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Lung and liver growth and retinoic acid status in human fetuses with congenital diaphragmatic hernia
Christine K C Loo1, Michael A Pearen2, Tamara N Pereira2
1Dept of Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Sydney, Australia; Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Insights
Fetal retinoic acid (RA) status, indicated by hepatic stellate cell (HSC) numbers, impacts lung growth in congenital diaphragmatic hernia (CDH) fetuses. Diaphragm contact also influences liver development in these cases.
Area of Science:
- Developmental Biology
- Fetal Medicine
- Teratology
Background:
- Abnormal retinoic acid (RA) signaling is a key factor in congenital diaphragmatic hernia (CDH).
- Pulmonary hypoplasia and hypertension are primary complications of CDH, impacting infant mortality.
- Existing animal models do not fully replicate human CDH, necessitating studies in human fetuses.
Purpose of the Study:
- To investigate the relationship between retinoic acid (RA) status and lung/liver growth in human fetuses with CDH.
- To use hepatic stellate cell (HSC) numbers as a biomarker for fetal RA status.
- To correlate HSC numbers with organ weights in CDH cases.
Main Methods:
- Autopsy fetal liver tissue was analyzed for hepatic stellate cells (HSCs) using cRBP-1 immunohistochemistry.
- HSC numbers, representing RA stores, were manually counted.
- HSC counts were correlated with liver and lung weights relative to normal biometric values or fetal body weight.
Main Results:
- A significant positive correlation was found between cRBP-1+ HSC numbers and contralateral lung weight (r=0.82, p=0.025) and combined lung weight (r=0.78, p=0.039).
- No significant correlation was observed between HSC numbers and ipsilateral lung weight (r=0.43, p=0.33).
- Liver growth was influenced by diaphragmatic contact but not significantly correlated with cRBP-1 expression (r=0.52, p=0.056).
Conclusions:
- Fetal RA stores, as indicated by cRBP-1+ HSCs, play a role in lung development in human fetuses with CDH.
- Diaphragm presence and contact influence liver growth in fetuses with CDH.
- These findings highlight the importance of RA signaling in human fetal development and CDH pathogenesis.
Background:
Abnormal retinoic acid (RA) signalling is considered a major cause of congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia and pulmonary hypertension are the major causes of morbidity and mortality in infants born with CDH. Experimental studies in animals have found that RA signalling is involved in lung and liver development, but animal models of CDH do not directly correlate with CDH in human fetuses. This study investigated if RA status is also linked to lung and liver growth in human fetuses with CDH.
Study Design And Patients:
Hepatic stellate cells (HSC) in autopsy human fetal liver tissue were identified using cRBP-1 immunohistochemistry and the numbers of HSC manually counted. In mammals, RA is principally stored in HSC complexed to cRBP-1 and therefore cRBP-1+ HSC numbers were used as an indicator of fetal RA status. The number of HSCs was correlated with liver and lung weights, calculated relative to either normal biometric values or fetal body weight.
Results:
The number of cRBP-1+ HSCs correlated with lung weight contralateral to the side of the diaphragmatic hernia (r=0.82, p=0.025) and combined lung weight (r=0.78, p=0.039) but not with ipsilateral lung weight (r=0.43, p=0.33), in fetuses with right and left CDH and a case of giant omphalocoele. Liver growth was influenced by contact with diaphragm but not significantly correlated with cRBP-1 expression (r=0.52, p=0.056).
Conclusion:
Fetal RA stores, reflected in the number of cRBP-1+ HSCs, influence lung growth as well as diaphragm development in human fetuses with CDH. Contact with diaphragm influenced liver growth.
