The burden of mortality related to liver cancer is increasing worldwide. Prevention and control of viral hepatitis will be vital in combating this burden, but curbing the growing epidemic of obesity must also be seen as a key part of liver cancer prevention, according to Rosmawati Mohamed, MD, of the University Malaya Medical Centre, Kuala Lumpur, Malaysia.¹ In addition to prevention, early detection by surveillance will be a crucial strategy in decreasing mortality related to hepatocellular carcinoma.

Between 1990 and 2015, new cases of liver cancer increased by 75%, of which 47% were driven by changing population age structures and 35% were due to population growth. Estimated age-standardized incidence and mortality rates show that the number of new cases of liver cancer is nearly equal to the number of deaths, underscoring its poor prognosis.²

Lethality of Liver Cancer

Eighty percent of liver cancers arise from cirrhotic livers; in most cases, the underlying cirrhosis is not diagnosed at the time of cancer presentation. Liver cancer is unique because its prognosis is dependent on both the stage of the tumor and the severity of the underlying liver disease.

Two-thirds of liver cancer deaths are caused by hepatitis. Commitment to prevention and control of hepatitis is desperately needed.

— Rosmawati Mohamed, MD

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Hepatocellular carcinoma usually involves multiple foci, and when it spreads, it progresses rapidly to invade blood vessels. “What makes hepatocellular carcinoma so lethal is that it rarely produces symptoms until it is very advanced,” said Dr. Mohamed, at the 2018 World Cancer Congress in Kuala Lumpur. “So, most patients are diagnosed at a later stage, not just in terms of the late stage of the tumor, but also the advanced severity of the cirrhosis, which affects the prognosis.”

Looking at global causes of hepatocellular carcinoma, hepatitis B virus (HBV) accounts for the majority of liver cancers at 33%, followed by alcohol use at 30%, hepatitis C virus (HCV) at 21%, and other causes (including other causes of hepatitis) at 16%.²

There is substantial variation in the underlying causes of liver cancer around the world, but what is consistently shown is that viral hepatitis accounts for the majority of deaths from liver cancer. “Two-thirds of liver cancer deaths are caused by hepatitis,” she stressed. “Commitment to prevention and control of hepatitis is desperately needed.”

Chronic Hepatitis Worldwide

The global burden of hepatitis is rising as a cause of death. It is now known that viral hepatitis is the seventh leading cause of death worldwide, rising by 63% since the 1990s in terms of death rates.³ Compared with a downward trend in deaths due to HIV, malaria, and tuberculosis, the estimated global number of deaths due to viral hepatitis is still rising. According to the Centers for Disease Control and Prevention, the rise in viral hepatitis deaths is mainly attributed to HCV.

However, HBV-related deaths are slowly decreasing, which can be directly attributed to the availability of treatment. “We know that the key component in preventing HBV is vaccination in newborns,” she said. “So, HBV-related liver cancer is a preventable cancer.”

There is no vaccine for HCV, so prevention will rely on encouraging universal precautions to reduce transmission via different modalities, including strengthening harm reduction programs (ie, needle exchange), reducing nosocomial infection, and implementing universal screening of donated blood products.⁴ Given the lack of an effective vaccine for HCV, and because it is curable, the optimal treatment of chronic HCV infection is now perceived as a “must” in terms of public health strategy, she said.

Hepatitis Trends: Successes and Concerns

According to Dr. Mohamed, hepatitis trends have demonstrated both successes and concerns. Incident cases of liver cancer due to HBV would have decreased between 1990 and 2015 if the demographic profile and population size had remained the same. However, liver cancer caused by HCV and alcohol use would have increased due to a rise in age-specific rates.²

HBV-related liver cancer is a preventable cancer.

— Rosmawati Mohamed, MD

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Primary liver cancer prevention through HBV vaccination is starting to show successes in many countries, but the concern, she said, is that health-care systems will have to do more than simply invest in prevention strategies. They will also have to plan for the increasing numbers of patients with liver cancer they will face despite prevention programs, due to those infected with chronic viral hepatitis.² “And that has not quite been translated to action in many countries,” she noted.

Dr. Mohamed said the best recognized strategy to reduce liver cancer and other complications of those infected by HCV and HBV is through early detection as well as linkage to care and treatment. This can reduce the chances of progression to cirrhosis, liver cancer, and death.

Issue of ‘Globesity’

Expanding waist circumference due to nonalcoholic fatty liver disease is now the most common liver disease worldwide, and it is recognized as another major health problem. Nonalcoholic steatohepatitis is the most severe form of nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis–induced cirrhosis is rapidly becoming an important risk factor for hepatocellular carcinoma. According to Dr. Mohamed, the incidence of obesity and diabetes—the two most common risk factors for fatty liver—has risen to epidemic proportions in some countries.

“This change in etiology is a global phenomenon,” she said. “Global obesity statistics are getting very scary, even in Asia.”

A study conducted between 2006 and 2009 found that cryptogenic cirrhosis resulting from nonalcoholic steatohepatitis accounted for 16% of all cases of liver cancer in Malaysia.⁵ Another study in the United States showed that, compared with individuals with a body mass index (BMI) less than 25 kg/m², those with a BMI greater than 35 kg/m² have a much higher risk of developing liver cancer, with a relative risk of 4.52 vs less than 2 for other cancers.⁶ “This is really worrisome,” added Dr. Mohamed.

Strategies for Decreasing Mortality

According to Dr. Mohamed, target populations for hepatocellular carcinoma surveillance should include all patients with cirrhosis, regardless of etiology; patients with chronic HBV, particularly Asian men older than age 40 and women older than age 50; individuals with a family history of hepatocellular carcinoma; African and North American black individuals older than age 20 with HBV; and patients with noncirrhotic HCV and bridging fibrosis.^7,8 A meta-analysis of 13 studies showed that ultrasound is the best screening tool, with a pooled sensitivity of 0.94 and a specificity of 0.94.⁹

There is still a paucity of literature on bridging the gap between viral hepatitis and liver cancer, according to Dr. Mohamed. However, one European Parliamentary Workshop document highlighted the need for “education and awareness-raising, particularly among policymakers…to improve the prevention and management of viral hepatitis, cirrhosis, and liver cancer.” The same document also stressed the importance of screening high-risk groups.¹⁰

The World Health Organization adopted a Global Health Sector Strategy on viral hepatitis (2016–2021). “This signaled the greatest global commitment to viral hepatitis to date,” stated Dr. Mohamed. “The goal of this strategy is to eliminate viral hepatitis as a major health problem.”

The global targets for elimination have been set, and they will require governments to put policies in place to address the burden of viral hepatitis. The targets in the strategy include a 90% reduction in new cases of chronic HBV and HCV by 2030 as well as treatment of 80% of patients with chronic HCV and HBV infections by 2030.

“If these measures are achieved, it could potentially lead to a 65% reduction in complications related to HBV and HCV by 2030, and that would include liver cancer,” concluded Dr. Mohamed. ■

DISCLOSURE: Dr. Mohamed reported no conflicts of interest.

REFERENCES

1. Mohamed R: Overview of global burden of liver cancer and hepatitis. 2018 World Cancer Congress. Presented October 4, 2018.

2. Global Burden of Disease Liver Cancer Collaboration, Akinyemiju T, Abera S, et al: The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: Results from the Global Burden of Disease Study 2015. JAMA Oncol 3:1683-1691, 2017.

3. Stanaway JD, Flaxman AD, Naghavi M, et al: The global burden of viral hepatitis from 1990 to 2013: Findings from the Global Burden of Disease Study 2013. Lancet 388:1081-1088, 2016.

4. GBD 2013 Mortality and Causes of Death Collaborators: Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 385:117-171, 2015.

5. Raihan R, Azzeri A, H Shabaruddin F, et al: Hepatocellular carcinoma in Malaysia and its changing trend. Euroasian J Hepatogastroenterol 8:54-56, 2018.

6. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003.

7. Bruix J, Sherman M; American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma: An update. Hepatology 53:1020-1022, 2011.

8. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer: EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 56:908-943, 2012.

9. Singal A, Volk ML, Waljee A, et al: Meta-analysis: Surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis. Aliment Pharmacol Ther 30:37-47, 2009.

10. European Parliament Workshop: Bridging the gap between viral hepatitis and liver cancer: Policy recommendations of the European Expert Group for Better Control of Liver Cancer by optimally managing viral hepatitis. November 22, 2011.