Kenneth Setchell (Presenter)
Cincinnati Children’s Hospital Medical Center
Bio: Kenneth D. Setchell, PhD, joined the tenured faculty of the Department of Pediatrics, University of Cincinnati College of Medicine in 1984, having moved from the Clinical Research Centre of the Medical Research Council, (UK) where he previously held a tenured scientific position. In 1973 he obtained a PhD in steroid biochemistry from the University of London. He was then awarded a fellowship from The Royal Society for post-doctoral studies at the Karolinska Institute in Stockholm, Sweden (1974-1975) in the application of mass spectrometry to clinical and biomedical problems specifically relating to the steroid hormone field. He returned to the United Kingdom to a scientific position in the Division of Clinical Chemistry at the Medical Research Council's Clinical Research Centre where he continued his research in the field of steroids, expanding into cholesterol and bile acid metabolism as it related to gastrointestinal diseases. His parallel research discoveries of the first mammalian lignans later led to the discovery of soy isoflavones in humans, their association with soy intake, and established his research in the area of bioactive plant constituents and human nutrition and disease.
In September 1984, Dr. Setchell moved to Cincinnati to become director of a new Clinical Mass Spectrometry facility at Cincinnati Children's Hospital Medical Center, and he is now a tenured professor in the Department of Pediatrics at the UC College of Medicine. His research program is internationally recognized as a leader in several areas of research that established collaborations with other groups from England, Italy, Germany, France Sweden, Canada and Australia. He has consulted with pharmaceutical and food companies, and to industries involved in clinical and biochemical research. Dr. Setchell cites >200 scientific publications and has presented over 250 papers at national and international symposia, while serving on national and international committees and editorial boards of international journals. Dr. Setchell was awarded the 1997 Gilbride award by the Canadian Liver Foundation for his contributions to the diagnosis and treatment of liver disease. He received awards from the AOCS at the 3rd International Symposium on the "Role of Soy in Preventing and Treating Chronic Disease" in 1999 for his outstanding contributions to increasing understanding and awareness of the health benefits of soy foods and soybean constituents, and from North American Menopause Society (NAMS) 2000 annual award for his research on soy and women's health. He received the Roche 2003 International Award for Innovative Research in Human Nutrition for his discoveries of classes of phytoestrogens and the 2004 Adolf Windaus Prize for research on bile acids and the discovery of genetic defects in the cholesterol-bile acid pathway causing liver disease.
| Short Abstract This presentation will highlight how mass spectrometry was successfully applied to define new genetic defects in the cholesterol-bile acid biosynthetic pathway as a specific class of metabolic liver disease. Bile acid synthesis disorders due to single enzyme defects generally present in infancy or early childhood with a progressive cholestatic hepatitis that, unchecked, lead to cirrhosis, liver failure, and death. Prior to the seminal work of Setchell and colleagues in identifying 6 genetic diseases as discrete entities, and conceiving of an effective therapy, children with these autosomal recessive diseases either underwent liver transplantation, or more commonly, were given supportive care until they died of liver failure of unknown origin. To be described are the combined use an untargeted and targeted approach with FAB-MS, GC-MS and ESI-LC-MS/MS that led to the elucidation of the biochemical basis of these diseases, the development of an international screening program, and the evaluation of the therapeutic responses that served to ultimately gain regulatory approval from the FDA for a life-saving therapy based on oral administration of cholic acid. This application of mass spectrometry to clinical chemistry has been a game-changer that has led to a radical change in the evaluation and treatment of patients with idiopathic progressive familial intrahepatic cholestasis syndromes.1 |
Long Abstract
In 1919 Adolf Windaus made the critical discovery that coprostane could be oxidized to cholanic acid and thereafter recognized the close relationship between cholesterol and bile acids, and later, steroids and vitamin D. The pathway for bile acid synthesis was defined >60 years ago and the importance of bile acids in facilitating lipid absorption and liver function realized. The formation of bile acids in the liver involves a complex multi-stepped sequence of reactions in which the neutral sterol cholesterol is converted to the acidic steroids, cholic and chenodeoxycholic acids, referred to as primary bile acids1. The reactions in this pathway are catalyzed by at least 17 hepatic enzymes, but only in the last two-plus decades have disorders in bile acid synthesis become a recognizable cause of progressive familial intrahepatic cholestasis (PFIC), fatal forms of liver disease, thus defining a new category of ‘metabolic liver disease’. These discoveries were exclusively the result of the application of mass spectrometric techniques involving the use of the soft ionization technique of FAB-MS complemented by GC-MS, and later LC-MS/MS approaches to the metabolic profiling of a ‘drop of urine’ – it can be considered to represent an early successful example of ‘metabolomics’ long predating the coining of the ‘omics’ terminology. Rapid analysis of bile acids directly in urine samples with minimal sample preparation led to the discovery of the first 6 autosomal recessive single-enzyme genetic defects in the bile acid synthetic pathway. The biochemical basis of each defect was characterized, and these defects have accounted for approximately 2% of patients with idiopathic cholestasis screened in an international diagnostic screening program established in 1985 at Cincinnati Children’s Hospital Medical Center. Biochemically, all share the common feature of an absence of hepatic synthesis of the normal primary bile acids, cholic and chenodeoxycholic acids, that are essential for the promotion of bile flow, with concomitant elevated levels of atypical bile acids that are cholestatic and hepatotoxic. The clinical manifestation includes varying degrees of progressive intrahepatic cholestasis, fat-soluble vitamin malabsorption, and neurological disease. The poor prognosis for many of these patients prompted our development of a highly successful therapy based on oral administration of cholic acid. The hypothesis being that the toxic, hydrophobic bile acid intermediates that accumulate to abnormally high levels could through a feedback mechanism be suppressed with the expectation of a profound therapeutic effect in normalizing liver function. This hypothesis was confirmed by monitoring the disappearance of atypical bile acids with FAB-MS and ESI tandem mass spectrometry. Long-term survival and impressive clinical improvements including normalization in serum liver enzymes, and improvement in growth and liver histology is now the norm. Based on this successful therapeutic strategy, cholic acid therapy was recently approved by the European Medicines Agency and by FDA. This research program spanning some 30+ years highlights how mass spectrometry has been successfully applied to investigations of idiopathic liver disease in infants and children to define biochemical defects in cholesterol-bile acid biosynthetic pathway as the underlying cause, understanding the mechanism of liver injury, and developing a life-saving therapy.
References & Acknowledgements:
1. Russell DW, Setchell KDR. Bile Acid Biosynthesis. Biochemistry 1992; 31:4737-4749.
2. Clayton PT, Leonard JV, Lawson AM, Setchell KDR, Andersson S, Egestad B, Sjövall J. Familial giant cell hepatitis associated with synthesis of 3β,7α-dihydroxy- and 3β,7α,12α-trihydroxy-5-cholenoic acids. J. Clin. Invest. 1987;79:1031-1038.
3. Setchell K, Suchy F, Welsh M, Zimmer-Nechemias L, Heubi J, Balistreri W. Δ4-3-Oxosteroid 5β-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis. J. Clin. Invest. 1988;82:2148-2157.
4. Setchell KDR, Schwarz M, O'Connell N, Lund E, Davis D, Lathe R, Thompson H, Tyson R, Sokol R, Russell D. Identification of a new inborn error in bile acid synthesis: Mutation of the oxysterol 7α-hydroxylase gene causes severe neonatal liver disease. J. Clin. Invest. 1998;102:1690-1703.
5. Setchell KDR, Heubi JE, Bove KE, O'Connell NC, Brewsaugh T, Steinberg SJ, Moser A, Squires J, R. H. Liver disease caused by failure to racemize trihydroxycholestanoic acid: Gene mutation and effect of bile acid therapy. Gastroenterology 2003;124:217-232.
6. Setchell KDR, Heubi J. Defects in bile acid synthesis - diagnosis and treatment. J Pediatric Gastroenterol Nutr. 2006; 43:S17-S22.
7. Heubi JE, Setchell KDR, Bove K. Inborn errors of bile acid metabolism. Seminars in Liver Disease 2007;27: 282-294.
9. Setchell KDR, Bragetti P, Zimmer-Nechemias L, Daugherty C, Pelli MA, Vaccaro R, Gentili G, Distrutti E, Dozzini G, Morelli A, et al. Oral bile acid treatment and the patient with Zellweger syndrome. Hepatology 1992;15:198-207.
10. Gonzales E, Gerhardt MF, Fabre M, Setchell KDR, Davit-Spraul A, Vincent I, et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology 2009 Oct;137(4):1310-20 e1-3.
11. Molho-Pessach V, Rios JJ, Xing C, Setchell KDR, Cohen JC, Hobbs H. Homozygosity mapping identifies a bile acid synthetic defect in an adult with cirrhosis of unknown etiology. Hepatology 2012; 55:1139-1145.
12. Setchell KDR, Heubi JE, Shah S, Lavine JE, Suskind D, Al-Edreesi M, Potter C, Russell DW, O’Connell NC, Wolfe B, Jha P, Zhang W, Bove KE, Knisely AS, Hofmann AF, Rosenthal P, Bull LN. Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology 2013;144(5):945-55.
13. Heubi JE, SETCHELL KDR, Jha P, Buckely D, Zhang W, Rosenthal P, Potter C, Horslen S, Suskind D. Treatment of bile acid amidation defects with glycocholic acid. Hepatology 2014; 61(1): 268-274.
14. Zhang W, Jha P, Wolfe B, Gioiello A, Pellicciari R, Wang J, Heubi J, SETCHELL KDR. Tandem mass spectrometric determination of atypical 3β-hydroxy-Δ5-bile acids in patients with 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency: Application to diagnosis and monitoring of bile acid therapeutic response. Clinical Chemistry 2015; 61(7):955-963.
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