Serum sodium based modification of the MELD does not improve prediction of outcome in acute liver failure
© Manka et al.; licensee BioMed Central Ltd. 2013
Received: 11 December 2012
Accepted: 21 March 2013
Published: 3 April 2013
Acute liver failure (ALF) is a devastating clinical syndrome with a high mortality rate. The MELD score has been implied as a prognostic tool in ALF. Hyponatremia is associated with lethal outcome in ALF. Inclusion of serum sodium (Na) into the MELD score was found to improve its predictive value in cirrhotic patients. Therefore the aim of this study was to determine whether inclusion of serum Na improves the predictive value of MELD in ALF compared to established criteria.
In a prospective single center study (11/2006–12/2010), we recruited 108 consecutive ALF patients (64% females / 36% males), who met the criteria defined by the “Acute Liver Failure Study Group Germany”. Upon admission, clinical and laboratory data were collected, King’s College Criteria (KCC), Model of End Stage Liver Disease score (MELD), and serum sodium based modifications like the MELD-Na score and the United Kingdom Model of End Stage Liver Disease score (UKELD) were calculated and area under the receiver operating characteristic curve analyses were performed regarding the prediction of spontaneous recovery (SR) or non-spontaneous recovery (NSR; death or transplantation).
Serum bilirubin was of no prognostic value in ALF, and Na also failed to predict NSR in ALF. The classical MELD score was superior to sodium-based modifications and KCC.
We validated the prognostic value of MELD-Na and UKELD in ALF. Classic MELD score calculations performed superior to KCC in the prediction of NSR. Serum Na and Na-based modifications of MELD did not further improve its prognostic value.
KeywordsALF MELD MELD-Na UKELD Sodium
Acute liver failure (ALF) is a potentially lethal clinical syndrome with a high mortality rate. Nonetheless, immediate intensive care, specific therapies and liver transplantation (LTx) have improved the prognosis of ALF patients significantly [1–3]. According to the European Liver Transplant registry, approximately nine percent of LTx were related to ALF . King’s college (KCC) and Clichy criteria are etiology specific, prognosis predicting allocation tools to warrant timely transplantation and fair organ distribution [5, 6]. However, their accuracy to reliable predict patients’ individual prognosis and to discriminate those patients who will survive without LTx remains a major challenge [7, 8].
The model of end-stage liver disease (MELD), initially established to predict survival following transjugular intrahepatic portosystemic shunt (TIPS) procedure and later as an allocation tool for patients with cirrhosis, has been implied as a prognostic tool in ALF and was proven to be superior to the KCC and Clichy criteria [9–11]. Recently, various modifications of the MELD have been introduced and improved accuracy in both, chronic liver failure and ALF [12, 13]. Since hepatic encephalopathy (HE) is associated with a fulminant course of ALF and a decrease in extracellular fluid osmolality is associated with an increase in brain swelling, factors that modulate fluid osmolality were taken into account as prognostic markers [14, 15]. Patients with serum sodium between 145 and 150 mmol/l are known to have fewer episodes of intracranial hypertension and consequently a higher risk to develop brain edema. Thus, hyponatremia might worsen the prognosis in ALF . As hyponatremia is associated with poor prognosis in cirrhosis, inclusion of serum sodium (Na) into the MELD was found to improve its predictive value in chronic liver diseases [13, 17]. Two sodium containing MELD modifications, “UKELD” and “MELD-Na”, were proposed to enhance its prognostic ability in chronic liver failure [18, 19]. A potential predictive value of these modifications in ALF has not been evaluated yet.
The aim of this study was to determine whether inclusion of serum sodium into the MELD score improves its predictive value in ALF, compared to established criteria. By evaluating these tools in a large prospective single-center study with ALF patients, we demonstrate that the sodium based MELD modifications do not improve the prognostic value of the standard MELD formula.
Patients and ethical considerations
Patient’s general characteristics and laboratory parameter by outcome
Spontaneously recovered (SR) (n=65)
Not spontaneously recovered (NSR) (n=43)
Transplanted ( LTx) (n=24)
Deceased (†) (n=19)
SR vs. NSR
SR vs. †
SR vs. LTx
LTx vs. †
Gender female (%)
BMI (kg/m 2 ) **
Direct bilirubin [mg/dl]**
Total bilirubin [mg/dl]**
23.55 ± 0.66
36.37 ± 0.68
36.33 ± 0.8638
36.42 ± 1.12
58.39 ± 0.57
65.12 ± 0.73
66.29 ± 0.8666
63.47 ± 1.20
24.5 ± 0.65
36.49 ± 0.65
36.67 ± 0.81
36.24 ± 1.1
Assessment of prognosis
Model of end-stage liver disease (MELD) formula and sodium dependent modifications
MELDNa = MELD − Na − [0.025 × MELD × (140 − Na)] + 140
Differences between parameters were evaluated by one-way Analysis of Variance, repeated-measure Analysis of Variance, or paired Student’s t-test and t-test for independent samples t-test. For MELD and modified MELD statistics the Mann–Whitney test was used. For categorical variables, frequencies and percentages were estimated. χ2 or Fisher’s exact tests were used for categorical factors. ROC calculations were undertaken where applicable. Screening, optimal, and diagnostic cutoff values were calculated, and the optimal cutoff, including specificity and sensitivity as well as the AUC are shown in boxes included in the ROC plots. A p < 0.05 was considered statistically significant. All values are given as means ± standard error of means. Analyses were performed with SPSS 19.0.1, version 2008 (SPSS, Chicago, IL, USA).
Patient’s general characteristics and laboratory parameter by outcome in cases of non-acetaminophen induced acute liver failure
SR vs. NSR
SR vs. Deceased
Sodium levels fail to predict outcome in ALF
Sodium based modifications fail to improve MELD in ALF
The classical MELD score showed a strong correlation with the clinical outcome (Figure 3B: MELD: AUC 0.967; CI 0.935 – 0.998; p < 0.01). Since hyponatremia is associated with an unfavorable prognosis, inclusion of serum sodium into the MELD score was found to improve its predictive value in cirrhotic patients [13, 17]. However, in our ALF cohort, the classical MELD was superior to sodium based modifications like the MELD-Na (AUC: 0.960; CI: 0.924-0.966; p < 0.01) or the UKELD (AUC: 0.828; CI: 0.738-0.918; p < 0.01).
MELD and MELD-Na are more sensitive than KCC in predicting NSR in non-acetaminophen induced ALF
Comparison of the predictive values, sensitivity, specificity and diagnostic accuracy of the King’s College Criteria, MELD and MELD-Na at the date of maximum MELD during four weeks after admission and the MELD at date of admission
Prediction of lethal outcome for MELD and its sodium modifications depends on the extent of liver injury
A comparison of the MELD score at time of admission and the timepoint with a maximum MELD score within four weeks after admission in non-acetaminophen induced ALF revealed a better performance of the “maximum MELD” based scores (Table 4). Concerning sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and overall diagnostic accuracy the maximum MELD values were superior to the initial ones (initial MELD: AUC: 0.839; CI: 0.757-0.922; p < 0.01 Sensitivity: 0.78, Specificity: 0.76, PPV: 0.73, NPV: 0.81, diagnostic accuracy: 0.772, initial MELD-Na: AUC: 0.825; CI: 0.738-0.913, p<0.01 Sensitivity: 0.80, Specificity: 0.76, PPV: 0.72, NPV: 0.83, diagnostic accuracy 0.780).
Discussion and conclusion
To our knowledge, this is the first study to evaluate a potential predictive role for serum sodium based MELD modifications in the clinical setting of ALF in a large prospective cohort. Compared to the individual MELD parameters and in contrast to patients with chronic liver disease or post-transplant outcomes for acute liver failure , we could not find a clear association between serum sodium levels and clinical outcome in ALF which is in line with recent studies . Accordingly, the serum sodium based MELD modifications MELD-Na and UKELD failed to improve the predictive value of the MELD in ALF patients. However, in our cohort the classic MELD as well as MELD-Na was superior to KCC in predicting outcome of ALF patients. Interestingly, hypernatremia was associated with lethal outcome in our ALF cohort. In contrast in chronic liver disease hyponatremia is associated with a worse outcome even for mid to long term survival , the rational for utilizing UKELD and MELD-Na in cirrhosis.
Several studies have demonstrated a good specificity for KCC in ALF, however, the sensitivity to predict lethal outcome was modest in the vast majority of studies, especially in non-acetaminophen induced ALF [2, 6, 26]. Here, we found a fairly good specificity for KCC to predict NSR and as previously published only a modest sensitivity. Recent studies identified MELD as a prognostic tool with better sensitivity compared to KCC [21, 27]. Specifically, in patients with non-acetaminophen induced ALF, MELD was superior to KCC in predicting outcome . This is in line with our findings, which show a better performance of MELD and MELD-Na compared to KCC in non-acetaminophen ALF.
MELD was primarily introduced as a prognostic tool for survival of patients with cirrhosis and portal hypertension following TIPS procedure . Later, it was found to be useful in organ allocation for patients with chronic liver disease awaiting liver transplant and is therefore widely used in Western societies . As hyponatremia is a common clinical problem in patients with end stage liver disease, especially in those individuals with portal hypertension, ascites and hepatorenal syndrome, sodium based modifications of the MELD have been introduced. In the UK, the UKELD is utilized instead of the MELD for organ allocation . Murphy et al. identified hyponatremia as an independent risk factor for brain edema, a fatal complication of ALF [16, 29]. Furthermore hyponatremia has been investigated extensively in the management of traumatic cerebral edema [30, 31]
In our study we could not find an advantage of sodium based MELD modifications, compared to MELD or KCC in ALF. This is most likely due to the absence of ascites or hepatorenal syndrome in ALF, both common co-morbidities of cirrhosis [32, 33]. In our cohort, we did not find a difference in sodium levels between SR and NSR. Although Murphy et al. showed that patients with serum sodium between 145 and 150 mmol/l had fewer episodes of intracranial hypertension. There has been no difference in outcome . Taken together we confirm previous publications, establishing MELD as a powerful prognostic tool for non-acetaminophen induced ALF patients.
Furthermore, our data revealed a crucial problem with the assessment of any prognostic factor. We found significant differences in its predictive value between the MELD at the time of admission and at the time-point of its biggest dimension. The maximum MELD performed best in predicting outcome in ALF, underlining the need for continuous clinical assessment of patients with ALF, given the heterogeneity and dynamic of this disease. However, this also shows the need for novel prognostic models and surrogate parameters for the degree of liver injury and disease progression . While other possible MELD modifications might improve its accuracy in the future , sodium based MELD modifications are of little prognostic value in the clinical setting of ALF. Remien et al., in contrast to other modifications of the KCC and MELD-Score, developed the MALD score which is novel as it builds upon the KCC by utilizing an understanding of the dynamics of hepatocyte damage following APAP overdose in the form of a dynamic mathematical model . As ALF is a devasting clinical condition, it is worth it to evaluate new prognostic tools to improve outcome in this patients.
Acute liver failure
Kings college criteria
Model of end-stage liver disease
Negative predicte value
No spontaneous remission
Positive predictive value
Transjugular intraheptic portosystemic shunt.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG, grant CA267/6-1 and CA267/8-1), and the Wilhelm Laupitz Foundation to AC.
- Wigg AJ, Gunson BK, Mutimer DJ: Outcomes following liver transplantation for seronegative acute liver failure: experience during a 12-year period with more than 100 patients. Liver Transpl. 2005, 11: 27-34. 10.1002/lt.20289.View ArticlePubMedGoogle Scholar
- Nguyen NTT, Vierling JM: Acute liver failure. Curr Opin Organ Transplant. 2011, 16: 289-296. 10.1097/MOT.0b013e328346c8ee.View ArticlePubMedGoogle Scholar
- Bernal W, Wendon J: Liver transplantation in adults with acute liver failure. J Hepatol. 2004, 40: 192-197. 10.1016/j.jhep.2003.11.020.View ArticlePubMedGoogle Scholar
- Burroughs AK, Sabin CA, Rolles K, Delvart V, Karam V, Buckels J: 3-month and 12-month mortality after first liver transplant in adults in Europe: predictive models for outcome. Lancet. 2006, 367 (9506): 225-232. 10.1016/S0140-6736(06)68033-1.View ArticlePubMedGoogle Scholar
- Bernuau J, Goudeau A, Poynard T, Dubois F, Lesage G, Yvonnet B: Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology. 1986, 6: 648-651. 10.1002/hep.1840060417.View ArticlePubMedGoogle Scholar
- O’Grady JG, Alexander GJ, Hayllar KM, Williams R: Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989, 97: 439-445.View ArticlePubMedGoogle Scholar
- Choi W-C, Arnaout WC, Villamil FG, Demetriou AA, Vierling JM: Comparison of the applicability of two prognostic scoring systems in patients with fulminant hepatic failure. Korean J Intern Med. 2007, 22: 93-100. 10.3904/kjim.2007.22.2.93.View ArticlePubMedPubMed CentralGoogle Scholar
- Canbay A, Tacke F, Hadem J, Trautwein C, Gerken G, Manns MP: Acute liver failure: a life-threatening disease. Dtsch Arztebl Int. 2011, 108: 714-720.PubMedPubMed CentralGoogle Scholar
- Yantorno SE, Kremers WK, Ruf AE, Trentadue JJ, Podestá LG, Villamil FG: MELD is superior to King’s college and Clichy’s criteria to assess prognosis in fulminant hepatic failure. Liver Transpl. 2007, 13: 822-828. 10.1002/lt.21104.View ArticlePubMedGoogle Scholar
- Schmidt LE, Larsen FS: MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury. Hepatology. 2007, 45: 789-796. 10.1002/hep.21503.View ArticlePubMedGoogle Scholar
- Perkins JD: Another formula to determine the prognosis of patients with acute liver failure. Liver Transpl. 2009, 15: 986-991. 10.1002/lt.21823.View ArticlePubMedGoogle Scholar
- Bechmann LP, Jochum C, Kocabayoglu P, Sowa J-P, Kassalik M, Gieseler RK: Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepatol. 2010, 53: 639-647. 10.1016/j.jhep.2010.04.029.View ArticlePubMedGoogle Scholar
- Biggins SW, Kim WR, Terrault NA, Saab S, Balan V, Schiano T: Evidence-based incorporation of serum sodium concentration into MELD. Gastroenterology. 2006, 130: 1652-1660. 10.1053/j.gastro.2006.02.010.View ArticlePubMedGoogle Scholar
- Häussinger D, Schliess F: Pathogenetic mechanisms of hepatic encephalopathy. Gut. 2008, 57: 1156-1165. 10.1136/gut.2007.122176.View ArticlePubMedGoogle Scholar
- Badaut J, Lasbennes F, Magistretti PJ, Regli L: Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab. 2002, 22: 367-378.View ArticlePubMedGoogle Scholar
- Murphy N, Auzinger G, Bernel W, Wendon J: The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology. 2004, 39: 464-470. 10.1002/hep.20056.View ArticlePubMedGoogle Scholar
- Ruf AE, Kremers WK, Chavez LL, Descalzi VI, Podesta LG, Villamil FG: Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl. 2005, 11: 336-343. 10.1002/lt.20329.View ArticlePubMedGoogle Scholar
- Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT: Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008, 359: 1018-1026. 10.1056/NEJMoa0801209.View ArticlePubMedPubMed CentralGoogle Scholar
- Barber K, Pioli M, Blackwell J: Development of a UK score for patients with end-stage liver disease. Hepatology. 2007, 46: 510A-Google Scholar
- Hadem J, Tacke F, Bruns T, Langgartner J, Strnad P, Denk GU: Etiologies and outcomes of acute liver failure in Germany. Clin Gastroenterol Hepatol. 2012, 10: 664-669. 10.1016/j.cgh.2012.02.016. e2View ArticlePubMedGoogle Scholar
- Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL: A model to predict survival in patients with end-stage liver disease. Hepatology. 2001, 33: 464-470. 10.1053/jhep.2001.22172.View ArticlePubMedGoogle Scholar
- O’Grady JG, Gimson AE, O’Brien CJ, Pucknell A, Hughes RD, Williams R: Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology. 1988, 94: 1186-1192.View ArticlePubMedGoogle Scholar
- Jin Y-J, Lim Y-S, Han S, Lee HC, Hwang S, Lee SG: Predicting survival after living and deceased donor liver transplantation in adult patients with acute liver failure. J Gastroenterol. 2012, 47: 1115-1124. 10.1007/s00535-012-0570-7.View ArticlePubMedGoogle Scholar
- Poddar B, Saigal S, Kumar A, Singh RK, Azim A, Gurjar M: Factors associated with outcome in acute liver failure in an intensive care unit. Indian J Gastroenterol. 2012, Epub ahead of printGoogle Scholar
- Vitale A, Bertacco A, Gambato M, D’Amico F, Morales RR, Frigo AC: Model for end-stage liver disease-sodium and survival benefit in liver transplantation. Transpl Int. 2013, 26: 138-144. 10.1111/tri.12008.View ArticlePubMedGoogle Scholar
- McPhail MJW, Wendon JA, Bernal W: Meta-analysis of performance of Kings’s College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure. J Hepatol. 2010, 53: 492-499. 10.1016/j.jhep.2010.03.023.View ArticlePubMedGoogle Scholar
- Polson J: Assessment of prognosis in acute liver failure. Semin Liver Dis. 2008, 28: 218-225. 10.1055/s-2008-1073121.View ArticlePubMedGoogle Scholar
- Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC: A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000, 31: 864-871. 10.1053/he.2000.5852.View ArticlePubMedGoogle Scholar
- Larsen FS, Wendon J: Prevention and management of brain edema in patients with acute liver failure. Liver Transpl. 2008, 14 (Suppl 2): S90-96.View ArticlePubMedGoogle Scholar
- Rahman M, Friedman WA: Hyponatremia in neurosurgical patients: clinical guidelines development. Neurosurgery. 2009, 65: 925-935. 10.1227/01.NEU.0000358954.62182.B3. discussion 935–936View ArticlePubMedGoogle Scholar
- Graziani G, Cucchiari D, Aroldi A, Angelini C, Gaetani P, Selmi C: Syndrome of inappropriate secretion of antidiuretic hormone in traumatic brain injury: when tolvaptan becomes a life saving drug. J Neurol Neurosurg Psychiatry. 2012, 83: 510-512. 10.1136/jnnp-2011-300576.View ArticlePubMedGoogle Scholar
- Betrosian A-P, Agarwal B, Douzinas EE: Acute renal dysfunction in liver diseases. World J Gastroenterol. 2007, 13: 5552-5559.View ArticlePubMedPubMed CentralGoogle Scholar
- Vaa BE, Asrani SK, Dunn W, Kamath PS, Shah VH: Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis. Mayo Clin Proc. 2011, 86: 37-42. 10.4065/mcp.2010.0281.View ArticlePubMedPubMed CentralGoogle Scholar
- Samuel D, Ichai P: Prognosis indicator in acute liver failure: Is there a place for cell death markers?. J Hepatol. 2010, 53: 593-5. 10.1016/j.jhep.2010.06.002.View ArticlePubMedGoogle Scholar
- Remien CH, Adler FR, Waddoups L, Box TD, Sussman NL: Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: Early discrimination between survival and death. Hepatology. 2012, 56: 727-734. 10.1002/hep.25656.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/13/58/prepub
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