Incidence and risk factors for hypoglycemia in patients with hepatocellular carcinoma


 AimTo evaluate the incidence and risk factors for hypoglycemia in patients with hepatocellular carcinoma (HCC).MethodsWe collected and analyzed the clinical data of patients with HCC in our cancer center between April 2020 and June 2021. Univariate and multivariate logistic regression analyses were performed to identify the risk factors associated with hypoglycemia.ResultsThe incidence rate of hypoglycemia in patients with HCC was 28.9% (67/232). Multivariate logistic regression analysis showed a significant association between hypoglycemia and Child-Pugh grade C (odds ratio [OR]=7.3, 95% confidence interval [CI] 2.28–23.31, p=0.001), alpha-fetoprotein (AFP) level (OR=1.000035, 95% CI 1.000007–1.000063, p=0.015), and glycated hemoglobin (HbA1c) level (OR=0.46, 95% CI 0.29–0.73, p=0.001).ConclusionChild-Pugh stage and HbA1c and AFP levels were associated with hypoglycemia in patients with HCC. Our study suggests that these three factors should be comprehensively considered when estimating the risk of hypoglycemia in these patients, and the diagnosis, treatment, and nursing plan should be adjusted in time to reduce the incidence of hypoglycemia.


Introduction
Hepatocellular carcinoma (HCC) with hypoglycemia is one of the clinical features of primary liver cancer with paraneoplastic syndrome, with an incidence rate of 4-27%. 1 There are several mechanisms by which this occurs, including the following 2-6 : (1) tumor cells' production of insulin-like substance growth factor 2, (2) inhibition of hormones that antagonize insulin, (3) consumption of a signi cant number of glucose by a tumor, (4) hepatic glycogen production disorder, (5) reduced inactivation of insulin and increased insulin level in the blood, and (6) patients having poor appetite, dyspepsia, and decreased intake and absorption capacity. The symptoms of hypoglycemia in patients with hepatocellular carcinoma are easily concealed and ignored by the symptoms of liver cancer and confused with hepatic coma when consciousness disorder occurs, which leads to misdiagnosis or missed diagnosis, thus missing the best treatment opportunity. Reducing the incidence of hypoglycemia in patients with HCC and avoiding hypoglycemia-induced impairment of the heart, brain, and other organs are important issues for healthcare personnel. At present, there are few studies on the assessment of the risk of hypoglycemia in patients with HCC according to clinical characteristics. This study aimed to explore the incidence and risk factors for hypoglycemia in patients with HCC.

Participants
This study collected the clinical data of patients with HCC at the Cancer Center, Guangdong Provincial People's Hospital from April 2020 to June 2021. The collected data included demographic characteristics, clinical symptoms, previous history of disease, medication history, laboratory test data, and dietary conditions. Hypoglycemia was de ned as blood glucose < 3.9 mmol/L 7 . The patients were divided into a hypoglycemia group and a non-hypoglycemia group according to whether there was two or more hypoglycemia in the 3 months before enrollment. The inclusion criteria were as follows: patients (1) diagnosed with primary hepatocellular carcinoma by histology or cytology and with at least one episode of hypoglycemia in the past 3 months; (2) with an estimated survival period of not less than 3 months; (3) with no past and current serious mental disorders (brain organic mental disorder, schizophrenia, bipolar disorder, severe depression, mental disorder caused by psychoactive substances, hysteria), central nervous system diseases, primary or metastatic brain tumors, and unconscious disorder; and (4) who voluntarily participated in the study and an signed informed consent form. The exclusion criteria were as follows: (1) patients who declined to participate and (2) patients with hypoglycemia caused by using hypoglycemic drugs. The study protocol was approved by the ethics committee of the hospital (KY-Z-2020-615-02), and written informed consent was obtained from all patients.

Statistical analyses
The Statistical Package for the Social Sciences software (version 25.0, International Business Machines Corporation; Armonk, NY, USA) was used for the statistical analysis. Continuous variables were statistically described by observed number, mean, standard deviation, median, minimum, maximum, and quartile. Frequencies and percentages were used as categorical variables. Student's t-test or rank sum test was used to compare continuous variables between the two groups. Chi-squared test or Fisher's exact test was used to compare categorical variables between the two groups. Multivariate analyses were performed using logistic regression (stepwise forward selection) to determine the signi cant factors for hypoglycemia in patients with HCC. The p value was set at two sides with a signi cance level of 0.05.

Demographic and clinical characteristics
The study enrolled 232 patients with HCC, of which 67 (28.9%) were in the hypoglycemia group and 165 (71.1%) in the non-hypoglycemia group. The median age was 56 (range: 28-84) years. Most of the patients were men (207 [89.2%]). In total, 54 (23.3%), 143 (61.6%), and 35 (15.1%) patients had educational levels of primary, secondary, and university education, respectively. There was no signi cant difference between the two groups in terms of sex and age (p>0.05), but the difference in the composition ratio of educational level was statistically signi cant (χ 2 =7.22, p=0.027). The proportion of patients in the hypoglycemia group with secondary education was higher than that of patients in the non-hypoglycemia group. The proportion of patients with Child-Pugh grades A, B, and C in the hypoglycemia group were 20.9%, 26.9%, and 50.7%, respectively. In the non-hypoglycemia group, the proportions were 32.1%, 28.5%, and 39.4%, respectively. There was a signi cant difference in the Child-Pugh stage between the two groups (χ 2 =35.93, p<0.001). The incidence rates of mild, moderate, and severe ascites in the two groups were 14.9%, 20.9%, 17.9% and 7.3%, 10.9%, and 9.7%, respectively, and the difference was statistically signi cant. In addition, the incidence rates of diarrhea (17.9% and 7.3%, χ 2 =5.82, p=0.016) and lower extremity edema (34.3% and 13.9%, χ 2 = 12.46, p<0.001) and the patient's diet (χ 2 =19.20, p<0.001) were signi cantly different between the two groups. However, there were no signi cant differences in diabetes history, Barcelona staging, hepatic encephalopathy, persistent vomiting, or use of somatostatin between the two groups (p>0.05). Detailed information is shown in Table1.   Table 2). The TBIL, DBIL, PT, AFP, and AST levels of patients in the hypoglycemia group were higher than those in the non-hypoglycemia group.   Patients with Child-Pugh grade C had a 7.3 times higher risk of hypoglycemia than grade A. Every percent increase in HbA1c was associated with a 0.56 decrease in the risk of hypoglycemia. patients had Child-Pugh grades A, B, and C, respectively. The higher the Child-Pugh classi cation, the higher the incidence of hypoglycemia. It is well known that the liver is an important organ for the body to maintain a relatively stable blood sugar level and has the ability to synthesize and decompose glycogen. Liver diseases, such as liver cirrhosis, liver ukes, and liver malignant tumors, can lead to impaired liver cell function and abnormal glycogen synthesis and decomposition capabilities, which are also known as abnormal glucose metabolism. Previous studies have shown that the worse the liver function of patients with liver diseases, the more severe the abnormal glucose metabolism. 10 Patients with Child-Pugh grade A had the lowest probability of hypoglycemia, and patients with Child-Pugh grade C had the highest probability of hypoglycemia. 11,12 The results of this study suggest that clinical nurses need to pay attention to the liver function of patients with HCC, especially when the patient's liver function is abnormal. To prevent hypoglycemia and reduce the incidence of hypoglycemia strengthening blood glucose management and observation of patients, intervening in potential hypoglycemia-prone behaviors, and implementing relevant care for patients are considered bene cial.
HbA1c is the product of a combination of hemoglobin and glucose in human red blood cells. Its synthesis process is slow and irreversible and directly proportional to the blood glucose concentration and can be used to monitor the overall blood glucose level of patients in the past 120 days. [13][14][15] This study found that a high HbA1c level (OR = 0.46, 95% CI 0.29-0.73, p = 0.001) was a protective factor for HCC hypoglycemia. Numerous large-scale clinical studies have shown that HbA1c can re ect the risk of hypoglycemia, but the law of its occurrence has not yet formed a uni ed argument.
AFP can re ect liver damage and prognosis, which is closely associated with liver function. [16][17][18] The level of AFP in patients with abnormal liver function is signi cantly higher than that in patients with normal liver function. The results of this study show that AFP level is a risk factor for hepatocellular carcinoma with hypoglycemia. However, the range of AFP in this study was 0.9-54000, resulting in only a little increase in the risk of hypoglycemia for every 1 ng/ml increase in AFP.
A previous study has found that the risk of hypoglycemia increases when the HbA1c level is < 7%. Although controlling HbA1c level to < 6.0%, the incidence rate of hypoglycemia did not increase signi cantly. Therefore, lower or higher HbA1c levels are associated with an increased risk of hypoglycemia. The more drastic the uctuation of blood glucose, the greater the risk of hypoglycemia. [19][20][21] The results of this study were different from those of previous studies, which may be caused by individual differences in the study population enrolled in each study. The association between HbA1c level and the risk of hypoglycemia in patients with HCC requires further study.
This study showed that Child-Pugh stage and HbA1c and AFP levels were associated with the incidence of hypoglycemia in patients with HCC. Therefore, when medical workers provide nursing services to such patients, they need to be alert to the occurrence of hypoglycemia and adjust the diagnosis and treatment and care plan according to the situation to reduce the occurrence of hypoglycemia.