Poor Access to Liver Transplantation and Survival of Children With Acute Liver Failure, Acute-on-chronic Liver Failure or Chronic Liver Disease

We describe the survival of children with acute liver failure (ALF), chronic liver disease (CLD), or acute-on-chronic liver failure (ACLF) with poor access to liver transplantation (LT). A retrospective cohort study of 42 patients <18 years of age was conducted in the Hospital Civil de Guadalajara “Dr. Juan I. Menchaca”. The median age was 76 months; 57.1% were female, 40.5% presented with ALF, 35.7% with CLD, and 23.8% with ACLF. Also, 38.1% (16/42) presented liver disease of unknown etiology. Death occurred in 45.2%; 14.3% were transferred to another hospital, and none received LT. Mortality in ALF, CLD, and ACLF was 76%, 0%, and 60%, respectively. In the survival analysis, within the first 20 months after diagnosis, the mortality rate was greater than 50% with ALF. The importance of having referral programs that perform liver transplantation is highlighted by the poor prognosis of the patients, despite conservative treatment.


INTRODUCTION
Acute Liver Failure (ALF) in children is a rapidly progressive condition with high morbidity and mortality (1). The most prevalent causes are infections, drug toxicity, or in association with immunological or metabolic diseases; however, a high percentage of cases have an undetermined etiology (2).
Chronic hepatitis is characterized by elevated transaminase levels for more than 3 months, and its main causes are infections, anatomical anomalies, autoimmune and metabolic diseases, and nonalcoholic steatohepatitis (3)(4)(5). An exception to this classification is infection by hepatitis B virus since it is classified as chronic when elevated transaminase levels and HBsAg persist for more than 6 months. In events where liver damage persists, the risk of developing liver fibrosis or cirrhosis is increased, with a higher occurrence of serious complications such as portal hypertension, ascites, bleeding from esophageal varices, hepatic encephalopathy, electrolyte imbalance, or hepatorenal syndrome (4,5).
No consistent definition of acute-on-chronic liver failure (ACLF) and the events that precipitate it are not clear. However, according to the Asian Pacific Association for the Study of the Liver, ACLF is an acute hepatic insult manifesting as jaundice (serum bilirubin ≥5 mg/dL) and coagulopathy (international normalized ratio [INR] ≥1.5 or prothrombin activity <40%) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease (CLD)/ cirrhosis (6,7).
Although management consists of treating the specific etiology and its complications, in some cases the only intervention that significantly improves patient survival is liver transplantation (LT) (2). In developing countries, access to healthcare centers with the capacity of performing a liver transplant is limited. The objective of this study was to describe the survival of children with ALF, CLD, or ACLF in an environment where children have limited access to LT.

METHODS
A retrospective cohort study was conducted at the Hospital Civil de Guadalajara "Dr. Juan I. Menchaca" (HCGJIM), in Guadalajara, Mexico. The institution is a tertiary referral center that includes the specialty of pediatric gastroenterology and an intensive care unit and is capable of providing dialysis. However, there is no hepatology service, and LT is not currently provided.
Charts of patients <18 years of age who were hospitalized and diagnosed with ALF, CLD, or ACLF between 2015 and 2020 in the pediatric gastroenterology service were reviewed. The diagnostic protocol in first-admission patients with ALF, CLD, or ACLF includes blood cytometry, liver enzyme and function tests, blood gas tests, serological tests for HIV, cytomegalovirus, Ebstein Barr virus, Herpes Simplex and hepatitis A, B, and C; serum levels of transferrin and ferritin, serum lipids, metabolic screen; hepatobiliary

What Is Known
• It is important to have healthcare systems with the capacity of providing liver transplantation for children diagnosed with acute liver failure, chronic or acute-on-chronic liver disease.

What Is New
• In a hospital located in western Mexico, survival in children with acute or acute-on-chronic liver failure was less than 25% during the first 2 years after diagnosis.
ultrasound; antinuclear, antismooth muscle, and liver and kidney microsomal type 1 antibodies (anti-LKM-1). Serum ammonia, ceruloplasmin, and urinary excretion of copper are conducted in outside laboratories. Liver biopsies are guided by ultrasound and are performed if the patient is hemodynamically stable. The sequence of studies is determined by the treating physician based on the main diagnostic consideration. The patient's general condition at the time of the study was recorded and included their survival rate, transfers to other hospitals, or occurrence of death. The age of the patient when ALF, CLD, or ACLF was diagnosed, the date of their last visit, demographic characteristics, clinical variables, nutritional status, complications, and biochemical parameters of their last visit were recorded.

DEFINITIONS
ALF: biochemical evidence of acute liver damage and coagulopathy not corrected by vitamin K, with prothrombin time (PT) of 15-19.9 seconds or an INR of 1.5-1.9 if accompanied by encephalopathy. In events without encephalopathy and without known liver disease, the biochemical evidence of liver damage and the presence of PT >20 seconds or INR >2 were classified as ALF (8).
CLD: increased transaminase levels that persist ≥3 months or in the case of hepatitis B virus infection, persistence of HBsAg and elevated transaminase levels ≥6 months (9).
Cirrhosis: hepatic fibrosis with distortion of the duct architecture and compression of the vasculature and biliary structures (5). The diagnosis was established by histology (Scheuer Scale, F4).

STATISTICAL ANALYSIS
Frequencies and percentages were estimated for qualitative variables and median with interquartile ranges (IQR) for quantitative variables. The chi-square test or Fisher's exact test was used as hypothesis tests for proportions and the Mann-Whitney U or Kruskal-Wallis test for median comparisons.
Survival rate was estimated with 95% confidence intervals (95% CI) and Kaplan-Meier survival curves were performed with the log-rank test for the hypothesis contrast in the comparison of subgroups. A P value <0.05 was considered statistically significant.
We analyzed the discriminatory capacity of the Pediatric Chronic Liver Failure Sequential Organ Failure Assessment Score (pCLIF-SOFA) to predict death using the area under the curve (AUC) (11); an acceptable value of ≥0.70 was considered. IBM SPSS (Statistical Package for the Social Sciences) Statistics version 25 was used.
The pediatric end-stage liver disease/model for end-stage liver disease (PELD/MELD ) are prognostic scales useful for assessing liver function but do not assess other organs and systems, in this study, we analyzed the accuracy of the scores to predict mortality in patients with liver disease; PELD risk score was calculated for patients younger than 12 years old and MELD score for older than 12 years old. It used an online calculator from the Mayo Clinic (12,13) (https:// www.mayoclinic.org/medical-professionals/transplant-medicine/ calculators/meld-model/itt-20434705, https://www.mdcalc.com/ calc/87/peld-score-pediatric-end-stage-liver-disease-younger-12).
The project was approved by the Ethics and Research Committee of the HCGJIM, with registration number 0494/21. The median values of serum laboratory tests at the last visit were: total bilirubin 8.  Table 1 shows the values depending on the syndrome in which each patient was classified.
For the survival analysis, Kaplan-Meier curves were estimated for the total sample and as a function of the type of liver disease. We observed that in the first 20 months after the diagnosis of ALF, CLD, or ACLF a mortality rate greater than 50% was reached, being significantly higher in patients with ALF (Fig. 1). Six patients were referred to a hospital with a liver transplant unit, but none received LT, 1 continues under surveillance without achieving transplantation criteria, 2 died, and 3 were lost to follow-up.
We observed that the median in the PELD/MELD scores was 18 (IQR, 25.6) during their last assessment. The median of the scale for patients with ALF, CLD, or ACLF was 20, 0, and 28.45, respectively, showing a significant difference (P < 0.001). This instrument had an AUC of 0.84 (95% CI, 0.72-0.96) for the prediction of death, with a cutoff point ≥13, the scale showed sensitivity and specificity of 100% and 69.6%.
We also evaluated the pCLIF-SOFA, an instrument that has been validated in children that analyzes liver function in addition to respiratory, cardiovascular, renal, hematologic, and neurologic function. The maximum score is 24 and the higher the severity, the higher the score. When comparing the median scale scores between those who survived and those who died, we identified significant differences (4 vs. 13, P ≤ 0.001). The AUC was 0.97, 95% CI, 0.91-1.0. With a cutoff point of ≥10, the instrument presented sensitivity and specificity of 100% and 91.3%, while the negative and positive predictive values were 100% and 90.5% (Fig. 2).

DISCUSSION
Our cohort revealed an overall mortality rate of 45.2% in children with ALF, CLD, or ACLF, however, it occurred more rapidly compared with other studies. One-year survival in children with ALF was less than 20%, a situation that highlights the importance of implementing healthcare centers with access to LT.
Bitar et al (14) identified the cause in 94% of children with early-onset and nontransplanted ALF, and found that the 1-year Liver Transplantation and Survival of Children survival rate was 50%. Infants with galactosemia, tyrosinemia, and panhypopituitarism had the best prognosis. Different series have described survival with native liver of 24% to 60% (15). Our study found that children with ALF and ACLF presented with higher mortality. In these groups, an undetermined etiology was also more frequent, which suggests that not having an accurate diagnosis could influence the children's prognosis. Other authors have reported that between 5% and 54% of children with ALF have an undetermined origin, while in chronic hepatobiliary disorders, the predominant causes are biliary atresia and storage diseases (4). In the HCGJIM's patients, the majority of etiologies of ALF, CLD, or ACLF were undetermined (16/42), metabolic or autoimmune disease (12/42), and anatomical causes (7/42).
Lone et al (15) described that patients with unknown etiologies had worse outcomes. Alam et al (6) described poor survival at 28 days in children with ACLF with a mortality index of 25% and observed a worse prognosis in patients with unknown etiology.
We observed that ACLF had a 1-year survival rate of less than 25% and the clinical presentation of these patients included ascites (90%), hepatic encephalopathy (50%), and gastrointestinal bleeding (40%). In patients with CLD who are candidates for LT, it is important to refer the patient in a timely manner to care centers where this resource is available because the complications of the disease invariably progress to decompensation and death.