EDITORIAL

How Much Is Too Much?Timothy M. McCashland, MDUniversity of Nebraska Medical Center, Omaha, NE

Received November 9, 2010; accepted December 1, 2010.

See Article on Page 129

Ascites is the most common complication of portalhypertension associated with cirrhosis. The developmentof ascites is a harbinger of a poor prognosis and impairedquality of life. The mortality rate is approximately 50% 2years after the development of ascites.1 Independentfactors associated with ascites-related mortality includehyponatremia, increased serum creatinine levels, lowarterial pressure, and low urine sodium levels.1,2 Amongthese variables, only the serum creatinine level is part ofthe formulation of the Model for End-Stage Liver Disease(MELD), which predicts 90-day mortality for patientsawaiting liver transplantation. Therefore, the develop-ment of a risk prediction model to further improve riskprofiling, especially for patients on the transplant waitinglist, remains a top priority. Unfortunately, ascites is asubjective clinical marker that is difficult (if not impos-sible) to incorporate into defined, objective survivalmodels. Heuman et al.3 previously demonstrated thathyponatremia and persistent ascites are MELD-indepen-dent predictors of early mortality and are especiallyimportant in patients with MELD scores lower than 21.

In the field of liver transplantation, the greatestchallenge continues to be the shortage of donororgans. The landscape has morphed and nowincludes the risk of using extended criteria donorsbecause this might be the only opportunity or chancefor patients. Therefore, developing an accurate, objec-tive survival model that is fair and totally inclusive inassociation with donor allocation may be as difficultas total health care reform! In this issue of LiverTransplantation, Somsouk et al.4 address the daunt-ing question of ascites and mortality risk whilepatients wait for liver transplantation.

Using the Organ Procurement and TransplantationNetwork database, Somsouk et al.4 examined all newregistrations for liver transplantation from 2005 to2007 with follow-up to 90 days. Patients who wereremoved from the waiting list and died later were alsoconsidered to have died while they were waiting. Asciteswas entered into the database by transplant coordina-tors at their centers at the time of registration and wasclassified as none, small, or moderate; 57% were notedto have small ascites, and 25% were noted to havemoderate ascites. The study group consisted of 18,124patients, and 1498 (8.3%) died. The mortality rate wasgreater in patients with moderate ascites versus thosewith no or small ascites (15.4% versus 4.1% and 15.4%versus 6.6%, respectively). With adjustments for theMELD score, the risk of death was doubled for patientswith moderate ascites. Furthermore, in comparison withMELD and Model for End-Stage Liver Disease plus serumsodium (MELD-Na) scores, moderate ascites offered addi-tional risk discrimination for predicting 90-day mortality.Somsouk et al. found that the mortality rate was higherin patients with moderate ascites, and the effect wasmore prominent with MELD scores lower than 21 (equalto 4.7 MELD units) and with MELD-Na scores lower than21 (equal to 3.5 MELD-Na units). Lastly, the risk of deathin high-demand US allocation regions for patients withMELD scores lower than 21 and moderate ascites was8% higher than the risk in lower demand regions.

There are several key points to this article.4 Thesedata confirm previous studies reporting that moderateascites is an independent risk factor associated withdeath, especially in patients with low MELD scores.Moreover, the authors quantify what this risk is withrespect to risk-adjusted MELD scores. Lastly, patientswith moderate ascites in high-demand regions havehigher wait-list mortality.

Abbreviations: DRI, donor risk index; MELD, Model for End-Stage Liver Disease; MELD-Na, Model for End-Stage Liver Diseaseplus serum sodium.

Address reprint requests to Timothy M. McCashland, MD, University of Nebraska Medical Center, 983285 NHS University, Omaha, NE68198-3285. Telephone: 402-559-8859; FAX: 402-559-3434; E-mail: tmccashland@unmc.edu

DOI 10.1002/lt.22241View this article online at wileyonlinelibrary.com.LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

LIVER TRANSPLANTATION 17:102-103, 2011

VC 2011 American Association for the Study of Liver Diseases.

There are limitations to this study.4 Moderate ascitesis defined as a subjective variable in this study andremains ill defined by the International Ascites Club(moderate ascites evident by moderate symmetricaldistension of the abdomen).5 The data were entered bya liver transplant coordinator, most likely after a reviewof a clinical assessment note or an ultrasound report,and this leaves interpretation bias on the table. Thedata were registration data at the time of listing fortransplantation; therefore, it is unknown how manypatients, if any, had progressive or difficult-to-controlascites during their wait-list follow-up, and informationabout diuretic use and dosage was not available. How-ever, because 25% of the patients were considered tohave moderate ascites, it is very unlikely that most ofthese patients had refractory ascites (the median sur-vival time was approximately 6 months). The causes ofdeath for the patients were not available. I wonderwhether most of the deaths were related to complica-tions of ascites, such as spontaneous bacterial perito-nitis and the development of hepatorenal syndrome.Lastly, even if patients are told that their risk of deathis higher than the MELD-calculated risk because ofmoderate ascites, the use of extended criteria donorsin this particular group in high-demand regions mayor may not increase their chances for transplantation.A review of United Network for Organ Sharing regionalvariation by the donor risk index (DRI) for 2006-2008showed uniformity in all regions except region 9(1.37 in region 1, 1.54 in region 2, 1.50 in region 3,1.37 in region 4, 1.37 in region 5, 1.37 in region 6,1.48 in region 7, 1.43 in region 8, 1.86 in region 9,1.45 in region 10, and 1.42 in region 11; S. Feng, per-sonal communication, 2010). Therefore, patients inhigh-demand regions do not seem to be gainingincreased access to high-DRI livers in comparison withpatients in low-risk regions.

Why do patients with MELD scores lower than 21and moderate ascites have a higher risk of death? Ibelieve that this is most likely related to the high por-tal pressure in these patients, which is not reflectedin the MELD score. Investigators from Spain havenoted that the hepatic venous pressure gradient is anindependent variable predicting death: each 1 mm Hgincrease in the hepatic venous pressure gradient pre-dicts a 3% increase in the risk of death!6 A majorbreakthrough would be the development of a noninva-sive, objective variable that reliably reflects the portalpressure and could be incorporated into survival/allo-cation models. As noted by the authors,4 further stud-ies are needed to define an objective definition of mod-erate ascites. In addition, the authors do not proposethe replacement of the current MELD allocation sys-tem with a subjective variable of ascites; the elimina-tion of subjective variables was one of the intents ofthe MELD system in the first place.

Multiple reports have noted an inverse correlationbetween the DRI and the MELD score.7-8 Therefore, onepremise of this study seems to be in line with currentclinical practice: high-DRI donors (expanded criteria

donors) may be appropriate for patients with moderateascites and low MELD scores. In contrast, others believethat high-DRI livers yield better survival benefits in can-didates with MELD scores greater than 20.9

How do we use this information? Yes, I believe thatpatients with moderate or difficult-to-control ascites(especially those with hyponatremia) have a higher riskof death not reflected by the MELD score. With thecurrent US-based MELD allocation system, the onlychoice is to apply for exception points to increase theMELD score to reflect a patient’s true mortality risk.Currently, 30% of patients on the waiting list receiveMELD exception points; however, exception points arerarely granted for ascites. This study estimates anappropriate MELD increase and might increase theprobability of acceptance for exception points. I do notbelieve that the transplant community wants to goback to including subjective criteria as part of the allo-cation formula. Informing patients of their true risk ofdeath on the waiting list and the inherent risk ofpotential donors (eg, high-DRI donors) should bestandard practice for any transplant program.

REFERENCES

1. Guevara M, Cardenas A, Uriz J, Gines P. Prognosis inpatients with cirrhosis and ascites. In: Gines P, Arroyo V,Rodes J, Schrier RW, eds. Ascites and Renal Dysfunctionin Liver Disease: Pathogenesis, Diagnosis and Treatment.Malden, MA: Blackwell; 2005:260-270.

2. Llach J, Gines P, Arroyo V, Rimola A, Tito L, BadalamentiS, et al. Prognostic value of arterial pressure, endogenousvasoactive systems and renal function in cirrhotic patientsadmitted to the hospital for treatment of ascites. Gastro-enterology 1988;94:482-487.

3. Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stra-vitz RT, Sanyal AJ, et al. Persistent ascites and low serumsodium identify patients with cirrhosis and low MELDscores who are at high risk for early death. Hepatology2004;40:802-810.

4. Somsouk M, Kornfield R, Vittinghoff E, Inadomi JM, Big-gins SW. Moderate ascites identifies patients with lowMELD awaiting liver transplantation with high mortalityrisk. Liver Transpl 2011;17:129-136.

5. Moore KP, Wong F, Gines P, Bernardi M, Ochs A, SalernoF, et al. The management of ascites in cirrhosis: report onthe consensus conference of the International AscitesClub. Hepatology 2003;38:258-266.

6. Ripoll C, Banares R, Rincon D, Catalina MV, Lo Iacono O,Salcedo M, et al. Influence of hepatic venous pressure gra-dient on the prediction of survival of patients with cirrho-sis in the MELD era. Hepatology 2005;42:793-801.

7. Volk ML, Lok AS, Pelletier SJ, Ubel PA, Hayward RA.Impact of the Model for End-Stage Liver Disease allocationpolicy on the use of high-risk organs for liver transplanta-tion. Gastroenterology 2008;135:1568-1574.

8. Maluf DG, Edwards EB, Kauffman HM. Utilization ofextended donor criteria liver allograft: is the elevated riskof failure independent of the Model for End-Stage LiverDisease score of the recipient? Transplantation 2006;82:1653-1657.

9. Schaubel DE, Sima CS, Goodrich NP, Feng S, Merion RM.The survival benefit of deceased donor liver transplanta-tion as a function of candidate disease severity and donorquality. Am J Transplant 2008;8:419-425.

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