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HCV/Women - "menopausal state was independently associated with accelerated fibrosis progression.... Long-term benefit of estrogen exposure"
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"The most relevant finding was that the menopausal state was independently associated with accelerated fibrosis progression. It is unlikely that this effect is due simply to aging, because this variable was controlled for in our multivariate analyses. Moreover, the deleterious effect of menopause was not apparent in women who had received HRT, suggesting that hormone deficiency is indeed the culprit. This finding has important clinical implications for the management of postmenopausal women with chronic hepatitis C. Although osteoporosis may be encountered in HCV-infected women,14 many physicians are reluctant to prescribe HRT because of concerns regarding potential hepatotoxicity."
"In conclusion, our study suggests that estrogens may have a protective effect on histopathological lesions over the long-term in women with chronic hepatitis C. Postmenopausal status is characterized by accelerated fibrosis progression. In contrast to previous reports,13 pregnancy does not appear to have a deleterious impact on hepatic histology and may in fact be protective against the progression of fibrosis. Oral contraceptives appear safe with respect to liver fibrosis progression in women with chronic hepatitis C. Finally, HRT may have an antifibrotic effect, but its potential benefits on liver fibrosis in postmenopausal women need to be confirmed and must be balanced against other health risks."
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Progression of liver fibrosis in women infected with hepatitis C: Long-term benefit of estrogen exposure
Hepatology 2004
Vincent Di Martino,1 Pascal Lebray,1 Robert P. Myers,1 Emmanuelle Pannier,2 Valerie Paradis,3 Frederic Charlotte,4Joseph Moussalli,1 Dominique Thabut,1 Catherine Buffet,5 and Thierry Poynard1
Abstract
Female sex is a protective factor for the progression of fibrosis in patients with chronic hepatitis C virus (HCV) infection. Experimental data suggest that estrogens may have an antifibrotic effect. The objective of this study was to evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV-infected women. Four hundred seventy-two HCV-infected women received a survey regarding prior pregnancies, menopause, and the use of oral contraceptives and HRT. The impact of these variables on liver fibrosis and its progression were evaluated using multivariate analyses considering all putative confounding factors. Two hundred one women completed the survey (43% response rate), 157 of whom had an estimated date of HCV infection (96 postmenopausal women, 96 women with previous pregnancies, and 105 women with past use of oral contraceptives). Through multivariate analyses, the estimated rate of fibrosis progression was higher in postmenopausal (P < .05) and nulliparous (P = .02) women and was associated with greater histological activity (P < .001). Prior use of oral contraceptives had no significant influence. Among postmenopausal women, the estimated rate of fibrosis progression (±SE) was lower in women who received HRT compared with untreated patients (0.099 ± 0.016 vs. 0.133 ± 0.006 METAVIR units/yr; P = .02) and was similar to that of premenopausal women (0.093 ± 0.012 METAVIR units/yr; P value not significant). In conclusion, menopause appears to be associated with accelerated liver fibrosis progression in HCV-infected women, an effect that may be prevented by HRT. Pregnancies may have a beneficial impact on the long-term progression of liver fibrosis.
Despite a similar prevalence, chronic infection with hepatitis C virus (HCV) has been reported to be more severe in males than females. Progression to both cirrhosis1, 2 and hepatocellular carcinoma3-5 is indeed more common in HCV-infected males. In a large crosssectional study modeling the rate of HCV-related liver fibrosis progression, male sex was an independent predictor of progression to cirrhosis, increasing the risk over 2.5-fold.1 A low risk of cirrhosis in nondrinking women was confirmed by the true longitudinal observations of female cohorts infected by anti-D immunoglobulin.6, 7
Several factors may account for the apparent beneficial influence of female sex on the outcome of chronic HCV infection, including a lower prevalence of alcohol and tobacco consumption1, 8 and a lower probability of iron overload and overweight, factors that negatively influence the course of chronic hepatitis C.9, 10 Recent data strongly suggest that estrogens and/or estrogen receptors have an impact on the course of liver disease. A decrease in estrogen receptors, marked after menopause, was reported to be associated with increased lipid peroxidation and impaired superoxide dismutase function, leading to increased susceptibility to hepatocellular carcinoma.11 Moreover, experimental data in the dimethylnitrosamine rat model of liver fibrogenesis showing a protective effect of endogenous and exogenous estrogens on liver fibrosis provide consistent evidence of a direct beneficial effect of estrogens on fibrogenesis.12
The effect of estrogens on HCV-related liver fibrosis in humans has rarely been examined. In a small case-control study, pregnancy was reported to increase the severity of necroinflammatory lesions,13 but its long-term impact on liver fibrosis progression was not determined. Based on predominantly anecdotal reports, many physicians have been reluctant to prescribe oral contraceptives to HCV-infected women. Similarly, despite the recently reported risk of osteoporosis as an extrahepatic manifestation of chronic hepatitis C,14 many avoid prescribing hormone replacement therapy (HRT) to postmenopausal women because of concerns regarding potential hepatotoxicity.
The objective of this study was to assess the long-term impact of estrogens on the progression of liver fibrosis in HCV-infected women. Specifically, past pregnancies, menopausal status, and the use of oral contraceptives and HRT were examined as determinants of estrogen exposure.
Discussion
Our study of the events of reproductive life and exogenous estrogen therapy provides consistent evidence that estrogens may have a protective effect on the long-term course of chronic hepatitis C in females.
Several limitations must be acknowledged. First, the concept of dynamic fibrosis progression1 restricts the analyses to patients with a "known" duration of infection and is limited by the assumption of linearity in the progression of fibrosis. It also restricts the analysis to one liver biopsy sample to eliminate posttreatment biopsies from analyses and to avoid a selection bias if considering only patients with serial liver biopsy samples available without anti-HCV therapy. The concept of linear fibrosis progression does not account for late acceleration of liver fibrosis that was recently suggested in various forms of chronic liver diseases and may be influenced by menopause.19 Second, our retrospective study was built on the basis of self-administered questionnaires of a small proportion of our general population. However, we did not find any significant difference between the studied population and the general population with respect to demographic, virological, or histological findings (see Table 1). The use of self-administered questionnaires may also have introduced recall bias that may have introduced inaccuracies, especially regarding the use of oral contraceptives. The absence of a significant impact of the use of oral contraceptives on the variability of HCV-related liver fibrosis progression may partially result from such a bias. However, we can assume that the records of past pregnancies, menopause, and the use of HRT that are either major or recent estrogen-associated events were not hampered by recall bias. Third, we are unable to provide definitive evidence of a protective effect of HRT on liver fibrogenesis. Only an appropriately powered, randomized trial with serial liver biopsy specimens could resolve this issue. Moreover, the small number of postmenopausal women receiving this therapy did not permit multivariate analysis. However, the comparison of fibrosis progression rates between premenopausal women and postmenopausal women with or without HRT (see Fig. 2) is intriguing. Nevertheless, our findings should be considered hypothesis-generating and in need of confirmation.
The most relevant finding was that the menopausal state was independently associated with accelerated fibrosis progression. It is unlikely that this effect is due simply to aging, because this variable was controlled for in our multivariate analyses. Moreover, the deleterious effect of menopause was not apparent in women who had received HRT, suggesting that hormone deficiency is indeed the culprit. This finding has important clinical implications for the management of postmenopausal women with chronic hepatitis C. Although osteoporosis may be encountered in HCV-infected women,14 many physicians are reluctant to prescribe HRT because of concerns regarding potential hepatotoxicity.
Our findings suggest that this treatmentŅor at least the combination of transdermal estrogen and oral progesteroneŅis safe and potentially beneficial with respect to liver fibrosis. We also found that pregnancy did not have a deleterious effect on HCV-related necroinflammatory activity or fibrosis when assessed over the long term. Indeed, women with a prior history of pregnancy, regardless of the outcome or duration, had a lower estimated rate of fibrosis progression. This effect was independent of age, BMI, and histological activity.
Prior studies examining the impact of pregnancy on chronic hepatitis C have reported an increase of serum aminotransferases and HCV viral load following delivery20-23; pregnancy-induced changes in the immune system have been implicated. This was not a focus of our study. To our knowledge, only one prior study has examined the impact of pregnancy on histopathological lesions in women with chronic hepatitis C. In a case-control study of 12 women biopsied before and after delivery, Fontaine and colleagues13 reported an increase in necroinflammatory activity in 83% of cases versus only 25% of nonpregnant controls (P = .02); fibrosis also tended to progress post partum. The authors concluded that pathological exacerbation could occur following delivery in HCV-infected women and that in rare cases irreversible deterioration may be observed. Our study suggests that in general, the long-term impact of pregnancy on HCV-related histological lesions is benign and potentially protective with respect to fibrosis progression.
Two thirds of the women in our study reported prior therapy with oral contraceptives. The majority had taken low-dose preparations of ethinylestradiol and progesterone; the mean duration of therapy was approximately 5 years. Oral contraceptive therapy had no impact on the grade of necroinflammatory activity or estimated rate of fibrosis progression, although mean fibrosis scores were higher in nonusers. However, in multivariate analyses, the effect of oral contraceptives on both fibrosis score and fibrosis progression rate was not statistically significant. This may be a true finding; alternatively, the low doses of ethinylestradiol may have been insufficient to increase serum estrogen levels to a level at which a significant antifibrotic effect could be observed.24 The apparent protective effect of oral contraceptives on the stage of fibrosis seen in the univariate analysis may have been due to a higher proportion of postmenopausal and nulliparous women (both having a deleterious impact) in the group that did not receive this therapy. It also should have been influenced by the younger age of women who received oral contraceptives compared with others. Nevertheless, our data suggest that oral contraceptives are well tolerated from a long-term hepatic perspective in women with chronic hepatitis C. However, rare cases of acute cholestasis secondary to these agents warrant careful observation following their initiation.25
In our study, the long-term effects of pregnancy, oral contraceptives, menopause, and HRT on liver fibrosis progression were assessed via multivariate analyses considering the factors known to influence HCV-related fibrosis (age, BMI, and hepatic necroinflammatory activity). We employed the concept of liver fibrosis progression1 that considers the duration of HCV infection and is more sensitive than the fibrosis score for assessing significant differences between small groups. Alcohol consumption was not included in our multivariate models because only 6% of the studied women reported daily alcohol consumption in excess of 20 g, and this variable did not influence liver fibrosis in the univariate analyses. Moreover, we evaluated separately the impact of previous pregnancies, oral contraceptives, and menopause on fibrosis and the estimated rate of fibrosis progression. These analyses were designed to decrease the probability of a type II error and to take into account colinearity between the three studied variables.
Our results from clinical observation support experimental data showing an antifibrotic effect of estrogens in liver, lung, kidney, and skin tissue.12, 26-29 In a rat model of liver fibrosis induced by dimethylnitrosamine, Yasuda and colleagues12 compared liver fibrosis in males and females administered exogenous estrogen versus those with hypoestrogenemia induced by antiestrogen antibodies or ovariectomy. Compared with females with normal levels of estrogen, increased fibrosis was observed in males and females with hypoestrogenemia. An in vitro study showed that proliferation of hepatic stellate cells in primary culture and fibrogenesis were blocked by estrogens.12
In conclusion, our study suggests that estrogens may have a protective effect on histopathological lesions over the long-term in women with chronic hepatitis C. Postmenopausal status is characterized by accelerated fibrosis progression. In contrast to previous reports,13 pregnancy does not appear to have a deleterious impact on hepatic histology and may in fact be protective against the progression of fibrosis. Oral contraceptives appear safe with respect to liver fibrosis progression in women with chronic hepatitis C. Finally, HRT may have an antifibrotic effect, but its potential benefits on liver fibrosis in postmenopausal women need to be confirmed and must be balanced against other health risks.
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