Chronic pancreatitis

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.     

Hereditary aspects of pancreatitis

Pancreatitis presents clinically as acute and chronic form. A common characteristic of these two forms is enzymatic autodigestion of pancreas in the course of the disease. It results from premature activation of pancreatic digestive enzymes and disturbance of subtle balance between proteolytic enzymes and their inhibitors. The way to understand the character of mechanisms leading to development of pancreatitis has been simplified by discovery of genetic factors, which are able to initiate pathological changes at tissue level. Mutations in the PRSS1 gene (first of all R122H and N29I mutations), which encodes for cationic trypsin, cause trypsin to be protected from autodegradation. These mutations also cause precursor of trypsin - trypsinogen, to be activated easier. On the other hand mutations in the SPINK1 gene have been identified. SPINK1 gene encodes for the most important protease inhibitor of the pancreatic fluid. The most frequent mutation, namely N34S, decrease SPINK1 protein in its activity. The link between the genotype and phenotype is not clear in every case. It is probable that pancreatitis will be recognized as poligenic with many genes engaged in the disease development. Pancreatic cancer is a frequent consequence of pancreatitis. It is a very invasive cancer with high mortality. In the course of pancreatic inflammation intensive cell proliferation takes place for regeneration of pancreas damage. It is the chance for amplification of pathological changes in DNA, which have arisen as a ROS's (Reactive Oxygen Species) and RNOS's (Reactive Nitrogen Oxide Species) action effect. ROS and RNOS are generated in the course of pancreas inflammation.     

Childhood‐onset hereditary pancreatitis with mutations in the CT gene and SPINK1 gene

Hereditary pancreatitis (HP) is an autosomal‐dominant gene disorder. The affected genes have been identified as the cationic trypsinogen (CT) gene and the serine protease inhibitor Kazal type 1 (SPINK1) gene. These gene abnormalities alone, however, do not necessarily regulate the onset or severity of pancreatitis, suggesting the involvement of other gene abnormalities and environmental factors. Reported herein is the case of a 9‐year‐old boy with early‐onset HP due to mutations in the CT and SPINK1 genes. The patient had a p.R122H heterozygous mutation in the CT gene and a p.N34S heterozygous mutation in the SPINK1 gene. The father had heterozygous mutation of the SPINK1 gene, and the mother had heterozygous mutation of the CT gene, although neither had a prior history of pancreatitis. In this patient, early onset of HP was attributed to the presence of gene abnormalities in the CT and SPINK1 genes.     

Hereditary pancreatitis

Hereditary chronic pancreatitis (HCP) is a rare disease in which chronic pancreatitis develops in childhood. HCP has autosomal dominant inheritance with approximately 80% penetrance. Diagnostic criteria are not universally agreed upon but the EUROPAC trial defined it as two first-degree relatives or at least 3 second-degree relatives in two or more generations, with chronic pancreatitis for which there is no other etiology. The gene for HCP was originally identified on chromosome 7 and subsequently many other genes have been reported to be associated with HCP. To date, no single genetic alteration has been found that is necessary for the development of HCP. In a recent study, 81% of patients with HCP were found to have a mutation of the PRSS1 gene. Patients with HCP are at risk for developing exocrine and endocrine insufficiency and there is a 50-fold increased risk of pancreatic cancer in HCP patients as compared with the general population.     

Chronic pancreatitis with pancreaticolithiasis and pseudocyst in a 5-year-old boy with homozygous SPINK1 mutation

We report a 5-year-old boy with a 5-month history of symptoms owing to chronic pancreatitis. Abdominal imaging revealed a large pseudocyst in the pancreatic tail and concretions in the main pancreatic duct. Successful endoscopic papillotomy and stent implantation were performed. Genetic testing showed homozygous SPINK1-N34S mutation, which is an established risk factor for chronic pancreatitis.     

Increased serum trypsin and elastase-1 levels in patients undergoing L-asparaginase therapy

Although there is abundant literature on the association of L-asparaginase and acute pancreatitis in patients undergoing chemotherapy, few studies have investigated the usefulness of pancreatic enzyme measurement in the early diagnosis of L-asparaginase-induced acute pancreatitis. We measured levels of serum pancreatic enzymes before, during, and after L-asparaginase therapy in nine children with acute lymphocytic leukaemia or non-Hodgkin lymphoma. Serum levels of amylase, pancreatic isoamylase, and lipase did not change between the 1st and 30th day of L-asparaginase administration. However, the serum trypsin and elastase-1 levels, 10 and 20 days after beginning L-asparaginase therapy, were significantly higher than those prior to therapy. Conclusion L-asparaginase may induce subclinical pancreatitis and the estimation of serum trypsin and elastase-1 may be useful in the early diagnosis of L-asparaginase-induced acute pancreatitis. Received: 15 September 1997 / Accepted in revised form: 15 December 1997     

Atypical CF and CF related diseases

The clinical characteristics of atypical CF are: symptoms that may start in infancy but the disease become clinically significant only after 10 years of age, survival into adulthood, chronic sinopulmonary disease, pancreatic sufficiency, and sweat chloride <60 meq/L. Other patients may present with single organ involvement such as CBAVD, biliary cirrhosis and portal hypertension, chronic or recurrent pancreatitis, giant nasal polyposis or hypochloremic alkalosis. It is recommended to refer such patients for CFTR genotyping, however, absence of known common mutation does not rule out CFTR associated disease, since mutations causing atypical CF are rare and whole genome scan is required for their identification. Nasal PD measurements may be helpful to establish the diagnosis of these patients; however, measurements might be also atypical. Several explanations have been suggested to explain the atypical CF disease.     

The pancreas in cystic fibrosis

The pancreas secretes a bicarbonate-rich fluid containing digestive enzymes via the ampulla of Vater into the duodenum. Defective secretion leads to maldigestion of fat and protein with increased faecal losses. Cystic fibrosis (CF) is the major cause of pancreatic exocrine failure in childhood, whereas pancreatic insufficiency in adults is commonly associated with chronic pancreatitis and alcohol ingestion. In cystic fibrosis, pancreatic function correlates with genotype; pancreatic-sufficient (PS) patients have a milder course of respiratory disease, improved survival and lower mean sweat chloride concentrations than those with pancreatic insufficiency. Recent observations suggest that mutant CF alleles are over-represented in patients with chronic pancreatitis. Few show evidence of sino-pulmonary disease or high sweat electrolyte concentrations.     

Early decline of pancreatic function in cystic fibrosis patients with class 1 or 2 CFTR mutations

BACKGROUND: Most cystic fibrosis (CF) patients develop steatorrhea and require pancreatic enzyme replacement therapy. However, there are few data regarding the decline of exocrine pancreatic function within the first years of life in relation to CF genotype. We assessed the decline of pancreatic function in CF infants carrying class 1 or 2 CFTR mutations who were diagnosed in a neonatal screening program. MATERIALS AND METHODS: Twenty-eight CF patients were included in the study and 27 completed the study. In all subjects, fecal pancreatic elastase-1 concentrations and fecal fat excretion were scheduled to be determined at diagnosis, at 6 months of age and subsequently at 6-month intervals. RESULTS: In all CF patients, fecal pancreatic elastase-1 concentrations of the first assay after diagnosis (3 to 4 months of age) were lower than the cut-off level for normals of <200 microg/g stool. Steatorrhea was found in 81.5% of these subjects. At the age of 6 months, all screened CF subjects had fecal pancreatic elastase-1 concentrations <100 microg/g and at the age of 12 months all were pancreatic insufficient. At that time, having proved pancreatic insufficiency in all studied subjects, we stopped the scheduled further assessment. CONCLUSION: CF patients require careful monitoring of pancreatic status from diagnosis onwards. In patients carrying class 1 or 2 CFTR mutations, pancreatic insufficiency develops in the first months of life. The proper assessment of pancreatic insufficiency and intestinal malabsorption is crucial for the early introduction of pancreatic enzymes.     

Acute recurrent pancreatitis and heterozygous mutation of the cystic fibrosis gene: a case report]

Recurrent pancreatitis is seldom associated with CFTR (Cystic Fibrosis Transmembrane Regulator) gene mutation. CASE REPORT: A 17-year-old boy presented with isolated idiopathic pancreatitis. CFTR gene mutations study revealed delta F508 heterozygous mutation. CONCLUSION: Mutations for the CFTR gene should be explored in case of recurrent pancreatitis.     

Gallstone pancreatitis in children: atypical presentation and review

Pancreatitis in children is less common than in adults and is mostly related to trauma, infection and anatomical anomalies. Gallstone pancreatitis is an even rarer entity in infants and children. We present an unusual case of gallstone pancreatitis in a 17- month-old girl who presented with jaundice of 1 month duration. The laboratory studies showed conjugated hyperbilirubinaemia with associated acute pancreatitis and pseudo-hyponatraemia secondary to the markedly elevated lipid profile. Further evaluations revealed obstruction at the Ampulla of Vater with no evidence of a choledochal cyst and no mass lesion seen in the pancreas. The patient initially underwent urgent decompressive cholecystostomy with intraoperative cholecystography. When the biochemical parameters improved, the patient underwent formal cholecystectomy with common bile duct exploration, extraction of multiple impacted stones in the ampullary region and Fogarty balloon sphincterotomy. The post-operative course was uneventful. Conclusion:Acute gallstone pancreatitis in children may present as jaundice or abdominal pain. Recognition, early diagnosis and surgical intervention are the mainstay for a good outcome.     

Pancreatitis: etiology, diagnosis, and management.

Inflammation of the pancreas (pancreatitis) has many presentations in children and adolescents, ranging from intrauterine congenital onset with sequelae of early exocrine pancreatic insufficiency as in the diseases of cystic fibrosis and Shwachman-Diamond syndrome to postnatal onset as a consequence of embryologic anomalies affecting pancreatic drainage postulated to exist in pancreas divisum, or of traumatic, obstructive, hemodynamic, metabolic or biochemical insults. The etiology is often elusive with up to 30% of cases being idiopathic. Modern imaging modalities of endoscopic ultrasonography and magnetic resonance cholangiopancreatography extend the diagnostic power of conventional abdominal ultrasonography and computed tomography. In addition, there is increasing pediatric experience with endoscopic retrograde cholangiopancreatography. Medical management remains supportive, with optimal timing and indications for surgery in cases of pancreatic necrosis and pseudocyst assessed. Three temporal patterns of pancreatitis appear in children: acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis. Acute pancreatitis is of abrupt onset, often attributable to a specific cause, and of variable severity and duration but self-limited with eventual resolution. Acute attacks of pancreatitis recurring after periods of remission characterize acute recurrent pancreatitis and indicate an intrinsic problem or susceptibility. Chronic pancreatitis is present in most of these cases in which pancreatic inflammation and destruction never completely remits.     

Fecal elastase-1: a useful test in pediatric practice]

AIM: To study fecal elastase-1 (E1F) and chymotrypsin (ChT) in stools for the diagnosis of pancreatic insufficiency in pediatric practice. MATERIALS AND METHODS: E1F and ChT were measured in stools of 198 children divided in 3 groups: 49 children without any digestive disease (group A), 71 children with pancreatic diseases (group B), and 78 children with non-pancreatic digestive diseases (group C). RESULTS: In group B, E1F values were very low in 64 children and normal in 7 children without pancreatic insufficiency (6 children with cystic fibrosis and 1 with chronic pancreatitis). ChT values were normal in children without pancreatic insufficiency but also in half of children treated with pancreatic enzymes. Decreased E1F values were seen in 2 children (4%) in the group A and 22 children (28%) in the group C, especially those with acute gastroenteritis or celiac disease. CONCLUSION: E1F is a simple, non-invasive, useful tool for the diagnosis of pancreatic insufficiency in children with growth failure or chronic diarrhea, and those with cystic fibrosis. Nevertheless, low values may be found in diseases with villous atrophy or very liquid stools.     

Phenotype of CF and the effects of possible modifier genes

Cystic fibrosis is an inherited multi-system disease, characterised by progressive lung disease and pancreatic insufficiency that is classically attributed to the dysfunction of a single gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). The widely diverse phenotypic expression of CF is likely influenced by other genetic traits separate from the CFTR locus or modifier genes. Many of the genes currently under study as potential modifiers of CF, particularly those which influence the severity of lung disease, are involved in the control of infection, immunity and inflammation. Some of these include HLA class II antigens, mannose-binding lectin, alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, glutathione-S-transferase, nitric oxide synthase type I, TNF-alpha, TGF-beta, IL-1beta and IL-1Ra.     

Multidisciplinary management of surgical disorders of the pancreas in childhood

OBJECTIVES: To describe the frequency and range of pancreatic disorders in children requiring surgical intervention and to highlight the importance of multidisciplinary management. METHODS: An audit of all children under 17 years of age referred with surgical disorders of the pancreas or pancreatitis to a regional pediatric gastroenterology unit in the United Kingdom during a 10-year period. A retrospective chart review of clinical features, pathology and outcome was undertaken. RESULTS: Surgical intervention was required for the following pancreatic disorders: persistent hyperinsulinemic hypoglycemia of infancy (n = 4), pancreatic tumors (n = 5), pancreaticobiliary malunion (n = 12), pancreatic trauma (n = 6) and pancreatitis (n = 10). The indications for surgery in acute pancreatitis were a persistent pseudocyst (n = 1) and treatment of an underlying cause of pancreatitis (n = 4); in chronic pancreatitis, surgery was used to treat symptomatic pancreatic duct strictures (n = 4). One child died of a progressive lymphoma but all others who underwent surgery are alive and well. All 33 children with acute pancreatitis, including four with pancreatic necrosis, survived. CONCLUSIONS: Surgery for pancreatic disorders in children is rarely required but may be necessary a) for definitive management of primary pancreatic pathology, b) to treat sequelae of acute or chronic pancreatitis and c) to treat an underlying cause of pancreatitis. There is a broad spectrum of potential pathologies. These patients are best managed by a multidisciplinary team approach.     

Endoscopic ultrasonography in a child with chronic pancreatitis

In a case with chronic pancreatitis and pseudocysts related to muscular cytochrome—c oxidase deficiency, endoscopic ultrasonography (EUS) was performed to morphologically examine the pancreas for features that may have been missed by abdominal computed tomography and pancreatography. Conventional abdominal sonography had failed to show valuable diagnostic information of chronic pancreatitis in this case. EUS demonstrated several new findings. Parenchymal atrophy was remarkable, especially in the pancreatic tail, and a dilated pancreatic main or branch duct was clearly found in the region. Moreover, pancreatic stones in the main duct were also distinctly proved. EUS may become a useful new diagnostic method in pediatric gastroenterology, especially when sufficient findings are not obtained by conventional imaging techniques. However, an ultrasonographic endoscope with a shorter rigid portion and smaller caliber should be developed for pediatric patients.     

Why not choledochal cyst?

With excision as a standard procedure for treating choledochal cyst, early diagnosis becomes a central issue in reducing morbidity and mortality from that disorder. In a retrospective analysis of 35 patients treated over a 10-year period, we found the diagnosis was delayed for an average of 11.9 months from the beginning of presenting symptoms. Three factors were responsible: (1) a random combination of non specific presenting symptoms such as pain and vomiting or jaundice and hepatomegaly frequently led to a diagnosis such as acute pancreatitis or hepatitis, in which conservative treatment was considered most appropriate; (2) the three parameters commonly used to diagnose acute pancreatitis (serum amylase, lipase, and Cam/Ccr) may all be elevated in patients with a choledochal cyst; and (3) a combination of several noninvasive examinations such as radionuclide cholescintigraphy, ultrasonography, and upper gastrointestinal X-rays may fail to diagnose some difficult cases of choledochal cyst. To obviate such problems, we recommend a routine ultrasound examination of biliary tract in children with recurrent or progressive obstructive jaundice or unexplained acute pancreatitis. When these noninvasive examinations fail to solve the problem, endoscopic retrograde cholangiopancreatography should be considered. Offprint requests to: J.-H. Chuang