HCV & HCV/HIV Rates of Fibrosis Progression
"A comparison of fibrosis progression in chronic liver diseases"
Journal of Hepatology, Vol. 38 (3) (2003) pp. 257-265. Thierry Poynard et al.
Service d'Hepato-Gastroenterologie, Groupe Hospitalier Pitie-Salpetriere, Paris, France
The authors said: "This study demonstrates the propensity for fibrosis progression in the setting of HIV-HCV co-infection; extraordinarily rapid rates of progression were observed even in these young patients. This rapid progression is not only explained by alcohol consumption and immunosuppression. Our data suggest that almost all of these patients will progress to cirrhosis if they do not die from another cause, and argues for the treatment of chronic hepatitis C in co-infected patients at the earliest possible stage."
No study has compared the liver fibrosis progression rates among chronic liver diseases and the risk factors in order to better organize screening strategies. A total of 4852 patients were retrospectively studied (chronic hepatitis C (HCV) [n=2313], human immunodeficiency virus (HIV)-HCV co-infection (HIV-HCV [n=180]), hepatitis B (HBV [n=777]), alcoholic liver disease (ALD [n=701]), primary biliary cirrhosis (PBC [n=406]), genetic hemochromatosis (GH [n=383]) auto-immune hepatitis (AIH [n=57]) and delta hepatitis (n=35). The fibrosis progression rates were estimated from birth and from the date of exposure, when known, to the first biopsy. There were highly significant differences in the rates of fibrosis progression, the most rapid being HIV-HCV co-infection (50% cirrhosis percentile at 52 years of age) and the slowest being PBC (50% cirrhosis percentile at 81 years). There was an acceleration of fibrosis progression with aging. Fibrosis progression was slower in females compared with males for HCV, HBV, GH, and PBC. In contrast, in ALD, the fibrosis progression was more rapid in females. Conclusions: Rates of fibrosis progression differ markedly between the predominant causes of chronic liver disease, and according to age and gender. Patients with HIV-HCV co-infection are at particularly high risk of fibrosis progression.
"..When fibrosis progression was expressed according to the duration of risk exposure, the 50% probabilities for cirrhosis were 28 years of exposure
for HCV-HIV co-infection, 35 years for ALD, 43 years for HCV and 64 years for HBV. Almost all of the comparisons between these percentages
were highly significant (P<0.001).... The ages at which the probability for cirrhosis was 50% were 52 years for HCV-HIV co-infection, 61 years for ALD, 65 years for HBV, 72 years for HCV, 74 years for GH, and 81 years for PBC. Three diseases had early onset of cirrhosis beyond 40 years of age: auto-immune hepatitis, delta hepatitis and co-infection HIV-HCV...For GH and HCV, the rates of fibrosis progression (life modelling) were significantly higher in males than females..Female gender was associated with slower fibrosis progression in HCV and more rapid progression in ALD independent of age...
...Alcohol consumption was associated with fibrosis progression in patients infected by HCV, HBV and in GH. The 50% probability for cirrhosis (exposure modelling) was consistently earlier in subjects declaring heavy alcohol consumption vs. abstainers or moderate drinkers: 19 vs. 28 years in HIV-HCV co-infection; 29 vs. 43 years in HCV; 46 vs. 75 years in HBV; and 61 vs. 75 years in GH..
...Patients with delta chronic hepatitis have a more rapid fibrosis progression than patients with chronic hepatitis B both for transition rates to cirrhosis (log-rank=17.2 P<0.001) and to septal fibrosis (log-rank=17.5 P<0.001).
Patients with moderate or severe necroinflammatory activity had more rapid fibrosis progression than patients with no or minimal activity when infected by HIV-HCV (50% cirrhosis at 49 years vs. more than 60 years; log-rank=14; P<0.001); HCV (71 vs. 73 years; log-rank=10; P=0.001); HBV (59 vs. 67 years; log-rank=8; P=0.006) and in patients with PBC (75 vs. more than 80 years; log-rank=9; P=0.003).
Alcohol of greater than 50 grams per day increased progression to cirrhosis by 6.5 times.M
The slopes of fibrosis progression suggest a biphasic slope in females, whereas in males, there seem to have three or four acceleration phases. In females, a steep acceleration occurred around 50 years in patients with ALD and HBV and around 60 years for GH, HCV and PBC. The graphic analysis of the slopes also showed that fibrosis started earlier and occurred faster for ALD in females compared with males.
The analysis according to the duration of exposure showed that for alcohol there was a more rapid progression to cirrhosis in females (20 years)
than in males (35 years; P<0.001). This was not seen for life exposure as exposure to alcohol started later in females (median=34 years) than in
males (median=24 years; P<0.001).
Discussion by authors
The major finding of this study is the variability of fibrosis progression according to the aetiology of liver disease, age and gender. These results
have important implications for the implementation of screening strategies for fibrosis. The modelling methodology allowed us to assess the cumulative prevalence of fibrosis progression according to age and to the duration of exposure.
It is difficult to use cross-sectional, observational data to estimate longitudinal parameters. The main limitation of our study is the absence of multiple liver biopsies in the same patients; slopes were generated through modelling rather than plotted from prospective data. There is also no information about disease progression up to the time of the single liver biopsy. However, in a previous study of 170 biopsies in 70 patients with chronic hepatitis C, we found similar rates of fibrosis progression when we assessed progression between the periods of two biopsies and based on the duration of infection in a single biopsy. We have also applied this modelling to other longitudinal studies published by other groups. It is difficult to conduct studies in which patients remain untreated for their chronic liver diseases yet undergo repeated liver biopsies.
The second limitation is the presumed variability in the estimate for duration of exposure. In the absence of prospective follow-up of patients from
the date of contamination by HCV or HBV until the date of the liver biopsy, any estimate of the duration of infection must rely on patient history. We used the day of the first transfusion or the first use of injection drugs as the presumed date of infection for HCV and the date of birth for vertically transmitted HBV. In patients with PBC and GH, we used the date of birth as the onset of exposure since both diseases are at least partly genetically determined. By assuming that fibrosis in these diseases begins at birth, an assumption that has not been substantiated, we likely underestimated the rapidity of progression in these patients. This is probably even more inappropriate in women with GH and in PBC that is not a single gene disorder.
Another methodological limitation is that estimating the probability of septal fibrosis required for the exclusion of patients with biopsies revealing a
higher stage. There is no obvious bias, since the time to biopsy seems to be random. The results for the analysis of septal fibrosis were similar to those for cirrhosis that was not prone to this weakness.
By using cross-sectional data from secondary and tertiary cares, our study may have been affected by selection bias. We may have ignored patients too sick to be referred as well as asymptomatic individuals who were too well to be diagnosed. However, for all of the disease states, different populations were included which should decrease this risk. For HBV and HCV, patients with normal aminotransferases were biopsied as well as patients with decompensated liver disease. For GH and PBC, there was no selection of patients. For alcoholic liver disease, the cohort was prospectively collected and biopsies were performed in all patients with heavy alcohol consumption and serum biochemical abnormalities. Moreover, the wide range of fibrosis stages argues against significant selection bias in our study population.
This study demonstrates the propensity for fibrosis progression in the setting of HIV-HCV co-infection; extraordinarily rapid rates of progression
were observed even in these young patients. This rapid progression is not only explained by alcohol consumption and immunosuppression. Our data suggest that almost all of these patients will progress to cirrhosis if they do not die from another cause, and argues for the treatment of chronic hepatitis C in co-infected patients at the earliest possible stage.
In patients with chronic hepatitis B, our study did not demonstrate significant differences according to the presence or the absence of detectable HBV DNA on the day of the liver biopsy. This analysis is limited by the failure to obtain repeated assessments. Furthermore, the assays used for HBV DNA detection were heterogeneous. Patients with undetectable HBV DNA by non-sensitive methods represent a spectrum of `healthy' carriers and patients with chronic active hepatitis with flares. Among those with detectable HBV DNA, patients with anti-HBe seemed at higher risk of fibrosis progression than patients positive for HBeAg. Other studies with longitudinal follow-up, are needed. The sample size for delta was small but there was a very significant increase in fibrosis progression rates vs. HBV hepatitis alone. The direct cytotoxicity of delta agent hepatocytes may play a major pathogenic role in fibrosis progression.
This study demonstrates that for all liver diseases, as observed earlier for chronic hepatitis C, it is impossible to assess the rate of fibrosis
progression or any risk factors for fibrogenesis without considering age and gender. The mechanism(s) behind the deleterious effect of aging may
be related to a higher vulnerability to environmental factors, especially oxidative stress, to a reduction in blood flow, or to limited mitochondrial or
immune capacities. The only disease for which there was no steep acceleration of fibrosis rates with age was auto-immune hepatitis. Despite the small sample size there was a clear early onset of septal fibrosis with very constant transition rates according to age, suggesting different mechanisms in fibrosis production than in other liver disease.
In males, the progression of liver fibrosis seems to accelerate with decades for HCV, HBV, ALD and GH. Screening for fibrosis should be recommended between the ages of 35 and 40 years for at-risk males.
In females, the progression of fibrosis also accelerates with decades for ALD, but seems much more biphasic for HCV, HBV, GH, and PBC. Screening should be recommended around 40 years of age for females with heavy alcohol consumption and those infected with HBV or HCV. For PBC, 45 years of age seems adequate and 60 years for GH. Probably due to the depletive effect of menstruation on total body iron stores, progression rates in females with GH were particularly slow in females before 50 years of age. Studies have suggested a protective effect of estrogens on fibrogenesis via the inhibition of stellate cell proliferation. Females are more vulnerable to alcohol because of their smaller volumes of distribution and reduced gastric alcohol dehydrogenase activity. The `female paradox' observed in patients with ALD (that is, more rapid fibrosis progression in females than males) compared with chronic HCV (slower fibrosis progression in females than males) warrants further evaluation.
A major reservation about Poynard et al.'s study must be the use of cross-sectional data to model longitudinal changes. Once the concept of a
fibrosis progression rate has been established it follows that such a rate may be subject to acceleration or deceleration. At its simplest level the rate of progression may be assumed to be linear. Care must be taken not to confuse more rapid development of fibrosis in certain circumstances with accelerating fibrosis rates. Evidence emerging in hepatitis C suggests that the rate of progression of fibrosis may increase with the duration of infection and this may apply to all chronic liver diseases. Prospective data acquired over an appropriate period of time and more complex modelling will be required to address this issue but such studies will take a long time and may never be completed. In the meantime the approach used by Poynard et al. is a reasonable substitute that has precedence in studies of cancer survival.
The authors found that male gender adversely affects progression to cirrhosis in viral hepatitis but not in alcoholic liver disease when duration of exposure and age at onset of drinking are considered. The reasons behind these findings warrant further study. It may be that female sex hormones are generally antifibrotic but that the greater dose per kilogram of body weight of alcohol in females causes more damage, cancelling the protective effects of oestrogens. Alternatively there may be a behavioural explanation. Sex differences in fibrosis certainly warrant further research.
Poynard et al. attempt to draw upon their findings to suggest ages at which patients might be screened for hepatic fibrosis. This may be over-ambitious due to the considerable uncertainty that must surround the estimates of duration of exposure and thus fibrosis progression rates in the diseases studied. It is an important and sufficient contribution to show that evidence of fibrosis should be sought in middle-aged men and women and that heavy alcohol consumption by patients with hepatic co-morbidity will accelerate the progression of fibrosis. No conclusions should be drawn about HHC or PBC on the basis of the exposure modelling in this study.
Attempts such as those of Poynard et al. to develop more accurate models of prognosis in chronic liver disease are of great importance. Further studies employing more appropriate methodology must be conducted in order to answer the remaining questions relating to basic patho-biology. Better understanding of prognosis would benefit patients and those responsible for resource allocation. Measurement of the rate of fibrosis progression can be used in the evaluation of interventions and to assess modification of risk factors.
The ideal research methodology that would generate this knowledge is prospective cohort studies. A group of subjects with liver disease of
interest should be assembled early in the course of their disease at a defined point in the natural history of the condition and followed prospectively. Follow-up should be as complete as possible and for a sufficient period of time to allow the evolution of fibrosis to cirrhosis and end-stage complications. Information about predetermined outcome measures that reflect hepatic fibrosis should be recorded at regular and frequent intervals. The accuracy with which these outcome measures reflect hepatic fibrosis should be known and should be high.
Examination of this list of methodological requirements reveals why determining rates of fibrosis progression is so difficult in chronic liver
diseases. Careful thought will be required to select appropriate time-points from which to calculate the duration of exposure to disease,
particularly for immune and genetic liver diseases. The slow progression of fibrosis will require follow-up to be conducted over decades.
The most significant barrier to accurate studies of fibrosis progression is the need for an accurate measure of fibrosis. Any study of fibrosis
progression is dependent on a reliable and reproducible measure of fibrosis.
There are numerous reasons why histological examination of a liver biopsy is a sub-optimal way to measure liver fibrosis. Obtaining a liver
biopsy is painful for the patient, hazardous, time consuming and costly. Sampling error is a distinct problem particularly in some disorders.
Interpretation of biopsies using fibrosis stage scoring systems is problematic. The stages are assigned ordinal scores but these numbers are
ciphers for qualitative descriptors of histology rather than quantitative measures of fibrosis. Progression from one stage to another does not
necessarily represent an ordinal progression in matrix accumulation. For example, a biopsy with a fibrosis score of 4 may contain many times
more than double the amount of matrix that is found in a biopsy with a score of 2. Inter-observer variation in interpretation introduces
quantifiable errors that are well documented and compare unfavourably with automated pathology assays. If liver biopsy is to remain the means
by which fibrosis is assessed, other approaches incorporating histological image analysis to quantify fibrosis may provide more accurate
measures of matrix accumulation. The tools currently available for the assessment of liver fibrosis are inadequate particularly in advanced
disease. None of the existing fibrosis staging systems distinguishes between differing degrees of severity of cirrhosis. Clinical scoring systems
have been developed to stage the progressive deterioration of liver function in cirrhotic patients and at least two of these have been validated as prognostic scoring systems. Thus, a comprehensive study of liver fibrosis from initiation to end-stage cirrhosis would require the combination of both histological and clinical scoring systems incorporating clinical end-points as the metric of fibrosis such as the onset of complications of cirrhosis, portal pressure measurements and death.
Inability to perform frequent and repeated liver biopsies and errors in interpretation confound attempts to answer many of the questions about
the progression of chronic liver diseases.
Ultimately reliable, reproducible, non-invasive surrogate indicators would be most useful. Recent interest has focussed on the use of surrogate serum markers of liver fibrosis to monitor fibrosis progression. This approach has the advantages that serum samples can be obtained frequently with minimum risk and inconvenience to the patient. Studies have shown that algorithms combining these markers can reflect the severity of fibrosis in a concurrent liver biopsy with reasonable accuracy. Their use in monitoring fibrosis progression and as prognostic markers remains to be evaluated. Serum markers of liver fibrosis may hold great promise but prospective validation studies in which irrefutable outcomes are assessed will be needed.
Further studies of rates of fibrosis progression and the factors that influence them will undoubtedly provide important insights into chronic liver diseases and liver fibrosis. Careful selection of research methods and data interpretation will be vital.