Hereditary pancreatitis is defined as chronic or recurrent acute pancreatitis that occurs as a result of abnormalities of specific pancreatitis-causing genes [1, 2]. Hereditary pancreatitis has three different inheritance patterns: autosomal dominant hereditary pancreatitis, autosomal recessive pancreatitis, and complex genetics. Autosomal dominant hereditary pancreatitis usually derives from a mutation in the PRSS1 (serine protease 1) gene. Autosomal recessive pancreatitis is most commonly from chronic pancreatitis associated with cystic fibrosis; however an autosomal recessive pattern can also emerge due to a mutation in the SPINK1 (serine protease inhibitor Kazal type 1) gene. Finally, multiple family members can face recurrent acute or chronic pancreatitis due to a combination of genetic and environmental factors—most commonly seen through patients with heterozygous SPINK1 mutations. No matter what the inheritance pattern, the basis of hereditary pancreatitis lies in having a specific disease-causing gene mutation.

There are many different gene mutations that can result in hereditary pancreatitis. Eighty percent of patients with hereditary pancreatitis have mutations in their PRSS1 gene. This gene codes for trypsin-1 (cationic trypsinogen). Mutations in the PRSS1 gene lead to malfunctioning trypsin-1 in which intracellular trypsinogen is converted to trypsin too early while still within the pancreas. Premature activation of trypsinogen then causes pancreatitis. The defense mechanism which allows for the premature activation is inhibited by mutations in the PRSS1 gene and in genes that encode molecules that protect the pancreas from active trypsin (these include SPINK1, CTRC, and CFTR).

The most common mutations in the PRSS1 gene include point mutations at the p. R122H and p. N291 loci—both of which have high penetrance. More than 20 PRSS1 mutations are known with new ones routinely being discovered. Nearly all mutations are associated with one of trypsin’s two regulatory sites.

The SPINK1 gene is expressed in pancreatic acinar cells during an inflammatory process in which it inhibits trypsin secretion from the pancreas. Many people have a SPINK1 mutation; however <1% of carriers develop pancreatitis. The majority of patients with a SPINK1 mutation are heterozygous for that mutation. SPINK1 is only required by the body to work correctly when there is recurrent trypsin activation, and thus it most likely acts as a disease modifier where it lowers the threshold for developing pancreatitis due to other genetic or environmental factors. If some environmental or genetic incident causes the amount of trypsin activation to spike, SPINK1 would act as the feedback inhibitor that would perform the protective duty required to combat the trypsin. If the SPINK1 gene is mutated, this response won’t occur, the pancreas won’t be protected from activated trypsinogen, and pancreatitis may result.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene is the most common gene that is coupled with SPINK1 resulting in hereditary pancreatitis [3–6]. The CFTR gene encodes for proteins that create channels for sodium and bicarbonate. These cross-membrane channels create gradients for cell-produced material to move freely in and out of adjacent cells. These channels are needed in cells that create mucus, sweat, saliva, tears, and digestive enzymes. Properly functioning chloride channels are incredibly important for many organs and tissues as they allow for the production of thin and free-flowing mucus to protect the walls of the respiratory system, digestive tract, reproductive system, etc. The channels also ensure the proper secretion/activation rate of pancreatic enzymes that help digest foods by lining the pancreatic duct walls. Mutations in the CFTR gene (located on chromosome 7) result in cystic fibrosis (CF). CF mostly affects the lungs but also has the potential to damage the pancreas, liver, and vas deferens. The mutated CFTR causes the channels to malfunction resulting in a thick (instead of thin) mucus layer to line the duct walls, which in turn obstructs the minor duct and doesn’t allow for proper secretion. This in turn causes premature activation of pancreatic enzymes within the acinar cell which leads to pancreatitis.