Management of Acute and Chronic Pancreatitis

2.5.1 Types of acute pancreatitis

Two different types of AP have been characterized: Interstitial edematous pancreatitis and necrotizing pancreatitis.

Interstitial edematous pancreatitis is an acute inflammation of pancreatic parenchyma and peri-pancreatic tissues, but without recognizable tissue necrosis. Developed by the majority of patients (80–85%), it is characterized by diffuse (or occasionally localized) enlargement of the pancreas, due to inflammatory edema; the clinical symptoms usually resolve within the first week.

Necrotizing pancreatitis is, instead, the presence of inflammation associated with pancreatic parenchymal necrosis and/or peri-pancreatic necrosis. The natural history of necrotizing pancreatitis is variable and this scenario evolves over several days because necrosis can remain solid or liquefy, can remain sterile or become infected, persist or disappear over time. This explains why an early CT made for assessment of AP may underestimate the eventual extent of pancreatic and peri-pancreatic necrosis. Moreover, most evidence suggest no correlation between the extent of necrosis and the risk of infection and duration of symptoms and usually infected necrosis is rare during the first week. Developed by 15–20% of patients with AP, this type of evolution of AP has increased morbidity and mortality compared to patients with interstitial edematous pancreatitis [5, 7].

2.5.2 Severity of acute pancreatitis

A preliminary overview of complications of AP is mandatory, because the comprehension of these terminologies is central to definition and stratification of severity.

• Local complications: acute peri-pancreatic fluid collection, pancreatic pseudocyst, acute necrotic collection (sterile or infected), walled of necrosis (sterile or infected), gastric outlet dysfunction, splenic and portal vein thrombosis, ischemic colitis, colonic necrosis, enteric fistulas, hemorrhages.

• Systemic complications: exacerbation of preexisting comorbidities, such as chronic obstructive pulmonary disease, coronary artery disease or chronic liver disease.

• Organ failure is defined using the modified Marshall scoring system, that has the advantage of being simple, universally applicable, objective and easily repeatable daily. In AP three organ systems have to be assessed: respiratory, cardiovascular and renal. Respiratory failure is defined with a PaO₂/FiO₂ ratio <300, cardiovascular failure with a systolic blood pressure <90 mmHg non responsive to fluid administration and renal failure with a serum creatinine level ≥1.9 mg/dl (Table 2) [7, 9]. If organ failure affects more than one organ system, it is termed multiple organ failure (MOF).

• Transient organ failure is defined as organ failure existing for less than 48 hours, while persistent organ failure is organ failure persisting for more than 48 hours [7].

There are three degrees of severity of AP:

• Mild AP: absence of organ failure and absence of local or systemic complications

• Moderately severe AP: presence of transient organ failure (<48 hours) and/or presence of local or systemic complications (in absence of persistent organ failure)

• Severe AP: presence of persistent organ failure (>48 hours), that can involve single or multiple organs [7].

Usually, mild AP account for 80–85% of cases, while severe AP is reported in 15–30% of patients [6].

2.5.3 Phases of acute pancreatitis

AP is a dynamic disease with variable scenarios of evolution, but it has two overlapping phases that need to be considered separately to better understand the progression and consequences of this disease.

The early phase usually takes place in the first and second weeks of the disease. It is characterized by the host response to local pancreatic injury and inflammation, with activation of the cytokine cascades that can lead to SIRS (Table 3).

In this phase the scenario of AP is still evolving and local complications may be recognized but they are mutable and inaccurate to determine the grade of severity. Furthermore, the morphologic changes due to local complications are not correlated to the extension of organ damage and the severity of organ failure [7].

Instead, the presence of SIRS and his persistence over time are known to be correlated to an increased risk of developing organ failure, are associated to high mortality and are established as early indicator of the likely severity of AP [2, 10, 11]. Persistent SIRS (>48 hours) is associated with a mortality rate of 25% compared with 8% of transient SIRS [3].

Consequently, the determinant of severity in the early phase of AP is the presence and duration of organ failure, that is assessed thorough clinical criteria [7] (see Section 2.6.1 Initial Assessment, Table 4) and appears to be related to the development and persistence of SIRS [6].

In this phase, death occurs as a result of the development, the persistence and the progressive nature of organ dysfunction; the reversal of early organ failure has been shown to be important in preventing morbidity and mortality in patient with AP. Therefore, if SIRS is identified in this phase of the disease, patients must be treated according to the treatment of a severe AP [6].

The late phase usually develops after the second week of the disease and can extent from weeks to months; it is delineated by the persistence of systemic signs of inflammation or by the presence of local complications. Consequently, this scenario develops only in patients with moderately severe or severe AP.

In this phase the disease is still evolving and local complications need to be assessed and characterized with radiological imaging because they may need a specific management. Therefore, although the main determinant of severity in this phase is the persistence of organ failure, the need of radiological definition of local complications requires both clinical and morphological criteria [7].

In the natural history of AP, half of all deaths occur in the first 2 weeks and are mainly due to failure of multiple organ systems while the other half occur after 2 weeks and are mainly due to pancreatic and extrapancreatic infections [5].

2.5.4 Prediction of severity

The three severity degrees of AP have distinct characterizations that have direct implications for clinical management and are associated with different outcome and mortality:

• Mild AP: self-limited disease that occurs in approximately 80–85% of patients [5]. By 48 hours after the admission, these patients typically would have substantially improved [6]. Radiological imaging is routinely not mandatory and discharge generally occurs during the early phase. Mortality is rare (<2%) [5, 7].

• Moderately severe AP: usually radiological imaging is required to assess the presence and extent of local complications, that may resolve without the need of intervention but that may request prolonged specialist support and care. Mortality is low (<5%) [5, 7].

• Severe AP: specific and aggressive treatment and specialist support and care are needed. Mortality is high, ranging from 36% to 50%, and reflects the presence and persistence of SIRS and the development of single or MOF [7, 11].

Persistent SIRS (more than 48 hours) is related to a mortality rate of 25.4% and persistent MOF is associated with a mortality reported to be as great as 42% [10]. Infection of the pancreatic and peripancreatic necrosis occurs in about 20–40% of patients and is associated with worsening organ dysfunctions [2].

Therefore, there are important reasons to define and stratify the severity of AP: the correlation between grade of severity and outcome and mortality, the need to identify patients with potentially severe AP that require aggressive early treatment, the need to identify patients that need transfer from a secondary care center to a specialist one or to intensive care unit, the need to stratify patients into subgroups based on the presence of organ failure and local or system complications to enable patient-tailored treatment that may require a variety of interventions.

Consistently with the definitions of the degrees of severity, the real severity of AP cannot be assessed on admission to the hospital or on first observation because it is not known whether the patient will have transient or persistent organ failure.

Moreover, the evolutions and changes of morphological features of local and systemic complications over time ensure that it is generally not necessary to perform radiological imaging during the first week of admission. When necessary, a CT scan performed 5–7 day after the admission is more reliable in establishing the presence and extent of local complications.

For all these reasons, the dynamic and evolving scenario that characterizes AP need to be reassessed on a daily bases in the early phase of the disease and convenient time points to re-evaluate the patients are usually 24 hours, 48 hours and 7 days after admission to the hospital [7].

Different predictors of severity of AP have been developed over time to improve clinical judgment, including single serum markers and scoring systems incorporating clinical, radiological and laboratory findings. The features of the best predictive criteria are: simplicity, universal applicability across international centers, ability to stratify disease severity easily and objectively, possibility for use at presentation and daily repetition.

Serum lipase or amylase levels are central to diagnosis of AP, but their degree on bloodstream and their decrease have no prognostic value [5, 7].

Many authors consider an acute-phase reactant, the C-reactive protein (CRP), as the “gold standard” for disease severity assessment. An elevated CRP concentration of greater than 150 mg/l indicates that AP will have a complicated course with a sensitivity of 85% in the first 72 hours after the onset of symptoms. The major drawback of CRP is that peak levels are reached only after 48–72 hours from the onset of symptoms and therefore is a predictor of severity that takes 72 hours to become accurate. Furthermore, CRP is not disease-specific and can be elevated in other inflammatory conditions [2, 12].

Procalcitonin (PCT) is another acute-phase protein considered as a valuable marker for the detection of severe pancreatitis, with a cut-off value of 0.5 ng/ml. An increased PCT concentration in AP should be observed since the onset of the disease and therefore it is useful in the early prediction of severe AP; nevertheless, some authors suggest that it is more beneficial to measure the PCT level within 24–36 hours from the occurrence of symptoms [13, 14]. A PCT value of 3.8 ng/ml or higher within 96 hours after the onset of symptoms indicated a pancreatic necrosis with a sensitivity and specificity of 93% and 79%. Moreover, an elevated PCT predicts infected necrosis in patients with confirmed pancreatic necrosis and has the ability to indicate a status of bacterial infection [2, 12, 13, 14].

Several scoring systems have been developed over time: Ranson score (1974) [15], Glasgow-Imrie score (1978) [16], Acute Physiology and Chronic Health Evaluation II (APACHE-II) (1983) [17], APACHE combined with scoring for obesity (APACHE-O), Simplified Acute Physiology Score (SAPS II) (1984) [18], CT Severity Index (CTSI) (1990) [19, 20], Bedside Index for Severity in Acute Pancreatitis (BISAP) (2008) [21], Harmless Acute Pancreatitis Score (HAPS) (2009) [22], Sequential Organ Failure Assessment (SOFA) (2013) [23], Japanese Severity Score (JPN) (2013 revision) [24].

Ranson score is moderately accurate in stratifying patients in terms of severity but required full 48 hours to be completed, with eleven criteria to be valuated (in additions, some data are not routinely ordered during hospitalization) [15, 25]. APACHE-II is very complex: it evaluates the chronic health score and 12 physiologic measurement, is not designed for day to day evaluation and is not specific for AP [2, 17, 25]. CTSI is based on local complications showed on CT scan findings and has the drawback of not reflecting the systemic inflammatory response [19, 20, 25]. BISAP is one of the most accurate, is very simple (only five criteria), applicable in every day clinical practice and easily applied in the early phases [2, 21, 25].

The International Association of Pancreatology (IAP) and the American Pancreatic Association (APA) evidence-based guidelines for the management of AP, advised the use of SIRS to predict severe acute pancreatitis (SAP) on admission and at 48 hours. SIRS can be diagnosed on the basis of four routine clinical measurement (Table 3) and persistent SIRS (>48 hours) is associated with MOF and mortality (25% compared with 8% of transient SIRS). Arguments to recommend SIRS over the other predictive scoring systems are widespread familiarity, simplicity and the possibility for repetitive measurements; none of the other scoring systems are considered clearly superior or inferior to (persistent) SIRS [3].

Evidence on the predictive performance of all these scoring systems is variable and their sensitivity and specificity for predicting severe AP range between 55% and 90%, depending on the cut-off value and the timing of scoring. Limitations of these scoring systems have been either the inability to obtain a complete score until at least 48 hours into the illness (missing a potentially valuable early therapeutic window) or the complexity of the scoring system itself [2, 12].

For all these reasons, there are no “gold standard” prognostic scores for predicting severe AP [2]. They are still useful to prove or exclude severe disease but they cannot replace ongoing evaluation by an experienced clinician and a good clinical judgment.

2.6.1 Initial assessment

Severity score systems are complex, cumbersome and typically require 48 hours to become accurate.

In absence of any available test to determine severity, clinicians need to be aware of clinical finding associated with a severe course. These includes patient’s age, comorbid health problems, body mass index, presence of SIRS, signs of hypovolemia (such as elevated blood urea nitrogen (BUN) or elevated hematocrit) and presence of pleural effusion (Table 4). These intrinsic patient-related risk factors for the development of severe disease should be used for initial risk assessment and to consequentially provide adequate initial management to patients presenting with AP [6].

2.6.2 Initial management

An adequate initial management should be provided to all patients presenting with AP and patients with organ failure and/or SIRS should be admitted to an intensive care unit whenever possible.

Initial management includes fluid resuscitation with early aggressive hydration, pain management and adequate nutrition. Routine use of prophylactic antibiotics in patients with severe AP and/or sterile necrosis is not recommended.

Early aggressive fluid administration, defined as 250–500 ml/hour of isotonic crystalloid solution, is an effective intervention that is most beneficial during the first 12–24 hours and should be provided to all patients (unless cardiovascular, renal or other related comorbidities preclude it, as the main risk is fluid overload). It amounts to a total infusion of 2500–4000 ml within the first 24 hours and it seems to be sufficient to reach the resuscitation goals within these first hours [2, 3, 5, 6]. Fluid requirement should be reassessed at frequent intervals within 6 hours of admission and for the next 24–48 hours [6]. The response to fluid resuscitation should be based on clinical monitoring of fluid status (heart rate < 120 beats/minute, mean arterial pressure between 65 and 85 mmHg, urinary output >0.5–1 ml/kg/hour) [3, 5] and on biochemical targets (such as decreasing BUN and hematocrit and maintaining normal creatinine) [5, 6].

Pain is the cardinal symptom of AP and its relief is a clinical priority. All patients must receive analgesia and there is no evidence about any restriction in pain medications: the best recommendations is to adhere to the most current acute pain management guidelines, in a multimodal approach including non-steroidal anti-inflammation drugs (NSAID), opioids, epidural analgesia and patient-controlled analgesia (PCA) [2].

In patients with mild AP there is no need for complete resolution of pain or normalization of pancreatic enzyme levels before oral feeding is started. A low-fat soft or solid diet is safe and can be started soon after admission in the absence of nausea, vomiting, severe abdominal pain and ileus [5, 6]. Need for nutritional support may be predicted in severe AP or over day 5 from admission if the symptoms continue to be severe or there is inability to oral feedings [5]. When artificial feeding is required, enteral nutrition should be the preferred treatment and it is recommended to prevent infectious complications. Nasogastric or nasoduodenal feeding are clinically equivalent. Total parenteral nutrition should be avoided and reserved for the cases in which the enteral route is not available, not tolerated or nutritional goals are not met [2, 6].

Infectious complications (both pancreatic and extrapancreatic) are a major cause of morbidity and mortality in patients with AP. Furthermore, patients with infected pancreatic necrosis have a higher mortality rate when compared with patients with sterile necrosis.

Although it was previously believed that preventing the development of infected necrosis was important, different trials have shown no benefit of prophylaxis with antibiotic therapy [5]. Now is established that the role of antibiotics is to treat confirmed infected necrosis instead of prevent infectious complications in patients with sterile necrosis. Antibiotics known to penetrate pancreatic necrosis are carbapenems (such as imipenem), quinolones, fluoroquinolones, clindamycin, piperacillin and metronidazole and their administration may be useful in delaying or avoiding intervention.

Consequently, routine use of prophylactic antibiotics in patients with any type of AP is not recommended unless infection is suspected or confirmed. Furthermore, routine use of antifungal agents, along with antibiotics, is not recommended. Nevertheless, antibiotics should be given for extrapancreatic infections such as cholangitis, catheter-acquired infections, bacteremia, urinary tract infections and pneumonia [2, 3, 6, 26].

There is no current available pharmacologic therapy to mitigate AP and current treatment is largely supportive. Considering that pancreatic injury is mediated by autodigestive enzymes, anti-secretory agents such as glucagon and somatostatin have been tested as potential therapies with limited results. Use of protease inhibitors agents (such as gabexate mesilate) have been studied with the aim of blocking intrapancreatic activation of digestive enzymes but several trials showed conflicting results on clinical benefit. Also administration of indomethacin and steroid therapy have been assessed in clinical trials but their role remains to be determined [27]. A recent Cochrane review about pharmacological intervention for AP stated that there was no evidence of difference in short-term mortality between the groups in any of the comparisons. Despite this evidence, the authors underlined that interventions with at least two clinical benefits were: octreotide (somatostatin analog), which was associated with fewer serious adverse events and a lower proportion of people with organ failure; and gabexate mesilate, which was associated with fewer adverse events and a lower proportion of people requiring an additional invasive intervention compared to inactive intervention [28].

2.6.3 Patient-tailored management (of late phase of acute pancreatitis)

Whether AP progresses to the late phase of the disease, patients may require a variety of interventions that go beyond the initial management. Patient-tailored management may include ERCP, endoscopic ultrasonography (EUS), endoscopic and/or radiological drainage or surgical intervention for treatment of local complications and referral for cholecystectomy to prevent recurrent attacks and potential biliary sepsis [6].

ERCP is indicated in patients with biliary pancreatitis with common bile duct obstruction and/or cholangitis [3, 5].

Asymptomatic acute peripancreatic fluid collections and asymptomatic pseudocysts do not require therapy. The development of infection in the necrotic collection is the main indicator for therapy and treatment should be delayed preferably for more than 4 weeks [3, 5, 6]. Clinical and imaging signs are accurate and routine percutaneous fine needle aspiration and culture is not required [3, 5].

The optimal intervention strategy is always a step-up approach: initial broad-spectrum antibiotics administration, subsequent percutaneous radiological interventions followed, if needed, by endoscopic transmural drainage or endoscopic debridement and eventually by surgical approach [3, 5, 6]. Minimally invasive operative methods of necrosectomy and minimally invasive surgical approaches are always preferred to open necrosectomy [6]. The optimal strategy must be individualized for every patient and should be discussed by a multidisciplinary group of experts.

To prevent recurrence of AP, cholecystectomy should be performed before discharge in patient with mild gallstone AP. In this subgroup of patients, cholecystectomy performed 25–30 days after discharge has a higher rate of complications as compared with cholecystectomy performed during the initial hospitalization and a delay of cholecystectomy for more than a few weeks is associated with a high risk of relapse (up to 30%) of AP. Instead, in patient with necrotizing biliary AP, cholecystectomy should be delayed until active inflammation and fluid collections resolve or stabilize [3, 6]. In AP without biliary etiology, other protective measures to prevent relapses are mandatory such as smoking cessation, abstinence of alcohol intake, withdraw of implicated medications and tight control of hyperlipidemia.

3.3.1 Risk factors

The most common risk factor for CP is alcohol abuse [36, 37]. In 1995, a study from Levy et al. demonstrated a logarithmic relationship between the relative risk of developing CP and the quantity of consumed alcohol, although the type of alcohol consumed is irrelevant [38]. There is not a threshold value, but a minimum of 80 g alcohol per day for a period of at least 6 years is considered to be a risk factor for the development of CP. An average of 18 ± 11 years elapses between the start of excessive alcohol consumption and the development of pancreatitis [39, 40].

Smoking is an independent risk factor. It accelerates the progression of CP, even with alcohol abstinence. It leads to pancreatic pain exacerbations and to calcifications. All patients should be advised to quit smoking [41, 42, 43]. In 2009, Yadav et al. published the results of the North American Pancreatitis Study 2 that prospectively enrolled 540 patients with CP. A dose-dependent association between smoking and CP was demonstrated; and patients without an history of alcohol but with 21–35 pack years have an increased risk of CP with a 3.26 odds ratio [44].

Primary hyperparathyroidism (pHPT) can lead to CP, with or without calcifications. 1% of patients with CP suffers from pHPT, conversely 12% of patients with pHPT also have pancreatitis, thus leading to a 28-fold increased risk of developing pancreatitis in this cohort of patients [45, 46].

Whether the anatomic anomaly pancreas divisum (the most common congenital malformation of the pancreas) is a risk factor for the development of CP is still a matter of debate. The S3-consensus conference on CP have reached an agreement on the following statement: “the presence of pancreas divisum without any further risk factors tend not to lead to chronic pancreatitis” [47].

Several genes have been associated with the diagnosis of CP. Genetic testing aim is to provide early information about the etiology of disease-related disorders that are contributing to the pathogenic process, to assist in decision making, and to help prevent the development of irreversible CP [48].

The most important genetic risk factors are variants in cationic trypsinogen (PRSS1), SPINK1 and carboxypeptidase A1 (CPA1). Further genetic susceptibility genes are CFTR, chymotrypsinogen C (CTRC) and carboxyesterlipase (CEL) [49, 50, 51, 52, 53, 54].

Trypsinogen is a key molecule in the pathogenesis of pancreatitis, up to 66% of patients with hereditary pancreatitis have a mutation of the PRSS1 gene. Such mutations lead to CP with a penetrance of up to 80% and an autosomal dominant inheritance pattern [55, 56, 57, 58].

Mutations of the SPINK1 gene predispose to idiopathic CP, occurring in as many as 30% of patients, however only in 1–2% of the general population. The N34S mutation in the gene encoding SPINK1 bears an odds ratio of 11.0 in developing CP.

Cystic fibrosis is an autosomal recessive disease with an estimated incidence of 1:2500. The first description of an association between CFTR variants and CP was published in 1998 [59]. The association between gene mutations and CP has an odds ratio of around 3–5 [55, 60]. CP patients carrying CFTR variants harbor at least one mild variant allele giving them residual CFTR function. Pancreas involvement may vary from a complete loss of exocrine and endocrine function to almost normal function. Molecular changes in the CFTR gene are associated to up to 30% of patients with idiopathic pancreatitis.

Patients with a CTRC mutation have an increased risk of developing CP. The first report dates back to 2008 [52]. Such mutations occur in 3.3% of patients with idiopathic pancreatitis.

In addition to those etiologic factors, autoimmune pancreatitis has been recently characterized. First reported in 1961 by Sarles [61], Yoshida first postulated this clinical entity in 1995 [62]. This is a systemic fibroinflammatory disease in which the pancreas is one of the affected organs. Men are affected twice than women. Clinical symptoms include abdominal pain, jaundice and recurrent episodes of pancreatitis. Radiological findings include “sausage-shaped pancreas” and diffuse or segmental Wirsung stenosis, often without prestenotic dilation. Serum levels of immunoglobulin (Ig) G and IgG4 have been found increased in the Asian patients, but only in 50% of European ones. Diagnosis is reached according to the HiSORT criteria (Table 6) [63] which include histology, serology, other organ involvement and response to steroid therapy [64, 65, 66].

3.3.2 Classification models

Distinct classification systems have been developed but, so far, no globally accepted classification system has been established. Classification systems currently in use are: Manchester classification; ABC classification; M-ANNHEIM; TIGAR-O; and Rosemont classification. Only the Toxic/metabolic, Idiopathic, Genetic, Autoimmune, Recurrent acute pancreatitis, and Obstructive (TIGAR-O) and the pancreatitis with Multiple risk factors-Alcohol consumption, Nicotine consumption, Nutritional factors, Hereditary factors, Efferent duct factors, Immunological factors, Miscellaneous and rare metabolic factors (M-ANNHEIM) classification systems take the etiology of CP into account.

The M-ANNHEIM system is a multirisk factor classification system. It adds information on disease activity and stage, evaluating the role of various risk factors on the course of CP [67]. Relying upon traditional clinicopathologic criteria, and resulting in a score between 0–25, it provides diagnostic criteria for etiology, clinical and diagnostic stage (Table 7).

The TIGAR-O classification system comprises six etiologic groups: toxic-metabolic, idiopathic, genetic, autoimmune, recurrent AP, and obstructive groups. It has been validated in multiple international studies, and in 2019 it was revised to include new insights from the past 20 years. It is designed as a hierarchical checklist to quickly document and track specific factors that may contribute to progressive pancreatic disease (Table 8) [68].

3.5.1 Pain

Abdominal pain is the most common complication and prevailing symptom of CP. It can manifest through a spectrum of intensity, form mild and intermittent to severe unrelenting. Pain is experienced by 75% of patients at the time of presentation and up to 97% during the clinical course. The pathophysiology is multifactorial and results from pancreatic and extra-pancreatic causes. Pancreas-related causes include: parenchymal and nerve sheaths inflammatory infiltrates, augmented pressure by obstruction flow of pancreatic juice and increased pancreatic capsule tension due to raised pancreatic parenchymal pressure. Extra-pancreatic causes include gastric or duodenal ulcers and meteorism caused by bacterial overgrowth and maldigestion [47, 86].

The NAPS-2 Study categorized five distinct pain patterns according to severity and pain control (Table 9) [87].

The only pain score explicitly validated for assessing pain in patients with CP has been published in 1995 by Bloechle et al. [88]: the visual analogue scale. Pain management should follow the WHO three-step analgesic ladder. However, WHO pain management has not been consistently used in the available literature, thus the question about its effectiveness cannot be answered.

The natural course of pain in CP is characterized by a variable percentage of patients (47−80%) achieving spontaneous pain relief from 10 to 15 years from onset. However, a part of patients will suffer of pain indefinitely. Waiting for a spontaneous pain relief has been defined not reliable by the American Gastroenterological Association (AGA) [36].

Endoscopic treatment (ET) is recommended as a first-choice therapy in patients with an obstructive type of pancreatic pain and in patients with a pancreatic duct dilatation. This could, also, be useful as a bridge to surgery. The aim of ET is decompression of an obstructed main pancreatic duct, it decreases the numbers of hospitalizations for pancreatic pain and reduces analgesics intake. Extracorporeal shock wave lithotripsy (ESWL) therapy in painful CP is indicated if the stone size is >5 mm, the stone is located in the head or pancreatic body, and there are no strictures of the main pancreatic duct. It should be combined with ET in cases of large stones with pancreatic duct stricture [36, 47].

Surgical options for pain are classified into three categories: decompression (focusing on ductal hypertension), resection (focusing on inflammatory masses in the pancreatic head), and mixed techniques. Decompression is recommended in patients with a main pancreatic duct >7–8 mm and no inflammatory mass. Pain relief is achieved in 66–91% of patients, however, the long-term results show up to 50% recurrences. Resection in patients with an inflammatory mass or an obstructive CP of the body or tail. Pancreaticoduodenectomy is effective in 75% of patients but with a significant morbidity (20%), as such most authors favor the more conservative mixed techniques. Mixed techniques achieve a short-term pain relief in up to 70–100% of patients and a long-term pain relief in 82–100%. Mixed techniques are based on the resection of the inflammatory mass in the pancreatic head and drainage of the obstructed main pancreatic duct (body and tail). The most widely used techniques are the duodenal preservation (Berger) or the Frey method which consists in a longitudinal pancreaticojejunostomy and in the coring out of the pancreatic head [47, 89].

A pain management strategy must be well structured and conducted with a logical approach to minimize long term complication and sequelae. Is recommended to early involve a pain management specialist during the clinical course, as delays lead to poorer health and pain control [90].

3.5.2 Lifestyle

Complete cessation of alcohol and tobacco use is of utmost importance. Patients must be aware that ongoing use will sustain the cycle of pain and lead to further progression of the disease. Cognitive and mindfulness-based therapies should be offered to all patients, especially for those who need assistance with abuse disorder.

3.5.3 Enzyme replacement

A weight loss of more than 10% of the body weight, steatorrhea with a fecal fat excretion of more than 15 g/die (or a pathological pancreatic function test) in combination with clinical signs of malabsorption (dyspeptic symptoms with severe meteorism or diarrhea) are a clinical indication for pancreatic enzyme replacement therapy. Abdominal complaints (diarrhea/steatorrhea, abdominal distension/meteorism and pain) may be due to intestinal motility disorders caused by maldigestion and malabsorption [91]. Enzyme supplements are administered by gastric-acid-protected encapsulated microsphere and contain pancreatin, with the main components being lipase, amylase, trypsin and chymotrypsin. A successful treatment is measured by improvement of the disease symptoms. Therapy with pancreatin purely as a trial for 4–6 weeks may also be beneficial if symptoms are unclear [91, 92, 93, 94].

An untreated severe EPI results in a severe malabsorption syndrome that manifests in the form of steatorrhea, deficiency of fat-soluble vitamins, weight loss and finally cachexia [71, 95, 96]. The success of enzyme replacement therapy should be monitored using clinical parameters (weight gain, long-term normalization of the vitamin status, cessation of abdominal symptoms).