Transplantation evaluation is generally started after the onset of hepatic decompensation. The details of the evaluation of potential candidates for LT are summarized in Table 1.
Table 1. Evaluation of potential recipients before liver transplantation
|General evaluation: |
| Age and body mass index|
| Blood group for listing purposes|
| HLA typing|
| History survey and physical examination|
| History of alcohol consumption and substance abuse|
| Infection: syphilis, cytomegalovirus, Epstein–Barr virus and herpes simplex virus|
| Abdominal imaging (Doppler ultrasound, CT, MR angiography and MR cholangiopancreatography to determine vascular and biliary anatomy, calculate liver volume and assess steatosis|
| Screening for colon, breast, cervical and prostate cancer|
| Cardiopulmonary status evaluation: chest roentgenography, electrocardiogram, 2-D echocardiogram|
| Thallium stress test and coronary angiography for high-risk patients|
| Pulmonary function tests|
|Studies for patients with the following conditions:|
| Hepatitis B: HBV–DNA, HBeAg, anti-HBe Ab, anti-delta Ab|
| Hepatitis C: HCV-RNA, HCV genotype|
| Autoimmune hepatitis: immunoglobulin G, antinuclear antibody, antismooth muscle antibody, liver–kidney microsomal antibody|
| α1-Antitrypsin deficiency: α1-antitrypsin level and phenotype|
| Wilson disease: ceruloplasmin, 24-h urine copper, hepatic copper|
| Hemochromatosis: iron saturation, ferritin, HFE gene test|
| HCC: bone scan, chest radiography|
| Hepatopulmonary syndrome: arterial blood gas, transthoracic contrast echocardiography, arterial oxygen response to 100% oxygen, quantification of intrapulmonary shunting using macroaggregated albumin scan|
| Primary sclerosing cholangitis: colonoscopy (to exclude ulcerative colitis) and ERCP (to exclude cholangiocarcinoma)|
|To detect underlying contraindicated conditions:|
| Arterial blood gas to screen for the presence of severe portopulmonary hypertension|
| Serum α-fetoprotein, CA-199, liver ultrasound, CT, and/or MRI: to exclude HCC, cholangiocarcinoma|
| Doppler ultrasound to exclude portal vein thrombosis|
| Bone densitometry to check the presence of severe osteoporosis|
| Neuropsychological testing: optional|
| Infection: HIV|
There is no specific age limitation for LT.23,24 However, older patients have a poorer long-term survival after transplantation compared with younger patients, mainly because of an increased risk of death from malignancies.25
The risk of hepatic artery thrombosis appears to be significantly increased among chronic smokers. This effect disappears if nicotine use has been discontinued 2 years before transplantation.26 The long-term post-transplantation survival of smokers is also poorer because of an increase in cardiac and malignancy-related mortality.25
Alcohol and substance use
The deleterious effects of continued alcohol consumption on the long-term survival of recipients has been noticed, usually as a result of cardiovascular diseases and malignancy.27 Psychological evaluation for patients with alcoholic cirrhosis is therefore part of the review process in pretransplant assessment.28 This is essential in predicting the compliance to post-transplant medications, especially in those with alcohol dependence or abuse.29 Abstinence of 6 months or more, although still controversial, is required by most transplantation centers to determine the suitability for LT. This is in part derived from the assumption that a 6-month abstinence period is more likely to predict a recidivism-free post-transplant course.30
Current toxicology screening methods provide a positive result of screening for cannabinoids up to 2 months after the patient's last use.31 In contrast, other toxicology screening tests, such as those for cocaine and alcohol, become negative soon after use. In a recent survey, patients who tested positive for marijuana had similar survival rates compared to those with negative test results.32 Whether patients who regularly use marijuana should be excluded from the waiting list remains a controversial issue.
Liver cirrhosis is associated with malnutrition and often after LT, with the development of obesity and the failure to gain lean body mass. Briet et al. found that low pretransplant peripheral blood mononuclear cell complex I activity could be a useful marker of poor nutritional status by predicting metabolic disturbances and an inability to regain fat-free mass after LT.33 Further evaluation is required to assess its feasibility in the clinical setting. Osteoporosis is also a common complication among patients with cirrhosis.34 It is of special interest in pretransplantation evaluation because of the potential loss of bone density and the risk for pathological fractures in the perioperative period.35
Obesity of the potential recipient, which is more often encountered in women and in patients with cryptogenic cirrhosis, is another important concern. A study showed that morbid obesity, defined as a body mass index (BMI) higher than 40 kg/m2, was associated with decreased 30-day, 1-year and 2-year postoperative survival; in addition, the 5-year survival was significantly reduced in patients with morbid and severe obesity (BMI higher than 35 kg/m2).36
Coronary artery disease
The perioperative mortality of LT is high in patients with coronary artery disease.37 Chronic smokers, patients older than 50 years and those with a clinical or family history of heart disease or diabetes mellitus should be evaluated for coronary artery disease. Many studies have indicated that dobutamine stress echocardiography seems to be an effective screening test for occult coronary disease in this setting.38 Nevertheless, cardiac catheterization should be performed in patients with positive stress tests to clarify the extent of the coronary disease.37
The preoperative evaluation of patients suspected of having HPS should include arterial blood pO2 determination, transthoracic contrast echocardiography, arterial oxygen response to 100% oxygen administration and quantification of intrapulmonary shunting using the macroaggregated albumin (MAA) scan.39 With careful management, moderate abnormalities of gas exchange are not an obstacle to successful LT. However, patients with severe hypoxia have increased perioperative mortality.39 Preoperative PaO2 of 50 mmHg or less, alone or in combination with a MAA shunt fraction of 20% or more, are the strongest predictors of postoperative mortality.39 Patients with HPS and PaO2 of less than 60 mmHg on room air without underlying lung disease are usually provided with an enhanced prioritization for organ allocation.
LT for hepatocellular carcinoma (HCC) provides excellent outcomes with 5-year survival rates similar to patients undergoing LT for non-malignant indications.40 The current liver graft allocation system favors patients with small HCC within the Milan criteria (a single tumor up to 5 cm in diameter or up to three lesions, none larger than 3 cm).40 This model has been challenged with less restrictive criteria by Yao et al., who demonstrated good outcomes with LT for patients with a single HCC up to 6.5 cm in diameter or with up to three HCC, none larger than 4.5 cm, with a cumulative diameter up to 8 cm, the so-called University of California at San Francisco (UCSF) criteria. They reported that similar excellent outcomes (94% of patients free of recurrence at 5 years) could be achieved on the basis of preoperative imaging.41 In a Korean study,42 the 3-year survival rates among patients meeting the Milan versus the UCSF criteria were 91.4% and 90.6%, respectively, according to a retrospective analysis of 312 HCC patients. Nowadays, the UCSF criteria have been accepted by most Western countries and some Eastern countries, including Japan and Hong Kong. In Japanese collective data comprising 316 HCC patients undergoing living donor LT (LDLT), the 3-year survival among recipients who met the Milan criteria was 78.7% versus 60.4% among those who did not.43 Investigators advocated that the indication of LDLT for HCC should be no extrahepatic metastasis or major vascular invasion.44,45 Further evaluation is required to address this issue.
It has been found that a calculated total tumor volume (TTV) cut-off of 115 cm3 predicts more HCC recurrence and lower patient survival following LT.46 In an overview of 6478 adult recipients, of all the tested variables (tumor number, largest tumor size and Milan and UCSF criteria), the combined TTV and α-fetoprotein score efficiently predicted post-transplant survival.47
Graft dysfunction occurs in up to 13% of patients during the first year after transplantation and rises to 35% by 5 years.48 It is well known that the modulation of immune response, both cellular and humoral, is primarily driven by various cytokines. The serum level of tumor necrosis factor (TNF)-α protein in patients with liver rejection was significantly higher than that in patients without rejection.49 It is thus conceivable that cytokines play a pivotal role in the immunological response after transplantation and are intimately implicated in graft rejection. Previous studies on Caucasian populations have revealed that the TNF-α-308 polymorphism was associated with graft rejection.50 In the Asian population, graft rejection and hepatitis B virus (HBV) recurrence are two major immunological complications after LT. However, in a survey enrolling 186 Chinese LT recipients, genetic polymorphisms of interleukin-10, TNF-α and transforming growth factor-β1 did not play a major role in graft rejection and HBV recurrence after LT.51 The population-dependent distribution of cytokine alleles and genotypes, as well as the relatively small sample sizes, might be responsible for the divergent results.
The most common surgical contraindication to LT is the absence of a viable splanchnic venous inflow system. If the entire portal venous system is occluded or atrophied, transplantation will be associated with a high risk of graft loss and perioperative mortality.52 Computed tomographic and magnetic resonance angiography can provide accurate preoperative assessment of both hepatic arterial anomalies and the integrity of portal inflow to the liver.
The shortage of donor livers is still a major problem in most Asian countries. Because of various social and cultural reasons, cadaveric donor organ allocation remains below five per one million per year.53 To cope with the limited availability, extending donor criteria, split LT and LD have been developed, but some high-risk donors might induce adverse recipient outcomes. Feng et al. identified nine donor factors predicting graft failure after transplantation, including age, height, donation after cardiac death, split liver donation, black race, death from cerebrovascular accident, regional sharing and cold ischemia time.54 They proposed the idea of a donor risk index: donor age older than 40 years, donation after cardiac death, split/partial grafts, African American race, shorter stature, prolonged cold ischemia time, cerebrovascular accident and other causes. The routine survey for potential organ donors for LT is summarized in Table 2.
Table 2. Evaluation of potential donors for living donor liver transplantation
|Age, relation to recipient, body mass index, medical history and blood group|
|History survey and physical examination|
|History of alcohol consumption and substance abuse|
|Contraindicated surgical history: previous major abdominal surgery|
|Contraindicated major medical conditions: diabetes, severe or uncontrolled hypertension, hepatic, cardiac, renal or pulmonary disease|
|* Complete blood count with differential count|
|* Coagulation profiles|
|* Liver and kidney biochemistries, triglycerides, cholesterol|
|* Fasting blood glucose level|
|* Ferritin, transferring saturation, α-1-antitrypsin, ceruloplasmin, antinuclear antibody|
|Virus infection: hepatitis B and C, HIV, cytomegalovirus, Epstein–Barr virus and herpes simplex virus|
|Cardiopulmonary survey: arterial blood gas, electrocardiography, chest radiography, pulmonary function test, echocardiography and Doppler ultrasound|
|Liver volume and vascular, biliary anatomy estimation: abdominal ultrasound, CT or MRI|
|Presence of steatosis: liver images and/or liver biopsy|
|Optional: celiac angiography, ERCP, stress electrocardiography|
|Psychological and ethical evaluation|
The accurate pretransplant estimation of donor or recipient standard liver volume (SLV) is crucial to ensure donor safety and to avoid small-for-size syndrome.55 One-year graft survival after elective LDLT can reach 92% if the graft size is large (graft–recipient weight ratio [GRWR] > 1), but the number could drop to 42% with a small graft size (GRWR < 0.8).55 The safety of right-lobe hepatectomy in the donor also depends on the volume of the remaining left lobe. Makuuchi et al. proposed that those with a large right lobe (> 70% of total liver volume) should not be accepted as suitable donors.56 Safe donation is possible only when the estimated residual liver volume is greater than 30% of the donor's total liver volume. A recent survey in Taiwan revealed that anatomic considerations were not the main reason excluding potential donors. Rather, an inadequate remnant liver volume of less than 30% was the crucial decision point for the adult LDLT.57
However, the estimation of the SLV is complex and is influenced by race. Several formulae have been generated at Asian or Western centers to estimate the SLV.58–60 The variables in the formulae include body surface area, sex and age. Liver volume was positively related to body surface area and negatively correlated with age. Previous studies also indicated a negative correlation between age and SLV.58,59
Many donor livers have hepatic steatosis.61 The negative impact of severe hepatic steatosis on graft dysfunction during the immediate post-transplant period has long been recognized.62 Macrovesicular steatosis leads to hepatic inflammation and fibrosis, and recipients of a liver graft with macrovesicular steatosis are potentially more susceptible to graft damage, such as preservation injury and acute cellular rejection.63 Severe macrovesicular steatosis greater than 60% is often associated with primary non-function, resulting in serious sequelae for recipients.64 Furthermore, the acceptable level of steatosis in LDLT is thought to be lower than that in deceased donor LT, because of the smaller-sized graft.65 To ensure recipient safety, most centers only use liver grafts with up to 30% macrovesicular steatosis.64 A recent study further indicates that mild macrovesicular steatosis can be related to adverse outcomes in living liver donors who undergo right hepatectomy.66 This is of special concern regarding donor safety.
Donors with prolonged intensive care unit (ICU) admissions and those rescued by cardiopulmonary resuscitation and use inotropic agents carry a higher risk of conveying potential infections. However, a recent survey showed that donors with positive bacterial cultures did not significantly induce graft infection, nor did it adversely affect recipient ICU or hospital stay or overall survival rate.67 Further large-scale surveys are required to clarify the relevant influences.
Marginal donor livers
Considering the shortage of donor livers at particular times, when the demand for LT is persistently increasing, the criteria of feasible donor livers have been under intense debate, aiming to expand the donor pool. The potential marginal donors include those with a history of being exposed to hepatitis B or C virus, steatotic liver, older donors, those with a high-risk social history (drug abuse, alcohol abuse or sexual history), history of cancer, a small degree of liver disease that is undetectable on laboratory tests and liver biopsy, those who test positive for human T-cell lymphotrophic virus and those with sustained cardiac death. Nevertheless, without strong evidence supporting the benefit rather than harm, it is still questionable to use marginal donor livers.