Showing posts with label disease progression. Show all posts
Showing posts with label disease progression. Show all posts

Tuesday, August 13, 2013

Alcoholic liver disease increases the risks for liver-related mortality

Alcoholic liver disease increases the risks for liver-related mortality

According to the study individuals with alcoholic liver disease are at an increased risk to die from liver-related causes, but not cardiovascular-related or overall mortality.

"Long-term alcohol use has synergistic effects with other causes of chronic liver disease to accelerate progression of liver disease. For example, patients with Hepatitis C who regularly consume alcohol experience an accelerated progression to fibrosis, and a higher incidence of cirrhosis and hepatocellular carcinoma (HCC)"

Mortality associated with alcohol-related liver disease

Alimentary Pharmacology & Therapeutics
G. Trimble1,2, L. Zheng1,2, A. Mishra1,2, S. Kalwaney1,2, H. M. Mir1, Z. M. Younossi1,2,

* Article first published online: 28 JUL 2013 DOI: 10.1111/apt.12432

Excessive alcohol use has been reported to be responsible for 80 000 annual deaths in the United States. However, the exact cause of death related to the excessive use of alcohol has not been fully explored.

To assess the effect of alcoholic liver disease (ALD) on all-cause, liver-related and cardiovascular mortality using population-based data.

Data were obtained from the Third National Health and Nutrition Examination Survey (NHANES III) Linked Mortality Files. Alcohol consumption was estimated as grams per day. Multivariate Cox proportional hazards model was utilised to assess the effects of ALD on follow-up time to mortality from all causes, cardiovascular disease and liver disease. Results A total of 8,306 participants were included [ALD (n = 148)]. Mortality follow-up data were available for a median time of 178.27 months. Participants with ALD had increased risk for liver-related mortality [adjusted hazard ratios or aHR 7.06 (2.09–23.79)], but not for overall mortality [aHR 1.14 (0.70–1.85)] or cardiovascular mortality [aHR 0.61 (0.11–3.25)].

Alcoholic liver disease increases the risks for liver-related mortality but not for cardiac or overall mortality.

Introduction Only
Full Text Available Online :
Alimentary Pharmacology & Therapeutics

Excessive alcohol consumption and alcohol dependence are a chronic, relapsing disease, which affects nearly 10% of the population in the United States and Europe.[1] In the United States, significant healthcare costs and the development of chronic disease comorbidities are associated with alcohol consumption. More than half of the US adult population has consumed alcohol in the last 30 days, and 5% of the American adult population is reported to consist of heavy drinkers.[2] Excessive alcohol use was responsible for 80 000 deaths in the United States annually from 2001 to 2005.[3] However, even small amounts of alcohol consumption after the onset of liver disease are associated with increased mortality.[1]
Alcoholic liver disease (ALD) is an important cause of cirrhosis and a direct consequence of excessive alcohol use. ALD encompasses a broad spectrum of liver pathology, from simple steatosis to alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma.[4-8] Long-term alcohol use has synergistic effects with other causes of chronic liver disease to accelerate progression of liver disease.[1] For example, patients with Hepatitis C who regularly consume alcohol experience an accelerated progression to fibrosis, and a higher incidence of cirrhosis and hepatocellular carcinoma (HCC).[9] In the United States, alcohol-related liver deaths account for 48% of cirrhosis-associated deaths.[4] However, the impact of alcoholic liver disease on overall and cause-specific mortality in the US general population is not fully understood. The aim of this study was to assess the impact of ALD on overall mortality, liver-related mortality and cardiovascular mortality as ALD can be considered an entirely preventable disease through screening and appropriate treatment strategies.[1, 7, 10]

Discussion Only
Full Text Available Online :
Alimentary Pharmacology & Therapeutics

This study used population data collected for NHANES III to assess the impact of ALD on overall mortality and cause-specific mortality in the US general population. These data show that patients with ALD are at increased risk for liver-related mortality, but not for overall mortality or cardiovascular mortality. In this population-based analysis, subjects with ALD were more likely to be of age 55–64 (non-ALD had a higher proportion of >65), male, and have Mexican American and non-Hispanic white ethnicity than controls.
Despite the increased prevalence of vascular risk factors such as smoking, insulin resistance and hypertension, liver disease proved to be the most common cause of death in the ALD population, accounting for 18.5% of all deaths. This is different from a similar population-based analysis of patients with non-alcoholic fatty liver disease (NAFLD).[17] Using the same NAHNES III database, NAFLD patients have been shown to have a higher overall mortality compared with the general population, with cardiovascular disease being the primary cause of death, accounting for 25% of all deaths.[18] Our study showed that the ALD population did not have an increased risk for overall mortality or cardiovascular mortality, but only liver-related mortality.
One possible explanation for the cardiovascular outcomes noted in this trial is the previously observed benefit of alcohol consumption and the reduction in cardiovascular events.[19, 20] A recent meta-analysis showed the minimal dose of wine at which maximal protection could be obtained for cardiovascular mortality to be 24 g/day, with similar findings for beer consumption.[19] A more recent study found that the possible mechanistic reason for the cardioprotective effect of a moderate use of alcohol was related to the AKT and nuclear factor (NRF2) mechanism to regulate the oxidative stress response.[10] As ALD was presumed in participants who reported alcohol use greater than 20 g/day with elevated liver enzymes, we can assume that the ALD population in this study would experience the potential benefits described. Also, in the largest prospective study of alcohol use and mortality, the greatest reduction in mortality from coronary artery disease occurred among drinkers who had the presence of heart disease, stroke or other pre-existing risk of cardiovascular disease at enrolment, which were characteristics with a high prevalence in ALD cohort.[21]
In patients at risk for liver disease, any possible benefit from a cardiovascular perspective seems to be countered by the significantly higher risk of liver-related mortality. Of the patient characteristics associated with a higher risk of liver-related mortality, only advanced age proved to be statistically significant.
Despite its long-term follow-up and in-depth clinical and mortality data, our study does have some weaknesses. The most important weakness is the relative small sample size of patients with ALD, which may have led to our inability to show some important potential associations as well as being responsible for the large confidence interval seen in some of the hazard ratios. Nevertheless, the long-term follow-up mortality data make this study quite unique and important. It is also important to recognise that the NHANSES III database is based on a complex multistage probability sample design. The sampling weights incorporate the differential probabilities of selection and include adjustments for noncoverage and nonresponse. Different weights may be associated with each individual in the survey. After applying weights in the analysis, the same observed events may end up with different estimated rates.[15]
In summary, our study finds that patients with ALD are at an increased risk for liver-related mortality. This recognition of ALD as an important cause of preventable mortality at the population level should prompt the availability of resources to address this important public health issue both nationally and globally.

Monday, August 12, 2013

Hepatitis C - A Look At Disease Progression

After receiving a hepatitis C diagnosis, understanding how the virus damages the liver soon becomes the task at hand.

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 and has been proven to be highly variable. For instance studies have shown alcohol consumption is associated with HCV progression; active alcohol use increases the relative risk of hepatocellular carcinoma when compared to people who do not drink. Co-infection with HCV and HBV may also lead to a greater risk of hepatocellular carcinoma and more severe liver disease than does HCV infection alone.

Researchers in the 2012 issue of Seminars in Liver Disease found here, named the above mentioned in addition to smoking, age and duration of HCV infection as host factors relevant in determining the progression of hepatitis C;

 (1) the duration of HCV infection; (2) the presence of cofactors for development of liver fibrosis (such as male gender,  ethnicity, older age at infection, heavy alcohol intake,  HIV or chronic hepatitis B virus (HBV) co-infection, diabetes,  obesity, and hepatic steatosis); (3) access to HCV therapy and a favorable treatment response; and (4) competing mortality risk (such as HIV and illicit drug-related overdose).
The generally slowly progressive nature of chronic HCV, with limited advanced liver disease in the initial 10 to 15 years of infection (even in those individuals with cofactors for fibrosis development), means that duration of HCV infection and its surrogate, age, are key determinants of mortality risk.
Thus, a 50-year-old individual with 30 years chronic HCV is likely to have a higher HCV-related mortality risk, even in the absence of liver disease cofactors, than a 30-year-old individual with 5 to 10 years infection and several cofactors. However, the 50-year-old individual with 30 years infection, with heavy alcohol intake, obesity, and regular cannabis smoking (recently shown to be a liver fibrosis cofactor) will be at particularly high risk.

Out Of 100 People Who Contract HCV

Some studies describing hepatitis C progression can be confusing, and may have conflicting results. However, there is a general consensus after acquiring the virus it takes 10 to 15 years before evidence of the disease appears on biopsy, 20 or so years to develop cirrhosis, and around another decade to develop liver cancer. The statistics are overwhelming, Medscape offers a clear perspective in this 2012 article:

Hepatitis C Therapy Update
Lisa C. Casey, William M. Lee
Curr Opin Gastroenterol. 2012;28(3):188-192. 

Out of 100 people that contract the infection, 75–85 people will develop chronic infection, 60–70 people will develop chronic liver disease, five to 20 people will develop cirrhosis over the course of their chronic infection and one to five people will die of complications including hepatocellular carcinoma (HCC).

A therapy update published in 2013 from the same authors is available @ Medscape.  

*Free registration  required

Unique Study Cohort

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 and 917 German women exposed to hepatitis C from contaminated Anti-D immunoglobulin  in 1977–8 from a single source. Researchers have studied the aging population of women at 17, 20, 25 and 35 years after infection. A few of those studies have been added to this summary, with more recent research following each study. Offering an interesting comparison of data. Other highlights include: disease progression- including host factors, achieving SVR in relation to disease outcome, mother to child transmission (from the cohort of women) and the risk for HCV-related liver and non-liver diseases. A few links to learning activities for anyone contemplating treatment with triple therapy and a recent report on the promise of interferon-free therapy.

Spontaneous Clearance

1999 - 2000
Irish women - German women

Early research found the rates of viral clearance in the Irish women were high. Out of the 704 young Irish women infected research from (Kenny-Walsh 1999; Wiese 2000) found only 390 or 55% had detectable HCV RNA. The remaining 45% were HCV-antibody-positive, but had no detectable viremia. Wiese and colleagues observed similar rates of viral clearance among young women in the cohort of 917 German women. Of the 85% (779/917) with antibodies to hepatitis C, only 55% (428/779) had detectable HCV RNA.

Current Research

IL28B, HCV genotypes, sex linked to spontaneous acute HCV clearance 
August 9, 2013

A recent study reported female patients and those with HCV genotype 1 and/or IL28B CC genotype were more likely to experience spontaneous clearance of acute hepatitis C infection. Commentary on the study is available online at Healio.


Irish Women

Pregnancy and pregnancy outcome in hepatitis C type 1b

Full Text Published in QJM (July 2000)
Oxford Journals

The introduction of anti‐D immunoglobulin has proved extremely effective in the management of rhesus haemolytic disease, with deaths attributed to rhesus immunization falling dramatically from 46 per 100 000 births before 1969 to 1.6 per 100 000 in 1990.17 While intravenous immunoglobulin was thought to be a relatively safe product,18 there have been two reported epidemics of hepatitis C as a result of its use. Two distinct cohorts of Irish women became infected following exposure to contaminated anti‐D immunoglobulin in 1977/8 and 1991/3, respectively.1 Intravenous anti‐D immunoglobulin was implicated in the large scale transmission of hepatitis C in the former East Germany in 1978.19 
Production of anti‐D immunoglobulin in Ireland was commenced by the Blood Transfusion Service Board (BTSB) in 1970. Freeze‐dried intravenous anti‐D immunoglobulin was prepared from plasma containing a high concentration of anti‐D antibody procured in Ireland by the Hoppe method.20 The Hoppe method was refined in 1972, with the main objective of increasing the volume of anti‐D produced. The 1972 method replaced the process of ethanol precipitation with an ultrafiltration step, and also involved a quarantine period of 6 months before using plasma for the preparation of anti‐D. Hoppe believed that by pooling and fractionating only those plasmas which had been stored at least 6 months at −40°C provided a further safeguard against transmitting hepatitis. He believed that storing the plasma until the donor had been examined and repeatedly tested would provide further protection. However, modification of the Hoppe method21 in 1972 was not implemented by the Irish BTSB. 
We have studied women who were primipara and received contaminated anti‐D immunoglobulin post delivery in 1977/8. This represents a unique group of patients for whom the source and time of infection are clearly defined. While mindful of the relatively small size of the study group, we have found no evidence of either an increased risk of miscarriage or an adverse effect on subsequent pregnancies. Indeed in the general population, the incidence of spontaneous miscarriage has been estimated at 15–20% of all pregnancies,22 as compared with just 12.4% in the study group. Our study indicates that obstetric intervention and mode of delivery (including normal vaginal delivery, forceps/vacuum delivery and caesarean section) is not significantly influenced by the presence of HCV infection. Our study also shows that HCV infection does not increase the risk of obstetric complications and obstetric interventions. 
The favourable outcome of pregnancy and the low transmission rate of HCV may be explained partially by the endogenous production of interferon (IFN). Evidence of this production is indicated by findings from a number of studies. For example, the human placenta has been demonstrated to be a site of IFN manufacture.23 Interferon activity has also been detected in human amniotic fluid,24,,25 in placental blood26 and in perfused placenta.27 Immunohistochemical studies have demonstrated IFNs in feto‐placental units.28 
Vertical transmission of HCV occurred in one pregnancy in the study group. While we noted two major congenital abnormalities in the affected group, the number of cases is too small to test any hypothesis as to the possible role of HCV infection.  

Continue to full text.......

Current Research 

Mother to child vertical transmission

Chronic HCV infection: epidemiological and clinical relevance
BMC Infectious Diseases 2012, 12(Suppl 2):S2 doi:10.1186/1471-2334-12-S2-S2
Published: 12 November 2012

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. The role of elective cesarean section to reduce mother-to-child transmission rates is debated and controversial and the guidelines of the European Association for the Study of the Liver (EASL) does not recommend cesarean section to prevent HCV vertical transmission...........

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

*The risk is 2–3 times greater if the woman is coinfected with HIV.

Irish Women

21/22 years of infection

Published in GUT (February 2001)

An international peer-reviewed journal 

The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection 
The aim of this study was to investigate some of the unresolved issues regarding the natural history of HCV infection in a representative subgroup of women (with chronic infection or spontaneous self limited infection) derived from the Irish cohort. The clinical and histological status of these women was investigated at the time of diagnosis in 1994/95 and after 4–5 years of follow up (21/22 years after inoculation). Other features investigated included: symptomalogy, psychosocial impact of HCV infection, extrahepatic manifestations, and HLA class II associations. 

Discussion Only

Full Text Available Here 

This study investigated the natural course of HCV genotype 1b infection in a representative subgroup of a larger homogenous cohort (n=795) who were infected with HCV via contaminated anti-D immunoglobulin in 1977.5 The 87 women with chronic HCV infection and 68 with spontaneous viral clearance described in this study shared similar ethnic origin, sex, demographic characteristics, duration of disease, mode of acquisition, viral genotype, and lacked other possible causes of liver disease. A benign course of HCV infection, lack of disease progression, and low incidence of extrahepatic manifestations were observed in women with chronic HCV infection after a 22 year period.  
This benign and non-progressive course of chronic HCV infection was reflected clinically in the mildly elevated serum ALT activity at presentation (17 years after inoculation) (mean 50.6 (31) IU/l) and after five years of follow up (mean 51 (37.5) IU/l). Similarly, the mild histological activity observed at presentation was reflected in the mean HAI and fibrosis scores of 4.1 (1.4) and 1.1 (1.3), respectively. Histological deterioration was not observed after a five year follow up period as the mean follow up HAI and fibrosis scores were 4.1 (1.2) and 1.0 (1.0), and 22.7% (10/44) of biopsies even showed a spontaneous reduction in HAI score.19 Cirrhosis or hepatocellular carcinoma was not observed on the first or subsequent liver biopsy. These results confirm the findings of fellow investigators on Irish anti-D patients showing lack of disease progression over similar time spans but conflict with other studies observing significant fibrosis, cirrhosis, and advanced liver disease within 20 years of disease duration.6 19-26 Several variables have been suggested to influence the progression of HCV, including older age at infection and diagnosis, male sex, excess iron, increased alcohol consumption, and coinfection with hepatitis B virus and human immunodeficiency virus.27-33 Mode of transmission is also thought to be important as patients infected via transfusion receive a more infectious inoculum while those who acquire HCV via anti-D immunoglobulin receive a partially attenuated virus.34 The relatively young age (late 20s) of the women in this study at infection, together with the mode of transmission, and absence of excess alcohol consumption, iron on liver biopsy, and coinfection with other viruses probably contributes to the favourable outcome observed in this unique cohort. 
Sixty eight females considered to have spontaneous viral clearance were also investigated in this study. Of these, 32 (47.1%) were still antibody positive 18 years after inoculation. Debate exists as to whether these individuals have truly resolved infection or actually have current infection undetectable in serum but detectable in liver (as viral levels have been demonstrated to be 104-fold higher in the liver than in serum). Furthermore, it has been demonstrated in two separate studies that antibody positive serum PCR patients have similar clinical, histological, and virological profiles as serum PCR positive individuals.35-39 In this study, the mean serum ALT was significantly lower in PCR negative women compared with PCR positive women (p=0.000) (table 3). Similarly, the mean HAI and fibrosis scores of the 27 (40%) PCR negative women who underwent liver biopsy were also significantly lower than those of PCR positive women (p=0.000) (table 3). Furthermore, HCV RNA was not detectable in liver biopsies from serum PCR negative women but was detectable in biopsies from all serum PCR positive women, thus providing evidence that the negative serum PCR status is indeed a true reflection of cleared past infection. Steatosis was however observed at a higher frequency in PCR negative liver biopsies (48%v 10.3% in PCR positive biopsies; p=0.000). In a recent study of a larger group of serum PCR negative individuals, we have demonstrated that 63.6% (21/33) were overweight or obese, as determined by calculation of body mass index, and the histological findings of these women were more suggestive of non-specific reactive changes, steatosis, or non-alcoholic steatohepatitis rather than chronic HCV.40 
The 68 women with viral clearance described in this study represent a subgroup of a much larger group with spontaneous viral clearance. The findings from the total infected cohort from 1977 (n=704) may therefore indicate that more individuals spontaneously clear HCV than previously reported, as 314 (45%) of the original cohort were antibody positive but PCR negative for HCV RNA when tested in 1994.4 5Moreover, an additional 74 recipients of 1977 contaminated anti-D volunteered a history of jaundice shortly post partum and are now known to test both antibody and PCR negative.5 In this (table 1) and in another Irish study, a history of acute icteric hepatitis after inoculation has been demonstrated to be associated with spontaneous viral clearance.41 Why such a large proportion of women spontaneously cleared infection while the remainder went on to develop chronic HCV is unclear as the difference in disease outcome cannot be accounted for by differences in age, sex, source/duration of infection, size of inoculum, or alcohol consumption. These findings may therefore suggest that immune-host factors play an important role in the spontaneous clearance of HCV, and in this study the class II DRB1*01 allele was significantly increased in women with spontaneous viral clearance compared with those with chronic HCV infection. These results confirm the findings of a previous study on a larger cohort of these patients and also the findings of two other studies of separate groups of women from the same homogenous cohort.14 42 43  
A wide spectrum of extrahepatic manifestations has been traditionally ascribed to chronic HCV infection, with varying strengths of association. The best described of these include cryoglobulinaemia, sicca complex, autoimmune thyroiditis, membranoproliferative glomerulonephritis, and porphyria cutanea tarda.44-46 In our experience, cryoglobulinaemia is the most common of these HCV associated autoimmune disorders. Our observed prevalence rate of 12.7% among PCR positive patients and 0% among PCR negative patients further supports the role of the HCV virus in the pathogenesis of cryoglobulinaemia. In keeping with observations made in Britain, type 3 cryoglobulinaemia was the predominant type.47 However, we have previously demonstrated that Irish anti-D/HCV patients without cryoglobulinaemia were as likely to experience significant fatigue as those with cryoglobulinaemia.15 Tranet al reported a high prevalence of thyroid autoantibodies among patients with chronic HCV infection but did not include the known prevalence rate in healthy controls for comparison.48 The well conducted Wickham survey designed 20 years ago and recently updated provided an ideal sex matched population in the community for this purpose.16 17 Our surprising finding of significantly less autoimmune thyroid disease among the PCR positive population compared with that observed in the Wickham survey does not support the earlier investigators' claims. The observed prevalence rate of thyroid autoantibodies among our PCR negative group may mirror the prevalence among healthy women in the community. Indeed, current studies have failed to establish an association between autoimmune thyroid disease and hepatitis C.49 50 It is likely that the only significance of thyroid autoantibodies in patients with HCV lies in their positive predictive value for interferon associated thyroid dysfunction.51 
Glomerulonephritis and HCV dermopathy, including porphyria cutanea tarda and lichen planus, and antibodies to liver-kidney microsome 1 were not detected in this study group.  
Initially the symptom profile of the PCR positive and negative women presented in this study (PCR positive patients were found to have fewer complaints of fatigue and arthralgia than PCR negative patients at presentation) was contrary to what might be expected, but when calendar year was taken into account there were no differences in complaints of fatigue between the two groups. This observation, together with the psychological profile of 66 of these women, suggested that when suddenly diagnosed with chronic HCV the identity of this illness as chronic, infectious, and associated with intravenous drug misuse may have caused great concern to the infected women. The impact of such a diagnosis on psychological well being may have been even further compounded by the high legal profile related to this patient group.5 While accepting the uniqueness of this patient cohort, recent studies in other patient cohorts have also documented problems in quality of life and mental health.52-54  
In conclusion, this study investigated the natural course of HCV infection in a homogenous cohort almost half of whom now have spontaneous viral clearance. A benign course of HCV genotype 1b infection, lack of disease progression, and low incidence of extrahepatic manifestations was observed in women with chronic HCV after a 22 year period. The host HLA class II DRB1*01 allele was found to be associated with spontaneous viral clearance which supports the notion that host factors may play an important role in disease outcome. Finally, although the outcome of HCV infection was favourable, this study also demonstrated that the diagnosis of HCV was a very stressful event for these women who reported high levels of psychological distress and poor quality of life. It is hoped that longer term follow up of this unique cohort may further provide valuable information regarding the natural course of HCV infection.

Continue reading.....

2005 - German cohort of women after 25 years of infection

While reviewing the research the reader can not help but notice in both groups of women the severity of liver disease increases with the duration of infection. A comment from Atif Zaman, MD, MPH, (provided below) published in the 2005 October issue of Journal Watch, noted in the German cohort of women - after 25 years of infection - the rate of progression to cirrhosis increased during the last 5 years of the study.  It's worth noting the women had few coexisting medical conditions and alcohol consumption was minimal. In that, the outcomes in the cohort cannot be generalized to all HCV patients, Zaman concluded in his comment.

Published in the Journal of Hepatology (October 2005) researchers wrote:

One can conclude that a woman infected with HCV in her mid-20's has a near 50% chance of spontaneous recovery and in those with persistent infection, there is only a 5% probability of developing bridging fibrosis, cirrhosis or HCC during the first 25 years of infection


HCV Natural History: study in women exposed to HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany in 1978-79

Published in Journal Watch Gastroenterology October 25, 2005

Slow Rate of Disease Progression in HCV-Positive Women

Most data on the natural history of hepatitis C virus (HCV) infection are retrospective and suggest that progression to cirrhosis occurs during 20 to 30 years. In this prospective study, researchers reported 25-year outcomes in a cohort of women in East Germany who acquired HCV infection from a single-source outbreak of contaminated anti-D immunoglobulin in 1978 and 1979.  
Researchers reexamined 1980 women from 15 medical centers (70% of the initial cohort). Mean age at infection was 24; 9.7% of women were obese, and 2.6% had diabetes. Only 3% drank more that 40 g of alcohol daily, and 42% did not drink alcohol at all.  
After 25 years, 62% of patients complained of constitutional symptoms, such as headaches, myalgias or arthralgias, and fatigue. Overall, 54% had cleared the virus (48% spontaneously and 6% in response to interferon). Only 9 patients (0.5%) had developed overt cirrhosis, 30 patients (1.5%) had developed advanced fibrosis, and 1 patient had developed hepatocellular carcinoma. Of the 10 patients who had died of HCV-related complications, half had comorbidities (e.g., alcohol abuse). The rate of disease progression increased slightly between the 20-year and the 25-year follow-up evaluations: During these last 5 years, six women developed cirrhosis, and nine developed advanced fibrosis. 
Comment: In this unique cohort of HCV patients with known dates of infection, the overall rate of disease progression during 20 years was low. However, because the women had few comorbidities and minimal alcohol consumption, the outcomes cannot be generalized to all HCV patients. The rate of progression to cirrhosis increased during the last 5 years of the study.

-Atif Zaman, MD, MPH


HCV natural history: The retrospective and prospective in perspective

Journal of Hepatology
Volume 43, Issue 4 , Pages 550-552, October 2005

The key word in this Editorial, Ôiatrogenic,' is derived from the Greek Ôiatros' meaning physician and Ôgenic' meaning Ôproduced by' or Ôrelated to.' In addition, in current usage, an iatrogenic occurrence must be unintended. Thus, the Merriam Webster definition of iatrogenic is, Ôinduced inadvertently by a physician, surgeon, medical treatment or diagnostic procedure'. Two almost identical and temporally related inatrogenic events involving HCV-contaminated lots of Rh immunoglobulin occurred in Ireland and Germany in the late 1970's. Thousands of women were inadvertently infected with HCV and these Ôexperiments in nature' have, through diligent investigation and long-term follow-up, provided enormous insights into the natural history of HCV infection. 
The long-term outcomes of HCV infection have had differing interpretations during the decades since the predecessor virus, non-A, non-B, was first recognized [1]. In the 1970's, non-A, non-B hepatitis (NANBH) was viewed by many as an asymptomatic illness of minor consequence; some considered it merely a non-specific transaminitis. However, as these cases were followed prospectively, it became clear that as many as 20% evolved into cirrhosis [2]. This dramatic outcome stimulated clinical interest in NANBH and in the 1980's increasingly dire reports of severe outcomes emerged. In a now classic study by Tong et al. [3] 46% of post-transfusion hepatitis cases had biopsy evidence of cirrhosis and 11% had hepatocellular carcinoma. However, this and similar severe outcome data in the 1980's, reflected referral bias rather than worsening prognosis. Because of early treatment trials and the emergence of specialized hepatitis centers, the most severe cases of NANBH were being referred and then reported. This is not to impugn the relevance of these observations because Ôa case of cirrhosis is a case of cirrhosis' whether it is found prospectively or retrospectively and confirms that dire outcomes can be part of the natural history of HCV infection. However, such retrospective studies do not provide perspective on the proportion of infected individuals who will manifest these severe outcomes over the lifetime of their infection. In the early 90's, after the monumental cloning of HCV by Houghton and associates [4] and the development of sensitive assays to detect antibody to HCV [5], it became possible to introduce an alternate study design (retrospective-prospective) that allowed testing of unselected samples from decades-old serum repositories and then recall of infected patients and controls to assess outcomes over intervals that that extended from 20 to 45 years. These retrospective-prospective studies, free of selection bias, provided several key insights into the natural history of HCV infection. First, it was observed that the spontaneous recovery rate was higher than previously reported and might approach 25% in adults [6]. Other cohort studies have shown spontaneous recovery rates in children [7] and in some adults [8] to be as high as 45-55%, respectively. The other major finding of retrospective-prospective studies that included liver biopsy data was that the incidence of cirrhosis after approximately 20 years was lower than 15% and sometimes less than 5% and that HCV-related mortality over 20 years only marginally differed from that in uninfected controls [6]. In one, albeit small, study of persons infected as young military recruits, the frequency of cirrhosis after almost 50 years was only 6% [9]. Hence, the outcome of hepatitis C, both in terms of spontaneous recovery and severity, tended to ameliorate as one studied defined cohorts rather than referral cases. 
The ideal study to assess HCV natural history is one in which the onset of infection is precisely defined, the infection emanates from a single identified source, where case ascertainment is high, the study population is large, and where follow-up is prospective, comprehensive and of long-duration. Such an idealized combination of study parameters is very difficult to achieve since acute HCV infection is rarely identified, since large common-source outbreaks are unusual and since long-term prospective studies are difficult to support. The iatrogenic outbreaks of hepatitis C related to contaminated Rh immune globulin, though tragic in their occurrence, provide almost all the elements of the perfect natural history study. This is well exemplified in the 25-year follow-up data of Wiese and co-workers [10]. Basically in 1978-79, 14 batches of HCV (genotype 1b)-contaminated Rh immunoglobulin were administered to 2867 women in East Germany. The investigators were able to trace and then follow 1980 women representing 70% of the exposed cohort. Importantly, there was no selection of participants based on outcome, but solely on whether they could be located and were willing to participate in the study. The major findings in this study are highly relevant to HCV natural history assessment and can be summarized as follows: (1) 7% of those with a documented parenteral exposure did not manifest either biochemical or serologic evidence of HCV infection; it is unclear why this sizeable proportion were protected from this highly infectious inoculum and further genetic, molecular and immunologic study of these patients is warranted; (2) of 1718 untreated subjects, a remarkable 49% (836 patients) spontaneously recovery from their HCV infection as evidenced by normal ALT and the absence of HCV RNA; (3) the spontaneous recovery rate was higher in patients who were jaundiced during their acute hepatitis compared to those who were symptomatic but anicteric and those who were asymptomatic (66% vs., 46% vs. 45%, respectively; P<0.001); (4) of the 868 (51%) who developed chronic hepatitis C, 683 were untreated allowing for assessment of natural history over the 25-year duration of the study. Over this prolonged span, only 9 (1.3%) developed cirrhosis, 1 (0.1%) developed HCC and 30 (4.4%) had significant fibrosis that might evolve to cirrhosis; HCV-related mortality was 0.35%; (5) Although <5% progressed to severe fibrosis between years 15 to 25, the trend to escalating severity with increasing time from disease onset was significant by linear regression analysis. 
As an epidemiologic aside, in the absence of an iatrogenic transmission, it is now quite rare in Germany or other industrialized nations to be exposed to HCV because the blood supply has been protected, because occupational exposures have been minimized and because sexual and perinatal transmissions are rare. New HCV infections in the developed world are now almost exclusively in persons who put themselves at risk through shared needle exposures in the course of intravenous drug abuse. Further prevention is more a sociologic issue than a medical issue. The situation is different in developing nations where traditional risks are still prevalent. 
In sum, from the study of Wiese et al. [10] and a similar study in Ireland [11], one can conclude that a woman infected with HCV in her mid-20's has a near 50% chance of spontaneous recovery and in those with persistent infection, there is only a 5% probability of developing bridging fibrosis, cirrhosis or HCC during the first 25 years of infection. These relatively benign outcomes are quite encouraging, but this population represents a best-case scenario because of the young age and general good health at the onset of infection, and the rarity of co-morbid factors. Risk might increase slightly in males and would increase significantly in those infected at ages beyond 40, those with immunodeficiency states, those with excessive alcohol intake and perhaps those with high body mass index. Nonetheless, the 25-year outcome in the natural history of HCV infection is one of higher than expected spontaneous recovery and lower than predicted morbidity and mortality. In addition, one can now anticipate that 50% of those with genotype 1 or 4 infection and 80% of those with genotype 2 or 3 infection can be Ôcured' by combination treatment with pegylated interferon and ribavirin. Hence, if one conservatively assumes a 25% spontaneous clearance rate, a mild, non-progressive course in 20% of those chronically infected and a 50% sustained treatment response, one can estimate that in immune-competent persons acutely infected with HCV, the probable lifetime risk of severe liver disease will be less than 30%. This percentage will continue to diminish as therapies improve. While these numbers are encouraging and give reasonable hope to the individual patient who has access to treatment, they do not address the global burden of HCV infection. It is estimated that 170 million persons worldwide are chronically infected with HCV, most of whom reside in developing nations and many of whom may be coinfected with HIV and/or HBV and have very limited access to treatment. Even if only 10% of such individuals advanced to cirrhosis, the global burden of this infection is staggering. Thus HCV, like HIV, is a disease of two worlds, one where new infections are rare and effective treatments are available and one where high population density, inadequate preventive strategies and inaccessible treatments maintain HCV as a common disease with devastating consequences. It is a ÔTale of Two Cities' and we must address them both with equal measure.

Current Research

Chronic HCV infection: epidemiological and clinical relevance
BMC Infectious Diseases 2012, 12(Suppl 2):S2 doi:10.1186/1471-2334-12-S2-S2
Published: 12 November 2012


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.

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

Current Research 

JAMA - Deaths from liver disease increased from 1990 to 2010

According to a July 10, 2013 article published in the JAMA Journal of The American Medical Association – “The State of US Health, 1990-2010: Burden of Diseases, Injuries, and Risk Factors” – deaths from liver disease increased from 1990 to 2010. Liver disease also rose as a contributor to premature mortality. The most common causes of both cirrhosis and liver cancer are viral hepatitis, alcoholism, and obesity-related fatty liver disease. However, it is hepatitis C that is the most likely cause of the emergence of liver disease as a growing threat to American lives, according to a recent comment in this AASLD press release.

The report in JAMA is the first comprehensive analysis of disease burden in the United States in more than 15 years. It includes estimates for death and disability from 291 diseases, conditions, and injuries as well as 67 risk factors

Additionally, NATAP reported the rates of liver cancer in the U.S. more than doubled between 1990 and 2010 while deaths resulting from cirrhosis jumped 43 percent, slides and data available @ the National AIDS Treatment Advocacy Project (NATAP).

Current Research 

German cohort 35 years of infection

Mild but significant disease progression at 35 years after infection
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

Evaluation of liver disease progression in the German HCV (1b)-contaminated anti-D cohort at 35 years after infection

Manfred Wiese1,*, Janett Fischer2, Micha Löbermann3, Uwe Göbel4, Kurt Grüngreiff5, Wolfgang Güthoff6, Ulrike Kullig7, Franziska Richter1, Ingolf Schiefke8, Hannelore Tenckhoff2, Alexander Zipprich9, Thomas Berg2,†, Tobias Müller2,‡, for the EAST GERMAN HCV STUDY GROUP‡

Accepted manuscript online: 8 AUG 2013 07:53AM EST | DOI: 10.1002/hep.26644

The natural course of HCV infection remains controversial. The German HCV (1b)-contaminated anti-D cohort provides an ideal population to investigate the natural course of HCV infection in a large and homogenous cohort of young women from the date of HCV inoculation.  
Our previous follow-up studies at 20 years and 25 years after infection suggested slow fibrosis progression rates in this unique cohort.  
The aim of our prospective community-based multicenter study was to re-evaluate the liver disease progression in 718 patients of the original anti-D cohort at 35 years after infection.  
Patients with self-limited HCV infection (n=189) were compared to those who failed to eliminate the virus spontaneously (n=529), comprising patients who were treatment naive (n=197) or achieved a sustained virological response (SVR, n=149) respectively failed to clear the virus (non-SVR, n=183) after antiviral therapy.  
In the overall cohort, 9.3% of patients showed clinical signs of liver cirrhosis at 35 years after infection. Liver disease progression largely depended on the HCV infection status. The highest proportion of patients with clinical signs of end-stage liver disease was observed in the non-SVR group (15.3%), whereas decreased cirrhosis rates were detected in the SVR group (6%) and in patients with self-limited HCV infection (1.1%, p=6.2x10−6).  
Overall survival was significantly enhanced following SVR compared to treatment naive patients or non-SVR (p=0.027).  
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.

(Hepatology 2013; 00:000-000)

Current Research 

In a study, published online in the August 15th 2012 edition of the Journal of Infectious Diseasesresearchers found increased deaths from both liver-related and non-liver related diseases in patients with active infections who had not cleared their infection

Except from the 2012 press release

The study, published in the Journal of Infectious Diseases and available online, found increased mortality in patients with chronic HCV infection—that is, with detectable levels of HCV genetic material, or RNA, in their blood—suggesting that chronic HCV infections, even in people who have no symptoms, can lead to increased mortality from liver disease or a variety of other causes. The findings highlight the importance of people getting tested for HCV antibodies and for active HCV infection—and of evaluating patients for antiviral treatment when they are found to have an active HCV infection, even when they feel well.  
Chien-Jen Chen, ScD, and researchers from the Genomic Research Center in Taipei, Taiwan, enrolled more than 23,000 adults in Taiwan in their study and followed them from 1991 to 2008. Blood samples were collected at study entry and at follow-up health examinations. Researchers found increased mortality from liver-and non-liver-related diseases—including cancers of the esophagus, prostate, and thyroid, as well as circulatory and renal diseases—among those infected with HCV. Mortality was higher in HCV-infected participants with detectable serum levels of HCV RNA, indicating they had active infections; subjects with previous infections who only had HCV antibodies, but not HCV RNA, in their blood did not have increased mortality on follow-up. The study, published in the Journal of Infectious Diseases and available online, found increased mortality in patients with chronic HCV infection—that is, with detectable levels of HCV genetic material, or RNA, in their blood—suggesting that chronic HCV infections, even in people who have no symptoms, can lead to increased mortality from liver disease or a variety of other causes. The findings highlight the importance of people getting tested for HCV antibodies and for active HCV infection—and of evaluating patients for antiviral treatment when they are found to have an active HCV infection, even when they feel well.

Full text can be found online here, press release here.

Current Research 

SVR reduced all-cause mortality risk in patients with HCV, advanced fibrosis
Van der Meer AJ. JAMA. 2012;308:2584-2593.
December 26, 2012

Patients with chronic hepatitis C and advanced hepatic fibrosis were less likely to die from any cause or from liver-related issues after achieving sustained virologic response to interferon-based therapy in a recent study 
In an international, multicenter study, researchers evaluated 530 patients with chronic HCV and cirrhosis or advanced fibrosis (defined as Ishak scores between 4 and 6), who received interferon-based treatment between 1990 and 2003. Incidence of all-cause or liver-related mortality, liver failure, hepatocellular carcinoma (HCC) and liver transplant was recorded over a median of 8.4 years of follow-up. 
Sustained virologic response (SVR) occurred in 36% of cases, including 125 participants who achieved SVR with initial treatment and 67 who experienced SVR with retreatment after a median of 5.8 years. 
During follow-up, 113 participants died, including 13 who achieved SVR. Investigators noted a significant difference in the 10-year cumulative all-cause mortality rates for the groups (8.9% for patients who achieved SVR vs. 26% for those who did not, P<.001). 
Liver-related death occurred in three SVR cases and 70 non-SVR cases, and liver transplant was not required for patients who achieved SVR. Transplant was necessary for 46 patients without SVR (including 13 who subsequently died). Researchers calculated 10-year cumulative liver transplant or liver-related mortality incidence rates of 27.4% for patients who did not achieve SVR and 1.9% who did. HCC occurred in seven SVR cases and 76 non-SVR cases, for cumulative incidence rates of 5.1% and 21.8%, respectively. Four SVR patients experienced liver failure compared with 111 without SVR, with incidence rates of 2.1% and 29.9%, respectively (P<.001 for all comparisons). 
Multivariate analysis indicated associations between SVR and reduced risk for all-cause (HR=0.26, 0.14-0.49) and liver-related mortality or liver transplant (HR=0.06, 0.02-0.19). Patients who achieved SVR also were less likely to develop HCC (aHR=0.19, 0.08-0.44) or liver failure (aHR=0.07, 0.03-0.20) (95% CI for all). 
“Our study indicates that SVR was associated with improved overall survival in patients with chronic HCV infection and advanced hepatic fibrosis,” the researchers concluded. “In addition, we were able to further establish and quantify the risk reduction of HCC, liver failure and liver-related mortality or liver transplantation in patients with SVR.”

Disclosure: See the study for a full list of relevant disclosures
Source - Healio

Current Research 

Long-term Outcome of Chronic Hepatitis C After Sustained Virological Response to Interferon-based Therapy
C. Koh, T. Heller, V. Haynes-Williams, K. Hara, X. Zhao, J. J. Feld, D. E. Kleiner, Y. Rotman, M. G. Ghany, T. J. Liang, J. H. Hoofnagle

Aliment Pharmacol Ther. 2013;37(9):887-894.
May 7 2013


The initial 5 of 10 patients treated with antiviral therapy in 1986 at the NIH for chronic HCV achieved an SVR and had both biochemical and histological evidence of improvement in the year following treatment. These five patients have now been followed up for more than 20 years and remain HCV RNA-negative and have normal or near-normal serum enzyme levels.  
Liver biopsies on these patients 10 years after initial therapy showed resolution of the disease activity and regression of fibrosis in some. After this initial study, patients at the NIH were enrolled in various therapeutic trials for chronic hepatitis C. As of 2003, a total of 103 patients had achieved an SVR, all in response to interferon-based therapy. The duration of subsequent follow-up in these 103 patients varied from a few months to as long as 23 years. In this cohort, three patients relapsed, and the remaining 100 patients had markedly improved liver tests at the time of follow-up evaluation and none had clinical evidence of advanced cirrhosis, hepatic decompensation or end-stage liver disease.  
These findings indicate that an SVR from interferon-based therapies for chronic HCV is usually durable and associated with improvement in biomarkers of disease, a favourable long-term prognosis and lack of evidence of progression of liver disease. 
Similar findings after SVR in chronic HCV have been published in other cohorts. However, the current analysis extends this experience to more than 20 years after therapy. Importantly, while patients who achieved an SVR did not develop progressive liver disease, at least one case of HCC still occurred. In this cohort, one patient who had cirrhosis before treatment developed HCC despite having had an SVR 12 years previously. The occurrence of HCC after SVR has been reported in several cohorts, although the rate of liver cancer appears to be far less than occurs among untreated patients with advanced fibrosis or cirrhosis due to chronic hepatitis C. Such findings suggest that patients with an SVR should continue to have regular surveillance for HCC if they had histological evidence of cirrhosis before treatment. 
A shortcoming of this study is the lack of a control group of patients with chronic hepatitis C who were not treated or a comparison group of patients who were treated but did not achieve an SVR. However, it was not feasible or considered ethical to randomise patients to therapy vs. no therapy and follow them for an indefinite period. In early controlled trials of interferon for hepatitis C, some patients were not treated for the initial 1–2 years after randomisation. However, the controls from those studies were subsequently offered therapy on an open-label basis and some achieved an SVR and are a part of this analysis. Since 1992 and the approval of interferon as therapy of hepatitis C, all large 'controlled' trials of treatment have compared one interferon-based regimen to another and patients were not given placebo or randomised to no therapy. 
Another approach to assessment of the possible benefit of an SVR is to compare patients who achieve an SVR to those who relapse or do not respond. However, multiple studies have shown that patients who have an SVR have a durable loss of HCV RNA and are less likely to have advanced fibrosis or cirrhosis. For these reasons, such comparisons require careful balancing of risk factors. Among the 262 patients treated in at this centre, the majority of the non responders were retreated at one time or another, with differing regimens and often at different institutions. 
Use of transient elastography, a non-invasive marker for hepatic fibrosis, suggested that 41% of the cohort had residual evidence of fibrosis at the time of last follow-up 3–23 years after SVR. The elevated elastography scores were not associated with residual abnormalities of serum aminotransferase levels but were more likely to be abnormal in patients who had advanced fibrosis or cirrhosis before treatment.  
This suggests that some degree of fibrosis persists despite the resolution of disease activity as assessed by serum enzymes. Slight decreases in platelet counts at the time of final follow-up also correlated with the initial liver histology. Elastography scores were not available from before treatment, but improvements in other markers of advanced disease (platelet count, direct bilirubin, immunoglobulin levels) suggest that SVR may be associated with subsequent improvement in portal hypertension and perhaps partial regression of fibrosis. These findings suggest that the greatest benefit from successful eradication of HCV may be in non-cirrhotic patients, but that even patients with advanced disease, gain a benefit from treatment. 
In summary, with continued follow-up of patients with chronic hepatitis C for up to 23 years after achieving sustained clearance of HCV RNA, progressive liver disease was not seen. Among patients who had advanced fibrosis and cirrhosis before being treated, evidence from platelet counts and transient elastography suggested the persistence of some degree of hepatic fibrosis and a low but continued risk for HCC.

View Full Text @ Medscape

Current Research

Women With Chronic Hepatitis C Virus Infection

Southern Medical Journal 2013;106(7):422-426.
Mary Jane Burton, MD, James B. Brock, MD, Stephen A. Geraci, MD
July 24, 2013

The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited. 
Women also manifest slower progression to two major chronic HCV infection complications, cirrhosis and hepatocellular carcinoma. In a cohort of 376 Irish women chronically infected with HCV from contaminated anti-D immunoglobulin, only 1.9% had progressed to histological cirrhosis after a mean of 17 years following exposure. The low rate of fibrosis progression was confirmed in a 25-year follow-up study of 167 women, of whom 1.2% developed histological cirrhosis.  Male sex was identified as an independent risk factor for developing hepatocellular carcinoma in several studies. This sex-specific predilection for complications of liver disease is not completely understood. Some experts posit that higher estrogen states exert a protective effect on the liver. Animal models suggest that estrogen suppresses hepatic fibrosis, and a recent in vitro study proposed that estrogen inhibits the production of HCV virions. Multiparous women exhibit lower stages of fibrosis than nulliparous women, and fibrosis progression accelerates after menopause. In observational studies, women who received hormone therapy (HT) appeared to have a slower progression to fibrosis; however, the benefits of HT in women with HCV have not been established. HT appears to be safe in women with liver disease when indicated for other reasons.

Complete article and additional information on Women and HCV found here.

Article Source - Medscape

2013 - Treatment Updates

Progress in Treating Hepatitis C Infection

June 6 2013

Video - Hepatitis C: The Pace of  Progress
In recently published studies, sofosbuvir combined with ribavirin alone was shown to be effective for hepatitis C genotype 2 and 3 and possibly genotype 1. This regimen offers a low incidence of side effects, a relatively short duration of treatment, and was effective against all genotypes. These advantages may lower the threshold for HCV treatment for both patients and physicians.

Source - Medscape Medical News from: Digestive Disease Week (DDW) 2013

*Free registration  required

2013 July 12

Video Vignettes -Current Outlook On Hepatitis C Treatment
The Doctor's Channel released a four part video series last month offering key information for anyone considering triple therapy. Sofosbuvir is also included in the series, as is the future of HCV therapy.

2013 "HCV Treatment Pipeline" - By Tracy Swan

Hepatitis C Drug Development Catapults Onward
By Tracy Swan

HCV Treatments in Phase II and Phase III
The Best Combinations
Interferon-Free Regimens in Development for HCV Genotype 1
Interferon-Free Regimens in Development - HCV Genotypes 2, 3, & 4
Cross-company Trials
Next in Line: Simeprevir, Faldaprevir, and Sofosbuvir
Without a PEG to Stand on: The Sofosbuvir Saga Goes on
Biting the (Magic) Bullet
Twinkle, Twinkle, Little (Lone) Star
AbbVie: All Hands on Deck
Bristol-Myers Squibb: All In!
(Genotype) 3 is the new 1
SVR in HCV Genotypes 2 and 3
Cirrhosis: From Frontier to Proving Ground
HIV/HCV Coinfection
Faldaprevir plus PEG-IFN/RBV
Simeprevir plus PEG-IFN and RBV
From Excess to Access
Where Should All the Research Go?
Access the report here.........

Of Interest


July 2012

(Trent HCV Study)
Adam John Lawson
BMedSci, BM, BS, MMedSci (Clin Ed)
Thesis submitted to the University of Nottingham for the degree of Doctor of Medicine


Published in the 2006 issue of the International Journal Of Medical Sciences a paper on the natural history of hepatitis C discussing the virus in both acute and chronic phases, disease progression including host factors, liver fibrosis, cirrhosis, and hepatocellular carcinoma.  

Hopefully, this small summary will leave you with a better understanding of the natural history of  hepatitis C. As once a patient with hepatitis C, understanding disease progression was on the top of my list, followed by starting treatment and finally curing the virus. I achieved all three, may you all safely do the same.

Photo Credit:

Sunday, April 21, 2013

Disease progression in chronic hepatitis C patients with normal alanine aminotransferase levels

World J Gastroenterol. 2013 Apr 14;19(14):2256-2261.

Disease progression in chronic hepatitis C patients with normal alanine aminotransferase levels

Sinn DH, Gwak GY, Shin JU, Choi MS, Lee JH, Koh KC, Paik SW, Yoo BC.

Source- World J Gastroenterol
April 14, 2013|Volume 19|Issue 14|

Download Full Text Here

Dong Hyun Sinn, Department of Internal Medicine, Sanggye Paik Hospital, Inje University School of Medicine, Seoul 139-707, South Korea.

Core tip: Recent studies have indicated that the upper limit of normal for the serum alanine aminotransferase (ALT) level should be lowered. However, outcome studies based on the development of adverse events during long-term follow-up are limited. In this present study, among patients infected with chronic hepatitis C virus who had normal ALT levels, the risk of disease progression differed between patients with “high-normal” and “low-normal” ALT levels, even within the currently accepted normal levels. This finding suggests that lowering the normal threshold of ALT levels may be necessary to better identify patients who are at increased risk for disease progression.


To investigate whether the disease progression of chronic hepatitis C patients with normal alanine aminotransferase (ALT) levels differs by ALT levels.

A total of 232 chronic hepatitis C patients with normal ALT (< 40 IU/L) were analyzed. The patients were divided into "high-normal" and "low-normal"ALT groups after determining the best predictive cutoff level associated with disease progression for each gender. The incidence of disease progression, as defined by the occurrence of an increase of ≥ 2 points in the Child-Pugh score, spontaneous bacterial peritonitis, bleeding gastric or esophageal varices, hepatic encephalopathy, the development of hepatocellular carcinoma, or death related to liver disease, were compared between the two groups.

Baseline serum ALT levels were associated with disease progression for both genders. The best predictive cutoff baseline serum ALT level for disease progression was 26 IU/L in males and 23 IU/L in females. The mean annual disease progression rate was 1.2% and 3.9% for male patients with baseline ALT levels ≤ 25 IU/L (low-normal) and > 26 IU/L (high-normal), respectively (P = 0.043), and it was 1.4% and 4.8% for female patients with baseline ALT levels ≤ 22 IU/L (low-normal) and > 23 IU/L (high-normal), respectively (P = 0.023). ALT levels fluctuated during the follow-up period. During the follow-up, more patients with "high-normal" ALT levels at baseline experienced ALT elevation (> 41 IU/L) than did patients with "low-normal" ALT levels at baseline (47.7% vs 27.9%, P = 0.002). The 5 year cumulative incidence of disease progression was significantly lower in patients with persistently "low-normal" ALT levels than "high-normal" ALT levels or those who exhibited an ALT elevation > 41 U/L during the follow-up period (0%, 8.3% and 34.3%, P < 0.001).

A "high normal" ALT level in chronic hepatitis C patients was associated with disease progression, suggesting that the currently accepted normal threshold of serum ALT should be lowered.

Alanine aminotransferase, Disease progression, Hepatitis C virus, Hepatocellular carcinoma, Upper limits of normal

Follow link to full text article

Monday, July 23, 2012

NIH scientists identify likely predictors of hepatitis C severity

Monday, July 23, 2012
Contact:Nalini Padmanabhan, NIAID
(301) 402-1663
Maggie McGuire, NIH Clinical Center
(301) 594-5789

NIH scientists identify likely predictors of hepatitis C severity

Viral evolution and host protein levels predict rapid disease progression

Scientists at the National Institutes of Health have identified several factors in people infected with the hepatitis C virus that may predict whether the unusually rapid progression of disease from initial infection to severe liver conditions, such as cirrhosis, will occur. Knowing whether a patient's condition is likely to deteriorate quickly could help physicians decide on the best course of treatment.

The study was conducted by an international team of researchers led by Patrizia Farci, M.D., chief of the Hepatic Pathogenesis Section in the Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH; and Harvey Alter, M.D., chief of clinical studies and associate director of research in the Department of Transfusion Medicine at the NIH Clinical Center. Their findings appeared online July 23 in the Proceedings of the National Academy of Sciences.

“Treatment for hepatitis C is often expensive and poorly tolerated,” said NIAID Director Anthony S. Fauci, M.D. “Tools that would enable physicians to better predict the course of disease progression in hepatitis C patients would help guide treatment decisions. This small study is a potentially important step in developing such tools.”

Symptoms of acute infection with the hepatitis C virus, one of five viruses that cause acute and chronic hepatitis, include fatigue, jaundice and loss of appetite. Between 70 and 80 percent of people infected with the hepatitis C virus develop chronic infection, which over a patient's lifetime may result in severe liver diseases, such as liver cancer and cirrhosis. The World Health Organization estimates that 130 million to 170 million people live with chronic hepatitis C. Approximately 2.7 million to 3.9 million of those people live in the United States, according to the Centers for Disease Control and Prevention.

After a person is infected with hepatitis C, the virus evolves and circulates in the body in the form of several closely related strains, which allows it to adapt to drug treatments and avoid elimination. Some genetic differences between these strains result in changes to the proteins they encode, while others do not.

“A major mystery in the study of hepatitis C is that the disease course can be highly variable,” explained lead researcher Dr. Farci. “Some patients show no symptoms for decades and eventually die of other causes. Other patients rapidly develop cirrhosis and liver cancer, leading to liver-related death in less than ten years.”

Studies have found that having a weakened immune system — for example, as the result of HIV infection or organ transplantation — can exacerbate hepatitis C-related disease. But this does not fully explain which hepatitis C patients will ultimately experience a more rapid health decline. At present, there is no way to predict how the disease will progress in any given patient.

The new study involved samples collected from six patients who were infected with hepatitis C via contaminated blood transfusions in the 1970s, before the virus was identified. Blood donations have been routinely tested for hepatitis C since 1990. The patients’ symptoms and clinical outcomes were closely followed from the day they received the transfusion for up to 30 years, and ranged from mild and stable chronic hepatitis C to rapid disease progression and death.

Dr. Alter and his Clinical Center colleagues periodically collected blood serum samples from each of the six patients. Dr. Farci and her NIAID colleagues used up to 17 of these archived samples per patient to obtain and analyze a total of 1,876 genetic sequences of the hepatitis C virus. The researchers used the genetic sequences to reconstruct the evolution of two particular hepatitis C genes, E1 and E2, and the research team analyzed the types of genetic changes that took place in order to understand their relationship with disease progression. They also studied the levels of 39 blood serum proteins during the acute and chronic phases of disease.

“We thoroughly characterized the biological changes that occurred in these patients, and we discovered that patients who developed rapidly progressive disease had specific changes in their blood that were detectable since the early acute phase of infection,” said Dr. Farci. Patients with rapid disease progression had significantly higher levels of a protein known as MCP-1, which is believed to play a major role in the development of liver fibrosis, and, eventually, cirrhosis. Moreover, in these patients, the genetic changes in the virus as it evolved over time were less likely to result in changes to the virus proteins.

The researchers say genetic and blood serum markers may one day enable physicians to identify hepatitis C patients at risk for rapid progression and to use this information to adjust their treatment. Additional markers may exist, Dr. Farci explained. The research team is working to increase the sample size by doing similar analyses on the remaining stored samples.

“Now that we know what to look for, we believe it is extremely important to extend our observation to a larger number of patients,” Dr. Farci said.

NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website at

The NIH Clinical Center (CC) is the clinical research hospital for the National Institutes of Health. Through clinical research, clinician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health. For more information, visit

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

Saturday, May 5, 2012

Natural history of hepatitis C

Monday, 23 April 2012 09:20
Written by Linda McInnes

The natural history of hepatitis C virus infection begins with a generally unrecognized acute phase occurring during the initial 6 months following exposure to the virus. Acute infection may resolve spontaneously during that time, but the majority of cases progress to chronic infection. The key features of acute and chronic hepatitis C virus infection are reviewed in this section.

Primary Infection and Acute Hepatitis C
Primary infection with hepatitis C virus (HCV) is mostly asymptomatic, rendering its timely diagnosis difficult. Furthermore, some patients may be reluctant to seek medical consultation because this may involve admitting habits leading to infection, such as illicit drug use. As a result, the true incidence rate is underestimated.[Armstrong 2000; CDC 2007] Because there are no specific markers of primary HCV infection, it is diagnosed via a documented seroconversion to anti-HCV in a person who was previously anti-HCV negative, with or without an increase in alanine aminotransferase (ALT) levels. In most Western countries, when underreporting and asymptomatic cases are factored in, incidence rates may reach 15 per 100,000 per year.[Armstrong 2000] Incidence has declined during the past 20 years owing to generalized screening of blood donors and prevention measures among injection drug users. Currently, in the West, injection drug use is by far the most important factor associated with HCV transmission, although sexual transmission has recently emerged as a strong risk factor among HIV-infected men who have sex with men.[van de Laar 2010] In resource-limited countries, a high proportion of infections occur following invasive procedures or injection-based therapies with contaminated instruments.[Hauri 2004]
For more information from in Practice on transmission of HCV, click here.

Following HCV exposure, HCV RNA cannot be detected in serum until after a 1- to 3-week window (Table 8).[Santantonio 2008] The most common symptoms, when present, are fatigue, jaundice, flulike symptoms, dyspepsia, and abdominal pain, and may occur 2-12 weeks after exposure. Because most symptoms are mild and not specific, patients often do not report to their physicians. The first sign of liver injury may be evident 4-12 weeks after infection in the form of an elevated ALT level. Wide fluctuations of serum ALT are common, but severe liver damage is infrequent, and in general ALT peaks below 1000 IU/L. A fulminant course is very rare. Seroconversion may take place 4-10 weeks following HCV exposure.

Table 8. Most Common Signs and Symptoms of Acute Hepatitis C (If Present)

Time Frame, Wks from exposure Symptoms
  • Fatigue
  • Jaundice
  • Flulike symptoms
  • Dyspepsia
  • Abdominal pain
  • Seroconversion
  • Elevated or fluctuating ALT (sign of liver injury)

Acute hepatitis C has a high propensity to progress to chronicity. Chronic infection with HCV is defined by viremia persisting more than 6 months. The risk of chronicity ranges between 55% and 85%.[McHutchison 2004; Seeff 2002] However, this risk has been assessed in prospective studies in which symptomatic cases were prevalent; because a symptomatic course may be associated with increased likelihood of spontaneous resolution,[Gerlach 2003] when asymptomatic primary infections are considered, the progression to chronicity is likely to occur in the vast majority of cases. Spontaneous remission following the establishment of chronic HCV infection rarely occurs among adults,[Yoshikawa 2001] but has been reported to occur in 8% to 45% of children.[Fujisawa 1997; Iorio 2005; Vogt 1999] Table 9 lists chronicity rates by subgroup from several studies.

Spontaneous resolution most often occurs during the first 3 months of infection.[Santantonio 2006] Apart from the presence of symptoms, other factors favoring spontaneous eradication of HCV infection are host genes (IL28B polymorphisms)[Thomas 2009] and the vigor of the cellular immune response.[Santantonio 2008] Coinfection with HIV seems to hinder resolution.[Schnuriger 2009; Danta 2008] The role of the type of exposure, size of inoculum, age, sex, and previous exposure to HCV with subsequent recovery is controversial. An important aspect is that eradication, either spontaneous or treatment induced, does not confer protection, and patients (especially those with high-risk behavior) should be advised that HCV reinfection may occur.

Table 9. HCV Chronicity Rates by Subgroup

Study and Subgroup HCV Chronicity Rate, %
Gerlach et al[Gerlach 2003]
  • Symptomatic patients (n = 46)
  • Asymptomatic patients (n = 9)
Danta et al[Danta 2008]
  • HIV coinfection (n = 55)
  • No HIV coinfection (n = 8)
Thomas et al[Thomas 2009]
  • IL28B CC genotype
  • IL28B CT genotype
  • IL28B TT genotype

Chronic Hepatitis C
Chronic hepatitis C is a progressive disease, taking decades to reach the final stage of cirrhosis. The latter then may evolve toward liver failure or hepatocellular carcinoma (HCC) (~ 2% to 4% yearly) (Figure 5). The variability of progression is remarkable and influenced by several cofactors; it is indeed the combination of these factors that accounts for the extreme diversity of liver disease progression observed in chronic hepatitis C.[Poynard 1997] For example, females infected with hepatitis C virus (HCV) at a young age who did not drink alcohol developed cirrhosis in a very small proportion of cases (2%) 25 years after infection.[Wiese 2005] By contrast, 17% of males who acquired HCV via blood transfusion later in life developed cirrhosis after a comparable follow-up.[Seeff 2001]
A review of factors involved in liver disease progression among patients with chronic hepatitis C are outlined in Table 10.

The most important factor influencing liver disease progression is the extent of intrahepatic inflammation elicited by HCV.[Leandro 2006] In keeping with this finding, patients with persistently normal alanine aminotransferase (ALT) present a slow liver disease progression,[Mathurin 1998] although a small minority of them may have advanced liver disease.

Serum HCV RNA level is not associated with prognosis, at variance with other viral infections.[Bochud 2009] However, there is some evidence that genotype 3 is associated with accelerated fibrogenesis.[Bochud 2009] The risk of developing HCC was reported to be higher in HCV genotype 1b infection relative to other genotypes in a meta-analysis.[Raimondi 2009] However, other studies have not supported this association.[Yotsuyanagi 1995; Yamada 1994; Benvegnù 1997; Han 1997]

Host factors are much more relevant in determining the progression of HCV-related liver disease. Male sex is associated with accelerated fibrogenesis and HCC incidence.[Bochud 2009; Chiba 1996] However, with the onset of menopause, the rate of fibrosis progression increases substantially in women.[Di Martino 2004] Estrogen replacement therapy and the number of pregnancies may protect women from liver fibrosis progression.[Di Martino 2004] The contribution of host genes is debated and has not been clarified with the advent of powerful methods of analysis such as genomewide association studies, underscoring the multifactorial nature of liver fibrogenesis. Candidate gene–based studies have proposed single nucleotide polymorphisms or their combinations to identify patients at higher risk of progression.[Marcolongo 2009] However, the contribution of such genetic signatures seems small and overshadowed by more important cofactors. Whether race affects fibrosis progression rate is also a matter of debate. A study assessing the fibrosis progression rate in black vs white Americans failed to show a significant difference.[Terrault 2008] Age at infection affects prognosis,[Poynard 1997; Minola 2002] as persons infected with HCV at a young age, including children[Rerksuppaphol 2004] and young females,[Wiese 2005] have a reduced risk of progressing to cirrhosis, at least for the first 1-2 decades. For subsequent time points, one must keep in mind that the rate of progression is not linear and that stage-specific rates should be applied in formulating prognosis.[Poynard 2001; Thein 2008a]

Environmental factors play a major role in liver disease progression among patients infected with HCV. The most important is excessive alcohol consumption, which impacts both fibrosis progression and risk of HCC.[Poynard 1997; Tagger 1999] Tobacco smoking has been shown to be associated with increased intrahepatic inflammation (histologic activity score), which in turn was associated with increased fibrosis score.[Hézode 2003] In chronic hepatitis C, this effect seems relevant, especially for cannabis smoking.[Hézode 2005] On the other hand, several studies have shown the protective effect of coffee on both fibrosis[Freedman 2009] and HCC.[Ohishi 2008]

A worrying synergism exists between hepatitis C and the metabolic syndrome, considering the evolving epidemiology of both diseases.[Kanwal 2011] Steatosis,[Leandro 2006; Pekow 2007] insulin resistance,[Hui 2003; Hung 2010] and type 2 diabetes[Hu 2009; Veldt 2008] increase liver fibrosis progression and risk of HCC. Among metabolic disturbances, iron overload is also associated with advanced fibrosis.[Bonkovsky 2003] Coinfections are relevant due to their prevalence and synergistic effects on HCV-related morbidity. Although the effect of coinfection with the hepatitis B virus (HBV) on fibrosis is unclear, the risk of HCC in patients coinfected with HCV and HBV is significantly increased.[Tagger 1999] Large meta-analyses have confirmed that liver fibrosis progression is accelerated in patients coinfected with HIV.[Thein 2008b; Deng 2009] Control of HIV replication and immune restoration by highly active antiretroviral therapy does not seem to completely reverse this effect.[Thein 2008b]

Liver disease progression is accelerated after liver transplantation relative to nontransplant patients; a variety of diverse factors may be associated with accelerated posttransplantation fibrogenesis.[Meriden 2010]

Figure 5. Natural history of HCV infection.
[McHutchison 2004; Seef 2002; Liang 2000; Fattovich 1997]

Table 10. Relationship Between Patient Factors and Liver Disease Progression

Factor Impact on Liver Disease Progression
Intrahepatic inflammationGreater inflammation equates to greater disease progression; persistently normal ALT levels represent slower disease progression in most, but not all, cases
HCV RNA levelNot associated with disease progression*
HCV genotypeGenotype 3 appears to be associated with accelerated fibrogenesis;
risk of HCC development highest with genotype 1b
Patient sexMale sex associated with accelerated fibrogenesis and HCC incidence
After onset of menopause, rate of fibrosis progression increases in women
Alcohol consumptionIncreased risk of progression and HCC development
Tobacco smokingAssociated with increased intrahepatic inflammation and in turn with increased fibrosis
Coffee consumptionProtective against fibrosis progression and HCC
Metabolic syndromeSteatosis, insulin resistance, and type 2 diabetes increase liver fibrosis progression and HCC risk
Iron overloadIncreased fibrosis progression
HBV coinfectionIncreased risk of HCC development
HIV coinfectionIncreased fibrosis progression
Liver transplantationIncreased disease progression

*HCV RNA level was associated with spontaneous remission of chronic HCV infection among children in 1 study.[Fujisawa 1997]