Liver transplantation is the only definitive cure for liver cirrhosis, a procedure that is challenging to achieve. In many parts of the world, the acceptability of liver transplantation programs remains limited. The fourth country with the largest population globally, Indonesia currently has only one active liver transplantation center, limited to a living donor.2 Generally, patients with cirrhosis do not survive due to delayed liver transplantation. Bridging therapy to improve the general condition while waiting for liver transplantation becomes a choice to prolong patient’s survival. This study aimed to find a bridging therapy for pediatric cirrhosis patients waiting for liver transplantation.
Granulocyte colony-stimulating factor (G-CSF) has been used and studied broadly for acute-on-chronic liver failure. The benefit of using G-CSF had been proven by many studies.7, 13, 14 However, other randomized control trials showed no significant benefit and revealed that the use of G-CSF for decompensated liver failure had been proven to lack benefit.15, 16 All of the studies mentioned were performed on adult patients. To our knowledge, there was only one study conducted on pediatric patients with acute-on-chronic liver failure that showed a beneficial outcome.17
There is a postulation that G-CSF can beneficially mobilize pluripotent hematopoietic stem cells from the bone marrow to the systemic circulation, which are potentially engrafted into the liver, hence may stimulate the differentiation of cells of the hepatocyte lineage.18
In our study, G-CSF only improved ALT while other liver function tests showed insignificant changes. AST showed an improvement trend, although statistically insignificant. AST and ALT are enzymes related to the transfer of amino acids to ketoglutaric acid, which become markers of hepatocellular injury. Alanine transaminase is a more sensitive marker than aspartate transaminase.19 In our study, patients who received G-CSF possibly had temporary improvement of hepatocellular injury within three months. The improvement of these markers indicates a probability of transient optimization of patients who are awaiting liver transplantation.
In our study, we did not observe any improvement in the PELD score. This parameter has been used as a guide to prioritize organ transplantation among patients on the waiting list at our center and to evaluate their 90-day mortality risk based on liver function and growth status. This result is in opposition with Sharma et al.,17 who demonstrated early survival benefits by an improvement of PELD score.
G-CSF therapy has been believed to enhance liver function and improve fibrosis by inducing the mobilization of autologous bone marrow-derived stem cells, thereby stimulating the release of hepatic progenitor cell activity and hematopoietic stem cells for cell differentiation and restoration of hepatocytes.20 CD34 + is known to be one of the markers of bone marrow stem cell mobilization. Bone marrow stem cells in the peripheral blood have paracrine properties that elicit anti-inflammatory cytokine activity to initiate liver regeneration.21 In our study, we observed that the circulating level of CD34 + stimulated bone marrow cell mobilization in children with decompensated cirrhosis is three times higher in the intervention group. However, it is statistically insignificant (p = 0,66). The finding of CD34 + was similar to those of other studies that treated adult decompensated cirrhosis, and pediatric acute liver failure with G-CSF.17, 20, 22, 23 Other studies mentioned that effective treatment using growth factors requires a healthy baseline of bone marrow function,24 which is not evident in patients with decompensated liver cirrhosis.
The leukocytes and neutrophil counts in the intervention group showed a significant increase, parallel with G-CSF administration. The peak was seen on Day 18. Contrary to the concerns of G-CSF causing potentially fatal leukocytosis, our studies confirmed G-CSF use in children to be safe as no adverse events were recorded during the highest peak of the leukocyte count.
Malnutrition and infection are the main problems of pediatric cirrhosis patients who are waiting for liver transplantation. We evaluated nutritional factors between the groups regarding changes in body weight, height, and mid-arm circumference. Our study did not reveal significant improvements in these nutritional parameters, which contrasts with the previous findings of Verma et al.,23 who demonstrated a substantial increase in MAC.
The reported death in the control group is higher than the intervention, although it is statistically insignificant. The reported deaths of patients from our study were unlikely to be related to G-CSF administration. Two patients died more than ten days following G-CSF administration in the intervention group because of esophageal variceal bleeding. G-CSF reaches its peak concentration in four hours, and the half-life is approximately eight hours.18 The clearance rate of G-CSF is reported to be 0,6 mL/min/KgBW.25 The incidents of death that occurred did not chronologically match with the administration of the treatment, even though this finding needs further evaluation.
Our study revealed that parents of patients reported subjective improvement from the intervention group throughout a certain period of G-CSF administration. Parents reported enhanced quality of sleep, less irritability, and displayed significant mood improvement. The reason for this remains obscure. General improvement of the quality of life is thought to be associated with cytokine levels, which will be evaluated in future studies. This study showed the benefit of G-CSF administration as a bridging therapy. The lack of statistical significance of our results might be due to the small size of our study sample. Further studies will be carried out with more significant study samples and evaluation of cytokines as a parameter for changes in the systemic milieu that potentially stimulate liver regeneration.