Functional anatomy of the exocrine pancreas

The pancreas is a digestive gland that is both a ductal gland (exocrine) and a ductless gland (endocrine). The exocrine pancreas consists of epithelial cells that synthesize and secrete pancreatic digestive enzymes and comprise over 90% of pancreatic mass. The human endocrine gland consists of about a million islets of Langerhans that are formed by clusters of endocrine cells containing insulin, glucagon, pancreatic polypeptide, and somatostatin (primary hormones that define cell subtypes) that are suspended in a sea of exocrine tissues.

The function of the exocrine pancreas can be classified into the function of the acinar cells that synthesize digestive enzymes and the duct cells that form the ducts and secrete fluid and, to a lesser extent, mucus, to transport the pancreatic digestive enzymes from the acinar cells to the duodenum. The organization of the two major exocrine pancreatic cell types is given in Figure 40.1.

Pancreatitis is inflammation of the exocrine pancreas that is initiated by processes internal to the pancreas (i.e., occurring in the acinar cells, duct cells or duct) or external to the pancreas (i.e., distal duct obstruction). A review of the microanatomy of the pancreas (Figure 40.2 and Figure 40.3) and physiological models illustrates some of the key principles underlying pancreatitis.

Acinar cell molecular pathology

Hereditary pancreatitis (HP) is an autosomal dominant Mendelian genetic disorder of the pancreas with high penetrance and all the typical features of acute pancreatitis, recurrent acute pancreatitis and chronic pancreatitis, and pancreatitis‐associated diabetes and high risk of pancreatic ductal adenocarcinoma. It serves as an excellent model of pancreatitis and its complications.

In 1996, the gene causing HP was discovered to be a gain‐of‐function mutation in the cationic trypsinogen gene (PRSS1). This finding linked together evidence from clinical observations, animal models, and molecular experiments, with subsequent studies demonstrating the requirement for trypsin activation to initiate acute pancreatitis, the effect of recurrent acute pancreatitis in causing chronic pancreatitis, and the effect of smoking and other confounding factors to alter disease severity and various complications. It explained one of the mechanisms of driving acute pancreatitis with hypercalcemia or hyperstimulation (increasing intracellular calcium) by pointing to the critical calcium binding site within the trypsin molecule that makes it resistant to self‐destruction through the autolysis pathway. It also led to the discovery of another important gene, the pancreatic secretory trypsin inhibitor (SPINK1), and common variants that alter stress‐associated expression or function. Figure 40.4 is a ribbon model of the trypsin molecule highlighting the calcium binding pocket and the location of SPINK1 as a “suicide” inhibitor, blocking the catalytic site for trypsin’s proteolytic action.

Chronic pancreatitis

After an episode of acute pancreatitis, there is growing evidence that, unless there is pancreatic necrosis or other problems, the pancreas may regenerate to some degree. However, with recurrent or persistent injury, the ongoing inflammation and fibrosis begin destroying the pancreas in a patchy, nonuniform way.

Figure 40.5 illustrates the normal appearance of the human pancreas and some of the common observed patterns of progressive destruction of acini by fibrosis or fatty replacement of acini in other cases.

Duct cell molecular pathology

Successful secretion of trypsinogen and other zymogens from the acinar cell is only the first step in delivering the pancreatic digestive enzyme proteins to the duodenum where they are normally activated and begin digesting a meal. The duct system is critical for transporting the zymogens the remaining length of the pancreas and into the duodenum.

The key molecule for normal duct function is the cystic fibrosis transmembrane conductance regulator (CFTR). This molecule is an anion transporter on the apical membrane of the upstream duct cells that is responsible for generating the vast majority of fluid, such as sodium bicarbonate, to clear the duct of proteins and other substances. The importance of CFTR is illustrated in another Mendelian disorder, the multiorgan disease known as cystic fibrosis (CF). The pancreas is unusually sensitive to damaging mutation in the CFTR molecule and destruction of the pancreas in patients with two severe CFTR mutations (homozygous or compound heterozygous) begins in utero, during the phase of development where trypsinogen is first synthesized and secreted.

The term “cystic fibrosis” refers to the appearance of the pancreas in infants who died of malabsorption and malnutrition due to cystic fibrosis. Figure 40.6 is an example of a cystic fibrosis pancreas.

The histology of the pancreas in patients with CF reveals the duct system filled with proteins along with chronic inflammation, cysts, and fibrosis (Figure 40.7). This histology is different from the histology in most other etiologies such as hereditary pancreatitis, alcoholic pancreatitis, and idiopathic pancreatitis (compare with Figure 40.5).

Structure of the CFTR molecule

In the pancreas, the CFTR molecule is located in the upstream pancreatic duct, with centroacinar cells near the acinar cells. CFTR is a regulated channel that localizes to the apical membrane with numerous intracellular sites for regulation. A computer‐generated image of the proposed structure of CFTR is given in Figure 40.8.