Pathophysiology
Clinical meaning
Meconium ileus represents the earliest clinical manifestation of cystic fibrosis, occurring in approximately 15-20% of CF neonates. The molecular basis lies in mutations of the CFTR gene on chromosome 7q31.2, which encodes a cyclic AMP-regulated chloride channel expressed on the apical membrane of epithelial cells throughout the body. Over 2,000 CFTR mutations have been identified, classified into six functional classes: Class I (no protein synthesis, e.g., G542X), Class II (misfolding and proteasomal degradation, e.g., F508del - the most common mutation worldwide, present in approximately 70% of CF alleles), Class III (gating defects, e.g., G551D), Class IV (reduced conductance), Class V (reduced synthesis), and Class VI (accelerated turnover). The severity of meconium ileus correlates with the degree of CFTR dysfunction and resultant pancreatic insufficiency. In the intestinal epithelium, dysfunctional CFTR channels impair chloride and bicarbonate secretion into the intestinal lumen. This reduces water content of luminal secretions, creating a dehydrated, viscous mucosal environment. Simultaneously, pancreatic duct CFTR dysfunction leads to inspissation of pancreatic secretions, progressive acinar destruction, and exocrine pancreatic insufficiency (present in 85-90% of CF patients). The absence of pancreatic...