Rohit Govindarajan1†
Jiancong Chen
Dan Xu
Ming Kuang- 1General Practice Research and International Collaboration, Faculty of Health Sciences, Curtin Medical School, Curtin University, Perth, WA, Australia
- 2Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- 3Department of Medical Education, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- 4Centre for Clinical Research and Education, Faculty of Health Sciences, Curtin School of Population Health, Curtin University, Perth, WA, Australia
Hypoglycemia is rarely highlighted as a complication that requires close monitoring in patients with chronic liver disease, despite substantial evidence of its occurrence in cirrhotic patients. This narrative review aims to evaluate whether hypoglycemia in liver cirrhosis patients, irrespective of diabetes status, exacerbates complications and warrants targeted management strategies. Our analysis reveals that hypoglycemia is prevalent in cirrhotic patients and is associated with increased mortality and complications compared to normoglycemic patients. Although literature in this topic is limited, our review suggests that early identification of high-risk liver disease patients and the implementation of novel, clinically relevant strategies to minimize hypoglycemia may improve clinical outcomes and health-related quality of life as well as reduce morbidity and mortality. Further research will be required to validate thesel strategies.
Introduction
Hypoglycemia is commonly discussed in relation to diabetic patients, particularly those using oral hypoglycemic agents or insulin therapy. However, its occurrence in patients with liver disease is also notable. This can be attributed to various factors, including the liver’s critical role in glucose metabolism. Despite this, the significance of hypoglycemia in chronic liver disease is rarely addressed, and international clinical guidelines for cirrhosis often overlook its management. This narrative review aims to bridge this gap by critically reviewing the current literature to elucidate the relationship between hypoglycemia and liver cirrhosis. We aim to assess whether protocol implementation to identify and prevent hypoglycemia could improve patient outcomes, irrespective of diabetes status. By focusing on this unexplored aspect of liver disease management, we seek to highlight gaps in the existing literature and contribute to better clinical practice and improved care for patients with liver cirrhosis.
Methods
The authors conducted an extensive literature review in Ovid Medline, Ovid Embase, CINHL, Web of Science, and PsychINFO (OVID), employing the following Medical Subject Headings (MeSH) terms: hypoglycemia, chronic liver disease, cirrhosis, acute on chronic liver disease and decompensated cirrhosis. The review identified 222 studies related to the association between hypoglycemia and chronic liver disease. After scanning the titles and abstracts to remove duplicates, case reports, and editorial comments, 12 publications were selected for full-text screening to explore the significance of hypoglycemia in hospitalized patients with chronic liver disease. The Oxford Equator PRISMA checklist was applied to ensure that the review adhered to evidence-based standards for narrative reviews. This checklist, an internationally recognized guideline, ensures transparency, integrity, and validity in reporting systematic and narrative reviews.
Overview
Hypoglycemia is defined by serum glucose levels typically below 3.9 mmol/L (1). It is a well-known and feared complication in the management of diabetic patients (2). Severe hypoglycemia refers to any hypoglycemic event that requires external assistance for recovery (3). It is associated with falls, neurological disease, cardiovascular events, cognitive impairment, and increased mortality (4).
Cirrhosis is a chronic progressive, end-stage liver disease characterized by the replacement of normal liver tissue with fibrous scar tissue, which disrupts the liver’s normal structure and function (5). This includes alterations in key hepatic metabolic processes, such as gluconeogenesis and glycogenolysis, both of which normally contribute to maintaining higher serum glucose levels (6).
During a 2–6 h fast, hepatocytes initiate glycogenolysis, breaking down stored glycogen to release glucose for energy (2). In a state of prolonged fasting, hepatocytes utilize substrates like lactic acid, amino acids, and glycerol to synthesize glucose through gluconeogenesis (2). However, abnormal liver metabolism or cellular damage impairs the liver’s ability to regulate blood glucose. Approximately 5%–7% of cirrhotic patients progress to decompensated cirrhosis each year (7). Decompensated cirrhosis is an advanced stage of the disease, marked by severe complications such as hepatic encephalopathy, ascites, and/or variceal bleeding (7).
Is hypoglycemia prevalent among cirrhotic patients without diabetes
Hypoglycemia is frequently observed in cirrhotic patients. Singh et al. (8) reported hypoglycemia in 67% of cirrhotic patients without diabetes, while Noul et al. (9) found it in 50% of individuals hospitalized for septicemia (8, 9), none of whom were on hypoglycemic agents (9). Majeed et al. (10), through a cross-sectional study, also found hypoglycemia in 51.2% of liver cirrhosis patients after excluding those with diabetes, although significant grammatical errors in the study affected its reliability. While less pronounced, Gladys-Oryhon et al. (11) still observed hypoglycemic events in 34.7% of non-diabetic cirrhotic inpatients.
Several factors contribute to the high prevalence of hypoglycemia in cirrhotic patients, including (i) persistent cachexia, especially in decompensated cirrhosis, (ii) reduced hepatocyte mass, leading to decreased gluconeogenic capacity, (iii) sarcopenia, which limits the availability of amino acids necessary for hepatic gluconeogenesis, and (iv) comorbid conditions such as congestive heart failure, chronic pancreatitis with glucagon deficiency, chronic kidney disease, and hepatorenal syndrome. As the liver function deteriorates, the incidence of fasting hypoglycemia rises significantly, indicating the liver’s inability to regulate insulin glucose homeostasis in chronic disease (12).
What do current guidelines suggest regarding hypoglycemia in cirrhotic patients?
Whilst continual glucose monitoring is strongly emphasized in hospitalized diabetic patients, regardless of cirrhosis, the European Association for the Study of the Liver (EASL) clinical practice guidelines do not mention tight glucose control for patients admitted with decompensated cirrhosis (13). Similarly, guidelines for compensated liver cirrhosis, such as those by Yoshiji et al. (14) and the British Society of Gastroenterology, do not address hypoglycemia management in non-diabetic cirrhotic patients (15). Whether hypoglycemia should be a concern in cirrhotic patients admitted for reasons other than decompensation, warrants further review.
Another important question is whether avoiding hypoglycemic episodes in hospitalized cirrhotic patients, decompensated or otherwise, could improve outcomes. The only guideline we found that explicitly addresses this is from the American Society of Critical Care Medicine, which states that preventing hypoglycemia in ICU patients with acute-on-chronic liver disease can improve outcomes (16). However, this recommendation is limited to ICU patients, and no clear guidance exists for managing hypoglycemia in non-ICU cirrhotic inpatients, whether admitted with decompensation, acute-on-chronic disease, or other conditions.
Although hypoglycemia management is not specifically included in liver disease guidelines, the American Society of Parenteral and Enteral Nutrition and the European Society for Clinical Nutrition and Metabolism recommended that patients with severe liver dysfunction consume extra nighttime meals to prevent hypoglycemia during temporary fasting.
However, these guidelines do not elaborate on whether this practice should be generalized to all cirrhotic patients (17, 18).
The current literature clearly indicates that hypoglycemia is common amongst cirrhotic patients, irrespective of their diabetes status. To address the significance of identifying hypoglycemia, we reviewed the available evidence. Our goal was to determine whether hypoglycemia is linked to poor outcomes and whether preventing these hypoglycemic events could lead to improved patient outcomes.
Increased adverse outcomes in hypoglycemic patients with cirrhosis admitted to hospital
Obeidat et al. (19) conducted a retrospective study involving 1,778,829 in-patients with cirrhosis, excluding those with diabetes. The study revealed that in-patient mortality was significantly higher than in the hypoglycemia group compared to the non-hypoglycemia group of cirrhotic patients (OR 6.8; CI 95% 6.4–7.24, P-value < 0.001) (19). Additionally, patients in the hypoglycemic group had a longer and more complicated hospital stay, with increased likelihood of vasopressor use, mechanical ventilation, cardiac arrest, and ICU admission (19).
Similarly, Hung et al. (20) reported a 30 days mortality rate of 30.2% in the hypoglycemic group, compared to 7.4% in the non-hypoglycemic group (P < 0.001) among hospitalized cirrhotic patients without diabetes. This study further found that the 30 days mortality was even higher in patients with hypoglycemia and hepatocellular carcinoma (HCC), with a hazard ratio of 6.11 (95% CI 4.40–8.49, P < 0.001) compared to 4.96 (95% CI 4.05–6.08, P < 0.001) for patients without either condition (20).
Although many studies have demonstrated poor outcomes in cirrhotic patients with hypoglycemia, the benefit of preventing hypoglycemia remains unclear. Additionally, there are no current consensus guidelines for monitoring glucose levels in cirrhotic patients. It is also unclear whether hypoglycemia prevention should be applied universally to all cirrhotic patients or targeted specifically to higher-risk groups. Future studies are needed to address these questions and potentially improve the clinical outcome of cirrhotic patients.
Increased adverse outcomes in hypoglycemic patients with cirrhosis admitted in hospital with decompensated cirrhosis
The study by Pfortmueller et al. (21) explored the relationship between hypoglycemia on admission in patients presenting to the emergency department with acutely decompensated cirrhosis. The study found that patients with hypoglycemia were significantly more likely to be admitted to the ICU compared to normoglycemic patients (20.4% vs 10.3%, P < 0.011). Additionally, the hypoglycemic group had a higher mortality rate rather than the normoglycemic group (28.6% vs 10.3%, P < 0.049), with an estimated survival of 36 days compared to 54 days for the normoglycemic group (P < 0.007) (21).
The study also showed a significant association between hypoglycemia and hepatorenal syndrome in decompensated cirrhosis, which may contribute to the increased mortality in the hypoglycemic group (21, 22). Olson et al. (22) highlighted that there are currently no recommendations to treat hypoglycemia in these patients on admission, despite clear evidence of worse prognosis and clinical outcomes. Therefore, the author suggests evaluating whether prophylactic glucose administration could improve clinical outcomes in hypoglycemic patients (22). Future studies should investigate the potential benefit of preventing hypoglycemia in cirrhotic patients through strategies such as prophylactic glucose and nighttime carbohydrate consumption (18, 22).
Increased adverse outcomes in hypoglycemic patients who were admitted to hospital with acute on chronic liver failure
Acute-on-chronic liver failure is a syndrome characterized by the acute deterioration of liver function in patients with pre-existing chronic liver disease, often triggered by factors such as infection, gastrointestinal bleeding, or alcohol consumption (23). A study by Yang et al. (24) involving 218 patients with acute-on-chronic liver failure found hypoglycemia in 45.41% of cases. Hypoglycemia was associated with significantly higher 90 days mortality compared to non-hypoglycemic patients (72.73% vs 48.74%, P < 0.001).
The increased mortality was further reflected in additional findings, with hypoglycemic patients showing higher levels of AST (264 vs 216), total bilirubin (379 vs 308), and MELD score (31 vs 25), consistent with the findings of Olsen et al. (22). The analysis of risk factors for hypoglycemia in these patients revealed that liver cirrhosis (OR 5.16) and higher MELD score (OR 1.29) were significant risk factors for hypoglycemia (24). Conversely, higher fibrinogen levels appeared to reduce the risk of hypoglycemia (OR 0.17) (24).
These findings suggest that hypoglycemia may serve as an early indicator of acute-on-chronic liver failure, as evidenced by elevated AST, INR, creatinine, and bilirubin level in hypoglycemia patients, which were not observed in normoglycemic individuals (22).
These findings not only reinforce the evidence of increased adverse outcomes in hypoglycemic cirrhotic patients but also suggest a potential pathway for stratifying and identifying the most at-risk cohorts. This stratification could be based on various criteria, including AST, bilirubin, INR, creatinine, MELD scores and fibrinogen levels (22, 24). Further exploration may provide insights into how stratification can be applied to ensure that high-risk patients are promptly identified and closely monitored.
Hypoglycemia among cirrhosis patients as a predictor of bacteremia and septicemia?
In addition to the increased mortality seen in cirrhotic patients experiencing hypoglycemia, a study by Yedidya et al. (25) demonstrated that hypoglycemia is predictive of bacteremia. Among 1,274 cirrhosis admissions, glucose levels below 5.6 mmol/L increased the likelihood of subsequent bacteremia, even in normothermic patients (25). This study suggests that hypoglycemia could be used as a clinical predictor for bacteremia, raising the question of whether prophylactic antibiotic therapy may be warranted in cirrhotic patients with hypoglycemic events. There is some supporting evidence that prophylactic antibiotics might reduce acute exacerbations of chronic liver diseases (25).
Another study by Nouel et al. (9) found that 50% of cirrhotic patients with septicemia had asymptomatic hypoglycemia. The study also noted that hypoglycemia is commonly seen in cirrhotic patients with septic shock, potentially secondary to endotoxemia. Tanveer et al. (26) further established that hypoglycemia in decompensated cirrhotic patients was consistently associated with septicemia.
Ultimately, future studies are needed to determine whether early identification of hypoglycemia could serve as a predictor for septicemia and justify the use of prophylactic antibiotics or further investigations, such as blood cultures, to improve patient outcomes.
Is there a clear protocol or recommendation for managing hypoglycemia among cirrhosis patients to improve clinical outcomes?
On the balance of the current literature review, a few recommendations can be clearly summarized as follows:
1. Preventing hypoglycemia in ICU patients with acute-on-chronic liver disease and decompensated liver cirrhosis.
2. Preventing hypoglycemia in cirrhotic patients with severe liver dysfunction.
3. Preventing hypoglycemia in cirrhotic patients with acute-on-chronic liver failure.
4. Preventing hypoglycemia in cirrhotic patients with hepatorenal syndrome.
5. Hypoglycemia can be used as a clinical predictor for bacteremia and septicemia, and prophylactic antibiotics can be used in cirrhotic patients to reduce acute exacerbations of chronic liver diseases.
These recommendations are targeted specifically to higher-risk groups without an overarching statement to declare that hypoglycemia prevention can be applied universally to all cirrhotic patients due to the study’s small sample size and methodological limitations. Future studies with large sample sizes and improved methodological design are needed to address these questions and limitations as well as the related study biases for the potential improvement of clinical outcomes with cirrhotic patients.
Conclusion
Although current chronic liver disease management guidelines rarely address hypoglycemia in non-diabetic patients, this review highlights its significance in hospitalized patients with liver disease. There is limited but compelling evidence linking hypoglycemia to poor clinical outcomes in liver disease patients, whether admitted with another condition, decompensated cirrhosis, or acute-on-chronic liver disease, independent of diabetes (9, 18–26).
Given the scarcity of studies on hypoglycemia in cirrhotic patients, there is significant potential for multi-center trials to explore these uncertainties and inform updates to existing management guidelines. This includes developing tools that utilize clinical parameters such as MELD score, AST, bilirubin, and others to (1) identify and stratify patients at high risk for hypoglycemia and (2) prevent hypoglycemic events, thereby reducing associated poor outcomes such as mortality, ICU admissions, and complications like septicemia (22–24).
While hypoglycemia is clearly associated with poor clinical outcomes, it remains unclear whether prevention strategies-such as prophylactic glucose administration, nighttime carbohydrate intake, and early identification -will improve patient outcomes (18, 22).
Moreover, the interaction between septicemia, cirrhosis, and hypoglycemia raises important questions about the potential benefits of (1) administering prophylactic antibiotics and (2) conducting prompt blood cultures when hypoglycemia is detected, or when a cirrhotic patient is identified as being at high risk for hypoglycemic events (25, 26).
Furthermore, the mechanism of hypoglycemia in cirrhotic patients has been shown to be related to reduced hepatic glycogen stores in patients with liver cirrhosis (27). The conclusion of this study is that patients with alcoholic or biliary cirrhosis have decreased hepatic glycogen stores per volume of hepatocytes and per liver, and decreased glucokinase activity may be the important underlying mechanism (27). Identification of the mechanism of hypoglycemia with cirrhotic patients will be one of the priorities for future research.
Table 1 has a detailed summary of the characteristics, main results and possible bias of the included studies for discussion and analysis in this mini review to raise our research questions for overcoming the above-mentioned limitations. Addressing these questions through future research could significantly improve the management and clinical outcomes of hospitalized patients with liver cirrhosis, which may translate into improved quality of life, reduced morbidity, or even mortality.
Table 1. Characteristics, main results, possible bias of included studies.
Author contributions
RG: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Project administration, Software, Validation, Writing – original draft, Writing – review and editing. JC: Data curation, Investigation, Methodology, Software, Validation, Writing – review and editing. KZ: Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing – review and editing. WH: Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing – review and editing. DX: Conceptualization, Data curation, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing. MK: Conceptualization, Investigation, Methodology, Resources, Supervision, Validation, Visualization, Writing – review and editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Generative AI was used in the creation of this manuscript.
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Keywords: hypoglycemia, chronic liver disease, cirrhosis, complications, clinical guidelines
Citation: Govindarajan R, Chen J, Zhang K, Hu W, Xu D and Kuang M (2025) Association between hypoglycemia and poor clinical outcomes in hospitalized non-diabetic patients with liver cirrhosis:– a narrative review. Front. Med. 12:1541471. doi: 10.3389/fmed.2025.1541471
Received: 07 December 2024; Accepted: 21 April 2025;
Published: 16 May 2025.
Edited by:
Evelyn Nunes Goulart Da Silva Pereira, Oswaldo Cruz Foundation (Fiocruz), BrazilReviewed by:
Ayesha Fatima, Nishtar Medical College, PakistanRaouia Saidani, Tunis El Manar University, Tunisia
Marie-Astrid Piquet, Centre Hospitalier Universitaire de Caen, France
Copyright © 2025 Govindarajan, Chen, Zhang, Hu, Xu and Kuang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dan Xu, ZGFuaWVsLnh1QGN1cnRpbi5lZHUuYXU=; Ming Kuang, a3VhbmdtQG1haWwuc3lzdS5lZHUuY24=
†These authors have contributed equally to this work
‡ORCID: Dan Xu, orcid.org/0000-0001-6649-1111