Disrupted antioxidant balance linked to the development of “Skellefteå disease”

Researchers at Umeå University have identified changes in the body’s major antioxidant systems in patients with hereditary transthyretin (TTR) amyloidosis. From left Anushree Bachhar, Melisnur Sahin, Intissar Anan och Anders Olofsson. 

ImageUmeå university

ATTR amyloidosis is a serious and progressive disease in which the protein transthyretin, TTR, misfolds and forms amyloid deposits in the body’s tissues. These deposits can damage the nerves, heart, gastrointestinal tract and other organs. In northern Sweden, the disease is relatively common because of the hereditary TTR-Val30Met mutation, which has given rise to the name “Skellefteå disease”.

Although the genetic cause has been known for many years, it remains unclear why some mutation carriers develop the disease early, others later in life, and some not at all.

In the current study, the researchers investigated whether the body’s redox balance - the balance between oxidising and reducing processes - may play an important role in disease development. Attention was given to glutathione, GSH, which is one of the body’s most important defenses against oxidative stress.

The results showed that patients with clinically manifest ATTR amyloidosis had markedly elevated levels of pyroglutamate, PGA, a marker that reflects glutathione metabolism. The researchers also found signs of increased activity of the enzyme IDO1, which is associated with inflammation. Taken together, the findings indicate that disrupted antioxidant balance and inflammatory activation are closely linked to disease development.

“Our results support a model in which the genetic TTR variant is not the only factor that determines whether and when the disease develops. The body’s ability to maintain a functional redox balance may also be important,” says Anders Olofsson, Associate Professor and Senior Lecturer at the Department of Clinical Microbiology at Umeå University, who led the study.

New biomarkers may identify individuals at risk

The findings have also enabled the development of a biomarker model based on PGA and the inflammatory marker IDO1. The model can identify individuals at increased risk of developing the disease with an accuracy of approximately 80 percent in women and close to 90 percent in men.

The results raise the possibility of identifying mutation carriers who are approaching the onset of symptoms and introducing appropriate preventive measures before tissue damage becomes permanent.

“These biomarkers could become a valuable complement to the clinical monitoring of individuals with hereditary ATTR amyloidosis,” says the study’s first author, Anushree Bachhar, a postdoctoral researcher at the Department of Clinical Microbiology at Umeå University.

May pave the way for new treatment strategies

The findings also strengthen the hypothesis that oxidative stress and inflammation contribute to the disease process. This raises the question of whether treatments that affect the body’s antioxidant defences could slow or delay disease development.

However, the researchers emphasise that the current study does not demonstrate that antioxidant treatment is effective in ATTR amyloidosis. Clinical studies in which the effects of different interventions are monitored over time will be required to investigate this possibility. Work to initiate such studies is ongoing and is considered a high priority.