Pancreatic pathophysiology in cystic fibrosis

Abstract

The pancreas is one of the earliest, and most commonly affected, organs in patients with cystic fibrosis (CF). Studying the pathogenesis of pancreatic disease is limited in CF patients, due to its early clinical onset, co-morbidities and lack of tissue samples from the early phases of disease. In recent years, several new CF animal models have been developed that have advanced our understanding of both CF exocrine and endocrine pancreatic disease. Additionally, these models have helped us to better define the influence of pancreatic lesions on CF disease progression in other organs, such as the gastrointestinal tract and lung.

Keywords: cystic fibrosis; cystic fibrosis transmembrane conductance regulator; diabetes; pancreas; pancreatic insufficiency; pathology.

Figure 1

H&E images of lesions of the pancreas in the wild-type and CF pig, ferret and zebrafish. A. Wild-type newborn pig pancreas. B. CF newborn pig pancreas highlighting dilated acinus tissue (inset) filled with lightly eosinophilic secretions (arrow). Bars = 200µm (inset bars = 20µm). C. Adult pig pancreas showing normal exocrine and endocrine (arrows) pancreatic tissue. D. CF adult pig pancreas demonstrating dilated pancreatic ducts (arrows), loss of exocrine pancreatic tissue and fatty infiltration (asterisks) (Bars = 200 µm). E. Wild-type newborn ferret pancreas. Inset highlights a normal islet surround by exocrine tissue. F. CF newborn ferret pancreas with acinus dilation (arrows) Bars = 200µm (inset bars = 20µm). G. Wild-type adult ferret pancreas showing normal pancreatic islets (arrows) surrounded by exocrine pancreatic tissue. H. CF adult ferret pancreas with abundant loose fibrous connective tissue (asterisks), multifocal inflammatory cell infiltrates and multifocal islands of dilated acini and ducts filled with lightly eosinophilic secretions (arrows) (Bars = 100 µm). I. Wild-type zebrafish pancreas at 1 year post fertilization. J. cftr mutant zebrafish pancreas at 1 year post fertilization showing loss of exocrine pancreas, fibrosis and dilated pancreatic ducts (white arrows) (bars = 50 µm) (reprinted with permission) [12].

Figure 2

Insulin immunohistochemistry (IHC) images of pancreatic islets from CF pigs, ferrets and human patients. A, B, C. Adult pancreata stained with insulin from WT pig (A), WT ferret (B) and normal human (C) Bars = 100 µm. D. Newborn CF pig pancreas stained with insulin to show abundance of islets even with exocrine pancreatic destruction. Bar = 200 µm. E. Insulin IHC of newborn CF ferret pancreas. Bar = 200 µm. F. Higher magnification images of B demonstrating the different sized islets present. There were more small islets (S) in CF ferrets compared to WT with fewer large (L) islets while medium (M) sized islets were not different (19). Bar = 20µm. G, H. Insulin IHC performed on human CF patients highlighting the lack of exocrine tissue with remnant insulin immunoreactive islets (arrows). I. Insulin IHC on a human CF patient with CFRD demonstrating a paucity of insulin immunoreactivity and abundance of adipose tissue.