Liver Disease in Cystic Fibrosis: Illuminating the Black Box
Authors: Carla Colombo, Gianfranco Alicandro
Journal: Hepatology (2018)

Potential conflict of interest: Nothing to report. SEE ARTICLE ON PAGE 1648 Cystic fibrosis–associated liver disease (CFLD) has received increasing attention over the last three decades and has been recognized as a major comorbidity of cystic fibrosis (CF), with potential impact on morbidity and survival of affected patients. CFLD is currently considered a black box in hepatology because its pathogenic mechanisms remain in part unknown and long‐term effective treatments are lacking.1 Accurate and consistent data on incidence, risk factors, and outcome were obtained from prospective studies with careful monitoring of hepatic status.2 Overall, these studies showed that CFLD is a pediatric complication that occurs mainly before puberty, with up to 40% of patients developing biochemical or ultrasonographic signs of liver involvement by 12 years of age and with only a few incident cases after 18 years of age.2 In the absence of a specific diagnostic marker, in these studies CFLD was defined by presence of hepatomegaly on clinical examination and persistent abnormalities in liver biochemistry and at ultrasonography (excluding steatosis), which led to the inclusion of both early and advanced disease with cirrhosis and portal hypertension. These diagnostic criteria were published within the standard‐of‐care initiatives of EUROCARE CF (the comprehensive project on CF within the Sixth EU Research Framework Programme).5 However, the diagnostic definition of CFLD remains controversial,1 and alternative algorithms, including more advanced and noninvasive tools, are under evaluation.6 In contrast to cross‐sectional studies often carried out in tertiary hepatology centers, prospective2 and registry7 studies documented the slow progression of CFLD, with development of cirrhosis and portal hypertension in no more than 5%‐10% of patients in addition to the long‐term preservation of hepatic function and the rare occurrence of liver‐related events. As a result, designing clinical trials to establish the long‐term usefulness of therapeutic interventions for CFLD is quite challenging; this was also the case for ursodeoxycholic acid (UDCA), the only treatment currently available. Despite beneficial effects on liver biochemistry, biliary drainage at hepatobiliary scintigraphy, histopathological alterations, and liver stiffness, the long‐term effects of UDCA on clinically relevant endpoints such as survival or need for transplantation could not be assessed, because of the limited number of patients and the short follow‐up period of the studies carried out so far. Therefore, the efficacy of UDCA is presently under discussion, and clinical practice varies among CF centers. The European guidelines for CFLD recommend its use at a dosage of 20 mg/kg/day as soon as diagnosis is established.5 In this issue of hepatology, Boelle et al. report new data on incidence and risk factors of CFLD, and the effects of UDCA treatment on the incidence of severe liver disease. Their results are based on a cohort study of 3,328 patients with CF born after 1985 and enrolled in the French CF Modifier Gene Study since 2004, with data collected retrospectively until 2004 and prospectively thereafter.8 Although data regarding risk factors are consistent with those obtained by prospective studies, incidence values during childhood are remarkably lower, probably because of the problematic detection of early CFLD in the context of a retrospective study. In addition, the study found that CFLD not only develops in childhood but also in adulthood. Although several retrospective studies in adult patients reported that development of CFLD is unusual in adulthood, more recently, a prospective study with long‐term follow‐up documented a second wave of CFLD incidence occurring at a median age of 37 years in patients without evidence of liver abnormalities in the pediatric age.6 However, the pathogenesis of liver disease presenting in adulthood may be different from that in childhood and, to some extent, unrelated to the CF basic defect. Adult patients may be affected by forms of the noncirrhotic portal hypertension spectrum due to obliterative portal venopathy, as was the case in the population described by Boelle et al.8 Nodular regenerative hyperplasia has been also reported and was possibly related to chronic drug‐induced liver injury from long‐standing antibiotic use.6 The prevalence and outcome of these conditions need to be better defined. One of the greatest challenges in the management of patients with early CFLD is to prevent the progression to cirrhosis, portal hypertension, and related complications. The retrospective analysis by Boelle et al., based on a subset of the whole cohort (2,516 patients born between 1986 and 2005), suggests that UDCA treatment does not prevent the development of severe liver disease. To avoid the risk of protopathic bias, i.e., finding a higher incidence of CFLD in patients who received UDCA for subclinical manifestations of CFLD, an instrumental variable analysis was performed. This analysis requires the selection of valid instrumental variables that should not have a direct effect on the outcome of interest. In this study, two instrumental variables were selected, namely calendar year of birth (before and after 1995) and being followed in an early or late prescriber center (prescription rate at age 5 years <5% or ≥5%, respectively). Irrespective of the birth cohort or the UDCA practice of the center, the cumulative incidence of severe CFLD did not differ significantly. However, a direct relationship between both instrumental variables and the diagnosis of severe liver disease cannot be excluded. Patients of younger cohorts and those who were followed up in early prescribing centers may have had a higher chance of a more accurate hepatic monitoring through ultrasonography, resulting in a higher rate of severe liver disease diagnosed by imaging. Therefore, the instrumental variable analysis used to assess the efficacy of UDCA treatment may not be fully appropriate. Also of interest is the impressive rate of patients being treated with UDCA before diagnosis of liver disease (83% of patients treated with UDCA), suggesting low adherence to guidelines.5 In summary, the study by Boelle et al. provides new information on incidence, risk factors, and response to UDCA treatment in patients with CF. The authors are to be commended for performing a comprehensive analysis to better characterize CFLD on a very large population of patients with CF, probably the largest cohort ever studied for this purpose. Their data will certainly contribute to illuminating the black box of CFLD and promoting research on the more controversial issues. Prospective studies are needed to better characterize CFLD developing in adulthood, with particular regard to pathogenesis, response to UDCA treatment, and clinical outcome. Evidence available so far (Fig. 1) suggests efficacy of UDCA treatment in improving liver biochemistry and potential benefit on liver morphology, whereas evidence of the long‐term effects on clinically relevant outcomes is still lacking. However, this is not sufficient to recommend to centers that prescribe UDCA to change their clinical practice.Figure 1: Evidence and unanswered questions on the effect of UDCA on liver outcomes in cystic fibrosis. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma‐glutamyl transferase.Concerns have been raised about the possible biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid, with possible serious adverse events, as observed in adult patients with primary sclerosing cholangitis treated with high‐dose UDCA. In patients with CF, however, UDCA has been prescribed for almost three decades, and no significant side effects related to its long‐term use have been reported; in addition, serum concentrations of lithocholic acid during chronic UDCA administration were found to be very low (below the limit of detection in most cases).9 Prospective long‐term studies involving large numbers of patients with clinically relevant endpoints are needed to draw definitive conclusions about the real benefits of UDCA as well as of any other treatments for CFLD.