Hypoglycemia on admission in patients with acute on chronic liver failure: a retrospective cohort analyzing the current situation, risk factors, and associations with prognosis
Highlight box
Key findings
• This study found that hypoglycemia is common in patients with acute on chronic liver failure, which is related to poor patient prognosis. Patients with cirrhosis, a high MELD score, and a significant decrease in fibrinogen are more likely to suffer from hypoglycemia.
What is known and what is new?
• A hypoglycemic attack can increase the incidence of adverse events in patients with acute on chronic liver failure.
• This study confirmed that the prognosis of acute on chronic liver failure patients with hypoglycemia was poor, providing a theoretical basis and reference for the follow-up blood glucose management and intervention of such patients.
What is the implication, and what should change now?
• This study suggests that medical staff should pay attention to the blood glucose management of such patients, and avoid hypoglycemia by strengthening blood glucose monitoring, adjusting diet structure, and adding meals before sleep.
Introduction
Acute on chronic liver failure is a serious clinical syndrome characterized by acute liver dysfunction in patients with chronic liver disease, which has a high mortality rate and poor prognosis (1). In China, hepatitis B virus infection is the leading cause of acute on chronic liver failure. Since the liver is the most important organ for the synthesis, storage, decomposition, and release of glycogen in the body, it plays a vital role in maintaining and regulating the stability of blood glucose levels. Patients with acute on chronic liver failure are more likely to develop hypoglycemia in the presence of massive hepatocyte necrosis, which seriously affects the synthesis, storage, and release of glycogen and weakens the inactivation of hypoglycemic hormones such as insulin by the liver (2). Previous studies (3-5) have shown that abnormal glucose metabolism is extremely common in patients with liver disease, and the incidence of hypoglycemia in patients with severe liver disease is as high as 56%. Hypoglycemia can not only increase the incidence of adverse events in patients but also exerts adverse effects on long-term prognosis. There are few studies on hypoglycemia in patients with acute on chronic liver failure, and most of the available studies focused on the mechanism of gluconeogenesis. There is also a lack of research on blood glucose management, risk factors, and prognosis in these patient populations. To the best of our knowledge, studies that explored the predictive role of hypoglycemia in acute on chronic liver failure remain scarce. Therefore, to bridge this gap, this study aims to clarify the risk factors of hypoglycemia and explore its impact on the outcome of patients with acute on chronic liver failure. We present the following article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1422/rc).
Methods
Subjects
In this retrospective study spanning from January 2019 to August 2021, 218 patients with acute on chronic liver failure were selected (Figure 1). Assuming that a 5% difference in hypoglycemia rate is clinically significant, 201 patients were estimated to be needed to achieve 80% power with a two-sided significance level of 0.05 based on the sample size calculation for retrospective cohort study. The inclusion criteria were as follows: (I) patients aged ≥18 years old; and (II) patients who met the diagnostic criteria of chronic and acute liver failure in the Guidelines for the Diagnosis and Treatment of Liver Failure (2018 edition). The exclusion criteria were as follows: (I) patients with abnormal glucose metabolism (such as diabetes) and impaired fasting glucose diagnosed before the presence of liver disease; (II) those with malignant liver tumors or severe renal insufficiency; (III) patients taking medications that disrupt blood glucose, such as insulin, oral hypoglycemic medications, glucocorticoids, and others; (IV) special patient populations, such as pregnant women, alcohol-dependent patients, and others; and (V) patients with incomplete clinical and laboratory examination data. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2018LSK-217) and informed consent was obtained from all patients.
Research methods
The patients’ general clinical characteristics and laboratory examination data on admission were collected through the electronic medical record. General clinical characteristics collected included patient age, gender, body mass index (BMI), co-morbidities (hypertension, chronic heart failure), Child-Pugh score, hepatic encephalopathy, liver cirrhosis, gastrointestinal bleeding, hepatic ascites, and hepatorenal syndrome. Laboratory tests included alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), serum albumin (Alb) and prealbumin, serum creatinine (Scr), international normalized ratio (INR), white blood cell count (WBC), fibrinogen (FIB), and model for end-stage liver disease (MELD) score (6).
According to the diagnostic criteria of hypoglycemia in the 2013 China Guidelines for the Prevention and Treatment of Type 2 Diabetes, a fasting blood glucose ≤2.8 mmol/L during hospitalization is characteristic of hypoglycemia. The prognosis of patients was defined as the survival state at 90 days from the onset of acute on chronic liver failure, as the majority of the mortalities occurred within 3 months after disease onset. The patients were divided into the deceased group and the survival group.
Statistical analysis
SPSS 25.0 software (SPSS Inc., Chicago, IL, USA) was used for data analysis. The enumeration data were expressed as numbers and percentages and compared with the chi-square test. The measurement data were expressed as the mean ± standard deviation or median with interquartile range and compared using the independent sample t-test or the non-parametric Mann-Whitney U test, as appropriate. The risk factors for hypoglycemia were first screened by univariate analysis, and the significant factors were further subject to multivariate binary logistic regression. A two-sided P<0.05 denoted statistical significance.
Results
Comparison of the patients’ general characteristics and laboratory test results
Among the 218 cases included, 99 cases (45.41%) had hypoglycemia. As shown in Table 1, compared with the non-hypoglycemic group, the proportion of liver cirrhosis and ascites, AST, TBIL, and MELD in the hypoglycemic group were significantly higher, whereas FIB was significantly lower. The 90-day mortality rate in the hypoglycemia group was markedly higher than that in the non-hypoglycemia group (72.73% vs. 48.74%, P<0.001).
Table 1
| Variables | Hypoglycemia group (n=99) | Non-hypoglycemia group (n=119) | t/χ2/Z value | P value |
|---|---|---|---|---|
| Age (years) | 69.67±5.85 | 70.34±5.65 | −0.86 | 0.39 |
| Gender, n (%) | 0.55 | 0.46 | ||
| Male | 67 (67.68) | 86 (72.27) | ||
| Female | 32 (32.32) | 33 (27.73) | ||
| Body mass index (kg/m2) | 22.57±2.91 | 22.16±3.07 | 1.02 | 0.31 |
| Hypertension, n (%) | 11 (11.11) | 23 (19.33) | 2.77 | 0.10 |
| Chronic heart failure, n (%) | 15 (15.15) | 20 (16.81) | 0.11 | 0.74 |
| Child-Pugh score, n (%) | 1.61 | 0.45 | ||
| A | 4 (4.05) | 7 (5.88) | ||
| B | 49 (49.49) | 67 (56.30) | ||
| C | 46 (46.46) | 46 (38.66) | ||
| Hepatic encephalopathy, n (%) | 23 (23.23) | 25 (21.01) | 0.16 | 0.69 |
| Liver cirrhosis, n (%) | 64 (64.65) | 49 (41.18) | 11.92 | <0.001 |
| Gastrointestinal bleeding, n (%) | 6 (6.06) | 8 (6.72) | 0.04 | 0.84 |
| Hepatic ascites, n (%) | 78 (78.79) | 68 (57.14) | 11.45 | <0.001 |
| Hepatorenal syndrome, n (%) | 5 (5.05) | 4 (3.36) | 0.39 | 0.53 |
| ALT (U/L) | 335 [276, 437] | 314 [243, 400] | −1.66 | 0.10 |
| AST (U/L) | 264 [207, 308] | 216 [161, 276] | −3.85 | <0.001 |
| TBil (μmol/L) | 379 [317, 424] | 308 [260, 370] | −4.99 | <0.001 |
| Alb (g/L) | 32.9 [30.0, 36.2] | 33.4 [31.0, 35.7] | −0.91 | 0.36 |
| Prealbumin (mg/L) | 36.4 [30.0, 42.8] | 35.7 [30.8, 42.2] | −0.36 | 0.72 |
| Scr (μmol/L) | 71 [58, 82] | 67 [58, 78] | −1.15 | 0.25 |
| INR | 2.50 [2.21, 2.81] | 2.53 [2.23, 2.76] | −0.43 | 0.67 |
| WBC (×109/L) | 7.10 [5.40, 8.80] | 6.80 [5.10, 8.61] | −0.91 | 0.36 |
| FIB (g/L) | 1.30 [1.11, 1.60] | 1.60 [1.21, 1.80] | −3.71 | <0.001 |
| MELD score (points) | 31 [27, 33] | 25 [20, 29] | −7.10 | <0.001 |
| 90-day mortality, n (%) | 72 (72.73) | 58 (48.74) | 12.92 | <0.001 |
Data are expressed as n (%), median [interquartile range] or mean ± standard deviation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBil, total bilirubin; Alb, serum albumin; Scr, serum creatinine; INR, international normalized ratio, WBC, white blood cell count; FIB, fibrinogen; MELD, model for end-stage liver disease.
Analysis of the risk factors for hypoglycemia
The multivariate binary logistic regression (Table 2) results showed that liver cirrhosis [odds ratio (OR) =5.16] and a higher MELD score (OR =1.29) were risk factors for hypoglycemia in patients with acute on chronic liver failure, whereas FIB was a protective factor for hypoglycemia (OR =0.17).
Table 2
| Variables | β | Standard error | Wald value | OR (95% CI) | P value |
|---|---|---|---|---|---|
| Liver cirrhosis | 1.64 | 0.46 | 12.99 | 5.16 (2.11–12.60) | <0.001 |
| Hepatic ascites | 0.81 | 0.4 | 3.07 | 2.24 (0.23–4.89) | 0.94 |
| AST (U/L) | 0.01 | 0.003 | 0.29 | 1.01 (0.54–2.00) | 0.76 |
| TBil (μmol/L) | 0.01 | 0.002 | 0.28 | 1.00 (0.87–1.23) | 0.44 |
| FIB (g/L) | −1.77 | 0.53 | 11.12 | 0.17 (0.06–0.48) | 0.001 |
| MELD score (points) | 0.26 | 0.04 | 36.28 | 1.29 (1.19–1.41) | <0.001 |
AST, aspartate aminotransferase; TBil, total bilirubin; FIB, fibrinogen; MELD, model for end-stage liver disease; OR, odds ratio; CI, confidence interval.
Univariate analysis of the risk factors for 90-day mortality
A total of 130 (59.63%) of the 218 included patients died within 90 days of onset (Table 3). Compared with the patients in the survival group, the deceased group had a significantly higher proportion of patients with liver cirrhosis, hepatic encephalopathy, gastrointestinal bleeding, hepatic ascites, higher MELD scores, and hypoglycemia.
Table 3
| Variables | Deceased group (n=130) | Survival group (n=88) | t/χ2/Z value | P value |
|---|---|---|---|---|
| Age (years) | 69.94±5.54 | 70.17±6.05 | −0.29 | 0.77 |
| Gender, n (%) | 0.46 | 0.50 | ||
| Male | 89 (68.46) | 64 (72.73) | ||
| Female | 41 (31.54) | 24 (27.27) | ||
| Body mass index (kg/m2) | 22.26±3.03 | 22.47±2.97 | −0.50 | 0.62 |
| Hypertension, n (%) | 19 (14.62) | 15 (17.05) | 0.24 | 0.63 |
| Chronic heart failure, n (%) | 24 (18.46) | 11 (12.50) | 1.38 | 0.24 |
| Child-Pugh score, n (%) | 2.94 | 0.23 | ||
| A | 7 (5.38) | 4 (4.55) | ||
| B | 63 (48.46) | 53 (60.23) | ||
| C | 60 (46.15) | 31 (35.23) | ||
| Hepatic encephalopathy, n (%) | 39 (30.00) | 9 (10.23) | 11.95 | <0.001 |
| Liver cirrhosis, n (%) | 82 (63.08) | 31 (35.23) | 16.30 | <0.001 |
| Gastrointestinal bleeding, n (%) | 12 (9.23) | 2 (2.27) | 4.23 | 0.04 |
| Hepatic ascites, n (%) | 95 (73.08) | 51 (57.95) | 5.43 | 0.02 |
| Hepatorenal syndrome, n (%) | 5 (3.85) | 4 (4.55) | 0.07 | 0.80 |
| ALT (U/L) | 328 [252, 404] | 331 [267, 406] | −0.30 | 0.76 |
| AST (U/L) | 253 [188, 300] | 225 [172, 286] | −1.49 | 0.14 |
| TBil (μmol/L) | 342 [288, 398] | 342 [279, 386] | −0.52 | 0.60 |
| Alb (g/L) | 33.0 [30.4, 35.9] | 33.4 [30.9, 35.6] | −0.36 | 0.72 |
| Prealbumin (mg/L) | 35.8 [30.0, 42.1] | 36.1 [31.3, 43.2] | −0.72 | 0.47 |
| Scr (μmol/L) | 68 [57, 80] | 70 [63, 81] | −0.95 | 0.34 |
| INR | 2.52 [2.22, 2.76] | 2.52 [2.24, 2.83] | −0.07 | 0.94 |
| WBC (×109/L) | 7.05 [5.10, 8.48] | 6.71 [5.40, 8.60] | −0.29 | 0.77 |
| FIB (g/L) | 1.51 [1.10, 1.80] | 1.55 [1.20, 1.77] | −0.10 | 0.92 |
| MELD score (points) | 30 [26, 33] | 25 [22, 29] | 5.21 | <0.001 |
| Hypoglycemia, n (%) | 72 (55.38) | 27 (30.68) | 12.92 | <0.001 |
Data are expressed as n (%), median [interquartile range] or mean ± standard deviation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; TBil, total bilirubin; Alb, serum albumin; Scr, serum creatinine; INR, international normalized ratio, WBC, white blood cell count; FIB, fibrinogen; MELD, model for end-stage liver disease.
Multivariate analysis of 90-day mortality
Binary logistic regression analysis (Table 4) showed that hepatic encephalopathy, cirrhosis, a higher MELD score, and hypoglycemia were associated with an increased risk of 90-day mortality in patients with acute on chronic liver failure.
Table 4
| Variables | β | Standard error | Wald value | OR (95% CI) | P value |
|---|---|---|---|---|---|
| Hepatic encephalopathy | 1.80 | 0.46 | 15.09 | 6.02 (2.43–14.89) | <0.001 |
| Cirrhosis | 1.17 | 0.33 | 12.17 | 3.21 (1.67–6.17) | <0.001 |
| Gastrointestinal bleeding | 0.10 | 0.38 | 0.07 | 1.10 (0.53–2.32) | 0.80 |
| Hepatic ascites | 0.61 | 0.35 | 2.98 | 1.83 (0.92–3.65) | 0.09 |
| MELD score (points) | 0.14 | 0.03 | 17.80 | 1.16 (1.08–1.24) | <0.001 |
| Hypoglycemia | 2.17 | 0.86 | 6.28 | 8.72 (1.60–7.42) | 0.01 |
OR, odds ratio; CI, confidence interval; MELD, model for end-stage liver disease.
Discussion
This study examined the incidence, risk factors, and impact of hypoglycemia on the short-term prognosis in patients with acute on chronic liver failure. We found that the incidence of hypoglycemia in the present study was 45.41%, which was similar to those reported previously (7). The specific mechanism of hypoglycemia in patients with acute on chronic liver failure remains unclear. It is speculated that factors such as reduced food intake, compromised liver metabolic capacity, glycogen depletion and gluconeogenesis disorders, and disruption of the inactivation of hypoglycemic hormones (8,9) may account for the occurrence of hypoglycemia in patients with severe liver dysfunction. At present, the research on hypoglycemia in patients with liver failure (10-12) is mostly limited to animal experiments, primarily discussing the related molecular regulation mechanism, and there is still a lack of research on the clinically significant topic of risk factors and prognosis of hypoglycemia in patients with acute on chronic liver failure.
The present study confirmed that hypoglycemia was related to liver cirrhosis, a higher MELD score, and lower FIB. Patients with liver cirrhosis often have portal hypertension, which leads to gastrointestinal congestion and decreased appetite. In addition, patients often need to avoid consuming foods rich in protein to prevent hepatic encephalopathy, resulting in a negative nitrogen balance in energy metabolism. The MELD score has been widely used to evaluate liver function and prognosis. A higher MELD score directly reflects poor liver function, in which the inactivation of insulin is substantially compromised (13,14). Honda et al. (15) found that with the deterioration of liver function, the proportion of patients with fasting hypoglycemia and postprandial hyperglycemia increased significantly, reflecting the failure of the liver to regulate insulin hormones. FIB is one of many coagulation factors synthesized by the liver, and it has been demonstrated to be decreased in acute liver failure (16). In this study, FIB reduction was found to significantly increase the risk of hypoglycemia, which is consistent with previous relevant reports (17).
Univariate and multivariate analysis showed that the short-term prognosis of patients with hypoglycemia was significantly worse than that of patients without hypoglycemia. A study of 636 patients with decompensated cirrhosis without diabetes by Hung et al. (18) found that the 30-day mortality of patients with hypoglycemia was as high as 30.2%. In contrast, the 30-day mortality of patients without hypoglycemia was only 7.4%, which was similar to the results of this study. The 2020 guidelines of the American Society of Critical Care Medicine also suggested that preventing and improving hypoglycemia in patients with severe liver disease helps to improve patient outcomes (19). In a meta-analysis comprising eight previous clinical trials, Chen et al. (20) found that adding meals before bedtime for patients with severe liver disease reduced the risk of fasting hypoglycemia the next day and helped to improve liver function. Currently, the American Society for Parenteral and Enteral Nutrition (21) and the European Society for Clinical Nutrition and Metabolism (22) recommend that patients with severe liver dysfunction should consume extra night-time meals to improve their nutritional metabolism and prevent the adverse effects of hypoglycemia.
This study is the first to systematically investigate the incidence, risk factors, and prognosis of hypoglycemia in patients with acute on chronic liver failure. However, this study also had several limitations, including its retrospective nature, single-center design, and small sample size. Therefore, it is necessary to carry out prospective, multi-center studies with larger sample sizes in the future to validate and generalize the results of this study.
Conclusions
In conclusion, this study found that hypoglycemia was common in patients with acute on chronic liver failure, and is related to poor prognosis. Patients with cirrhosis, a higher MELD score, and a significant decrease in FIB were more likely to develop hypoglycemia. Therefore, medical staff should pay attention to blood glucose management and avoid hypoglycemia by enhancing blood glucose monitoring, adjusting diet structure, and adding meals before bed. However, given that this study is a single-center, retrospective analysis, future prospective, multi-center research is needed.
Acknowledgments
Funding: This project was supported by the hospital-level project of the First Affiliated Hospital of Xi’an Jiaotong University (No. 2018HL-10).
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1422/rc
Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1422/dss
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1422/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 the Ethics Committee of The First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF2018LSK-217) and informed consent was obtained from all 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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(English Language Editor: A. Kassem)
