The National Institute of Diabetes & Digestive & Kidney Diseases

Liver disease presents a unique confluence of many disciplines, in both the clinical and basic science realms. The central interest of the Liver Diseases Branch is viral hepatitis, the area in which I am most deeply involved. Viral hepatitis especially allows for questions which can be answered both at the bench and the bedside. There are few authentic models of viral hepatitis and I am interested in testing hypotheses in clinical situations which can be translated into laboratory projects. This is in many ways better than a model, it is a direct study of the relevant biology.

The study of acute hepatitis C is an example of this concept. How does hepatitis C, a RNA virus, develop into a persistent infection? The corollary is how is it cleared? The answer has implications for new therapies and the establishment of protective immunity. To this end we have studied people who have had exposure to hepatitis C and those who have developed acute hepatitis C. These patients are then treated if necessary. There is an obvious clinical aspect to this and we are exploring the virology through quasispecies evolution and sequence analysis. Furthermore through collaboration with Dr. Barbara Rehermann, the immunology of the acute infection, and changes in the immunology while patients are being treated, are also studied. A second current clinical project carried out in the same manner is the treatment of hepatitis D.

The Liver Diseases Branch has other treatment protocols for hepatitis B and C, nonalcoholic steatohepatitis, autoimmune hepatitis and primary biliary cirrhosis in which I participate. I also have clinical collaborations with other groups defining liver disease in unusual situations such as Turners Syndrome, Sickle Cell Disease, Chronic Granulomatous Disease, and Congenital Hepatic Fibrosis.

The laboratory work can be divided into two areas. Firstly the development of a tissue culture model for hepatitis C virion production and in turn utilizing this model to search for possible new therapies, as well as to elucidate the biology of hepatitis C. I am particularly interested in assembly and release of virions. While the development of the replicon has had a tremendous impact on furthering the understanding of replication, it does not model assembly and release of virions. This is a particularly unexplored part of the hepatitis C viral lifecycle. This model also permits study of different hepatitis C genotypes and their biological differences in hepatocytes.

Acute hepatitis C with treatment. Rahman et al Hepatology (40): 87-97 , 2004.(Click on image to enlarge)

Electron microscopy of hepatitis C particles (arrow) purified by sucrose gradient centrifugation. Bar represents 100nm. Heller et al. Proc Natl Acad Sci U S A (102): 2579-83 , 2005.
(Click on image to enlarge)

The second area of my laboratory research is the virology related to the clinical studies such as acute hepatitis C and hepatitis D. This represents a unique opportunity to assess basic virology in a well defined cohort of patients and to relate findings to clinical outcomes. It affords understanding of the clinical outcomes in terms of virology in individuals and groups of patients.

All of my work is carried out in the Liver Diseases Branch with the direct mentorship of T. Jake Liang, M.D., the branch chief. The clinical projects also benefit from the involvement and direction of Jay Hoofnagle, M.D.

1. Hussain N, Feld JJ, Kleiner DE, Hoofnagle JH, Garcia-Eulate R, Ahlawat S, Koziel DE, Anderson V, Hilligoss D, Choyke P, Gallin JI, Liang TJ, Malech HL, Holland SM, Heller T Hepatic abnormalities in patients with chronic granulomatous disease. Hepatology(45): 675-83, 2007. [Full Text/Abstract]

2. Saito S, Heller T, Yoneda M, Takahashi H, Nakajima A, Liang JT Lifestyle-related diseases of the digestive system: a new in vitro model of hepatitis C virion production: application of basic research on hepatitis C virus to clinical medicine. J Pharmacol Sci(105): 138-44, 2007. [Full Text/Abstract]

3. Kato T, Matsumura T, Heller T, Saito S, Sapp RK, Murthy K, Wakita T, Liang TJ Production of infectious hepatitis C virus of various genotypes in cell cultures. J Virol(81): 4405-11, 2007. [Full Text/Abstract]

4. Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, Borg B, Loomba R, Liang TJ, Premkumar A, Hoofnagle JH The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology(46): 424-9, 2007. [Full Text/Abstract]

5. Gunay-Aygun M, Avner ED, Bacallao RL, Choyke PL, Flynn JT, Germino GG, Guay-Woodford L, Harris P, Heller T, Ingelfinger J, Kaskel F, Kleta R, Larusso NF, Mohan P, Pazour GJ, Shneider BL, Torres VE, Wilson P, Zak C, Zhou J, Gahl WA Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a First National Institutes of Health/Office of Rare Diseases conference. J Pediatr (149): 159-164, 2006. [Full Text/Abstract]

6. Lutchman G, Promrat K, Kleiner DE, Heller T, Ghany MG, Yanovski JA, Liang TJ, Hoofnagle JH Changes in serum adipokine levels during pioglitazone treatment for nonalcoholic steatohepatitis: relationship to histological improvement. Clin Gastroenterol Hepatol (4): 1048-52, 2006. [Full Text/Abstract]

7. Little JA, McGowan VR, Kato GJ, Partovi KS, Feld JJ, Maric I, Martyr S, Taylor JG 6th, Machado RF, Heller T, Castro O, Gladwin MT Combination erythropoietin-hydroxyurea therapy in sickle cell disease: experience from the National Institutes of Health and a literature review. Haematologica (91): 1076-83, 2006. [Full Text/Abstract]

8. Garcia-Eulate R, Hussain N, Heller T, Kleiner D, Malech H, Holland S, Choyke PL CT and MRI of hepatic abscess in patients with chronic granulomatous disease. AJR Am J Roentgenol (187): 482-90, 2006. [Full Text/Abstract]

9. O''Brien K, Hussain N, Warady BA, Kleiner DE, Kleta R, Bernardini I, Heller T, Gahl WA Nodular regenerative hyperplasia and severe portal hypertension in cystinosis. Clin Gastroenterol Hepatol (4): 387-94, 2006. [Full Text/Abstract]

10. Reshamwala PA, Kleiner DE, Heller T Nodular regenerative hyperplasia: not all nodules are created equal. Hepatology (44): 7-14, 2006. [Full Text/Abstract]

11. Perumalswami P, Kleiner DE, Lutchman G, Heller T, Borg B, Park Y, Liang TJ, Hoofnagle JH, Ghany MG Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology (43): 780-7, 2006. [Full Text/Abstract]

12. Heller T, Rehermann B Acute hepatitis C: a multifaceted disease. Semin Liver Dis (25): 7-17, 2005. [Full Text/Abstract]

13. Heller T, Saito S, Auerbach J, Williams T, Moreen TR, Jazwinski A, Cruz B, Jeurkar N, Sapp R, Luo G, Liang TJ An in vitro model of hepatitis C virion production. Proc Natl Acad Sci U S A (102): 2579-83, 2005. [Full Text/Abstract]

14. Soza A, Heller T, Ghany M, Lutchman G, Jake Liang T, Germain J, Hsu HH, Park Y, Hoofnagle JH Pilot study of interferon gamma for chronic hepatitis C. J Hepatol (43): 67-71, 2005. [Full Text/Abstract]

15. Heller T, Seeff LB Viral load as a predictor of progression of chronic hepatitis C? Hepatology (42): 1261-3, 2005. [Full Text/Abstract]

16. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang TJ, Yanovski JA, Kleiner DE, Hoofnagle JH A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology (39): 188-96, 2004. [Full Text/Abstract]

17. Rahman F, Heller T, Sobao Y, Mizukoshi E, Nascimbeni M, Alter H, Herrine S, Hoofnagle J, Liang TJ, Rehermann B Effects of antiviral therapy on the cellular immune response in acute hepatitis C. Hepatology (40): 87-97, 2004. [Full Text/Abstract]

18. Radaeva S, Jaruga B, Kim WH, Heller T, Liang TJ, Gao B Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C. Biochem J (379): 199-208, 2004. [Full Text/Abstract]

19. Liang TJ, Heller T Pathogenesis of hepatitis C-associated hepatocellular carcinoma. Gastroenterology (127): S62-71, 2004. [Full Text/Abstract]

20. Promrat K, McDermott DH, Gonzalez CM, Kleiner DE, Koziol DE, Lessie M, Merrell M, Soza A, Heller T, Ghany M, Park Y, Alter HJ, Hoofnagle JH, Murphy PM, Liang TJ Associations of chemokine system polymorphisms with clinical outcomes and treatment responses of chronic hepatitis C. Gastroenterology (124): 352-60, 2003. [Full Text/Abstract]

21. Heller T, Hoofnagle JH Denying the wolf access to sheep''s clothing. J Clin Invest (112): 319-21, 2003. [Full Text/Abstract]

22. Hoofnagle JH, Ghany MG, Kleiner DE, Doo E, Heller T, Promrat K, Ong J, Khokhar F, Soza A, Herion D, Park Y, Everhart JE, Liang TJ Maintenance therapy with ribavirin in patients with chronic hepatitis C who fail to respond to combination therapy with interferon alfa and ribavirin. Hepatology (38): 66-74, 2003. [Full Text/Abstract]

23. Triyatni M, Saunier B, Maruvada P, Davis AR, Ulianich L, Heller T, Patel A, Kohn LD, Liang TJ Interaction of hepatitis C virus-like particles and cells: a model system for studying viral binding and entry. J Virol (76): 9335-44, 2002. [Full Text/Abstract]

24. Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat K, Park Y, Liang TJ, Hoofnagle JH Neutropenia during combination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology (36): 1273-9, 2002. [Full Text/Abstract]

25. Sarkodee-Adoo C, Pittarelli L, Jaffe E, Sorbara L, Raffeld M, Yao X, Haddad R, Heller T Regression and clonally distinct recurrence of human immunodeficiency virus related Burkitt-like lymphoma during antiretroviral therapy. Leuk Lymphoma (42): 1125-31, 2001. [Full Text/Abstract]

26. Heller T, Drachenberg CB, Orens JB, Fantry GT Primary posttransplant lymphoproliferative disorder of the gallbladder in a lung transplant patient presenting with acute cholecystitis. Transplantation (69): 668-70, 2000. [Full Text/Abstract]

27. Darwin P, Zangara J, Heller T, Haluszka O, Laurin J Unsedated esophagoscopy for the diagnosis of esophageal varices in patients with cirrhosis. Endoscopy (32): 971-3, 2000. [Full Text/Abstract]

28. Heller T, James SP, Drachenberg C, Hernandez C, Darwin PE Treatment of severe esophageal Crohn''s disease with infliximab. Inflamm Bowel Dis (5): 279-82, 1999. [Full Text/Abstract]

29. Heller T, Yin S, Tsarev SA, Purcell RH, Emerson SU False-positive serologic test resulting from a probable yeast infection in a chimpanzee. Clin Diagn Lab Immunol (3): 614-5, 1996. [Full Text/Abstract]

30. Tobi M, Darmon E, Phillips T, Heller T, Rozen P, Nochomovitz L, Steinberg W Increased expression of a putative adenoma-associated antigen in pre-colonoscopic effluent of patients with colorectal cancer. Cancer Lett (51): 21-5, 1990. [Full Text/Abstract]