Cirrhosis of mixed etiology (hepatitis C virus and alcohol): Posttransplantation outcome—Comparison with hepatitis C virus–related cirrhosis and alcoholic-related cirrhosis

Authors

  • Victoria Aguilera,

    Corresponding author
    1. Liver Surgery and Transplant Unit, Hospital La Fe de Valencia, Valencia, Spain
    2. Hepatogastroenterology Unit, Hospital Universitario La Fe, Valencia, Spain
    • Hepatogastroenterology Unit, Hospital Universitario La Fe, Avenida Campanar 21, Valencia 46009, Spain
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    • Telephone: 011-34-96-386-8792; FAX: 011-34-96-398-7333

  • Marina Berenguer,

    1. Liver Surgery and Transplant Unit, Hospital La Fe de Valencia, Valencia, Spain
    2. Hepatogastroenterology Unit, Hospital Universitario La Fe, Valencia, Spain
    3. Faculty of Medicine, University of Valencia, Valencia, Spain
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  • Angel Rubín,

    1. Liver Surgery and Transplant Unit, Hospital La Fe de Valencia, Valencia, Spain
    2. Hepatogastroenterology Unit, Hospital Universitario La Fe, Valencia, Spain
    3. Liver Surgery and Transplant Unit, Hospital Universitario La Fe, Valencia, Spain
    4. Pathology Service, Hospital Universitario La Fe, Valencia, Spain
    5. Faculty of Medicine, University of Valencia, Valencia, Spain
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  • Fernando San-Juan,

    1. Liver Surgery and Transplant Unit, Hospital Universitario La Fe, Valencia, Spain
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  • Jose-Miguel Rayón,

    1. Pathology Service, Hospital Universitario La Fe, Valencia, Spain
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  • Martín Prieto,

    1. Liver Surgery and Transplant Unit, Hospital La Fe de Valencia, Valencia, Spain
    2. Hepatogastroenterology Unit, Hospital Universitario La Fe, Valencia, Spain
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  • José Mir

    1. Liver Surgery and Transplant Unit, Hospital Universitario La Fe, Valencia, Spain
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Abstract

Hepatitis C virus (HCV)-related liver disease is enhanced by alcohol consumption. Of HCV-related liver transplantation (LT) recipients, 25% have a history of alcohol intake. The purpose of this research was to determine whether LT outcome differs between patients with cirrhosis of mixed etiology compared to HCV or alcohol alone. Of 494 LT (1997-2001), recipient/donor features, post-LT histological, metabolic complications [hypertension, diabetes–diabetes mellitus (DM)], and de novo tumors were compared in 3 groups [HCV-related cirrhosis = 170 (HCV group), alcohol-related cirrhosis (alcohol group) = 107, and cirrhosis of mixed etiology (mixed group) = 60]. Protocol biopsies were done in HCV patients. Severe recurrent HCV disease was defined as: 1-year fibrosis >1, cholestatic hepatitis, recurrent cirrhosis, or HCV-related liver retransplantation (reLT) within 5 years. Patients in the mixed group were younger (mean age: HCV group = 59 years; mixed group = 49 years; alcohol group = 53 years; P < 0.05) and mainly men (% men: HCV group = 51%; mixed group = 97%; alcohol group = 87%). Hepatocellular carcinoma (HCC) was more frequent in HCV patients (HCV group = 44%; mixed group = 35%; alcohol group = 18%; P = 0.05). Five-year survival was lowest in the HCV group (HCV group = 49% versus mixed group = 73% versus alcohol group = 76%; and P < 0.01 for the HCV group versus the alcohol group or the HCV group versus the mixed group; P = 0.74 for the alcohol group versus the mixed group). Metabolic complications and de novo tumors were more frequent in the alcohol groups. Severe HCV disease was similar in the HCV+ groups (HCV group = 45%; mixed group = 45%; P = 0.66). Patients with in the mixed group were more frequently treated with antivirals (32% versus HCV group = 18%; P = 0.03). In HCV patients, factors independently associated with lower survival were older donor age, LT indication (HCV alone), and increased body mass index (BMI). Antiviral therapy was a protective factor. Post-LT survival was lower in the isolated HCV group compared to the alcohol or mixed groups despite a similar recurrence of HCV disease. A greater use of antiviral therapy in the mixed group may explain these differences. The incidence of metabolic complications and de novo tumors was greater in the alcohol groups. Liver Transpl 15:79–87, 2009. © 2008 AASLD.

Cirrhosis due to hepatitis C virus (HCV) infection is the leading cause of liver transplantation (LT) in adults in the Western world.1 Thirty percent of HCV-infected transplantation candidates have a history of significant alcohol intake prior to transplantation.2 Alcoholic cirrhosis is the second leading cause of transplantation in our setting. Although the outcome of patients undergoing transplantation for alcoholic liver disease is considered good, with an overall 60% survival rate at 10 years,3 the outcome of patients undergoing transplantation for HCV-related cirrhosis is impaired by the recurrence of hepatitis C. Indeed, in a relatively large proportion of cases, HCV recurrence has an aggressive course, with progression to cirrhosis within 5 years, resulting in survival rates of less than 65%.4–6 Few studies in the literature have assessed the posttransplantation outcome of patients with cirrhosis due to mixed etiology (HCV+alcohol).7–10

In immunocompetent patients, alcoholic liver disease is associated with other diseases, such as HCV infection, hepatitis B virus (HBV) infection, hemochromatosis, porphyria cutanea tarda, and hepatocellular carcinoma (HCC), with the most frequently associated disease being chronic HCV infection (20%-30% of patients have anti-HCV antibodies and positive viremia). The combination of alcohol and HCV results in a more rapid progression of liver disease, with development of cirrhosis in a shorter period than in patients with hepatitis C alone.11 Higher viral loads, alterations in the immune response, alcohol-induced aggravation of histological lesions, or interference by alcohol of hepatocyte regeneration are potential factors explaining this accelerated disease course.12–14

Factors associated with posttransplantation hepatitis C progression include: genetic background, immunological status, excessive immunosuppression in the context of rejection treatment, high viral load prior to LT, HCV genotype 1b, human immunodeficiency virus coinfection, cytomegalovirus infection, donor age greater than 50 years, hepatic steatosis, and prolonged ischemia time.15, 16 It is not known whether a pretransplantation history of alcoholism can determine changes in the posttransplantation course of patients undergoing transplantation for HCV-related cirrhosis. In fact, the majority of studies have included the group of patients with mixed liver disease (HCV+alcohol) in the group of patients undergoing transplantation for HCV and/or have compared the group of patients undergoing transplantation for alcohol-related liver disease with those undergoing transplantation for HCV+alcohol–related cirrhosis.7, 9, 10, 17–19 In addition, results are controversial. From a theoretical point of view, the impact of alcohol disappears after LT and only HCV remains as a perpetuating factor of graft damage.

The primary aim of this study was to analyze the clinical and histological outcome of patients undergoing transplantation for cirrhosis of mixed etiology (HCV+alcohol–cirrhosis; ie, the mixed group) and to compare it with that of patients undergoing transplantation for HCV-related cirrhosis (the HCV group) or alcohol-related cirrhosis (also alcoholic cirrhosis; ie, the alcohol group). The secondary aims were as follows: (1) to describe and compare baseline clinical, laboratory, and microbiological characteristics in the 3 patient groups; (2) to analyze the causes of graft loss and patient death; (3) to analyze and compare the 3 groups with respect to the prevalence of posttransplantation metabolic complications and de novo tumors; and (4) to assess posttransplantation alcohol intake.

Abbreviations

BMI, body mass index; CI, confidence interval; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HT, hypertension; DM, diabetes mellitus; LIA, linear immunoblotting assay; LT, liver transplantation; OR, odds ratio; reLT, liver retransplantation; RT-PCR, reverse transcription-polymerase chain reaction.

PATIENTS AND METHODS

Patients

Between January 1997 and December 2001, 494 LTs were performed at our institution. Of these, 337 were for HCV-related cirrhosis, alcohol-related cirrhosis (alcoholic cirrhosis), or cirrhosis of mixed etiology (HCV+alcohol): the HCV group (n = 170), the alcohol group (n = 107), and the mixed group (n = 60). All patients with HCV or mixed cirrhosis had a positive HCV serology (enzyme-linked immunosorbent assay + confirmatory line immunoassay) and a positive viral load (reverse-transcription polymerase chain reaction). Genotype was determined by the INNO-LiPA HCV assay (Innogenetics, Belgium). Pretransplantation alcohol intake was assessed by the attending physician at the time of the LT workup. Significant alcohol consumption was defined as >50 g/day for a period of >5 years or >80 g/day for a shorter period. This information was obtained from chart review, particularly from the pretransplantation protocol used in our center. All patients with alcoholic cirrhosis fulfilled criteria for abstinence from alcohol for greater than 6 months and were evaluated by a psychiatrist prior to transplantation; in contrast, not all patients belonging to the mixed group underwent this evaluation because they had stopped drinking alcohol several years before in order to be considered for LT.

Variables Potentially Related to Posttransplantation Outcome

Age at transplantation, gender, presence of HCC, Child-Turcotte-Pugh score at the time of inclusion on the waiting list, nutritional status and body mass index (BMI), pretransplantation prevalence of hypertension and diabetes mellitus (DM), history of smoking and HBV serology (antibody to HBV core antigen and antibody to HBV surface antigen) were determined. Donor characteristics were determined, including age, gender, BMI, positive antibody to HB core antigen, and degree of steatosis. Posttransplantation variables included cold and warm ischemia times, reperfusion syndrome during surgery, initial graft function, incidence and treatment of rejection and type of initial immunosuppression.

The development of de novo tumors, diabetes, and hypertension were recorded.

Immunosuppression

Induction immunosuppression was variable, but generally consisted of calcineurin inhibitors + steroids (usually discontinued at 1 year posttransplantation) ± azathioprine (usually withdrawn at 6 months posttransplantation).

Histological Evaluation

The presence of significant histological disease was determined by protocol liver biopsies at 1, 3, and 5 years posttransplantation in patients with HCV-related cirrhosis and at 5 years in patients with alcoholic cirrhosis. The method used to measure fibrosis severity in HCV-positive patients was the Knodell score. Severe recurrent HCV disease was considered to be present when: (1) the first annual biopsy showed a fibrosis stage >1; (2) progression to cirrhosis occurred within the first 5 years after LT; (3) if the patient developed fibrosing cholestatic hepatitis; and/or (4) if retransplantation was required for cirrhosis secondary to HCV graft infection in the first 5 years posttransplantation. The incidence of severe recurrent HCV disease was compared between the patient groups transplanted for HCV-related or HCV+alcohol cirrhosis (ie, cirrhosis of mixed etiology).

Endpoints Analyzed

Patient and Graft Survival

The causes of death were recorded in the 3 patient groups. Patient and graft survival were compared at 1, 3, 5, and 7 years posttransplantation in the 3 patient groups and individually by cirrhosis etiology subgroup (HCV-related versus HCV+alcohol–related, HCV-related versus alcohol-related, and alcohol-related versus HCV+alcohol–related).

Histological Analysis

Only patients without concomitant disease associated with HCV were included in the histological analysis. Eighty-nine patients were excluded from the histological analysis for the following reasons: (1) follow-up less than 1 year, provided that it was not due to aggressive recurrence of HCV resulting in death of the patient or the need for retransplantation (n = 45); (2) associated biliary or vascular problems (n = 3); (3) development of de novo HBV infection (n = 10); (4) retransplantation (except for those performed in the first week due to primary graft failure) (n = 5); and (5) lack of histological follow-up for other causes (n = 26).

Metabolic Complications

The incidence of diabetes, hypertension, dyslipidemia, and obesity was recorded. Posttransplantation DM was defined as the need for insulin therapy, oral antidiabetics, or dietetic treatment to maintain fasting glucose levels below 120 mg/dL at any time following withdrawal of steroids. Posttransplantation dyslipidemia was defined as the presence of persistently elevated cholesterol and/or triglyceride levels (total cholesterol >250 mg/dL and/or triglycerides >150 mg/dL) on more than 3 consecutive laboratory measurements at any time in the posttransplantation follow-up after the withdrawal of steroids. Posttransplantation hypertension was defined as a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥90 mm Hg. Overweight was defined by a BMI between 25 and 29.9, and obesity by a BMI >30 at any time in the posttransplantation follow-up.

Posttransplantation Alcohol Consumption

Posttransplantation alcohol consumption of any type or amount was assessed. Relapse and/or de novo alcohol intake was considered significant if intake had a frequency of at least 1 drink per week during a period of at least 6 months or if intake was higher in frequency or amount. Sporadic intakes were not considered a relapse. Alcohol intake was assessed through a detailed questionnaire masked by questions on other aspects (diet, exercise, quality of life) and/or by reviewing the medical charts.

Statistical Analysis

The mixed group was compared to each of the other 2 groups. Categorical variables were compared using the χ2 test or the Fisher exact test, as appropriate. Continuous variables were expressed as mean ± standard deviation if they followed a normal distribution and compared using Student t test. If not normally distributed, continuous variables were expressed as median values and ranges and compared using the Mann-Whitney test. Patient and graft survival after transplantation were calculated using Kaplan-Meier survival curves and compared using the log-rank test. A multivariate Cox regression analysis was performed to assess independent variables associated with survival. A P value ≤0.05 was considered significant. Variables with a P ≤ 0.1 were entered in the multivariate analysis.

RESULTS

Pretransplantation Baseline Features

The study included 170 (50%) patients undergoing transplantation for HCV-related cirrhosis, 60 (18%) patients undergoing transplantation for HCV+alcohol–related cirrhosis (mixed etiology), and 107 (32%) patients undergoing transplantation for alcoholic cirrhosis (Table 1). Patients undergoing transplantation for cirrhosis of mixed etiology were significantly younger compared to the other groups and were predominantly men. Patients with alcoholic cirrhosis were sicker at the time of transplantation than those of the other 2 groups. The incidence of HCC was higher in patients with HCV infection. A history of tobacco consumption was more frequently reported in patients undergoing transplantation for alcohol cirrhosis (a very significant difference compared to those with viral cirrhosis only). A history of pretransplantation diabetes and/or hypertension was more frequent in patients undergoing transplantation for alcohol cirrhosis than in the other groups. The predominant genotype was type 1. BMI, nutritional status, and renal function were similar between the groups.

Table 1. Baseline Pretransplant Characteristics by Group
 HCV Group (n = 170)HCV+Alcohol Group (n = 60)Alcohol Group (n = 107)P*
  • Abbreviations: anti-HBc, anti-hepatitis B core antibody; BMI, body mass index; DM, diabetes mellitus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HT, hypertension; LT, liver transplantation.

  • *

    All the other comparisons were not statistically significant.

Age in years [median (range)]59 (29–68)49.5 (32.5–66.5)53 (32–67)HCV versus mixed: 0.00; HCV versus alcohol: 0.00
Gender (% men)519787HCV versus mixed:0.05; HCV versus alcohol:0.001
HCC75 (44%)21 (35%)19 (18%)Alcohol versus mixed: 0.01; HCV versus alcohol: 0.00
Child–Turcotte-Pugh C51 (30%)26 (43%)50 (47%)Alcohol versus mixed: 0.01; HCV versus alcohol: 0.00
Child-Turcotte-Pugh score8 (5–13)9 (5–14)9 (5–13)HCV versus alcohol: 0.00
Bilirubin (mg/dL)2 (0.4–29)2.4 (0.4–11.2)2.8 (0.4–15.8)HCV versus alcohol: 0.01
Prothrombin time (%)66 (35–100)55 (17–98)72.5 (34–100)HCV versus alcohol: 0.00
Creatinine (mg/dL)0.9 (0.3–7.4)0.9 (0.5–12.3)0.9 (0.3–5.4) 
Poor nutritional status; fair-poor48 (32%)27 (43%)20 (38.5%) 
Time on waiting list (days)56 (2–748)52 (5–408)87 (1–727) 
Pre-LT DM27/168 (16%)9/60 (15%)26/100 (26%)HCV versus alcohol: 0.04
Pre-LT HT20/170 (12%)4/57 (7%)18/105 (17%) 
Pre-LT smoking39/162 (24%)42/58 (72%)70/102 (68%)HCV versus mixed: 0.00; HCV versus alcohol: 0.00
BMI at LT26.3 (11.4–46.8)26.6 (17.4–36.6)26.2 (16.9–58.3) 
Genotype: 1a or 1b86 (92.5%)30 (81%)  
Anti-HBc(+)37 (28%)14 (27.5%)12 (20%) 
Donor gender (% male)101 (59%)44 (73%)71 (66%)HCV versus mixed: 0.05
Donor age (years)47 (13–78)53 (15–74)45 (10–76) 
Donor anti-HBc(+)18/128 (14%)7/48 (15%)13/99 (13%) 
Donor BMI25 (18–70.7)25.7 (18.9–34)25.3 (18–43) 

Patient and Graft Survival

More deaths occurred in the group undergoing transplantation for HCV-related cirrhosis than in the group with mixed cirrhosis (P = 0.001) or alcohol cirrhosis (P = 0.001) (56% in the HCV group, 35% in the mixed group, and 27% in the alcohol group) (Table 2). The main causes of death were recurrence of primary disease (hepatitis C) and complications related to excessive immunosuppression such as sepsis. Disease recurrence was the cause of death in a significantly greater proportion of patients undergoing transplantation for HCV-related cirrhosis than in those undergoing transplantation for alcoholic cirrhosis. Patients undergoing transplantation for alcoholic cirrhosis died more frequently from complications related to excessive immunosuppression, with sepsis and de novo tumors as the main causes of death. Systemic causes, frequently related to risk factors such as diabetes, obesity, and arterial hypertension, were also a frequent cause of death in patients undergoing transplantation for alcoholic cirrhosis (Table 3).

Table 2. Posttransplantation Outcome
 HCV Group (n = 170)HCV+Alcohol Group (n = 60)Alcohol Group (n = 107)P*
  • Abbreviations:BMI, body mass index; DM, diabetes mellitus; HCV, hepatitis C virus; HT, hypertension; IS, immunosuppression; LT, liver transplantation.

  • *

    All the other comparisons were not statistically significant.

Deaths95 (56%)21 (35%)29 (27%)HCV versus mixed: 0.00; HCV versus alcohol: 0.00
Graft loss95 (56%)25 (42%)35 (33%)HCV versus alcohol: 0.00
Re-LT7 (4%)8 (13%)4 (4%)HCV versus mixed: 0.01; Alcohol versus mixed: 0.03
Severe HCV-recurrent disease54/122 (45%)22/49 (45%)  
Antiviral therapy31 (18%)19 (32%) HCV versus mixed: 0.03
Potent induction IS25 (15%)9 (15%)22 (21%) 
Rejection32/169 (19%)9/60 (15%)17/100 (17%) 
Post-LT DM36/144 (25%)18/54 (33%)35/92 (38%)HCV versus alcohol: 0.04
Post-LT HT64/145 (44%)30/54 (55.5%)60/98 (61%)HCV versus alcohol: 0.01
Post-LT dyslipidemia20/117 (17%)14/51 (27.5%)34/89 (38%)HCV versus alcohol: 0.00
De novo tumor10/167 (6%)2/67 (3%)14/107 (13%)Alcohol versus mixed: 0.05; HCV versus alcohol: 0.04
BMI at 3 years27 (18.5–37)26 (17.5–37)28 (16–39)Alcohol versus mixed: 0.00; HCV versus alcohol: 0.00
Alcohol relapse4/133 (3%)4/50 (8%)15/83 (18%)HCV versus alcohol: 0.00
Table 3. Causes of Death by Group
 HCV Group (n = 95/170) (%)HCV+Alcohol Group (n = 21/60) (%)Alcohol Group (n = 29/107) (%)
  1. NOTE: All the comparisons were not statistically different between groups with the exception of disease recurrence (alcohol group versus mixed group, P = 0.04; HCV group versus alcohol group, P = 0.001).

  2. Abbreviation:HCC, hepatocellular carcinoma; HCV, hepatitis C virus.

Causes of death   
 Disease recurrence44 (26)9 (15)3 (3)
 Immunosuppression34 (20)8 (13)20 (19)
 Systemic15 (9)4 (7)5 (5)
 Surgical2 (1)01 (1)
Specific etiology   
 HCV recurrence34 (20)8 (13)0 (0)
 HCC recurrence11 (6)1 (2)1 (1)
 Sepsis26 (15)7 (12)7 (6.5)
 Cellular rejection1 (0.5)0 (0)1 (1)
 De novo tumor6 (3.5)2 (3.5)9 (8)
 Other17 (10)3 (5)11 (10)

Survival was significantly higher in patients undergoing transplantation for alcoholic cirrhosis or mixed cirrhosis than in patients with HCV-related cirrhosis. More specifically, patient survival at 1, 5, and 7 years was 72%, 49%, and 43%, respectively, in the HCV group, 86%, 73%, and 63%, respectively, in the mixed group, and 90%, 76%, and 67%, respectively, in the alcohol group (HCV group versus mixed group, P = 0.004; HCV group versus alcohol group, P = 0.0001; mixed group versus alcohol group, P = 0.74; Fig. 1).

Figure 1.

Patient survival curves in the 3 groups.

Similarly, more graft losses occurred in patients undergoing transplantation for HCV-related cirrhosis than in those undergoing transplantation for alcohol-related cirrhosis (56% versus 33%; P = 0.001) and mixed cirrhosis (56% versus 42%; P = 0.06). There were no differences in graft loss between alcohol cirrhosis compared to mixed cirrhosis. The rate of retransplantation was higher in patients undergoing transplantation for mixed cirrhosis compared to HCV-related cirrhosis and alcohol-related cirrhosis [HCV group, n = 7 (4%); mixed group, n = 8 (13%); alcohol group, n = 4 (4%); HCV group versus mixed group, P = 0.01; alcohol group versus mixed group, P = 0.03; Table 2]. The main cause of retransplantation in the HCV groups was viral recurrence (HCV group, n = 6; mixed group, n = 5) (data not shown).

Graft survival was significantly lower in patients with HCV-related cirrhosis compared to the other 2 groups. Graft survival at 1, 3, 5, and 7 years posttransplantation was 71%, 54%, 48%, and 43%, respectively, in the HCV group; 83%, 70%, 63%, and 56%, respectively, in the HCV+alcohol (mixed) group; and 89%, 81%, 76%, and 67%, respectively, in the alcohol group.

Posttransplantation Histology

Eighty-nine patients were excluded from the histological analysis for the previously specified reasons. No differences were found in the incidence of severe recurrent HCV disease (45% in the HCV group versus 45% in the mixed group, P = 0.660; Table 2), acute hepatitis (26% in the HCV group versus 28% in the mixed group, P = 0.854), or fibrosis stage >1 at 1 year (34% in the HCV group versus 35% in the mixed group, P = 0.88) between patients undergoing transplantation for HCV-related cirrhosis alone compared to those with cirrhosis of mixed etiology.

Variables Associated with Survival

All Patients Included

In the univariate analysis, variables associated with survival were: LT indication (P = 0.0001), HCC (P = 0.007), recipient gender (P = 0.0001), pretransplantation use of tobacco (P = 0.009), reperfusion injury (P = 0.06), age at transplantation (P = 0.02), and donor age (P = 0.0001). In the multivariate analysis, the only variable associated with reduced survival was donor age [odds ratio (OR), 1.024; 95% confidence interval (CI), 1.014-1.034; P = 0.0001] and the variables associated with a better outcome were: male gender (OR, 0.653; 95% CI, 0.447-0.953; P = 0.027) and LT indication (alcoholic cirrhosis) (OR, 0.507; 95% CI, 0.349-0.738; P = 0.0001).

HCV-Positive Patients

In the univariate analysis, variables associated with survival were: donor age (P = 0.0001), antiviral treatment posttransplantation (P = 0.0001), gender (P = 0.018), pretransplantation use of tobacco (P = 0.011), LT indication (P = 0.005), use of potent induction immunosuppression (triple/quadruple therapy; P = 0.081), and BMI at transplantation (P = 0.019). In the multivariate analysis, the variables associated with reduced survival were as follows: increased donor age (OR, 1.025; 95% CI, 1.014-1.037; P = 0.0001), increased BMI (OR, 1.054; 95% CI, 1.008-1.103; P = 0.022), and LT indication (HCV-related cirrhosis; OR, 2.296; 95% CI, 1.337-3.944; P = 0.003), and the only variable associated with a better outcome was the use of anti-HCV therapy post-LT (OR, 0.378; 95% CI, 0.210-0.681; P = 0.001).

Posttransplantation Metabolic Complications, Alcohol Intake, and Development of De Novo Tumors

Arterial hypertension, DM, and dyslipidemia were more prevalent in the group of patients undergoing transplantation for alcohol-related cirrhosis than in those undergoing transplantation for HCV-related cirrhosis (hypertension: alcohol group = 61%, HCV group = 44%, P = 0.01; DM: alcohol group = 38%, HCV group = 25%, P = 0.04; dyslipidemia: alcohol group = 38%, HCV group = 17%, P = 0.00). Patients undergoing transplantation for alcohol-related cirrhosis had a higher prevalence of obesity at 3 years than those undergoing transplantation for HCV-related or mixed cirrhosis. The incidence of significant alcohol intake and de novo tumors was higher in patients undergoing transplantation for alcoholic cirrhosis than in the other 2 groups (Table 2).

DISCUSSION

Posttransplantation outcome in HCV-infected transplant recipients is adversely affected by recurrence of hepatitis C.1, 6, 20 In turn, outcome in patients undergoing transplantation for alcoholic cirrhosis is acceptable. Although in these patients, alcohol relapse occurs in a significant percentage of cases, it does not appear to significantly affect patient or graft survival.21–23 To date, there are few data in the literature on the outcome of patients undergoing transplantation for cirrhosis of mixed etiology (HCV+alcohol). The knowledge of the posttransplantation natural history in this group of patients is important, to know their expectations prior to transplantation as well as potential complications. Our aim was to analyze the outcome of transplantation in this specific group of patients and to compare it with that of patients undergoing transplantation for liver disease due to a single etiology (HCV or alcohol). The fact that the study was conducted at a highly active transplant center with a high number of patients undergoing transplantation for the 3 etiologies (HCV, alcohol, and mixed etiology), and that the performance of serial biopsies in the follow-up protocol was included, are, in our opinion, the 2 strong points of this study. The most significant results are summarized in the following points:

  • 1About a quarter of patients undergoing transplantation for HCV-related cirrhosis had a history of significant alcohol consumption, which partially determined the course of the disease before transplantation. In that sense, it is interesting to note that the age at transplantation was lower and the Child-Turcotte-Pugh score higher in this subgroup compared to the remainder. On the other hand, 36% of patients undergoing transplantation for alcohol-related cirrhosis had associated chronic HCV infection. Interestingly, HCC was more prevalent in the 2 groups of patients in whom HCV infection was positive compared to the alcohol group, emphasizing the oncogenicity of this virus.
  • 2Posttransplantation survival was significantly lower in the group of patients undergoing transplantation for HCV-related cirrhosis than in the groups of patients undergoing transplantation for alcoholic cirrhosis or cirrhosis of mixed etiology.
  • 3Histological damage, that is, progression of recurrent hepatitis C, was similar in patients from the HCV and mixed groups.
  • 4Donor age was the strongest factor associated with survival, both in the overall study groups as well as in the HCV-positive groups, a finding reported by us and others.6
  • 5The majority of the metabolic complications, such as arterial hypertension, DM, and dyslipidemia, developed more frequently in the group of patients undergoing transplantation for alcoholic cirrhosis than in the patients from the other groups.
  • 6As with the metabolic complications, the development of de novo tumors was more frequent in patients undergoing transplantation for alcoholic cirrhosis than in those undergoing transplantation for HCV-related cirrhosis or cirrhosis of mixed etiology.

The results regarding posttransplantation survival largely support the findings of previous studies, including ours, in which HCV-infected patients had worse survival compared to other groups, mainly the group of patients undergoing transplantation for alcoholic cirrhosis. A notable finding of our study was the similar survival observed in patients undergoing transplantation for cirrhosis of mixed etiology or alcohol alone. Although there are few data in the literature similar to ours,7, 10 these findings contrast with our initial study hypothesis. Indeed, we had hypothesized a worse outcome for those undergoing transplantation due to cirrhosis of mixed etiology than for alcoholic cirrhosis, and possibly similar to that of patients undergoing transplantation for HCV alone. This hypothesis was based on the known fact that hepatitis C recurs in all patients infected with HCV, independently of the presence of associated cofactors. And in fact, despite a greater survival, recurrent hepatitis C progressed similarly in patients undergoing transplantation for cirrhosis of mixed etiology and in those undergoing transplantation for cirrhosis secondary to HCV alone. The greater use of antiviral treatment in the mixed group versus the HCV group (32% versus 18%; P = 0.03), might explain these findings, possibly because patients belonging to this group were younger and therefore more predisposed (both in terms of patient and physician motivation) to receive an antiviral treatment considered highly toxic and difficult to tolerate. We would also like to point out that the beneficial effects of antiviral therapy have only been recently reported.24 Indeed, in a recent study from our group in which treated patients were compared to untreated contemporaneous disease-matched controls, survival was found to be significantly greater in the former compared to the latter group.24 In addition, as previously stated, patients from the mixed group were younger. Even though age does not appear to have influence on the natural history of recurrent hepatitis C, it is a factor that has been consistently associated with survival. These 2 factors might explain in part the greater survival of the mixed group. Thus, in the group of patients undergoing transplantation for cirrhosis of mixed etiology, it is likely that alcohol had determined to a large extent the progression of liver disease prior to transplantation. After transplantation, when this factor disappeared in the large majority of patients, the course of recurrent disease was possibly determined by the interaction between HCV and its new environment, an interaction likely to be the same as that occurring in patients without a history of alcohol intake prior to transplantation; this would explain the similar histologic HCV-progression in both groups.

Other aspects of interest are the metabolic complications, the development of de novo tumors, and the incidence of posttransplantation alcohol intake (relapse and de novo). With regard to metabolic complications, a higher incidence of arterial hypertension and dyslipidemia was observed in patients with a history of alcoholism, especially in those with a greater trend to overweight. These results confirm the data in the literature in which an association has been shown between alcoholism and the majority of atherogenic metabolic complications. Interestingly, despite the data in the literature regarding the association between hepatitis C and DM both pretransplantation25, 26 and posttransplantation,27, 28 the prevalence of diabetes before and after transplantation was higher in the group of patients with alcoholic cirrhosis as compared to the group with HCV-related cirrhosis. As previously reported by us and other groups, the incidence of de novo tumors was higher in patients undergoing transplantation for alcohol-related cirrhosis than in the other groups.29 Interestingly, de novo tumors were more frequent in the alcohol groups than in the mixed group, a finding not reported previously. The fact that most tumors belonged to the oropharyngeal area might be related to a longer life-time history of alcohol intake in the alcohol group, taking into account that they were older at transplantation than those of the mixed group.

As expected, the group of patients with a higher incidence of significant alcohol intake after transplantation was the group of patients undergoing transplantation for alcohol-related cirrhosis. The rate of alcohol relapse was lower in the group of patients with mixed etiology, possibly because a large proportion of these patients had a pretransplantation alcohol intake that did not fulfill the criteria for alcohol dependence. Although not very significant, it is interesting that significant alcohol intake posttransplantation was discovered in a small group of patients transplanted for HCV-related cirrhosis alone. In these cases, and given the high prevalence of HCV infection in patients with a history of alcoholism, it is likely that this intake already existed before transplantation, but was not diagnosed in the pretransplantation evaluation. An alternative explanation is the development of de novo significant alcohol intake after transplantation due to external causes not identified in this study.

In conclusion, survival of patients undergoing transplantation for HCV-related cirrhosis was lower than that of patients undergoing transplantation for alcoholic cirrhosis or HCV+alcohol–related cirrhosis. The natural history of recurrent hepatitis C followed a similar course in patients undergoing transplantation for HCV-related cirrhosis compared to those undergoing transplantation for cirrhosis of mixed etiology. Potential explanations for the greater survival of patients in the mixed group than in the HCV group are the younger age and the greater use of antiviral treatment in these patients. Further studies are needed, however, with good virological and not only histological follow-up, to clarify the uncertain aspects of our study. The majority of metabolic complications, such as hypertension, dyslipidemia, DM, and overweight, as well as de novo tumors, were diagnosed more frequently in patients undergoing transplantation for alcohol-related cirrhosis than in the other groups.

Ancillary