Abstract
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Background
- Acute hepatitis can occur in association with systemic diseases outside the liver. Acute severe hepatitis with markedly elevated transaminase levels following extrahepatic infection has been reported in children. However, research on this condition remains limited. This study aimed to investigate its etiology, clinical course, and outcomes.
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Methods
- We retrospectively reviewed data from 2013 to 2020 for children under 12 years old with elevated liver enzymes following systemic infection. Acute severe hepatitis was defined as serum transaminase levels exceeding 1,000 IU/L in the absence of underlying liver disease. We analyzed hepatitis-associated pathogens, liver enzyme trends, and factors influencing recovery.
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Results
- A total of 39 patients were included in this study. The most common age group was 7–12 months (54.8%), and 53.8% were male. Respiratory infections were the most common (61.5%), followed by gastrointestinal infections (23.1%), meningitis (10.3%), and urinary tract infections (5.1%). The median peak alanine transaminase (ALT) level was 1,515.8±424.2 IU/L, with a median time to peak ALT of 4.4±2.3 days from symptom onset. ALT levels normalized within 21 days in 71.2% of patients and within 28 days in 94.9%. Younger age was associated with delayed ALT normalization, whereas hepatoprotective agent use was associated with faster normalization.
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Conclusions
- Acute severe hepatitis can develop following respiratory and other systemic infections. Younger children were more susceptible and had a more prolonged disease course.
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Key Words: child; hepatitis; infection; prognosis
INTRODUCTION
Acute hepatitis is a clinical diagnosis commonly caused by viral infections, toxins, drugs, or other inflammatory processes that directly injure the liver. However, secondary or reactive hepatitis refers to liver inflammation resulting from extrahepatic factors, including systemic infections, hemodynamic instability, or autoimmune diseases [1]. Although reactive hepatitis is common in pediatric patients, research on this condition is limited. The highest incidence occurring in children 1–2 years of age and alanine transaminase (ALT) elevation is typically 4–5 times the upper limit of normal. Respiratory and gastrointestinal infections are the primary causes. The condition usually resolves within 7–10 days without specific treatment [1]. Experimental studies have shown that CD8+ T lymphocytes expand as part of the immune response to various infections, with respiratory infections being a major trigger [2].
In some cases, reactive hepatitis presents as severe hepatitis, characterized by transaminase levels exceeding 500–1,000 IU/L. Markedly elevated liver enzymes require careful differential diagnosis and critical decision-making. However, studies on acute severe hepatitis caused by extrahepatic infections remain limited. Therefore, this study aims to analyze the clinical course and risk factors of acute severe hepatitis in children.
MATERIALS AND METHODS
This study received approval from the Institutional Review Board of Chonnam University Hospital (No. BTMP-2021-317). Informed consent was waived because of the retrospective nature of the study and the analysis used anonymous clinical data.
Subjects
A retrospective study was conducted using the medical records of patients (<12 years of age) admitted to a single tertiary referral center for acute hepatitis from January 2013 to December 2020. To focus on severe cases, only patients with peak serum transaminase levels above 1,000 IU/L were included in the study. Exclusion criteria included chronic liver disease, hepatobiliary anomalies, genetic or metabolic disorders, and other conditions affecting liver function.
Clinical and Laboratory Data
Clinical data, including age, sex, presenting symptoms and signs, length of hospital stay, and outpatient follow-up duration, were collected. Laboratory data included complete blood counts, total protein, albumin, total and direct bilirubin, aspartate aminotransferase (AST), ALT, alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and renal function tests. The peak ALT level was defined as the highest ALT value recorded following symptom onset. The time from symptom onset to peak serum ALT level and the time from peak ALT level to normalization were calculated for each patient. A review of pathogen detection tests was also conducted, including serologic antibody tests, polymerase chain reaction (PCR) tests performed on blood samples, multiplex PCR tests performed on nasal discharge or stool samples, and cultures obtained from blood, urine, and stool.
The respiratory multiplex PCR test using Allplex Respiratory Panel 1, 2, and 3 kit (Seegene Inc.) can detect 19 kinds of respiratory viruses: influenza A virus subset (H1, H1pdm09, H3), adenovirus, respiratory syncytial virus A/B, influenza virus A/B, parainfluenza virus 1/2/3/4, coronavirus (229E, OC43/HKU1, NL63), metapneumovirus, rhinovirus A/B, enterovirus, bocavirus 1/2/3/4. The stool multiplex PCR using Allplex GI-Virus Assay kit (Seegene Inc.) can detect 6 kinds of gastrointestinal viruses: astrovirus, adenovirus, rotavirus, sapovirus, and norovirus-GI/GII. Finding of liver ultrasonography were also reviewed.
Statistical Analysis
Descriptive statistics were used to summarize patient characteristics, including means and standard deviations for continuous variables and frequencies with percentages for categorical variables. Ranges were provided where applicable. To identify risk factors associated with prolonged ALT normalization, multivariable analysis was conducted using multiple linear regression. Variables with P<0.1 in univariate analysis were included in the multivariable model. A P-value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS statistics version 21.0 (IBM Corp.).
RESULTS
During the study period, a total of 77 patients presented with symptoms of infection, such as fever or respiratory and gastrointestinal symptoms, and were diagnosed with acute severe hepatitis on admission. Thirty-eight patients were excluded due to underlying liver disease or other conditions, and two were lost to follow-up. The final analysis included 39 patients (Figure 1). Demographic data are summarized in Table 1. Twenty-one patients (53.8%) were male; the median age at diagnosis was 9.9±11.2 months (range, 1–71 months). Acute severe hepatitis was rare in children older than 6 years. The mean length of hospital stay was 5.7±1.5 days. Liver ultrasonography was performed in 38 patients. Normal findings were observed in 55.3%, while increased liver echogenicity (36.8%) and hepatomegaly with periportal tracking (7.9%) were also detected.
Classification by Type of Infection
Prodromal symptoms included fever, respiratory symptoms, and gastrointestinal symptoms. Fever was the most common, occurring in 36 patients (92.3%), followed by respiratory symptoms in 24 patients (61.5%) and gastrointestinal symptoms in 9 patients (23.1%). Among those with fever, four patients were diagnosed with meningitis and two with urinary tract infections. Respiratory virus multiplex PCR, performed in 22 patients, was positive in 18 (81.8%), with five patients showing co-infection with two respiratory viruses. Stool virus multiplex PCR, conducted in six patients, detected adenovirus in two and norovirus in one. Among the four patients with meningitis, three tested positive for enterovirus in stool or cerebrospinal fluid (Table 1).
Clinical Course and Risk Factors
The mean duration from symptom onset to peak ALT level was 4.4±2.3 days. The mean duration from symptom onset to ALT recovery was 19.0±5.2 days (10–29 days). ALT levels normalized within 3 weeks in 71.2% of patients (28/39) and within 28 days in 94.9% of patients (37/39). The mean peak ALT level among all patients was 1,515.8±424.2 IU/L (range, 1,060–2,793 IU/L), and the corresponding AST, ALP, GGT levels measured on the same day were 1,031.7±265.9 IU/L (range, 608–1,605 IU/L), 317.2±86.4 IU/L (range, 182–506 IU/L), and 99.0±70.6 IU/L (range, 27–327 IU/L), respectively.
ALT trends were visualized based on age and concurrent infection. Younger age groups exhibited higher and more prolonged ALT elevation, while the type of concurrent infection did not significantly affect the trends (Figure 2). Multiple linear regression analysis demonstrated that younger age was significantly associated with a longer recovery period, whereas the use of hepatoprotective agents was associated with a shorter recovery period. Pathogen type, sex, bilirubin levels, and prothrombin time-international normalized ratio showed no significant association with recovery duration (Table 2).
DISCUSSION
In 2022, the World Health Organization reported globally occurring cases of acute severe hepatitis of unknown origin in children. Among the reported cases, adenovirus was identified as the primary cause, with high viral load associated with poor prognosis [3]. Although the global outbreak of severe hepatitis has subsided, sporadic cases continue to be observed. Acute severe hepatitis as a form of reactive hepatitis is rare. Reactive hepatitis occurs as a secondary inflammatory response without a primary liver lesion [4]. Pathologically, it is characterized by fatty degeneration and microscopic focal necrosis of the liver due to immune cell infiltration, rather than direct viral invasion on biopsy [5]. Treatment primarily focuses on managing the underlying illness, and hepatitis typically resolves once the primary condition is treated.
CD8+ T lymphocyte-mediated immunopathology is considered a key mechanism in the development of liver inflammation following infections. Patients with hepatitis following influenza virus infection, histopathological analysis revealed fatty degeneration and focal micronecrosis of liver tissue without detectable virus in the liver. These findings suggest that an inflammatory response initiated by respiratory tract infection subsequently promoted the expansion of CD8+ T cells in the liver [6].
The mechanism by which CD8+ T cells attack hepatocytes without antigen recognition remains unclear. One hypothesis suggests that lymphocyte activation occurs as a bystander effect, mediated by cytokines such as type I type I interferon, interleukin (IL)-15, and IL-18. Under pathological conditions, Kupffer cells may contribute to the formation of inflammatory foci by producing CXCL10, which promotes T-cell-mediated hepatitis and exacerbates the inflammatory process [7,8].
In our study, respiratory virus infections were identified as the primary cause of acute severe hepatitis, consistent with findings in milder cases of reactive hepatitis. Jang et al. [1] also reported that respiratory and gastrointestinal infections are the most common causes of reactive hepatitis. Recent epidemiological study in Europe have identified influenza virus and human metapneumovirus as the most frequent pathogens associated with elevated liver enzymes in respiratory infections [9], while adenovirus was linked to more severe cases, consistent with our findings [10-12].
Children aged 6–12 months exhibited a peak incidence of severe reactive hepatitis, followed by a gradual decline. Several factors may contribute to this pattern. Maternal passive antibodies, which persist through early infancy (<6 months), may neutralize antigens and reduce CD8+ T cell differentiation and activation. Additionally, this age group has higher infection and hospitalization rates for respiratory and gastrointestinal viruses. Regardless of etiology, the trend of ALT changes followed a similar pattern. During an acute respiratory infection, CD8+ T cells play a critical role in clearing viral antigens. Their response typically peaks at 7–10 days post-infection, after which they gradually degrade or differentiate into memory T cells over 1–2 months [2]. This temporal pattern of CD8+ T cell expansion and resolution appears to correspond with the ALT dynamics observed in our study, providing a possible explanation for the clinical course of reactive hepatitis.
Hepatoprotective agents, including ursodeoxycholic acid and diphenyl dimethyl bicarboxylate, may reduce liver inflammation through various mechanisms, such as antioxidant effects, anti-apoptotic properties, and immunomodulation. While the efficacy of these agents in acute liver failure remains debated, they appeared to promote a more rapid recovery in cases of reactive hepatitis, as observed in this study.
The limitations of this study include its retrospective design and small sample size. Variations in drug administration based on underlying conditions may have influenced the outcomes. However, despite the lack of standardized testing or follow-up protocols, most patients underwent similar diagnostic and follow-up evaluations, ensuring the collection of consistent data. Furthermore, to the best of our knowledge, this study is the first report the clinical course of acute severe hepatitis associated with systemic infections in children, highlighting the significance of our findings.
This study found that acute severe hepatitis in children following extrahepatic infection was most commonly associated with respiratory infections, followed by gastrointestinal infections. Infants younger than one year were more susceptible and experienced a more severe disease course. Given that the duration of illness was independent of the causative pathogen, our findings suggest that immune dysregulation plays a key role in the pathogenesis of this condition. Future research should focus on elucidating the underlying immune mechanisms and developing effective treatment and prevention strategies.
KEY MESSAGES
▪ In cases of acute severe hepatitis following extrahepatic infection, respiratory infections accounted for over half of the cases, with adenovirus and parainfluenza virus being the most frequently identified pathogens.
▪ Peak alanine transaminase (ALT) levels occurred within 1 week of symptom onset, and most patients' ALT levels normalized within 28 days.
▪ Younger age was associated with more severe disease, whereas use of hepatoprotective agent appeared to mitigate disease severity.
▪ The causative pathogen was not associated with the disease course.
NOTES
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CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
-
FUNDING
None.
-
ACKNOWLEDGMENTS
None.
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AUTHOR CONTRIBUTIONS
Conceptualization: SHK. Methodology: SHK. Formal analysis: SL, YOK. Data curation: SL, YOK. Visualization: SL. Project administration: SHK. Writing - original draft: SL. Writing - review & editing: YOK, SHK. All authors read and agreed to the published version of the manuscript.
Figure 1.Study diagram. AST: aspartate aminotransferase; ALT: alanine transaminase. a) Hematologic malignancy, drug side effects, sepsis/septic shock.
Figure 2.Trend of liver transaminase changes. (A) Aspartate aminotransferase (AST) and alanine transaminase (ALT) levels. ALT levels by infection type (B) and by age group (C).
Table 1.Clinical characteristics of study populations
|
Variable |
Variable |
|
Age (mo) |
10±11 (1‒71) |
|
Male |
21 (53.8) |
|
Clinical presentation and confirmed pathogen |
|
|
Fever |
36 (92.3) |
|
Respiratory symptoms |
24 (61.5) |
|
Adenovirus |
7 (17.9) |
|
Parainfluenza virus |
7 (17.9) |
|
Respiratory syncytial virus |
4 (10.2) |
|
Bocavirus |
3 (7.7) |
|
Rhinovirus |
2 (5.1) |
|
Gastrointestinal symptoms |
9 (23.1) |
|
Adenovirus |
2 (5.1) |
|
Norovirus |
1 (2.6) |
|
Meningitis |
4 (10.3) |
|
Enterovirus |
3 (7.7) |
|
Urinary tract infection |
2 (5.1) |
|
Alanine aminotransferase in serum |
|
|
Peak level (IU/L) |
1,515.8±424.2 (1,060‒2,793) |
|
Interval from the symptom-onset to peak (day) |
4.4±2.3 (0‒8) |
|
Interval from the peak to normal (day) |
19.0±5.2 (10-42) |
|
Liver ultrasound (n=38) |
|
|
Normal |
21 (55.3) |
|
Increased echogenicity |
14 (36.8) |
|
Hepatomegaly with periportal tracking |
3 (7.9) |
|
Duration of hospitalization (day) |
5.7±1.5 (2‒9) |
Table 2.Factors associated with the time to ALT normalization
|
Variable |
β (95% CI) |
P-value |
|
Age <1 yr |
2.1 (0.4 to 3.8) |
0.015 |
|
Male |
0.5 (–0.8 to 1.8) |
0.412 |
|
Serum albumin <3.0 g/dl |
–1.5 (–3.7 to 0.7) |
0.182 |
|
Serum total bilirubin >3 mg/dl |
0.2 (–0.3 to 0.7) |
0.185 |
|
Use of hepatoprotective agents |
–2.8 (–4.5 to –1.1) |
0.003 |
|
Respiratory infection (reference) |
- |
- |
|
Gastrointestinal infection |
–0.05 (–0.12 to 0.02) |
0.098 |
|
Other infections |
0.1 (–0.2 to 0.4) |
0.361 |
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