Hereditary pancreatitis, K86.1

Chronic hereditary pancreatitis is defined as:

rare, autosomal-dominantly inherited, gastroenterological disease, with onset usually in early childhood, characterized by recurrent acute pancreatitis and/or chronic pancreatitis in at least 2 first-degree relatives or 3 or more second-degree relatives in 2 or more generations, and for which no other predisposing factors have been identified.

The estimated prevalence of hereditary chronic pancreatitis is 1-9 / 1,000. 000 (about 1/800,000 in Germany, about 1/330,000 in France about 1/175,000 in Denmark).

The exact pathophysiological background, why e.g. the described point mutations in the cationic trypsinogen gene can result in pancreatitis, is still unclear today. Already in 1896 (Chiari H 1896) Hans Chiari suspected a "self-digestion" of the pancreas as the cause of pancreatitis.

The most frequent mutations (in the cationic trypsinogen gene ) lead to base exchange in the trypsinogen gene with the consequence of an altered expression of trypsinogen. Trypsin plays a key role in the activation of pancreatic digestive enzymes and can activate itself as well as all other pancreatic proteolytic proenzymes (Lerch MM et al.2000).

Several mechanisms protect the pancreas from activation of the pancreatic enzyme cascade and self-digestion (Rinderknecht H et al. 1968). These include synthesis of digestive enzymes as inactive proenzymes (zymogens), localization of the activating enzyme enteropeptidase outside the pancreas in the small intestine, and a low intrapancreatic calcium concentration. Even in normal pancreatic tissue, small amounts of trypsinogen are converted to active trypsin by autolysis. This trypsin activity is antagonized by two mechanisms. First, trypsin is inactivated by binding to the serine protease inhibitor Kazal type 1 (SPINK1). Second, active trypsin can be degraded by itself and by mesotrypsin (Rinderknecht H et al 1986).

The serine protease inhibitor Kazal type 1, also known as pancreatic secretoryTrypsin inhibitor (PSTI), is a specific intrapancreatic trypsin inhibitor, but it exhibits the phenomenon of "temporary inhibition" because it itself serves as a substrate for trypsin (19).

In 2000, the N34S mutation in the SPINK1 gene on chromosome 5 was identified in patients in whom mutations in the PRSS1 gene had previously been excluded (Witt H et al.2000). The N34S mutation involves a base exchange from A to G in exon 3, resulting in an amino acid exchange from asparagine (N) to serine (S) at position 34. The proximity of the mutation to the reactive center in the molecule suggests a decreased inhibitory capacity (Witt H et al.(2001). The N34S mutation is found primarily in patients with no family history of pancreatitis and no risk factors for chronic pancreatitis (Witt H et al.2000). At the present time, SPINK mutations appear to play a minor role in the spectrum of hereditary pancreatitis (Brockmann, A. 2007).

Known are various. Mutations that predispose to chronic pancreatitis are known. These include:

• PRSS1: mutations in the PRSS1 (7q34) gene, which codes for cationic trypsinogen type 1 (75% of cases have this mutation)
• PRSS2: Mutations in the PRSS2 gene (7q34), which encodes cationic trypsinogen type 2
• SPINK1: mutations in the serine protease inhibitor, Kazal type 1 gene (5q32)
• Other genes are associated in lower frequency with chronic pancreatitis (idiopathic and hereditary). These include:
• CFTR: the cystic fibrosis transmembrane conductance regulator (CFTR; 7q31.2).
• CTRC: chymotrypsinogen C (CTRC; 1p36.21) (Cohn JA et al. 1998; Sharer N et al.1998).

Other rare mutations are associated with HCP and idiopathic chronic pancreatitis with early onset. This involves the genes:

• CPA1: carboxypeptidase A1 (CPA1; 7q32.2)
• CEL: carboxylester lipase (CEL; 9q34.13) and
• PNLIP: Pancreatic lipase (PNLIP; 10q25.3)

Special case: Complex multigenic pancreatitis: In this form of hereditary pancreatitis, typically only a few family members are affected. A variable number of germline mutations in genes that play a role in trypsin regulation are present in affected patients. In addition to heterozygous variants in PRSS1, CFTR and SPINK1, alterations in other genes such as CASR, CTRC, CLDN2 and CPA1 play a role.

The diagnosis of HCP is based on the clinical features together with the family history of chronic pancreatitis, the absence of precipitating factors and the exclusion of known causes of chronic pancreatitis, as well as on imaging techniques. It is to be supported by the detection of mutations of the genes mentioned.

Imaging (abdominal ultrasound, endoscopic ultrasound, extraordinary endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP)) shows morphological changes such as pancreatic calcifications, pancreatic duct changes, pseudocysts and bile duct and duodenal obstruction (signs of chronic pancreatitis).

Differential diagnoses include other forms of chronic pancreatitis, especially alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, and autoimmune pancreatitis.

The mainstays of medical management are pain control, nutritional support, treatment of diabetes mellitus, and pancreatic enzyme supplementation for exocrine insufficiency. Surgery may be indicated to treat acute and chronic complications of HCP and includes debridement, drainage, decompression, and very rarely pancreatectomy. Additional risk factors for chronic pancreatitis (smoking, alcohol) should be avoided.

The prognosis of patients with HCP is unpredictable; it is worsened by an increased risk of developing pancreatic cancer.

Syndrome-linked pancreatitis " occurs in association with the following clinical syndromes:

• Pearson marrow pancreas syndrome
• CEL Maturity-Onset Diabetes of the Young (CEL-MODY)
• Johanson-Blizzard syndrome
• Cystic fibrosis (CF)
• Shwachmann-Diamond syndrome
• Wilson's disease
• Familial Adenomatous Polyposis.

1. Brockmann, A. (2007) Clinical characterization and evaluation of endoscopic diagnostics and therapy in patients with hereditary pancreatitis. Inaugural dissertation from the Medical Clinic A of the University Hospital of the Ernst Moritz Arndt University Greifswald.
2. Chiari H (1896): On self-digestion of the human pancreas. Journal of medical science 17: 69 - 96
3. Cohn JA et al (1998) Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. New England Journal of Medicine 339: 653 - 658
4. Lerch MM, Gorelick FS: Early trypsinogen activation in acute pancreatitis. Gastroenterology Clinical North America 84: 549-563
5. McGaughran JM et al.(2004) Hereditary pancreatitis in a family of Aboriginal descent Journal Pediatric Child Health 40: 487-489.
6. Raphael KL et al (2016) Hereditary pancreatitis: current perspectives. Clin Exp Gastroenterol 9:197-207.
7. Rinderknecht H (1986). Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Digestive Disease Science 31: 314-321.
8. Sharer N et al.(1998) Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. New England Journal of Medicine 339:645-52.
9. Witt H et al.(2000) Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nature genetics 25: 213-216.
10. Witt H et al.(2001) Genetic aspects of chronic pancreatitis. Deutsche Medizinische Wochenschrift 126: 988-993)