From the Journals

Patients with viral hepatitis are living longer, increasing risk of extrahepatic mortality

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Nonliver diseases such as heart disease and cancer should take more focus

Chronic liver disease is one of the leading causes of death in the United States. Whereas mortality from other causes (e.g., heart disease and cancer) has declined, age-adjusted mortality from chronic liver disease has continued to increase. There have been a few major advances in the treatment of several chronic liver diseases in recent years. These include nucleos(t)ide analogues for hepatitis B virus (HBV) and direct-acting antiviral agents for the treatment of hepatitis C virus infection (HCV). Many studies show that these treatments are highly effective in improving patient outcomes, including patient survival. However, whether these individual-level benefits have translated into population-level improvements remains unclear.

Dr. Fasiha Kanwal

This study used the U.S. Census and the National Center for Health Statistics mortality records from over an 11-year period to examine population level changes in overall mortality, including mortality from liver- and nonliver (extrahepatic) complications of viral hepatitis, alcoholic liver disease, and nonalcoholic liver disease in the United States.

Overall, the results were mixed; they were encouraging for viral hepatitis but concerning for alcoholic and nonalcoholic liver disease. Specifically, all-cause mortality from HCV was on an upward trajectory in the first 7 years (from 2007 to 2014) but the trend shifted from 2014 onward. Importantly, this inflection point coincided with the timing of the new HCV treatments. Most of this positive shift post 2014 was related to a strong downward trend in liver-related mortality. In contrast, upward trends in mortality related to extrahepatic causes (such as cardiovascular mortality) continued unabated. The authors found similar results for HBV. The story, however, was different for alcohol and nonalcohol-related liver disease – both conditions lacking effective treatments; liver-related mortality for both continued to increase during the study period.

Although we cannot make causal inferences from this study, overall, the results are good news. They suggest that HBV and HCV treatments have reached enough infected people to result in tangible improvements in the burden of chronic liver disease. We may now need to shift the focus of secondary prevention efforts from liver to nonliver (extrahepatic) morbidity in the newer cohorts of patients with treated HCV and HBV.

Fasiha Kanwal, MD, MSHS, is an investigator in the clinical epidemiology and comparative effectiveness program for the Center for Innovations in Quality, Effectiveness, and Safety in collaboration with the Michael E. DeBakey VA Medical Center, as well as an associate professor of medicine in gastroenterology and hepatology at Baylor College of Medicine in Houston. She has no conflicts of interest.



Patients with viral hepatitis may live longer after treatment with direct-acting antiviral agents (DAAs), but their risk of extrahepatic causes of death may rise as a result, according to investigators.

Importantly, this increasing rate of extrahepatic mortality shouldn’t be seen as a causal link with DAA use, cautioned lead author Donghee Kim, MD, PhD, of Stanford (Calif.) University, and colleagues. Instead, the upward trend is more likely because of successful treatment with DAAs, which can increase lifespan, and with it, time for susceptibility to extrahepatic conditions.

This was just one finding from a retrospective study that used U.S. Census and National Center for Health Statistics mortality records to evaluate almost 28 million deaths that occurred between 2007 and 2017. The investigators looked for mortality trends among patients with common chronic liver diseases, including viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD), noting that each of these conditions is associated with extrahepatic complications. The study included deaths due to extrahepatic cancer, cardiovascular disease, and diabetes.

While the efficacy of therapy for viral hepatitis has improved markedly since 2014, treatments for ALD and NAFLD have remained static, the investigators noted.

“Unfortunately, there have been no significant breakthroughs in the treatment of [ALD] over the last 2 decades, resulting in an increase in estimated global mortality to 3.8%,” the investigators wrote in Gastroenterology.

“[NAFLD] is the most common chronic liver disease in the world,” they added. “The leading cause of death in individuals with NAFLD is cardiovascular disease, followed by extrahepatic malignancies, and then liver-related mortality. However, recent trends in ALD and NAFLD-related extrahepatic complications in comparison to viral hepatitis have not been studied.”

The results of the current study supported the positive impact of DAAs, which began to see widespread use in 2014. Age-standardized mortality among patients with hepatitis C virus rose until 2014 (2.2% per year) and dropped thereafter (–6.5% per year). Mortality among those with hepatitis B virus steadily decreased over the study period (–1.2% per year).

Of note, while deaths because of HCV-related liver disease dropped from 2014 to 2017, extrahepatic causes of death didn’t follow suit. Age-standardized mortality for cardiovascular disease and diabetes increased at average annual rates of 1.9% and 3.3%, respectively, while the rate of extrahepatic cancer-related deaths held steady.

“The widespread use, higher efficacy and durable response to DAA agents in individuals with HCV infection may have resulted in a paradigm shift in the clinical progression of coexisting disease entities following response to DAA agents in the virus-free environment,” the investigators wrote. “These findings suggest assessment and identification of risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals who have been successfully treated and cured of HCV infection.”

In sharp contrast with the viral hepatitis findings, mortality rates among patients with ALD and NAFLD increased at an accelerating rate over the 11-year study period.

Among patients with ALD, all-cause mortality increased by an average of 3.4% per year, at a higher rate in the second half of the study than the first (4.6% vs 2.1%). Liver disease–related mortality rose at a similar, accelerating rate. In the same group, deaths due to cardiovascular disease increased at an average annual rate of 2.1%, which was accelerating, while extrahepatic cancer-related deaths increased at a more constant rate of 3.6%.

For patients with NAFLD, all-cause mortality increased by 8.1% per year, accelerating from 6.1% in the first half of the study to 11.2% in the second. Deaths from liver disease increased at an average rate of 12.6% per year, while extrahepatic deaths increased significantly for all three included types: cardiovascular disease (2.0%), extrahepatic cancer (15.1%), and diabetes (9.7%).

Concerning the worsening rates of mortality among patients with ALD and NAFLD, the investigators cited a lack of progress in treatments, and suggested that “the quest for newer therapies must remain the cornerstone in our efforts.”

The investigators reported no external funding or conflicts of interest.

SOURCE: Kim D et al. Gastroenterology. 2019 Jun 25. doi: 10.1053/j.gastro.2019.06.026.

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