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Page 2 of 10 Zierke et al. Rare Dis Orphan Drugs J 2023;2:10 https://dx.doi.org/10.20517/rdodj.2022.17

[1]
annual incidence of 13-45/100,000 inhabitants . Although acute pancreatitis is mostly characterized by a
mild course with edematous changes of the organ and complete recovery, a severe disease course occurs in
10%-15% of patients, leading to organ failure and high mortality. Necrotizing pancreatitis is observed in up
to 20% of patients and can lead to further complications such as secondary infections requiring further
interventions . Alcohol abuse and migrating gallstones are the most common causes of acute pancreatitis
[2]
and account for approximately 80% of all cases. Less frequent causes include genetic factors, drug-induced
effects, anatomic variants, autoimmune diseases, and metabolic disorders such as hypertriglyceridemia or
[3]
hypercalcemia . This review aims to provide insights into current concepts in the pathophysiology of
autoimmune and hereditary pancreatitis by emphasizing the pathogenic function of neutrophil granulocytes
and neutrophil serine proteases (NSPs).

HEREDITARY PANCREATITIS
The term hereditary pancreatitis classically refers to mutations in the cationic trypsinogen gene (PRSS1) that
are inherited in an autosomal-dominant pattern with high penetrance . Patients present with recurrent
[4-6]
attacks of acute or chronic pancreatitis without an obvious underlying cause. An autosomal dominant
pattern of inheritance was first reported in 1952 by Comfort and Steinberg in a family with chronic
pancreatitis , and the genetic basis was studied intensively in the following years. A breakthrough was
[7]
reached in 1996 when mutations in the PRSS1 gene (PRSS1) leading to a gain-of-function were discovered.
These led to hereditary pancreatitis . Since 1996, many other genetic variants of PRSS1 have been reported,
[8]
underlining the pathogenic role of trypsinogen in pancreatitis. More rarely, homozygous mutations in the
cystic fibrosis transmembrane conductance regulator (CFTR) and the serine protease inhibitor Kazal-type 1
(SPINK1) genes are linked to hereditary pancreatitis. Other genetic factors increase the risk of recurrent
acute or chronic pancreatitis and include variants of carboxypeptidase A1 (CPA1), elastase 3B (CELA3B),
and chymotrypsin C (CTRC) genes, as well as heterozygous SPINK1 or CFTR mutations. These variants are
considered to have disease-modifying functions together with environmental factors. If acute recurrent or
chronic pancreatitis occurs in families with a frequency higher than expected by chance, familial
pancreatitis can be suspected. These genes act in a direct or indirect way in the intracellular protease
activation cascade and encode proteases and their inhibitors [9,10] [Table 1]. Patients who have hereditary
pancreatitis or carry genetic susceptibility factors without Mendelian inheritance patterns mostly suffer
from their first acute phase at a significantly younger age compared to patients with other etiologies, and
they often have a family history of pancreatitis [11,12] . In addition, a number of genetic mutations are related to
faster disease progression and a higher probability of pancreatitis-related complications such as
pancreatogenic diabetes (Type 3c), exocrine pancreatic insufficiency, and pancreatic adenocarcinoma [10,11] .

The best-characterized variants are localized in the cationic trypsinogen gene (PRSS1) and implicate
different biochemical reactions: while some mutations are linked to an increase in autocatalytic activation
and enhanced stability of active trypsin [4,8,13] , others are connected to increased transactivation of anionic
trypsinogen , the second major trypsinogen isoform, or even protein misfolding, which results in chronic
[14]
pancreatitis mediated by increased endoplasmic reticulum stress .
[15]
SPINK1 is an essential part of the protective mechanism against premature and intracellular trypsin
activation. The most frequently observed pancreatitis-associated genetic variant is the N34S mutation , but
[16]
no functional change has been elucidated to date. Because this mutation is very common in the general
population, it is considered to be more likely a disease-modifying mutation or a component of a polygenic
model . Other mutations of the SPINK1 gene are related to reduced secretion of trypsin and increased
[17]
intracellular autodigestion of acinar cells . Chymotrypsin C (CTRC) forms another part of the protective
[18]
machinery against intracellular trypsin-dependent digestion. This enzyme is minor human chymotrypsin