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HBV Genotype C Carries Greater Risk for HCC Than Other Genotypes

Below is a publication from “Healio Hepatology, January 23, 2013 –HBV Genotype C Carries Greater Risk for HCC Than Other Genotypes“, showing the risk of hepatocellular carcinoma among the different hepatitis B genotypes based on a meta-analysis of 43 studies. There are 8 identified HBV genotypes ranging from genotypes A through H. These different genotypes are concentrated in distinct geographic areas of the globe, and may influence the course of disease, as noted below with the greater risk of liver cancer for those with genotype C. 

Patients with hepatitis B genotype C are more likely to develop hepatocellular carcinoma than patients with other HBV genotypes, according to recent results.

Researchers performed a meta-analysis of 43 studies (34 cross-sectional, four case-control, four prospective or retrospective cohort studies and one randomized controlled trial) published between 1999 and 2010 assessing the risk for hepatocellular carcinoma (HCC) across the major genotypes of hepatitis B.

Analysis included data on 14,545 patients with HBV, with 517 cases of genotype A, 4,417 of B, 7,750 of C, 1,506 of D, 57 with A and D in combination and 298 with other and/or mixed genotypes. There were 2,841 patients with HCC across all studies.

In 33 studies comparing genotypes B (n=4,417) and C (n=6,060), HCC was significantly more common among participants with genotype C (25% of patients vs. 12%), with an OR of 2.05 (1.52-2.76). Patients with genotypes A (n=517) and D (n=1,506) were at similar risk for HCC across 12 studies (14% for A vs. 11% for D, OR=0.94, 0.67-1.32). Patients with genotype C (n=1,659) were at significantly higher risk than those with genotypes A or D (n=1,403) in 10 studies (30% vs. 7%, OR=2.34, 1.63-3.34). Analysis of HBV subgenotypes Ce (n=1,440) and Cs (n=715) in eight studies indicated a similar risk for HCC between subgenotypes (OR=1.13, 0.76-1.67) (95% CI for all).

“Genotype C HBV is associated with a higher risk of HCC than genotypes A, B and D HBV based on studies largely observational,” the researchers wrote. “This partly explains a higher risk of HCC among patients in Southeast Asia where genotype C HBV is prevalent. Patients infected with genotype C HBV, which is often associated with more active liver disease and higher risk of liver cirrhosis, should be closely monitored for HCC development and considered for antiviral therapy.”

Disclosure: See the study for a full list of relevant disclosures.

Aspirin Use Associated With Lower Risk of Developing Hepatocellular Carcinoma and Dying of Chronic Liver Disease

HBF welcomes special guest bloggers, Vikrant V. Sahasrabuddhe, M.B.B.S., M.P.H., Dr.P.H and Katherine A. McGlynn, Ph.D, M.P.H. both researchers at the National Cancer Institute of the NIH, and study authors of the recent Journal of the National Cancer Institute publication.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer.  New cases of HCC and deaths related to HCC have been increasing in the United States since the 1980s.  Most cases of HCC occur in individuals with chronic liver disease (CLD).  CLD is caused by chronic inflammation related to viral infection, excess alcohol consumption or other causes.  While HCC is relatively rare in the U.S., occurring in fewer than 10 per 100,000 persons per year, CLD is more common.  Unfortunately, CLD is among the top 10 causes of death in adults between the ages of 45 and 75 years.

In a new study from the National Cancer Institute, researchers investigated whether reduction of inflammation, through the use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, could reduce the risk of developing HCC or death due to CLD. The study was published in the Journal of the National Cancer Institute on November 28, 2012.

The researchers studied a cohort of over 300,000 men and women between the ages of 50 and  71 years who were enrolled in the NIH-AARP Diet and Health Study.  Aspirin and non-aspirin NSAID (for example Advil, Motrin) use was compared among persons who developed HCC or died from CLD and those who did not develop these outcomes.  In all, 250 study participants developed HCC and 428 died from CLD.  Almost three-fourths of the participants reported using aspirin and approximately one-half reported using non-aspirin NSAIDs.

The study found that participants who reported taking aspirin were 41% less likely to develop HCC, and 45% less likely to die from CLD than those who did not take aspirin. Use of non-aspirin NSAIDS did not reduce the risk of developing HCC, but did reduce the risk of dying from CLD by 26%. The researchers note that additional studies will be required to confirm these findings.

While this study will not lead to any immediate changes in clinical practice, it raises interesting new questions on the role of inflammation in risk for HCC.  Although the researchers took into consideration the effect of alcohol intake (a major risk factor for HCC) as well as smoking and body mass index, the study had no information on hepatitis B virus (HBV) or hepatitis C virus (HCV) status of the study participants.  In addition, NSAID use was only measured for the past 12 months, and the study had no information on the indication, duration or dose.  To partially overcome such limitations, results were analyzed after excluding participants who reported hypertension or cardiovascular disease at the beginning of the study. Those individuals might be taking a low-dose aspirin for a longer duration for the prevention of cardiovascular disease. The results were similar after excluding these participants, which suggests that the main results are likely valid regardless of the indication, duration or dose of aspirin.

The study is the largest population-based study to date to assess development of HCC and risk of death due to CLD in relation to NSAID use.  HCC and CLD involve chronic, long-term inflammatory changes in liver cells, which are caused by enzymes such as cyclooxygenases (COX).  One of the primary ways that NSAIDs modulate the risk of chronic inflammation is by stopping or inhibiting the action of COX enzymes; thus inflammatory changes that contribute to the development of CLD and HCC are reduced.  It is also speculated that aspirin may have other anti-inflammatory mechanisms.  NCI researchers are investigating these hypotheses through basic and translational research studies, as well as assessing the risk of developing HCC and dying of CLD in association with NSAID intake in other epidemiologic studies.

The full study is by:

Vikrant V. Sahasrabuddhe, Munira Z. Gunja, Barry I. Graubard, Britton Trabert, Lauren M. Schwartz, Yikyung Park, Albert R. Hollenbeck, Neal D. Freedman and Katherine A. McGlynn. Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma. J Natl Cancer Inst (2012). Published online at: doi: 10.1093/jnci/djs452

Editorial Comments by W. Thomas London, HBF Senior Medical Advisor

In previous blogs I reported that several drugs commonly used to treat or prevent diseases or conditions other than liver cancer or chronic liver disease may also prevent these serious liver diseases.  These included propranolol used to reduce pressure in the portal vein; metformin used to treat diabetes; and statins for the lowering of cholesterol and reducing the risk of heart disease.

The above report adds aspirin to this list, but people with chronic hepatitis B or C should not begin taking aspirin immediately.  Aspirin may cause serious bleeding that is sometimes fatal.  In order for blood to clot, platelets (cell fragments in blood) must clump.  One of aspirin’s actions is to prevent platelets from aggregating (clumping). This action may be the main reason that regular aspirin may prevent heart attacks. Patients with CLD are already at risk of developing serious bleeding.  The take home message is that patients with chronic hepatitis B or C should consult their doctor before taking aspirin or any other drug.

About the blog authors:

Vikrant Sahasrabuddhe,M.B.B.S., M.P.H., Dr.P.H.

Associate Investigator in the Hormonal and Reproductive Epidemiology Branch and is currently detailed to the NCI from the faculty at Vanderbilt University School of Medicine.

Katherine A. McGlynn, Ph.D., M.P.H.

Deputy Chief, Hormonal and Reproductive Epidemiology Branch 


More on Metformin and Statins: Drugs Approved by the FDA for Other Purposes That May Prevent Liver Cancer

From HBF’s expert Guest Blogger, Dr. Thomas London

In an earlier blog, I pointed out that the available drugs to treat or prevent primary liver cancer (hepatocellular carcinoma, HCC) have been disappointing.  I noted that there may be drugs used for other purposes that may work against HCC.  The most promising of these was an old drug called metformin that has been used to treat type II diabetes for 17 years.  Now a new study on metformin provides the most intriguing results yet.

At the 2012 Digestive Disease Week meeting in San Diego, an enormous study from Taiwan was reported that encompassed almost all of Taiwan’s 23 million people. (I am indebted to Christine Frangou for her excellent report in Gastroenterology and Endoscopy News and have quoted from it extensively.) The investigators used the Taiwan National Insurance Database to identify all cases of HCC diagnosed from 1997 to 2008. There were 97,430 patients with HCC (most of whom would have had chronic hepatitis B). They were compared with 200,000 controls matched to the HCC cases by age, gender, and date of first physician visit.  Using the same database they linked all patients with diabetes and their treatment methods to patients with and without HCC.

From this they were able to show that patients with diabetes had a 2.3-fold increased risk of developing HCC.  In those patients who were taking metformin, however, HCC occurred about 20% less often than in those who were not treated with metformin. Furthermore, the longer patients took metformin, the lower their risk of HCC; about 7% lower for each year that they took the drug.

This study is not the final answer.  We don’t know why some diabetic patients were treated with metformin and some were not.  It is possible that the patients who did not take metformin had some unknown liver abnormality and were deliberately not treated with metformin.  Nevertheless, anti-tumor effects of metformin in experimental animals and in cell culture systems continue to be reported.  I will keep my eye out for more research on metformin and HCC and report it as it hits the medical press.

Statins are another group of drugs that are in common use. They were first approved by the FDA in 1987 to lower serum cholesterol levels and thereby prevent heart disease.  Statins inhibit an enzyme in the liver used to make cholesterol.  Several isolated reports suggested that statins might also help prevent HCC.  This month investigators at the Mayo Clinic in Rochester, Minnesota reported a meta-analysis (a statistical method to combine results from different studies) of all the reports in the medical literature of new cases (incidence) of HCC and exposure to statin therapy.  Ten studies reporting a total of 4,928 HCC cases in 1,459,417 patients were analyzed.  Overall, patients who were treated with statins had a 40% lower risk of developing HCC than those who were untreated.  The results varied from population to population. Asian populations which were more likely to also have chronic hepatitis B, had a 50% lower risk of developing HCC, while western populations had about a 30% lower risk.

At this time we do not know what the mechanism of a preventative effect of statins on HCC might be.  Nor do we know whether statins might have been withheld from patients with high cholesterol levels because they had a liver abnormality. It is likely, however, that more information on these issues will become available in the near future.  When that happens I will report it to you.


Dr. Tom London – Hepatitis B and Liver Cancer

Hep B Talk is pleased to introduce Guest Blogger W.Thomas London, MD. Dr. London is internationally renowned for his many decades of work on hepatitis B and liver cancer, which started with his joining the research team  that discovered the hepatitis B virus. Dr. London has been at the forefront of liver cancer prevention and has written extensively about hepatitis B from the perspective of an epidemiologist, a clinician and a virologist. As founder and director of the Liver Cancer Disease Prevention Division at Fox Chase Cancer Center in Philadelphia, PA, he  developed one of the first successful community-based strategies to help people reduce their cancer risk through the early detection of chronic HBV infection. Dr. London has received the Distinguished Interdisciplinary Research Award  from the American Cancer Society and the Distinguished Scientist Award from the Hepatitis B Foundation where he currently serves as Vice-Chair of the Board and as the Senior Medical Advisor.  

Liver cancer, hepatocellular carcinoma (HCC), is the 3rd most common cause of death in the world.  Little attention was paid to HCC in the United States until recently because it was thought to be rare, but now it is one of the few cancer types that is rising in incidence (number of new cases per year). It is now the most rapidly increasing cancer in men in the US. The prognosis of HCC is poor; one year survival in the United States from the time of diagnosis is only 50%.  Detection of tumors when they are very small, less than 2 cm in diameter, and can be removed surgically is the best chance for cure.  Liver transplantation is often done if there is more than 1 tumor and the cancers are less than 3 cm in diameter.  Unfortunately, most HCCs are diagnosed when they are too large for successful surgical resection or transplantation.

Chemotherapy for HCC has been disappointing. Recently, the drug, Sorafenib (Nexavar), has been shown to be active against HCC, but it only extended survival time by a few months.  Thousands of drugs have been developed by the pharmaceutical industry for a great variety of conditions.  Of these, 983 have approved by the FDA.  That is they were tested in clinical trials, found to be safe and were beneficial for the purposes that they were approved

Scientists at the Hepatitis B Foundation and elsewhere have raised the question, are there drugs on the currently approved FDA list that are used for other purposes that might have a role in the treatment or prevention of HCC?  Recent publications suggest 2 candidates.  One is metformin (Glucophage), which is derived from the French lilac, and has been used in Europe since 1958 to treat Type 2 diabetes and in the United States since 1995. The other is propranalol, which is used to treat patients with cirrhosis who have varicose veins in the lower end of their esophagus (esophageal varices).

Diabetes is a recognized risk factor for HCC, particularly in persons who are obese and have a fatty liver. (Diabetics are also at increased risk of acquiring hepatitis B). Because patients with diabetes are often treated with metformin, investigators in China and France have looked at whether treatment with metformin lowers the risk of developing HCC.  By examining the records of diabetic patients who were treated with metformin or not, they observed that the risk of HCC was lower in the treated patients.  Furthermore, an experimental study of liver cancer in mice showed that metformin reduced the number and size of liver tumors.

Propranolol is used to lower the pressure in the portal vein and thereby in esophageal varices.  A group of physicians in France looked at the occurrence of HCC in patients with hepatitis C and esophageal varices who received propranolol treatment and those who did not.  There was about a 75% reduction in the incidence of HCCs in the propranolol treated patients.  Propranolol blocks receptors for epinephrine (adrenalin) and nor-epinephrine on cells in the body.  Such receptors are particularly rich on the surface of tumor cells, including HCCs. Experimentally propranolol has been effective in reducing the size and number of  several different kinds of tumors.

The studies that have been done so far are intriguing, but they are not conclusive.  Neither drug has been studied in a clinical trial to either treat established HCCs or to prevent HCC from occurring in the first place.  Such studies are in the planning stages.  Keep watching for progress on this front.