Dengue fever, caused by the dengue virus (DENV), is one of the most prevalent mosquito-borne viral diseases worldwide, affecting millions of individuals annually. ^[1] The disease is endemic in over 100 countries, with an estimated 390 million infections occurring each year, of which approximately 96 million manifests clinically. ^[2] Children are particularly vulnerable to severe dengue due to their developing immune systems and smaller body size, which can exacerbate complications such as plasma leakage, hemorrhage, and organ impairment. ^[3]   Thrombocytopenia, defined as a platelet count below 150,000/μL, is a common hematological abnormality observed in dengue-infected patients. ^[4] It is often associated with bleeding manifestations, such as petechiae, epistaxis, and gastrointestinal bleeding, and is considered a marker of disease severity. ^[4] The pathogenesis of thrombocytopenia in dengue is multifactorial, involving mechanisms such as bone marrow suppression, peripheral platelet destruction, and immune-mediated clearance. ^[5] However, the role of liver dysfunction in the development of thrombocytopenia remains underexplored, particularly in pediatric populations. ^[6]

The liver is a primary target organ for dengue virus replication, and hepatic involvement is frequently observed in dengue-infected patients. ^[7] Elevated liver enzymes, such as ALT and AST, are common indicators of hepatocellular injury, while increased bilirubin levels may suggest cholestasis or severe hepatic dysfunction. ^[8] Studies in adult populations have demonstrated a correlation between liver dysfunction and thrombocytopenia, but limited data exist for children. ^[9] Given the unique physiological and immunological characteristics of pediatric patients, it is essential to investigate this relationship further to improve clinical management and outcomes. ^[10]

This study aimed to evaluate the correlation between liver indices (ALT, AST, and bilirubin levels) and thrombocytopenia in dengue-infected children. By exploring this relationship, we hope to provide insights into the pathophysiology of thrombocytopenia in pediatric dengue cases and identify potential biomarkers for disease severity.

Study Design and Setting

This cross-sectional study was conducted in the Department of Biochemistry, at the Mamata Academy of Medical Sciences over a period of six months (January to June 2021). The study was approved by the institutional ethics committee, and written informed consent was obtained from the parents or guardians of all participants.

Study Population

A total of 150 children aged 1 to 14 years, diagnosed with dengue fever based on clinical criteria and positive serological tests (NS1 antigen or IgM antibodies), were enrolled. Patients with pre-existing liver disease, hematological disorders, or co-infections (e.g., hepatitis, malaria) were excluded from the study.

Data Collection

Demographic and clinical data, including age, gender, duration of illness, and clinical manifestations, were recorded. Blood samples were collected from all participants for complete blood count (CBC) and liver function tests (ALT, AST, and bilirubin levels). Platelet counts were categorized as follows:

• Mild thrombocytopenia: 100,000–150,000/μL
• Moderate thrombocytopenia: 50,000–100,000/μL
• Severe thrombocytopenia: <50,000/μL

Laboratory Methods

1. Complete Blood Count (CBC): Platelet counts were measured using an automated hematology analyzer.
2. Liver Function Tests:
• ALT and AST levels were measured using standard enzymatic methods.
• Bilirubin levels were measured using the diazo method.

Statistical Analysis

Data were analyzed using SPSS version 25.0. Continuous variables were expressed as mean ± standard deviation (SD), while categorical variables were expressed as frequencies and percentages. Pearson’s correlation coefficient was used to assess the relationship between liver indices and platelet counts. A p-value <0.05 was considered statistically significant.

The mean age of the study population was 7.2 ± 3.1 years, with a male-to-female ratio of 1.3:1. Thrombocytopenia was observed in 85% of patients, with 45% classified as moderate and 25% as severe. Elevated ALT and AST levels were detected in 70% and 80% of patients, respectively. 

Table 1: Demographic and Clinical Characteristics of the Study Population

The mean duration of illness at the time of enrollment was 4.5 ± 1.2 days. This indicates that most patients were in the early to mid-phase of dengue infection, a critical period for the development of complications such as thrombocytopenia and liver dysfunction. 85% of the patients had thrombocytopenia, highlighting its high prevalence in dengue-infected children. Thrombocytopenia is a well-known complication of dengue and is often associated with disease severity.

The severity of thrombocytopenia was categorized as follows: Mild (100,000–150,000/μL): 30% of patients. Moderate (50,000–100,000/μL): 45% of patients. Severe (<50,000/μL): 25% of patients. The majority of patients (45%) had moderate thrombocytopenia, while a significant proportion (25%) had severe thrombocytopenia, which is concerning as it increases the risk of bleeding complications.

Table 2: Liver Indices in Dengue-Infected Children

A significant inverse correlation was found between platelet counts and liver enzyme levels (ALT: r = -0.62, p < 0.001; AST: r = -0.58, p < 0.001). No significant correlation was observed between bilirubin levels and platelet counts (r = -0.12, p = 0.18). Patients with severe thrombocytopenia had significantly higher ALT and AST levels compared to those with mild or no thrombocytopenia (p < 0.05).

Table 3: Correlation Between Liver Indices and Platelet Counts

The findings of this study demonstrate a significant inverse correlation between elevated liver enzymes (ALT and AST) and thrombocytopenia in dengue-infected children. This suggests that liver dysfunction may play a critical role in the pathogenesis of thrombocytopenia in pediatric dengue cases. The liver is a primary target organ for dengue virus replication, and hepatic involvement is a well-documented feature of dengue infection. The observed elevation in ALT and AST levels indicates hepatocellular injury, which may contribute to thrombocytopenia through several mechanisms. ^[11]

This indicates that most patients were in the early to mid-phase of dengue infection, a critical period for the development of complications such as thrombocytopenia and liver dysfunction. 85% of the patients had thrombocytopenia, highlighting its high prevalence in dengue-infected children. Thrombocytopenia is a well-known complication of dengue and is often associated with disease severity. The severity of thrombocytopenia was categorized as follows: Mild (100,000–150,000/μL): 30% of patients. Moderate (50,000–100,000/μL): 45% of patients. Severe (<50,000/μL): 25% of patients. The majority of patients (45%) had moderate thrombocytopenia, while a significant proportion (25%) had severe thrombocytopenia, which is concerning as it increases the risk of bleeding complications.

One possible mechanism is the impairment of thrombopoietin production. Thrombopoietin, a glycoprotein produced primarily in the liver, is essential for platelet production and maturation. ^[12] Liver dysfunction caused by dengue virus replication may lead to reduced thrombopoietin synthesis, resulting in decreased platelet production in the bone marrow. ^[13] This hypothesis is supported by studies in adults, which have shown a correlation between low thrombopoietin levels and thrombocytopenia in dengue infection. ^[14]

Another potential mechanism is immune-mediated platelet destruction. Dengue virus infection triggers a robust immune response, characterized by the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). ^[15] These cytokines can induce platelet activation and aggregation, leading to increased platelet consumption and destruction. ^[16] Additionally, hepatic inflammation may exacerbate this process by promoting the release of platelet-destructive antibodies and immune complexes. ^[17]

A significant inverse correlation was found between platelet counts and liver enzyme levels (ALT: r = -0.62, p < 0.001; AST: r = -0.58, p < 0.001). No significant correlation was observed between bilirubin levels and platelet counts (r = -0.12, p = 0.18). Patients with severe thrombocytopenia had significantly higher ALT and AST levels compared to those with mild or no thrombocytopenia (p < 0.05).

The lack of a significant correlation between bilirubin levels and thrombocytopenia suggests that hepatocellular injury, rather than cholestasis, is the primary driver of thrombocytopenia in dengue-infected children. ^[18] This finding is consistent with previous studies, which have reported that elevated bilirubin levels are less common in dengue infection compared to elevated liver enzymes.

The unique vulnerability of pediatric patients to liver dysfunction and thrombocytopenia in dengue infection may be attributed to their developing immune systems and smaller liver size. ^[19] Children may experience more pronounced hepatic involvement due to higher viral loads and a less robust immune response compared to adults. ^[19] This underscores the importance of monitoring liver function tests in pediatric dengue cases, as elevated liver enzymes may serve as an early indicator of disease severity and thrombocytopenia risk. ^[20]

These findings have important clinical implications. Early identification of liver dysfunction in dengue-infected children may help clinicians predict the likelihood of thrombocytopenia and implement appropriate management strategies, such as close monitoring of platelet counts, timely administration of platelet transfusions, and supportive care to prevent bleeding complications. ^[21] Furthermore, these results highlight the need for further research into the mechanisms underlying liver dysfunction and thrombocytopenia in dengue infection, with a focus on potential therapeutic interventions targeting hepatic inflammation and thrombopoietin production. ^[22].

This study provides evidence of a significant correlation between elevated liver indices (ALT and AST) and thrombocytopenia in dengue-infected children. These findings suggest that liver dysfunction may contribute to the pathogenesis of thrombocytopenia in pediatric dengue cases. Monitoring liver function tests in dengue-infected children may help identify patients at risk of severe thrombocytopenia and guide clinical management. Further research is needed to elucidate the underlying mechanisms and explore potential therapeutic interventions targeting liver dysfunction in dengue infection.

1. World Health Organization (WHO). Dengue: Guidelines for Diagnosis, Treatment, Prevention, and Control. Geneva: WHO; 2009.
2. Guzman MG, Harris E. Dengue. Lancet. 2015;385(9966):453-465.
3. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature. 2013;496(7446):504-507.
4. Simmons CP, Farrar JJ, Nguyen VV, Wills B. Dengue. N Engl J Med. 2012;366(15):1423-1432.
5. Trung DT, Thao le TT, Hien TT, et al. Liver involvement associated with dengue infection in adults in Vietnam. Am J Trop Med Hyg. 2010;83(4):774-780.
6. Kuo CH, Tai DI, Chang-Chien CS, et al. Liver biochemical tests and dengue fever. Am J Trop Med Hyg. 1992;47(3):265-270.
7. Soundravally R, Hoti SL. Pathogenesis of thrombocytopenia in dengue infection: A review. J Infect Dev Ctries. 2015;9(3):273-280.
8. Wills BA, Oragui EE, Stephens AC, et al. Coagulation abnormalities in dengue hemorrhagic fever: Serial investigations in 167 Vietnamese children with dengue shock syndrome. Clin Infect Dis. 2002;35(3):277-285.
9. Basu A, Chaturvedi UC. Vascular endothelium: The battlefield of dengue viruses. FEMS Immunol Med Microbiol. 2008;53(3):287-299.
10. Hottz ED, Oliveira MF, Nunes PC, et al. Dengue induces platelet activation, mitochondrial dysfunction, and cell death through mechanisms that involve DC-SIGN and caspases. J Thromb Haemost. 2013;11(5):951-962.
11. Laoprasopwattana K, Kaewjungwad L, Jarumanokul R, Geater A. Differential diagnosis of chikungunya, dengue viral infection, and other acute febrile illnesses in children. Pediatr Infect Dis J. 2012;31(5):459-463.
12. Kalayanarooj S. Clinical manifestations and management of dengue/DHF/DSS. Trop Med Health. 2011;39(4 Suppl):83-87.
13. Gulati S, Maheshwari A. Atypical manifestations of dengue. Trop Med Int Health. 2007;12(9):1087-1095.
14. Mohan B, Patwari AK, Anand VK. Hepatic dysfunction in childhood dengue infection. J Trop Pediatr. 2000;46(1):40-43.
15. Itha S, Kashyap R, Krishnani N, Saraswat VA, Choudhuri G, Aggarwal R. Profile of liver involvement in dengue virus infection. Natl Med J India. 2005;18(3):127-130.
16. Souza LJ, Alves JG, Nogueira RM, et al. Aminotransferase changes and acute hepatitis in patients with dengue fever: Analysis of 1,585 cases. Braz J Infect Dis. 2004;8(2):156-163.
17. Sam SS, Omar SF, Teoh BT, Abd-Jamil J, AbuBakar S. Review of dengue hemorrhagic fever fatal cases seen among adults: A retrospective study. PLoS Negl Trop Dis. 2013;7(5):e2194 .
18. Lum LC, Lam SK, Choy YS, George R, Harun F. Dengue encephalitis: A true entity? Am J Trop Med Hyg. 1996;54(3):256-259.
19. Malavige GN, Velathanthiri VG, Wijewickrama ES, et al. Patterns of disease among adults hospitalized with dengue infections. QJM. 2006;99(5):299-305.
20. Wang CC, Lee IK, Su MC, et al. Differences in clinical and laboratory characteristics and disease severity between children and adults with dengue virus infection in Taiwan, 2002. Trans R Soc Trop Med Hyg. 2009;103(9):871-877.
21. Srikiatkhachorn A, Green S. Markers of dengue disease severity. Curr Top Microbiol Immunol. 2010;338:67-82.
22. Halstead SB. Dengue. Lancet. 2007;370(9599):1644-1652.