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Chronic Liver Disease

Nonalcoholic Fatty Liver Disease under a microscope

Chronic liver disease can result from many causes, the two most common being viral hepatitis—including hepatitis B, C, and D—and nonalcoholic fatty liver disease (NAFLD). Rates of chronic hepatitis B in foreign-born individuals in the United States remain high, and hepatitis C has increased across the population in recent years, largely due to the opioid overdose epidemic. The frequency of hepatitis C in the general population and success of treatments have led to the recommendation to screen all adults for this infection and treat anyone infected. NAFLD is increasing in the U.S. population, driven largely by increasing obesity rates. The most serious form of NAFLD, nonalcoholic steatohepatitis, threatens to eclipse other causes of disability and death from chronic liver disease. NASH can also develop in those who are not obese, and rates vary greatly with race/ethnicity. Any form of chronic liver disease can progress to cirrhosis (scarring of the liver), liver cancer, and end-stage liver disease, often requiring a liver transplant, for which donor organs are in limited supply. NIDDK-supported research has yielded important knowledge that has improved the lives of people with many forms of chronic liver disease.

Yesterday, Today, and Tomorrow

Yesterday

  • NIDDK supported many basic research studies characterizing viruses that cause chronic hepatitis, including the Nobel prize-winning discovery of the “Australia antigen” by an NIDDK scientist in 1963, which in 1969 was found to be the hepatitis B virus and used as a diagnostic test.
  • In 1967, an NIDDK grantee performed the first human liver transplant, which would become the standard of care for end-stage liver disease. The shortage of donor livers led to introduction of living donor liver transplantation, which was shown to reduce wait times and improve survival in studies from NIDDK’s Adult to Adult Living Donor Liver Transplant Cohort Study.
  • Advances in understanding hepatitis B led to an effective and safe vaccine, available since 1982 and recommended as a universal vaccine for newborns in 1991. Hepatitis B rates decreased by almost 90 percent and could be further reduced in adults at risk. The NIDDK sponsored clinical trials testing safety and effectiveness of therapies for chronic hepatitis B and C. In the 1980s, NIDDK intramural scientists tested the first effective treatment for chronic hepatitis C (long-term therapy with interferon). This was followed by clinical trials of a combination of interferon with other antiviral agents and of improved forms of interferon (peginterferon). Side effects and incomplete responses limited this therapy, but it cured the infection in tens of thousands.

Today

  • In the last ten years, further research on hepatitis C using techniques developed by NIH-funded researchers led to identification of several direct-acting antiviral (DAA) drugs, which, when combined, cured 95-100 percent of people. These therapies, which have been recommended for anyone with chronic hepatitis C infection and cured millions worldwide, promise to ultimately eliminate this important form of chronic liver disease, a landmark advance for medicine.
  • For chronic hepatitis B, both interferon and DAA drugs have been shown to be highly effective in suppressing viral infection and treating liver disease. But these drugs must be taken long-term if not indefinitely, and only cure the disease in a proportion of individuals. Studies by the NIDDK’s Hepatitis B Research Network show that careful management of patients with chronic hepatitis B leads to long-term survival and low rates of cirrhosis, liver cancer, and end-stage liver disease with only rare adverse effects. Better regimens of DAAs and interferon promise to further improve outcomes.
  • Chronic hepatitis D is a rare but severe form of chronic viral hepatitis that occurs only in persons who also have hepatitis B, but does not respond to treatments for hepatitis B. NIDDK intramural researchers have conducted early phase studies of promising new DAA agents for hepatitis D and are now participating in trials combining one such agent (lonafarnib) with interferon.

Tomorrow

  • Results of the NIDDK’s Hepatitis B Research Network’s clinical trials suggest that a limited course of peginterferon and entecavir may be an effective treatment in a subset of patients. Building on these findings, future studies can help to identify treatments that cure a larger proportion of infected individuals.
  • NIDDK-supported researchers will continue their efforts to identify new targets for future vaccines and therapies for preventing and treating hepatitis C.
  • The NIDDK is also working on ways to increase support for research to assess and limit the progression of cirrhosis and development of liver cancer, two common outcomes of advanced chronic liver diseases such as chronic viral hepatitis.

Yesterday

  • Nonalcoholic fatty liver disease (NAFLD), or its more severe form of nonalcoholic steatohepatitis (NASH), was first recognized as a separate disease from alcoholic hepatitis in the 1980s. In these studies, liver fat accumulation and inflammation, similar to that seen in alcoholic disease, were found in people who did not abuse alcohol, but were usually affected by obesity and diabetes. Initially, treatment was limited to weight loss through diet and exercise. In cases that progressed to cirrhosis and end-stage liver disease, a liver transplant was the only option.
  • In 2002, the NIDDK created the NASH Clinical Research Network (CRN) to perform pioneering clinical studies of the causes, natural history, complications, diagnosis, and therapy of NAFLD, particularly NASH, in both children and adults, with participation by partners at the NIH and in the pharmaceutical industry. An early study by the Network showed promising improvements in aspects of adult NASH in response to the natural form of vitamin E and the insulin-sensitizing drug pioglitazone. Subsequent studies defined the criteria for a beneficial response to therapy of NASH—criteria that are used currently in most treatment studies.
  • NIDDK-sponsored studies in the past decade uncovered genetic risk factors for NAFLD/NASH.

Today

  • Estimates show that 30 to 40 percent of U.S. adults now have NAFLD, and 3 to 12 percent have NASH. People with end-stage nonalcoholic fatty liver disease make up an increasing proportion of those needing a liver transplant. NAFLD rates across the nation are relatively higher in people of Hispanic and Asian descent, and lower in African Americans. The NIDDK provides support for studies to estimate the prevalence of NAFLD/NASH as part of the CDC’s National Health and Nutrition Examination Survey.
  • Studies by the NASH CRN and others have uncovered more genetic and racial/ethnic factors that contribute to NASH. Studies have also continued to test new treatments for NAFLD/NASH.
  • Building on NIDDK-sponsored studies such as those conducted by the NASH CRN, private partners in the pharmaceutical industry, as well as NIDDK intramural scientists, are now pursuing a host of new potential drug targets toward developing a dedicated treatment for NAFLD/NASH.

Tomorrow

  • Science continues to identify disease pathways active in NAFLD/NASH. For example, NIDDK-supported scientists working with models of human fatty liver disease, such as organoids from an individual’s cells, can enable more personalized disease studies and new treatment development. Studies are also identifying noninvasive means of demonstrating disease responses that can be applied to therapeutic trials, avoiding the need for a liver biopsy and accelerating new therapies.