In this study of the UNOS database, we sought to examine the effects of pre-LT functional status on post-LT outcomes, stratified by etiology of ESLD. We found patients with MASH cirrhosis to be impacted by any impairments in functional status prior to LT, with respect to graft failure (some or total assistance versus no assistance) and mortality (total assistance versus no assistance). Patients with hepatitis C, AID, and ALD had higher all-cause mortality associated with a requirement of total assistance. Notably, MELD scores were significantly higher in all ESLD etiology cohorts requiring total assistance, though functional status in hepatitis B and hereditary disorders was not associated with increased mortality. Interestingly, those with hereditary etiologies of ESLD requiring some assistance were relatively protected from all-cause mortality. To the best of our knowledge, this study represents the first large-scale investigation of such factors on post-LT outcomes.
The effects of impaired functional status have been well documented to correlate with poor outcomes post-LT. In a retrospective study using the UNOS database, Thuluvath et al demonstrated that low and intermediate KPS scores (analogous to total and some assist in this study, respectively) were associated with a higher incidence of graft failure and mortality after LT8. They further found that low KPS before LT, which did not improve within 3-12 months post-LT, was also linked to poor survival. Dolgin et al, in an UNOS-based study focusing on 1-year outcomes, similarly demonstrated higher rates of all-cause mortality and graft failure in low and intermediate KPS5. In a single-center study in Korea, frailty was assessed with the Short Physical Performance Battery (SPPB), and scores lower than 10 were found to be correlated with higher post-LT mortality compared to scores over 109. These findings persisted after controlling for MELD scores. Overall, the literature has demonstrated that poor functional status is associated with worsened survival after LT. However, we hypothesized that the etiology of ESLD would limit the generalizability of KPS for post-LT outcomes. The findings of our study support this hypothesis, revealing distinct associations in mortality and graft failure in patients with poor functional status depending on their specific underlying disease.
We have found patients with MASH requiring total assistance in this study to have the worst overall outcomes amongst the ESLD etiologies, given a higher risk for both all-cause mortality and graft failure. This finding may be partly explained by the higher prevalence of comorbidities in these patients, including diabetes mellitus, hypertension, and coronary artery disease12–13. These comorbidities play a significant role in contributing to functional status impairments themselves and are not reversible with LT alone14. In a study comparing frailty in MASH cirrhosis versus alcoholic cirrhosis, patients with MASH exhibited similar rates of frailty compared to those with alcoholic cirrhosis15. However, frailty was found to have a stronger association with all-cause mortality in MASH compared to alcoholic cirrhosis. The authors of that study explain that their findings likely reflect the impact of the above-mentioned comorbidities of MASH patients, where higher mortality rates may occur as a synergistic product of frailty and disease burden. Therefore, when comparing MASH to other etiologies of ESLD that carry fewer comorbidities, such as Hepatitis B or AID, it is plausible that we are observing a similar impact of pre-LT functional status on MASH patient outcomes post-LT.
Poor functional status in ALD had a modest increase in rates of all-cause mortality in our study, with no differences seen in graft failure rates. In a single-center study assessing frailty and sarcopenia in MASH and ALD patients, a lower prevalence of frailty was found in the ALD cohort, despite a higher prevalence of sarcopenia16. The study also found no association between frailty and length of stay for hospitalization, LT waitlist mortality, or delisting. The higher rates of sarcopenia in ALD is well-documented and likely due to direct toxic effects from alcohol17–19. While patients with ALD tend to have fewer metabolic comorbidities compared to MASH, we suspect that comorbid chronic pancreatitis or alcohol-induced cardiomyopathy may contribute to the observed effects of poor functional status on mortality post-LT.
Patients with chronic hepatitis C tend to have fewer metabolic comorbidities and a lower prevalence of frailty compared to alcoholic cirrhosis and MASH20. Despite this, there remained a higher rate of all-cause mortality in LT-recipients with hepatitis C requiring total assistance. The causes of death were diverse and included cardiac, renal, infectious etiologies, and graft rejection. This contrasts with the findings of the functionally impaired hepatitis B cohort of this study. One possible explanation for this finding is the relatively high prevalence of psychiatric disorders in patients with hepatitis C21. A single center retrospective study found that psychiatric diagnoses prior to LT were associated with worsened all-cause mortality and graft survival22. The authors of that study hypothesized that psychiatric symptoms may worsen following LT due to the patient’s need for adjusting to a new body and lifestyle. Additionally, they noted that the transplant team typically takes over a patient’s medications in the early post-surgical period, which may potentially delay appropriate dose titration of psychotropic medications that would typically be managed by psychiatry or primary care. These issues may theoretically be compounded in a patient who is unable to care for themself. Further studies are ultimately needed to investigate these findings and explore disease-specific aspects of hepatitis C that may interact with functional status.
Patients with hereditary disorders did not show statistically significant findings in terms of all-cause mortality or post- LT complications associated with total assistance. We observed a lower rate of mortality in patients who required some assistance compared to those who required no assistance. While this is an interesting finding, further investigation is warranted through a dedicated study that stratifies patients based on specific hereditary diseases such as Wilson’s Disease, hemochromatosis, and others.
In the AID cohort, we observed a higher rate of mortality associated with total assistance, but no significant association was found between functional impairment and the risk of recurrent disease or graft failure. Autoimmune hepatitis has a high rate of recurrence after LT, as reported in a large multicenter study with recurrence rates of 20% at 5 years and 31% at 10 years23. The authors of that study found younger age at transplant, immunosuppression with mycophenolate mofetil, donor-recipient sex mismatch, and high serum IgG levels to be associated with risk of recurrence. Similarly, primary biliary cholangitis and primary sclerosing cholangitis have high rates of recurrence following LT 24, 25. While we initially hypothesized that poor functional status would pose challenges in immunosuppression following LT, our study did not find a significant association with graft failure, disease recurrence, or infectious complications. Our results may reflect other disease-specific comorbidities, such as low bone mineral density and nutrient deficiency in the cholestatic diseases, that are interacting with KPS score.
Our study has several limitations that should be acknowledged. The retrospective design inherently introduces the possibility of selection bias and confounding variables. Although the use of a national database provides robust, multi-center data, it does limit our ability to analyze the specific practices at different centers. Additionally, we lack information on different interventions that may have been attempted on functionally debilitated individuals, as well as a comprehensive understanding of post-LT follow-up and medication management, as previously theorized with respect to psychiatric comorbidities in hepatitis C. Regarding our intervention tool, while the KPS score is a well validated instrument in the field of oncology, its applicability in cirrhosis lacks substantial evidence. Furthermore, the grouping of the 11-point scale into categories of no assistance, some assistance, and total assistance may result in some loss of granularity.