Ursodeoxycholic Acid Therapy in Cystic Fibrosis Liver Disease

A Retrospective Long-term Follow-up Case-Control Study

M. Kappler; C. Espach; A. Schweiger-Kabesch; T. Lang; D. Hartl; A. Hector; C. Glasmacher; M. Griese


Aliment Pharmacol Ther. 2012;36(3):266-273. 

In This Article

Material and Methods

Subjects and Study Design

Between January 1989 and December 2005, all 382 CF-patients treated at our centre (mean age in 2005 was 16.3 years, median 15.4, range 0.1–41) were screened quarterly for signs of liver disease.

Criteria for UDCA Therapy Liver disease was defined as (i) elevation of one or more serum liver enzymes (aminotransferases (ALT, AST), γ-glutamyltransferase (γ-GT), glutamate dehydrogenase (GLDH)) ≥1.5 times of the upper normal limit and persisting for ≥6 months, or (ii) liver enlargement >2 cm for ≥6 months. Continuous therapy with UDCA (20 mg per kg body weight) was initiated in 98 patients fulfilling these criteria. Other potential causes of liver disease such as alpha 1 antitrypsin deficiency were excluded in all these patients.

The primary study endpoint, overt liver disease, was defined as the presence of one or more of the following signs of portal hypertension (i) splenomegaly along with hypersplenism (persistent thrombocytopenia <80 000/μl) (ii) ascites; (iii) varices of the oesophagus (with or without haemorrhage).

We selected two groups for comparison (Figure 1):

Figure 1.

Schematic presentation of CF patients included in the study. Left side: Between 1975 and 1988, 352 CF patients were treated at the Munich CF centre. Screening for early CF-related liver disease (CFRLD) was not yet established. Of these patients, 9 developed overt liver disease and were used as historic controls. Right side: Between 1989 and 2005, 382 CF patients were treated at the Munich CF centre. Regular screening for early CF-related liver disease (CFRLD) was continuously conducted. By this way, early CFRLD was detected in 98 subjects in whom UDCA treatment was initiated. In one of these 98 patients, early liver disease progressed to overt liver disease. Early CFRLD was excluded in 284 subjects of whom 98 served as contemporary matched control group.

A historic control group consisting of 352 CF patients who attended our centre in the pre-UDCA era between January 1975 and December 1988: The clinical endpoint 'overt liver disease' had been documented in a database of these patients and all patients fitting this criterion were retrieved from the database. The serum liver enzymes and FEV1 were not regularly and completely investigated during this period and therefore could not be used in this group.

A matching contemporary control group of CF patients without CF-related liver disease: We matched the 98 CF patients with CF-related liver disease with 98 CF patients, who attended our centre between 1989 and 2005 and who had no liver disease, according to (i) gender; and (ii) age. Data were collected from the time when UDCA was started in the matched patient. Baseline characteristics of all patients are shown in Table 1.

Monitoring Annual (±3 months) serum liver enzyme values were extracted from the charts after start of UDCA. Details of weight and height were extracted at the beginning of the study and the weight for height was calculated using the percentile standards of Prader et al.[21]

For each subject, all FEV1 values (% predicted) were extracted from the time point when UDCA was initiated and for the matched partner from the corresponding time; in each case, the average annual value was calculated.

Serum Chemistry

Serum was analysed using the Integra 800 (Roche, D-68298 Mannheim, Germany) according to the guidelines of the International Federation of Clinical Chemistry. Asparate transaminase (AST), alanine transaminase (ALT) and glutamate dehydrogenase (GLDH) were determined using kinetic UV tests,[22] the γ-glutamyltransferase (γ-GT) was determined by an enzymatic test with gamma-Glutamyl-3-carboxy-4-nitroanilid,[22] and thrombocytes were determined by impedance aggregometry using Sysmex test systems (Sysmex, D-22848 Norderstedt, Germany).

The laboratory standard for the determination of ALT, AST and γ-GT changed in March 2003 from 25°C to 37°C,[23,24] leading to a change in the normal upper limits. Values obtained after March 2003 therefore were converted for comparison by calculating 'new' values as a percentage above the upper normal limit and re-converting this percentage to a value in relation to the 'old' upper normal value.

Statistical Methods

Analyses were performed using spss version 14.0 for Windows (SPSS Inc., Chicago, IL, USA) or sas version 9.1 and 9.2 (SAS Institute Inc., Cary, NC, USA). Continuous data were summarised as mean, standard deviation and range, and categorical data were summarised as absolute number and percentage of cases per category. The effect of UDCA treatment was assessed by comparing the absolute changes from baseline to follow-up (annual assessment of GLDH, AST, ALT, γ-GT and thrombocytes) using the Wilcoxon signed rank test. A hierarchical approach was used to compare lung function with the matched control group. First, a linear regression for lung function (criterion) over time (predictor) was calculated for each individual patient. The slope of this linear regression model summarised the overall patient's disease progression (negative slope, i.e. decline in lung function) or recovery (positive slope, i.e. increase in lung function). Secondly, the individual slopes of paired CF patients with and without CF-related liver disease were compared using the Wilcoxon signed rank test. Slopes were only determined for patients who provided ≥5 measurements as a sufficient number of measurements were required to give a reliable estimate of the linear regression. The slopes of patients with <5 measurements were treated as missing values. By this means multiple measurements were merged to one single summary measurement and hence, an inflation of alpha error due to multiplicity of comparisons was avoided. The frequencies of overt liver disease in the contemporary patient group and the historic control group were tabulated and compared using Fisher's exact test.

The study was approved by the local institutional review board for human studies of the University Children's Hospital, Munich.


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