Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21^(st) century

Restitution of normal fat absorption in exocrine pancreatic insufficiency remains an elusive goal. Although many patients achieve satisfactory clinical results with enzyme therapy, few experience normalization of fat absorption, and many, if not most, will require individualized therapy. Increasing the quantity of lipase administered rarely eliminates steatorrhea but increases the cost of therapy. Enteric coated enzyme microbead formulations tend to separate from nutrients in the stomach precluding coordinated emptying of enzymes and nutrients. Unprotected enzymes mix well and empty with nutrients but are inactivated at pH 4 or below. We describe approaches for improving the results of enzyme therapy including changing to, or adding, a different product, adding non-enteric coated enzymes,(e.g., giving unprotected enzymes at the start of the mealand acid-protected formulations later), use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration. Because considerable lipid is emptied in the first postprandial hour, it is prudent to start therapy with enteric coated microbead prior to the meal so that some enzymes are available during that first hour. Patients with hyperacidity may benefit from adjuvant antisecretory therapy to reduce the duodenal acid load and possibly also sodium bicarbonate to prevent duodenal acidity. Comparative studies of clinical effectiveness of different formulations as well as the characteristics of dispersion, emptying, and dissolution of enteric-coated microspheres of different diameter and density are needed; many such studies have been completed but not yet made public. We discuss the history of pancreatic enzyme therapy and describe current use of modern preparations, approaches to overcoming unsatisfactory clinical responses, as well as studies needed to be able to provide reliably effective therapy.

Alteration of chaperonin60 and pancreatic enzyme in pancreatic acinar cell under pathological condition

AIM： To investigate the changes of chaperonin60 （Cpn60） and pancreatic enzymes in pancreatic acinar cells, and to explore their roles in the development of experimental diabetes and acute pancreatitis （AP）. METHODS： Two different pathological models were replicated in Sprague-Dawley rats： streptozotocininduced diabetes and sodium deoxycholate-induced AP. The contents of Cpn60 and pancreatic enzymes in different compartments of the acinar cells were measured by quantitative immunoo/tochemistry. RESULTS： The levels of Cpn60 significanUy increased in diabetes, but decreased in AP, especially in the zymogen granules of the pancreatic acinar cells. The elevation of Cpn60 was accompanied with the increased levels of pancreatic lipase and chymotrypsinogen in diabetes. However, a decreased Cpn60 level was accompanied by high levels of lipase and chymotrypsinogen in AP. The amylase level was markedly reduced in both the pathological conditions. CONCLUSION： The equilibrium between Cpn60 and pancreaUc enzymes in the acinar cells breaks in AP, and Cpn60 content decreases, suggesting an insufficient chaperone capacity. This may promote the aggregation and autoactivation of the premature enzymes in the pancreatic acinar cells and play roles in the development of AR

The Influence of Feed Intake and Conditioned Reflex on Exocrine Pancreatic Function in Broiler Chicks

The data of an experimental study of the influence of feeding and the conditional stimulus on digestive function in birds is presented. It is stated that feed consumption is a powerful stimulator of pancreatic secretion in broiler chicks. The secretory response of the pancreas was the highest in the morning when secretion of pancreatic juice was 1.8 times higher, amylase activity 3.2 times, proteases activity 3.3 times, lipase activity 2.1 times higher than before feeding (basal levels). The regulation of pancreatic activity is known to be complex-reflex with conditioned-reflex component being very important since it provides 25% higher juice secretion and 42% - 74% higher enzyme secretion compared to the basal levels during few minutes after the conditional signal.

Hypothesis that alpha-amylase evokes regulatory mechanisms originating in the pancreas,gut and circulation,which govern glucose/insulin homeostasis

The anti-incretin theory involving the abolishment of diabetes type(DT)II by some of methods used in bariatric surgery,first appeared during the early years of the XXI century and considers the existence of anti-incretin substances.However,to date no exogenous or endogenous anti-incretins have been found.Our concept of the acini-islet-acinar axis assumes that insulin intra-pancreatically stimulates alpha-amylase synthesis(“halo phenomenon”)and in turn,alphaamylase reciprocally inhibits insulin production,thus making alpha-amylase a candidate for being an anti-incretin.Additionally,gut as well as plasma alphaamylase,of pancreatic and other origins,inhibits the appearance of dietary glucose in the blood,lowering the glucose peak after iv or oral glucose loading.This effect of alpha-amylase can be interpreted as an insulin down regulatory mechanism,possibly limiting the depletion of pancreatic beta cells and preventing their failure.Clinical observations agree with the above statements,where patients with high blood alpha-amylase concentrations are seldom obese and seldom develop DT2.Obese-DT2,as well as DT1 patients,usually develop exocrine pancreatic insufficiency(EPI)and vice versa.Ultimately,DT2 patients develop DT1,when the pancreatic beta cells are exhausted and insulin production ceases.Studies on biliopancreatic diversion(BPD)and on BPD with duodenal switch,a type of bariatric surgery,as well as studies on EPI pigs,allow us to observe and investigate the above-mentioned phenomena of intra-pancreatic interactions.

Impacts of pancreatic exocrine insufficiency on gut microbiota

Pancreatic exocrine insufficiency(PEI)can be induced by various kinds of diseases,including chronic pancreatitis,acute pancreatitis,and post-pancreatectomy.The main pathogenetic mechanism of PEI involves the decline of trypsin synthesis,disorder of pancreatic fluid flow,and imbalance of secretion feedback.Animal studies have shown that PEI could induce gut bacterial overgrowth and dysbiosis,with the abundance of Lactobacillus and Bifidobacterium increasing the most,which could be partially reversed by pancreatic enzyme replacement therapy.Clinical studies have also confirmed the association between PEI and the dysbiosis of gut microbiota.Pancreatic exocrine secretions and changes in duodenal p H as well as bile salt malabsorption brought about by PEI may affect and shape the abundance and composition of gut microbiota.In turn,the gut microbiota may impact the pancreatic exocrine acinus through potential bidirectional crosstalk.Going forward,more and higher-quality studies are needed that focus on the mechanism underlying the impact of PEI on the gut microbiota.

The Hong Kong consensus recommendations on the diagnosis and management of pancreatic cystic lesions

Background:The finding of pancreatic cystic lesions(PCL)on incidental imaging is becoming increasingly common.International studies report a prevalence of 2.2-44.7%depending on the population,imaging modality and indication for imaging,and the prevalence increases with age.Patients with PCL are at risk of developing pancreatic cancer,a disease with a poor prognosis.This publication summarizes recommendations for the diagnosis and management of PCL and post-operative pancreatic exocrine insufficiency(PEI)from a group of local specialists.Methods:Clinical evidence was consolidated from narrative reviews and consensus statements formulated during two online meetings in March 2022.The expert panel included gastroenterologists,hepatobiliary surgeons,oncologists,radiologists,and endocrinologists.Results:Patients with PCL require careful investigation and follow-up due to the risk of malignant transformation of these lesions.They should undergo clinical investigation and pancreas-specific imaging to classify lesions and understand the risk profile of the patient.Where indicated,patients should undergo pancreatectomy to excise PCL.Following pancreatectomy,patients are at risk of PEI,leading to gastrointestinal dysfunction and malnutrition.Therefore,such patients should be monitored for symptoms of PEI,and promptly treated with pancreatic enzyme replacement therapy(PERT).Patients with poor response to PERT may require increases in dose,addition of a proton pump inhibitor,and/or further investigation,including tests for pancreatic function.Patients are also at risk of new-onset diabetes mellitus after pancreatectomy;they should be screened and treated with insulin if indicated.Conclusions:These statements are an accurate summary of our approach to the diagnosis and management of patients with PCL and will be of assistance to clinicians treating these patients in a similar clinical landscape.

Isolated Acute Rheumatic Pancreatitis—A Case Report

Aim: To emphasize the role of antibiotics in acute pancreatitis as prophylactic and therapeutic benefits. Case Report: A 32-year-old obese male was admitted with acute abdomen in the emergency room. He was supported with intravenous fluids and the blood chemistry revealed elevated amylase and lipase levels, raised ESR and a positive ASO titer test. CT abdomen suggested interstitial edematous pancreatitis (IEP) and no fluid collection. Patient was treated with IV cefotaxime and IV metronidazole, his condition remarkably improved with therapy, blood parameters returned normal at the end of 4 weeks, and follow-up CT revealed no abnormal findings and symptom free thereafter. Conclusion: Acute pancreatitis is usually a sterile inflammatory process caused by chemical autodigestion of pancreas. The edematous form of acute pancreatitis needs to correct its etiological factor to avoid recurrence. It is observed as an initial manifestation of group A beta hemolytic streptococcal infection in this patient and antibiotics play a role as curative and prophylactic in selected cases.

Pancreatic exocrine insufficiency guidelines:more questions than answers!

Pancreatic exocrine insufficiency(PEI)has classically been described as a maldigestive disorder resulting from decreased secretion or altered function of pancreatic digestive enzymes(1).As a result of this maldigestion and ensuing malabsorption,patients can experience symptoms such as steatorrhea and weight loss as well as complications related to the loss of fat-soluble vitamins and micronutrients.PEI has been most extensively studied in cystic fibrosis,but other causes include acute and chronic pancreatitis(CP),pancreatic adenocarcinoma(PDAC),and rarely,congenital syndromes such as Shwachman-Diamond and Johnson-Blizzard(2).

GSDME with a moonlighting function in pancreatic ductal adenocarcinoma: a narrative review

Pancreatic ductal adenocarcinoma(PDAC)originates in the exocrine pancreas and accounts for 95%of pancreatic cancers,with 5-year survival rates of approximately 10%.Multiple factors are involved in PDAC pathogenesis,including internal genetic alterations and external inflammation-related stimuli.Overflow of exocrine pancreatic enzymes caused by PDAC obstruction inevitably results in autolysis of surrounding normal cells and extracellular matrix,generating tissue damage-related inflammation;however,this process does not cause autolysis of PDAC cells.How tumor cells acquire resistance to pancreatic enzymatic digestion has been ignored for a long time.In this review,we discuss how PDAC cells mobilize gasdermin E,a pore-forming protein,to achieve resistance to autolysis by pancreatic digestive enzymes.

GSDME with a moonlighting function in pancreatic ductal adenocarcinoma:a narrative review

Pancreatic ductal adenocarcinoma(PDAC)originates in the exocrine pancreas and accounts for 95%of pancreatic cancers,with 5-year survival rates of approximately 10%.Multiple factors are involved in PDAC pathogenesis,including internal genetic alterations and external inflammation-related stimuli.Overflow of exocrine pancreatic enzymes caused by PDAC obstruction inevitably results in autolysis of surrounding normal cells and extracellular matrix,generating tissue damage-related inflammation;however,this process does not cause autolysis of PDAC cells.How tumor cells acquire resistance to pancreatic enzymatic digestion has been ignored for a long time.In this review,we discuss how PDAC cells mobilize gasdermin E,a pore-forming protein,to achieve resistance to autolysis by pancreatic digestive enzymes.

From cradle to grave:seamless management of chronic pancreatitis but consider the special requests for children

We have read the position paper by A.Jay Freeman and the members of the Pancreas Nutrition Committee of the North American and the European Societies for Pediatric Gastroenterology,Hepatology,and Nutrition(NASPGHAN and ESPGHAN)(1).That paper focused on chronic pancreatitis(CP)in children and endoscopic procedures about which NASPGHAN published a second position paper(2).There are clinical practice guidelines for the management of CP in adults but not for CP in children(3).

Exocrine pancreatic insufficiency: more compromise than precision

Exocrine pancreatic insufficiency(EPI)can be defined as a reduction in the secretion or intraluminal activity of pancreatic enzymes at a level that does not allow the normal digestion of nutrients contained in food.This condition is difficult to diagnose and treat and has long been misunderstood,underestimated,and overlooked to some extent.