Since the United Network for Organ Sharing was awarded the Organ Procurement and Transplantation Network contract in 1987, priority has always been given to those liver transplant candidates having the highest urgency. In 1987, the term “UNOS-stat” was used to identify such candidates who were expected to live less than 24 hours. At this time no distinction was made between adults and pediatric recipients, and the category included patients with both acute and chronic liver disease. This occurred at a time when there was a limited number of liver transplant programs, less than 2,000 patients on the waiting list, and the mean waiting time to receive a deceased donor organ was less than a mean of 125 days. However, the UNOS-stat criteria were poorly defined and, indeed, such patients often had multiorgan failure and/or systemic infection and, in fact, were patients who were often too sick to be transplanted, and lead to poor outcomes. Furthermore, the lack of objective criteria led to generous interpretations of which candidates had a life expectancy of less than 24 hours.
In 1991, the Status 4 category was defined, which was later changed to Status 1. The Status 1 category was defined by patients in the intensive care unit who were judged to have a life expectancy of less than 7 days. The Status 1 category included patients with both acute and chronic liver disease as well as adult and pediatric patients. Overall waiting time determined which Status 1 patients received a donor organ. In 1991, the Status 1 definition suffered from the same problems that plagued the UNOS-stat definition; namely, that severity of illness and probability of dying on the waiting list were not well represented by the ICU location and waiting time criteria.
It was not until 1997 that the definition for Status 1 for adults was redefined to include only those candidates with acute liver failure who were in the intensive care unit with a life expectancy without liver transplantation of less than 7 days. The definition of acute liver failure included patients with acute fulminant hepatitis, defined as onset of portosystemic encephalopathy within 8 weeks of the first liver symptoms, and without a history of preexisting liver disease. The criteria for the diagnosis of acute fulminant hepatitis included the presence of portosystemic encephalopathy (stage 2 or greater), hyperbilirubinemia (serum bilirubin level ≥ 15 mg/dL), and a prolonged international normalized ratio of >2.5 or hypoglycemia (not defined). Other candidates defined for status 1 included recipients who developed primary graft nonfunction (PNF) occurring within 7 days of liver transplantation (not further defined) and patients with hepatic artery thrombosis (HAT) diagnosed on ultrasound or angiogram within 7 days of their primary transplant. In addition, patients with acute Wilson's Disease were also included in the Status 1 definition.
In 1998, the first attempt was made at a separate definition for Status 1 criteria for children was introduced. Pediatric candidates <18 years of age could be listed for Status 1 if the patient was located in the intensive care unit (criteria undefined) with acute or chronic liver disease, and experienced 1 of the following complications: gastrointestinal bleeding, hepatorenal syndrome, refractory ascites, uncontrolled portosystemic encephalopathy, and, by the clinician's assessment, had an estimated life expectancy without liver transplant of less than 7 days. Furthermore, each Status 1 recipient was reviewed by a Regional Review Board to determine the appropriateness of Status 1 listing. These changes set the stage for Regional 1 sharing for Status 1 patients for both adults and children, which commenced in early 1999. Even with the implementation of the model for end-stage liver disease (MELD) / pediatric end-stage liver disease (PELD) allocation system in 2002, the Status 1 definition remained unchanged. Figures 1 and 2 show the impact of changing the Status 1 definition and the institution of the use of Regional Review Boards in 1997 on the number of Status 1 deaths on the waiting list, as well as on the number of Status 1 liver transplants performed each year (Figs. 1 and 2).
MELD, model for end-stage liver disease; PNF, primary nonfunction; FHF, fulminant hepatic failure; PELD, pediatric end-stage liver disease; FHF-NA, fulminant hepatic failure not related to acetaminophen; FHF-A, fulminant hepatic failure related to acetaminophen; HAT, hepatic artery thrombosis.
Selection Criteria for Liver Transplantation in Patients with FHF
Acute liver failure or fulminant hepatic failure (FHF) is a syndrome characterized by an abrupt onset of jaundice and hepatic encephalopathy in the absence of preexisting liver disease. The causes of FHF vary, but all are associated with a high morbidity and mortality, with up to 80% of patients dying from the syndrome without the intervention of orthotopic liver transplantation. With liver transplantation, the course of FHF has been markedly altered, since post–liver transplant survival remains just slightly less than that achieved in patients with chronic liver disease.
Early determination of prognosis and prompt decision-making regarding liver transplantation is important in the management of patients with FHF.1–5 Indeed, 2 prognostic models have been evaluated for their ability to predict mortality and to serve as a guide for listing patients with FHF for liver transplantation. These 2 prognostic indices include the London criteria and the Clichy criteria (Table 1). However, both the London and the Clichy criteria have been found to have a low negative predictive value (less than .60) and thus do not identify a subgroup of patients with a low risk of death. This could result in inappropriate use of liver transplantation in a subgroup of patients with acute fulminant hepatitis who would otherwise recover without transplantation. In a recent study, the London and Clichy criteria were compared to the MELD score in patients presenting with FHF of various etiologies, but excluding patients having FHF related to acetaminophen (FHF-A). The study found that the MELD score appeared to be an excellent predictor of outcome in both adults and children with FHF, with a diagnostic accuracy of 95% and a C-statistic score of 0.96.6 Compared to the London and Clichy prognostic criteria, MELD was associated with the lowest rate of false-negative results (Table 2). The data support the conclusion that the MELD score is the better predictor of mortality in both adults and children with FHF. However, further studies will be needed to confirm these single-center results.
Table 1. Models to Predict Prognosis in Fulminant Hepatic Failure
INR > 6.5 or any 3 of the following:
Age < 10 or > 40 years
Duration of jaundice before onset
Encephalopathy > 7 days
INR > 3.5
Bilirubin > 17.5 mg/dL
Factor V < 20% age < 30 years
<30% age > 30 years
MELD/ PELD ≥ 30
Table 2. Assessment of Prognosis in Fulminant Hepatic Failure*
Abbreviations: PPV, positive predictive value; NPV, negative predictive value; MELD, model for end-stage liver disease; DA, diagnostic accuracy.
Outcomes of Adult Status 1 Patients in the United States
With the introduction of the new Status 1 criteria in 1997, an analysis was performed of the outcomes of Status 1 patients undergoing liver transplant between November 1999 and March 2002. During this period of time, 836 adult patients (18 years of age or older) were listed as Status 1 for liver transplantation in the United States. Of these Status 1 patients, 733 met the strict definition for United Network for Organ Sharing Status 1. There were 103 patients (12.3%) who did not fulfill the criteria for Status 1 listing, but were granted Status 1 by their Regional Review Board, who scrutinized all urgent listings. Many of these patients had chronic liver disease and experienced a complication of portal hypertension such as refractory ascites, portosystemic encephalopathy, or variceal bleeding, and were estimated to be at high risk of dying on the waiting list.
The mean age of the Status 1 cohort was 44.3 years and the majority of patients were Caucasian (66.2%), African-American (14.5%), and Hispanic (12.4%). The mean MELD score of these Status 1 patients was 32.5. Of the patients meeting the United Network for Organ Sharing Status 1 criteria, 312 (42.5%) had acute FHF not related to acetaminophen (FHF-NA), 76 patients (10.3%) had acute FHF-A, 268 patients (36.5%) had acute hepatic failure related to PNF within 7 days of transplant, and 64 patients (8.7%) had HAT occurring within 7 days of the original liver transplant (Table 3). An additional 13 patients had acute FHF related to Wilson's disease. Patients with FHF-NA or FHF-A were younger, more often female, and had significantly higher MELD scores compared to Status 1 patients with PNF or HAT (Table 3).7 Furthermore, estimated 7-day survival on the waiting list was significantly better in patients with PNF and HAT compared to patients with FHF-NA or FHF-A (Fig. 3). In patients with FHF-NA, the MELD score was predictive of mortality (P < .0001) (Fig. 4). However, the MELD score was not predictive of pretransplant mortality for patients with FHF-A, HAT, and PNF. Following liver transplantation, patients with FHF-A had the poorest survival, while the best posttransplant survival was observed in patients undergoing liver transplant for FHF-NA (Fig. 5). Patients having FHF-NA had the greatest benefit, with a 30-day estimated survival with transplantation of 91% and an estimated 30-day survival without liver transplantation of 58% (P < .0001) (Fig. 6). This compares to the patients with PNF, in which the 30-day estimated survival with transplantation was 75% and the 30-day estimated survival without liver transplant was 82% (Fig. 6). Conclusions from this study suggest that there are marked survival differences between the various Status 1 diagnostic groups of adult patients. The data suggests that patients with FHF-NA with high MELD scores should be given the highest priority for organ allocation because of an increased risk of death on the waiting list and their excellent short-term survival following liver transplantation. The data suggest that the criteria for highest urgency in Status 1 category should be redefined. The data also suggest that more objective measures predictive of mortality are needed in patients with PNF and HAT if we are to optimize the use of our donor organ supply.
Table 3. Characteristics of UNOS Status 1 Patients Listed Between November 1999 and March 2002
Outcomes of Pediatric Status 1 Patients in the United States
Following the institution of the MELD / PELD allocation system, it became obvious that some regions in the country had an unusually high number of pediatric candidates who were being transplanted at Status 1. The study showed wide regional variations in the percent of pediatric listings at Status 1, ranging from as low as 7% to as high as 75%. The impact of this practice led to increasing difficulty for pediatric candidates with chronic liver disease and who had a relatively high PELD score (i.e., greater than 25) to get transplanted in a timely manner in regions where higher proportions of patients were being transplanted as Status 1. Indeed, between 2002 and 2003, 587 of 1,328 pediatric transplants (44%) were performed for Status 1 recipients. Furthermore, it was found that in the MELD era, 76 of 275 (27.6%) of these Status 1 patients were exceptions to the Status 1 definition, meaning the patient did not meet the defined criteria for Status 1, but were granted status 1 standing by the Regional Review Board. The argument was that these pediatric patients were judged by the clinician to be at high risk of dying on the waiting list before an acceptable donor organ could be found.8 However, in an analysis performed by the Scientific Registry of Transplant Recipients (SRTR), the pediatric Status 1 exceptions had a significantly lower death rate compared to pediatric patients having FHF, PNF, HAT, or those with chronic liver disease having a PELD score of greater than 25 (Fig. 7). Furthermore, these exceptional pediatric patients had very low PELD scores (median of 8) compared to the other Status 1 patients (Fig. 7). On the basis of these findings, changes in criteria for Status 1 designation have been proposed for pediatric and adult candidates.
Proposed Adult Criteria for Status 1a
1FHF, defined as onset of hepatic encephalopathy within 8 weeks of the 1st symptoms of liver disease. The absence of preexisting liver disease is critical to the diagnosis. One of the 3 criteria below must be met to list an adult patient who must be in the intensive care unit.
bRequiring dialysis or continuous venous-venous hemofiltration
cInternational normalized ratio greater than 2.5
2PNF of a transplanted liver within 7 days of implantation defined with the following criteria:
aAlanine aminotransferase greater than 2,000 IU/L, or 1 or both of the following:
iInternational normalized ratio greater than 2.5
iiAcidosis defined as having a pH of less than 7.3 and/or a lactate level of greater than or equal to 2 times normal
4HAT in a transplanted liver within 7 days of implantation, defined with the same criteria as for PNF above. Patients with HAT not meeting the primary non-function biochemical criteria will be listed with a MELD of 40.
5Acute decompensated Wilson's disease.
Proposed Pediatric Definitions for Status 1a and 1b
Pediatric patients listed at 1a or 1b should both be in the hospital intensive care unit. Criteria for 1a status in pediatric patients are as follows:
1FHF defined as the onset of hepatic encephalopathy within 8 weeks of the 1st symptoms of liver disease. The absence of preexisting liver disease is critical to the diagnosis. One of 3 criteria below must be met to list a pediatric patient with FHF:
bRequiring dialysis or continuous venous-venous hemofiltration
cInternational normalized ratio greater than 2.5
2PNF of the transplanted liver in which the diagnosis is made within 7 days of implantation. Additional criteria to be met for this indication include 2 of the following:
aAlanine aminotransferase greater than or equal to 2,000 IU/L
bInternational normalized ratio greater than 2.5 or a total bilirubin greater than or equal to 10 mg/dL. All laboratory values must be from the same blood draw within 24 hours in the 7 days following the transplant.
3Diagnosis of HAT in a transplanted liver within 14 days of implantation.
4Acute decompensated Wilson's disease.
Criteria for status 1b for pediatric patients include the following:
1A patient with chronic liver disease in the intensive care unit with 1 of the following criteria:
aOn mechanical ventilator
bHaving a calculated PELD score of greater than 25 or a calculated MELD score of greater than 25 for adolescents (12-17 years of age) and gastrointestinal bleeding requiring at least 30 cc/kg of red blood cell replacement within the previous 24 hours.
cHaving a calculated PELD score of greater than 25 or a calculated MELD score of greater than 25 for adolescent candidates (12-17 years of age) and renal failure or renal insufficiency defined as requiring dialysis or continuous venous-venous hemofiltration.
dHave a calculated PELD score of greater than 25 or a calculated MELD score greater than 25 for adolescent (12-17 years of age) and a Glasgow Como score of less than 10.
ePatient with urea cycle defect or Crigler-Najjar disease type 1 may be listed as Status 1b.
fPediatric liver candidates with hepatoblastoma may be listed as 1b.
Liver allocation has evolved since the inception of the United Network for Organ Sharing program in 1987. Indeed, patients with FHF, PNF, or HAT have now been shown to have a higher probability of dying on the waiting list as compared to patients with chronic liver disease, and thus, should be given priority over such patients. In adults, patients with FHF have the highest probability of dying on the list and have the best outcome when liver transplant is performed expeditiously. On the other hand, patients developing HAT and PNF are less at risk for dying on the waiting list, and have less favorable outcomes after liver transplantation. Indeed, better criteria will be needed to define patients within the PNF and HAT group who are indeed at the highest risk of dying while waiting for transplantation. Their rate of death on the waiting list needs to be compared to patients with FHF.
In the pediatric population, the major problem has been the large number of exceptional cases that have been granted by the Review Board. Current data indicate that the risk of death is significantly less for such exceptional patients at Status 1, and therefore, stricter definitions will be needed so that pediatric Status 1 patients with acute liver failure, PNF, or HAT are not put at a disadvantage. In addition, it has shown that pediatric patients with Status 1 chronic liver disease having a PELD score of greater than 25 also have a high mortality risk and, therefore, should be given higher priority. The current recommendation is to include patients with acute liver failure, PNF, or HAT in a Status 1a category that would take priority over patients listed as Status 1b, and would include patients with chronic liver disease. The elimination of Status 1 by exception is being considered.
These proposed changes for Status 1 recipients should have a positive impact, better prioritizing patients within the Status 1 category based on probability of dying while waiting for a deceased donor organ. In addition, recent proposals to have a national review board with a more uniform approach to the interpretation of the definitions of Status1 might be helpful. Further data will be collected if and when these proposed changes to Status 1 definition are approved.