Motion – Genetic testing is useful in the diagnosis of nonhereditary pancreatic conditions: Arguments against the motion

This article was originally presented at a symposium entitled, “Controversies in Gastroenterology”, sponsored by Axcam Pharma, Toronto, Ontario, April 8 to 10, 2002 Division of Gastroenterology, Duke University Medical Center, Durham North Carolina 27710-001, USA Correspondence: Dr JA Cohn, Division of Gastroenterology, Duke University Medical Center, 314 Sands Building, Box 3378, Durham, North Carolina 27710-001, USA. Telephone 919-684-6879, fax 919-684-4983, e-mail cohn0001@mc.duke.edu JA Cohn. Motion – Genetic testing is useful in the diagnosis of nonhereditary pancreatic conditions: Arguments against the motion. Can J Gastroenterol 2003;17(1):53-55.

Idiopathic chronic pancreatitis (ICP) is the leading cause of chronic pancreatitis in children and nonalcoholic adults.Because most cases are sporadic, genetic factors were not ini-tially implicated in its pathogenesis.Nonetheless, three facts suggest that CFTR mutations might predispose to ICP: the earliest pathological finding in ICP often consists of plugging of the smaller pancreatic ducts which is reminiscent of the early findings in cystic fibrosis.ICP can cause sweat test abnormalities and pancreatitis is a rare complication of cystic fibrosis (with a lifetime incidence of 1%) (2).These considerations led two groups to test ICP patients for CFTR mutations (1,2,12).A total of 86 subjects with ICP were studied, and 20% had common cystic fibrosis-causing CFTR mutations.This is approximately five times the expected prevalence of cystic fibrosis carriers.
On average, cystic fibrosis carrier status increases the risk of ICP by five-fold.This is important, because 3% to 4% of white people in the United States are carriers (2,13).Because fewer than 1% of these carriers develop ICP, a key question is whether all carriers are at similar risk for ICP.To address this question, Noone et al (12) recently tested a series of ICP patients with common CFTR mutations to determine whether the other copy of the gene was also abnormal.In most cases, the authors found an atypical or uncommon mutation involving the other copy of the gene.The subjects with ICP each had one CFTR mutation with virtually no function (eg, causing over 98% loss of function) together with a milder mutation of the other copy of their gene (eg, causing an 80% loss of function).These compound heterozygous genotypes are associated with a 90% reduction of CFTR function, which explains why these individuals do not develop cystic fibrosis lung disease.The amount of residual CFTR function -roughly 10% of normal -is sufficient to protect these patients from lung injury.ICP risk is increased about 50-fold in individuals with these compound heterozygous genotypes.
The large increase in ICP risk strongly implicates defective CFTR function in the pathogenesis of ICP.At least 95% of CFTR compound heterozygotes, however, do not develop ICP.Thus, unlike cystic fibrosis lung disease, ICP exhibits non Mendelian (or complex) inheritance (Table 1).Virtually all individuals with two cystic fibrosis-causing mutations develop cystic fibrosis (13).In contrast, CFTR compound heterozygosity increases the risk of ICP, but does not always cause the disease.One implication of this finding is that environmental influences and gene-gene interactions might be important in determining which individuals are susceptible to develop ICP.
One mutation of the PSTI gene (N34S) has also been associated with many forms of pancreatitis (8,14).The N34S PSTI mutation occurs in roughly 1% of the general population, and it increases the risk of pancreatitis by 20-fold (12,14).Because pancreatitis does not develop in 99% of individuals who harbour N34S, the inheritance pattern is also non Mendelian.
Additional studies have shown that the N34S PSTI mutation is not associated with autosomal dominant hereditary pancreatitis (15).On the other hand, one recent report indicates that N34S is associated with ICP in individuals who have CFTR mutations.For CFTR compound heterozygotes who also have N34S, the risk of ICP was increased by 900-fold (12).The additive impact of CFTR and PSTI mutations on pancreatitis risk is consistent with the fact that these genes are expressed at different sites in the exocrine pancreas: CFTR occurs mainly in the apical membrane of duct cells (16,17), while PSTI occurs maily in the zymogen granules of acinar cells (4).These data imply that PSTI genetic testing might help to identify CFTR compound heterozygotes who are at especially high risk for ICP.Even when PSTI and CFTR mutations are both present in a single individual, however, the risk of developing ICP is still less than 50%.
From a practical standpoint, CFTR and PSTI genetic testing may be useful in selected individuals with unexplained pancreatitis.It can help patients to understand their disease, and it can allow earlier recognition of extra-pancreatic CFTRrelated problems that may be associated with ICP (eg, male infertility).In addition, it can identify cystic fibrosis carriers who may benefit from genetic counselling, and it can identify rare patients with cystic fibrosis in whom pancreatitis is the initial clinical problem.In most patients with CFTR mutations, the amount of residual CFTR protein function can be predicted from the genotype and this correlates with the clinical diagnosis (Table 2).
However, there are important limitations to CFTR and PSTI genetic testing for the diagnosis of pancreatitis.First, most patients with CFTR-related ICP have uncommon or atypical mutations that cannot be detected using genetic testing methods that are currently available for clinical use.This means that caution is required when a clinical testing lab   Genetic testing is thus unable to definitively predict who will develop ICP, even though it can identify persons who are at increased risk.Finally, the results of CFTR and PSTI testing do not affect clinical management of pancreatitis at this time.For these reasons, it seems premature to recommend CFTR and PSTI genetic testing as routine procedures during the diagnostic evaluation of nonhereditary pancreatitis.

TABLE 2 Cystic fibrosis transmembrane conductance regulator gene (CFTR) genotypes correlate with clinical diagnoses
PS Pancreatic sufficiencyreports a nondiagnostic mutational analysis.Second, genetic counselling guidelines do not exist for individuals who have either normal or abnormal results.Third, most patients with mutations of the CFTR and/or PSTI genes do not develop ICP.
CBAVD Congenital bilateral absence of the vas deferens; CF Cystic fibrosis; ICP Idiopathic chronic pancreatitis; PI Pancreatic insufficiency;