Deaths from liver cirrhosis are expected to rise over the next decade, but the causes of advanced liver disease are changing, according to study findings published in Nature Reviews Gastroenterology & Hepatology.

Cirrhosis was responsible for 2.4% of global mortality in 2019. As obesity and alcohol consumption have increased around the world, prevention and treatment of viral hepatitis have improved. Both these trends have had an impact on the epidemiology of cirrhosis.

Over time, chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), heavy alcohol consumption and other causes can lead to severe liver disease, including cirrhosis, liver cancer and the need for a liver transplant. Fatty liver disease, often associated with obesity and diabetes, is a growing cause of advanced liver disease worldwide. At the same time, widespread hepatitis B vaccination and direct-acting antiviral treatment for hepatitis C are reducing the global burden of viral hepatitis.

“The etiology of cirrhosis is changing, and the global burden of NAFLD-associated cirrhosis is steadily rising in parallel with the epidemic of obesity and type 2 diabetes mellitus,” wrote Rohit Loomba, MD, of the University of California at San Diego, and colleagues. “More resources should be directed towards primary prevention, early detection of liver disease and linkage to care to reduce the global burden of cirrhosis.”

Loomba and colleagues carried out a literature review on the epidemiology of cirrhosis around the world using various sources. His team previously reported that the causes of liver cancer are also changing.

Information about global and regional mortality were obtained from the Global Burden of Disease Study, which includes data on the burden of cirrhosis and chronic liver disease. Current and complete data were not available for some countries, so the researchers used modeling to extrapolate from previous trends. In regions with lower standards of health care, cirrhosis is likely to be underreported, they cautioned.

Causes of Cirrhosis, Liver Failure and Death 

While viral hepatitis continues to be the leading cause of cirrhosis around the world, fatty liver disease and alcohol-driven cirrhosis are increasing in several regions.

In the Americas, the dominant causes of cirrhosis have shifted over the past 10 to 20 years, with NAFLD and alcohol-related liver disease becoming more common than viral hepatitis. In Europe, too, cirrhosis is now more likely to be associated with NAFLD and alcohol consumption and less so with viral hepatitis.

Studies suggest that cirrhosis in these regions is more likely to be due to alcohol, NAFLD or viral hepatitis that has been treated or cured, rather than active infection. While antivirals can eliminate hepatitis C from the body in most cases, they cannot always reverse existing liver damage, so people who are cured remain at risk.

Studies in the Western Pacific region suggest that viral hepatitis remains the dominant cause of cirrhosis, but NAFLD- and alcohol-associated cirrhosis are increasing. Data on the causes of cirrhosis are lacking for Africa, Southeast Asia and the Eastern Mediterranean. The prevalence of hepatitis B is particularly high in Asia. Estimates suggest that hepatitis B and C are the most common causes of cirrhosis in Africa, followed by alcohol use, although there is substantial variation between Northern and sub-Saharan Africa.

Previous studies found that around 5% to 12% of cirrhosis cases will lead to hepatic decompensation, or substantial loss of liver function and liver failure, every year. From 1990 to 2017, the number of such cases has doubled, from 5.2 million to 10.6 million globally.

From 2010 to 2019, the number of cirrhosis-related deaths worldwide rose by 10%, to approximately 1,472,000. In 2019, the global age-standardized death rate was 18 deaths per 100,000 people. But regional estimates varied widely, from 10 per 100,000 in the Western Pacific to 36 per 100,000 in the Eastern Mediterranean region. Between 2012 and 2017, age-standardized death rates for cirrhosis due to hepatitis B, hepatitis C and alcohol declined, but they rose for NAFLD-associated cirrhosis.

Future Projections 

Although the number of cases of decompensated cirrhosis caused by hepatitis C is projected to increase worldwide by 2030, the rate per 100,000 people is expected to remain stable. The prevalence of active HCV infection is expected to decline, but the global hepatitis elimination target for 2030 is unlikely to be attained if current trends persist, according to the study authors.

Data on the projected global burden of cirrhosis caused by hepatitis B are limited. While new HBV infections are expected to fall, HBV-related deaths are expected to rise through 2030. Despite the availability of vaccines and antiviral therapy, hepatitis B remains severely underdiagnosed, and most people do not receive treatment, the researchers noted.

Based on one modeling study, the age-standardized death rate for decompensated cirrhosis due to alcohol use is expected to rise 77%, from 9.9 cases per 100,00 person-years in 2019 to 17.5 cases per 100,000 person-years in 2040.

The burden of NAFLD-associated cirrhosis is set to rise significantly by 2030, based on various projections. Looking at NAFLD-related compensated cirrhosis, the lowest projected increase is 64% in Japan, and the highest is 156% in France. Considering decompensated cirrhosis, projected increases range from 75% in Japan to 187% in France.

“The burden of cirrhosis remains substantial owing to underdiagnosis and undertreatment of chronic liver disease, and the number of deaths and cases of decompensated cirrhosis are projected to rise in the next decade,” the study authors concluded. “[T]hese data highlight the need for increased efforts to identify liver disease at an earlier stage. Earlier identification would enable the use of preventive measures, thereby reducing the burden of decompensation.

The COVID-19 pandemic has resulted in setbacks related to liver health. Over the course of the pandemic, the incidence of fatty liver disease and alcohol-related liver disease rose with increasing alcohol consumption. Cirrhosis mortality has also risen during the same period. Further, people with NAFLD or cirrhosis are more likely to develop severe COVID. In addition to changes in habits such as more alcohol consumption and less exercise, limited access to health care at the start of the pandemic might have played a role. The pandemic also set back global progress on hepatitis B and C elimination.

Fortunately, cirrhosis can often be prevented. In the case of hepatitis C, timely antiviral therapy can prevent loss of liver function. Limiting alcohol consumption, healthier dietary habits and exercise can reduce the risk of cirrhosis and loss of liver function due to alcohol-associated liver disease and NAFLD. National policies that encourage a healthier lifestyle and discourage heavy alcohol use are needed, the authors argue.

“Despite advances in the diagnosis, treatment and management of cirrhosis, medical interventions often have limited benefit on long-term survival, necessitating the use of resource-heavy treatments such as liver transplantation,” they wrote. “Therefore, the focus of care should be shifted upstream, from the management of complications to prevention and early treatment.”

Click here to read the study in Nature Reviews Gastroenterology & Hepatology.