Persistently elevated serum gamma-glutamyl transferase is associated with pancreatic cyst development: A sex-stratified propensity score matched multicenter cohort study

Abstract

Backgrounds/Aims

Elevated gamma-glutamyl transferase (GGT) levels have been linked to various malignancies, yet their relationship with pancreatic cyst development remains largely unexplored. This study aimed to investigate the association between persistently elevated serum GGT levels and pancreatic cyst formation.

Methods

This retrospective cohort study utilized data from TriNetX. Adult patients were categorized by sex into high and low GGT cohorts based on quartile values (males: ≥ 57 U/L vs. ≤ 23 U/L; females: ≥ 26 U/L vs. ≤ 14 U/L). Patients were required to have sustained GGT measurements at three different time points. The primary outcomes included pancreatic cyst development, all-cause mortality, and hospitalization over a three-year follow-up period.

Results

Pancreatic cyst development occurred in 0.4% of the high GGT group compared to 0.2% in the low GGT group for both sexes. Males with elevated GGT had a hazard ratio (HR) of 1.924 (95% confidence interval [CI] 1.223–3.025, p = 0.004) for pancreatic cyst formation, while females exhibited a HR of 1.957 (95% CI 1.108–3.455, p = 0.018). All-cause mortality was higher in the high GGT groups (males: HR 2.670, 95% CI 2.452–2.908; females: HR 3.372, 95% CI 2.892–3.931). Hospitalization rates were also elevated (males: HR 1.546; females: HR 1.551).

Conclusions

Persistently elevated serum GGT levels were associated with an approximately two-fold increase in the hazard of pancreatic cyst diagnosis in both sexes. However, the absolute event rate was low, and the outcome was identified through diagnostic coding without imaging or pathological confirmation.

INTRODUCTION

Pancreatic cysts are increasingly identified as incidental findings on cross-sectional imaging, with prevalence estimates ranging from 2% to 20%, depending on the imaging modality and patient population [1,2]. While most pancreatic cystic lesions are asymptomatic and exhibit benign behavior, certain subtypes, particularly mucinous cystic neoplasms and intraductal papillary mucinous neoplasms, have malignant potential and require careful monitoring [3,4]. Identifying non-invasive biomarkers to stratify patients at increased risk for pancreatic cyst development remains a significant clinical challenge [5]. Gamma-glutamyl transferase (GGT) is a membrane-bound enzyme that plays a vital role in glutathione metabolism and maintaining cellular redox homeostasis [6]. Traditionally recognized as a marker for hepatobiliary disease and chronic alcohol consumption, growing evidence suggests that elevated serum GGT levels may indicate systemic oxidative stress and chronic low-grade inflammation, processes associated with carcinogenesis across various organ systems [7,8]. Recent epidemiological studies have shown a correlation between elevated GGT levels and an increased risk of several malignancies, including pancreatic ductal adenocarcinoma [9,10]. A landmark nationwide cohort study from Korea, involving over 2.6 million participants, found that higher serum GGT levels were linked to an increased risk of pancreatic cystic neoplasms, demonstrating a clear dose-response relationship across GGT quartiles [11]. The biological mechanisms linking elevated GGT levels to pancreatic pathology involve several interconnected processes. GGT contributes to the production of reactive oxygen species in the presence of transition metals, potentially leading to oxidative tissue damage and cellular transformation [7,12]. Additionally, emerging evidence points to bidirectional associations between hepatic and pancreatic tissues through the gut-liver-pancreas axis, whereby metabolic dysfunction in one organ may correlate with pathological changes in the other [13,14]. Non-alcoholic fatty liver disease and fatty pancreas often coexist, with metabolic dysfunction-associated steatotic liver disease increasing the odds of pancreatic steatosis by more than sixfold [14,15]. Furthermore, sex-specific differences in GGT metabolism and reference ranges warrant stratified analyses, as hormonal influences and body composition variations between males and females may affect the relationship between GGT and disease outcomes [16,17]. Despite these compelling associations, the relationship between GGT levels and pancreatic cyst development has not been thoroughly investigated across diverse populations using contemporary electronic health record platforms. The primary objective of this retrospective cohort study was to explore the association between persistently elevated serum GGT levels and the development of pancreatic cysts within a large, diverse U.S. population, with separate analyses for male and female cohorts to account for sex-specific GGT reference ranges. Secondary objectives included examining the relationships between GGT elevation and all-cause mortality and hospitalization rates. This study adhered to the Strengthening the Reporting of Cohort Studies in Surgery guideline [18].

MATERIALS AND METHODS

Study design and data source

This retrospective cohort study analyzed data from the TriNetX US Collaborative Network, a federated health research platform that provides access to electronic medical records from 70 healthcare organizations across the United States. To address sex-specific differences in GGT reference ranges, the analysis was conducted separately for males and females. Data extraction and analysis took place on November 27, 2025.

Study population

The study population was stratified by sex, with distinct analyses for male and female cohorts. Eligible male patients were aged ≥ 18 years with documented serum GGT measurements. They were divided into two cohorts based on GGT quartile values: the high GGT cohort (Q4), with GGT ≥ 57 U/L (n = 20,684 before matching) and the low GGT cohort (Q1) with GGT ≤ 23 U/L (n = 17,412 before matching). Similarly, eligible female patients were aged ≥ 18 years with documented serum GGT measurements and were stratified into two cohorts: the high GGT cohort (Q4) with GGT ≥ 26 U/L (n = 40,690 prior to matching) and the low GGT cohort (Q1) with GGT ≤ 14 U/L (n = 9,122 prior to matching).

Exclusion criteria

Patients were excluded from the study if they had any of the following diagnoses documented within one year prior to the index event: acute pancreatitis (International Classification of Diseases, 10th Revision [ICD]-10 K85), alcohol-induced chronic pancreatitis (ICD-10 K86.0), other chronic pancreatitis (ICD-10 K86.1), pseudocyst of the pancreas (ICD-10 K86.3), cyst of the pancreas (ICD-10 K86.2), or benign neoplasm of the pancreas (ICD-10 D13.6). Additionally, patients were excluded if their index event occurred more than 20 years ago. The application of these exclusion criteria resulted in the removal of 1,163 male patients from the high GGT cohort and 992 from the low GGT cohort. In the female cohorts, 2,572 patients were excluded from the high GGT group and 469 from the low GGT group.

Index event and GGT measurement

The index event was defined as the first serum GGT measurement that met the specific threshold criteria for each cohort. To confirm sustained GGT elevation or normality, patients were required to have consistent GGT measurements taken at three different time points:

1. At index (baseline)

2. Within 6 months after index

3. Between 6 months and 1 year after index

Serum GGT was measured as enzymatic activity per volume in serum or plasma, reported in U/L (TriNetX code: TNX:9051).

Follow-up period

The analysis included outcomes within a time window that began 1 day after the index event and ended 1,095 days (3 years) later. For males, the mean follow-up after propensity score matching was 768.5 ± 407.1 days in the high GGT group and 810.6 ± 392.4 days in the low GGT group. For females, the mean follow-up was 817.5 ± 387.6 days in the high GGT group and 821.8 ± 383.7 days in the low GGT group. The median follow-up was 1,095 days for all groups.

Outcome definitions

Three primary outcomes were examined, defined using standardized diagnostic and demographic codes:

1. Pancreatic Cyst: Diagnosis of cyst of pancreas (ICD-10 K86.2)

2. All-Cause Mortality: Deceased status in demographic records

3. Hospitalization: Inpatient encounter (HL7 V3.0 Visit Type: IMP)

All analyses included patients with the outcome occurring prior to the time window, as these represent chronic or recurrent conditions.

Propensity score matching

To minimize confounding, propensity score matching was performed using a 1:1 nearest-neighbor matching algorithm without replacement. Matching variables included:

a. Demographic variables

• Age at index event

• Race/ethnicity (White, Black/African American, Asian, American Indian/Alaska Native, Native Hawaiian/Pacific Islander, Other, Unknown)

b. Clinical comorbidities

• Essential (primary) hypertension (ICD-10 I10)

• Diabetes mellitus (ICD-10 E08-E13)

• Chronic kidney disease (ICD-10 N18)

• Chronic ischemic heart disease (ICD-10 I25)

• Disorders of lipoprotein metabolism and other lipidemias (ICD-10 E78)

• Overweight and obesity (ICD-10 E66)

• Tobacco use (ICD-10 Z72.0)

• Alcohol-related disorders (ICD-10 F10)

• Nicotine dependence (ICD-10 F17)

• Alcoholic liver disease (ICD-10 K70)

c. Laboratory values

• Alanine aminotransferase (ALT) (TNX:9044)

• Aspartate aminotransferase (AST) (TNX:9047)

• Body mass index (TNX:9083)

After propensity score matching, the male cohort analysis included 12,565 patients per group, while the female cohort analysis included 8,177 patients per group. Balance was assessed using standardized differences, with values less than 0.10 indicating adequate balance.

Statistical analysis

Risk analysis was conducted to calculate the proportion of patients experiencing each outcome during the follow-up period. This analysis computed four key measures of association: risk, defined as the proportion of patients with the outcome (calculated as the number of patients with the outcome divided by the total number of patients in the cohort); risk difference (RD), representing the absolute difference in risk between high and low GGT cohorts, along with 95% confidence intervals (CIs); risk ratio (RR), defined as the ratio of risk in high versus low GGT cohorts; and odds ratio (OR), calculated as the ratio of odds in high versus low GGT cohorts. Statistical significance of these measures was assessed using z-tests, with two-tailed p-values < 0.05 considered statistically significant.

Survival analysis was performed using Kaplan-Meier methods applied to daily time intervals, with patients censored after their last documented medical visit in the electronic health record. For each outcome, several key survival parameters were calculated, including the median survival time (defined as the number of days when the survival probability drops below 50%), the survival probability at the end of the time window (expressed as the percentage of patients event-free at 3 years), and the log-rank test statistic (a chi-square statistic with degrees of freedom and an accompanying p-value used to compare survival curves between cohorts). Additionally, the hazard ratio (HR) was calculated to quantify the instantaneous rate of outcome occurrence in the high versus low GGT cohorts, along with corresponding 95% CI. Lastly, a test for proportional hazards was performed to assess whether the proportional hazards assumption underlying the Cox regression model was satisfied. All statistical analyses were conducted using the TriNetX analytics platform (TriNetX, LLC).

Ethical approval

Since this study utilizes raw and processed data from TriNetX (a global federated health research network providing access to de-identified electronic medical records from participating healthcare organizations), it is exempt from ethical approval. Since this study utilizes de-identified data, informed consent is not applicable.

RESULTS

Study population characteristics

Male cohort

After propensity score matching, 12,565 patients were included in each group. The baseline characteristics post-matching showed excellent balance between the cohorts (Table 1). Standardized differences for all demographic and clinical variables were less than 0.10, indicating successful balance after matching. As expected, liver enzyme levels (ALT and AST) were significantly higher in the high GGT cohort.

Table 1.

Baseline characteristics of male patients after propensity score matching (N = 12,565)

Characteristic	High GGT (> 57 U/L)	Low GGT (< 23 U/L)	p-value	Std. Diff.
Demographics
Age at index (yr)	49.9 ± 18.3	50.9 ± 21.5	< 0.001	0.051
Race/ethnicity
White	8,852 (70.4)	8,642 (68.8)	0.004	0.036
Black/African American	1,424 (11.3)	1,504 (12.0)	0.116	0.020
Asian	552 (4.4)	583 (4.6)	0.346	0.012
American Indian/Alaska Native	47 (0.4)	52 (0.4)	0.615	0.006
Native Hawaiian/Pacific Islander	60 (0.5)	57 (0.5)	0.781	0.004
Other	523 (4.2)	569 (4.5)	0.155	0.018
Unknown	1,107 (8.8)	1,158 (9.2)	0.261	0.014
Comorbidities
Essential hypertension	5,067 (40.3)	4,906 (39.0)	0.038	0.026
Diabetes mellitus	2,711 (21.6)	2,503 (19.9)	0.001	0.041
Chronic kidney disease	1,914 (15.2)	1,985 (15.8)	0.216	0.016
Chronic ischemic heart disease	1,873 (14.9)	1,863 (14.8)	0.859	0.002
Dyslipidemia	4,554 (36.2)	4,504 (35.8)	0.511	0.008
Overweight/obesity	2,108 (16.8)	1,993 (15.9)	0.050	0.025
Tobacco use	419 (3.3)	400 (3.2)	0.500	0.009
Alcohol-related disorders	751 (6.0)	692 (5.5)	0.110	0.020
Nicotine dependence	1,535 (12.2)	1,516 (12.1)	0.714	0.005
Alcoholic liver disease	225 (1.8)	201 (1.6)	0.241	0.015
Laboratory values
ALT (U/L)	69.0 ± 100.7	24.3 ± 22.0	< 0.001	0.615
AST (U/L)	60.9 ± 154.5	25.0 ± 19.5	< 0.001	0.326
BMI (kg/m2)	28.5 ± 6.3	27.3 ± 5.8	< 0.001	0.191

Values are presented as mean ± standard deviation, number only, or number (%).

GGT, Gamma-glutamyl transferase; Std. Diff., standardized differences; BMI, body mass index.

Female cohort

After propensity score matching, 8,177 patients were included in each group. Baseline characteristics are presented in Table 2. All standardized differences were less than 0.10, except for nicotine dependence (0.046), indicating an excellent balance between the matched cohorts.

Table 2.

Baseline characteristics of female patients after propensity score matching (N = 8,177)

Characteristic	High GGT (> 26 U/L)	Low GGT (< 14 U/L)	p-value	Std. Diff.
Demographics
Age at index (yr)	43.5 ± 20.8	43.7 ± 21.3	0.550	0.009
Race/ethnicity
White	5,938 (72.6)	5,933 (72.6)	0.930	0.001
Black/African American	721 (8.8)	698 (8.5)	0.523	0.010
Asian	431 (5.3)	453 (5.5)	0.447	0.012
American Indian/Alaska Native	22 (0.3)	19 (0.2)	0.639	0.007
Native Hawaiian/Pacific Islander	31 (0.4)	36 (0.4)	0.540	0.010
Other	394 (4.8)	401 (4.9)	0.799	0.004
Unknown	640 (7.8)	637 (7.8)	0.930	0.001
Comorbidities
Essential hypertension	2,009 (24.6)	1,929 (23.6)	0.143	0.023
Diabetes mellitus	1,019 (12.5)	999 (12.2)	0.634	0.007
Chronic kidney disease	703 (8.6)	695 (8.5)	0.823	0.003
Chronic ischemic heart disease	455 (5.6)	464 (5.7)	0.760	0.005
Dyslipidemia	2,089 (25.5)	2,013 (24.6)	0.170	0.021
Overweight/obesity	1,270 (15.5)	1,254 (15.3)	0.729	0.005
Tobacco use	123 (1.5)	136 (1.7)	0.415	0.013
Alcohol-related disorders	174 (2.1)	188 (2.3)	0.457	0.012
Nicotine dependence	594 (7.3)	695 (8.5)	0.003	0.046
Alcoholic liver disease	36 (0.4)	25 (0.3)	0.158	0.022
Laboratory values
ALT (U/L)	58.2 ± 126.1	18.0 ± 13.6	< 0.001	0.448
AST (U/L)	52.6 ± 133.1	21.6 ± 13.2	< 0.001	0.328
BMI (kg/m2)	28.7 ± 8.0	26.5 ± 6.8	< 0.001	0.300

Values are presented as mean ± standard deviation, number only, or number (%).

GGT, Gamma-glutamyl transferase; Std. Diff., standardized differences; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index.

Primary outcomes

Male cohort

(1) Pancreatic cyst

During the 3-year follow-up period, pancreatic cyst development occurred in 53 patients (0.4%) in the high GGT group, compared to 29 patients (0.2%) in the low GGT group. Risk analysis demonstrated a significant association between elevated GGT and pancreatic cyst formation, with an absolute RD of 0.2% (95% CI 0.1%–0.3%, z = 2.655, p = 0.008). Males with persistently elevated GGT (> 57 U/L) had an 83% increased risk of developing pancreatic cysts compared to those with low GGT (< 23 U/L), as indicated by a RR of 1.828 (95% CI 1.163–2.872) and an OR of 1.831 (95% CI 1.164–2.881).

Kaplan-Meier survival analysis revealed that the 3-year cyst-free survival probability was 99.41% in the high GGT group, versus 99.70% in the low GGT group (Fig. 1). The log-rank test confirmed a statistically significant difference between the survival curves (χ² = 8.310, df = 1, p = 0.004). The HR of 1.924 (95% CI 1.223–3.025) indicates that at any given time during the follow-up, the instantaneous rate of pancreatic cyst development was approximately twice as high in the high GGT group. The proportional hazards assumption was satisfied (χ² = 0.080, df = 1, p = 0.777), confirming the validity of the Cox regression model.

Fig. 1.

Kaplan-Meier curve depicting pancreatic cyst-free survival over 3 years in males with high versus low serum gamma-glutamyl transferase (GGT) levels.

(2) All-cause mortality

All-cause mortality was the most common outcome observed during the 3-year follow-up period. A total of 1,862 patients (14.8%) in the high GGT group died, compared to 734 patients (5.8%) in the low GGT group, representing an absolute RD of 9.0% (95% CI 8.2%–9.7%). Males with elevated GGT had a 2.5-fold increased risk of all-cause mortality over 3 years compared to those with low GGT (RR 2.537).

Kaplan-Meier survival analysis revealed that the 3-year survival probability was substantially lower in the high GGT group (81.85%) than in the low GGT group (92.57%), reflecting a 10.7 percentage point difference in absolute survival (Fig. 2). The log-rank test indicated a highly significant difference between the survival curves (χ² = 316.774, df = 1, p < 0.001). The HR of 2.670 (95% CI 2.452–2.908) shows that, at any point during the follow-up, the instantaneous rate of death was 2.67 times higher in the high GGT group compared to the low GGT group. The proportional hazards assumption was violated (χ² = 13.316, df = 1, p < 0.001), suggesting that HRs varied over the course of the 3-year follow-up period.

Fig. 2.

Kaplan-Meier curve showing overall survival over 3 years in males stratified by high and low serum gamma-glutamyl transferase (GGT) levels.

(3) Hospitalization

Hospitalization occurred in 3,972 patients (31.6%) in the high GGT group, compared to 2,799 patients (22.3%) in the low GGT group during the 3-year follow-up period, resulting in an absolute RD of 9.3% (95% CI 8.2%–10.4%). Males with elevated GGT had a 42% increased risk of hospitalization compared to those with low GGT (RR 1.419). Kaplan-Meier analysis revealed that the 3-year hospitalization-free survival rate was significantly lower in the high GGT group (62.30%) than in the low GGT group (73.23%), reflecting an 11 percentage point difference (Fig. 3). The log-rank test confirmed a highly significant difference between the survival curves (χ² = 183.235, df = 1, p < 0.001). The HR of 1.546 (95% CI 1.473–1.623) indicates a 55% higher instantaneous rate of hospitalization in the high GGT group at any point during follow-up. Additionally, the proportional hazards assumption was violated (χ² = 7.817, df = 1, p = 0.005), suggesting that the relative hazard of hospitalization between groups changed over time during the follow-up period.

Fig. 3.

Kaplan-Meier curve illustrating hospitalization-free survival over 3 years in males with high versus low serum gamma-glutamyl transferase (GGT) levels.

Female cohort

(1) Pancreatic cyst

During the 3-year follow-up period, pancreatic cyst development occurred in 35 patients (0.4%) in the high GGT group, compared to 18 patients (0.2%) in the low GGT group. Kaplan-Meier survival analysis demonstrated a 3-year cyst-free survival probability of 99.46% in the high GGT group versus 99.71% in the low GGT group (Fig. 4). The log-rank test revealed a statistically significant difference between the survival curves (χ² = 5.562, df = 1, p = 0.018). Females with elevated GGT (> 26 U/L) had approximately twice the hazard of developing pancreatic cysts compared to those with low GGT (< 14 U/L), as indicated by a HR of 1.957 (95% CI 1.108–3.455). The proportional hazards assumption was satisfied (χ² = 1.226, df = 1, p = 0.268), confirming the validity of the Cox regression model and indicating that the HR remained relatively constant throughout the 3-year follow-up period.

Fig. 4.

Kaplan-Meier curve depicting pancreatic cyst-free survival over 3 years in females with high versus low serum gamma-glutamyl transferase (GGT) levels.

(2) All-cause mortality

During the 3-year follow-up period, all-cause mortality was observed in 707 patients (8.6%) in the high GGT group, compared to 212 patients (2.6%) in the low GGT group. This resulted in a significant association, with an absolute RD of 6.1% (95% CI 5.4%–6.8%, z = 16.808, p < 0.001). Female with elevated GGT levels faced a 3.3-fold increased risk of all-cause mortality compared to those with low GGT, as indicated by a RR of 3.335 (95% CI 2.869–3.876) and an OR of 3.556 (95% CI 3.040–4.159).

Kaplan-Meier survival analysis revealed that the 3-year survival probability was significantly lower in the high GGT group (89.59%) than in the low GGT group (96.64%), reflecting a 7.1 percentage point difference in absolute survival (Fig. 5). The log-rank test confirmed a highly significant difference between the survival curves (χ² = 272.088, df = 1, p < 0.001). The HR of 3.372 (95% CI 2.892–3.931) indicated that at any point during follow-up, the instantaneous rate of death was 3.4 times higher in the high GGT group compared to the low GGT group. Additionally, the proportional hazards assumption was violated (χ² = 14.337, df = 1, p < 0.001), suggesting time-varying effects and indicating that the relative mortality hazard between the groups changed throughout the 3-year follow-up period.

Fig. 5.

Kaplan-Meier curve showing overall survival over 3 years in females stratified by high and low serum gamma-glutamyl transferase (GGT) levels.

(3) Hospitalization

During the 3-year follow-up period, hospitalization occurred in 2,273 patients (27.8%) in the high GGT group, compared to 1,551 patients (19.0%) in the low GGT group. This resulted in an absolute RD of 8.8% (95% CI 7.5%–10.1%, z = 13.339, p < 0.001). Females with elevated GGT had a 47% increased risk of hospitalization compared to those with low GGT, as indicated by a RR of 1.466 (95% CI 1.385–1.551) and an OR of 1.645 (95% CI 1.528–1.770).

Kaplan-Meier analysis showed that the 3-year hospitalization-free survival rate was lower in the high GGT group (67.24%) than in the low GGT group (77.28%), reflecting a 10 percentage point difference (Fig. 6). The log-rank test indicated a highly significant difference between the survival curves (χ² = 180.560, df = 1, p < 0.001). The HR of 1.551 (95% CI 1.454–1.654) suggests a 55% higher instantaneous rate of hospitalization in the high GGT group at any time during the follow-up. The proportional hazards assumption was satisfied (χ² = 1.359, df = 1, p = 0.244), confirming the validity of the Cox regression model throughout the follow-up period.

Fig. 6.

Kaplan-Meier curve illustrating hospitalization-free survival over 3 years in females with high versus low serum gamma-glutamyl transferase (GGT) levels.

Sex-based comparisons

Comparing HRs between male and female cohorts revealed both similarities and notable differences in the association between elevated GGT levels and clinical outcomes. The link between elevated GGT and pancreatic cyst formation was strikingly similar for both sexes, with HRs of 1.924 (95% CI 1.223–3.025) for males and 1.957 (95% CI 1.108–3.455) for females, indicating approximately a two-fold increase in hazard for both groups. Similarly, the association with hospitalization was almost identical between sexes, with HRs of 1.546 (95% CI 1.473–1.623) for males and 1.551 (95% CI 1.454–1.654) for females.

In contrast, females exhibited a higher HR for all-cause mortality compared to males (3.372 [95% CI 2.892–3.931] vs. 2.670 [95% CI 2.452–2.908]), despite the use of lower baseline GGT cutoff values for stratification in the female cohort (> 26 U/L vs. > 57 U/L in males). This suggests that even modest elevations in GGT may have greater prognostic significance in female than in male.

DISCUSSION

This large retrospective cohort study demonstrates that persistently elevated serum GGT is associated with an approximately two-fold increased hazard of pancreatic cyst development over a three-year follow-up period in both male and female populations. Males with GGT ≥ 57 U/L exhibited a HR of 1.924 (95% CI 1.223–3.025) for pancreatic cyst formation compared to those with GGT ≤ 23 U/L, while females with GGT ≥ 26 U/L demonstrated a HR of 1.957 (95% CI 1.108–3.455) compared to those with GGT ≤ 14 U/L. These findings are consistent with recent evidence from a Korean nationwide cohort study of 2.6 million participants, which reported adjusted HRs of 1.065 for the third GGT quartile and 1.109 for the fourth quartile relative to the first quartile for pancreatic cystic neoplasm development [11].

The observed associations between GGT elevation and pancreatic cyst formation are biologically plausible through several interconnected mechanisms. GGT plays a dual role in cellular redox homeostasis: while it facilitates glutathione metabolism to maintain antioxidant defenses, it may also participate in the generation of reactive oxygen species in the presence of iron or other transition metals, thereby potentially contributing to oxidative stress and cellular damage [7,12,19]. Pancreatic β-cells demonstrate low expression of catalase and glutathione peroxidases, rendering them particularly vulnerable to oxidative injury [20]. Moreover, pancreatic tissues rely substantially on hepatic glutathione production rather than de novo synthesis, creating a functional dependence on liver-derived antioxidant capacity [21]. The bidirectional relationship between hepatic steatosis and pancreatic pathology provides additional mechanistic insights, with metabolic dysfunction-associated steatotic liver disease showing increased odds of fatty pancreas by 6.18-fold and fatty pancreas showing increased metabolic dysfunction-associated steatotic liver disease (MASLD) odds by 9.56-fold [14,22]. Fatty pancreas is associated with increased risks of hypertension, diabetes mellitus, and metabolic syndrome [15,22].

This large retrospective cohort study demonstrates that persistently elevated serum GGT is associated with an approximately two-fold increased hazard of pancreatic cyst development over a three-year follow-up period in both male and female populations. Males with GGT ≥ 57 U/L exhibited a HR of 1.924 (95% CI 1.223–3.025) for pancreatic cyst formation compared to those with GGT ≤ 23 U/L, while females with GGT ≥ 26 U/L demonstrated a HR of 1.957 (95% CI 1.108–3.455) compared to those with GGT ≤ 14 U/L. These findings align with recent evidence from a Korean nationwide cohort study involving 2.6 million participants, which reported adjusted HRs of 1.065 for the third GGT quartile and 1.109 for the fourth quartile relative to the first quartile for the development of pancreatic cystic neoplasm development [11].

The observed associations between GGT elevation and pancreatic cyst formation are biologically plausible through several interconnected mechanisms. GGT plays a dual role in cellular redox homeostasis: it facilitates glutathione metabolism to maintain antioxidant defenses while also potentially contributing to the generation of reactive oxygen species in the presence of iron or other transition metals, which may lead to oxidative stress and cellular damage [7,12,19]. Pancreatic β-cells exhibit low expression of catalase and glutathione peroxidases, making them particularly vulnerable to oxidative injury [20]. Moreover, pancreatic tissues heavily depend on hepatic glutathione production rather than de novo synthesis, creating a functional reliance on liver-derived antioxidant capacity [21]. The bidirectional relationship between hepatic steatosis and pancreatic pathology provides additional mechanistic insights, with metabolic dysfunction-associated steatotic liver disease showing increased odds of fatty pancreas by 6.18-fold and fatty pancreas showing increased MASLD odds by 9.56-fold [14,22]. Fatty pancreas is associated with increased risks of hypertension, diabetes mellitus, and metabolic syndrome [15,22].

Elevated GGT levels are strongly linked to components of metabolic syndrome, which are themselves associated with pancreatic diseases. Population studies indicate that increased GGT is correlated with the onset of impaired glucose tolerance and type 2 diabetes, with ORs exceeding 1.6 even after adjusting for factors such as body fat, alcohol consumption, and insulin levels [23,24]. Diabetes mellitus has been identified as a risk factor for the development of intraductal papillary mucinous neoplasms, showing ORs of 1.79 in multivariate analyses, which rise to 6.03 among patients who require insulin therapy [25]. Additionally, being overweight or obese is linked to the progression of branch-duct intraductal papillary mucinous neoplasms under surveillance, with a body mass index greater than 26.4 associated with a HR of 1.72 for disease progression [26]. These relationships suggest that GGT may act as an integrative biomarker reflecting cumulative metabolic and oxidative stress.

The dose-response relationship between GGT levels and cancer risk further emphasizes the clinical significance of GGT as a prognostic biomarker. A systematic review and meta-analysis found that patients with GGT levels above 60 U/L had a HR of 1.32 for overall cancer incidence [27]. Specifically, for pancreatic cancer, prospective analyses from the UK Biobank cohort, which included over 421,000 participants, showed that each standard deviation increase in log-transformed GGT level was associated with a 14% higher risk of pancreatic cancer. HRs were 1.72 for male with GGT levels of 50.2 U/L or higher and 1.75 for female with levels of 31.6 U/L or higher [10]. Additionally, Mendelian randomization studies suggest potential causal relationships, indicating that genetically determined GGT levels are associated with an increased risk of acute pancreatitis (OR 1.180, 95% CI 1.021–1.365) [28].

An unexpected finding was the stronger association between GGT elevation and all-cause mortality in females compared to males, despite the use of significantly lower GGT thresholds for female cohort stratification. Females with elevated GGT had a 3-year mortality HR of 3.372 (95% CI 2.892–3.931), compared to 2.670 (95% CI 2.452–2.908) in males. These observations align with previous analyses indicating that even modest GGT elevations in female carry substantial prognostic significance [16,29]. Hormonal influences on GGT expression differ between sexes; testosterone therapy in transgender male is linked to increased GGT levels, while estrogen therapy in transgender female is associated with stable GGT levels [30]. The lower baseline GGT levels in female may make any elevation more indicative of pathological processes rather than normal physiological variation [31].

The clinical implications require careful consideration in light of current pancreatic cyst surveillance guidelines. Multiple consensus statements advocate for imaging surveillance of pancreatic cystic lesions primarily based on cyst size, morphological features, and growth rate [32,33]. However, identifying individuals at increased risk before cyst detection remains a challenge. The cumulative incidence of malignancy in small pancreatic cysts (< 15 mm) after five years is approximately 0.94%, rising to 3.37% at ten years [34]. In this study, the absolute incidence of pancreatic cyst diagnoses was low in both sexes (0.4% in the high GGT groups compared to 0.2% in the low GGT groups). These findings should be interpreted cautiously and should not be taken as support for GGT as a standalone screening test or an established risk-stratification biomarker for pancreatic cysts. Instead, persistently elevated GGT may indicate broader metabolic or inflammatory dysfunction that warrants further prospective validation. The association between elevated GGT and increased hospitalization rates (HRs of 1.546 for males and 1.551 for females) reflects the wider health implications of chronic metabolic dysfunction. Furthermore, elevated GGT has consistently been linked to increased cardiovascular disease mortality, with HRs of 1.66 in male and 1.64 in female for each log-unit GGT increase [35].

This study has several limitations. First, its retrospective observational design using an electronic health record network is susceptible to residual confounding, missing data, and potential coding inaccuracies. Second, the exposure definition required three concordant GGT measurements within one year after the index test, which may introduce selection bias and immortal time or look-ahead bias, as it preferentially includes patients with greater healthcare contact and comorbidity burden. Third, pancreatic cyst outcomes were identified using a single ICD-10 diagnostic code (K86.2) without imaging confirmation, cyst size, morphology, or histopathology, preventing differentiation between clinically significant cystic neoplasms and incidental or benign cystic findings. Fourth, exclusions were limited to diagnoses documented within one year before the index event, which may not fully eliminate prevalent pancreatic cyst disease and could lead to outcome misclassification when the goal is to assess incident cyst development. Fifth, detection or surveillance bias is likely, as patients with elevated GGT may undergo more frequent investigations and imaging due to their underlying comorbidities, increasing the probability of incidental cyst detection independent of biological risk. Sixth, the proportional hazards assumptions were violated for key outcomes (including mortality in both sexes and hospitalization in males), indicating time-varying effects; therefore, single HR estimates over the entire follow-up period should be interpreted with caution. Finally, the low absolute incidence of pancreatic cyst diagnoses over three years (0.4% vs. 0.2%) limits precision.

Despite these limitations, this study has several notable strengths. The large sample size, which includes over 20,000 matched participants, provides adequate statistical power and allows for sex-stratified analyses. The requirement for sustained GGT elevation across three time points over one year improves specificity. Additionally, the comprehensive propensity score matching approach balanced multiple demographic, metabolic, and laboratory variables between the cohorts. The use of a federated health research network comprising 70 diverse healthcare organizations further enhances generalizability.

In conclusion, this large retrospective cohort study shows that persistently elevated serum GGT is associated with nearly a two-fold increase in the risk of pancreatic cyst diagnosis in both males and females. These results align with emerging evidence linking GGT to the risk of pancreatic disease and suggest potential mechanisms involving oxidative stress, hepatopancreatic metabolic interactions, and shared metabolic risk factors. However, the low absolute event rate and the reliance on coding-based outcome definitions without imaging or pathological confirmation limit the interpretation of these findings. Prospective studies that utilize imaging-verified cyst phenotyping are necessary to validate these associations; for now, these findings should be considered hypothesis-generating rather than practice-changing.