Conservative Treatment of Chronic Pancreatitis: A Practical Approach

Abstract

Background:

Chronic pancreatitis is a long-standing, inflammatory condition of the pancreas that leads to the progressive damage and loss of function of pancreatic parenchyma and to the development of possible locoregional and systemic medical complications.

Materials and methods:

In this review, we tried to summarize the current evidence on non-surgical treatment trying to suggest a practical approach to the management of chronic pancreatitis.

Results:

Besides the unclear pathophysiological mechanism and a poorly unknown epidemiology, chronic pancreatitis is a complex syndrome that displays different possible challenges for physicians. Despite being traditionally considered as a benign disease, chronic pancreatitis encompasses 10-year mortality rates which are superior to the ones reported for some of the most common cancers.

Conclusions:

Chronic pancreatitis encompasses the management of multiple and complex medical co-morbidities that needs to be understood and addressed in a multidisciplinary specialist context.

Definition and Epidemiology

Chronic pancreatitis is a long-standing, inflammatory condition of the pancreas triggered by different endogenous or exogenous factors, that leads to the progressive damage of pancreatic parenchyma, to the loss of acinar and islet components, to the development of scar tissue, and eventually to endocrine and/or exocrine pancreatic insufficiency. Once the process is triggered it cannot be reversed, although clinical and endoscopic management can modulate its evolution over time (1). The disease itself often encompasses systemic involvement and might be accompanied by the presence of persistent or recurrent abdominal pain. Once the organ-damage progresses, signs and symptoms of maldigestion and malabsorption might also occur. Histologically, chronic pancreatitis is characterized by inflammatory infiltration (first macrophages and polymorphonucleates, later mononucleate cells), progressive acinar component loss and fibrosis (activation of pancreatic stellate cells). The presence of inflammatory reaction allows the distinction between chronic pancreatitis and other entities, such as pancreas aging, diabetic pancreatopathy, and pancreatic cancer–related desmoplastic changes, which are often encountered in clinical practice. The true incidence of chronic pancreatitis is unknown but seems to be higher in men than in women, respectively, 12 cases versus 6 cases per 100,000 inhabitants (2, 3). The prevalence, often epidemiologically regarded as “the tip of the iceberg,” has been reported between 41.76 and 91.9 per 100,000 inhabitants (4, 5). The reason beyond such fluctuations in epidemiological data among different studies, is that much of the information about incidence and prevalence, is derived from retrospective register studies that do not allow the extraction of high-quality data (1).

Studies analyzing overall survival in patients with chronic pancreatitis reported 10 years mortality ranging between 13.7% and 34%, which is actually superior to what reported for some of the most common cancers (6, 7).

Risk Factors and Clinical Course

Risk factors for chronic pancreatitis are summarized by acronym TIGAR-O, which encompasses one of the most used classifications of chronic pancreatitis, where the T stands for Toxic, the I for Idiopathic, the G for Genetic, the A for Autoimmune, the R for Recurrent and the O for Obstructive. In addition to the first version of TIGAR-O classification (TIGAR-O_V1), another version has been recently proposed (TIGAR-O_V2) (8–10). The latter, comprehensive of a short and long version, proposes a revised hierarchical checklist (8). Another interesting classification of chronic pancreatitis which considers possible interactions of multiple risk factors is the M-ANNHEIM classification where M stands for multiple risk factors, A stands for alcohol, N for nicotine consumption, N stands for nutrition, H stands for hereditary, E stands for efferent pancreatic duct, I stands for immunological, M stands for miscellaneous and metabolic (11).

Exposure to toxic agents remains the most common etiology. Both smoking and alcohol abuse are the most prevalent risk factors and display both a direct toxic effect on the ductal epithelium and an indirect one driven by the increase in oxidative stress burden (1). It is esteemed that between 44% and 77% of chronic pancreatitis cases are somehow linked to alcohol abuse (12). Interestingly, the pathogenic effect of alcohol linearly correlates with increased intakes. A threshold amount of five units (equivalent to 80 g of alcohol) is reported to confer three times the risk for the occurrence of chronic pancreatitis (13). Alcohol influences both the risk of recurrence of acute pancreatitis and the risk of developing chronic pancreatitis and its complications (14). The risk of diabetes mellitus, which is a possible long-term complication, has been reported to be more than doubled in alcoholic etiology compared with biliary or idiopathic (20.6% vs. 9.1% vs. 9.9%) (8, 15). Tobacco smoking is also linearly associated with the risk of developing chronic pancreatitis and active smokers display circa three times the risk of general population. Former smokers display double risk compared with general population (16). Machicado et al.(17) reported, in a U.S. population study in the interval 2001–2013, overall prevalence of alcoholism in 21.3% and tobacco abuse in 24.2% of patients. Therefore, all patient with chronic pancreatitis should be obviously encouraged to quit smoking and to decrease/stop alcohol drinking. High plasmatic calcium (>12.0 mg/dL or 3 mmol/L), high plasmatic triglycerides (fasting >300 mg/dL; non-fasting >500 mg/dL), chronic kidney disease/end-stage kidney disease, and several drugs have also been reported as possible etiological causes of chronic pancreatitis (8). Chronic pancreatitis unrelated to alcohol and smoking is reported to cause between 20% and 50% of cases (1). According to a wide North America study (NAP2) the weight of genetic causes might account for 1.6%–10.2% of cases (12). Nevertheless, when considering the cohort of patients with non-toxic non-genetic chronic pancreatitis, possible unknown genetic overlaps should be considered. Jalaly et al. (18) showed that 58% of patient with recurrent idiopathic pancreatitis and 27% of the ones with idiopathic chronic pancreatitis, displayed genetic alteration even in the absence of a positive family history. Therefore, genetic background might justify at least part of the chronic pancreatitis that had been previously classified in the spectrum of idiopathic and recurrent ones. Moreover, a comprehensive map of all possible genes associated to chronic pancreatitis is still far to be achieved. Genetic screening is of utmost importance in pediatric population (9), as genetic alterations are as common as 75% of cases. Moreover, the actuarial incidence of chronic pancreatitis in children is increasing and (2 cases:100,000 people/year, with overall prevalence of 6 cases:100,000 inhabitants). The most common genetic alterations are SPINK1, PRSS1, CEL-HYB, CFTR, CAP1, CTRC, CEL (18, 19). After the exclusion of more obvious and prevalent toxic causes such as smoking and alcohol, rarer metabolic toxic agents should be screened for, in the index visit. Genetic testing should be considered in recurrent idiopathic pancreatitis and in idiopathic chronic pancreatitis, especially in younger ages. Autoimmune etiology has been evaluated in a cohort of patients referred for acute pancreatitis to tertiary centers in Germany. Although incidence is low (circa 1:100,000 inhabitants), the prevalence in patients with chronic pancreatitis can be as high as 7.5%, especially if etiology is not alcoholic (20). Vujasinovic et al. reported the results of a Swedish, cohort study on patients with autoimmune pancreatitis, reporting 76% of pancreatic exocrine insufficiency (PEI) and 21% of endocrine insufficiency in a long-term follow-up. In this series, 81% of patient have undergone medical treatment. Steroid treatment was the first line therapy in 79% patients. A minority of patients was treated with steroids-free regimens such as azathioprine (12% of cases), mycophenolate mofetil (3%) or immunosuppressive treatments such as rituximab/vedolizumab or cyclosporine (3%). After a median follow-up of 46 months, clinical remission and radiologically complete response were achieved, respectively, in 92% and 70% of patients. Steroid treatment consisted in metilprednisolone 40 mg for 4 weeks with progressive 5 mg/week tapering afterwards (21). Efficacy of steroid treatment has been confirmed also by a large multicenter study on 1064 patients. In such a series, both type 1 or 2 autoimmune pancreatitis patients were extremely responsive to steroid treatment (remission, respectively, in 99% and 92%). Steroids have been described to possibly partially reverse exocrine and endocrine insufficiency (22). Recurrences, that might be as high as 31% especially in type 1 autoimmune pancreatitis, can successfully undergo retreatment with steroids and/or treatment with steroid free regimens (e.g. azathioprine 2–2.5 mg/kg/day) (23). The presence of possible autoimmune etiology should always be considered in patients with autoimmune co-morbidities, typical enlargement of the entire gland and positive IgG4 antibodies. It is of utmost importance to always rule out pancreas cancer, which has 10 times higher incidence than autoimmune pancreatitis (1). This is particularly true in type 2 mass forming focal autoimmune pancreatitis, for which cancer often represents a challenging differential diagnosis. Pancreatic cancer, periampullary cancers, and intraductal papillary mucinous neoplasm (IPMNs) should always be ruled out, as they might cause mass effect, ductal obstruction, obstructive/recurrent pancreatitis and main pancreatic duct dilation. Del Chiaro et al. (24) recently reported that patients operated for invasive IPMN displayed an history of acute pancreatitis in 16.8% of cases. The progressive obstruction of ducts from mucus (in IPMNs) or the progressive narrowing of the ductal system, due to mass effect with the development of upstream obstructive chronic pancreatitis, is the main possible pathophysiological background. Other possible obstructive causes, such as pancreatic ductal stones and strictures should be investigated carefully, while anatomic variants such as “pancreas divisum” should be regarded as possible facilitating factor but alone cannot justify the occurrence of acute and chronic pancreatitis (8, 25).

General Approach

Chronic pancreatitis rather than a single, organ-specific, disease is a complex medical syndrome. Diagnosis is often challenging as the disease itself can remain undiagnosed for long time. Undiagnosed chronic pancreatitis leads patients to acquire secondary medical co-morbidities that can turn into major risk factors for overall morbidity and mortality. This is particularly true for older patients (26). The correct management cannot disregard from a good knowledge of symptoms, signs, and risk factors that might rise the clinical suspicion of chronic pancreatitis, as well as from a good knowledge of the incidence and prevalence of other pancreatic diseases, that often are involved as differential diagnosis. Pain, PEI, and diabetes should be treated whenever present. Patients should be screened for the presence of possible occult systemic complications such as osteoporosis, malnutrition, liposoluble vitamin deficiency, small bacterial intestinal overgrowth (SIBO), as well as locoregional ones, such as biliary or gastric outlet obstruction, vein thrombosis, pseudocyst and main pancreatic duct (MPD) strictures or stones (Fig. 1) (27–29). Cancer should be excluded at diagnosis and acknowledged among the endpoints of medical follow-up, especially in cases harboring a genetic background (PRSS1) or with long-standing risk factors (smoking, alcohol, diabetes, family history for cancer) (30). Considering that many patients suffer from long-standing non-cancer-pain, therapy should be tailored to prevent iatrogenic narcotic drugs dependence/abuse (31). Fig. 2 shows a possible practical approach for the management of chronic pancreatitis and its complications.

Fig. 1.

The figure represents the possible major locoregional complications of chronic pancreatitis.

Fig. 2.

A possible approach for the management of chronic pancreatitis and its complications.

PEI

The pancreatic acinar component produces digestive enzymes, although the epithelium of pancreatic ducts secretes bicarbonates. Pancreatic stimulation takes place during the intestinal phase of digestion, following the contact between the fatty acid/amino acids–enriched chyme and the duodenal mucosa through a cholecystokinin-mediated stimulus. Pancreatic enzymes play an important role allowing the digestion of carbohydrates, fats, and proteins into micro-molecules that can be absorbed by intestinal brush border. A first important distinction must be made between pancreatic exocrine deficiency (PED) and PEI. PED is defined as deficiency in the secretion of bicarbonate and pancreatic enzymes, regardless of the cause and the entity of it. PEI is defined as an insufficient activity of pancreatic enzymes to grant digestion of food in the lumen phase (32). Although PED accounts for many cases of the PEI, extra-pancreatic disorders often remain undiagnosed and untreated. Both impaired qualitative–quantitative activity and uncoordinated secretion of pancreatic enzymes into the intestinal lumen may lead to PEI. Impairment in enzymes and bicarbonate secretion can be the result of several inflammatory and neoplastic diseases of the exocrine pancreas. In addition to chronic pancreatitis, pancreatic cancer and previous pancreatic surgery should be acknowledged among the most frequent causes of parenchyma-related PED (32, 33). The degree of PEI has been reported to be linearly related to prognosis in pancreatic cancer patients (34). Clinical symptoms of PEI do not linearly correlate with the decrease in pancreatic secretion. In fact, clinical appearance of PEI is a late event that appears evident when lipase levels are reduced by 90%–95% (1, 9). Therefore, less significant decreases in pancreatic enzyme secretion might not necessarily result, in manifest signs of pancreatic insufficiency. Even non-pancreatic abdominal surgery, such as bariatric surgery or gastroesophageal surgery, can lead to functional PEI by altering the digestive hormone axis and therefore the coordination between bolus progression and enzymes secretion (34). Abdominal imaging can detect various degrees of PEI by providing indirect semi-quantitative esteems through the assessment of duodenal fluid volume after the administration of exogenous secretin. Anyhow, non-invasive exocrine function tests suffer from low sensitivity and specificity, especially in early stages of chronic pancreatitis. When the disease progresses, such tests become more accurate but possibly clinically less important. Invasive tests for the measurement of exocrine function such as pancreatic juice analysis after stimulation with secretin, have been progressively abandoned. The most used non-invasive tests for the direct assessment of exocrine function are: (1) the 13C-mixed triglycerides (13C-MTG) breath test, (2) the elastase fecal. Fecal fat excretion quantification is rarely performed (32). The 13C-MTG test evaluates the degradation products excretion of labeled triglycerides ingested through a standardized meal, through the analysis of exhaled air. The amount of labeled 13C is absorbed and then excreted, proportionally to the intestinal enzymatic degradation of triglycerides. A value below 29% correlates with a poor digestion of triglycerides by the pancreatic lipase, providing an indirect estimate of the degree of insufficiency with a sensitivity greater than 90%. The fecal elastase test remains the most used one. Values of fecal elastase below 200 µg/g of feces are consistent with the presence of PEI. Values between 200 and 500 represent a gray zone that probably reflects a quantitative decrease in exocrine secretion, while values above 500 are associated with a normal secretion of pancreatic enzymes (33). However, fecal elastase suffers from possible false positives, such as in cases of diarrhea and is not a sensitive and specific test after resection of the pancreatic parenchyma (35). Therefore, it should not be used in a post-surgical diagnostic context. The 13C-MTG test seems to be particularly attractive and useful in the assessment of pancreatic exocrine function in the pediatric population, in post resection status and in cases in which the result of fecal elastase is suspect to be associated to a false positive result. This last scenario might reflect cases in which, low values of fecal elastase are accompanied to the absence of risk factors for chronic pancreatitis and to a radiological normal pancreas. In such cases, 13C-MTG test for triglycerides offers a further possibility to confirm or rule out the presence of exocrine insufficiency. PEI leads to liposoluble vitamin (A–D–E–K) absorption deficiency and therefore to potential symptoms such as ecchymoses (vitamin K), ataxia/neuropathy (vitamin E), impaired vision (vitamin A) and/or osteoporosis (vitamin D) (9).

Particularly osteopenia or osteoporosis should be ruled out in all patients with severe insufficiency, through the execution of a dual-energy X-ray absorptiometry (DEXA) (36). From a clinical perspective, symptoms of PEI are consistent with generalized abdominal bloating, flatulence, pain, steatorrhea. Treatment should aim at substitution by pancreatic enzymes and by encouraging the abandonment of voluptuous and dietary habits associated with a worsening of exocrine function such as alcohol and cigarette smoking (32). There is currently no indication to reduce the intake of lipids with the diet. The enzyme dosage should range between 25,000 PhU for breakfast and snacks and 50,000 PhU that support replacement during main meals. In any case, the patient should be instructed to optimize the intake of enzymes according to the total amount of fat introduced with the diet (9). Pancreatic enzymes replacement therapy (PERT) should be ingested during the meal. The United European Gastroenterology Guidelines suggest doubling or tripling the dose or PERT and to add proton pump inhibitors in non-responder patients (37). PERT is a porcine derivate and does not interfere with human fecal elastase that is used to test exocrine function. All patients, including the ones with Islamic and Jewish faith, can be under PERT treatment (28). PERT usually works, is well tolerated without side effects, and can be administered in all patients. The only known possible side effect is fibrosing disease of the colon which has been rarely described in patients affected by cystic fibrosis (28, 32).

Pancreatogenic Diabetes Mellitus

Diabetes mellitus is characterized by the presence of persistent hyperglycemia. The most common forms of diabetes mellitus are, respectively, type 1 and type 2, the former characterized by autoimmune destruction of pancreatic beta cells component, the latter characterized by inadequate insulin response secondary to impaired insulin sensitivity (38). Diagnostic criteria are fasting plasma glucose (FPG) ⩾7.0 mmoL/L (126 mg/dL) or HbA1c ⩾48 mmoL/mol (6.5%). In cases of ambiguous result, a 75-g oral glucose tolerance test (2 h fasting glucose ⩾ 11.1 mmoL/L; 200 mg/dL) should be performed to confirm/exclude diagnosis (9). Diabetes secondary to diseases of the exocrine pancreas parenchyma has been classified as pancreatogenic diabetes.

Chronic pancreatitis accounts for the great majority of cases (79%), followed by cancer (8%), by metabolic disease such as hemochromatosis (7%), and cystic fibrosis (4%) and eventually previous pancreatic resections (2%). In this form of diabetes, inadequate function/representation of Langerhans islet coexists together with insulin resistance (39). The prevalence of type pancreatogenic diabetes mellitus varies among different studies but is probably around 4%–5%. Considering that the reported prevalence of diabetes mellitus in the United States in 2014 was 22 million inhabitants, almost 1 million people suffer from pancreatogenic diabetes mellitus in United States (38). Evidence-based diagnostic criteria are currently lacking for pancreatogenic diabetes but Ewald et al. have proposed some major criteria, such as the presence of pancreatic abnormalities, the presence of PEI, and the absence of autoimmune markers of type 1 diabetes mellitus. Minor criteria are an impaired beta cell function, a decreased incretin secretion, the absence of a clear insulin resistance, and the presence of liposoluble vitamin deficiency. The prevalence of pancreatogenic diabetes mellitus in chronic pancreatitis is very high and can reach 80% of cases, also depending on duration of disease and possible associated risk factors (40). Clinically, pancreatogenic diabetes represents a challenging entity because hyperglycemia is alternated to occasional episodes of hypoglycemia (79% of cases). Severe episodes of hypoglycemia occur in up to 17% of cases (1). Moreover, pancreatogenic diabetes harbors risk of possible complications such as diabetic retinopathy (37%), nephropathy (29%), and peripheral ischemic artery disease (26%). The risk for pancreatic ductal adenocarcinoma (PDAC) ranges in different studies. Population studies reported 33.5-fold risk for PDAC development, other studies reported a milder association (odds ratio (OR) 4.7) (41, 42). What is more noteworthy, is that overall pancreatogenic diabetes displays considerable mortality, with a reported 8.7-year median survival. As type pancreatogenic diabetes harbors risk for both hyperglycemia and hypoglycemia, its management should be tailored to avoid both conditions (1). Pancreatogenic diabetes mellitus can be distinguished from type 1 and type 2 because of the absence of pancreatic polypeptide response after the ingestion of mixed nutrients (40). A balanced diet, an adequate PERT, alcohol abstinence, a proper management of postprandial pain, and ability to grant a sufficient food intake are all strategies that might achieve appropriate glycemic control. In any case, PERT dose should be optimized on an individual basis, considering symptoms and nutritional status. For diabetes control, long-acting insulin can provide a basal glycemic control while short-term insulin might help the management of glycemic peak. Guidelines support the use of insulin because it addresses the lack of hormone secondary to islet vanishing. On the contrary, especially in patients displaying high peripheral insulin sensitivity, a major drawback is the possible development of severe hypoglycemia, due to the lack of counter-regulatory glucagon. Metformin can be used to achieve normo-glycemic status especially in patients with mild–slightly elevated glycemia (HbA1c <8% or blood glucose <64 mmol/mol) (38, 40). The role of other oral anti-diabetic drugs is less clear. The use of incretin seems to be contraindicated because possible increase in the incidence of acute pancreatitis and pancreas cancer. Therefore, in the beginning, if glycemia is just slightly elevated and HbA1c <8%, a good approach could be a trial with metformin. As the glycemia worsens a suggested approach is to start low doses of long-acting insulin and to privilege short acting insulin. Adjustments should be made after a strict monitoring of glycemic curve, keeping in mind patient’s peripheral insulin sensitivity and eventual quantity and entity of hypoglycemic peaks.

Management of Pain

Pain probably represents the most challenging problem in chronic pancreatitis and is reported to afflict more than 70% of patients (43, 44). Abdominal pain is reported as a dull or sharp sensation in the upper quadrants of the abdomen with possible irradiation toward the back, sometimes patients report nagging sensation. Pain might worse after food intake. Classically, there are two specific patterns of abdominal pain: type-A in which pain episodes are alternated to pain-free periods and type-B, in which there is a constant persistence of pain, often presenting in clusters. Type-A is present in 44% of patients, while type-B is present in circa 45% of patients (43, 45). Long-lasting pain is more difficult to treat and often leads to therapeutic failures. This phenomenon is due to central neuroplasticity and peripheral sensitization and neuropathy (46). Sensitization can be both peripheral and central and is characterized by a decreasing threshold of pain (hyperalgesia). When generalized, it is defined as allodynia, namely the perception of pain for stimuli that usually should not induce pain at all. In perception of central pain, several excitatory and inhibitory descending ways are involved. The balance between pain inhibition/facilitation is altered in chronic pain patients. On that respect, an interesting phenomenon is “temporal summation,” namely a perception of increased pain due to repetitive painful stimulations with the same intensity. Another interesting phenomenon, involving the descendent modulation of pain, happens when concomitant painful stimuli are applied, resulting in a negative modulation of the perception of pancreatic pain (44). In chronic pancreatitis, the management of pain should include first the exclusion of other possible extra pancreatic causes of abdominal pain, such as peptic ulcer, constipation, intestinal bacteria overgrowth, and biliary gallstone disease. Then, once identified and confirmed the pancreatic origin of pain, a work up should exclude the possible development of complications or comorbidities of pancreas that might justify a painful condition (e.g. duodenal stenosis, pseudocyst, pancreatic cancer, vein thrombosis, pancreatic stones, pancreatic strictures) (9). Pain should be objectively reported using one or multiple dimensional scales when collecting anamnesis to properly quantify pain episodes and provide a proper characterizing of it. Patients should be encouraged to stop alcohol drinking and to quit cigarette smoking since alcohol abstinence leads to an overall decrease in pain episodes, while cigarette smoking instead potentiate alcohol toxicity (32, 47). Pharmacological management of pain follows the guidelines from World Health Organization (WHO; pain relief ladder) and should start with paracetamol that should be preferred to non-steroidal anti-inflammatory drugs (NSAIDs) because of the known gastrointestinal toxicity. High doses of PERT and multiple-antioxidants should be added since data are still discordant but some trials have shown a certain effect of such approach (48). Considering the complexity of pain, a combined approach with psychological evaluation and quantitative sensory testing (QST) has been suggested to tailor the management of pain in chronic pancreatitis patients non-responding to paracetamol/NSAIDs (44). In cases of absence of alteration at QST or in the presence of generalized hyperalgesia either cognitive behavior therapy or low dose opioids should be considered. Cognitive behavior therapy might also be helpful in cases of tendency to catastrophizing the description of symptoms. Deficiency of the conditioned modulation of pain and psychological status such as depression and/or anxiety might be treated with serotonin reuptake inhibitors or tricyclic antidepressants. The ascertained presence of segmental hyperalgesia or the temporal summation phenomenon might be effectively treated with gabapentinoids such as gabapentin and pregabalin. In non-responders, opioids might be considered. Attention should be paid in avoiding narcotic bowel syndrome. Rotation of opioids together with the use of co-adjuvant treatment (clonidine, antipsychotics, ketamine) and the addition to complementary therapies might help in such a scope. Surgery or splanchiectomy should be also considered (43). In patients with poor control of pain, medical treatment should be optimized together with a pain specialist.

Endoscopic Management

Endoscopic therapy in chronic pancreatitis has main aim to improve pain and to manage chronic pancreatitis local complications. The main locoregional complications of chronic pancreatitis, often also involved in the genesis of pancreatic pain, are MPD stones or strictures, the biliary strictures, and the development of pseudocysts (28, 49). MPD stones might be multiple or solitary and affect up to 62% of patients. A single stone is present in 10%–62% of cases. A multicenter Italian study identified alcoholic etiology, male sex, and smoking to be independent risk factors. MPD stones are associated to a MPD stricture in circa 50% (50). Endoscopic stone removals should be limited to symptomatic stones that cause pain or recurrent obstructive acute pancreatitis episodes. Exclusive endoscopic therapy with extraction devices such as balloon and baskets is seldom effective. A successful endoscopic retrograde cholangiopancreatography (ERCP) with therapeutic stone clearance have been achieved in 9% of cases, as reported in a single-center retrospective study (51). In a survey involving 125 hospitals and more than 1834 patients, successful stone clearance have been achieved in 14% of cases. Therefore, the European Society of Gastrointestinal Endoscopy (ESGE) guidelines recommend against the use of exclusive, upfront, ERCP in patients with MPD stones suggesting the use of extracorporeal shock wave lithotripsy (ESWL) as a first step (49). Such technique, that has been traditionally used for the treatment of kidney stone disease, has been associated to successful MPD stone extraction after a first upfront endoscopic failure in 80% of cases. In head-to-head clinical trial comparing the use of ESWL alone versus the use of endoscopy plus ESWL, the first group achieved the same success rate but overall three times less costs and hospital stay (52). Data supporting the use of ESWL comes even from a recent meta-analysis on 27 studies, involving 3189 patients. A complete spontaneous clearance was achieved in 70% of cases, while a partial one in 22%. After a mean 2 years follow-up, 52% of patients reported no pain. But how to define a successful MPD stone clearance after ESWL? The removal of >90% of MPD stones can be considered as a therapeutic success and therefore as a complete clearance, the removal of 50%–90% of MPD stones should be considered as an incomplete clearance and while the removal of less than 50% of MPD stones should be regarded as a treatment failure (53). The ESGE guidelines recommend ESWL as a first approach for radiopaque stones, located in pancreatic head and with a caliber exceeding 5 mm. ESGE recommends upfront ERCP when stones are <5 mm and a combined approach in cases of failure of ESWL (49). As a further strength, Tandan et al. has recently reported the results of a large retrospective study on the issue. In total, 5124 patients have undergone ESWL because of MPD in the head region (55.1%). A successful clearance was achieved in 72.6% of cases and 85.5% of patients required ⩽3 ESWL sessions. Pain-free condition was achieved in 82.6% after 6 months follow-up. A total of 22% of patients displayed self-limiting complications (54). ESWL has some contraindications such as pregnancy, coagulation disorders, lung disease, and the concomitant presence of calcific vessels. ESWL harbors the risk of possible complications such as pancreatitis (1%–4.2%). Overall, severe complications, such as perforations or bleedings have been reported in 1% of patients. In cases in which ESWL has failed or is contraindicated, an alternative approach is represented by the pancreatoscopic guided application of electrohydraulic lithotripsy (EHL) (55). Such approach is extremely promising because allows the application of concomitant diagnostic and therapeutic procedure on the MPD. Moreover, the application of lithotripsy under visual guidance might tailor the treatment, avoiding traumatic complications of the epithelium of the MPD. So far anyway, a strong body of evidence is lacking and randomized controlled trial (RCT) is strongly needed to assess safety, clinical success, and cost effectiveness. MPD strictures can be defined according to their nature as benign or malignant or according to their radiological/pancreatographic appearance, as a single/multiple or dominant/non-dominant. A dominant stricture is defined as a stricture displaying >6 mm upstream dilation of the MPD, non-allowing contrast outflow alongside a 6-Fr catheter during ERCP or causing abdominal pain during saline irrigation through a naso-pancreatic catheter. Several studies have shown the effectiveness of endoscopic treatment as a surgery sparing alternative to decompress the MPD stricture and therefore to provide improvement of pain (56, 57). Endoscopic therapy should aim at ruling out the presence of a malignant stricture and at treating symptomatic patients, by bypassing the stricture through stenting of the MPD. For the first purpose, repeated brush cytology samples might be applied despite such approach suffers from low sensitivity and specificity. A promising tool, in analogy to what has been used on the biliary side for the investigation of dominant strictures in sclerosing cholangitis patients, or dilation of the MPD in suspect IPMN patients, is the application on peroral single operator pancreatoscopy plus biopsy (58, 59). Such approach has so far been reported in small series and deserve further validation but could potentially allow target biopsy and an improvement in the overall diagnostic yield. For the treatment of symptomatic strictures, ESGE guidelines recommend the deployment of a pancreatic stent through the stricture. From a technical point of view, there is not enough body of evidence regarding the need for a pancreas sphincterotomy before stent positioning. Regarding the caliber of stents, it has been shown that “the bigger the better” with 10-Fr stents harboring 3-fold less hospitalization and pain compared with 8.5 Fr (49). If the MPD stricture do not respond to the dilative treatment with a single stent, a multiple plastic stents strategy can also be tried (28). Costamagna et al. reported in a prospective study on 19 patients that the insertion of multiple pancreatic stents could achieve therapeutic success after the failure of single plastic stent strategy. The success rate was 94% at 6–12 months and 84% at 38 months (60). The same group has recently reported the updated long-term results of their technique. A total of 48 patients with MPD refractory dominant stricture were treated with multiple stent strategy after a previous failure on single stenting. After multiple stent removal, 40/48 patients (83.3%) displayed a dominant stricture resolution, five (10.41%) displayed a stricture resolution after further session of ERCP with multiple stenting strategy, while three (6.25%) experience a treatment failure. After a mean follow-up of 9.5 years, 74.4% of patients successfully treated displayed resolution of pain while 25.6% of patients experience recurrence of pain or pancreatitis (57). The use of both uncovered metal stents and fully covered metal stents has provided disappointing results, the first category because of the possible ingrowth of inflammatory tissue within the threads of stent with successive impossibility to withdraw it. The second category because of possible risks for dislocation (15%–46%) and “de novo” strictures occurrence (16%–27%) and severe pain (7%–20%). Even plastic stents display possible complications such as acute pancreatitis (2.6%), sepsis (2.6%), cholangitis (2.3%), and bleedings (1.5%) (57, 61). Pancreatic pseudocysts are a common event in clinical course of chronic pancreatitis, accounting in 20%–40% of cases. Spontaneous regression is an uncommon event, happening in circa 27% of cases. Asymptomatic, small pseudocyst below 4 cm should not be treated. Treatment should be reserved to pseudocyst causing symptoms or with complications (such as bleeding and infections). Technical success is defined as the placement of a stent between the pseudocyst and the intestinal lumen, the improvement of symptoms and either the disappearance of the pseudocyst or its volume shrinking to less than 2 cm. Two possible endoscopic approaches should be acknowledged: (1) trans-papillary drainage that should be reserved to pseudocyst <5 cm, located in the pancreatic head and (2) endoscopic ultrasound (EUS) guided transmural drainage, which should be applied to the remnant cases. Besides the use of classical double pigtails stents, a new approach using lumen apposing metal stents (LAMS) has been recently proposed (49). Evidence regarding safety and efficacy is still currently contradictory. Some papers suggest a superiority of LAMS on double pigtail stent in terms of therapeutic success and complication rate, while a systematic review has found major costs without a straightforward consistent clinical advantage (28). The major drawback of LAMS is anyway the need for early removal (ideally within 4 weeks) to avoid stent ingrowth. The use of fully covered self-expanding metal stent (FCSEMS) versus double pigtail plastic stents has been evaluated in two meta-analysis that have shown equally effectiveness, lower morbidity of FCSEMS: OR 0.4 (0.21–0.73), higher success rate of FCSEMS: OR 5.35 (1.35–21.19). Biliary strictures complicate 3%–23% of chronic pancreatitis and are often due to inflammatory and edematous-inflammatory reaction due to re-acutization of acute pancreatitis over a chronic condition. Biliary strictures display 46% of prevalence but also 20%–50% rate of spontaneous resolution. Secondary biliary cirrhosis can complicate 7.3% of cases when jaundice is long lasting. The main indications for endoscopic treatment are (1) to rule out malignancy; (2) to avoid acute cholangitis; and (3) to avoid secondary biliary cirrhosis. Both FCSEMS and multiple plastic stents are equally effective in jaundice resolution (62, 63). Their placement should be considered when jaundice persists for over 1 month. A RCT including 60 patients compared multiple plastic stents versus FCSEMS reporting comparable results in terms of success rates at 2-year follow-up (90% vs. 92%) and in stent migration (10% vs. 7%) (64). The ESGE guidelines suggest the temporary insertion of multiple plastic stents or FCSEMS. FCSEMS should be left in place for 1 year. Plastic stents should be exchanged every 3 months and with a total treatment duration of up to 1 year (49).

Conclusion

Chronic pancreatitis is a complex syndrome displaying an extreme variability in terms of clinical presentation, complications, and clinical outcomes. Some complications can be clinically silent but still strongly impact patient’s prognosis. Such complications should be specifically investigated to achieve an early treatment. A better understanding of chronic pancreatitis and of its underlining pathophysiological mechanisms will probably help in the next future to develop strategies of personalized medicine with overall improvement in quantity and quality of life in such a complex category of patients.