Comparison Between Era1 (2003-2009) and Era2 (2009-2015)
Recipients in Era2 were statistically older (43.2 years vs 41.7 years, P = 0.03), but there was no difference in the sex or ethnicity distribution compared with Era1. There were significant differences in the distribution of the disease etiology. In the latter era a greater proportion of patients received a liver transplant due to AIH, while a smaller proportion was transplanted for nonspecified ALF or retransplantation (Table 2).
The mean waiting time significantly decreased in Era2 compared with Era1 (41.4 days vs 56.7 days, P = 0.005) but there was no difference in the proportion who received a liver within 7 days. These data are confusing because 76% of patients in the entire cohort were transplanted within 7 days, and likely reflect differences in a relatively small group of patients with AIH who were listed with chronic disease but changed to a fulminant course at some point. Such patients would be noted as having long waitlist times, though the actual amount of time while in status-1 may have been short. Also, in the latter period, patients with AIH were more likely to be transplanted within 7 days compared with the previous era.
Donors were significantly younger and there were minor differences in ethnicity in the later era. Fewer patients in Era2 received an ABO-incompatible graft. Overall survival was significantly better for patients in Era2 compared with patients in Era1 (see Figure 3). After controlling for potential confounders, the risk of death for patients in Era1 was significantly higher than for patients in Era2 (HR, 1.28; 95% CI, 1.06-1.55). The lower 5-year survival rate from the latter period is likely skewed, as 5-year data was not available for most of that cohort. Indeed, all other measures of survival (1- and 3-year survivals, overall percentage alive, and retransplants) were significantly improved in the latter era (Supplemental material, SDC,http://links.lww.com/TP/B492).
Subgroups of Patients by Cause of Liver Failure
There were 367 cases of AIH (15.2% of total cases) and of the specific disease etiology groups, this was the only group that had an increase in the number of cases over time (219 vs 148 in Era2 vs Era1) and a higher proportion (19.9% vs 11.3% in Era2 vs Era1) Survival was significantly better for Era2 than for Era1 patients on univariate analysis, (P = 0.05), with a nonsignificant trend favoring Era2 patients after adjusting for potential confounders (HR, 1.72; 95% CI, 0.98-3.01) (Figure 3). Mean waiting times and transplant within 7 days did not differ between the eras. However, waiting times were long compared to other disease etiology groups (Table 3).
Drug-Induced Liver Disease
There were 626 cases of DILI which comprised 26% of the entire cohort. The drugs responsible included: acetaminophen (n = 300), antibiotics (n = 30), antituberculous medications (n = 30), HDS (n = 20), antiepileptic medications (n = 15), nonsteroidal anti-inflammatory drugs (n = 12), statins (n = 10), antivirals for HIV therapy (n = 4), antihypertensive medication (n = 4), disulfiram (n = 4), propylthiouracil (n = 4), methotrexate (n = 2), anesthetics (n = 2), amiodarone (n = 2), and narcotics (n = 2). Seventeen cases were due to multiple drugs, 14 due to “other drug,” and 154 cases did not list a specific drug. There was no difference in the proportion of cases that were DILI between eras (341 cases in Era1 vs 285 cases in Era2). Acetaminophen was the leading cause of non-HDS DILI in both Era1(n = 155, 11.8%) and Era2 (n = 145, 13.2%). HDS were the cause of DILI in 6 cases in Era1 and 14 cases in Era2. (P = 0.04). There was no significant difference in survival in DILI patients between Era2 and Era1 patients (adjusted HR, 1.37; 95% CI, 0.94-2.01) (Figure 3).
Nonspecified Fulminant Hepatic Failure
The nonspecified ALF group comprised the largest group at 1046 patients (43.4%) however, there were fewer cases and a smaller proportion of these patients in the later era. The mean waiting time improved significantly in Era2 (12.1 days vs 47.7 days, P = 0.001), and more patients were transplanted within 7 days (85.2% vs 75.7%, P < 0.001). Survival among Era2 and Era1 patients was not significant on univariate (P = 0.31) or adjusted analysis (HR, 1.13; 95% CI, 0.83-1.54) (Figure 3).
In the entire cohort, 201 retransplants occurred in 192 patients. Nine patients received 3 transplants each. Of the 201 retransplants, 145 patients were initially transplanted for chronic reasons with MELD allocation. Reasons for retransplantation included: 76 hepatic artery thrombosis, 52 primary nonfunction and 3 with severe acute rejection. The remaining 14 patients had other reasons including chronic issues, nonspecific ALF, and ischemic cholangiopathy. Forty-seven patients were initially transplanted as a status-1 and required retransplant, again at status-1. Patients who underwent retransplant had the worst 1- and 3-year survival compared with other etiologies for status-1 transplantation. There was no significant difference in survival between Era2 and Era1 patients (Figure 3).
Viral, Chronic Disease, Metabolic, Other
Status-1 liver transplant for viral etiologies comprised 2.9% of the cohort. Of these 70 patients, 44 patients had fulminant hepatitis B and 16 had an unknown viral etiology. Other viral illnesses included: 4 herpes virus, 3 hepatitis E, 2 hepatitis C/human immunodeficiency virus, 2 and 1 cytomegalovirus infection. In comparing eras, there was no difference in 1-, 3-, and 5-year survival, mean waiting times or proportion waiting less than 7 days.
Thirty-nine (1.6%) patients had chronic diseases listed as the etiology for liver transplant that received a status-1 liver transplant. Ten patients had hepatitis C cirrhosis and 10 had fat-related liver problem listed as either “fatty liver,” “nonalcoholic steatohepatitis,” or “steatosis.” Eight patients had “end-stage liver disease” without additional details. Two patients had an acute alcohol related liver failure. Other diagnosis included polycystic liver disease, family hypercholesterolemia, Eagle-Barrett syndrome, primary sclerosing cholangitis, and familial adenomatous polyposis. Waiting times were long in this group, and there was limited detail to determine the reason for status-1 LT.
Ten patients had metabolic problems as a reason for status-1 LT including 9 with Wilson disease and 1 with hyperhomocysteinuria. Finally, there were 49 patients who had various etiologies that could not be combined into a single large group. Sixteen patients required LT for an acute vascular problem including portal vein thrombosis (n = 13) and Budd-Chiari syndrome (n = 3). Thirteen patients had ALF related to pregnancy/postpartum (acute fatty liver [n = 6], hemolysis/elevated liver enzymes/low platelet syndrome [n = 5], and nonspecified ALF [n = 2]). Eight patients had liver failure as a result of a surgical catastrophe or traumatic injury, including 4 liver resections, 3 ruptured livers due to trauma/benign tumor, 1 cholecystectomy, and 1 iatrogenic arterial injury. The remaining cases included mushroom toxicity (n = 5), heatstroke (n = 3), and 1 case of epitheloid angiosarcoma. Survival rates for the category of “all others” were excellent and unchanged between the eras, although the heterogeneity of the cases may be too small to draw conclusions. Mean waiting time for transplant improved in the “other” group in Era2 (4.0 days vs 56.2 days for Era1, P = 0.05); however, the proportion who waited 7 days or less was similar.
Use of the status-1 designation for urgent LT comprises a small but important fraction of patients receiving LT annually. Status-1 patients have a high mortality on the waiting list and potentially poor outcome if transplantation is not done in a timely manner. Despite these challenges, this study demonstrated that outcome is excellent and overall survival from status-1 LT has improved over time. With time, there have been fewer cases of status-1 liver transplant, fewer retransplants, lower mean waiting time and fewer ABO-incompatible transplants. About 75% to 80% of these patients were able to receive an LT within 7 days.
Just which patients should be considered for urgent LT is becoming increasingly important as the demand for LT increases and patients get sicker while waiting for suitable donors.8 Indeed, recent studies show that patients with end-stage liver disease and MELD scores greater than 35 have higher waitlist mortality compared to patients qualifying for status-1 (ALF and urgent retransplants).9,10 Status-1 has been traditionally reserved for the sickest patients whose death is thought to be imminent without urgent LT. This study demonstrated a marked decrease in the number of patients listed with the status-1 designation over the last 12 years. The overall number of urgent LT was relatively constant with successive years, but has decreased as a proportion of the overall number of LT. What are the causes for these changes? Almost certainly, one of the major reasons is an overall improvement in the care of patients with ALF.11,12 Transplant-free survival for patients with ALF has increased significantly over the last decade, probably due to better clinical understanding of the syndrome and improved critical care management. These changes have occurred in the face of an unchanging incidence of ALF.12 Data from the 2015 annual OPTN/SRTR statistics on liver transplant noted that the pretransplant mortality rates for ALF have remained stable at 18% to 20% over the same period.13 One can conclude from this data in combination with ours that many patients were listed, not transplanted, and recovered without the need for transplant, especially in the earlier years. Similarly, the significant decline in status-1 listings over time in face of stable waitlist mortality rate suggests that the transplant community has become more proficient at identifying patients actually needing transplant for the most urgent indications. Although it is unclear from the data which etiologies of ALF have accounted for the decrease in listings, the likely etiology is acetaminophen overdose, given significant advances in identification, treatment, and intensive care unit care for these patients.
Our study also demonstrated a decrease in the need for urgent retransplant and better survival in recent years. Improved surgical techniques and vigilant ultrasound monitoring to detect early vascular problems may be contributing to early recognition and timely surgical rescue.14,15 More recently, nonoperative endovascular techniques may allow salvage of hepatic artery stenosis/thrombosis to avoid the need for retransplant.16-21 Use of donors after circulatory death may have more ischemic cholangiopathy, but the need for urgent retransplant in this group may not be different from a standard donor. Allen et al reviewed 950 cases of retransplantation in the SRTR and this showed only 0.7% of donors after circulatory death transplants compared to 3.8% of standard criteria donor required status-1 retransplant.22 Although the exact reasons for decreased urgent retransplant is beyond the scope of this study, appropriate donor selection and recipient management of vascular issues likely have contributed.
AIH is one of a few liver diseases that may initially present as a chronic condition but later transition to ALF. Nonfulminant AIH can progress to cirrhosis and about 10% of all patients with AIH will eventually need liver transplant.23 Because AIH may present as a chronic and relatively stable condition, these patients are frequently placed on the transplant list electively, only later to have an acute flare and be reclassified as ALF (and given the status-1 designation). Data from this study support this notion, with long mean waiting time likely reflecting time on the list while in a chronic phase of the disease. In the more recent period, more patients received urgent LT for AIH compared with the earlier period. This “increase” in urgent LT for AIH likely reflects improved recognition of AIH as the cause of ALF. Indeed, the most significant decrease in etiology of liver disease receiving urgent LT was “nonspecified ALF,” probably because many of these patients were more promptly diagnosed with AIH in more recent years. This is also supported by the changes in mean waiting time for nonspecified ALF (decrease) and AIH (increase) over time, likely because some of the patients in the nonspecified ALF in the earlier era were actually AIH (and correctly identified in the recent era) In our series, patients with AIH had longer waiting times compared to the overall cohort (49.7 days) and only 42-50% waited less than 7 days. These patients may have initially been listed with the MELD scheme but then changed to status-1 after rapid progression of disease but the available data could not determine this exactly. Regardless of these waiting times, 1-, 3-, and 5-year survival have remained excellent over time and similar to multiple reported series.24-26
Our study represents the largest series of DILI requiring status-1 liver transplant and an update of previous analyses of the SRTR in 2004 and 2009.27,28 The proportion of patients receiving urgent LT for DILI was unchanged over the periods we studied (about 25% of urgent LT), and the relative proportions of acetaminophen and nonacetaminophen as indications for urgent LT were also stable (approximately 50% each). These numbers are remarkable as the incidence of acetaminophen-related hepatotoxicity is increasing in the United States and Europe.29,30 That there are not increasing numbers of urgent LT for acetaminophen toxicity likely speaks to the higher transplant-free survival for these patients compared to nonacetaminophen etiologies as well as increasing numbers of patients with acetaminophen toxicity and psychiatric contraindications to LT.31 Patients undergoing urgent LT for acetaminophen continue to enjoy excellent 1-, 3-, and 5-year posttransplant survival rates, but there has been a striking decrease in 5-year survival for nonacetaminophen DILI patients for unclear reasons.
Other nonacetaminophen drugs such as HDS have become more culpable in recent years.32,33 Specifically there were 6 cases HDS in Era1 compared to 14 cases in Era2 (P = 0.04). HDS will likely continue to impact the demand for liver transplant as dietary supplements constitute a US $29 billion industry and more than half of the US population takes some type of supplement.34 The National Medicine Comprehensive Database has more than 54,000 dietary supplement products of which only a third have some level of safety and effectiveness, while 12% have known safety concerns.35 The Drug-Induced Liver Injury Network (DILIN), which prospectively studies hepatotoxicity, noted that 15.5% of the patients enrolled had injury from an HDS and this proportion increased from 7% to 20% during the 10 years studied.36 One-, 3-, and 5-year survival for DILI are excellent and unchanged over time and similar to that reported previously.28 Early survival in the nonacetaminophen DILI is good; however, the 5-year survival is significantly worse in the later era. Newer drugs including HDS may impact the need and survival for status-1 LT and will need to be monitored closely in the future.
Limitations of the study reflect limitations of the SRTR database. A significant number of status-1 cases (>40%) were classified as having a “nonspecified” etiology for ALF, which may skew the results. The data show that more recently the transplant community has been better at reporting specific diagnoses, but many cases remain without identified etiology. Although the number of nonspecified ALF is likely to further decrease in the future, there will always be a significant proportion of ALF with unrecognized cause. Increasing recognition of DILI and AIH will hopefully decrease some uncertainty in the future. Second, the large number of patients with prolonged waiting times as status-1 highlights the limitations of this retrospective database. More detailed data as to whether patients were waiting in a MELD-based status before conversion to status-1 would be necessary to truly make conclusions about waiting time. Finally, the SRTR includes only patients listed for transplant—not the entire population of ALF patients for whom liver transplant might be indicated. This limitation prevents true assessment for the marked decrease in status-1 listing over time. Future studies using ALF/acute liver injury databases in conjunction with SRTR data are clearly warranted.
Despite these limitations, our study showed that status-1 LT continues to yield good survival, but fewer transplants and retransplants were performed more recently likely due to improvements in management of patients with ALF. Mean waiting times are improved and 75% to 80% of those who underwent liver transplant were able to obtain a liver within a week. Transplant centers are improving in their assignment of a specific diagnosis but continued efforts should be made to identify etiologies for fulminant failure and report these, so we can educate the public and medical community on potential hepatotoxic agents and preventable etiologies. Minimizing the need for status-1 liver transplant will ultimately allow more donor livers to be available for chronic, nonpreventable illnesses.
The authors would like to thank Guang Xiang Zhang for his statistical assistance and expertise.
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