End-Stage Liver Failure: Liver Transplant Evaluation

Chapter 8
End-Stage Liver Failure: Liver Transplant Evaluation

Sebastián Marciano¹ and Adrián Gadano²

¹Liver Unit, Hospital Italiano Buenos Aires Argentina

²Department of Medicine and Liver Unit, Hospital Italiano Buenos Aires Argentina

Introduction

The first attempt at human liver transplantation (LT) was performed by Thomas Starzl in 1963, but it was not until 1967 that a successful procedure was performed. As the initial immunosuppressive regimens were not potent enough, an acceptable survival was not possible. The implementation of more efficient immunosuppressive therapy, particularly cyclosporine in the 1980s, was associated with an improvement in survival. Since then other major developments in surgical techniques, newer immunosuppression regimens and preservation solutions have continued to impact favorably on the long-term postoperative course.

LT should be considered in patients with irreversible acute or chronic liver failure, in selected patients with malignant liver tumors, and in patients with genetic or metabolic disorders in which the liver is responsible for the damage to other organs. As with any other medical intervention, it is indicated when the risk of death related to the liver disease is outweighed by the benefits to be obtained from LT. Risks and benefits are not always easy to balance, but if the selection of candidates is precise, successful outcomes can be achieved. The ideal scenario to transplant a patient would be at the exact moment when the predicted life expectancy related to the liver disease is estimated to be shorter than the one that would be achieved with LT. Unfortunately, the identification of this very precise moment is challenged by at least two factors. First, organ donation is far from being plentiful enough to meet the requirements of the candidates on the waiting list. Second, mortality on the waiting list is not always accurately predicted.

Cirrhosis-related end-stage liver disease is the leading cause of LT worldwide. This chapter reviews how to select and evaluate patients with cirrhosis for LT.

Epidemiology

The etiology of cirrhosis leading to LT varies worldwide. Chronic hepatitis C is the leading cause in the United States, Europe, and Latin American countries [1–3]. In other regions such as Southeast Asia and Sub-Saharan Africa, chronic hepatitis B is the main cause of cirrhosis leading to LT [4].

A recent report from the European Liver Transplant Registry stated that cirrhosis was the indication for LT in 58% of patients, with the following distribution: viral (39%), alcoholic (33%), primary biliary cirrhosis (9%), unknown (8%), autoimmune (4%), and other (7%) [1]. No definitive cause for cirrhosis can be identified in up to 20% of patients who have end-stage liver disease (cryptogenic cirrhosis); however, many of these patients most likely have “burned-out” nonalcoholic steatohepatitis [5].

Data reported by the Organ Procurement Transplant Network (OPTN) from the United States show that the average age of adult recipients has increased steadily over the past 10 years. In 2009, approximately 75% of adult recipients were older than 50 years and male recipients predominated, with a 2 : 1 male : female ratio [6].

Surgical Aspects of Liver Transplantation

It is not the objective of this chapter to review surgical issues in detail. However, some strategies aimed to increase the availability of transplantable livers are discussed.

In most cases livers are procured from cadaveric donors. In an attempt to increase the availability of cadaveric donors, some countries have implemented transplantation from donors after cardiac death, known as DCD donors. This strategy is associated with a greater risk of complications after LT, especially biliary complications [7]. To minimize the risk, careful selection of these donors is mandatory.

Split LT is a strategy in which a liver from a cadaveric donor is used to transplant two patients, generally a child and an adult [8]. Domino LT is a more recent strategy that consists of transplanting the explanted livers of patients that are undergoing LT for metabolic or genetic diseases that do not compromise liver function [9]. The largest experience is with hereditary amyloidosis, which is an autosomal dominant disease characterized by the production of a mutant protein (most often transtiretin) by the liver. These patients develop progressive neuropathy and cardiomyopathy but if LT is performed in a timely manner the symptoms can stabilize or regress. As it takes two to five decades for patients to develop the symptoms, these normally functioning livers can be transplanted into patients with decompensated cirrhosis or hepatocellular carcinoma (HCC). Of course, the risk for the recipient of these livers is the development of hereditary amyloidosis so this strategy should not be used in young patients.

Living donors are also used in LT. In fact, in some countries, cadaveric donor LT is not performed because of religious or cultural issues and living donors are exclusively used [10]. The main impediment to this technique is the balance between the donor’s and the recipient’s risks. The remnant liver in the donor and the transplanted liver in the recipient must be sufficient to provide an adequate liver function. This balance is easily achieved in an adult donor and a pediatric recipient. In Figure 8.1 an algorithm for the evaluation of a possible living donor is shown.

**Figure 8.1** Evaluation of a potential living donor for liver transplantation.

Patient Selection

LT in patients with cirrhosis is indicated when life expectancy related to the end-stage liver disease is considered to be significantly reduced. Less frequently, LT in patients with cirrhosis is indicated when the quality of life is compromised as a result of specific complications that are not necessarily related to a reduced life expectancy, for example, severe intractable pruritus in patients with cholestatic diseases.

The risk of death in patients with cirrhosis is mainly related to its specific complications, which determine the transition from compensated to decompensated cirrhosis. As reviewed in other chapters, survival of patients with compensated cirrhosis has been reported to average 10–12 years [11]. Performing LT in these patients would imply more risks than benefits. However, when complications such as encephalopathy and ascites arise, survival at 5 years is reduced to 20–50% [11]. As the survival rate at 5 years after LT is around 75% in large series, performing LT in these patients is justified [12].

The use of scores such as the Child–Turcotte–Pugh (CTP) and the model for end-stage liver disease (MELD) [13,14] constitutes another way of predicting survival in patients with cirrhosis (Figure 8.2).

**Figure 8.2** Evaluation of patients with end-stage liver disease for liver transplantation. CTP, Child–Turcotte–Pugh score; MELD, model for end-stage liver disease.

The quality of life of patients with cirrhosis is not reflected by any of the scores and it is difficult to assess on clinical grounds. Mostly, quality of life is reduced as the complications of cirrhosis appear. When evaluating a patient with cirrhosis in terms of LT candidacy, attention has to be focused on the development of clinical complications, on the calculation of the CTP and MELD scores, and on the assessment of quality of life. Specific aspects of each of these issues are reviewed.

Complications of Cirrhosis

The development of ascites, encephalopathy, hyperbilirubinemia, or variceal bleeding is considered by most authors to mark the transition from compensated to decompensated cirrhosis. Survival in these patients is reduced to less than 50% at 5 years [11] and then LT is justified. The particular case of variceal bleeding as the only complication in patients with well-preserved liver function (CTP A) must be considered separately. In this scenario, in which strategies aimed at reducing the risk of new bleeding events can offer the patient an acceptable life expectancy, LT should not be indicated.

Other complications like HCC and hepatopulmonary syndrome (HPS) are clearly associated with a reduction in survival, even though they are not recognized as causes of “decompensation” of cirrhosis by most authors. These complications share the fact that they are clear indications for LT. Nevertheless, they must fulfill specific criteria for the transplantation to be safe (see contraindications).

LT is an excellent treatment for early (stage A) HCC because it removes not only the tumor, but also the oncogenic parenchyma [15]. The downside of LT in patients with HCC is recurrence. The best results are achieved when the Milan criteria are applied: one solitary nodule <5 cm or up to three nodules <3 cm without vascular invasion or extrahepatic spread [15]. The study performed by Mazzaferro et al. [15] that was responsible for the wide application of these criteria showed a survival rate of 83% at 4 years, with a chance of recurrence of 8% in patients fulfilling these criteria. The possibility of expanding these criteria to larger nodules or more than three nodules has been evaluated with variable results. What is clear from the experience is that the risk of recurrence increases when transplanting patients with higher tumor burdens [16].

In many countries, patients with HCC fulfilling Milan criteria are prioritized on the waiting list. Once listed, if a long waiting period is anticipated (>6 months), strategies such as transarterial chemoembolization or percutaneous ablation are applied to control tumor growth [17].

In selected patients with cirrhosis, single small nodules (<2 cm), no portal hypertension, and well-preserved liver function, surgical resection or percutaneous ablation achieves great results and should be the treatment of choice as long as patients do not have other indications for LT [16].

HPS is associated with a 2-year survival rate of less than 50% [18]. As there is no other specific treatment for this condition, LT is indicated. Resolution of the hypoxemia occurs in most cases in a variable time after LT. However, the severity of abnormality of gas exchange has to be evaluated with caution before LT. Patients with HPS are also prioritized on the waiting list in many countries in order to prevent progression of disease and worsening of hypoxemia [19].

In conclusion, patients with cirrhosis who develop any of the following complications in the absence of contraindications have to be referred for LT: ascites, encephalopathy, jaundice, variceal bleeding (except CTP A), HCC, and HPS.

Scores That Predict Mortality: CTP and MELD

The CTP score was originally designed to predict mortality following portosystemic shunts, [13] then it was found to be a good predictor of mortality in many other settings. As three of the five variables included in the CTP score are clinical complications of cirrhosis (i.e., ascites, encephalopathy, and jaundice), patients with high CTP scores have already developed these complications and have a clear indication for LT. A CTP score of ≥7 are considered to be sufficient criteria to list a patient for LT [20].

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