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January 23, 2023

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Discovery of pancreatitis treatment target offers new hope

by Hudson Institute of Medical Research

It's a disease in search of a remedy, but Hudson Institute researchers have identified a new pancreatitis treatment target, giving hope to sufferers worldwide.

Pancreatitis is a serious inflammatory gastrointestinal disorder which can lead to severe conditions , with as many as 20% of patients going on to experience multiple organ failure.

But despite its prevalence and impact, there are no specific and effective therapies to treat or prevent pancreatitis.

Pancreatitis treatment target identified

Now researchers have identified a key enzyme called ADAM17, which acts as a central molecular switch that leads to pancreatic inflammation—giving them a starting point for the development of new drugs to potentially treat pancreatitis.

Hudson Institute researcher, Dr. Mohamed Saad, explains that ADAM17 acts as a "scissor" to cut off particular inflammatory proteins on the cell membranes.

"These released proteins then activate inflammatory processes that lead to the development of pancreatitis," he said.

Drugs to treat pancreatitis

"This discovery paves the way for developing inhibitor drugs that target ADAM17 activity to potentially treat pancreatitis.

"Pancreatitis is a multifactorial inflammatory disorder and a leading cause for gastrointestinal disease -related hospitalization, which is associated with substantial morbidity, mortality, and economic burden ," Dr. Saad said.

"Our research is the first to implicate ADAM17 in the pathogenesis of pancreatitis, and to demonstrate the anti-inflammatory activities of an ADAM17 inhibitor; that gives us hope that we have found the key to new, effective treatments for this condition."

This research was published in the journal Proceedings of the National Academy of Sciences ( PNAS ).

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• Management of chronic...

Management of chronic pancreatitis

• Related content
• Peer review
• O Joe Hines , professor 1 ,
• Stephen J Pandol , professor 2
• 1 Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
• 2 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
• Correspondence to: S J Pandol Stephen.Pandol{at}cshs.org

Chronic pancreatitis results from repeated episodes of pancreatic inflammation and associated fibrosis leading to the loss of functional exocrine and endocrine pancreatic function. The disease is manifested by abdominal pain, deterioration in quality of life, food maldigestion and malabsorption, diabetes, and an increased risk for pancreatic adenocarcinoma. This review summarizes the latest evidence on the diagnosis and management of chronic pancreatitis and its manifestations. In particular, this review discusses advances in understanding of the role of genetic disorders in the mechanisms of the disease and surgical options for patients refractory to medical therapy. Furthermore, clinical trials are under way to develop medical therapeutics.

Introduction

Chronic pancreatitis is a “suffering” disorder owing to pain and related reduction in multiple quality of life measures resulting from a fibroinflammatory response to injury in the exocrine pancreas. In addition to pain, chronic pancreatitis can lead to exocrine and endocrine failure (that is, exocrine pancreatic insufficiency and diabetes) and an increased risk for pancreatic cancer. No cure for chronic pancreatitis exists, but understanding of the mechanisms of the disorder is increasing and significant progress in management has been made. The objective of this review is to summarize the latest information on chronic pancreatitis and provide suggestions for further research to improve the management for patients with this disease.

Sources and selection criteria

We searched PubMed from 1980 to April 2022 for systematic reviews, meta-analyses, randomized controlled trials (RCTs), and international guidelines in the English language, using the search term “chronic pancreatitis”. This found 23 457 articles and 285 clinical trials. We expanded the search to include observational studies on the topics of severity, management and treatment, interventional techniques, and complications of chronic pancreatitis. We excluded case reports and case series with fewer than 25 patients. We prioritized studies by design in the order noted above, national guidelines, and high quality studies with large patient numbers. In addition, we reference published guidelines and consensus statement for chronic pancreatitis.

Epidemiology

The prevalence of chronic pancreatitis is about 50 per 100 000 people. 1 This information comes mostly from survey and health system database studies in the United States, 1 2 3 4 5 Japan, 6 China, 7 8 India, 7 9 and Europe. 10 11 Usually, chronic pancreatitis develops from recurrent episodes of non-gallstone acute pancreatitis. Variations in prevalence occur between regions and are based on differences in the causes of acute pancreatitis. That is, populations with high rates of gallstone acute pancreatitis compared with non-gallstone acute pancreatitis have a lower prevalence of chronic pancreatitis, whereas populations with a high rate of non-gallstone acute pancreatitis (that is, due to alcohol misuse) have a higher prevalence of chronic pancreatitis. Other factors that contribute to variation in prevalence estimates across populations include differences in approaches to establish the diagnosis and study methods used for reporting.

Natural history

The original descriptions of the pathologic sequence of chronic pancreatitis come from the historical case series of 29 patients published in 1946. 12 The authors proposed that episodes of repeated acute pancreatitis can lead to chronic pancreatitis on the basis of their histological findings in patients. This progression of findings of acute inflammatory necrosis to fibrosis with calcification is referred to as the necrosis-fibrosis theory. Further details about this progression have been recorded with case series, histological analyses, consensus reports, and a subsequent mechanism based model. 13 14 15 16 17 These mechanisms are described in this review. In clinical practice, tissue is rarely available because of risks associated with biopsy, so the definitive diagnosis of chronic pancreatitis relies on advanced imaging or advanced endoscopic techniques identifying ductal abnormalities, parenchymal fibrosis, calcifications, and other findings such as ductal stones or pseudocysts. 1 18 19 However, in clinical practice, the term acute-on-chronic pancreatitis is often used to describe recurrent relapses of pancreatitis symptoms consistent with the necrosis-fibrosis theory. Recently, a consensus definition from a group of international pancreatitis experts described acute-on-chronic pancreatitis with worsening of the inflammatory process associated with chronic pancreatitis, resulting in a deterioration of the patient's clinical condition and increased pancreatic pain. 20

Because these diagnostic entities are not widely available, especially in poorly resourced countries, the exact prevalence of chronic pancreatitis is unknown. That is, determination of the true prevalence of chronic pancreatitis requires the complex assessment that is necessary to establish the diagnosis. Consequently, most series reporting the prevalence of chronic pancreatitis do so from the perspective of hospital admissions and varying levels of expertise in establishing the diagnosis, so an underestimate of the true disease prevalence in the entire population is likely. 21

One frequently cited population based study from the Mayo clinic examined 106 cases of chronic pancreatitis between 1977 and 2006. 4 Half of the cases were caused by alcohol and 58% were in men, with the age and sex adjusted incidence rate being 2.9 cases/100 000 person years between 1977 and 1986. The incidence increased to 4.4/100 000 between 1997 and 2006. These data are somewhat old, and the increasing prevalence noted more than a decade and a half ago suggests that the current prevalence of chronic pancreatitis is higher than previously thought.

Chronic pancreatitis can result in both pancreatic exocrine insufficiency and diabetes. Diabetes associated with pancreatitis is observed in up to 90% of patients depending on duration of chronic pancreatitis, according to a cohort study of more than two thousand patients. 22 Furthermore, chronic pancreatitis is the strongest identified risk factor for pancreatic ductal adenocarcinoma (PDAC) according to case series and increases the risk at least 13.3-fold. 23 Importantly, the risk for PDAC in patients with both pancreatitis and diabetes is increased 33-fold. 24 A study from the Karolinska University Hospital (Stockholm) found that subpopulations of patients are at the greatest risk for PDAC by following 581 patients with chronic pancreatitis from 2003 to 2018 using available electronic medical records. 25 The results show that patients with diabetes and a high body mass index or with pancreatic exocrine insufficiency and a low body mass index at diagnosis of chronic pancreatitis are at the greatest risk for PDAC. Patients with chronic pancreatitis have a shortened lifespan, with death most often occurring from causes unrelated to the pancreas. 1 4 15 26 27

Environmental, genetic, and anatomic factors

Chronic pancreatitis is more common in men than in women for all causes of the diseases. 28 Of note, gallstone acute pancreatitis usually does not progress to recurrent and chronic pancreatitis unless gallstones remain untreated resulting in recurrent attacks that lead to chronic disease. 1 Alcohol misuse is the most common cause of chronic pancreatitis ( box 1 ). 1 A review indicated that that a threshold of five drinks or more per day is associated with the development of chronic pancreatitis. 29 However, less than 5% of heavy drinkers develop chronic pancreatitis, suggesting that additional factors are involved in disease development. One additional factor is smoking. That is, smoking and drinking are common coexisting behaviors that combined may contribute to the development of chronic pancreatitis. 30 The risk of pancreatitis associated with current smoking was highest among men who consumed more than four drinks a day (hazard ratio 2.06, 95% confidence interval 1.28 to 3.30) according to a multiethnic cohort study. 31 Recent studies suggest that alcohol misuse and smoking act synergistically for the risk of chronic pancreatitis. 32

Risk factors to consider in patients with chronic pancreatitis

Alcohol misuse

Genetic alterations

Duct obstruction

Pancreas divisum

Hereditary pancreatitis represents a genetic cause of chronic pancreatitis. This disorder was first described in six family members over three generations. 33 The underlying genetic defect was discovered in 1996 as a gain of function mutation in the PRSS1 gene that codes for the key pancreatic digestive enzyme, trypsin. 34 These patients have early onset pancreatitis with recurrent attacks of acute pancreatitis and a family history of pancreatitis. Inheritance occurs as an autosomal dominant trait with variable expression. 35 Chronic pancreatitis is also associated with loss of function gene mutations. Examples include serine protease inhibitor Kazal-type 1 (SPINK1) and chymotrypsin C (CTRC) genes encoding for two different proteins that both inhibit trypsin activity. 36 37 Thus, both gain of function and loss of function mutations lead to increased activation of trypsin, pointing out the importance of trypsin in the pathogenesis of pancreatitis.

Of note, the mutations of PRSS1, SPINK1, and CTRC involve digestive enzymes in the acinar cell of the exocrine pancreas. 38 Genetic variants involving pancreatic ductal cell functions are also associated with progression of pancreatitis. The commonly associated variants are in the cystic fibrosis transmembrane regulator (CFTR). The physiologic importance of CFTR is that it is necessary for ductal ion and water secretion to carry digestive enzymes secreted by the acinar cells to the duodenum. 39 Mutations in CFTR are associated with chronic pancreatitis. 40 Also, studies have shown that alcohol misuse inhibits CFTR function, supporting a crucial role for normal ductal function in preventing pancreatitis. 41 42

Recently, a functional coding mutation inTRPV6 (which encodes the transient receptor potential cation channel subfamily V member 6) was identified as a risk factor for the disease. 43 44 45 46 Importantly, functional mutations in TRPV6 often present in combination with other known risk factors including SPINK1, CTRC, and CFTR mutations. 45 These findings emphasize that genetic variants often function in combination to set the stage for development of disease.

Genetic testing for patients is now available and should be considered in those without an otherwise known cause for their disease. Finding a genetic variant that underlies a patient’s disease is important as it enables them to explain their disease to care providers not familiar with the potential for genetic causes. For example, the knowledge can help to dispel the impression that they have chronic pancreatitis because of alcohol misuse and that they are drug seekers when asking for pain relief in an emergency setting. The knowledge also provides information for families to learn about genetic transmission. Finally, the testing will identify patients eligible for therapeutics that will be developed for specific genetic causes or consideration for pancreatectomy when the identified genetic abnormality is associated with an elevated risk for pancreatic cancer.

Ductal obstruction can occur from inflammatory strictures or tumors, which can progress from recurrent acute pancreatitis to chronic pancreatitis. Pancreas divisum is a common normal variant of ductal anatomy defined as non-fusion of the dorsal and ventral pancreatic ducts occurring in up to 7% of the general population. This anatomic variant means that most of the pancreatic secretions enter the duodenum through the smaller duct of Santorini, emptying into the duodenum through an accessory papilla. This anatomy is believed to increase pressure in the pancreatic duct, predisposing to pancreatitis. However, this concept is controversial, including the fact that patients with pancreas divisum and chronic pancreatitis may also have underlying genetic mutations, which may be involved in chronic pancreatitis pathogenesis. 47 48 Most experts believe that if pancreas divisum is involved in the pathogenesis of chronic pancreatitis, it may be a co-factor and not the sole causative factor. 47

Finally, chronic pancreatitis can be a presentation of the multi-organ IgG4 related disorder referred to as autoimmune pancreatitis when the disorder involves the pancreas. Autoimmune pancreatitis can present as acute or chronic pancreatitis, but the most common clinical presentation is painless jaundice. Autoimmune pancreatitis more commonly occurs in patients over age 60 with a three to one male predominance. An increased concentration of circulating IgG4 is a serologic marker for autoimmune pancreatitis. This entity is important to identify as it is most often responsive to steroid treatment or alternatively to other immune modulators in steroid resistant cases. 48

Mechanism of the fibro-inflammatory response and pain of chronic pancreatitis

The key histologic features of chronic pancreatitis include fibrosis, inflammation, and ductal changes with loss of acinar tissue and islets. The mechanisms of the fibro-inflammatory response and pain are interconnected by intercellular communications. The pathways described here are ones that we hypothesize are involved in the promotion of chronic pancreatitis. Important disorders in parenchymal cells of the pancreas that represent the acute injury response are reviewed elsewhere. 49 Many of these acute injury pathways are identified in chronic pancreatitis, indicating the continuum from acute forms to chronic forms of pancreatitis. 50 Experiments in animal models show that the pathogenesis of chronic pancreatitis is due to interactions with pancreatic stellate cells (PSCs) or activated macrophages. Transforming growth factor β (TGF-β) and Smad3 signaling play key roles in the fibro-inflammatory response and the pain of this pancreatic disease. 51 52

In normal pancreas, PSCs are in a quiescent state, characterized by lipid droplets containing vitamin A in their cytoplasm and minimal production of fibrosing extracellular matrix protein production. 53 However, in the environment of inflamed pancreatic tissue, PSCs become activated and produce abundant extracellular matrix proteins leading to fibrosis as well as inflammatory cytokines, 54 55 which promote influx of myeloid cells and convert them to alternatively activated macrophages. 52 These macrophages sustain the activated state of PSCs by secreting TGF-β, creating a feed-forward process by the fibro-inflammatory state of PSCs. 52 Two specific cytokines, interleukin 4 and interleukin 13, secreted by activated PSCs, stimulate the conversion of monocytes and macrophages to their alternatively active state, which secrete prodigious amounts of TGF-β. 52 Of note, the role of TGF-β in the fibro-inflammatory response of chronic pancreatitis is well established. 56 57 58 The TGF-β secreted by the macrophage maintains the PSC in its activated state, promoting more secretion of interleukins 4 and 13. 52 This interplay between activated PSCs and alternatively activated macrophages creates a feed-forward process promoting the fibro-inflammatory response of chronic pancreatitis, 52 and it provides for the production of TGF-β that mediates the pain of these pancreatic diseases by direct effects on sensory neurons in the pancreas mediated by SMAD3 signaling in the sensory neuron. 51 The role of TGF-β in the mechanism of pain may represent one of many pathways involved. For example, studies show that chronic pancreatitis causes reorganization of brain networks, with involvement of alterations in descending inhibitory pathways and metabolic disturbances. 59 60 61 62

Figure 1 shows the pathways described here. Agents that interrupt one or more nodes in these pathways will have a benefit for treatment in chronic pancreatitis. Of note, because chronic pancreatitis results from recurrent episodes of acute pancreatitis, agents that can beneficially affect mechanisms of acute pancreatitis may have a role in chronic pancreatitis. An example is use of Orai-1 inhibitor therapy currently under investigation for acute pancreatitis. 63 64 65 A role also exists for lymphoid cells in addition to myeloid cells in chronic pancreatitis. 66 A recent study showed that molecules in cigarette smoke acting through the aryl hydrocarbon receptor on T cells cause stimulation of PSCs to promote fibrosis through the interleukin 22 pathway. 67 These findings again show an important interplay between inflammatory and immune cells and PSCs in the pathogenesis of chronic pancreatitis. The relative roles for myeloid and lymphoid cells in the pathogenesis of chronic pancreatitis may depend on the causative factors of the disease.

Pathways of inflammatory, fibrosis, and pain response of chronic pancreatitis. In the environment of inflamed pancreatic tissue, pancreatic stellate cells (PSCs) become activated. Interleukin (IL)-4 and IL-13, secreted by activated PSCs, stimulate the conversion of macrophages to their alternatively active state. These macrophages sustain the activated state of PSCs by secreting transforming growth factor β-1 (TGF-β), advancing the fibro-inflammatory state of chronic pancreatitis. TGF-β mediates pain via intracellular Smad3 signaling in sensory neurons in the pancreas. We hypothesize that agents that interfere with one or more nodes in this scheme may provide treatment benefit for patients with chronic pancreatitis

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Diagnosis of chronic pancreatitis

The diagnosis of chronic pancreatitis is based largely on imaging; it is associated with calcification and pancreatic duct abnormalities in advanced cases but can be challenging in less advanced cases ( box 2 ). In contrast to acute pancreatitis, which is defined by increases in serum amylase and lipase concentrations with abdominal pain typical of pancreatitis, these pancreatic enzymes are often not elevated in pancreatitis even with an exacerbation. The reason is a loss of functional pancreatic tissue containing these enzymes with chronic pancreatitis. 68 Circulating biomarkers for the diagnosis of chronic pancreatitis are not established. However, the Consortium on Chronic Pancreatitis, Diabetes and Pancreatic Cancer is making a significant effort to develop biomarkers to aid in diagnosis. 69 70 71

Approaches to diagnosis and characterization of chronic pancreatitis

Determine previous episodes of pancreatitis

Obtain symptoms and environmental risk history

Test for presence of exocrine insufficiency

Obtain cross sectional imaging (computed tomography or magnetic resonance imaging)

Monitor for diabetes

In selected cases:

Endoscopic ultrasonography

Endoscopic retrograde cholangiopancreatography

Genetic testing

Pancreatic biopsy

Imaging plays a principal role in diagnosing chronic pancreatitis because of the absence of circulating biomarkers and reluctance to do risky pancreatic biopsies. 72 Among imaging modalities available for the diagnosis, computed tomography and magnetic resonance imaging (MRI) are the initial studies used for the evaluation of abdominal pain with chronic pancreatitis as a potential cause. Consistent with this practice, an expert panel of the American College of Gastroenterology published guidelines that recommend computed tomography or MRI for the first line diagnosis of chronic pancreatitis, suggesting that “either test should be the first choice for the diagnosis of chronic pancreatitis.” 73 The panel further stated that “endoscopic ultrasonography (EUS), because of its invasiveness and lack of specificity, should be used only if the diagnosis is in question after cross-sectional imaging is performed.” The panel noted that other imaging modalities such transcutaneous ultrasonography, endoscopic retrograde cholangiopancreatography (ERCP), pancreatic elastography, and contrast enhanced endoscopic ultrasonography are potential imaging methods for diagnosis; 74 75 76 77 78 “high-quality randomized controlled trial evidence is not available to warrant their inclusion as first-line diagnostic tests for chronic pancreatitis in place of cross-sectional imaging or EUS.”

Features of chronic pancreatitis on computed tomography include calcifications and atrophy and pancreatic duct dilations ( fig 2 ). MRI and magnetic resonance cholangiopancreatography (MRCP) have an additional advantage of detecting ductal changes in addition to parenchymal changes. 79 80 Also, the administration of secretin to stimulate fluid secretion during an MRCP can further define pancreatic function and ductal pathology. 81 82 83 84 Of note, in addition to developing circulating biomarkers for the diagnosis of chronic pancreatitis, the Consortium on Chronic Pancreatitis, Diabetes and Pancreatic Cancer is greatly involved in advancing quantitative MRI for improved diagnostic ability in different stages of chronic pancreatitis, taking advantage of the unique T1 relaxation of the pancreas owing to its high protein content and the ability of MRI to measure extracellular volume (equivalent to fibrosis) and the presence of fat. 70 85 86 The envisioned goal is to approximate tissue histology with MRI measures. 87

Abdominal computed tomography scan of patient with chronic pancreatitis, showing calcifications and dilation of the pancreatic duct, especially in the tail

In cases in which morphologic evidence of pancreatitis is still needed despite the studies listed above, endoscopic ultrasonography of the pancreas can be used to identify disease at an early stage or with minimal change. Criteria for diagnosis by endoscopic ultrasonography include hyperechoic foci, hyperechoic strands, lobular contour, and cysts of the parenchyma, as well as ductal features of main duct dilatation, duct irregularity, hyperechoic duct margins visible side branches, and stones. 69 Finally, in patients whose diagnosis remains in question, histologic examination of a pancreatic biopsy is appropriate.

Of particular importance is the state of disease when no morphologic evidence is found using the imaging technology listed above. This state is often referred to as early chronic pancreatitis. 88 Further research is needed to develop molecular and/or imaging biomarkers associated with genetic and environmental risks to better identify patients with this state. Importantly for establishing the diagnosis, chronic pancreatitis is a clinical diagnosis that requires integration of clinical information including risk factors (genetics as appropriate) and exclusion of other disorders in the differential diagnosis together with the validation of imaging studies.

Relation between cause of chronic pancreatitis and potential complications

A cross sectional study of 1071 patients with chronic pancreatitis did a cluster analysis between the causes of pancreatitis and types of complications. 89 The analysis showed that complications potentially resulting from the continuing inflammatory process such as pseudocysts, ascites, pleural effusion, pancreatic fistula, and portal or splenic vein thrombosis are more likely with alcohol misuse related pancreatitis than with non-alcohol misuse related causes of pancreatitis (odds ratio 2.00, 95% confidence interval 1.38 to 2.90; P<0.001). On the other hand, fibrosing complications such as pancreatic duct lesions, common bile duct stenosis, and duodenal stenosis (odds ratio 2.23, 1.56 to 2.32; P<0.001) and complications such as exocrine pancreatic insufficiency (odds ratio 1.42, 1.00 to 2.01; P=0.046) were more likely associated with smoking.

Exocrine and endocrine insufficiency: identification and treatment

Failure of exocrine and endocrine function are common consequences of chronic pancreatitis. Pancreatic exocrine insufficiency (PEI) occurs when more than 90% of exocrine pancreatic function is lost, resulting in steatorrhea. 90 Patients with steatorrhea have oily or greasy stools and may describe bulky, pale, foul smelling, and/or floating stools. Additionally, the patient may have weight loss and fat soluble vitamin deficiency despite normal caloric intake. The classic measurement of fat in the stools collected for 72 hours in a person ingesting a diet adequate in fat (70-100 g/day) is considered an effective means of diagnosing steatorrhea. Normally, 7% or less of ingested fat appears in the stool. A simple qualitative microscopic examination of a single stool for oil is almost as sensitive as quantitative measurements for fat, making the measurement of steatorrhea more accessible. 91 92 Additional practical tests for PEI include measurements of fecal chymotrypsin and elastase-1. Both enzymes are produced by the pancreas and remain constant throughout the gastrointestinal tract. Elastase-1 has been shown to be more specific than chymotrypsin, with sensitivity approaching 100% for significant insufficiency. 93 94 Measurement of serum trypsin has also been shown to associate with severe PEI. 95

In contrast to the widely available methods listed above for diagnosis of PEI, specialized centers may provide direct testing of pancreatic function, which can be useful in diagnosing chronic pancreatitis. In these tests, the exocrine pancreas is stimulated with a secretagogue such as secretin for testing ductal function or cholecystokinin for testing acinar function, followed by measurement of the volume and concentration of analytes into the duodenum collected by aspiration with a duodenal tube designed to prevent interference with gastric secretions or an endoscope aspirating at site of the pancreatic outflow into the duodenum. 96 97 98 Currently, testing the ductal function with secretin stimulation and measurement of peak bicarbonate concentration prevails over testing acinar function with cholecystokinin stimulation.

Treatment of PEI is essential to reverse and prevent its consequences, which include weight loss, fat soluble vitamin deficiency, metabolic bone disease, and sarcopenia. 99 Osteoporosis and osteopenia are highly prevalent in this population and are associated with an increased risk of fractures. 100 101 102 A recommended starting dose 40 000–50 000 USP units of lipase taken with each meal is recommended. 99 Treatment monitoring includes improvements in steatorrhea, weight, fat soluble vitamins, and measures of bone density and muscle mass. Dose adjustments may be necessary.

Endocrine insufficiency manifested as diabetes mellitus can occur in chronic pancreatitis. 103 104 105 106 This form of diabetes mellitus is referred to as diabetes of the exocrine pancreas, pancreatogenic diabetes, post-pancreatitis diabetes (PPDM) or type 3c diabetes. The mechanism of this form of diabetes mellitus, differences from type 1 and type 2 diabetes mellitus, and the most appropriate approach to treatment are under intensive investigation. 103 104 107 108 109 110 111 PPDM is generally managed by starting with metformin, but insulin may eventually be needed. Incretin therapy is avoided considering the risk of pancreatitis. Patients with PPDM have an added complexity for management. That is, these patients need consistent treatment of PEI to ensure nutrient absorption for prevention of hypoglycemia and additional vigilance to prevent hypoglycemia because of potential loss of counter-regulatory glucagon secretion.

Interventions for pain

Pain is the most common manifestation of chronic pancreatitis and can be debilitating and unrelenting. 112 113 114 Moreover, the pain of chronic pancreatitis is associated with debilitation in several physical, mental, and social health outcomes. 64 67 115 116 Patients experience epigastric or mid-abdominal pain, which can be accompanied by back pain. The cause is the presence of inflammatory mediators, which increase interstitial pressure leading to diminished blood perfusion, low oxygen tension, and consistent gland inflammation. 37 These symptoms may be constant or intermittent and exacerbated by a meal, and it is important to consider alternate diagnoses including peptic ulcer disease, complications of pancreatitis, and cancer, which these patients develop at higher rates than those without chronic pancreatitis.

Medical management of pain

Abstinence from alcohol and smoking should be recommended, and support programs to facilitate this should be offered. Abstinence will extend life and slow the evolution of chronic pancreatitis but not stop it. Smoking increases the risk of developing pancreatic cancer and accelerates chronic pancreatitis. A meta-analysis of 10 case-control studies and two cohort studies including 1705 patients identified a dose-response effect of tobacco on risk of chronic pancreatitis (odds ratio one pack 2.4 (95% confidence interval 0.9 to 6.6); more than one pack 3.3 (1.4 to 7.9). This risk was diminished with smoking cessation. 115

Analgesics provide treatment for pain from chronic pancreatitis and include non-opioid and opioid medications. Non-opioids are recommended as first line therapy and opioids for worsening and persistent pain. When the patient transitions to consistent opioid use, management by a chronic pain specialist should be started.

Adjunctive medications including tricyclic gabapentinoids, antidepressants, and selective serotonin reuptake inhibitors can decrease opioid requirements and treat neuropathic pain. An RCT that randomized 64 patients to pregabalin or placebo for three weeks found that pregabalin significantly improved pain relief (36% v 24%; P=0.02). 117 Antioxidant therapy has been used in chronic pancreatitis with varying results. A Cochrane review including 12 RCTs and involving 585 patients concluded that pain was less in the antioxidant group (mean difference −0.33, 95% confidence interval −0.64 to −0.02). 118

Pancreatic enzyme replacement therapy has long been used to decrease pain from chronic pancreatitis despite little evidence to support this. To date, nine clinical trials, seven of them randomized, have shown inconsistent data on pain; because of this, enzyme replacement is not recommended to treat this symptom. 116 119 120 121 122 123 124 125

Celiac plexus blockade has varying efficacy as reported in the literature. The procedure involves the injection of local anesthetic and a steroid into the celiac ganglia and can be done under endoscopic ultrasound guidance, percutaneously, or directly during surgery. A meta-analysis of six studies including randomized studies, prospective studies, and case series evaluating endoscopic guided block estimated that pain relief based on validated pain score assessment or decrease in opioid use was 51.46%. 126 For patients who have exhausted medical management of pain, a celiac plexus blockade should be considered. However, the pain relief is usually transient.

Endoscopic treatment

Chronic pancreatitis can cause strictures of the main pancreatic duct and stone formation contributing to diminished flow, inflammation, and pain. For patients with a dilated duct, endoscopic or surgical techniques to decompress the duct can relieve pain and may preserve pancreatic exocrine and endocrine function.

Endoscopic treatment of pain in patients with pancreatic duct strictures and stones is feasible, and some patients may benefit from long term pancreatic duct stenting to manage pancreatic duct strictures. A meta-analysis of 13 studies involving 298 patients found that pain improved by 89% after pancreatic stent compared with before stenting. 127 A randomized trial comparing endoscopy and lithotripsy with lithotripsy alone found a similar decrease in the number of pain episodes per year (mean decrease 3.7, 95% confidence interval 2.6 to 4.9; P<0.001) over a four year period, suggesting that lithotripsy alone is sufficient. 128

Surgical approaches to chronic pancreatitis

Surgery for pain from chronic pancreatitis is generally reserved for patients with severe disease manifested by substantial and longstanding symptoms in the presence of pancreatic duct dilation or stones. Surgery for chronic pancreatitis may be performed safely and with minimal perioperative morbidity or mortality. Several operations have been developed whereby varying amounts of the pancreas are removed to ensure improved drainage of pancreatic fluid from the duct to the gastrointestinal tract. To maintain exocrine and endocrine pancreatic function, most modern procedures are parenchyma sparing approaches rather than a pancreatectomy, unless this is done concomitantly with an islet cell transplant. These surgeries include a pancreatoduodenectomy (Whipple), duodenum preserving pancreatic head resection (Frey and Beger/Berne), distal pancreatectomy, and drainage procedures such as longitudinal pancreatojejunostomy (Puestow) ( fig 3 ). The operation recommended is based on the pancreatic duct anatomy and distribution of the disease in the gland.

Pancreatoduodenectomy (Whipple), duodenum preserving pancreatic head resection (Frey and Beger/Berne), distal pancreatectomy, and longitudinal pancreatojejunostomy (Peustow)

Eleven RCTs have compared different dyads of operations for chronic pancreatitis pain. When the pancreatic head is removed patients have the best outcomes related to pain, and if the duodenum can be preserved pancreatic function and quality of life seem to be improved. This is especially true when most of the disease is limited to the head. A meta-analysis of four trials included 173 patients who had a duodenum preserving pancreatic head resection or pancreatoduodenctomy for pain relief in chronic pancreatitis. In this analysis, the duodenum preserving approach showed no difference in pain relief (odds ratio 1.08, 95% confidence interval 0.88 to 1.33) or endocrine insufficiency (odds ratio 0.49, 0.22 to 1.09), but the duodenal preserving procedure had less exocrine insufficiency (odds ratio 0.20, 0.06 to 0.66) and improved quality of life (weighted mean difference 25.07, 18.83 to 31.21). 129 The follow-up ChroPac trial randomized 250 patients to pancreatoduodenectomy or duodenum preserving pancreatic head resection and found no difference in quality of life at 24 months, which included an assessment of pain. 130

Most long term studies report that 60-80% of patients have improvement in pain following surgery. Although duodenum preserving pancreatic head resection is a more complicated procedure than a longitudinal pancreatojejunostomy, some types of parenchymal resection such as a Frey procedure that completely exposes the duct and allows for all stones to be removed is essential to secure the best pain relief. A tailored approach accounting for the distribution of the pancreatic inflammation, ductal anatomy, and patient’s condition should be used to determine the optimal operation for each patient.

Total pancreatectomy with islet autotransplantation

In patients with painful chronic pancreatitis who have exhausted medical management and completed endoscopic or surgical intervention, total pancreatectomy offers an option to tackle pain by removing the entire gland, the source of the inflammatory pain cascade. This is also an option for patients with hereditary pancreatitis who have a substantial increase in risk for pancreatic cancer. A pancreatectomy accompanied by an islet autotransplantation of islet isolated from the resected gland and infused into the liver via the portal vein promises improved glucose homeostasis after the procedure. This procedure is appropriate for patients with normally functioning islets before the surgery. The available data to support this approach come from observational series. The Dutch Pancreatitis Study Group published a meta-analysis of 15 observational studies including 1255 patients, and at one year after surgery the opioid-free rate had improved from between 0% and 15% to 63% (95% confidence interval 46% to 77%) and the insulin-free rate had decreased from between 89.5% and 100% to 30% (20% to 43%). 131 In patients who have no other options and have access to a skilled center providing this service, total pancreatectomy with islet autotransplantation is a reasonable approach to manage pain from chronic pancreatitis.

Endoscopic versus operative approaches

Evidence from randomized trials suggests that surgery should be considered over endoscopic therapy for the long term treatment of painful chronic pancreatitis with ductal obstruction. Three RCTs investigating endoscopic and surgical treatment of pain have been completed and concluded that surgery was superior to endoscopic techniques. Recent practice guidelines from both the American College of Gastroenterology and the American Gastroenterological Association include this recommendation based on what each judged to be moderate to strong evidence. 53 114

The first RCT randomized 140 patients to endoscopic treatment including sphincterotomy, stenting, and stone removal or surgery. 132 The initial outcomes related to pain were similar, but at five years complete absence of pain was twice as high in the surgery group (37% v 14%) and partial relief was similar (49% v 51%). In addition, patients who underwent surgery had improved increased body weight measurements, and the incidence of new onset diabetes was no different (34-43%). The authors concluded that surgery was superior to endotherapy and that endotherapy could be offered as initial treatment followed by surgery in cases in which pain persisted.

Two years later, an RCT from the Netherlands was published, which randomized 39 patients between endoscopic treatment and lithotripsy or pancreatojejunostomy that included removal of some pancreatic parenchyma. Patients who had surgery reported lower pain scores (P<0.001) and better physical health (P=0.003). Striking pain relief was seen in 75% of surgery patients and only 32% of the endoscopic group (P=0.007), and the endoscopic group received eight interventions whereas the surgery patients had three. 133

The third RCT, the ESCAPE trial from the Dutch Pancreatitis Study Group published in 2020, led to the current guideline recommendations. 134 This multicenter RCT included 88 patients and compared best medical management with endoscopic treatment versus upfront surgery for painful chronic pancreatitis. Pain scores were significantly better in the surgery group (Izbicki pain score 37 v 49; −12 points, 95% confidence interval −22 to −2; P=0.02), and pain relief was achieved in 58% of surgery patients versus 39% of the endoscopy group (P=0.10). Pancreatic function, complication rates, and quality of life were similar between groups. An important consideration of this study is that when the duct was cleared endoscopically, pain was improved at a similar rate between treatment arms. It was notable that pain was not better in 62% of the patients in the endoscopy group, and half of this group ultimately had surgery to manage this. This trial provides the strongest evidence to date informing treatment of chronic pancreatitis in patients with a dilated pancreatic duct and stones and pain. A Cochrane review found that surgery offers a higher likelihood of pain relief than endoscopic treatment in the medium term (2-5 years: risk ratio 1.62, 1.22 to 2.15) and at long‐term follow‐up (≥5 years: 1.56, 1.18 to 2.05). 135 With this evidence, surgery should be considered early in the management of these patients.

Complications of chronic pancreatitis

Pancreatic pseudocysts and acute fluid collection occur in patients with chronic pancreatitis owing to exacerbations of inflammation and ductal disruption. Pseudocysts are less likely to resolve in chronic pancreatitis because this condition does not spontaneously resolve as it does in acute pancreatitis, so invention is more commonly needed ( fig 4 ). Patients with symptomatic collections resulting in pain, gastric or duodenal obstruction with weight loss, or biliary obstruction should undergo endoscopic ultrasound guided transgastric or transduodenal drainage with plastic stents or lumen apposing metal stents. Alternatively, transpapillary drainage can be attempted. However, a meta-analysis including 1355 patients found that success using transmural drainage and resolution of the pseudocyst was substantially higher than that using a transpapillary approach (90.6% (95% confidence interval 81.0% to 95.6%) versus 58.5% (36.7% to 77.4%)). 136 Transpapillary drainage has been successfully deployed for a disconnected pancreatic duct. The same study showed that surgical drainage results in success rates comparable to those of endoscopic treatment (82% (68.6% to 90.5%) versus 87.4% (81.2% to 91.8%); P=0.389). Percutaneous drainage is largely ineffective with very high recurrence rates, particularly in chronic pancreatitis. As the morbidity of endoscopic drainage is substantially less than with surgery, this method is the recommended treatment for pseudocysts in chronic pancreatitis.

Abdominal computed tomography scan showing a pancreatic pseudocyst expanded anteriorly against the stomach

Biliary stricture occurs in 10-15% of patients with chronic pancreatitis, and the first concern should be to rule out the possibility of malignancy with imaging and endoscopic ultrasound guided biopsy. Benign biliary strictures typically have a tapered appearance on cholangiography. Once malignancy has been excluded, endoscopic, surgical, and interventional radiologic techniques are available to treat the stricture. RCT data suggest that endoscopic treatment is reliable. One study enrolled 60 patients to self-expandable metallic stent versus plastic stent and showed a two year, stricture-free success rate of 90% (72% to 97%) in the plastic stent group and 92% (70% to 98%) in the metal stent group. 137 Similar success rates were seen in an RCT using stents for benign biliary stricture (92.6%). 138 Additionally, if the patient is having surgery for chronic pancreatitis, a biliary bypass or decompression of the bile duct with the pancreatic operation can be safely performed with outstanding long term resolution of the stricture.

Vascular complications of chronic pancreatitis include pseudoaneurysms of the surrounding arterial vessels, particularly the splenic artery, or venous thrombosis. A meta-analysis of endovascular embolization for pseudoaneurysms in pancreatitis including 29 studies and 849 patients found a clinical success rate of 88% (83% to 91%; I 2 =0%) at 12 months. 139 Splenic infarction was the most common complication, seen in 5.5% of patients, which nearly always resolves. Patients with thrombosis of the splenic vein can usually be managed expectantly, but left sided portal hypertension manifested by gastric bleeding may occur in up to 12.3% according to a meta-analysis of 99 reports including 805 patients. 140 For these patients, splenic artery embolization may be therapeutic and splenectomy definitive.

Differentiating chronic pancreatitis from cancer

Determining whether a patient has pancreatic cancer in the setting of chronic pancreatitis is challenging. Maintaining vigilance for the possibility of pancreatic cancer with frequent assessment and ultimately no diagnosis of cancer is a common approach. One pooled analysis of 13 studies found that a nearly eightfold risk for cancer at five years from diagnosis of chronic pancreatitis diminished to 3.5-fold after nine years (7.90 (95% confidence interval 4.26 to 14.66) and 3.53 (1.69 to 7.38)). 141 In other words, if the patient has not developed cancer over time while under medical supervision the risk of doing so decreases. However, the establishment of true risk is difficult because some patients may have been misclassified as having chronic pancreatitis when in fact cancer is present. Chronic inflammation is known to contribute to carcinogenesis. Imaging with computed tomography, MRI, and endoscopic ultrasonography assists in identifying a suspicious lesion that should be biopsied at the time of endoscopic ultrasonography to determine the diagnosis. CA 19-9 can be elevated in chronic pancreatitis, especially with biliary obstruction, but elevation increases the suspicion of pancreatic cancer. A pooled analysis of the ability of CA 19-9 concentration to differentiate pancreatic cancer from chronic pancreatitis that included 3125 patients showed a sensitivity of 0.81 (95% confidence interval 0.80 to 0.83), a specificity of 0.81 (0.79 to 0.82), a positive likelihood ratio of 4.08 (3.39 to 4.91), a negative likelihood ratio of 0.24 (0.21 to 0.28), and a diagnostic odds ratio of 19.31 (14.40 to 25.90). 142 Patients with hereditary pancreatitis should be entered into a screening program with yearly imaging and consideration for pancreatectomy.

Emerging treatments

Understanding of the mechanisms of chronic pancreatitis is revealing potential therapeutic approaches in animal models of chronic pancreatitis, which are being applied in human clinical trials. For example, inhibition of the effects of interleukins 4 and 13 has been shown to decrease chronic pancreatitis. 52 Pirfenidone, an agent that inhibits TGF-β actions to promote fibrosis and is approved by the US Food and Drug Administration for treatment of idiopathic pulmonary fibrosis, has shown benefit in models of chronic pancreatitis. 143 Simvastatin, by inhibiting the inflammatory response of pancreatitis through correcting autophagic mechanisms of the acinar disordered in pancreatitis, has the potential for therapeutic benefit in chronic pancreatitis and is in clinical trials (ClinicalTrials.gov NCT04021498 and NCT02743364 ). 144 145 146 147 148 Another potential mechanism based therapeutic agent is a highly potent vitamin D analog, paricalcitol, which returns activated PSCs to their quiescent state and which is in an early clinical trial ( NCT05664880 ). 149 150

Management summary and guidelines

Box 3 provides a summary list of key management actions for patients with chronic pancreatitis based on this review). Box 4 provides a list of guidelines and consensus statements that provide further details for the diagnosis and management of chronic pancreatitis.

Management of patients with chronic pancreatitis

Stop alcohol use and smoking

Monitor and treat exocrine insufficiency and diabetes

Maintain nutritional intake

Monitor for macro-nutritional and micro-nutritional deficiencies

Monitor bone health

Consider dietary alterations

Use analgesics safely

Endoscopic treatments

Surgical treatments

Published guidelines and consensus statements for chronic pancreatitis

Guidelines for Risk Factors in Chronic Pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 151

Clinical Guideline for Chronic Pancreatitis

American College of Gastroenterology 73

Clinical Practice Guidelines for Chronic Pancreatitis

Japanese Society of Gastroenterology 152

Harmonizing diagnosis and treatment of Chronic Pancreatitis across Europe.

Working Group on Harmonizing the diagnosis and treatment of chronic pancreatitis across Europe of the United European Gastroenterology 153

Evidence-based Guidelines for the diagnosis and therapy of Chronic Pancreatitis

United European Gastroenterology 154

International consensus statements on early Chronic Pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 88

Guidelines for the Diagnostic Cross-Sectional Imaging and Severity Scoring of Chronic Pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 155

Guidelines on the role of diagnostic endoscopic ultrasound in the management of Chronic Pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 156

Guidelines on the histopathology of Chronic Pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 157

Diagnosis and treatment of exocrine pancreatic insufficiency in Chronic Pancreatitis

An international expert survey for the Dutch Pancreatitis Study Group 158

Consensus Guidelines for the management of pain of Chronic Pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 60

Guidelines on interventional endoscopy in chronic pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 159

Guideline on clinical nutrition in acute and chronic pancreatitis

European Society for Clinical Nutrition and Metabolism 160

Consensus guidelines for surgery and the timing of intervention in chronic pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 161

The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis

A report from the International Consensus Guidelines in chronic pancreatitis 162

Guidelines on surveillance for pancreatic cancer in chronic pancreatitis

International Consensus Guidelines Working Group for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society and European Pancreatic Club 163

Chronic pancreatitis remains a vexing condition with some partially effective treatments to reduce symptoms and complications but no cure. Multiple approaches to improve outcome are underway. ClinicalTrials.gov lists 210 studies for chronic pancreatitis. As the pathobiology of this disease continues to be defined, we hope that future research may find a cure.

Glossary of abbreviations

CFTR—cystic fibrosis transmembrane regulator

CTRC—chymotrypsin C

ERCP—endoscopic retrograde cholangiopancreatography

MRCP—magnetic resonance cholangiopancreatography

MRI—magnetic resonance imaging

PDAC—pancreatic ductal adenocarcinoma

PEI—pancreatic exocrine insufficiency

PPDM—post-pancreatitis diabetes

PSC—pancreatic stellate cell

RCT—randomized controlled trial

SPINK1—serine protease inhibitor Kazal-type 1

TGF-β—transforming growth factor β

Questions for future research

What are the mechanisms to inhibit and reverse the fibro-inflammatory process underlying chronic pancreatitis?

How do we develop and evaluate additional agents for preventing the progression and treating chronic pancreatitis?

Can we establish reliable and simple tests to establish the diagnosis of both chronic pancreatitis and exocrine pancreatic insufficiency?

How can we determine the long term nutritional and metabolic consequences of chronic pancreatitis, and how should these be managed and prevented?

What new medications and interventions will be most effective in treating pain from chronic pancreatitis considering subpopulations of patients with chronic pancreatitis with potentially different pain mechanisms?

How patients were involved in the creation of this manuscript

This work was reviewed by Mission:Cure ( https://mission-cure.org ), which is a community of patients, families, scientists, clinicians, and generous supporters, driving new research, accelerating drug discovery and development and creating hope for improved quality of life for patients with chronic pancreatitis. The reviewing organization agreed with the article and made minimal edits.

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: OJH and SP contributed to the planning, conduct, writing, editing, and reporting of this article and are equally responsible for the overall content as guarantors.

Competing interests: We have read and understood the BMJ policy on declaration of interests and declare the following interests: none.

Provenance and peer review: Commissioned; externally peer reviewed.

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Acute Pancreatitis

Current clinical approaches, molecular pathophysiology, and potential therapeutics.

Wiley, Mark B. PhD ∗ ; Mehrotra, Kunaal BA ∗ ; Bauer, Jessica PhD ∗ ; Yazici, Cemal MD, MS † ; Bialkowska, Agnieszka B. PhD ‡ ; Jung, Barbara MD ∗

From the ∗ Department of Medicine, University of Washington, Seattle, WA

† Department of Medicine, University of Illinois Chicago, Chicago, IL

‡ Department of Medicine, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY.

Received for publication December 12, 2022; accepted June 28, 2023.

Address correspondence to: Barbara Jung, MD, Department of Medicine, 1959 NE Pacific St, RR-512, Seattle, WA 98195-6420 (e-mail: [email protected] ).

The authors declare no conflict of interest.

This work is funded by the NIH National Cancer Institute (grant no. CA141057).

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective 

Severe acute pancreatitis (SAP), pancreatic inflammation leading to multiorgan failure, is associated with high morbidity and mortality. There is a critical need to identify novel therapeutic strategies to improve clinical outcomes for SAP patients.

Materials and Methods 

A comprehensive literature review was performed to identify current clinical strategies, known molecular pathophysiology, and potential therapeutic targets for SAP.

Results 

Current clinical approaches focus on determining which patients will likely develop SAP. However, therapeutic options are limited to supportive care and fluid resuscitation. The application of a novel 5-cytokine panel accurately predicting disease outcomes in SAP suggests that molecular approaches will improve impact of future clinical trials in AP.

Conclusions 

Inflammatory outcomes in acute pancreatitis are driven by several unique molecular signals, which compound to promote both local and systemic inflammation. The identification of master cytokine regulators is critical to developing therapeutics, which reduce inflammation through several mechanisms.

Acute pancreatitis (AP) related healthcare expenses exceed $2.5 billion per year, and the number of emergency department visits for AP has increased by 18% over the last 15 years. 1,2 Despite climbing incidence, research on pancreatitis has decreased more than any other GI disease over 50 years. In addition, the number of clinical studies is limited with significant issues surrounding patient recruitment. 3–9 This has led to a considerable gap in knowledge of disease etiology and treatment options.

It was proposed over 115 years ago that AP is caused by premature activation of trypsinogen to trypsin in the pancreas, stimulating pancreatic injury and subsequent inflammation. 10 Premature trypsinogen activation has been confirmed in several animal models, further supporting this hypothesis. 11–14 Despite the role of trypsin digestion of tissue in the initiation of AP, clinical trials with trypsin inhibitors have shown no benefit for patients. 15

Approximately 80% of AP cases are related to alcohol abuse or gallstone disease. 16 The remainder of cases occur post–endoscopic retrograde cholangiopancreatography or are classified as idiopathic. 17 Social and cultural risk factors also alter AP incidence as for instance increases in ethanol-related AP are observed in the United Kingdom during the Christmas and New Year weeks. 17 Several other risk factors that contribute to progression of mild AP to SAP include the following: sex, age, diet, and body mass index; however, they do not seem to cause disease. 17 Nicotine has been shown to impair pancreatic blood flow and increase pancreatic acinar cell Ca 2+ levels suggesting that cigarette smoke can directly induce pancreatitis. 18–20

Many of the early events observed in AP occur in acinar cells, where disruptions in Ca 2+ signaling are observed leading to local and systemic inflammation. 21–23 The acute inflammatory response during AP is followed by a cytokine surge and systemic inflammatory response syndrome (SIRS), which is associated with early organ injury. 24–27 There is a second phase of AP, which includes a systemic anti-inflammatory response. This phase is associated with a significant risk of infection in the pancreatic fluid caused by translocation of intestinal microbiota due to the failure of the intestinal barrier. 28 This results in 2 peaks of mortality in the early phase due to organ failure and in the late phase due to infection. 28 Acute pancreatitis severity is classified into mild, moderate, or severe disease based on the Revised Atlanta Classification. 24 Those with SAP have mortality rates up to 30%, with nearly half of those deaths occurring within 14 days of diagnosis, driving the need for early therapeutic markers and intervention methods. 29,30

CURRENT CLINICAL STRATEGIES

Currently, there are no validated models to predict AP severity early on, and therapeutic options are limited to supportive care. 29,31–34 However, several diagnostic tools exist that attempt to classify patients into subgroups to determine whether admission into the intensive care unit (ICU) is probable.

Diagnostic Tools

Contrast-enhanced computed tomography is the preferred imaging technique for determining the extent of pancreatic inflammation and identifying complications such as (peri)pancreatic necrosis stemming from AP. 31,34 However, the risk associated with repeated radiation exposure limits contrast-enhanced computed tomography as a monitoring tool for AP patients. Magnetic resonance imaging is preferred when minimal radioactive exposure or better evaluation of the pancreatic duct is required. 31,35 Although imaging evidence of pancreatitis is only one of the three criteria for diagnosis of AP, these modalities are also helpful in identifying potential complications. Right upper quadrant ultrasound is also used to identify gallstones as a potential AP etiology. 33–37 Endoscopic ultrasound can be performed to screen for microlithiasis or choledocholithiasis when clinical suspicion is high, but right upper quadrant ultrasound is negative. 34 Disease severity is determined using either the Revised Atlanta Classification or the Determinant-Based Classification of Acute Pancreatitis Severity. 24,38 Each of these classification systems was published in the same year, with similar categories for patients based on organ failure. Both classification systems have been compared extensively across several studies, with no significant difference being observed between the two in their ability to accurately classify the severity of AP in subgroups of patients. 39–41

Prognostic Tools

The Ranson score was among the first scoring systems aiming to classify the severity of AP. It was designed primarily for alcohol-induced AP, but the minimum criteria were modified to assess gallstone pancreatitis. 42 The Glasgow score includes key clinical and biochemical variables ( Table 1 ) and is considered a useful prognostic tool for mortality regardless of etiology. 43 The primary disadvantage to both of these scoring systems includes the 48-hour requirement for calculation.

The Acute Physiology and Chronic Health Evaluation II (APACHE-II) score was intended to evaluate patients with acute illness admitted to the ICU and is an accurate predictor of mortality in AP. 31,44,47,48 The Bedside Index of Severity in Acute Pancreatitis (BISAP) score was developed in 2008 and can be calculated within 24 hours of admission. 45 The BISAP system relies upon the Classification and Regression Tree analysis and continues to be credited as an accurate and valid method for predicting patient outcomes in AP. 49–51 The Pancreatitis Activity Scoring System (PASS) includes the following 5 parameters: SIRS, abdominal pain, opiate requirement, organ failure, and oral intake tolerance. 46 Recently, the PASS was updated to remove the morphine equivalent dosage (opiate requirement) as a parameter to improve SAP prediction. 52 A summary of these 5 prognostic tools is included in Table 1 .

Therapeutic Options

Currently, therapeutic options include adequate resuscitation, especially during initial presentation, early feeding, and maximizing supportive care if patients develop local/systemic complications. Clinical findings suggest that early fluid resuscitation is critical to improving outcomes in AP. 53 Lactate has been shown to reduce IL-1β production both in vitro and in vivo, 54 which may account for the evidence suggesting that patients receiving lactated Ringer's solution instead of saline have reduced ICU admission rates and reduced length of hospital stay. 55 Recent data obtained from the WATERFALL clinical trial suggests that aggressive (20 mL/kg bolus for 2 hours, then 3 mL/kg/hour infusion) fluid resuscitation via lactated Ringer's solution increases the risk of volume overload without improvement in primary outcome of AP patients when compared with moderate (10 mL/kg bolus only if hypovolemic, then 1.5 mL/kg/hour infusion) fluid resuscitation. 56 This data is supported by evidence that aggressive hydration is associated with worse outcomes in patients with systemic inflammatory diseases including sepsis, 57 acute lung injury, 58 and critical care patients. 59 The American Gastroenterology Association guidelines strongly suggest early (within 24 hours) oral feeding when tolerated. 32 Antibiotics are recommended only if an infection has been confirmed. 31,60–62 No effective pharmacological treatments have been identified despite the completion of several clinical trials. 31,63–66 Promising preliminary data from a recently completed study suggest that targeting Ca 2+ signaling in AP patients via the Orai1 inhibitor (Auxora) may improve outcomes; however, more human trials are necessary to determine the safety and efficacy of this therapeutic. 67

Furthermore, existing health inequalities in AP will likely limit the availability of potential therapeutic agents in minorities. African Americans are at an increased risk for AP and have higher rates of organ failure and mortality. 68–70 Similar disparities are observed in other populations, as challenges with timely access to care during AP attacks are also seen in Hispanics. 71 Therefore, reporting race and ethnicity data in clinical AP studies are crucial for potential subgroup analysis and can increase our ability to address health inequities in AP. 72

THE PROINFLAMMATORY RESPONSE TO AP

Several cytokines have been found to be upregulated in SAP patients, which are likely to contribute to inflammatory responses locally and systemically. Severity of AP is positively correlated with the intensity of inflammation, indicating that the development of therapeutics targeting inflammatory cytokines may inhibit disease progression. 73–75

Inflammatory Cytokines of AP

Several inflammatory cytokines are upregulated in circulation in patients with SAP. 31,47 Key molecules regulating cytokine cascade must be identified to aid in development of life-saving therapeutics in SAP patients.

Acute Phase Response in AP

The acute phase response is a broad term used to describe the reaction in an organism shortly after an insult. 76 This response includes several proteins upregulated or downregulated in response to the proinflammatory cytokines: tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6. 76–78 Pancreatic acinar cells produce TNF-α and its receptor and, through this signaling, mediate injury-induced cell death. 79 However, previous research identified no differences in the levels of TNF-α in serum between patients who developed severe or mild AP. In addition, polymorphisms in the gene encoding TNF-α are not associated with an increase in AP susceptibility. 80,81 Interleukin-1β levels have been shown to correlate with severity of AP; however, mechanistic studies of how IL-1β signaling may be driving disease are lacking. 82,83 The primary induction of acute phase protein production is caused by IL-6, produced by macrophages. 47,76,77 In a cerulein-induced mouse model of AP, IL-6 knockout mice displayed an increased survival rate, which was reversed when exogenous IL-6 was administered. 84 In addition, this study proved that IL-6 signals through STAT3 in acinar cells to stimulate CXCL1 production, a neutrophil chemoattractant, to drive disease progression. 84 These findings were recently further confirmed in a study that found that disease progression and inflammatory cytokine production are reduced via manipulation of upstream regulators of the IL-6/STAT3 signaling axis in vitro and in vivo. 85 The early release of IL-6 provides an attractive marker of progression in AP; however, rapid IL-6 clearance and the cost of IL-6 quantitation provide major drawbacks for widespread use in the clinic. 86–89

C-reactive protein (CRP) is an acute phase reactant produced in the liver in response to IL-6 and has been used in diagnosis, prognosis, and mortality prediction in patients with severe inflammation. 78 Traditionally, CRP has been used in the clinic to monitor AP progression, where it has been reported to increase in circulation with disease progression. 90–92 However, conflicting evidence indicates that the timing of CRP measurement and quantitation of other serum markers (ie, IL-6) are critical to predicting disease outcomes. 93 Furthermore, a recent retrospective analysis determined that CRP measurement at admission or at 48 hours does not predict the likelihood of developing complications from AP. 93 In addition, liver disease may alter CRP production, which may be a significant factor in patients experiencing AP stemming from alcohol abuse. 94,95

Procalcitonin has been identified to be a key marker in circulation for patients experiencing severe bacterial infections and/or multiorgan failure. 96 Measurement of this molecule has been shown to predict the risk for development of severe AP and infected pancreatic necrosis with a sensitivity of 0.72 and 0.80, respectively, and a specificity of 0.86 and 0.91, respectively. 97 Synthesis of physiologic blood proteins (albumin, transferrin, and others) is downregulated in the acute phase response, and lower levels of circulating albumin throughout AP are predictive of organ failure and mortality. 76,98,99 Despite these published studies surrounding the acute phase proteins and their clinical relevance, very few mechanistic studies have been published implicating these proteins, limiting the advancement of AP clinical trials.

Damage-Associated Molecular Patterns and the Complement Cascade in AP

Early in the disease, an inflammatory injury will lead to leakage of prematurely activated pancreatic enzymes, further stimulating apoptosis, autophagy, necrosis, and release of damage-associated molecular patterns (DAMPs). 100,101 These DAMPs recruit innate immune effector cells, generating an inflammatory response in the tissue. 31,100 Paradoxically, apoptosis of acinar cells has shown to be somewhat protective in AP, which may be due to a reduction in DAMP release in response to apoptosis compared with necrotic cell death. 102–104 As necrosis and/or excessive autophagy of acinar cells occurs, contents within these cells are released into the environment, including several DAMPs: IL-33, high mobility group box 1, and ATP. 105 All of these molecules are known activators of the innate immune system and have been proposed to be the critical molecules initiating disease in AP. 105

Interleukin 33, typically stored in the nucleus of the cell, is passively released from cells upon cell necrosis and/or during tissue damage and acts as an “alarm” for the immune system. 106 Duct ligation-induced AP in both mice and rats has been shown to induce elevated levels of IL-33 in the pancreas. 107 In addition, intraperitoneal injections of IL-33 alone induced neutrophil and macrophage infiltration coupled with perivascular edema. 107 Chen et al 108 found that pancreatic ductal administration of an adenoviral vector that activates NF-κB is sufficient to induce AP and is reduced via coadministration of an NF-κB inhibitor. It is likely that the effect of the activation state of the NF-κB pathway is immune cell specific. More specifically, the pathways activated in neutrophils are particularly interesting as the depletion of these cells in a taurocholate-induced mouse model of AP reduces pancreatic injury and inflammation. 109 In addition, high mobility group box 1 is elevated in pancreatic tissue throughout AP and has been shown to contribute to AP progression in a toll-like receptor 4 and NF-κB–dependent manner. 110 Extracellular ATP has been found to be increased in the circulation of mice regardless of the method of AP induction, and this ATP was found to stimulate neutrophil migration and activation. 111 The increase in released ATP may be due to the dysfunctional Ca 2+ signaling observed in acinar cells and is known to contribute to mitochondrial dysfunction and improper ATP production. 112 Taken together, DAMPs released in response to acinar cell damage provide a potent proinflammatory environment in the tissue to perpetuate disease progression.

In addition to direct stimulation of neutrophils and other inflammatory cells, DAMPs can activate the complement cascade, a critical component of innate humoral immunity. This complement system has been extensively studied in the context of AP because of its known role in mediating local and systemic inflammation. 113 Recently, the critical complement component 3 (C3) was identified as a key regulator of neutrophil recruitment and activation in a taurocholate-induced mouse model of AP. 114 In addition, C5 has been determined to stimulate pancreatic stellate cells in 2 mouse models of chronic pancreatitis, indicating that this system may activate both inflammatory cells and pancreatic stromal cells in the disease. 115 In humans, elevated levels of C3a and sC5b-9 are observed early in AP and act as a strong predictor of pancreatic necrosis with a sensitivity of 0.93 and sensitivity of 0.88. 116 Interestingly, C5a has also been found to exert anti-inflammatory properties in the context of AP 117 and sepsis 118 suggesting that the complement cascade is a complex communication network, which must be further studied to properly target in AP patients.

Another cytokine implicated in AP is IL-8, which is predictive of severe AP in patients with similar sensitivity and specificity as IL-6. 119–121 However, mechanistic studies involving IL-8 in AP are lacking, and only a weak association between an IL-8 polymorphism and AP has been identified. 122 The interferon-γ–inducing factor IL-18 is another proinflammatory cytokine, which has been shown to activate the NF-κB pathway. 123 Circulating IL-18 is significantly upregulated in AP patients as early as day 1 and as late as day 5 compared with healthy controls. 124 In addition, IL-18 is positively correlated with several other inflammatory markers found in circulation in AP patients (CRP, IL-6, IL-8). 124–126

In conclusion, the inflammatory response in AP is complex, with several cascades and cytokines mediating cellular-specific outcomes to maintain a proinflammatory environment in the tissue, which becomes systemic. Furthermore, whether DAMPs precede the acute phase response in AP is unclear. Therefore, therapeutic targets that reduce DAMP and acute phase protein production or signaling may provide the most significant potential.

POTENTIAL THERAPEUTIC STRATEGIES

Despite the development of minimally invasive drainage/debridement techniques for pancreatic necrosis in SAP, there have been little to no improvements in patient outcomes. 127 Recently, a 5-cytokine panel including angiopoietin 2 (Ang-2), hepatocyte growth factor (HGF), IL-8, resistin, and TNF-receptor superfamily IA has been reported to accurately predict persistent organ failure (POF) in AP with a 10-fold cross-validated accuracy of 0.89. 128 Each cytokine was carefully chosen for this panel because of their specific roles in the POF cascade including activation of the innate immune system (TNF-α, IL-8), lipolysis of peripancreatic/intrapancreatic fat (resistin), microvascular dysfunction (Ang-2), and early organ injury (HGF) ( Fig. 1 ). 128,129 In addition, these measurements can be taken within 24 hours from the onset of the symptoms to predict POF in AP, which may significantly improve future clinical trials that require early identification of SAP patients. 128 These findings suggest therapeutic strategies and clinical interventions focused on circulating cytokines may significantly benefit SAP patients as these molecules are targetable and upregulated early in disease. Future clinical trials may consider targeting several of these 5 cytokines to inhibit disease progression and POF.

Interleukin-10 Master Regulator

Interleukin 10 has been extensively studied in the context of several inflammatory disorders and has been identified as a critical regulator of tissue homeostasis by restricting excessive inflammatory responses. 130 Indeed, several studies have determined that IL-10 is produced by nearly all subsets of leukocytes, including macrophages, 131 T-cells, 132 and neutrophils 133 to signal in an autocrine/paracrine manner to exert anti-inflammatory effects on these cells. More specifically, IL-10 has been determined to reduce cytokine production of several of the inflammatory cells found in AP, providing an attractive therapeutic target. 134 Multiple animal studies have identified that exogenous administration of IL-10 reduces chemically induced SAP. 135,136 However, a clinical trial performed in 2001 identified no benefit from 8 μg/kg of IL-10 for endoscopic retrograde cholangiopancreatography–induced pancreatitis indicating that alternative cytokine regulators must be identified and targeted to prevent POF in SAP patients. 137 Interestingly, a recent study determined that administration of pirfenidone increases IL-10 production in a mouse model of AP, which may provide an alternative method for increasing circulating IL-10 in SAP patients and should be further explored in humans. 138

Alternative Cytokine Targets

Activin A, a member of the transforming growth factor β superfamily, is a cytokine with critical roles in cell differentiation, cancer, secretion of other cytokines, and inflammation. 139–142 The cytokine cascade observed in severe AP patients with SIRS is similar to sepsis, a critical illness where serum activin A is a predictor of sepsis severity in early disease. 143 In addition, activin A is released in response to LPS downstream of the DAMP receptor toll-like receptor 4, indicating that activin A may be a critical component of the acute phase response. 144 Activin A has been shown to induce IL-1β, IL-6, and TNF-α production in peripheral blood mononuclear cells from human donors. 145 In addition, recent evidence indicates activin A signals in an autocrine manner to drive IL-6 production in cancer cells, further supporting the notion that activin A drives IL-6 production and the initial inflammatory events leading to the acute phase response. 146

Activin A seems to interact with several of the cytokines included in the 5-cytokine panel, which provides an attractive target for potential AP therapeutics. Administration of TNF-α to isolated human neutrophils induces activin A secretion, indicating that neutrophils may also provide a significant source of activin A in an inflammatory setting. 147 Inhibition of activin A signaling reduced TNF-α secretion and inflammatory infiltrate in a mouse model of malaria infection, further supporting to the proinflammatory role of activin A. 147 These data suggest a potential positive feedback loop in which TNF-α enhances activin A production and vice versa to enhance the inflammatory response. Moreover, IL-8 production is induced in human endometrial stromal cells when activin A is administered, further confirming the proinflammatory role of the molecule. 148 Activin A has been shown to activate several pathways but has been classically identified to activate the SMAD pathway, where SMAD4 translocation into the nucleus results in transcriptomic changes. 149 Inhibition of SMAD4 has recently been shown to increase transcription for the gene encoding Ang-2 providing evidence that activin A may inhibit Ang-2 production and reduce vascularization to the injured pancreas in AP. 150 There is little to no evidence explaining the potential relationship of activin A to HGF or resistin, and further research is required to elucidate what interactions may exist.

These data suggest that activin A promotes a significant upregulation in several cytokines, which increase in the circulation of AP patients. In addition, the role of activin A in enhancing TNF-α and IL-8 production while reducing the effects of Ang-2 suggests that this molecule may promote inflammation while reducing pancreatic vascularity for repair.

Pancreatic acinar cells have been shown to produce significant amounts of activin A in a mouse model of cerulein-induced AP with little production under homeostatic conditions, suggesting a specific role for activin A in response to pancreatic insult. 151 Clinical data indicate that AP patients' circulating activin A levels are increased compared with controls, independent of body mass index. 152 This study also found that levels of circulating activin A raised in a stepwise fashion relative to disease severity, with the highest amount of activin A found in severe AP patients. 152 Importantly, high levels of activin A at admission were predictive of a more extended hospital stay when compared with low and intermediate levels. 152 Activin A seems to play a critical role in the mechanism driving disease severity in in vivo models of AP. Ob/ob mice injected with cerulein develop severe AP, which is reduced in anti–activin A–treated mice that also display an increased survival rate in this model when compared with vehicle-treated controls. 152 Anti–activin A intervention has been shown to reduce pancreatic inflammation and tissue damage. 153 Pancreatic stellate cells are also a source of activin A production in the inflamed pancreas. 153 Upon stimulation, neutrophils have also been shown to produce large quantities of activin A, which can signal in an autocrine/paracrine fashion. 147 Previous research has identified that when neutrophils are depleted in mice, AP development is diminished with reductions in the inflammatory infiltrate and tissue damage demonstrating an attractive immune cell target for anti-AP therapeutics. 154

These data suggest that anti–activin A intervention will improve SAP patient outcomes through several distinct anti-inflammatory pathways. In addition, anti–activin A therapy is well tolerated in humans providing excellent potential for future anti–activin A clinical trials. 155

CONCLUSIONS

Acute pancreatitis remains a major clinical challenge because of the lack of therapeutic options to prevent disease progression. The significant knowledge gap surrounding AP mechanisms is due to the complex nature of the disease and the shortage of well-designed clinical trials. 3 The application of a 5-cytokine panel seems to have the most significant potential in predicting patient outcomes ( Fig. 1 ), which should be leveraged for future clinical trials. 128 The success of this panel suggests that a molecular approach designed to inhibit the production of several inflammatory mediators may provide tremendous success in the clinic. Activin A seems to promote the production and secretion of several critical inflammatory cytokines associated with the cytokine cascade observed in AP. 152,153 Given that activin A regulates several cytokines of interest in AP and anti–activin A therapeutics are well tolerated in humans, therefore activin A is an attractive target for clinical trials ( Fig. 2 ). 155 Future research should identify the mechanism by which activin A promotes disease progression. Alternatively, targeting Ca 2+ signaling may provide significant therapeutic potential given the preliminary success of Auxora. 67 More human studies must be completed to determine the safety and efficacy of targeting Ca 2+ signaling via Orai1 inhibition.

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Interventions for Pancreatitis: New Approaches, Knowledge Gaps, and Research Opportunities

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This one-day workshop aims to inform investigators of new developments in the field and identify the knowledge gaps and research opportunities that might inform possible future funding initiatives for NIDDK.

Recent NIDDK Workshops have focused on the requirements for designing and conducting clinical trials in pancreatitis.

The breadth and variety of currently planned or underway interventions include behavioral interventions, nutritional studies, studies with pharmacologic and biologic agents, and mechanical studies with endoscopy and surgery.

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July 26, 2023

Keynote Presentations

Session 1: Behavioral Interventions in Pancreatitis Moderators: Christie Jeon, D.Sc., M.S., Cedars-Sinai Medical Center/University of California, Los Angeles and Tonya Palermo, Ph.D., Seattle Children’s Hospital/University of Washington

Session 2: Nutritional Interventions in Pancreatitis Moderators: Phil Hart, M.D., The Ohio State University and Stephen Pandol, M.D., Cedars-Sinai Medical Center/University of California, Los Angeles

Session 3: Pharmacological and Biological Approaches for Pancreatitis: Promising, New, or Novel Treatments Moderators: Vikesh Singh, M.D., M.Sc., Johns Hopkins University and David Whitcomb, M.D., Ph.D., University of Pittsburgh

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New cancer research breakthrough has the potential to save lives

Researchers at umass chan discovered a way to shrink tumors in mice, by jeff saperstone • published september 20, 2024 • updated on september 20, 2024 at 6:39 pm.

Pancreatic cancer is one of the deadliest forms, but new research could one day lead to lives being saved.

Researchers at UMass Chan Medical School in Worcester discovered that using something called nanoparticles can effectively shrink tumors in mice. They hope to someday move this research to human trials and be able to save lives.

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"If we are successful and we can engineer this correctly for the next generation, it could be quite transformative, we think," said Prabhani Atukorale, an assistant professor at UMass Amherst.

Pancreatic cancer accounts for about 66,440 cases this year. It’s one of the most deadly forms of cancer, with only a 12% survival rate after five years.

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“So we're attempting to build a 'smart therapy,' if you will," Atukorale said. "Just like your smartphone."

The researchers showed NBC10 Boston ultrasound images of a tumor before and after treatment. The team says 10 mice with tumors were treated using nanoparticles, which are so small you can't see them under a normal microscope.

Out of the 10 trials, two remained tumor-free for a long time, and eight others' tumors had been significantly reduced.

"This was quite astounding to see how stark of a difference in tumor volume size we were able to achieve with our treatment," said Marcus Ruscetti, an assistant professor at UMass Chan Medical School. "It was absolutely exciting."

Ruscetti said nanoparticles are able to go through the blood stream undetected so more of them can get to the tumor.

"We envision that this could work in patients with very late stage tumors that unfortunately haven't responded to chemotherapy, other types of therapies as a way to activate the immune system to come in and target this cancer," said Ruscetti. "Our goal ... is eventually to take what we're doing in mice are in cells and the hope is to really change people's lives."

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Pancreatic cancer vaccine trial offers hope of lowering deaths from deadly form of disease

Pancreatic cancer, which killed apple’s steve jobs in 2011, is one of the deadliest forms of cancer. clinical trials of a vaccine have begun.

A cancer patient in Britain has become the first person in Europe to sign up to a groundbreaking clinical trial for a new pancreatic cancer vaccine.

Pancreatic cancer, which killed Apple co-founder Steve Jobs in 2011, is the 12th most common cancer globally – and among the most deadly. Experts said the launch of the European arm of the trial means that “hope is on the horizon”.

Pancreatic Cancer UK said that the potential of the vaccine “cannot be understated” and it could become a “vital new weapon” against the disease.

The patient, who has not been named, was enrolled in the trial at Queen Elizabeth Hospital in the English city of Birmingham.

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Acute pancreatitis: current perspectives on diagnosis and management

Adarsh p shah.

Department of Surgery, Hereford County Hospital, Hereford, UK

Moustafa M Mourad

Simon r bramhall.

The last two decades have seen the emergence of significant evidence that has altered certain aspects of the management of acute pancreatitis. While most cases of acute pancreatitis are mild, the challenge remains in managing the severe cases and the complications associated with acute pancreatitis. Gallstones are still the most common cause with epidemiological trends indicating a rising incidence. The surgical management of acute gallstone pancreatitis has evolved. In this article, we revisit and review the methods in diagnosing acute pancreatitis. We present the evidence for the supportive management of the condition, and then discuss the management of acute gallstone pancreatitis. Based on the evidence, our local institutional pathways, and clinical experience, we have produced an outline to guide clinicians in the management of acute gallstone pancreatitis.

Introduction

A patient complaining of sudden onset of epigastric pain radiating to the back, associated with nausea and vomiting, requires rapid exclusion of a wide range of life-threatening conditions involving the cardiovascular (myocardial infarction, ruptured, and/or dissecting aortic aneurysm) and gastrointestinal (peptic ulcer disease with perforation or bleeding, acute pancreatitis) systems. The clinician’s history and examination findings are augmented by relevant investigations in narrowing the differential diagnoses to eventually guide the management and treatment of a certain condition and its associated complications.

The incidence of acute pancreatitis in the UK is ~56 cases per 100,000 persons per year, 1 while in the US over 220,000 hospital admissions annually are attributed to acute pancreatitis. 2 An epidemiologic study that utilized UK and European data demonstrated an increasing incidence in all-cause acute pancreatitis. 3 The incidence of acute pancreatitis was also noted to increase with age. 3 , 4 The male population had an incidence that was 10%–30% higher than females. 4 Despite a reduction in the case fatality being observed over time, the population mortality has remained largely unchanged. 3 Of all hospital admissions with acute pancreatitis, ~20%–30% of patients have a severe course, 1 while severe life-threatening complications will develop in ~25% of these patients. 4 The mortality in severe acute pancreatitis can be as high as 30%, 2 but the overall mortality in acute pancreatitis is estimated to be 5%. 1

Gallstones remain the most common cause for acute pancreatitis. Gallstone-related acute pancreatitis accounts for approximately half of all UK cases, while up to 25% of acute pancreatitis cases can be attributed to alcohol. 1 Epidemiologic data have shown a linear increase in the incidence of gallstone pancreatitis across the UK and European countries studied. However, the UK has a much lower incidence of alcohol-induced pancreatitis compared with European studies. 3 Alcohol-induced acute pancreatitis is more common in middle-aged men. Idiopathic acute pancreatitis accounts for 20%–34% of cases and its incidence is similar in both men and women. 3 The incidence of idiopathic acute pancreatitis depends on the extent to which a clinician investigates a patient’s episode of acute pancreatitis for its causative etiology. Recent advances in laboratory pathology tests and radiologic imaging techniques have contributed to a reduction in the number of acute pancreatitis cases being labeled as idiopathic.

The incidence of gallstone-related acute pancreatitis in both men and women increases with age, with women over the age of 60 years at higher risk. 2 , 3 Patients with gallstones smaller than 5 mm, microlithiasis, or biliary sludge are thought to be at higher risk of gallstone pancreatitis. Microlithiasis causes a functional obstruction at the sphincter of Oddi, which subsequently results in bile and/or biliary-pancreatic secretion reflux that injures the pancreatic duct. 5 The common channel theory in the pathogenesis of acute gallstone pancreatitis has been refuted by some. 6 Instead, it has been postulated that acute gallstone pancreatitis is the result of pancreatic acinar hyperstimulation secondary to ductal obstruction that triggers trypsin release, which induces a cascade of enzyme-led pancreatic and peripancreatic inflammation. 6 Others speculate that duodenal content reflux is more causative of pancreatic ductal injury than bile reflux. 7 There are multiple theories implicated in the pathogenesis of acute pancreatitis, and all remain controversial.

Inappropriate release and activation of pancreatic enzymes induce acute pancreatitis. The key enzyme in the activation of pancreatic zymogens has been thought to be trypsin. The inappropriate activation of trypsinogen to trypsin and the lack of prompt pancreatic clearance of active trypsin result in pancreatic inflammation and subsequent triggering of the inflammatory cascade. 2 Cytokines including interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor a , and platelet-activating factor are released. 7 These in turn induce the hepatic synthesis of acute phase reaction proteins such as C-reactive protein (CRP). Leukocyte migration and activation may represent the major determining factor for both local and systemic complications. 4

Diagnosis of acute pancreatitis

In their 2005 guidelines, the UK Working Party on Acute Pancreatitis suggested that the etiology should be determined in at least 80% of cases of acute pancreatitis. Furthermore, the classification of cases of idiopathic acute pancreatitis should be no more than 20%. 8 Therefore, patients are subjected to extensive investigations to determine the underlying etiology.

The pretest probability of acute pancreatitis is determined by the clinician’s index of suspicion, which is largely based on the patient’s history and clinician’s examination findings. 4 The classical teaching is that a serum amylase level that is three or four times greater than the upper limit of normal is diagnostic of acute pancreatitis. While the measurement of serum pancreatic enzymes such as amylase is the “gold standard” for the diagnosis of acute pancreatitis, the measured value for the serum pancreatic enzymes should be interpreted by considering the duration of patient’s symptoms.

In acute pancreatitis, the pancreatic enzymes amylase, lipase, elastase, and trypsin are simultaneously released into the bloodstream. As the clearance of each of these enzymes varies, the timing of the blood sampling from the onset of acute pancreatitis affects the test’s sensitivity. 4 Lipase has a higher diagnostic accuracy compared to amylase as the serum lipase levels are elevated for a longer period. 9 Caution should be exercised when interpreting amylase results in patients with hypertriglyceridemia as they can have a falsely low amylase result.

During an attack of acute pancreatitis, the elevation of alanine aminotransferase to >150 IU/L is a predictive factor for biliary cause of acute pancreatitis. 10 A previous meta-analysis has indicated that this threefold elevation in alanine aminotransferase has a positive predictive value of 95% in diagnosing acute gallstone pancreatitis. 11

The biochemical measurement of trypsinogen activation peptide (TAP) and trypsinogen-2 is more useful as a diagnostic marker for acute pancreatitis due to their accuracy, but their evaluation is limited by availability. 9 Early elevated levels of urinary TAP have been shown to be associated with severe acute pancreatitis. 4 Other markers such as IL-6 and IL-8, 9 as well as phospholipase A2 have been summarized well elsewhere, 12 and are not routinely measured in clinical practice in the UK.

Management of acute pancreatitis

Classification of severity.

Mastery of the management of acute pancreatitis is an art that can challenge experienced clinicians at the best of times. One facet to the art of managing acute pancreatitis is classification of the disease severity so that one can recognize, anticipate, and treat accordingly complications of the disease. The revised 2012 Atlanta criteria for classification of the severity of acute pancreatitis are widely accepted. 13 This revised classification defines transient organ failure as organ failure which resolves completely within 48 hours, whereas failure of resolution of organ failure is defined as persistent. The presence of persistent organ failure, usually with one or more local complications, indicates severe acute pancreatitis. On the other hand, the absence of organ failure without any local or systemic complications indicates mild acute pancreatitis. “Moderately severe acute pancreatitis”, indicated by transient organ failure and/or local or systemic complications in the absence of persistent organ failure, is the new grade of severity between mild and severe that was introduced in the revised classification. 13 Multiple scoring systems for the prediction of the disease severity and prognostic implications exist. 12 , 14 The prognostic features aid the clinician in predicting complications of acute pancreatitis. 8

The Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system has demonstrated the highest accuracy for predicting severe acute pancreatitis when compared with other scoring systems. 15 Other markers of severe acute pancreatitis based on evidence from the literature have been outlined in Box 1 . The APACHE II score can be repeated daily and its trends correlate well with clinical progress or deterioration. However, there is no significant difference in the prognostic accuracy between the APACHE II and multiple factor scoring systems such as Ranson, computed tomography severity index (CTSI), 15 , 16 and the bedside index for severity in acute pancreatitis. 17

The clinical, biochemical, and radiologic markers that assist in the classification of severity of an acute pancreatitis episode

• Obesity 4 , 8
• APACHE II score ≥8 on admission 4 , 8 , 20
• Evidence of organ dysfunction on admission
• CRP ≥ 150mg/L at 48 hours post-admission 4 , 8 , 12 , 18 , 20
• Glasgow score >3 at 48 hours post-admission 15 , 16
• Evidence of necrosis on contrast-enhanced CT (CECT) 25
• Procalcitonin >1.8 ng/mL 19 , 24

Notes: These aid the clinician with identifying patients who should have early intensive care input or treatment. Patients with any combination of the above should be classed as severe acute pancreatitis and thus monitored for complications within an escalated level of care.

Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CRP, C-reactive protein.

The CRP is a reliable, easily accessible, single marker of assessing severity. It has demonstrated good prognostic accuracy for severe acute pancreatitis, pancreatic necrosis, and in-hospital mortality when measured at 48 hours following hospital admission. 18 , 19 Another cheap and easily obtainable parameter indicative of the severity of acute pancreatitis is the hematocrit. An admission hematocrit ≥44% or failure of the hematocrit to decrease at 24 hours following admission is indicative of severe acute pancreatitis in the early stage of the disease. 20 Additionally, some studies have demonstrated that hemoconcentration has been associated with the risk of developing necrotizing pancreatitis and organ failure, 20 , 21 while others refute this observation. 22 , 23 The absence of hemoconcentration on admission has a high negative predictive value for the development of necrosis. 22 , 23 Other markers such as procalcitonin 19 , 24 and IL-8, not used routinely in the UK, have been shown to have high predictive accuracy in classifying the severity of necrotizing pancreatitis in the first days of the disease.

The inflammatory response varies between each individual patient. The release of intrapancreatic enzymes triggers the release of proinflammatory mediators and macrophage activation within acinar cells resulting in local complications of acute pancreatitis, which include pancreatic necrosis with or without infection, pancreatic pseudocyst formation, pancreatic duct disruption, and peripancreatic vascular complications. It is unclear why in some patients the local pancreatic inflammation triggers a systemic release of proinflammatory mediators. However, this systemic inflammatory response manifests as organ failure, and its recognition and treatment are important in altering the clinical course of acute pancreatitis.

Imaging plays an important role in the diagnosis and management of acute pancreatitis. As 50% of acute pancreatitis cases are gallstone-related, transabdominal ultrasound is the most common initial radiologic investigation of choice. Ultrasonography has the highest sensitivity for detection of gallbladder stones, but a poor sensitivity for choledocholithiasis ( Table 1 ). The retroperitoneally sited pancreas is usually difficult to visualize in acute pancreatitis during ultrasonography, which can be further compounded by overlying bowel gas, large patient body habitus, and abdominal pain. In the assessment of the presence or absence of gallstones, it is recommended that at least two good quality ultrasound examinations are obtained. Where the first exam is negative and cannot detect gallstones, the most sensitive test for diagnosis of gallstones that may have been initially missed remains a further ultrasound examination. 4

Comparison of the different imaging modalities available when diagnosing choledocholithiasis

Abbreviations: CECT, contrast-enhanced CT; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography.

In patients with suspected acute pancreatitis, dynamic contrast-enhanced CT (CECT) is the imaging modality of choice. CECT plays a role in establishing the diagnosis, staging the severity of the disease, and assists in the detection of complications. 4 , 25 However, it must be borne in mind that the staging of severity and detection of complications depend on the timing of CT scanning. In the first 24–48 hours, the CT findings of necrosis may be equivocal as only 25% of patients with acute pancreatitis develop necrosis. Additionally, pancreatic necrosis may not develop within the first 48 hours. 20 In severe acute pancreatitis, unless the patient is critically ill and in need of emergency intervention, the initial CT scan should ideally be obtained at least 72 hours following symptom onset. 4

The use of CECT in the localization of site and/or extent of pancreatic necrosis enhances the accuracy in outcome prediction, as evident from the development of the CTSI. High CTSI scores correlate with worsening severity and prognosis, pancreatic infection, and need for intervention. 26 , 27 For example, patients with necrosis of the pancreatic head have similar poor outcomes in comparison to patients whose entire pancreas was affected. 28 A modified CTSI has been developed for evaluating the severity of acute pancreatitis, but no significant differences have been observed when compared to the original CTSI. However, both CTSI scoring systems have demonstrated superior accuracy in diagnosing clinically severe acute pancreatitis when compared to the APACHE II severity scoring system. 29

Magnetic resonance imaging in the form of magnetic resonance cholangiopancreatography (MRCP) has become a popular imaging modality for evaluation of the bile ducts and pancreatic duct. Its benefits in acute pancreatitis are outlined in Box 2 . MRCP is reliable in diagnosing choledocholithiasis, and is only superseded by endoscopic ultrasound (EUS) in its sensitivity for detecting choledocholithiasis ( Box 2 ). The limitations of MRCP include contraindication in patients with pacemakers and other metal objects, long image acquisition times, and difficulty with scanning critically ill patients.

The advent of MRCP and EUS has dramatically reduced the need for ERCP as a diagnostic tool in choledocholithiasis. EUS is the most reliable pretherapeutic diagnostic modality for choledocholithiasis, 34 and when utilized with MRCP, both imaging modalities provide a safer method for investigating choledocholithiasis compared to ERCP, which is itself associated with a risk of postprocedural pancreatitis. EUS is particularly useful in the assessment of microlithiasis, which has been attributed as a cause of recurrent acute pancreatitis in patients with no evidence of choledocholithiasis visible using other imaging modalities. EUS also confers the ability to evaluate ductal abnormalities.

The benefits of magnetic resonance imaging in acute pancreatitis. 36

• Nonionizing radiation – useful in following up patients with repeated scans;
• Ability to detect choledocholithiasis;
• Ability to demonstrate the presence of a disconnected pancreatic duct – useful in predicting complications and of some prognostic value;
• Ability to characterize pancreatic and parenchymal collections or abscesses – detecting complications of acute pancreatitis, therefore guiding management;
• With angiography, useful in identifying hemorrhage within pancreatic or peripancreatic collections or pseudocysts, and identifying pseudoaneurysms to guide further management.

Fluid therapy in acute pancreatitis

The initial management of acute pancreatitis is largely supportive, with fluid replacement and optimization of electrolyte balance, providing adequate caloric support, and preventing or identifying and treating local and systemic complications.

The local and systemic inflammatory response in acute pancreatitis results in fluid depletion in the form of vomiting, reduced oral fluid intake, third-space fluid loss, and increased insensible losses in sweat and respiration. Fluid replacement in acute pancreatitis can be undertaken using crystalloid, colloid, or a combination of both. Ringer’s lactate is the preferred crystalloid fluid, 37 but caution should be exercised in hypercalcemic patients. The literary evidence for recommendations for fluid resuscitation has been summarized previously. 38 However, to date, there is no clear agreed consensus regarding the ideal fluid type and regimen for fluid resuscitation. 39 , 40 The goal of fluid resuscitation is to achieve a urine output of ≥0.5 mL/kg/h and a target heart rate <120/min, and maintain hematocrit between 35% and 44%. 39 Supplemental oxygen should complement fluid resuscitation to maintain arterial oxygen saturations >95%.

Nutrition in acute pancreatitis

Acute pancreatitis results in the rapid metabolism of fat and protein due to the hypercatabolic state. Nutritional support aims to provide adequate caloric intake and modulate the oxidative stress response during the initial phase of acute pancreatitis, thereby counteracting the catabolic effects. 41 Additionally, enteral nutrition maintains intestinal motility, which preserves the gut barrier function and subsequently reduces the risk of secondary infections – it has been hypothesized that the infective complications of acute pancreatitis arise because of bacterial translocation from the gut, a consequence of altered intestinal motility, bacterial overgrowth, and increased intestinal permeability. 39 Enteral nutrition, compared to total parenteral nutrition, in acute pancreatitis is associated with better clinical outcomes. 42

Immediate oral feeding with the introduction of a soft diet, 43 low-fat solid diet, 44 or a full solid diet 45 is safe in patients with mild acute pancreatitis whose pain is settling. Oral feeding in mild acute pancreatitis has been shown to result in shorter duration of hospitalization with no significant pain relapse noted after initiation of refeeding. 43 , 45 However, caution should be exercised in patients whose pain relapses following early oral refeeding, as this has been shown to increase their hospital stay. 46

In patients with severe acute pancreatitis, there is good evidence that enteral nutrition is preferred over total parenteral nutrition. Total parenteral nutrition is associated with a significant increase in local and systemic infective complications, multiorgan failure, and mortality. 42 , 47 , 48 Enteral nutrition within 48 hours of admission modulates the inflammatory and sepsis response, 41 , 49 which has demonstrated clinically significant reduction in all infections and mortality in one study. 50 However, two randomized clinical trials comparing early enteral feeding vs delayed enteral feeding in acute severe pancreatitis failed to demonstrate superiority of early enteral feeding in reducing complications, organ failure, and mortality in these patients. 51 , 52 Enteral feeding can be administered via the nasogastric and nasojejunal routes. Nasogastric feeding is safe and has comparable outcomes to nasojejunal feeding in severe acute pancreatitis. 53 , 54 The UK Working Party on Acute Pancreatitis recommends the use of the enteral route for nutritional support, if tolerated, in patients with severe acute pancreatitis. It also acknowledges that the evidence to support the use of enteral nutrition in all patients with severe acute pancreatitis is not conclusive. 8

Antibiotic therapy in acute pancreatitis

Secondary infective complications of acute pancreatitis are associated with increased mortality. 8 The widespread use of antimicrobial therapy across all areas of health care has resulted in the need for targeted antimicrobial therapy to achieve better outcomes while simultaneously minimizing the risk of developing antimicrobial resistance. Like the debate surrounding nutrition in acute pancreatitis, there have been controversies with the use of antimicrobials in acute pancreatitis.

The spectrum of microorganisms responsible for infected necrosis is changing. 4 Although Gram-negative aerobic bacteria are commonly yielded in cultures of infected pancreatic necrosis, Gram-positive bacteria, anaerobes, and fungi have also been isolated. 55 Penicillins, first-generation cephalosporins, aminoglycosides, and tetracyclines are ineffective in acute pancreatitis. Antibiotics that are active against Gram-negative bacteria such as imipenem, clindamycin, piperacillin, fluoroquinolones, and metronidazole have adequate tissue penetration and bactericidal properties in infected pancreatic necrosis. 56 Compared with other intravenous antibiotics, carbapenems are associated with a significant reduction in mortality, while use of imipenem significantly reduced the incidence of infected pancreatic necrosis. 55 , 57 Caution should be exercised when interpreting results of the meta-analyses as the patient numbers are relatively small. 57 , 59

Studies conducted two decades ago focused on the use of antibiotic prophylaxis in preventing the infective complications in severe acute pancreatitis. Systematic reviews and meta-analysis of these studies demonstrated a reduction in mortality with antibiotic prophylaxis. 58 , 59 Two decades later, there is now good evidence to suggest that there is no significant decrease in mortality when patients with acute pancreatitis are treated with prophylactic antibiotics. Furthermore, prophylactic antibiotics are not associated with a significant reduction in infective complications of pancreatic necrosis. 57 , 60 , 61

Surgical intervention in acute pancreatitis

The surgical management for acute pancreatitis can be divided into the surgical management of acute gallstone pancreatitis and the surgical management of complications of acute pancreatitis. Figure 1 summarizes the management of mild acute pancreatitis, including cases whose etiology is related to gallstones.

A flowchart encompassing the patient’s journey from diagnosis of acute pancreatitis through to further investigation and definitive management.

Abbreviations: CBD, common bile duct; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; HIDA, fatty meal hepatobiliary iminodiacetic acid scan; LFT, liver function test; MRCP, magnetic resonance cholangiopancreatography; TUS, transabdominal ultrasound.

In patients with mild acute gallstone pancreatitis who are fit for cholecystectomy, the guidelines recommend that the procedure should ideally be performed at the index admission, 62 and should not be delayed by >2 weeks. 8 , 63 Early laparoscopic cholecystectomy in this cohort of patients can shorten the total hospital stay. 64 On the other hand, studies involving patients with mild acute gallstone pancreatitis who underwent interval (delayed) cholecystectomy observed a high risk of readmission with recurrent biliary events. 8 , 65 For patients who are at high risk or unfit for cholecystectomy, or in centers where in-patient cholecystectomy during the index admission is not a feasible option, ERCP and endoscopic sphincterotomy (ES) alone may be sufficient. ES can reduce the short-term risk of a second attack of pancreatitis by at least 50%. 4

All patients with acute gallstone pancreatitis should have imaging of the common bile duct to assess for choledocholithiasis ( Box 2 ). Preoperative imaging utilizes noninvasive methods such as transabdominal ultrasound and/or MRCP, while intraoperative cholangiography provides real-time imaging of the common bile duct. Management of choledocholithiasis is reliant upon availability of local expertise and can be broadly classified into 1) the single-stage approach – laparoscopic or open cholecystectomy with intraoperative cholangiography and common bile duct exploration, or 2) two-stage approach – preoperative ERCP with or without ES followed by laparoscopic or open cholecystectomy. There is no significant difference in the morbidity, mortality, retained stones, and failure rate between the two management approaches for choledocholithiasis. 66 , 67

In centers where the availability of appropriate surgical expertise allows the single-stage definitive management of mild acute gallstone pancreatitis, promising results have been yielded. Low complication and conversion rates have been observed, although the selection of patients with uncomplicated mild acute gallstone pancreatitis may account for this. 68 , 69 Postoperative MRCP and/or ERCP are options available to clinicians should there be any concern regarding retained stones or alternative pathologies. 68 The combination of laparoscopic cholecystectomy and preoperative ES has also demonstrated a safe and reliable approach in dealing with choledocholithiasis during acute gallstone pancreatitis. 70

In patients with severe acute gallstone pancreatitis with choledocholithiasis and/or cholangitis, the evidence suggests that performing ERCP within 72 hours of admission reduces the morbidity and mortality in this group of patients. 71 Furthermore, ERCP reduces the length of hospital stay in patients with acute severe gallstone pancreatitis. To date, there is no evidence for or against early laparoscopic cholecystectomy for patients with severe acute gallstone pancreatitis.

Local complications of acute pancreatitis include pancreatic necrosis with or without infection, pancreatic pseudocyst formation, pancreatic duct disruption, and peripancreatic vascular complications. These local complications can be managed using a combination of endoscopic, radiologic, and surgical techniques, and have been reviewed previously. 72 Open surgical debridement requires multiple laparotomies and is consequently associated with a high postoperative morbidity. However, surgical techniques have evolved to become minimally invasive, which may be associated with better outcomes. 73

The “skunk procedure” utilizes imaging to advance catheters (drains) over their guidewires into the infected area within the lesser sac. Closed continuous lavage is then initiated once the catheters are in a satisfactory position. 74 The drainage catheters facilitate a pathway into the lesser sac when performing a video-assisted minimally invasive retroperitoneal pancreatic necrosectomy. Endoscopic transgastric or transduodenal drainage of infected pancreatic necrosis or pancreatic pseudocysts is another technique associated with lower morbidity than open surgical debridement. The minimally invasive techniques for dealing with complications of acute pancreatitis require a multidisciplinary approach with specialist personnel, skills, and equipment. The procedures should ideally be undertaken in centers where there is readily available expertise to manage any complications.

Acute pancreatitis is frequently encountered on the emergency surgical take. Once the diagnosis is made, clinical efforts should simultaneously concentrate on investigating for the underlying etiology and managing the condition by anticipating its complications, which can be aided by using any of the severity scoring systems described. Management of acute pancreatitis is largely supportive. There is still no consensus on the ideal type and regimen of fluid for resuscitation, but goal-directed fluid therapy is associated with better outcomes. Early enteral nutrition modulates the inflammatory response and improves outcomes by decreasing infective complications of acute pancreatitis. Antibiotics should be used judiciously as prophylactic antibiotics have not shown any benefit in preventing infective complications of acute pancreatitis. Patients with mild acute gallstone pancreatitis should be recommended to undergo a laparoscopic cholecystectomy at the index admission, while those with severe gallstone pancreatitis and evidence of cholangitis and/or choledocholithiasis benefit from early ERCP. Patients with mild acute gallstone pancreatitis and concurrent choledocholithiasis benefit from single-stage laparoscopic cholecystectomy and bile duct exploration, subject to available local expertise. There is no difference in mortality and morbidity between the single-stage and double-stage management of choledocholithiasis. However, the single-stage approach reduces the length of hospital stay and need for recurrent admissions.

The authors report no conflicts of interest in this work.

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City of Hope officials Wednesday were celebrating the receipt of a $150 million gift from philanthropists A. Emmet Stephenson Jr. and his daughter Tessa Stephenson Brand to support pancreatic cancer research — the largest donation in the hospital’s history.

According to the hospital, the donation is equivalent to nearly two-thirds of the total annual research budget for pancreatic cancer from the National Cancer Institute.

The donation was made in honor of Toni Stephenson, who survived lymphoma but died from pancreatic cancer in 2020. Emmet and Toni met in kindergarten and were married for nearly 53 years.

“We want to ignite interest and encourage pancreatic cancer research worldwide. We know that cancer discoveries require significant funding, which is why Tessa and I believe multiple elements of this gift will make a difference in fighting this terrible disease,” A. Emmet Stephenson Jr. said in a statement. “This initiative is a purposeful investment to spur ingenuity and ensure that the most promising advances move forward as fast as possible. We believe City of Hope is an excellent partner for this program to facilitate lifesaving work.”

Included in the gift is the $1 million Stephenson Prize, described as one of the largest privately funded awards for scientific investigation. It will be awarded annually to a leading scientist or team “making the most promising advancements in pancreatic cancer research, treatment and cures.”

The prize, the first of which will be awarded next year, will be open to individual investigators and teams of researchers at institutions around the world.

“The Stephensons are entrepreneurs who believe in groundbreaking innovation, and City of Hope is a pioneer driving transformational change in cancer care. We are honored to receive their visionary gift, the single largest in City of Hope’s 111-year history,” Robert Stone, CEO of City of Hope and the Helen and Morgan Chu Chief Executive Officer Distinguished Chair, said in a statement. “It is evidence that City of Hope is best positioned to catalyze collaboration among the nation’s top scientific minds, disrupting traditional research models and accelerating breakthroughs that ultimately lead to cures.”

According to City of Hope, pancreatic cancer is one of the deadliest types of cancer, resulting in the third-most deaths of any cancer type and the worst average five-year survival rate, at 13%.

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Pancreatitis articles within Nature Reviews Gastroenterology & Hepatology

Clinical Outlook | 21 June 2023

Advances in the management of acute pancreatitis

Recent randomized controlled trials in acute pancreatitis have provided evidence that challenges current approaches to management, including fluid resuscitation, antibiotic administration, management of infected necrosis and use of early endoscopic retrograde cholangiopancreatography. The evidence means that we need to reassess the current management guidelines.

• Enrique de-Madaria
•  &  James L. Buxbaum

News & Views | 06 January 2023

Is less more? Challenging dogma for individualized fluid resuscitation

New data suggest that moderate fluid resuscitation is safer in acute pancreatitis than the standard aggressive fluid resuscitation. The findings suggest that an approach that includes safety and goal-directed checkpoints could enable treatment to be individualized and highlight the importance of clinical evidence in challenging dogma and improving evidence-based medicine.

• Sara Regnér

Research Highlight | 31 October 2022

Stopped clock promotes fibrosis in chronic pancreatitis

Review Article | 08 November 2021

IgG4-related diseases of the digestive tract

Autoimmune pancreatitis and IgG4-related cholangitis are frequent manifestations of IgG4-related disease (IgG4-RD). Here, Löhr and colleagues present current understanding of the pathophysiology of IgG4-RD and describe all IgG4-RD manifestations in the digestive tract. Diagnosis, prognosis and treatment of IgG4-RD are also discussed.

• J.-Matthias Löhr
• , Miroslav Vujasinovic
•  &  Ulrich Beuers

In Brief | 01 November 2021

Catheter drainage in necrotizing pancreatitis

• Eleni Kotsiliti

Comment | 17 November 2020

COVID-19 and acute pancreatitis: examining the causality

Case reports and retrospective cohort studies have reported an association between acute pancreatitis and COVID-19. As SARS-CoV-2 (the causative agent of COVID-19) receptors are expressed in the pancreas and endothelial damage can occur, this association is plausible. However, this hypothesis has many biases and needs further investigation.

•  &  Gabriele Capurso

Research Highlight | 06 February 2020

Pancreatitis: a loss of FGF21 function disease with potential for correction

• Iain Dickson

Review Article | 28 May 2019

New insights into acute pancreatitis

The incidence of acute pancreatitis is increasing worldwide, and it is one of the most common gastrointestinal causes for hospital admission. In this Review, the authors provide a summary of advances in acute pancreatitis with an emphasis on pathophysiological mechanisms and clinical management.

• Peter J. Lee
•  &  Georgios I. Papachristou

Review Article | 27 November 2018

Global epidemiology and holistic prevention of pancreatitis

In this Review, Yadav and Petrov discuss the most up-to-date epidemiological data on acute and chronic pancreatitis. The authors also present strategies to reduce the burden of pancreatitis and its associated metabolic disorders.

• Maxim S. Petrov
•  &  Dhiraj Yadav

Review Article | 16 August 2017

Regenerative medicine and cell-based approaches to restore pancreatic function

Endocrine (such as diabetes) and exocrine (such as pancreatitis) disorders of the pancreas have a substantial burden worldwide. This Review explores the potential of regenerative medicine and cell-based approaches to restore both endocrine and exocrine pancreatic function, describing insights into cell replacement, implantation and reprogramming.

• , Adam Ramzy
•  &  Timothy J. Kieffer

Review Article | 15 March 2017

What's unique about acute pancreatitis in children: risk factors, diagnosis and management

In this Review, Husain and Srinath discuss the risk factors, diagnosis and management of acute pancreatitis in children. Aetiological differences between acute pancreatitis and acute recurrent pancreatitis are also explored, as well as strategies to prevent disease recurrence.

• Sohail Z. Husain
•  &  Arvind I. Srinath

Research Highlight | 22 February 2017

Tumour-derived EVs for diagnosis

• Katrina Ray

Review Article | 09 November 2016

Imaging in pancreatic disease

Effective diagnostic imaging can improve prognosis for patients with pancreatic diseases such as pancreatitis, pancreatic cancer and diabetes mellitus, which benefit from early treatment. Here, Kelly and colleagues review current and future technologies for imaging pancreatic disease, and discuss the development of new contrast agents and molecular imaging targets.

• Julien Dimastromatteo
• , Teresa Brentnall
•  &  Kimberly A. Kelly

Research Highlight | 03 November 2016

Cigarette smoke factor aggravates pancreatitis

• Charlotte Ridler

Research Highlight | 05 October 2016

Mapping malignant tissue dynamics

News & Views | 21 September 2016

Gastrointestinal safety of incretin therapies: are we there yet?

The gastrointestinal safety of incretin-based therapies is controversial. Two new studies find no effect of GLP-1 receptor agonists on acute pancreatitis risk, but increased risk of bile duct and gallbladder disease. However, no retrospective epidemiological studies can provide definitive answers, and nausea, vomiting and diarrhoea remain the most clinically relevant adverse effects of these drugs, compromising long-term adherence.

• Juris J. Meier
•  &  Julio Rosenstock

Review Article | 14 September 2016

IgG4-related hepatobiliary disease: an overview

IgG4-related hepatobiliary diseases are part of a multiorgan fibroinflammatory condition termed IgG4-related disease. In this Review, Chapman and Culver provide an overview on the natural history, manifestations and aetiopathogenesis of IgG4-related hepatobiliary disease with an emphasis on IgG4-sclerosing cholangitis.

• Emma L. Culver
•  &  Roger W. Chapman

Research Highlight | 16 March 2016

Sensory neuron ablation ameliorates PDAC

Essay | 09 March 2016

Timing of catheter drainage in infected necrotizing pancreatitis

Acute pancreatitis is a common cause of acute hospitalization, and infected (extra)pancreatic necrosis is a potentially lethal complication. In this Perspectives, the authors discuss challenges in the management of infected necrotizing pancreatitis, particularly in relation to the timing of catheter drainage.

• Janneke van Grinsven
• , Hjalmar C. van Santvoort
•  &  Marc G. Besselink

Research Highlight | 28 January 2016

Fixing necrotizing pancreatitis

• Gillian Patman

Research Highlight | 21 January 2016

KMO inhibitor for multi-organ failure in experimental acute pancreatitis

Review Article | 13 October 2015

Neural plasticity in pancreatitis and pancreatic cancer

The concept that the nervous system can adapt to gastrointestinal disorders is a new concept. In this Review the authors discuss neural plasticity in pancreatic diseases such as pancreatitis and cancer. Given the translational importance of neuropathic changes in pancreatic disorders the authors look at the available mouse models we have to study the phenomenon and highlight areas of research that still need investigation.

• Ihsan Ekin Demir
• , Helmut Friess
•  &  Güralp O. Ceyhan

Research Highlight | 30 June 2015

MPTP pore opening proves crucial for experimental pancreatitis

Research Highlight | 02 June 2015

Alternatively activated macrophages mediate fibrosis

• Christine Weber

Year in Review | 06 January 2015

Pancreatic fibrosis and standard diagnostics

In 2014, pancreatic fibrosis has increasingly been recognized as a key determinant of the pathogenesis, therapy response and disease progression of chronic pancreatitis and pancreatic cancer. In addition, secretin-stimulated magnetic resonance cholangiopancreatography has gained increasing importance, especially in visualizing pancreatic duct abnormalities. However, the true imaging capacity has not been fully analysed.

• Güralp O. Ceyhan
•  &  Helmut Friess

Research Highlight | 25 November 2014

Mislocalization of CFTR by alcohol promotes pancreatitis

In Brief | 07 October 2014

The HLA-DQA1–HLA-DRB1 haplotype is linked to risk of thiopurine-induced pancreatitis in IBD

News & Views | 16 September 2014

Advances in understanding and care of pancreatic diseases

Clinical and basic science discoveries over the past decade have led to considerable improvements in our understanding and care of pancreatic diseases. Findings reported in 10 key papers highlight results that have already substantially altered the care of patients with acute pancreatitis, chronic pancreatitis and pancreatic cancer (or soon will).

• Randall E. Brand

News & Views | 15 July 2014

Secretin increases the diagnostic yield of MRCP

The presence of ductal abnormalities after an unexplained acute attack of acute pancreatitis or in patients with recurrent acute pancreatitis might lead to a misdiagnosis of chronic pancreatitis or complications of acute pancreatitis. A new study suggests secretin administered during magnetic resonance cholangiopancreatography (MRCP) leads to a better diagnostic yield than MRCP alone.

• Raffaele Pezzilli

Review Article | 10 June 2014

Treatment options for chronic pancreatitis

The goals of treatment of chronic pancreatitis can roughly be divided into three categories: pain management, prevention and management of complications of pancreatitis, and correction of pancreatic insufficiency. In this Review, the authors discuss the merits and drawbacks of various treatment modalities for chronic pancreatitis, with a focus on management of pain.

• , Marco J. Bruno
•  &  Marja A. Boermeester

Review Article | 25 March 2014

Treatment options for acute pancreatitis

Several important changes in disease classification and improvements in the management of patients with acute pancreatitis have been achieved in the past few years. This Review provides an overview of these changes, the effect on patient management and outcome, and outlines their scientific basis.

• Olaf J. Bakker
• , Yama Issa
•  &  Hein G. Gooszen

News & Views | 04 February 2014

Is TPIAT the answer for treatment of chronic pancreatitis?

Traditional surgical therapy for chronic pancreatitis includes drainage of the dilated pancreatic duct or segmental resection of affected pancreas. Another option gaining increasing favour is that of total pancreatectomy with islet autotransplantation (TPIAT). A consensus conference, with proceedings published in 2013, discusses the current state-of-the-art information surrounding this procedure, and outstanding questions.

• Greg Beilman

Research Highlight | 03 September 2013

Global role for CPA1 variants in the pathogenesis of chronic pancreatitis

• Natalie J. Wood

Research Highlight | 23 April 2013

T cells have a pivotal role in autoimmune pancreatitis in an experimental mouse model

In Brief | 27 November 2012

Genetic advances in alcohol-associated pancreatitis

In Brief | 13 November 2012

Revised classification criteria for acute pancreatitis

News & Views | 19 June 2012

Can rectal NSAIDs prevent post-ERCP pancreatitis?

Acute pancreatitis is the most common and feared complication following endoscopic retrograde cholangiopancreatography (ERCP). Pharmacological prevention of post-ERCP pancreatitis has been disappointing, especially in high-risk patients. However, a prospective multicentre trial has demonstrated the efficacy of rectal administration of indomethacin for preventing post-ERCP pancreatitis in high-risk cases.

• Pier Alberto Testoni

Opinion | 22 May 2012

What is personalized medicine and what should it replace?

Personalized medicine is a new framework for medical care that involves modelling and simulation of a disease on the basis of underlying mechanisms. In this article, David Whitcomb uses chronic pancreatitis and an example to outline the limitations of the 20 th century framework for medical care and examines the advantages of personalized medicine.

• David C. Whitcomb

In Brief | 24 April 2012

Most cases of acute pancreatitis can be diagnosed or ruled out by urinary trypsinogen-2 dipstick test

News & Views | 28 February 2012

Treating pain in chronic pancreatitis—is the dilemma over?

The early stages of chronic pancreatitis are characterized by frequent painful episodes, which usually disappear over time. Currently, endoscopy is a bridge to surgery for patients who are in a critical condition and cannot immediately undergo surgery. Surgery in carefully selected patients remains the best approach to treating chronic pancreatitis.

Review Article | 24 January 2012

Unraveling the mystery of pain in chronic pancreatitis

Managing the pain of chronic pancreatitis is an important unmet medical need; its treatment has been largely empirical, with variable outcomes. The pathogenesis of pain in chronic pancreatitis is poorly understood but current theories have shifted towards a neurobiological rather than a purely mechanical basis. Pankaj Jay Pasricha discusses some of the specific molecules that might be involved and that might provide potential therapeutic targets.

• Pankaj Jay Pasricha

Research Highlight | 17 January 2012

Cortical thickness—a useful indicator in painful chronic pancreatitis?

News & Views | 13 December 2011

Histological diagnostic criteria for autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is becoming increasingly recognized as a unique form of chronic pancreatitis. Its diagnosis, based on clinical and pathological parameters, is challenging. AIP is currently divided clinicopathologically into type 1 and type 2. Histological diagnostic criteria for type 1 and type 2 AIP have now been proposed by an international consensus study.

• Terumi Kamisawa
•  &  Tooru Shimosegawa

Research Highlight | 06 December 2011

Unsaturated fatty acids aggravate acute pancreatitis

In Brief | 15 November 2011

Acute pancreatitis risk higher in current tetracycline users

Research Highlight | 15 November 2011

Oral microbiota and pancreatic disease

• Katherine Smith

Research Highlight | 08 November 2011

Microglial activation key to pain in chronic pancreatitis

In Brief | 02 November 2011

Quality of life after total pancreatectomy and islet autotransplant in children with chronic pancreatitis

News & Views | 04 October 2011

Is smoking a risk factor for acute pancreatitis?

Smoking is known to be a risk factor for chronic pancreatitis. However, to date, few studies have investigated the association between smoking and the risk of acute pancreatitis. A recent prospective, population-based study provides strong evidence that smoking should be considered a risk factor for acute pancreatitis.

• Albert B. Lowenfels
•  &  Patrick Maisonneuve

Research Highlight | 04 July 2011

Blood urea nitrogen levels predict mortality risk in acute pancreatitis

• Iley Ozerlat

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