Acute liver failure in children: They really are not just small adults: Acute liver failure in children: The first 348 patients in the Pediatric Acute Liver Failure Study Group. Squires RH Jr, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz, et al. J Pediatr 2006;148:652-658.

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The Pediatric Acute Liver Failure (PALF) study group was formed in 1999 to develop a database to facilitate an improved understanding of the pathogenesis, treatment, and outcomes of acute liver failure (ALF) in children. The study group designed a prospective multicenter case study to collect data on children 0-18 years of age with ALF. Study sites totaled 24 acute pediatric centers, 21 in the United States, 1 in Canada, and 2 in the United Kingdom. This report from the PALF study group summarizes the group's findings on short-term outcomes for children with ALF and discusses prognostic factors for the course of pediatric ALF. This research nicely balances the study in adults conducted by the Acute Liver Failure Study Group, reviewed in “Liver Transplantation Worldwide” earlier this year.¹

The etiology of pediatric ALF includes infections, toxins, metabolic disorders, infiltrative diseases, acute hepatitis, ischemia, and irradiation damage; however, the great majority of causes of ALF in children are undetermined.² The authors, as well as others, point out that the major difference between pediatric and adult ALF concerns hepatic encephalopathy (HE), which reveals itself differently and is more difficult to diagnosis in children than in adults. Additionally, HE is not necessary for the diagnosis of pediatric ALF, as it is for the diagnosis of adult ALF.^2,3 Patients were entered into the PALF study group database on the basis of (1) having no known evidence of chronic liver disease, (2) biochemical evidence of acute liver injury, and (3) hepatic-based coagulopathy defined as a prothrombin time ≥15 seconds or international normalized ratio ≥1.5 not corrected by vitamin K in the presence of clinical HE, or a prothrombin time ≥20 seconds or international normalized ratio ≥2 regardless of the presence or absence of clinical HE.

This report from the PALF study group included 348 children enrolled from December 1999 to December 2004. The investigators noted that children under 3 years of age accounted for 36.5% (127/348) of their study patients. Acetaminophen toxicity was rare for children under 3, but it was a leading cause of ALF for those older than 3. HE was more frequent in non-acetaminophen toxicity in older children. Younger age groups were more likely to develop ascites, require ventilatory support, and require red blood cell and plasma infusions than the older groups. As noted in earlier studies, the etiology of ALF was not identified in 49% of all patients, and also not identified in 54% of children under 3. In contrast to adults, only 3 of the pediatric study patients had acute hepatitis A virus infection. One patient had hepatitis C, and no patients had hepatitis B identified as the cause of liver failure. Spontaneous recovery was greatest in children with acetaminophen toxicity (45/48; 94%) as compared to recovery from ALF from indeterminate causes (73/169; 43%). Patients who did not develop HE were more likely to recover than those who did develop HE (78.9% vs. 40.1%). Logistic regression analysis to predict death or the need for liver transplantation identified total bilirubin of ≥5 mg/dL, international normalized ratio ≥2.55, and HE as risk factors if present at time of admission.

As pointed out by the authors, the overall nature of ALF in children is different from that in adults. The large number of indeterminate causes of ALF in children necessitates further study on this subject. We look forward to more reports from the PALF study group.

Abbreviations

PALF, Pediatric Acute Liver Failure; ALF, acute liver failure; HE, hepatic encephalopathy; CyA, ; TIPS, transjugular intrahepatic portal systemic shunts; DSRS, distal splenorenal shunts; DCs, dendritic cells.

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COMMENTS

The practice of using all possible donor livers has led to the designations “standard liver donors” vs. “marginal livers” and the current term “extended criteria donors.”¹At the World Transplant Congress 2006, held July 22-27, 2006, in Boston, MA, over 50 abstracts were presented on current practices with extended criteria donors or marginal livers. This is no surprise in view of the tremendous world shortage of liver donors, demanding that all possible livers be successfully transplanted.

From the early days of liver transplantation, it has been obvious that characteristics of the donor liver influence the graft's postoperative function.² Several strategies had been tried for testing the metabolic function of donor livers to assess donor liver suitability or postoperative liver function. The majority of these attempts were unsuccessful. Most often, donor liver metabolic function was evaluated with the monoethylglycinexylidide test, and overall conclusions were that this test was not sufficient to predict posttransplantation liver function.^3,4

This paper by Casale et al. highlights the pharmacokinetics of marginal vs. standard livers. Are the pharmacokinetics different among transplant recipients who receive standard livers and those who receive marginal livers? The study criteria for a marginal liver was donor age >65 and/or microsteatosis >20%. Microemulsion (CyA; Neoral) was administered with azathioprine and tapered steroids. No tacrolimus was given. Study blood samples were collected at day 3 and day 10 following orthotopic liver transplantation and at 0, 15, 30, 45, 60, 75, and 90 minutes and 1, 2, 3, 4, 6, 8, and 12 hours after administration of microemulsion CyA. The authors found different kinetic profiles of microemulsion CyA between recipients of standard and marginal liver grafts. Recipients of marginal livers had a lower measure of drug exposure at day 10 posttransplantation than the recipients of standard livers. The authors were concerned that the lower CyA levels observed in the marginal livers might lead to potential higher rejection episodes, as are sometimes seen in marginal liver reports. The authors concluded that drug exposure measurement at 2 hours post-CyA administration is best for standard livers but is not sufficient for marginal livers, due to delayed or poor absorption and disposition in those livers. On the basis of their observations, the authors recommend sampling between 4 and 6 hours as a better measure of CyA levels in recipients of marginal livers.

As increasing numbers of marginal livers are transplanted into increasing numbers of patients, attention should be paid not only to donor criteria, but also to maximizing survival with particular livers after transplantation. Once a marginal liver is transplanted, consideration needs to be given to the immunosuppression protocol best suited to that liver. Comparing the pharmacokinetics of CyA between standard and marginal livers is an excellent step in that direction. Further studies on the pharmacokinetics of other commonly used medications such as tacrolimus are needed to assess differences between standard and marginal livers. Use of specific protocols for varying liver types is another way to save more lives using an expanded donor pool.

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COMMENTS

For patients who experience refractory variceal bleeding while awaiting liver transplantation, it has become routine practice to place transjugular intrahepatic portal systemic shunts (TIPS) to decompress portal hypertension. Supportive evidence for using TIPS in these patients has been the significant reduction in ascites at 3 months after the procedure, and the reported 20% cumulative recurrence rate of variceal bleeding at one year following TIPS.¹ The drawback is that TIPS requires repeated interventions. Additionally, only 48% of the patients in 1 study group were primarily patent at a mean of 168 days; however, repeated intervention is not a great disadvantage to those waiting for transplantation since they are followed closely at a liver transplant center.^1–3

Questions still remain on the use of TIPS compared to other therapies in patients with Child-Turcotte-Pugh Class A and B cirrhosis. Several comparative studies have been published.^2,4–7 A report by Helton et al. in 2001 concluded that good-risk patients with portal hypertensive bleeding should have a surgical shunt.⁶ As recently as 2006, Elwood et al. reported that distal splenorenal shunts (DSRS) are safe and effective for the treatment of recurrent variceal hemorrhage in Child-Turcotte-Pugh Class A and B cirrhotic patients when TIPS has failed.⁷

In the present report, Henderson et al. describe their prospective randomized clinical trial on 140 patients with Child-Turcotte-Pugh Class A and B cirrhosis and refractory variceal bleeding. Study patients were randomized into 2 groups, 1 receiving TIPS and the other receiving DSRS. Study follow-up was conducted for 2-8 years (mean, 46 ± 26 months) for primary end points of variceal bleeding and encephalopathy and secondary end points of death, ascites, thrombosis and stenosis, liver function, need for transplant, quality of life, and cost. The results revealed no significant differences between the 2 procedures with respect to rebleeding rate or development of encephalopathy. Additionally, there were no significant differences in survival, development of ascites, need for retransplantation, quality of life, or cost. The only differences between the 2 groups were in reintervention, stenosis, and thrombosis. Of the patients who received TIPS, 82% required repeat dilatation to maintain patency compared to only 11% following DSRS.

The authors rightly point out that the particular therapy selected for a given patient should be based on local expertise and the ability to maintain follow-up. All patients who receive either TIPS or DSRS should be followed for the development of hepatocellular carcinoma. If a patient from either group develops ascites or encephalopathy, it is an indication that the patient needs liver transplantation.

Prospective randomized controlled trials such as this study should direct the future of liver care. All kinds of studies today are performed, and each kind has its own value. But a prospective, randomized trial helps answer—not just subjectively, but also directly—how we should choose our therapy.

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COMMENTS

Cross-communication between innate and adaptive immunity is a fascinating topic. Innate immunity is mediated mainly by macrophages, dendritic cells, and natural killer cells, and the complement system destroys most microorganisms within hours, leaving no lasting protective immunity. Adaptive immunity, mediated by antigen-specific lymphocytes, generates specific immunological memory and provides long-lasting protection. With increasing knowledge of the interactions between these 2 immunities, the boundaries have become blurred. There are now known links between the immunities, but it is still not completely understood how innate immunity controls the initiation of adaptive immunity or if the feedback mechanisms of adaptive immunity influence innate immunity. One example is how interferon-α and -β induce dendritic cells (DCs) to stimulate CD4⁺ T cells to produce interferon-γ and interleukin-10.1 Natural killer T cells have been reported to stimulate DCs to produce CD4⁺ effector and CD8⁺ cytolytic T lymphocytes.2 Other examples exist.3, 4

The complement system in its regulation of adaptive immunity was reviewed by Carroll in 2004.5 Complement is activated by 3 different pathways: classical, lectin, and alternate. All 3 have the common step of activation of the central component, C3. Curiosity was piqued about the role of C3 in rejection when it was found that C3-deficient mouse kidneys, when transplanted into allogeneic wild-type mice, survived >100 days compared to only 14 days for C3-sufficient mouse kidneys.6

The paper by Peng et al. expands on another link between innate and adaptive immunity and gives insight on why the C3-deficient mouse kidneys survived. The authors reviewed that although the liver is the primary site for the synthesis of C3, other cells also have the capacity to synthesize C3. Using a mouse model with C3^−/− and C3^+/+ mice strains, it was shown that DCs can synthesize C3. C3-producing DCs stimulated CD4⁺ T cells to respond by producing the Th1 cytokine pattern, releasing interferon-γ and interleukin-2. C3-deficient DCs produced interleukin-10 in large amounts. Finally, C3-deficient DCs produced a delay in allograft rejection when compared to C3-producing DCs. The study concluded that the endogenous production of C3 by DCs is responsible for enhancement of potent antigen presenting cells.

Studies such as this one have been going on for only a few years; nevertheless, it is now an acknowledged fact that the innate and adaptive immunities interact. This interaction is inevitable in organ transplantation, since all transplanted organs are first stimulated by innate immunity (due to unavoidable tissue damage from ischemic reperfusion) and then affected by adaptive immunity after transplantation. Skill in controlling the interaction to tip the balance from organ rejection to transplant tolerance will be the reward of continued research.