The main reason I had to highlight this article is the study period was 42 years!!! (1977-2019, n=236 children). Key findings: “Unique HLA profiles are seen in each subgroup of juvenile AILD: DRB1*03 for AIH-1, DRB1*03 plus DRB1*07 for AIH-2, and DRB1*13 for ASC. DRB1*03 and the A1-B8-DR3 haplotype are disease-predisposing genes for all three subgroups. The influence of HLA class II genes on disease severity is strong, DRB1*03 homozygosity and possession of DRB1*13 being associated to histologically more advanced disease from onset, while DRB1*07 is linked to the least optimal response to immunosuppression”
The “EVIDENCES IV study was a multicenter, randomized, double-blind, placebo-controlled phase 2 study to evaluate the safety and efficacy of saroglitazar.” n=106. Key findings:
For ALT: mean percent change from baseline at week 16 was −25.5% (5.8), −27.7% (5.9), and −45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all)
Compared with placebo, saroglitazar 4 mg improved liver fat content on MRI PDFF (4.1% [5.9] vs. −19.7% [5.6]), adiponectin (−0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment–insulin resistance (−1.3 [1.8] vs. −6.3 [1.7]), and triglycerides (−5.3 mg/dL [10.7] vs. −68.7 mg/dL [10.3]) (P < 0.05 for all)
Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27)
My take: This study shows the potential of one agent for pharmacologic therapy for NAFLD/MAFLD.
“A majority of LT recipients (75%) identified themselves as survivors. Integral to the definition of survivorship was overcoming hardship (including experiences on the waiting list) and the unique experience of being given a “second chance” at life. Motivations to survive included a new chance at life (55%), family (40%), spirituality/faith (30%), and fear of rejection (15%)”
A recent retrospective study (SA Taylor et al. J Pediatr 2020; 219; 89-97) examined patients enrolled in the Society of Pediatric Liver Transplantation (SPLIT) registry, including 547 before 2002 and 1477 after 2002.
Before 2002, patient and graft survival were 81% and 90%.
After 2002, patient and graft survival were 90% and 97%. This improvement is perhaps more impressive as there was evidence of increased disease severity at time of transplantation in the later cohort.
The reasons for these improved outcomes include reduced relisting for transplant, less rejection, less culture-proven infection, fewer reoperations, and less vascular complications (eg. hepatic artery thrombosis and portal vein thrombosis).
Donor age (0-5 months) was a risk factor for graft loss; compared to 1-17 years, the hazard ratio was 5.525. However, in the later group, recipient age of ≤11 months was no longer a risk factor for patient death.
Bacterial infection or sepsis remain the leading cause of death after transplantation.
Due to improvement in survival, the authors note that some have advocated for primary liver transplantation instead of Kasai portoenterostomy. “A report of 626 patients with biliary atresia, of whom 50% underwent primary liver transplantation without Kasai portoenterostomy, demonstrated improved survival.” (JAMA Surg 2019; 154: 26-32)
My take: This information about survival is certainly encouraging –though many challenges remain, especially to improve comorbidities.
Projected outcomes with split LT (28% of 2007-2018 cohort) are similar to outcomes with whole LT
My take: While projections can overestimate and underestimate survival rates, the clear trend has been a remarkable improvement in long-term outcomes. This published data can provide current expectations when counseling families, though with ongoing improvements in management/development of tolerance, the hope is for even better outcomes.
A recent article and editorial (DH Leung et al. Liver Transpl 2016; 22: 1584-92 & editorial by JC Bucuvalas, S Feng 1466-68) provides a better picture of long-term survival for pediatric patients facing the prospect of liver transplantation.
Among patients less than 2 years in the UNOS data sharing registry, there were 994 with biliary atresia (BA) and 221 with other chronic liver disease.
The key data:
The overall postlisting mortality was 19.6% with most of this due to wait-list mortality (12.4%). Posttransplant mortality was 8%.
The non-BA patients had a higher wait-list mortality compared with BA patients: 23.9% vs 9.8%
Risk factors for mortality included lack of exception points (HR 5.8), and initial creatinine >0.5. In addition, BA patients without prior abdominal surgery (eg Kasai) was higher (risk was 1.6 times greater) than in those with BA with presumed Kasai.
Reviewing the article, it is not clear to me if patients removed the waitlist (eg due to sepsis and other causes) are included in this analysis. Thus, the true postlisting mortality may be higher than 20% if all needy individuals are considered.
From the editorial -other aspects:
Only one-third of pediatric recipients have optimal outcomes which would include normal LFTs, maintained on monotherapy immunosuppression, normal growth, and free of comorbidity. In addition, even among those with ‘optimal’ outcomes, many would still have histologic injury.
The “incidence of nonstandard exception requests has increased 5-fold and is now used on behalf of 44% of wait-listed children.” Importantly, children with public insurance were less likely to have petitions for exception PELD points.
My take (with help from editorial): To improve outcomes, this means starting with candidate selection and working on each step: traversing wait-list management and optimizing posttransplant care.