Higher gamma-glutamyl transferase levels predict greater systemic sclerosis risk
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Key takeaways:
- A study found that risk for systemic sclerosis was greatest in patients with the highest gamma-glutamyl transferase levels.
- The finding could lead to early SSc diagnosis and treatment.
Patients with higher levels of gamma-glutamyl transferase, and particularly men, demonstrate a significantly higher risk for systemic sclerosis, according to data published in Nature Scientific Reports.
“Early detection of SSc and timely implementation of treatment are important for better outcomes,” Oh Chan Kwon, MD, of Yonsei University College of Medicine, in Seoul, South Korea, and colleagues wrote. “Identification and close monitoring of individuals who are at a high risk of developing SSc could lead to earlier diagnosis and treatment.
“Given its pro-oxidant reactions, the implication of [gamma-glutamyl transferase (GGT)] in the pathogenesis of several diseases, including cardiovascular diseases, cancers, lung inflammation, and neurological diseases, is being actively researched,” they added. “However, currently there are no studies evaluating the implication of GGT in SSc. Considering that oxidative stress plays a crucial role in the pathogenesis of SSc, GGT may be a marker associated with the development of SSc.”
To examine the link between gamma-glutamyl transferase levels and the risk for SSc, Kwon and colleagues conducted a nationwide, retrospective cohort study of more than 6 million adults without SSc from the Korean National Health Insurance Service database.
The researchers classified baseline gamma-glutamyl transferase levels by quartile, with quartile one — less than21 IU/L for males andless than13 IU/L for females — representing the lowest 25%, and quartile four — 49 IU/L or greater for males, and22 IU/L or greater for females — representing the highest 25%. They then estimated the risk for developing SSc in each quartile from 2009 to 2019 using multivariable Cox proportional hazard models.
During a mean follow-up period of 9.2 ± 1.1 years, 654 — out of a total of 6,091,788 — developed SSc, representing an incidence rate of 1.16 per 100,000 person-years. After adjusting for covariates — age, sex, BMI, income, smoking status, alcohol consumption, physical activity, hypertension, type 2 diabetes, dyslipidemia and chronic kidney disease — those in the fourth quartile of gamma-glutamyl transferase levels demonstrated the highest risk for SSc, compared with those in the first quartile (adjusted HR = 1.807; 95% CI, 1.446-2.259), according to the researchers.
From there, the risk for SSc decreased through the third (aHR = 1.221; 95% CI, 0.971-1.536) and second (aHR = 1.034; 95% CI, 0.807-1.324) quartiles.
According to the researchers, a subgroup analysis suggested that the link between higher gamma-glutamyl transferase levels and SSc was more prominent in men than women. Men in the fourth quartile demonstrated an adjusted HR of 2.483 for developing SSc compared with men in quartiles one through three, while fourth-quartile women had an adjusted HR of 1.504 compared with women in the lower quartiles.
“Higher GGT levels were independently associated with an increased risk of incident SSc,” Kwon and colleagues wrote. “The effect size increased gradually as the GGT level rose within the upper normal limit, and exponentially increased when the GGT level rose above the upper normal limit. Regardless of whether the GGT level was above the upper normal limit or not, the effect size increased significantly as the GGT level rose. Our data suggest that individuals with higher levels of GGT could be considered as having an increased risk of developing SSc.
“Thus, the clinicians should be aware that close monitoring for the development of SSc is warranted in individuals with higher GGT levels,” they added. “This could eventually lead to an early diagnosis and treatment of SSc.”
Perspective
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David A. McLain, MD, MACR, FACP, FRCP
Gamma-glutamyl transferase (GGT) is found in the cell membranes of various tissues, including the kidneys, bile duct, pancreas, gallbladder, spleen, heart, brain and seminal vesicles. Its primary function at the cellular level involves the metabolism of extracellular reduced glutathione (GSH), facilitating the assimilation of precursor amino acids for intracellular GSH synthesis.
Interestingly, recent experimental studies propose that cellular GGT may also play a role in generating reactive oxygen species when exposed to iron or other transition metals. Although the correlation between cellular GGT and serum GGT remains unclear, the latter is commonly used as a marker for excessive alcohol consumption or liver diseases. Consistent research findings suggest that serum GGT within its normal range might serve as an early and sensitive indicator of oxidative stress.
Notably, studies reveal inverse, dose-response relationships between serum GGT levels within its normal range and antioxidant vitamins in both serum and diet. Conversely, dietary heme iron shows a positive correlation with serum GGT levels. Moreover, serum GGT within its normal range positively predicted increased levels of oxidative damage, a product of arachidonic acid, as well as markers of inflammation such as fibrinogen and C-reactive protein.
These discoveries imply that the robust connections between serum GGT and various cardiovascular risk factors or events may be explained by mechanisms linked to oxidative stress.
Abnormal liver function tests (LFTs) have been reported among patients with SSc since 1934, and primary biliary cholangitis (PBC) is a leading cause of liver disease in SSc. Other liver diseases that are associated with SSc are primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH), but their prevalence is relatively rare. GGT is primarily an LFT. The composition of the “LFT” panel varies, with bilirubin, albumin, alanine aminotransferase (ALT), and alkaline phosphatase (ALP) being nearly universal components.
In contrast, GGT has been removed for economic reasons, with the justification being that alkaline phosphatase is of similar significance. GGT, despite its connection to biliary disease and ALP, exhibits sensitivity in diagnosing and prognosing liver disease, possibly attributed to its role in redox status regulation. Widely recognized as a marker for alcohol excess, recent research suggests that slightly elevated serum GGT also correlates with cardiovascular disease, actively being investigated as a cardiovascular risk indicator.
Notably, GGT accumulation in atherosclerotic plaques hints at a potential role in the pathogenesis of cardiovascular diseases. This aligns with its robust association with metabolic syndrome and non-alcoholic fatty liver disease (NAFLD).
GGT finds utility in various diagnostic and prognostic algorithms or scores designed for liver disease assessment. It stands out as one of the most potent predictors for identifying the presence or development of liver disease, particularly in patients with initial abnormal LFTs.
A study found significant predictors of liver disease included elevated GGT, reduced albumin, alcohol dependency, female gender, heightened ALP, socioeconomic deprivation, and younger age. In the model, albumin emerged as the primary predictor of risk, followed by GGT, with both playing crucial roles. Additionally, GGT demonstrates heightened sensitivity as a detector of NAFLD compared with ALT.
Big data studies, such as this one, may help to elucidate mechanisms of disease and the potential for testing in our patients, but need further elucidation before widespread use, particularly when the test in question is within the normal range and its only significance is found with statistical analysis.
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