Herbert L. Bonkovsky, MD
Vice President for Research, Carolinas HealthCare System
Director of Liver, Digestive, and Metabolic Disorders Laboratory
Department of Internal Medicine
Professor, University of Connecticut
Professor, University of North Carolina at Charlotte
Professor, University of North Carolina at Chapel Hill

Prior Positions and Experience

2007-present	Vice President for Research at Carolinas Medical Center, Carolinas HealthCare System
2008-present	Professor of Biology, University of North Carolina and University of North Carolina at Charlotte
2005-2008	Consulting Staff, Hartford Hospital
2007-present	Attending and Consulting Staff, Carolinas Medical Center
2002-2007	Director, The General Clinical Research Center and the Liver-Biliary-Pancreatic Center, University of Connecticut Health Center (Farmington, Conn.)
2002-present	Professor of Medicine and Molecular Biology, University of Connecticut Health Center (Farmington, Conn.)
2002-present	Attending physician, John Dempsy Hospital

Education

AB (summa cum laude): 1963, Earlham College (Richmond, Ind.)
MD: 1967, Case Western Reserve University (Cleveland)

Clinical and Translational Research in Liver, Digestive, and Metabolic Diseases

Throughout a medical career now spanning more than 40 years, Dr. Bonkovsky has been committed to Clinical and Translational Research. His research career began in medical school when he performed studies on interactions of iron with mitochondria in the laboratories of L.T. Webster, Jr. and J.W. Harris at Case Western Reserve University School of Medicine. This began a continuing interest in the study of iron metabolism and disorders of iron metabolism, especially various forms of hemochromatosis. During this time, Dr. Bonkovsky also worked closely with G. Gabuzda and L. Shear. This work led to a landmark paper that described clearly the occurrence of renal tubular acidosis in a subset in patients with hepatic cirrhosis and its importance as a risk factor for development of hepatic encephalopathy [NEJM 1969; 280: 1-7].

Dr. Bonkovsky spent two years as a clinical associate in the Metabolism Branch in the National Cancer Institute, where his mentors were N.I. Berlin and D.P. Tschudy. During this time, he carried out groundbreaking studies in the laboratory and in the general clinical research center on the nature of the enzymatic defects that underlie the porphyrias. He was among the first to show that hepatic porphyrin and heme synthesis is under the negative feedback regulatory control of heme itself, acting chiefly to down-regulate delta-aminolevulinic acid (ALA) synthase-1 the rate controlling enzyme for heme synthesis. This led Dr. Bonkovsky to develop parenterally-administered heme as therapy of acute attacks of porphyria, which is still today the treatment of choice for these life-threatening attacks.

In other work on the porphyrias, Dr. Bonkovsky identified deficiency of ferrochelatase, the final enzyme in the heme synthetic pathway as the fundamental metabolic defect in erythropoietic protoporphyria. Studies on the regulation of hepatic heme metabolism, especially the mechanisms and factors that regulate ALA synthase and heme oxygenase have been the subject of a large number of studies, both in the basic research laboratory and the clinical research center during the past 25 years. Dr. Bonkovsky has been fortunate to have had major RO1 grant funding from NIH (NIDDK) continually for the past quarter century to help support this research.

Other areas of special interest and accomplishment have more recently included a number of clinical trials and studies in chronic viral hepatitis, especially chronic hepatitis C. Dr. Bonkovsky continues to serve as one of the principal investigators of the NIH-sponsored HALT-C Trial, which has been designed to try and improve the treatment and outcome for patients with difficult to cure chronic hepatitis C. He has performed a number of investigator-initiated and industry-sponsored trials of possible new therapies for chronic hepatitis C, including phase 1 to phase 4 studies. Because the conquest of chronic hepatitis C continues to be elusive, Dr. Bonkovsky continues to be actively involved in such studies now carried out at the Center for Clinical and Translational Research at Carolinas Medical Center.

Another major cause of liver disease is liver injury due to drugs and other chemicals. Dr. Bonkovsky has performed both basic and clinical studies on alcoholic liver disease and its management and on drug-induced liver injury (DILI). He is one of the principal investigators of the NIH–supported national Drug Induced Liver Injury Network (DILIN). This ongoing active network has developed a registry of patients with clinically important DILI and repositories of serum, DNA, urine and other samples from such patients. Other ongoing activities of the network include several important ancillary studies examining the genetic underpinnings of toxicity caused by drugs and chemicals, genome wide association studies looking for new genetic variations that increase the risk of development of DILI, the characterization of infiltrating lymphocytes in liver biopsies of patients with DILI and the development of improved laboratory methods for lymphocyte stimulation tests as an aide to the diagnosis of DILI and the assignation of causative agents in DILI.

The overarching vision of Dr. Bonkovsky for research at Carolinas HealthCare System is to develop core facilities and infrastructure needed for investigators throughout the system to be successful and productive in performing both bench and clinical and translational research of all kinds that is at the cutting edge with the ultimate goals always to relieve human suffering and improve the art and science of contemporary medicine.

Recent Publications

Sendi H, Mehrab-Mohseni M, SHahraz S, Norder H, Seyed-Moayed A, Noorinayer B, Zali MR, Pumpens P, Bonkovsky HL, Magnius LO. CTL escape mutations of core proteins are more frequent in strains of HBeAg negative patients with low levels of HBV DNA. J Clin Virol 46(3): 259-264. [PMID: 19748824]

Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 29: 412-422, 2009 [PMID:19826975]

Rusti VK, Lee WM, Lawitz E, Gordon SC, Afdhal N, Poordad F, Bonkovsky HL, Bengtsson L, Chandorkar G, Harding M, McNair L, Aalyson M, Alam J, Kauffman R, Gharakhanian S, McHutchison JG, on behalf of the MErimepodib Triple cOmbination (METRO) Study Group. Merimepodib, pegylated interferon, and ribavirin in genotype-1 chronic hepatitis C pegylated interferon and ribavirin non-responders: a randomized study. Hepatology, 2009. Epub ahead of print [PMID: 19852040]

Panov A, Schonfeld P, Dikalov S, Hemendinger R, Bonkovsky HL, Brooks BR. The neuromediator glutamate, through specific substrate interactions, enhances mitochondrial ATP production and ROS generation in nonsynaptic brain mitochondria. J Biol Chem 284: 14, 448-56, 2009 [PMID: 19304986]

Welzel TM, Morgan TR, Bonkovsky HL, Naishadham D, Pfeiffer RM, Wright EC, Hutchinson AA, Crenshaw A, Bashirova A, Carrington M, Dotrang M, Sterling RK, Lindsay KL, Fontana RJ, Lee WM, Di Bisceglie AM, Ghany MG, Gretch DR, Chancok SJ, Chung RT, O'Brien TR, HALT-C Trial Group. Variants in interferon-alpha pathway genes and response to pegylated interferon-alpha 2a plus ribavirin for treatment of chronic hepatitis C virus infection in the hepatitis C antiviral long-term treatment against cirrhosis trial. Hepatology 49: 1847-1858, 2009 [PMID: 19434718]

Hou W, Rossi L, Shan Y, Zheng J-Y, Lambrecht RW, Bonkovsky HL. Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells. World J Gastroent 15: 4499-4510, 2009. [PMID: 1977608]

Fontana RJ, Bonkovsky HL, Naishadham D, Dienstag JL, Sterling RK, Lok ASF, Su GL, and the HALT-C Trial Group. Serum fibrosis markers during pegylated interferon and ribavirin treatment of patients with chronic hepatitis C: a report from the HALT-C Trial. [Publication #36 from the HALT-C Trial Group] Clin Gastroent & Hepatol 7: 219-226, 2009 [PMID: 19068241]

Venkataraman K, Lee YM, Michaud J, Ai Y, Thangada S, Ai Y, Bonkovsky HL, Parikh NS, Habrukowich C, and Hla T. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circulation Research 102: 669-676, 2008. [PMID: 18258856] 

Desai TK, Jamil LH, Balasubramanian M, Koff RS, and  Bonkovsky HL. Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials. Digestive Diseases and Sciences 53: 815-822, 2008. [PMID: 17846887] 

Fontana RM, Goodman ZD, Dienstag JL, Bonkovsky HL, Naishadham D, Sterling RK, Su GL, Ghosh M, Wright EL, and the HALT-C Trial Group. Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. (Paper #26 from the HALT-C Trial Group). Hepatology 47: 789-798, 2008. [PMID: 18175357] [Comment in Hepatology 48: 688-689; author reply 689-690, 2008]

Lindsay KL, Morishima C, Wright EC, Dienstag JL, Shiffman ML, Everson GT, Lok ASF, Bonkovsky HL, Lee WM, Morgan TR, Ghany MG, and the HALT-C Trial Group. Blunted cytopenias and weight loss: new correlates of virologic null response to retreatment of chronic hepatitis C. (Paper #15 from the HALT-C Trial Group). Clin Gastroenterol Hepatol 6: 234-241, 2008. [PMID: 18237873] 

Zheng J, Tian Q, Hou W, Watts JA, Schrum LW, Bonkovsky HL. Tissue-specific expression of expression of ALA synthase-1 and heme oxygenase-1 and their expression in livers of rats chronically exposed to ethanol.  FEBS Letters 528: 1829-1834, 2008. [PMID: 18472004]

Bonkovsky HL, Tice AD, Yapp RG, Bodenheimer HC Jr., Monto A, Rossi SJ, Sulkowski MS. Efficacy and safety of peginterferon alfa-2a/ribavirin in methadone maintenance patients: randomized comparison of direct observed therapy and self-administration. Amer J Gastroenterology 103: 1-9, 2008. [PMID: 18684176] 

Thapar M, Bonkovsky HL. The diagnosis and management of erythropoietic protoporphyria. Gastroenterology & Hepatology 4: 561-566, 2008.

Morgan TR, Lambrecht RW, Bonkovsky HL, Chung RT, Naishadham D, Sterling RK, Fontana RJ, Lee WM, Ghany MG, Wright EC, O'Brien TR, and the HALT-C Trial Group. DNA polymorphisms and response to treatment in patients with chronic hepatitis C: results from the HALT-C Trial. (Publication #30 from the HALT-C Trial Group). J Hepatology 49: 548-556, 2008. [PMID: 18619701] 

Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary hemochromatosis: time for targeted screening. Annals of Internal Medicine 149: 270-272, 2008. [PMID: 18711158] 

Bonifaz V, Shan Y, Lambrecht RW, Donohue SE, Moschenross D, Bonkovsky HL. Effects of silymarin on hepatitis C virus and haem oxygenase-1 gene expression in human hepatoma cells. Liver Intl 29: 366-373, 2009. [PMID: 18694403]

Lok AS, Seeff LB, Morgan TR, Di Bisceglie AM, Sterling RK, Curto TM, Everson GT, Lindsay KL, Lee WM, Bonkovsky HL, Dienstag JL, Ghany MG, Morishima C, Goodman ZD, and the HALT-C Trial Group. Incidence of Hepatocellular Carcinoma and Associated Risk Factors in Hepatitis C-Related Advanced Liver Disease. Gastroenterology 2009; 136: 138-148 [PMID: 18848939]

Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J, for the DILIN Study Group. Rationale, design and conduct of the Drug-Induced Liver Injury Network (DILIN) prospective study. Drug Safety, 32: 55-68, 2009. [PMID: 19132805] [Publication #2 from the US DILIN]

Zheng J-Y, Shan Y, Lambrecht RW, Donohue SE, Bonkovsky HL. Differential regulation of human 5-aminolevulinate synthase 1 (ALAS1) mRNA and protein levels by heme and cobalt protoporphyrin. Molecular and Cellular Biochemistry, 2008; ePub. Mcbi-2059.1. Doi 10.1007/s 11010-008-9888-0. [PMID: 18719978]

Di Bisceglie AM, Shiffman ML, Lindsay KL, Everson GT, Lindsay, KL, Everhart JE, Wright EC, Lee WM, Bonkovsky HL, Morgan TR, Dienstag JL, Ghany MG, Morishima C, Snow KK, for the HALT-C Trial Group.  Prolonged therapy of advanced chronic hepatitis C with low-dose peginterferon (Publication #29 from the HALT-C Trial Group). N Engl J Med 2008; 359: 2429-2441. [PMID: 19052125]

Bonkovsky HL, Siao P, Roig Z, Hedley-Whyte ET, Flotte T.  A woman with abdominal pain and weakness after gastric bypass surgery.  Diagnosis--acute porphyria.  Case Records of the Massachusetts General Hospital.  N Engl J Med 2008; 358: 2813-2825 [PMID: 18579817].

Seeff LB, Curto TM, Szabo G, Everson GT, Bonkovsky HL, Dienstag JL, Shiffman ML, Lindsay KL, Lok ASF, Di Bisceglie AM, Lee WM, Ghany MG, and the HALT-C Trial Group.  Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial.  Hepatology 2008;47: 605-612 [PMID: 18157835]

Current, Recent and Pending Grant Support

Grant Title: The drug-induced liver injury network
Funding Agency: NIH, NIDDK, UO1 Award
Role: Principal Investigator
Years: 2003-2013

Grant Title: Regulation of hepatic heme metabolism
Funding Agency: NIH, NIDDK—RO1 Award
Role: Principal Investigator
Years: 1987-2010

Grant Title: Heme oxygenase in health and disease
Funding Agency: American Porphyria Foundation
Role: Principal Investigator
Years: 2007-2009

Grant Title: The HALT-C Trial
Funding Agency: NIH, NIDDK—NO1 Award
Role: Principal Investigator
Years: 1999-2009

Grant Title: The North Carolina Hepatitis B Clinical Research Network
Funding Agency: NIH, NIDDK
Role: Co-Investigator
Years: 2008-2015