Both CF and A1ATD are severe autosomal recessive inherited diseases, affecting the lungs and the liver [1, 2]. CF lung disease is characterized by a large neutrophil burden with normal levels of anti-proteases, while neutrophil burden is normal in A1ATD but levels of antiproteases are decreased [1, 2].
In the reported case, the diagnosis of A1ATD was established because the severity of the liver disease could not be explained fully by CF. Risk factors for the development of CFDL include male sex, CFTR genotype, later age at diagnosis of CF, meconium ileus, severity of pulmonary disease, pancreatic insufficiency and persistent failure to thrive . Moreover, the SERPINA1 Z-allele has been proven an additional risk factor for CFDL .
CFLD can present with neonatal cholestasis and at later ages, from asymptomatic elevation of transaminases to cirrhosis, end-stage liver disease and portal hypertension . However the majority of patients have focal changes of the liver parenchyma without clinical significance.
Liver disease in our case may be predominantly determined by A1ATD with CF. Intestinal failure associated liver disease (IFALD) is a potentially contributing factor due to the intestinal failure and period of parenteral nutrition. Moreover, the need for repeated broad-spectrum antibiotics may have influence on liver disease as well.
The incidence of A1ATD lies in the same range as the incidence of cystic fibrosis within the Caucasian populations.
The associated lung disease is caused by a “loss-of-function” defect of A1AT leading to proteolytic damage to the connective tissue matrix of the lung resulting in pulmonary emphysema, chronic obstructive pulmonary disease (COPD) and/or bronchiectasis from young adulthood .
A1ATD associated liver disease is caused by retention of the mutant Z A1AT within the endoplasmic reticulum (ER) of hepatocytes activating a cascade of apoptotic liver cell death with compensatory hepatocellular proliferation, leading to end-organ injury. Presenting symptoms are protracted neonatal jaundice, liver enzyme elevation, hepatitis, liver cirrhosis, hepatocellular carcinoma and rarely fulminant hepatic failure. If there is an A1AT level lower than 1.1 g/L or a strong clinical suspicion, genetic analysis is needed to establish a definite diagnosis .
Rapidly progressive liver disease leading to liver failure is unusual in the context of CF liver disease as well as A1ATD. We hypothesize that the combination of these 2 genetic diseases together with the need for prolonged parenteral feeding caused severe liver disease. The rapid progression may have been triggered by respiratory infection.
Exogenous alpha-1-proteinase inhibitor (alpha1-PI) has been studied as CF treatment because it inhibits neutrophil elastase activity and may reduce inflammation but further studies are needed to prove efficacy .
Alpha-1 -PI is the only licensed and primary disease-specific treatment solely for A1AT lung disease but there are few data in children . Liver transplantation is the only curative option for A1ATD liver disease .
Multidisciplinary tertiary care is needed to ensure adequate treatment and follow-up. However, one team should take the lead to optimize coordination of care and to facilitate the communication between parents and the hospital. In our hospital, the CF team coordinates the care with multidisciplinary follow up of the pediatric solid organ transplant team together with hepatology and gastroenterology.
To the best of our knowledge this is the first reported case of a child born with both CF and A1ATD. It is an illustration of the complexity of care of a child with two severe diseases as well as post solid organ transplant care.
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