Herbert Bokovsky

Herbert L. Bonkovsky, MD

Professor of Medicine
Senior Advisor for Research, Atrium Health
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

Education

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

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. Dr. Bonkovsky serves as one of the Principal Investigators of the U.S. Porphyria Consortium, one of the Rare Diseases Consortia, supported by the NIH and Office of Rare Diseases Research. CHS is one of six clinical sites across the country that serve as Clinical Centers of Excellence in the Porphyrias.

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 Atrium Health 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

Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Buckett D, Porter-Gill P, Kohaar I, Brand N, Chen S, Tarway McA, Mumy A, Asatemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O’Brien TR.  A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus.  Nature Genetics 2013;45(2):164-171. [PMID 23291588]

Balwani M, Doheny D, Bishop DF, Nazarenko I, Yasuda M, Dailey HA, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, Liu L, Desnick RJ.  Loss-of-function ferrochelatase and gain –of –function erythroid 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutation and a high prevalence of X-linked protoporphyria.  Molec Medicine. 2013 Apr;19:26-35.  [PMID: 23364466]

Bonkovsky HL, Guo JT, Hou W, Li T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. Compr Physiol. 2013 Jan;3(1):365-401. [PMID: 23720291]

Bonkovsky HL, Hou W, Steuerwald N, Tian Q, Parsons J, Hamilton A, Hwang S, Schrum L.  Heme status affects human hepatic messenger RNA and microRNA expression.  World J Gastroenterol. 2013 Mar;19 (10): 1593-1601.  [PMID  23538684]

Larion S, Caballes FR, Hwang S-I, Lee J-G, Rossman WE, Parsons J, Steuerwald N, Li T, Maddukuri V, Groseclose G, Finkielstein CV, Bonkovsky HL.  Circadian rhythms in acute intermittent porphyria—a pilot study.  Eur J Clin Invest. 2013 Jul; 43(7): 727-739, 2013. [PMID 23650938]

Maddukuri VC, Russo MW, Ahrens WA, Emerson SU, Engle RE, Purcell RH, Thompson EB, Bonkovsky HL.  Chronic hepatitis E with neurologic manifestations and rapid progression of liver fibrosis in a liver transplant recipient.  Dig Dis Sci. 2013;58(8): 2413-16. [PMID 23512404]

Fontana RJ, Hayashi PH, Bonkovsky HL, Kleiner DE, Kochbar S, Gu J, Ghabril M.  Presentation and outcomes with clinically apparent interferon beta hepatotoxicity.  [Publication #19 from the US Drug-Induced Liver Injury Network].  Dig Dis Sci.,2013 Jun;58(6): 1766-1775. [PMID 23377559]

Ghabril M, Bonkovsky HL, Kum C, Davern T, Hayashi PH, Kleiner DE, Serrano J, Rochon J, Fontana RJ, Bonacini M, for the US Drug-Induced Liver Injury Network Investigators.  Liver injury from tumor necrosis factor alpha antagonists:  analysis of thirty-four cases.  [Publication #21 from the US Drug-Induced Liver Injury Network].  Clin Gastroenterol Hepatol.  2013 May;11(5): 558-564.  [PMID: 23333219]

Rakoski MO, Brown MB, Fontana RJ, et al. Mallory-Denk bodies are associated with outcomes and histologic features in patients with chronic hepatitis C. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2011;9:902-9 e1. [PMID: 21782771]

O'Brien TR, Everhart JE, Morgan TR, et al. An IL28B genotype-based clinical prediction model for treatment of chronic hepatitis C. PloS one 2011;6:e20904. [PMID: 21760886]

Tian Q, Li T, Hou W, Zheng J, Schrum LW, Bonkovsky HL. Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells. The Journal of biological chemistry 2011;286:26424-30. [PMID: 21659532]

Panov AV, Kubalik N, Zinchenko N, et al. Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology. American journal of physiology Regulatory, integrative and comparative physiology 2011;300:R844-54. [PMID: 21248309]

Dienstag JL, Ghany MG, Morgan TR, et al. A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C. Hepatology 2011;54:396-405. [PMID: 21520194]

Di Bisceglie AM, Stoddard AM, Dienstag JL, et al. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon. Hepatology 2011;53:1100-8. [PMID: 21480316]

Mehrab-Mohseni M, Sendi H, Steuerwald N, Ghosh S, Schrum LW, Bonkovsky HL. Legalon-SIL downregulates HCV core and NS5A in human hepatocytes expressing full-length HCV. World journal of gastroenterology : WJG 2011;17:1694-700. [PMID: 21483629]

Lambrecht RW, Sterling RK, Naishadham D, et al. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology 2011;140:1490-500 e3. [PMID: 21335007]

Li T, Bonkovsky HL, Guo JT. Structural analysis of heme proteins: implications for design and prediction. BMC structural biology 2011;11:13. [PMID: 21371326]

McKinney KQ, Lee YY, Choi HS, et al. Discovery of putative pancreatic cancer biomarkers using subcellular proteomics. Journal of proteomics 2011;74:79-88. [PMID: 20807598]

Lok AS, Everhart JE, Wright EC, et al. Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C. Gastroenterology 2011;140:840-9; quiz e12.[PMID: 21129375]

Fontana RJ, Dienstag JL, Bonkovsky HL, et al. Serum fibrosis markers are associated with liver disease progression in non-responder patients with chronic hepatitis C. Gut 2010;59:1401-9. [PMID: 20675691]

Steuerwald NM, Parsons JC, Bennett K, Bates TC, Bonkovsky HL. Parallel microRNA and mRNA expression profiling of (genotype 1b) human hepatoma cells expressing hepatitis C virus. Liver Int. 2010;30:1490-504. [PMID: 20825557]

Narang TK, Sendi H, Scobey M, Bonkovsky HL. Iron and hepatitis C. Current Hepatitis Reports 2010;9:169-77

Morgan TR, Ghany MG, Kim HY, et al. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology 2010;52:833-44. [PMID: 20564351]

Shiffman ML, Morishima C, Dienstag JL, et al. Effect of HCV RNA suppression during peginterferon alfa-2a maintenance therapy on clinical outcomes in the HALT-C trial. Gastroenterology 2009;137:1986-94. [PMID: 19747918]

Current, Recent and Pending Grant Support

Grant Title: The drug-induced liver injury network
Funding Agency: NIH, NIDDK, UO1 Award
Role: Principal Investigator
Years: 2003-2018

Grant Title: Effect of heme on mRNA and miRNA profiles
Funding Agency: NIH, NHLBI, R15 Award
Role: Principal Investigator
Years: 2013-2015

Grant Title: The US Porphyria Consortium
Funding Agency: NIH, NIDDK, Office of Rare Diseases, U54 Award
Role: Principal Investigator
Years: 2014-2018

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