Introduction

Acromegaly is a rare condition (0.2–1.1 cases/100,000 people per year). Mostly, it is caused by pituitary adenoma with excessive production of growth hormone (GH) and subsequent insulin-like growth factor-1 (IGF-1) [1]. Cardiovascular, diabetes mellitus (DM), and hypertension diseases all are public in acromegaly and contribute to increased risk of mortality [2]. The disease can be diagnosed and monitored depending on clinical signs and symptoms, in addition to the biochemical assessments [3]. Important factors such as body mass index (BMI), malnutrition, DM, renal, and liver disease can affect the secretion and action of GH and IGF-1 [4]. The complex diagnostic methods for patients with acromegaly and discrepancies between GH and IGF-1 levels may lead to delay in the diagnosis or difficulty in adjustment of treatment. In addition to the lack of studies to find an accurate diagnostic biomarker for the disease, galectin-3 (Gal-3) was evaluated for patients with acromegaly in this study. Galectin-3 is a part of the galectin family, which are β-galactosids-binding lectins with more than or equal one evolutionary preserved carbohydrate recognition domain. It binds proteins in a carbohydrate dependent. It is included in the regulation of numerous physiological cellular functions, like cellular growth, proliferation, apoptosis, differentiation, cellular adhesion, and tissue repair [5]. Gal-3 play a main role in the pathological remodeling of the myocardium in response to heart injury, chronic stress, or inflammation, which then leads to myocardial fibrosis, atrial fibrillation, and heart failure. In addition, Gal-3 is in the list of validated cardiovascular (CVD) biomarkers [6, 7]. Other studies indicate that there is an interaction between Gal-3 and IGF-1[8, 9]. Recent studies have revealed the high prevalence of CVD in acromegaly patients due to effect of GH and IGf-1 excess on the cardiac morphology and function in different mechanisms [10, 11]. Taken all above together, this study aimed to compare Gal-3 levels with two conventional biomarkers used for the diagnosis of acromegaly, GH, and IGF-I.

Materials and methods

Study design

In this single center, a randomized case control study was performed in the National Diabetes Center/Mustansiriyah University between August and October, 2023, 50 patients who were previously diagnosis to have acromegaly more than 5 years based on the endocrine society clinical practice guideline [12], aged between 20 and 55 years were included. Moreover, 43 apparently healthy subjects (HS) matched both age and BMI with no history of pituitary disease or other inflammatory diseases and normal for biochemical tests serve as controls group. Subjects with active malignancies, inflammatory comorbidities, or use of systemic immune-suppressive medication were excluded, all of which were anchored in the systematic questionnaire. All patients had a history of radiologically and biochemically established active acromegaly.

Ethical approval

The study was performed in accordance with the Declaration of Helsinki (2013) and approved by our local ethical committee in Mustansirayh University/National Diabetes Center. All participants informed written agreement to enroll in this study.

Collection of blood sample and laboratory analysis

Blood samples were collected from all subjects who full filled the inclusion criteria between 8 and 10 am after at least 8 h overnight fasting. Samples were centrifuged at 3000 rpm for 10 min, and serum was divided into aliquots and stored at – 70 °C until analysis. IGF-1 and GH levels were measured with commercial ELISA tests kits (DRG-USA) according to the manufacturer’s instruction. Furthermore, a sandwich enzyme immunoassay kit (ELISA) was used to quantify human Gal-3 in vitro at my BioSource, USA, by ELISA plate reader (Human Reader, Germany). Other biochemical test (FBG, lipid profile) was determined using an automated chemical analyzer standard of the relevant Diabetic National Center.

Statistical analysis

Normality assumption of the variables were examined by Shapiro–Wilk and the Kolmogrorov-Smirnov tests. All variables are presented using mean and standard division (SD). For comparisons between different groups were analyses by parametric independent t-test. The predictive value of serum Gal-3 was evaluated by measuring the area under the receiving operating characteristic curve (AUC). Also using DeLong et al. test for correlated ROC curve [13, 14]. The optimal threshold value was obtained by calculating the Youden index [15]. SSPS (version 24), GraphPad Prism (version 8), and Medcalc (version 20.027) performed all analysis.

Result

Subject characteristic

There are 50 patients ((50.40 ± 12.229), 50% of male), and 43 HS with similar ages and gender distribution. As shown in Table 1, the BMI of patients with acromegaly is higher than HS (P = 0.001).

Table 1 Demographics feature and laboratory test of study groups
Full size table

Biochemical and traditional biomarkers tests

Fasting blood glucose (FBG) and lipid profile were remarkably higher in acromegaly patients compared to HS (P = 0.001 for each). The traditional biomarkers GH and IGF-1 were remarkably higher in the acromegaly patients than HS (P = 0.001). Table 1 shows the comparative results for laboratory tests belonging to the groups.

Serum galectin-3 in study groups

The levels of Gal-3 were significantly elevated in acromegaly patients when compared to age-matched HS [41.87 ± 9.074, 11.90 ± 1.324 ng/ml], respectively, at P = 0.0001, as shown in Fig. 1.

Fig. 1
figure 1

Comparison of Gal-3 in acromegaly patients and HS groups

Full size image

Receiving operating characteristic curve (ROC)

To assess the ability of Gal-3 levels to discriminate between acromegaly patients and HS, ROC curve was plotted (Fig. 2A). Gal-3 serum levels revealed AUC of 1.00 (95% CI 92.9–100.0 P = 0.001) and cut off value (Youdens index) of less than 14.363 ng/ml with sensitivity 100.0 and specificity 100.0, as shown in Table 2.

Fig. 2
figure 2

A ROC curves for serum Gal-3 discriminating the acromegaly from HS. B The comparison predicted of Gal-3 serum levels and traditional tests

Full size image
Table 2 AUC and the validity of Gal-3 to discriminants between acromegaly and HS groups
Full size table

Table 3 and Fig. 2B show the combined prediction of Gal-3 with traditional tests (GH and IGF-1) using DeLoongs test for correlated ROC curves. As there was significant difference between Gal-3 and GH, IGF at P = 0.0001 for each, differences between areas are 0.209 and 0.248, respectivly.

Table 3 Comparison between Gal-3 and traditional tests to determine the discrimination power of each biomarkers using DeLong et al. test for correlated ROC curve
Full size table

Discussion

Acromegaly is a multi-organ disease caused by excessive production of GH. As mentioned above GH and IGF-1 have numerous immunological, metabolic, and CDV effects [10]. The high prevalence of CDV disturbances in acromegaly patients [16, 17], and Gal-3 is listed as biomarker of CDV. Patients with conflicting biochemical data from GH and IGF-I have provided special diagnostic and monitoring challenges for acromegaly.

Serum levels of GH and IGF-I are used as biomarkers in the diagnosis of acromegaly, but they have not yet undergone systematic validation [3, 18]. Therefore, reevaluation of the novel biomarker Gal-3 is a substitute for reliable biochemicals in the diagnosis of acromegaly. To date there are limited reports of biomarker assays in this disease; therefore, our study aimed to estimate the role of GAL-3 in the diagnosis and monitoring of the disease in patients with acromegaly and compare with traditional tests. In this study, we found serum Gal-3 concentration is remarkably increased in patients with acromegaly. This is consistent with the only recent study that dealt with measuring the biomarker and comparing it with the pulse wave velocity in acromegaly patients [19,20,21]. The Gal-3 is involved in inflammation and fibrosis in different diseases impacting vital organs such as the heart, liver, kidney, lungs, and the brain [22]. The main cell types implicated in Gal-3-driven disease processes are myofibroblasts, epithelial cells, endothelial cells, and macrophages. Gal-3 is a potential biomarker for the early stages of several of diseases, even though it is not a disease-specific marker per se [23].

The traditional biomarkers of acromegaly show significant increase in acromegaly patients compared to HS. Similar results were reported by Farhan LO et al. [24], and Hepşen S [1]. The FBG and lipid profile show significant increase in acromegaly patients and this agreed with previous study [21, 25].

In this study the validity of Gal-3 was evaluated by ROC curve which revealed that serum Gal-3 have AUC 1.00 with sensitivity 100.0 and specificity 100.0 specific for diagnosis acromegaly. Moreover, when compare Gal-3 serum levels with traditional tests (GH and IGF-1) by DeLoongs test for correlated ROC curves show significant difference to discriminate acromegaly more accurate than traditional tests. In addition, this conclude that GAL-3 is a biomarker particularly sensitive to excess growth hormone.

There are certain limitations as the study was conducted at a single center. The number of patients, particularly serve ones, were relatively small to draw clear conclusion. In addition, given the rarity of acromegaly, the small sample size of the patients might be acceptable.

In order to prevent bias, we also used strict exclusion criteria and eliminated all patients who had renal failure, heart disease, or any inflammatory condition.

Conclusion and future directions

This study revealed that the Gal-3 is a new and effective prediction biomarker for patients with acromegaly compared with traditional tests. It may play a role in monitoring acromegaly. Gal-3 is a promising biomarker to diagnose acromegaly with high sensitivity and specificity. Its close association with GH secretory status and status make it a helpful tool, particularly in cases where measurements of GH and IGF-I provide discrepant information.

However, a larger study is needed to confirm these findings particularly in newly diagnosed acromegaly particularly those with CVD. Prospective studies should look into whether this can be used to enhance long-term outcome prediction.