When to Refer for Liver Transplantation

Educational Objectives

The goal of this program is to improve survival of patients with liver disease through appropriate referral for liver transplantation (LT). After hearing and assimilating this program, the clinician will be better able to:

1. Select appropriate candidates for LT.
2. Recognize contraindications to LT.
3. Optimize patients with portopulmonary hypertension to improve eligibility for LT.

Summary

Liver Transplantation (LT) Statistics

Introduction: 2021 Scientific Registry Of Transplant Recipients data show that several key differences have occurred in LT over the past decade; >9000 LTs were performed in 2021; the data show a sharp (almost exponential) incline in the rate of LT for alcoholic liver disease (ALD), including severe alcoholic hepatitis (sAH) and chronic ALD, whereas LT for other indications remained stable or decreased (eg, hepatitis C); the rate for nonalcoholic steatohepatitis (NASH) is a “distant second”; in 2021, ALD was the indication for ≈40% of LTs (vs ≈17.5% in 2011)

Distinct differences between 2011 and 2021: wait time — LT occurred within 90 days in 52.6% in 2021 vs 43.7% in 2011 (likely related to higher Model for End-stage Liver Disease [MELD] scores in patients with ALD); rate of transplants from donation after circulatory death (DCD) — increased from ≈4.6% to >10% (likely attributable to changes in allocation policy, the increased use of marginal organs related to extended liver criteria, and the advent of machine perfusion pumping)

Survival without LT in patients with cirrhosis: the likelihood of survival drops significantly in decompensated cirrhosis (DC), compared with compensated cirrhosis (CC); patients with CC have good survival rates; patients with DC can develop ascites, hepatic encephalopathy (HE), coagulopathy, and sarcopenia; without LT, significant mortality within 1 yr (≈57%) is seen in patients with stage 3 or 4 DC, bleeding varices, and ascites

Organ Allocation and Patient Evaluation for LT

MELD score: implemented in 2002; MELD exceptions were added to increase equitability; changes were made to the score to incorporate significant factors that enable early transplantation, eg, MELD-Na; MELD 3.0 includes albumin and sex; distribution changes — from Share 35 to the development of acuity circles and continuous distribution

Importance of MELD scores: designed to improve standardization for organ allocation (higher priority for patients with higher scores); MELD scores accurately predict 90-day mortality; the survival rate begins to decrease at a MELD score of ≈15; the 3-mo survival rate is dismal with MELD scores >30

Limitations: MELD scores do not capture all patient characteristics that contribute to mortality; do not reflect the true mortality risk for certain situations, eg, hepatocellular carcinoma (HCC), portopulmonary hypertension (POPH), and hepatopulmonary syndrome (HPS); the United Network for Organ Sharing (UNOS) has assigned MELD exception points for these conditions to “artificially raise” MELD scores; the median MELD score required for LT varies across regions

Barriers to LT: MELD score that does not capture the severity of illness; residing a long distance from the closest transplantation center; poor family support; psychosocial issues; overcoming barriers requires a multidisciplinary approach; in addition to the primary evaluation team, this should include a social worker, mental health provider, nutritionist, other medical specialists (eg, cardiologists, nephrologists) to optimize comorbid conditions, and palliative care

Determining Candidacy for LT

Considerations: include the patient’s medical evaluation, transplant outcomes, and results of a psychosocial evaluation

Stanford Integrated Psychosocial Assessment for Transplant (SIPAT) score: assesses, eg, patient readiness, acceptance, knowledge about the transplantation process and the reason for LT, the patient’s adherence to medical recommendations, and his or her support system, psychological stability, and risk for recurrent substance abuse; scores <21 are ideal for LT; higher scores indicate greater risk for a negative outcome; scores of 21 to 39 may be acceptable, with certain caveats; patients with scores ≥40 may be required to, eg, make lifestyle changes, to qualify

Assessing frailty: difficult in inpatients; Liver Frailty Index (LFI) — a score <3.5 indicates that the patient is robust and ideal for LT; patients with scores ≥4.5 are considered frail; LFI score can be combined with the MELD score to predict waitlist mortality (the survival rate decreases as MELD and LFI scores increase)

Contacting the transplantation center: always indicated for patients with significant LD, acute liver failure, significant DC (with ascites, variceal bleeding, and significant HE), or HCC, hilar cholangiocarcinoma, or another diagnosis approved for automatic exception; evaluate patients with cirrhosis for LT prior to planned elective surgery (postsurgical hepatic decompensation may occur); other indications — severe acute alcoholic hepatitis; acute-on-chronic liver failure (ACLF)

Contraindications to LT: absolute contraindications — severe cardiopulmonary disease, uncontrolled infection or sepsis, active extrahepatic malignancy, history of noncompliance, lack of adequate social or financial support, technical and anatomic barriers to LT, and uncontrolled psychiatric disorders; relative contraindications — advanced age (>70 yr), low MELD score, morbid obesity (typically, body mass index >40), extensive portal vein thrombosis, active alcohol, nicotine, or substance abuse, and HCC outside the Milan criteria

Acute-on-chronic liver failure: described as acute hepatic decompensation in patients with underlying cirrhosis or chronic liver disease, resulting in multiorgan system dysfunction; short-term mortality risk is high; grading of ACLF is based on the number of involved organ systems and the severity of involvement in each; the probability of LT-free survival and survival on the waitlist for >30 days without LT decreases as ACLF severity increases (Sundaram et al [2019])

Severe alcoholic hepatitis: rates of ACLF have increased, particularly in patients with sAH, who now comprise the majority of LT candidates; this demographic change is partially attributed to increased alcohol consumption during the COVID-19 pandemic (however, rates have not decreased since); patients with sAH have higher MELD scores and longer hospitalizations

Scoring the severity of AH: options include the Maddrey discriminant function (MDF; most common) and MELD score; 90-day mortality is ≈50% for sAH with severe liver disease; MDF score <32 — managed conservatively; MDF score ≥32 — predicts poor outcome; patients receive supportive care, psychosocial resources, and nutrition consultation; abstinence is recommended; in the past, steroids were routinely administered

Steroids for sAH: Thursz et al (2015) — assessed the effectiveness of steroids or pentoxifylline vs placebo for sAH; steroids were found to reduce the risk for mortality at 28 days; however, there was no improvement in survival rates at 3, 6, or 12 mo; patients in the steroid group had more infections (13% vs 7%); Arab et al (2021) — a retrospective study of >3000 patients with sAH found that steroids improve survival at 28 days in patients who have sAH with MELD scores of 25 to 39; no improvement in outcomes was seen at 3 or 6 mo; steroids did not benefit patients with higher MELD scores

Criteria for LT in patients with sAH: first episode of hepatic decompensation or AH; disease severity that precludes treatment via supportive care and medical management; patients must have good insight into their disease, willingness to undergo alcohol support therapy, and good psychosocial status

Sustained Alcohol Use Post-LT (SALT) score: predicts risk for recidivism after LT; a SALT score of <5 has a 95% negative predictive value; patients with a score >5 are more likely to resume drinking after LT

Lee et al (2018): in the ACCELERATE-AH study, the survival rate of patients who underwent early LT for sAH was 94%; post-LT alcohol use was found in 10% of the patients; although some patients resume drinking, benefits of LT far outweigh the risk for death without LT

Musto et al (2022): found that risk for mortality is high among patients denied early LT for sAH; in patients who recovered without LT, survival rates dropped after 1 yr (attributed to cirrhosis with eventual hepatic decompensation, or continued alcohol use); factors associated with greater probability of spontaneous recovery include younger age (<44 yr), low international normalized ratio, and peak MELD <34 (the probability was 81% in patients with these characteristics, vs 0.3% in those >44 yr of age with higher MELD scores)

LT for Hepatocellular Carcinoma

Candidacy for LT: patients with HCC have low MELD scores; LT improves survival when performed in patients with early-stage disease who are not candidates for resection; the Milan criteria state that LT may be performed in those with a single tumor of ≤5 cm or 3 tumors that are each ≤3 cm; MELD exception points — eligible patients with HCC receive a MELD upgrade based on the median MELD score of patients qualifying for LT at the institution minus 3 points

Recent treatment algorithm for HCC: in 2017, UNOS adopted a policy that permitted MELD exception points for people who were successfully downstaged to within Milan criteria; candidates must have a single pretransplantation lesion of ≤8 cm, 2 to 3 lesions of ≤5 cm with total diameter <8 cm, or 4 to 5 lesions of ≤3 cm with a total diameter ≤8 cm; the survival rate is significantly lower for patients with tumors that progress beyond these criteria; downstaging patients with HCC to within Milan criteria enables LT and results in better survival rates and lower recurrence rates

Immunotherapy: IMbrave150 trial — patients with unresectable advanced HCC who received immunotherapy had better outcomes, including longer survival, compared with those who received standard treatment with sorafenib (Finn et al [2020]); LT after immunotherapy — as large randomized studies are lacking, definitive conclusions cannot be drawn; however, available data suggest that LT within a short timeframe after immunotherapy is associated with poorer outcomes and more adverse events; holding immunotherapy for 3 mo before LT has been advocated to reduce severe adverse reactions; additionally, doing so aids in selecting patients for LT (those who recur within 3 mo are ineligible)

Other Conditions Eligible for MELD Exception Points

Background: eligible conditions include POPH and HPS, which are directly linked to liver disease; persistent, severe POPH and HPS can be fatal without appropriate LT; LT is curative for these conditions

Portopulmonary hypertension: defined as elevated pulmonary artery systolic pressure on echocardiography >40 mm Hg; mean pulmonary pressure (MPP) 35 to 50 mm Hg or greater — to ensure eligibility for MELD exception points and allow listing for LT, consult with a cardiologist for help in reducing MPP to <35 mm Hg

Hepatopulmonary syndrome: diagnosed by the presence of intrapulmonary vasodilation; mortality increases with severity; to be eligible for MELD exception points, shunting must be identified, PaO₂ must be maintained <60 mm Hg, and the patient must have no evidence of chronic pulmonary disease

Polycystic liver disease: patients eligible for MELD exception points are those who are not surgical candidates and do not have any alternative option for therapy, plus fulfill one additional criterion, ie, hepatic decompensation or evidence of complications related to portal hypertension, need for hemodialysis or glomerular filtration rate <20 mL/min, prior history of liver-kidney transplantation, severe malnutrition (documented via a nutrition evaluation), or obvious sarcopenia

Readings

Arab JP, Díaz LA, Baeza N, et al. Identification of optimal therapeutic window for steroid use in severe alcohol-associated hepatitis: A worldwide study. J Hepatol. 2021;75(5):1026-1033. doi:10.1016/j.jhep.2021.06.019; Biolato M, Galasso T, Marrone G, et al. Upper limits of downstaging for hepatocellular carcinoma in liver transplantation. Cancers (Basel). 2021;13(24):6337. Published 2021 Dec 17. doi:10.3390/cancers13246337; Cheng AL, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-873. doi:10.1016/j.jhep.2021.11.030; Deutsch-Link S, Weinberg EM, Bittermann T, et al. The Stanford Integrated Psychosocial Assessment for Transplant is associated with outcomes before and after liver transplantation. Liver Transpl. 2021;27(5):652-667. doi:10.1002/lt.25975; Farkas S, Hackl C, Schlitt HJ. Overview of the indications and contraindications for liver transplantation. Cold Spring Harb Perspect Med. 2014;4(5):a015602. Published 2014 May 1. doi:10.1101/cshperspect.a015602; Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745; Galle PR, Finn RS, Qin S, et al. Patient-reported outcomes with atezolizumab plus bevacizumab versus sorafenib in patients with unresectable hepatocellular carcinoma (IMbrave150): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(7):991-1001. doi:10.1016/S1470-2045(21)00151-0; Kim WR, Mannalithara A, Heimbach JK, et al. MELD 3.0: The model for end-stage liver disease updated for the modern era. Gastroenterology. 2021;161(6):1887-1895.e4. doi:10.1053/j.gastro.2021.08.050; Kwong AJ, Ebel NH, Kim WR, et al. OPTN/SRTR 2021 Annual Data Report: Liver. Am J Transplant. 2023;23(2 Suppl 1):S178-S263. doi:10.1016/j.ajt.2023.02.006; Lee BP, Mehta N, Platt L, et al. Outcomes of early liver transplantation for patients with severe alcoholic hepatitis. Gastroenterology. 2018;155(2):422-430.e1. doi:10.1053/j.gastro.2018.04.009; Musto J, Stanfield D, Ley D, et al. Recovery and outcomes of patients denied early liver transplantation for severe alcohol-associated hepatitis [published correction appears in Hepatology. 2022 Nov;76(5):1552-1553]. Hepatology. 2022;75(1):104-114. doi:10.1002/hep.32110; Sundaram V, Jalan R, Wu T, et al. Factors associated with survival of patients with severe acute-on-chronic liver failure before and after liver transplantation. Gastroenterology. 2019;156(5):1381-1391.e3. doi:10.1053/j.gastro.2018.12.007; Sundaram V, Shah P, Wong RJ, et al. Patients with acute on chronic liver failure grade 3 have greater 14-day waitlist mortality than status-1a patients. Hepatology. 2019;70(1):334-345. doi:10.1002/hep.30624; Thursz M, Forrest E, Roderick P, et al. The clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH): a 2 × 2 factorial randomised controlled trial. Health Technol Assess. 2015;19(102):1-104. doi:10.3310/hta191020; Weinfurtner K, Forde K. Hepatopulmonary syndrome and portopulmonary hypertension: current status and implications for liver transplantation. Curr Hepatol Rep. 2020;19(3):174-185. doi:10.1007/s11901-020-00532-y.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Deising was recorded at the 37th Annual New Treatments in Chronic Liver Disease, held March 18-19, 2023, in San Diego, CA, and presented by Scripps Health. For information on upcoming CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

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