Decoding prognosis in dengue-induced hepatitis: Model for end-stage liver disease vs albumin-bilirubin for predicting liver failure and survival

Abstract

In this editorial, we comment on the article by Teerasarntipan et al published in a recent issue of the World Journal of Gastroenterology. Dengue infection is a major mosquito-borne disease with global significance. Dengue-induced severe hepatitis (DISH) is a rare complication though severe, as it can lead to acute liver failure (ALF) with an incidence rate between 0.7% and 2.0% and mortality rates from 47.0% to 58.8%. In this context, the identification of patients at risk of ALF could improve prognosis in DISH patients. Teerasarntipan et al retrospectively enrolled 2532 dengue patients, counting 193 DISH and 20 ALF. The authors explored the prognostic role of liver-specific scores, as the model for end-stage liver disease (MELD) score, albumin-bilirubin (ALBI) score, easy (EZ)-ALBI score, and platelet-ALBI (PALBI) score. Univariate analysis identified international normalized ratio (INR), total bilirubin, albumin, and creatinine as independent laboratory factors associated with ALF, while age, gender, and liver comorbidities were not linked to in-hospital mortality. The presence of dengue shock syndrome significantly increased mortality, with an odds ratio (OR) of 28.05 (95%CI: 7.21-109.18, P < 0.001). High INR and low albumin were laboratory markers associated with death from DISH, with ORs of 5.83 (95%CI: 2.59-13.12, P < 0.001) and 0.15 (95%CI: 0.05-0.44, P < 0.001), respectively. Multivariate analysis confirmed that INR remained the only significant predictor of both ALF and death, with adjusted ORs of 19.54 (95%CI: 3.37-113.38, P < 0.001) and 3.86 (95%CI: 1.13-13.18, P = 0.031), respectively. Among prognostic models, the MELD score performed best in predicting ALF, with a very high accuracy [area under the receiver operating characteristic curve (AUROC) of 0.929, 87.5% sensitivity, 89.3% specificity at a cutoff of 16], followed by the EZ-ALBI, ALBI, and PALBI scores, with AUROCs of 0.865, 0.832, and 0.797, respectively. As MELD remains the best scoring system for predicting poor outcomes in DISH-related ALF, EZ-ALBI is a valid adjunct tool that could improve medical care in these patients.

Key Words: Dengue-induced severe hepatitis; Acute liver failure; Easy-albumin-bilirubin; Model for end-stage liver disease; Dengue

Core Tip: Although dengue infection can result in liver injury, it rarely manifests as dengue-induced severe hepatitis (DISH). Since DISH can rapidly progress to acute liver failure, it appears crucial to early identify patients at risk in order to improve medical care and prognosis. In this context, liver specific prognostic scores, as model for end-stage liver disease or easy-albumin-bilirubin, proved effective when combined.

TO THE EDITOR

Dengue is a viral illness transmitted by mosquitoes, specifically caused by one of four distinct serotypes of the dengue virus (DENV-1, DENV-2, DENV-3, and DENV-4). This disease has become a significant global health challenge, affecting millions each year in over 100 countries located in tropical and subtropical regions[1]. Aedes mosquitoes, particularly Aedes aegypti, are the main vectors responsible for spreading the virus. Generally, mosquitoes lay their eggs on moist surfaces near stagnant water, where they can remain dormant until favorable conditions arise. Upon contact with water, the eggs hatch into larvae, progressing through four stages before transforming into pupae and eventually into adult mosquitoes. Female mosquitoes feed on blood to mature their eggs. Dengue transmission occurs when an uninfected mosquito bites an infected individual, acquiring the virus, which then replicates within the mosquito for 8-12 days. Once infectious, the mosquito transmits the virus to another human through a bite, spreading it into their immune system[2].

Dengue presents with a wide range of clinical symptoms, from mild or asymptomatic cases (non-severe dengue) to severe forms like dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), both of which can have life-threatening outcomes[3].

DSS represents a progression from DHF, marked by severe plasma leakage that results in hypovolemic shock, which can be fatal without prompt intervention through intravenous fluids and close monitoring. Furthermore, dengue infection can lead to liver injury, manifesting as dengue-induced severe hepatitis (DISH)[4], with liver damage being particularly pronounced in cases associated with DSS. Plasma leakage in DSS exacerbates liver injury by causing hypoxia, resulting in hepatocyte necrosis due to reduced blood supply[5]. Additionally, the hyperinflammation response in DSS contributes to oxidative stress and hepatocyte apoptosis[6]. Liver injury in the DSS situation can also lead to complications such as coagulopathy, an escalation of hemorrhagic symptoms and multiorgan dysfunction. Although DISH infrequently advances to acute liver failure (ALF), with an incidence between 0.7% and 2.0%, the outlook remains unfavorable, especially for hyperacute (within 7 days of noting jaundice) and ALF (between 8 and 28 days of noting jaundice). Indeed, mortality rates range from 47.0% to 58.8%, underscoring the urgent need for early identification of patients at elevated risk for adverse outcomes[4].

ALF risk for dengue-associated hepatitis

The development of liver injury in dengue infection is significantly influenced by complex interactions between the virus and liver cells, as well as by the damage arising from the host’s immune response[7,8]. Evidence suggests that hepatic damage in dengue is driven by multiple factors, including the virus's direct cytopathic effects, immune-mediated inflammation, and disturbances in hepatic microcirculation[9,10]. In fact, the DENV enters hepatocytes via specific membrane receptors, where it undergoes replication and induces direct cellular damage, leading to cellular necrosis, typically evidenced by elevated transaminase levels, hepatomegaly, and, in more severe cases, hepatocellular necrosis and liver failure[9].

Liver enzymes play a crucial role in assessing liver function. The normal levels of liver enzymes are as follows: Alanine aminotransferase (ALT) 7 to 56 units per liter (U/L), aspartate aminotransferase (AST) 10 to 40 U/L, alkaline phosphatase (ALP) 44 to 147 U/L, gamma-glutamyl transferase (GGT) 9 to 48 U/L, and Bilirubin 0.1 to 1.2 milligrams per deciliter (mg/dL). During dengue infection, liver enzyme levels often rise, particularly in severe forms such as DHF or DSS. ALT and AST are the most elevated enzymes, often increasing 2 to 10 times the normal value. ALT usually shows a more pronounced elevation than AST, as it primarily reflects hepatocellular injury caused by the virus. While ALP and GGT may show mild increases, especially in cases with biliary involvement, they are less affected compared to ALT and AST. Bilirubin levels can also rise, leading to jaundice in more severe cases. In most instances, as the infection resolves, liver enzymes return to normal levels, but in severe cases, prolonged elevations may indicate significant liver dysfunction. Thus, monitoring liver enzymes is essential in managing dengue and assessing the severity of the infection[11].

The immune response against the DENV triggers the release of inflammatory cytokines, including tumor necrosis factor α, interferon-γ, and interleukins (IL-6, IL-8), which can contribute to hepatic inflammation and exacerbate hepatocellular necrosis, potentially leading to ALF.

In the article published in a recent issue of World Journal of Gastroenterology by Teerasarntipan et al[4] named “Validation of prognostic scores for predicting acute liver failure and in-hospital death in patients with dengue-induced severe hepatitis” the authors compared the efficacy of different liver specific scores for prediction of ALF in DISH patients. Among the 2532 dengue patients enrolled, 193 developed DISH and 20 out of 193 ALF. Model for end-stage liver disease (MELD) score, platelet-albumin-bilirubin (PALBI), ALBI score and easy (EZ)-ALBI score were calculated for each patient.

In the context of the univariate analysis conducted in this study, the authors identified independent laboratory factors linked to ALF, including international normalized ratio (INR), total bilirubin, albumin, and creatinine. Conversely, age, gender, and liver comorbidities did not show any association with in-hospital mortality. DSS significantly incremented the risk of mortality, with an odds ratio (OR) of 28.05 (95%CI: 7.21–109.18, P < 0.001). Low albumin and high levels of INR were found to be associated with mortality due to DISH, with adjusted ORs of 0.15 (95%CI: 0.05–0.44, P < 0.001) and 5.83 (95%CI: 2.59–13.12, P < 0.001), respectively. The multivariate analysis revealed that INR was the only parameter which significantly predicted both mortality and ALF, with adjusted ORs of 3.86 (95%CI: 1.13–13.18, P = 0.031) and 19.54 (95%CI: 3.37–113.38, P < 0.001), respectively.

Among the various prognostic models, MELD score is the most effective in predicting ALF, demonstrating excellent accuracy with an area under the receiver operating characteristic curve (AUROC) of 0.929, along with 87.5% sensitivity and 89.3% specificity at a cutoff score of 16. This is followed by the EZ-ALBI, ALBI, and PALBI scores, which have AUROCs of 0.865, 0.832, and 0.797, respectively.

The EZ-ALBI score is a streamlined scoring system derived from the ALBI score, designed to evaluate liver function and predict outcomes in patients with liver disease[12,13]. In cases of acute hepatitis, it can assist in assessing the extent of liver impairment and monitoring recovery. For patients with chronic hepatitis B or C, the score is useful for evaluating liver fibrosis and informing management strategies. Additionally, in individuals progressing to cirrhosis as a result of chronic hepatitis, the EZ-ALBI score serves as an important tool for risk assessment and predicting survival outcomes[14].

These results are consistent with a similar study previously published by the same authors. They identified several potential prognostic factors for ALF or mortality at univariate analysis, including age, sex, hematocrit, platelet count, white blood cell count, atypical lymphocyte count, bilirubin levels, serum ALT, serum AST, ALP, albumin, INR, creatinine, MELD score, the presence of liver comorbidities, and the presence of capillary leak syndrome[11]. However, the multivariate analysis identified the MELD score as the sole predictor of ALF, with an adjust OR of 1.3. Specifically, an initial MELD score of 15 or higher was associated with ALF due to DISH, achieving an AUROC of 0.91, with a specificity and sensitivity of 87.3% and 88.2%respectively[11].

The comparison of effects between EZ-ALBI and MELD score is described in literature for assessing liver reserve following transarterial chemoembolization in hepatocellular carcinoma or for evaluation of the prognosis of hepatitis B virus-associated acute-on-chronic liver failure[15,16]. However, to the best of our knowledge, Teerasarntipan et al[4] was the first to analyze these results in liver damage caused by the DENV. Among the limits of this study, it should be noted that the prognostic scores analyzed are usually applied in chronic liver diseases rather than acute liver condition and since Dengue does not cause chronic liver disease, these scores could not be ideal for acute liver injury evaluation. Future studies on this topic should explore scores applied in acute condition, like chronic liver failure consortium organ failure score[17].

CONCLUSION

ALF in patients with DISH represents a potentially lethal condition where timing is essential for therapy. Therefore, the early identification of patients at risk for developing ALF is vital, as it could significantly enhance their prognosis and reduce mortality rates. While MELD score is widely regarded as the most reliable scoring system for predicting poor outcomes in DISH-related ALF, the EZ-ALBI score is a valid adjunct tool that could improve medical care in these patients. By incorporating both MELD and EZ-ALBI scores into patient assessments, healthcare providers can achieve a more comprehensive understanding of liver function and the risk of progression to ALF. This dual approach can lead to better-targeted therapies and improved patient outcomes. However, further studies are essential to evaluate the combined efficacy of these scoring systems and determine their optimal use in clinical practice. Research should focus on larger cohorts and diverse populations to validate findings and refine protocols for risk stratification in patients with DISH. By advancing our understanding of these tools, we can enhance medical care and improve survival rates for individuals affected by dengue-related liver damage.