Chronic pancreatitis (CP) is a disease characterized by a syndrome of symptoms and clinical manifestations related to functional abnormalities that develop as the result of glandular fibrosis and atrophy due to acute and chronic inflammation (1). CP most commonly occurs because of environmental insults, with an increased risk in patients with genetic and/or anatomic predispositions. CP may be preceded by antecedent episodes of acute pancreatitis (AP), but is increasingly recognized in patients without a preceding history of AP or abdominal pain. Diagnosis is typically based on the presence of morphologic changes on either computed tomography or MRI, which are frequently associated with functional changes (Figures 1 and 2) (2). Disease-related complications are progressive and generally irreversible (3). Unfortunately, there are no medical therapies to interrupt or reverse disease progression, so management primarily consists of screening for and providing early management of complications. Surgery is generally reserved for patients who develop refractory symptoms related to anatomic changes. There are a large number of remaining clinical questions that are being investigated to help clinicians better manage this difficult disease.
CP is a rare disease (with an estimated prevalence <200,000) in the United States. Although it can develop at an early age of onset in those with a genetic predisposition, this is primarily a disease of adult onset. Despite methodological variation in studies, prevalence estimates have remained relatively consistent at approximately 35–50 per 100,000 adults, with an incidence rate of 5 per 100,000 patient years (4–6). A recent report suggests a 2-fold higher prevalence of disease, but this estimate is likely inflated because of the use of diagnostic coding in an administrative database for case ascertainment (7). Considering the poor positive predictive value (∼50%) for the CP diagnostic code, the true prevalence is likely <50 per 100,000 adults (8).
A slight male predominance of disease has been noted for decades, and the recent association with changes at the Claudin (CLDN)2 locus on the X chromosome may partially explain the sex distributions observed in alcohol-induced CP (9,10). Racial differences have been observed in CP, with black patients being more likely to have advanced morphologic changes on imaging and more severe pain and disability compared with whites (11). These changes are likely partially explained by a greater frequency of underlying alcohol and/or tobacco use as risk factors. Historically, alcohol was felt to be the primary etiology of CP, but it is now recognized that this is the attributable etiology in <50% of patients (10). Thus, patients should not be universally profiled as having an alcohol use disorder, which is often inaccurate and hinders the ability to establish rapport. It has been estimated that patients must consume 4–5 alcoholic drinks per day consistently for over 5 years to be at risk (12). There are multiple effects of alcohol exposure to the pancreas, but despite common perceptions, it is believed to sensitize the pancreas to injury rather than directly causing CP (13).
The deleterious effects of cigarette smoking on the pancreas have recently been established from an epidemiologic standpoint, and there are emerging translational studies potentially explaining the pathogenesis. Previously, the association between CP and cigarette smoking was felt to be confounded by concurrent alcohol consumption, but Yadav et al. (14) convincingly demonstrated an independent, dose-dependent response of cigarette smoking on the risk for developing CP. Importantly, cigarette smoking is a strong risk factor for recurrent AP, which often progresses to CP. Recent studies using the cerulean-induced model of CP demonstrated that the negative effects of cigarette smoking are related to the induction of interleukin-22 secondary to aryl hydrocarbons, which promote pancreatic fibrosis (15). Collectively, the importance of avoiding heavy alcohol consumption and cigarette smoking cannot be overstated and should be strongly recommended to all patients at risk for the development of CP because of a history of AP, recurrent AP, or with a known genetic predisposition.
Although historically CP was categorized as alcoholic or idiopathic, an increasing proportion of patients originally considered idiopathic are now recognized to have an underlying genetic factor. A pivotal discovery in the genetics of AP and CP was the observation that an autosomal dominant mutation of the cationic trypsinogen (PRSS1) gene can independently lead to the development of AP and/or CP (16). This so-called hereditary pancreatitis has an autosomal dominant inheritance pattern with a high penetrance of disease (∼80%), but it should be noted that patients can also develop the mutation de novo. Other mutations associated with an increased, albeit modest, risk for CP include the genes that encode serine peptidase inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C (CTRC), calcium-sensing receptor (CASR), and the aforementioned CLDN2 gene (17). Investigations to identify additional genetic mutations remain underway, including carboxypeptidase A1 (CPA1) and carboxyl ester lipase (CEL) genes (18–22).
Although uncommon, there are 2 unique subtypes of CP with clinical features that warrant mention. The first subset is referred to as tropical pancreatitis (previously fibrocalculous pancreatitis), because it is geographically concentrated in those from Southeast Asia, particularly in India. Mutations in SPINK1 are commonly observed (40%–50%) in tropical pancreatitis, but are not associated with the differences in clinical phenotype (23). Previously, cassava root ingestion was suspected to have an etiologic role; however, this hypothesis has not been supported by more recent studies, and the differences in pathogenesis remain unexplained (23). These patients tend to have a rapidly progressive disease course. The other unique subtype of CP is autoimmune pancreatitis (AIP), which includes both type 1 AIP (lymphoplasmacytic sclerosing pancreatitis) and type 2 AIP (idiopathic ductcentric pancreatitis) (24). AIP is distinct from other types of CP based on specific histopathologic features, which define the 2 subtypes. There are differences in the clinical course for patients with AIP related to extrapancreatic manifestations (seen only in type 1 AIP) and inflammatory disease relapses. Patients may develop pancreatic calcifications (and subsequent pancreatic insufficiencies) that are indistinguishable from CP and are more likely in patients with ≥1 disease relapse (25). This topic has been recently reviewed in detail, so it is not discussed further (26).
Clinical management of CP
In the absence of disease-modifying medical therapies, the clinical management of CP primarily consists of screening for and managing disease-related complications. The contributing pathogenic mechanisms to the development of these complications include damage caused by acute inflammation, low grade chronic inflammation, pancreatic duct obstruction, and/or indirect systemic effects of the disease.
The most common symptomatic complaint of patients with CP is chronic abdominal pain, which may affect up to 80% of patients. The pain is classically described as epigastric with radiation to the back, but may present variably. This symptom can be debilitating and is strongly associated with a reduced quality of life, particularly when the pain is constant (as opposed to intermittent) (27). Interestingly, the pattern of morphologic changes does not correlate with different pain patterns, illustrating the complex nature of pain in CP (28). The origin for abdominal pain in CP is related to parenchymal ischemia caused by either acinar cell injury or pancreatic duct obstruction (29). Local ischemia induces inflammation that in turn leads to the generation of nociceptive stimulation of peripancreatic nerves. Even when signals are intermittent, repetitive stimulation can lead to the development of permanent changes in the spinal cord and the cerebral cortex (referred to as central sensitization) (30,31). This remodeling explains how some patients have persistent pain despite complete removal of the noxious stimulus (e.g., total pancreatectomy).
The treatment of abdominal pain in patients with CP may consist of combinations of medical, endoscopic, and/or surgical approaches. Unfortunately, these approaches are often not effective or have major consequences, so novel options are needed. Generally, treating pain involves addressing either anatomic or neurologic contributions to pain. Patients with significant anatomic obstruction (evidenced by a dilated main pancreatic duct) are considered candidates for endoscopic or surgical therapy. The aim of an endoscopic approach is to remove obstructing pancreatic duct stones (Figure 1C). When stones are large, intraductal or extracorporeal shock wave lithotripsy (ESWL), depending on local expertise, may be required for stone fragmentation. Historically, endoscopic retrograde cholangiopancreatography (ERCP) was performed following ESWL. However, 2 studies failed to demonstrate additional benefit, so ERCP is generally reserved for situations in which there is no spontaneous clearance of stones after adequate fragmentation by ESWL (32–34). Pancreatic duct strictures can also be treated with serial pancreatic duct stenting, but tend to require prolonged stent placement and often remain refractory (34). Surgical options include lateral pancreaticojejunostomy (modified Puestow), Frey procedure, and pancreaticoduodenectomy (Whipple), which have different anatomic advantages. The improvement in pain is significantly better and more durable in patients undergoing surgery; however, endoscopy is often considered for those who are poor surgical candidates (35). Endoscopy is also often considered as a therapeutic trial to identify patients who are most likely to benefit from surgery. Although this approach is intuitive, the clinical evidence to support this approach is not robust and further methods to predict pain response are urgently needed to avoid unhelpful interventions (36).
Medical therapies are typically recommended for patients without pancreatic duct obstruction, or those with a lower severity of pain. There have been a few recent randomized controlled trials looking at the use of antioxidants and pregabalin. The proposed mechanism for using antioxidant therapy (including vitamins A, C, and E, selenium, and methionine) is to decrease nociceptive signaling from the pancreas by reducing systemic oxidative stress and thereby reducing ischemia in the tissue. Two large studies demonstrated mixed results, which may be the consequence of differences in the study populations (age and etiology of CP) and slight variations in the antioxidant formulations (37,38). Although this is generally a well-tolerated regimen, patients often decline because of the perception of limited efficacy. In another randomized study, pregabalin was shown to have improved efficacy in reducing daily pain scores compared with placebo during a 3-week study; however, significant central nervous symptoms were seen in at least one-quarter of subjects on pregabalin, which can limit its clinical utility (39).
A variety of other therapies have previously been studied and either demonstrated no effect or the sample sizes were too small to confidently assess efficacy including octreotide, pancreatic enzymes, and enteral nutrition. As a result, pain is often managed using the step-wise approach recommended by the World Health Organization, including the use of nonsteroidal anti-inflammatory drugs, then low potency opioids, and then higher potency and long-acting opioids. Although it is still commonly used, in clinical practice, the evidence base supporting the efficacy of celiac plexus block (either endoscopic or percutaneous) in CP remains weak. Importantly, in the absence of sham-controlled studies, it is not possible to rule out a placebo effect, which can be inflated in patients receiving an interventional procedure (40). In patients who do respond to injections, the effect is temporary, lasting 3–4 months. Finally, for patients with abdominal pain attributed to CP and no severe ductal obstruction (sometimes referred to as small duct disease), total pancreatectomy may be carefully considered. To reduce the risk of difficulty in treating diabetes, islet autotransplantation is concurrently performed (i.e., total pancreatectomy with islet autotransplantation [TPIAT]), if technically feasible (41). A proper discussion of the nuances of TPIAT is beyond the scope of this review, but it is worth emphasizing that TPIAT is not a panacea and improved methods of patient selection to identify those at risk of persistent opioid dependence (i.e., no pain response) are urgently needed, particularly when recommended for patients without pancreatic calcifications where the diagnosis of CP is controversial (42).
CP-related diabetes mellitus
Diabetes mellitus (DM) is a frequent complication of CP with a point prevalence of 40% (43,44). CP-related DM (CP-DM) represents the most common cause of pancreatogenic DM (which has also been referred to as type 3c DM). DM onset generally develops many years following disease onset and may ultimately affect up to 80% of patients during their lifetime (45). Because of the high prevalence of CP-DM, annual screening for DM is recommended (46,47). A recent study of 1,171 subjects with CP demonstrated that DM was more likely to occur in subjects who were older, obese, male, black race, or with a family history of DM, while factors independently associated with DM included both obesity and the presence of exocrine pancreatic insufficiency (EPI) (43). Other factors that have been associated with CP-DM include a prolonged duration of CP, absence of pain, cigarette smoking, and increased visceral adipose tissue (48,49).
The proposed pathogenic mechanism of CP-DM is primarily insulin deficiency secondary to fibrotic replacement of islets. However, insulin resistance occurs early in the disease course and is explained, in part, by hepatic insulin resistance mediated by pancreatic polypeptide deficiency (45). Another contributing factor is an impaired incretin hormone response, but the relative contribution of this abnormality is uncertain, particularly for those without EPI. In the absence of clinical trial evidence to guide treatment decisions, metformin has been recommended as first-line therapy based on the experience with type 2 DM and translational studies suggesting potential antineoplastic effects (46). Insulin is recommended as second-line therapy or first-line therapy for patients with severe hyperglycemia. In addition to directly addressing the primary pathologic insult, we speculate that insulin may also provide secondary benefits through reversing some of the catabolic processes observed in CP. A detailed characterization of the changes in glucose homeostasis compared with type 2 DM is needed to more clearly understand the pathogenesis and inform the prevention and treatment of CP-DM (50).
Exocrine pancreatic insufficiency
EPI refers to inadequate production and/or secretion of pancreatic enzymes for nutrient digestion. Because there is a relatively small degree of redundancy to salvage lipids, the predominant symptoms from EPI are related to fat malabsorption. Symptoms of mild EPI include abdominal bloating or discomfort, while severe EPI can lead to overt steatorrhea and weight loss. Many patients deliberately restrict dietary fat intake, so symptoms often underestimate the severity of EPI. Considering the extraordinary reserve of the exocrine pancreas and redundant mechanisms to digest protein and carbohydrates, EPI does not develop until more than a decade after disease onset (51). Ultimately, EPI affects over 70% of patients with CP during their lifetime and is particularly common in those with proximal obstruction of the pancreatic duct or a history of pancreatic resection (51). Because quantitative pancreatic function testing (i.e., cholecystokinin stimulated measurement of enzyme output) is no longer used, a reduced coefficient of fat absorptio is generally considered the gold standard for diagnosis of EPI. Even though this is a highly accurate test for fat malabsorption, it is rarely used in clinical practice because of the patient burden to collect stool for 72 hours. Fecal elastase-1 is an indirect measure of exocrine function that is performed on a random stool sample. False positive test results are commonly encountered if a nonformed specimen is analyzed because the elastase measurement is a concentration that will appear falsely low when there is increased water content in the stool. Therefore, the fecal elastase-1 test should not be used for evaluation of patients with unexplained diarrhea.
The lack of an accurate and convenient test to diagnose and monitor treatment of EPI remains one of the greatest challenges with management of EPI (52,53). In the absence of an ideal testing approach, most clinicians initiate treatment based on the combination of symptoms and pretest probability. Treatment involves the use of pancreatic enzyme replacement therapy (PERT) at a dose of 25,000–50,000 units of lipase with meals and 50% of the meal time dose with snacks (3). In the absence of a suitable test to guide titration of the dose, we recommend increasing the dose at least until there is resolution of symptoms (particularly when overt steatorrhea is present). In addition, patients often benefit from taking a higher dose for meals or snacks with a high fat content. Although weight-based dosing is used in the pediatric population (e.g., cystic fibrosis), this is not recommended for adults because the medication is not systemically absorbed. In patients with EPI with persistent symptoms despite the initiation of PERT, additional management options to consider include escalation of PERT dose, addition of a proton pump inhibitor (if not currently using), consideration of alternative etiologies of symptoms in CP, such as small intestinal bacterial overgrowth or lactose intolerance, and consideration of other causes of fat malabsorption (54).
Metabolic bone disease
Metabolic bone disease is an increasingly recognized complication of CP and has also been referred to as CP-associated osteopathy. A meta-analysis of 10 studies estimated that the pooled prevalence of both osteopenia and osteoporosis is 65% (55). Furthermore, patients with CP have an increased risk of low trauma fractures (56). Although there are no societal guidelines to recommend screening for osteoporosis in CP, baseline screening with a DEXA scan is reasonable considering the higher odds of fractures compared with other gastrointestinal conditions, such as celiac disease, cholestatic liver disease, and inflammatory bowel disease, for which this has been widely adopted (47,56).
The high prevalence of CP-associated osteopathy is partly explained by shared risk factors, including cigarette smoking and heavy alcohol usage. In addition, chronic inflammation from CP likely contributes to a pro-inflammatory milieu that produces net bone loss (57). Finally, patients with CP are at a high risk for vitamin D deficiency, particularly when EPI is present (58). The management of CP-associated osteopathy follows general treatment principles, including supplementation with calcium and vitamin D, weight-bearing exercises, and smoking cessation. When indicated, treatment with oral bisphosphonates should be carefully monitored to ensure patients tolerate therapy, and transitioning to alternate antiresorptive therapies should be considered if there are problems. Finally, uncontrolled data suggest that PERT may potentially reduce the risk of fractures in subjects with CP, but further studies are needed before this can be universally recommended (59).
Epidemiologic studies have consistently shown an increased risk of pancreatic cancer (i.e., pancreatic ductal adenocarcinoma [PDAC]) in patients with CP, which is felt to be a consequence of chronic inflammation leading to hyperproliferation of pancreatic stellate cells (60). The cumulative life time risk of PDAC is approximately 4%–5%; however, a history of cigarette smoking and the onset of CP-DM may increase this risk further (61,62). The risk is extraordinarily high in both hereditary and tropical pancreatitis. In hereditary (PRSS1) pancreatitis, the cumulative risk for developing PDAC has traditionally been estimated at over 40%, but a recent publication suggests the risk is likely closer to 10% (63). The relative risk in patients with tropical pancreatitis may exceed 100; however, contemporary updates are needed to determine if there has been a similar decline over time (64). Although screening for PDAC is not endorsed, maintaining a high clinical suspicion in those with unexplained symptoms, such as unexplained weight loss or a change in abdominal pain characteristics, is recommended (47). Unfortunately, even when pursued, cross-sectional imaging can be challenging because of the baseline morphologic changes in the pancreas (particularly main pancreatic duct dilation), which can make it difficult to identify a small neoplasm. Similarly, there is a risk for sampling error with EUS-guided fine needle aspiration in patients with multiple calcifications, which can obscure changes in the parenchyma.
A variety of anatomic complications can develop in CP secondary to the local effects of inflammation or glandular fibrosis. One of the common anatomic complications is the development of pancreatic pseudocysts, which may develop in 10%–40% of patients during their lifetime (Figure 1B) (65). Depending on the anatomic location and size, pseudocysts can lead to gastroduodenal outlet obstruction and/or biliary obstruction. If they become symptomatic, endoscopic intervention using a cystogastrostomy and stent placement is generally preferred over surgical intervention as a first step (66). Alternatively, gastroduodenal outlet obstruction and biliary obstruction can simultaneously develop secondary to inflammation and fibrosis involving the pancreatic head, when disease is centered around the pancreaticoduodenal groove (i.e., groove pancreatitis) (67). When related to inflammation, management is generally supportive. However, when the obstruction is fixed, intervention is required. Although endoscopic intervention is typically entertained as the first step in managing a fibrotic biliary stricture (Figure 1D), gastric outlet obstruction has historically been managed with surgery (either a gastrojejunostomy or pancreaticoduodenectomy). Recently, groups have reported endoscopic gastrojejunostomy for palliation of malignant disease, but the unknown durability limits the role in patients with CP. Finally, thrombosis of the splanchnic vasculature (portal, splenic, and superior mesenteric veins) may develop in up to 20% of patients and is felt to primarily be a consequence of local inflammation near the vascular beds (68,69). The use of anticoagulation has not been rigorously studied, but is generally not recommended, especially if there are chronic vascular changes such as collateralization.
Although our understanding of the pathogenesis and epidemiology of CP has grown over the last couple of decades, major knowledge gaps remain in the natural history and clinical management of CP. There are several factors that make clinical research studies of CP challenging, including the low disease prevalence, lack of standardized study definitions, long time to develop important clinical outcomes, and the lack of validated surrogate measures for those clinical outcomes. Although CP can be accurately diagnosed in the advanced stages of disease when severe morphologic changes such as pancreatic calcifications are present, the diagnosis of early CP is challenging and controversial. In the absence of a diagnostic biomarker, prospective follow-up of patients with indeterminate clinical and imaging features over many years is required to determine who truly develops CP or simply has a condition with overlapping symptoms, such as a functional gastrointestinal disorder. Fortunately, the critical nature of this gap has been recognized and is being actively pursued by multicenter consortia (44,70). In addition, the characterization of pediatric pancreatitis and its progression into adulthood are under investigation (71). The development of biorepository platforms is included in these studies and is needed to identify and validate biomarkers associated with the aforementioned disease-related complications. We are hopeful that translational studies will provide further insights into potential mechanisms of these complications that are currently considered irreversible. Identification of markers of disease progression is needed to prioritize pathways that can potentially be targeted by medical therapies. Considering the low disease prevalence, the process of drug development and testing for CP must be carefully considered. It will likely require a combination of evolving animal models (72,73), novel mathematical approaches (74), and repurposing existing anti-inflammatory or biologic agents to make clinically meaningful improvements.
CP is a chronic disorder, which is frequently accompanied by multiple disease-related complications, including abdominal pain, DM, EPI, metabolic bone disease, and pancreatic cancer. Current management of CP involves avoidance of cigarette smoking and heavy alcohol usage as well as a vigilant clinical follow-up for screening and treatment of complications (Table 1). Although an early diagnosis would conceptually provide a suitable time window for early intervention, this is not currently feasible. Studies are ongoing to better understand the natural history of CP and its complications, which is needed to close the knowledge gaps required to transform the care of our patients with CP.
CONFLICTS OF INTEREST
Guarantor of the article: Phil Hart, MD.
Specific author contributions: P.A.H.: literature search, drafting of original manuscript, review and intellectual input into revisions, and approval of final manuscript. D.L.C.: review and intellectual input into revisions, and approval of final manuscript.
Financial support: Research reported in this publication was supported by the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under award number U01DK108327 (P.A.H., D.L.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Potential conflicts of interests: P.A.H. has received consulting and honorarium fees from Kangen Pharmaceuticals and Abbvie, Inc.
The authors would like to thank Dr. Mitch Ramsey, MD, for his assistance in developing a draft of the Table.
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