Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_683_Библиотеки_им_академика_М_И_Перельмана

The serine protease inhibitor, Kazal type 1 (SPINK1; PST1) is a trypsin inhibitor secreted from pancreatic acinar cells. Loss- of- function mutations in SPINK1 reduce its protec­tive function and predispose to pancreatitis [34]. Mutations are found in ~2% of the population and confer a 12- fold increased risk for pancreatitis[34]. Still, less than 1% of SPINK1 carriers develop pancreatitis. Biallelic loss of function mutations in SPINK1 may lead to autosomal recessive pancreatitis. However, the majority of affected patients with SPINK1 mutations are heterozygous, indi­cating the presence of complex gene–gene and gene– environment interactions[35]. For example, SPINK1 can act as a disease modifier, and compound heterozygosity for pathogenic variants in SPINK1/PRSS1 and, more com­monly, SPINK1/CFTR has been reported[25,36].

Single- gene or Mendelian diseases are caused by highly penetrant pathogenic mutations in a single gene that follow a clear pattern of inheritance (e.g., autosomal dominant, autosomal recessive). Mendelian forms of pancreatitis, such as PRSS1- HP, are rare. Instead, most patients have a complex etiology resulting from multiple low- to- moderate effect risk alleles in combination with environmental and physiologic risk factors. Complex risk variants are defined as variants with variable effect sizes, ranging in frequency from rare to common, that do not cause disease in isolation. Instead, the combination of multiple interacting risk variants and other factors work in concert to initiate the disease process. In patients with pancreatitis, several common risk variants have been identified, including the CTRC c.180T>G (p.G60=) and SPINK1 p.N43S variants (described above), a PRSS1- PRSS2 haplotype[44], risk alleles in CLDN2[44], and the CEL- HYB risk allele[45]. Heterozygous carriers of CFTR variants associated with cystic fibrosis or a CFTR- related disorder have also been associated with an increased risk for pancreatitis as a part of a complex etiology [46]. Known risk factors for pancreatitis are outlined in the Toxic- metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and severe acute pancreatitis and Obstructive Pancreatitis Risk/Etiology Checklist (TIGAR- O_ V2) [27], which functions as an organizational tool to document and track patient risk and etiological factors. Although the identification of complex risk variants may lend insights into a patient’s disease process, the quanti­fication of risk to develop pancreatitis in asymptomatic patients or to progress to severe disease in symptomatic patients based on multiple complex variants and nonge­netic factors remains challenging and imprecise.

predicting outcomes after a total pancreatectomy and islet autotransplantation lessons learned from over 500 cases. Ann Surg 2015;262:610–622.

affect function of calcium channel TRPV6 are associated with early- onset chronic pancreatitis. Gastroenterology 2020;158:1626–1641.

trypsinogens. Purification, molecular properties, and N- terminal sequences. Biochemistry 1978;17:1669–1675.

increases severity of subsequent episodes in mice. Gastroenterology 2021;161(5):1692–4.

encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25:213–216.

chronic pancreatitis: decoding the role of the high- risk SPINK1N34S haplotype using meta- analysis. PLoS ONE 2008;3:e2003.