Pancreatic exocrine insufficiency, diabetes mellitus and serum nutritional markers after acute pancreatitis

AIM: To investigate impairment and clinical significance of exocrine and endocrine pancreatic function in patients after acute pancreatitis (AP).

Yield of testing for micronutrient deficiencies associated with pancreatic exocrine insufficiency in a clinical setting: An observational study

BACKGROUND Pancreatic exocrine insufficiency(PEI)can be difficult to diagnose and causes maldigestion symptoms and malabsorption.There has been a number of studies that have identified PEI associated micronutrient deficiencies(PEI-MD),however there is variation in both the frequency and type of PEI-MD reported,with the majority of studies including patients with PEI due to chronic pancreatitis(CP)or CP without PEI.There is a paucity of information regarding the prevalence of PEIMD in patients with PEI without CP and the yield of testing for PEI-MD in a clinical setting in patients with suspected benign pancreatic diseases.AIM To prospectively assess the yield and type of PEI–MD in patients with and without PEI secondary to benign pancreatic disease.METHODS Patients investigated for maldigestion symptoms with Faecal Elastase-1(FEL-1)and suspected or proven benign pancreatic disease were prospectively identified.At the time of FEL-1 testing,serum samples were taken for micronutrients identified by previous studies as PEI-MD:prealbumin,retinol binding protein,copper,zinc,selenium,magnesium and later in the study lipid adjusted vitamin E.FEL-1 was recorded,with a result<200μg/g considered diagnostic of PEI.Patients underwent computed tomography(CT)imaging when there was a clinical suspicion of CP,a new diagnosis of PEI recurrent,pancreatic type pain(epigastric abdominal pain radiating to back with or without previous acute pancreatitis attacks)or weight loss.RESULTS After exclusions,112 patients were recruited that underwent testing for FEL-1 and PEI-MD.PEI was identified in 41/112(36.6%)patients and a pancreatic CT was performed in 82 patients.Overall a PEI-MD was identified in 21/112(18.8%)patients.The yield of PEI-MD was 17/41(41.5%)if PEI was present which was significantly higher than those without 4/71(5.6%)(P=0.0001).The yield of PEI–MD was significantly higher when PEI and CP were seen together 13/22(59.1%)compared to CP without PEI and PEI without CP(P<0.03).Individual micronutrient assessment showed a more frequent occurrence of prealbumin 8/41(19.5%),selenium 6/41(14.6%)and magnesium 5/41(12.2%)deficiency when PEI was present(<0.02).The accuracy of using the significant micronutrients identified in our cohort as a predictor of PEI showed a positive predictive value of 80%-85.7%[95%confidence interval(CI):38%-100%]and a low sensitivity of 9.8%-19.5%[95%CI:3.3%-34.9%].CONCLUSION Testing for PEI-MD in patients with suspected pancreatic disease has a high yield,specifically when PEI and CP are found together.PEI-MD testing should include selenium,magnesium and prealbumin.

Associations with pancreatic exocrine insufficiency:An United Kingdom single-centre study

BACKGROUND Pancreatic exocrine insufficiency(PEI)is said to be associated with numerous conditions both within and outside the gastrointestinal(GI)system.The majority of research has been concerned with conditions that reduce the volume of functioning pancreatic tissue or prevent adequate drainage to the small bowel,such as chronic pancreatitis,cystic fibrosis,pancreatic cancer and pancreatic resection.However,the evidence base supporting an association with extrapancreatic conditions,such as coeliac disease,diabetes mellitus and congestive cardiac failure,is heterogeneous.AIM To strengthen the evidence base by studying all previously reported associations with PEI in a large cohort of outpatients.METHODS A single-centre retrospective study was performed.General gastroenterology outpatients tested for PEI with faecal elastase-1(FE1)were identified and information retrieved from the electronic patient record.PEI was defined as FE1<200μg/g.Patients already taking pancreatic enzyme replacement therapy were excluded.Multiple imputation was used to handle missing data.Univariable logistic regression was used to study which presenting symptoms predicted PEI.Multivariable logistic regression was used to explore the relationship between all previously reported associations and PEI.RESULTS Of 1027 patients were included.182 patients(17.7%)were diagnosed with PEI.Steatorrhoea[odds ratios(OR):2.51,95%confidence intervals(CI):1.58-3.98]and weight loss(OR:1.49,95%CI:1.08-2.06)were the only presenting symptoms that predicted PEI.Chronic pancreatitis(OR:7.98,95%CI:3.95-16.15),pancreatic cancer(OR:6.58,95%CI:1.67-25.98),upper GI surgery(OR:2.62,95%CI:1.32-5.19),type 2 diabetes(OR:1.84,95%CI:1.18-2.87),proton pump inhibitor therapy(OR:1.87,95%CI:1.25-2.80)and Asian ethnicity(OR:2.11,95%CI:1.30-3.42)were significantly associated with PEI in the multivariable analysis.None of the other historically reported associations with PEI were significant after adjustment for the other variables included in our multivariable analysis.CONCLUSION PEI is common in patients with chronic pancreatitis,pancreatic cancer,upper GI surgery and type 2 diabetes.Proton pump inhibitor therapy may also be associated with PEI or a false positive FE1.

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.

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).

A Chinese consensus statement on the diagnosis and treatment of pancreatic exocrine insufficiency after pancreatic surgery(2018)

A consensus statement on the diagnosis and treatment of pancreatic exocrine insufficiency(PEI)after pancreatic surgery was developed based on the latest references,combined with China’s actual situation.More than 20 Chinese excellent experts participated in this work and contributed many thorough discussions.This consensus discusses the definition,epidemiology,diagnosis,treatment,and follow-up of PEI after pancreatic surgery.The authors hope this consensus will promote the standard procedure of diagnosis and treatment of PEI in China.

Less common etiologies of exocrine pancreatic insufficiency

Exocrine pancreatic insufficiency(EPI), an important cause of maldigestion and malabsorption, results from primary pancreatic diseases or secondarily impaired exocrine pancreatic function. Besides cystic fibrosis and chronic pancreatitis, the most common etiologies of EPI, other causes of EPI include unresectable pancreatic cancer, metabolic diseases(diabetes); impaired hormonal stimulation of exocrine pancreatic secretion by cholecystokinin(CCK); celiac or inflammatory bowel disease(IBD) due to loss of intestinal brush border proteins; and gastrointestinal surgery(asynchrony between motor and secretory functions, impaired enteropancreatic feedback, and inadequate mixing of pancreatic secretions with food). This paper reviews such conditions that have less straightforward associations with EPI and examines the role of pancreatic enzyme replacement therapy(PERT). Relevant literature was identified by database searches. Most patients with inoperable pancreatic cancer develop EPI(66%-92%). EPI occurs in patients with type 1(26%-57%) or type 2 diabetes(20%-36%) and is typically mild to moderate; by definition, all patients with type 3 c(pancreatogenic) diabetes have EPI. EPI occurs in untreated celiac disease(4%-80%), but typically resolves on a gluten-free diet. EPI manifests in patients with IBD(14%-74%) and up to 100% of gastrointestinal surgery patients(47%-100%; dependent on surgical site). With the paucity of published studies on PERT use for these conditions, recommendations for or against PERT use remain ambiguous. The authors conclude that there is an urgent need to conduct robust clinical studies to understand the validity and nature of associations between EPI and medical conditions beyond those with proven mechanisms, and examine the potential role for PERT.

Exocrine pancreatic function during the early recovery phase of acute pancreatitis

BACKGROUND:Exocrine pancreatic dysfunction has been reported in humans in the convalescent period after acute pancreatitis,but the data are scarce and conflicting.This study aimed to prospectively assess the exocrine pancreatic function in patients with acute pancreatitis at the time of their refeeding. METHODS:Fecal elastase-1 was determined on the day of refeeding in all consecutive acute pancreatitis patients with their first episode of the disease.They were 75 patients including 60(80.0%)patients with mild acute pancreatitis and 15(20.0%)patients with severe acute pancreatitis. Etiologically 61 patients(81.3%)had biliary disease,1(1.3%) had alcoholic disease and 3(4.0%)had hypertriglyceridemia. No causes of acute pancreatitis were found in the remaining 10 patients(13.3%).The mean(±SD)refeeding time after the attack of acute panereatitis was 11.2±10.2 days. RESULTS:Pathological values of FE-1 were found in 9 of the 75 patients(12.0%):7(9.3%)patients with mild pancreatitis and 2(2.7%)patients with severe pancreatitis(P=1.000). The frequency of the pathological values of fecal elastase-1 was significantly different from that of various etiologies of the disease(P=0.030).It was significantly lower in patients with biliary pancreatitis(9.8%;P=0.035)than in one patient with alcoholic pancreatitis(P=0.126),one patient with hypertriglyceridemia-induced pancreatitis(33.3%; P=0.708),and one patient with idiopathic pancreatitis (10.0%;P=0.227).Pathological fecal elastase-1 was not significantly related to sex,age or day of refeeding.CONCLUSION:Exocrine pancreatic function should be routinely assessed in patients with acute pancreatitis at the time of refeeding in order to supplement their diet with pancreatic extracts.

Relationship between the exocrine and endocrine pancreas after acute pancreatitis

AIM: To determine the prevalence and time course of pancreatic exocrine insufficiency in individuals with newly diagnosed prediabetes or diabetes mellitus after acute pancreatitis.

Update on endoscopic pancreatic function testing

Hormone-stimulated pancreatic function tests (PFTs) are considered the gold standard for measuring pancreatic exocrine function. PFTs involve the administration of intravenous secretin or cholecystokinin, followed by collection and analysis of pancreatic secretions. Because exocrine function may decline in the earliest phase of pancreatic fibrosis, PFTs are considered accurate for diagnosing chronic pancreatitis. Unfortunately, these potentially valuable tests are infrequently performed except at specialized centers, because they are time consuming and complicated. To overcome these limitations, endoscopic PFT methods have been developed which include aspiration of pancreatic secretions through the suction channel of the endoscope. The secretin endoscopic pancreatic function test (ePFT) involves collection of duodenal aspirates at 15, 30, 45 and 60 min after secretin stimulation. A bicarbonate concentration greater than 80 mmol/L in any of the samples is considered a normal result. The secretin ePFT has demonstrated good sensitivity and specificity compared with various reference standards, including the "Dreiling tube" secretin PFT, endoscopic ultrasound, and surgical histology. Furthermore, a standard autoanalyzer can be used for bicarbonate analysis, which allows the secretin ePFT to be performed at any hospital. The secretin ePFT may complement imaging tests like endoscopic ultrasound (EUS) in the diagnosis of early chronic pancreatitis.This paper will review the literature validating the use of ePFT in the diagnosis of exocrine insufficiency and chronic pancreatitis. Newer developments will also be discussed, including the feasibility of combined EUS/ ePFT, the use of cholecystokinin alone or in combination with secretin, and the discovery of new protein and lipid pancreatic juice biomarkers which may complement traditional fluid analysis.

The in vitro digestion fates of diacylglycerol under different intestinal conditions:a potential lipid source for lipid indigestion patients

The in vitro digestion models mimicking the gastrointestinal(GI)tract of general population and lipid indigestion patients(with lower levels of bile salts or pancreatic lipase)were selected to investigate whether diacylglycerols(DAGs)are potential good lipid sources for these patients.Linseed oil-based DAG(LD)and linseed oil(LT)were selected.LD-based emulsion((83.74±1.23)%)had higher lipolysis degree than LT-based emulsion((74.47±1.16)%)when monitoring the GI tract of normal population as previously reported.Indigestion conditions seriously decreased the digestive degree of LT-based emulsion((40.23±2.48)%-(66.50±3.70)%)while showed less influence on LD-based emulsion((64.18±2.41)%-(81.85±3.45)%).As opposed to LT-based emulsion,LD-based emulsion exhibited preference for releasing unsaturated fatty acids(especially oleic acid andα-linolenic acid)due to their different glycerolipid compositions.LD-based emulsion showed potential for providing lipids and nutrients(including essential fatty acids)for lipid indigestion patients.

Pancreatic disorders in inflammatory bowel disease

An increased incidence of pancreatic disorders either acute pancreatitis or chronic pancreatitis has been recorded in patients with inflammatory bowel disease (IBD) compared to the general population. Although most of the pancreatitis in patients with IBD seem to be related to biliary lithiasis or drug induced, in some cases pancreatitis were defined as idiopathic, suggesting a direct pancreatic damage in IBD. Pancreatitis and IBD may have similar presentation therefore a pancreatic disease could not be recognized in patients with Crohn&rsquo;s disease and ulcerative colitis. This review will discuss the most common pancreatic diseases seen in patients with IBD.

Staging chronic pancreatitis with exocrine function tests: Are we better?

Chronic pancreatitis(CP) is an inflammatory disease of the pancreas evolving in progressive fibrotic disruption of the gland with exocrine and endocrine pancreatic insufficiency. Although imaging features of CP are well known, their correlation with exocrine pancreatic function tests are not obvious, particularly in the early stage of the disease. There are many clinical classification of CP, all suggested for better distinguish and manage different forms based on etiological and clinical factors, and severity of the disease. Recently, a new classification of CP has been suggested: the M-ANNHEIM multiple risk factor classification that includes etiology, stage classification and degree of clinical severity. However, more accurate determination of clinical severity of CP requires a correct determination of exocrine function of the pancreas and fecal fat excretion. Recently, Kamath et al demonstrated that the evaluation of exocrine pancreatic function by acid steatocrit and fecal elastase-1(EF-1) was helpful, but EF-1 was able to detect exocrine pancreatic insufficiency in more patients, upgrading some patients in higher stage of disease according to M-ANNHEIM classification. So, EF-1 is a more accurate test to determine exocrine pancreatic insufficiency and to stage chronic pancreatitis in the M-ANNHEIM classification. On the contrary, EF-1 determination shows low sensitivity in detecting exocrine pancreatic insufficiency in early stage of the disease.

Perioperative Care of the Adult Patient with Johanson-Blizzard Syndrome

Johanson-Blizzard syndrome (JBS) is a rare genetic disorder characterized by multiple craniofacial abnormalities, intellectual disability, sensorineural hearing loss, pancreatic exocrine insufficiency, and involvement of other organ systems to varying degrees. Patients with JBS may require surgical intervention to address the underlying phenotypic abnormalities. The many craniofacial abnormalities found in patients with JBS are a concern for the anesthesiologist. We present the case of an adult patient with JBS who is undergoing implantation of a leadless pacemaker. Considering the many cardiac and craniofacial abnormalities in these patients, the anesthesiologist should order diagnostic tests such as echocardiography to assess cardiac function, as well as be prepared to perform advanced airway techniques for difficult airways. The anesthetic provider should be aware of the varied phenotypic expression of JBS and should individualize the anesthetic plan to each patient. Prior medical literature on the anesthetic management of these patients is scarce and limited to pediatric patients. This is the first case report addressing anesthetic concerns in an adult patient with JBS.

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.

Chronic pancreatitis and the heart disease:Still terra incognita?

BACKGROUND It has been suggested that chronic pancreatitis(CP)may be an independent risk factor for development of cardiovascular disease(CVD).At the same time,it seems that congestive heart failure(CHF)and CP share the responsibility for the development of important clinical conditions such as sarcopenia,cachexia and malnutrition due to development of cardiac cachexia and pancreatic exocrine insufficiency(PEI),respectively.AIM To explore the evidence regarding the association of CP and heart disease,more specifically CVD and CHF.METHODS A systematic search of MEDLINE,Web of Science and Google Scholar was performed by two independent investigators to identify eligible studies where the connection between CP and CVD was investigated.The search was limited to articles in the English language.The last search was run on the 1st of May 2019.The primary outcomes were:(1)Incidence of cardiovascular event[acute coronary syndrome(ACS),chronic coronary disease,peripheral arterial lesions]in patients with established CP;and(2)Incidence of PEI in patients with CHF.RESULTS Out of 1166 studies,only 8 were eligible for this review.Studies regarding PEI and CHF showed an important incidence of PEI as well as associated malabsorption of nutritional markers(vitamin D,selenium,phosphorus,zinc,folic acid,and prealbumin)in patients with CHF.However,after substitution of pancreatic enzymes,it seems that,at least,loss of appetite was attenuated.On the other side,studies investigating cardiovascular events in patients with CP showed that,in CP cohort,there was a 2.5-fold higher incidence of ACS.In another study,patients with alcohol–induced CP with concomitant type 3c diabetes had statistically significant higher incidence of carotid atherosclerotic plaques in comparison to patients with diabetes mellitus of other etiologies.Earlier studies demonstrated a marked correlation between the clinical symptoms in CP and chronic coronary insufficiency.Also,statistically significant higher incidence of arterial lesions was found in patients with CP compared to the control group with the same risk factors for atherosclerosis(hypertension,smoking,dyslipidemia).Moreover,one recent study showed that PEI is significantly associated with the risk of cardiovascular events in patients with CP.CONCLUSION Current evidence implicates a possible association between PEI and malnutrition in patients with CHF.Chronic pancreatic tissue hypoxic injury driven by prolonged splanchnic hypoperfusion is likely to contribute to malnutrition and cachexia in patients with CHF.On the other hand,CP and PEI seem to be an independent risk factor associated with an increased risk of cardiovascular events.

Impact of parenchyma-preserving surgical methods on treating patients with solid pseudopapillary neoplasms:A retrospective study with a large sample size

BACKGROUND Solid pseudopapillary neoplasm of the pancreas(SPN)is a rare neoplasm that mainly affects young women.AIM To evaluate the impact of parenchyma-preserving surgical methods(PPMs,including enucleation and central pancreatectomy)in the treatment of SPN patients.METHODS From 2013 to 2019,patients who underwent pancreatectomy for SPNs were retrospectively reviewed.The baseline characteristics,intraoperative index,pathological outcomes,short-term complications and long-term follow-up data were compared between the PPM group and the conventional method(CM)group.RESULTS In total,166 patients were included in this study.Of them,33 patients(19.9%)underwent PPM.Most of the tumors(104/166,62.7%)were found accidentally.Comparing the parameters between groups,the hospital stay d(12.35 vs 13.5 d,P=0.49),total expense(44213 vs 54084 yuan,P=0.21),operation duration(135 vs 120 min,P=0.71),and intraoperative bleeding volume(200 vs 100 mL,P=0.49)did not differ between groups.Regarding pathological outcomes,tumor size(45 vs 32 mm,P=0.07),Ki67 index(P=0.53),peripheral tissue invasion(11.3%vs 9.1%,P=0.43)and positive margin status(7.5%vs 6%,P=0.28)also did not differ between groups.Moreover,PPM did not increase the risk of severe postoperative pancreatic fistula(3.8%vs 3.0%,P=0.85)or tumor recurrence(3.0%vs 6.0%,P=0.39).However,the number of patients who had exocrine insufficiency during follow-up was significantly lower in the PPM group(21.8%vs 3%,P=0.024).CM was identified as an independent risk factor for pancreatic exocrine insufficiency(odds ratio=8.195,95%confident interval:1.067-62.93).CONCLUSION PPM for SPN appears to be feasible and safe for preserving the exocrine function of the pancreas.

Johanson-Blizzard syndrome

Johanson-Blizzard syndrome(JBS) is a rare autosomal recessive disease characterized by exocrine pancreatic insufficiency,hypoplastic or aplastic nasal alae,cutis aplasia on the scalp,and other features including developmental delay,failure to thrive,hearing loss,mental retardation,hypothyroidism,dental abnormalities,and anomalies in cardiac and genitourinary systems.More than 60 cases of this syndrome have been reported to date.We describe the case of a male infant with typical symptoms of JBS.In addition,a new clinical feature which has not previously been documented,that is anemia requiring frequent blood transfusions and mild to moderate thrombocytopenia was observed.A molecular study was performed which revealed a novel homozygous UBR1 mutation.Possible explanations for this new association are discussed.

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.