**1.2 Indication of liver transplantation and survival models**

Liver transplantation is the treatment of choice in acute and chronic irreversible liver failure of different etiologies, in primary liver tumors and when an impaired quality of life appears by manifestations of liver disease, as intractable pruritus and hepatic osteodystrophy.

The most commonly used survival models to assess the degree of liver failure and to prioritize patients on the waiting list for liver transplantation are: the Child-Pugh score (Oellerich M, 1991) and Model for End Stage Liver Disease (MELD) score (Malinchoc M, 2000). Although currently used primarily MELD, both have been included among the criteria for liver allocation in the United States and Europe (Freeman RB Jr, 2004; Adler M, 2005).

The Child-Pugh score has been widely used both in research and in clinical practice. For these reason, candidates for liver transplantation were prioritized mainly by these score, which included subjective measures of encephalopathy and ascites, and time waiting on the list. However, the need for a more accurate system in which the urgency of assignment was a relevant criterion, determined the introduction of the MELD score that is also very valuable as a predictor of mortality and allocation of organs for patients on the waiting list. The MELD score had been previously validated as a predictor of 3-month mortality for patients with chronic liver disease. (D'Amico G, 2006; Botta F, 2003)

The MELD system appears superior for comparing populations and has had a positive impact on allocation and survival in liver transplantation; however, it is still far from perfect. One of the disadvantage of the MELD formula is the loss of prognostic accuracy in periods longer than 3 months. The Child-Pugh classification provides superior results for periods exceeding one year. For these reasons, some authors recommend implementing both systems. (Forman LM, 2001; D'Amico G, 2006; Prieto M, 2007; Durand F, 2005.)

The Child-Pugh score evaluates five parameters: ascites, encephalopathy, bilirubin, prothrombin time and albumin. Although never formally validated, has been the most

Along with ascites, there may be other serious complication such as spontaneous bacterial peritonitis. In these cases, the probability of survival one year after this complication appears is only 40%. This is a strong reason for evaluating these patients as candidates for transplantation. (Corrao 1997) Similarly, other complications may appear such as hepatic encephalopathy and hepatic-renal syndrome. Both also worsen the prognosis. (Mandaya

Variceal hemorrhage occurs in 30 to 40% of patients with liver cirrhosis. In the past two decades, even with the improvement achieved in the treatment and in the prognosis after bleeding, mortality at six weeks is still high. It is estimated between 15 and 30% in patients

After a first episode of hepatic encephalopathy the survival of cirrhotic patients is 42% in the

Hepatocellular carcinoma is another major complication and can occur at any stage of cirrhosis. It is recognized as the leading cause of death in the compensated phase, especially

Liver transplantation is the treatment of choice in acute and chronic irreversible liver failure of different etiologies, in primary liver tumors and when an impaired quality of life appears by manifestations of liver disease, as intractable pruritus and hepatic osteodystrophy.

The most commonly used survival models to assess the degree of liver failure and to prioritize patients on the waiting list for liver transplantation are: the Child-Pugh score (Oellerich M, 1991) and Model for End Stage Liver Disease (MELD) score (Malinchoc M, 2000). Although currently used primarily MELD, both have been included among the criteria for liver allocation in the United States and Europe (Freeman RB Jr, 2004; Adler M,

The Child-Pugh score has been widely used both in research and in clinical practice. For these reason, candidates for liver transplantation were prioritized mainly by these score, which included subjective measures of encephalopathy and ascites, and time waiting on the list. However, the need for a more accurate system in which the urgency of assignment was a relevant criterion, determined the introduction of the MELD score that is also very valuable as a predictor of mortality and allocation of organs for patients on the waiting list. The MELD score had been previously validated as a predictor of 3-month mortality for

The MELD system appears superior for comparing populations and has had a positive impact on allocation and survival in liver transplantation; however, it is still far from perfect. One of the disadvantage of the MELD formula is the loss of prognostic accuracy in periods longer than 3 months. The Child-Pugh classification provides superior results for periods exceeding one year. For these reasons, some authors recommend implementing

The Child-Pugh score evaluates five parameters: ascites, encephalopathy, bilirubin, prothrombin time and albumin. Although never formally validated, has been the most

both systems. (Forman LM, 2001; D'Amico G, 2006; Prieto M, 2007; Durand F, 2005.)

first year, and 23% in the following three years. (Mendez-Sanchez 2005)

in patients with HCV. (Capocaccia R, 2007; Perz, J.F, 2006)

**1.2 Indication of liver transplantation and survival models** 

patients with chronic liver disease. (D'Amico G, 2006; Botta F, 2003)

2004)

2005).

with stage C of Child-Pugh. (Hands 2008)

widely used for decades. It is easy to apply and has proved useful in estimating the prognostic index of survival. But some limitations are pointed out such as, not all variables have an independent effect, it includes subjective variables like ascites and encephalopathy, the cutoff points for quantitative variables are not optimal, and it does not take into account certain important prognostic factors such as renal function. (Oellerich M, 1991; Prieto M, 2007)

The MELD model uses a mathematical formula with simple and objective variables such as, serum concentrations of bilirubin, creatinine and international normalized ratio (INR) of prothrombin time. From these variables, you get a score that is predictive of survival. Initially it also included the etiology of the disease, but this variable was excluded because a minimal influence was observed. (Vargas V 2003) Nevertheless, its application is less practical because of the need of computer systems. One of its major limitations is its variability due to changes in creatinine and bilirubin. These parameters can be altered by treatment, sepsis or hemolysis. The value of creatinine is often affected by diuretics and other factors such as age, sex and body mass, which may introduce a bias independent of the severity of liver disease. Moreover, the severity of some medical complications, are not well reflected in the MELD score. (Prieto M, 2007; Vargas V, 2003; de la Mata, 2004)

Research is still going in an effort to improve this mathematical model. Many studies have proposed the addition of variables that may be of prognostic significance. Recently it has been suggested that the addition of sodium to the MELD formula could improve its accuracy. Some studies showed that serum sodium lower than 126 mEq/L is an independent predictor of mortality among patients listed for transplantation, and the addition of sodium to the MELD score increases its prognostic value. In patients with portal hypertension and cirrhosis, hyponatremia may be the earliest harbinger of refractory ascites and hepatorenal syndrome, and possibly a more sensitive marker than rising creatinine. (Taddei TH, 2007) However, this new formula is also subject to interassay variations, as well as the potential manipulation can be generated inadvertently by the use of diuretics. It is also unknown if its use can lead to increased mortality by neurological causes. For all this, it seems premature to use as long as no data are available for validation in larger groups and different cohorts. (Cárdenas A, 2008; Jiang M, 2008) Among the new proposals are to include the introduction of the measurement of the Hepatic Venous Pressure Gradient (Taddei TH, 2007), to include ascites, encephalopathy (Ripoll C, 2005; Stewart CA, 2007), sex (S Huo; 2007) or exclude the INR (Heuman DM, 2007). But is too premature to make conclusions.

Recently, a new estimator has been projected: the Cuban model Bioclim. This is a score calculated by a mathematical model that evaluates the creatinine and bilirubin biochemical parameters. It also takes into account: clinical encephalopathy, ascites and variceal upper gastrointestinal bleeding, considering the positive or negative response to treatment. Compared with Child-Pugh and MELD, the authors of this model (Vilar E, 2009) concluded that Bioclim score seems to have a greater discriminatory power in the short-term survival (4 to 12 weeks), intermediate term (24 to 52 weeks) and long-term (104 weeks).

#### **1.3 Studies of survival and prognostic factors**

In order to improve prognostic models many factors have been studied in relation to the survival of patients with liver cirrhosis.

In a review of 118 studies conducted by D'Amico (D'Amico G, 2006) the Child-Pugh was reported as the best predictor of mortality in cirrhosis, followed by the five components measured individually.

Said (Said A, 2004) noted that in one year follow up of cirrhotic patients, male gender, MELD score, Child-Pugh and encephalopathy, were associated with increased mortality. Independent predictors were the Child-Pugh and encephalopathy.

Botta (Botta F, 2003) compared the survival of cirrhotic patients at 6 and 12 months using a multivariate analysis including variables of Child-Pugh, MELD and a quantitative test of liver function test monoetilglicinexylidide (MEGX). At six months, MEGX, creatinine and prothrombin time were disposed as predictive factors of lower survival. The ascites was added at 12 months.

Attia (Attia KA, 2008) reported as independent predictors of mortality in 172 African patients with cirrhosis, the Child-Pugh score, MELD index, and creatinine.

London (London MC, 2007), in a study of 308 cirrhotic patients on the waiting list for liver transplantation, described the serum sodium and MELD score as independent predictors of survival at 3 and 12 months.

Samada (Samada M, 2008) conducted a study in 144 patients with liver cirrhosis and transplant candidates. The variables associated with lower survival at 12 months were: prothrombin time, bilirubin, albumin, cholesterol, serum sodium, sex, history of ascites and encephalopathy. Also MELD index and Child-Pugh stages were evaluated. But only the Child-Pugh score and spontaneous bacterial peritonitis were independent predictors of survival.

In conclusion we can state that detailed clinical evaluation of patients with liver cirrhosis and knowledge of prognostic factors associated with survival, could lead to proper management of these patients, the appropriate indication for liver transplantation and increased survival. This has been the principal motivation of the present study, in order to recognize the prognostic factors for survival in patients with cirrhosis within a three year period.
