The impact of liver disease on children with cystic fibrosis.

Leeuwen, L. (2013) The impact of liver disease on children with cystic fibrosis. thesis, Medicine.

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Abstract

Background and objectives: Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disorder in the Caucasian population, with an incidence of approximately 1 in every 3000 live births worldwide. As the life expectancy of children and adults with CF has progressively improved over past decades, non-respiratory complications of CF such as liver disease have become increasingly important. The earliest manifestation of liver involvement in CF is neonatal cholestasis. Neonatal cholestasis in CF patients is an uncommon condition that is poorly described in literature. Therefore, little is known about the true incidence, course and effects of cholestasis in infants with CF. Cystic Fibrosis-associated Liver Disease (CFLD) is a later hepatobiliary complication of CF that has become increasingly important, as it is regarded as the third leading cause of death in CF patients. However, many discrepancies exist about the effect of CFLD on the morbidity and mortality in patients with CF. The aims of this study are: 1. To determine the incidence and course of cholestasis in infants with CF 2. To identify risk factors for the development of cholestasis in infants with CF. 3. To investigate whether the presence of cholestasis in infancy is associated with the development of CFLD. 4. To examine the impact of CFLD on the clinical course of children with CF. Methods: All CF patients admitted to the Children’s Hospital at Westmead, previously known as Royal Alexandra Hospital for Children, between 1 January 1986 and 31 December 2011 were included. The diagnosis CF was suggested either by a positive newborn screening result or by the presence of meconium ileus (MI) and confirmed by sweat testing or genotyping. Firstly, all CF infants with cholestasis were identified based on their liver function tests in early infancy. Cholestatic infants were divided into 2 cohorts: 1) infants with cholestasis diagnosed with MI (MI group) and 2) infants with cholestasis without MI (non-MI group). We collected all liver function tests of cholestatic infants and checked their medical records to report their clinical outcomes. Secondly, we identified CF patients with CFLD (CFLD group) and compared them to an age- and sex-matched CF control group (non-CFLD group). We compared clinical outcomes of both groups regarding pulmonary function, nutritional status, bacterial colonisation, Shwachman clinical scores, need for transplant and survival until the age of transfer to adult care. Results: During the 26-year study period, a total of 476 patients with CF were referred to our centre. The overall incidence of cholestasis in our cohort was 5.7%. There was a significantly higher incidence of cholestasis in infants with MI (27.1%) compared to those without MI (1.2%) (P<0.001). Infants with MI had a 30.36-fold increased risk of developing cholestasis compared to those without MI (odds ratio: 30.36, 95% confidence interval (CI): 9.93-92.86, P<0.001). Cholestasis resolved in all children, at the median age of 9.2 (0.8-53.2) months in the MI group and 10.2 (2.0-19.4) months in the non-MI group. The overall incidence of CFLD in cholestatic infants was 13.0%, so the majority of cholestatic infants did not develop clinically significant liver disease during follow-up. The prevalence of CFLD in this total cohort of CF patients was 5.5%. During the 18 years of follow-up (i.e. birth until transfer to adult care), there were no differences in lung function, nutritional status, colonisation with bacterial pathogens and Shwachman clinical scores between CF patients with CFLD and CF patients without CFLD. Sixty-four percent of CFLD patients in our cohort were transferred to adult care without having experienced any complications of CFLD. The presence of CFLD was not associated with a poorer survival rate at the age of transition to adult care. However, 20.0% of CFLD patients in our cohort underwent liver transplantation prior to the age of 18 years. At the age of transfer to adult care, CFLD patients had a 5.51-fold higher risk of dying or need for liver or lung transplantation compared to patients without CFLD (hazard ratio: 5.51, 95% CI: 1.19-25.56) (P=0.03). All liver transplant recipients remained well after transplantation. Conclusions: Cholestasis is a rare condition in CF affecting only 5.7% of the newborn CF population. The greatest risk factor for developing cholestasis is the presence of MI. In general, the presence of cholestasis and MI in infants does not appear to be a risk factor for the development of CFLD. CFLD displays a slowly progressive course in the majority of patients. The presence of CFLD is not associated with worse pulmonary function, poorer nutritional status, more severe disease or lower survival. However, CFLD patients have a significantly higher risk of death or need for liver or lung transplantation at the age of transition to adult care, with all liver transplant recipients in this cohort remaining well after transplantation. These results suggest that a subset of patients with severe CFLD may gain benefit from liver transplantation as life-prolonging therapy.

Item Type:	Thesis (Thesis)
Supervisor name:	Kallenberg, Prof. C.G.M.
Supervisor name:	Fitzgerald, Prof. D.A. and Gaskin, Prof. K.J. and The Children’s Hospital at Westmead and Brand, Prof. P.L.P. and Department of Paediatrics and Amalia Children’s Clinic, Zwolle
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:58
Last Modified:	25 Jun 2020 10:58
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/1822

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