Pediatric acute liver failure ( PALF) is a clinical condition of liver damage in children with no history of known chronic liver disease who develop an INR (international normalized ratio) of 2.0 or more, or 1.5 or more than do not respond to vitamin K in the presence of encephalopathy.1 Presenting signs in children may include jaundice, abdominal pain, nausea, and malaise.
Encephalopathy is not essential for diagnosis, but may occur simultaneously with the development of multiple organ dysfunction.2 The precise incidence in children is unknown, but is estimated to be between one and ten cases per million people per year at all ages (including adults). ),3 with a mortality of 5 to 10%. Currently, around 20% of children with PALF undergo liver transplantation.4,5
Among all human organs, the liver has the greatest potential to spontaneously regenerate and recover from an acute problem.
The liver continually regenerates as part of homeostasis, but can also regenerate after acute or chronic injury with restoration of size and function through proliferation of parenchymal cells, control of the inflammatory response, and revascularization of damaged areas. However, this restorative capacity could be overwhelmed, leading to multiorgan failure and death in the absence of liver transplantation in a subset of patients.
Although liver transplantation completely revolutionized the poor outlook for patients with PALF, the shortage of donor organs, the scarcity of resources for transplantation worldwide, the risks of major surgery, and the complications of lifelong immunosuppression ( including growth retardation, risk of infection and risk of malignancy6) provide a boost to achieve spontaneous liver regeneration.
The proportion of patients surviving with their native liver intact has increased in recent decades from 15% in 1985–93 (the beginning of the transplant era) to 73% in 2008–12.5 This success could be attributed to a better understanding of the condition management combined with continuous improvements in critical care.
This review, therefore, provides an overview of recent advances in the medical management of pediatric acute liver failure (PALF), with a focus on understanding the pathophysiology of PALF and therefore , how best to sustain multiple organ failures to promote spontaneous regeneration and recovery of the native liver, encompassing current standards of care, novel therapies, and future directives.
| The pathophysiology of PALF |
Two main functions of the liver are the synthesis of vital proteins such as coagulation and detoxification factors. of toxins such as ammonia and other intermediate molecules. Failure of the synthetic or detoxification pathways leads to the common observations, including prolongation of prothrombin time and elevation of serum ammonia. The accumulation of toxins leads to secondary organ dysfunction. Secondary organ dysfunction manifests as cardiovascular instability, renal dysfunction, encephalopathy, adrenal dysfunction, bone marrow dysfunction, and immune paresis.
Historically, the two main contributors to mortality in pediatric acute liver failure (PALF) were cerebral edema leading to elevated intracranial pressure and hepatic encephalopathy, and sepsis with multiple organ failure. Only 40% of patients with PALF develop hepatic encephalopathy.4 The more rapid the development of encephalopathy, the more likely it is that the patient will also develop elevated intracranial pressure.
The first factor identified as a causal link and a treatment point for hepatic encephalopathy was blood ammonia . Ammonia causes cytotoxic brain edema after ammonia and glutamate are converted to glutamine, causing an increase in intracellular osmolarity leading to neuronal edema.7 Ammonia causes further changes in neurotransmitter synthesis and release, function mitochondrial, neuronal oxidative stress and further contributes to the development of hepatic encephalopathy by promoting neuroinflammation through microglia activation.7,8
Hyperammonemia at presentation and persistently high ammonia concentrations predict increased intracranial pressure and mortality. 9.10
However, the incidence of cerebral edema, previously thought to be the most common cause of death in acute liver failure (ALF) and PALF, appears to be decreasing.
A review of 3300 adult patients with ALF showed that the proportion of patients with intracranial hypertension has gradually decreased from 76% in 1984–88 to 20% in 2004–08.11 This reduction reflects improvements in preventive medical care with special attention to neuroprotection by minimizing edema, as well as the use of emergency liver transplantation. Better understanding of the liver as an immune organ and the use of prophylactic antimicrobials are additional factors in minimizing complications and increasing the likelihood of native liver regeneration.
| The liver, an immune organ |
It is vital to understand the role of the immune system in the spread of the many complications of pediatric acute liver failure (PALF), hence the potential role of immunomodulators in improving outcomes. As a gatekeeper between the entrance to the intestines and the systemic circulation, the liver has unique functions and complex immunological properties that allow it to tolerate potentially immunogenic or inflammatory foreign molecules while maintaining immunosurveillance for infectious pathogens.12
The very small diameters of the hepatic sinusoids allow the liver’s resident macrophages, Kupffer cells, to scan, detect and eliminate circulating endotoxins, bacteria and activated immune cells through pathogen recognition receptors, complement receptors and Fc receptors. and prevent collateral cellular damage to the host.13
Kupffer cells respond to the physiological concentration of lipopolysaccharides by producing proinflammatory cytokines IL-6 and tumor necrosis factor alpha (TNF-α) and the anti-inflammatory cytokine IL-10.
| The role of immune-mediated injury in PALF |
Consequently, many of the advances in native liver survival come from a greater understanding that pediatric acute liver failure (PALF) causes critical illness secondary to disruption of this finely balanced immune environment, with a exaggerated and dysfunctional immune system to liver damage. The stages of injury can be divided into primary liver injury, and secondary organ dysfunction or failure.
The primary injury is specific to the cause, as in ALF induced by paracetamol toxicity, whereby the metabolite N-acetyl-p-benzoquinone imine, a highly active oxidant, leads to liver cell death, 14 or In the case of viruses, they cause the direct death of liver cells by damaging the synthesis and detoxification functions of the liver.
Secondary organ dysfunction or failure occurs as a reaction to pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The presence of DAMPs and PAMPs leads to the activation of the innate immune system. After hepatocyte death, monocytes are sent to the liver leading to an expanding population of macrophages, which are influenced by the microenvironment and the presence of pro-inflammatory cytokines in a pro-inflammatory M1 state, leading to elevated numbers of cytokines. proinflammatory cells such as TNF-α, IL-12, and IL-23 and to the expression of major histocompatibility complex class 2 molecules in antigen-presenting cells.15
The overflow of cytokines and vasoactive mediators into the systemic circulation leads to a low systemic level of vascular resistance, low mean arterial pressures, poor target organ perfusion, systemic inflammatory response (SIRS) and, consequently, multi-organ failure. The presence of SIRS is strongly correlated with mortality in ALF.16
The pathogenesis of hepatic encephalopathy and cerebral edema in PALF is also related to the presence of inflammatory cytokines, chemokines, infection, and loss of cerebral autoregulation in addition to the accumulation of toxins such as ammonia.
The presence of inflammatory cytokines modulates cerebral endothelial permeability to neurotoxins, leading to altered cerebral blood flow, and therefore hyperperfusion of the brain.17,18 There is evidence that infection and systemic inflammatory response (SIRS) also are risk factors for encephalopathy (hepatic and brain neuroinflammatory axis).16 Extracorporeal therapies that reduce circulating concentrations of ammonia, neurotoxins, and SIRS mediators could improve outcomes.
| Supportive treatment |
A management plan should be drawn up for each patient in collaboration with the local liver center, with management tailored to any known cause and local facilities. Patients with PALF should be discussed with the liver center or referred early to a liver center with experience in pediatric liver transplantation. Easy and early access to critical care is necessary.
Standard care support should begin at the referring hospital and involve multisystem monitoring to identify early multiorgan dysfunction. Frequent assessment of neurological status (particularly in patients with fluctuating level of consciousness) is vital and these patients should be managed with standard neuroprotective measures.
Acute kidney injury is common; therefore, close monitoring of volume status, creatinine, and urine output is important.
Hypoglycemia is a risk in PALF and continuous glucose infusions of up to 10–15 mg/kg per minute may be required to achieve a target blood sugar concentration of 4–8 mmol/L.2,19 However, solutions Hypotonic dextrose should be used with caution as there is a risk of hyponatremia.
Other supportive measures include maintenance of normothermia, treatment of fever with antipyretics, enteral nutrition with 1 g/kg protein, and protection of the gastric mucosa with proton pump inhibitors or sucralfate. Although patients with acute liver failure often develop coagulopathy with a high INR, spontaneous bleeding is rare, due to a balanced reduction of procoagulant and anticoagulant factors.20
Blood products should only be administered if there is clinical evidence of bleeding or before invasive procedures. Frequent monitoring of INR, kidney function, blood glucose, and blood gases is recommended. Hepatotoxic and nephrotoxic drugs should be avoided if possible. Many centers start broad-spectrum antibiotics early due to the high risk of subsequent bacterial infections.
Indications for endotracheal intubation include the need for airway protection after the development of encephalopathy and in case of respiratory failure (incidence 23.5% in PALF4) in the context of sepsis, pulmonary hemorrhage or fluid overload.2
| Treatment based on cause |
Early extensive cause-based investigations (panel) and initiation of cause-specific treatment will provide the best chance of recovery without transplant. The outcome of PALF depends on the cause, the likelihood of recovery of the native liver, and the potential to benefit from targeted therapies. Additionally, specific causes may have implications for future pregnancies (alloimmune gestational disease) or contraindications for listing for liver transplantation (hemophagocytic lymphohistiocytosis).
A systematic review of the causes of PALF identified 49 causes in studies from high-income countries, and 37 from low- and middle-income countries.21 Causes most likely to survive native liver include acetaminophen toxicity, ischemic hepatitis, and hepatitis A. .5 Causes with a worse prognosis include indeterminate PALF, Wilson’s disease, idiosyncratic drug reactions, and multisystem conditions such as hemophagocytic lymphohistocytosis.5
The ability to identify the cause and instigate cause-specific treatment contributed to improved native liver survival. However, in about 50% of all patients with PALF, the cause remains undetermined. In 2022, an increase in cases of non-EA hepatitis in children was reported, with some progressing to fulminant liver failure.25,26 Although adenovirus was isolated from whole blood, the absence of adenovirus in explants from patients who received liver transplants makes the causal relationship is less likely. Several of these patients were seropositive for antibodies against SARS-CoV-2.
However, despite progress in identifying cause-specific therapies, successful universal management strategies are important for three reasons. First, identification of a cause is often delayed; second, these children are often so critically ill with extrahepatic complications that this precludes timely treatment of the underlying cause; and, thirdly, because a substantial proportion of patients21 develop PALF for an unidentified cause and this is associated with a lower probability of survival of the native liver.
Encouragingly, new technologies, such as next-generation genetic sequencing,27 show promise in reducing the proportion of patients with an unknown cause. However, such techniques must be rapid enough to assist in clinical decision making. Therefore, it is important that effective bridging and supportive therapies are applied early in PALF, while potential causes are evaluated.
| Liver immune response during liver regeneration |
Activation of liver regeneration after injury represents a crucial and necessary step for recovery and survival after PALF and is the goal of high-quality intensive care, including extracorporeal therapies.
The potential of the liver for regeneration is best illustrated by auxiliary liver transplantation; In a review of 45 patients with PALF who had received ancillary transplants, 68∙6% of the 35 survivors were successfully weaned from immunosuppression.28 However, the exact mechanism that organizes liver regeneration and parenchymal plasticity during Liver damage is not fully understood.
The anti-inflammatory response reduces the extent of injury to the liver itself (the compensatory anti-inflammatory response syndrome), and leads to anti-inflammatory, pro-regenerative M2 polarization of macrophages.15 Important processes that are necessary for liver regeneration ( and disruption of which can affect the probability of survival of the native liver) include phagocytosis of dead cells, localization and activation of monocytes, and production of IL-4 by inactivated variant of natural killer T cells.29,30
Hepatocyte proliferation and division represents another crucial step in PALF recovery, and is driven by cytokines. Kupfer cells play an important role in the priming stage of hepatocytes through the secretion of IL-6 and TNF-α. 31 Disruption of any of these stages of hepatocyte regeneration will delay or inhibit the response to liver injury and regeneration.
Although anti-inflammatory mediators help with liver regeneration, the release of these mediators into the systemic circulation can be harmful and lead to deactivation of functional monocytes, dysfunction of systemic immunity and predisposition to infection, and therefore clinical deterioration.32
Bacterial infections have been recorded in up to 80% of adult patients with ALF and fungal infections in 32% of these patients, 33 with infectious complications observed in 25% of patients with PALF in one case series, 34 and sepsis continues to be an important predictor of mortality.16
A better understanding of the phases of liver injury, complexities of regeneration, and associated multiorgan dysfunction has improved native liver survival rates. This increased understanding has inspired research into early targeted therapies, including immunomodulators and extracorporeal therapies.
| Evidence of extracorporeal liver support in PALF? |
This increased understanding of the pathophysiology of PALF has propagated research into extracorporeal therapies such as continuous renal replacement systems (CKRT) and extracorporeal liver support (ECLS), such that some of these devices are now being incorporated into routine management. for PALF. Its role is to provide bridging therapies that support patients until recovery of the native liver or to maintain stability until transplantation.
Although continuous renal replacement (CKRT) is not strictly a liver assist device, it is the most commonly used extracorporeal device in pediatric intensive care units due to staff familiarity. CKRT achieves the clearance of small molecules including ammonia and urea and promotes survival in PALF, with a recent study model that for every 10% decrease in baseline ammonia achieved at 48 h, there was a 50% increase in the probability of survival. 35 CKRT in PALF has unique characteristics compared to its use in critically ill patients without PALF with respect to potential indications, timing of initiation, dosage, and anticoagulation.
Acute kidney injury itself is not uncommon in PALF, occurring in 17-73% of patients, 4,36 and patients with PALF could be considered for CKRT treatment in case of persistent oliguria, fluid overload and metabolic or lactic acidosis. Additionally, clinicians should consider starting continuous renal replacement (CKRT) in PALF in the event of hyperammonemia (ammonia >150 μmol/L)37 and grade 3 or 4 hepatic encephalopathy even in the absence of renal indications. Over the past 10 years, nonrenal indications have constituted the majority of reasons for CKRT initiation in PALF.
Studies also suggested that early initiation of CKRT has potential beneficial effects.35 Studies in 2014 and 2016 in adults and children have suggested that higher doses of CKRT (up to 120 mL/kg per h) may improve ammonia elimination, the degree of hepatic encephalopathy and hemodynamic stability.35,38,39 However, due to the non-selective nature of CKRT membranes, it is important to note that the elimination of beneficial substances (drugs and micronutrients) with increasing doses of anticoagulation is Extremely important in CKRT to reduce clotting and prolong circuit life. This is because, although patients with PALF have altered coagulation parameters, they are clinically prothrombotic, with rebalanced hemostasis due to the reduction of pro-coagulant and anticoagulant proteins and a high generation of potential endogenous thrombin.40
Anticoagulation options include low-dose heparin, careful use of regional citrate anticoagulation (monitoring citrate blockade), antiplatelet agents such as prostacyclin, and thrombin inhibitors such as mesillar nafamostat.
Despite its advantages, CKRT is not effective at removing larger albumin-bound molecules, including bilirubin and cytokines. This finding highlights the potential value of ECLS, which may mimic the detoxification function of the liver to salvage these patients until recovery of the native liver or until successful liver transplantation. A 2020 meta-analysis of ECLS in ALF showed a significant association between ECLS use and reduced hepatic encephalopathy severity and mortality.41
Key ECLS systems include the Molecular Adsorbent Recirculating System (MARS); one-step albumin dialysis; and the separation and adsorption of fractionated plasma (Prometheus).42 In MARS, the patient’s blood is dialyzed against a 20% human albumin solution, which eliminates albumin-bound toxins that could be involved in the spread of extrahepatic complications .
A 2015 meta-analysis and a 2022 multicenter propensity score study found that MARS improved survival and transplant-free survival in adults with ALF.43,44 However, in children, most of the evidence for the use of these systems comes from retrospective observational studies and high-quality randomized studies are expected.
The artificial liver support modality with the greatest evidence of benefit in ALF and PALF is therapeutic plasma exchange.45
Plasma turnover complements both the synthetic and detoxifying functions of the liver. The patient’s plasma (including cytokines, metabolites, and toxins that accumulate in PALF) is removed through a central venous catheter and exchanged with human albumin solution or fresh frozen plasma, or both, before being returned to the venous circulation. The use of fresh frozen plasma as the exchange solution allows replacement of clotting factors.
In 2016, Larsen and colleagues reported a randomized controlled trial in adults with ALF of high-volume plasma exchange compared to conventional therapies, and demonstrated a significant improvement in survival to hospital discharge in the intervention group (58.7% vs 47.8%, risk 0.56 [95% CI 0.36–0.86], p=0.0083).46 Subsequently, the American Society of Apheresis now recommends high-volume plasma exchange as first-line treatment line in ALF, and is also recommended by the European Association for the Study of the Liver.47,48 In pediatrics, a number of retrospective studies and case series described the safety, feasibility, and positive outcomes, including improved survival free of transplants, since the application of plasmapheresis in PALF.45,49–52
As with CKRT, there is increasing evidence that prioritizing early treatment with plasma exchange may be beneficial. The study by Larsen and colleagues showed improvements in particular inflammatory markers for patients who received plasmapheresis within 48 h of admission to the intensive care unit.46
A 2020 study of 63 children receiving plasmapheresis and continuous veno-venous hemodiafiltration for various indications including ALF or acute-on-chronic liver failure, the time to initiation of plasmapheresis, once admitted to the pediatric intensive care unit, was significantly longer longer in the group that did not survive than in the survivors.53 This finding could be due to many factors, but could be related to the observation that in the initial phase of liver injury, macrophages and other components of the immune system response They act in a pro-inflammatory rather than pro-regenerative manner, so extracorporeal therapies at this early stage are more beneficial in limiting SIRS and multiple organ failure.15
Novel extracorporeal immunomodulatory therapies that can potentially target cytokine release and intractable inflammation in PALF include blood purification or cytokine removal modalities, which work on the principle of adsorption as opposed to convection or dialysis in standard CKRT.54
Most artificial ECLS devices tend to eliminate cytokines, which are activated by activated monocytes and neutrophils; however, the source of cytokine production still persists. A new blood purification device is described that works in series with a CKRT circuit and selectively binds activated neutrophils and monocytes in a low-calcium, low-flux environment, thereby inactivating the source of the cytokine storm.55 This could potentially serve as an extracorporeal device in PALF, although its use has not yet been studied in this cohort.
Finally, case reports and case series have described the use of extracorporeal membrane oxygenation (ECMO) in critically ill patients with PALF and refractory hypoxemia who may otherwise have been too unwell to undergo transplantation, being successfully linked to transplantation. .56 The use of ECMO requires careful evaluation of the risks and benefits and the probability of survival after the operation, given the limited supply of grafts.
In the future, hybrid therapies that apply a combination of these techniques could be used. However, considerable resources are required to implement all of these therapies, and most of the evidence in PALF regarding hybrid therapies comes from case reports or case series (e.g., one study described a combination of CKRT, plasma exchange and MARS).
Most extracorporeal devices or machines are first tested in adults and are often not approved for children with low body weight. More research in children is recommended to evaluate these therapies. More work is also needed to understand the best time to initiate extracorporeal therapies, optimal doses, the ideal anticoagulation regimen for CKRT, the value of high-volume plasma exchange, and which replacement fluids are most beneficial and how these therapies can be used. in children at extreme weight.
| Neuromonitoring and neuroprotection |
Aggressive monitoring and early detection of cerebral edema and intracranial hypertension is vital to address morbidity and mortality in PALF.
However, detection is challenging, because in the early stages of liver disease encephalopathy may be difficult to identify by neurological examination in children and may not be present until advanced stages of liver failure.1
Therefore, neuromonitoring in these patients is essential. Direct monitoring of intracranial pressure can only be achieved by inserting an intracranial pressure transducer into the dural space or brain parenchyma to allow timely use of intracranial pressure reduction therapies and pressure optimization. intracranial before transplantation. However, there are potential risks of bleeding and infection, and little data to support better outcomes.
A small retrospective study of 14 pediatric patients showed that placement of intracranial pressure monitoring had a bleeding complication rate of 7% and was associated with a high survival rate despite severe hepatic encephalopathy. In contrast, a multicenter retrospective study of 629 adults demonstrated that the use of intracranial pressure monitoring showed no 21-day mortality benefit in acetaminophen-related ALF and was associated with a worse prognosis in non-paracetamol-related ALF. 57,58 Therefore, the decision to initiate invasive intracranial pressure monitoring must balance the need for constant monitoring in an intubated, comatose patient against the risk of complications.
Progression of hepatic encephalopathy to grade 3 or 4 with elevated ammonia concentrations of more than 200 μmol/L despite CKRT and CT or MRI evidence of cerebral edema, or an electroencephalogram (EEG) showing subclinical seizures or focal, could justify the placement of an intracranial pressure monitor, particularly in patients awaiting transplant.
There is insufficient evidence to support the use of any single non-invasive neuromonitoring method to measure continuous and quantitative cerebral perfusion pressure in PALF.59 A systematic review of non-invasive monitoring devices in PALF described the use of transcranial Dopplers, optic nerve sheath, jugular venous oximetry, near-infrared spectroscopy, and tympanic membrane displacement; no device showed a reliable correlation with intracranial pressure elevation due to study bias and variability. 59 However, in practice, more liver units have moved away from invasive intracranial pressure monitoring and started using noninvasive neuromonitoring methods.
Neuroimaging has its own limitations.
CT findings have variable sensitivity and specificity for increased intracranial pressure.60,61 Conventional MRI techniques also do not reliably show signal abnormalities to indicate the presence of cerebral edema. Diffusion-weighted MRI is the preferred modality as it can differentiate vasogenic from cytotoxic edema (the key cause of edema in PALF).62 In general, the benefits of neuroimaging must be weighed against the potential risks of destabilization or bleeding during transportation.
Continuous EEG monitoring can be very informative for the detection of progression of hepatic encephalopathy and subclinical seizures. In a retrospective observational study of patients with PALF who received continuous EEG monitoring, EEG abnormalities such as slower or epileptiform discharges were observed in 59% of patients, and a nonconvulsive discharge was identified in one of 19 patients. 63 None of these EEG abnormalities were associated with CT or MRI findings of cerebral edema. Spectral EEG (sEEG) analysis is a method for automated analysis of EEG patterns.64 sEEG correlates with outcome and can quantify and classify the degree of hepatic encephalopathy in children with PALF and may be beneficial for younger children .64
The general principles of neuroprotective measures for PALF remain the same as for children with traumatic brain injury. The head should be kept at 30 degrees in the midline, normocarbia should be maintained, hypoxemia, hyponatremia and triggers of increased intracranial pressure should be avoided, and age-dependent cerebral perfusion pressure should be maintained through the use of vasopressors. . Hyperosmolar therapy using hypertonic saline can be used while targeting serum sodium concentrations of 140–150 mmol/L.
Hypertonic saline is preferred to mannitol, which is indicated only in cases of impending hernia. Temperatures above 38°C should be avoided and normothermia should be maintained except in the case of elevated intracranial pressure where a target of 35–36°C is preferred. When these measures fail to control intracranial hypertension, deep sedation and analgesia with thiopental or pentobarbital can be used to suppress cerebral metabolism.
There is no strong evidence base to support the use of nonabsorbable antibiotics or lactulose in PALF; If used, it is important to monitor for ileus, abdominal distension, and electrolyte disturbances. Neuroprotective measures should be applied in addition to monitoring and treating ammonia levels and initiating early extracorporeal liver support.35 If the patient remains hemodynamically unstable, an emergency hepatectomy can be performed to dampen innate immune activation by reducing levels of circulating cytokines. that cause multiple organ dysfunction.65
| New transplant technologies for native liver survival |
> Hepatocyte transplant
Hepatocyte transplantation has been shown to complement the synthetic and detoxifying function of the liver in small animal models with subsequent human application in ALF and PALF.66,67 Case reports and case series of hepatocyte transplantation have been described to date in more than 40 human patients with ALF.68 The transplanted cells supplement the function of the failing liver, and in the same way as with auxiliary transplantation, can support the patient until their native liver regenerates.
The potential advantages of hepatocyte transplants in this setting are considerable. Hepatocytes are derived from donated grafts, which are otherwise unsuitable for transplantation, can be cryopreserved, and thus provide a ready-to-use treatment in PALF, which could avoid a long wait for an appropriate organ.
The cells can be injected into the host intravascularly (via the portal vein or splenic artery) or placed in the intraperitoneal cavity. Ideally, transplanted hepatocytes should be protected from the host’s immune system, and one such solution is to encapsulate the cells in a bioinert material, which also serves as a scaffold, such as an alginate microsphere. This encapsulation allows protection against immune attack while allowing substances to pass freely.
However, there are some limitations to hepatocyte transplantation. Predominantly, there is a relatively restricted availability of good quality hepatocytes. The ability of hepatocytes to survive and function well in the intraperitoneal cavity for several weeks until the native liver recovers is unknown, although encapsulation with alginate microspheres could be useful.67
> Mesenchymal stromal cells
Mesenchymal stromal cells are growing multipotent adherent cells, which have shown promise in the field of cell therapy in ALF. These cells are readily available, have shown benefits in animal models,69 and can be derived from bone marrow, adipose tissue, umbilical cord, placenta and peripheral blood. There are several hypothesized effect mechanisms.
A potential mechanism could be the formation of extracellular vesicles or exosomes derived from these cells. The extensive work in this area suggests that a potentially cell-free form of therapy using exosomes or other small vesicles derived from mesenchymal stromal cells could be a promising therapy in ALF.70
| Research for the future |
There has been much progress over the past 30 years in the medical management of PALF, due to improvements in intensive care aimed at promoting spontaneous liver regeneration. As a priority, randomized controlled trials should be organized in CKRT and plasmapheresis in PALF, as they are the extracorporeal modalities with the greatest evidence of benefit at present. Such studies could help determine the timing, dose, and duration of treatment.
Among other possible avenues of research for the future, increased understanding of the phases of liver injury in PALF has led to the suggestion that biomarkers could be used to define the phase of liver injury. Serum neopterin and soluble CD163 have been proposed as markers of macrophage activation in the early stage of liver damage propagation. 71 Similarly, alpha-fetoprotein has been suggested as a marker of resolution and regeneration of the liver injury phase.15
Biomarkers to identify the phase of liver damage and the state of the patient’s immune system response (pro-inflammatory or pro-regenerative) could help doctors decide when extracorporeal therapies, or cellular therapies, would be most beneficial. beneficial.
The combination of all the recent innovations in management has meant that patients with PALF comprise an increasingly small, but still considerable, subgroup of liver transplant recipients. Designing a personalized prognostic model for PALF to aid transplant listing decisions remains an ongoing research priority, one that can differentiate children according to the following categories: those who would do well or poorly after transplant , those who are unlikely to survive, and those who are likely to survive with native liver with medical management.5
| Conclusions |
Increasing understanding of the pathophysiology of PALF, as well as continued improvements in medicine and intensive care, has led to a greater proportion of patients surviving with native liver.
Most patients who survive now avoid liver transplantation and its associated complications. Innovative and timely intensive care, with cause-specific therapies, neuromonitoring and neuroprotection, and early CKRT have been the main contributors, and the use of specific liver assist therapies, such as plasma exchange, continue to be evaluated promisingly.
Cellular therapies such as hepatocytes and mesenchymal stromal cells have the potential to replace liver transplantation in some patients, while awaiting the discovery of small molecules that could enhance native liver regeneration.
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