Aminotransferase Elevation as an Independent Predictor of Severity and Mortality in Dengue Fever: A Prospective Cohort Study from Western India

Abstract

Background:

Hepatic involvement is a frequent but often underestimated manifestation of dengue infection. Elevation of liver enzymes reflects both hepatocellular injury and systemic inflammatory response and may provide valuable prognostic information for assessing disease severity and outcome.

Aim:

This study aimed to evaluate the prognostic significance of aminotransferase, namely aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation in dengue fever (DF) and its correlation with disease severity, thrombocytopenia, duration of hospitalisation and mortality.

Methods:

A prospective observational study was conducted on 250 serologically confirmed dengue patients admitted to a tertiary-care hospital in Jaipur, Rajasthan, between October 2019 and November 2020. Patients with pre-existing liver disease, viral hepatitis or hepatotoxic drug exposure were excluded. Clinical and biochemical parameters were analysed in accordance with the World Health Organisation (WHO) 2009 dengue classification and aminotransferase levels were categorised based on multiples of the upper limit of normal (ULN).

Results:

Elevated AST and ALT levels were observed in 92% and 87.6% of patients, respectively. Mild to moderate elevation (2–10× ULN) was most frequent, while 13.6% of patients exhibited marked elevation (>10× ULN). Severe hepatic enzyme elevation was significantly associated with dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), prolonged hospital stay (6.2 ± 1.5 days versus 4.1 ± 1.1 days, P < .05) and mortality (80% of deaths). Platelet count showed a negative correlation with AST (r = –0.32, P = .002) and ALT (r = –0.35, P = .001), suggesting that greater hepatic dysfunction paralleled worsening thrombocytopenia.

Conclusion:

Marked aminotransferase elevation (>10× ULN), particularly of AST, serves as a reliable biochemical indicator of severe dengue and adverse outcomes. Early liver function assessment, when combined with haematological monitoring, offers a simple and cost-effective tool for triage and prognostication in dengue management within resource-limited settings.

Introduction

Dengue fever (DF) is a rapidly spreading mosquito-borne viral infection and a major public health concern, especially in tropical and subtropical regions. It is caused by the dengue virus (DENV), an Ribonucleic Acid (RNA) virus belonging to the Flaviviridae family, which includes four antigenically distinct serotypes (DENV-1 to DENV-4). According to the World Health Organisation (WHO), approximately 390 million dengue infections occur worldwide each year, of which about 96 million manifest clinically.^[1] India contributes significantly to the global burden, with frequent seasonal outbreaks, increasing case fatality rates and rising incidence of severe forms such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS).^[2,3]

The disease demonstrates a wide clinical spectrum ranging from self-limiting febrile illness to severe, life-threatening conditions characterised by plasma leakage, coagulopathy and multi-organ failure. Hepatic dysfunction is one of the most frequent complications, attributed to a combination of direct viral cytopathic effects on hepatocytes, immune-mediated cytokine injury and ischaemic damage secondary to shock and hypoxia.^[4,5] Among biochemical parameters, aminotransferases, namely aspartate aminotransferase (AST) and alanine aminotransferase (ALT), are the most consistently deranged enzymes in dengue infection. Multiple studies have reported elevated AST/ALT levels in over 60%-95% of cases, with AST values frequently exceeding ALT because of its additional release from skeletal and cardiac muscle.^[6–8] Elevated aminotransferase levels correlate with clinical severity, duration of hospitalisation and mortality, suggesting their potential as simple prognostic biomarkers in DF.^[9–12]

Despite growing recognition of hepatic involvement, data from northwestern India, particularly Rajasthan, remain limited. Given the recurrent seasonal epidemics and the need for cost-effective early severity indicators, liver function testing offers an accessible tool for risk stratification, even in resource-limited settings.

Therefore, this study was designed to evaluate the prognostic significance of aminotransferase elevation in DF and to determine its correlation with disease severity, duration of hospitalisation and mortality. Specifically, we examined the prevalence and magnitude of AST and ALT elevation among serologically confirmed dengue patients, assessed their association with WHO clinical categories, classical dengue, DHF and DSS and evaluated whether markedly elevated enzyme levels (>10× upper limit of normal [ULN]) were linked to adverse outcomes. Furthermore, we analysed relationships between hepatic enzyme derangement, thrombocytopenia, coagulopathy and hypoalbuminemia to determine whether early liver function testing could serve as a practical triage tool for risk stratification in dengue.

Recent studies have highlighted complementary predictors of dengue severity. Chidambaram and Kumarasamy^[13] demonstrated that elevated interleukin-6 (IL-6) and interleukin-8 (IL-8) levels were associated with severe dengue, supporting the role of immune-mediated hepatic injury. Similarly, Suwanbamrung et al.^[14] developed community-based dengue risk prediction models in Thailand, emphasising the importance of integrating clinical and epidemiological predictors for timely prevention and management.

Materials and Methods

Study Design and Setting

This was a prospective observational cohort study conducted at the Department of General Medicine, Government R.D.B.P. Jaipuria Hospital, Jaipur, Rajasthan, a tertiary-care referral centre catering to urban and semi-urban populations. The study period extended from October 2019 to November 2020, encompassing a seasonal outbreak period of DENV infection.

Ethical Considerations

Approval for the study was obtained from the Institutional Ethics Committee (IEC) (Approval No.: RDBP/2020/12; dated September 15, 2019). Written informed consent was obtained from all patients or from their guardians in the case of minors, before participation. The study was conducted in accordance with the principles of the Declaration of Helsinki^[15] and complied with the applicable Indian Council of Medical Research ethical guidelines. Trial registration was not applicable for this prospective observational study, as no interventions were administered and the study did not fall under mandatory registration criteria.

Study Population

A total of 250 consecutive patients, aged 15–70 years, with serologically confirmed dengue infection were enrolled. Diagnosis was based on Non-structural Protein-1 (NS1) antigen and/or Immunoglobulin M (IgM) Enzyme-Linked Immunosorbent Assay (ELISA) positivity, as per National Vector Borne Disease Control Programme (NVBDCP) guidelines.

Inclusion Criteria

Patients aged between 15 and 70 years of either sex, admitted within 5 days of symptom onset and having serologically confirmed dengue infection (positive NS1 antigen and/or IgM ELISA), were included in the study. Individuals with controlled hypertension or diabetes without hepatic involvement were also enrolled to maintain generalisability.

Exclusion Criteria

Patients with chronic liver disease, viral hepatitis, alcoholic liver disease or other known hepatic pathology were excluded. Those with co-infections such as malaria, leptospirosis or hepatitis B or C, as well as individuals using hepatotoxic drugs, pregnant women or those with uncontrolled systemic illnesses such as diabetes, chronic kidney disease or hypothyroidism, were also excluded.

Sample Size Calculation

The minimum sample size was calculated using the formula N = Z² × p × (1 − p) / E², where Z = 1.96 for a 95% confidence level, P = .82 (based on the prevalence of elevated ALT reported in a previous Indian study^[9]) and E = 0.05 as the allowable error.

N = Z² × p × (1−p)/ E²

Z = 1.96 (for 95% confidence),

P = .82 (proportion),

E = 0.05 (margin of error).

This yielded a sample size of 227, which was rounded to 250 patients to account for potential attrition.

Classification of Disease Severity

All enrolled patients underwent detailed clinical and laboratory evaluation at the time of admission. Disease severity was classified according to the WHO 2009 criteria.^[16] into three categories: Classical DF, DHF and DSS.

Clinical Data Collected

Clinical data were systematically collected using a structured proforma. Demographic details such as age, sex and duration of fever were recorded. The presence of warning symptoms, including bleeding manifestations, myalgia, vomiting and abdominal pain, was noted and physical examination focused on detecting hypotension, hepatomegaly and evidence of plasma leakage such as ascites or pleural effusion. Duration of hospital stay and clinical outcome (discharge or death) were documented for every patient.

Laboratory evaluation included comprehensive haematological and biochemical assessments. Liver function tests comprised estimation of AST, ALT, total and direct bilirubin, serum albumin, alkaline phosphatase and total protein levels. Coagulation parameters, including PT, international normalised ratio and aPTT, were measured to assess hepatic synthetic function. Haematological indices such as platelet count and haematocrit were analysed to identify thrombocytopenia and hemoconcentration, respectively. In addition, abdominal ultrasonography was performed in all patients to detect hepatomegaly, gallbladder wall oedema or free fluid suggestive of plasma leakage.

All patients were managed according to the WHO and NVBDCP guidelines for dengue. Supportive management included careful intravenous fluid therapy tailored to clinical status and haematocrit trends, avoidance of hepatotoxic medications and timely blood or plasma transfusion when indicated. No liver-specific drugs were used and none of the patients required liver transplantation.

Definition of AST/ALT Categories

Patients were categorised into four groups based on the degree of aminotransferase elevation:

Normal: ≤1× ULN

Mild to moderate: 2–4× ULN

Severe: 4–10× ULN

Very severe: >10× ULN

For this study, the ULN was taken as 40 IU/L for both AST and ALT, consistent with international laboratory standards.

Outcome Measures

The primary outcome measures included the relationship between aminotransferase levels and clinical severity and the association of markedly elevated AST/ALT (>10 × ULN) with mortality and duration of hospitalisation. Secondary outcomes assessed correlations between liver enzyme elevation and haematological parameters, including platelet count, coagulopathy and hypoalbuminemia.

Statistical Analysis

All data were entered into Microsoft Excel and analysed using International Business Machines Corporation (IBM) Statistical Package for the Social Sciences (SPSS) Statistics for Windows, version 27.0 (Armonk, NY: IBM Corp). Quantitative variables were expressed as mean ± standard deviation and categorical variables were summarised as frequencies and percentages. Associations between categorical variables were evaluated using the chi-square test or Fisher’s exact test as appropriate. A P value <.05 was considered statistically significant.

Results

Baseline Demographics and Clinical Profile

A total of 250 patients with serologically confirmed dengue infection were enrolled. The mean age was 33.2 ± 11.8 years, with the highest frequency in the 18–35-year age group (43.6%). Males comprised 74.4% (n = 186) of the cohort, while females accounted for 25.6% (n = 64). Common presenting symptoms included fever (100%), myalgia (76%), vomiting (35.6%) and bleeding manifestations (24%). Clinical signs of plasma leakage, such as ascites, hypotension and gallbladder wall oedema, were more prevalent in patients with severe dengue.

Distribution of Dengue Severity

According to the (WHO, 2009) classification, among the 250 patients included in the study, 74 (29.6%) were diagnosed with classical DF, 94 (37.6%) presented with DHF and 82 (32.8%) developed DSS. The distribution indicates that nearly two-thirds of patients experienced one of the severe forms of dengue, emphasising the considerable burden of complicated disease in the present cohort. A significant association was noted between increasing dengue severity and aminotransferase elevation, as detailed below [Table 1 and Figure 1].

Table 1.

Distribution of aminotransferase levels and dengue severity

Aminotransferase Category	Classic DF	DHF	DSS	Total (n, %)
Normal (≤1× ULN)	12	6	2	20 (8.0)
2–4× ULN	38	35	21	94 (37.6)
4–10× ULN	22	41	39	102 (40.8)
>10× ULN	2	12	20	34 (13.6)

Figure 1.

Study flowchart depicting patient selection, exclusion criteria, clinical and laboratory evaluation and classification based on disease severity in DF. Of 280 patients assessed for eligibility, 30 were excluded due to chronic liver disease, hepatotoxic drug/alcohol use, co-infections or pregnancy. The remaining 250 patients underwent clinical assessment and laboratory evaluation (CBC, AST, ALT, albumin, prothrombin time [PT]/ activated partial thromboplastin time [aPTT]) and were classified as classic DF, DHF or DSS based on severity

Liver Enzyme Elevation (AST/ALT) and Severity

Elevated liver enzyme levels were observed in the majority of patients, with AST elevated in 92% and ALT elevated in 87.6% of cases. Based on the degree of elevation above the ULN, 37.6% of patients demonstrated mild elevation (2–4× ULN), 40.8% had moderate elevation (4–10× ULN) and 13.6% exhibited marked elevation exceeding 10× ULN. Among the 34 patients with markedly elevated aminotransferases, 72% were classified as having DHF or DSS, indicating a strong association between high enzyme levels and disease severity. Furthermore, nearly 80% of all fatalities occurred within this subgroup, underscoring the prognostic significance of extreme transaminase elevation (Table 1 and Figure 2).

Figure 2.

Distribution of dengue severity across aminotransferase categories

(Use a stacked bar chart showing proportions of DF, DHF, DSS in each AST/ALT elevation group.).

Stacked bar chart illustrating the number of patients with classic DF, DHF and DSS within each aminotransferase category. Enzyme elevation >10× ULN was predominantly associated with DHF and DSS.

Correlation Between Platelet Count and Aminotransferases

Thrombocytopenia, defined as a platelet count below 150,000/μL, was observed in 88.8% of patients in the study cohort. A statistically significant negative correlation was noted between platelet count and serum aminotransferase levels. Specifically, platelet count showed an inverse relationship with AST (r = –0.32, P = .002) and ALT (r = –0.35, P = .001), indicating that lower platelet counts were associated with higher liver enzyme values. Furthermore, patients with severe thrombocytopenia (platelet count <50,000/μL) exhibited markedly elevated AST and ALT levels compared to those with higher platelet counts, highlighting a parallel between worsening hepatic injury and declining platelet levels [Table 2]; [Figure 3] and [Figure 4].

Table 2.

Correlation of platelet count with liver enzymes

Parameter	Correlation (r)	P Value
Platelet vs AST	–0.32	.002*
Platelet vs ALT	–0.35	.001*

Note: *Statistically significant.

Figure 3.

[A] Scatter plot showing correlation between platelet count and AST levels. A significant inverse linear correlation is observed; lower platelet counts are associated with higher AST levels. [B] Scatter plot showing correlation between platelet count and ALT levels. ALT levels also show a statistically significant negative correlation with platelet count, supporting liver injury with thrombocytopenia

Figure 4.

[A] Box plot of AST levels across platelet count categories. Patients with lower platelet counts (<50 k/µL) demonstrate higher median AST values, suggesting more severe liver involvement. [B] Box plot of ALT levels across platelet count categories. ALT levels are elevated in groups with thrombocytopenia, with a trend toward normalisation in higher platelet categories

Hospital Stay and Mortality

The mean duration of hospitalisation among all dengue patients was 4.7 ± 1.4 days. However, patients with markedly elevated aminotransferases (AST or ALT > 10× the ULN) had a significantly longer mean hospital stay of 6.2 ± 1.5 days compared to those with lesser enzyme elevations (4.1 ± 1.1 days, P < .05). The overall mortality rate in the present cohort was 2.0% (n = 5). Notably, four of these five patients (80%) had AST or ALT levels exceeding 10× ULN, further reinforcing the strong association between severe hepatic involvement and adverse clinical outcomes [Table 3 and Figure 5].

Table 3.

Hospital stay and mortality Versus aminotransferase levels

Aminotransferase Category	Mean Hospital Stay (days)	Mortality (n, %)
Normal	3.5 ± 0.9	0
2–4× ULN	4.2 ± 1.0	0.5% (n = 1)
4–10× ULN	5.1 ± 1.3	1.0% (n = 2)
>10× ULN	6.2 ± 1.5	11.8% (n = 4)

Figure 5.

Hospital stay and mortality rate across aminotransferase categories. Combined bar and line graph: AST/ALT categories vs hospital stay and mortality (Bar = Mean days; line = % mortality) The blue bars represent the mean hospital stay (in days), while the red line shows the corresponding mortality rate (%) across aminotransferase level categories. Patients with >10× elevation of AST/ALT had the longest hospital stay (6.2 days) and the highest mortality rate (11.8%)

Enzyme Distribution Curve

The distribution histogram of AST and ALT levels [Figure 6] demonstrates that a large proportion of patients exhibit elevated enzyme levels, with right-skewed distributions for both parameters. These findings reinforce the observation that liver dysfunction is common and variable in severity among patients with dengue.

Figure 6.

Histogram showing the distribution of AST and ALT levels among dengue patients

The distribution of AST and ALT levels demonstrates a right-skewed pattern, with a significant number of patients showing elevated liver enzymes. This reflects the high frequency and wide variability of hepatic involvement in DF.

Discussion

Dengue infection continues to pose a major global health challenge, with expanding geographic distribution and rising incidence of severe clinical forms. The pathogenesis of severe dengue is multifactorial, involving viral virulence, host immune responses and genetic predisposition. In this study, elevation of aminotransferases, particularly AST, was observed in the majority of patients, confirming that hepatic dysfunction is a consistent and important feature of dengue infection. The degree of enzyme elevation correlated with the severity of disease, duration of hospitalisation and mortality, consistent with earlier studies from India and Southeast Asia.^[7,13]

The mechanisms underlying hepatic injury in dengue are complex and may involve direct viral cytopathic effects, immune-mediated inflammatory injury and circulatory compromise due to plasma leakage. Hepatocytes, Kupffer cells and endothelial cells act as targets for dengue viral replication, leading to cellular necrosis and apoptosis. The greater elevation of AST compared with ALT observed in most patients can be attributed to the enzyme’s additional release from myocytes and erythrocytes, reflecting the combined hepatic and systemic nature of dengue-associated injury.^[13] Similar findings were reported by Souza et al.,^[6] who noted that AST levels exceeding ALT are characteristic of dengue infection rather than primary viral hepatitis, thereby providing a useful diagnostic clue in endemic regions.^[14]

The present study also demonstrated that marked transaminase elevations (>10× ULN) were associated with severe dengue, indicating their potential as simple biochemical prognostic markers. Lee et al. and Chatterjee et al. reported comparable trends, showing significant correlations between aminotransferase levels and clinical severity, duration of illness and mortality rates.^[12,9] Importantly, these elevations are often reversible and usually normalise during convalescence, supporting the hypothesis that hepatic dysfunction in dengue is largely transient and immune-mediated rather than progressive hepatocellular failure.^[7]

Recent evidence emphasises the immunopathogenic contribution to dengue severity. Chidambaram and Kumarasamy demonstrated that elevated IL-6 and IL-8 concentrations correlated with severe dengue cases, highlighting the role of cytokine-driven inflammation and vascular permeability in disease progression.^[13] This ‘cytokine storm’ model aligns with our findings, where enzyme elevation reflected inflammatory hepatocellular stress secondary to systemic immune activation. While cytokine assays may provide mechanistic insight, their cost and limited availability restrict routine use in low-resource settings. In contrast, aminotransferase measurement represents a rapid, inexpensive and clinically meaningful tool for severity assessment.

Dengue diagnosis remains challenging because clinical manifestations overlap with other febrile illnesses such as malaria, leptospirosis and chikungunya. Chidambaram and Kumarasamy further emphasised that delayed recognition of warning signs, variability in NS1 and IgM detection windows and inconsistent sensitivity of serological tests contribute to diagnostic uncertainty in endemic regions.^[13] Our findings reinforce the need for integrated diagnostic algorithms combining serology, haematology and biochemical markers to improve early case detection and risk stratification.

At a broader level, Suwanbamrung et al. proposed a community-level dengue risk prediction model incorporating environmental, behavioural and epidemiological variables.^[14] Their participatory approach to identify ‘high-risk’ villages in Thailand underscores that biochemical markers such as aminotransferases should complement, rather than replace, public health surveillance measures. Applying similar models in India could strengthen early detection programmes and guide resource allocation in outbreak-prone districts.

Our study also highlights the dynamic nature of dengue, in which hepatic dysfunction mirrors systemic disease activity. Severe cases showed longer hospitalisation and slower recovery of liver function, reaffirming the need for continuous monitoring of hepatic parameters. While enzyme elevation alone cannot fully predict outcomes, its combination with clinical parameters (haematocrit, platelet count and warning signs) can enhance prognostic accuracy.

Clinical Implications

The present study emphasises that early recognition of aminotransferase elevation, particularly when AST or ALT levels exceed ten times the ULN, can serve as a simple and accessible prognostic tool in dengue management. In resource-limited and outbreak settings, such biochemical monitoring allows clinicians to identify high-risk patients at an early stage of the illness, facilitating timely triage and appropriate level-of-care decisions. The integration of liver function tests with haematological parameters, such as thrombocytopenia, enhances clinical risk stratification and can guide referral decisions for intensive monitoring or fluid resuscitation protocols. Furthermore, awareness of hepatic dysfunction in dengue underscores the importance of avoiding hepatotoxic agents such as paracetamol or anti-tubercular drugs during the acute phase. From a public health perspective, incorporating aminotransferase-based triage in hospital and community settings may optimise bed allocation, improve outcome prediction and ultimately reduce dengue-related morbidity and mortality.

Limitations

This study has several limitations that should be acknowledged. It was conducted at a single tertiary-care centre in western India, which may limit the generalisability of the findings to other geographic or healthcare settings. DENV serotyping (DENV-1 to DENV-4) was not performed, even though different serotypes and co-infections can influence the extent of hepatic involvement. Liver enzyme levels were assessed only at admission without serial follow-up measurements, restricting insight into the temporal evolution or recovery kinetics of hepatic injury. Additionally, the study did not evaluate advanced inflammatory biomarkers such as IL-6, ferritin or lactate dehydrogenase, which could have provided further mechanistic understanding. The number of deaths was relatively small, which, while consistent with dengue mortality trends, limits statistical power for outcome prediction. Final, patients were not followed after discharge to document normalisation of liver function tests. Future multicenter, longitudinal studies incorporating dengue serotyping, cytokine profiling and serial biochemical monitoring would help validate and extend the present findings.

Conclusion

The present study highlights that elevation of aminotransferases, particularly AST, is a frequent biochemical abnormality in patients with DF and correlates significantly with disease severity, prolonged hospitalisation and adverse outcomes. Hepatic dysfunction in dengue largely reflects immune-mediated and ischaemic hepatocellular injury rather than irreversible liver damage. Routine monitoring of liver enzymes, along with haematocrit and platelet trends, provides an accessible and reliable approach to assess disease progression in resource-limited settings. Early recognition of marked transaminase elevation (>10× ULN) may serve as a practical marker for identifying patients at risk of developing severe dengue or DSS. Integrating biochemical parameters with clinical warning signs and community-level surveillance frameworks could strengthen dengue management strategies and reduce morbidity and mortality in endemic regions.