A surgical nursing perspective analysis of glucose variability in BCLC stage B–C hepatocellular carcinoma patients with and without T2D within 1 year of hepatectomy: a retrospective cohort study from 2016 to 2020
Highlight box
Key findings
• Compared to the hepatocellular carcinoma (HCC) patients without type 2 diabetes (T2D), those with T2D with Barcelona Clinic Liver Cancer (BCLC) stage B–C showed greater variability in glucose levels at 1 month and 1 year post-surgery.
What is known and what is new?
• Variability in glucose levels has been reported to be correlated with a variety of patient characteristics in Colorectal cancer (CRC).
• This retrospective study sought to describe variability in glucose levels and identify the factors correlated with higher levels of variability in glucose levels in a sample of patients with HCC.
What is the implication, and what should change now?
• It is possible that a greater awareness and understanding of variability in glucose levels can be gained by conducting nursing research on patients with HCC.
Introduction
Hepatocellular carcinoma (HCC) remains one of the greatest challenges in the field of liver disease (1-3). Some patients with Barcelona Clinic Liver Cancer (BCLC) B–C stage suffer from chronic hepatitis and cirrhosis, the latter of which is correlated with a poor survival (4,5). In addition, cirrhosis is strongly correlated with diabetes mellitus (DM) as a result of disruptions in glucose metabolism in the damaged liver (5-7). A significant number of patients with HCC suffer from diabetes (8-10). Many epidemiological research studies have shown that DM also leads to an increased risk of cancer, particularly HCC, for every 1 nmol/L increase in blood sugar, the risk of HCC increased by 4% (11,12).
The presence of DM has also been shown to be a factor that is independent of the prognosis of HCC patients, hyperglycemia increase the incidence of surgical site infections as low immune system function due to metabolic disorders (13). Individuals who suffer from type 2 diabetes (T2D) are unable to maintain their blood sugar levels within a therapeutic range (4,5). A high level of blood sugar, which is an important part of cellular metabolism, is correlated with DM, which in turn is correlated with an increased risk of HCC (5). Numerous studies have examined the relationship between T2D and HCC, and it has been found that patients with T2D have an increased risk of developing HCC (6-8). The prognosis of HCC patients with or without T2D can be improved by stabilizing their blood glucose (9). The development of a standard definition and practice guidelines for the management of glycemic control in cancer patients is still in its infancy.
Researches indicate that cancer patients, regardless of whether or not they have T2D, have high levels of variability in glucose levels (14,15). Variability in glucose levels is currently measured by the standard deviation (SD) and/or coefficient of variation (CV) of the mean blood glucose level (14,15). Despite the fact that the reporting methods of variability in glucose levels and the definitions of unstable glycemic control scores are not uniform, a CV value of >36% has been identified as the cut-off value for distinguishing between stable glycemic control and unstable glucose control in patients with diabetes using continuous glucose monitoring systems (14). A CV cut-off point for glycemic control in cancer patients has not yet been established.
With the exception of colon cancer, only limited research has been conducted on the association between variability in glucose levels and a variety of patient characteristics in cancer patients. Several factors may contribute to variability in glucose levels, including patient demographics, clinical characteristics, and health behaviors. Further, variability in glucose levels has been shown to increase the risk of adverse events, including positive blood cultures and infections (16-18).
This retrospective study sought to describe variability in glucose levels and identify the factors correlated with higher levels of variability in glucose levels in a sample of patients with HCC. We present the following article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-163/rc).
Methods
Samples
This retrospective study was conducted with BCLC stage B–C HCC patients, with or without T2D, treated at the Eastern Hepatobiliary Surgery Hospital and Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. To be eligible for inclusion in this study, the patients had to meet the following inclusion criteria: (I) have HCC; (II) be aged ≥18 years; (III) have been diagnosed with BCLC stage B–C between January 2016 and December 2020; (IV) have received surgical therapy with or without chemotherapy; and (V) have had 2 or more blood glucose values recorded within 1 year of surgery. Among the identified patients,
39 met the criteria for T2D. A total of 60 patients with type 1 diabetes (a distinctly different disease) were excluded from the study to ensure the homogeneity of our sample. Additionally, patients who had received chemotherapy for a malignancy other than HCC within 1 year of their surgery were excluded from the research. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (No. XHECC-D-2023-070) and Eastern Hepatobiliary Surgery Hospital (No. EHBHKY2020-02-011). Informed consent was taken from all the patients. Clinical details were extracted from admission.
Hepatectomy
An incision was made in the right subcostal region to perform the hepatectomy under general anesthesia. If possible, a surgical margin of at least 1 cm was made when resecting the tumor. A 1-cm surgical margin could not be made when a tumor was adjacent to major blood vessels, but the tumor resection margin made was wide enough to prevent residual tumors. In cases of multiple tumors, a single liver resection or multiple liver resections were performed, depending on the location of the tumors. The procedure was routinely conducted via a 15-minute/5-minute clamp and unclamp cycle using the Pringle’s maneuver. The transection of the liver was performed with an ultrasonic scalpel or by clamp crushing.
Measures
The primary outcome variable was blood glucose variability at 1 month and within 1 year of HCC surgery. Variability in glucose levels was determined based on the SD (mg/dL) and CV of all the available blood glucose measurements within 1 year of surgery. To calculate the CV, the following formula was used: CV = (SD/mean value) × 100% (19). In the absence of any information regarding the timing of the glucose testing with respect to eating, glucose scores were considered to represent random, non-fasting assessments. During the hospital follow-up, data on household income were obtained. The variables in the data were recorded and cleaned before the analysis.
Statistical analysis
An analysis of the data was conducted using SPSS 26 (IBM Corporation, Armonk, NY, USA). Null scores were assigned to any missing data. The analyses were conducted within and between groups. The medians [interquartile ranges (IQRs)] are presented for the continuous variables. The frequencies [N (%)] are presented for the categorical variables. Kolmogorov-Smirnov test was used to determine normality. Mann-Whitney U test was used to compare the continuous variables. A Chi-squared (χ2) test or Fisher’s exact test was used to compare the categorical characteristics between the groups. A Spearman’s correlation analysis was performed. A P value <0.05 was set as the threshold for statistical significance.
Results
Clinical and demographic characteristics at the baseline
Over the course of the study, 7,106 glucose measurements were taken. Table 1 provides a detailed description of the demographic characteristics of the patients. The sample comprised 30 patients (31.6%) with a documented diagnosis of T2D before undergoing surgery. The age of patients with T2D was greater than that of patients without T2D (mean age: 70.3±8.45 vs. 60.4±11.27 years, P=0.031). Compared to the patients without T2D, those with T2D had higher blood glucose measurements within 1 month (33 vs. 7) and 1 year (46.5 vs. 22.5, P<0.001) of surgery. As Table 2 shows, the T2D patients had higher preoperative blood glucose levels (186 mg/dL) than the non-T2D patients (99 mg/dL, P<0.001). Among the T2D patients, 33.33% used insulin, and 43.33% used oral anti-diabetic drugs, such as metformin (40.6%). Within 1 year of surgery, the patients with T2D received a lower cumulative dose of steroids (121 mg) than those without T2D (1,476 mg, P=0.032). The T2D patients and non-T2D patients did not differ in terms of chemotherapy medication or other characteristics.
Table 1
| Characteristic | With diabetes (N=30) | Without diabetes (N=65) | P valuea |
|---|---|---|---|
| Baseline BMI (kg/m2), median [IQR] | 28.00 [22.15–38.41] | 28.33 [21.17–37.52] | 0.372 |
| Age in years, mean ± SD | 70.3±8.45 | 60.4±11.27 | 0.031 |
| Gender, n | 0.635 | ||
| Male | 15 | 23 | |
| Female | 15 | 42 | |
| Marital status, n | 0.361 | ||
| Married | 22 | 40 | |
| Divorced | 5 | 10 | |
| Widowed | 1 | 6 | |
| Single | 2 | 9 | |
| Insurance status, n | |||
| Private | 15 | 55 | 0.028 |
| Sociate | 15 | 10 | |
| Median household income (RMB, Yuan), median [IQR] | 30,432 [28,130–50,277] | 30,086 [28,184–50,662] | 0.874 |
a, patients with diabetes vs. patients without diabetes by Mann-Whitney U, chi-squared (χ2), or Fisher’s exact tests. BMI, body mass index; IQR, interquartile range; SD, standard deviation.
Table 2
| Characteristic | With diabetes (N=30) | Without diabetes (N=65) | P valuea |
|---|---|---|---|
| Preoperative glucose, mg/dL (n=72), median [IQR] | 186 [153–231] (n=28) | 99 [97–109] (n=44) | <0.001 |
| Preoperative glucose >140 mg/dL, n | 25 | 9 | <0.001 |
| BCLC stage, n | 0.215 | ||
| B | 20 | 55 | |
| C | 10 | 10 | |
| Number of oral diabetes medications, n | |||
| 1 | 10 | 0 | |
| 2 | 1 | 0 | |
| Diabetes therapy at time of surgery, n | <0.001 | ||
| Insulin | 10 | 0 | <0.001 |
| Oral therapyb | 13 | 0 | <0.001 |
| Insulin and oral therapy | 7 | 0 | <0.001 |
| Steroid dose over 1 month following surgery, prednisolone equivalent (mg), median [IQR] | 53 [22–67] (n=10) | 67 [52–103] (n=20) | 0.783 |
| Steroid dose over 12 months following surgery, prednisolone equivalent (mg), median [IQR] | 121 [56–872] (n=10) | 1,476 [68.5–2,367.5] (n=20) | 0.032 |
| Antibiotic use over 12 months, n | 0.261 | ||
| None | 27 | 50 | |
| 1 time | 0 | 5 | |
| 2 times | 2 | 8 | |
| ≥3 times | 1 | 2 | |
| Positive blood cultures within 1 month following surgery, n | 2 | 6 | 0.873 |
| Positive blood cultures within 12 months following surgery, n | 1 | 5 | 0.452 |
a, patients with diabetes vs. patients without diabetes by Mann-Whitney U, chi-squared (χ2), or Fisher’s exact tests. b, DPP-4 inhibitors, metformin, SGLT2 inhibitors, sulfonylureas. BCLC, Barcelona Clinic Liver Cancer; IQR, interquartile range.
Patients with and without T2D: variability in glucose levels
Table 3 sets out the mean blood glucose, SD, and CV of the patients with and without diabetes. Compared to the patients without T2D, there was a significant increase in all blood glucose indicators in the T2D patients at 1 month and 1 year post-surgery (P<0.001).
Table 3
| Study variable | With diabetes (N=30), median [IQR] | Without diabetes (N=65), median [IQR] | P valuea |
|---|---|---|---|
| Mean of glucose measurements, nb | <0.001 | ||
| 1 month | 33 [13.5–46.50] | 7 [4.50–12.0] | |
| 1 year | 46.5 [23.50–69.50] | 22.5 [11.00–46.50] | |
| Mean glucose, mg/dLb | <0.001 | ||
| 1 month | 145.33 [117.96–179.56] | 115.36 [103.44–135.96] | |
| 1 year | 139.55 [121.25–200.06] | 113.32 [102.13–135.44] | |
| SD, mg/dLb | <0.001 | ||
| 1 month | 46.43 [31.88–59.37] | 21.56 [13.28–29.77] | |
| 1 year | 42.49 [30.61–57.13] | 20.45 [13.92–29.32] | |
| CVb | <0.001 | ||
| 1 month | 23.50 [21.33–35.48] | 13.21 [11.54–26.21] | |
| 1 year | 26.14 [21.59–37.49] | 17.36 [12.96–25.64] | |
Glycemic variability was determined by the SD (mg/dL) and CV. a, with diabetes vs. without diabetes by Mann-Whitney U; b, Tukey’s hinges. SD, standard deviation; CV, coefficient of variation; IQR, interquartile range.
Indicators of variability in glucose levels and demographic and clinical characteristics
Table 4 shows the Spearman correlation coefficients for variability in glucose levels and the demographic and clinical characteristics of the patients with T2D. In the T2D patients, a higher 1-month SD was correlated with a lower cumulative dose of steroids (r=–0.645, P<0.01) and a lower baseline body mass index (BMI) (r=–0.431, P<0.05) within 1 year of surgery, and administering insulin during surgery (r=0.355, P<0.05). A correlation was found between a higher 1-month CV and a lower baseline BMI (r=–0.464, P<0.01). Additionally, correlations were found between a higher 1-year SD and preoperative blood glucose levels
>140 mg/dL (r=0.423, P<0.01), being male (r=0.368, P<0.05), being married (r=–0.339, P<0.05).
Table 4
| Covariate | 1 month mean glucose | 1 month SD | 1 month CV | 1 year mean glucose | 1 year SD | 1 year CV |
|---|---|---|---|---|---|---|
| Age at surgery | 0.103 | 0.115 | –0.035 | –0.066 | –0.036 | –0.229 |
| BMI | –0.077 | –0.431* | –0.464** | 0.062 | –0.235 | –0.336 |
| Gendera | 0.361 | 0.243 | 0.192 | 0.452** | 0.368* | 0.136 |
| Employment statusb | 0.016 | –0.112 | –0.155 | 0.078 | 0.162 | 0.161 |
| Marital statusc | –0.235 | –0.162 | –0.123 | –0.328 | –0.339* | –0.225 |
| Median household income | 0.135 | 0.024 | –0.063 | 0.123 | 0.236 | 0.192 |
| Preoperative glucose | 0.322 | 0.192 | 0.037 | 0.505** | 0.435** | 0.292 |
| Preoperative glucose >140 mg/dL | 0.298 | 0.135 | 0.064 | 0.436** | 0.423** | 0.265 |
| Cumulative steroid dose 1 month following surgery | –0.250 | –0.230 | –0.105 | –0.436 | –0.288 | 0.123 |
| Cumulative steroid dose 1 year following surgery | –0.636** | –0.645** | –0.252 | –0.298 | –0.305 | 0.064 |
| Taking insulin at time of surgery | 0.359* | 0.355* | 0.196 | 0.343* | 0.286 | 0.164 |
| Taking insulin 1 year following surgery | 0.323* | 0.246 | 0.193 | 0.361* | 0.335* | 0.282 |
| Positive blood culture within 1 month following surgery | –0.166 | –0.235 | –0.286 | –0.113 | –0.262 | –0.295 |
| Positive blood culture within 1 year following surgery | –0.182 | –0.236 | –0.262 | –0.176 | –0.246 | –0.262 |
| Number of antibiotics prescribed within 1 month following surgery | –0.035 | –0.160 | –0.126 | –0.145 | –0.029 | 0.056 |
| Number of antibiotics prescribed within 1 year following surgery | –0.192 | –0.138 | –0.067 | –0.248 | –0.119 | 0.035 |
0.00–0.19 = very weak; 0.20–0.39 = weak; 0.40–0.59 = moderate; 0.60–0.79 = strong; 0.80–1.0 = very strong. a, Female = 0, male = 1. b, retired = 0, working = 1, other = 2. c, married = 0, not married = 1. *, P<0.05; **, P<0.01. SD, standard deviation; CV, coefficient of variation; BMI, body mass index.
Patients without T2D
As Table 5 shows, among the patients without T2D, higher SDs at 1 month and 1 year were correlated with an older age (r=0.253, r=0.291, P<0.05) and being prescribed more antibiotics within 1 month of surgery (r=0.292, r=0.139, P<0.05). Additionally, higher 1-month and 1-year CVs were correlated with a greater number of antibiotic prescriptions within 1 month of surgery (r=0.136, r=0.122; P<0.05).
Table 5
| Covariate | 1 month mean glucose | 1 month SD | 1 month CV | 1 year mean glucose | 1 year SD | 1 year CV |
|---|---|---|---|---|---|---|
| Age at surgery | 0.188* | 0.253* | 0.179 | 0.235** | 0.291* | 0.168 |
| BMI | –0.006 | –0.061 | –0.055 | 0.195 | 0.134 | 0.077 |
| Gendera | 0.029 | –0.124 | –0.136 | –0.085 | –0.119 | –0.146 |
| Employment statusb | –0.144 | –0.163 | –0.092 | –0.173 | –0.035 | –0.065 |
| Marital statusc | 0.166 | 0.191 | 0.122 | 0.236* | 0.164 | 0.123 |
| Median household income | –0.065 | –0.133 | –0.105 | –0.111 | –0.166 | –0.114 |
| Preoperative glucose | 0.373** | 0.162 | 0.055 | 0.316** | 0.135 | 0.062 |
| Preoperative glucose>140 mg/dL | 0.182 | 0.065 | –0.013 | 0.176 | 0.089 | 0.023 |
| Cumulative steroid dose 1 month following surgery | –0.012 | –0.046 | –0.099 | –0.022 | 0.025 | 0.038 |
| Cumulative steroid dose 1 year following surgery | –0.236 | –0.222 | –0.116 | –0.263 | –0.191 | –0.127 |
| Positive blood culture within 1 month following surgery | –0.070 | 0.053 | 0.029 | 0.066 | –0.031 | –0.085 |
| Positive blood culture within 1 year following surgery | –0.136 | 0.063 | 0.055 | 0.062 | 0.163 | 0.194 |
| Number of antibiotics prescribed within 1 month following surgery | 0.166 | 0.292* | 0.136* | 0.166 | 0.139* | 0.122* |
| Number of antibiotics prescribed within 1 year following surgery | 0.153 | 0.142 | 0.163 | 0.105 | 0.176* | 0.184* |
0.00–0.19 = very weak; 0.20–0.39 = weak; 0.40–0.59 = moderate; 0.60–0.79 = strong; 0.80–1.0 = very strong. a, Female = 0, male = 1. b, retired = 0, working = 1, other = 2. c, married = 0, not married = 1. *, P<0.05; **, P<0.01. SD, standard deviation; CV, coefficient of variation; BMI, body mass index.
Discussion
Recent research has shown that DM negatively affects the prognosis of HCC patients following hepatectomy (20-22). As far as we know, this was the first study to evaluate postoperative variability in glucose levels among HCC patients with BCLC stage B–C using 2 calculation methods (SD and CV). Only a few studies have examined variability in glucose levels in HCC patients, and no research appears to have been conducted that incorporated variability in glucose levels as an outcome measure (23). We found that patients with T2D had higher blood glucose variability at 1 month and 1 year post-surgery than patients without T2D. The variability in the glucose levels of patients with T2D has been reported to be higher than that of non-T2D patients (24) and the range of variability in the glucose levels is broader (25).
We found an association between a higher variability in glucose levels and demographic and clinical characteristics among T2D patients and non-T2D patients. We observed that the differences in the demographic and clinical variables were correlated with a higher variability in glucose levels over 1 month and 1 year post-surgery, and in the measurement method (i.e., SD and CV). Consistent with previous research (26), we also found that an older age was correlated with greater variability in glucose levels among patients without T2D. Variability in glucose levels may be caused by age-related changes in the cells, such as increased oxidative stress and cellular senescence (27), which are known risk factors for inflammation and hyperglycemia. T2D patients had higher overall blood glucose levels and lower age variability. Despite the fact that T2D is correlated with a higher BMI, higher variability in glucose levels cannot be predicted among patients with T2D and a high BMI (27). There may be differences in pathophysiology between overweight and obese patients and non-overweight and obese patients in relation to pancreatic β-cell function and body fat percentage, which may affect variability in glucose levels (28,29). Further research should be conducted to determine whether other factors, including a patient’s overall health, underlying physiology, and comorbidities, may have contributed to such findings.
A weak association was found between men with T2D and higher 1-year SDs. We also observed a moderate association involving a higher 1-year SD and marital status among the T2D patients. Preoperative hyperglycemia, insulin use, and a lower cumulative dose of steroids were clinical features correlated with a higher variability in glucose levels in T2D patients. According to limited evidence, variability in glucose levels is correlated with an increased risk of infection in cancer patients (24,30). We intended to investigate the relationship between blood glucose changes and infection by identifying positive blood cultures; however, only a few patients had positive blood cultures. Despite the finding that prescribing more antibiotics within 1 month and 1 year of surgery was weakly correlated with the1-month and 1-year SDs among patients without T2D, it is unclear whether these antibiotics were prescribed prophylactically or as a result of active infection. To enable interventions to be established to improve outcomes for cancer patients, further research needs to be conducted to investigate the relationship between infection and variability in glucose levels.
Conclusions
As expected, a higher variability in glucose levels was observed in BCLC stage B–C HCC patients within 1 month and 1 year of surgery. To effectively manage the care of cancer patients and those with T2D, it is important to understand blood glucose fluctuations, especially their amplitudes. Future studies will focus on greater awareness and understanding of variability in glucose levels that can be gained by conducting nursing research on patients with HCC. There are many uncertainties in retrospective research, which increase the deviation of research results. We will enlarge sample size and bias analysis to solve the problem.
Acknowledgments
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-163/rc
Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-163/dss
Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-163/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-163/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (No. XHECC-D-2023-070) and Eastern Hepatobiliary Surgery Hospital (No. EHBHKY2020-02-011). Informed consent was taken from all the patients.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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