Now research performed at Washington University School of Medicine in St. Louis sheds light on the mechanisms that contribute to liver disease in alpha-1-AT deficiency patients. Using an experimental mouse model of the disorder, the researchers investigated the effects of a non-steroidal anti-inflammatory drug (NSAID) on liver injury. An estimated 15 to 20 million people in the United States take NSAIDs like ibuprofen and naproxen on a long-term basis.
The findings, published in the October issue of the journal Hepatology, show that the NSAID indomethacin (Indocin), administered at doses typically nontoxic to mice, significantly increased liver damage in the experimental mice.
The mice carried a mutated form of the human alpha-1-AT gene (called the alpha-1-ATZ gene), the most common form of the gene associated with the development of liver disease in people with alpha-1-AT deficiency. Greater expression of the mutant alpha-1-ATZ gene and increased amounts of alpha-1-ATZ protein in the liver accompanied the increase in liver injury in the experimental mice given the NSAID.
"These data demonstrate that environmental factors such as drug administration can affect the development of liver injury in this animal model," says lead author David Rudnick, M.D., Ph.D., assistant professor of pediatrics and of molecular biology and pharmacology. "And they raise the possibility that NSAIDs could have similar effects on gene and protein expression and perhaps on liver injury in people with alpha-1-AT deficiency."
Approximately 1 in 2,000 individuals has alpha-1-AT deficiency. Rudnick points out that even though alpha-1-AT deficiency is the most common genetic indication for pediatric liver disease and liver transplantation, a study to investigate whether NSAIDs affect human alpha-1-AT patients may not be feasible because of the disorder's relative rarity.
"But I tell my patients with any form of chronic liver injury they should avoid NSAIDs," says Rudnick, a pediatric gastroenterologist at St. Louis Children's Hospital. "The drugs have an established potential hepatotoxicity. I would say alpha-1-AT deficiency liver disease is another example where these drugs should be avoided."
Normally, the liver secretes alpha-1-AT protein into the bloodstream, but the abnormal protein, alpha-1-ATZ, can get "stuck" in liver cells. Liver biopsies of alpha-1-AT deficiency patients reveal that their liver cells have numerous globules containing alpha-1-ATZ protein.
The defective alpha-1-ATZ doesn't reach the lungs, where alpha-1-AT normally regulates enzymes that digest protein. Loss of alpha-1-AT's regulation of protein-digesting enzymes in the lungs can result in tissue damage and emphysema.
In ways not yet entirely understood, accumulation of alpha-1-ATZ in the liver can lead to both liver damage and liver cancer. In the mice carrying the human alpha-1-ATZ gene, the NSAID indomethacin not only caused liver cells to accumulate even more of the abnormal alpha-1-ATZ protein but also to proliferate or multiply faster than usual -- a hallmark of liver response to injury.
People who have alpha-1-AT deficiency vary widely in the severity of liver injury: some patients never have liver problems while others will require a liver transplant before they are two years old. Only 10 to 20 percent of infants with alpha-1-ATZ genes will develop clinically overt liver damage.
"We don't yet know the mechanism accounting for such wide variability in this disorder, but other genetic and environmental factors must contribute," Rudnick says. "The effect of indomethacin on these transgenic mice suggests that NSAIDs may be an example of such an environmental influence."
Gwen Ericson | EurekAlert!
'Lipid asymmetry' plays key role in activating immune cells
20.02.2018 | Biophysical Society
New printing technique uses cells and molecules to recreate biological structures
20.02.2018 | Queen Mary University of London
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
20.02.2018 | Life Sciences
20.02.2018 | Medical Engineering
20.02.2018 | Physics and Astronomy