Liver Disease: Good News and Bad News

Digestive Disease Week 2012

William F. Balistreri, MD


June 01, 2012

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Emerging Data in Liver Disease

Hello, I am Dr. Bill Balistreri, Professor of Pediatrics and Medicine at the University of Cincinnati College of Medicine and Cincinnati Children's Hospital. I am here at Digestive Disease Week (DDW) in San Diego to discuss emerging data on liver disease for Medscape.

Studies presented at DDW 2012 have highlighted 2 major issues that have received attention over the past year. The first issue is new strategies for the treatment of hepatitis C virus (HCV) infection, including the possibility of an interferon-free regimen. The second issue is concern about the rising incidence and impact of obesity-related liver diseases: nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

The Good News: Treatment for HCV Infection

First, the good news: Combination therapy with pegylated interferon and ribavirin has long stood as the standard of care for patients with chronic HCV infection. Although effective in achieving high response rates, this regimen is associated with troublesome side effects. Thus, the development and approval of 2 effective protease inhibitors, telaprevir and boceprevir, was hailed as a new era of therapy for patients with hepatitis C genotype 1 infection.

Several studies were presented to document that these direct-acting antiviral agents allow more effective and shorter durations of treatment. For example, in patients infected with HCV genotype 1, for whom previous standard therapy failed to eliminate the virus, treatment with either of these protease inhibitors was shown to be significantly more effective, with sustained viral response rates 2- to 3-fold higher compared with traditional therapy.

An American Association for the Study of Liver Diseases (AASLD) plenary session presentation[1] reported that when telaprevir was used in combination with peginterferon and ribavirin, the dose of ribavirin was able to be substantially reduced. Ribavirin dose reduction to less than 600 mg/day had no substantial effect on sustained viral response (SVR) rates in patients given telaprevir combination treatment. In another study,[2] when boceprevir was used in combination with peginterferon and ribavirin, SVR was achieved in patients who had been nonresponsive to previous therapy.

Despite the optimism about the prospects for this treatment of HCV, a remaining concern is the fact that telaprevir and boceprevir must be used in combination with peginterferon and ribavirin. This is far from the ideal regimen. In fact, because of poor tolerability, many treatment candidates will decide not to pursue treatment or to defer treatment until a simpler regimen is available.

However, other studies suggest that an interferon-free regimen (and perhaps even a ribavirin-free regimen) is no longer a dream. A number of compounds encompassing several distinct drug classes are currently under development. These drugs bring us one step closer to the long sought-after ideal: the ability to delete interferon injections from treatment strategies.

In the interim, how can we tailor therapy and predict response rates? Investigators noted that patients infected with hepatitis C genotypes 2 and 3 achieve SVR rates between 70% and 80% in clinical trials. However, in real-life settings, lower SVR rates in the range of 55%-65% are reported. In work presented here,[3] predictive factors for nonresponsive patients with genotypes 2 and 3 included daily alcohol intake greater than 40 g, HIV co-infection, low thyroid-stimulating hormone (TSH) levels, the presence of cirrhosis, and the duration of infection. These risk factors should be assessed and may suggest the need for an intensified treatment course.

Further data[4] were presented on a major genetic predictive factor: a single nucleotide polymorphism in the upstream region of the interleukin-28B gene. Genotype CC is the strongest factor predictive of SVR in patients with HCV genotype 1 treated with peginterferon and ribavirin. This CC genotype was also shown to be associated with a significantly higher rate of spontaneous clearance in both white and African American patients with exposure to HCV. This information will be of value when counseling patients.

The Bad News: Fatty Liver Disease on the Rise

Now the bad news: NAFLD has become the leading cause of liver disease in North America, as a result of the rapidly increasing prevalence of obesity. However, accurate population-based data on the incidence of NASH are sparse, in part because the diagnosis requires histopathologic documentation.

In a study presented here,[5] the temporal trend in the prevalence of NASH in one US county over the past 30 years was reported. In this Mayo Clinic review of 555 autopsy records, there was a significant increase between 1981 and 2010 in mean body mass index, as well as in the prevalence of obesity, in this county. There was also a striking increase in the prevalence of steatosis and NASH. Among persons who were obese, the prevalence of steatosis increased from 23% in the 1980s to 49% in the 1990s, and to 60% in the most recent era. Even in nonobese patients, the prevalence of steatosis increased from 12% (1980s) to 27% (1990s) to 36% (today).

In a related study,[6] investigators examined trends in the prevalence of NAFLD in children over the past 2 decades. They used nationally representative data from the National Health and Nutrition Examination Survey (NHANES) data sets, spanning 1988-2008. More than 10,000 adolescents were included in this analysis. The percentage of adolescents who were obese increased from 11% to 21% over this 30-year period. Suspected NAFLD increased from 4% to 10%. Among obese adolescents, the prevalence of elevated aminotransferase levels increased 120%, from 17% to 37%.

The bottom line is that suspected NAFLD in children is increasing in prevalence and affects about 10% of all adolescents. Of note, the increase in NAFLD was not solely defined by the number of overweight children. The increased prevalence of NAFLD was much greater than the increase in the prevalence of obesity. These data strongly support recommendations to screen for NAFLD in obese adolescents. This raises the question as to the best screening and confirmation methods. Specifically, is there a noninvasive way to diagnose NASH?

Several studies[7,8] presented here indicate that this is possible, to a degree, using serum biomarkers of hepatocyte apoptosis and oxidative stress. Circulating markers of hepatic cell death -- cytokeratin 18 fragments and soluble Fas (Fas ligand) -- were shown to be useful for the diagnosis of NAFLD and NASH. A prediction model was also developed. A combination of these markers had superior diagnostic performance for detecting NASH compared with measurement of the individual markers.

In addition, newer magnetic resonance techniques, such as measurement of the proton-density fat fraction, correlate with histology-determined steatosis grade in adults with NAFLD. However, a study[9] reported here documented that the amount of hepatic steatosis on imaging does not necessarily correlate with the severity of liver disease, and steatosis is not linearly related to disease progression. Future studies will need to explore the natural history of NAFLD, the interplay between hepatic steatosis and fibrosis, and whether novel imaging or MRI techniques can be used as a noninvasive means to study disease progression by fat mapping and changes in fat distribution over time.

Why are we concerned? Obese patients with fatty liver are at increased risk for early morbidity and mortality. This begins during adolescence. A study presented at DDW 2012[10] evaluated the association among obesity, fatty liver, and cardiovascular risk in pediatric patients. They documented that obesity may in fact confer a cardiovascular disease risk burden that is comparable to that of patients with familial dyslipidemias. Thus, earlier recognition and medical intervention is warranted.

Another study[11] reported that moderately severe obstructive sleep apnea and hypoxia are common in obese patients with biopsy-proven NAFLD. Obstructive sleep apnea and hypoxia were also associated with more advanced fibrosis in pediatric patients. A large multicenter cohort further documented that NAFLD is a predisposing condition for hepatocellular carcinoma. Of concern, NAFLD-associated hepatocellular carcinoma often occurs in the absence of cirrhosis. This may suggest the need to revise current guidelines, which suggest surveillance programs for cancer in patients with cirrhosis.

Finally, one study[12] reported the long-term follow-up of a liver-related death rate in patients with nonalcoholic fatty liver disease and alcoholic-related fatty liver disease. A similar proportion of patients with NAFLD and with alcoholic fatty liver disease developed cirrhosis. However, patients with NAFLD had a worse overall survival than patients with alcoholic-related fatty liver disease. These sobering studies underscore the urgent need to enhance our efforts to reduce the trend in obesity rates and the prevalence of fatty liver disease.

Thank you for listening. This is Bill Balistreri, for Medscape.


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