SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Severe liver disease affects 4.5% to 10% of individuals with cystic fibrosis (CF) and is the third-leading cause of death. Liver transplantation (LT) is an accepted therapy, but the effects of liver disease and LT on pulmonary function in patients with CF are controversial. Our aim was to characterize changes in pulmonary function in LT patients with CF. Using mixed effect models, we analyzed pulmonary function before and after transplantation in 168 LT patients and 840 non-LT patients with CF who were matched by age, sex, pancreatic status, infections with US CF Foundation Patient Registry data (1989-2007). The primary outcome was the change in the forced expiratory volume in 1 second (FEV1; percent predicted) in LT and non-LT in the 3-years periods before or after transplantation; second we compared FEV1 changes. In the 3 years before transplantation, LT had lower initial FEV1 values (71.5% ± 1.9%, P < 0.001) and a slower decline (+0.1% ± 0.4%/year, P < 0.001) than non-LT (79.6% ± 1.3% and −1.3% ± 0.2%/year, respectively). There was no difference in the FEV1 decline after transplantation (−1.4% ± 0.4%/year for LT versus −2.1% ± 0.2%/year for non-LT, P = 0.14). Both the (P = 0.003) and (P = 0.001) had a slower FEV1 decline in the period before transplantation versus after transplantation. In conclusion, pulmonary function is lower and declines more slowly in patients with CF before LT versus, but parallels the decline in non-LT after transplantation. LT is neither beneficial nor detrimental to pulmonary function in CF but returns FEV1 decline to the same trajectory found for matched non-LT individuals with CF. Liver Transpl, 2012. © 2012 AASLD.

Cystic fibrosis (CF) is characterized by progressive lung disease and gastrointestinal symptoms, which lead to frequent morbidities and early mortality. Despite improved treatments that are increasing the median survival time, cystic fibrosis–related liver disease (CFLD) continues to be a significant complication starting in children and adolescents with CF.1 Liver disease is the third-leading cause of death for patients with CF and is a significant source of morbidity.1-3

The reported frequency of CFLD ranges from 4% to 75%4-6 and varies with age and the definition of liver disease. Three prospective studies, which defined liver disease by laboratory measurements (2 or more consecutively elevated liver function tests) or clinically (cirrhosis, splenomegaly, hepatomegaly, or portal hypertension), reported that elevated liver function tests are present for approximately 35% of all CF patients, and cirrhosis develops in 4.5% to 10%.7-9

Cirrhosis is the most significant hepatic complication in patients with CF. Its incidence increases with age through adolescence, with few cases diagnosed after the age of 18 or 20 years.5, 9-11 Males with CF have a higher incidence of cirrhosis than females5, 9-12; cirrhosis is more likely in individuals who have a pancreatic insufficiency10, 12 or a history of meconium ileus.8, 9, 11 Individuals with CFLD are more likely to have cystic fibrosis transmembrane conductance regulator (CFTR) mutations associated with a pancreatic insufficiency, although no definitive phenotype-genotype associations with CFLD and CFTR mutations have been identified.10, 13 Several gene variants, including alpha-1-antitrypsin,14, 15 angiotensin-converting enzyme,16 transforming growth factor β1,16 mannose-binding lectin,17 and glutathione S-transferase,18 have been reported to increase the risk of liver disease in patients with CF. Although there are several known risk factors for the development of CFLD, it is unclear why only 4.5% to 10% of CF patients develop cirrhosis and why only one-third of patients develop milder clinical liver disease.

Liver transplantation (LT) is an accepted but relatively rare therapy for CF cirrhosis with persistent complications. Between the mid-1980s and 1990, LT was performed for 1 to 5 CF patients each year. Since 1991, 13 LT procedures have been performed on average for CFLD each year in the United States (range = 7-19).1 The 1-year survival rates are 75% or greater, whereas the 5-year survival rates are 60% to 80%.19-30 Despite the increase in LT for patients with CF, many questions about long-term pulmonary outcomes remain unanswered. Anecdotally, it has been suggested that CF patients with chronic liver disease have better pulmonary function and that their pulmonary function improves after LT. Several studies have compared preoperative pulmonary function to postoperative pulmonary function; most have shown a postoperative stabilization or improvement of 5% to 20% in forced expiratory volume in one second (FEV1).19, 20, 22, 23, 27, 29, 31-33 However, many of these studies measured postoperative pulmonary function within 1 year of transplantation. Reports of pulmonary function measured more than 1 year after transplantation have shown the greatest improvement in the first year after transplantation, with stabilization in successive years.20, 22, 23, 27, 33 To date, no studies have compared lung function in individuals with severe liver disease and individuals without liver disease.

In order to better understand the effects of liver disease and LT on pulmonary function in patients with CF, we used the longitudinal database of the US Cystic Fibrosis Foundation Patient Registry to analyze changes in pulmonary function in LT patients with CF in the 3 years before transplantation and in the 3 years after transplantation. We also compared changes in pulmonary function between CF patients who underwent isolated LT and those who did not undergo LT.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Patient Population

The source of our patient population was the US Cystic Fibrosis Foundation Patient Registry (1989-2007). Approximately 95% of the patients with CF in the United States are captured by the registry (H. Quinton, Dartmouth Medical Center, personal communication, November, 2011). Approval for data analysis was received from the Colorado Multiple Institutional Review Board.

LT Status

Individuals were designated as recipients of isolated LT if they had undergone LT between 1989 and 2007 (232 transplants in 226 individuals). For the 6 individuals who underwent LT twice, we used the first transplant for the analysis. Individuals were excluded if another organ (heart, lungs, kidney, or pancreas) was also transplanted at the same time (n = 17). Another 14 transplant patients were excluded because they had received another organ transplant prior to their LT. Two individuals more than 40 years old at the time of transplantation were excluded because of the concern that their cirrhotic liver disease might not have been due to CF. Individuals who were less than 6 years old at the time of LT were excluded from the analysis because they did not have reliable pulmonary function tests (n = 16). One additional case did not have any pulmonary function tests. After the aforementioned exclusions, there were 176 individuals eligible for the analysis.

Non-LT Individuals

The non-LT group consisted of individuals in the US Cystic Fibrosis Foundation Patient Registry who had never reported CFLD as a complication in the registry; this was defined as cirrhosis, noncirrhotic liver disease, gallbladder disease requiring surgery, or variceal hemorrhaging/gastrointestinal bleeding. We also excluded individuals who were ever listed for a transplant. Because of the high number of CF patients with elevated liver enzymes and the lack of a definitive association between elevated liver enzymes and liver disease, individuals with the isolated abnormality of elevated liver enzymes were eligible for the non-LT group.34

Because the diagnosis of liver disease can vary by center, centers that have not referred any patients for LT might have screening practices different from those of centers that have referred patients for transplantation. Thus, the non-LT comparison pool was limited to only those centers that also had LT cases (106 centers).

Matching of LT Individuals to Non-LT Individuals

Non-LT individuals were matched to LT individuals in a 5:1 ratio, and matching was based on the age of the LT case at the time of transplantation. We also matched by sex, the Pseudomonas aeruginosa and Burkholderia cepacia status, and the CFTR mutation status (high risk or low risk).35 An individual was considered positive for P. aeruginosa or B. cepacia if he or she had 1 or more positive sputum cultures in the past 3 years. Individuals with high-risk CFTR genotypes (classes I, II, and III) have severely reduced production of CFTR, which is associated with higher mortality rates. Individuals with low-risk CFTR genotypes (classes IV and V) have some CFTR function, which is associated with a lower risk of death.35 For individuals with an unknown genotype, we used pancreatic enzyme use (yes or no) as a surrogate for the CFTR mutation status (high-risk mutations will likely result in pancreatic insufficiency; therefore, the use of pancreatic enzymes equates with a high-risk CFTR mutation status). Treatment and care practices have changed for CF between 1989 and 2007 (ie, the introduction of recombinant human deoxyribonuclease in 1994 and the introduction of tobramycin solution for inhalation in 1999). In order to account for differences in treatment and care over time, we matched patients by the year of birth (within 1 year). Lastly, we matched patients by the number of clinic visits during the pretransplant period or posttransplant period to ensure the adequate collection of pulmonary function test data. For each 3-year period, fewer than 6 visits were considered low, whereas 6 visits or more were considered adequate.

We used a greedy matching algorithm designed by Bergstralh and Kosanke36 that selected the closest matching individual for each case. The algorithm was modified for use with longitudinal repeated measures data, so that each individual who did not undergo transplantation could be selected for only 1 individual who underwent transplantation.

LT individuals who were missing data for any of the matching variables (n = 8; all were missing data for the P. aeruginosa and B. cepacia status) were not included in the analysis; this left 168 LT individuals for the analysis.

Statistical Analysis

The primary outcome variable was FEV1 (percent predicted); forced vital capacity (FVC; percent predicted) was also analyzed. FEV1 and FVC were calculated with the methods of Hankinson et al.37 and Wang et al.38 The body mass index, weight-for-age, and height-for-age z scores were calculated with Centers for Disease Control and Prevention methods.39 The best pulmonary function per quarter was used for each subject (the measurement with the best of each FEV1 and FVC).

We used a longitudinal mixed effects model to characterize changes in FEV1 over time; this accounted for repeated measures and allowed for subject-specific slopes and intercepts with an unstructured covariance structure. An additional random effect was included to account for each case-control cluster. Linear contrasts were used to test differences specified a priori. All analyses were carried out with SAS 9.2. To calculate the confidence bands for the slope of FEV1 over time, we used a variation of the Scheffé method,40 which appropriately corrects for calculating the confidence interval at multiple times by using an F distribution to calculate the standard error associated with the mean FEV1 line. To assess the effects of poor pulmonary function immediately before and after transplantation, we repeated the analysis but removed the data for the calendar year of transplantation; we used the same mixed effects model described previously. The results did not change (data not shown). We also performed a secondary analysis of changes in FEV1 for the year before transplantation and the year after transplantation with the same mixed effects model.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

We report demographic data and other data for 168 individuals with CF who underwent isolated LT and 840 corresponding matched individuals who did not undergo transplantation (Table 1). The LT and non-LT groups did not differ by the age at diagnosis, but they did differ by the mode of diagnosis (P = 0.002), with the LT patients being more likely to have been diagnosed by meconium ileus (29.8%) than the non-LT patients (20.0%) and less likely to have been diagnosed by other symptoms. The LT patients between 6 and 20 years old had significantly lower weight-for-age and height-for-age z scores than the non-LT group (P < 0.001 for both). The LT patients were more likely to die than the non-LT patients during the 3 years of follow-up after transplantation/matching (P < 0.001), and they were younger at the time of death, although this was not significant (P = 0.10). The causes of death also differed between the LT and non-LT groups (P < 0.001), with the LT patients more likely to have died from liver disease or liver failure and transplant-related complications and less likely to have died from respiratory or cardiorespiratory causes.

Table 1. Descriptive, Diagnostic, and Anthropometric Characteristics of 168 Patients With CF Who Underwent LT Between 1989 and 2007 and 840 Matched Patients With CF Who Did Not Undergo LT. Significant differences between LT and non-LT are indicated in bold.
 LT Patients (n = 168)Non-LT Patients (n = 840)P Value
  • *

    The patients were matched on the parameter.

  • The data are presented as means and standard deviations.

  • The values do not sum to 100% because of rounding.

  • §

    The data are expressed as medians and interquartile ranges.

  • Measured during the year before transplantation for LT patients and during the year before matching for non-LT patients. The values are the best measurements for the year.

  • Patients between the ages of 6 and 20 years (there were data for 135 LT patients and 679 non-LT patients).

  • #

    Patients older than 20 years (there were data for 32 LT patients and 159 non-LT patients).

Male sex [n (%)]103 (61.3) NA*
Age at transplantation (years)16.52 ± 6.53 NA*
Age group [n (%)]   
 Pediatric (≥6 to ≤12 years)43 (25.6) NA*
 Adolescent (>12 to ≤18 years)73 (43.5) NA*
 Adult (>18 years)52 (31.0) NA*
Genotype group [n (%)]  NA*
 High risk111 (66.1) NA*
 Low risk1 (0.6) NA*
 Unknown56 (33.3) NA*
Positive P. aeruginosa status [n (%)]133 (79.2) NA*
Positive B. cepacia status [n (%)]9 (5.4) NA*
Ever taken pancreatic enzymes [n (%)]167 (99.4) NA*
Age at diagnosis (months)§6.0 (2.0-30.5)6.0 (2.0-26.0)0.81
Mode of diagnosis [n (%)]   
 Meconium ileus50 (29.8)168 (20.0)0.002
 Newborn or prenatal screen2 (1.2)25 (3.0) 
 Symptoms/other109 (64.9)634 (75.5) 
 Unknown7 (4.2)13 (1.5) 
Race [n (%)]   
 Non-Hispanic white154 (91.7)770 (91.7)0.25
 Hispanic white9 (5.4)30 (3.6) 
 Black5 (3.0)25 (3.0) 
 Other0 (0.0)15 (1.8) 
Anthropometric measurements   
 Body mass index z score−0.60 ± 1.03−0.54 ± 1.180.60
 Body mass index (kg/m2)#20.68 ± 2.3921.25 ± 3.920.43
 Height-for-age z score−1.48 ± 1.08−0.93 ± 1.07<0.001
 Weight-for-age z score−1.34 ± 1.13−0.94 ± 1.29<0.001
Death during follow-up within the 3 years after transplantation/matching [n (%)]31 (18.5)68 (8.1)<0.001
Cause of death [n (%)]   
 Respiratory/cardiorespiratory6 (19.4)59 (86.8)<0.001
 Liver disease or liver failure6 (19.4)1 (1.5) 
 Trauma1 (3.2)1 (1.5) 
 Transplant16 (51.6)3 (4.4) 
 Other1 (3.2)2 (2.9) 
 Unknown1 (3.2)2 (2.9) 
Age at death (years)§18.17 (13.75-20.92)20.00 (16.63-24.92)0.10

FEV1

Three years before transplantation/matching, the LT group had lower initial FEV1 values (71.5% ± 1.9%) than the non-LT group (79.6% ± 1.3%, P < 0.001; Fig. 1A,B). Before transplantation/matching, the LT group had no change in FEV1 (0.1% ± 0.4%/year), whereas the non-LT group had declining FEV1 values (−1.3% ± 0.2%/year, P < 0.001; Fig. 1A,C). At the time of transplantation/matching, the LT group continued to have lower FEV1 values (71.8% ± 1.9%) than the non-LT group (75.7% ± 1.2%, P = 0.03; Fig. 1A,B). After transplantation/matching, the LT group had a similar decline in FEV1 (−1.4% ± 0.4%/year for the LT group versus −2.1% ± 0.2%/year for the non-LT group, P = 0.14; Fig. 1A,C). Three years after transplantation/matching, the LT and non-LT groups had similar FEV1 values (67.7% ± 2.3% for the LT group versus 69.5% ± 1.4% for the non-LT group, P = 0.41; Fig. 1A,C). Both the LT group and the non-LT group had slower FEV1 declines in the period before transplantation/matching versus the period after transplantation/matching (0.1% ± 0.4%/year versus −1.4% ± 0.4%/year for the LT group, P = 0.003; −1.3% ± 0.2%/year versus −2.1% ± 0.2%/year for the non-LT group, P = 0.001; Fig. 1A,C). We did not find any significant differences in the changes in FEV1 between the sexes (data not shown).

thumbnail image

Figure 1. (A) Comparison of changes in FEV1 between LT and non-LT individuals with CF from 3 years before transplantation to 3 years after transplantation. The solid black lines represent the changes in FEV1 in the 3 years before or after transplantation/matching. The light-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the LT group, whereas the medium-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the non-LT group. The dashed lines represent the change in FEV1 for the LT group in the year before or after transplantation. (B) Comparison of FEV1 between LT and non-LT individuals 3 years before transplantation/matching (−3 years), at the time of transplantation/matching (0 years), and 3 years after transplantation/matching (3 years). The FEV1 values are presented as means and standard errors. (C) Comparison of percentage point declines in FEV1 between LT and non-LT individuals before and after transplantation/matching. The time P values represent comparisons of FEV1 between the period before transplantation/matching and the period after transplantation/matching. The group P values represent comparisons of FEV1 percentage point declines between the LT and non-LT groups. The FEV1 values are presented as means and standard errors of the percentage point decline per year.

Download figure to PowerPoint

In the year before transplantation, the LT group had a significant improvement in FEV1 [5.6% ± 1.3%, P < 0.001; Fig. 1A (dashed line from −1 to 0)], whereas in the year after transplantation, the LT group had no significant change in FEV1 [0.6% ± 1.5%, P = 0.69; Fig. 1A (dashed line)]. In comparison with non-LT patients, LT patients had improved FEV1 in the year before transplantation (−1.9% ± 0.6% for the non-LT group, P < 0.001) but had similar changes in FEV1 in the year after transplantation (−1.0% ± 0.6% for the non-LT group, P = 0.32).

Age Stratification

We stratified the analyses by the age at transplantation: ≥6 to ≤12 years old (pediatric), >12 to ≤18 years old (adolescent), and >18 years old (adult).

Pediatric Group (Fig. 2)

In the pediatric group, the LT patients had lower initial FEV1 values (78.2% ± 3.1%) than the non-LT patients (86.2% ± 1.7%, P = 0.01; Fig. 2A,B). Before transplantation/matching, the LT group had an increase in FEV1 (3.1% ± 0.8%/year) in comparison with the non-LT group (0.1% ± 0.4%/year, P < 0.001; Fig. 2A,C). At the time of transplantation/matching, the LT and non-LT groups had similar FEV1 values (87.6% ± 2.9% for the LT group versus 86.6% ± 1.7% for the non-LT group, P = 0.73; Fig. 2A,B). After transplantation/matching, the LT group and the non-LT group had similar declines in FEV1 (−1.3% ± 0.8%/year for the LT group versus −0.7% ± 0.4%/year for the non-LT group, P = 0.73; Fig. 2A,C). Three years after transplantation/matching, the LT and non-LT groups had similar FEV1 values (83.7% ± 3.8% for the LT group versus 84.6% ± 2.0% for the non-LT group, P = 0.81; Fig. 2A,C). FEV1 improved in the period before transplantation versus the period after transplantation in the LT group (3.1% ± 0.8%/year versus −1.3% ± 0.8%/year, P < 0.001) but not in the non-LT group (0.1% ± 0.4%/year versus −0.7% ± 0.4%/year, P = 0.10; Fig. 2A,C).

thumbnail image

Figure 2. Pediatric group (≥6 to ≤12 years of age). (A) Comparison of changes in FEV1 between LT and non-LT individuals with CF from 3 years before transplantation to 3 years after transplantation. The solid black lines represent the changes in FEV1 in the 3 years before or after transplantation/matching. The light-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the LT group, whereas the medium-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the non-LT group. The dashed lines represent the change in FEV1 for the LT group in the year before or after transplantation. (B) Comparison of FEV1 between LT and non-LT individuals 3 years before transplantation/matching (−3 years), at the time of transplantation/matching (0 years), and 3 years after transplantation/matching (3 years). The FEV1 values are presented as means and standard errors. (C) Comparison of percentage point declines in FEV1 between LT and non-LT individuals before and after transplantation/matching. The time P values represent comparisons of FEV1 between the period before transplantation/matching and the period after transplantation/matching. The group P values represent comparisons of FEV1 percentage point declines between the LT and non-LT groups. The FEV1 values are presented as means and standard errors of the percentage point decline per year.

Download figure to PowerPoint

FEV1 improved in the year before transplantation for the pediatric LT patients [11.6% ± 2.8%, P < 0.001; Fig. 2A (dashed line from −1 to 0)]. During the year after transplantation, the LT group had an FEV1 change of −3.4% ± 3.1% [P = 0.27; Fig. 2A (dashed line from 0 to 1)]. In comparison with the non-LT group, the LT group had improved FEV1 in the year before transplantation (−0.8% ± 1.3% for the non-LT group, P < 0.001), but there was no difference in the FEV1 change in the year after transplantation (2.2% ± 1.3% for the non-LT group, P = 0.10).

Adolescent Group (Fig. 3)

In the adolescent group, 3 years before transplantation/matching, the LT patients had lower initial FEV1 values (76.0% ± 2.6%) than the non-LT patients (85.4% ± 1.4%, P < 0.001; Fig. 3A,B). Before transplantation/matching, the LT group had a similar decline in FEV1 (−1.1% ± 0.5%/year for the LT group versus −1.8% ± 0.2%/year for the non-LT group, P = 0.19; Fig. 3A,C). At the time of transplantation/matching, the LT group had lower FEV1 values (72.7% ± 2.6%) than the non-LT group (79.9% ± 1.3%, P = 0.008; Fig. 3A,B). After transplantation/matching, FEV1 declined in both the LT group (−1.8% ± 0.6%/year) and the non-LT group (−2.9 ±0.2%/year; Fig. 3A,C), although the decline did not reach statistical significance (P = 0.06). Three years after transplantation/matching, FEV1 was 67.3% ± 3.1% for the LT group and 71.2% ± 1.5% for the non-LT group (P = 0.23; Fig. 3A,B). No difference in the FEV1 decline was identified in the period before transplantation/matching versus the period after transplantation/matching in the LT group (−1.1% ± 0.5%/year versus −1.8% ± 0.6%/year, P = 0.31), but a faster rate of decline was found for the non-LT group after transplantation/matching (−1.8% ± 0.2%/year versus −2.9% ± 0.2%/year, P < 0.001; Fig. 3A,C). In the year before transplantation and the year after transplantation, the adolescent LT patients had positive but nonsignificant improvements in FEV1 [3.4% ± 1.7% before transplantation, P = 0.05; 2.7% ± 1.9% after transplantation, P = 0.16; Fig. 3A (dashed lines from −1 to 0 and from 0 to 1)]. The non-LT group had significant declines in the year before transplantation/matching (−2.6% ± 0.8%, P = 0.002) and in the year after transplantation/matching (−2.4% ± 0.8%, P = 0.01).

thumbnail image

Figure 3. Adolescent group (>12 to ≤18 years of age). (A) Comparison of changes in FEV1 between LT and non-LT individuals with CF from 3 years before transplantation to 3 years after transplantation. The solid black lines represent the changes in FEV1 in the 3 years before or after transplantation/matching. The light-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the LT group, whereas the medium-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the non-LT group. The dashed lines represent the change in FEV1 for the LT group in the year before or after transplantation. (B) Comparison of FEV1 between LT and non-LT individuals 3 years before transplantation/matching (−3 years), at the time of transplantation/matching (0 years), and 3 years after transplantation/matching (3 years). The FEV1 values are presented as means and standard errors. (C) Comparison of percentage point declines in FEV1 between LT and non-LT individuals before and after transplantation/matching. The time P values represent comparisons of FEV1 between the period before transplantation/matching and the period after transplantation/matching. The group P values represent comparisons of FEV1 percentage point declines between the LT and non-LT groups. The FEV1 values are presented as means and standard errors of the percentage point decline per year.

Download figure to PowerPoint

Adult Group (Fig. 4)

In the adult group, 3 years before transplantation/matching, the LT group had lower initial FEV1 values (58.8% ± 3.5%) than the non-LT group (65.8% ± 2.2%, P = 0.04; Fig. 4A,B). Before transplantation/matching, the LT group had a slower decline in FEV1 (−0.5% ± 0.6%/year) than the non-LT group (−1.8% ± 0.3%/year, P = 0.04; Fig. 4A,C). At the time of transplantation/matching, the LT and non-LT groups had similar FEV1 values (57.5% ± 3.5% versus 60.3% ± 2.2%, P = 0.38; Fig. 4A,B). After transplantation/matching, the LT group had a slower FEV1 decline (−0.2% ± 0.8%/year) than the non-LT group (−2.0% ± 0.3%/year, P = 0.046; Fig. 4A,C). Three years after transplantation/matching, the LT and non-LT groups had similar FEV1 values (56.7% ± 4.2% for the LT group versus 54.5% ± 2.4% for the non-LT group, P = 0.60; Fig. 4A,B). Both the LT group and the non-LT group had similar rates of decline in the periods before and after transplantation/matching (−0.5% ± 0.6%/year versus −0.2% ± 0.8%/year for the LT group, P = 0.81; −1.8% ± 0.3%/year versus −2.0% ± 0.3%/year for the non-LT group, P = 0.72; Fig. 4A,C).

thumbnail image

Figure 4. Adult group (>18 years of age). (A) Comparison of changes in FEV1 between LT and non-LT individuals with CF from 3 years before transplantation to 3 years after transplantation. The solid black lines represent the changes in FEV1 in the 3 years before or after transplantation/matching. The light-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the LT group, whereas the medium-gray filled-in area represents the 95% confidence interval associated with the change in FEV1 for the non-LT group. The dashed lines represent the change in FEV1 for the LT group in the year before or after transplantation. (B) Comparison of FEV1 between LT and non-LT individuals 3 years before transplantation/matching (−3 years), at the time of transplantation/matching (0 years), and 3 years after transplantation/matching (3 years). The FEV1 values are presented as means and standard errors. (C) Comparison of percentage point declines in FEV1 between LT and non-LT individuals before and after transplantation/matching. The time P values represent comparisons of FEV1 between the period before transplantation/matching and the period after transplantation/matching. The group P values represent comparisons of FEV1 percentage point declines between the LT and non-LT groups. The FEV1 values are presented as means and standard errors of the percentage point decline per year.

Download figure to PowerPoint

In the year before transplantation, the adult LT patients had a positive but nonsignificant improvement in FEV1 [3.6% ± 2.4%, P = 0.13; Fig. 4A (dashed line from −1 to 0)], whereas in the year after transplantation, the LT group had no significant change in FEV1 [0.3% ± 2.9%, P = 0.91; Fig. 4A (dashed line from 1 to 0)]. In comparison with the non-LT group, the LT group had improved FEV1 in the year before transplantation (−1.7% ± 1.0% for the non-LT group, P = 0.04), but the change in FEV1 was similar in the year after transplantation (−1.8% ± 1.2% for the non-LT group, P = 0.49).

FVC

The results for the FVC changes in the LT and non-LT groups were very similar to those for FEV1 (Supporting Figs. 1-4).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

In this comprehensive analysis of the US Cystic Fibrosis Foundation Patient Registry, the LT group had lower FEV1 values 3 years before transplantation than the non-LT individuals, but the pulmonary function stayed stable during the 3 years before transplantation; in contrast, the non-LT group experienced a decline in FEV1. FEV1 increased significantly during the year immediately before LT. Taken together (stable FEV1 values over a period of 3 years with a sharp increase in the year immediately before transplantation), these data may point to intense medical care that the patients may have received in preparation for transplantation.

We found that the change in FEV1 varied with the age at transplantation. The marked improvement in FEV1 in the pediatric population in the 3 years before transplantation could be attributed to several factors. In comparison with adolescents and adults, individuals in the pediatric population are likely to be diagnosed with liver disease at a younger age when their pulmonary function may be more reversible with intensive medical care. Adherence to recommended therapies may also be better during childhood in comparison with adolescence and adulthood. In the first year after transplantation, the pediatric LT group had a decline in FEV1, but an examination of the data 3 years after transplantation showed that the decline was much more modest and was equivalent to the decline in the non-LT group. This could be due to the effect of immunosuppression in increasing bacterial or viral lung infections in this age group. It could also be due to decreased chest movement caused by transplant-related abdominal pain. In the first year after transplantation, the adolescent subgroup had stable FEV1 values, but they improved in comparison with the non-LT patients; in the 3-year period after transplantation, FEV1 declined in a manner similar to that for the matched controls. In the adult age group, FEV1 remained stable after transplantation according to the analysis of both the first year after transplantation and the 3 years after transplantation.

We did not have data on indications for transplantation, which might have affected lung function after transplantation. For instance, if an individual who had undergone LT had ascites, massive splenomegaly, repeated endoscopy for variceal hemorrhaging, or a severe failure to thrive, we might expect the lung function to decline preoperatively but to improve markedly postoperatively.

In both the pediatric and adolescent populations, the decline in FEV1 in the 3 years after transplantation/matching was similar to the decline in the non-LT group, and in the adult population, the decline was significantly less than the decline in the non-LT group. This demonstrates that in the pediatric and adolescent age groups, LT did not cause additional deterioration or significant preservation of pulmonary function, but it returned the pulmonary function decline to a level similar to that of non-LT patients. In contrast, FEV1 was stabilized after LT in adults, and this resulted in an improvement in comparison with the continued decline in FEV1 in matched non-LT individuals.

Overall, we observed an increase in FEV1 in the year before transplantation, although this was primarily driven by the pediatric subgroup and was likely due to increased pretransplant care in all age groups. In the first year after LT, FEV1 remained stable, whereas on average in the 3 years after transplantation, the LT group had a decline in FEV1 similar to that of matched nontransplant controls. These results indicate that LT does not accelerate or reverse the decline in FEV1 but returns LT patients to a level similar to that of non-LT patients. These findings are in contrast to published reports showing 5% to 20% increases in FEV1 in the majority of subjects in the year after transplantation.19, 20, 22, 23, 29, 31-33 This discrepancy may be due in part to the small sample sizes of the reports (usually 5-15 patients) and the lack of an adequately matched nontransplant group. Most previous studies measured FEV1 before and after transplantation; however, many did not indicate the timing of the measurements and did not report 3-year trends. Our results show that FEV1 does improve in the year before transplantation and remains stable in the first year after transplantation. The timing of the FEV1 measurements in previous studies may have greatly influenced the results because of intense medical care administered to the patients in the pretransplant period. Additionally, many of these studies provide only 1 posttransplant measurement of FEV1. The studies reporting longitudinal pulmonary function for 1 to 5 years after transplantation23, 33 have suggested that an improvement in FEV1 is observed within the first year of transplantation, but it then stabilizes or starts to decline over time; this supports our findings. These data indicate the need to measure FEV1 for several years after LT in order to assess the effect of LT on lung function in patients with CF.

The LT group had a higher rate of mortality 3 years after transplantation/matching. A further examination of the causes of mortality showed that individuals who underwent LT were more likely to have died from causes related to liver dysfunction or other transplant-related complications and were less likely to have died from respiratory or cardiorespiratory complications. Although the lung disease (reflected by pulmonary function tests) of the LT group did not accelerate, there were still risks to this group from LT complications, which increased the overall mortality in comparison with non-LT individuals.

This study examined longitudinal pulmonary function both before and after LT in a large population of CF patients and compared them to matched CF individuals who did not undergo transplantation from the US Cystic Fibrosis Foundation Patient Registry. We have demonstrated that CF individuals who undergo LT have worse pulmonary function before transplantation but have a slower decline in FEV1 before transplantation in comparison with matched non-LT individuals. LT restores pulmonary function, as indicated by the return of the FEV1 decline to a trajectory similar to that of individuals with CF but no liver disease. Pediatric patients with CF who undergo LT appear to have improving pulmonary function before transplantation, perhaps because of more intensive medical care; however, their posttransplant decline in pulmonary function is the same as that of non-LT matched patients. Although LT confers clinical benefits to CF patients with end-stage liver disease, there is no benefit from LT for pulmonary function in patients with CF, and the mortality risk remains higher in comparison with the risk for CF patients without end-stage liver disease.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

The authors thank Dennis Lezotte for providing SAS programming expertise and Gary Zerbe for providing statistical expertise.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  8. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
LT_23389_sm_SuppFig1.eps1235KSupporting Figure 1: Comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. A: Comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. Solid black lines represent the change in FVC in the three years pre- or post-transplant/match. Light gray filled in area represents the 95% confidence interval associated with the change in FVC for the LT, while medium gray filled in area represents the 95% confidence interval associated with the change in FVC for the non-LT. Dashed lines represent the change in FVC for the LT group in the one year prior to or post-transplant. B: Comparison of FVC between LT and non-LT individuals at 3 years pre-transplant/match (time = -3 years), time of transplant/match (time = 0 years), and 3 years post-transplant/match (time = 3 years). FVC values are mean and standard error. C: Comparison of percentage point decline in FVC between LT and non-LT individuals pre-transplant/match and post-transplant/match. Time p-values represent the comparisons in FVC between the pre-transplant/match and post-transplant/match time periods. Group p-values represent the comparisons in FVC percentage point decline between LT and non-LT groups. FVC values are the mean and standard error of percentage point decline per year (%/year).
LT_23389_sm_SuppFig2.eps1239KSupporting Figure 2: Pediatric group (≥6 to ≤12 years of age) comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. A: Comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. Solid black lines represent the change in FVC in the three years pre- or post-transplant/match. Light gray filled in area represents the 95% confidence interval associated with the change in FVC for the LT, while medium gray filled in area represents the 95% confidence interval associated with the change in FVC for the non-LT. Dashed lines represent the change in FVC for the LT group in the one year prior to or post-transplant. B: Comparison of FVC between LT and non-LT individuals at 3 years pre-transplant/match (time = -3 years), time of transplant/match (time = 0 years), and 3 years post-transplant/match (time = 3 years). FVC values are mean and standard error. C: Comparison of percentage point decline in FVC between LT and non-LT individuals pre-transplant/match and post-transplant/match. Time p-values represent the comparisons in FVC between the pre-transplant/match and post-transplant/match time periods. Group p-values represent the comparisons in FVC percentage point decline between LT and non-LT groups. FVC values are the mean and standard error of percentage point decline per year (%/year).
LT_23389_sm_SuppFig3.eps1237KSupporting Figure 3: Adolescent group (>12 to ≤18 years of age) comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. A: Comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. Solid black lines represent the change in FVC in the three years pre- or post-transplant/match. Light gray filled in area represents the 95% confidence interval associated with the change in FVC for the LT, while medium gray filled in area represents the 95% confidence interval associated with the change in FVC for the non-LT. Dashed lines represent the change in FVC for the LT group in the one year prior to or post-transplant. B: Comparison of FVC between LT and non-LT individuals at 3 years pre-transplant/match (time = -3 years), time of transplant/match (time = 0 years), and 3 years post-transplant/match (time = 3 years). FVC values are mean and standard error. C: Comparison of percentage point decline in FVC between LT and non-LT individuals pre-transplant/match and post-transplant/match. Time p-values represent the comparisons in FVC between the pre-transplant/match and post-transplant/match time periods. Group p-values represent the comparisons in FVC percentage point decline between LT and non-LT groups. FVC values are the mean and standard error of percentage point decline per year (%/year).
LT_23389_sm_SuppFig4.eps1244KSupporting Figure 4: Adult group (>18 years of age) comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. A: Comparison of change in FVC between liver transplantation (LT) and non-LT CF individuals from 3 years pre- to 3 years post-transplant. Solid black lines represent the change in FVC in the three years pre- or post-transplant/match. Light gray filled in area represents the 95% confidence interval associated with the change in FVC for the LT, while medium gray filled in area represents the 95% confidence interval associated with the change in FVC for the non-LT. Dashed lines represent the change in FVC for the LT group in the one year prior to or post-transplant. B: Comparison of FVC between LT and non-LT individuals at 3 years pre-transplant/match (time = -3 years), time of transplant/match (time = 0 years), and 3 years post-transplant/match (time = 3 years). FVC values are mean and standard error. C: Comparison of percentage point decline in FVC between LT and non-LT individuals pre-transplant/match and post-transplant/match. Time p-values represent the comparisons in FVC between the pre-transplant/match and post-transplant/match time periods. Group p-values represent the comparisons in FVC percentage point decline between LT and non-LT groups. FVC values are the mean and standard error of percentage point decline per year (%/year).

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.