Major adverse events, pretransplant assessment and outcome prediction

Authors

  • Hui-Chun Huang,

    1. Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan and
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  • Fa-Yauh Lee,

    1. Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan and
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  • Teh-Ia Huo

    Corresponding author
    1. Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
    2. Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
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Professor Teh-Ia Huo, Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Email: tihuo@vghtpe.gov.tw

Abstract

Liver cirrhosis and portal hypertension pose enormous loss of lives and resources throughout the world, especially in endemic areas of chronic viral hepatitis. Although the pathophysiology of cirrhosis is not completely understood, the accumulating evidence has paved the way for better control of the complications, including gastroesophageal variceal bleeding, hepatic encephalopathy, ascites, hepatorenal syndrome, hepatopulmonary syndrome and portopulmonary hypertension. Modern pharmacological and interventional therapies have been designed to treat these complications. However, liver transplantation (LT) is the only definite treatment for patients with preterminal end-stage liver disease. To pursue successful LT, the meticulous evaluation of potential recipients and donors is pivotal, especially for living donor transplantation. The critical shortage of cadaveric donor livers is another concern. In many Asian countries, cultural and religious concerns further limit the number of the donors, which lags far behind that of the recipients. The model for end-stage liver disease (MELD) scoring system has recently become the prevailing criterion for organ allocation. Initial results showed clear benefits of moving from the Child–Turcotte–Pugh-based system toward the MELD-based organ allocation system. In addition to the MELD, serum sodium is another important prognostic predictor in patients with advanced cirrhosis. The incorporation of serum sodium into the MELD could enhance the performance of the MELD and could become an indispensable strategy in refining the priority for LT. However, the feasibility of the MELD in combination with sodium in predicting the outcome for patients on transplant waiting list awaits actual outcome data before this becomes standard practice in the Asia–Pacific region.

Pathophysiology of cirrhosis

Liver injury, either acute or chronic, leads to subsequent repair with formation of fibrous tissue bands and regenerative nodules. Leaving the process unchecked, the normal liver architecture will be disrupted, followed by increased intrahepatic vascular resistance, which impedes portal blood inflow. Apart from the mechanical factor, the contraction of activated hepatic stellate cells and vascular smooth muscle cells constitutes a dynamic component of an enhanced intrahepatic vascular tone.1 The exaggerated release of peripheral and splanchnic vasodilatory substances that occurs with splanchnic hyperemia, together with increased portal blood inflow, causes portal pressure to gradually rise.2 Clinically, significant portal hypertension is defined when portal pressure, determined by its equivalent, the hepatic venous pressure gradient (HVPG), exceeds a threshold value of 10 mmHg. In an attempt to decompress the portal system, a portosystemic collateral circulation develops, followed by the dreaded complications, such as gastroesophageal variceal bleeding and hepatic encephalopathy (HE).

The peripheral vasodilatation also lowers systemic vascular resistance and effective intravascular volume; these changes are initially compensated by the heart with tachycardia and increased cardiac output, the so-called hyperdynamic circulatory syndrome. As renal perfusion is compromised by the inadequate intravascular volume, endogenous antinatriuretic and vasoconstrictive systems, including the rennin–angiotensin–aldosterone axis, sympathetic nervous system and antidiuretic hormone are triggered. Together, these are responsible for sodium and water retention and formation of ascites.3 Even worse, marked vasoconstriction of the kidney under such a circumstance can further compromise the renal perfusion. At the end, hepatorenal syndrome (HRS) supervenes, characterized by functional renal failure.4

In pulmonary circulation, intrapulmonary vasodilatation and shunt formation leads to hepatopulmonary syndrome (HPS), which presents clinically with ventilation-perfusion mismatch and hypoxemia. On the contrary, portopulmonary hypertension (PPH) can evolve, characterized by a marked increase of pulmonary vascular resistance due to endothelial dysfunction and vascular remodeling.5

Major complications of cirrhosis

Gastroesophageal variceal bleeding

Gastroesophageal varices are found in 30% of patients with compensated cirrhosis and 60% of patients with decompensated cirrhosis.6 Variceal bleeding usually does not occur until the HVPG is above 12 mmHg. Each episode of bleeding carries a 20% mortality rate.7 If the varices are left untreated, after survival from the first episode, the rebleeding risk can be up to 70% within 1 year and is a major cause of death in patients with cirrhosis.8 The mainstays of medical treatment are endoscopic variceal ligation and non-selective beta blockers. Although ligation is better at preventing first variceal bleeding than non-selective beta blockers,9 Norberto et al.10 showed that among candidates for cadaveric liver transplantation (LT), prophylactic variceal ligation was associated with a 6.5% increased risk of clinically significant post-banding bleeding for local ulceration. LT remains the best way to decompress the portal system.

HE

HE is a neuropsychiatric complication of cirrhosis in which clinical manifestations range from subtle personality changes or sleep disorder to stupor and coma. The mechanism is complex, but can reasonably be ascribed to the failure of the liver to detoxify blood arising from the intra-abdominal organs and the diversion of such unprocessed blood into the systemic circulation. Brain function is thus impaired by the excessive toxins. Regarding the influence of LT on HE, in a previous survey, although marked neuropsychological recovery was observed at 1 year after LT, it was incomplete, that is, some residual degree of cognitive impairment remained.11 Furthermore, although LT can resume a normal mental state in cirrhotic patients, minimal HE might persist in some patients due to undefined irreversible changes in the brain.12

Ascites and hepatorenal syndrome

Refractory ascites occur in 5–10% of cirrhotic patients and carries a mortality rate of more than 50% at 2 years.13 In a Korean series investigating the natural history of patients with hepatitis B-related cirrhosis hospitalized to control ascites, the overall median survival was 12.4 months. The 1- and 3-year survival rates were 51% and 19%, respectively. Moreover, patients were prone to develop gastrointestinal variceal bleeding, HE, spontaneous bacterial peritonitis (SBP) and HRS at approximately 1 year after the development of ascites, reflecting the poor prognosis of patients with ascites.14 LT evaluation therefore should be instituted whenever refractory ascites develop.

Hepatorenal syndrome is characterized by renal vasoconstriction in response to renal hypoperfusion from low systemic effective circulating volume. The annual incidence of HRS in patients with cirrhosis and ascites is approximately 8%.15 It is classified as either type 1 or 2. Type 1 HRS is rapidly deteriorating with the doubling of serum creatinine to a level greater than 2.5 mg/dL, or with a 50% reduction in creatinine clearance to a level below 20 mL/min in less than 2 weeks. Without treatment, patients with type 1 HRS have a median survival of only 2 weeks.15 Type 2 HRS is characterized by slowly progressed kidney dysfunction with a serum creatinine over 1.5 mg/dL. Acute renal failure from HRS usually improves dramatically after LT and does not appear to have an impact on post-transplant survival.16

Pulmonary complications

As introduced earlier, two distinct pulmonary vascular disorders can be found in cirrhosis: HPS and PPH. HRS consists of the clinical triad of chronic liver disease, arterial deoxygenation and widespread intrapulmonary vasodilatation with shunt formation. It is seen in 8–17% of cirrhotic patients and carries a median survival of 11 months.17 LT may resolve HPS in the majority of patients. Therefore, HPS has become an indication for urgent transplantation.18

PPH is seen in 2–4% of patients with cirrhosis.19 LT yields variable consequences. The presence of mild or moderate PPH does not influence the outcome of LT. In contrast, among patients with severe pulmonary hypertension, the postoperative mortality was 42% at 9 months and 71% at 36 months.20 LT is thus contraindicated when pulmonary arterial pressure is higher than 35–45 mmHg because of more than 50% perioperative mortality.21 Nevertheless, occasional patients with severe PPH who have been medically controlled have undergone transplantation smoothly. In many of these patients, PPH gradually resolves within 4–6 months after transplantation, and medical treatment can then be discontinued.22

Pretransplant assessment

Recipients

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
  1. CT, computed tomography; delta Ab, antibody to hepatitis D virus; ERCP, endoscopic retrograde cholangiopancreatography; HBeAg, hepatitis B e antigen; HBV–DNA, hepatitis B viral DNA; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HFE, hemochromatosis; HLA, human leukocyte antigen; MR, magnetic resonance; MRI, magnetic resonance imaging.

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

Age

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

Cigarette smoking

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.

Nutrition

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

Hepatopulmonary syndrome

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.

Hepatocellular carcinoma

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

Genetic polymorphism

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.

Surgical consideration

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.

Donor

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
  1. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; MRI, magnetic resonance imaging.

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
Laboratory survey
* 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

Liver volume

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

Steatosis

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.

Infection

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.

Outcome prediction for advanced cirrhosis

Introduction of the model for end-stage liver disease

The policies of organ allocation have gone through various stages of evolution. In the USA, transplant candidates were prioritized to receive organs for LT based on the United Network of Organ Sharing (UNOS) status that primarily reflected their Child–Turcotte–Pugh (CTP) scores. The model for end-stage liver disease (MELD) was later introduced in an attempt to fairly allocate donor livers. Nowadays, many European and Asian countries have adopted this transplant policy because the MELD score can more accurately predict the severity and outcome of patients with advanced liver cirrhosis.

The MELD score is calculated based on three serum biochemical variables: bilirubin, creatinine and an international normalized ratio of prothrombin time. After modification by the UNOS, the currently-used MELD equation to calculate the severity score is as follows: 9.6 × loge (creatinine mg/dL) + 3.8 × loge (bilirubin mg/dL) + 11.2 × loge (international normalized ratio) + 6.4. Minimal values are set to 1 for calculation purposes. The maximal serum creatinine level considered within the MELD score equation is 4 mg/dL to avoid higher MELD scores in uremic patients. Since donor livers are allocated to the recipients according to the severity of underlying disease (the ‘sickest first’ policy), the UNOS suggested using the MELD system to prioritize adult patients on the transplantation waiting list. Thus, in February 2002, the liver allocation system was changed from a status-based algorithm using CTP scores to one using a continuous MELD severity scores as a reference system to prioritize adult patients on the waiting list in the USA.

A major contrast between the CTP and MELD systems is that the factor of renal function is taken into consideration in the MELD for outcome prediction. Renal dysfunction is a common event occurring in up to 75% of cirrhotic patients during the course of the disease, and the severity of liver cirrhosis was identified as a factor contributing to renal insufficiency in previous studies.68,69 Using the MELD can avoid potentially subjective interobserver bias that can confound the order of organ allocation, because only objective laboratory variables are included in the calculation. Several studies have subsequently shown that an allocation process based on the MELD rather than clinical judgement could alter organ allocation and reduce waiting list mortality.70,71

Current status of the MELD

Many studies have demonstrated that the MELD is a better prognostic model than the CTP system for outcome prediction in cirrhotic patients at the population level.72–74 Most of these studies adopted the approach of comparing the concordance (c-statistic) equivalent to the area under the receiver operating characteristic curve for the MELD and CTP score to assess the ability for outcome prediction. However, inconsistent results have been reported from other countries,75–77 suggesting that the MELD was not necessarily better than the CTP system. In addition, many physicians still prefer to use the CTP system because it is relatively simple to use and is more intuitive at bedside evaluation. However, no study to date has shown the MELD to be statistically inferior to the CTP system. Alternatively, by expanding the cut-offs used in the traditional CTP system, we proposed a modified CTP system with a CTP class D category to overcome the ceiling effect and improve the overall predictive accuracy in cirrhotic patients.78

The application of the MELD system has been further extended to other clinical fields. It correlated with the hepatic venous pressure gradient, which reflects portal pressure in cirrhotic patients,79 and was shown to be a feasible model in predicting outcomes in cirrhotic patients undergoing major surgical procedures.80 Moreover, the MELD has been proposed to be incorporated into the staging system for HCC to replace the traditional CTP system, which is the major reference to indicate the severity of liver cirrhosis. Independent studies from Taiwan and Hong Kong, where hepatitis B infection is highly prevalent, have shown that the modified staging systems have an increased predictive accuracy in comparison to the original, CTP-based staging systems for HCC.81,82 These findings imply that, although the MELD was originally designed to predict 3-month mortality risk in patients undergoing transjugular intrahepatic portosystemic shunt procedure,83 it can also be used to predict the long-term outcome related to the clinical spectrum of liver cirrhosis.

The MELD can harbor some intrinsic drawbacks. Some important prognostic predictors, such as profound HE, esophageal variceal bleeding and SBP, which are common adverse complications in cirrhosis, are not included in the MELD system. The occurrence of these complications indicates a status of ongoing deterioration of residual liver function that precedes the eventual development of hepatic failure. Patients with these complications might sometimes not have a higher baseline MELD score, which is necessary to prioritize them on the waiting list. As a result, some patients with high need (poor prognosis) could be potentially overlooked during organ allocation in the MELD era.84 This concern was supported in a study showing that hepatic encephalopathy can provide additional prognostic information, independent of the MELD score.85 Even so, the major strength of the MELD over CTP score is that the MELD is based on objective and reproducible clinical data and is more accurate, especially at a population level. Another advantage of MELD over the CTP score is that the MELD is a continuous scale and lacks either a ceiling or floor effect, with a wide range of discrimination. Whether the presence of severe complications of cirrhosis might have additional prognostic information independent of the MELD deserves further study to clarify.

Improving the performance of the MELD

Cirrhotic patients often have dilutional hyponatremia, which is frequently associated with severe cirrhosis-related complications. A serum sodium level of < 126 mEq/L at listing for transplantation is a strong predictor of mortality.86 In addition, serum sodium is predictive of transplant or death independent of the MELD score.87 The addition of sodium to the MELD can improve its predictive accuracy, especially for patients with lower range MELD scores.88 Mathematical equations based on both MELD and Na, known as MELD-Na and MELDNa, have been developed to predict short-term mortality in cirrhotic patients awaiting LT.89,90 The MELDNa was reported to potentially avoid 7% of deaths on the transplant waiting list.90 Other prognostic models that include the MELD and Na were the integrated MELD (iMELD) score (containing age, MELD and Na) and MESO index (MELD-to-sodium ratio).91,92 Recent studies have shown that the iMELD and MELD-Na may better predict the 3- and 6-month mortality in cirrhotic patients,93,94 suggesting that MELD in combination with Na could be a more accurate model for outcome prediction (Fig. 1). Comparisons of the differences between the CTP, MELD and MELD in combination with sodium are shown in Table 3. More research is urgently needed to clarify the role of the Na-containing prognostic models in predicting the outcomes of patients with advanced cirrhosis.

Figure 1.

Predictive accuracy for short-term mortality in patients with advanced cirrhosis using the area under the receiver operative characteristics (ROC) curve. Vertical bars indicate the range of the area under the ROC curve in different published studies. While the model for end-stage liver disease (MELD) is generally better than the Child–Turcotte–Pugh (CTP) system, the MELD in combination with serum sodium can have an enhanced prognostic ability (integrated data from references 72–74,93,94).

Table 3.  Comparison of the first- (CTP), second- (MELD) and third-generation (MELD in combination with sodium) prognostic models for cirrhosis
GenerationModelsVariablesAdvantagesDisadvantages
  1. 89,90,92,91. CT, computed tomography; CTP, Child–Turcotte–Pugh; iMELD, integrated MELD; INR, international normalized ratio; MELD, model for end-state liver disease; MESO, MELD-to-sodium ratio; Na, sodium.

FirstCTPBilirubin, INR, albumin, ascites, encephalopathyEasy to use, more intuitiveCeiling effect, interobserver bias
SecondMELDBilirubin, creatinine, INRObjective, continuous variableNeeds logarithmic transformation
ThirdMELD-Na89MELD, NaObjective, continuous variableNeeds logarithmic transformation
MELDNa90MELD, Na
iMELD92MELD, Na, age
MESO91MELD, Na

Conclusions

Patients with advanced liver cirrhosis often have profound splanchnic and systemic circulatory dysfunction that is closely linked with the development of severe and fatal complications. Although there are many modern pharmacological and interventional therapies to treat these complications, the only definite treatment for advanced cirrhosis is a timely LT. In Asia, the level of donors is even more restricting to the effective application of LT than it is in Western countries. Pretransplant assessment requires a detailed evaluation for donors and recipients and should be performed by both transplant hepatologists and surgeons to achieve the best post-transplant outcome. The MELD scoring system has become the prevailing criterion for organ allocation. The initial results of using the MELD showed clear benefits of moving from the CTP-based system toward the MELD-based organ allocation system. However, the currently-used MELD might need fine tuning to accommodate patients with serious cirrhosis-related complications, such as hepatic encephalopathy and SBP. In addition to the MELD, serum sodium is another important prognostic predictor in patients with advanced cirrhosis. The incorporation of sodium into the MELD could enhance the performance of the MELD and could become an indispensable strategy in refining the MELD. The feasibility of the MELD in combination with sodium in predicting the outcome for patients on transplant waiting list awaits actual outcome data for justification.

Ancillary