Liver transplantation: Indications and general considerations

The first human orthotopic liver transplant was carried out by Starzl in 1963. In the subsequent two decades, only a relatively small number of patients received grafts, usually those who were moribund with end-stage disease, and survival results were disappointing. However, with increasing surgeon experience and confidence, better anesthesia, and improved microbiologic and immunologic treatments, results started to improve. Increasingly more patients were grafted, with a major increase in the number of transplant centers. In both Europe and the United States, more than 7000 procedures are performed annually. Results are such that many centers are currently reporting 1-year survival rates greater than 90% in elective cases.

It is difficult to identify any one cause for the increase in transplant success. The contribution of better surgical and anesthetic techniques (see Chapters 106 and, 125 ), improved postoperative care ( Chapters 26 , 106 , and 111 ), and availability of better immunosuppressive agents ( Chapter 104 ) have all contributed to the improvements in survival. There is also a better understanding of indications and contraindications for the procedure, and patients are now generally referred for transplantation at a stage when they are likely to have the greatest chance of success. However, the increasing success of liver transplantation and the reduction in contraindications have meant that the number of potential recipients is increasing, while the number of donors in many countries is either remaining static or falling. The increasing discrepancy between supply and demand means that the mortality of patients awaiting a transplant is increasing; the patients often wait longer, so they are sicker; and the chance of survival decreases while resource utilization increases. Increasing the donor pool by using split livers, organs from selected donors after circulatory death (DCD), donors with higher risk profiles, and organs from living donors, and a better understanding of the contraindications to grafts and the use of machine perfusion both to evaluate graft function and intervene to improve graft function have had a significant impact but have not met the need.

Different healthcare administrations have adopted a variety of approaches to provide a transparent approach to selection and allocation that balances the needs for equity, utility, need, and benefit. In North America and many European countries, the method of allocation is based on need with a focus on reducing the risk of death on the waiting list (see Model for End-Stage Liver Disease [MELD] score; see Chapter 4 ). In almost all cases, this has resulted in the reduced mortality of patients awaiting liver transplantation without an appreciable effect on survival after transplantation, although with an increase in resource utilization. Increasingly, organs are allocated according to benefit rather than need (that is, the estimated difference in survival with and without transplantation). Also, those responsible for allocation policies are looking at quality of life (QOL) as an additional measure on which to base allocation. Nonetheless, there remains a need to define futility, that is to identify those patients, whether referred for listing or actual transplant candidates, when transplantation is futile. Transplant units and liver units must make palliative care an option in such cases.

The shortage of deceased donors has stimulated the use of livers from living donors. Limitations include the risks to the donor; even after careful evaluation, the risk of donor death is approximately 1 in 250 (risk depends on lobe[s] removed), and morbidity is approximately 30%, although a lack of obligatory reporting and national registries in many countries makes it difficult to assess the true risk. In general, the indications for transplantation in recipients of living donor livers mirror those for deceased donation, although some centers are expanding the indications, especially for liver cancer and alcohol.

General indications and contraindications

In general, the indications for transplantation are relatively easy to define, although the application of these principles is often much more difficult. The two broad indications for grafting are

1.
A survival benefit from transplant (compared with nontransplant) and
2.
ΘΟΛ (because of the liver disease) unacceptable to the patient.

However, where organs are allocated solely on the basis of need, such as to those with intractable symptoms, there may be a very long wait for transplantation unless there is access to living donors where there is targeted allocation.

Transplantation should be considered for an individual patient with the following ( Box 105.1 ):

A survival benefit as evidenced by MELD score of greater than 17 (see Chapter 4 )
Signs of decompensation, including ascites, encephalopathy, and renal impairment (see Chapters 77 and 78 )
Liver cell cancer for which other measures are considered less effective (see Chapters 89 and 108A )
Hepatopulmonary or portal pulmonary hypertension (see Chapters 74 , 78 , and 79 )
Intractable pruritus
Intractable encephalopathy

BOX 105.1

MELD, Model for End-Stage Liver Disease.

Indications for Referral for Consideration of Liver Transplantation in Adult Patients With Cirrhosis

Symptoms

Hepatic decompensation
Increasing ascites unresponsive to medical/diet therapy
Recurrent variceal bleeding
Spontaneous bacterial peritonitis

Side effects of liver disease

Increasing osteopenia
Hepatopulmonary syndrome
Portopulmonary hypertension
Intractable ascites
Intractable encephalopathy
Development of hepatocellular carcinoma
Muscle wasting and increasing frailty

Biochemical markers

MELD Score >17
Serum albumin <30 g/dL
Serum bilirubin >50 μmol/L for parenchymal disease
Serum bilirubin >100 μmol/L for cholestatic disease

Development of any of these criteria does not necessarily mean that transplantation is indicated, but merely that it should be considered.

Absolute contraindications to liver transplantation include the following:

The patient is not fit enough to withstand surgery (e.g., because of advanced cardiac or pulmonary disease).
The patient is unlikely to survive the procedure (e.g., active sepsis).
Survival after transplantation may be too short to justify the risks of transplantation (e.g., with metastatic disease).
The postoperative QOL may be unacceptable to the patient (e.g., severe intractable depression).
Surgery is technically not possible (e.g., patients with extensive venous thromboses).
The patient does not choose to undergo the operation.

Relative contraindications to transplantation include the following and are discussed below:

Age: Few centers have an upper age limit, but older age is a risk factor for poor outcomes.
Obesity: Those with body mass index (BMI) greater than 40 kg/m ² have a poorer outcome.
Cholangiocarcinoma: Considered only in highly selected patients in agreed protocols with chemotherapy and irradiation because of early recurrence (see Chapters 51 and 108B ).
Metastatic colon cancer: It is available in selected centers (see Chapter 90 ).
Chronic or refractory active infections: Depending on type of infection and whether amenable to cure with available therapy.
Poor social support: Despite full interventions that will adversely impact on graft or patient survival, particularly in biologically older patients with anticipated prolonged recovery after transplant.
Ongoing tobacco use or illegal drug use.
Active alcohol use.
Frailty.

In 2019, in the United States, there were 8372 liver transplants from deceased donors and 524 from living donors ( https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/# ). During that year, 1179 died awaiting a graft and 1186 were removed as they had become too sick. As of April 30, 2020, there were 12,706 patients awaiting a transplant in the United States.

There have been many changes in the demographics of transplantation. The proportion of patients grafted for alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD; see Chapter 69 ) is rising.

The proportion of patients grafted for cholestatic diseases is falling and the number of patients being grafted for hepatitis C virus (HCV) infection is falling because of the success of effective treatment (see Chapter 68 ).
The use of living donors (see Chapters 109 and 121 ) has not made a significant impact on the number of transplants in Europe and North America. However, living liver donation remains a major source of activity in many Asian and Far Eastern countries.
Use of organs from DCD, in contrast to living donors, has been increasing (see Chapter 109 ). Rates are lower in the United States (about 5%) than in United Kingdom, where the proportion of DCD is about 30%. These livers may develop ischemic cholangiopathy months after transplantation.
Σplitting livers allows two transplants from a single donor. Criteria for splitting are well established. Use of split livers has greatly reduced the mortality of patients on the paediatric waiting list

General considerations

Malnutrition and frailty (see Chapters 26 and 27 )

Malnutrition is a common finding in end-stage cirrhosis, with a prevalence of up to 60% (see Chapter 26 ) (see Box 105.1 ; Box 105.2 ). Malnutrition in these patients has many causes: the disease itself, poor intake, dietary restrictions (often inappropriate in those with encephalopathy), and malabsorption (which itself has many causes). Hyperammonemia will also increase sarcopenia. Malnutrition and sarcopenia are associated with increased susceptibility to infection and poor healing.

BOX 105.2

Some Diseases Treated by Transplantation in Adults

Acute liver failure

Multisystem disorder in which severe acute impairment of liver function with encephalopathy occurs within 8 weeks of the onset of symptoms and no recognized underlying chronic liver disease

Subacute liver failure (late-onset hepatic failure)

Chronic liver disease

Cirrhosis which may be due to

Fatty liver disease
- Alcohol
- Nonalcohol related
Chronic viral hepatitis B
Chronic viral hepatitis C
Primary biliary cholangitis,
Primary sclerosing cholangitis
Autoimmune hepatitis
Genetic hemochromatosis
Wilson disease
α ₁ -Antitrypsin deficiency
Congenital hepatic fibrosis and other congenital or hereditary liver diseases
Secondary biliary cirrhosis

Liver tumors

Hepatocellular carcinoma
Unresectable hepatoblastoma (without active extrahepatic disease)
Unresectable benign liver tumors with disabling symptoms
Hepatic epithelioid hemangioendothelioma

Variant syndromes, metabolic diseases, and other indications

Intractable pruritus
Hepatopulmonary syndrome
Cirrhotic cardiomyopathy
Familial amyloidosis
Primary hypercholesterolemia
Polycystic liver disease
Recurrent cholangitis
Nodular regenerative hyperplasia
Hereditary hemorrhagic telangiectasia
Glycogen storage disease
Ornithine transcarbamylase deficiency
Primary hyperoxaluria
Maple syrup urine disease
Porphyria
Amyloidosis
Alagille’s syndrome
Progressive familial intrahepatic cholestasis
Caroli syndrome

Although there is no convincing evidence that improving the nutritional state will alter the outcome of liver transplantation, it seems prudent to optimize nutrition: the use of branch-chain amino acid and vitamin supplementation remains uncertain.

It has been recognized that frailty is a strong predictor not only of outcome in those with cirrhosis but also for survival and QOL after transplant and as the risk of acute cellular rejection. Frailty is a multidimensional construct that represents the end manifestation of derangements of multiple physiologic systems leading to decreased physiologic reserve and increased vulnerability to health stressors. Investigation of frailty has largely focused on physical frailty, which includes functional performance, functional capacity, and disability. It is recommended that all liver transplant candidates should be assessed at baseline and longitudinally using a standardized frailty tool, which should guide the intensity and type of nutritional and physical therapy in individual liver transplant candidates. Both the optimal tool for assessment and management of frailty are uncertain : simple scores such as the Charlson Frailty Index, Karnofsky performance scale, and the Liver Frailty Index (hand grip, balance, and chair stands) have been used. A recent meta-analysis found 11 exercises improve VO ₂ peak, anaerobic threshold, 6-minute walk distance, muscle mass/function, and QOL in patients. Improvements were greater with a combination of aerobic and resistance exercises at moderate-high intensity .

Thus both malnutrition and frailty are markers of a higher mortality both before and after transplantation. Neither marker should be used as an absolute contraindication to transplantation. If accepted for transplantation, the time awaiting an offer of a graft should be used to improve both frailty and malnutrition. Formal dietetic advice and, where appropriate, nutritional supplementation and home-based exercise regimens are likely to benefit both well-being and outcome after transplant.

Obesity

Obesity, especially associated with metabolic syndrome, is increasingly common, and NAFLD is an increasing indication for liver transplant (see Chapter 69 ). The data on the effect of obesity on outcome are conflicting, in part because of the careful selection and assessment and the difficulty in distinguishing the effect of obesity itself with the associated conditions of diabetes, cardiovascular disease, and other comorbidities. Most studies indicate that transplantation can be done safely in those with a BMI up to 40 kg/m ² . Some centers undertake bariatric surgery in the peritransplant period, although the timing and risks and benefits remain uncertain.

Psychological assessment

Transplantation is associated with major psychological stress, both for the patient and the family. More than half of liver transplant candidates have a wide range of psychological health problems. However, full psychological and psychiatric assessment of all potential transplant candidates is rarely undertaken as routine practice. However, psychiatric assessment of potential liver transplant recipients is becoming increasingly common in clinical practice. Risk factors associated with a poor outcome include

Mood disorders,
Lack of social support,
Substance misuse, and
Alcohol dependence.

Chronic poor health, possibly associated with subclinical encephalopathy and future uncertainties, makes it difficult sometimes to predict the patient’s outcome accurately. When the patient has a history of psychiatric illness, expert assessment by a multidisciplinary team is required because some people with psychiatric illness not responsive to therapy or with a history of recurrent episodes of self-harm may not be suitable candidates for transplantation. It is not unreasonable to withhold from transplantation patients who, despite optimal treatment and support, are likely to have an unacceptable QOL. The transplant team should also assess the likelihood of noncompliance (irrespective of cause), and when noncompliance, despite full social and other types of support, is likely to lead to graft loss, it is acceptable to exclude the patient from listing. This is a particular issue in adolescents and those in their early 20s; the use of transitional and handover clinics together with newer technologies may mitigate this problem.

Tobacco use

Ongoing tobacco use is associated not only with an increased risk of cardiovascular and lung diseases and cancer (before and after transplantation), but also increased morbidities. Some centers will withhold listing from those who continue to smoke cigarettes or do not comply with nicotine withdrawal programs.

Illicit drug use

As with tobacco users, some centers will exclude from transplantation those with active illicit drug use and those who fail to engage in withdrawal treatment. Such patients may have other codependencies. However, in contrast to those who use tobacco, outcomes are not worse in those who have or are using marijuana and other illicit drugs. Those who are well stabilized on methadone as opioid replacement therapy should not be excluded and generally should continue on a stable dose. Outcomes are good although perioperative management may be a challenge.

Age

There is no agreed upper age limit, but increasing age is associated independently with mortality after transplant. The concept of biologic age has superseded that of chronologic age, although the former cannot readily be defined or quantified. Outcomes of carefully selected patients over age 70 are encouraging, although older age does remain an independent predictor of survival both before and after transplantation.

Previous abdominal surgery

The presence of adhesions, especially in the patient with portal hypertension, adds considerably to the difficulties of surgery and may affect outcome, especially when this involves surgery to the biliary tree.

Infection

Active bacterial, fungal, or protozoal sepsis is an absolute contraindication to transplantation. Once appropriate therapy has been instituted, however, the patient is a suitable candidate for the procedure.

Human immunodeficiency virus

Although early studies showed patients with HIV infection fared poorly (Rubin et al., 1987), with the introduction of highly active antiretroviral therapy (HAART), the natural history of HIV infection has been greatly altered. The majority of those with HIV infection who develop end-stage liver disease have HCV coinfection, and current treatments for HCV have also affected the need for liver transplantation. An analysis of the European and North American Registries showed that from 2008 to 2015, around 1% of recipients were HIV infected with a declining proportion with HCV infection. Outcomes have improved over time. Indications are becoming better defined and include (1) end-stage liver disease, (2) low or undetectable levels of HIV RNA, (3) no AIDS-defining complication, and (4) CD4 count greater than 200 cells/μL.

Cardiovascular disease

As with other diseases, the prognosis of patients with cardiovascular diseases will dictate whether liver replacement is an appropriate therapy. Cardiac disease is common in liver transplant candidates and an important cause of perioperative and postoperative disease. There are many causes of cardiac dysfunction, including the cardiovascular disease, valvular disease, cardiomyopathies due to causes such as cirrhotic cardiomyopathy (CCM), metabolic diseases such as amyloidosis, hemochromatosis, and toxins as alcohol. Tools to assess the degree of cardiac disease and to define those where transplantation is not indicated are lacking.

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