Acute recurrent pancreatitis:Etiopathogenesis, diagnosis and treatment

Acute recurrent pancreatitis (ARP) refers to a clinical entity characterized by episodes of acute pancreatitis which occurs on more than one occasion. Recurrence of pancreatitis generally occurs in a setting of normal morpho-functional gland, however, an established chronic disease may be found either on the occasion of the first episode of pancreatitis or during the follow-up. The aetiology of ARP can be identified in the majority of patients. Most common causes include common bile duct stones or sludge and bile crystals; sphincter of oddi dysfunction; anatomical ductal variants interfering with pancreatic juice outflow; obstruction of the main pancreatic duct or pancreatico-biliary junction; genetic mutations; alcohol consumption. However, despite diagnostic technologies, the aetiology of ARP still remains unknown in up to 30% of cases: in these cases the term “idiopathic” is used. Because occult bile stone disease and sphincter of oddi dysfunction account for the majority of cases, cholecystectomy, and eventually the endoscopic biliary and/or pancreatic sphincterotomy are curative in most of cases. Endoscopic biliary sphincterotomy appeared to be a curative procedure per se in about 80% of patients. Ursodeoxycholic acid oral treatment alone has also been reported effective for treatment of biliary sludge. In uncertain cases toxin botulin injection may help in identifying some sphincter of oddi dysfunction, but this treatment is not widely used. In the last twenty years, pancreatic endotherapy has been proven effective in cases of recurrent pancreatitis depending on pancreatic ductal obstruction, independently from the cause of obstruction, and has been widely used instead of more aggressive approaches.

Is acute recurrent pancreatitis a chronic disease?

Whether acute recurrent pancreatitis is a chronic disease is still debated and a consensus is not still reached as demonstrated by differences in the classification of acute recurrent pancreatitis. There is major evidence for considering alcoholic pancreatitis as a chronic disease ab initio while chronic pancreatitis lesions detectable in biliary acute recurrent pancreatitis (ARP) seem a casual association. Cystic fibrosis transmembrane con-ductance regulator (CFTR) gene mutation, hereditary and obstructive pancreatitis seem an acute disease that progress to chronic pancreatitis, likely as a consequence of the activation and proliferation of pancreatic stellate cells that produce and activate collagen and therefore fibrosis. From the diagnostic point of view, in patients with acute recurrent pancreatitis Endoscopic ultrasound (EUS) seems the more reliable technique for an accurate evaluation and follow-up of some ductal and parenchymal abnormalities suspected for early chronic pancreatitis.

Role of genetic disorders in acute recurrent pancreatitis

There was remarkable progress in the understanding of the role genetic risk factors in chronic pancreatitis. These factors seem to be much more important than thought in the past. The rare autosomal-dominant mutations N29I and R122H of PRSS1 (cationic trypsinogen) as well as the variant N34S of SPINK1 (pancreatic secretory trypsin inhibitor) are associated to a disease onset in childhood or youth. Compared to chronic alcoholic pancreatitis the progression is slow so that for a long time only signs of acute-recurrent pancreatitis are found. Only at later time points (more than 10-15 years) there is evidence for chronic pancreatitis in the majority of patients. Acute recurrent pancreatitis may therefore be regarded as a transition state until definite signs of chronic pancreatitis are detectable.

Ampullary adenomyoma presenting as acute recurrent pancreatitis

Adenomyoma is a term generally applied to nodular lesions showing proliferation of both epithelial and smooth muscle components. Despite its benign nature,ampullary adenomyoma is usually presented as biliary obstruction. Most cases are misdiagnosed as carcinoma or adenoma by preoperative endoscopic or radiologic procedure. Therefore,it is frequently treated with extensive surgery. To our knowledge,this is the first reported case in English literature of adenomyoma located in the peripancreatic orifice resulting in intermittent pancreatic duct obstruction and recurrent pancreatitis diagnosed by the endoscopic piecemeal resection.

Favorable response after radiation therapy for intraductal papillary mucinous neoplasms manifesting as acute recurrent pancreatitis:A case report

BACKGROUND There has been an increasing number of elderly patients with intraductal papillary mucinous neoplasm(IPMN),who are surgically intolerant and require less invasive treatment options,which are limited.In the present study,we report a case of IPMN presenting with acute recurrent pancreatitis(ARP),in which radiation therapy effectively prevented further attacks of ARP and reduced tumor volume.CASE SUMMARY An 83-year-old man was referred to our hospital with an asymptomatic incidental pancreatic cyst.Endoscopic ultrasound imaging and magnetic resonance cholangiopancreatography revealed a multiloculated tumor in the head of the pancreas,with dilated pancreatic ducts and mural nodules.The patient was diagnosed with mixed-type IPMN,and five years later,he developed ARP.Several endoscopic pancreatic ductal balloon dilatations failed to prevent further ARP attacks.Surgery was considered clinically inappropriate because of his old age and comorbidities.He was referred to our department for radiation therapy targeted at those lesions causing intraductal hypertension and radiation was administered at a dose of 50 Gy.An magnetic resonance imaging scan taken ten weeks after treatment revealed a decrease in tumor size and improvement of pancreatic duct dilatation.Fourteen months later,he remains symptom-free from ARP.CONCLUSION This case highlights the important role of radiation therapy in mitigating the signs and symptoms of ARP in patients with inoperable IPMN.

Diagnostic approach to patients with acute idiopathic and recurrent pancreatitis,what should be done?

Acute recurrent pancreatitis (ARP) is a common clinical condition that may be difficult to diagnose. Endoscopic ultrasound (EUS) is proposed to be a safe first line test of choice in the majority of patients. When interventions are needed to remove biliary stones, evaluate sphincter of Oddi or pancreas divisum, endoscopic retrograde cholangiopancreatography (ERCP) is recommended. Magnetic resonance cholangiopancreatography (MRCP) can be a suitable alternative from a diagnostic standpoint although may not be widely available. Finally, genetic testing is increasingly used to detect certain mutations that are associated with this diagnosis.

Effect of acetyl-L-carnitine on hypersensitivity in acute recurrent caerulein-induced pancreatitis and microglial activation along the brain’s pain circuitry

BACKGROUND Acute pancreatitis(AP)and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis.The validated caerulein-(CAE)induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.AIM To determine efficacy of acetyl-L-carnitine(ALC)to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.METHODS Pancreatitis was induced with 6 hly intraperitoneal(i.p.)injections of CAE(50μg/kg),3 d a week for 6 wk in male C57BL/6J mice.Starting in week 4,mice received either vehicle or ALC until experiment’s end.Mechanical hypersensitivity was assessed with von Frey filaments.Heat hypersensitivity was determined with the hotplate test.Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests.Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1(Iba1).RESULTS Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies,indicating ongoing pain.Treatment with ALC attenuated inflammation-induced hypersensitivity,but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted.Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls.Treatment with ALC resulted in increased numbers of rearing activity events,but time spent in“safety”was not changed.After all the abdominal injections,pancreata were translucent if excised at experiment’s end and opaque if excised on the subsequent day,indicative of spontaneous healing.Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC.Microglial Iba1 immunostaining was significantly increased in hippocampus,thalamus(intralaminar nuclei),hypothalamus,and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.CONCLUSION CAE-induced pancreatitis caused increased pain-related behaviors,pancreatic fibrosis,and brain microglial changes.ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.

PRSS1 and SPINK1 mutations in idiopathic chronic and recurrent acute pancreatitis

AIM: To identify gene mutations in PRSS1 and SPINK1 in individuals with early onset idiopathic chronic or recurrent acute pancreatitis.

Continuing episodes of pain in recurrent acute pancreatitis: Prospective follow up on a standardised protocol with drugs and pancreatic endotherapy

AIM To assess the outcomes of drug therapy(DT)followed by pancreatic endotherapy for continuing painful episodes in recurrent acute pancreatitis.METHODS DT comprised of pancreatic enzymes and antioxidants failing which,endotherapy(ET;pancreatic sphincterotomy and stent placement)was done.The frequency of pain,its visual analogue score(VAS),quality of life(Qo L),serum C peptide and faecal elastase were compared between baseline and after 1 year of follow up in all patients and in the two subgroups on DT and ET.Response was defined as at least 50%reduction in the severity of pain to below a score of 5.RESULTS Of the thirty nine patients analysed,21(53.9%)responded to DT and 18(46.1%)underwent ET.The VAS for pain(7.0±2.0 vs 1.3±2.5,P<0.001)and the number of days with pain per month decreased[1.0(1.0,2.0)vs 1.0(0.0,1.0),P<0.001],and the Qo L scores[55.0(44.0,66.0)vs 38.0(32.00,51.00),P<0.01]improved significantly during follow up.Similar significant improvements were seen in patients in the subgroups of DT and ET except for Qo L in ET.The serum C-peptide(P=0.001)and FE(P<0.001)levels improved significantly in the entire group and in the two subgroups of patients except for the C peptide levels in patients on DT.CONCLUSION A standardised protocol of DT,followed by ET decreased the intensity and frequency of pain in recurrent acute pancreatitis,enhanced Qo L and improved pancreatic function.

Endoscopic ultrasonography for evaluating patients with recurrent pancreatitis

Acute recurrent pancreatitis (ARP) is still a complex diagnostic and therapeutic challenge in clinical practice. In up to 30% of cases of ARP, it is not possible to establish the etiology of the disease. In the other 70%, many factors play an etiological role in ARP: microlithiasis, sphincter of Oddi dysfunction (SOD), pancreas divisum, hereditary pancreatitis, cystic fibrosis, a choledochocele, annular pancreas, an anomalous pancreatobiliary junction, pancreatic tumors or chronic pancreatitis are diagnosed. EUS should be useful in ARP as it is sensitive for diagnosing bile duct stones, gallbladder sludge, pancreatic lesions, ductal abnormalities and chronic pancreatitis. Endoscopic ultrasound (EUS) appears to be diagnostic in the majority of patients with previously unexplained pancreatitis, and offers an alternative to endoscopic retrograde cholangiopancreatography (ERCP) as the initial diagnostic test in patients with ARP.

Hereditary pancreatitis:An updated review in pediatrics

Hereditary Pancreatitis(HP)has emerged as a significant cause of acute,acute recurrent and chronic pancreatitis in the pediatric population.Given that it presents similarly to other causes of pancreatitis,a positive family history and/or isolation of a gene mutation are vital in its designation.Inheritance patterns remain complex,but mutations involving the PRSS1,SPINK1,CFTR and CTRC genes are commonly implicated.Since being first described in 1952,dozens of genetic alterations that modify the action of pancreatic enzymes have been identified.Among children,these variants have been isolated in more than 50%of patients with chronic pancreatitis.Recent research has noted that such mutations in PRSS1,SPINK1 and CFTR genes are also associated with a faster progression from acute pancreatitis to chronic pancreatitis.Patients with HP are at increased risk of developing diabetes mellitus,exocrine pancreatic insufficiency,and pancreatic adenocarcinoma.Management follows a multi-disciplinary approach with avoidance of triggers,surveillance of associated conditions,treatment of pancreatic insufficiency and use of endoscopic and surgical interventions for complications.With significant sequela,morbidity and a progressive nature,a thorough understanding of the etiology,pathophysiologic mechanisms,diagnostic evaluation,current management strategies and future research considerations for this evolving disease entity in pediatrics is warranted.

Risk factors and prediction score for chronic pancreatitis: A nationwide population-based cohort study

AIM To explore the risk factors of developing chronic pan-creatitis （CP） in patients with acute pancreatitis （AP） and develop a prediction score for CP.METHODS Using the National Health Insurance Research Database in Taiwan, we obtained large, population-based data of 5971 eligible patients diagnosed with AP from 2000 to 2013. After excluding patients with obstructive pancreatitis and biliary pancreatitis and those with a follow-up period of less than 1 year, we conducted a multivariate analysis using the data of 3739 patients to identify the risk factors of CP and subsequently develop a scoring system that could predict the development of CP in patients with AP. In addition, we validated the scoring system using a validation cohort.RESULTS Among the study subjects, 142 patients （12.98%） developed CP among patients with RAP. On the other hand, only 32 patients （1.21%） developed CP among patients with only one episode of AP. The multivariate analysis revealed that the presence of recurrent AP （RAP）, alcoho-lism, smoking habit, and age of onset of 〈 55 years were the four important risk factors for CP. We developed a scoring system （risk score 1 and risk score 2） from the derivation cohort by classifying the patients into low-risk, moderate-risk, and high-risk categories based on similar magnitudes of hazard and validated the performance using another validation cohort. Using the prediction score model, the area under the curve （AUC） [95% confdence interval （CI）] in predicting the 5-year CP incidence in risk score 1 （without the number of AP episodes） was 0.83 （0.79, 0.87）, whereas the AUC （95%CI） in risk score 2 （including the number of AP episodes） was 0.84 （0.80, 0.88）. This result demonstrated that the risk score 2 has somewhat better prediction performance than risk score 1. However, both of them had similar performance between the derivation and validation cohorts.CONCLUSIONIn the study,we identifed the risk factors of CP and devel-oped a prediction score model for CP.