ABSTRACT. Key words : Chronic pancreatitis; Fibrosis; Pancreatic insufficiency; Hereditary pancreatitis; PRSS1; SPINK1; CFTR.

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1 61 Symposium : Gastroenterology & Hepatology-III Chronic Pancreatitis Keith J. Lindley Pancreatic and Gastroenterology Services, UCL Institute of Child Health and Great Ormond Street Hospital for Children, 30 Guilford Street, London WC1N 1EH, UK. ABSTRACT Chronic pancreatitis (CP) is characterised by pancreatic inflammation and fibrosis leading eventually to destruction of pancreatic parenchyma and loss of exocrine and endocrine function. A model of interactions between environmental triggers of pancreatic inflammation and disease susceptibility or modifying genes (including PRSS1, SPINK1 and CFTR) provides a framework within which to understand disease pathogenesis. Early in the disease, when fibrosis is mild and pancreatic damage limited, it is difficult to distinguish CP from recurrent acute pancreatitis (RAP) although it is likely these represent opposite ends of a spectrum of disease with a common aetiology in which CP represents either a later disease stage or disease in individuals predisposed to generate a chronic fibrogenic inflammatory response. Pain is a dominant feature resulting in part from neuroimmune interactions within the pancreas. Diagnosis at an early stage of disease is challenging, though in later stages is dependent upon the demonstration of pancreatic fibrosis and duct ectasia using one or more imaging modalities including transabdominal and endoscopic ultrasound, CT and MRCP or ERCP. Current treatments are largely supportive and reactive. The challenge for pediatricians is to achieve diagnosis at an early stage of the disease and to develop treatments that can alter its natural history. [Indian J Pediatr 2006; 73 (10) : ] k.lindley@ich.ucl.ac.uk Key words : Chronic pancreatitis; Fibrosis; Pancreatic insufficiency; Hereditary pancreatitis; PRSS1; SPINK1; CFTR. Chronic pancreatitis (CP) is characterised by pancreatic inflammation and fibrosis the endpoint of which is destruction of pancreatic parenchyma with eventual loss of exocrine and endocrine function. The genesis of these endpoints of pancreatic injury may follow years of continual or recurrent injury, implying that pre-clinical or pauci-symptomatic disease is likely to exist earlier in life. Recognition of CP at this pre-clinical or paucisymptomatic stage is an important challenge for paediatricians when there are opportunities to alter the natural history of CP with the goal of prevention of progression to exocrine and endocrine pancreatic failure and intractable pancreatic pain. CP is characterised by pancreatic inflammation and fibrosis manifest as irregular glandular sclerosis and (focal or diffuse) destruction of exocrine acinar parenchyma. In later stages, pancreatic duct dilatation, stricture or stone formation are found. CP arises when pancreatic injury is followed by a sustained immune activation in which fibrosis dominates. In normal pancreas, pancreatic stellate cells (PSCs) are quiescent. In response to pancreatic injury or inflammation PSCs may be activated into highly Correspondence and Reprint requests : Dr. Keith J. Lindley, Pancreatic and Gastroenterology Services, UCL Institute of Child Health and Great Ormond Street Hospital for Children 30, Guilford Street, London WC 1N EH, UK. proliferative myofibroblast-like cells that express the cytoskeletal protein α-smooth muscle actin (α-sma) and produce extracellular matrix components including type I collagen. Hence fibrosis follows PSC activation. In the sentinel acute pancreatic event (SAPE) hypothesis it is suggested that the initiating event(s) in CP is an acute event in the pancreatic acinar cells which causes an inflammatory response and that induction of a pro-fibrotic chronic inflammatory response follows one or more SAPE(s). A number of aetiological factors are recognised to trigger/predispose to SAPEs, which are best considered in the framework of the TIGAR-O classification of aetiological factors (table 1). 1 The process leading to CP is likely to involve interactions between environmental factors, factors that lead to recurrent pancreatic injury and factors predisposing to an altered immune response resulting in chronic inflammation and fibrosis. 2 The principal genetic influences (see below) include mutations of PRSS1 (protease, serine 1), the gene encoding the pancreatic acinar enzyme cationic trypsinogen, 3 SPINK1, the gene encoding serine protease inhibitor Kazal type 1 4 and ABCC7, the gene encoding the cystic fibrosis conductance regulator (CFTR). 5, 6 Other less well established genetic influences include polymorphisms of TGFβ 7 which alter the nature of the immune response towards a pro-fibrotic phenotype. Many of the genetic risk factors for chronic pancreatitis actually increase the risk of developing acute pancreatitis Indian Journal of Pediatrics, Volume 73 October,

2 62 Keith J. Lindley et al TABLE 1. Aetiological Factors Associated with Chronic Pancreatitis: TIGAR-O Classification System Modified from Etemad et al 1 Toxic metabolic Hypercalcaemia Hyperlipidaemia Chronic renal failure Drugs Toxins (eg DBTC) (alcohol and smoking) Idiopathic Early onset Late onset Tropical Genetic PRSS1 mutations SPINK1 mutations ABCC7 (CFTR) mutations Autoimmune Isolated autoimmune CP Syndromic autoimmune CP in association with: Sjogren s syndrome/ibd/pbc Recurrent acute pancreatitis RAP Post-necrotic Vasculitis Post-irradiation Obstructive Pancreas divisum Sphincter of Oddi dysfunction Duct obstruction (eg stones, post-inflammatory, posttraumatic) (AP), and it is widely accepted that episodes of recurrent AP (RAP) may lead eventually to CP. However the utility of genetic screening in individuals with RAP and CP is probably limited to PRSS1 as this is both diagnostic and predictive (although not universally so) of pancreatic disease see below. 8 Intuitively the concept of interactions between genetic factors which influence susceptibility to pancreatic injury and inflammation and environmental influences (for example pancreatic duct obstruction or drugs) which serve to initiate or perpetuate inflammation in CP is attractive providing a rational framework within which to investigate/treat individuals with CP (fig 1). Fig. 1. Multifactorial origins of pancreatitis illustrating the interrelationships between genetic factors protecting the pancreas from injury, genetic and other factors affecting the immune response and environmental variables capable of injuring the pancreas. Adapted from Whitcomb. 2 Cell biology of fibrogenesis The initiating event leading to fibrogenesis in the pancreas is an injury that may involve the interstitial mesenchymal cells, duct cells, and/or acinar cells induced by inflammation, acinar cell death and necrosis or ductal 908 obstruction. The injury results in cytokine triggered transformation of resident fibroblasts/pscs into myofibroblasts and the subsequent production and deposition of extracellular matrix. In normal pancreas, low numbers of PSC are located in periacinar and interlobular regions. PSCs become activated and adopt a myofibroblast phenotype following stimulation by proinflammatory cytokines, ligation of the peroxisome proliferator activated receptor (PPAR)γ or stimulation of the mitogen activated protein kinase (MAP kinase) pathways which include p38 MAP kinase, ERK1/ 2 and c-jun N-terminal kinase (JNK). Upon activation PSCs respond to proliferative and profibrogenic growth factors including platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β) and proinflammatory cytokines. TGFβ and PDGF are released by platelets aggregating in injured tissues and TGFβ and PDGF are produced by inflammatory cells invading the injured pancreas. bfgf (basic fibroblast growth factor) is released by duct and acinar cells. PDGF is a powerful mitogen. bfgf and TGF-β 1 are potent fibrogenic mediators stimulating extracellular matrix synthesis. Genetic influences (i) PRSS1 (Cationic trypsinogen) : Studies of families with inherited forms of pancreatitis led to the observation that mutations in the gene encoding cationic trypsinogen (PRSS1 protease, serine 1) are associated with hereditary pancreatitis (HP). 3, 9 Cationic trypsin, the activation product of cationic trypsinogen, is a potent protease which, in addition to its digestive function, is pivotal in activating other acinar pro-enzymes. PRSS1 mutations associated with RAP and CP are in essence activating mutations resulting in impaired autolysis or enhanced autoactivation of cationic trypsinogen within the pancreatic acinar cell resulting in acinar cell necrosis and inflammation (reviewed in 9). The clinical phenotype is most usually one of recurrent episodes of acute pancreatitis leading to chronic pancreatitis. Data from the European Registry of Hereditary Pancreatitis documents that 19% of individuals with HP lack a PRSS1 mutation suggesting that HP is heterogenous. The median age of first symptoms in individuals with the most common PRSS1 mutation (R112H) was 10 years compared with 14.5 years for mutation negative patients. The cumulative risk of pancreatic exocrine failure by age 50 was 37.2% and of endocrine failure 47.6%. 10 PRSS1 would appear to be less important in other ethnic groups and may not be implicated at all in chronic pancreatitis in parts of Asia. 11 Twin and family studies demonstrate that carriage of a disease associated PRSS1 mutation does not however inevitably result in pancreatitis implying that other genetic or environmental influences are also of importance. (ii) SPINK1 : One of the first lines of defence against inappropriately activated cationic trypsinogen is the pancreatic secretory trypsin inhibitor (PSTI), otherwise Indian Journal of Pediatrics, Volume 73 October, 2006

3 63 Chronic Pancreatitis known as the serine protease inhibitor, Kazal type 1 (SPINK1) which is able to inhibit the inappropriately activated enzyme by blocking the active site of the enzyme. Loss of function mutations of SPINK1 are a risk factor for RAP and CP, being found in ~19% of individuals with RAP/CP vs ~2% of controls. 4 Individuals with idiopathic chronic pancreatitis (ICP) and SPINK1 mutations have earlier onset disease than those without mutations as well as younger age of exocrine and endocrine pancreatic failure. SPINK1 is therefore a disease modifier, mutations of which increase susceptibility to pancreatitis in both an autosomal recessive manner and as a complex genetic trait. (iii) CFTR : CFTR, the cystic fibrosis conductance regulator, is a member of a family of proteins collectively known as ATP binding cassette (ABC) proteins, and is encoded by the gene ABCC7. Whilst classical cystic fibrosis (CF) is associated with low levels of functional CFTR at the cell surface it is now appreciated that individuals with CFTR related disease, which includes individuals with congenital bilateral absence of the vas deferens, recurrent sinusitis and idiopathic chronic pancreatitis (ICP), 5, 6 have higher levels of functional CFTR. A recent prospective study in an Hispanic population underlines the observations that pancreatitis is rare in individuals with CF who are pancreatic insufficient (~0.9%), more common in individuals with at least one mild mutation (~11.9%) and greatest (~19%) in individuals who carry an R334W mutation. 12 It is now appreciated that CFTR is able to function as both a chloride channel and a bicarbonate channel and that the conductance of these cations is independently regulated. Moreover predisposition to RAP and ICP is related to defective bicarbonate conductance rather than chloride conductance. Emerging evidence suggests that mutations in CFTR might also be intrinsically pro-inflammatory and that CFTR influences the balance between apoptosis and necrosis following cell injury. Both these factors are likely to influence the severity and duration of inflammatory response within the pancreas. More detailed discussion of these and other influences can be found elsewhere 13. Suffice it to summarize that CFTR dysfunction in the absence of classical cystic fibrosis can predispose to CP. (iv) Other genes : The search for other genetic influences, for example in families with HP not associated with PRSS1 mutations is ongoing. Studies in adults have identified polymorphisms in UDP glucuronosyltransferase, an enzyme important in detoxification within the liver as a risk factor for ICP. 14 The intensity of acute inflammatory response following pancreatic injury is also influenced by monocyte chemotactic protein-1 genotype. 15 Taken together it is easy to envisage a model whereby genotypes at these 3 or more genetic loci might influence susceptibility to pancreatitis as a complex genetic trait. Environment Environmental influences can both trigger pancreatic inflammation and also modulate the severity of the inflammatory response. For example, mumps virus infection is known to precipitate an episode of AP in susceptible individuals. In animals ingestion of alcohol, which is a risk factor for chronic pancreatitis in adults, sensitises pancreatic acinar cells to a non-pathogenic strain of coxsackie virus facilitating the development of pancreatic acinar necrosis and inflammation. It is known that alcohol exposure regulates activation of the inflammatory transcription factor NFkB and lowers the threshold for initiation of acute pancreatitis. Hence one or more environmental factors may act synergistically to cause pancreatitis. Anatomical/physical causes of impaired pancreatic duct drainage are also important in the genesis of pancreatitis as exemplified by the frequency of gallstone associated AP in adult. Congenital abnormalities of pancreatic duct anatomy may predispose to pancreatitis. In pancreas divisum (PD) there is failure of the normal fusion of dorsal and ventral pancreatic elements. The result is that the main pancreatic duct enters the duodenum through the minor papilla and that the short ventral portion of the pancreatic duct enters the duodenum via the major papilla. PD affects up to 10% of the population and in at least some patients will be associated with inefficient pancreatic duct drainage. The role, if any, of PD in the pathogenesis of pancreatitis remains a point of debate. PD might become a risk factor for ICP when combined with other factors for example a CFTR mutation. Other forms of pancreatitis Tropical Pancreatitis : Tropical chronic pancreatitis (TCP) is a juvenile form of chronic pancreatitis prevalent in tropical developing countries. TCP differs from temperate zone pancreatitis in its younger age of onset, more accelerated course, higher prevalence of pancreatic calculi and diabetes, and greater propensity to pancreatic malignancy TCP involves the main pancreatic duct resulting in large ductal calculi. 16 TCP is highly associated with the SPINK1 N34S mutation. Autoimmune Pancreatitis Autoimmune pancreatitis is not well recognised in paediatric practice. It differs form other forms of CP as the pancreas is bulky/swollen and typically there is an absence of calcification. It may occur in isolation or in combination with other autoimmune diseases including inflammatory bowel disease, primary sclerosing cholangitis and Sjogren s syndrome. 17 There is usually evidence of hypergammaglobulinaemia with raised IgG 4 and the presence of autoantibodies including ANA, anti- SMA, anti-carbonic anhydrase and anti lactoferrin. Histologically there is infiltration of the pancreas with lymphocytes and IgG 4 positive plasma cells along with some fibrosis. This form of pancreatitis is clearly steroid Indian Journal of Pediatrics, Volume 73 October,

4 64 Keith J. Lindley et al responsive. Diagnosis and Clinical Approach The diagnosis of CP is currently heavily dependent upon imaging. A major challenge for pediatricians is the development of methods which allow detection of chronic pancreatic inflammation at an earlier stage when intervention(s) might alter the natural history of the disease. Chronic pancreatitis with calcification(s) can frequently be identified on plain abdominal radiography or transabdominal ultrasound. These methods however lack the sensitivity of abdominal CT scanning and MRI, endoscopic retrograde pancreatography (ERP) and endoscopic ultrasound (EUS). ERP is a sensitive and specific test for the diagnosis of chronic pancreatitis. In early disease dilation and irregularity of the smaller ducts and branches of the pancreas are found and in more advanced disease the changes also seen in the main pancreatic duct. Duct tortuosity, stricture, calcification, cystic dilatation may be visualised in more severe disease. ERP requires considerable technical expertise and has a finite morbidity principally relating to post ERP pancreatitis. Secretin stilumated MRCP is being used increasingly in pediatrics for non-interventional pancreatic imaging and is proving highly sensitive and specific. EUS is able to generate high resolution images of pancreatic parenchyma and duct in CP demonstrating irregularity and dilation of the main pancreatic duct with hyperechoic duct margins and hyperechoic stranding in the pancreatic parenchyma in early stages of CP. Commercially available endoscopic U/ S scopes are currently too large for use in small children limiting the utility of this sensitive method. Miniprobes, which can be passed via the biopsy channel of a standard gastroscope can, however, visualise the pancreatic parenchyma through the posterior wall of the stomach and may provide useful information in the pediatric age group. The clinical approach to children with CP should include efforts to gain an understanding of causation including the contribution of genetic and environmental factors. Investigation should therefore include screening for disease associated mutations in PRSS1, SPINK1 and CFTR. CFTR screening is problematical as this is a large gene and the common mutations associated with classical CF are almost certainly not the most relevant in ICP. There is an argument for sequencing of CFTR, although this is not widely available. PRSS1 mutation screening is widely available though SPINK1 mutation screening is currently confined mainly to research laboratories. Toxic metabolic causes should be eliminated (table 1) and obstructive lesions excluded (table 1). Pancreatic exocrine function can be simply evaluated with measurement of fecal elastase 1 and pancreatic enzyme replacement therapy instituted if appropriate. In some institutions a combined exocrine-endocrine function test is used to evaluate the pancreatic function in chronic pancreatitis measuring urinary para amino benzoic acid (PABA) recovery and pancreatic polypeptide secretion in response to a meal simultaneously with an oral glucose tolerance test. Glucose intolerance is uncommon in children before adolescence. The prevalence of insulin dependent diabetes in individuals with CP associated with PRSS1 or SPINK1 mutations is less than 10% after 10 years of clinical disease, with a later onset in those without identified gene mutations. The pathophysiology of pain in chronic pancreatitis (CP) is incompletely understood and its management is frequently challenging. Increased intraductal pressure as a result of single or multiple strictures and/or calculi may result in pain in individuals with a dilated main pancreatic duct. However immunohistological studies have demonstrated increased amounts of neurotransmitters and their receptors (for eg calcitonin gene-related peptide, substance P and the neurokinin receptor) in afferent pancreatic nerves. A correlation is apparent between pain and perineural immune cell infiltration in CP underscoring the importance of neuroimmune interactions in pancreatic pain. Pain may also result from fibrotic stricturing of the bilary duct. Medical management of pain has included the use of proton pump inhibitors to alkalinise the duodenum and Fig. 2. Figure 1 Schematic representing genetic and environmental factors in the pathogenesis of chronic pancreatitis. ACP, alcoholic chronic pancreatitis; TCP, tropical calcific pancreatitis; ICP, idiopathic pancreatitis; HP, hereditary pancreatitis (from Witt 19 ) 910 Indian Journal of Pediatrics, Volume 73 October, 2006

5 65 Chronic Pancreatitis high doses of pancreatic enzyme (given as powder rather than a delayed release microsphere preparation) to predigest endogenous peptides produced in the stomach which regulate pancreatic exocrine secretion. This attractive approach which reduces pancreatic exocrine secretion is unevaluated. Traditional physical treatments for pain in CP have included either pancreatic resection (segmental or otherwise) or drainage procedures (endoscopic sphincterotomy, stone removal and stent placement or the Puestow longitudinal pancreaticojejunostomy). These treatments may be poorly efficacious (15-30% achieve pain relief in uncontrolled adult studies). Symptomatic analgesia using celiac axis nerve blockade, which may be placed using endoscopic ultrasound guidance, has not been evaluated in pediatric CP, although results in adult CP are in general favorable. The natural history of pain in CP is to decrease in severity / intensity with time and increasingly it is being recommended that individuals with short relapsing pain episodes (<10 days duration) are managed conservatively with the expectation of eventual improvement in pain levels as pancreatic acinar mass reduces. The place of antiinflammatory treatments remains to be defined, but would appear infinitely more attractive than the wait and watch approach. An approach to pancreatic enzyme replacement therapy and dietary management is discussed elsewhere. 18 An algorithm depicting the general overall approach to management is shown (fig. 3). Novel therapies With improved understanding of the cell biology of CP a number of novel therapeutic interventions have been proposed. Troglitazone, a PPARγ agonist, reduces the profibrogenic activity of PSCs and the progression of chronic pancreatitis in animal models of chronic pancreatitis. Retinol and its metabolites can reverse activation of PSCs in tissue culture and prevent ethanol induced PSC activation, both effects being mediated through the MAPK pathway. Camostat mesilate, an oral protease inhibitor, attenuates pancreatic fibrosis through inhibition of monocytes and pancreatic stellate cells in models of CP. Curcumin, which inhibits the proinflammatory transcription factors NF-kappaB and activator protein (AP)-1, may also ameliorate pancreatitis in animal models The role of these, and other, novel approaches in modifying the natural history of CP in childhood has not been evaluated. Summary and Conclusions Chronic pancreatitis is an example of a disease in which genetic and environmental factors jointly contribute to the pancreatic inflammation and fibrosis leading to destruction of the gland with pancreatic exocrine and endocrine failure. Current treatments are largely Repeat after interval Normal size calcification duct anatomy duct drainage Genetic studies Metabolic studies? drugs? toxins? Chronic Pancreatitis serum pancreatic enzymes abdominal US fecal elastase 1 Supportive treatment proton pump inhibitor pancreatin (powder) PERT (if necessary) LCT MCT diet Fat sol vits (Se ACE) PRSS1 SPINK1 CFTR Abnormal? CP. CT endoscopic US Ca lipids organic acids urea/creatinine immunoglobulins ICP MRCP endoscopic US (ERCP) CP likely Experimental treatment PPARy ligans Curcumin Retinol Camostat Thalidomide size homogeneity duct ectasia calcification cysts Disease specific investigations Fig. 3. Algorithm outlining the general investigative approach to chronic pancreatits supportive and reactive rather than proactive. The challenge for pediatricians is to achieve diagnosis at an early stage of the disease when the natural history can be altered and eventual pancreatic failure and increased risk of malignancy avoided. REFERENCES 1. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology Indian Journal of Pediatrics, Volume 73 October,

6 66 Keith J. Lindley et al 2001; 120 : Whitcomb DC. Mechanisms of disease: Advances in understanding the mechanisms leading to chronic pancreatitis. Nat Clin Pract Gastroenterol Hepatol 2004; 1 : Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Jr., Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14 : 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 1 are associated with chronic pancreatitis. Nat Genet 2000; 25 : 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 : 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 : Bendicho MT, Guedes JC, Silva NN, Santana GO, dos Santos RR, Lyra AC, Lyra LG, Meyer R, Lemaire DC. Polymorphism of cytokine genes (TGF-beta, IFN-gamma, IL-6, IL-10, and TNF-alpha) in patients with chronic pancreatitis. Pancreas 2005; 30 : Whitcomb DC. Value of genetic testing in the management of pancreatitis. Gut 2004; 53 : Whitcomb DC. Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 1999; 45 : Howes N, Lerch MM, Greenhalf W, Stocken DD, Ellis I, Simon P, Truninger K, Ammann R, Cavallini G, Charnley RM, Uomo G, Delhaye M, Spicak J, Drumm B, Jansen J, Mountford R, Whitcomb DC, Neoptolemos JP. Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol 2004; 2 : Chandak GR, Idris MM, Reddy DN, Mani KR, Bhaskar S, Rao GV, Singh L. Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and nonhereditary chronic pancreatitis. Gut 2004; 53 : Maisonneuve P, Campbell P, III, Durie P, Lowenfels AB. Pancreatitis in hispanic patients with cystic fibrosis carrying the R334W mutation. Clin Gastroenterol Hepatol 2004; 2 : Lindley KJ. Pancreatic involvement: clinical manifestations, pathophysiology and new treatments. In: Bush A, Alton EWFW, Davies JC, Griesenbach U, and Jaffe A, eds. Cystic Fibrosis in the 21st Century. Volume 34. Basel: S. Karger AG, 2006 : Ockenga J, Vogel A, Teich N, Keim V, Manns MP, Strassburg CP. UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer. Gastroenterology 2003; 124 : Papachristou GI, Sass DA, Avula H, Lamb J, Lokshin A, Barmada MM, Slivka A, Whitcomb DC. Is the monocyte chemotactic protein G allele a risk factor for severe acute pancreatitis? Clin Gastroenterol Hepatol 2005; 3 : Tandon RK, Garg PK. Tropical pancreatitis. Dig Dis 2004; 22 : Okazaki K, Uchida K, Matsushita M, Takaoka M. Autoimmune pancreatitis. Intern Med 2005; 44 : Anthony H, Collins CE, Davidson G, Mews C, Robinson P, Shepherd R, Stapleton D. Pancreatic enzyme replacement therapy in cystic fibrosis: Australian guidelines. Pediatric Gastroenterological Society and the Dietitians Association of Australia. J Pediatr Child Health 1999; 35 : Witt H. Chronic pancreatitis and cystic fibrosis. Gut 2003; 52 Suppl 2 : ii31-ii Indian Journal of Pediatrics, Volume 73 October, 2006