Hereditary Pancreatitis

 Genetics / Hereditary pancreatitis

• Suspect if 2nd episode of 'idiopathic' acute pancreatitis in patients <40 years of age

Trypsin Dependent Pathway: Trypsinogen (cationic / anionic forms) is a major protein produced in pancreas, which gets activated in dudoenum to trypsin and causes digestive proteolysis. Premature activation of Tryspin within pancreas is a major cause of development of hereditary pancreatitis.

Genes:

Dominant Gene:

                         PRSS1  - Autosomal dominant, Gain of function mutation

                                        Responsible for vast majority of cases of Hereditary pancreatitis

                                        Causes ⬆⬆cationic trypsinogen, leading to premature activation within pancreas

                                        80 -90% penetrance

                                        First episode of pancreatitis is often by age 10

                                        Dominant gene - can cause pancreatitis w/o other co-factor

Minor Genes:

                       SPINK1 - Autosomal Recessive

                                        SPINK protein neutralizes activated trypsin within pancreas

                                        Therefore, is significant only if abnormal amount of active trypsin is present

                                        Acts as a disease modifier, reducing risk of pancreatitis in presence of other. 

                                                                                                           genetic or environmental triggers

                                        Requires another co-factor with heterozygous mutation to cause pancreatitis

                                        2% of General population carry heterozygous mutation

                                        Although only 1% of carriers develop recurrent pancreatitis (requires cofactor)

                                        Most-common genetic co-factor with SPINK1 is CFTR

                       CFTR:     Autosomal Recessive

                                        Classic CF manifestation causes viscous secretion everywhere, raised sweat NaCl

                                        With AR - classic CF, chronic pancreatitis with PEI develops in-utero/ infancy

                                        Pancreatitis Risk is based on mutation type &, homozygosity  or                                                                                                                                                             compound heterozygosity

                                        Only 1% of carriers of Heterozygous carrier CFTR develop pancreatitis                                                        Heterozygous CFRT requires another co-factor 

                                  

                        CTRC:    Autosomal Recessive

                                        codes for protein which neutralizes activated trypsin within pancreas

                                        Confers moderate risk of pancreatitis, however requires a co-factor

CLDN2 - This is an interesting gene located on X chromosome, and present in 26% controls. While this gene does not cause pancreatitis, it is associated with progression of AP to CP. Therefore, this likely explains why high-risk alcohol drinking Men (XY) are more likely to develop CP, compared to women (XX). 

 Risk of PDAC in Hereditary Pancreatitis - 40% by age 70 (actual risk in non-smokers is lot lower to 10%)