High Blood Levels of Liver Enzyme Linked to Sex-specific Parkinson’s Risk in Korean Study

Elevated blood levels of the liver enzyme gamma-glutamyltransferase (GGT), a marker for liver disease, was found to be associated with an increased risk of Parkinson’s disease in Korean women and a lower risk in Korean men, a large-scale study  found.

These sex-specific associations held after adjusting for factors that influence GGT levels, such as age, income status, body mass index (BMI), smoking habits, and alcohol consumption.

Although this study was conducted only in a Korean population, its results suggest that blood tests for GGT may be a useful marker for Parkinson’s disease risk.

The study, “Serum gamma-glutamyltransferase activity and Parkinson’s disease risk in men and women,” was published in Nature Scientific Reports. 

A process known as oxidative stress is thought to be one of the underlying mechanisms that lead to nerve cell damage or death in Parkinson’s. 

Oxidative stress occurs when there is an imbalance in the production of reactive oxygen molecules — called free radicals — and molecules that neutralize free-radicals, known as antioxidants. An excess of free radicals can oxidize proteins, lipids, and DNA, damaging the cellular components. 

Gamma-glutamyltransferase (GGT) is an enzyme primarily located in the membrane of liver cells, and is a blood marker for various conditions affecting the liver. Elevated levels of GGT in the blood are also associated with conditions like heart disease and stroke, as well as with metabolic syndrome (high blood pressure, high blood sugar, and excess body fat) and dementia.

GGT has also been implicated in oxidative stress, and given the connection between oxidative stress and Parkinson’s disease, GGT may also be a blood marker for Parkinson’s. 

To determine if such a relationship exists, researchers at Seoul National University College of Medicine in South Korea designed a study tracking millions of Korean citizens via use of that country’s National Health Insurance Service (NHIS) database.

Registration in the NHIS database has been mandatory for all citizens since 1989, and people over the age of 40 are advised to undergo a health screening every two years. The database accordingly holds detailed patient information, including demographics, blood tests (including of liver enzymes), health habits, body measurements, and factors like heart attack and stroke risk.

These data allowed investigators to follow almost 6.1 million adults (6,098,405) from 2009 through 2016. They recorded newly diagnosed cases of Parkinson’s to compare with levels of GGT from blood tests. 

During a median follow-up of 6.4 years, 20,895 Koreans developed Parkinson’s disease. Of these, 9,512 were men (0.33%) and 11,383 were women (0.35%). 

Higher levels of GGT in women were found to be significantly associated with an increased risk of Parkinson’s, while in men, elevated GGT in men was significantly linked to a lower risk of developing the disease. 

Women with the highest GGT levels had a hazard ratio of 1.33, with ratios above 1 representing a higher Parkinson’s risk. But men with the highest GGT levels had a hazard ratio of 0.67, indicating a lower risk. 

An initial analysis of the data found blood levels of GGT varied based on factors such as age, income status, body mass index (BMI), smoking, and alcohol consumption. 

When the team statistically adjusted for these factors, and for exercise, high GGT levels still showed a significant link to Parkinson’s disease risk, with that risk again being greater in women and lesser in men. 

This relationship remained after analyzing this sex-specific association across age groups, except for men older than 80. 

“The biological mechanism of serum GGT in these conditions is suggested to be associated with inflammation and oxidative stress,” the study noted. “Because abnormal protein aggregation, mitochondrial dysfunction resulting in oxidative stress, and neuroinflammation are the possible pathogenic mechanism of PD, GGT may be linked to the risk of PD development through inflammatory and oxidative stress reactions.”

As GGT levels may be related to the presence of fatty liver, investigators also looked for a possible link between GGT and obesity or metabolic syndrome and the risk of Parkinson’s.

For both men and women, a risk of Parkinson’s was seen to be greater in those who were obese or had metabolic syndrome. This finding was in line with previous research. 

But while no significant link between GGT levels and obesity with Parkinson’s was seen in men, a positive significant association was identified for women.

Estrogen, the primary female sex hormone, may be a reason for these sex-specific differences, the researchers said. Previous studies suggest this hormone is protective against Parkinson’s, but as women in middle-age go through menopause, their estrogen levels fall.

GGT blood levels are also known to be “inversely associated with estrogen,” the researchers wrote, speculating that “this could partially explain the sex-specific relationship between GGT and PD.”

They concluded, “this nationwide big data cohort analysis showed that the serum GGT level has a significant impact on the risk of PD, with a differential association in men and women.”

Further research is now needed to validate “serum GGT as a marker predicting PD risk in other ethnic populations.”