The past decade marks great progress toward understanding. Gene Mutations and Idiopathic Chronic Pancreatitis: Clinical Implications and Testing

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1 1508 EDITORIALS GASTROENTEROLOGY Vol. 121, No Fennerty MB, Triadafilopoulos G. Barrett s-related esophageal adenocarcinoma: is chemoprevention a potential option? Am J Gastroenterol 2001;96: Iascone C, DeMeester TR, Little AG, Skinner DB. Barrett s esophagus. Functional assessment, proposed pathogenesis, and surgical therapy. Arch Surg 1983;118: Vaezi MF, Richter JE. The role of acid and duodenogastric reflux in gastroesophageal reflux disease. Gastroenterology 1996;111: Fitzgerald RC, Omary MB, Triadafilopoulos G. Dynamic effects of acid on Barrett s esophagus. An ex vivo proliferation and differentiation model. J Clin Invest 1996;98: Kaur BJ, Ouatu-Lascar R, Omary MB, Triadafilopoulos G. Bile salts induce or blunt cell proliferation in Barrett s esophagus in an acid-dependent fashion. Am J Physiol 2000;278:G Shirvani VN, Ouatu-Lascar R, Kaur BS, Omary MB, Triadafilopoulos G. Cyclooxygenase 2 expression in Barrett s esophagus and adenocarcinoma: ex vivo induction by bile salts and acid exposure. Gastroenterology 2000;118: Plummer SM, Hall M, Faux SP. Oxidation and genotoxicity of fecapentaene-12 are potentiated by prostaglandin H synthase. Carcinogenesis 1995;16: Boolbol SK, Danneberg AJ, Chadburn A, Martucci A, Jones E. Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res 1996;56: Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett s esophagus and the effects of acid suppression. Gastroenterology 1999;117: Ortiz A, Martinez LF, Parrilla P, Morales G, Molina J, Bermejo J, Lirm R, Aguilar J. Conservative treatment versus antireflux surgery in Barrett s oesophagus: long-term results of a prospective study. Br J Surg 1996;83: McDonald ML, Trastek VF, Allen MS, Deschamps C, Pairolero PC. Barrett s esophagus: does an antireflux procedure reduce the need for endoscopic surveillance? J Thorac Cardiovasc Surg 1996;111: Katz D, Rothstein R, Schned A, Dunn J, Seaver K, Antonioli D. The development of dysplasia and adenocarcinoma during endoscopic surveillance of Barrett s esophagus. Am J Gastroenterol 1998;93: Williamson WA, Ellis FH Jr, Gibb SP, Shabian DM, Aretz HT. Effect of antireflux operation on Barrett s mucosa. Ann Thorac Surg 1990;49: Spechler SJ, Lee E, Ahnen D, Goyal RK, et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease. Follow-up of a randomized controlled trial. JAMA 2001; 285: Ye W, Chou WH, Lagergren J, Yin L, Nyren O. Risk of adenocarcinomas of the esophagus and gastric cardia in patients with gastroesophageal reflux diseases and after antireflux surgery. Gastroenterology 2001;121: Lundell L, Miettinen P, Myrvold HE, et al. Continued (5-year) follow-up of a randomized clinical study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll Surg 2001;192: Perdikis G, Hinder RA, Lund RJ, Klinger PJ. Laparoscopic Nissen fundoplication. Where do we stand. Surg Laparosc Endosc 1997; 7: Address requests for reprints to: Joel E. Richter, M.D., Department of Gastroenterology, Center for Swallowing and Esophageal Disorders, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio by the American Gastroenterological Association /01/$35.00 doi: /gast Gene Mutations and Idiopathic Chronic Pancreatitis: Clinical Implications and Testing See article on page The past decade marks great progress toward understanding chronic pancreatitis. Several groups have led this advance. For example, one group has led the investigation of exploring the genetic causes of hereditary pancreatitis. 1 A second group is exploring the genetic associations with idiopathic chronic pancreatitis, which is published in this issue of GASTROENTEROLOGY. 2 This editorial focuses on idiopathic chronic pancreatitis. During the last 60 years, research in chronic pancreatitis has moved from attempting to understand the clinical manifestations of the different forms of the disorder to understanding the genetic basis of the disease. Remember that 100 years ago, alcohol was thought to be the only cause of chronic pancreatitis, which was called drunkard s pancreatitis. 3 Gradually, other forms of chronic pancreatitis were recognized. Perhaps the single most important work that provided the modern impetus toward understanding of chronic pancreatitis was the 1946 publication in GASTROENTEROLOGY by Comfort et al. 4 These authors, perhaps for the first time, outlined the natural history of chronic pancreatitis and implied there were different causes of chronic pancreatitis. For example, 1 of 29 patients had an inherited form of pancreatitis. This patient was the basis of the first definitive report of hereditary pancreatitis by Comfort and Steinberg in Ammann, 6,7 and more recently we 8 recognized late onset (termed senile by Ammann) and early onset (termed juvenile by Ammann) forms of idiopathic chronic pancreatitis. It is important to point out that in our studies, we included only persons who never drank as having either form of idiopathic chronic pancreatitis. Late onset or senile idiopathic chronic pancreatitis

2 December 2001 EDITORIALS 1509 occurs late in life. It may be painless and only recognized because of malabsorption and pancreatic calcification. 8 Importantly, cigarette smoking shortens the time to development of calcification 9 in persons with late onset chronic pancreatitis. Early onset idiopathic chronic pancreatitis occurs before age 35 and is clearly separate from hereditary pancreatitis. This form is characterized by pain and late development of calcification, diabetes, and malabsorption (median time 25 years after onset of pain). We have postulated that these different forms of chronic pancreatitis are a result of different underlying genetic predispositions and that the clinical course of late onset chronic pancreatitis may be accelerated by ingesting small amounts of alcohol. 10 It is important to point out that careful description of diseases, which is becoming a lost art, is still important in this age of molecular biology. These clinical descriptions formed the basis of segregating patients into clearly defined phenotypic expressions of chronic pancreatitis, which was necessary to begin unraveling some of the genetic secrets underpinning this disease. For example, Noone s group 2 took advantage of the different natural history of early and late chronic idiopathic pancreatitis and mostly selected patients with early onset idiopathic chronic pancreatitis for study. However, this study did not examine a uniform group of patients; they included persons who drank up to 15 alcoholic drinks per week and persons with onset of disease up to age 50. Although it is likely that most of the patients had early onset idiopathic chronic pancreatitis because the mean age was approximately 20, this possible mixture of different forms of chronic pancreatitis might have confounded the results of their study. For example, if early onset and late onset idiopathic chronic pancreatitis have different genetic causes, there would be a falsely low frequency of genetic mutations for the early onset group if patients with both types of idiopathic chronic pancreatitis were included in the analysis. (In Noone s study, if the genetic findings apply only to early onset disease, the frequency of the genetic mutations would have been higher if only these patients would have been included in the study.) In addition, including persons who drank even small amounts of alcohol may have obscured the interrelationship between the genetic mutations and alcohol consumption and the phenotypic expression of disease. Thus, there is still much to do. Future studies should discriminate more carefully among the forms of chronic pancreatitis if we are to understand the underlying genetic mutations and their relationship to the environmental factors (e.g., smoking, alcohol, and diet) that likely modify the expression (onset and rate of progression) of chronic pancreatitis. Nonetheless, the work of Noone and others 2,11 16 has resulted in very important discoveries that shed light on some genetic causes of chronic pancreatitis and may revolutionize treatment. The present paper by Noone et al. 2 is a natural extension of the group s original work on the association of CFTR mutations with idiopathic pancreatitis, 11 a discovery simultaneously reported by Braganza s group. 12 From these and other studies, it was estimated that approximately 18% of patients with idiopathic chronic pancreatitis had common CFTR mutations. However, because Noone s group suspected this was an underestimate, they attempted to better define the association of CFTR mutation with idiopathic pancreatitis by examining 39 patients with presumed idiopathic chronic pancreatitis, 26 from their previous study. 4 Twenty of these patients were subjected to comprehensive DNA sequencing of the CFTR gene to search for rare CFTR mutations. In addition, because mutations of the pancreatic secretory trypsin inhibitor gene (PSTI or SPINK1) have been associated with idiopathic chronic pancreatitis, it was postulated that CFTR and PSTI genes might independently increase the risk for chronic pancreatitis, particularly because the site of expression of the genes differs, ductular and acinar, respectively. Noone s group also performed nasal potential difference studies, as well as sweat and spirometry tests and sputum culture. Seventeen of the 36 patients (47%) had at least 1 CFTR mutation, similar to a preliminary report of another group that has performed gene sequencing of the CFTR gene. 21 However, the proportion of CFTR mutations is likely an underestimate because only 20 of the patients underwent full gene sequencing of the CFTR gene, and because the patients were a mixture of different forms of chronic pancreatitis. The striking findings were that chronic pancreatitis was associated with compound heterozygotes consisting of a severe CFTR mutation on one allele (a mutation that causes cystic fibrosis when present on both alleles) and a mild-variable mutation on the other allele (a mutation that causes variable phenotypes such as congenital absence of vas deferens when existing as a compound heterozygote with a severe mutation on the other allele). After excluding compound heterozygotes, pancreatitis was not associated with severe or mild-variable CFTR mutations. A total of 9 compound heterozygotes were found; 8 were of the severe/

3 1510 EDITORIALS GASTROENTEROLOGY Vol. 121, No. 6 mild-variable kind (22% of the 36 patients). Only 1 compound heterozygote was detectable by routine genetic testing; 8 of 9 required gene sequencing for detection. Nine patients (25%) had the N34S PSTI mutation (1 homozygous, 8 heterozygous), and 2 of them also were compound heterozygotes for CFTR mutations (suggests a 900-fold increase in pancreatitis risk in N34S carriers who are also CFTR compound heterozygotes). Thus, by sequencing the CFTR gene and performing an analysis for N34S mutation in a group of patients with idiopathic chronic pancreatitis, 50% would be expected to have a mutation associated with chronic pancreatitis. However, it is important to point out that the compound heterozygotes and N34S mutations associated with chronic pancreatitis are common in the general population, approximately 1 of 500 and 1 of 400 persons, respectively. Thus, about 1 2 million persons have each of these genetic abnormalities in the United States of America, but only 1 of 100 persons with one of these genetic abnormalities has chronic pancreatitis. This figure was calculated by making the assumptions that early onset idiopathic chronic pancreatitis comprises 6% of the prevalence of all forms of chronic pancreatitis 8 of 250,000 persons, that only 25% of idiopathic chronic pancreatits has one of the genetic abnormalities, and a total population of 300 million. These calculations have important clinical implications. Assuming the data in Noone s paper applies only to early onset disease, the sensitivity for detecting early onset chronic pancreatitis in this highly selected group of patients, if both abnormalities are considered together, is 50%. However, the positive predictive value is extremely low because of the prevalence of the abnormalities in the general population in persons who do not have chronic pancreatitis. Therefore, determining genetic makeup in the general population to determine persons at risk for chronic pancreatitis is not advisable because most persons with the CFTR or PSTI genetic abnormalities do not have, nor will they ever develop, chronic pancreatitis. Why most persons with these genetic abnormalities do not develop chronic pancreatitis is intriguing. The answer to this question may be the key to treatment and prevention. Certainly, there are other factors important in the expression of the disease that need to be discovered. With the meager data currently available, it is becoming increasingly clear that not only alcohol, but also cigarette smoking are important modulators of the expression of chronic pancreatitis. This suggests that elimination of smoking and alcohol, particularly in individuals who are especially susceptible to pancreatitis, would reduce the incidence and rate of progression of chronic pancreatitis. Although the sensitivity of the genetic tests described by Noone s group would probably detect fewer mutations in a less selected group of patients with idiopathic chronic pancreatitis, testing for genetic abnormalities in patients with suspected or proven chronic pancreatitis has some appeal. For example, one great advantage of genetic testing is that the results could bolster the diagnosis of chronic pancreatitis, particularly in patients who are having recurrent attacks of pain but no findings of chronic pancreatitis and might halt indiscriminate use of unproven treatments. Previously, 22 I lamented the wide use by some gastroenterologists and endoscopists of endoscopic procedures to treat pain in chronic pancreatitis. Perhaps, the emerging data on the genetics of chronic pancreatitis will focus more attention on intrinsic defects in acinar and ductular function as targets for preventing or treating chronic pancreatitis. In addition, finding a genetic mutation in a patient with chronic pancreatitis would lend support to a patient s declaration that alcohol is not the cause of his or her pancreatitis. These findings have potential treatment implications. CFTR maintains bicarbonate secretion and thus ductal volume flow and balance of lipids in membrane lipids in CFTR regulated cells. 23 Mutations of CFTR can lead to decreased bicarbonate secretion, protein plugging of pancreatic ducts, and acinar cell membrane instability. 23,24 Therefore, treatment to increase pancreatic bicarbonate secretion might prevent the occurrence of chronic pancreatitis if this were done before the onset of disease. Alternatively, if this treatment could be initiated and maintained after the onset of pain, it might reduce pain severity or disease progression to delay the development of diabetes, calcification, and malabsorption. Delayed progression might be possible because these complications tend to occur later in these patients than in alcoholic pancreatitis. 8 Patients who have CFTR and PSTI mutations are at much higher risk for developing chronic pancreatitis. In this situation, deficient bicarbonate secretion and activation of trypsin within the acinar cell may be responsible for the inception and progression of pancreatitis, and these patients might benefit from some combination of increasing bicarbonate secretion and intra-acinar trypsin inhibition. Even though treatments to achieve these effects have not been reported in patients with chronic pancreatitis, this would be a logical direction for future work. These tantalizing possibilities for prevention and treatment of chronic pancreatitis associated with specific

4 December 2001 EDITORIALS 1511 genetic abnormalities raise the question of whether genetic testing should be routinely performed for the clinical evaluation of patients who are suspected of having idiopathic chronic pancreatitis. This question can now be addressed because testing (gene sequencing of the CFTR gene) is practical and the benefits, discussed above, may outweigh the risks of denial of insurance and personal and family concerns of carrying a genetic muation. Relatively cheap ( $500) testing is already available to analyze the entire CFTR gene. 24 The D-HPLC technique detects 97% of the mutations, and likely before this editorial is published, other cost-effective technologies will be available to rapidly sequence the entire gene. Although, at present there is no proven treatment of the disease, as one who sees patients with suspected and proven idiopathic chronic pancreatitis and pancreatic pain, I come down on the side of adding genetic testing as a clinical test. However, full consent by the patient after genetic counseling to obtain a full understanding of the risks should precede genetic testing. Any such genetic testing should also include testing for the hereditary pancreatitis genetic abnormalities because sporadic cases of hereditary pancreatitis occur that might not be suspected because a family history is lacking. This was the situation of 3 patients investigated by Noone et al. 2 and these patients were excluded from their study. However, because the risk of chronic pancreatitis in persons who have the mutations is low, there is no need to screen the general population for the mutations. This is just the beginning of the genetic epoch of chronic pancreatitis. The results reported by Noone et al. 2 likely apply to approximately 6% of the total group of patients with chronic pancreatitis who are now classed as having idiopathic chronic pancreatitis. Hopefully, similar studies will unravel the genetic basis of the more prevalent forms of chronic pancreatitis, such as those associated with alcohol and late onset idiopathic chronic pancreatitis. EUGENE P. DiMAGNO Mayo Clinic and Mayo Foundation Rochester, Minnesota References 1. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich D. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14: Noone PG, Zhou Z, Silverman LM, Jowell PS, Knowles MR, Cohn JA. Cystic fibrosis gene mutations and pancreatic risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. Gastroenterology 2001;121: Friedrich N. Diseases of the pancreas. In: Cyclopedia of the practice of medicine. Volume 8. New York, NY: Wood, 1878: Comfort MW, Gambill EE, Bagenstoss AH. Chronic relapsing pancreatitis. Gastroenterology 1946;6: , Comfort MD, Steinberg AG. Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 1952;21: Ammann R, Sulser H. [ Senile chronic pancreatitis; a new nosologic entity? Studies in 38 cases. Indications of a vascular origin and relationship to the primarily painless chronic pancreatitis]. Schweiz Med Wochenschr 1976;106: Ammann R. [Idiopathic juvenile chronic pancreatitis (author s transl)]. [German] Dtsch Med Wochenschr 1976;101: Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses of early and late onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994;107: Imoto M, DiMagno EP. Cigarette smoking increases the risk of pancreatic calcification in late-onset but not early-onset idiopathic chronic pancreatitis. Pancreas 2000;21: Lankisch MR, Imoto M, Layer P, DiMagno EP. The effect of small amounts of alcohol on the clinical course of chronic pancreatitis. Mayo Clin Proc 2001;76: Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N Engl J Med 1998;339: Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med 1998;339: Castellani C, Bonizzato A, Rolfini R, Frulloni L, Cavallini GC, Mastella G. Increased prevalence of mutations of the cystic fibrosis gene in idiopathic chronic and recurrent pancreatitis (letter). Am J Gastroenterol 1999;94: Arduino C, Gallo M, Brusco A, Garnerone S, Piana MR, DiMaggio S, Promis GG, Ferrone M, Angeli A, Gaia E. Polyvariant mutant CFTR genes in patients with chronic pancreatitis. Clin Genet 1999;56: Choudari CP, Lehman GA, Sherman S. Pancreatitis and cystic fibrosis gene mutations. Gastroenterol Clin North Am 1999;28: Ockenga J, Stuhrmann M, Ballmann M, Teich N, Keim V, Dork T, Manns MP. Mutations of the cystic fibrosis gene, but not cationic trypsinogen gene, are associated with recurrent or chronic idiopathic pancreatitis. Am J Gastroenterol 2000;95: Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M. Mutations in the gene encoding the serine protease inhibitor, Kazal type I are associated with chronic pancreatitis. Nat Genet 2000;25: Pfutzer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, Furey WF, Whitcomb DC. SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000;119: Naruse S, Kitagawa M, Ishiguro H. Molecular understanding of chronic pancreatitis: a perspective on the future. Mol Med Today 1999;5: Ockenga J, Dork T, Stuhrmann M. Low prevalence of SPINK1 gene mutations in adult patients with chronic idiopathic pancreatitis (letter). J Med Genet 2001;38: Bishop MD, Freedman SD, Zielenski J, Tzountzouris J, Tsui L-C, Durie PR. Does complete DNA analysis identify a higher percentage of cystic fibrosis gene mutations in patients with idiopathic chronic and recurrent acute pancreatitis? Gastroenterology 1999;116:A Di Magno EP. Toward understanding (and management) of painful chronic pancreatitis. Gastroenterology 1999;116: Freedman SD, Blanco P, Shea JC, Alvaez JG. Mechanisms to

5 1512 EDITORIALS GASTROENTEROLOGY Vol. 121, No. 6 explain pancreatic dysfunction in cystic fibrosis. Med Clin North Am 2000;84: Le Marechal C, Audrezet MP, Quere I, Raguenes O, Langonne S, Ferec C. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counseling. Hum Genet 2001;108: Address requests for reprints to: Eugene P. DiMagno, M.D., Professor of Medicine, Mayo Clinic and Mayo Foundation, 200 First Street S.W., Rochester, Minnesota dimagno.eugene@mayo.edu; fax: (507) by the American Gastroenterological Association /01/$35.00 doi: /gast Irritable Bowel Syndrome: How Far Do You Go in the Workup? See article on page The diagnostic evaluation of patients with irritable bowel syndrome (IBS) can be challenging for several reasons. First, there is no biological marker for the disorder. The diagnosis is based primarily on the presence of a clustered set of symptoms relating to abdominal pain or discomfort and altered bowel habit. Second, it follows that a diagnosis based solely on symptoms can be unsettling; clinicians will struggle with the possibility of missing another diagnosis. This level of uncertainty may increase the risk of overdoing diagnostic studies, though many clinicians believe an extensive diagnostic effort justified: it seeks to satisfy the patient s request to find a specific diagnosis, as well as the physician s personal interest to leave no stone unturned. Unfortunately, this approach contributes to the disproportionately high health care costs for IBS relative to other gastrointestinal disorders as reported in one Health Maintenance Organization study. 1 Finally, developing a diagnostic algorithm for IBS can be challenging given the effect of psychosocial co-factors including psychiatric diagnosis, daily and life stress, and other psychosocial domains on IBS. 2 Currently, the diagnostic evaluation of patients presenting with IBS symptoms has no simple standard; it is based on the art and science of medicine. Several factors can influence the decision making: (1) symptom pattern and severity will influence, for example, whether mucosal biopsies are taken for diarrhea-predominant symptoms, or ultrasound or computerized tomography are done for pain and weight loss, 3 (2) demographic features such as older age on initial presentation or a family history of inflammatory bowel disease or colon cancer may lead to a more extensive (e.g., colonoscopic) evaluation, (3) a patient s pain communication style or illness-related behaviors must be appraised in the light of objective screening data; this, for example, will reduce the tendency merely to order tests based on urgent requests to do something ( furor medicus ), 4 and finally (4), the clinical setting will influence the prior probability of other medical disorders; so primary care physicians more than gastroenterologists will minimize diagnostic studies, treat the symptoms of IBS, and follow the patient expectantly, 5 simply because the likelihood of another serious medical disease in a primary care setting is far less than in a referral practice. Efforts to consolidate these many influences on diagnostic decision making have occurred by creating specific published guidelines obtained by consensus. 3,6,7 Most authors agree that an initial diagnosis of IBS should be fulfilled by: (a) meeting symptom-based diagnostic criteria, such as Rome II, 6,8 Rome I, 9,10 or occasionally, Manning 11 criteria, (b) obtaining a negative physical examination, and (c) performing a cost-effective, conservative set of screening studies. These usually include a sigmoidoscopy (or colonoscopy for patients older than 50 years), a few laboratory tests (e.g., complete blood count, stool for occult blood or ova and parasites), and additional studies if certain alarm features are found: fever, an abnormal physical examination, blood in the stool, an abnormal complete blood count or elevated sedimentation rate, significant weight loss, nocturnal symptoms that awaken the patient, or a family history of cancer or inflammatory bowel disease. 12,13 Several prospective studies now offer evidence that the proper application of such recommendations rarely leads to a revision in diagnosis, even for patients observed over many years. 6,14,15 In one study, the positive predictive value for the diagnosis of IBS using Rome I criteria and excluding red flags over 1-year follow-up was 98%. 12 Of course, the gastroenterologist in referral practice may not be content to accept these probabilities without first excluding those rare conditions overlooked by routine evaluations. So how far should the gastroenterologist go in the workup of patients referred to them who typically present with IBS, and have negative screening studies? One gastroenterologist recently commented to