2008, 49(4):625-33. PubMed Abstract | Publisher Full Text OpenURL

  17. Shores NJ, Maida I, Soriano V, Nunez M: Sexual transmission is associated with spontaneous HCV clearance in HIV-infected patients. J Hepatol 2008, 49:323-328. PubMed Abstract | Publisher Full Text OpenURL

  18. Thomson EC, Smith JA, Klenerman P: The natural history of early hepatitis C virus evolution; lessons from a global out break in human immunodeficiency virus-1-infected individuals. J Gen Virol 2011, 92:2227-2236. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  19. Carreño V, Bartolomé J, Castillo I, Quiroga JA: New perspectives in occult hepatitis C virus infection. World J Gastroenterol 2012, 18:2887-2894. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  20. Massard J, Ratziu V, Thabut D, Moussalli J, Lebray P, Benhamou Y, Poynard T: Natural history and predictors of disease severity in chronic hepatitis C. J. Hepatol 2006, 44:S19-S24. PubMed Abstract | Publisher Full Text OpenURL

  21. Puoti C, Guarisco R, Spilabotti L, Bellis L, Mitidieri O, Dell’Unto O, Elmo MG: Should we treat HCV carriers with normal ALT levels ? The “5Ws” dilemma. J Viral Hepat 2012, 19:229-235. PubMed Abstract | Publisher Full Text OpenURL

  22. Seeff LB: Natural history of chronic hepatitis C. Hepatology 2002, 36(5 Suppl 1):S35-S46. PubMed Abstract | Publisher Full Text OpenURL

  23. Poynard T, Bedossa P, Opolon P: Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997, 349(9055):825-32. PubMed Abstract | Publisher Full Text OpenURL

  24. Robinson JL, Doucette K: The natural history of hepatitis C virus infection acquired during childhood. Liver Int 2012, 32:258-270. PubMed Abstract | Publisher Full Text OpenURL

  25. Smit C, van den Berg C, Geskus R, Berkhout B, Coutinho R, Prins M: Risk of hepatitis related mortality increased among hepatitis C virus/HIV-coinfected drug users compared with drug users infected only with hepatitis C virus: a 20-year prospective study. J Acquir Immune Defic Syndr 2008, 47(2):221-225. PubMed Abstract | Publisher Full Text OpenURL

  26. Operskalski EA, Kovacs A: HIV/HCV Co-infection: pathogenesis, clinical complication, treatment and new therapeutic technologies. Curr HIV/AIDS Rep 2011, 8:12-22. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  27. Chen TY, Ding EL, Seage I GR, Kim AY: Meta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression. Clin Infect Dis 2009, 49(10):1605-15. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  28. d’Arminio Monforte A, Cozzi-Lepri A, Castagna A, Antinori A, De Luca A, Mussini C, Caputo SL, Arlotti M, Magnani G, Pellizzer G, Maggiolo F, Puoti M, ICONA Foundation Study Group: Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with or without liver cirrhosis. Clin Infect Dis 2009, 49(4):612-22. PubMed Abstract | Publisher Full Text OpenURL

  29. Sansonno D, Dammacco F: Hepatitis C virus, cryoglobulinemia, and vasculitis: immune complex relations. Lancet Infect Dis 2005, 5:227-36. PubMed Abstract | Publisher Full Text OpenURL

  30. Schuppan D, Afdhal NH: Liver cirrhosis. Lancet 2008, 371(9615):838-51. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  31. Associazione Italiana Registri Tumori: Rapporto AIRTUM 2010. webcite , accessed august 30th, 2012
  32. International Agency for Research on Cancer (IARC) 2012. webcite; [accessed August, 29th 2012]

  33. Bosetti C, Bianchi C, Negri E, Colomba M, La Vecchia C: Estimates of the incidence and prevalence of hepatocellular carcinoma in Italy in 2002 and projections for the years 2007 and 2012. Tumori 2009, 95:23-7. PubMed Abstract OpenURL

  34. Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 2003, 362:1907-1917. PubMed Abstract | Publisher Full Text OpenURL

  35. Lee JM, Trevisani F, Vilgrain V, Wald C: Imaging diagnosis and staging of hepatocellular carcinoma. Liver Transpl 2011, 17(Suppl 2):S34-43. PubMed Abstract | Publisher Full Text OpenURL

  36. Trinchet JC, Chaffaut C, Bourcier V, Degos F, Henrion J, Fontaine H, Roulot D, Mallat A, Hillaire S, Cales P, Ollivier I, Vinel JP, Mathurin P, Bronowicki JP, Vilgrain V, N’Kontchou G, Beaugrand M, Chevret S, Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire: Ultrasonographic survelliance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3 and 6 month periodicities. Hepatology 2011, 54:1987-97. PubMed Abstract | Publisher Full Text OpenURL

  37. Golfieri R, Renzulli M, Lucidi V, Corcioni B, Trevisani F, Bolondi L: Contribution of the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI to dynamic MRI in the detection of hypovascular small (</= 2 cm) HCC in cirrhosis. Eur Radiol 2011, 21:1233-42. PubMed Abstract | Publisher Full Text OpenURL

  38. Singal A, Volk ML, Waljee A, Salgia R, Higgins P, Rogers MA, Marrero JA: Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 2009, 30:37-47. PubMed Abstract | Publisher Full Text OpenURL

  39. Hatzakis A, Wait S, Bruix J, Buti M, Carballo M, Cavalieri M, Colombo M, Delaroque-astagneau E, Dusheiko G, Esmat G, Esteban R, Goldberg D, Gore C, Lok AS, Manns M, Marcellin P, Papatheodoridis G, Peterle A, Prati D, Piorkowski N, Rizzetto M, Roudot-Thoraval F, Soriano V, Thomas HC, Thursz M, Valla D, van Damme P, Veldhuijzen IK, Wedermeyer H, Wiessing L, Zanetti AR, Janssen HL: The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference. J Viral Hepat 2011, 18(suppl 1):1-16. PubMed Abstract | Publisher Full Text OpenURL

  40. European Centre for Disease Prevention and Control (ECDC): Hepatitis B and C in the EU neighborhood: prevalence, burden of disease and screening policies. Stockholm: ECDC; 2010. http:/ / en/ publications/ Publications/ TER_100914_Hep_B_C%20_EU_neighbourh ood.pdf webcite, accessed September 5th, 2012

  41. AISF (Associazione Italiana per lo Studio del Fegato): Libro Bianco AISF 2011. Fondazione Italiana per la Ricerca Epatologica; 2012.

  42. Angelico M, Cillo U, Fagiuoli S, Gasbarrini A, Gavrila C, Marianelli T, Costa AN, Nardi A, Strazzabosco M, Burra P, Agnes S, Baccarani U, Calise F, Colledan M, Cuomo O, De Carlis L, Donataccio M, Ettorre GM, Gerunda GE, Gridelli B, Lupo L, Mazzaferro V, Pinna A, Risaliti A, Salizzoni M, Tisone G, Valente U, Rossi G, Rossi M, Zamboni F, Liver Match Investigators: Liver Match, a prospective observational cohort study on liver transplantation in Italy: study design and a current practice of donor-recipient matching. Dig Liver Dis 2011, 43:155-164. PubMed Abstract | Publisher Full Text OpenURL

  43. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. Centers for Disease Control and Prevention. MMWR Recomm Rep 1998, 47:1-39. PubMed Abstract | Publisher Full Text OpenURL

  44. Vermehren J, Schlosser B, Domke D, Elanjimattom S, Muller C, Hintereden G, Hensel-Wiegel K, Tauber R, Berger A, Haas N, Walcher F, Mockel M, Lehmann R, Zeuzem R, Sarrazin C, Berg T: High prevalence of anti-HCV antibodies in two metropolitan emergency departments in Germany: a prospective screening analysis of 28,809 patients. PLos ONE 2012, 7(7):e41206. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  45. Coffin PO, Scott JD, Golden MR, Sullivan SD: Cost-effectiveness and population outcomes of general population screening for hepatitis C. Clin Infect Dis 2012, 54:1259-71. PubMed Abstract | Publisher Full Text OpenURL

  46. CDC Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, TB Prevention: Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep 2012, 61(RR-4):1-32. PubMed Abstract | Publisher Full Text OpenURL