Research Highlights
The independent research program in the Mass Spectrometry Laboratory at Children's Hospital Medical Center of Cincinnati has two major areas of focus:
- The role of nutrition, particularly phytoestrogens, in disease prevention and treatment
- The synthesis and metabolism of cholesterol and bile acids as they pertain to liver and gastrointestinal diseases
Role of Nutrition
We have a strong program of research on the role of nutrition, particularly phytoestrogens, in disease prevention and treatment for both adults and infants. Phytoestrogens are compounds that act like natural selective estrogen receptor modulators (SERMs) with the ability to confer the benefits, while lacking the negative characteristics of, estrogens. These compounds are found in soyfoods and flax, two foods now being intensely investigated for their health benefits.
Synthesis and Metabolism of Cholesterol and Bile Acids
We also are researching the synthesis and metabolism of cholesterol and bile acids as they pertain to liver and gastrointestinal diseases. As a result of the discovery of six genetic defects in bile acid synthesis, the division has developed an international clinical service for the screening, diagnosis and treatment of infants and children with liver disease caused by these inborn errors in bile acid metabolism.
Additionally, mass spectrometry supports the screening program for organic acidurias operated by the Division of Human Genetics, and we have begun to evaluate methods for detecting acylcarnitine deficiencies in newborn infants using electrospray mass spectrometry. The Micromass Quattro triple-quadrupole electrospray mass spectrometer, which complements the existing GC-MS techniques that are used, allows us to expand the repertoire of molecules that can be analyzed. This instrument has been used in a limited capacity to look at larger biomolecules and small molecules that are highly polar in nature. The instrument has been utilized to develop a number of drug assays and for limited protein analysis.
We are making progress in our continuing search for other explanations for familial cholestatic liver disease. We have identified a sixth defect in bile acid synthesis that presents as neonatal hepatitis. The defect involves a deficiency in the sterol 27-hydroxylase and results in diminished bile acid synthesis and, instead, the production of vast amounts of bile alcohol glucuronides and sulfates. The finding uncovers a new face on an old disease, since the same enzyme defect is associated with the rare lipid storage disease of cerebrotendinous xanthomatosis. This genetic defect is generally not detected in patients until the second or third decade of life and, to our knowledge, it has never previously been linked to neonatal hepatitis.
This discovery sheds light on the developmental pathways for bile acid synthesis and indicates that other typically minor pathways eventually kick in to compensate for reduced primary bile acid synthesis, leading to a resolution in the liver disease evident in early life. Diagnosis of this disorder is crucial to allow primary bile acid therapy to be initiated early to avoid the massive deposits of cholesterol that otherwise will occur in the brain and blood vessels of these patients if they are left untreated. Death is usually from atherosclerosis and dementia. In the case of this infant we have been able to initiate bile acid therapy in the first three months of life.
How to Reach Us
For more information, contact Kenneth D. Setchell, Ph.D., 513-636-4548.
