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Is Cirrhosis Inevitable in HCV?
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"Prevalence of Hepatitis C-Related Cirrhosis in Elderly Asian Patients Infected in Childhood"
Clinical Gastroenterology and Hepatology
September 2005
Raymond D'Souza_ Michael J. Glynn_, Ines Ushiro-Lumb, Roger Feakins, Paolo Domizio, Lisa Mears, Elspeath Alsced_, Parvar Kumar_, Caroline A. Sabin_, Graham R. Foster_
Hepatobiliary Group, Department of Adult and Pediatric Gastroenterology, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom
Department of Virology, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom
Department of Histopathology, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom
_ Department of Primary Care and Population Sciences, Royal Free and University College Medical School, London, United Kingdom
Remember, HIV can accelerate HCV progression up to 5 times more quickly than in HCV monoinfection. It is generally accepted, as also reported from this study, that HCV progresses slowly so if you live long enough cirhhosis will develop. Therefore, HIV/HCV coinfection becomes a more deadly disease. Many more coinfected patients appear to be at risk for developing cirrhosis within a much shorter time than moninfected.
"......infection with HCV for over 60 years causes cirrhosis in 71% of infected individuals. Because relationship between the severity of fibrosis and age in Asian patients is similar to that seen in Caucasian patients it is likely that similar rates of cirrhosis will be seen in other patients who are infected for more than 60 years...."
In an Editorial below, Leonard Seef says:
"....additional studies are needed in other patient populations that overcome the design limitations of the current study and to address the alternative interpretation of the data that, although during a lifetime there might indeed be progression to cirrhosis, this might only seldom result in end-stage liver disease or the development of HCC.... if the data gathered in the study are indeed a true reflection of the long-term impact of chronic HCV infection among Asian patients, and if the findings can be extended to other populations, this would clearly indicate that substantially more, perhaps most, persons infected with HCV are likely to reach end-stage liver disease than had been thought hitherto. It also implies that treatment should indeed be universal for all HCV-infected persons, regardless of their histologic status, in the hope of blunting this progression. In addition, it raises the issue of the need for even more transplantation services to accommodate the anticipated (on the basis of this study) "epidemic" of cirrhosis-related end-stage liver disease and cancer that awaits these patients. Such conclusions are currently premature..."
ABSTRACT
Background & Aims: Approximately 20% of hepatitis C virus (HCV) patients develop cirrhosis from infection after about 20 years. The proportion of patients developing cirrhosis for longer than 30 years after infection is unknown. Our objectives were to determine the prevalence of HCV-related cirrhosis in a population of Asian patients who were infected in childhood 20 to 80 years ago and compare this with the prevalence of cirrhosis in Caucasian patients referred to the same hospitals.
Methods: Retrospective analyses were performed of all patients who had detectable HCV-RNA levels and who attended local hospitals in northeast London between 1992 and 2003. Factors implicated in the development of cirrhosis were examined by multivariable analysis.
Results: A total of 143 adult Asian patients who had been infected with HCV for many decades were compared with 239 Caucasian patients. The prevalence of cirrhosis increased with age. Of Asian patients aged 61-80 years (n = 55) 78% had cirrhosis, whereas 25% of Caucasian patients aged 61-80 years (n = 55) had cirrhosis. Multivariable linear analysis revealed that fibrosis progression and age were similar in both groups and the difference in the prevalence of cirrhosis was not explained by any unique Asian characteristic other than prolonged infection.
Conclusions: The prevalence of cirrhosis in patients with chronic HCV increases with increasing duration of infection. In Asian patients infected at birth, infection for over 60 years causes cirrhosis in 71% of infected individuals. Because relationship between the severity of fibrosis and age in Asian patients is similar to that seen in Caucasian patients it is likely that similar rates of cirrhosis will be seen in other patients who are infected for more than 60 years.
EDITORIAL
Is Cirrhosis an Inevitable Consequence of Chronic Hepatitis C Virus Infection?
Leonard B. Seeff, MD, James E. Everhart, MD, MPH
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
Knowledge of the natural history of any disease is of great importance to the person with the illness, who obviously wishes information on what the future holds, as well as to the person's physician, who must assess the need for and the intensity of management and treatment. Also important is knowledge of patient and disease characteristics that might modify the course of illness, features that help to predict, in a given patient, what the risk is for having a good or bad outcome. This is particularly relevant for infection with HCV. Hepatitis C begins generally as a silent acute infection, advances equally silently to a chronic phase characterized by persistence of the viral infection and usually raised serum aminotransferase levels, and after a variable period, ranging from about 10-30 years, progresses in a proportion of instances to cirrhosis. A fraction of the patients with HCV-related cirrhosis will develop end-stage liver disease or hepatocellular carcinoma (HCC).1 Although this is a generally accepted scenario in persons infected with HCV, there remains uncertainty about the true frequency of evolution of the liver disease as well as its rate of progression.2 This should not be surprising because of the obvious difficulty in studying a disease whose onset is rarely identified, which progresses with such high frequency to chronicity, and which commonly, but not invariably, advances extremely slowly and usually without symptoms to a potentially fatal end point. Indeed, the condition is most often identified unexpectedly in its mid-course when laboratory tests are performed for routine evaluation or when persons are screened for high-risk behaviors and then tested for the virus, or late in the course of the disease when end-stage liver disease declares itself.
An ideal natural history study of hepatitis C requires that the infection be identified at its onset and that affected persons be followed without treatment to the point of demise. For obvious reasons, such an observational study cannot be performed.
Therefore, investigators have devised several different study strategies in an effort to gather information on the natural history of hepatitis C, but all strategies have had failings of one form or another.3 Thus, prospective studies that begin with recognized onset of acute hepatitis C have been too short in duration to fully establish the disease course. Retrospective and cross-sectional studies are the simplest to perform, often drawing conclusions from a single evaluation that includes a liver biopsy. However, they suffer from a number of potential biases and largely depend on unsupported historical information to establish the time of onset of acute infection and the risk factors for progression. A real limitation of such studies is that they substitute a potentially biased prevalence determination at a given time point rather than defining absolute risk or cumulative incidence that comes from following a defined cohort of patients over many years.
A third reasonably effective approach in assessing natural history has been to combine these 2 strategies. This takes advantage of cohorts infected and carefully studied in the past and then traces and reevaluates them years or even decades later. This approach has been termed a retrospective-prospective or a non-concurrent prospective study. Although such studies have clearly extended the follow-up duration and have unquestionably added important information, they have not yet fully established outcome during the course of a lifetime. Still, the current collective view, on the basis of the numerous studies of the natural history of hepatitis C, is that 70%-80% of acutely infected adults will advance to chronic hepatitis, 20%-30% of them will progress to cirrhosis within 20 years, and 1%-4% of those with cirrhosis will develop HCC annually.1,4 In contrast, only about 50% of acutely infected neonates, young children, and young women persist as carriers of the virus, and very few advance to cirrhosis during periods of 20-35 years.5-7 These estimates of differences in the natural history of HCV infection between younger and older infected persons might not be entirely accurate, but age at the time of infection does appear to be a major determinant of liver disease progression in persons with chronic HCV infection, in that younger infected patients spontaneously recover more commonly and less frequently advance to cirrhosis during the same time period as compared with persons infected at an older age. This fact, therefore, prompts the following question: If progression to cirrhosis in persons infected in early childhood remains minimal in the first 2-3 decades after infection, what can be expected during the decades that follow as these persons age? Will the rate of evolution to cirrhosis remain low, or will it increase exponentially and begin to emulate or even exceed the higher rate of progression that occurs among individuals first infected late in life?
The study reported by D'Souza et al8 in this issue attempts to address these important issues of age and duration of infection. The study was conducted in 3 regional hospitals in North East London, England; none of the hospitals are described as referral institutions for liver disease. A total of 206 adult Asian and 315 adult white patients with HCV infection were evaluated and compared, although the novel information came from the Asian group. The Asian patients were both first and second generation immigrants and hence were unlikely as a total group to have been exposed to HCV in the same fashion. The most common risk factor for infection among the Asian patients was receipt of blood products in 75%, mostly before the age of 20 years. The actual age of onset of infection could not be explicitly identified, but the investigators made assumptions about when infection was likely to have begun, on the basis of extrapolation of their linear regression analyses. Thus they concluded that the Asian patients had been infected at a far younger age than the white patients, with most infections occurring before the age of 20 years.
The most striking information in this study, however, was the findings in the liver biopsies, performed percutaneously in 73% of the cohort and transjugularly in 16%, the latter apparently because of hemophilia or decompensated liver disease, although no breakdown of this group was provided. Liver biopsies revealed that, in white patients, cirrhosis was present in 2% of those 20-40 years of age, in 13% of those 40-60 years of age, and in 25% of those older than 60 years of age. In contrast, cirrhosis was identified in 16% of Asian patients 20-40 years of age, increasing dramatically to 42% in those between 40-60 years and then to a staggering 71% of those older than 60 years of age. The authors also evaluated the rate of fibrosis progression, concluding that it was similar in the 2 ethnic groups. Accordingly, despite the observed difference in the frequency of cirrhosis between the ethnic groups, they suggested that white patients will probably achieve the same high frequency of cirrhosis as did the Asian patients after having been infected for the same duration of more than 60 years. This study thus extends the duration of follow-up to close to that of a lifetime for some and suggests that if they live long enough, persons chronically infected with HCV will almost invariably develop cirrhosis. The conclusion to be drawn from these data is that all HCV-infected persons must be treated, even if they show no evidence of fibrosis progression after decades of infection.
The 71% prevalence of cirrhosis in these 60-80-year-old Asian patients infected with HCV is the highest rate ever recorded for any such patient population that does not have an additional risk factor. Furthermore, the large increase in prevalence with increasing age is equally impressive. Yet the authors' conclusion that the risk of cirrhosis shows no sign of abating with increasing age among those infected at a young age needs to be cautiously considered because of a number of limitations in the study design. This was a clinic-based, cross-sectional study whose striking inferences depend on a number of unsupported assumptions. The most important assumption is that the opportunity for detection of HCV was the same across age groups. Thus, if testing for infection among older patients was limited primarily to patients with obvious liver disease, and testing among younger patients was more broad-based, then detection bias would have led to a higher prevalence of more severe fibrosis among the older patients. The authors also assumed that the Asian patients were infected at a very young age, largely on the basis of extrapolation of regression lines down to an age in which patients would presumably not have had fibrosis. This conclusion is speculative and goes well beyond the data presented in the study. Quite remarkable was the substantial increase in prevalence of cirrhosis among the Asian patients, from 42% at age 40-60 years to 71% at age 60-80 years. Because hepatitis C-related cirrhosis is not a stable condition, many if not most patients with cirrhosis would be expected to have succumbed during a 20-year period from end-stage liver disease or liver cancer.9,10 Therefore, an absolute increase of 30% in the prevalence of cirrhosis during a period of 20 years actually implies a much higher cumulative incidence because of the high proportion of deaths that would have occurred in the interim. Conversely, the survival of these patients with HCV infection for more than 60 years, even though culminating in HCV-related cirrhosis, might argue against the usual dire prognostic information provided to such patients regarding the risk of end-stage liver disease and HCC.
If the rapid rate in cirrhosis increase among Asian patients can be accepted as being accurate rather than as an artifact of study design, then this suggests an excess of risk factors for progression among these patients not present in other populations. Two factors known to be associated with more rapid progression, older age of infection and damaging levels of alcohol consumption, were excluded as contributing causes. Obesity, diabetes, insulin resistance, and associated fatty liver disease are other potential and related contributors to more rapid disease progression.11,12 The data and analyses provided were insufficient to exclude a contribution by these factors. Notably, the prevalence of cirrhosis according to these factors among Asian patients was not shown. No other potential risk factors were identified. Finally, there is no comment about treatment of these individuals with either interferon monotherapy or interferon/ribavirin combination therapy. In light of the significant histologic findings in the many liver biopsies that were performed, it would be surprising if treatment was not given to many of the patients. This information is of importance for its potential impact on the course of the disease.
In summary, if the data gathered in the study are indeed a true reflection of the long-term impact of chronic HCV infection among Asian patients, and if the findings can be extended to other populations, this would clearly indicate that substantially more, perhaps most, persons infected with HCV are likely to reach end-stage liver disease than had been thought hitherto. It also implies that treatment should indeed be universal for all HCV-infected persons, regardless of their histologic status, in the hope of blunting this progression.
In addition, it raises the issue of the need for even more transplantation services to accommodate the anticipated (on the basis of this study) "epidemic" of cirrhosis-related end-stage liver disease and cancer that awaits these patients. Such conclusions are currently premature. Specifically, additional studies are needed in other patient populations that overcome the design limitations of the current study and to address the alternative interpretation of the data that, although during a lifetime there might indeed be progression to cirrhosis, this might only seldom result in end-stage liver disease or the development of HCC.
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