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Hereditary pancreatitis in children: surgical implications with special regard to genetic background
Journal of Pediatric Surgery (2009) 44, 2078–2082
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Hereditary pancreatitis in children: surgical implications with special regard to genetic background Françoise Schmitt a , Gaelle Le Henaff b , Hugues Piloquet b , Marc D. Leclair a , Albert David c , Yves Heloury a , Guillaume Podevin a,⁎ a
Chirurgie infantile, HME, CHU de Nantes, France Clinique Médicale Pédiatrique, HME, CHU de Nantes, France c Génétique Médicale, Pôle biologie, CHU de Nantes, France b
Received 10 March 2009; revised 5 May 2009; accepted 15 May 2009
Key words: Hereditary pancreatitis; Chronic pancreatitis; Children
Abstract Purpose: Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature. Methods: All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes). Results: Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss. Conclusions: Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications. © 2009 Elsevier Inc. All rights reserved.
Chronic pancreatitis (CP) is a rare clinical entity in children, with unknown incidence and prevalence [1]. Whereas the most common etiology in adults is chronic alcohol consumption [2], CP during childhood is idiopathic or appears in a familial context. In the last decade, genetic factors have been implied in cases of familial CP, among them are mutations in PRSS1 (gene-encoding cationic ⁎ Corresponding author. E-mail address: [email protected] (G. Podevin). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2009.05.023
trypsinogen), SPINK1 (Serine Protease Inhibitor Kazal type 1), or CFTR gene (cystic fibrosis) [1]. Great progress has been made concerning the etiology of so-called hereditary pancreatitis (HP), but consensus has still to be reached concerning the familial screening of HP for a child presenting with an attack of pancreatitis with no other etiology, the best way to treat patients medically or surgically to prevent pancreatic deficiency, and the prophylactic screening of these patients and their families to prevent early pancreatic cancer [1]. We review the
Hereditary pancreatitis in children
2079
literature and analyze our study group of children with HP and propose guidelines for screening and treatment including surgical indications.
1. Materials and methods Medical charts of patients admitted from 1995 to 2007 in a single institution with a diagnosis of chronic or recurrent acute pancreatitis were retrospectively reviewed. Patients with clinical and/or genetic diagnosis of HP were included in the study. The diagnosis of HP was made when the patient had a mutation in the PRSS1 or SPINK1 genes, or when the patient's family satisfied the requirements of the EUROPAC (the European Registry of Hereditary Pancreatic Diseases) study [3], that is, if at least 2 first-degree relatives or 3 second-degree relatives in a minimum of 2 generations had recurrent acute pancreatitis or CP without other etiology. We excluded patients with CFTR mutations because of the multiorgan involvement of cystic fibrosis. In each case, we recorded the age and symptoms at first presentation; the chronic medical treatments; indication, type, and postoperative complications of the surgical procedures if required; the number of hospital stays; onset of pancreatic insufficiency; and evolution of weight status during the long-term follow-up. The aim of surgical procedures in HP was to perform internal drainage of the main pancreatic duct. In the so-called modified Puestow procedure, after an operative pancreatography, the main pancreatic duct was opened from the tail to the head of the gland, and a side-to-side pancreaticojejunostomy was performed with a transmesocolic Roux-en-Y jejunal loop [4]. Other surgical procedures involved drainage of pseudocysts, either by transgastric cystogastrostomy (Jurasz intervention) or through a side-to-side cystojejunostomy on a Roux-en-Y loop [5]. Two well-trained senior surgeons performed all procedures. Table 1
Clinical characteristics of the patients
No. of cases
Sex
1
Female
2 3 4 5 6 7 8 9 10
Female Female Female Female Female Male Female Female Male
Age at first crisis (y)
2. Results Among 14 children with the diagnosis of CP, 10 were included for clinical or genetic characteristics of HP (Table 1). The median age of first acute pancreatitis was 7 years (18 months to 10 years). Four patients without clinical criteria of HP were excluded. For 2 of them, the PRSS1 mutation was tested and had negative result. Six patients had a known familial history of HP. Two of them were tested for mutations in the PRSS1 gene and were found to contain the R122H mutation [6]. The 4 remaining patients were not investigated further as they belonged to a family well-known to carry the R122H mutation. Two other children presented with the R122H mutation of the PRSS1 gene (Table 1, cases 6 and 7) with no familial history of CP, although in one case, a pancreatic cancer was found in the girl's paternal grandmother (Table 1, case 6). First-degree relatives of both children were then screened, and in each case, a totally asymptomatic parent (including the father of the girl in question) presented with the same mutation. The last 2 patients, who presented with more than 3 acute pancreatitis crises in a 6-month period with dilation of the main pancreatic duct, were investigated for mutations in the SPINK1 gene. The N34S mutation was found at a heterozygous state in the boy, whose mother carried the same mutation, and at a homozygous state in the girl. Clinical symptoms of pancreatitis crisis were classical episodes of acute epigastric pain associated with nausea and vomiting (100%) and sometimes with transient bleached stools (30%). We noticed that these episodes often arose after a fatty meal and tended to be more frequent when the patients did not respect the fat-free diet that had been prescribed. Blood samples during these crises showed biologic signs of acute pancreatitis with increased serum amylase and lipase from 3 to 20 times higher than standard levels. Imagery with ultrasonography, computed tomographic scan and/or magnetic resonance cholangiopancreatography ruled out
No. of major crisis
Surgical treatment
Age at surgery (y)
Genetic status a
Follow-up (y)
1.5
3
8.5
Clinical HP
20
1.5 7.5 8 7 10 2 4.5 6 7
9 8 2 3 3 1 2 4 3
Jurasz intervention followed by cystojejunostomy No Modified Puestow procedure No No No Modified Puestow procedure No No No
– 13 – – – 14 – – –
Clinical HP Clinical HP PRSS1 +/− PRSS1 +/− PRSS1 +/− PRSS1 +/− PRSS1 +/− SPINK1 −/− SPINK1 +/−
18 12 5.5 5 5 3 3 1.5 0.5
a Patients categorized as PRSS1 +/− are heterozygous for the R122H mutation and as SPINK1, carries the N34S mutation at a homozygous (−/−) or heterozygous (+/−) status.
2080 congenital malformation of the pancreatic ducts, showing a dilated main pancreatic duct in 4 patients, intraductal calcifications in 2 patients, and acute complications in 2 other ones, respectively, pancreatic ascites and a pseudocyst. During our median follow-up of 12 years (0.5-20 years), none of the patients required chronic analgesia but only analgesics according to the level of an acute pain. There were no chronic complications of pancreatitis, such as diabetes mellitus or exocrine pancreatic insufficiency. Each patient had a good general status of health, and none of them were under the 2 SD line on body weight curves. Three patients required surgery. The first child was an 8.5year-old girl who developed a hemorrhagic pseudocyst at the pancreatic tail during an episode of acute pancreatitis with fever and anemia. The cyst was first drained via a surgical cystogastrostomy (Jurasz intervention), but a cystic infection on day 20 led to a redo surgery and to a new diversion by cystojejunostomy. The second patient was a girl with a long personal and family history of recurrent acute pancreatitis who presented at 13 years of age with a voluminous pancreatic ascites because of leakage of the pancreatic duct (Fig. 1A). She was operated on using the modified Puestow procedure. The third patient was a 14-year-old boy who had a 12-year history of recurrent abdominal pain originally attributed to constipation. After the first certified episode of acute pancreatitis, imaging studies including computed tomographic scan and magnetic resonance cholangiopancreatography showed a 20 mm dilated pancreatic duct with intraductal calcifications and morphological features suggesting severe CP (Fig. 1B). He was also treated using the modified Puestow procedure. No early postoperative complication occurred, and the median postoperative hospital stay was 11 days (7-17 days). All 3 were rehospitalized once, for abdominal pain 1 to 8 years after surgery, because of a new episode of pancreatitis for the 2 girls and constipation for the boy. None has presented clinical or
F. Schmitt et al. biologic signs of CP or dilation of the pancreatic duct to date (median follow-up, 6.5 years [3-8 years]).
3. Discussion Chronic pancreatitis is a chronic inflammatory illness of the pancreas that leads to irreversible morphological changes including inflammation, irregular fibrosis, and acinar and islet cell loss. Clinical manifestations are iterative episodes of acute pancreatitis associated with upper abdominal pain and increased serum pancreatic enzyme levels (N3 times the normal values), which led to progressive loss of exocrine and endocrine functions of the pancreas. According to the classification of Marseilles-Rome [7], in 1988, diagnostic assessment combines these clinical characteristics with morphological changes including intraductal calcifications, pancreatic ductal dilations, and parenchymal atrophy seen using radiologic imaging studies. Hereditary pancreatitis, described in 1952, is one of the chronic etiologies of pancreatitis. Hereditary pancreatitis was correlated in 1996 to a mutation in the PRSS1 gene located on 7q35 locus, namely R122H [6,8], which normally prevents intrapancreatic autolysis of prematurely activated trypsin [8] (Fig. 2). Other mutations, most commonly N29I, A16V, or K23R, were then described [9]. This autosomal dominant inherited disorder with an incomplete penetrance affects mostly the white population (80%) [8,10]. Compared to other CP, HP is characterized by a younger age of onset and a longer course of recurrent episodes of acute pancreatitis before reaching pancreatic insufficiency [3]. Hereditary pancreatitis has been correlated with a 40% cumulative risk of pancreatic ductal adenocarcinoma at the age of 70 compared to a 1% risk in the general population [3,11], which might concern asymptomatic carriers of the mutation, too.
Fig. 1 Imaging features. Figure A is a frontal view of magnetic resonance cholangiopancreatography realized for the 13-year-old girl (case 3) who had pancreatic ascites. Note the importance of the perihepatic and perisplenic effusion and the dilated main pancreatic duct (white arrow). Figure B shows the pancreas of the 14-year-old boy (case 7) on a frontal computed tomographic scan view. Note the major dilation of the duct (maximal diameter measured at 20 mm), associated with parenchymal atrophy; there are no calcifications to be seen.
Hereditary pancreatitis in children
2081
Fig. 2 Model of familial pancreatitis. Cationic trypsinogen and SPINK1 are produced at a 5:1 molar ratio in the acinar cells. When trypsinogen is prematurely activated within these cells, SPINK1 prevents the trypsin to activate the zymogen cascade by forming a heteroduplex trypsin-SPINK1. When SPINK1 is mutated or overwhelmed by too much trypsinogen activation, the protection against intrapancreatic trypsin effects depends on its autolysis, which begins by cleavage after the Arg122 residue. This site is mutated in HP, so in this case, the protection fails, and it eventually induces autodigestion of the pancreas, leading to acute pancreatitis (AP indicates activation peptide) [3].
Mutations in the Serine Protease Inhibitor Kazal type 1 gene (SPINK1) have been associated with some other forms of idiopathic CP and particularly with juvenile tropical pancreatitis [12]. The N34S missense mutation has not only been found in both heterozygous and homozygous states in patients with CP, but it is present in about 2% of the general population, too, perhaps, indicating that it is more an additional risk factor for CP than the only cause of the disease. In a normal state, SPINK1 is present at a ratio of 1:5 with trypsinogen and acts as the first line of defense against intrapancreatic activation of trypsin by binding itself with trypsin. The N34S mutation might alter the binding site of SPINK1, therefore, allowing premature activity of trypsin in the pancreas [13] (Fig. 1). Although the small size of our study group does not allow us to assess significant conclusions, this retrospective review supports further evidence that HP may be a major cause of CP and recurrent acute pancreatitis (AP) in childhood. Compared to other causes of pancreatitis, first symptoms of HP tend to appear at a younger age (mean age of onset of 5 years in our group) and to progress slowly toward CP. None of our 10 patients had diabetes mellitus or exocrine pancreatic insufficiency during childhood with a mean follow-up of 8.5 years, whereas some of them manifested morphological changes of the pancreatic gland compatible with severe CP. Medical treatment of the acute pancreatitis episodes consisted of bowel rest and analgesics as is often suggested in the literature. After resolution of clinical AP manifestations and because our patients seemed to be
particularly sensitive to higher fat intakes, a low-fat diet was instituted to prevent new episodes of pain. In addition, teenagers were informed about the risks of alcohol intake to try to preserve their long-term pancreatic functions, and of smoking, which can increase the risk of adenocarcinoma. Six of our patients received prophylactic enzyme supplementation, even without exocrine pancreatic insufficiency, in the hope of delaying further attacks of pancreatitis. This treatment did not stop recurrences but seemed to improve their quality of life and reduce their pain. The intention was to provide pancreatic rest, despite the lack of available data to our knowledge, supporting a real effect of these treatments on the amount of pancreatic secretions. Surgical treatment was proposed for acute complications of pancreatitis. This was effective in our 3 cases with respect to symptom resolution and relief of recurrent pain, with none of our patients showing progression of CP. In the literature, most authors advocate surgery either for acute complications of pancreatitis [5] or for drainage interventions in the case of patent lesions of CP associated with a dilated main pancreatic duct, even in an early stage of the disease [14,15]. The modified Puestow procedure has proved to be effective in reducing the need for pain relief medication in the long-term because of efficient decompression of the pancreatic duct obstructed by calcifications or fibrosis. Compared to pancreatectomy, this diversion procedure preserves functional pancreatic tissue as well as the spleen, the role of which remains essential in childhood. Whether surgery is effective in preserving long-term
2082 exocrine and endocrine functions of the pancreas remains controversial. Whereas some studies in adults [16] or children [14] tend to conclude in improvement or at least preservation of the pancreatic functions, some authors invalidate these results [17] or do not conclude [15]. Therefore, further prospective cohort studies are required to answer this question. Another point of debate with respect to hereditary pancreatitis concerns the genetic counseling. In fact, there is no clear consensus as to who exactly should be screened for mutations. Recent recommendations published by Rosendahl [1] give the following indications for PRSS1 and SPINK1 mutation testing in symptomatic patients: (1) recurrent unexplained attacks of acute pancreatitis or unexplained CP and a positive family history, (2) unexplained CP without a positive family history after exclusion of other causes, and (3) unexplained pancreatitis episode in children. Moreover, this screening should be performed only in experienced multidisciplinary centers and after informed consent of the patient. In our series, only 2 of the 6 children who had a familial history of HP were screened for the PRSS1 mutation, but all of them belonged to families known to carry this mutation. Two patients screened without familial history were positive for the mutation, after which firstdegree asymptomatic relatives were then also screened. This may confirm the interest of performing the test in children and young adults even after a first acute episode of otherwise unexplained pancreatitis, considering the seriousness of the disease and the lack of curative treatment. Knowing their genetic background may allow young patients to become aware of the importance of prophylactic measures (low-fat dietary intake, avoidance of alcohol, and smoking). Conversely, antenatal diagnosis should not be encouraged. Asymptomatic relatives in HP families should not be screened for the mutation because it may cause them greater difficulties (such as psychologic stress, problems with employers, and insurance companies), given that the higher risk of pancreatic cancer is more strongly correlated to long duration of pancreatitis, diabetes mellitus, and smoking than to mutation of the PRSS1 gene alone [18]. They might therefore have a very low risk of developing pancreatitis or cancer, for which there are neither ways to predict individual occurrence of pancreatitis nor preventive treatments [1]. The SPINK1 gene mutation, found in 2 of our youngest patients, should most probably be managed apart. This mutation is thought to act as an additional cofactor in the occurrence of idiopathic CP [13] and was particularly found to be associated with juvenile tropical pancreatitis [12]. This is a very special form of calcific CP encountered in Afro-Asian countries characterized by an early onset of diabetes mellitus and associated with malnutrition. In fact, 1 of our 2 patients was an adopted 6-year-old Madagascan girl who presented with recurrent AP and a homozygous N34S mutation of SPINK1 gene, although she neither had malnutrition nor diabetes
F. Schmitt et al. mellitus at the time of her diagnosis. We nevertheless ought to be careful about her in the future, despite that her first 1.5 years of follow-up were symptom-free. We initially made a diagnosis of idiopathic CP in the other case, a white boy without familial history of pancreatitis, but he and his asymptomatic mother were subsequently found to be heterozygous carriers of the mutation. All of our cases thus showed the great interest of looking for mutations (PRSS1 or SPINK1 genes) in every young patient having CP.
References [1] Rosendahl J, Bödeker H, Mössner J, et al. Review: hereditary chronic pancreatitis. Orphanet J Rare Dis 2007;2:1. [2] Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682-707. [3] Howes N, Lerch M, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004;2: 252-61. [4] Philip F, Partington MD, Robert E, et al. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg 1960;152: 1037-43. [5] Parshall WA, Remine WH. Internal drainage of pseudocysts of the pancreas. Arch Surg 1965;91:480-4. [6] Le Bodic L, Bognon JD, Raguénès O, et al. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet 1996;5: 549-54. [7] Sarles H, Adler G, Dani R, et al. The pancreatitis classification of Marseilles-Rome 1988. Scand J Gastroenterol 1989;24:641-2. [8] Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14: 141-5. [9] Teich N, Rosendahl J, Toth M, et al. Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. Hum Mutat 2006;27: 721-30. [10] Sossenheimer MJ, Aston CE, Preston RA, et al. Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. Am J Gastroenterol 1997;92:1113-6. [11] Lowenfels AB, Maisonneuve P, Di Magno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89:442-6. [12] Bhatia E, Choudhari G, Sikora SS, et al. Tropical calcific pancreatitis: strong association with SPINK 1 trypsin inhibitor mutations. Gastroenterology 2002;123:1020-5. [13] Witt H, Hennies HC, Classen M, et al. Mutations in the gene encoding the seine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25:213-6. [14] Scott HW, Neblett WW, O'Neill JA, et al. Longitudinal pancreaticojejunostomy in chronic relapsing pancreatitis with onset in childhood. Ann Surg 1984;199:610-22. [15] Clifton MS, Pelayo JC, Cortes RA, et al. Surgical treatment of childhood recurrent pancreatitis. J Pediatr Surg 2007;42:1203-7. [16] Nealon WH, Thompson J. Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression. A longitudinal prospective analysis of the modified Puestow procedure. Ann Surg 1993;217:458-68. [17] Warshaw AL, Popp JW, Schapiro RH. Long-term patency, pancreatic function and pain relief after lateral pancreaticojejunostomy for chronic pancreatitis. Gastroenterology 1980;79:289-93. [18] Whitcomb DC, Applebaum S, Martin SP. Hereditary pancreatitis and pancreatic carcinoma. Ann N Y Acad Sci 1999;880:201-9.
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Hereditary pancreatitis in children: surgical implications with special regard to genetic background Françoise Schmitt a , Gaelle Le Henaff b , Hugues Piloquet b , Marc D. Leclair a , Albert David c , Yves Heloury a , Guillaume Podevin a,⁎ a
Chirurgie infantile, HME, CHU de Nantes, France Clinique Médicale Pédiatrique, HME, CHU de Nantes, France c Génétique Médicale, Pôle biologie, CHU de Nantes, France b
Received 10 March 2009; revised 5 May 2009; accepted 15 May 2009
Key words: Hereditary pancreatitis; Chronic pancreatitis; Children
Abstract Purpose: Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature. Methods: All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes). Results: Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss. Conclusions: Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications. © 2009 Elsevier Inc. All rights reserved.
Chronic pancreatitis (CP) is a rare clinical entity in children, with unknown incidence and prevalence [1]. Whereas the most common etiology in adults is chronic alcohol consumption [2], CP during childhood is idiopathic or appears in a familial context. In the last decade, genetic factors have been implied in cases of familial CP, among them are mutations in PRSS1 (gene-encoding cationic ⁎ Corresponding author. E-mail address: [email protected] (G. Podevin). 0022-3468/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2009.05.023
trypsinogen), SPINK1 (Serine Protease Inhibitor Kazal type 1), or CFTR gene (cystic fibrosis) [1]. Great progress has been made concerning the etiology of so-called hereditary pancreatitis (HP), but consensus has still to be reached concerning the familial screening of HP for a child presenting with an attack of pancreatitis with no other etiology, the best way to treat patients medically or surgically to prevent pancreatic deficiency, and the prophylactic screening of these patients and their families to prevent early pancreatic cancer [1]. We review the
Hereditary pancreatitis in children
2079
literature and analyze our study group of children with HP and propose guidelines for screening and treatment including surgical indications.
1. Materials and methods Medical charts of patients admitted from 1995 to 2007 in a single institution with a diagnosis of chronic or recurrent acute pancreatitis were retrospectively reviewed. Patients with clinical and/or genetic diagnosis of HP were included in the study. The diagnosis of HP was made when the patient had a mutation in the PRSS1 or SPINK1 genes, or when the patient's family satisfied the requirements of the EUROPAC (the European Registry of Hereditary Pancreatic Diseases) study [3], that is, if at least 2 first-degree relatives or 3 second-degree relatives in a minimum of 2 generations had recurrent acute pancreatitis or CP without other etiology. We excluded patients with CFTR mutations because of the multiorgan involvement of cystic fibrosis. In each case, we recorded the age and symptoms at first presentation; the chronic medical treatments; indication, type, and postoperative complications of the surgical procedures if required; the number of hospital stays; onset of pancreatic insufficiency; and evolution of weight status during the long-term follow-up. The aim of surgical procedures in HP was to perform internal drainage of the main pancreatic duct. In the so-called modified Puestow procedure, after an operative pancreatography, the main pancreatic duct was opened from the tail to the head of the gland, and a side-to-side pancreaticojejunostomy was performed with a transmesocolic Roux-en-Y jejunal loop [4]. Other surgical procedures involved drainage of pseudocysts, either by transgastric cystogastrostomy (Jurasz intervention) or through a side-to-side cystojejunostomy on a Roux-en-Y loop [5]. Two well-trained senior surgeons performed all procedures. Table 1
Clinical characteristics of the patients
No. of cases
Sex
1
Female
2 3 4 5 6 7 8 9 10
Female Female Female Female Female Male Female Female Male
Age at first crisis (y)
2. Results Among 14 children with the diagnosis of CP, 10 were included for clinical or genetic characteristics of HP (Table 1). The median age of first acute pancreatitis was 7 years (18 months to 10 years). Four patients without clinical criteria of HP were excluded. For 2 of them, the PRSS1 mutation was tested and had negative result. Six patients had a known familial history of HP. Two of them were tested for mutations in the PRSS1 gene and were found to contain the R122H mutation [6]. The 4 remaining patients were not investigated further as they belonged to a family well-known to carry the R122H mutation. Two other children presented with the R122H mutation of the PRSS1 gene (Table 1, cases 6 and 7) with no familial history of CP, although in one case, a pancreatic cancer was found in the girl's paternal grandmother (Table 1, case 6). First-degree relatives of both children were then screened, and in each case, a totally asymptomatic parent (including the father of the girl in question) presented with the same mutation. The last 2 patients, who presented with more than 3 acute pancreatitis crises in a 6-month period with dilation of the main pancreatic duct, were investigated for mutations in the SPINK1 gene. The N34S mutation was found at a heterozygous state in the boy, whose mother carried the same mutation, and at a homozygous state in the girl. Clinical symptoms of pancreatitis crisis were classical episodes of acute epigastric pain associated with nausea and vomiting (100%) and sometimes with transient bleached stools (30%). We noticed that these episodes often arose after a fatty meal and tended to be more frequent when the patients did not respect the fat-free diet that had been prescribed. Blood samples during these crises showed biologic signs of acute pancreatitis with increased serum amylase and lipase from 3 to 20 times higher than standard levels. Imagery with ultrasonography, computed tomographic scan and/or magnetic resonance cholangiopancreatography ruled out
No. of major crisis
Surgical treatment
Age at surgery (y)
Genetic status a
Follow-up (y)
1.5
3
8.5
Clinical HP
20
1.5 7.5 8 7 10 2 4.5 6 7
9 8 2 3 3 1 2 4 3
Jurasz intervention followed by cystojejunostomy No Modified Puestow procedure No No No Modified Puestow procedure No No No
– 13 – – – 14 – – –
Clinical HP Clinical HP PRSS1 +/− PRSS1 +/− PRSS1 +/− PRSS1 +/− PRSS1 +/− SPINK1 −/− SPINK1 +/−
18 12 5.5 5 5 3 3 1.5 0.5
a Patients categorized as PRSS1 +/− are heterozygous for the R122H mutation and as SPINK1, carries the N34S mutation at a homozygous (−/−) or heterozygous (+/−) status.
2080 congenital malformation of the pancreatic ducts, showing a dilated main pancreatic duct in 4 patients, intraductal calcifications in 2 patients, and acute complications in 2 other ones, respectively, pancreatic ascites and a pseudocyst. During our median follow-up of 12 years (0.5-20 years), none of the patients required chronic analgesia but only analgesics according to the level of an acute pain. There were no chronic complications of pancreatitis, such as diabetes mellitus or exocrine pancreatic insufficiency. Each patient had a good general status of health, and none of them were under the 2 SD line on body weight curves. Three patients required surgery. The first child was an 8.5year-old girl who developed a hemorrhagic pseudocyst at the pancreatic tail during an episode of acute pancreatitis with fever and anemia. The cyst was first drained via a surgical cystogastrostomy (Jurasz intervention), but a cystic infection on day 20 led to a redo surgery and to a new diversion by cystojejunostomy. The second patient was a girl with a long personal and family history of recurrent acute pancreatitis who presented at 13 years of age with a voluminous pancreatic ascites because of leakage of the pancreatic duct (Fig. 1A). She was operated on using the modified Puestow procedure. The third patient was a 14-year-old boy who had a 12-year history of recurrent abdominal pain originally attributed to constipation. After the first certified episode of acute pancreatitis, imaging studies including computed tomographic scan and magnetic resonance cholangiopancreatography showed a 20 mm dilated pancreatic duct with intraductal calcifications and morphological features suggesting severe CP (Fig. 1B). He was also treated using the modified Puestow procedure. No early postoperative complication occurred, and the median postoperative hospital stay was 11 days (7-17 days). All 3 were rehospitalized once, for abdominal pain 1 to 8 years after surgery, because of a new episode of pancreatitis for the 2 girls and constipation for the boy. None has presented clinical or
F. Schmitt et al. biologic signs of CP or dilation of the pancreatic duct to date (median follow-up, 6.5 years [3-8 years]).
3. Discussion Chronic pancreatitis is a chronic inflammatory illness of the pancreas that leads to irreversible morphological changes including inflammation, irregular fibrosis, and acinar and islet cell loss. Clinical manifestations are iterative episodes of acute pancreatitis associated with upper abdominal pain and increased serum pancreatic enzyme levels (N3 times the normal values), which led to progressive loss of exocrine and endocrine functions of the pancreas. According to the classification of Marseilles-Rome [7], in 1988, diagnostic assessment combines these clinical characteristics with morphological changes including intraductal calcifications, pancreatic ductal dilations, and parenchymal atrophy seen using radiologic imaging studies. Hereditary pancreatitis, described in 1952, is one of the chronic etiologies of pancreatitis. Hereditary pancreatitis was correlated in 1996 to a mutation in the PRSS1 gene located on 7q35 locus, namely R122H [6,8], which normally prevents intrapancreatic autolysis of prematurely activated trypsin [8] (Fig. 2). Other mutations, most commonly N29I, A16V, or K23R, were then described [9]. This autosomal dominant inherited disorder with an incomplete penetrance affects mostly the white population (80%) [8,10]. Compared to other CP, HP is characterized by a younger age of onset and a longer course of recurrent episodes of acute pancreatitis before reaching pancreatic insufficiency [3]. Hereditary pancreatitis has been correlated with a 40% cumulative risk of pancreatic ductal adenocarcinoma at the age of 70 compared to a 1% risk in the general population [3,11], which might concern asymptomatic carriers of the mutation, too.
Fig. 1 Imaging features. Figure A is a frontal view of magnetic resonance cholangiopancreatography realized for the 13-year-old girl (case 3) who had pancreatic ascites. Note the importance of the perihepatic and perisplenic effusion and the dilated main pancreatic duct (white arrow). Figure B shows the pancreas of the 14-year-old boy (case 7) on a frontal computed tomographic scan view. Note the major dilation of the duct (maximal diameter measured at 20 mm), associated with parenchymal atrophy; there are no calcifications to be seen.
Hereditary pancreatitis in children
2081
Fig. 2 Model of familial pancreatitis. Cationic trypsinogen and SPINK1 are produced at a 5:1 molar ratio in the acinar cells. When trypsinogen is prematurely activated within these cells, SPINK1 prevents the trypsin to activate the zymogen cascade by forming a heteroduplex trypsin-SPINK1. When SPINK1 is mutated or overwhelmed by too much trypsinogen activation, the protection against intrapancreatic trypsin effects depends on its autolysis, which begins by cleavage after the Arg122 residue. This site is mutated in HP, so in this case, the protection fails, and it eventually induces autodigestion of the pancreas, leading to acute pancreatitis (AP indicates activation peptide) [3].
Mutations in the Serine Protease Inhibitor Kazal type 1 gene (SPINK1) have been associated with some other forms of idiopathic CP and particularly with juvenile tropical pancreatitis [12]. The N34S missense mutation has not only been found in both heterozygous and homozygous states in patients with CP, but it is present in about 2% of the general population, too, perhaps, indicating that it is more an additional risk factor for CP than the only cause of the disease. In a normal state, SPINK1 is present at a ratio of 1:5 with trypsinogen and acts as the first line of defense against intrapancreatic activation of trypsin by binding itself with trypsin. The N34S mutation might alter the binding site of SPINK1, therefore, allowing premature activity of trypsin in the pancreas [13] (Fig. 1). Although the small size of our study group does not allow us to assess significant conclusions, this retrospective review supports further evidence that HP may be a major cause of CP and recurrent acute pancreatitis (AP) in childhood. Compared to other causes of pancreatitis, first symptoms of HP tend to appear at a younger age (mean age of onset of 5 years in our group) and to progress slowly toward CP. None of our 10 patients had diabetes mellitus or exocrine pancreatic insufficiency during childhood with a mean follow-up of 8.5 years, whereas some of them manifested morphological changes of the pancreatic gland compatible with severe CP. Medical treatment of the acute pancreatitis episodes consisted of bowel rest and analgesics as is often suggested in the literature. After resolution of clinical AP manifestations and because our patients seemed to be
particularly sensitive to higher fat intakes, a low-fat diet was instituted to prevent new episodes of pain. In addition, teenagers were informed about the risks of alcohol intake to try to preserve their long-term pancreatic functions, and of smoking, which can increase the risk of adenocarcinoma. Six of our patients received prophylactic enzyme supplementation, even without exocrine pancreatic insufficiency, in the hope of delaying further attacks of pancreatitis. This treatment did not stop recurrences but seemed to improve their quality of life and reduce their pain. The intention was to provide pancreatic rest, despite the lack of available data to our knowledge, supporting a real effect of these treatments on the amount of pancreatic secretions. Surgical treatment was proposed for acute complications of pancreatitis. This was effective in our 3 cases with respect to symptom resolution and relief of recurrent pain, with none of our patients showing progression of CP. In the literature, most authors advocate surgery either for acute complications of pancreatitis [5] or for drainage interventions in the case of patent lesions of CP associated with a dilated main pancreatic duct, even in an early stage of the disease [14,15]. The modified Puestow procedure has proved to be effective in reducing the need for pain relief medication in the long-term because of efficient decompression of the pancreatic duct obstructed by calcifications or fibrosis. Compared to pancreatectomy, this diversion procedure preserves functional pancreatic tissue as well as the spleen, the role of which remains essential in childhood. Whether surgery is effective in preserving long-term
2082 exocrine and endocrine functions of the pancreas remains controversial. Whereas some studies in adults [16] or children [14] tend to conclude in improvement or at least preservation of the pancreatic functions, some authors invalidate these results [17] or do not conclude [15]. Therefore, further prospective cohort studies are required to answer this question. Another point of debate with respect to hereditary pancreatitis concerns the genetic counseling. In fact, there is no clear consensus as to who exactly should be screened for mutations. Recent recommendations published by Rosendahl [1] give the following indications for PRSS1 and SPINK1 mutation testing in symptomatic patients: (1) recurrent unexplained attacks of acute pancreatitis or unexplained CP and a positive family history, (2) unexplained CP without a positive family history after exclusion of other causes, and (3) unexplained pancreatitis episode in children. Moreover, this screening should be performed only in experienced multidisciplinary centers and after informed consent of the patient. In our series, only 2 of the 6 children who had a familial history of HP were screened for the PRSS1 mutation, but all of them belonged to families known to carry this mutation. Two patients screened without familial history were positive for the mutation, after which firstdegree asymptomatic relatives were then also screened. This may confirm the interest of performing the test in children and young adults even after a first acute episode of otherwise unexplained pancreatitis, considering the seriousness of the disease and the lack of curative treatment. Knowing their genetic background may allow young patients to become aware of the importance of prophylactic measures (low-fat dietary intake, avoidance of alcohol, and smoking). Conversely, antenatal diagnosis should not be encouraged. Asymptomatic relatives in HP families should not be screened for the mutation because it may cause them greater difficulties (such as psychologic stress, problems with employers, and insurance companies), given that the higher risk of pancreatic cancer is more strongly correlated to long duration of pancreatitis, diabetes mellitus, and smoking than to mutation of the PRSS1 gene alone [18]. They might therefore have a very low risk of developing pancreatitis or cancer, for which there are neither ways to predict individual occurrence of pancreatitis nor preventive treatments [1]. The SPINK1 gene mutation, found in 2 of our youngest patients, should most probably be managed apart. This mutation is thought to act as an additional cofactor in the occurrence of idiopathic CP [13] and was particularly found to be associated with juvenile tropical pancreatitis [12]. This is a very special form of calcific CP encountered in Afro-Asian countries characterized by an early onset of diabetes mellitus and associated with malnutrition. In fact, 1 of our 2 patients was an adopted 6-year-old Madagascan girl who presented with recurrent AP and a homozygous N34S mutation of SPINK1 gene, although she neither had malnutrition nor diabetes
F. Schmitt et al. mellitus at the time of her diagnosis. We nevertheless ought to be careful about her in the future, despite that her first 1.5 years of follow-up were symptom-free. We initially made a diagnosis of idiopathic CP in the other case, a white boy without familial history of pancreatitis, but he and his asymptomatic mother were subsequently found to be heterozygous carriers of the mutation. All of our cases thus showed the great interest of looking for mutations (PRSS1 or SPINK1 genes) in every young patient having CP.
References [1] Rosendahl J, Bödeker H, Mössner J, et al. Review: hereditary chronic pancreatitis. Orphanet J Rare Dis 2007;2:1. [2] Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001;120:682-707. [3] Howes N, Lerch M, Greenhalf W, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004;2: 252-61. [4] Philip F, Partington MD, Robert E, et al. Modified Puestow procedure for retrograde drainage of the pancreatic duct. Ann Surg 1960;152: 1037-43. [5] Parshall WA, Remine WH. Internal drainage of pseudocysts of the pancreas. Arch Surg 1965;91:480-4. [6] Le Bodic L, Bognon JD, Raguénès O, et al. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet 1996;5: 549-54. [7] Sarles H, Adler G, Dani R, et al. The pancreatitis classification of Marseilles-Rome 1988. Scand J Gastroenterol 1989;24:641-2. [8] Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14: 141-5. [9] Teich N, Rosendahl J, Toth M, et al. Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. Hum Mutat 2006;27: 721-30. [10] Sossenheimer MJ, Aston CE, Preston RA, et al. Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. Am J Gastroenterol 1997;92:1113-6. [11] Lowenfels AB, Maisonneuve P, Di Magno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89:442-6. [12] Bhatia E, Choudhari G, Sikora SS, et al. Tropical calcific pancreatitis: strong association with SPINK 1 trypsin inhibitor mutations. Gastroenterology 2002;123:1020-5. [13] Witt H, Hennies HC, Classen M, et al. Mutations in the gene encoding the seine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25:213-6. [14] Scott HW, Neblett WW, O'Neill JA, et al. Longitudinal pancreaticojejunostomy in chronic relapsing pancreatitis with onset in childhood. Ann Surg 1984;199:610-22. [15] Clifton MS, Pelayo JC, Cortes RA, et al. Surgical treatment of childhood recurrent pancreatitis. J Pediatr Surg 2007;42:1203-7. [16] Nealon WH, Thompson J. Progressive loss of pancreatic function in chronic pancreatitis is delayed by main pancreatic duct decompression. A longitudinal prospective analysis of the modified Puestow procedure. Ann Surg 1993;217:458-68. [17] Warshaw AL, Popp JW, Schapiro RH. Long-term patency, pancreatic function and pain relief after lateral pancreaticojejunostomy for chronic pancreatitis. Gastroenterology 1980;79:289-93. [18] Whitcomb DC, Applebaum S, Martin SP. Hereditary pancreatitis and pancreatic carcinoma. Ann N Y Acad Sci 1999;880:201-9.