Biolato M, Miele L, Marrone G, Tarli C, Liguori A, Calia R, Addolorato G, Agnes S, Gasbarrini A, Pompili M, Grieco A. Frequency of and reasons behind non-listing in adult patients referred for liver transplantation: Results from a retrospective study. World J Transplant 2024; 14(2): 92376 [PMID: 38947971 DOI: 10.5500/wjt.v14.i2.92376]
Corresponding Author of This Article
Marco Biolato, MD, PhD, Staff Physician, Department of Medical and Surgical Sciences, CEMAD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome 00168, Italy. marco.biolato@policlinicogemelli.it
Research Domain of This Article
Transplantation
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Marco Biolato, Luca Miele, Giuseppe Marrone, Claudia Tarli, Antonio Liguori, Rosaria Calia, Giovanni Addolorato, Salvatore Agnes, Antonio Gasbarrini, Maurizio Pompili, Antonio Grieco, Department of Medical and Surgical Sciences, CEMAD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
Marco Biolato, Luca Miele, Giuseppe Marrone, Claudia Tarli, Antonio Liguori, Rosaria Calia, Giovanni Addolorato, Salvatore Agnes, Antonio Gasbarrini, Maurizio Pompili, Antonio Grieco, Department of Translational Medicine and Surgery, Catholic University of Sacred Heart, Rome 00168, Italy
Author contributions: Biolato M designed the study and wrote the paper; Marrone G, and Tarli C collected the data; Liguori A and Miele L analyzed the data; Calia R, Addolorato G, Pompili M, Agnes S, Gasbarrini A, and Grieco A revised the manuscript with an important intellectual contribution.
Institutional review board statement: The study was approved by the Institutional Review Board of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy, on 04 July 2019 Prot. 20048/19.
Informed consent statement: All subjects understood and agreed to the study protocol and voluntarily signed the informed consent form.
Conflict-of-interest statement: Dr. Biolato has nothing to disclose.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Marco Biolato, MD, PhD, Staff Physician, Department of Medical and Surgical Sciences, CEMAD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Rome 00168, Italy. marco.biolato@policlinicogemelli.it
Received: January 23, 2024 Revised: April 12, 2024 Accepted: April 26, 2024 Published online: June 18, 2024 Processing time: 142 Days and 13.2 Hours
Abstract
BACKGROUND
Few studies have evaluated the frequency of and the reasons behind the refusal of listing liver transplantation candidates.
AIM
To assess the ineligibility rate for liver transplantation and its motivations.
METHODS
A single-center retrospective study was conducted on adult patients which entailed a formal multidisciplinary assessment for liver transplantation eligibility. The predictors for listing were evaluated using multivariable logistic regression.
RESULTS
In our center, 314 patients underwent multidisciplinary work-up before liver transplantation enlisting over a three-year period. The most frequent reasons for transplant evaluation were decompensated cirrhosis (51.6%) and hepatocellular carcinoma (35.7%). The non-listing rate was 53.8% and the transplant rate was 34.4% for the whole cohort. Two hundred and five motivations for ineligibility were collected. The most common contraindications were psychological (9.3%), cardiovascular (6.8%), and surgical (5.9%). Inappropriate or premature referral accounted for 76 (37.1%) cases. On multivariable analysis, a referral from another hospital (OR: 2.113; 95%CI: 1.259–3.548) served as an independent predictor of non-listing.
CONCLUSION
A non-listing decision occurred in half of our cohort and was based on an inappropriate or premature referral in one case out of three. The referral from another hospital was taken as a strong predictor of non-listing.
Core Tip: Because of organ shortage and the need to optimize graft survival, patient candidates for liver transplantation must undergo an intensive multidisciplinary work-up to determine their suitability for registration on the waitlist. Few studies have evaluated the ineligibility rate for liver transplantation and its motivations. In this single-center, retrospective cohort study, the observed non-listing rate was 53.8% and about one out of three non-listing reasons was an inappropriate or premature referral. The external referral was a predictor of non-listing, so the betterment of the education and the training of referring physicians is recommended.
Citation: Biolato M, Miele L, Marrone G, Tarli C, Liguori A, Calia R, Addolorato G, Agnes S, Gasbarrini A, Pompili M, Grieco A. Frequency of and reasons behind non-listing in adult patients referred for liver transplantation: Results from a retrospective study. World J Transplant 2024; 14(2): 92376
Because of organ shortage and the need to optimize graft survival, patient candidates for liver transplantation must undergo an intensive multidisciplinary work-up to determine their suitability for registration on the waitlist[1]. The primary purpose of the evaluation process is to select candidates with a projected 5-year post-transplant survival rate of more than 50%[2]. The American Association for the Study of Liver Diseases guidelines[3] consider the following medical and non-medical non-listing reasons for liver transplantation: A Model for End-stage Liver Disease (MELD) Score < 15 (without other exceptions)[4], severe cardiac or pulmonary disease[5,6], Acquired Immuno-Deficiency Syndrome[7], ongoing alcohol or illicit substance abuse[8], hepatocellular carcinoma (HCC) with metastatic spread[9], uncontrolled sepsis[10], anatomic abnormality that precludes liver transplantation[11], intrahepatic cholangiocarcinoma[12], extrahepatic malignancy[13], acute liver failure (ALF) with sustained intracranial hypertension[14], hemangiosarcoma[15], persistent noncompliance or the lack of an adequate social support system[16,17]. Few studies have evaluated the ineligibility rate for liver transplantation and its motivations. This study aims to assess the ineligibility rate for liver transplantation and its motivations among potential candidates for liver transplantation.
MATERIALS AND METHODS
This is a retrospective cohort study that has been conducted at Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy). All adult patients with liver diseases who were referred for a formal multidisciplinary assessment of eligibility for liver transplantation from 1 January 2015 to 31 December 2017 were included in the study. The primary outcome was the percentage of evaluations that resulted in non-listing for liver transplantation (non-listing rate).
Our transplant center is included in the transplant program of the Lazio region; according to the program’s rules[18], only patients with a MELD sodium (MELD Na) score ≥ 15[19] or with the HCC within the up-to-7 criteria[20] are eligible for liver transplant waitlist. Moreover, our transplant center serves as a referral center for patients in the Abruzzo and Molise regions in a “hub-and-spoke” network. Hence, we admit a high percentage of patients who are referred from other hospitals (approximately 30%).
All patients were identified from a clinical referral database that contains information on all patients who are referred for liver transplant evaluation. We collected demographic and baseline clinical data on patients who were waitlisted and non-waitlisted for liver transplantation during the study period. In patients who suffered from more than one disease that led to liver dysfunction, we considered all possible components. In patients with more than one reason behind non-listing, we recorded all the non-listing reasons. The reasons behind the non-listing of patients were categorized as follows: Contraindications, incorrect indication, patient decision, and complications during the evaluation process.
Multidisciplinary evaluation process
The evaluation work-up was carried out on either an outpatient or an inpatient basis, according to the patient’s clinical conditions. All patients underwent an evaluation of their complete medical history and physical examination, including risk-appropriate cardiopulmonary evaluation. Laboratory work-up included the following: Complete blood count, coagulation tests, blood chemistry, ABO-Rh blood group determination, tumor markers, thyroid function, serologic tests for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), cytomegalovirus, Epstein-Barr virus, Herpes-simplex virus, Herpes-zoster virus, Syphilis, Toxoplasma, Rubella, molecular HBV-DNA, and HCV-RNA assays, both tuberculin skin test and QuantiFERON test for latent tuberculosis infection and both bacterial and fungal culture on blood, urine, stool and throat swab.
The cardiovascular work-up included electrocardiography, echocardiography, exercise or pharmacologic stress myocardial perfusion imaging by single-photon emission computed tomography (CT), followed by coronary angiography if it was indicated. Respiratory work-up included acid-base-balance, spirometry, and pulmonary artery systolic pressure estimation by echocardiography. The patients underwent total body CT scan with contrast medium to assess the anatomical variants of abdominal vessels, the possible presence of arcuate ligament syndrome, the possible presence and staging of portal vein thrombosis, the diagnosis and staging of HCC, and the search for lesions or occult abscesses in other districts. They also underwent portal vein Doppler ultrasound, supra-aortic vessels and vascular access Doppler ultrasound, electroencephalogram, gastroscopy, and colonoscopy if their age was more than 50 years. The nutritional consultant and the dietitian carried out nutritional assessment and education. Additionally, the women underwent a Papanicolaou smear screening test, transvaginal echography, and mammography, while the men underwent a prostate-specific antigen screening test. All patients underwent alcohol disorder evaluation conducted by a dedicated consultant (Addolorato G) and assessment by a dedicated psychologist (Calia R); subsequent psychiatric consultation was performed on a case-to-case basis. The dental evaluation included digital panoramic radiography, visits, and extractions if they were needed. In conclusion, patients underwent anesthesia and surgical assessment.
Patients with a diagnosis of ALF[21] were evaluated according to an accelerated protocol for possible listing in case of the urgent need for transplantation (status 1, according to the United Network for Organ Sharing). The accelerated protocol includes only a recapitulation of medical history and physical examination, complete blood count, coagulation tests, blood chemistry, ABO-Rh blood group determination, serologic tests for HAV, HBV, HCV, HIV, Cytomegalovirus, Epstein-Barr Virus, hepatitis E virus, electrocardiography, echocardiography, urgent cardiology consultation, and total body CT scan with a contrast medium.
Statistical analysis
Continuous data were expressed by mean ± SD and categorical data were expressed by frequencies and percentages. Independent samples student’s t-test and χ2 test were used for group comparisons wherever it was appropriate. Multivariable logistic regression was used to evaluate the predictors for listing. The differences were reported as statistically significant if the P value was less than 0.05. Statistical analysis was performed using SPSS version 17.0 (SPSS Inc., Chicago, IL).
RESULTS
In the 2015–2017 timeframe, 327 adult patients were referred to our center for liver transplant evaluation. Most patients (75%) were male and their mean age was 54.6 years. Since for 13 of the patients, a listing decision had not yet been taken as of 31 December 2017, our study cohort included 314 patients for whom the evaluation process for being registered in the liver transplantation waitlist was completed (Table 1). The most common reason behind the indication of listing was decompensated cirrhosis in 162 (51.6%) patients, followed by HCC in 112 (35.7%) patients, confirmed or suspected to be ALF in 34 (10.8%) patients, and other indications in 6 (1.9%) patients (5 patients for polycystic liver disease and 1 patient for portal hypertensive biliopathy). Most patients (87.3%) had liver cirrhosis; the most common etiologies were alcoholic liver disease (41.4%), HCV (22.3%), and non-alcoholic steatohepatitis (13.7%). Other etiologies are described in Table 2.
Table 1 Adult patients evaluated for liver transplantation by year.
Among the 314 evaluated patients, 145 (46.2%) patients were listed. Their final outcome was transplantation in 108 (34.4%) patients, still on the waitlist as of 31 December 2017 in 21 (6.7%) patients, and delisting in 16 (5.1%) patients (9 patients because of complications during waitlist, 3 because of HCC progression, 2 because of non-compliance and 2 after liver function improvement). In 169 patients, the decision to non-listing for the 2015–2017 period was made and, hence, the non-listing rate was 53.8% in our cohort.
Table 3 reports the reasons behind non-listing. The presence of contraindications accounted for 44.4% of the non-listing reasons; in particular, liver transplant contraindications were more frequently psychological (9.3%), cardiovascular (6.8%), and surgical (5.9%). An inappropriate or premature referral summed up for 37.1% of non-listing reasons and included 16.1% of cases where the patient had a low MELD Na score (below < 15), 10.2% of cases of recovery after conservative management for confirmed or suspected ALF and 7.8% cases of HCC beyond the up-to-7 criteria that were not amenable for downstaging. Moreover, there were 7.8% of cases where patients refused transplantation, 2.9% where people chose another center, and 1.5% where patients lost to follow-up. Finally, 6.3% of patients developed complications during the evaluation process and subsequently died. In 30 patients, there was more than one reason behind non-listing. Hence, we recorded 205 non-listing reasons out of our cohort of 169 patients.
Table 3 Reasons behind non-listing for liver transplantation.
Recovery after conservative management for confirmed or suspected ALF
21
10.2%
HCC beyond up-to-7 criteria and not amenable to downstaging
16
7.8%
Low Mayo Risk Score
4
2.0%
HCC successfully treated (T0)
2
1.0%
Patient decision
Refused transplantation
16
7.8%
25
12.2%
Chose another center
6
2.9%
Lost to follow-up
3
1.5%
Complications during evaluation
13
6.3%
13
6.3%
Total
205
100%
205
100%
According to patient features between the listed and non-listed patients (Table 2), we showed that male sex, the presence of HCC, past-HBV infection, and the presence of TIPS were significantly more frequent in patients who were listed, while a working diagnosis of confirmed or suspected ALF or a referral from another hospital were significantly more frequent in patients who were non-listed. In the multivariable analysis (Table 4), only the referral from another hospital (OR: 2.113; 95%CI: 1.259–3.548) and past HBV infection (OR: 0.373; 95%CI: 0.164–0.852) were confirmed to be significant predictors of non-listing and listing, respectively.
Table 4 Multivariate analysis of predictors for listing.
Variable
P value
OR (95%CI)
Referred from another hospital
0.005
2.113 (1.259–3.548)
Past HBV infection
0.019
0.373 (0.164–0.852)
HCC
0.068
0.623 (0.374–1.037)
Male sex
0.067
1.699 (0.964-2.994)
TIPS
0.116
0.439 (0.157–1.226)
ALF/Severe acute hepatitis
0.310
1.584 (0.651–3.852)
DISCUSSION
In this study, the observed non-listing rate was 53.8%. Few studies have evaluated the frequency of and the reasons behind a candidate’s refusal to enlist for liver transplantation. A single-center retrospective cohort study on 309 adult patients, evaluated in Singapore in the 1990–2001 timeframe, reported a non-listing rate of 65.7%[22]. The transplant center of Pisa (Italy), by adopting a step-by-step approach (preemptive evaluation, preliminary evaluation, and complete evaluation), obtained a non-listing rate of 73.7% in the 1996–2004 timeframe[23]. Another single-center retrospective cohort study among 314 adult patients completely evaluated in the British Columbia transplant center, Canada, in the 1997–2001 timeframe reported a non-listing rate of 46.8%[24]. The non-listing rate of Mayo Clinic (United States) in 2005, after the institution of the MELD scoring system for organ allocation, was found to be 53.1%[25]. A cohort study on 337 adult patients evaluated in London Ontario, Canada, in the 2009–2011 timeframe documented a non-listing rate of 49.3%[26]. According to the report by Mount Sinai Medical Center in New York, its non-listing rate was 58% in the 2000–2012 timeframe, reaching a rate of 82% in the HIV-positive population[27]. These older studies refer to an era in which the effect of anti-HBV and anti-HCV antiviral treatments had not yet been routinely applied; in recent years, waitlist registrations for HBV and HCV patients have been drastically reduced because of decompensation, persisting only registrations because of HCC, HDV co-infection or HBV-related ALF[28,29]. Our study confirms a non-listing rate of approximately 50% in a population predominantly suffering from alcohol-based and metabolic liver disease.
In our study, about one out of three non-listing reasons was inappropriate or premature referral. This is in line with other experiences[22-27] including those reported in a study in Tampa (United States) that was conducted among 242 evaluated candidates who were not listed for liver transplantation during the 2004–2006 period; retrospectively, the most common reasons behind non-listing were early referrals, psychosocial factors, and medical contraindications[30]. On the one hand, early referral undoubtedly entails a cost (for patients, family members, and healthcare providers) and subtracts the availability of resources from other candidates. On the other hand, it provides some benefits such as the optimization of patient care and monitoring, strengthens the doctor-patient relationship, and improves their understanding of the surgery. As per the reports by Mayo Clinic, many patients who were initially refused for liver transplant listing because of too early referral or because of psychosocial reasons, were subsequently re-presented and listed for liver transplantation. The authors concluded that early referral was beneficial for patients because the management of end-stage liver disease could consequently be initiated, and the psychosocial issues could be timely manner. Despite these observations, it is currently unclear whether early referrals influence (either positively or negatively) clinical outcomes and liver transplantation programs.
Moreover, it is unclear whether non-listing rates relate to the appropriateness of referrals from providers and/or to the effectiveness of the screening of referrals in the liver transplantation program. According to the multivariable analysis, the referral from another hospital was a significant predictor of non-listing. Given that our center has decided not to provide a preemptive evaluation, a possible explanation behind this decision is related to the heterogeneity of the spoke centers regarding the balance of potential contraindications to liver transplant. A potential perspective of our study is to implement better training of the spoke centers to optimize the referral process.
The main limitation of our study is that this is a single-center study and its external validity may be limited. A potential perspective of our study is to perform a multicenter study, possibly endorsed by a scientific society, to overcome this limitation and provide data that better reflect the national (or preferably international) state-of-the-art of liver transplant evaluation.
CONCLUSION
In conclusion, even in the post-Direct Antiviral Agents era, a final decision of ineligibility for liver transplantation was observed in half of our cohort. Inappropriate or premature referral occurred in one case out of three, but this did not necessarily amount to a flaw. Since the referral from other hospitals was considered a strong predictor of non-listing, the betterment of the education and the training of referring physicians is recommended.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Transplantation
Country of origin: Italy
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade A
P-Reviewer: Pan GD, China S-Editor: Lin C L-Editor: A P-Editor: Zhang YL
Neuberger J, Gimson A, Davies M, Akyol M, O'Grady J, Burroughs A, Hudson M; Liver Advisory Group; UK Blood and Transplant. Selection of patients for liver transplantation and allocation of donated livers in the UK.Gut. 2008;57:252-257.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 167][Cited by in F6Publishing: 149][Article Influence: 9.3][Reference Citation Analysis (0)]
Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.Hepatology. 2014;59:1144-1165.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 581][Cited by in F6Publishing: 620][Article Influence: 62.0][Reference Citation Analysis (0)]
Lentine KL, Costa SP, Weir MR, Robb JF, Fleisher LA, Kasiske BL, Carithers RL, Ragosta M, Bolton K, Auerbach AD, Eagle KA; American Heart Association Council on the Kidney in Cardiovascular Disease and Council on Peripheral Vascular Disease; American Heart Association; American College of Cardiology Foundation. Cardiac disease evaluation and management among kidney and liver transplantation candidates: a scientific statement from the American Heart Association and the American College of Cardiology Foundation: endorsed by the American Society of Transplant Surgeons, American Society of Transplantation, and National Kidney Foundation.Circulation. 2012;126:617-663.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 186][Cited by in F6Publishing: 191][Article Influence: 15.9][Reference Citation Analysis (0)]
Dew MA, Rosenberger EM, Myaskovsky L, DiMartini AF, DeVito Dabbs AJ, Posluszny DM, Steel J, Switzer GE, Shellmer DA, Greenhouse JB. Depression and Anxiety as Risk Factors for Morbidity and Mortality After Organ Transplantation: A Systematic Review and Meta-Analysis.Transplantation. 2015;100:988-1003.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 203][Cited by in F6Publishing: 187][Article Influence: 20.8][Reference Citation Analysis (0)]
Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, Camerini T, Roayaie S, Schwartz ME, Grazi GL, Adam R, Neuhaus P, Salizzoni M, Bruix J, Forner A, De Carlis L, Cillo U, Burroughs AK, Troisi R, Rossi M, Gerunda GE, Lerut J, Belghiti J, Boin I, Gugenheim J, Rochling F, Van Hoek B, Majno P; Metroticket Investigator Study Group. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.Lancet Oncol. 2009;10:35-43.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 1267][Cited by in F6Publishing: 1478][Article Influence: 92.4][Reference Citation Analysis (1)]
European Association for the Study of the Liver; Clinical practice guidelines panel, Wendon, J; Panel members, Cordoba J, Dhawan A, Larsen FS, Manns M, Samuel D, Simpson KJ, Yaron I; EASL Governing Board representative, Bernardi M. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.J Hepatol. 2017;66:1047-1081.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 417][Cited by in F6Publishing: 537][Article Influence: 76.7][Reference Citation Analysis (1)]
Wai CT, Prabhakaran K, Kaur M, Lee YM, Dan YY, Sutedja DS, Aw MM, Quak SH, Mak K, Isaac J, Lee KH, Lim SG. Successful listing of patients for liver transplant was related to participation of referring doctor in the transplant program.Transplant Proc. 2004;36:2230-2231.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 2][Cited by in F6Publishing: 2][Article Influence: 0.1][Reference Citation Analysis (0)]
Martel-Laferrière V, Michel A, Schaefer S, Bindal S, Bichoupan K, Branch AD, Huprikar S, Schiano TD, Perumalswami PV. Clinical characteristics of human immunodeficiency virus patients being referred for liver transplant evaluation: a descriptive cohort study.Transpl Infect Dis. 2015;17:527-535.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 2][Cited by in F6Publishing: 2][Article Influence: 0.2][Reference Citation Analysis (0)]
Belli LS, Perricone G, Adam R, Cortesi PA, Strazzabosco M, Facchetti R, Karam V, Salizzoni M, Andujar RL, Fondevila C, De Simone P, Morelli C, Fabregat-Prous J, Samuel D, Agarwaal K, Moreno Gonzales E, Charco R, Zieniewicz K, De Carlis L, Duvoux C; all the contributing centers (www. eltr.org) and the European Liver and Intestine Transplant Association (ELITA). Impact of DAAs on liver transplantation: Major effects on the evolution of indications and results. An ELITA study based on the ELTR registry.J Hepatol. 2018;69:810-817.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 162][Cited by in F6Publishing: 164][Article Influence: 27.3][Reference Citation Analysis (0)]
