ARRA IMPACT REPORT:
Chronic Liver Disease: Pathogenesis, Treatment and Prevention


Public Health Burden
Cirrhosis, or scarring and impairment of the liver, results from chronic injury caused by such agents as the hepatitis C virus, heavy alcohol consumption, excess fat in the liver often associated with obesity (nonalcoholic fatty liver disease), or a drug reaction, among others. This condition can progress to a form of liver cancer called hepatocellular carcinoma. Cirrhosis is the twelfth leading cause of death by disease in the U.S., accounting for more than 30,000 deaths each year.1 In 2004, liver disease and viral hepatitis accounted for approximately 5.9 million visits to ambulatory care centers in the U.S., making them the third leading diagnosis seen at these centers.2

Advancing Insight into the Pathogenesis of Chronic Liver Diseases
Major causes of chronic liver disease in the U.S. include hepatitis C and nonalcoholic fatty liver disease, among others. Liver injury caused by drugs is also an increasing cause of liver disease and the need for transplantation in the U.S.

ARRA funds have helped to support studies illuminating the disease processes involved in these forms of liver disease, including:

  • T cell microparticles fuse with fibrotic cells: Patients with active hepatitis C found to have elevated blood levels of T cell “microparticles”, small cell membrane vesicles released from cells during cell death or activation. These microparticles were shown to fuse with liver cells involved in fibrosis (scar formation) and increase their tendency to break down, rather than form, scar tissue. This finding enhances understanding of hepatitis C progression and may lead to new diagnostic and therapeutic strategies.3
  • MicroRNA may serve as non-invasive biomarker to improve chronic liver disease diagnosis: Another group of scientists identified microRNAs—small, non-coding stretches of RNA that control gene expression—that were elevated in the blood of patients with chronic hepatitis C or nonalcoholic fatty liver disease. These microRNAs were highest in those with more severe disease. Therefore, these molecules may serve as non-invasive biomarkers for diagnosing and assessing severity of these liver diseases.4
  • Genetic variability in immune cell markers provides insight into liver failure susceptibility: A study with partial ARRA funding support, which combined data from the Drug-Induced Liver Injury Network and other international databases, identified genetic variants in immune cell markers associated with susceptibility to liver injury resulting from the combination antimicrobial therapy amoxicillin and clavulanate. This study helps to explain why some individuals develop acute liver failure following liver injury from this drug combination, while most people spontaneously recover.5

Advancing the Treatment of Chronic Liver Diseases
Pharmaceutical and surgical treatments, such as liver transplantation, continue to evolve and improve the lives of those with chronic liver diseases. For example, research is identifying possible therapeutic approaches for diseases where no specific treatments exist, such as nonalcoholic fatty liver disease, including the more severe form of the disease known as nonalcoholic steatohepatitis, which increasingly affects adults and children in the U.S. Children are also affected by such potentially devastating liver diseases as biliary atresia. ARRA support has enabled scientists to perform basic and clinical research aimed at developing treatments for adults and children with liver disease, including:

  • Development of alternative sources of liver cells for transplantation: ARRA-funded scientists generated hepatocytes (liver cells) using induced pluripotent stem (iPS) cells from adult human skin cells.6 In another study, scientists were able to transform skin cells from the human placenta of full-term births into liver cells that could be transplanted into mice.7 Both of these advances may provide an alternative source of liver cells for transplantation, in lieu of donor livers, as well as a material for in vitro screening for drug toxicity and finding new therapeutics for chronic liver diseases.
  • Vitamin E shows promise in treatment of severe nonalcoholic fatty liver disease: The Nonalcoholic Steatohepatitis Clinical Research Consortium tested two molecules: 1) the natural form of the antioxidant vitamin E or 2) the insulin-sensitizing drug pioglitazone as treatments for nonalcoholic fatty liver disease in adults and children. Both trials showed promising improvements in treating severe nonalcoholic fatty liver disease with vitamin E. These trials represent important milestones in the search for effective treatments for this common form of liver disease.8

Advancing the Prevention of Chronic Liver Diseases
Hepatitis C infection is one of the most common causes of chronic liver disease in the U.S. In contrast to hepatitis B, for which development of a vaccine and immunization program led to a remarkable reduction in disease prevalence, no vaccine yet exists for hepatitis C. Due to the hepatitis C virus’s restriction to primate hosts, vaccine research has historically been conducted in chimpanzees. Due to recent limitations placed on chimpanzee research, there is need to develop new research models to study hepatitis C. ARRA-funded researchers have made progress toward developing means of preventing hepatitis C infection.

Scientists, supported in part by NIDDK and NIAID, developed a mouse with genetic modifications to “humanize” it by expressing human genes required for hepatitis C infection. This small animal model serves as a valuable research tool to test effective preventive and therapeutic approaches against hepatitis C infection.9 For example, in a follow-up study, the researchers used this small animal model of hepatitis C infection to identify human antibodies with the ability to broadly neutralize several types of hepatitis C viruses. This information will be useful for designing and developing widely effective vaccine candidates against the hepatitis C virus.10

Contributing NIH Institutes & Centers

  • National Center for Research Resources (NCRR)
  • National Institute of Allergy and Infectious Diseases (NIAID)
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  1. http://www.cdc.gov/nchs/data/nvsr/nvsr60/nvsr60_03.pdf
  2. http://www2.niddk.nih.gov/AboutNIDDK/ReportsAndStrategicPlanning/BurdenofDisease/DigestiveDiseases
  3. 5R21DK075857-02, http://www.ncbi.nlm.nih.gov/pubmed/20979056 - SCHUPPAN, DETLEF - BETH ISRAEL DEACONESS MEDICAL CENTER - BOSTON - MA
  4. 3R01DK066840-05S1 - BERETTA, LAURA - FRED HUTCHINSON CANCER RESEARCH CENTER - SEATTLE - WA
    3R01DK066840-05S2 - BERETTA, LAURA - FRED HUTCHINSON CANCER RESEARCH CENTER - SEATTLE - WA
    http://www.ncbi.nlm.nih.gov/pubmed/21886843
  5. 3U01DK065176-07S1 - ROCHON, JAMES - DUKE UNIVERSITY - DURHAM - NC
    3U01DK065176-07S2 - ROCHON, JAMES - DUKE UNIVERSITY - DURHAM - NC
    3U01DK065211-07S1 - CHALASANI, NAGA P. - INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS - INDIANAPOLIS - IN
    5UL1RR025761-03 - SHEKHAR, ANANTHA - INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS - INDIANAPOLIS - IN
    5UL1RR025747-03 - PISANO, ETTA D - UNIVERSITY OF NORTH CAROLINA CHAPEL HILL - CHAPEL HILL - NC
    5UL1RR024986-04 - PIENTA, KENNETH J. - UNIVERSITY OF MICHIGAN AT ANN ARBOR - ANN ARBOR - MI
    http://www.ncbi.nlm.nih.gov/pubmed/21570397
  6. 1RC1DK087377-01 - DUNCAN, STEPHEN AMEDICAL COLLEGE OF WISCONSIN - MEDICAL COLLEGE OF WISCONSIN - MILWAUKEE - WI
    5RC1DK087377-02 - DUNCAN, STEPHEN A - MEDICAL COLLEGE OF WISCONSIN - MILWAUKEE - WI
    http://www.ncbi.nlm.nih.gov/pubmed/19998274
  7. 1RC1DK086135-01 - STROM, STEPHEN C - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
    5RC1DK086135-02 - STROM, STEPHEN C - UNIVERSITY OF PITTSBURGH AT PITTSBURGH - PITTSBURGH - PA
    http://www.ncbi.nlm.nih.gov/pubmed/21374689
  8. 3U01DK061718-08S1 - NEUSCHWANDER-TETRI, BRENT A - SAINT LOUIS UNIVERSITY - SAINT LOUIS - MO
    3U01DK061728-09S1 - KOWDLEY, KRIS - BENAROYA RESEARCH INST AT VIRGINIA MASON - SEATTLE - WA
    3U01DK061731-08S1 - SANYAL, ARUN J - VIRGINIA COMMONWEALTH UNIVERSITY - RICHMOND - VA
    3U01DK061732-08S1 - MCCULLOUGH, ARTHUR JOSEPH - CLEVELAND CLINIC LERNER COLLEGE OF MED - CLEVELAND - OH
    3U01DK061734-09S1 - LAVINE, JOEL EDWARD - COLUMBIA UNIVERSITY HEALTH SCIENCES - NEW YORK - NY
    3U01DK061737-08S1 - CHALASANI, NAGA P. - INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS - INDIANAPOLIS - IN
    3U01DK061737-08S2 - CHALASANI, NAGA P. - INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS - INDIANAPOLIS - IN
    3U01DK061737-09S1 - CHALASANI, NAGA P. - INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS - INDIANAPOLIS - IN
    3U01DK061738-08S1 - BASS, NATHAN M - UNIV OF CALIFORNIA AT SAN FRANCISCO - SAN FRANCISCO - CA
    3U01DK061730-08S1 - TONASCIA, JAMES A - JOHNS HOPKINS UNIVERSITY - BALTIMORE - MD
    3U01DK061730-09S1 - TONASCIA, JAMES A - JOHNS HOPKINS UNIVERSITY - BALTIMORE - MD
    3U01DK061713-08S1 - DIEHL, ANNA MAE ELIZABETH - DUKE UNIVERSITY - DURHAM - NC
    5UL1RR024989-04 - DAVIS, PAMELA B - CASE WESTERN RESERVE UNIVERSITY - CLEVELAND - OH
    5UL1RR024128-05 - CALIFF, ROBERT M - DUKE UNIVERSITY - DURHAM - NC
    5UL1RR024131-05 - JOHNSTON, S. CLAIBORNE - UNIV OF CALIFORNIA AT SAN FRANCISCO - SAN FRANCISCO - CA
    5UL1RR025014-04 - DISIS, MARY L. - UNIVERSITY OF WASHINGTON - SEATTLE - WA
    http://www.ncbi.nlm.nih.gov/pubmed/20427778, http://www.ncbi.nlm.nih.gov/pubmed/21521847
  9. 1RC1DK087193-01 - RICE, CHARLES M - OHIO STATE UNIVERSITY - NEW YORK - NY
    5RC1DK087193-02 - RICE, CHARLES M - OHIO STATE UNIVERSITY - NEW YORK - NY
    http://www.ncbi.nlm.nih.gov/pubmed/21654804
  10. 1RC1DK087193-01 - RICE, CHARLES M - OHIO STATE UNIVERSITY - NEW YORK - NY
    5RC1DK087193-02 - RICE, CHARLES M - OHIO STATE UNIVERSITY - NEW YORK - NY
    5R21AI080916-02 - LAW, MANSUN - SCRIPPS RESEARCH INSTITUTE - LA JOLLA - CA
    http://www.ncbi.nlm.nih.gov/pubmed/22492964