Assessment of Prognostic Factors of Acute Hepatitis Among Pediatric Patients: A Cross-Sectional Study
Funding: The authors received no specific funding for this work.
ABSTRACT
Introduction
Early identification of acute hepatitis etiology and specific management is crucial for reducing morbidity and mortality. Therefore, this study aims to investigate the prognostic factors of acute hepatitis in children.
Methods
This cross-sectional study was conducted on children with diagnosis of acute hepatitis According to the criteria of ESPHAGAN, admitted to the Children's Hospital from March 2018 to March 2023. Data were analyzed using SPSS statistical software.
Results
A total of 164 patients with acute hepatitis were included, comprising 78 patients with acute liver failure and 86 patients without acute liver failure. Viral infections were identified as the most common etiology of acute hepatitis and were significantly more prevalent in patients without acute liver failure. Wilson's disease was significantly more prevalent in patients with acute liver failure. All patients with viral etiology recovered. Among the 24 patients with Wilson's disease, 14 (58.3%) underwent transplantation, 4 (16.6%) were deceased, and 6 (25%) survived without transplantation. Patients with other etiologies did not experience any mortality, with only 13.8% undergoing transplantation due to autoimmune causes. Low albumin (< 2.5), prolonged PT (> 22), elevated INR (> 3), encephalopathy, low phosphorus (< 3), and a duration of more than 7 days between symptom onset and hospitalization significantly increased the risk of mortality or need for transplantation in patients with acute liver disease.
Conclusion
Albumin levels, PT, INR, encephalopathy, phosphorus levels, and the duration between symptom onset and hospitalization are significant prognostic factors for acute hepatitis in pediatric patients.
1 Introduction
Acute hepatitis is a short-term inflammatory response of the hepatic parenchyma, manifesting as a combination of clinical signs and disruption of serum liver enzymes, caused by various etiologies [1-4]. The underlying causes of acute hepatitis range from intracellular inclusions in viral hepatitis to microvesicular steatosis in alcohol abuse, and other pathologies in Wilson's disease and drug-induced hepatitis [5-7]. While the most prevalent etiology of acute hepatitis is viral infection, several other etiologies exist [8, 9].
The clinically emergent nature of acute hepatitis arises from the fact that delayed diagnosis leads to significant mortality and complications, including acute liver failure. Several studies have focused on the prognostic factors in fulminant hepatitis, identifying the etiology of the disease as a key factor [10-13]. These studies have attempted to determine which parameters are associated with the survival of patients with fulminant hepatitis. However, fulminant hepatitis is a rare event, and the broader scope would be to identify predictive factors of fulminant hepatitis in patients with acute hepatitis. Elucidating the clinical and paraclinical factors that may contribute to the survival of acute hepatitis patients could aid in clinical decisions and treatment choices.
This study aimed to identify prognostic factors of acute hepatitis that may lead to fulminant hepatitis by conducting a cross-sectional study among pediatric patients with acute hepatitis admitted to a tertiary hospital.
2 Methods
2.1 Study Subjects and Baseline Data Collection
This cross-sectional study was conducted on pediatric patients diagnosed with acute hepatitis and admitted to Children's Medical Center Hospital between March 2018 and March 2023. These patients were hospitalized due to acute clinical symptoms such as fever, abdominal pain, diarrhea, vomiting, and jaundice. Inclusion criteria were children aged 2–18 years admitted to the Children's Medical Center with a confirmed diagnosis of acute hepatitis. Patients with a history of chronic pre-existing liver diseases were excluded. Demographic variables including age, gender, body mass index (BMI), duration between symptom onset and hospitalization, etiology of acute hepatitis, laboratory and ultrasonography findings, and clinical symptoms observed during hospitalization were recorded. The primary outcomes of interest were overall survival rates and the need for liver transplantation. Patient files meeting the mentioned criteria were retrieved, and relevant information was recorded in the researcher's questionnaire until discharge or death.
2.2 Diagnosis of Acute Hepatitis
The cause of acute hepatitis was determined through a comprehensive evaluation of clinical information and laboratory results, guided by the expertise of a pediatric gastroenterologist. Viral hepatitis was confirmed by detecting specific serological markers, including IgM antibodies against hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis E virus (HEV), as well as anti-HCV antibodies and HCV RNA. Acute hepatitis A infection was diagnosed by positive anti-HAV IgM, while acute hepatitis B was identified by positive anti-HBc IgM and HBsAg levels. Acute HCV infection was diagnosed by the presence of HCV RNA in serum, irrespective of anti-HCV antibody status. HBV/hepatitis D virus (HDV) co-infection was recognized by positive HDV-IgM antibodies in patients with acute hepatitis, whereas acute HDV superinfection was indicated by positive HDV-IgM antibodies in patients with chronic hepatitis B.
In cases where viral tests yielded negative results, investigations for nonhepatotropic viruses such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV), COVID-19, influenza, and other infections were conducted. Suspicion of autoimmune etiology prompted evaluation of autoantibody levels (ANA, LKM-1, ASMA) and total IgG. Evaluation for drug-induced or toxin-related hepatitis relied on a thorough patient history obtained upon admission. The diagnosis of Wilson's disease was established based on plasma copper levels, plasma ceruloplasmin levels, 24-h urine copper levels, the presence of Kayser-Fleischer rings in the eyes, and liver biopsy findings. Budd-Chiari syndrome diagnosis was determined through abdominal ultrasound imaging. If no definitive cause was identified, a liver biopsy was performed for further evaluation.
2.2.1 Acute Hepatitis
Acute hepatitis refers to a sudden inflammation of the liver, typically caused by infections (such as viral infections like hepatitis A, B, C, or by other factors like alcohol use, toxins, medications, or autoimmune diseases). It is characterized by a rapid onset of symptoms, such as jaundice (yellowing of the skin and eyes), fatigue, nausea, abdominal pain, and elevated liver enzymes in the blood (such as ALT and AST). Acute hepatitis can vary in severity, ranging from mild illness that resolves on its own to severe cases that may lead to liver dysfunction or failure.
2.2.2 Liver Failure
Liver failure is a condition where the liver's ability to perform its vital functions deteriorates significantly. There are two types of liver failure: Acute liver failure (ALF): This is a rapid loss of liver function, often occurring within days or weeks, and typically caused by factors such as viral hepatitis, drug toxicity (e.g., acetaminophen overdose), or autoimmune liver diseases. Acute liver failure can lead to life-threatening complications, including bleeding, encephalopathy (brain dysfunction), and organ failure. Chronic liver failure: This occurs over a longer period, usually due to ongoing liver diseases like cirrhosis or chronic viral hepatitis. The liver gradually loses its function, often leading to complications like portal hypertension, ascites, and liver cancer.
Pediatric autoimmune liver diseases in this study included Autoimmune Hepatitis (AIH), Primary Sclerosing Cholangitis (PSC), and Autoimmune Cholangiopathy. Furthermore, the term “idiopathic causes” refers to cases of acute hepatitis in children where the underlying cause is unknown or cannot be identified despite thorough investigation. In other words, the term “idiopathic” means that no specific, identifiable cause (such as viral infections, drug toxicity, autoimmune disorders, or metabolic diseases) is found to explain the liver inflammation.
2.3 Anthropometric Measurements
A number of anthropometric factors were assessed at the time of entry of the study. Pediatrics were dressed simply and without shoes when their height and weight were recorded. The Seca digital scale (manufactured in Germany) was used to measure each subject's weight twice, with an accuracy of 0.01 kg. At the start and conclusion of the research, participants' heights were measured standing up with a tape measure, without shoes, with an accuracy of 0.5 cm; measurements were taken twice each time, and the average was recorded. Weight in kilograms divided by height in meters squared was used to calculate BMI.
2.4 Biochemical Studies
The patient collected fecal samples for calprotectin measurement at home the day before and delivered them refrigerated to the laboratory for examination. Following the freezing and thawing process, all fecal samples were analyzed using an enzyme-linked immunosorbent assay method (Ridascreen Calprotectin test; R-Biopharm, Darmstadt, Germany). Also, after studying the files of the eligible people and entering the patients into the study based on the include and exclude criteria, as well as obtaining informed consent, blood samples were taken for the tests evaluated in this study. After clotting in the medium, the serum was separated as soon as possible by centrifugation and stored at −70°C until it was sent to the laboratory for testing. Serum levels of Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured using a colorimetric enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN) as per the manufacturer's instructions. Calcium and phosphorus were also measured by related kits. The method used to detect HAV was performed using the enzyme-linked immunosorbent assay (ELISA) as well as polymerase chain reaction (PCR) to confirm the results and was performed with a Bio company kit.
2.5 Statistical Analysis
Data analysis was performed using SPSS statistical software. The frequency command was employed to determine the distribution of qualitative variables, with descriptive statistics such as number and percentage used for qualitative variables and mean and standard deviation for quantitative variables if the data followed a normal distribution. In cases of nonnormal data distribution, the median and interquartile range (IQR) were utilized. For comparing the means of quantitative variables across qualitative subgroups, independent t-tests and Chi-Square tests were employed, while nonparametric conditions warranted the use of the Mann–Whitney U test. Additionally, ANOVA was applied to compare means across multiple independent groups. Bivariate and Pearson correlation coefficients were utilized to examine correlations among quantitative variables. For exploring relationships between two qualitative variables, the crosstab command and Wilcoxon test were employed under non-parametric conditions. Logistic regression analysis was conducted to identify predictive factors for acute hepatitis outcomes based on established risk factors. In Table 6, the selection of cutoff values was based on the usual guidelines [11, 14]. A p-value < 0.05 was considered significant.
2.6 Ethical Consideration
This research received approval from the ethics committee of Children's Medical Center Hospital and Tehran University of Medical Sciences (NO: IR.TUMS.CHMC.REC.1400.224). Informed written consent was obtained from the parents of the patients. Patients' anonymity was preserved by using assigned codes instead of names. Assurance of confidentiality was provided to both the research units and the parents of the patients. The research methodology was thoroughly explained to the parents, who were also informed of their right to withdraw from participation at any time without affecting their access to care or services.
3 Results
In this study, 164 patients diagnosed with acute hepatitis were included, among whom 78 patients had acute liver failure, while 86 did not. The demographic and clinical characteristics of patients with or without acute liver failure are summarized in Table 1. Age, sex, family history of acute liver disease, and the duration between symptom onset and hospitalization did not differ significantly between the two groups. Patients with acute liver failure exhibited significantly higher rates of symptoms such as encephalopathy, edema, ascites, and metabolic acidosis compared to those without acute liver failure. Conversely, acholia was significantly lower in the acute liver failure group. No significant differences were observed between the two groups regarding other clinical symptoms, including abdominal pain, fever, diarrhea, vomiting, jaundice, anorexia, and hypoglycemia.
| Variable | Patients with acute liver failure (N = 78) | Patients without acute liver failure (N = 86) | p |
|---|---|---|---|
| Age (year) | 8.02 (4.41) | 7.62 (3.49) | 0.605 |
| Sex (female) | 18 (52.9) | 35 (44.3) | 0.399 |
| Family history of acute liver disease | 16 (21.2) | 24 (28.0) | 0.458 |
| Duration between symptom onset and hospitalization (day) | 12.74 (15.93) | 11.04 (9.74) | 0.510 |
| Fever | 20 (26.5) | 23 (26.3) | 0.980 |
| Abdominal pain | 48 (61.8) | 663 (73.8) | 0.201 |
| Diarrhea | 13 (17.6) | 6 (7.5) | 0.106 |
| Vomiting | 32 (41.2) | 46 (53.8) | 0.219 |
| Jaundice | 75 (96.9) | 81 (94.9) | 0.656 |
| Edema | 12 (15.6) | 2 (2.6) | 0.011 |
| Ascites | 39 (50.0) | 19 (22.5) | 0.004 |
| Encephalopathy | 19 (24.2) | 1 (1.3) | < 0.001 |
| Anorexia | 23 (29.41) | 18 (21.5) | 0.354 |
| Acholia | 11 (14.7) | 17 (20.25) | 0.039 |
| Hypoglycemia | 4 (5.9) | 1 (1.3) | 0.166 |
| Metabolic acidosis | 39 (50.0) | 13 (15.1) | < 0.001 |
- Note: Quantitative variables are presented as mean (standard deviation), while qualitative variables are expressed as number (percentage).
Table 2 presents the common laboratory parameters in patients with or without acute liver failure. Our results indicated that patients with acute liver failure exhibited higher levels of total and direct bilirubin, international normalized ratio (INR), ammonia, prothrombin time (PT), neutrophil count, C-reactive protein (CRP), and blood urea nitrogen (BUN). Additionally, average levels of albumin, hemoglobin, calcium, and phosphorus were lower in patients with acute liver failure compared to those without. No significant differences were observed regarding other laboratory parameters.
| Variable | Patients with acute liver failure (N = 78) | Patients without acute liver failure (N = 86) | p |
|---|---|---|---|
| BS (mg/dL) | 89.79 (28.32) | 83.53 (17.97) | 0.162 |
| AST (IU/L) | 1617.05 (2395.55) | 1152.10 (943.14) | 0.139 |
| ALT (IU/L) | 1449.50 (2299.59) | 1373.93 (950.19) | 0.804 |
| ALP (IU/L) | 765.94 (567.43) | 900.97 (389.30) | 0.145 |
| GGT (IU/L) | 146.58 (176.38) | 156.22 (116.68) | 0.733 |
| Total bilirubin (mg/dL) | 20.87 (15.61) | 10.45 (10.04) | < 0.001 |
| Direct bilirubin (mg/dL) | 12.81 (9.25) | 6.99 (5.73) | < 0.001 |
| INR | 3.20 (1.42) | 1.32 (0.22) | 0.001 |
| Ammonia (μg/dL) | 88.25 (49.31) | 59.11 (29.61) | < 0.001 |
| Albumin (g/dL) | 3.19 (0.66) | 3.96 (0.55) | < 0.001 |
| Hemoglobin (g/dL) | 10.79 (2.10) | 12.04 (1.80) | 0.002 |
| PT | 34.10 (13.34) | 16.75 (3.56) | < 0.001 |
| Neutrophil count | 5727.69 (3506.84) | 3563.08 (2180.36) | < 0.001 |
| Lymphocyte count | 2664.39 (1286.42) | 2963.56 (1515.43) | 0.323 |
| ESR (mm/h) | 18.40 (20.68) | 21.71 (20.88) | 0.450 |
| CRP (mg/L) | 9.76 (10.81) | 5.33 (8.62) | 0.023 |
| BUN (mg/dL) | 11.65 (6.55) | 9.43 (3.42) | 0.020 |
| Creatinine (mg/dL) | 0.44 (0.20) | 0.48 (0.16) | 0.265 |
| Sodium (mEq/L) | 137.19 (3.97) | 137.97 (2.75) | 0.248 |
| Potassium (mEq/L) | 4.02 (0.54) | 4.16 (0.39) | 0.117 |
| Calcium (mg/dL) | 8.27 (0.78) | 8.93 (0.68) | < 0.001 |
| Phosphorus (mg/dL) | 3.47 (1.26) | 4.29 (0.84) | < 0.001 |
| Magnesium (mg/dL) | 1.96 (0.34) | 2.03 (0.24) | 0.258 |
- Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transferase; BS, blood sugar; BUN, blood urea nitrogen; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GGT, gamma-glutamyltransferase; INR, international normalized ratio; PT, prothrombin time.
Viral infections, including hepatitis A virus (HAV), coronavirus disease 2019 (COVID-19), and Epstein–Barr virus (EBV), were identified as the most common etiologies of acute hepatitis, accounting for 58 cases. Autoimmune diseases, idiopathic causes, Wilson's disease, and medication-related causes were noted in 29, 35, 37, and 5 patients, respectively (Table 3). Among the reported causes, viral infections were significantly more prevalent in patients without acute liver failure (55.0%) compared to those with acute liver failure (14.7%). Specifically, hepatitis A accounted for the highest proportion of viral infections, with 43.0% of cases in the group without acute liver failure and 5.9% in the acute liver failure group. Additionally, a statistically significant percentage of patients with acute liver failure were diagnosed with Wilson's disease (44.1%), contrasting with only 2.5% of patients without acute liver failure. No significant differences were observed between the two groups regarding other etiological factors (Table 3).
| Etiology | Patients with acute liver failure (N = 78) | Patients without acute liver failure (N = 86) | p |
|---|---|---|---|
| Viral infections | 11 (14.7) | 47 (55.0) | < 0.001 |
| HAV | 4 (5.9) | 37 (43.0) | < 0.001 |
| EBV | 0 (0) | 2 (2.5) | 0.352 |
| COVID-19 | 7 (8.8) | 8 (10.0) | 0.846 |
| Wilson's disease | 35 (44.1) | 2 (2.5) | < 0.001 |
| Autoimmune diseases | 9 (11.8) | 20 (23.2) | 0.087 |
| Medication-related causes | 3 (2.9) | 2 (2.5) | 0.893 |
| Idiopathic causes | 20 (26.5) | 15 (17.5) | 0.275 |
- Abbreviations: COVID-19, coronavirus disease 2019; EBV, Epstein–Barr virus; HAV, hepatitis A virus.
Table 4 presents abnormal ultrasound findings and outcomes among patients with or without acute liver failure. Among the various abnormal ultrasound findings, such as liver, spleen, kidney, and gallbladder abnormalities, and ascites, the prevalence of ascites was notably higher in the acute liver failure group (70.5%) compared to the group without acute liver failure (46.5%). For other findings, no significant difference was reported between the two groups of patients.
| Variable | Patients with acute liver failure (N = 78) | Patients without acute liver failure (N = 86) | p |
|---|---|---|---|
| Hepatic abnormality | 52 (66.6) | 65 (75.5) | 0.763 |
| Splenic abnormality | 11 (14.1) | 4 (4.6) | 0.055 |
| Ascites | 55 (70.5) | 40 (46.5) | 0.005 |
| Renal abnormality | 0 (0.0) | 0 (0.0) | — |
| Gallbladder abnormality | 48 (61.5) | 54 (62.7) | 0.742 |
Table 5 displays outcomes based on the etiology of acute hepatitis. Notably, all patients with viral etiology recovered without any fatalities or transplantations. In contrast, among the 24 patients with Wilson's disease, 14 (58.3%) underwent transplantation, 4 (16.6%) were deceased, and 6 (25%) survived without transplantation. Patients with other etiologies, including autoimmune, medicinal, and idiopathic causes, did not experience any mortality, with only 13.8% undergoing transplantation due to autoimmune causes.
| Etiology | Mortality (N = 4) | Transplantation (N = 19) | Survival without transplantation (141) | p |
|---|---|---|---|---|
| Viral infections | 0 (0.0) | 0 (0.0) | 70 (100.0) | 0.001 |
| Wilson's disease | 4 (16.6) | 14 (58.3) | 6 (25) | < 0.001 |
| Autoimmune diseases | 0 (0.0) | 5 (13.8) | 31 (86.1) | 0.623 |
| Medication-related causes | 0 (0.0) | 0 (0.0) | 4 (100.0) | 0.786 |
| Idiopathic causes | 0 (0.0) | 0 (0.0) | 30 (100.0) | 0.132 |
Table 6 demonstrates an analysis of the likelihood of mortality or transplantation compared to survival based on clinical parameters in patients with acute hepatitis. The study findings indicate that several factors, including albumin levels < 2.5 g/dL, prolonged PT (> 22 s), elevated INR (> 3), presence of encephalopathy, low phosphorus levels (< 3 mg/dL), and duration between symptom onset and hospitalization exceeding 7 days, significantly elevate the risk of death or transplantation in patients with acute hepatitis.
| Variable | Odds ratio | 95% CI | p |
|---|---|---|---|
| Total Bilirubin > 17 | 2.48 | 0.817–7.55 | 0.109 |
| INR > 3 | 20.57 | 5.29–79.86 | < 0.001 |
| Albumin < 2.5 | 62.56 | 13.67–286.21 | < 0.001 |
| PT > 22 | 22.50 | 4.65–108.81 | < 0.001 |
| Phosphorus < 3 | 6.15 | 1.77–21.37 | 0.004 |
| Encephalopathy | 12.77 | 56.66–2.90 | 0.001 |
| Duration between symptom onset and hospitalization > 7 days | 3.57 | 1.03–12.30 | 0.044 |
4 Discussion
In this cross-sectional study, we have demonstrated that the incidence of liver failure is associated with serum phosphorus, CRP, BUN, bilirubin, INR, ammonia, neutrophil count, and clinical findings such as ascites, edema, metabolic acidosis, and encephalopathy. The most significant predictive factors of treatment failure in our study are hepatic encephalopathy, albumin levels < 2.5 g/dL, elevated INR (> 3), low phosphorus levels (< 3 mg/dL), duration between symptom onset and hospitalization exceeding 7 days, and a prothrombin time of more than 22 s.
Our findings are consistent with several studies on fulminant hepatitis patients. For example, in a recent study by Lal et al. among 131 HAV patients, those who manifested jaundice, encephalopathy, and coagulopathy had the highest mortality rates [13]. In another study, Chien et al. showed that among 23 patients with acute hepatitis, ammonia levels above 190 μg/dL correlated with overall survival and the need for liver transplantation [15]. The novelty of our findings lies in identifying several serum biomarkers that could provide clinicians with better insight into treatment options.
Several underlying etiologies were observed among the patients in this study, with the most common being HAV, followed by autoimmune, idiopathic, and drug-related hepatitis. Our data represented HAV as the most common yet most benign etiology of acute hepatitis, as HAV patients had the lowest incidence of liver failure. In one study conducted on 4226 pediatric liver failure patients, HAV was found to be the cause in 92% of cases [16]. Moreover, several other studies have indicated that the majority of liver failure patients are dealing with viral hepatitis, with HAV being the most common [17]. In another study focusing on liver transplantation prevalence among pediatric patients with liver failure in a developed region, HAV still prevailed as the most frequent etiology at 23%, despite preventive approaches [18]. However, HAV vaccination is highly recommended in order to prevent acute hepatitis cases. It is a safe, efficient, and recommended vaccine. These findings are consistent with ours, showing that while most liver failures are due to HAV, most cases of HAV are benign, and only a small proportion of patients develop liver failure. Among other viral agents, HBV is another major cause of liver failure among unvaccinated patients [19]. In conclusion, although HAV-associated acute hepatitis is generally benign and does not carry high mortality rates, most liver failure cases are secondary to HAV due to its high prevalence.
Another finding in our study was the overall high survival rates of acute hepatitis due to several treatment options, including liver transplantation. Epidemiologic studies have demonstrated a significant rise in the survival of patients with liver failure from 28% to 58% in recent years, likely due to timely diagnosis, improved patient care, higher transplantation availability, and novel surgical approaches in liver transplantation [20-22]. In a prospective study conducted by Lee et al. among 97 pediatric patients with liver failure, only 61% survived despite treatment approaches including transplantation. Our analysis shows approximately 20% higher survival rates in liver failure, which may stem from the different study populations; Lee et al. reported metabolic hepatitis as the most common etiology, whereas viral hepatitis was significantly higher among our patients [10]. Due to the relative rarity of metabolic disorders in the overall population, it can be assumed that since viral hepatitis is the leading cause of liver failure, higher survival rates should be considered than those described by Lee et al. Nevertheless, our study and several others have shown lower mortality rates among liver failure patients in recent years due to improved healthcare and higher availability of liver transplantation [10, 19, 20].
Our results also showed that albumin, PT, INR, encephalopathy, phosphorus level, and the duration of the onset of symptoms with hospitalization are very important survival factors for patients with acute hepatitis. According to this finding, in a study in Argentina, INR was an independent prognostic factor in the mortality rate of these patients or the need for transplantation [17]. Furthermore, in this study, it was clearly shown that encephalopathy, bilirubin, and low PT were significantly associated with mortality or the need for transplantation. In an article [10] similar to our results, the findings showed that children who had a delay between the first symptom of liver disease and the onset of hepatic encephalopathy and had higher levels of plasma bilirubin, PT, and ALT levels had a higher probability of death due to severe liver failure during hospitalization and the need for liver transplantation Significant independent predictors for final failure of conservative treatment in this study included time to onset of hepatic encephalopathy > 7 days, PT > 55 s, and ALT ≤ 2384 IU/L on admission. In general, it was shown in this study that children with severe liver failure with severe coagulation disorder, low ALT during hospitalization, and a long duration of the disease before the onset of hepatic encephalopathy are likely to need a liver transplant. Furthermore, according to the recent NASPGHAN guideline, the use of a mixed growth model that included clinical data (INR, encephalopathy, total bilirubin) collected over 7 days identified different pathways that were associated with different probabilities of death or survival [23].
However, no comparable studies have been conducted on the other factors examined in our research. Nonetheless, previous evidence [14, 24] suggests that, in addition to the factors already discussed, albumin levels and electrolyte levels, including phosphorus, may serve as indicators of disease progression or severity, ultimately influencing outcomes such as mortality or the need for transplantation. Therefore, identifying and managing these predictive factors could play a crucial role in improving patient survival or reducing the necessity for transplantation, particularly if addressed through early intervention. However, further studies with long-term follow-up are required to thoroughly investigate these potential predictive factors.
Major etiologies of acute hepatitis, including viral infections, drug-induced liver injury, and autoimmune conditions, play a crucial role in influencing key predictive factors such as albumin, PT, INR, encephalopathy, and phosphorus levels [11]. A decline in albumin levels reflects reduced liver synthetic capacity, which is common in severe liver dysfunction caused by these etiologies. Abnormal PT (prothrombin time) and elevated INR indicate impaired production of clotting factors, a hallmark of significant hepatic injury [25]. The presence of hepatic encephalopathy suggests the accumulation of neurotoxins like ammonia, often resulting from extensive liver damage. Meanwhile, low phosphorus levels may point to disruptions in energy metabolism within hepatocytes, frequently observed in fulminant liver failure [26]. These factors not only highlight the severity of liver injury but also serve as valuable tools for predicting outcomes, including mortality risk and the potential need for liver transplantation [26]. Accurate monitoring and management of these indicators are essential to improve patient prognosis and guide therapeutic decisions.
Several limitations apply to our study. Firstly, due to its cross-sectional nature, we were unable to apply statistical methods that could better hint at causal associations. Future studies may aim to utilize multivariate survival analysis to report the hazard ratio of each predictive factor or regression assessments to elucidate the sensitivity and specificity of each parameter. Nevertheless, our study has paved the way for future research by proposing several novel serum markers associated with liver failure incidence.
5 Conclusion
We have demonstrated that several non-etiologic factors play a predictive role in the incidence of liver failure. Our study highlights the importance of serum phosphorus, CRP, BUN, bilirubin, INR, ammonia, neutrophil count, and clinical findings such as ascites, edema, metabolic acidosis, and encephalopathy for clinicians to be aware of the potential liver failure incidence. Furthermore, the most significant predictive factors of treatment failure in our study are hepatic encephalopathy, albumin levels < 2.5 g/dL, elevated INR (> 3), low phosphorus levels (< 3 mg/dL), duration between symptom onset and hospitalization exceeding 7 days, and a prothrombin time of more than 22 s.
Acknowledgments
The authors have nothing to report.
Ethics Statement
This study was approved by the research council and Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
