The reported prevalence of liver disease in CF pediatric patients has revealed a wide variability,3,5,11,12
greatly influenced by the study design (retrospective/prospective) and by the selected diagnostic criteria. In fact, the absence of diagnostic markers sufficiently sensitive and specific, is a major recognized limitation and the use of the current standard criteria for evaluation of liver disease in this setting, probably underestimates its true prevalence. Furthermore, liver biopsy, which should be the election technique to diagnose liver disease, has been considered of questionable interest due to its invasivity and the heterogeneous distribution of the hepatic lesions in CF.4
Some studies have suggested the potential association between the development of liver disease and the previous history of meconium ileus and the presence of pancreatic insufficiency.5
In our series, no case had previous history of meconium ileus, but severe pancreatic insufficiency was present in all cases at the diagnosis, accordingly to ΔF508 genotype. The mean age of liver disease diagnosis, 8 years, is in agreement with previous reports describing a characteristic presentation in the first two decades of life, with a peak at prepuberty age.3
Hepatomegaly or hepatosplenomegaly was detected in only 3/7 cases, furthermore confirming that the absence of physical signs does not necessarily exclude the presence of potentially advanced liver disease.5,11
Moreover, an intermittent elevation of the liver enzymes due to pulmonary exacerbations requiring antibiotic therapy is a common occurrence in these patients. For this reason, an enzyme increase for a period superior to 6 months outside the pulmonary exacerbation period is usually a required criterion for detection of liver involvement.13
Similarly as Colombo et al.
reporting a frequency of 56% of patients with raised liver enzymes, we noticed, in our series (using identical diagnostic criteria), an increase in liver enzymes in 42.5% of the patients.(3/7 cases) As predictable, the liver synthesis parameters remained preserved, with the exception of the case that progressed to end-stage liver disease. On the other hand, we also observed, as usually recognized, that the liver enzymes can be normal or just slightly raised in patients with clinically evident disease, as it was the case of patient 4. Our results clearly emphasize the role of ultrasonography in the screening of liver disease in this setting, as it detected abnormalities in 4/7 children without laboratory or physical findings, with three of them having advanced liver disease. Given the low sensitivity and specificity of other diagnostic tests, ultrasound is a non-invasive tool of relevance in the early assessment of liver disease in the CF, if performed by an experienced radiologist.14,15
The relevance of an early diagnosis of the liver involvement has also therapeutic implications, since early therapy with UDCA is recommended. The available evidence shows an improvement of the biliary secretion, reflected by persistent normalization of cholestasis markers and histology improvement.6,7
Although in our series all cases have been submitted to treatment with UDCA since the diagnosis of liver disease, it is difficult to evaluate objectively its contribution to the natural history of the disease. The morbidity associated with liver involvement in CF arises mainly from complications of portal hypertension, including upper gastrointestinal bleeding and hypersplenism. The management of portal hypertension is one of the most problematic and controversial aspects in CF patients. Several therapeutic modalities have been recommended, including conventional support therapy (variceal banding or sclerosis), portosystemic shunts,16,17
or other alternatives such as splenectomy or selective splenic embolization.18–20
The results of these therapeutic interventions are of difficult evaluation given the reduced number of patients included in the available reports. Patient 4 in our series, concerning a child with end-stage liver disease, which required liver transplant, is illustrative of the therapeutic dilemmas in this clinical setting. Refractory bleeding secondary to oesophageal varices, associated with progressive deterioration of liver function in the setting of preserved lung function, determined the choice of an isolated liver transplant. The potential indication to perform a porto-systemic shunt at an earlier stage has been questioned by several authors, as a previous surgery in the portal area might determine technical constraints to liver transplantion. Liver transplantion should be considered in patients with progressive liver failure and/or evidence of major portal hypertension, in the absence of significant pulmonary involvement (forced expiratory volume at 1 second >50%).8,9
The reported survival rate one year after the liver transplant has been of approximately 80% (similarly to the reported survival in other indications for liver transplant)8
and in most cases it is associated with evident benefit in the pulmonary function, in the nutritional state and in the quality of life, as illustrated by our patient.21–23
In conclusion, the present series, representing a first national report concerning liver involvement in the setting of CF, aimed to further contribute to the knowledge of its prevalence and clinical expression at pediatric age. Our data confirmed that although advanced liver disease is a relatively rare event at this age group, early isolated liver transplantation might have to be considered. Emerging evidence from novel studies evaluating putative polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene, may further elucidate CF-related liver disease pathogenesis.24
It is predictable that liver disease occurring both at childhood and adulthood, will have an increasing impact on survival and quality of life of these patients, emphasizing the importance of its early recognition and intervention, as well as of an adequate coordination between the Pediatric and Adult CF teams in this setting.