Still, even non-responders and those who relapse can see a benefit from the medication, depending on the length of time that they take it, according to doctors in the Academic Department of Medicine at Hippokration Hospital of Athens, Greece.

Clarifying the Mystery
The researchers wanted to learn more about the specific effect that this standard hepatitis therapy has on their patients with fibrosis of the liver. Currently, the only measure of interferon treatment failure or success is a patient's ability to achieve an SVR, or sustained virological response, defined as maintaining undetectable levels of the virus for at least 6 months after therapy is discontinued.

Fibrosis is scarring of the liver that occurs in hepatitis infection. It can potentially progress to cirrhosis, a type of chronic liver disease in which normal cells are damaged and replaced by scar tissue. Cirrhosis ranks as the eighth leading cause of death in the United States.²

"The possible effect of interferon-alfa on liver fibrosis progression has not been adequately studied in chronic hepatitis B,” wrote George Papatheodoridis, MD, and his colleagues.

Comparing Treated with Untreated Patients
In an attempt to come up with more answers, Papatheodoridis' group retrospectively evaluated 147 patients with chronic hepatitis B who were also E antigen-negative. That's a mutant form of hepatitis B that tends to be more resistant to treatment. "In fact, there were suggestions that only nucleoside analogues have a beneficial effect on liver histology" in these patients, explained Papatheordoridis, an associate professor in Medicine and Gastroenterology who led the study, in an interview with Priority Healthcare. Nucleoside analogs like Hepsera (adefovir dipivoxil) and Epivir-HBV (lamivudine) interfere with the activity of an enzyme that the hepatitis B virus uses to make copies of itself.³

One hundred twenty patients had previously been treated with interferon alfa, and the remaining 27 had not. Each patient had undergone at least 2 biopsies previously, as well.

Papatheodoridis and his colleagues found fibrosis improved in about 17 percent of the treated patients, overall, compared to just 4 percent of those who didn't receive therapy. Those who achieved sustained virological responses  had the most improvement in liver fibrosis compared to relapsers, who had the worst improvement.

Even Relapsers and Nonresponders Benefited
They also learned that interferon induced a sustained response in 30 patients, but 57 only had an initial response, and then subsequently relapsed. The remaining 33 had no response.

Fibrosis also worsened in about a third of those treated—the worst progression mostly in nonresponders. But that compares to some 70 percent of those who didn't undergo interferon therapy at all, the researchers found.

"The annual rate of fibrosis progression was worse in the untreated than in treated patients," Papatheodoridis and his colleagues wrote, a significant finding, even considering nonresponders and relapsers.

The research team also discovered that several key factors increased the likelihood of fibrosis progression: older age, and worse liver disease or lower fibrosis level at the beginning of this study.

Interferon Benefits Found in All Cases
After collecting their data, the researchers summarized that "interferon alfa significantly reduces the rate of fibrosis progression, but such an effect is mainly observed in patients with sustained biochemical responses." In those who relapse after initial treatment with interferon and in non-responders, the beneficial effect on fibrosis depends on how long treatment is given, they said.

"Sustained off-therapy response should remain the measure of interferon efficacy," Papatheodoridis told Priority Healthcare. "However, we showed that, although sustained off-therapy response is the optimal outcome and results in significant improvement of fibrosis, the worsening of liver fibrosis is slower in patients without such a response (relapsers or non-responders) compared with untreated cases."

Though the benefit for non-responders and relapsers may be temporary, other antiviral agents could be subsequently prescribed, Papatheodoridis explained.

'First Therapeutic Option'
Intron-A is the form of interferon alfa used to treat people with hepatitis B. But it's not necessarily intended for every HBV patient. Those who are chronically infected, have higher liver enzyme levels and actively replicating virus are typical candidates for this therapy. Clinical studies have shown that approximately 45 percent of patients prescribed Intron-A respond to the therapy.⁴

"We will continue further studies in more detailed aspects of this area," Papatheodoridis said. "I think that our study further strengthens the suggestions that interferon should be the first therapeutic option for patients with HBV E antigen-negative chronic hepatitis B."

1. Papatheodoridis GV, Petraki K, Cholongitas E, Kanta E, Ketikoglou I, Manesis EK. J Viral Hepat 2005 Mar;12(2):199-206.
2. American Liver Foundation. What Are the Diseases that Affect the Liver? Available at: http://www.liverfoundation.org/cgi-bin/dbs/articles.cgi db=articles&uid=default&ID=1043&view_records=1.
Accessed March 11, 2005.
3. Zoulim F, Trepo C. New antiviral agents for the therapy of chronic hepatitis B virus infection. Intervirology 1999;42(2-3):125-44.
4. Hepatitis Neighborhood. HBV Medications: Intron-A, Epivir HBV & Hepsera. Available at: http://www.hepatitisneighborhood.com/content/
treatment_options/medications_for_hepatitis_287.aspx.
Accessed March 11, 2005.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

http://www.hepatitisneighborhood.com/content/in_the_news/archive_2283.aspx

Relationship Between Serum Ferritin, Hepatic Iron Staining, Diabetes Mellitus and Fibrosis Progression in Patients with Chronic Hepatitis C  
 

Chronic infection with the hepatitis C virus affects over 170 million individuals worldwide and 20% of patients develop cirrhosis after 20 years. Increased iron stores and hepatic iron content have been suggested as important contributors to fibrosis progression. As well, the increased prevalence of diabetes mellitus has been associated with increased iron deposits in patients with chronic hepatitis C.

The aim of the current study was to assess the potential relationship between serum ferritin and hepatic iron staining and liver fibrosis in patients with chronic hepatitis C virus infection and whether these factors are increased in diabetic patients with hepatitis C virus.

This was a cross-sectional, multi-centre study involving hospitals in the north-east of London between 1992 and 2003. Chronic hepatitis C patients with a liver biopsy and data concerning age, sex, basal metabolic index, diabetes mellitus or impaired glucose tolerance, alcohol intake, serum ferritin level and ethnicity were enrolled. Each biopsy was scored for fibrosis and stained for hepatic iron.

Three hundred and thirty nine patients (200 Caucasian; 139 Asian) were enrolled. Fifty three patients had no fibrosis, 131 had mild fibrosis (stage one to two Modified Ishak), 68 moderate fibrosis (stage three to four) and 87 cirrhosis (stage five to six).

Findings

4.4% of patients had elevations in serum ferritin, while 11% had increased hepatic iron staining;

The serum ferritin and hepatic iron staining were unrelated to the degree of fibrosis;

Serum ferritin was significantly higher in patients with diabetes or impaired glucose tolerance compared to non-diabetics;

No association was seen between diabetes and hepatic iron staining.

Conclusions

The authors conclude, “Many patients with chronic hepatitis C virus infection may have elevated serum ferritin and/or iron deposition within the liver. However, neither played a significant role in the progression of hepatitis C virus-related liver injury.”

“The association between chronic hepatitis C virus infection and type II diabetes mellitus exists, however the biological mechanism of this association still remains to be elucidated.”

Hepatobiliary Group, Institute of Cellular and Molecular Science, Queen Mary's School of Medicine and Dentistry, London, UK.

03/09/05

Reference
R F C D'Souza and others. Relationship between serum ferritin, hepatic iron staining, diabetes mellitus and fibrosis progression in patients with chronic hepatitis C. Alimentary Pharmacology & Therapeutics 21(5): 519-24. March 1, 2005.

Estrogen May be Prophylactic
Vincent Di Martino, MD, and his associates with Service d'Hepato-Gastroenterologie at Pitie-Salpetriere Hospital in Paris wanted to "evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV-infected women."

Doctors have hypothesized in previous scientific studies that estrogens may exert an antifibrotic effect in some way.

"Recent data strongly suggest that estrogens and/or estrogen receptors have an impact on the course of liver disease," wrote Di Martino and the study investigators. But the effect that estrogens play on liver fibrosis risk hasn't been studied extensively, they added.

Survey Questions Distributed
For the analysis, Di Martino and his colleagues circulated a survey among the respondents, asking them about their pregnancy history, whether or not they had reached menopause, and their use of oral contraceptives and HRT.

When patient characteristics were analyzed, the investigators learned that the average age of the women when they underwent liver biopsy was 48, 60 percent had a history of blood transfusion, and nearly a fifth of the women had been prior IV drug users. Almost two-thirds of the survey respondents were infected with genotype 1 hepatitis C, the most common and the most difficult to treat of all the hepatitis genotypes.²

In evaluating the women's exposures to estrogen, they reported their age at first menstrual period, on average, was 13 and there was an average of nearly 30 years of fertility before they underwent liver biopsy indicating hepatitis infection. In addition, nearly two-thirds had had at least one pregnancy prior to their hepatitis diagnosis. Another 61 percent reported they were menopausal when their hepatitis infection was confirmed. The investigators found that 67 percent of the women were taking oral contraceptives before liver biopsy, one-fifth of whom were on the pill at the time of biopsy.

When the researchers looked at HRT use, more than half of the women in the survey said they had been prescribed the therapy previously, and a large majority in that group had been taking HRT at the time their hepatitis infection was confirmed.

Estrogen Exposure and Fibrosis Risk
The investigators then measured fibrosis stage and development in each of the women. They found that the rate of fibrosis development was "significantly higher" in women who had never been pregnant compared to those who had given birth at least once previously. They also found that postmenopausal women tended to have more advanced fibrosis compared to premenopausal females. That, after taking into account other factors that could have caused more advanced fibrosis like age and level of liver inflammation. Women who had no history of HRT also tended to have more advanced fibrosis and faster fibrosis development compared to those who had been previously prescribed the therapy, Di Martino and his colleagues found. "In fact, the mean estimated rate of fibrosis progression of the postmenopausal women who had received HRT was similar to that of premenopausal women," the investigators noted.

Fibrosis was less advanced, on average, in women who had previously used oral contraceptives, as well. However, oral contraceptive use had no impact on the rate of fibrosis development, they reported. This could be due, they theorized, to insufficient levels of estradiol in the medication, which wouldn't have increased estrogen levels to a point at which they might have provided the protection.

"Our study of the events of reproductive life and estrogen therapy provides consistent evidence that estrogens may have a protective effect on the long-term course of chronic hepatitis C in females," write Di Martino and his colleagues.

Researchers: Our Results Are 'Intriguing'
Still, the researchers admit their study had several limitations, such as the possibility that women may not have recalled certain information accurately, which would have a direct effect on the results.

The findings are "intriguing" they wrote, but quickly adding that the results "should be considered hypothesis-generating and in need of confirmation." Of particular interest is the link between fibrosis development and HRT use in postmenopausal women, they wrote. "The menopausal state was independently associated with accelerated fibrosis progression," a finding that has valuable implications for physicians treating women with HCV who've reached menopause. Doctors are often reluctant to prescribe HRT for these women, they pointed out, because of the drugs' potential toxicity to the liver in those cases. "Our findings suggest that this treatment—or at least the combination of transdermal estrogen and oral progesterone—is safe and potentially beneficial with respect to liver fibrosis."

The Estrogen/Liver Cancer Link
While there hasn't been much research on whether or not women possess a hormonal protection against fibrosis development, doctors in Taiwan in late 2003 found that women were similarly protected against the development of hepatocellular carcinoma, possibly for similar reasons.³

In their study of nearly 1,000 women, doctors at National Taiwan University found that women who had a history of more pregnancies faced a significantly lower risk of developing hepatocellular carcinoma compared to those females who had had fewer pregnancies. They also learned that those who were older at menopause tended to have a lower risk of liver cancer compared to those who entered menopause earlier. "Use of hormone replacement therapy was associated with a lower risk of hepatocellular carcinoma, and there was a trend in the risk with increasing duration of HRT," they wrote.

Based on these findings, the Taiwanese physicians suspected that greater exposure to estrogen may be protective against liver cancer.

Similarly, some of the same doctors at Pitie-Salpetriere hospital in Paris published a study earlier that same year that examined the factors that increased or slowed the rate of fibrosis development in nearly 5,000 people with varying types of liver diseases. Among other factors, they found that being female tended to slow the development of fibrosis, though they didn't examine the possible causes. By contrast, the investigators also noted that this was not the case in alcoholic liver disease. Women with that disease tended to develop fibrosis faster, they wrote.

1. Di Martino V, Lebray P, Myers RP et al. Progression of liver fibrosis in women infected with hepatitis C; long-term benefit of estrogen exposure. Hepatology 2004 Dec;40(6):1426-33.
2. Fried MW. Viral factors affecting the outcome of therapy for chronic hepatitis C. Rev Gastroenterol Disord 2004;4(Suppl 1):S8-S13.
3. Yu MW, Chang HC, Chang SC et al. Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B-and C-related risk. Hepatology 2003 Dec;38(6):1393-400.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include coverage of health news for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.