Cirrhotic Cardiomyopathy in Children With Biliary Atresia: A New Objective Parameter to Predict Morbidity and Mortality on the Wait List—and Beyond!
Authors: Elizabeth B. Rand
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. See article on page 1206 Pediatric wait‐list morbidity and mortality is high overall but unpredictable in individual cases, resulting in poor stratification and general dissatisfaction with our current system of liver allocation in infants and children. The scope of this problem is broad, but has harshest consequences on our youngest candidates who suffer disproportionately from biliary atresia (BA). There is ample evidence that young children and infants are uniquely disadvantaged in liver graft allocation. To determine waitlist mortality in infants, Leung et al. analyzed United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network data 4/2003 to 3/2013 for infants younger than 2 years old with chronic liver disease.1 Of the 1,215 listings, 994 (82%) had biliary atresia; the infants experienced 12.5% wait‐list mortality. The authors concluded that the incidence of death suggested that Pediatric End‐Stage Liver Disease (PELD) scores may be inadequate to stratify organ allocation. Wait‐list mortality for young infants has improved but lags that of adults of all ages.2 Measured in deaths per 100 wait‐years, mortality for infants younger than 1 year of age has declined from over 40 in 2006 to 12.5 in 2016; however, mortality for adults fell from 12.5 to 10 over that period. The young infants' death rate per 100 wait‐years is closest to that of adults over 65 years old (17.5 in 2006, 12.5 in 2016). In a study of children younger than 5 years of age with BA on the Eurotransplant wait list 2001‐2014, van der Doef et al. found 90% of wait‐list mortality occurred in infants less than 1 year old at listing.3 A striking 21% of infants listed before 6 months of age with a European Model for End‐Stage Liver Disease (MELD) greater than 20 died before transplant. These studies underscore the uniquely poor wait‐list survival for the youngest infants. The PELD/MELD system attempts to rectify the disconnect between urgency and calculated scores using automatic (standard) and narrative exception scores. The automatic system works well for children with specific disorders such as certain metabolic diseases, malignancy, and acute liver failure, who are assigned predetermined scores or status 1A/1B. A transplant physician who assesses that the calculated PELD/MELD score does not accurately reflect urgency for a patient may submit a narrative summary (nonstandard exception request or NSER) explaining the discrepancy to request additional points. This system is in widespread use, most notably for young infants. Hsu et al. analyzed UNOS data regarding NSERs in pediatric liver transplant candidates, demonstrating a striking 5‐fold increase in NSERS from 2002 to 2013, and documented that an approved NSER increased the likelihood of transplant.4 Although one's NSER status increased the likelihood of transplant (hazard ratio for transplant 2.9 with confidence interval 2.62‐3.21; P < 0.01), there were disturbing disparities in the use of NSER by geography, race, and insurance status. Braun and Perito et al. examined Scientific Registry of Transplant Recipients data from 2009‐2014, analyzing outcomes for 2,581 wait‐listed children (ages 0‐18) by NSER status: A total of 1,134 (44%) had an NSER submitted; of those, 1,060 (93%) were approved.5 Those with NSER status were transplanted at a higher rate (954 of 1,060, 90.2%) than those without (1,104 of 1,447, 76.3%). In a subsequent analysis of NSER narratives, Perito et al.6 analyzed the content of 1,272 NSERs. Multiple variables in clinical content were examined; however, ultimately "in multivariable analysis, the likelihood of NSER approval was associated with age at listing and region—but none of the NSER justifications." From these studies we can conclude that infants have disproportionately increased death rates awaiting transplant, that the PELD system is inadequate for stratification, and that although the use of NSERs ameliorates the inadequacies, it does so in a haphazard way that may increase disparities in health care access. These problems apply disproportionately for the diagnosis of BA, which is the single most common indication for liver transplant in infants. In the absence of improved organ availability through increased deceased and live donation, new objective parameters for the PELD scoring system for infants are urgently needed. In their paper "Clinical consequences of cardiomyopathy in children with biliary atresia requiring liver transplantation," Gorgis et al. present a likely candidate for risk stratification.7 Cirrhotic cardiomyopathy (CCM) is characterized in adults by cardiac dysfunction (systolic and/or diastolic), left ventricular hypertrophy, and/or prolonged QT interval corrected for the heart rate.8 Adult diagnostic clinical criteria were proposed in 2005 from the World Gastroenterology Congress, including diastolic and systolic dysfunction with reduced response to stress and electrophysiologic changes. Found in 50% of adult liver recipients, CCM is associated with a wide range of cardiac and extracardiac adverse events, including mortality. Although CCM is known to reverse after liver transplant, there is no known medical therapy. Bile acids have been shown to produce CCM in elegant mouse models,9 an intriguing factor considering the marked cholestasis characteristic of infants with BA. In their single‐center, retrospective study of CCM in BA (BA‐CCM), Gorgis et al. analyzed 2‐dimensional (2D) echocardiographic findings in 69 infants who had studies performed before liver transplant. The current study started with CCM parameters defined in their earlier report,10 but through further statistical analysis the authors refined the parameters to optimize objective, reliable criteria for BA‐CCM using left ventricular mass index (LVMI) and relative wall thickness. The authors examined primary outcomes of mortality and a composite of serious adverse events (CSAE) that included all forms of acute graft failure, severe hemorrhage, tracheostomy, and renal replacement therapy at discharge. They showed that LVMI had striking correlation with the primary outcomes. Using the newly formulated definition, 34 of 69 subjects had BA‐CCM at listing; BA‐CCM regressed after transplant in survivors as in adults. Overall, 11 of 69 subjects died, 4 while awaiting liver transplant and 7 following transplant; remarkably all 11 of these infants had BA‐CCM, whereas there were no deaths among 35 subjects without CCM. Similarly, 20 children who experienced any CSAE all had BA‐CCM, whereas none of the children without CCM experienced any CSAE. Notably, the LVMI was higher in subjects who died on the wait list than for those who reached transplant; LVMI was also higher in subjects with multiple CSAEs compared with those with a single CSAE. The association of the presence versus absence of LVMI with mortality and CSAEs is a powerful tool, but the additional finding that the severity of LVMI correlates with early death (while awaiting and after transplant) and with the number of adverse events could transform allocation schema for BA patients. These correlations also have great importance for directing preoperative, intraoperative, and postoperative management in these high‐risk patients. If the findings reported are found in other forms of cirrhosis and age groups, incorporation of CCM into allocation algorithms could revolutionize liver distribution and outcomes. In addition, anicteric children with BA (with or without cirrhosis) may be pruritic and have elevated bile acid levels despite normal bilirubin—another group of patients to explore with respect to mechanism and risk. Echocardiography is routinely done at the time of listing; however, the prognostic importance of CCM shown in this study raises the question of whether 2D echocardiography should be performed as part of ongoing routine assessment in BA. Finally, the correlation of increased severity of BA‐CCM with higher morbidity and mortality following liver transplant will raise important/unsettling questions regarding the utility of transplant in advanced cases. Given the need for improved objective parameters to stratify recipients (of all ages) for liver allocation, the work by Gorgis et al. opens an important new area for further investigation.