Krishnan A, Khan S, Gips J, Alqahtani SA, Vaidya D, Liu YS, Kim A, Su A, Gurakar A, Hamilton JP, Woreta TA. Body mass index and its association with clinical outcomes in acute liver failure. World J Clin Cases 2025; 13(30): 109212 [DOI: 10.12998/wjcc.v13.i30.109212]
Corresponding Author of This Article
Tinsay A Woreta, MD, Assistant Professor, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Hal 407, Baltimore, MD 21287, United States. tworeta1@jhmi.edu
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Arunkumar Krishnan, Saleh A Alqahtani, Ahyoung Kim, Amanda Su, Ahmet Gurakar, James P Hamilton, Tinsay A Woreta, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
Arunkumar Krishnan, Department of Supportive Oncology, Atrium Health Levine Cancer, Charlotte, NC 28204, United States
Arunkumar Krishnan, Department of Medicine, Wake Forest University School of Medicine, Winston Salem, NC 28204, United States
Sameer Khan, Julia Gips, Dhananjay Vaidya, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
Saleh A Alqahtani, Liver Transplant Center, King Faisal Specialist Hospital and Research Center, Riyadh 12713, Saudi Arabia
Yi-Si Liu, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21287, United States
Author contributions: Krishnan A performed the interpretation of data; Krishnan A and Khan S performed writing the original draft; Krishnan A, Khan S, Hamilton JP, Gurakar A, and Woreta TA revised the manuscript for important intellectual content; Krishnan A and Woreta TA conceptualized, designed, and drafted the methodology of the research; Krishnan A, Gips J, Kim A, and Su A performed data collection; Vaidya D and Liu YS performed the formal analysis; Woreta TA supervised the project; all authors reviewed, revised, and approved the final version of the article, including the authorship list.
Institutional review board statement: The study protocol was approved by the Institutional Review Board of the Johns Hopkins University School of Medicine, No. 00250968.
Informed consent statement: Informed consent was waived for a retrospective review of patient charts.
Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Tinsay A Woreta, MD, Assistant Professor, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Hal 407, Baltimore, MD 21287, United States. tworeta1@jhmi.edu
Received: May 6, 2025 Revised: May 25, 2025 Accepted: August 12, 2025 Published online: October 26, 2025 Processing time: 161 Days and 20.9 Hours
Abstract
BACKGROUND
Acute liver failure (ALF) is a life-threatening multisystemic condition with high short-term mortality. With the growing prevalence of obesity and metabolic syndrome, it is important to investigate the clinical implications of high body mass index (BMI) on survival outcomes in ALF.
AIM
To explore the impact of overweight and obesity on the clinical outcomes of patients with ALF.
METHODS
A retrospective observational cohort study was conducted involving patients with ALF admitted to the Johns Hopkins Health System between January 1, 2000 and May 1, 2020. We performed Cox proportional hazards regression to identify outcomes, including the need for liver transplantation (LT) or all-cause mortality.
RESULTS
A total of 196 patients were included, the median age was 43.5 years, 63.3% were female, and 59.7% were of Caucasian ethnicity. Acetaminophen-induced ALF was the most common etiology (45%). The mean BMI was significantly greater among patients who underwent LT or died (29.64 kg/m2vs 26.59 kg/m2, P = 0.008) than among survivors. Patients with overweight and obesity had a higher risk of all-cause mortality or need for LT by 2.22-fold (95%CI: 1.30-3.78) and 2.04-fold (95%CI: 1.29-3.39), respectively. Elevated BMI was associated with renal failure and higher grades of hepatic encephalopathy. Derangements in serologic markers, including alanine transaminase, lactate, and ammonia, were associated with a mortality risk or need for LT.
CONCLUSION
In this large, retrospective study, with a diverse cohort of United States patients, Overweight and obese were independently associated with an increased risk of all-cause mortality or need for LT. This work highlights the importance of closely monitoring ALF patients who are overweight or obese for adverse complications and measures to improve outcomes in this vulnerable patient population.
Core Tip: The most common causes of acute liver failure (ALF) were acetaminophen toxicity, drug-related hepatitis, and other etiologies. Patients who underwent liver transplantation (LT) or died were older, had a higher body mass index (BMI), and were more likely to have higher-grade hepatic encephalopathy and cerebral edema. They also had higher levels of lactate and phosphate. Overweight and obese patients with ALF had a higher risk of mortality or the need for LT than normal-weight patients. Factors such as increasing age, other etiologies of ALF, higher BMI, and abnormal laboratory values were associated with an increased risk of poor outcomes in ALF patients.
Citation: Krishnan A, Khan S, Gips J, Alqahtani SA, Vaidya D, Liu YS, Kim A, Su A, Gurakar A, Hamilton JP, Woreta TA. Body mass index and its association with clinical outcomes in acute liver failure. World J Clin Cases 2025; 13(30): 109212
Acute liver failure (ALF) is an uncommon clinical syndrome of sudden and severe hepatic injury in a patient in the absence of known preexisting liver disease, which leads to a rapid loss of liver function. It is characterized mainly by the development of altered mentation and coagulopathy[1]. Although rare, with fewer than ten cases per million in developed nations, ALF is a critical illness that occurs mainly in young adults and is associated with high mortality and morbidity[2,3]. Recent guidelines emphasized ALF's evolving epidemiology, including rising metabolic risk factors that may modify disease presentation[1]. The most frequent causes of ALF include acetaminophen toxicity, viral hepatitis, drug-induced hepatitis, hypoxia-induced liver injury, and autoimmune hepatitis; however, many cases have no discernible cause[4,5]. The clinical course of ALF varies from complete recovery of liver function to rapid deterioration with the development of cerebral edema and multiorgan failure. The prognosis of patients with ALF is highly variable, and it depends on the cause of the ALF, the patient's age, the grade of encephalopathy, the course of the disease, and underlying comorbidities[5,6]. ALF is the most frequent indication for emergency liver transplantation (LT), which has been shown to improve survival and remains the cornerstone of treatment in selected patients with ALF[7].
From a clinical standpoint, it is well-known that the mortality in ALF is associated with a dysregulated inflammatory response producing a cytokine storm that drives the development of organ failure[8,9]. The resulting activation of systemic inflammatory responses shares pathophysiologic features with severe sepsis and septic shock, which may also progress to multiorgan failure[10]. Given the significance of immune dysregulation in the progression of ALF, the role of obesity as an independent risk factor for hepatic decompensation is an active area of interest[11,12]. Prior studies have shown that obesity results in a chronic low-grade inflammatory state. In 2006, Rutherford et al[13] performed a prospective cohort study of 782 patients from the Acute Liver Failure Study Group (ALFSG) to assess the association between obesity and ALF. They found that the prevalence of obesity in ALF patients was 29%, comparable to the general prevalence of obesity at 30% at the time of the study. Obese and severely obese patients had a 1.6-1.9 times higher risk of LT or death from ALF. One major limitation of the study was that body mass index (BMI) data were not recorded for 27% of patients. The ALFSG's 2023 position report identified obesity as an emerging modifier of both etiology and outcomes, though studies are lacking[1]. Hence, further studies are needed to examine the prevalence of medical comorbidities in patients with obesity and ALF.
No studies have been published about ALF and high BMI in the last decade in the United States. Given the prevalence of obesity and metabolic syndrome, it is important to investigate and understand the effects of elevated BMI on survival in patients with ALF. In this study, we assessed how the prevalence of obesity in patients with ALF has changed over the past 15 years and evaluated the impact of BMI on clinical outcomes in these patients. We also investigated differences in demographic characteristics, etiology of ALF, and clinical and laboratory data between overweight/obese and normal-weight patients with ALF.
MATERIALS AND METHODS
Study design and setting
In this retrospective observational cohort study, we analyzed consecutive patients who were admitted with an ALF diagnosis at the Johns Hopkins Health System between January 1, 2000 and May 1, 2020 (Figure 1). The study protocol was approved by the Institutional Review Board (No. 00250968) of the Johns Hopkins University School of Medicine, and informed consent was waived for a retrospective review of patient charts. The study and analysis of this study were performed consistently with Strengthening the Reporting of Observational studies in Epidemiology guidelines.
Figure 1 Study flow chart.
AASLD: American Association for the Study of Liver Diseases; ALF: Acute liver failure; BMI: Body mass index; LT: Liver transplantation.
Study participants and identification of ALF
Individuals were included if they were adults at least 18 years old and had a diagnosis of ALF, defined as the presence of an International Classification of Diseases 9 and 10 codes from the Johns Hopkins electronic health record for this cohort study. Identified adult patients with the diagnosis of ALF were reviewed manually by two independent reviewers to confirm the diagnosis of ALF based on the American Association for the Study of Liver Diseases (AASLD) guidelines, which define ALF based on the rapid deterioration of liver function with impaired synthetic function [international normalized ratio (INR) ≥ 1.5] and the development of any degree of encephalopathy, in the absence of chronic liver disease, with a duration of illness of fewer than 26 weeks[14]. Patients with severe acute liver injury were not included in this cohort study. In addition, we excluded patients who were less than 18 years old, underweight (BMI < 18.5 kg/m2), diagnosed with acute-on-chronic liver failure, or those with a prior history of LT. Also, patients who did not fully meet the AASLD criteria for ALF or had incomplete details of height, weight, and clinical or laboratory data were excluded. Details of the diagnosis codes used for patient selection are described in the supplementary.
Data collection
The following variables were obtained from the electronic medical records and follow-up documents: (1) Age; (2) Sex; (3) Height; (4) Weight; (5) Underlying etiology; (6) Cause of ALF; (7) Grade of hepatic encephalopathy (HE) on admission; (8) Time from onset of illness to the development of HE; (9) The Charlson comorbidity index (CCI); (10) Laboratory parameters; (11) Imaging findings; (12) Medication use; and (13) Treatment details. A modified version of the CCI was used to stratify results according to comorbidity conditions[15]. Each indicated diagnosis is assigned a weight and summed to provide a patient's total score. Drugs were implicated as aetiological agents based on the detailed medical history at admission. Viral etiology was confirmed based on the screening for serological markers of hepatitis A viral (HAV), hepatitis B viral (HBV), hepatitis C viral, and hepatitis E viral infections, including immunoglobulin M antibodies against HAV and HBV, and for auto-antibodies. The clinical notes assessed Wilson's disease diagnosis as the presence of the Kayser-Fleischer ring, family history, serum copper, and ceruloplasmin levels, whereas the diagnosis of Budd-Chiari syndrome was confirmed on abdominal imaging. Toxic etiology was established based on the positive history of drug ingestion or mushroom ingestion. HE was determined according to the following criteria from the medical records: (1) Loss of sleep rhythm, anxiousness, confusion, or flapping tremors; (2) Loss of sphincter control, drowsiness, or behavioral disorder; (3) Persistent coma, but still responding to shouts; and (4) Deep coma with no consciousness. The onset of HE was determined based on the occurrence of HE within 26 weeks of the onset of jaundice in patients with no preexisting cirrhosis (Supplementary material)[16].
Obesity classification and prognostic models
For the analysis, the primary predictor was obesity, defined as a BMI ≥ 30 kg/m2. BMI (kg/m2) was calculated from weight (kg) and height (m) measured on admission to the study. World Health Organization criteria were used for BMI into three groups: (1) Normal weight: BMI between 18.5 kg/m2 and 24.9 kg/m2; (2) Overweight: BMI between 25.0 kg/m2 and 29.9 kg/m2; and (3) Obese: BMI is ≥ 30 kg/m2. We used the most commonly used prognostic models to determine mortality risk, namely the King's College Criteria[17], the model for end-stage liver disease (MELD)[18], and MELD-Sodium (MELD-Na).
Study outcomes
We defined the primary study outcome as death or need for LT. Death was assessed at the end of the study period. Outcomes were examined at 21 days from the time of hospitalization with a confirmed diagnosis of ALF. Secondary analyses stratified outcomes into three groups: (1) Survival without LT; (2) LT; and (3) Death to explore granular associations. Patients who did not have a follow-up period of 21 days were excluded from the study. The defined outcomes at 21 days were used based on the fact that prior studies have shown that 93% of patients had a definitive outcome at 21 days[1,19]. Furthermore, the clinical outcomes were observed until May 1, 2020, the final follow-up date.
Statistical analysis
Categorical variables were summarized as frequencies (percentages). The χ² test were used to compare categorical variables. Group comparisons were performed using the Wilcoxon rank-sum or Fisher's exact test for continuous variables and the χ² test for categorical variables. The results are presented as mean with SD or median with interquartile range (IQR). In crude analysis, univariable relationships were tested by using logistic regression. Univariable logistic regression identified candidate predictors; multivariable Cox models adjusted for confounders [age, gender, ethnicity, race, BMI, etiology of ALF, preexisting comorbidities, lactate, phosphate, alpha-fetoprotein (AFP), MELD, and grades of HE, use of renal replacement therapy (RRT) and vasopressors]. Finally, the Kaplan-Meier method was used to assess differences in mortality by the different categories of BMI. The cumulative incidence of death or LT was estimated using the Kaplan-Meier method, and significance was evaluated with the log-rank test. All tests were two-tailed, and statistical significance was determined at P values < 0.05. All statistical data analyses were conducted with Stata software (version SE16; StataCorp, College Station, TX, United States).
RESULTS
During the study period, 196 patients fulfilled the criteria for ALF and were included in the study. The median age was 43.5 years (IQR: 30-56.5 years), with 63.3% female and 59.7% Caucasian ethnicity. The etiology of ALF was as follows: (1) 45.4% acetaminophen toxicity (n = 89); (2) 10.7% drug-related hepatitis (n = 21); (3) 35.2% other etiologies [mushroom intoxication, ischemia, autoimmune vascular diseases, and Wilson's disease (n = 69)]; and (4) 8.7% viral hepatitis (n = 17).
Patient characteristics stratified by outcomes
A total of 94 patients (47.9%) survived with medical management, whereas 102 patients (52.1%) underwent LT or died at the end of the study. Demographic and laboratory data comparing patients who underwent LT or died with those who survived are summarized in Table 1. Among 102 patients (52.1%) with poor outcomes, 38 patients (19.4% overall) underwent LT, and 64 patients (32.7% overall) died. LT recipients were younger (median: 42 years vs 50 years, P = 0.03) and had lower MELD scores (32 vs 35, P = 0.02) than non-survivors. Non-survivors had higher rates of cerebral edema (68% vs 42%, P = 0.01) and renal failure (41% vs 24%, P = 0.04). The mean BMI for patients who underwent LT or died was significantly greater than the BMI of spontaneous survivors at 29.6 kg/m2vs 26.6 kg/m2 (P = 0.008). There was no difference in the CCI between these groups (P = 0.07). Patients who underwent LT or died were more likely to have a higher grade (3 or 4) of HE along with a higher percentage of cerebral/brain edema. The use of blood products and vital signs was similar between the LT or death and the spontaneous survivor groups. The overall median lactate levels were significantly higher in the LT or death group as compared with the spontaneous survivors group. In contrast, the median level of AFP was higher in patients in the spontaneous survivors' group. As expected, the LT or death group patients had higher rates of mechanical ventilation. However, spontaneous survivors received more vasopressor support and RRT than LT or death group patients. The prognostic scores were significantly higher in patients in the LT or death group, with the mean MELD (33.5 vs 23.5, P < 0.001) and MELD-Na (24 vs 8, P < 0.001) scores. The median time from admission to death was 10 days (IQR: 3-241 days).
Table 1 Baseline demographic and clinical characteristics of patients with acute liver failure by outcome, n (%).
The median age was significantly higher for patients with overweight and obesity obese (45 years vs 48 years) compared to patients with normal weight (36 years, P = 0.006). Table 2 summarizes the study population's characteristics stratified by different BMI categories. Non-Hispanic patients had a higher BMI (P = 0.004) than Hispanics. However, there were no significant differences in terms of gender, race, etiologies, and CCI between these groups. Drug-related hepatitis and other etiologies of ALF were more prevalent among obese patients. Higher grade HE (grade 3 or 4) was significantly more prevalent among those with overweight (51.6%, P = 0.04) and obese (70.2%, P = 0.04), as compared to patients with normal weight (49.3%). Cerebral edema was observed in 34.8% of patients in the normal weight group, 40.2% in patients in the overweight range, and 53.8% in patients with obesity (P = 0.11). On Figure 2, the prevalence of fatty liver was similar between the three BMI categories: (1) 14.5% in the normal weight group; (2) 19.2% in the overweight group; and (3) 15.3% in the obese group (P = 0.84). On hospital admission, abnormal liver chemistries were commonly seen among all patients. However, patients with overweight had higher alanine aminotransferase (ALT) and aspartate aminotransferase compared to patients in other categories. However, no difference was observed between these three groups in median prothrombin time.
Of note, the patients in the normal weight group had significantly higher serum albumin levels than those in the overweight and obese groups (3.4 g/L vs 3.2 g/L vs 2.7 g/L, P < 0.001, respectively). ALF patients with normal weight had significantly higher total protein (P = 0.007) and estimated glomerular filtration rate (eGFR) (P < 0.001) than the overweight or obese group. In addition, serum creatinine was significantly elevated in the obese group compared to the lower BMI groups (P = 0.005). There was no difference in the median level of MELD and MELD-Na, along with total bilirubin level and INR, among different BMI categories.
Predictors of outcome in ALF
The univariable Cox proportional hazards model, evaluating predictors of end-point mortality or need for LT in patients with ALF, is depicted in Supplementary Table 1. Unadjusted analysis revealed patient-centered variables that increased the risk of all-cause mortality or need for LT were increasing age [hazard ratio (HR) = 1.02 per year; 95%CI: 1.01-1.03; P = 0.006], other etiologies of ALF (HR = 3.05, 95%CI: 1.29-7.16, P = 0.01), higher CCI (HR = 1.33, 95%CI: 1.02-1.74, P = 0.035), and having higher grades (3 or 4) of HE (HR = 2.37, 95%CI: 1.14-4.91, P = 0.02) (Supplementary Table 1). Moreover, the results showed that abnormal levels of ALT, total protein, fasting blood glucose, ammonia, lactate, and phosphate significantly increased the risk for all-cause mortality or need for LT in patients with ALF. In addition, compared to patients with normal BMI, all-cause mortality or need for LT significantly increased by 2.22-fold (95%CI: 1.30-3.78, P = 0.003) in overweight patients and increased 2.04-fold (95%CI: 1.29-3.39, P = 0.006) in patients who were obese. Similarly, an increase in the levels of MELD and MELD-Na was associated with a significantly increased risk of all-cause mortality. Age, gender, ethnicity, race, BMI, etiology of ALF, comorbid illness, lactate, phosphate, AFP, MELD, and grades of HE, and use of RRT and vasopressors were adjusted as confounders in the multivariable Cox proportional hazards model (Table 3). Of note, other etiologies of ALF (HR = 2.98, 95%CI: 1.15-7.73, P = 0.02) were independently associated with an increased mortality risk after adjusting for confounders. However, age was not an independent predictor in multivariable analysis (P = 0.83). As shown in Table 3, overweight patients with ALF had 2.20-times (95%CI: 1.23-3.92, P = 0.007) hazards of undergoing transplantation or dying, whereas obese ALF patients had 2-times (95%CI: 1.15–3.38, P = 0.001) hazards of this outcome in multivariable-adjusted analyses. This was also supported by the Kaplan-Meier survival analysis plot for the most significant risk factors. As depicted in the survival curves, there was a lower survival rate in patients with overweight and obesity than in patients with normal weight (Log-rank test: P = 0.004; Figure 3). In addition, there was a significant difference observed in mortality between overweight and obese patients compared to those with normal BMI (Log-rank test: P = 0.002, P = 0.004; Figure 4A and B).
Figure 4 Kaplan–Meier analysis curve based on the patient's body mass index.
A: Kaplan-Meier survival analysis comparing normal weight [body mass index (BMI) 18.5-24.9 kg/m²] vs obese (BMI ≥ 30 kg/m²) patients with acute liver failure (ALF); B: Kaplan-Meier survival analysis comparing normal weight (BMI: 18.5-24.9 kg/m²) vs overweight (BMI: 25.0-29.9 kg/m²) patients with ALF. BMI: Body mass index.
Table 3 Adjusted Cox proportional hazards model to predict the relationship of body mass index to outcome in acute liver failure.
In this retrospective cohort study, we evaluated patients with ALF and the association of BMI with outcomes of ALF in a large, diverse cohort of United States patients treated at a single, large tertiary care hospital. The overall prevalence of overweight and obese patients amongst all patients with ALF resembled the general population. However, we found that amongst patients in ALF, an elevated BMI is independently associated with an increased risk of all-cause mortality or need for LT. On average, the BMI of patients who spontaneously survived ALF was less than that of their counterparts who underwent LT or died. Two notable associations were observed when examining the specific factors that explain the increased mortality and need for LT in patients with a higher BMI. Firstly, severe HE was significantly more prevalent in overweight and obese patients and was a major independent risk factor for poor outcomes in ALF. Secondly, patients with obesity had significantly lower kidney function than those with a normal BMI.
Prior studies have attempted to decipher an association between obesity and ALF; however, either study size or design has often limited these. A retrospective study in 2005 evaluated 34 patients with acute and acute-on-chronic liver failure and found that BMI was significantly higher in patients with acute-on-chronic liver failure than in ALF[20]. The study compared two subtypes of liver failure rather than directly assessing BMI. A more direct and extensive study was performed in 2006 by Rutherford et al[13] and found that the mean BMI for patients who underwent LT or died (28.8 kg/m2) was significantly greater than that of spontaneous survivors (26.6 kg/m2). Patients with obesity and severe obesity also had a 1.63-1.93 times higher risk for LT or death than a control group of patients without obesity. One limitation of this study was that baseline characteristics, including BMI, were missing in 209 patients. Nonetheless, the findings supported the trend observed in our data, which shows that overweight and obesity independently increased the risk of all-cause mortality or need for LT compared to normal-weight patients by 2.22-fold and 2.04-fold, respectively.
Among possible confounders of the association between BMI and ALF outcomes, the most notable was age. On average, patients who underwent LT or died were 6.5 years older than those who survived. This would suggest that the increased risk for LT or death may be explained by the increased age of patients with ALF with elevated BMI. As part of this study, a multivariable analysis that adjusted for age amongst other confounders, showed that patients in the high BMI categories were still associated with 2 times the odds for LT or death.
The pathophysiology that explains the relationship between obesity and worsened outcomes in patients with ALF remains unknown. However, we suspect the link between high BMI and worsened ALF outcomes is likely related to the chronic inflammatory state associated with obesity. The increased production of cytokines in obesity contributes to a new inflammatory baseline that may aggravate the very factors that drive ALF[21]. Multiple studies have demonstrated a reduction in the activity of T regulatory cells, increased inflammatory mediators such as interleukin-6 and tumor necrosis factor-α, and reduced adiponectin levels as major dysregulatory factors in obesity[22]. Given the severe inflammatory response observed in ALF, we suspect the immune dysregulation linked with obesity may be a potential factor that predisposes patients with ALF to worse outcomes. This remains an area that is not well understood and requires further elucidation in future studies.
In our study, overweight patients with ALF had 2.20 times the hazards of undergoing LT or dying, whereas obese ALF patients had 2 times the hazards of this outcome in multivariable-adjusted analyses. Interestingly, overweight patients had slightly worse outcomes than obese patients. This relationship has been described before, and it is unclear if there are potential cardioprotective metabolic effects of increased body fat and higher metabolic reserves[23-25]. One possible explanation is that patients with a higher BMI may better tolerate the metabolic changes that occur in ALF, such as insulin resistance, impaired protein metabolism, and liver metabolism[26,27]. It is important to note that the connection between body weight and adverse outcomes in patients with ALF is not straightforward, and further studies are required to identify the underlying mechanisms.
HE is one of the most complex and worrisome complications in patients with ALF[28]. The rise of ammonia observed in HE causes cytotoxic cerebral edema, elevating intracranial pressure and increasing the risk of brain herniation and death[29]. Our study corroborates the morbidity and mortality associated with the feature of ALF. Patients who underwent LT or died were more than twice as likely to have higher grade HE (grade 3 or 4) than those who spontaneously survived. A similar difference in the rates of cerebral edema was seen between the patients who underwent LT or died and those who spontaneously survived. This study found that high-grade HE was significantly more prevalent in overweight and obese patients than in normal BMI patients. The increased risk for advanced HE in patients with a higher BMI in ALF may be partially responsible for the overall worsened outcomes in overweight and obese patients. These findings highlight the importance of neurologic monitoring and minimizing encephalopathy progression by infection prevention and stable cerebral perfusion in these patients.
Acute kidney injury is common in patients with ALF, and substantial renal dysfunction may occur in more than 50% of patients with ALF[30]. It has been associated with an increased risk of mortality in patients with ALF. In our study, overweight and obese patients were noted to have significantly lower eGFR than patients with normal weight. The higher rates of renal dysfunction may reflect the end-organ effects of comorbid diseases such as hypertension and diabetes. Nonetheless, it highlights an additional danger posed to patients who develop ALF who are overweight or obese. RRT is often considered in patients with ALF and may even be used to control hyperammonemia. RRT may be offered to manage acidosis, sodium imbalance, and hyperammonemia, and accelerate metabolic control and temperature[31]. In addition, Slack et al[31] have shown a clear correlation between ammonia clearance and creatinine clearance. Given the increased prevalence of both high-grade HE and renal dysfunction in overweight and obese patients, the use of RRT may play a significant role in these patients[32].
BMI as a metric of metabolic health has been under scrutiny for decades. A 2016 study of nearly 42000 patients in Australia demonstrated that patients were classified as obese by BMI. Still, the waistline circumference had significantly lower morbidity and mortality than counterparts who met both the BMI and waistline classification[33]. There is evidence to suggest that between 10%-30% of patients who are obese are metabolically healthy[34]. In this study, patients were sub-stratified into both overweight and obese categories. For the primary outcome, the risk for all-cause mortality or need for LT was even higher in overweight patients and those with obesity. This result may reflect the inaccuracy of BMI as a true measure of metabolic health, and we believe that, increasingly, future studies will have to use more reliable tools.
The strengths of this study include a long study duration, which allowed us to examine a large number of ALF cases over two decades. We also evaluated overweight and obese patients in separate categories, which allowed us to differentiate certain risks. We had access to detailed and credible baseline data regarding exposure status (objectively measured height and weight) on almost the entire study population during the study period. Our study provides strong evidence that being overweight and obese increases the risk of adverse outcomes in patients with ALF and reinforces previous concerns regarding the adverse health effects of excess weight. Among limitations, this was a single-center, retrospective study. Moreover, it was challenging to identify the extent of underlying liver disease among ALF patients. This was particularly true for patients with nonalcoholic fatty liver disease, as there had not been widespread adoption of nonalcoholic fatty liver disease surveillance over the years during which the data was collected for this study.
CONCLUSION
This study demonstrates that patients with ALF who are overweight or obese are at an increased risk of death or need for LT when adjusting for age, gender, ethnicity, race, etiology of ALF, and comorbid illness. The results emphasize the importance of assessing BMI in patients with ALF to better understand the prognosis. Our findings suggest that BMI should be more heavily considered in the risk assessment of patients with ALF to identify those at higher risk of worse clinical outcomes and that overweight or obese patients should be targeted for more aggressive treatment to prevent complications, particularly as it relates to the increased risk of HE and renal dysfunction.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Medicine, research and experimental
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade A, Grade A, Grade B, Grade B
Novelty: Grade B, Grade B, Grade B, Grade B
Creativity or Innovation: Grade A, Grade A, Grade B, Grade C
Scientific Significance: Grade A, Grade A, Grade B, Grade C
P-Reviewer: Feyissa GD, Assistant Professor, Ethiopia; Wang N, MD, United States S-Editor: Luo ML L-Editor: A P-Editor: Zhao S
Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM; U. S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.Ann Intern Med. 2002;137:947-954.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 1562][Cited by in RCA: 1466][Article Influence: 63.7][Reference Citation Analysis (0)]
Canbay A, Chen SY, Gieseler RK, Malago M, Karliova M, Gerken G, Broelsch CE, Treichel U. Overweight patients are more susceptible for acute liver failure.Hepatogastroenterology. 2005;52:1516-1520.
[PubMed] [DOI]
Leithead JA, Ferguson JW, Bates CM, Davidson JS, Lee A, Bathgate AJ, Hayes PC, Simpson KJ. The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure.Gut. 2009;58:443-449.
[RCA] [PubMed] [DOI] [Full Text][Cited by in Crossref: 105][Cited by in RCA: 86][Article Influence: 5.4][Reference Citation Analysis (0)]
