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Association between the C-reactive protein–albumin–lymphocyte index and metabolic syndrome: evidence from the 2003–2010 national health and nutrition examination survey

Diabetology & Metabolic Syndrome volume 17, Article number: 39 (2025) Cite this article

Abstract

Background

Metabolic syndrome (MetS) is a global public health problem that significantly impacts human health and quality of life. The relationship between MetS and the C-reactive protein–albumin–lymphocyte (CALLY) index is uncertain.

Methods

This study analyzed the data of 7,534 individuals from the National Health and Nutrition Examination Survey cycles (2003–2010 cycles). Weighted logistic regression and weighted restricted cubic spline (RCS) curve analyses were used to identify the relationships between the CALLY index and MetS, as well as its components.

Results

Of the 7,534 participants, 2,086 were diagnosed with MetS. The estimated prevalence of MetS decreased with an increase in the CALLY index (P < 0.001). Multivariable logistic regression analysis showed that the odds ratio of MetS was 0.25 (95% confidence interval 0.20–0.32, P < 0.001) in the highest CALLY index quartile compared with the lowest quartile after adjusting for confounding variables. The RCS curve analysis revealed non-linear relationships between the CALLY index and MetS or its components.

Conclusions

This study revealed an inverse relationship between the CALLY index and MetS risk. The CALLY index might be valuable for identifying individuals who are at a high risk of MetS.

Clinical trial number

Not applicable.

Introduction

Metabolic syndrome (MetS) refers to a group of metabolic abnormalities encompassing elevated fasting plasma glucose (FPG), hypertension, obesity, triglyceride (TG) elevation, and low high-density lipoprotein cholesterol (HDL-C) [1]. As a non-communicable disease, MetS poses a considerable global health risk, and its prevalence continues to increase steadily each year [2]. MetS has a complex pathophysiology, with insulin resistance and dyslipidemia playing central roles in its development [3]. Furthermore, extensive research has demonstrated that MetS significantly increases the risk of type 2 diabetes mellitus, cancer, cardiovascular disease, and all-cause mortality [4,5,6,7,8].

Research has shown that many factors contribute to MetS, including inflammation, immune function, and nutritional status, and the control of inflammation is key to alleviating metabolic disorders. The prevailing perspective is that chronic low-grade inflammation and oxidative stress, which are frequently observed in MetS, play significant roles in the metabolic status and pathophysiology of MetS [9, 10]. Inflammatory factors released from adipose tissue contribute to the onset of metabolic disorders by triggering the systemic inflammatory response [11]. In terms of immune function, immune cell activation is implicated in the progression of diseases associated with metabolic disorders [12, 13]. For instance, Satoshi et al. found that CD8+ T cells activate macrophages in adipose tissue, causing a shift in the immune microenvironment from an anti-inflammatory to a pro-inflammatory state [14, 15]. Furthermore, nutrition has also been associated with MetS risk [16]. Malnutrition can lead to deficiencies in essential nutrients in the body, which affects the metabolic regulation of blood glucose, lipids, and weight. Meanwhile, MetS itself can affect the nutritional state of the body. Insulin resistance and lipid abnormalities may interfere with cellular energy metabolism, affecting nutrient absorption, utilization, and storage. According to the above evidence, the combination of inflammation, immune function, and nutritional status indicators is considered a reliable predictor of patient prognosis [17, 18].

The C-reactive protein–albumin–lymphocyte (CALLY) index developed by Iida et al. [19], is a novel inflammation–nutrition–immunity index based on C-reactive protein (CRP), albumin concentration, and lymphocyte count. The CALLY index has been used for prognostic assessment in patients with various cancers, including gastric cancer, colorectal liver metastases, and non-small-cell lung cancer [20,21,22,23,24,25,26,27]. Additionally, the CALLY index has been found to be effective in selecting cancer treatment regimens, predicting treatment efficacy, and assessing prognosis. Yang et al. revealed that the CALLY index has superior prognostic value in patients with colorectal cancer compared to conventional prognostic factors, including the platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, systemic immune inflammation index, and modified Glasgow prognostic score [28]. The CALLY index reliably predicts the survival of patients with cancer who undergo surgery, with a critical score of ≥ 3. Adjuvant therapies like chemotherapy and targeted treatments can improve the long-term survival of patients with a CALLY index of < 3 and unfavorable postoperative prognoses [29]. The CALLY index is a non-invasive quantitative metric. A low CALLY index may inform the risk of MetS risk due to the associations among inflammation, immunity, and nutrition.

However, the relationship between the CALLY index and MetS is unclear. Thus, we evaluated the association of the CALLY index with MetS among participants included in the National Health and Nutrition Examination Survey (NHANES).

Methods

Study population and design

The NHANES is a cross-sectional study conducted by the National Center for Health Statistics in the United States. The aim of the NHANES is to evaluate the health and nutritional status of the general population. The survey is conducted every 2 years with different participants included in each cycle. Approval is required from the Institutional Review Board of the Centers for Disease Control and Prevention (CDC), and the participants must provide written informed consent to participate. Detailed information on the NHANES study design and data can be found at the official website of the CDC (https://www.cdc.gov/nchs/nhanes/). The present study involved secondary data analysis without personal identifiers; therefore, it did not require institutional review.

The research data were obtained from four NHANES cycles (2003–2010) involving a total of 41,156 participants. We excluded participants aged < 20 years and with incomplete data on the CALLY index, incomplete MetS information, and incomplete covariate data, as well as those who were pregnant. Figure 1 shows the participant selection flowchart.

Fig. 1
figure 1

Flowchart of participant inclusion and exclusion in the current study

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CALLY index definition

The CALLY index was calculated using the following formula: CALLY index = albumin concentration (g/L) × lymphocyte count (109/L) ÷ [CRP concentration (mg/L) × 10]. The CRP concentrations were quantified using latex-enhanced nephelometry on a Behring Nephelometer. Lymphocyte counts were analyzed using the Beckman Coulter MAXM Instrument. Additionally, serum albumin concentration was measured using the Roche modular P and Roche Cobas 6000 chemistry analyzers. For a comprehensive understanding of the laboratory processing methodology, please refer to the CDC website [30]. Based on the respective CALLY index values, the participants were stratified into four quartiles: Q1: 0.18 ≤ CALLY index < 1.68, Q2: 1.68 ≤ CALLY index < 4.09, Q3: 4.09 ≤ CALLY index < 9.97, Q4: 9.97 ≤ CALLY index < 139.7.

MetS definition

The definition of MetS involves specific criteria outlined in the Adult Treatment Program III of the National Cholesterol Education Program [31]. The diagnostic criteria for MetS include (1) TG ≥ 150 mg/dL; (2) Low HDL-C (< 40 mg/dL in men and < 50 mg/dL in women); (3) FPG ≥ 6.1 mmol/L; (4) elevated waist circumference (WC), defined as > 102 cm in men and > 88 cm in women; and (5) elevated blood pressure (BP), defined as systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg.

Covariates

The participants completed standardized questionnaires to provide sociodemographic and lifestyle information [32], including sex, age, race (Mexican–American, other Hispanic, Non-Hispanic Black, Non-Hispanic White, other race), poverty-to-income ratio (categorized as ≤ 1, >1 to ≤ 3, and > 3), educational attainment (less than high school, high school, above high school), marital status (married, living alone, or divorced), smoking status (never smoker [< 100 cigarettes prior to the survey], ever smoker [> 100 cigarettes prior to the survey but quit prior to the survey], and current smoker [> 100 cigarettes prior to the survey and smoked during the survey period]), and drinking habits (consumed at least 12 drinks of any type of alcoholic beverage within the last year). Additionally, any self-reported history of cancer and family history of diabetes mellitus were also recorded.

Statistical analysis

Sample weights, clustering, and stratification were integrated into all analyses following the NHANES analytic and reporting guidelines. Continuous variables are summarized as the mean ± standard deviation, while categorical variables are summarized as frequency (percentage). The characteristics of the participants were compared across the CALLY index quartile using one-way analysis of variance for continuous variables and Pearson’s chi-square test for categorical variables. Multivariable logistic regression was used to analyze the associations between the CALLY index and MetS and its components. The crude model was unadjusted; Model 1 was adjusted for age, race, and sex; Model 2 was adjusted for the variables in Model 1, as well as history of cancer, family history of diabetes mellitus, smoking status, alcohol consumption, educational attainment, and poverty-to-income ratio. Tests for a linear trend were performed by entering the CALLY index as a continuous variable. Restricted cubic spline (RCS) regression was used to investigate the non-linear relationships between the CALLY index and MetS and its components. Likelihood ratio tests were used to confirm the relationships. Subgroup analyses of the correlation between the CALLY index and MetS were performed to determine if the predictive ability of the CALLY index varied among subgroups.

P < 0.05 was considered statistically significant. The statistical analysis was conducted using R version 4.2.1 and the Free Statistics software (version 1.9).

Results

Population characteristics

The data of 7,534 participants were analyzed. The mean age of the participants was 46.68 ± 16.56 years, and 3,876 of the 7534 participants were male (weighted percentage, 50.02%). Among them, 2,086 participants (23.96%) were diagnosed with MetS. The prevalence of MetS was 36.87% in Q1, 31.38% in Q2, 19.85% in Q3, and 10.80% in Q4. Table 1 presents the baseline characteristics of the participants based on the CALLY index quartiles. Individuals in the highest CALLY index quartile were more likely to be male, younger, wealthier, and to have a higher level of education. They were also more likely to have a history of cancer, a family history of diabetes mellitus, to consume alcohol, and to never smoke (all P < 0.05).

Table 1 Weighted baseline characteristics according to the CALLY index quartiles
Full size table

Association between the CALLY index and MetS

Table 2 presents the results of the weighted logistic regression analysis. In the unadjusted models, higher CALLY index quartiles were associated with a lower risk of MetS (P trend < 0.001). This association remained significant after adjusting for age, sex, and race, history of cancer, family history of diabetes mellitus, smoking status, alcohol consumption, educational attainment, and poverty-to-income ratio in Model 2 (Ptrend < 0.001). We next investigated the association between the CALLY index and the specific components of MetS, including elevated WC, elevated FPG, elevated BP, elevated TG, and low HDL-C. We found that higher CALLY index quartiles were negatively associated with elevated WC, BP, FPG, and TG, as well as with reduced HDL-C level in the fully adjusted models (all Ptrend < 0.001).

Table 2 Weighted logistic analysis model between CALLY index and MetS and its components
Full size table

The weighted RCS curve analysis indicated a significant non-linear relationship between the log-transformed CALLY index and MetS, even after adjusting for multiple covariates in Model 2 (P < 0.001, Fig. 2A). The risk of MetS decreased with an increase in the CALLY index. Furthermore, when evaluating the specific components of MetS, significant non-linear associations were observed between the log-transformed CALLY index and elevated WC (Fig. 2B), elevated TG (Fig. 2E), and low HDL-C (Fig. 2F). The relationship between the log-transformed CALLY index and elevated TG exhibited an inverted U-shaped pattern. The risk of TG elevation peaked at a CALLY index close to 0 and then declined sharply, with a significant non-linear relationship (P < 0.0001). The analysis also revealed a significant inverse association between the log-transformed CALLY index and both FPG elevation (Fig. 2C) and BP elevation (Fig. 2D), indicating a linear relationship (Pnon−linearity > 0.05).

Fig. 2
figure 2

Dose-response relationships between MetS (A), elevated WC (B), elevated FPG (C), elevated BP (D), elevated TG (E), low HDL (F) and the CALLY index

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Subgroup analyses

In the subgroup analyses (Fig. 3), females demonstrated a significantly lower risk of MetS than males (Pinteraction = 0.005). Furthermore, age-stratified subgroups revealed that individuals aged < 60 years exhibited a lower risk of MetS than those aged ≥ 60 years (Pinteraction <0.001). There were no significant interactions in the other subgroups (all Pinteraction > 0.05).

Fig. 3
figure 3

Subgroup analysis of the associations between MetS and the CALLY index

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Discussion

This cross-sectional study of 7,534 adults investigated the associations between the CALLY index and MetS. A lower CALLY index was significantly associated with an increased risk of MetS and its components. Nonlinear associations were observed with MetS, elevated WC, reduced HDL-C, and elevated TG, while linear associations were found with elevated BP and elevated FPG. Subgroup analyses showed that the association between a lower CALLY index and increased risk of MetS was more pronounced in females and individuals under 60 years of age.

MetS is a pathological condition that is characterized by a cluster of metabolic abnormalities, including abdominal obesity, insulin resistance, hypertension, and hyperlipidemia [2]. MetS is considered to be an emerging epidemic. In terms of the prevalence of MetS and individual MetS components, our results were comparable to those previously reported in the literature, with obesity being the most common (91.86%) and hyperglycemia the least common (23.96%) type of MetS. The prevalence of each MetS component was much higher for participants who met the criteria for MetS. The CALLY index is a predictor of cancer treatment efficacy and prognosis. In addition to cancer, the predictive value of the CALLY index for MetS has attracted our attention. We observed a significant correlation between the CALLY index and different MetS components. In particular, the CALLY index demonstrated a correlation with obesity, hypertension, hyperglycemia, high TG, and low HDL-C. This finding suggests that MetS may not only be associated with the CALLY index as a whole, but that it may also be closely associated with its constituent factors. Consequently, it may be hypothesized that the components of the CALLY index play an important roles in the pathogenesis of MetS.

MetS is associated with various risk factors and plays a crucial role in disease progression [16, 33]. There is mounting evidence illustrating an association between MetS and inflammation, nutritional status [34,35,36], and immune function. MetS causes modifications in cell signaling pathways, resulting in elevated inflammatory markers, lipid peroxides, and free radicals [37]. The use of CRP as an inflammatory biomarker is becoming more common in the assessment of cardiovascular risk [38,39,40,41], with CRP elevation linked to key MetS risk factors, such as insulin resistance, hyperglycemia, and abdominal adiposity [42, 43]. A previous study showed that CRP was significantly elevated in patients with MetS [44], highlighting the inflammatory state of the body and underscoring the importance of chronic inflammation in the pathogenesis of MetS, which is consistent with the findings of the present study.

T lymphocytes, which are crucial players in the adaptive immune response, intricately contribute to inflammation in patients with obesity [45]. Individuals with obesity and those with MetS exhibit elevated T lymphocyte counts, disrupting the delicate balance between pro-inflammation and anti-inflammation [15, 31, 46]. Some studies have associated heightened lymphocyte counts with an increased risk of diabetes mellitus due to insulin resistance. Although some studies have suggested compromised lymphocyte function, evidenced by increased apoptosis or decreased immune response capacity, conflicting findings have emerged. The present study confirmed that individuals with MetS had significantly higher peripheral blood lymphocyte counts than healthy controls, supporting their role in MetS pathogenesis. This finding is consistent with emerging evidence illustrating the crucial role of the immune system in MetS development and highlighting the complex relationship between immune dysregulation and metabolic disturbances.

The serum albumin concentration is linked to the severity of malnutrition and plays a crucial role as an antioxidant by scavenging hydroxyl radicals and reducing reactive oxygen species production [47, 48]. Albumin also regulates inflammation by suppressing pro-inflammatory cytokines [49, 50] and activating the nuclear factor-κB pathway [51], which can impact cellular signaling pathways and MetS development. Low albumin is associated with heightened inflammation [52, 53]. The interaction of inflammatory markers, such as the CRP/albumin ratio, has been shown to play a significant role in disease progression and outcomes, as demonstrated in studies on cardiovascular conditions [54, 55]. Furthermore, there are negative correlations between the albumin concentration and obesity, lipid metabolism abnormalities [51, 56], and insulin sensitivity [57, 58]. A previous study suggested that increasing the serum albumin concentration over time may prevent MetS development [59]. However, excessive dietary protein intake may exacerbate hyperinsulinemia, hyperglycemia, hypertension, and lipid abnormalities, potentially contributing to MetS [60]. Other studies have suggested that there is a positive correlation between the increase in baseline serum albumin and the prevalence of MetS [61,62,63]. In the present study, we observed a lower albumin concentration in patients with MetS than in those without MetS. This finding supports the results of a previous study on blood changes in patients with MetS. For example, lower serum albumin is linked to coronary heart disease risk [64]. Xu et al. showed that microalbuminuria and high 24-hour urinary albumin excretion are risk factors for MetS, indicating lower albumin levels in these patients [65].

This study takes full advantage of the independent predictive value of these three indicators, as well as their interactions. The findings suggest that the combination of these three common indices within the CALLY index may have greater potential to investigate the association between the baseline CALLY index and MetS risk. The CALLY index may influence the occurrence and progression of MetS through various pathways. First, serving as a comprehensive indicator of metabolic health, the CALLY index likely reflects an individual’s nutritional status and lifestyle habits. These factors are closely associated with the pathophysiological mechanisms of MetS. For instance, a diet high in fat, sugar, and salt may lead to weight gain, insulin resistance, and elevated BP, thereby promoting MetS development. Second, the CALLY index may be linked to metabolic activity, influencing energy and lipid metabolism within the body. Inappropriate energy metabolism and lipid storage patterns can result in fat accumulation, insulin resistance, and metabolic dysregulation, consequently increasing MetS risk. Additionally, the CALLY index may reflect the level of inflammation and immune function within the body. Inflammation and immune dysfunction are crucial components in the pathogenesis of MetS, leading to metabolic disturbances and tissue damage, thereby facilitating MetS progression.

The subgroup analyses showed that a stronger association between the CALLY index and MetS was observed in females (Pinteraction = 0.005) and participants aged < 60 years (Pinteraction < 0.001). Differential responses to sex hormones may explain the sex difference in the relationship between the CALLY index and MetS [66]. A meta-analysis discovered that reduced sex hormone-binding globulin and elevated estradiol concentrations increased the risk of diabetes mellitus in women [67]. In those aged ≥ 60 years, the association between the CALLY index and MetS was present, but it was relatively weak. This may be related to the decline in immune cell function and immune cell proliferation [68], and the reduction in the number of pattern recognition receptors in the elderly. Moreover, chronic diseases in the elderly also inhibit normal immune system function [69].

Strengths of this study include the use of NHANES database, which ensures a nationally representative sample and broad generalizability, as well as the identification of the CALLY index as a novel, non-invasive biomarker with potential to enhance MetS risk assessment. However, this study also has several limitations that should be considered. First, the NHANES design only allowed for certain counts to be measured at a single time point, potentially affecting the accuracy of the results. Moreover, the exclusion of participants with incomplete data may have introduced selection bias. Second, the retrospective cross-sectional nature of this study rendered our observations susceptible to inherent bias, and causality could not be established, allowing for only an interpretation of the associations [70]. Despite these limitations, the findings of this study are clinically relevant. By utilizing routine laboratory markers, the CALLY index could serve as a practical and cost-effective tool for primary care physicians to identify individuals at high risk for MetS. Its potential clinical application may facilitate early detection and timely intervention, thereby potentially slowing or even preventing the progression of MetS. Given the inverse relationship between the CALLY index and MetS, patients with a lower index may benefit from individualized treatment approaches focused on reducing inflammation and improving nutritional status. Interventions such as anti-inflammatory therapies and dietary modifications could enhance metabolic health, thereby preventing the progression of MetS. However, further studies are needed to validate these hypotheses.

Conclusion

Our analysis showed that a higher CALLY index was associated with a lower risk of MetS among adults from the United States. The CALLY index may provide additive value for identifying individuals who are at a higher risk of developing MetS. Further prospective studies are needed to validate our findings.

Data availability

Publicly available datasets were analyzed in this study. These data are accessible at the following website: www.cdc.gov/nchs/nhanes/.

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Acknowledgements

The authors thank the NHANES 2003-2010 participants for their invaluable contributions.

Funding

This project was supported by the National Outstanding Youth Science Fund Project of National Natural Science Foundation of China. (No.82100263).

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Author notes

  1. Lanlan Wu and Dunzheng Han contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China

    Lanlan Wu, Dunzheng Han, Yuting Xue, Shangfei He, Zhuang Ma, Shuwen Su, Peixin Li, Shenrong Liu & Haobin Zhou

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  1. Lanlan Wu
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Contributions

Study concept and design: HB Zhou, SR Liu and DZ Han; Acquisition of data: LL Wu, SW Su, and Z Ma; Analysis and interpretation of data: YT Xue and SF He; Drafting of the manuscript: LL Wu, PX Li and SW Su; Critical revision of the manuscript: HB Zhou, SR Liu and DZ Han. All authors have reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Shenrong Liu or Haobin Zhou.

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Ethics approval and consent to participate

The National Center for Health Statistics and the Ethics Review Board approved the protocol for NHANES, and all participants provided written informed consent. The authors have disclosed no conflicts of interest.

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All authors have reviewed and approved the final version of the manuscript.

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The authors declare no competing interests.

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Wu, L., Han, D., Xue, Y. et al. Association between the C-reactive protein–albumin–lymphocyte index and metabolic syndrome: evidence from the 2003–2010 national health and nutrition examination survey. Diabetol Metab Syndr 17, 39 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-025-01609-8

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Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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