Liver Transplantation: A Comprehensive Guide for Patients

Table of Contents

• Introduction to Liver Transplantation
• Challenges in Access to Liver Transplantation
• Patient Referral, Assessment, and Selection
• Living-Donor Liver Transplantation
• Risk Scores and Liver Transplantation
• Transplantation in Patients with Cancer
• Transplantation in Patients with Alcohol-Associated Liver Disease
• Allocation and Acceptance of Livers from Deceased Donors
• Expanding the Pool of Livers from Deceased Donors
• Management of Donated Livers Before Transplantation
• Clinical Implications for Patients
• Limitations and Considerations
• Source Information

Introduction to Liver Transplantation

Liver transplantation, first performed in humans 60 years ago, has evolved into the standard treatment for patients with life-threatening liver disease. This remarkable medical procedure offers a second chance at life for those facing end-stage liver failure, but it remains a demanding therapy for patients, healthcare providers, and society as a whole.

The journey from diagnosis to transplantation involves multiple complex steps, including thorough evaluation, waitlisting, and extensive post-transplant care. This article explores the current state of liver transplantation, focusing particularly on developments in adult transplantation while also addressing issues affecting children who need transplants.

Challenges in Access to Liver Transplantation

Despite liver transplantation being performed in more than 100 countries during 2020-2021, the sobering reality is that most patients with life-threatening liver disease worldwide still lack access to this life-saving procedure. The disparities in access are particularly pronounced in the United States, where limited access has been consistently linked to several socioeconomic factors.

Research shows that Black race, poverty, rural residence, poor health literacy, and lack of medical insurance all contribute to reduced access to transplantation. The statistics from 2022 reveal that 9,528 liver transplantations were performed in the United States, with only 526 of these performed in patients under 18 years of age.

The waiting list reality is challenging: only 54.4% of transplant recipients received their graft within one year after placement on the transplant waiting list. The rate of death among patients awaiting transplantation was 12.2 deaths per 100 waiting-list years, highlighting the urgent need for these procedures.

Children face particularly difficult circumstances, with 5% of children placed on the waiting list dying or becoming too ill to undergo transplantation. The highest pretransplantation mortality occurs among children under 1 year of age, making timely intervention critically important for this vulnerable population.

Patient Referral, Assessment, and Selection

Patients at risk for death from liver disease should be referred to a liver transplantation center for evaluation. The referral process typically begins when a patient experiences either acute liver failure or decompensated chronic liver disease.

Acute liver failure presents as the sudden onset of liver failure in a previously healthy person, manifested by markedly elevated serum aminotransferase levels (liver enzymes), altered mental status, and coagulopathy (blood clotting problems). This condition accounts for less than 5% of liver transplantations performed annually in the United States.

The vast majority of transplantations (over 95%) are undertaken to treat patients with chronic fibrotic liver disease, portal hypertension (increased blood pressure in the liver vein system), liver cancer, or combinations of these conditions. The transition from compensated cirrhosis to clinically apparent liver disease often begins with a decompensating event such as new-onset ascites (fluid accumulation in abdomen), altered mental status (hepatic encephalopathy), or gastrointestinal bleeding related to portal hypertension.

In the United States, the Model for End-Stage Liver Disease (MELD) score, or the complementary Pediatric End-Stage Liver Disease (PELD) score for children under 12 years, has been used since 2002 to assess the need for transplantation. Patients with objective evidence of advanced chronic liver disease with a MELD score of 15 or higher (on a scale from 6 to 40, with higher scores indicating more severe liver failure) or a PELD score of 12 or higher should be referred for transplantation consideration.

The comprehensive evaluation for liver transplantation includes:

• Assessment of urgency based on prognosis without transplantation
• Evaluation of potential impediments to successful long-term outcomes
• Individualized testing based on diagnosis and liver impairment severity
• Mitigation plans for coexisting conditions
• Infectious disease risk assessment and vaccination administration
• Complete psychosocial assessment

The COVID-19 pandemic highlighted the critical importance of ensuring vaccinations are completed while transplantation candidates are still immunocompetent, before they receive immunosuppressive therapy that reduces vaccine responsiveness.

Living-Donor Liver Transplantation

Living-donor liver transplantation offers a vital alternative for patients with serious liver disease who face high risk of death while waiting for a deceased donor liver. This approach accounts for 6% of all liver transplantations performed in the United States but represents 90% of liver transplants in Asian countries other than China.

The outcomes after living-donor liver transplantation have been shown to be as good as or better than outcomes after deceased-donor transplantation, with survival benefits observed even in patients with MELD scores as low as 11. This makes living donation an important option for patients who might otherwise face long wait times.

However, living donation involves significant considerations for donors:

• Donors may be related or unrelated to the recipient
• Donation must be completely voluntary with verified understanding of risks
• Blood type compatibility is required
• Ideal donor age is 21-55 years, though 18-20 or 56-60 may be considered case-by-case
• Preferred BMI (body mass index) is under 35
• Comprehensive evaluation of liver anatomy, physical health, and mental health is essential

While donation is considered safe at experienced centers, serious injuries to physical or mental health, including death, have occurred on rare occasions. Up to 40% of donors experience less severe complications, and postoperative recovery typically requires a 3-month absence from work.

Risk Scores and Liver Transplantation

In the United States, prioritization of patients awaiting transplants from deceased donors follows the federal "final rule" for transplantation, which mandates that centers allocate donor livers based on greatest medical urgency while reducing inequities based on waiting time or geography. The MELD and PELD scores serve as the primary tools for this prioritization.

The MELD score has undergone several modifications to improve accuracy and reduce bias. Additional points may be added to calculated MELD and PELD scores for waitlisted patients with specific conditions where these scores fail to capture accurate prognosis, including hepatocellular carcinoma (HCC), portopulmonary hypertension, and hepatopulmonary syndrome.

Since 2010, patients placed on liver transplant waiting lists in Western countries have tended to be older and more ill than patients in earlier eras. Additionally, the introduction of direct-acting antiviral therapies has dramatically reduced the number of patients listed due to hepatitis C virus infection.

The landscape of liver transplantation indications has shifted significantly:

• Alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) have become predominant indications
• In Asia, chronic viral hepatitis and virus-associated hepatocellular carcinoma continue to predominate
• The percentage of transplantations performed for HCC decreased from 17.2% in 2010 to 12.6% in 2020

Transplantation in Patients with Cancer

Patients with extensive hepatocellular carcinoma may become acceptable transplantation candidates after successful antitumor treatment that reduces tumor size before transplantation. The evaluation process for cancer patients involves careful assessment by a multidisciplinary team that includes transplantation specialists.

In some circumstances, patients with other primary liver tumors such as neuroendocrine tumors or metastatic colon cancer may also be considered suitable transplantation candidates. Each case requires individualized evaluation based on tumor type, extent, and response to previous treatments.

The management of liver cancer in transplantation candidates has evolved significantly, with stricter criteria ensuring that transplantation provides the best possible outcomes while making the most efficient use of limited donor organs.

Transplantation in Patients with Alcohol-Associated Liver Disease

The approach to transplantation for patients with alcohol-associated liver disease has evolved considerably. In 1997, professional societies endorsed 6 months of abstinence as a prerequisite for waitlisting patients with ALD. However, research has shown that selected patients with severe alcohol-associated hepatitis unresponsive to medical therapy can benefit from transplantation even without meeting the 6-month abstinence rule.

Current guidelines emphasize that selection of ALD patients for transplantation should be based on detailed psychosocial evaluation linked with management of alcohol use disorder, rather than strictly on the 6-month abstinence timeline. This evaluation includes assessment of the patient's treatment history, commitment to sobriety, and social support network.

The selection process is particularly crucial for this population, as studies show that among ALD patients with high MELD scores but limited sobriety who were denied waitlisting, the 90-day mortality exceeded 50%. This highlights the life-or-death nature of transplantation decisions for these patients.

Allocation and Acceptance of Livers from Deceased Donors

The allocation system for deceased donor livers in the United States prioritizes candidates based on their MELD or PELD scores and their proximity to the donor hospital, aiming to reduce geographic inequities. The assessment of liver viability from deceased donors traditionally relies on the donor's history, biochemical function, gross appearance, and histological evaluation.

Livers obtained using extended criteria (from donors with potential issues such as age over 60 years, HCV positivity, abnormal liver function tests, extended ICU stays, or requiring blood pressure support medications) were historically associated with higher rates of donor-liver dysfunction leading to graft loss and sometimes recipient death.

Concerningly, as many as 70% of livers from potential deceased donors in the United States and United Kingdom are discarded based on subjective assessment. The fact that livers declined by one center may be successfully transplanted at another center indicates the need for better methods to estimate donor liver viability.

Expanding the Pool of Livers from Deceased Donors

Several strategies are being employed to expand the pool of available donor livers. Most deceased-donor livers come from persons with irreversible brain injury who are on life support. Expansion strategies include using organs from carefully selected donors infected with HCV or HIV, and donation after circulatory death (where death is declared based on cessation of circulatory and respiratory function).

There is particularly urgent need to increase livers available for pediatric candidates, especially infants. One successful strategy involves splitting a liver from a deceased donor into two allografts, typically transplanting one piece in a small child and the other in an adult. Research from the United Kingdom shows that a national "intention to split" policy can significantly reduce mortality among children on waiting lists.

Management of Donated Livers Before Transplantation

Several advanced approaches are now used to preserve donor livers before transplantation, each with distinct advantages and limitations:

Static Cold Storage: This traditional method is simple and inexpensive, using cooling to reduce cellular metabolism. However, it doesn't enable viability assessment and carries ischemic risks with limited preservation time.

Normothermic Regional Perfusion: Provides oxygenated perfusion during early preservation, diminishing risk of ischemic cholangiopathy but is technically challenging and expensive.

Normothermic Machine Perfusion: Restores circulation, minimizes cold storage time, and enables viability assessment based on liver function measures. However, it recirculates inflammatory mediators and is technically complex.

Hypothermic Oxygenated Perfusion: Provides oxygen, recharges ATP energy molecules, and diminishes cholangiopathy risk, but offers limited opportunity for therapeutic intervention during perfusion.

Clinical Implications for Patients

For patients facing liver disease, this research highlights several important considerations. Early referral to a transplantation center is crucial when MELD scores reach 15 or higher or when decompensating events occur. Patients should work closely with their healthcare team to ensure all vaccinations are current before transplantation, as immunosuppression afterward reduces vaccine effectiveness.

Those with alcohol-associated liver disease should engage actively with alcohol treatment programs and build strong social support networks, as these factors significantly influence transplantation eligibility. Patients with liver cancer should maintain regular surveillance and work with multidisciplinary teams to optimize their transplantation candidacy.

For all patients, understanding the allocation system, waitlist realities, and potential alternatives like living donation can help in making informed decisions about their treatment journey.

Limitations and Considerations

While liver transplantation offers life-saving treatment, several limitations must be acknowledged. The severe organ shortage means many patients will not receive transplants in time. The evaluation process is extensive and not all patients will qualify due to medical or psychosocial contraindications.

The transplantation journey requires significant commitment to lifelong immunosuppression, frequent monitoring, and lifestyle adjustments. Outcomes, while generally excellent, vary based on original disease, recipient factors, and donor organ quality.

Geographic disparities in access remain a significant challenge, as do socioeconomic factors that influence both referral patterns and post-transplant outcomes. Ongoing research continues to address these limitations and improve the transplantation system for all patients.

Source Information

Original Article Title: Liver Transplantation
Authors: Michael R. Lucey, M.D., Katryn N. Furuya, M.D., and David P. Foley, M.D.
Editor: Julie R. Ingelfinger, M.D.
Publication: The New England Journal of Medicine, 2023;389:1888-1900
DOI: 10.1056/NEJMra2200923

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine and provides comprehensive information about current developments in liver transplantation for educated patients and their families.