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Pancreatitis
time. Clinicians evaluating patients with pancreatitis must be familiar with the be administered by a knowledgeable gastroenterologist or a certified
diagnostic and predictive aspects of genetic testing. genetic counselor. Genetic counseling may be likened to presenting the
‘risks, benefits, and alternatives’ of testing.
Blood testing is now commercially available to screen for all three known
pancreatitis-associated gene defects (PRSS1, CFTR, and SPINK1). A Potential ‘risks’ of genetic testing include:
temptation might exist to order a full genetic panel in every patient with
idiopathic pancreatitis to provide insight into etiological factors. • loss of privacy;
However, the decision to order genetic testing must be informed based • loss of (or difficulty obtaining) insurance and possibly employment;
on a thorough understanding of gene penetrance and genetic testing • emotional harm pertaining to the lifelong impact of the genetic defect
guidelines. Furthermore, the social, emotional, and practical implications (e.g. risk of pancreatic cancer in HP);
of genetic testing for patients and their families must be kept in mind. • difficult decisions to notify family members based on identification of
gene mutations. For example, the identification of a severe CFTR
The concept of gene penetrance is vital for making rational decisions mutation warrants discussion of screening asymptomatic relatives
regarding genetic testing. Penetrance is high for PRSS1 and low for CFTR because of the potential for classic cystic fibrosis in offspring; and
and SPINK1. PRSS1 mutations are quite rare in the population. However, • consequences to family members in whom the gene is identified.
when a PRSS1 mutation is present there is a high likelihood of developing
pancreatitis and pancreatic cancer. Conversely, CFTR and SPINK1 mutations Potential ‘benefits’ of genetic testing include:
are fairly common in the population (2–3% for SPINK1). However, when a
CFTR or SPINK1 mutation is present the chance of developing pancreatitis • improved insight into the reason for the development of pancreatitis;
remains low. The high penetrance observed for PRSS1 provides part of the • better understanding of prognosis (e.g. likelihood of recurrent episodes,
rationale for the guideline recommendation for screening. The identification development of chronic pancreatitis or pancreatic cancer);
of the PRSS1 gene has significant implications for patient management, • potential for future targeted disease-modifying treatments;
including pancreatic cancer surveillance, screening of family members, and • qualification for experimental treatment protocols;
entrance into research trials or disease registries. On the other hand, • qualification for experimental pancreatic cancer surveillance programs;
guidelines avoid strong recommendations on widespread screening for the • further incentive to eliminate risk factors for HP progression such as
low-penetrance CFTR and SPINK1 mutations at the present time, except in smoking and alcohol; and
research studies. Recommendations may change as targeted therapies • consideration of adoption as an alternative to potential transmission of
become available to counter the adverse disease-modifying effects of these gene defect to offspring.
genetic defects (e.g. drugs to promote bicarbonate secretin for CFTR-
mutation-positive patients). These points must be carefully explained to patients and their
understanding should be verified prior to obtaining DNA testing.
An international working group published guidelines for genetic testing in Concerns about disease penetrance and a lack of effective preventive and
HP in 2001.
9
Current guidelines recommend genetic testing should be treatment options must be explained. This involves meeting patients ‘at
limited to PRSS1. Diagnostic PRSS1 testing is recommended for patients their own level’ and patiently answering all questions. A consultation with
with a family history of acute recurrent pancreatitis, childhood pancreatitis, a certified genetic counselor is generally advisable, and is best carried out
idiopathic acute recurrent pancreatitis, or idiopathic chronic pancreatitis. before the testing is performed. Informed consent should be documented
after the patient has made his or her decision to obtain testing.
A more recent review elaborated on these guideline recommendations by
providing an algorithmic approach to genetic testing.
10
Consideration of CFTR Summary
screening is suggested for PRSS1-negative patients with unexplained chronic The rapid advance in knowledge of genetic factors underlying pancreatitis
pancreatitis in whom there remains a strong suspicion for a hereditary cause. has provided improved insight into the etiology and pathogenesis of this
SPINK1 screening is considered as a last step for patients who are CFTR- disease. Currently, testing for the PRSS1 gene is recommended for patients
negative. However, an alternative suggestion is made not to screen for SPINK1 with possible hereditary pancreatitis. Testing for SPINK1 and CFTR may be
or to screen in the context of research studies. This approach is reasonable if considered in the clinical care of select patients, but is generally reserved for
genetic counseling is administered at each step and the questionable research protocols. All genetic testing must be preceded by a genetic
significance of low-penetrance genes is explained carefully to patients. counseling and informed consent process. Further understanding of these
and other genes is needed to uncover the complex genetic interaction in the
Genetic testing differs from other laboratory testing because the results are development of pancreatic disease. An enhanced understanding of genetic
‘permanent’ within the life of the individual. As such, careful counseling is mechanisms may eventually result in targeted therapies designed to reverse
necessary to protect the autonomy of the patient. Genetic counseling can these processes. ■
1. Whitcomb DC, Gorry MC, Preston RA, et al., Nat Genet, 1998;339:645–52. 7. Pfutzer RH, Barmada MM, Brunskill AP, et al., Gastroenterology,
1996;14:141–5. 4. Monaghan KG, Jackson CE, Kuruga DL, Feldman G., Am J Med 2000;119:615–23.
2. Howes N, Lerch MM, Greenhalf W, et al., Clin Gastroenterol Genet, 2000;94:120–24. 8. Cohn JA, Mitchell RM, Jowell PS, Clin Lab Med, 2005;25:79–100.
Hepatol, 2004;2:252–61. 5. Cohn JA, Neotolemos JP, Feng J, et al., Hum Mutat, 2005;26:303–7. 9. Ellis I, Lerch MM, Whitcomb DC, Pancreatology, 2001;1:405–15.
3. Sharer N, Schwarz M, Malone G, et al., N Eng J Med, 6. Witt H, Luck W, Hennies HC, et al., Nat Genet, 2000;25:213–16. 10. Ellis I, Gastroenterol Clin N Am, 2004;33:839–54.
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