Utilizing Macrosteatotic Allografts for Nonalcoholic Steatohepatitis Recipients

The pressing need for available organs is growing as the field of liver transplantation evolves and responds with expanding criteria and utilization of marginal allografts for certain recipients.⁽¹⁾ Over the past 15 years, patient and graft outcomes of marginal allografts including donation after circulatory death, advanced age donors, and macrosteatotic allograft have improved.⁽²⁾ Altshuler and colleagues contribute further to clinically useful insights into increased organ availability utilizing macrosteatotic allografts in recipients with nonalcoholic steatohepatitis (NASH) cirrhosis.⁽¹⁾

Early transplantation experience was highly selective; over time, the criteria for recipients as well as allograft selection have been expanded. Alongside this, the population prevalence of nonalcoholic fatty liver disease (NAFLD) has increased, now affecting nearly 25% of the global population. This epidemiologic pattern is accompanied by an increase in NASH, a more advanced subtype of NAFLD, which has a multifactorial etiology with complex interplay between genetic, environmental, and lifestyle factors contributing to disease progression to cirrhosis.⁽³⁾ Further progression of this disease spectrum results in end-stage liver cirrhosis or hepatocellular carcinoma, which necessitates consideration for transplantation for 1 in 5 patients with NASH.⁽⁴⁾ This epidemiologic reality impacts both recipient and donor pools.

Altshuler and colleagues used the Organ Procurement and Transplantation Network database to compare NASH and non-NASH transplantation recipients (January 1, 2004-June 12, 2020), categorized into 3 relevant strata of liver allograft steatosis (<5%, 5%–29%, ≥30%) with clinically appropriate milestones including patient and graft survival at 30 days, 1 year, 5 years, and 10 years.⁽¹⁾ Consistent with usual clinical care, there is variability in the selection of individual grafts and recipient characteristics by center or individual surgeons which cannot be captured and is an inherent limitation of this study design. The authors used propensity score matching to try to minimize cohort discrepancies and adjusted for the proportion of patients with NASH by identifying patients with cryptogenic cirrhosis having NASH-associated medical comorbid conditions.

Historically, allografts with ≥30% fat are associated with an increased risk of primary nonfunction.⁽²⁾ The authors concluded that recipients with NASH have similar clinical outcomes using ≥30% macrosteatotic allografts compared with patients with non-NASH cirrhosis. Within the NASH cohort, use of a ≥30% macrosteatotic allograft is associated with slightly decreased 30-day and 1-year graft and patient survival; long-term outcomes for graft and patient survival were comparable.⁽¹⁾ These results are in line with existing literature suggesting that severely steatotic grafts are associated with somewhat higher rates of primary nonfunction and early allograft dysfunction.⁽⁵⁾ Once the early risk of posttransplantation allograft dysfunction is mitigated, long-term success is often dependent on recipient selection. As highlighted by the authors and others, while NASH transplant candidates have good graft and patient outcomes as compared with other subgroups of cirrhosis, only a relatively small proportion of patients with NASH cirrhosis become potential transplant recipients because of associated medical comorbidities.⁽⁶⁾

While no grafts were lost to disease recurrence in the NASH cohort at 10 years, the role of the underlying metabolic and genetic milieu in both the donor and recipient may provide insights into transplant outcomes for these subsets of patients. Emerging research is advancing our understanding of the genetic variables that affect the progression of NASH to cirrhosis, facilitating better insights into donor and recipient risk factors. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a nonsynonymous single-nucleotide polymorphism (C->G) that is associated with hepatic steatosis, steatohepatitis, fibrosis, and cirrhosis.⁽⁴⁾ Obesity enhances the effects of this genetic variant on the development of NASH. Existing data suggest that the underlying PNPLA3 genotype of either the donor or the recipient may impact long-term fat accumulation within the allograft and potential disease recurrence.^(7,8) Other genetic markers, such as HSD17B13, may offer protection for recurrent disease in some patients.⁽⁴⁾

The impact of additional thoughtful research that considers the full spectrum of donor and recipient characteristics will continue to increase appropriate utilization of available organs for medically optimized recipients. Given the limited feasibility of randomized allocation trials in liver transplantation, studies such as this will be needed to inform clinical care. Further studies are needed to determine whether early therapeutic treatment using antisteatotic strategies may help further expand the utilization of macrosteatotic allografts by lowering primary nonfunction rates. Another gap in knowledge is whether the assessment of donor allograft steatosis can be done noninvasively without requiring a liver biopsy assessment and if serum lipidomic testing can be informative in this setting. This manuscript offers data in support of utilizing macrosteatotic allografts in carefully selected patients and encourages centers to consider expansion of allograft and recipient criteria.

Abbreviations:

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

PNPLA3

patatin-like phospholipase domain-containing protein 3