Disparities in liver transplantation in the post–model for end-stage liver disease era: Are we there yet?^†

Moylan CA, Brady CW, Johnson JL, Smith AD, Tuttle-Newhall JE, Muir AJ. Disparities in liver transplantation before and after introduction of the MELD score. JAMA 2008;300:2371-2378. (Copyright © 2008 American Medical Association. All rights reserved. Reprinted with permission.)

Abstract

In February 2002, the allocation system for liver transplantation became based on the Model for End-Stage Liver Disease (MELD) score. Before MELD, black patients were more likely to die or become too sick to undergo liver transplantation compared with white patients. Little information exists regarding sex and access to liver transplantation. OBJECTIVE: To determine the association between race, sex, and liver transplantation following introduction of the MELD system. DESIGN, SETTING, AND PATIENTS: A retrospective cohort of black and white patients (> or = 18 years) registered on the United Network for Organ Sharing liver transplantation waiting list between January 1, 1996, and December 31, 2000 (pre-MELD cohort, n = 21 895) and between February 28, 2002, and March 31, 2006 (post-MELD cohort, n = 23 793). MAIN OUTCOME MEASURES: Association between race, sex, and receipt of a liver transplant. Separate multivariable analyses evaluated cohorts within each period to identify predictors of time to death and the odds of dying or receiving liver transplantation within 3 years of listing. Patients with hepatocellular carcinoma were analyzed separately. RESULTS: Black patients were younger (mean [SD], 49.2 [10.7] vs 52.4 [9.2] years; P < .001) and sicker (MELD score at listing: median [interquartile range], 16 [12-22] vs 14 [11-19]; P < .001) than white patients on the waiting list for both periods. In the pre-MELD cohort, black patients were more likely to die or become too sick for liver transplantation than white patients (27.0% vs 21.7%) within 3 years of registering on the waiting list (odds ratio [OR], 1.51; 95% confidence interval (CI), 1.15-1.98; P = .003). In the post-MELD cohort, black race was no longer associated with increased likelihood of death or becoming too sick for liver transplantation (26.5% vs 22.0%, respectively; OR, 0.96; 95% CI, 0.74-1.26; P = .76). Black patients were also less likely to receive a liver transplant than white patients within 3 years of registering on the waiting list pre-MELD (61.6% vs 66.9%; OR, 0.75; 95% CI, 0.59-0.97; P = .03), whereas post-MELD, race was no longer significantly associated with receipt of a liver transplant (47.5% vs 45.5%, respectively; OR, 1.04; 95% CI, 0.84-1.28; P = .75). Women were more likely than men to die or become too sick for liver transplantation post-MELD (23.7% vs 21.4%; OR, 1.30; 95% CI, 1.08-1.47; P = .003) vs pre-MELD (22.4% vs 21.9%; OR, 1.08; 95% CI, 0.91-1.26; P = .37). Similarly, women were less likely than men to receive a liver transplant within 3 years both pre-MELD (64.8% vs 67.6%; OR, 0.80; 95% CI, 0.70-0.92; P = .002) and post-MELD (39.9% vs 48.7%; OR, 0.70; 95% CI, 0.62-0.79; P < .001). CONCLUSION: Following introduction of the MELD score to the liver transplantation allocation system, race was no longer associated with receipt of a liver transplant or death on the waiting list, but disparities based on sex remain.

Comment

Liver transplantation (LT) is the only life-saving treatment option available for many patients with end-stage liver disease (ESLD). There were 6650 LT procedures performed in the United States in 2006, and this number continues to slowly rise each year. The number of patients on the LT waiting list has surpassed the finite resource of available donor livers. Equitable allocation of this scarce resource to patients with ESLD remains a difficult task. Prior to 2002, allocation of donor livers to patients on the transplant waiting list in the United States was based on urgency, which was assessed with the Child-Turcotte-Pugh (CTP) score, and accumulated time on the list. This system was flawed because it gave an unfair advantage to patients placed on the list when they were relatively well, while penalizing patients who, for whatever reason, were not placed on the list until later in their clinical course. When CTP class was adopted as the arbiter of urgency in transplant candidates on the transplant list, it had not been subjected to prospective validation as an accurate predictor of mortality in patients awaiting transplantation. It is, at best, a blunt instrument to gauge urgency. It incorporates two subjective variables, ascites and encephalopathy, and leads to just three broad classes. CTP class C, for example, may encompass patients with widely disparate short-term urgency.

A new allocation system, based on the Model for End-Stage Liver Disease (MELD) score, was implemented in February 2002 to allocate donor livers more fairly to patients in need. The MELD score, first reported in 2000, had been initially validated as a predictor of mortality risk in patients with portal hypertensive complications undergoing transjugular intrahepatic portosystemic shunt.1 It is calculated by an equation that uses 3 clinical laboratory measurements (creatinine, total bilirubin, and international normalized ratio). Thus, the MELD score objectively measures liver disease severity and has been validated as an excellent predictor of 3-month mortality risk across a broad spectrum of liver diseases. Donor livers are allocated to patients wait-listed with the highest MELD score, or highest mortality risk, at that time. An arbitrary provision of MELD scores to patients not well served by its estimate of urgency, such as patients with hepatocellular cancer (HCC), was adopted from the start.

Since its introduction, the MELD score has proven to be an unexpectedly robust measure of short-term mortality in a wide range of acute and chronic liver diseases and of surgical outcome in non–LT surgery in patients with cirrhosis.2 Although further modifications may improve on this record, the MELD allocation system has been a great success.3, 4 Part of the reason for the success is the dynamic way in which it has allowed adjustment of allocation of deceased donor livers with the goal of creating the most equitable scheme, whether through the provision of exception scores for HCC patients or by inhibition of allocation of donor livers to patients with low urgency.5 One such modification, the adoption of a regional sharing protocol whenever there is no local recipient with a MELD score of 15 or greater, has all but eliminated the use of donor livers in low-urgency patients.5 At the same time, the MELD system has resulted in a reduction of waitlist times, particularly in patients with HCC, and has contributed to the reduction of waitlist mortality without reducing posttransplant survival.

Racial and ethnic disparities represent a serious problem in the current healthcare system in the United States and have been documented for various disease outcomes. Several studies have shown that race and ethnicity affect access to LT. In the retrospective study presented in JAMA, Moylan and colleagues6 used a national (United Network for Organ Sharing) database to ask the question whether the introduction of MELD has had a beneficial effect on the fairness of the LT allocation system according to the race or sex of the recipient. Prior to the implementation of the MELD system, African Americans were less likely to receive LT than whites, had a higher mortality rate on the LT waiting list, and were sicker at the time of transplantation. Many factors are thought to be responsible for this, including socioeconomic status (limited financial resources and lack of insurance), poorer quality of healthcare, and limited and often delayed referral of black patients to transplant centers, which results in a later stage and often greater severity of disease at the time of listing. This study reports a reduction in the waitlist mortality for African Americans patients, who were just as likely as whites to die on the LT waiting list and just as likely as whites to receive LT within 3 years of listing. However, the elimination of racial disparity in LT does not translate into equal access to this life-saving treatment. This is reflected in the study by the findings of higher MELD scores at listing and shorter listing periods for blacks, which suggest delayed referral and greater disease severity at the time of listing. Furthermore, the African American population represents a smaller proportion of total LT recipients, despite having a greater burden of chronic liver disease, particularly hepatitis C infection, than the general population.7

Although Moylan et al.6 refer to their study as an investigation into “access to liver transplantation,” it would be more accurately described as an investigation into racial and gender bias in the allocation of donor livers to persons placed on the waiting list. Their methodology, which starts with the population placed on the list, does not allow consideration of events prior to listing. This population does not inform us about unmet need for LT among blacks that have no access to transplant medicine or transplant centers, nor does it consider biases in the transplant centers, which might discriminate on the basis of race or sex. We know that such biases exist in relation to diagnosis, alcoholic liver disease being a prime example, and it is naïve to assume that the transplant selection process is free of all other biases.8 In addition, their study does not address events after the transplant. Recently, Merion and colleagues9 used the concept of survival benefit, which encompasses the interval from placement on the list to last follow-up, including follow-up after transplant. The conclusions of the present study would be stronger were the benefits in more equitable waiting times and transplant rates experienced by African Americans accompanied by equity in survival benefit. In other words, if the better transplant rates are accompanied by worse posttransplant survival, the African American population might be the recipient of a Pyrrhic victory.

A disappointing conclusion from Moylan et al.'s analysis6 is that women with ESLD who do not carry a diagnosis of HCC are at a disadvantage in the allocation of deceased donor livers, even in the post-MELD era. The authors speculate that this is a result of inherent limitations in the calculation of the MELD score as well as differences in the etiologies of ESLD between the sexes. The inclusion of serum creatinine in the current allocation system has increased the prioritization of candidates with renal impairment. However, the accuracy of using serum creatinine, the most sensitive parameter in the MELD equation, as a surrogate of renal function is compromised because it is affected by factors such as the patient's age, sex, race, lean muscle mass, and medications. Cholongitas et al.10 demonstrated that women have a lower glomerular filtration rate (GFR) and thus worse renal function than men for the same serum creatinine value, and this is not accounted for in the MELD score. Correcting the creatinine in females to reflect the same GFR as that in their male counterparts showed that the current scoring system may give significantly lower MELD scores, despite similar renal function, thus placing females at a lower priority for LT in comparison with males. Also, women are more likely than men to suffer from chronic cholestatic and autoimmune liver diseases, all of which are less likely than hepatitis C to lead to renal impairment. In fact, this study did show that women listed under the MELD allocation system without a diagnosis of HCC had a significantly higher risk of death on the waiting list or becoming too ill for LT within 3 years of listing than men. On the basis of these findings, MELD score adjustment in females to reflect their true GFR may be a reasonable strategy to ensure fair allocation of donor livers and merits further investigation.

Moylan and colleagues6 report regional variation in the delivery of LT both before and after the implementation of MELD. As other studies have previously shown, geographic disparities in LT continue to occur despite the adoption of MELD, so patients with equal MELD scores have very different waiting times prior to receiving a deceased donor liver and different chances of undergoing LT at times according to where they live.11 Geographic disparities in the fair allocation of donor livers likely translate into higher waitlist mortality rates, especially in blacks, who tend to be concentrated in large urban centers with longer waitlist times. This population is less able to afford to travel to transplant centers operating in localities with shorter lists or lower MELD scores.

In summary, since its introduction, the MELD-based system of allocation has met many of the original goals. It is an objective system that places the emphasis on urgency, and it has removed the waiting time as a determinative factor. The “sharing at 15” rule has all but eliminated transplantation of healthy recipients. The present report shows that MELD also provides an equal chance to those African Americans who are able to gain access to the waiting list. That said, racial and ethnic differences in access to LT remain and will become remedied only after there are fundamental changes in healthcare policy and delivery in the United States. The present study has brought to our attention significant gender disparities related to LT that will require adjustment of the MELD score to reflect the renal function in women and ensure equitable prioritization on the waiting list. Inequality in access to LT based on geography continues to be a challenging problem for patients and the transplant community at large.