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


Patients With CF-related Liver Disease: Baseline Characteristics

The mean age at initiation of UDCA was 14.8 years with a range 0.6–36 years. The peak of distribution was skewed to younger ages (Figure 2a) due to 17/98 patients (17%) having a history of meconium ileus. The overall incidence of meconium ileus in all patients was comparable (16%); however, liver disease in patients with meconium ileus manifested at a significant younger age (P = 0.010) (Figure 2c). In contrast, the age distribution in subjects without meconium ileus was nearly Gaussian (Figure 2b). Meconium ileus and early manifestation of liver disease were not associated with dF508 homozygosity (P = 0.20) (Figure 2a–c).

Figure 2.

Age distribution at onset of CF-related liver disease: Liver disease in CF starts in all age groups with a median around 15 years, but earlier in patients with a history of meconium ileus. In the pre-UDCA period (historic control), liver disease progressing to overt liver disease started at younger ages. (a) All CF patients with CF-related liver disease in the UDCA period (n = 98) (b) Subset of patients without history of meconium ileus (n = 75); approximate Gaussian distribution of age with first signs of liver disease. (c) Subset of patients with history of meconium ileus (n = 23); earlier start of CF-related liver disease in this group of patients. * P = 0.010 in Wilcoxon Rank Sum Test comparing age distribution of B (without meconium ileus) to C (with meconium ileus). (d) All CF patients with overt liver disease in the pre-UDCA period (n = 9); early start of CF-related liver disease in historic controls who proceeded towards overt liver disease. CFTR molecular genetics: Black: dF508/dF508 Gray: dF508/other White: other/other. Vertical arrows: Median.

Changes From Baseline in Annual Values of GLDH, AST, ALT and γ-GT

After treatment with UDCA, there was a significant and persistent decline in liver enzymes from baseline (see supplementary Tables S1 and S2, published online) and a corresponding increase in the number of individuals with normal serum liver enzymes (Figure 3). Persistent elevation (>50% of observations) was noted in 11 patients: Three had intrahepatic gall stones, two were taking anabolic steroids (as self-medication, not prescribed), one had an autoimmune disease affecting the liver, three patients had advanced liver disease, which was present before UDCA was introduced, one patient had unexplained persistent elevations and one patient, a 24-year-old woman, developed overt liver disease after 4.5 years on UDCA, confirmed by ultrasound and magnetic resonance imaging.

Figure 3.

Patients with CF-related liver disease: Long-term follow-up of elevated serum liver values under UDCA. The number of patients with one or more elevation of serum liver values >1.5 times the upper normal limit declines rapidly and persistently under UDCA. Detailed values for alanine transaminase, aspartate transaminase, glutamate dehydrogenase, γ-glutamyltransferase, and descriptive statistics are given in supplemental Table S1 and supplemental Table S2.

Comparison With a Historic Control Collective

Between 1975 and 1988 UDCA was not administered to any of the 352 CF patients treated at our centre. Data from this historic control group were systematically searched for subjects with overt liver disease and 9 patients (2.6%, 8 males) were identified and analysed. The first signs of CF-related liver disease were seen early at a mean age of 7.6 years (2–15 years) and all subjects progressed within only 3.9 years (0.5–4.7 years) to overt liver disease (persistent thrombocytopenia <80.000/μL).

In contrast, between 1989 and 2005, only one of the 382 patients developed overt liver disease (P = 0.009, Fisher's exact test).

Lung Function in CF Patients With and Without CF-related Liver Disease

No difference was seen in loss of lung function over time between the two contemporary groups of subjects and only marginal differences were seen in their mean slope for decline of FEV1 (Figure 4). Analysing patients evaluable for unpaired analysis, it was -0.94%/year (±1.98) in the matched control group and −1.36%/year (±1.86) in the UDCA-treated subjects (P = 0.388 in Wilcoxon Signed Rank Test). A t-test for paired samples, which was performed additionally for exploratory purpose, supported this result (P = 0.335), as well as unpaired comparisons using the Wilcoxon–Mann–Whitney two-sample test and in addition including patients of incomplete pairs (P = 0.253).

Figure 4.

Long-term lung function values are comparable in UDCA-treated patients and controls. Average annual FEV1 values (% predicted) from baseline and in the long-term follow-up in 98 patients with liver disease under UDCA (•) and 98 matched control patients without liver disease (∘). Given are the arithmetic mean and standard deviations. Numbers of subjects at each time point are as follows: Control: 66, 71, 74, 75, 78, 77, 79, 70, 68, 60, 54, 46, 43, 36, 29, 25, 14, 11. UDCA: 76, 77, 85, 87, 84, 78, 74, 64, 59, 52, 47, 41, 35, 30, 27, 23, 15, 11.


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