Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Hereditary Chronic Pancreatitis

  • Gaetano Paolino
  • Veronica Lever
  • Claudio LuchiniEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_5511-1
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Definition

Hereditary chronic pancreatitis (HCP) was firstly described about 70 years ago as a rare form of early-onset chronic relapsing pancreatitis, inherited in an autosomal dominant manner, with incomplete (80%) penetrance and with a variable expression of disease. The specific gene for HCP was identified in the mid-1990s as the protease serine 1 (PRSS1), mapped on chromosome 7q and encoding for cationic trypsinogen.

PRSS1 mutations account for the vast majority (up to 80%) of all cases of autosomal dominant HCP.

However, alterations in other genes have been found to increase susceptibility to classic chronic pancreatitis, with either familial or sporadic patterns. Thus, the more general term “familial pancreatitis” (as opposed to the strictly defined “hereditary pancreatitis”) is currently in use to describe recessive or complex phenotypes of “genetic” chronic pancreatitis, in the absence of a known syndrome (such as cystic fibrosis or CFTR gene-related disorders). Particularly, mutations in two genes encoding proteins involved in controlling intrapancreatic trypsin 1 activity are strongly associated with recurrent acute and chronic pancreatitis: SPINK1 (serine protease inhibitor Kazal type 1) and CTRC (chymotrypsin C).

Clinical Features

  • Incidence

    PRSS1-related hereditary pancreatitis represents about 2–3% of all patients with chronic pancreatitis. The prevalence of hereditary pancreatitis is approximately 0.3/100,000 individuals in Western countries and Japan and has not yet been reported in Africa or in people of African ancestry.

  • Age and Sex

    The typical presentation of HCP is with recurrent acute pancreatitis in patients younger than 20 years (often before the age of 5 years). CFTR gene mutations are the most common etiology of chronic pancreatitis in children.

  • Treatment

    The most important purpose of clinical management is represented by a symptomatic treatment (most common symptoms include pain, exocrine insufficiency, and mellitus diabetes) and aims at preventing further disease progression and/or disease related complications.

    Pain control can require both medical management (e.g., analgesics, narcotics, antidepressants) and more invasive/surgical measurements. Dietary recommendations are also useful to help control pain and improve digestion.

    Lastly, all patients with genetic risk factors are strongly encouraged in avoiding other known risk factors for both pancreatitis and pancreatic cancer, such as smoking and alcohol consumption. A program for the identification of HCP patients and for secondary screening for early cancer has been implemented by European Registry of Hereditary Pancreatitis and Pancreatic Cancer. This program is based on multimodality imaging and molecular analysis of pancreatic juice obtained at endoscopic retrograde cholangiopancreatography, combined with clinical genetic counselling and consultation with a pancreatologist.

  • Outcome

    Patients with HCP are predisposed to develop both exocrine and endocrine pancreatic insufficiency and pancreatic pseudotumors due to the chronic fibrosis. Patients with HCP have an estimated 50-fold increased relative risk of developing pancreatic ductal adenocarcinoma. This high risk of cancer is probably related to the repeated and progressive tissue destruction and inflammation over a long period of time (up to 40% of patients with PRSS1 mutations develop pancreatic cancer at 70 years of age).

Macroscopy

PRSS1-related hereditary pancreatitis causes a progressive atrophy and diffuse fatty replacement of the pancreas (so-called lipomatous atrophy). Pancreatic ductal dilation, fibrosis, and intraductal calculi represent a common finding (Fig. 1). Intraductal mucinous plugs with secondary obstruction and ductal dilatation and extensive fatty replacement can also occur in patients with cystic fibrosis or CFTR gene-related disorders, which in fact show pathologic similarities with HCP, possibly because of the role played by obstruction in both diseases.
Fig. 1

Surgical pancreatic specimen (body and tail). Parenchymal fibrosis and atrophy as well as partial cystic dilation of pancreatic ducts are evident

Anecdotal evidence suggests that pancreatitis associated with SPINK1 mutations shares analogies with alcoholic chronic pancreatitis.

Microscopy

The microscopic features of PRSS1-related hereditary pancreatitis begin in childhood with central parenchymal loss and mild chronic inflammation; a loosely packed perilobular/interlobular fibrosis with patchy fatty replacement (from the periphery to the central portions, Fig. 2) is also present. These aspects progressively worsen as the patient age increases. Notably, the ductal epithelium may undergo neoplastic changes that are consistent with pancreatic intraepithelial neoplasia (PanIN).
Fig. 2

Atrophy of pancreatic parenchyma with some residual neuroendocrine islets (original magnification 4×)

CFTR mutations usually lead to prominent intraductal mucinous plugs (Fig. 3), dilated ducts, periductal fibrosis, and prominent fatty replacement, with patchy aggregates of residual islets of Langerhans.
Fig. 3

Atrophy of pancreatic parenchyma and a pancreatic duct with calcified concretions (original magnification 2×)

SPINK1 mutations are associated with loss of pancreatic acinar parenchyma, ductal structures, and islet cell parenchyma, with a concomitant peri- and interlobular fibrosis. Intraluminal proteinaceous plugs and calculi can be also documented.

Molecular Features

The four most common PRSS1 mutations are R122H, N29I, and, less frequently, R122C and A16V. PRSS1 mutations increase autocatalytic conversion of inactive trypsinogen to active trypsin 1 (or diminish the hydrolysis of active trypsin 1 to degradation products) and are thus believed to cause pancreatic damage through autodigestion of pancreatic proteins causing injury, an inflammatory response, and recurrent acute pancreatitis, leading to chronic pancreatitis. Furthermore, some mutations may cause chronic stress and pancreatic inflammation through the activation of the unfolded protein response.

Mutations in CFTR (cystic fibrosis transmembrane conductance regulator) can either severely impair the function of the protein (leading to “typical” cystic fibrosis) or result in a less severe phenotype, known as “atypical” cystic fibrosis or cystic fibrosis-related disorders. Recurrent acute pancreatitis and classic chronic pancreatitis are classified as cystic fibrosis-related disorders based on clinical features, genotyping, and functional studies.

SPINK1 mutations (N34S is the most common high-risk haplotype) have been associated with both hereditary and idiopathic chronic pancreatitis. SPINK1 is considered a “disease-modifying gene,” whose mutations can either lower the threshold of initiating pancreatitis or worsen its severity due to other etiologies, including alcohol and tropical pancreatitis. Combined CFTR and SPINK1 mutations markedly increase the risk of recurrent acute and chronic pancreatitis.

The CTRC G60G high-risk haplotype increases the risk of classic chronic pancreatitis in adults, especially in smokers.

Differential Diagnosis

The diagnosis of HCP requires exclusion of other causes of chronic pancreatitis in childhood and young adults, such as anatomical anomalies, metabolic disorders, cystic fibrosis, trauma, and viruses.

Fatty replacement is the most common degenerative lesion of the pancreas and regarded as “normal” in the obese and elderly. However, it typically presents focally and is not as extensive as seen in patients PRSS1- and CFTR-mutations.

As for other forms of chronic pancreatitis, one key differential diagnosis is represented by pancreatic ductal adenocarcinoma.

References and Further Reading

  1. Campbell, F., & Verbeke, C. S. (2013). Hereditary exocrine disorders in pathology of the pancreas – A practical approach (pp. 60–63). London: Springer.Google Scholar
  2. Kleeff, J., Whitcomb, D. C., et al. (2017). Chronic pancreatitis. Nature Reviews. Disease Primers, 3, 17060.CrossRefPubMedCentralGoogle Scholar
  3. Stram, M., Liu, S., et al. (2016). Chronic pancreatitis. Surgical Pathology Clinics, 9, 643–659.CrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Gaetano Paolino
    • 1
  • Veronica Lever
    • 1
  • Claudio Luchini
    • 1
    Email author
  1. 1.Section of Pathology, Department of Diagnostics and Public HealthUniversity and Hospital Trust of VeronaVeronaItaly