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

Disclosures

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

In This Article

Abstract and Introduction

Abstract

Background The prevention and treatment of liver disease associated with cystic fibrosis remain a significant unresolved problem.
Aim To assess the long-term effects of continuous ursodeoxycholic acid (UDCA) therapy in cystic fibrosis patients with constantly elevated serum liver enzymes.
Methods The primary endpoint was the incidence of overt liver disease. Between 1989 and 2005, UDCA treatment was started in 98 subjects from a cohort of 382 cystic fibrosis patients. These subjects were compared with a historic control group of 352 subjects who attended our centre between 1975 and 1989 before UDCA became standard treatment. For the long-term comparison of liver function and lung function tests, a group of 98 matched contemporary cystic fibrosis patients were compared with the 98 subjects treated with UDCA.
Results Overt liver disease developed in only one of the 382 patients who was treated with UDCA for increased serum liver enzymes compared with nine patients in the historic control group (P < 0.05). Serum liver enzyme levels declined in most patients receiving UDCA treatment during the 17-year follow-up (87/98, P < 0.05). No difference was seen in lung function between subjects with cystic fibrosis-related liver disease and the matched controls.
Conclusions Regular and systematic screening for liver involvement enables early introduction of UDCA therapy in affected cystic fibrosis patients, reduces the development of severe liver disease and leads to a significant and persistent improvement in serum liver tests, without impairing long-term pulmonary outcome.

Introduction

Liver disease is a major cause of morbidity in cystic fibrosis (CF),[1] a reason for shorter survival[2] and the second most frequent cause of death.[3] The pathognomonic hepatic lesion is focal biliary cirrhosis, which is mostly clinically asymptomatic,[4] and occurs in 25–30% of all CF patients; postmortem studies,[5] however, indicate that the frequency of intrahepatic biliary abnormalities is generally underestimated.

In CF-associated liver disease, the abnormal bile viscosity and the increased concentration of bile components are attributed to the impaired biliary epithelium secretion caused by the absence of the Cystic Fibrosis Transmembrane Regulator (CFTR) regulatory function at the apical domain of the epithelial bile duct cells.[6] Ursodeoxycholic acid (UDCA) is a hydrophilic, nontoxic bile acid that contributes nearly 3% to the normal bile acid pool in humans.[7] Around 1990, UDCA was introduced for the therapy of CF-related liver disease.[8,9] It is currently the only established drug for the treatment of chronic cholestatic liver disease and is supposed to have cytoprotective, anti-apoptotic, membrane stabilising, antioxidative and immunomodulatory effects.[10] The rationale for its use in CF-related liver disease is to reduce the viscosity of bile and to replace toxic bile acids, which accumulate in the hepatocytes.[4] These choleretic properties of UDCA were shown in CF patients by scintigraphic studies[11] and biochemically demonstrated in human cholangiocarcinoma cells.[12]

Within the last few years, support for the beneficial effects of UDCA on liver biochemistry in CF became evident from short-term controlled and uncontrolled trials,[8,9,13,14,15,16,17] and observations in small cohorts;[16,18] however, there are no long-term data for the clinically relevant endpoints such as overt liver disease, liver failure and death from liver disease.[7,19] One recent study showed improvement in liver morphology under UDCA therapy; however, the sample size was limited to 10 subjects followed up over a period of 2 years.[20]

From 1989, all CF patients, who were treated in our centre, were systematically and regularly screened for early signs of liver involvement and, if positive, continuous therapy with UDCA was initiated. Consequently, the systematic introduction of UDCA was possible using a simple diagnostic and therapeutic algorithm. We took advantage of this systematic approach and retrospectively analysed the long-term outcome of UDCA in CF.

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