The Model For End-Stage Liver Disease
The Model For End-Stage Liver Disease
The Model for End-stage Liver Disease (MELD) was initially created to predict survival in
patients with complications of portal hypertension undergoing elective placement of tran-
sjugular intrahepatic portosystemic shunts. The MELD which uses only objective variables
was validated subsequently as an accurate predictor of survival among different populations
of patients with advanced liver disease. The major use of the MELD score has been in
allocation of organs for liver transplantation. However, the MELD score has also been shown
to predict survival in patients with cirrhosis who have infections, variceal bleeding, as well as
in patients with fulminant hepatic failure and alcoholic hepatitis. MELD may be used in
selection of patients for surgery other than liver transplantation and in determining optimal
treatment for patients with hepatocellular carcinoma who are not candidates for liver trans-
plantation. Despite the many advantages of the MELD score, there are approximately 15%-
20% of patients whose survival cannot be accurately predicted by the MELD score. It is
possible that the addition of variables that are better determinants of liver and renal function
may improve the predictive accuracy of the model. Efforts at further refinement and valida-
tion of the MELD score will continue. (HEPATOLOGY 2007;45:797-805.)
F
ebruary 27, 2007 marked the fifth anniversary of liver conditions, its strengths and limitation, and current
the Model for End-Stage Liver Disease (MELD) and future efforts to refine and improve it further.
becoming the standard by which priorities in do-
nor liver allocation were determined. Since the score was Creation and Validation of MELD
first derived in a relatively small number of patients un- MELD was initially created to predict survival follow-
dergoing the transjugular intrahepatic portosystemic ing elective placement of TIPS.1 The model was subse-
shunts (TIPS) procedure, it has been validated in many quently validated as a predictor of survival in several
different populations of patients with liver disease. cohorts of patients with varying levels of liver disease se-
Within a relatively short period of time, MELD became a verity (e.g., hospitalized and ambulatory patients), as well
common metric by which the severity of liver disease as patients of geographically and temporally diverse ori-
could be accurately described. gin.2 The survival model was initially termed the “Mayo
In this paper, we review the initial development and End-Stage Liver Disease” or “MELD” model to acknowl-
validation of the MELD score, its application in organ edge the affiliation of the investigators who created the
allocation and management of patients with a variety of model. During discussions leading to the establishment of
MELD as the basis for prioritization of organs for liver
transplantation,3,4 we changed the name to “Model for
Abbreviations: ASA, American Society of Anesthesiologists; CTP, hild-Turcotte- End-Stage Liver Disease” which maintained the acronym
Pugh; HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Dis-
“MELD”, but removed the association with a particular
ease; SBP, spontaneous bacterial peritonitis; SOFA, Sequential Organ Failure;
TIPS, transjugular intrahepatic portosystemic shunts; UNOS, United Network of institution, a process that was thought would lead to
Organ Sharing. wider acceptance of the model.
From the Advanced Liver Disease Study Group, Miles and Shirley Fiterman MELD incorporates 3 widely available laboratory vari-
Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN.
Supported by grants from the National Institute of Diabetes, Digestive and ables including the international normalized ratio (INR),
Kidney Diseases (DK-34238 and DK-61617). serum creatinine, and serum bilirubin. The original
Address correspondence to: Patrick S. Kamath, M.D., Professor of Medicine, mathematical formula for MELD is: MELD ⫽ 9.57 ⫻
Mayo Clinic College of Medicine, Consultant in Gastroenterology and Hepatology,
Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, 200 First
loge(creatinine) ⫹ 3.78 ⫻ Loge(total bilirubin) ⫹ 11.2 ⫻
Street SW, Rochester, MN 55905. E-mail: [email protected]; fax: Loge(INR) ⫹ 6.43.
507-284-0538. The score can be calculated on handheld computing
Copyright © 2007 by the American Association for the Study of Liver Diseases.
devices, and is available at www.mayoclinic.org/gi-rst/
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.21563 mayomodel5.html. When the model was initially created
Potential conflict of interest: Nothing to report. the etiology of cirrhosis was also included. In the TIPS
797
798 KAMATH AND KIM HEPATOLOGY, March 2007
population, the etiology of liver disease was important in cirrhosis according to risk of mortality, replacing the then
that patients with alcoholic liver disease and cholestatic current CTP-based organ allocation system.3,4,8 In apply-
liver disease undergoing TIPS procedures had a better ing MELD to organ allocation, UNOS made several
survival than those patients with viral hepatitis-related or changes to how the MELD score was to be calculated. The
other causes of cirrhosis. lower limit for serum creatinine, serum bilirubin, and
In subsequent studies, we confirmed that the etiology INR was fixed at 1 so that there would be no negative
of cirrhosis was a less important variable in determining scores; the upper limit of serum creatinine was capped at
survival in other patient cohorts with end-stage liver dis- 4 mg/dl.
ease. Therefore, etiology of liver disease was removed as a Implementation of MELD led to an immediate reduc-
variable from the model while still preserving its accura- tion in liver transplant waiting list registrations for the
cy.5 The advantage of dropping etiology of cirrhosis as a first time in history of liver transplantation (12% decrease
variable was that the subjective element in determining in 2002)4 because accrual of waiting time was no longer
etiology was removed, and the model could be based necessary. Accurate prediction of short-term mortality in
purely on objective laboratory variables. the vast majority (83%-87%) of wait-listed candidates9
MELD has been validated as a predictor of survival in led to a reduction of almost 15% in the mortality on the
independent groups of patients with a wide variety of liver waiting list.10 The number of deaths of patients on the
diseases.5,6 In these studies, the accuracy of MELD was wait list increased up to 2001 (Fig. 1); since implementa-
evaluated by its ability to rank patients according to risk tion of MELD in 2002, the number of deaths showed a
for mortality determined by the “concordance statistic” or substantial decrease from 2046 in 2001 to 1364 in 2005.
the “c” statistic. For example, a c-statistic of 0.7 indicates Although this reduction in mortality is in part attribut-
that patients with a higher MELD score will die earlier able to a modest increase in available organs (4,671 in
than patients with a lower MELD score 7 of 10 times. A 2001 versus 5,160 in 2005), there is a wide consensus that
c-statistic of 0.7 is thought to have reasonable clinical MELD has made a significant contribution to reducing
utility, while a c-statistic of ⱖ0.8 in a prediction model the mortality on the waiting list.11 A recent analysis
lends strong support to its accuracy. Most studies that showed that the reduction in mortality occurred only
evaluated MELD to rank patients according to their risk among patients with chronic liver disease (in whom
of mortality have yielded “c”-statistics upwards of 0.8, MELD is used to allocate organs), but not among patients
and usually superior to the Child-Turcotte-Pugh (CTP) with fulminant liver disease in status 1 (in whom MELD
class. Addition of complications such as ascites, encepha- is not used), suggesting that at least part of the decrease in
lopathy, variceal bleed, and SPB do not improve MELD waitlist mortality may be attributed to MELD-based or-
significantly; quantitative tests of liver function are also gan allocation.12 Moreover, the median waiting time to
not superior to MELD in predicting survival.7 liver transplantation decreased from 656 days to 416 days
in the MELD era.13 Several countries have replaced the
Application of MELD CTP score with MELD to rank patients according to
MELD in Liver Transplantation
Prior to February 27, 2002, patients were prioritized
for receiving organs for liver transplantation based on
their United Network of Organ Sharing (UNOS) status,
a reflection of their CTP score. Given that the waiting list
for liver transplantation approached 20,000 patients, and
there were only 3 categories on the waiting list for patients
with cirrhosis, namely Status 2A, Status 2B, and Status 3,
time spent on the waiting list became the major determi-
nant of who would receive a liver transplant. Therefore,
this policy placed at a disadvantage patients who were at a
high risk for mortality but who were listed late in their
disease course and had not accrued enough waiting time.
In 1998, the Institute of Medicine decreed that a new
allocation policy be put in place based on objective vari-
ables and which de-emphasized waiting time, that is, the
Fig. 1. The number and ratio of LTx (liver transplant) candidates
“sickest first” policy. This led to MELD which is based on removed from the waiting list due to transplantation (gray) and death
objective variables and could accurately rank patients with (black) in the United States.
HEPATOLOGY, Vol. 45, No. 3, 2007 KAMATH AND KIM 799
mortality risk.14 In a study from Australia, clinical judg- earlier, reducing the number of “outliers” that incurred
ment, which is often used in centers to determine which astronomical costs to the health care system.
patient should rank higher on a waiting list for mortality, Patients undergoing retransplantation are at a higher
has been proven to be inferior to the MELD score in risk of mortality after transplantation than those under-
determining survival.15 going primary liver transplantation. The 2-year survival
In contrast to the clear benefit of accurately estimating after retransplantation is lower than that after primary
mortality on the waiting list, MELD has not been found liver transplantation, with the difference in survival being
to be as useful in predicting mortality following liver greatest in patients with MELD ⬎25. Moreover, retrans-
transplantation.16-19 Mortality in the post transplantation plantation more than 2 years after the primary transplan-
period is related not only to the degree of liver dysfunction tation is associated with poor survival independent of the
prior to transplantation, but to other factors, such as do- MELD score.27 These data notwithstanding, the most
nor characteristics, experience of the transplantation immediate question about MELD in allocation for re-
team, and random postoperative complications which transplantation is whether the risk of death on waiting list
cannot be predicted. Moreover, patient selection by phy- is different between primary and repeated liver transplant
sicians will tend to negate the effect of pre-transplant candidates. Retransplantation candidates are registered
MELD on post transplant survival. Consequently, almost on the waiting list with significantly higher MELD than
all models which attempt to determine post transplant primary liver transplant candidates (22 versus 14) and
survival are not clinically useful. Thus, MELD score be- thus retransplantation candidates as a whole experienced
higher mortality rate on the waiting list.
fore liver transplant is not predictive of post liver trans-
It is important to note that although the modifications
plant outcome because of relatively poor correlation
created by UNOS in calculating the MELD score have
between pre-transplant disease severity and post trans-
some rationale, the modifications have been empirical
plant outcome.
rather than based on validated studies. For instance, the
Likewise, in small studies on living donor liver trans-
upper value of serum creatinine has been capped at as high
plantation, pre-transplant MELD scores had little impact
as 4 mg/dl, allowing inclusion of patients with intrinsic
on post transplant survival.20 There have been proposals renal disease. Thus, there has been a higher rate of com-
that organ allocation take into account donor and recipi- bined kidney and liver transplants than previously, but
ent factors simultaneously such that marginal grafts not without significant change in survival.28 The need for
be used for patients with high MELD scores in the hopes renal replacement therapy is higher if MELD scores are
to improve post liver transplantation outcome.21,22 Simi- greater than 24,29 even though there is a suggestion that
larly, in patients with MELD scores ⱕ14, mortality with the prevalence of chronic renal disease up to 2 years after
transplantation was found to be higher than that of pa- transplantation has not increased.30
tients with the same MELD score not transplanted.23 One Another area which requires more validation is the as-
must exercise caution, however, in interpreting these re- signment of MELD scores to patients with hepatocellular
sults, because they are simply observational (as opposed to carcinoma. The initial recommendation for allocation of
randomized) data. 24 MELD points for patients with Stage 2 HCC was
To the degree that disease severity before liver trans- found to be too high, and this was later reduced to 22.31 It
plantation affects post transplantation morbidity and remains to be seen whether this reduction in score is more
complications, healthcare resources used correlate with accurately reflective of the patients with hepatocellular
pre-transplantation MELD score. At the level of individ- carcinoma removed from the waiting list because they
ual patient, resource utilization, as judged by days in in- exceeded the Milan criteria.
tensive care, red cell transfusions, and duration of
hospitalization was higher with higher pre-transplant Prediction of Long-term Survival in Patients with
MELD scores.24,25 On the other hand, on an aggregate Cirrhosis
level, MELD-based organ allocation has not increased In a recent systematic review of 118 studies outlining
healthcare resource utilization. Based on a nationally rep- the natural history and prognostic indicators of survival in
resentative hospital utilization database, we have shown cirrhosis,32 MELD and CTP score were recognized as
that resources used did not increase since MELD was predictors of long-term survival in patients with decom-
implemented.26 Thus, MELD-based allocation consis- pensated cirrhosis. Recently, both MELD and HVPG
tently directs organs to the sickest patients so that those were shown to be independent predictors of survival. The
patients in the previous era who had high MELD but “c” statistic for predicting survival was 0.71 for the
insufficient waiting time are undergoing transplantation MELD score, and the addition of HVPG and age in-
800 KAMATH AND KIM HEPATOLOGY, March 2007
creased the predictive mortality to 0.76, which was not oped FHF, MELD was less accurate in predicting
statistically significant. MELD is an accurate predictor of mortality.41 In a U.S. multicenter study in patients with
long-term mortality, even in patients with chronic hepa- FHF secondary to hepatitis A, MELD had a “c” statistic of
titis B, with or without cirrhosis.33 Whereas patients with only 0.7 in ranking patients according to mortality risk.42
NASH-related cirrhosis had a lower risk of mortality than These studies would suggest that, in patients with FHF in
patients with HCV-related cirrhosis, even when “decom- addition to the MELD score, there are other variables
pensated”; MELD was an accurate predictor of survival in such as the degree of intracranial pressure important in
both groups of patients.34 predicting mortality. The U.S. study demonstrated that a
model using serum creatinine, serum bilirubin, need for
Application of MELD Beyond ESLD endotracheal intubation, and vasopressor support had a
Variceal Bleeding. Retrospective studies have shown “c” statistic of 0.89. However, there were only 4 deaths,
that both MELD and CTP are accurate predictors of and only 9 of the 29 patients underwent liver transplan-
survival in patients with variceal bleeding.35 MELD and tation. Therefore, the limited number of endpoints for a 4
hepatocellular carcinoma were better predictors of sur- variable model (typically, 40 events would be necessary
vival than CTP score in a study of 172 patients with for internal validation of a 4 variable model) is likely to be
cirrhosis and first variceal bleed, with MELD score dis- associated with “model over-fitting”, and needs validation
criminating between patients at high risk (ⱖ15) and low in an independent data set before being widely used.
risk (⬍15) for mortality.36 Our own unpublished data Alcoholic Hepatitis. In all 3 studies that compared
confirms the superiority of MELD over the CTP score in the MELD score to the Maddrey score,43 MELD was a
determining mortality following a variceal bleed. more accurate predictor of mortality.44-46 This is not sur-
Infections in Patients with Cirrhosis. Both studies prising because the MELD score has both the variables
addressing the predictability of MELD in determining included in the Maddrey score, namely the prothrombin
mortality in patients with infections leading to renal fail- time and bilirubin but, in addition, has an index of renal
ure have demonstrated that the only predictors of survival dysfunction which is the serum creatinine. The cut-off of
in these patients were the MELD score, and the type of the MELD score for determining severe alcoholic hepati-
hepatorenal syndrome; CTP score was not independently tis is ⬎21 which is associated with 3-month mortality of
predictive of mortality.37,38 These data would suggest that 20%, whereas patients with MELD score ⱕ11 have ex-
patients with a high MELD score are either more likely to cellent survival.45
get infected, or that patients with a high MELD score are Other Chronic Liver Diseases. MELD has been
more likely to die as a result of spontaneous bacterial shown to be a useful predictor even in patients n whom
peritonitis (SBP) because outpatients with SBP typically cirrhosis was not clearly documented. In patients with
have lower MELD scores than inpatients with SBP, and chronic hepatitis B, MELD and antiviral treatments
better survival.39 (lamivudine) were independent predictors of survival.33
Fulminant Hepatic Failure. Among 312 patients In patients admitted to the Intensive Care Unit, the
with non-acetaminophen-induced FHF in the UNOS “Royal Free Model” had similar discrimination ability as
database, MELD was a highly significant predictor of 30 the MELD and Sequential Organ Failure (SOFA) score47
day mortality (P ⬍ 0.0001).40 Of note, patients with in predicting mortality. All three scores were superior to
primary graft nonfunction and patients with hepatic ar- APACHE II or CTP scores.48 It must be pointed out that
tery thrombosis had a lower risk of 30-day mortality than both the Royal Free Model and the SOFA score include
patients with FHF and did not show a significant associ- variables reflecting multiple system organ failure, and are
ation between transplantation and survival. On the other more likely to “reflect” the dying process rather than be-
hand, patients with FHF experienced the greater benefit ing predictors of mortality. Similarly, in patients with
with liver transplantation, survival improving from 58% acute on chronic liver failure, MELD and hepatic enceph-
at 30 days without transplantation to 91% with liver alopathy predicted survival,49 especially when MELD was
transplantation (P ⬍ 0.0001). This raises the question as ⱖ30.17
to whether MELD should also be used to prioritize can-
didates with FHF, that is, UNOS Status 1, for liver trans- MELD in the Management of Patients with ESLD
plantation. Transjugular Intrahepatic Portosystemic Shunts.
In a large prospective study from Denmark, the utility MELD was originally developed in patients undergoing
of MELD in determining the onset of FHF in patients TIPS and may be used most appropriately to predict
with acetaminophen-induced liver failure was demon- probability of survival after the procedure. The indication
strated (“c” statistic: 0.92). However, once patients devel- for TIPS, whether refractory ascites or variceal bleeding, is
HEPATOLOGY, Vol. 45, No. 3, 2007 KAMATH AND KIM 801
not an independent variable determining survival. Emer- therapies for HCC should probably be considered only in
gency TIPS, that is TIPS carried out in a patient actively patients with MELD score ⱕ10 and CLIP score ⱕ2.54
bleeding in spite of 2 sessions of endoscopic therapy car- Selection of Patients for Surgery Other Than Liver
ried out within 24 hours, is a predictor of mortality, but Transplantation. Traditionally, the CTP score has
these patients also usually have a higher MELD score.1 It been used to determine risk of postoperative mortality.
is not clear whether TIPS adds additional mortality to Additional risk factors for mortality have included serum
that predicted by the MELD score in patients with com- creatinine concentration, the American Society of Anes-
plications of portal hypertension. That is, it is not clear, thesiologists (ASA) physical status class, and cardiopul-
for example, whether a patient with a MELD score of 24 monary comorbidity.55 However, these variables have not
undergoing TIPS has a higher mortality than a patient been put together to create a model to quantitate the risk
with similar complications and a MELD score of 24 not of postoperative mortality.
undergoing TIPS. Nonetheless, TIPS is associated with a We have demonstrated that patients with cirrhosis are
higher risk of mortality than seen in patients on the wait- at low risk of mortality after hepatic resection for hepato-
ing list for liver transplantation with identical MELD cellular carcinoma (HCC) if their MELD score is 8 or
scores, at least a small additional risk of procedure-related less.56 This MELD cutoff of 8 for carrying out hepatic
mortality,50 and a risk of morbidity as well as additional resection for HCC has been confirmed by a study from
expense. Italy.57 The utility of MELD in determining postopera-
The importance of MELD as an independent predic- tive mortality has also been confirmed in patients under-
going cardiac surgery,58 as well as in abdominal
tor of death in patients undergoing TIPS has been con-
operations including cholecystectomy,59-61 However,
firmed by other studies.38,51 The MELD score within the
MELD was an inaccurate predictor of mortality in pa-
UNOS region at which patients are likely to receive a
tients without cirrhosis undergoing liver resection.62 In
transplant may also be used in determining whether a
our experience, MELD, the ASA physical status, and age
TIPS should be carried out before liver transplantation.
can be used to determine mortality following surgery in-
For instance, if a patient with a MELD score of 28 and
dependent of the procedure performed. We have demon-
refractory ascites is in a UNOS region where organs are strated a close relationship between MELD score and
available to patients whose MELD score is 28-30, contin- mortality, with the relationship persisting both short-
ued conservative measures rather than TIPS might be term and long-term following surgery, irrespective of the
recommended. In general, a MELD score of ⬎24 is asso- type of surgery being performed. Emergency surgery too
ciated with an increased risk of 3-month post TIPS mor- was not an independent predictor of mortality indepen-
tality,52,53 and consequently, TIPS should be avoided in dent of the MELD score.63 The MELD score, ASA phys-
such patients unless they are candidates for liver trans- ical status, and age may be used in determining whether
plantation. elective surgical procedures should be carried out before
The MELD score has been compared to both the or following liver transplantation.
Emory score,35 as well as the CTP score for prediction of
long-term survival in patients undergoing TIPS. The “c” Strengths and Limitations of MELD
statistic for the MELD score was superior to the Emory In many ways, MELD is an ideal survival model in
score but only slightly superior to or no better than the comparison to either models/scores used in patients with
CTP classification in predicting post procedure mortali- liver disease (Table 1). Its strengths derive from the robust
ty.38 statistical foundation in its development and the large
Hepatocellular Carcinoma. In our experience, he- number and variety of samples in which it was validated.
patic resection for HCC can be carried out safely in pa- The model is based on only objective variables that are
tients with cirrhosis and MELD score ⱕ8. Neither minor readily obtained. Inclusion of creatinine incorporates a
hepatic resections (ⱕ3 segment resection) nor major re- measure of renal function, a well-recognized predictor of
section (ⱖ4 segment) were associated with any mortality survival in patients with liver disease.64-66 Whereas the
30 days postoperatively if MELD score was ⱕ8. More- usefulness of CTP has been appreciated by clinicians for
over, patients with HCC smaller than 5 cm in diameter many decades, it did not have much statistical basis in its
and MELD score ⱕ8, had a 5-year survival of 80%. In development, nor did it undergo as rigorous validation as
patients undergoing ablation therapies for unresectable MELD. It also includes subjective variables such as ascites
HCC, patients with MELD score ⱕ10 and CLIP score and encephalopathy. In our initial validation study, the
ⱕ2 had the best outcome. In patients with MELD score c-statistic associated with the CTP score in the prediction
ⱖ10 and CLIP ⱖ2 the outcome was poor; therefore, local of 3-month survival was 0.84 (95% CI 0.78-0.90), in
802 KAMATH AND KIM HEPATOLOGY, March 2007
An Ideal Model ✓ – ✓ ✓ ✓ ✓
FHF ✓ ✓ ✓ – – –
SBP ✓ – ✓ – – –
HRS ✓ – ✓ – – –
Child-Pugh (“Decompensated Liver Disease”) ✓ ✓ ✓ – – ✓
MELD ✓ – ✓ (?)✓ ✓ ✓
comparison to 0.87 for MELD. Thus, the MELD scale is Second, the primary role that was asked of MELD was
thought to be at least as good as the CTP score in predict- to rank patients according to mortality risk in a relatively
ing short-term mortality, while it may overcome many homogenous population of registrants on the liver trans-
limitations of the CTP score, at least for the purpose of plant waiting list. Thus, depending on the population to
prioritization in donor organ allocation. which it is applied, mortality seen in patients with a given
Several authors pointed out that MELD has not been MELD score may not necessarily be the same. Similarly,
proven to be superior to the CTP score in patients listed hospitalized patients with cirrhosis who were not candi-
for liver transplantation or in a wider population of pa- dates for liver transplantation may have a higher mortality
tients with cirrhosis.48,67 When the score designation with than candidates for liver transplantation who are younger
regard to ascites and encephalopathy is done consistently and devoid of comorbidity. Thus, it is not possible to
from one patient to the next by an experienced observer, provide a universally applicable survival prediction by
the CTP score is probably as accurate and reproducible as MELD.
MELD.2 However, one of the drawbacks of the CTP Third, although the objectivity of the variables in-
system is that it is much more subject to variability and cluded in MELD is far superior to previous models, the
interpretation than MELD. This was one of the factors variables used in the MELD score may be subject to some
that made MELD more attractive as a standard for organ variability depending on how they are measured. The se-
allocation in that it minimizes the possibility of “gaming” rum creatinine typically measured by a colorimetric alka-
the system. Another advantage of MELD over the CTP line picric Jaffe method may be less accurate than when
score is that it has a much wider range of possible scores the enzymatic method for measuring serum creatinine is
and has a better precision with which to distinguish pa- used. When the serum bilirubin is above 25 mg/dl, the
tients according to their mortality risk. Finally, even the colorimetric method overestimates the serum creatinine.
most vocal skeptics of MELD agree that the serum creat- Accordingly, in patients with serum bilirubin ⬎25 mg/dl
inine is an important contribution of MELD in highlight- the enzymatic method for measuring serum creatinine is
ing the importance of renal function in the assessment of recommended. A somewhat related question regarding
mortality risk in patients with ESLD. A model developed bilirubin is whether the direct fraction of the serum bili-
by adding serum creatinine to the CTP score has not been rubin is a more accurate predictor of survival than the
proven to be more accurate than the MELD score.68 total serum bilirubin. In the absence of studies clarifying
There are some cautions to be exercised in applying this issue, the total serum bilirubin remains the preferred
MELD in individual patients. First, one must remember index for expressing overall liver function.
that MELD was created and validated in a cohort of pa- The prothrombin time is also subject to variability.
tients who were screened carefully with certain criteria, The thromboplastins available worldwide have an Inter-
which included absence of acute, reversible complica- national Sensitivity Index range from 1-3, the lower num-
tions, such as bacterial infection or azotemia associated bers indicating a more sensitive thromboplastin. The
with dehydration. In deriving the TIPS model, we used prothrombin time is more prolonged if a sensitive throm-
the prothrombin time and serum creatinine and bilirubin boplastin is used as compared with a less sensitive throm-
data recorded at the time when reversible factors had been boplastin. The INR for prothrombin time was introduced
excluded. This approach was taken because we were pri- as a means of decreasing this variability when measuring
marily interested in a measure most accurately reflective prothrombin times in patients on warfarin anticoagula-
of the underlying liver function. Therefore, in patients on tion. The accuracy of INR may be decreased as a measure
the waiting list for liver transplantation, the MELD score of the coagulation status in patients with liver disease,
should, in principle, be calculated only after acute revers- since there are other abnormalities in the coagulation
ible processes are adequately treated. pathway in those patients. However, its role in predicting
HEPATOLOGY, Vol. 45, No. 3, 2007 KAMATH AND KIM 803
survival in patients with liver disease has been demon- analysis highlighted that the current MELD is the most
strated repeatedly, especially when used to calculate the important predictor of survival, regardless how that
MELD score. It is possible that other methods of express- MELD was reached.12
ing prothrombin time such as the prothrombin index are MELD could potentially be improved with more ac-
more accurate reflectors of liver function, but these meth- curate indices of liver function and perhaps better ways of
ods have yet to be validated as being more accurate than assessing renal function. Recently, several studies have
the INR, both as indices of liver function and of coagula- shown that the addition of serum sodium can improve the
tion status. In our opinion, of measures of the prothrom- predictive accuracy of the MELD score.70-73 Our study,
bin time, the INR is superior to others because of it wide which is based on a multicenter database, shows that there
availability as well as the track record as a survival indica- is a linear relationship between serum sodium and mor-
tor in patients with ESLD. tality after adjusting for MELD. In addition, serum so-
Finally, some debate continues with regard to patients dium may be particularly relevant in patients with a low
with intractable complications of portal hypertension MELD score, e.g., MELD ⬍ 20.74 As was alluded to
such as ascites and hepatic encephalopathy. In our initial earlier, because of the small proportion affected by hypo-
evaluation of these complications in conjunction with natremia, the c-statistics of the model did not change
MELD, it was clear that when the c-statistic was used as substantially. However, with severe hyponatremia, the
the criterion to determine the degree of improvement in risk in mortality increased as much as what would be
the model associated with the addition of these complica- equivalent to an increase of more than 20 points in
tions, they had only minimal benefit to MELD. However, MELD. Whereas the impact of serum sodium is quite
as shown in the case with hyponatremia (see next section), large, it remains uncertain whether the addition of serum
if these complications occur in a small proportion of pa- sodium to the MELD score can be used to determine
tients, addition of them would not increase the model allocation of organs for liver transplantation, especially
c-statistic materially, because it changes the ranking of because of the possible poor post liver transplantation
only a few patients, even when they may have substantial outcome of patients with low serum sodium.75
impact in those few patients. To date, however, we are not In conclusion, based on its ability to rank patients with
aware of data to clearly demonstrate that such is the case, cirrhosis according to their short term mortality, MELD
except in the case of hyponatremia. If data strongly sup- has been recognized as a major contribution to the daily
portive of these and other complications add to the prog- practice of hepatology. Successful implementation of
nostic evaluation in patients with ESLD, the transplant MELD-based liver allocation in the United States has
community may be faced with a difficult decision whether been followed by widespread adoption of the system glo-
to re-incorporate these potentially subjective elements bally, attesting to its validity. In addition to organ alloca-
back to the organ allocation policy. tion, emerging data support MELD as a useful clinical
tool in a wide spectrum of disease severity and variety.
Further Refinement and Improvement of These achievements notwithstanding, MELD is by no
MELD means a perfect system. Users of MELD must be aware of
Patients with an increasing MELD score have been several features and limitations in its application. In the
thought to have an increased risk of mortality, whereas meantime, efforts for further refinement and validation
those with a decreasing MELD score have a lower risk of must continue.
mortality, even if their MELD scores are identical.69
Thus, it has been proposed that the change in MELD References
score, that is ⌬MELD, may add prognostic information 1. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, Borg PC. A
to the MELD score.69 Intuitively, a patient whose MELD model to predict poor survival in patients undergoing transjugular intra-
is increasing rapidly is more likely to have a worse out- hepatic portosystemic shunts. HEPATOLOGY 2000;31:864-871.
2. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM,
come than those with stable MELD. We conducted a Kosberg CL, et al. HEPATOLOGY 2001; 33:464-470.
study using the time-dependent analysis of the effect of 3. Wiesner RH, Kamath PS, Malinchoc M, Kremers WK, Krom RAF, Kim
the current MELD score and ⌬MELD (defined as the WR. MELD and PELD: Application of survival models to liver allocation.
Liver Transpl 2001;7:567-580.
difference between current MELD and the lowest MELD 4. Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al.
score measured within 30 days prior to current MELD). Model for end-stage liver disease (MELD) and allocation of donor livers.
Although all of these variables were significant in the uni- Gastroenterology 2003;124:91-96.
variate phase, ⌬MELD was no longer significant in the 5. Brandsater B, Broome U, Isoniemi H, Friman S, Hansen B, Schrumpf E,
et al. Liver transplantation for primary sclerosing cholangitis in the Nordic
multivariable analysis, especially when acute increases in countries: Outcome after acceptance to the waiting list. Liver Transpl
MELD in the last few days of life were excluded. This 2003;9:961-969.
804 KAMATH AND KIM HEPATOLOGY, March 2007
6. Said A, Williams J, Holden J, Remington P, Gangnon R, Musat A, et al. 28. Gonwa TA, McBride MA, Anderson K, Mai ML, Wadei H, Ahsan N.
Model for end-stage liver disease score predicts mortality across a broad Continued influence of preoperative renal function on outcome of ortho-
spectrum of liver disease. J Hepatol 2004;40:897-903. topic liver transplant in the US: Where will MELD lead us ? Am J Trans-
7. Botta F, Giannini E, Romagnoli P, Fasoli A, Malfatti F, Chiarbonello B, et plant 2006;6:2651-2659.
al. MELD scoring system is useful for predicting prognosis in patients with 29. Sanchez EQ, Gonwa TA, Levy MF, Goldstein RM, Mai ML, Hays SR, et
liver cirrhosis and is correlated with residual liver function: a European al. Preoperative and perioperative predictors of the need for renal replace-
study. Gut 2003;52:134-139. ment therapy after orthotopic liver transplantation. Transplantation 2004;
8. Freeman R. MELD: the holy grail of organ allocation? J Hepatol 2005;42: 78:1048-1054.
16-20. 30. Machicao VI, Srinivas TR, Hemming AW, Soldevilla-Pico C, Firpi RJ,
9. Biggins SW, Bambha K. MELD-based liver allocation: Who is under- Reed AI, et al. Impact of implementation of the MELD scoring system on
served? Semin Liver Dis 2006;26:211-220. the prevalence and incidence of chronic renal disease following liver trans-
10. Wiesner RH, Edwards E, Freeman R, Harper A, Kim WR, Kamath PS, et plantation. Liver Transpl 2006;12:754-761.
al. Model for End-Stage Liver Disease (MELD) and Allocation of Donor 31. Wiesner RH, Freeman RB, Mulligan DC. Liver transplantation for hepa-
Livers. Gastroenterology 2003;124:91-96. tocellular cancer: the impact of the MELD allocation policy. Gastroenter-
11. Brown RS Jr, Lake JR. The survival impact of liver transplantation in the ology 2004;127(Suppl 1):S261-S267.
MELD era, and the future for organ allocation and distribution [Com- 32. D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic
ment]. Am J Transplant 2005;5:203-204. indicators of survival in cirrhosis: A systematic review of 118 studies.
12. Bambha K, Kim WR, Kremers WK, Therneau TM, Kamath PS, Wiesner J Hepatol 2006;44:217-231.
R, et al. Predicting survival among patients listed for liver transplantation: 33. Chan HLY, Chim AML, Lau JTF, Hui AY, Wong VWS, Sung JJY. Eval-
an assessment of serial MELD measurements. Am J Transplant 2004;4: uation of model for end-stage liver disease for prediction of mortality in
1798-1804. decompensated chronic hepatitis B. Am J Gastroenterol 2006;101:1516-
13. Wiesner R, Lake J, Freeman R, Gish RG. Model for end-stage liver disease 1523.
(MELD) exception guidelines. Liver Transpl 2006;12(Suppl):S85-S87. 34. Sanyal AJ, Banas C, Sargeant C, Luketic VA, Sterling RK, Stravitz RT, et
14. Ravaioli M, Grazi GL, Ballardini G, Cavrini G, Ercolani G, Cascon M, al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic
Zanello M. Liver transplantation with the Meld system: a prospective steatohepatitis and hepatitis C. HEPATOLOGY 2006;43:682-689.
study from a single European center.Am J Transplant 2006;6:1572-1577. 35. Chalasani N, Kahi C, Francois F, Pinto AO, Marathe A, Bini EJ, et al.
15. Fink MA, Angus PW, Gow PJ, Berry SR, Wang BZ, Muralidharan V, et al.
Model for End-stage Liver Disease (MELD for predicting mortality in
Liver transplant recipient selection: MELD vs. clinical judgment. Liver
patients with acute variceal bleeding. HEPATOLOGY 2002;35:1282-1284.
Transpl 2005;11:621-626.
36. Amitrano L, Guardascione MA, Bennato R, Manguso F, Balzano A.
16. Habib S, Berk B, Chang CCH, Demetris AJ, Fontes P, Dvorchik I,
MELD score and hepatocellular carcinoma identify patients at different
Eghtesad B, et al. MELD and predictionof post-liver transplantation sur-
risk of short-term mortality among cirrhotics bleeding from esophageal
vival. Liver Transpl 2006;12:440-447.
varices [See comment]. J Hepatol 2005;42:820-825.
17. Yoo HY, Thuluvath PJ. Short-term post-liver transplant survival after the
37. Alessandria C, Ozdogan O, Guevara M, Restuccia T, Jimenez W, Arroyo
introduction of MELD scores for organ allocation in the United States.
V, et al. MELD score and clinical type predict prognosis in hepatorenal
Liver Int 2005;25:536-541.
syndrome: relevance to liver transplantation. HEPATOLOGY 2005;41:
18. Onaca N, Levy MF, Netto GJ, Thomas MJ, Sanchez EQ, Chinnakotla S,
1282-1289.
et al. Pretransplant MELD score as a predictor of outcome after liver
38. Schepke M, Appenrodt B, Heller J, Zielinski J, Sauerbruch T. Prognostic
transplantation for chronic hepatitis C. Am J Transplant 2003;3:626-630.
factors for patients with cirrhosis and kidney dysfunction in the era of
19. Saab S, Ly D, Nieto J, Kanwal F, Lu D, Raman S, et al. Hepatocellular
MELD: results of a prospective study. Liver Int 2006;26:834-839.
carcinoma screening in patients waiting for liver transplantation: a decision
analytic model. Liver Transpl 2003;9:672-681. 39. Evans LT, Kim WR, Poterucha JJ, Kamath PS. Spontaneous bacterial
20. Akyildiz M, Karasu Z, Arikan C, Kilic M, Zeytunlu M, Gunsar F, et al. peritonitis in asymptomatic outpatients with cirrhotic ascites. HEPATOL-
OGY 2003;37:897-901.
Impact of pretransplant MELD score on post-transplant outcome in living
donor liver transplantation. Transplant Proc 2004;36:1442-1444. 40. Kremers W, van IJperen M, Kim WR, Freeman R, Harper AM, Kamath
21. Briceno J, Padillo J, Rufian S, Solorzano G, Pera C. Assignment of steatotic PS, et al. MELD score as a predictor of pretransplant and post-transplant
livers by the Mayo model for End-stage liver disease. Transpl Int 2005;18: survival in OPTN/UNOS Status 1 patients. HEPATOLOGY 2004;39:764-
577-583. 769.
22. Burra P, Porte RJ. Should donors and recipients be matched in liver trans- 41. Schmidt LE, Larsen FS. MELD score as a predictor of liver failure and
plantation? J Hepatol 2006;45:488-494. death in patients with acetaminophen-induced liver failure. HEPATOLOGY.
23. Merion RM, Schaubel DE, Dykstra DM, Freeman R, Port FK, Wolfe RA. In press.
The survival benefit of liver transplantation. Am J Transplant 2005;5:307- 42. Taylor RM, Davern T, Munoz S, Han S-H, McGuire B, Larson AM, et al.
313. Acute Liver Failure study Group. Fulminant hepatitis A virus infection in
24. Nourmand H, Levin P, Enriquez R, Hiatt JR, Ghobrial RM, Former DG, the United States: incidence, prognosis an outcomes. HEPATOLOGY 2006;
et al. Preoperative characteristics and intra-operative transfusion and vaso- 44:1589-1597.
pressor requirements in patients with low vs. high MELD scores. Liver 43. Maddrey W, Boitnott J, Bedine M, Weber FJ, Mezey E, White RJ. Cor-
Transpl 2006;12:614-620. ticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75:193-
25. Washburn WK, Pollock BH, Nichols L, Speeg KV, Halff G. Impact of 199.
recipient MELD score on resource utilization. Am J Transplant 2006;6: 44. Srikureja W, Kyulo NL, Runyon BA, Hu KQ. MELD score is a better
2449-2454. prognostic model than Child-Turcotte-Pugh score or Discriminant Func-
26. Bambha K, Kim WR, Benson J, Therneau T, Wiesner R, Kremers W, et al. tion score in patients with alcoholic hepatitis. J Hepatol 2005;42:700-706.
Economic impact of MELD-based allocation of liver transplants [Ab- 45. Dunn W, Jamil LH, Brown LS, Wiesner RH, Kim WR, Menon KVN, et
stract]. Am J Transplant 2005;5(Suppl 11):425. al. MELD accurately predicts mortality in patients with alcoholic hepatitis.
27. Onaca N, Levy MF, Ueno T, Martin AP, Sanchez EQ, Chinnakotla S, et HEPATOLOGY 2005;41:353-358.
al. An outcome comparison between primary liver transplantation and 46. Sheth M, Riggs M, Patel T. Utility of the Mayo End-Stage Liver Disease
retransplantation based on the pretransplant MELD score. Transplant Int (MELD) score in assessing prognosis of patients with alcoholic hepatitis.
2006;19:282-287. BMC Gastroenterol 2001;2:2. Epub 2002 Jan 22.
HEPATOLOGY, Vol. 45, No. 3, 2007 KAMATH AND KIM 805
47. Wehler MK, J., Reulbach U, Hahn EG, Strauss R. Short-term prognosis in 61. Perkins L, Jeffries M, Patel T. Utility of preoperative scores for predicting
critically ill patients with cirrhosis assessed by prognostic scoring systems. morbidity after cholecystectomy in patients with cirrhosis. Clin Gastroen-
HEPATOLOGY 2001;34:255-261. terol Hepatol 2004;2:1123-1128.
48. Cholongitas E, Senzolo M, Patch D, Kwong K, Nikolopoulou V, Leandro 62. Schroeder RA, Marroquin CE, Bute BP, Khuri S, Henderson WJ, Kwo
G, et al. Risk factors, sequential organ failure assessment and model for PC. Predictive indices of morbidity and mortality after liver resection. Ann
end-stage liver disease scores for predicting short-term mortality in cir- Surg 2006;243:373-379.
rhotic patients admitted to intensive care unit. Aliment Pharmacol Ther 63. Teh SH, Nagorney DM, Stevens SR, Offord KP, Therneau TM, Plevak
2006;23:883-893. DJ, et al. Risk factors for mortality after surgery in patients with cirrhosis.
49. Du WB, Li LJ, Huang JR, Yang Q, Liu XL, Li J, et al. Effects of artificial Gastroenterology 2007. In press.
liver support system on patients with acute or chronic liver failure. Trans- 64. Gines A, Escorsell A, Gines P, Salo J, Jimenez W, Inglada L, et al. Inci-
plant Proc 2005;37:4359-4364. dence, predictive factors, and prognosis of the hepatorenal syndrome in
50. Boyer TD, Haskal ZJ. American Association for the Study of Liver Dis- cirrhosis with ascites. Gastroenterology 1993;105:229-236.
eases. The role of transjugular intrahepatic portosystemic shunt in the 65. Arroyo V, Gines P, Gerbes A, Dudley F, Gentilini P, Laffi G, et al. Defi-
management of portal hypertension. HEPATOLOGY 2005;41:386-400. nition and diagnostic criteria of refractory ascites and hepatorenal syn-
51. Salerno F, Merli M, Riggio O, Cazzaniga M, Valeriano V, Pozzi M, et al. drome in cirrhosis. HEPATOLOGY 1996;23:164-176.
Randomized controlled study of TIPS versus paracentesis plus albumin in 66. del Olmo J, Andrez P, Serra M, Wassel A, Benages A, Rodrigo J. Predictors
cirrhosis with severe ascites. HEPATOLOGY 2004;40:629-635. of morbidity and mortality after the first episode of upper gastrointestinal
52. Montgomery A, Ferral H, Vasan R, Postoak DW. MELD score as a pre- bleeding in liver cirrhosis. J Hepatol 2000;32:19-24.
dictor of early death in patients undergoing elective transjugular intrahe- 67. Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D,
patic portosystemic shunt (TIPS) procedures. Cardiovascular and Burroughs AK. Systematic review: the model for end-stage liver disease —
Interventional Radiology 2005;28:307-312.
should it replace Child-Pugh’s classification for assessing prognosis in cir-
53. Ferral H, Vasan R, Speeg KV, Serna S, Young CR, Postoak DW, et al.
rhosis? Aliment Pharmacol Ther 2005;22:1079-1089.
Evaluation of a model to predict poor survival in patients undergoing
68. Giannini EG, Botta F, Fumagalli A, Malfatti F, Testa E, Chiarbonello B, et
elective TIPS procedures. J Vascular and Interventional Radiol 2002;13:
al. Can inclusion of serum creatinine values improve the Child-Turcotte-
1103-1108.
Pugh score and challenge the prognostic yield of the model for end-stage
54. Testa R, Testa E, Giannini EG, Botta F, Malfatti F, Chiarbonello B, et al.
liver disease score in the short-term prognostic assessment of cirrhotic
Trans-catheter arterial chemoembolization for hepatocellular carcinoma in
patients? Liver Int 2004;24:465-470.
patients with viral cirrhosis: role of combined staging systems, Cancer Liver
69. Merion RM, Wolfe RA, Dykstra DM, Leichtman AB, Gillespie B, Held
Italian Program (CLIP) and Model for End-stage Liver Disease (MELD),
PJ. Longitudinal assessment of mortality risk among candidates for liver
in predicting outcome after treatment. Aliment Pharmacol Ther 2003;17:
transplantation [See comment]. Liver Transpl 2003;9:12-18.
1563-1569.
55. Ziser A, Plevak DJ, Wiesner RH, Rakela J, Offord KP, Brown DL. Mor- 70. Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault
bidity and mortality in cirrhotic patients undergoing anesthesia and sur- NA. Serum sodium predicts mortality in patients listed for liver transplan-
gery. Anesthesiology 1999;90:40-53. tation. HEPATOLOGY 2005;41:32-39.
56. Teh SH, Christein J, Donohue J, Que F, Kendrick M, Farnell M, et al. 71. Heuman D, Abou-assi SG, Habib A, Williams LM, Stravitz RT, Sanyal AJ,
Hepatic resection of hepatocellular carcinoma in patients with cirrhosis: et al. Persistent ascites and low serum sodium identify patients with cir-
Model of end-stage liver disease (MELD) score predicts perioperative mor- rhosis and low MELD scores who are at high risk for early death. HEPA-
tality. J Gastrointest Surg 2005;9:1207-1215. TOLOGY 2004;40:802-810.
57. Cucchetti A, Ercolani G, Vivarelli M, Cescon M, Ravaioli M, La Barba G, 72. Biggins SW, Kim WR, Terrault NA, Saab S, Balan V, Schiano T, et al.
et al. Impact of model for end-stage liver disease (MELD) score on prog- Evidence-based incorporation of serum sodium concentration into
nosis after hepatectomy for hepatocellular carcinoma on cirrhosis. Liver MELD. Gastroenterology 2006; 130:1652-1660.
Transpl 2006;12:966-971. 73. Ruf AE, Kremers W, Chavez LL, Descalzi VI, Podesta LG, Villamil FG.
58. Seaman A, Barnes DS, Zein NN, Levinthal GN, Connor JT, Carey WD. Addition of serum sodium into the MELD score predicts waiting list
Predicting Outcome After Cardiac Surgery in Patients with Cirrhosis: A mortality better than MELD alone. Liver Transpl 2005;11:336-343.
Comparison of Child-Pugh and MELD Score. Clin Gastroenterol Hepatol 74. Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stravitz RT, Sanyal
2004;2:719-723. AJ, et al. Persistent ascites and low serum sodium identify patients with
59. Befeler AS, Palmer DE, Hoffman M, Longo W, Solomon H, Di Bisceglie cirrhosis and low MELD scores who are at high risk for early death. HEPA-
AM. The safety of intra-abdominal surgery in patients with cirrhosis. Arch TOLOGY 2004;40:802-810.
Surg 2005;140:650-654. 75. Londono M, Guevara M, Rimola A, Navasa M, Taura P, Mas A, et al.
60. Northup PG, Wanamaker RC, Lee VD, Adams RB, Berg CL. Model for Hyponatremia impairs early post transplantation outcome in patients with
end-stage liver disease (MELD) predicts non-transplant surgical mortality cirrhosis undergoing liver transplantation. Gastroenterology 2006;130:
in patients with cirrhosis. Ann Surg 2005;242:244-251. 1135-1143.