PANCREATIC DISEASES Ljubljana, 2018 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology Editor: Rado JANŠA Ljubljana, 2018 Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology Editor: Rado Janša Reviewers: Vladka Salapura Veronika Kralj-Iglič Publisher: Josip Cholewa Foundation Dunajska cesta 106, SI–1000 Ljubljana Person in Charge: Borut Štabuc e-Textbook Ljubljana, 2018 EDITORIAL Our society is becoming older and the lifespan of However, that is not all. Particular attention is humans is getting longer with each decade. With paid to the quality of life of patients suffering age come struggles, problems and illnesses. from pancreatic diseases, as well as their families However, age alone is not the reason why the and relatives trying to make everyday life easier – number of certain illnesses and diseases in the so- information about nutrition, pain management and called western civilization is rising. An unhealthy psychiatric support. and stressful lifestyle – by too much eating, drinking, or smoking–, negative environmental I would like to express my deep gratitude to all influences, or genetics, are just some of the p articipants for their contributions. I hope that reasons why more and more people are getting this textbook will help to resolve open questions sick. and encourage new research. Fact is; we are not listening to our own bodies. Rado JANŠA, Editor Pain is the body’s way of telling us something is wrong. What starts as a pain or discomfort in the abdomen, can very likely be an early warning or s ign for a serious illness. Some of those are connected with the pancreas. The number of pancreatic diseases is rising. Due to the inaccessibility of it, lying behind the stomach in front of the spine, surrounded by the intestines, liver, and gallbladder, the evaluation of pancreatic diseases is very difficult. There are a number of disorders of the pancreas, the most common being acute, chronic or hereditary pancreatitis, and pancreatic cancer, which shown by recent studies is the fourth lead- ing cause of death by cancer in Europe. If no actions are taken, it is set to become the second by the year 2020. The purpose of the textbook is to present selected topics in clinical gastroenterology in connection with pancreatic diseases. From the most common to the rare. In addition, it presents multiple methods to evaluate the pancreas – from blood tests, physical evaluations to radiographic tests. The textbook presents new algorithms in diagnos- tics, endoscopic or surgical procedures and systemic treatments of pancreatic diseases. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 4 CONTENTS Rado Janša Editorial ........................................................................................................................................................... 4 Jan Drnovšek Acute Pancreatitis ............................................................................................................................................ 7 Luka Strniša Chronic Pancreatitis ........................................................................................................................................ 16 Lojze Šmid, Jan Drnovšek Hereditary and Autoimmune Pancreatitis ....................................................................................................... 26 Rusmir Mesihović New Algorithms in Diagnosing Biliopancreatic Pathology with Endoscopic Ultrasound ............................. 32 Sanjo Finderle, Borut Štabuc Risk Factors for Development of Pancreatic Ductal Adenocarcinoma .......................................................... 34 Samo Plut Endoscopic Procedures in Patient with Pancreatic Disease ........................................................................... 43 David Badovinac, Aleš Tomažič Novelties in Surgical Treatment of Pancreatic Diseases ................................................................................ 47 Borut Štabuc, Gašper Boltežar Systemic Treatment of Pancreatic Cancer ...................................................................................................... 59 Neli Vintar, Katja Režonja Pancreatic Pain Management .......................................................................................................................... 66 Rado Janša Exocrine Pancreatic Insufficiency .................................................................................................................. 72 Sanela Banović Nutrition in Acute and Chronic Pancreatitis ................................................................................................... 78 Zvezdana Snoj Psychiatric Treatment and Support for Chronically Ill Patients ..................................................................... 83 Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 5 CIP - Kataložni zapis o publikaciji Narodna in univerzitetna knjižnica, Ljubljana 616.37(082)(0.034.2) PANCREATIC Diseases [Elektronski vir] : Textbook of Selected Topics in Clinical Gastroenterology / Edi- tor Rado Janša. - Ljubljana : Josip Cholewa Foundati- on, 2018 ISBN 978-961-288-433-8 1. Janša, Rado 294814976 ACUTE PANCREATITIS Jan Drnovšek* University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT Acute pancreatitis is an inflammatory disorder of the pancreas. It is an acute gastrointestinal disorder and is one of the leading gastroenterological causes of admission to hospital worldwide with its increasing inci- dence. The diagnosis of acute pancreatitis requires two of the following three features: sudden abdominal pain, elevated pancreatic enzymes values at least three times greater than the upper limit of normal and char- acteristic radiographic findings of acute pancreatitis. Acute pancreatitis can be subdivided into two types: in- terstitial oedematous pancreatitis and necrotising pancreatitis. Management depends largely on severity of disease, which is defined by presence and duration of organ fail- ure. Medical treatment of mild acute pancreatitis is symptomatic. Treatment of severe acute pancreatitis re- quires intensive care. Recognizing patients with mild and severe acute pancreatitis is crucial for achieving op- timal outcomes, since severe acute pancreatitis is often related to increased mortality and morbidity. Key words: Acute pancreatitis, diagnosis, severity, complications INTRODUCTION The digestive enzymes of exocrine part drain into the Pancreatitis is an inflammatory process in which duodenum. In normal pancreatic function, up to 15 pancreatic enzymes autodigest the gland. The gland different types of digestive enzymes are manufactured sometimes heals without any impairment of function in the endoplasmic reticulum, targeted in the Golgi or any morphologic changes; this process is known as apparatus and packaged into zymogens as proen- acute pancreatitis. Pancreatitis can also recur intermit- zymes. When a meal is ingested, the vagal nerves, tently, contributing to the functional and morphologic vasoactive intestinal polypeptide, gastrin-releasing loss of the gland; recurrent attacks are referred to as peptide, secretin, cholecystokinin and encephalins chronic pancreatitis. stimulate release of these proenzymes into the pancreatic duct. Both forms of pancreatitis may present in the emer- gency department with acute clinical findings. Recog- In duodenum, the trypsinogen, which is the nizing patients with severe acute pancreatitis as soon proenzyme of trypsin, is activated via hydrolysis of an as possible is critical for achieving optimal outcomes. N-terminal hexapeptide fragment by the brush border Management depends largely on severity and organ enzyme enterokinase. Trypsin then facilitates the con- failure involvement (1). version of the other proenzymes into their active forms (1, 2, 19). PATHOPHYSIOLOGY The pancreas is a secretory structure with an endo- A feedback mechanism exists to limit pancreatic en- crine and an exocrine role. The endocrine part is com- zyme activation after appropriate metabolism has oc- posed of hormonal tissue distributed along the curred. It is hypothesized that elevated levels of pancreas in discrete units called islets of Langerhans. trypsin, having become unbound from digesting food, * Jan Drnovšek, MD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 7 lead to decreased cholecystokinin and secretin levels, creatic necrosis. As the mediators are excreted into the thus limiting further pancreatic secretion. circulation, systemic complications can arise, such as bacteremia due to gut flora translocation, acute respir- Because premature activation of pancreatic enzymes atory distresssyndrome (ARDS), pleural effusions, within the pancreas leads to organ injury and gastrointestinal (GI) hemorrhage and renal failure. pancreatitis, several mechanisms exist to limit this oc- currence. First, proteins are translated into the inactive The systemic inflammatory response syndrome proenzymes. Later, posttranslational modification of (SIRS) can also develop, leading to the development the Golgi cells allows their segregation into the unique of systemic shock and multiorgan failure (see Table 3) subcellular zymogen compartments. The proenzymes (1-6,19). are packaged in a paracrystalline arrangement with protease inhibitors. Zymogen granules have an acidic Etiology pH and a low calcium concentration, which are factors Long-standing alcohol consumption and biliary stone that guard against premature activation until after disease are the most common cause of acute pancrea- secretion has occurred and extracellular factors have titis, but numerous other etiologies are known. In triggered the activation cascade. Under various condi- 10–30% of cases, the cause is unknown, though stud- tions, disruption of these protective mechanisms may ies have suggested that as many as 70% of cases of occur, resulting in intracellular enzyme activation and idiopathic pancreatitis are secondary to biliary pancreatic auto digestion leading to acute pancreatitis microlithiasis. (1, 2, 3, 19). Biliary tract disease Acute pancreatitis may occur when factors involved in One of the most common causes of acute pancreatitis maintaining cellular homeostasis are out of balance. (accounting for approximately 40% of cases) is The initiating event may be anything that injures the gallstones passing into the bile duct and temporarily acinar cell and impairs the secretion of zymogen lodging at the sphincter of Oddi. The risk of a stone granules; examples include alcohol use, gallstones and causing pancreatitis is inversely proportional to its certain drugs. In addition, acute pancreatitis can size (7). develop when ductal cell injury leads to delayed or absent enzymatic secretion, as seen in patients with It is thought that acinar cell injury occurs secondary to the CFTR gene mutation. Once a cellular injury increasing pancreatic duct pressures caused by ob- pattern has been initiated, a cascade of cell injuries structive biliary stones at the ampulla of Vater, proceeds (1, 2). Lysosomal and zymogen granule although this has not been definitively proven in hu- compartments fuse, enabling activation of trypsinogen mans. Occult microlithiasis is probably responsible to trypsin for most cases of idiopathic acute pancreatitis (8). Intracellular trypsin triggers the entire zymogen Alcohol intake activation cascade. Secretory vesicles are extruded Alcohol use is a major cause of acute pancreatitis, ac- across the basolateral membrane into the interstitium, counting for at least 35% of cases (9). At the cellular where molecular fragments act as chemoattractants for level, ethanol leads to intracellular accumulation of inflammatory cells. Activated neutrophils exacerbate digestive enzymes, inducting their premature the inflamation by releasing superoxide or proteolytic activation. At the ductal level, it increases the enzymes (cathepsins B, D, and G; collagenase; and permeability of ductless, allowing enzymes to reach elastase). Finally, macrophages release cytokines that the parenchyma and cause pancreatic damage. Ethanol further mediate local and, in severe cases, systemic increases the protein content of pancreatic juice and inflammatory responses. The early mediators defined decreases bicarbonate levels and trypsin inhibitor to date are tumor necrosis factor-alpha (TNF-α), concentrations. This leads to the formation of protein interleukin (IL)-6, and IL-8 (1–5).These mediators of plugs that block pancreatic outflow (4, 18). inflammation cause an increased pancreatic vascular Most commonly, the disease develops in patients permeability, leading to hemorrhage, edema and pan- whose alcohol ingestion is habitual over 5-15 years. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 8 Occasionally, however, acute pancreatitis can develop echovirus, varicella-zoster virus, measles virus and in a patient with a weekend binging habit (10). rubella virus. Bacterial causes include Mycoplasma pneumoniae, Salmonella, Campylobacter, and Post - endoscopic retrograde cholangiopancreatog- Mycobacterium tuberculosis. Worldwide, Ascaris is a raphy pancreatitis recognized cause of pancreatitis resulting from the Pancreatitis occurring after endoscopic retrograde migration of worms in and out of the duodenal pa- cholangiopancreatography (ERCP) is probably the pillae (1–3). third most common type, accounting for approximately 5 % of cases (11). Hereditary pancreatitis Hereditary pancreatitis is an autosomal dominant dis- The risk of post-ERCP acute pancreatitis is increased order related to mutations of the cationic trypsinogen if the endoscopist is inexperienced, if the patient is gene ( PRSS1). Mutations in this gene cause premature thought to have sphincter of Oddi dysfunction, or if activation of trypsinogen to trypsin (1–3). manometry is performed on the sphincter of Oddi. Aggressive preintervention intravenous hydration has Hypercalcemia been durably shown to prevent post-ERCP pancreati- Hypercalcemia from any cause can lead to acute pan- tis in randomized studies. More recently, rectal indo- creatitis. Causes include hyperparathyroidism, exces- methacin has been employed; it has been shown to sive doses of vitamin D, familial hypocalciuric hyper- reduce the incidence of post-ERCP pancreatitis and is calcemia, and total parenteral nutrition (TPN). Rou- now widely accepted at most institutions (4). tine use of automated serum chemistries has allowed earlier detection and reduced the frequency of hyper- Abdominal trauma causes an elevation of amylase and calcemia manifesting as pancreatitis (2). lipase levels and in 1.5% cases clinical signs of pancreatitis. Pancreatic injury occurs more often in Developmental abnormalities of pancreas penetrating injuries than in blunt abdominal trauma. There are two developmental abnormalities common- Blunt injury to the abdomen or back may crush the ly associated with pancreatitis: pancreas divisum and gland across the spine, leading to a ductal injury. annular pancreas. Drugs Pancreas divisum is a failure of the dorsal and ventral Drug-induced pancreatitis is a relatively rare occur- pancreatic ducts to fuse during embryogenesis. It oc- rence, accounting for approximately 2% of cases. curs in approximately 5% of the population. It appears Druge induced pancreatitis is usually mild. Drugs that the presence of stenotic minor papillae and an definitely associated with acute pancreatitis include atretic duct of Santorini are additional risk factors that the following: azathioprine, sulfonamides, tetracy- together contribute to the development of acute pan- cline, valproic acid, didanosine, methyldopa estro- creatitis through an obstructive mechanism (1-4). gens, 6-mercaptopurine, pentamidine, 5- aminosalicylic acid and its compounds (1, 2). Hypertriglyceridemia Clinically significant pancreatitis usually does not oc- Less common causes cur until a person’s serum triglyceride level reaches The following causes each account for less than 1% of 1000 mg/dL. It is associated with type I and type V cases of pancreatitis. hyperlipidemia. Although this view is somewhat con- troversial, most authorities believe that the association Infection is caused by the underlying derangement in lipid me- Several infectious diseases may cause pancreatitis, tabolism rather than by pancreatitis causing hyper- especially in children. These cases of acute lipidemia. This type of pancreatitis tends to be more pancreatitis tend to be milder than cases of acute severe than alcohol- or gallstone-induced disease (1– biliary or alcohol-induced pancreatitis. 4). Viral causes include mumps virus, coxsackievirus, cytomegalovirus, hepatitis virus, Epstein-Barr virus, Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 9 Tumors (2) serum lipase activity (or amylase activity) at Obstruction of the pancreatic ductal system by a pan- least three times greater than the upper limit of nor- creatic ductal carcinoma, ampullary carcinoma, islet mal; cell tumor, solid pseudotumor of the pancreas, sar- (3) characteristic findings of acute pancreatitis on coma, lymphoma, cholangiocarcinoma or metastatic contrast-enhanced computed tomography (CECT) and tumor can cause acute pancreatitis. The chances of less commonly magnetic resonance imaging (MRI) or pancreatitis occurring when a tumor is present are ap- transabdominal ultrasonography. proximately 14%. Pancreatic cystic neoplasms, such as intraductal papillary-mucinous neoplasm (IPMN), The onset of acute pancreatitis is defined as the time mucinous cystadenoma, or serous cystadenoma, can of onsetof abdominal pain and not the time of admis- also cause pancreatitis (1–4). sion to the hospital (13). Toxins Different strategies have been used to assess the se- Exposure to organophosphate insecticide can cause verity of acute pancreatitis and predict outcome. Sev- acute pancreatitis. eral clinical scoring systems (e.g, Ranson criteria, Glasgow, Imrie) are available. The APACHE II scor- Surgical procedures ing system, though cumbersome, appears to be the Acute pancreatitis may occur in the postoperative pe- best validated (13, 20, 21). riod of various surgical procedures. Postoperative acute pancreatitis is often a difficult diagnosis to con- Acute pancreatitis can be subdivided into two types: firm and it has a higher complication rate than pancre- interstitial oedematous pancreatitis and necrotising atitis associated with other etiologies. pancreatitis. Autoimmune pancreatitis Interstitial oedematous pancreatitis Autoimmune pancreatitis, a relatively newly described The majority of patients with acute pancreatitis have entity, is an extremely rare cause of acute pancreatitis diffuse (or occasionally localised) enlargement of the with its estimaded prevalence of 0.82 per 100.000 in- pancreas due to inflammatory oedema. On contrast dividuals. The mechanism remains unclear, it is enhanced computer tomography (CECT), the pancre- thought to be related with inappropriate immune re- atic parenchyma shows relatively homogeneous en- sponse. hancement and the peripancreatic fat usually shows some inflammatory changes of haziness or mild EPIDEMIOLOGY stranding. There may also be some peripancreatic flu- Worldwide, the incidence of acute pancreatitis ranges id. The clinical symptoms of interstitial oedematous between 5 and 80 per 100.000 population. Generally, pancreatitis usually resolve within the first week (13). acute pancreatitis affects males more often than fe- males (3). The trend in rising incidence has been rec- Necrotising pancreatitis ognized over the past several decades. The median age About 5–10% of patients develop necrosis of the pan- at onset depends on the etiology. The median age of creatic parenchyma, the peripancreatic tissue or both. onset differs for various etiologies: alcohol-related - Necrotising pancreatitis most commonly manifests as 39 years, biliary tract–related - 69 years, trauma relat- necrosis involving both the pancreas and peripancreat- ed - 66 years, drug induced – 42 years, post ERCP - ic tissues and less commonly as necrosis of only the 58 years (12). peripancreatic tissue, and rarely of the pancreatic pa- renchyma alone. The impairment of pancreatic perfu- Diagnosis sion and signs of peripancreatic necrosis evolve over The diagnosis of acute pancreatitis requires two of the several days, which explains why an early CECT may following three features: underestimate the eventual extent of pancreatic and (1) abdominal pain consistent with acute pancreati- peripancreatic necrosis. Patients with peripancreatic tis (acute onset of a persistent, severe, epigastric pain necrosis alone have increased morbidity and interven- often radiatingto the back); tion rates compared to patients with interstitial oedem- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 10 atous pancreatitis. The natural history of pancreatic Mild acute pancreatitis and peripancreatic necrosis is variable, because it may Mild acute pancreatitis is characterized by the absence remain solid or liquefy, remain sterile or become in- of organfailure and the absence of local or systemic fected, persist, or disappear over time (13). complications. Patients with mild acute pancreatitis will usually be discharged during the early phase. Pa- DEFINITION OF SEVERITY OF ACUTE tients with mild acute pancreatitis usually do not re- PANCREATITIS quire pancreatic imaging, and mortality is very rare The determinant of the severity of acute pancreatitis (13). during the early phase is primarily the presence and duration of organ failure. This is described as Moderately severe acute pancreatitis “transient organ failure” if the organ failure resolves Moderately severe acute pancreatitis is characterized within 48 h or as “persistent organ failure” if organ by the presence of transient organ failure or local or failure persists for >48 h. If organ failure affects more systemic complications in the absence of persistent than one organ system, it is termed as multiple organ organ failure. An example of a symptomatic local failure (MOF). Although local complications may be complication is a peripancreatic collection resulting in identified during the early phase, they are not the pre- prolonged abdominal pain, leucocytosis and fever dominant determinants of severity. (13). Three organ systems should be assessed to define or- Mild acute pancreatitis gan failure: respiratory, cardiovascular and renal. Or- No organ failure gan failure is defined as a score of 2 or more for one No Local or systemic complications of these three organ systems using the modified Mar- Moderatley severe acute pancreatitis shall scoring system, shown in table 1 (13). Organ failure that resolves within 48h (transient organ failure) and/or This classification defines three degrees of severity: Local or systemic complications without mild acute pancreatitis, moderately severe acute pan- persistant organ failure creatitis and severe acute pancreatitis (see Table 1). Severe acute pancreatitis Terminology that is important in this classification Persistent organ faliurew (>48h) includes transient organ failure, persistent organ fail- Single organ failure ure, and local or systemic complications (13). Multiple organ failure Table 2: Grades of severity (13). Table 1: Modified Marshall scoring system for organ dysfunction (13). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 11 Severe acute pancreatitis 500mL/h). Analgesics are administered for pain relief. Severe acute pancreatitis is characterized by persistent After withdrawal of per mouth feeding, the following organ failure. Organ failure that develops during the should be started as soon as possible in the absence of early phase is set in motion by the activation of cyto- abdominal pain and vomitus (4, 14). kine cascades resulting in signs of Sistemic inflamma- tory response syndrome (SIRS) (Table 3). When SIRS If the cause of pancreatitis is believed to due to chole- is present and persistent, there is an increased risk that docholithiasis, ERCP should be performed in 24 hours the pancreatitis will be complicated by persistent or- after admission. In case of biliary pancreatitis with gan failure, and the patient should be treated as if they spontaneous gallstone resolution, cholecystectomy have severe acute pancreatitis. Persistent organ failure should be performed during the same hospital admis- may be single or multiple organ failure. sion (22). In case of suspicion, an endoscopic ultra- sound or MRCP can be proceded (2). Acute hyperlipe- Patients with persistent organ failure usually have one mic pancreatitis with elevated serum triglyceride level or more local complications. Patients who develop requires plasmapferesis (15). Patients with severe persistent organ failure within the first few days of the acute pancreatitis require intensive care to be provided disease are at increased risk of death, with a mortality with best supportive care. reported to be as great as 36–50% (13, 22) Most of the peripancreatic fluid collections, which last SIRS – defined by presence of two or more criteria: over four weeks, can be followed clinically. However, Heart rate >90 beats/min when they are symptomatic, infected or larger than 7 Core temperature <360C or >380C cm and are rapidly expanding in an acutely ill patient, White blood cound <4.000 or >12.000/mm3 intervention is required. Several different therapeutic Respiration >20/min or PCO2 <32 MM Hg13 approaches may be implemented, including percutane- ous, endoscopic or surgical approaches. In case of in- Table 3: Signs of systemic inflammatory response fected peripancreatic fluid collections, antibiotic treat- syndrome (13). ment is indicated. TREATMENT COMPLICATIONS Patients with acute pancreatitis lose a large amount of Local complications fluids to third spacing into the retroperitoneum and Local complications are acute peripancreatic fluid col- intra-abdominal areas. Therefore, prompt intravenous lection, pancreatic pseudocyst, acute necrotic collec- hydration is required within the first 24 hours (250– tion and walled-off necrosis (see Table 4). Usually develops in the early phase of interstitial oedematous pancreatitis, it is Acute peripancreatic fluid collec- confined by fascia of the retroperitoneum, may be multiple, mostly remain ster- tion ile and usually resolve spontaneously without intervention. It is a delayed (usually >4 weeks) complication of interstitial oedematous pan- creatitis, surrounded by a well-defined wall. It arises from disruption of the main pancreatic duct or its intra-pancreatic branches without any recognisable pancre- Pancreatic pseudocyst atic parenchymal necrosis. When there is evident solid necrotic material within the cavity, the term pseudo- cyst should not be used. Appears during the first 4 weeks and contains variable amounts of fluid and ne- Acute necrotic collection crotic tissue involving the pancreatic parenchyma and/or the peripancreatic tis- sues. This maturation occurs usually after 4 weeks after onset of necrotising pancrea- Walled-off necrosis titis. It consists of necrotic pancreatic and/or peripancreatic tissue and has a well -defined inflammatory wall. Table 4: Definition of pancreatic and peripancreatic collections (13). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 12 Other local complications of acute pancreatitis include REFERENCES gastric outlet dysfunction, splenic and portal vein 1. Acute panreatitis - Medscape. [available 28. April] thrombosis, and colonic necrosis. Local complications https://emedicine.medscape.com/article/181364-overview 2. Management of acute pancreatitis - UpToDate. should be suspected when there is persistence or re- [available 28. April]. https://www.uptodate.com/contents/ currence of abdominal pain, secondary increases in management-of-acute-pancreatitis serum pancreatic enzyme activity, increasing organ 3. Bank PA. Epidemiology, natural history, and pre- dysfunction, and/or the development of clinical signs dictors of disease outcome in acute and chronic pancreati- tis. Gastrointest Endosc. december 2002.;56(6 Suppl):S226 of sepsis, such as fever and leucocytosis (3, 4 13). –30. 4. Lankisch PG, Apte M, Banks PA. Acute pancrea- Infected pancreatic necrosis titis. Lancet. 4. julij 2015.;386(9988):85–96. Pancreatic and peripancreatic necrosis can remain 5. Phillip V, Steiner JM, Algül H. Early phase of acute pancreatitis: Assessment and management. World J sterile or become infected; most of the evidence sug- Gastrointest Pathophysiol. 15. avgust 2014.;5(3):158–68. gests no absolute correlation between the extent of 6. Schmid SW, Uhl W, Friess H, Malfertheiner P, necrosis and the risk of infection and duration of Büchler MW. The role of infection in acute pancreatitis. symptoms. Infected necrosis is rare during the first Gut. avgust 1999.;45(2):311–6. 7. Forsmark CE, Baillie J, AGA Institute Clinical week. The diagnosis of infected pancreatic necrosis is Practice and Economics Committee, AGA Institute Gov- important because of the need for antibiotic treatment erning Board. AGA Institute technical review on acute pan- and likely active. creatitis. Gastroenterology. May 2007.;132(5):2022–44. 8. Lerch MM, Saluja AK, Rünzi M, Dawra R, Saluja M, Steer ML. Pancreatic duct obstruction triggers acute Intervention (13, 16). The presence of infection can be necrotizing pancreatitis in the opossum. Gastroenterology. presumed when there is extraluminal gas in the pan- March 1993.;104(3):853–61. creatic and/or peripancreatic tissues on CECT or when 9. Whitcomb DC, Yadav D, Adam S, Hawes RH, percutaneous, image-guided, fine-needle aspiration Brand RE, Anderson MA, idr. Multicenter approach to re- current acute and chronic pancreatitis in the United States: (FNA) is positive for bacteria and/or fungi on Gram the North American Pancreatitis Study 2 (NAPS2). Pancre- stain and culture. The development of secondary in- atology. 2008.;8(4-5):520–31. fection in pancreatic necrosis is associated with in- 10. Migliori M, Manca M, Santini D, Pezzilli R, creased morbidity and mortality (13, 17). Gullo L. Does acute alcoholic pancreatitis precede the chronic form or is the opposite true? A histological study. J Clin Gastroenterol. March 2004.;38(3):272–5. Systemic complications 11. Aliperti G. Complications related to diagnostic Exacerbation of pre-existing co-morbidity, such as and therapeutic endoscopic retrograde cholangiopancrea- coronary artery disease or chronic lung disease, pre- tography. Gastrointest Endosc Clin N Am. April 1996.;6 (2):379–407. cipitated by the acute pancreatitis is defined as a sys- 12. Morinville VD, Barmada MM, Lowe ME. In- temic complication. In this document, we distinguish creasing incidence of acute pancreatitis at an American between persistent organ failure (the defining feature pediatric tertiary care center: is greater awareness among of severe acute pancreatitis) and other systemic com- physicians responsible? Pancreas. January 2010.;39(1):5–8. 13. Banks PA, Bollen TL, Dervenis C, Gooszen HG, plications, which are an exacerbation of pre-existing Johnson CD, Sarr MG, idr. Classification of acute pancrea- co-morbid disease (1, 2, 4, 13). titis--2012: revision of the Atlanta classification and defini- tions by international consensus. Gut. January 2013.;62 CONCLUSION (1):102–11. 14. Tenner S, Baillie J, DeWitt J, Vege SS, Ameri- Acute pancreatitis is being a serious medical condi- can College of Gastroenterology. American College of tion, which often related to increased mortality and Gastroenterology guideline: management of acute pancrea- morbidity. After setting the right diagnosis, prompt titis. Am J Gastroenterol. September 2013.;108(9):1400– treatment should be started. 15; 1416. 15. Hypertriglyceridemia-induced acute pancreatitis - UpToDate [Internet]. 28. november 2017. URL: https:// All patients with acute pancreatitis should be hospital- www.uptodate.com/contents/hypertriglyceridemia-induced ized. Management depends largely on severity of dis- -acute-pancreatitis?source=see_link#H7 ease. 16. van Santvoort HC, Bakker OJ, Bollen TL, et al. A conservative and minimally invasive approach to necrotizing pancreatitis improves outcome. Gastroenterolo- gy 2011;141:1254–63. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 13 17. Petrov MS, Shanbhag S, Chakraborty M, et al. 22. Mofidi R, Duff MD, Wigmore SJ, Madhavan Organ failure and infection of pancreatic necrosis as deter- KK, Garden OJ, Parks RW. Association between early sys- minants of mortality in patients with acute pancreatitis. temic inflammatory response, severity of multiorgan dys- Gastroenterology 2010;139:813–20. function and death in acute pancreatitis. Br J Surg. June 18. Lerch MM, Saluja AK, Rünzi M, Dawra R, Salu- 2006.;93(6):738–44. ja M, Steer ML. Pancreatic duct obstruction triggers acute 23. Uhl W, Müller CA, Krähenbühl L, Schmid SW, necrotizing pancreatitis in the opossum. Gastroenterology. Schölzel S, Büchler MW. Acute gallstone pancreatitis: tim- March 1993.;104(3):853–61. ing of laparoscopic cholecystectomy in mild and severe 19. Robert JH, Frossard JL, Mermillod B, Soravia C, disease. Surg Endosc. November 1999.;13(11):1070–6. Mensi N, Roth M, idr. Early prediction of acute pancreati- tis: prospective study comparing computed tomography scans, Ranson, Glascow, Acute Physiology and Chronic Health Evaluation II scores, and various serum markers. World J Surg. May 2002.;26(5):612–9. 20. Scherer J, Singh VP, Pitchumoni CS, Yadav D. Issues in hypertriglyceridemic pancreatitis: an update. J Clin Gastroenterol. March 2014.;48(3):195–203. 21. De Bernardinis M, Violi V, Roncoroni L, Boselli AS, Giunta A, Peracchia A. Discriminant power and infor- mation content of Ranson’s prognostic signs in acute pan- creatitis: a meta-analytic study. Crit Care Med. October 1999.;27(10):2272–83. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 14 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology CHRONIC PANCREATITIS Luka Strniša* University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT Chronic pancreatitis is a disease of constant or recurrent pancreatic inflammation of various aetiologies which leads to fibrosis of pancreas and loss of pancreatic exocrine end endocrine function with malabsorption and diabetes. This process is accompanied with acute exacerbations of inflammation similar to acute pancreatitis. The most common symptom of chronic pancreatitis is chronic abdominal pain which however is variable and does not correlate with the level of inflammation and loss of function of pancreas. The disease has a severe influence on quality of life and mortality. The diagnosis may be difficult in the early stages of the disease. The treatment must be multidisciplinary and include in most cases therapy of alcohol and tobacco dependence. Key words: Chronic pancreatitis, autoimmune pancreatitis, hereditary pancreatitis, idiopathic pankreatitis, endoscopic therapy, pancreatic exocrine insufficiency WHAT IS CHRONIC PANCREATITIS the population without chronic pancreatitis, with 70% Chronic pancreatitis is a disease of constant or recur- survival after 10 years and 45% survival after 20 rent inflammation of the pancreatic parenchyma of years. The continued use of alcohol is associated with various ethiologies leading to a fibrotic transformation worse survival (2, 3). 40% of patients with chronic of the organ with loss of exocrine and endo- pancreatitis are not employed or are retired with disa- crine functions with resulting malabsorption and dia- bility as a result of the disease or alcoholism. betes. These events can be accompanied by acute ex- acerbations of inflammation that are very similar to ETIOLOGY acute pancreatitis. The most common symptom of Alcohol is a causative factor for the emergence chronic pancreatitis is chronic abdominal pain which of chronic pancreatitis in 50–84% of cases. It is esti- however is variable and does not correlate with the mated that consumption of at least 80g of alcohol per level of inflammation and loss of function of pancre- day for at least 6–12 years, regardless of the type of as. The disease has a severe influence on quality of alcohol. However less than 5% of these excess alcohol life and mortality. drinkers develop chronic pancreatitis (4), the reason probably being the presence of other environmental EPIDEMIOLOGY and genetic factors. Smoking is an independent risk Chronic pancreatitis of all ethiologies combined has factor and leads to a faster progression of the disease, an incidence of 5–10 / 100,000 and a prevalence of even when alcohol consumption is stopped. It is asso- 120 / 100,000 inhabitants. The incidence varies and is ciated with worsening of pain and calcification of the correlated with the average amount of alcohol con- pancreas. Long-term smoking is also associated with sumed (1). Mortality is increased 3–4x compared to an increased risk of developing chronic pancreatitis even without alcohol intake (5). * Luka Strniša, MD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 16 Primary hyperparathyroidism (pHPT) is associated Pancreatitis in childhood is associated with certain with acute and chronic pancreatitis – only 1% of s yndromic genetic disorders, most commonly cyst- patients with pancreatitis have a pHTP, but 12% of ic fibrosis. patients with pHTP have chronic pancreatitis, with or without body calcifications. Autoimmune pancreatitis (AIP) includes two subtypes of chronic fibrotic inflammation of the pancreas that Mutations N29I and R128H in the trypsinogen gene are responsive to steroid therapy. It represents up to (SPINK1) are present in two thirds of hereditary pan- 5% CP incidence. creatitis with 80% penetrance and AD inheritance. Hereditary pancreatitis represents less Subtype I AIP represents 4–6% of all chronic pancrea- than 0.3% of the prevalence of chronic pancreatitis (6) titis. It is a chronic inflammation of the pancreas, and typically becomes symptomatic before age 20. which in 60% is accompanied by the involvement of other organs. In addition to pancreatic disorder, the Idiopathic (sporadic) chronic pancreatitis accounts for systemic inflammatory process can usually involve up to 28% of all cases of chronic pancreatitis. With the bile ducts, salivary glands, kidneys, retroperitone- 45% of this type of CP, genetic risk factors um and lymph nodes. In the affected organs a lympho- that greatly increase the likelihood of developing plasmocytic infiltratate with numerous IgG4-positive chronic pancreatitis are found (PRSS1, CPA1, CFTR, inflammatory malformations (more than 10 cells per CTCR, CEL). Some genetic risk factors are also more apparent field) is present. Serum IgG4 levesa are often common in alcoholics who develop alcoholic pancrea- elevated. We can talk about the pancreatic manifesta- titis. tion of 'IgG4 related disease'. A typical histological picture of lymphoplasmocytic sclerosing pancreatitis Chronic pancreatitis is not correlated develops in the pancreas. with cholecystolithiasis or choledocholithia- sis. Patients with hypertriglyceridemia may rarely Subtype 2 AIP is less common. In this AIP subtype, develop chronic pancreatitis. IgG4 levels and concurrent disorders of other organs are not present. The diagnosis can only be confirmed Chronic obstruction of the pancreatic duct may cause patohystologically. AIP type II is more common in chronic pancreatitis proximal to the obstruction. The patients with chronic inflammatory bowel disease. obstruction may be due to benign or malignant tu- mours, possibly even after a severe attack of acute In autopsies, a fibrotic pancreatic restructuring can pancreatitis with ductal disruption, usually in associa- often be found in patients who did not have clinical tion with necrotic collections. In most cases of chronic images of chronic pancreatitis. Asymptomatic pancre- pancreatitis protein precipitates form in the ducts atic fibrosis is common in chronic alcoholics, at ad- which can be calcifed and cause obstruction. 'Pancreas vanced age, and in patients with advanced renal dis- divisum' is an anatomical variant, in which there is no ease and diabetes. Because of this, only histological association between the ventral (main - Wirsung) and criteria are not sufficient for the diagnosis the dorsal (accessory - Santorini) part of the pancreat- of chronic pancreatitis. ic duct. This variant is present in 5–10% of people and is likely a factor in the development of chronic PATHOGENESIS pancreatitis in the presence of other risk factors. The pathogenesis of CP is not fully understood and has several factors. The first factor is the reduction of Tropical pancreatitis is a common form of chronic the bicarbonate secretion due to genetic factors, alco- pancreatitis in the tropical and subtropical regions hol or mechanical obstruction. Another factor is the of Asia. There are no clear criteria for separation from intraparenchymal activation of digestive enzymes, al- other types of idiopathic pancreatitis. As with idio- so due to genetic factors in combination with the in- pathic pancreatitis, genetic risk factors have been fluence of environmental factors (smoking and alco- identified. hol). Protein precipitates with secondary calcifications that lead to ductal hypertension and acinar atrophy Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 17 precipitate in pancreatic ducts. Increased pressure in and then ceases without a clear cause. Both pain-free the gland can cause chronic ischemia. The formation intervals and painful intervals are unpredictable and of free radicals, the level of which is increased with uneven, so the management of a patient with chronic smoking and alcoholism, is increased. pancreatitis is individual. Most studies have described a slow decrease in pain levels during disease progres- CLASSIFICATION sion in at least half of patients. In some patients the Several different clinical / functional / morphological pain remits completely, usually in the advanced stage scores and classifications (Manchester, Rosemont, of the disease with of pancreatic insufficiency and in ABC, M-ANNEHEIM) are available and can be used the presence of calcination (8, 9). Some patients with to divide the disease into stages. They are rarely used. CP do not have chronic pain - 10% develop chronic The latest European guidelines conclude that prospec- pancreatitis with pancreatic insufficiency without any tive validations of these scoring systems and their in- pain symptoms. clusion in therapeutic schemes are required. Chronic pain is partially caused by increased pressure CLINICAL PICTURE in the pancreatic ductal system because of obstruction. Chronic pancreatitis can present clinically in the form Patients with signs of ductal obstruction on imaging of recurrent acute attacks of pancreatitis (acute exacer- have a greater likelihood of a response to endoscopic bations of CP) and/or permanent pancreatic type pain. or surgical drainage therapy. However, a large propor- With the gradual destruction of the gland, malabsorp- tion of patients with chronic pain have no signs of ob- tion of nutrients occurs due to the exocrine insuffi- struction of the ducts (8, 10–12). The second etiology ciency and diabetes due to endocrine insufficiency. of pain is neurogenic because of direct activation of Biliary or duodenal obstruction because of mass effect nociceptive pathways and central reinforcement. of occur. Thrombosis of splenic or portal vein can oc- Therefore, chronic pancreatic pain can persist even cur with resulting symptoms of portal hypertension. after total pancreatectomy. Acute exacerbations Idiopathic chronic pancreatitis occurs in two subtypes The first symptoms of chronic alcoholic pancreatitis - an early type, presenting in the 2nd and 3rd decade; are most frequently recurrences of acute alcoholic and late type – presenting in the 6–7 decade. The early pancreatitis. Already at this point, most patients have subtype has a typical presentation with chronic pain histological signs of chronic pancreatitis, but up to and a very slow development of calcination and pan- 40% of patients will not develop a clinical picture of creatic insufficiency which develop over more than 20 chronic pancreatitis with exocrine and endocrine in- years. Most patients will need surgery because of pain sufficiency. The attacks are the result of prolonged and local complications. and not short-term excessive alcohol consumption (7). In the late subtype of idiopathic pancreatitis, Other forms of chronic pancreatitis are also often ac- pain is less pronounced and frequent, while calcina- companied by acute exacerbations, which are clinical- tion and exocrine and endocrine pancreatic insuffi- ly identical to the acute attack of non-chronic (e.g. bil- ciency develop faster and is the presenting feature in iary) pancreatitis. However, some patients with chron- 20% of cases. ic pancreatitis have no acute exacerbations. Pancreatic exocrine Insufficiency (PEI) Chronic pain Is a reduction in the excretion of pancreatic enzymes In most patients with chronic pancreatitis the main and bicarbonate. For steatorrhea, the amount of secret- symptom is chronic abdominal pain, which may be ed digestive enzymes must be reduced by 90-95%, episodic or almost constant. It is mostly located in the therefore this symptom occurs only in the advanced epigastrium with radiation in the back, often accompa- stage of chronic pancreatitis, usually 10–20 years after nied by the nausea. Pain is often worse after meals and the first symptoms of CP. The consequence of PEI is at night, consequently, patients are afraid to eat. The malnutrition (which may be present long before stea- pain often changes with time. It typically occurs at torrhea) and other abdominal symptoms (diarrhoea, intervals that last for a few days, weeks or months, meteorism, pain). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 18 Diabetes pathic pancreatitis but does not meet the above crite- In the advanced stage chronic pancreatitis also results ria, he should be classified as having familiar idio- in endocrine pancreatic insufficiency, which is more pathic pancreatitis. common after operative therapy and in tropical type pancreatitis. After long follow-up (25 years), diabetes Hereditary pancreatitis begins with recurrent episodes develops 40–83% of patients (9, 13). Concurrent with of acute pancreatitis, usually in childhood or adoles- insulin deficiency, there is also a deficiency of gluca- cence, but may first appear in young adults. The gon secretion which is why patients are at an in- course of these acute episodes is in no way different creased risk of severe and prolonged hypoglycaemias from acute pancreatitis of other causes. The patients (DM subtype IIIc). develop recurrent epigastric pain. Patients usually have two to four exacerbations a year. The chronic Other complications: pancreatitis which develops is indistinguishable clini- Pseudocysts are pancreatic or peri-pancreatic fluid cally from early idiopathic chronic pancreatitis. collections with a high content of pancreatic enzymes without necrosis. They develop frequently in CP, Autoimmune pancreatitis commonly after acute exacerbations. They may rarely The most common clinical presentation of AIP is ob- communicate with the main pancreatic duct. Larger structive jaundice, with or without pain and elevated collections may cause gastric outlet obstruction and levels of pancreatic enzymes. A pancreatic inflamma- biliary obstruction with hyperbilirubinemia. They may tory cell infiltrate is present in the pancreas, which on also cause sepsis after becoming infected. Spontane- imaging takes form of a solitary pancreatic tumour or ous perforations are possible into the peritoneal cavity a diffusely enlarged pancreas. The pancreatic duct or the intestine. A fistula in the pleura can form with may have long stricture without significant proximal resulting chronic pleural effusion and dyspnoea. Acute dilatation. In the chronic phase of the disease, pancre- bleeding into the pseudocyst is also possible. atic exocrine and endocrine insufficiency occurs. Cal- With chronic inflammation and fibrosis of the pancre- cination is observed rarely and only after prolonged as, the volume of the pancreatic head may increase. illness. This inflammatory tumour can also cause obstruction of the duodenum or biliary system. In subtype I, signs of other organ involvement can al- so be detected (bile ducts, salivary glands, kidneys, Acute haemorrhage with bleeding from gastric varices retroperitoneal organs and lymph nodes). Thus, the may occur after portal hypertension develops with pancreatic disorder can be accompanied by urethral splenic or portal vein thrombosis. Very rarely, arterial and biliary strictures, lymphadenopathy, sclerosing haemorrhage from erosion of splenic artery with pseu- sialoadenitits, retroperitoneal fibrosis, and tubulointer- do-aneurysm formation can occur. stitial nephritis. The involvement of other organs may occur before, at the same time or after the onset of The incidence of pancreatic cancer is elevated up to pancreatic disease. Stenosis of bile ducts has the same 13x with 4% lifetime risk. Patients with hereditary image appearance as in primary sclerosing cholangitis pancreatitis have an even greater risk (69x relative (PSC) but are responsive to steroid therapy. risk), especially if they smoke. Four out of ten patients with chronic hereditary pancreatitis will develop pan- In subtype I, the incidence for men is twice that of creatic cancer. women. The patients are usually older than 50, usually between the ages of 60 and 70, but the presentation is Hereditary pancreatitis (HP) also possible earlier. Subtype 2, which is less com- A strict definition is used by the European Register of mon, is equally common in both sexes and the inci- Hereditary Pancreatitis and Family Pancreatic Cancer dence is at 50 years old. Both subtypes clinically fre- (EUROPAC); the HP patient should have at least two quently mimic the symptoms of pancreatic cancer. first degree or three second degree relatives of two or more generations with chronic pancreatitis of unex- plained cause. When a patient has relatives with idio- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 19 DIAGNOSIS Possible chronic pancreatitis Chronic pancreatitis is a slow-moving dis- clinical picture without other criteria of mor- ease. Diagnostic tests can detect changes in exocrine phological or functional changes. pancreatic function and changes in the structure of the gland, which are rarely present in the initial phase of Pancreatic function tests the disease when fibrosis and inflammation are al- Direct pancreatic function tests measure the secretion ready clearly visible on histological samples (which in of pancreatic enzymes into the duodenum after stimu- practice are almost never availa- lation with CCK / secretin. They are the most sensi- ble). Serum laboratory tests are normal except in acute tive tests and are closest to a gold standard for diagno- exacerbations. Most patients have symptoms long be- sis. Unfortunately, there are invasive, time- fore the diagnosis which requires a combination of consuming and are not used in clinical prac- clinical images with image tests and functional tests. tice. Indirect tests measure pancreatic enzymes in fae- ces. The measurement of the amount of fat in a 3-day To establish the diagnosis, M-ANNHEIM diagnostic faces collection along a standard diet is sensitive but is criteria can be used to determine the likelihood of the in practice difficult to implement. The qualitative presence of chronic pancreatitis. In addition to a typi- analysis of a single sample of faeces for fat content cal clinical picture of chronic pancreatitis (recurrent strongly depends on the amount of fat consumed and acute pancreatitis or chronic abdominal pain), at least is only positive in patients with already developed ste- one criterion should be present: atorrhea. Proven chronic pancreatitis (one or more criteria) Measurement of elastase in a sample of faeces is com- calcination in the pancreas; monly used and reliably detects advanced pancreatic moderate or significant changes in pancreatic exocrine insufficiency but is poorly sensitive for mild ducts on imaging (according to the Cambridge forms. Low levels can also be seen with diarrhoea classification); and bacterial overgrowth of the small intestine. The severe pancreatic exocrine insufficiency cor- precision of the test is better than the measurement of rected with enzyme replacement therapy chymotrypsin in faeces. The C13 breath test with a typical histological picture. mixed triglycerides has good sensitivity and specifici- ty but is very time consuming to per- Probable chronic pancreatitis (one or more crite- form. Guidelines (14, 15) recommend performing a ria) faecal elastase test at a clinical suspicion of CP and mild changes in pancreatic ducts (according to when CP is diagnosed since the clinical signs of PEI the Cambridge classification); are unreliable (see Table 1). recurrent or persistent pseudocysts pathological test for pancreatic exocrine insuffi- Imaging ciency (e.g. faecal elastase); The first imaging study on suspected CP is usually endocrine insufficiency (e.g. pathological glu- an abdominal ultrasound, which has relatively poor cose tolerance test). sensitivity and can only demonstrate CP in the ad- vanced stage. EUS, MRI/MRCP, CT and Table 1 Mild PEI Moderate PEI Severe PEI senzitivnost senzitivnost senzitivnost Feacal elastase 54% 75% 95% 85% Faecal chimotrypsine <50% 60% 80/90% 70% Faecal fat content 0% 0% 78% 70% C13 breath test 62-100% 90-100% 80-90% Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 20 ERCP have much better diagnostic reliability. The infertility, sweat electrophoresis is sufficient, other- best diagnostic tests are EUS and ERCP. ERCP is no wise testing for frequent CFTR mutations is recom- longer used for diagnostic purposes due to the signifi- mended (14). cant potential for complications of the investiga- tion. EUS is the most reliable investigation in the ini- In patients with chronic pancreatitis unknown etiology tial stage of the disease, especially with the use of the despite this evaluation, autoimmune pancreatitis EUS classifications for chronic pancreatitis. EUS is which represents up to 5% of cases should be exclud- also the useful for screening patients with significantly ed by additional investigations or a therapeutic trial increased risk of cancer as with hereditary pancreati- (14). For the diagnosis of AIP we use international tis. In the presence of chronic pancreatitis, the charac- diagnostic guidelines based on a combination of imag- terization of lesions in the tissue is very difficult - ing, serum IgG4, core needle pancreatic biopsy or ma- EUS with FNA has the highest (but still relatively jor ampulla biopsy and response to corticosteroid ther- poor) sensitivity for pancreatic cancer (50– apy. 75%) in chronic pancreatitis, which is slightly better than MRI / MRCP. Using contrast and elastography, THERAPY the EUZ has the potential to improve diagnostic accu- Acute exacerbations racy. Therapy of acute exacerbations of chronic pancreatitis does not differ from the treatment of acute pancreati- Sensitivity for Specificity for tis. CP CP CT / / Chronic pain ERCP 70-80% 80-100% Chronic pain is the dominant symptom of chronic MRCP 88% 98% pancreatitis. They are present in most patients and sig- Abdominal US 60-81% 70-97% nificantly reduce the quality of life. The line of pain Endoscopic US 80-100% 80-100% (EUS) therapy of pain are analgesic medications. A standard escalation of therapy is recommended; paracetamol Based on the above, European guidelines recommend should be used as a first-grade analgesic, NSAIDs are abdominal ultrasound as the initial investigation. In effective but they have frequent gastrointestinal side case of a non-conclusive investigation and the persis- effects. Tramadol is a second-degree analgesic. Third tence of the clinical suspicion of CP a EUS should be grade analgesics include strong opioids, for which oral performed. CT and MRI are complementary investiga- use is recommended. If opioids are not effective, they tions. When evaluating imaging findings classification should be stopped. Up to 5% of opioid users develop schemes should be used (e.g. Cambridge criteria) 'narcotic bowel syndrome' in which pain deteriorates with opioid dose. Pregabalin therapy is also recom- Evaluation of etiology mended because of the neurogenic component of At diagnosis chronic pancreatitis, it is necessary to chronic pain. Antidepressants from the SSRI or TCA search for the etiology. Patients should be evaluated group can also be introduced. for alcohol consumption (with a standardized ques- tionnaire and CDT measurement) and smoking. Hy- Pancreatic exocrine insufficiency therapy with pancre- perlipidaemia and primary hyperparathyroidism atic enzymes (PERT) does not reduce pain. should be exclude and family history should be re- viewed. Patents with a positive family history for Ending alcohol consumption slows down the pro- chronic pancreatitis can be offered genetic testing for gression of the disease and reduces pain. Smoking is hereditary pancreatitis. associated with the rapid progression of disease, how- ever there is no definitive evidence to link it to wors- European guidelines also recommend that in all pa- ening pain. Most (90–95%) attempts to quit smoking tients with idiopathic CP, regardless of the time of are unsuccessful, and the guidelines therefore recom- presentation, a variant of cystic fibrosis should be ex- mend support for smoking cessation with education, cluded. If there are no pulmonary symptoms or male cognitive psychotherapy and drug therapy. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 21 Endoscopic and surgical therapy can be successful with a single stent. After an endoscopic procedure an in the treatment of chronic pain but do not slow the evaluation of the efficacy of therapy is required in 6–8 progression of pancreatic insufficiency. Pancreatic weeks. If unsuccessful, the patient must be evaluated surgery with resection can even accelerate the onset of by a multidisciplinary team (endoscopist, surgeon, diabetes and pancreatic exocrine insufficiency. In ran- radiologist) to examine the surgical options of thera- domized comparative studies, surgical pain therapy py. for patients with dilated pancreatic duct is on average, more effective than endoscopic therapy, with no de- In patients with an inflammatory tumour of the head tectable differences in mortality and morbidity. De- of the pancreas (head diameter > 4cm) and pain, the spite this, most of the guidelines recommend endo- resection of the pancreatic head with drainage of the scopic therapy as first line due to reduced invasive- main pancreatic duct is indicated with or without the ness (14). preservation of the duodenum. The purpose of the op- eration is to reduce pain and pressure on surrounding Endoscopic or surgical therapy should be considered structures. when the chronic pain is not controlled by analgesics of the first and second degrees. Interventions are more In patients with chronic uncontrolled pain without in- effective at an early stage of the disease. creased pancreatic head and with a dilated pancreatic duct, a drainage operation is indicated. Endoscopic therapy is effective only in obstructive pancreatic pain with dilated pancreatic water (> In patients with chronic uncontrolled without in- 5mm), with duct strictures and / or pancreatic intra- creased pancreatic head and without a dilated pancre- ductal stones. In endoscopic therapy, the goal is de- atic duct or in patients with poor response to prior en- compression of obstructed duct. Most guidelines rec- doscopic or operative therapy, a total pancreatectomy ommend endoscopic therapy as first-line therapy after is possible, possibly with the autotransplantation of B- unsuccessful drug therapy or necessity of opioid use. Langerhans islets. Endoscopic therapy is not indicated in asymptomatic disease, except in the case of biliary obstruction or Biliary obstruction pseudocysts with a high likelihood of complications. Endoscopic therapy for biliary obstruction with multi- ple parallel plastic stents or fully covered self- Endoscopic extraction of stones with a basket with expanding metal stents is successful in 90%. The pa- ERCP is unsuccessful in 80% for stones greater than tient must be relied upon to adhere to regular changes 5mm, therefore extracorporeal should wave lithotripsy of the stents with ERPC, otherwise septic complica- (ESWL) is recommended with subsequent removal of tions may occur. In non-compliant patients and in pa- fragments in the ERCP. The procedure is effective for tients with an inflammatory tumour of the pancreatic complete or partial improvement of pain in 70–96% of head, surgery is recommended. patients. ESWL with no subsequent ERCP is also ef- fective. Pseudocyst Pseudocysts are present in the course of chronic pan- With strictures of the main pancreatic duct (stricture creatitis in 20–40% of patients. Up to 40% of pseudo- with proximal dilation > 6mm and poor outflow of cysts that develop after an acute flare spontaneously contrast in ERCP), endoscopic dilatations and short- resolve. A spontaneous resolution is rare after 12 term stenting are not effective in the long run. Long- weeks. Complications that require intervention devel- term stenting (at least 1 year with at least one regular op in 2/3 cases. Pseudocysts larger than 5cm are asso- replacement) results in an eduring improvement in ciated with complications - pain, obstruction, infection pain even after the removal of the stent in 2/3 patients. or bleeding. Interventions may be endoscopic, surgical Very good results are also seen for insertion of multi- or radiological with similar efficacy but greater mor- ple parallel plastic stents for 7 months, with long-term bidity for surgical and radiological intervention thera- improvement of pain in 84% of patients - this therapy py. The guidelines recommend the endoscopic drain- is recommended after unsuccessful long-term stenting age of symptomatic pseudocysts as the first method of Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 22 choice. Endoscopic therapy of asymptomatic chronic Therapy of autoimmune pancreatitis (AIH) cysts > 5 cm can be performed because of the great Clinical response to systemic corticosteroids is one of potential of complications. Percutaneous drainage of the main features of AIP, so treatment efficacy is very chronic pseudocysts is not recommended because of high (99% for subtype I and 92% for subtype 2). the possibility of pancreatic-fistula formation. Treatment should be started with methylprednisolone at a dose of 30–40 mg daily, 0.6 mg per kg body Malnutrition weight. After the 4th week of treatment, we begin a Malnutrition is common in chronic pancreatitis due to stepwise reduction in the dose of corticosteroid up to pancreatic exocrine and endocrine insufficiency, complete cessation. chronic pain and nausea in combination with frequent excessive alcohol consumption and smoking. Treatment lasts up to 12 weeks. Rituximab may be used in when steroids are contraindicated. After two to Regular monitoring of nutritional status is recom- three weeks of treatment, there is a clinical improve- mended (eg NRS -2002) and, if necessary, the deter- ment and regression of morphological changes in the mination of levels in the fat-soluble vitamins (A, D, E, pancreas. The endocrine and exocrine function of the K), Zn, Mg, and glycated haemoglobin. Patients with pancreas also improve. Normalization of serum IgG4 malnutrition should begin oral replacement of pancre- occurs only after several months. The effect of treat- atic enzymes (PERT) and dietetic counselling. Low- ment is monitored by imaging, usually CT. In the case fat diets are not recommended, except in the case of of suspicion of pancreatic cancer, an imaging evalua- unmanaged steatorrhea. Most patients threated die- tion is required 2 weeks after initiation of therapy. tary counselling and PERT do not need additional oral One third of patients with AIH will have a recurrence nutritional supplements. of illness in 1-3 years, especially in type I. Patients with AIH type I with high activity of the disease can Patients with chronic pancreatitis have a high risk of be offered maintenance treatment – low-dose of corti- osteoporosis and pathological fractures, therefore reg- costeroid, azathioprine or rituximab are used. ular measurement of bone density and vitamin D lev- els is recommended (14). PROGNOSIS Yearly mortality is increased 3–4x compared to the Diabetes population without chronic pancreatitis, with 70% sur- Annual monitoring of Hb1Ac and fasting glucose is vival after 10 years and 45% survival after 20 years. recommended. DM type 3c is hard to manage and is Continuing alcohol consumption is associated with associated with frequent hypoglycaemias. In case of poorer survival. In 20% of patients, death is due to a mild hyperglycaemia and abstinence from alcohol, complication of acute exacerbation. In others death is metforminim therapy may be initiated, other oral anti- due to malnutrition or other smoking related illnesses. diabetes drugs are not recommended. In most cases, insulin therapy is required. REFERENCES 1. Etemad, B. & Whitcomb, D. C. Chronic pancreati- Cancer tis: diagnosis, classification, and new genetic develop- ments. Gastroenterology 120, 682–707 (2001). The diagnosis of early pancreatic cancer in the setting 2. Forsmark, C. E. Management of chronic pancreati- of chronic pancreatitis is very difficult, that is why tis. Gastroenterology 144, 1282–1291.e3 (2013). there are no recommendations for screen- 3. Uys, C. J., Bank, S. & Marks, I. N. The pathology ing. Screening with serum Ca 19-9 levels is not rec- of chronic pancreatitis in Cape Town. Digestion 9, 454– 468 (1973). ommended. In hereditary pancreatitis the risk is great- 4. Yadav, D. & Lowenfels, A. B. The epidemiology est so monitoring of Ca 19-9 and annual EUZ can be of pancreatitis and pancreatic cancer. Gastroenterology performed. A preventative total pancreatectomy is an 144, 1252–1261 (2013). option. 5. Yadav, D. et al. Alcohol Consumption, Cigarette Smoking, and the Risk of Recurrent Acute and Chronic Pancreatitis. Arch. Intern. Med. 169, 1035–1045 (2009). 6. Whitcomb, D. C. Genetic Risk Factors for Pancrea- tic Disorders. Gastroenterology 144, 1292–1302 (2013). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 23 7. Phillip, V. et al. Incidence of acute pancreatitis evidence-based guidelines for the diagnosis and therapy of does not increase during Oktoberfest, but is higher than chronic pancreatitis (HaPanEU). - PubMed - NCBI. Avai- previously described in Germany. Clin. Gastroenterol. lable at: https://cmk-proxy.mf.uni-lj.si:3077/pubmed/? Hepatol. Off. Clin. Pract. J. 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Schueler, G. Course and outcome of chronic pancreatitis. 17. Coté, G. A. et al. Alcohol and smoking as risk Longitudinal study of a mixed medical-surgical series of factors in an epidemiology study of patients with chronic 245 patients. Gastroenterology 86, 820–828 (1984). pancreatitis. Clin. Gastroenterol. Hepatol. Off. Clin. Pract. 11.Morgan, D. E., Smith, J. K., Hawkins, K. & J. Am. Gastroenterol. Assoc. 9, 266–273; quiz e27 (2011). Wilcox, C. M. Endoscopic stent therapy in advanced chro- nic pancreatitis: relationships between ductal changes, cli- nical response, and stent patency. Am. J. Gastroenterol. 98, 821–826 (2003). 12. Renou, C., Grandval, P., Ville, E. & Laugier, R. Endoscopic treatment of the main pancreatic duct: correla- tions among morphology, manometry, and clinical follow- up. Int. J. Pancreatol. Off. J. Int. Assoc. Pancreatol. 27, 143–149 (2000). 13. Cui, Y. & Andersen, D. K. Pancreatogenic diabe- tes: special considerations for management. Pancreatol. Off. J. Int. Assoc. Pancreatol. IAP Al 11, 279–294 (2011). 14. al, L. J., et. United European Gastroenterology Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 24 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology HEREDITARY AND AUTOIMMUNE PANCREATITIS Lojze Šmid*, Jan Drnovšek** University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, leading to emotional, physical, and financial human burden. The incidence is estimated 50 cases per 100.000 worldwide. Patients with AP typically present with epigastric or left upper quadrant pain, combined with elevated pancreatic la- boratory tests. The etiology of AP can be readily established in most patients. The most common cause of AP are gallstones (40–70 %) and alcohol abuse (25–35%). Other, but rare causes of AP are metabolic causes (hypercalcemia, hyperlipidemia), infectious agents, medications, and morphological features of pancreas and pancreatic injury due to iatrogenic causes. Hereditary pancreatitis (HP) and autoimmune pancreatitis (AIP) are rare causes of acute pancreatitis. HP is an autosomal dominant genetic condition, where mutations increase autocatalytic conversion of trypsinogen to active trypsin, while it is still in the pancreas, which leads to in- flammation. Autoimmune pancreatitis (AIP) is the pancreatic manifestation of a systemic fibroinflammatory disorder due to lymphocyte infiltration and fibrosis. Key words: chronic pancreatitis, hereditary pancreatitis, autoimmune pancreatitis, pancreatic cancer HEREDITARY PANCREATITIS Pathogenesis Introduction Precursors to pancreatic digestive enzymes are stored Hereditary pancreatitis (HP) is a rare cause of chronic in zymogen granules in pancreatic acinar cells. The pancreatitis and occurs with an autosomal dominant activation of zymogenes (e.g. cationic and anionic pattern of inheritance with high (80%) penetrance (1). trypsinogen) is tightly controlled and normally occurs It has to be differentiated form familial pancreatitis, in the duodenal lumen by proteolytic action of entero- which refers to chronic pancreatitis that occurs in pa- kinase. Premature activation of digestive enzymes in tients with at least one relative, regardless of the etiol- the pancreas is the major cause of pancreatic injury ogy (2). European Registry of Hereditary Pancreatitis and immune system activation, leading to acute pan- and Familial Pancreatic Cancer (EUROPAC) defines creatitis and later chronic pancreatitis. The primary pancreatitis as hereditary if it has no precipitating fac- defense against pancreatitis is to control trypsin activi- tors and occurs in two or more first-degree relatives or ty, either through prevention of premature activation three or more second-degree relatives in two or more of trypsinogen to trypsin, or by the destruction, inhibi- generations (3). All patients with chronic pancreatitis tion, or elimination of trypsin from the pancreas. The- have increased risk for developing pancreatic cancer. se defenses are weakened by mutations in the serine HP carries the highest risk of all etiologies, as pancre- protease 1 gene, which encodes cationic trypsinogen atic carcinoma occurs in four out of ten HP patients (PRSS1), or in genes coding for molecules that protect (4). the pancreas from active trypsin (SPINK1, CFTR) (5). * Lojze Šmid, MD, PhD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. ** Jan Drnovšek, MD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 26 Cationic trypsinogen - PRSS1. Clinical presentation Mutations in the serine protease 1 gene (PRSS1), The onset of HP is characterized by recurrent episodes which encodes cationic trypsinogen, are the most fre- of acute pancreatitis in childhood or early adulthood quent cause of HP. The most common mutation in (21). Acute episodes are indistinguishable from acute PRSS1 is the p.R122H at the autolysis site (6), which pancreatitis of other causes. The most common clini- renders trypsin resistant to autoproteolysis, thus inter- cal presentation is sudden recurrent upper abdominal fering with important mechanism that protects from pain (22) with two to four recurrences per year. Com- premature trypsin activation (7). The second most plications are rare and include formation of necrosis, common mutation N21I causes misfolding of trypsin thrombosis of splenic vein (23), pseudocyst formation and lowers its binding affinity for protease inhibitor (24) or death (25). Chronic pancreatitis develops after SPINK1 (8). Other mutations, associated with HP are several acute episodes and is indistinguishable from much less frequent (A16V, D22G in K23R) (9). idiopathic juvenile chronic pancreatitis in children or chronic alcoholic pancreatitis in adults (26, 27). EU- Serine protease in hibitor Kazal type 1 - SPINK1. ROPAC study estimated cumulative risk for the devel- Chronic pancreatitis is also associated with N34S mu- opment of exocrine pancreatic insufficiency in pa- tation in SPINK1 (10). SPINK1 mutations can cause tients with HP to 8.4% at the age of 20 years and familial pancreatitis with an autosomal recessive pat- 60.2% at 70 years. Endocrine insufficiency with dia- tern in families (11). However, the majority of pa- betes develops in 4.4% of patients at 20 years and tients with SPINK1 mutations and chronic pancreatitis 47.6% at the age of 50 years (3). HP appears to be as- are heterozygous. N34S mutation has been described sociated with 1–2% of all cases of acute pancreatitis in 43 % of patients with early-onset chronic pancreati- (28–30). tis (12). This mutation is also frequently found in pat- inets with chronic alcoholic (13) and tropical (14) Genetic testing pancreatitis and probably acts as a disease modifier, Genetic testing has become widely available in every- lowering the threshold for developing pancreatitis day clinical practice. Current IAP guidelines recom- from other genetic or environmental factors. mend the use of genetic testing only in symptomatic patients with idiopathic or recurrent pancreatitis and at Cystic fibrosis transmembrane conductance regu- least one close relative with similar condition, who are lator gene – CFTR. adequately informed and consent to testing (26). Chil- Mutations in the CFTR can cause pancreatitis with or dren can be tested during their first episode of etiolog- without associated manifestations of cystic fibrosis ically unexplained acute pancreatitis. Genetic testing (15, 16) and are also found in up to one third of pa- is also recommended in children with recurrent ab- tients with chronic pancreatitis of other etiologies (10, dominal pain and positive family history. Positive re- 11). sults of genetic testing should be explained to patients with clear emphasis of variability and unpredictability Environmental influences. of HP clinical course. Clear strategies for preventive The occurrence of HP is higher in two separate age measures and early detection and treatment of pancre- groups with the first peak around age 8 and the second atic cancer have to be communicated to HP patients. between ages 18 and 24. The onset of HP in early adulthood coincides with the onset of alcohol con- Pancreatic cancer in HP patients sumption (17, 18). Cigarette smoking also appears to Patients with chronic pancreatitis from any cause are be more prevalent in HP patients compared to healthy 3,8 to 16,5 times more likely to develop pancreatic controls (18). The roles of ethanol consumption and cancer than healthy individuals. The risk of pancreatic cigarette smoking in the development of HP have not cancer is significantly higher in patients with heredi- been statistically verified, but are in accordance with tary pancreatitis with a lifetime risk of 40% (4). known effect of smoking on the course of idiopathic or alcoholic chronic pancreatitis (19, 20). IAP therefore recommends risk reduction and early detection strategies (27). The frequency of acute epi- sodes is linked to risk of chronic pancreatitis and pa- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 27 tients with HP therefore have to be counseled regard- epidemiology, serology, disease course and response ing the risk of smoking and alcohol use. All patients to treatment. However, clear distinction between the with hereditary pancreatitis should undergo regular two types can sometimes be difficult due to overlap- imaging (endoscopic ultrasound - EUS and magnetic ping diagnostic criteria (51). resonance cholagiopancreatography - MRCP) after reaching the age of 40 (28). The roles of prophylactic Clinical presentation pancreatectomy or pancreatectomy with islet auto- Billiary obstruction, accompanied by pancreatic mass, transplantation as cancer preventing strategy have not is the most common clinical manifestation of AIP and yet been prospectively evaluated. can be confused with pancreatic malignancy. It is fre- quently accompanied by (often mild) abdomnial pain AUTOIMMUNE PANCREATITIS and elevation of pancreatic enzymes. AIP is a rare Introduction cause of recurrent acute and chrnic pancreatitis, which Autoimmune pancreatitis (AIP) is an infrequently rec- can lead to exocrine and endocrine pancreatic insuffi- ognized disorder of autoimmune etiology that is asso- ciency. A number of other organs can be involved in ciated with characteristic clinical, histologic, and mor- patients with AIP. These include the salivary glands phologic findings (31–34). (Sjögren's syndrome), bile duct strictures, lung nod- ules, autoimmune thyroiditis, and kidney (interstitial AIP frequently occurs in association with other disor- nephritis with an IgG4-positive plasma cell infiltrate ders of presumed autoimmune etiology, histologically and IgG4 deposits in the tubular basement membrane) characterized by lymphoplasmocytic infiltration and (52–54). fibrosis, including IgG4 cholangitis, salivary gland disorders, mediastinal fibrosis and retroperitoneal fi- Imaging brosis and tubulointerstitial disease (35–37). AIP ac- Transabdominal ultrasound examination is routinely counts for 4–6% of all cases of acute pancreatitis ac- performed in patients with cholestasis and abdominal cording to Japanese, Korean and Italian data. Estimat- pain. Hypoechoic pancreatic parenchyma and dilata- ed incidence rate of AIP in Japan is 0.82 cases per tion of main pancreatic duct can sometimes be visual- 100.000 persons per year (38–41). AIP is twice more ized. Computed tomography (CT) and MR have high- common in females than males and usually occurs in er sensitivity. Main findings that are diagnostic or the sixth and seventh decade (42–44). highly suggestive of AIP are a diffusely enlarged pan- creas with featureless borders and delayed enhance- Types of autoimmune pancreatitis ment with or without a capsule-like rim. EUS guided AIP is classified into two types (1 and 2). In type 1 biopsies are used for differentiation of AIP from pan- AIP (lymphoplasmacytic sclerosing pancreatitis), the creatic cancer (55–57). pancreas is involved as one part of a systemic IgG4- positive disease. Characteristic histologic findings in Serology inflamed gland tissue are IgG4-positive cells with Serologic testing for IgG4 is an important component periductal lymphoplasmacytic infiltrate, obliterative of evaluating a patient suspected of having autoim- phlebitis and acinar fibrosis. Type 2 AIP (idiopathic mune pancreatitis. A serum concentration of IgG4 that duct centric pancreatitis) is characterized by histologi- is twice the upper limit of normal (serum IgG4 ≤ 280 cally confirmed idiopathic duct centric pancreatitis mg/dL) is highly suggestive of AIP. However, it often with granulocytic lesions, but without IgG4- should be noted that up to 10% of pancreatic cancer positive cells and without systemic involvement (45– patients exhibit higher IgG4 concentrations and serol- 49). ogy can thus not be used as a test for exclusion of pan- creatic cancer (59). Type 1 AIP is more frequent and diagnostic algo- rithms are focused towards recognition of type 1 AIP. Diagnostic criteria The diagnosis of type 2 AIP can be established histo- Diagnostic criteria have been proposed by several logically. Fine needle aspiration biopsy is insufficient groups including the Japanese Pancreas Society, an for AIP diagnosis (50). The two types of AIP differ in expert group from Korea, and the Mayo Clinic in the Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 28 United States (55, 60). The diagnostic criteria pro- strongly associated with chronic pancreatitis. Gastroenter- posed by the Mayo Clinic (the "HISORt" criteria) are ology 1999; 117: 7–10. 10. Witt H, Luck W, Hennies HC, Classen M, Kage most commonly used and include the presence of di- A, LassU, et al. Mutations in the gene encoding the serine agnostic histology (H), characteristic imaging on com- protease inhibitor, Kazal type 1 are associated with puted tomography and/or pancreatography (I), elevat- chronicpancreatitis. Nat Genet 2000; 25: 213–6. ed serum IgG4 levels on serologic testing (S), other 11. Kuwata K, Hirota M, Nishimori I, Otsuki M, Og- awa M. Mutational analysis of the pancreatic secretory organ involvement (O) and response of pancreatic and trypsin inhibitor gene in familial and juvenile pancreatitis extrapancreatic manifestations to glucocorticoid thera- in Japan. J Gastroenterol 2003; 38: 365–70. py (Rt). 12. Truninger K, Witt H, Kock J, Kage A, Seifert B, Ammann RW, et al. 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IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod. Pathol. 2007; 20: 23-28. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 30 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology NEW ALGORITHMS IN DIAGNOSING BILIOPANCREATIC PATHOLOGY WITH ENDOSCOPIC ULTRASOUND Rusmir Mesihovic* Medical faculty University Sarajevo, Bosnia and Herzegovina and Medical Center Barsos Ljubljana, Slovenia *** ABSTRACT Endoscopic ultrasound (EUS) continues to present a rich source of innovation, allowing it to evolve from a diagnostic procedure to a therapeutic modality. EUS is one of the most important modalities for the diagnosis of biliopancreatic pathology. This review is the principle, indications, main literature results, limitations and future expectations for each of the methods presented. Endoscopic ultrasound is a very accurate imaging tech- nique with a relevant clinical impact in the diagnosis and staging of various conditions such as pancreatic- biliary lesions. New technologies in EUS evaluation have been developed because of the need to improve the EUS and EUS-fine needle aspiration (EUS-FNA) diagnostic rate. Several techniques of image enhancement have been developed in recent years in the attempt to make the technique less operator-dependent. Among them the most important appear to be contrast harmonic-endoscopic ultrasound and endoscopic ultrasound- elastography. Both techniques show promising applications in the study of pancreatic tumors including differ- ential diagnosis and providing guidance to fine needle aspiration. It is also useful for the discrimination of pancreatic masses based on their qualitative patterns. Needle confocal laser endomicroscopy offers useful in- formation about cystic lesions of the pancreas and is still under evaluation for use with solid pancreatic le- sions of lymph nodes. Key words: Endoscopic ultrasound, fine-needle aspiration, contrast-enhanced, elastography, endomicroscopy, endosonography-fine needle aspiration * Professor Rusmir Mesihovic, MD, PhD. Medical Faculty University Sarajevo, Bosnia and Herzegovina and Medical Center Barsos Ljubljana, Slovenia. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 32 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology RISK FACTORS FOR DEVELOPMENT OF PANCREATIC DUCTAL ADENOCARCINOMA Sanjo Finderle*, Borut Štabuc** University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT Pancreatic ductal adenocarcinoma is highly fatal and has a poor prognosis. The reasons for low survival are low rates of curative resection due to local infiltration and distant metastases. Risk factors can be non- modifiable (age, familial cancer syndromes, race, hereditary and other forms of chronic pancreatitis, blood group, diabetes mellitus) and modifiable (obesity, smoking, diet, alcohol intake). Key words: pancreatic cancer, risk factors, smoking, chronic pancreatitis, familial cancer syndromes INTRODUCTION survival of patients with resectable cancer is from 13 The pancreas gives rise to several malignant and be- to 24 months, depending on the stage, but fewer than nign neoplasms. The commonly used term "pancreatic 10% of tumors are detected early enough (6, 8, 9). cancer" usually refers to a ductal adenocarcinoma of the pancreas (including its subtypes), which represents Studies have identified certain risk factors which may about 85% of all pancreatic neoplasms. Ductal adeno- predict increased odds of developing pancreatic can- carcinoma may vary from well differentiated to poorly cer. differentiated, the most common being moderately differentiated cancer (1). RISK FACTORS FOR PANCREATIC CANCER Risk factors can be divided as either non-modifiable The incidence of pancreatic cancer has been rising in (host) and modifiable risk factors (enviromental). the last two decades (2). It is the eighth most common cancer in Europe (3). Thus, in men and women, it is Host factors ranked fourth in terms of mortality among all cancers Age (4). According to the Cancer Registry of Republic of Pancreatic cancer is rare in the first three decades of Slovenia there were 350 new cases of pancreatic can- life. After the age of 30, the incidence begins to in- cer in Slovenia (183 men and 167 women) in 2013. crease exponentially, reaching its peak in the 7th and 356 patients (175 men and 181 women) died. Five- 8th decade (10). Patients who are diagnosed with an year survival rate is only 5% (5). early disease stage, are on average 2.3 years younger than those with advanced disease. This suggests that Most cancers are diagnosed in an advanced stage the time of progression from early to advanced stage when the disease is already unresectable, so the medi- in about 1–2 years (11). an survival is from 3 to 11 months (6, 7). The median * Sanjo Finderle, MD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. ** Professor Borut Štabuc, MD, PhD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 34 Sex than 80% of pancreatic cancer develops due to sporad- Pancreatic cancer occurs more frequently in males ic mutations. A small proportion develops due to in- than in females (1.3:1 ratio). Several studies on hor- herited germline mutations. mone-related risk factors have been (12, 13). A recent meta-analysis concluded that reproductive hormones 1) Inherited Genetic mutations (Germline Muta- are not associated with a greater risk of developing tions) pancreatic cancer in women. This suggests that the Mutations in germline are associated with a higher difference between males and females could be at- risk of developing pancreatic cancer in certain genetic tributed to environmental factors. Nevertheless, we syndromes and in certain familial pancreatic cancer certainly do not yet know all of the genetic factors af- kindreds (see Table 1). fecting incidence and mortality in men and women (12). Familial Pancreatic Cancer: Familial Pancreatic Cancer is defined as the oc- Race currence of pancreatic cancer in at least two first Race is a known risk factor for the development of -degree relatives with pancreatic cancer. The pancreatic cancer. In the United States, the incidence risk of pancreatic cancer increases exponential- of pancreatic cancer is higher in African-Americans ly. When two first-degree relatives have pancre- than in Caucasians (14.8/100.000 in African Ameri- atic cancer, the risk is increased 18 fold. When cans compared to 8.8/100.000 in the general popula- three first-degree relatives have pancreatic can- tion) (9). In the past, higher incidence was attributed cer, the risk is 57-times higher (18). BRCA2 to dieting, alcohol consumption, smoking and vitamin mutation is the most common inherited muta- D deficiency. Recent epidemiological studies suggest tion, other mutations, such as PALB2, have also that other factors are likely to contribute to increased been reported. risk in African Americans (14). These factors include Family cancer syndromes: race specific genetic differences that contribute to a An increased risk of developing pancreatic can- higher risk of mutations due to exposure to known cer is found in many inherited cancer syn- toxins (e.g. the ability to detoxify products from to- dromes. These include Familial Dysplastic Neu- bacco use) (15, 16). romuscular Syndrome, hereditary pancreatitis, Peutz-Jeghers syndrome, cystic fibrosis, heredi- Blood type tary breast and ovarian cancer, Fanconi anemia, Large epidemiological studies have shown that there familial adenomatous polyposis, Li-Fraumeni is a link between ABO blood groups and the risk of syndrome and Lynch syndrome. These syn- developing pancreatic cancer. People with blood type dromes are associated with germline mutations A, AB, and B have a greater risk of developing this in certain genes such as BRCA2, p16, ATM, type of cancer than those with O blood type (the ORs STK11, PRSS1, SPINK1 and PALB2 (see Table for groups A, AB, and B are 1.38 (95% CI: 1.18- 1). 1.62), 1.47 (95% CI: 1.07-2.02) and 1.53 (95% CI: 1.21-1.92)). These findings are also supported by the 2) Acquired genetic mutations (Somatic Muta- results of a genomic study that identified variants in tions) the ABO locus (9q34), which is associated with a Genetic risk in Non-Familial Pancreatic cancer: higher risk of developing pancreatic cancer (17). The The mutations in somatic cells may also lead to pathogenetic mechanism behind this link is not yet the development of pancreatic cancer. The de- known. velopment is associated with mutations in four main genes: K-ras (95% tumors), CDKN2A Genetic factors (p16) (90%), p53 (75%) and SMAD4 (55%) (19 Pancreatic cancer is essentially a genetic disease –21). The development and growth of cancer caused by inherited and acquired mutations. Genetic takes place through several steps including initi- variations/mutations play an important role in both ation, progression, invasion and ultimately the familial and non-familial (sporadic) cancers. More spread of the disease. Pancreatic cancer origi- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 35 nates in the ductal epithelium and develops higher insulin levels and insulin resistance are associ- from a premalignant lesion to invasive cancer. ated with the higher risk of development of pancreatic The progression from minimally dysplastic epi- cancer (29). thelium (PanIN 1A and 1B) to severe dysplasia (PanIN 2 and 3), and finally to invasive carci- Anti-diabetic drugs and risk of pancreatic cancer noma, is accompanied by accumulation of mu- Basic and epidemiological studies suggest that insulin tations. These include activation of Kras2 onco- may increase the risk of developing pancreatic cancer. genes, inactivation of the tumor suppressor Insulin increases the use of glucose and proliferation gene CDKN2a/INK4a and finally inactivation of cancer cells by activating MAP kinases and PI3 ki- of tumor suppressor genes TP53 and DPC4/ nases. It also increases the expression of the GLUT-1 SMAD4 (22). On average there are 63 genetic receptor (30). Patients treated with insulin have a alterations, most of them are point mutations. higher risk of developing pancreatic cancer (OR 3.54; The changes affect 12 major signalling path- 95% CI: 2.27-6.16) than patients treated with oral an- ways and processes. They are found in 67– tidiabetic drugs (OR 1.53; 95% CI: 1.06-2.23) (31). In 100% of pancreatic cancers (23). contrast, patients who receive metformin might have reduced incidence of pancreatic cancer (OR 0.38; 95% Chronic pancreatitis CI: 0.22-0.69) (32). Chronic pancreatitis is a progressive inflammatory disease of the pancreas. It consists of the destruction Pancreatic cysts of acinar cells and pathological fibrosis. The most Pancreatic cysts are present in 15–20% of the popula- common etiologies are alcohol abuse, hereditary pan- tion. Patients with mucinous cystic neoplasms and in- creatitis and idiopathic pancreatitis. Chronic pancrea- tra-ductal papillary mucinous neoplasms of the pan- titis is a risk factor for the development of pancreatic creas (IPMN) have a greater risk of developing pan- cancer. Ten-year cumulative risk is 1.8% and twenty- creatic cancer. The median risk of developing pancre- year risk is for 4%, regardless of the etiology of the atic cancer in the main duct IPMN is 61.6%. The me- pancreatitis (24) dian risk for the branch duct IPMN is 25.5% (33). If IPMN develops into invasive cancer, it is usually re- The relationship between pancreatitis and pancreatic ferred to as IPMN associated with adenocarcinoma. cancer is very important in otherwise rare autosomal Patients with IPMN are also at risk of developing pan- dominant hereditary pancreatitis. The cancer risk is 70 creatic cancer, which occurs at a different location times greater than in general population, and the life- than cysts. Pancreatic cancer occurs in 2-9% of pa- time risk is 40–55% (25). Increased risk is due to in- tients who are monitored for IPMN (34). flammation accompanied by somatic and hereditary mutations. Smoking further contributes to increased Factors related to lifestyle risk. Obesity and physical activity Obesity (defined as Body Mass Index (BMI) ≥30 kg/ Diabetes mellitus m2) and elevated BMI are both risk factors for devel- Diabetes mellitus is a risk factor for the development oping pancreatic cancer. A recent meta-analysis of pancreatic cancer, but it may also be its manifesta- showed that obese men and women had a higher risk tion. A meta-analysis of 88 studies (50 cohort studies than normal body weight individuals (Men: RR 1.36; and 30 case studies with controls) showed a higher 95% CI: 1.07-1.73; Women: RR 1.34; 95% CI: 1.22- relative risk of pancreatic cancer in diabetic patients 1.46). Moderate physical activity has a beneficial ef- compared to patients without diabetes (RR 2.08; 95% fect on the risk of developing pancreatic cancer, espe- CI: 1.87-2.32) (26). The longer the patient has diabe- cially in those with BMI ≥25 kg/m2 (RR 0.45; 95% tes, the greater the risk (27). Patients with newly de- CI: 0.29-0.70) (35). tected pancreatic cancer have a greater risk of devel- oping diabetes, especially within three years of diag- There are several suggested pathogenetic mechanisms nosis (28). for increased risk of pancreatic cancer with higher Studies also suggest that hyperglycaemia, exposure to weight. Obesity may be associated with physical inac- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 36 tivity and unhealthy diet and lifestyle. Undetected ge- consumed spirits (RR 1.43; 95% CI: 1.17-174) (49). netic factors may also play a role in increasing the The effect of alcohol consumption on pancreatic can- risk. At the cellular level, adipocytes may release po- cer is usually difficult to assess due to ’due to exist- tential procarcinogenic mediators such as adipokines, ence of counfouders (e.g. smoking). IGF and VEGF. These mediators cause chronic in- flammation, which may play a role in the development Smoking of pancreatic cancer (36). Tobacco smoking is the most important environmental factor for the development of pancreatic cancer. Diet Smokers have a 25–35% higher risk (50). The pancre- Studies evaluating the relationship between diet and as, unlike the lungs, is not directly exposed to tobacco. pancreatic cancer are inconclusive: Carcinogens reach it through the blood stream or pos- Diets with high content of saturated fatty acids sibly via the bile or duodenum content, as most pan- and/or meat, especially smoked or processed, have creatic cancers occur in the head (51). A meta-analysis been associated with an increased risk of development of 30 cohort studies has shown that smokers have a of pancreatic cancer in several (15, 37–39) but not all 60% higher risk of developing cancer than those who (40–42) studies . have never smoked (HR 1.61; 95% CI: 1.12-2.32). Several (43–45) case-control studies report a After cessation, the risk decreases slowly and after 20 protective effect from the consumption of fresh fruits years it comes to baseline (18). Passive smoking is and vegetables, but prospective studies have not ob- also associated with an increased risk of developing served such association (46). cancer. A European prospective cohort study has The role of 25-hydroxyvitamin D has also been shown that in those who have been exposed to smok- studied. Higher levels were associated with a 35% re- ing the risk is doubled (52). Smoking also greatly in- duction in the risk of pancreatic cancer (47). creases the risk in people having other risk factors. Patients with hereditary pancreatitis who smoke have Alcohol a two-fold higher risk of developing pancreatic can- Alcohol has long been suspected of being a risk cer, which occurs at a significantly lower age (53). factor for the development of pancreatic cancer, be- cause of its role in the etiology of chronic pancreatitis. Helicobacter pylori infection Alcohol has various effects on the exocrine and endo- Studies also suggest the association of pancreatic can- crine function of the pancreas. It is believed that etha- cer with H. pylori infection. A meta-analysis involv- nol metabolism affects intracellular redox status, ing 1083 patients with pancreatic cancer and 1950 which could play a major role in the development of controls showed increased risk for those who were chronic pancreatitis and pancreatic cancer (48).The infected with H. pylori (OR 1.47; 95% CI 1.2-1.8) metabolism of ethanol through oxidation with alcohol (54). Further research will be needed to clarify this dehydrogenase or through the microsomal oxidation link better. system generates toxic metabolites such as acetalde- hyde and reactive oxygen species. These metabolites PROTECTIVE FACTORS activate pancreatic stellate cells, which leads to fibro- Statins sis and the release of inflammatory mediators Statins are medicines for lowering lipids that are pri- (cytokines, NF-kB, COX-2). Consequently, genetic marily used in the treatment of hyperlipidemia. They alteration and damage to cells may occur, which con- were also associated with other beneficial effects, tribute to carcinogenesis. such as reduced risk of developing cancer. Risk reduc- tion is probably due to pleotropic effects (changes in A meta-analysis of 19 prospective studies has shown growth signaling pathways, immunomodulatory and that low or moderate alcohol consumption had negli- anti-inflammatory effects). Some studies suggest that gible or low effect on the development of pancreatic the use of statins contributes to a lower risk of devel- cancer. High alcohol consumption was associated with oping pancreatic cancer and even contributes to a bet- an increased risk of pancreatic cancer (RR 1.15; 95% ter survival of patients with pancreatic cancer (55, 56). CI: 1.06-1.25). The risk was highest for those who Acetylsalicylic acid and non-steroidal anti- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 37 inflammatory drugs factors are cigarette smoking, high body mass and Data from laboratory and animal studies indicate that lack of physical activity, nonhereditary chronic pan- regular use of these medicines could inhibit pancreatic creatitis, hereditary risk factors (e.g. hereditary pan- carcinogenesis. Epidemiological studies in humans creatitis), other highly penetrant conditions caused by showed contradictory results (57, 58). germline mutations in known cancer-causing genes and familial pancreatic cancer, and pancreatic cysts. It Allergies is important to identify patients at higher risk and pro- Epidemiological studies show that patients with aller- vide them with appropriate advice on the factors that gies have a lower risk of developing pancreatic can- can be influenced. cer. Respiratory allergies (without asthma) reduce the risk by 37% and skin allergies by 34% (59). CONCLUSION Pancreatic cancer related mortality is not decreasing. This is attributed to the late detection of the disease and the lack of effective therapies. Several factors also affect the risk of this disease. The most important risk Lifetime risk for pancre- Relative risk for pancre- Group (mutated gene) Other characteristics atic cancer by age 70 atic cancer years (incidence) No history 1 0.5% Predisposition to breast, HBOC (BRCA1) 3 ovarian, prostate cancer 1.2% Predisposition to breast, ovarian, prostate cancer, HBOC (BRCA2) 3.5–10 Jewish ancestry in some 2–5% (refer for gene testing) HBOC (PALB2) unknown unknown Peutz-Jeghers syndrome (STK11) 132 11–66% Predisposition to melano- ma, multiple nevi, atypical FAMMM (CKDN2A) 13–36 moles (autosomal domi- 10–19% nant) Lynch II syndrome Predisposition to colorectal, (mismatch repair genes 8.6 endometrial cancer 3.7% MLH1, MSH2, MSH6) Li-Fraumeni (TP53) unknown unknown Pancreatic ductal adenocar- Familial PC + 1 FDR cinoma in an individual 4.6 affected with one affected FDR (sibling, parent, or child) Pancreatic ductal adenocar- Familial PC+ 2 FDR cinoma in an individual 6.4 affected (unknown) with two affected FDRs Pancreatic ductal adenocar- Familial PC + 3 FDR cinoma in an individual 32 affected (unknown) with three affected FDRs Hereditary pancreatitis Young-onset pancreatitis 50–82 (PRSS1, SPINK1) 25–44% (autosomal dominant) Table 1: Pancreatic cancer predisposition syndromes and risk of pancreatic cancer (60). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 38 Factor Relative risk Attributable fraction Tobacco 2 11–32% H. pylori infection 1.5 4–25% Non-0-blood group 1.4 13–19% Diabetes mellitus 1.4–2.2 1–16% Obesity 1.2–1.5 3–16% Red meat intake 1.1–1.5 2–9% Heavy alcohol intake 1.1–1.5 9% Low fruit and folate intake 0.5–1.0 <12% Table 2: Major non-genetic risk factors (61). REFERENCES SEARCH program of the IARC. Cancer Causes Control. 1. Kern SE, Goggins MG, Hruban R. Pancreas can- 2009;20(9):1757–62. cer: molecular biology and genetics. In: Gastrointestinal 14. Arnold LD, Patel AV, Yan Y, Jacobs EJ, Thun Oncology: Principal and Practise. Philadelphia, USA: Lip- MJ, Calle EE, et al. Are racial disparities in pancreatic can- pincott Williams and Wilkins; 2002. cer explained by smoking and overweight/obesity? Cancer 2. Parkin DM, Whelan S, Ferlay J, Raymond L, Epidemiol Biomarkers Prev. 2009;18(9):2397–405. Young J. Cancer Incidence in Five Continents. 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Familial risk factors for pancreatic cancer and screening of high-risk patients [Internet]. [cited 2017 Mar 1]. Available from: https://www.uptodate.com/contents/ familial-risk-factors-for-pancreatic-cancer-and-screening- of-high-risk-patients? source=search_result&search=pancreatic% 20cancer&selectedTitle=4~150. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 41 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology ENDOSCOPIC PROCEDURES IN PATIENT WITH PANCREATIC DISEASE Samo Plut* University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT Endoscopy has an important role in diagnosis and treatment of diseases of the pancreas. Endoscopic retro- grade cholangiopancreatography (ERCP) used to be the main diagnostic modality; however in modern times it is almost always preceded by less invasive modern imaging techniques as is computer tomography (CT), magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS). ERCP still has an important role as a therapeutic tool in treatment after diagnosis was made. Development of interventional EUS enables us better and safer diagnostic and treatment options. Both endoscopic diagnostic methods have become standard of care of modern management of patients with such pathology. Key words: ERCP, EUS, diseases of pancreas, diagnostic, treatment INTRODUCTION current diagnostic methods of choice. The learning Endoscopic retrograde cholangiopancreatography curve for ERCP is long, which is especially true for (ERCP) has been used in the diagnosis and treatment diagnosis and therapy in the pancreatic ductal system. of pancreatic and biliary disease for more than 40 Achieving endoscopic competence requires an experi- years. The procedure is performed with a duodeno- enced endoscopist with a sufficient number of proce- scope, which enables optimum display of papillae Va- dures done annually. teri and minor papillae due to lateral optics. The pres- ence of the elevator channel facilitates cannulation of Endoscopic ultrasound (EUS) probe is located on papilla and introduction of guiding wire into biliary the tip of an endoscope, which is introduced through and pancreatic duct as well as injecting a contrast the esophagus and stomach into the duodenum. This agent. ERCP is associated with a significant risk of enables us to place the probe very close to the pancre- developing iatrogenic pancreatitis (in 5-10% of cases), as and high-resolution display of even the smallest major complications include bleeding and perforation structures and changes. Development of linear EUS after endoscopic sphincterotomy or balloon dilatation enabled this primarily diagnostic method to evolve and post-ERCP cholangitis. Initially primarily diag- into a useful therapeutic method of fine needle aspira- nostic method evolved into almost exclusively thera- tion (FNA) cytology and histology tissue sampling as peutic intervention procedure. Modern non-invasive well as placement of lumen opposing stent placement imaging diagnostic methods, such as computed to- (LAMS). mography (CT), magnetic resonance imaging (MR and MRCP), and endoscopic ultrasound (EUS) are the * Samo Plut, MD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 43 Gastroscopy has a minor role in management of pati- sludge. EUS can diagnose any possible anatomical ents with pancreatic disease. By endoscopic placement abnormalities (pancreas divisum) or ampullary adeno- of metal stents, digestive tract obstruction in patients ma. Because the vast majority of biliary stones (up to with advanced pancreatic cancer is resolved. 80%) passes the bile duct spontaneously, ERCP is in- dicated only in patients with acute biliary pancreatitis ENDOSCOPY AND MALIGNANT DISEASE OF and persistent biliary obstruction or cholangitis, and in THE PANCREAS patients where non-invasive diagnostic methods (US, Pancreatic cancer remains a disease with grave prog- CT, MRI or EUS) diagnosed choledocholithiasis. nosis and difficult treatment. Clinically, the symptoms ERCP should be done as soon as possible, and no later of the disease appear late in course. Successful curati- than 24-72 hours. A retrospective study of Slovenian ve treatment is possible only in the early stages of the patients (Dpt. of gastroenterology, UMC Ljubljana) disease. Lesions in the pancreas may be either solid or showed that in patients’ acute biliary pancreatitis cystic. (ABP) and early ERCP (preformed within 24 hours of pancreatitis onset) compared to postponed ERCP Cystic pancreatic lesions are often a diagnostic and (later then 24h), local and systemic complications of therapeutic challenge. Pseudocysts are benign lesions pancreatitis as well as total hospital stay duration are with no malignant potential. Mucinous cystic neo- reduced. ERCP enables us to perform endoscopic plasms and intraductal papillary mucinous neoplasms sphincterotomy and / or dilatation of the papilla Vateri (IPMN) are premalignant lesions. Some malignant and extraction of biliary stones. The role of endoscop- tumors can include areas of cystic degeneration (solid ic sphincterotomy in patients with ABP, where stones pseudopapillary tumor, cystic neuroendocrine tumor have already spontaneously passed, is not entirely or even ductal adenocarcinoma). EUS plays a key role clear. It is recommended in patients who are not can- in management of cystic lesions, allows us identify a didates for cholecystectomy or it will not be made cystic lesion with possible solid inclusions, thickened within 4 weeks. Common complication of severe cyst wall and provides a good assessment of pancreat- acute pancreatitis is formation of pancreatic and peri- ic duct. Application of an intravenous contrast medi- pancreatic fluid collections. Smaller uninfected collec- um enhances diagnostic value of EUS even further. tions may resolve spontaneously. The intervention is EUS FNA enables aspiration of cysts and thus cyto- indicated in case of symptoms (abdominal pain, early logical and biochemical evaluation (determination of satiety, gastric outlet obstruction, icterus or weight CEA in cystic fluid), with high specificity (88–93%) loss) and the case of larger collections or if the collec- and good sensitivity (54–63%). ERCP is rarely used in tion gets infected. Endoscopic intervention is a good the diagnosis of cystic lesions, however a pathogno- alternative to surgery and is less invasive. It includes monic feature of main-branch IPMN can be seen en- papillotomy of the pancreatic sphincter and insertion doscopically - draining of mucus form the papilla of of a pancreatic stent (by ERCP) and endoscopic drain- Vater (fish-eye papilla). ERCP can provide a good age of pseudocysts and limited fluid collections (by imaging of the pancreatic ductal system, but is (due to ERCP or EUS) - cystogastrostomy or duodenostomy. the invasiveness of the procedure and potential com- It provides an endoscopic approach to retroperitoneum plications) used only after of adjunct to MRCP. Histo- and endoscopic necrosectomy. logical and cytological diagnostics of IPMN at ERCP (cytological brushing and biopsy) have relatively low Pancreas divisum is a congenital anomaly in the sensitivity (35%) and are rarely used. anatomy of pancreas with the absence of the dorsal and ventral pancreatic duct fusion in embryogenic de- ENDOSCOPY AND BENIGN DISEASE OF THE velopment. It is present in about 7% of people and is PANCREAS associated with recurrent acute and chronic pancreati- The etiology of acute pancreatitis is biliary in about tis. EUS is the diagnostic method of choice with better 40% cases. EUS has very good sensitivity (94%) and sensitivity as MRI and CT. ERCP with cannulation of specificity (95%) for detecting cholelithiasis, which is the minor papilla and contrast imaging is the best comparable to MRCP in stones greater than 10 mm, method, however due to technically difficult proce- while EUS is superior in smaller stones and biliary dure and potential complications, it is indicated only Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 44 in patients with unclear non-invasive diagnostics and creatoliths larger than 5 mm, ESWL is followed by for therapeutic purposes – symptoms improve in 60% ERCP and endoscopic removal of pancreatoliths. If of patients after endoscopic sphincterotomy of minor ESWL is not successful or feasible, intraductal me- papillary pancreatic sphincter. chanical lithotripsy may be considered. Endoscopic treatment is less effective as surgery, however as it is Oddi sphincter dysfunction (SOD) is considered to considerably less invasive, it is recommended as first be a functional pancreatic disease. Up to 72% of idio- line treatment (it can resolve symptoms in about a pathic recurrent pancreatitis are presumably caused by third of patients). The dominant stricture of the main SOD. By EUS we can accurately assess the pancreat- pancreatic duct is treated with ERCP and dilatation of ic duct and exclusion of other potential pathology. Ac- the stricture and insertion of 10Fr plastic stent. If stric- cording to the Milwaukee classification, SOD is clas- ture persists, placement of additional stents is advised. sified in three types. ERCP with sphincterotomy is Placement of uncovered self-expanding metal stents in indicated for type 1 (patients with typical pain, elevat- pancreatic duct is not indicated; there is currently not ed pancreatic enzymes and dilated pancreatic duct). In enough evidence to recommend the insertion of cov- the patients with type 2 and 3, the Oddi sphincter ma- ered self-expanding metal stents. Patients after failed nometry could have a diagnostic role, however it is endoscopic treatment are referred to surgery. rarely available and not performed in Slovenia. ERCP has an important role in conditions where the Chronic pancreatitis is an irreversible inflammatory major pancreatic duct is damaged (traumatic injury, process leading to the destruction and fibrosis of the iatrogenic damage during surgery or as a result of pancreatic parenchyma and formation of pancreatic acute necrotizing pancreatitis) with pancreatogenic duct strictures. Endoscopic diagnostics can be consid- ascites or pseudocysts. By ERCP and placement of ered in patients were non-invasive imaging and func- plastic pancreatic stent the leakage is resolved and the tional diagnostics of exocrine or endocrine dysfunc- pancreatic duct can heal. tion of the pancreas didn’t lead to diagnosis. EUS is the best method for diagnosing chronic pancreatitis by REFERENCES assessing changes in the parenchyma of the gland 1. J. Dumonceau et al. Endoscopic treatment of chro- (hyperehogenic areas, lobularity and cysts) and ena- nic pancreatitis: ESGE clinical guideline. Endoscopy 2012; bles good imaging of the pancreatic ductal system 44:784-796. 2. S. Tenner er al. ACG Guideline: Management of (dilation of the main pancreatic duct, irregularities in Acute pancreatitis. Am J Gastroentrol. 2013; 108(9):1400- the duct, hyperechogenic wall and pancreatolites). In 15. the absence of characteristic features, we can reliably 3. Muthusamy VR et al. The role of endoscopy in exclude chronic pancreatitis. As some morphologic diagnosis and treatment of cysic pancreatic neoplasms. Gastrointest Endosc 2016: 84(1):1-9. features of acute and chronic pancreatitis are similar, 4. Chandrasekhara V. et al. The role of endoscopy in EUS should be performed at least 4 weeks after acute benign pancreatic disease. Gastrointest Endosc 2015: 82 pancreatitis resolution. In the past, ERCP and contrast (2):203-14. 5. Mathusamy VR et al. The role of endoscopy in pancreatography were the gold standard of diagnosis diagnosis and treatment of inflammatory pancreatic fluid of chronic pancreatitis, with characteristic features of collections. Gastrointest Endosc 2016: 83(3):481-88. the pancreatic ductal system described by the Cam- 6. Eloubeidi MA et al. The role of endoscopy in the bridge classification. Due to the invasiveness of the evaluation and management of patients with solid pankcre- atic neoplasia. Gastrointest Endosc 2016: 83(1):17-28. procedure and the risk of acute exacerbation after 7. Lohr JM et al. UEG evidence-based guidelines for ERCP, it was replaced by non-invasive methods the diagnosis and therapy of chronic pancreatitis. UEG (MRCP and EUS). ERCP maintains the main thera- Journal 2017, 5(2): 153-199. peutic procedure in resolving pancreatic duct stric- tures (dilatation and stenting), removal of pancreato- liths, and less often in the acquisition of cytological samples (brushing and biopsy). Small pancreatoliths are treated with extracorporeal shock wave lithotripsy (ESWL), which is effective in 90% of patients. In pan- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 45 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology NOVELTIES IN SURGICAL TREATMENT OF PANCREATIC DISEASES David Badovinac*, Aleš Tomažič** University Medical Centre Ljubljana, Slovenia, Department of Abdominal Surgery *** ABSTRACT The incidence of different pancreatic diseases in the recent years has been rising worldwide and development of pancreatic surgery has been trying to cope with this trend. Different approaches and various techniques have been proposed and tested in order to treat the patients and minimise the risk of postoperative complica- tions. In treatment of acute pancreatitis, the step-up approach has been propagated in the past years. The main goal of this approach is the control of the septic focus and it relies on less invasive treatment modalities and mini- mally invasive surgery. Percutaneous or endoscopic drainage is usually attempted first. When insufficient, minimally invasive retroperitoneal necrosectomy can be performed. For chronic pancreatitis, different resection techniques have been developed in order to manage chronic pain. Partial pancreatectomies have long been the standard surgical approach, until the Beger procedure was devel- oped – a duodenum-preserving pancreatic head resection with a Roux-en-Y jejunum loop anastomosis. Later, some modifications were developed, but resection technique should be chosen for each patient individually. Pancreatic cancer remains the most troublesome disease of the pancreas, as the long-term survival in the past decades has only gradually improved. Surgery remains the standard of care with the main goal being negative resection margins. Borderline resectable disease is defined based on different criteria and these patients are first treated with induction chemotherapy. In approaching the resection of borderline cancer, there are more possible techniques, with the artery-first approach being most propagated. Key words: surgical treatment, acute pancreatitis, step-up approach, chronic pancreatitis, resection with drainage, pancreatic cancer, pancreaticoduodenectomy, distal pancreatectomy, borderline resectable dis- ease, artery-first approach INTRODUCTION cially cancer, is making the progress difficult. Despite The diversity of pancreatic diseases is enormous and numerous studies and innovations, the poor long-term complications they bring are not to be ignored. World- survival of patients with pancreatic cancer remains the wide, the incidence of different conditions in the re- most worrisome issue. Nevertheless, there are some cent years has been on the upswing and development reports of slight improvement in the overall 5-year of pancreatic surgery has been trying to cope with this relative survival of patients with pancreatic cancer trend. Different approaches and various techniques over the past decades (1–3). Furthermore, supportive have been proposed and tested in order to treat the pa- and perioperative patient care have improved consid- tients and minimise the risk of postoperative compli- erably and morbidity and mortality rates after differ- cations, but specificity of pancreatic diseases, espe- ent surgical procedures have consequently fallen. * David Badinovac, MD University Medical Centre Ljubljana, Slovenia, Department of Abdominal Surgery, Zaloska 7, Ljubljana, Slovenia. ** Professor Aleš Tomažič, MD, PhD University Medical Centre Ljubljana, Slovenia, Department of Abdominal Surgery, Zaloska 7, Ljubljana, Slovenia. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 47 This, however, comes at a high price. Pancreatic sur- tion. Nonetheless, it is sometimes difficult to achieve gery is not only time-consuming but also very expen- sufficient necrosectomy and establish an adequate sive, thus not only further research but also funding is drainage. Consequently, it is often necessary to repeat needed in the field. the procedure several times. However, if necessary, different procedures may be performed sequentially In this review we aim to highlight the more recent sur- without the first procedure compromising the later gical innovations for the three most common pancreat- ones, which is often the case in open necrosectomy ic pathologies and summarise the conclusion of some (11). There are two main approaches of the minimally studies that have evaluated these methods. invasive retroperitoneal necrosectomy (10). ACUTE PANCREATITIS Video-assisted retroperitoneal debridement The incidence of acute pancreatitis in the Western Video-assisted retroperitoneal debridement (VARD) countries has been increasing in the past years (4, 5). combines laparoscopy and a left small open lumboto- Even though the disease is usually mild and self- my close to the site of percutaneous drain. It is thus limiting, severe cases are still associated with high considered a hybrid procedure (13). The percutaneous morbidity and mortality (6). Conventional surgical drain is used as a guide to the retroperitoneal space, debridement was long propagated early in the course which is cleared of pus and necrosis under direct visu- of acute necrotising pancreatitis and thus far open ne- al control. By progression to the deeper parts, a single crosectomy still remains the gold standard. However, laparoscopic port can be administered at the incision the results of such approach are poor, with high mor- site, enabling introduction of a videoscope for further tality and severe postoperative complications (7–9). improvement of the visualisation of the cavity, which Therefore, a different, step-up approach was devel- can then be cleared of necrosis with laparoscopic in- oped and has been widely gaining popularity in the struments. Removing all the necrosis is not the aim recent years. and only large, loose bulks of necrosis are removed, while necrotic areas adherent to the surrounding tissue Step-up approach is left intact This way the risk of blood loss from the The main goal of the step-up approach is the control viable tissues is reduced. Extensive lavage of the ret- of the septic focus (10). It relies on less invasive treat- roperitoneal cavity is then performed and before fascia ment modalities and minimally invasive surgery and is closure two large drains are placed in the collection. thus a current alternative to open necrosectomy. The These two drains are used for further extensive lavage step-up approach allows optimisation of the patients’ in the following days. critical condition and planning of the surgical proce- dures, yet it has to be tailored to suit each individual Minimal access retroperitoneal pancreatic case (11). necrosectomy Minimal access retroperitoneal pancreatic necrosecto- Initially, percutaneous drainage is usually attempted my (MARPN) is another possible way of performing for treatment of infected pancreatic necrosis, with one retroperitoneal necrosectomy. To achieve this, a CT- or more percutaneous drains inserted under radiologi- guided pigtail catheter is first inserted into the necrotic cal guidance. Alternatively, endoscopic transgastric cavity by a radiologist. In general anaesthesia, a sur- drainage of the retroperitoneal space can be per- geon then exchanges the catheter over a guide wire formed. and uses renal dilator to achieve a 30 French tunnel. Using foreceps, the necrotic tissue is then removed Minimally invasive retroperitoneal necrosectomy is an and a large irrigating drain is put in place. Continuous upgrade of the previous techniques. It combines the irrigation of the necrosis cavity is then performed, advantages of the minimally invasive techniques and along with repeated debridement every 7–10 days in open necrosectomy, with simultaneously reducing the local anaesthesia (14). overall morbidity rate in comparison to the latter (12). The main goal is not removal of all necrosis in the ret- Regardless of the methods chosen to treat patients roperationeal space, but rather the control of the infec- with severe acute pancreatitis, a multidisciplinary ap- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 48 proach is always needed, as is also hospitalisation in a Later, the Beger procedure was developed – a duode- specialty centre. Personal experience and institution num-preserving pancreatic head resection (DPPHR) preferences still play a key role in dealing with these with a Roux-en-Y jejunum loop anastomosis to the patients. preserved small portion of pancreatic head tissue, ad- jacent to the bile duct, and the remaining left pancreat- CHRONIC PANCREATITIS ic stump (see Figure 1) (18, 19). Two modifications of The main indication for surgical treatment of chronic the original procedure have also been introduced, the pancreatitis is unmanageable chronic pain, which can- Frey and the Berne technique, both avoiding dissec- not be controlled by other means. For that reason, tion of the pancreas from the superior mesenteric vein nearly half of all patients with chronic pancreatitis (SMV) and the portal vein (PV). will require surgery at some point (15, 16). Other indi- cations include gastrointestinal or biliary obstructive The Frey procedure combines lateral incision of the complications, recurrent episodes of acute pancreatitis pancreatic duct over its full length and hollowing out and the risk of a developing malignancy (16, 17). of the inflamed pancreatic head tissue (see Figure 2). Treatment options include surgical drainage with a The open pancreatic duct and the cavity in pancreatic pancreaticojejunostomy, different kinds of resections head are then both drained into a Roux-en-Y jejunal or a combination of the two. loop (21). Pancreas resections and resections with drainage The Berne procedure is somewhat different, as it in- Partial pancreatectomies, whether pancreaticoduode- cludes subtotal resection of the pancreatic head, with nectomy (PD) or distal pancreatectomy (DP), have some tissue left towards the PV and the duodenum long been the standard surgical approach. For poten- (see Figure 3). The whole cavity, along with the pan- tial lesions or enlargement of the pancreatic head, a creatic duct, which is widely opened, is again drained Whipple procedure or pylorus-preserving pancreati- into a Roux-en-Y jejunal loop (22). coduodenectomy (PPPD) were routinely performed. Figure 1: The Beger procedure; A – transection of the pancreatic neck and subtotal removal of the pancreatic head, with preservation of the duodenum and the common bile duct; B – a Roux-en-Y jejunum loop anastomo- sis to the remaining portion of the pancreatic head and to the distal pancreas ( 20). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 49 Figure 2: The Frey procedure; A – local resection of the pancreatic head and lateral incision of the pancreat- ic duct over its full length; B and C – reconstruction with a side-to-side Roux-en-Y pancreaticojejunostomy (20). Figure 3: The Berne procedure; subtotal resection of the pancreatic head with a Roux-en-Y jejunum loop anastomosis to the pancreatic duct and cavity of the resected pancreatic head (20). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 50 Several studies compared the standard PD with differ- reducing the burden of post-surgical diabetes. By infu- ent modifications of DPPHR, and some have suggest- sion into the portal venous system, islets are carried ed superiority of the latter (23). Yet these trials were away to settle down in the liver. small and rather inconclusive. However, just recently, a large multicentre randomised controlled trial TPIAT is reported to improve patients’ quality of life (ChroPac) performed the same comparison (24). The and reduce pain symptoms (25–27). Nonetheless, al- study suggested that for surgical treatment of chronic most 50% of patients require opioids 1 year after sur- head pancreatitis both partial PD and DPPHR are ef- gery, and around 25% 5 years after TPIAT (25, 26). fective and comparable in terms of mortality, morbidi- Outcomes of diabetes control are more variable, as 30 ty between interventions and quality of life. While op- –50% of patients soon after TPIAT require no insulin erative times in DPPHR were shorter, there were also at all, while in some patients transplanted islets fail more readmission in comparison to partial PD, sug- completely (25, 28). gesting that partial PD was a more definitive solution. Nonetheless, the resection technique should be chosen PANCREATIC CANCER for each patient individually and no straightforward Surgery in pancreatic cancer remains the standard of recommendations can be made thus far. care with the main goal being negative resection mar- gins (R0 resection) (29). Resectability of tumours is Total pancreatectomy with islet auto- usually established on the basis of radiological find- transplantation ings, but clinical and biological parametres should al- In patients with genetic pancreatitis, diffuse small duct so be taken into consideration (30). In order to define disease or when lesser surgical treatment was unsuc- tumour resectability, presence of metastatic lesions cessful, total pancreatectomy with islet auto- and evaluation of potential involvement of major transplantation (TPIAT) may be another option (25). blood vessels in the proximity of the lesion must be Firstly, to relieve pain, complete pancreas resection is made on a CT scan. Involvement of the portal vein performed. The pancreas is then preserved in a cold (PV) and the superior mesenteric vein (SMV), the su- balanced electrolyte solution and the vessels are perior mesenteric artery (SMA), the coeliac axis (CA) flushed for exsanguination. In controlled laboratory and the common hepatic artery (CHA) must be evalu- conditions the pancreas is then enzymatically digested ated separately. Only patients amenable to a curative, and islets are isolated from the excessive tissue. Islet R0 resection are appropriate candidates for surgical auto-transplantation is then carried out with the aim of treatment (29). Pancreatic head or uncinate process Pancreatic body or tail Tumour contact with the SMA or the CA of >180° Tumour contact with the SMA or the Unresectable locally advanced tu- Tumour contact with the first jejunal CA of >180° mours SMA branch Tumour contact with the CA and the Tumour involvement or occlusion of aorta the SMA or the PV, not allowing Tumour involvement or occlusion of for safe reconstruction the SMA or the PV, not allowing Tumour contact with most proximal for safe reconstruction draining jejunal branch into SMV Table 1: Criteria defining unresectable locally advanced pancreatic cancer (31). Legend: SMA – superior mesenteric artery, CA – coeliac axis, SMV – superior mesenteric vein, PV – portal vein. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 51 Resectable tumours bias (38, 39). The results demonstrate no difference At the time of diagnosis, only 15–20% of tumours are regarding the post-operative results in terms of hospi- resectable. Presence of any distant metastases, includ- tal stay, mortality, morbidity, re-operation and pancre- ing non-regional lymph nodes metastases, makes pan- atic fistula rate. Furthermore, both approaches demon- creatic cancer unresectable. Resectable tumours has strated equal results in terms of free resection margin no arterial contact, whereas regarding the veins there and number of lymph nodes retrieved (40). Although should be no contact or contact of <180 °C, along with feasible, severely prolonged operative times and tech- no vein contour irregularities (31). In such cases, an nical difficulties of laparoscopic PD raise doubts of attempt of surgical resection should not be postponed, the procedure usefulness (39, 41, 42). Despite the ris- as resection represents the only possible curative treat- ing numbers of laparoscopic pancreas resections, ment. which have tripled in the past 15 years, laparoscopy is used in only 4.3% of PD (43). Besides 7 negative resection margins (anterior, poste- rior, medial or SMV groove, along the SMA, bile Robotic assisted PD is another option of minimally duct, enteric and pancreatic transaction), adequate invasive surgical approaches. Despite being very at- lymphadenectomy must be performed. At least 15 tractive for the reconstruction part of the procedure, lymph nodes must be retrieved from the standard re- along with anastomosis formation, the robotic PD has gions (32). Extended lymphadenectomy includes dis- not been shown to reduce the mortality and the inci- section of SMA, CT and hepatic arteries, as well as dence of postoperative complications. Furthermore, paraaortic and paracaval lymph nodes (33, 34), yet it operative times are considerably longer and the con- is not generally propagated. It does not improve the version rate is higher. Taking all of this into account, long-term survival of patients, but it does bring higher doubts of further development and training for robotic risk of postoperative complications, including the oc- PD have been raised (44, 45). currence of pancreatic and biliary fistulas (34, 35). Body and tail Head and uncinate process Standard treatment procedure for tumours of the pan- For tumours of the head and uncinate process, PD re- creas body and tail is distal DP. Resection of the pan- mains the only option. There are some possible varia- creas left to SMA and SMV in needed, as well as sple- tions of the procedure with the standard Whipple re- nectomy for assuring adequate lymphadenectomy. section (WR) and PPPD being the most common. More radical approach propagates additional dissec- There is some controversy whether one procedure is tion of SMA left to CA (46). superior to the other. While PPPD was thought to low- er the incidence of biliary reflux and dumping syn- The conventional retrograde DP proceeds in a left-to- drome (36), the newest evidence suggests there is no right fashion. The spleen and distal pancreas are mobi- difference between WP and PPPD in terms of morbid- lised first, with pancreas division being performed ity, mortality and long-term survival. No significant last. This approach is most commonly used, though it differences between the two techniques for the occur- provides late vascular control and limited visualisation rence of biliary leakage, postoperative bleeding and of the posterior plane (48, 49). pancreatic fistulas was found. Nonetheless, PPPD might have the advantage of reducing operating time, As an alternative, radical antegrade modular pancreat- but the benefits for postoperative morbidity remain osplenectomy (RAMPS) has been suggested. Unlike unclear. (37). conventional retrograde DP, RAMPS proceeds in a right-to-left fashion. Pancreas is transected early in the As in DP, minimally invasive approach is gaining its course and splenectomy is performed last. This ap- recognition even in cases of PD. There are no random- proach provides early control of the splenic vessels ised controlled trials comparing the open procedure to and more radical lymphadenectomy. Retroperitoneal the laparoscopic one in cases of malignancy. Availa- dissection plane can be fully visualised, thus R0 resec- ble studies included both benign and malignant lesions tion should be more readily achievable (46, 49, 50). and were all subject to careful patient selection and Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 52 However, no study has shown improved overall sur- Borderline resectable tumours vival with either operative approach (51). Further- Defining borderline resectable disease is sometimes more, there is no difference in the location of tumour difficult and different authors propagate different cri- recurrence (50). teria. Relatively high incidence of occult metastatic lesions complicates the evaluation of resectability Regarding minimally invasive surgery, laparoscopic even more (57). Internationally most recognised are DP is much more widespread than laparoscopic PD. the criteria launched by the National Comprehensive The procedure is already well established for treating Cancer Network (NCCN), which are also acknowl- benign and premalignant lesions of the pancreatic edged by the European Society for Medical Oncology body or tail and has been gaining recognition in treat- (ESMO) (see Table 2). ment of pancreatic carcinoma as well. The operation is feasible and safe and in some aspects it has been Prior to surgery, treatment of borderline resectable shown to offer even better results than open DP (52). cancer should primarily include induction chemother- Laparoscopic DP has been shown to reduce blood loss apy with gemcitabine or FOLFIRINOX regimen intraoperatively, shorten hospital stay and is compara- (fluorouracil [5-FU], leucovorin, irinotecan and oxali- ble or even superior to open DP in terms of lymph platin). This approach is believed to increase the nega- node yields and negative resection margin rates (53- tive margin and overall resection, as well as survival 55). However, most of the studies reporting this in- rate, yet this has not been completely confirmed (58– cluded patients undergoing laparoscopic DP for be- 60) Despite the fact that neoadjuvant treatment down- nign or premalignant lesions and in cases of PDAC, stages borderline resectable pancreatic cancer and the patients were carefully selected. No randomised makes it amenable for surgery in 40–60% of patients controlled studies exist on this matter and therefore, (61, 62), evidence to support such regimen have been no strong recommendations can be made for laparo- sparse (60). scopic treatment of pancreatic body and tail cancer. The duration of surgery is greater and with the excep- Another issue of borderline resectable disease is resec- tion of the well-known general benefits of a minimally tion of the affected blood vessels. As far as the venous invasive approach, the procedure does not offer im- involvement, resection of the affected veins has in- provement in post-operative complications and obvi- creasingly been performed in order to achieve nega- ous oncological benefit (56). tive margins (63, 64). It has even been recommended Pancreatic head or uncinate process Pancreatic body or tail Tumour contact with the SMA of Tumour contact with the CA of ≤180° ≤180° Tumour contact with the CHA, with- Tumour contact with the CA of out extension to the CA or the >180°, without involvement of the Borderline resectable tumour hepatic artery bifurcation, allow- aorta and the gastroduodenal ar- ing for safe resection/ tery reconstruction Tumour contact with the SMV or the Tumour contact with the SMV or the PV of >180° or contact of ≤180° PV of >180° or contact of ≤180° with contour irregularity or vein with contour irregularity or vein thrombosis but with suitable col- thrombosis but with suitable col- lateral vessels allowing for safe lateral vessels allowing for safe resection/vein reconstruction resection/vein reconstruction Tumour contact with the IVC Tumour contact with the IVC Table 2: Criteria defining borderline resectable pancreatic cancer (31). Legend: SMA – superior mesenteric artery, CHA – common hepatic artery, CA – coeliac axis, SMV – superior mesenteric vein, PV – portal vein, IVC – inferior vena cava. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 53 in cases of PV and SMV involvement when safe and whether it benefits the long-term survival is yet to be R0 resection is feasible. Postoperative morbidity and determined (74). mortality in case of venous resection and reconstruc- tion are comparable to the standard resection and there CONCLUSION is also no difference in long-term survival when R0 The important role of the pancreas in human physiolo- resection is achieved (65, 66). On the other hand, arte- gy and the diversity of pancreatic diseases are the rial resections are generally not encouraged, as they driving force of innovations in dealing with them. are associated with a higher mortality rate and inci- Degradation of quality of life is what affects patients dence of postoperative complications (67-69). most. Complications following different pathologies, with morbidity and mortality remaining high, demand Artery-first approach constant improvements in diagnostics and therapeutic In approaching the resection of borderline cancer, approaches. However, innovations in the field of sur- there are more possible techniques. One of the most gery are scarce and should be introduced with caution. widely used is the “artery-first” approach. Allegedly, Most of the trials comparing different approaches of- it reduces intra-operative blood loss and offers a better fer no clear recommendation and are seldomly conclu- likelihood of R0 resection (70, 71). Another ad- sive. Nevertheless, the surgeons must strive to evalu- vantage, especially in borderline cases of pancreatic ate the novelties based on the accessible literature and head tumours with a suspected SMA involvement, is their own experience and try to implement them in early recognition of actual resectability. their own practice if they are beneficial for the pa- tients. Measures towards centralisation of pancreatic Artery-first approach in DP has, thus far, rarely been surgery should be taken and patients should be re- advocated (72). On the contrary, for PD there are sev- ferred to high-volume centres with experienced surgi- eral variations of the artery-first approach, with the cal teams. The whole field of pancreatology demands posterior SMA first approach being most common new and well-designed clinical trials, thus we should (73). The latter begins by the Kocher manoeuvre and all take as much interest as possible in order to con- with subsequent retraction of the pancreatic head to duct them. the left in order to expose the origin of SMA. Excision of perivascular tissue alongside the SMA and posteri- REFERENCES or to the head of the pancreas is then performed, fol- 1. Sirri E, Castro FA, Kieschke J, Jansen L, Emrich K, Gondos A, et al. Recent trends in survival of patients lowed by dissection of SMA from the uncinated pro- with pancreatic cancer in Germany and the United States. cess (70). Posterior SMA first approach may signifi- Pancreas. 2016; 45(6):908-14. cantly improve lymphatic node yields and improve 2. Akhtar-Danesh GG, Finley C, Akhtar-Danesh N. tumour clearance of the posteromedial area. 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Artery-First Distal Pancreatectomy. Dig Surg. 2016; 33(4):314-9. 73.Vallance AE, Young AL, Pandanaboyana S, Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 57 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology SYSTEMIC TREATMENT OF PANCREATIC CANCER Borut Štabuc*, Gašper Boltežar** University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT The incidence of pancreatic cancer is rising and 357 new patients were recorded in Slovenia in 2009. Surgery remains the only potentially curative treatment and adjuvant therapy brings survival benefit. Treatment of metastatic disease was based on gemcitabine monotherapy for the past 15 years. Recent studies of 5-FU, iri- notecan and oxaliplatin regimen (FOLFIRINOX) and gemcitabine combination with nab-paclitaxel show sur- vival benefit and are new first-line treatment options for these patients. Combinations with nal –irinotecan is treatment of choice in second line treatment. Keywords: pancreatic cancer, chemotherapy, radiochemotherapy INTRODUCTION months and only four patients will be alive at five Pancreatic cancer is the 10th most common cancer years. On the other hand, radiation and chemotherapy diagnosed and the 4th most common cause of death or best supportive care are the treatment option for resulting from cancer. Median survival is 80% of patients with pancreatic cancer. The medium approximately three to six months, and only 2% of survival in this group of patients is between three and patients will be alive five years after diagnosis. Inci- six months and only 2% will be alive at three years. dence rates are virtually identical to mortality rates with a range of 2.1 to 18.5 per 100.000 people. ADJUVANT CHEMOTHERAPY AND According to the Slovenian Cancer Registry data for CHEMO-RADIATION THERAPY OF 2009, the incidence of pancreatic cancer was 18.5 per PANCREATIC CANCER 100.000, which means 357 new cases (1). According to the American Gastroenteorology Associ- ation medical position statement from 1999, adjuvant The only curative treatment of pancreatic cancer is therapy with 5-FU based chemo-radiation regimen radical surgery, however this type of treatment is pos- should be considered after surgical resection(2). This sible only with stage I (T1 – T2, N0) and sometimes medical position statement was based on one pivotal stage II (T3 N0, T1 – T3, N1) disease. It is well study, which supports adjuvant chemoradiotherapy in known that age is inappropriate criteria for patient patients with resected pancreatic cancer. This small selection and that extended lymphadenectomy brings study that enrolled 43 patients and showed a median no survival benefit; among 100 patients with pancrea- survival benefit of 20 months versus 11 months with tic cancer, radical resection is possible in 20 patients significant five-year survival difference (18% versus only. Median survival in this patient group is 15 8%) in patients who received bolus 5-FU with radiati- * Professor Borut Štabuc, MD, PhD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. ** Gašper Boltežar, MD University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 59 on therapy for one year compared to those with who on. Patients receiving chemoradiotherapy experienced did not (3). Small sample size was the most important longer median (21.2 versus 14.4 months; P < .001), 2- weakness of this study. year (43.9% v 31.9%), and 5-year (20.1% v 15.4%) survival in comparison to those who received no adju- However, EORTC study in 207 patients with pancrea- vant treatment (7). tic and ampullary cancer compared treatment with infusional 5-FU and radiotherapy given in split curses In a Randomized EORTC-40013-22012/FFCD-9203/ (40 Gy) or observation only and showed only a trend GERCOR phase II study, 90 patients were randomly towards benefit of chemoradiation in terms of medium assigned to receive either four cycles of gemcitabine or survival (24.5 months versus 19 months; p=0.2008) gemcitabine for two cycles followed by weekly gemci- (4). This study was criticized for its radiotherapy com- tabine with concurrent radiation (50.4 Gy). Median ponent - suboptimal lower dose and split curses. disease free survival was 12 months in the chemoradiotherapy arm and 11 months in the control ESPAC–1 enrolled 541 patients with resected pancrea- arm. Median overall survival was 24 months in both tic cancer comparing, in a complicated trial design, post arms. First local recurrence was less frequent in the operative observation, chemoradiation, chemotherapy CRT arm (11% vs. 24%) (8). and chemoradiation followed by chemotherapy. The chemotherapy-only arm showed statistically significant In the CONKO-001 study, Oettle et al. randomized benefit over the observation arm in median survival 368 patients with resected pancreatic cancer to gemci- (20.1 months versus 15.5 months; P=0.009), while the tabine chemotherapy for six months, or observation chemoradiation therapy arm showed worse median sur- only. This trial showed a statistically significant disea- vival (15.9 months versus 17.9 months; p=0.05). The se-free survival benefit (13.4 months versus 6.9 main weakness of this study was possible selection bias months; P<0.001) of gemcitabine versus observation . as patients and clinicians were allowed to select which Adjuvant treatment with gemcitabine showed a trend arm to enter. Additional concern was suboptimal toward overall survival benefit (22.1 months versus radiotherapy, allowing the final radiotherapy dose to 20.2 months; P=0.06), which was later reported be left to the judgment of the treating radiotherapists statistically significant (9). (5). These confusing and inconsistent results of the publis- Neoptolemos et al. report on ESPAC-3 study in which hed randomized trials, which failed to provide clear evi- 1088 patients with an R0/R1 resection for pancreatic dence in support to the use of chemoradiation as adju- ductal adenocarcinoma were randomized within 8 vant therapy after pancreatic cancer resection, spawned weeks of surgery to receive either bolus 5-FU/ several new studies. One retrospective study, covering a leucovorin or gemcitabine for 6 months versus observa- 30-year period at Mayo clinic, evaluated overall survi- tion. The median overall survival of patients treated val of 472 patients after radical (R0) resection of panc- with gemcitabine did not differ from that of patients reatic cancer. Significantly better survival was observed treated with 5-FU (23.6 months versus 23.0 months; in patients who received adjuvant chemoradiotherapy p=0.39) (10). However, safety and dose intensity favo- (25.2 months) compared to those with no adjuvant treat- red gemcitabine in this study. ment (19.2 months, p=0.001). The difference in survival can not be attributed to tumor biology - patients recei- Randomized phase III adjuvant chemotherapy study ving adjuvant therapy had more adverse prognostic fac- comparing gemcitabine versus S1 in patients with tors than those not receiving adjuvant therapy (p=0.001) resected pancreatic cancer (JASPAC 01) conducted in (6). Japan enrolled 385 patients. This trial showed significantly higher overall two-year survival of S1 tre- Analysis of Prospectively Collected Database at the ated patients in comparison to the gemcitabine arm Johns Hopkins Hospital of 616 patients showed similar (two-year over all survival 70% (95% confidence inter- effect of adjuvant concurrent FU-based val 63%–76%) versus 53% (46%–60%)). chemoradiotherapy. Results confirmed significant improvement in survival after pancreatic cancer resecti- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 60 There was also significant difference in median disease chemoterapy and/or chemoradiation in the preoperati- free survival with 23,2 months (95% confidence inter- ve period. val 17,5–32 months) in the S1 arm and 11,2 months (9.7–13.5 months) in the gemcitabine arm (11). Adju- The University of Texas MD Anderson Cancer Center vant chemotherapy with S1 for resected pancreatic can- evaluated neoadjuvant chemoradiation strategies for cer patients was shown to be superior to gemcitabine resectable pancreatic cancer in a series of nonrando- and S1 may be considered new standard treatment after mized phase II trials. The 276 patients enrolled in the- pancreatic cancer resection, especially in Asian popula- se trials met identical eligibility criteria, which inclu- tion. ded objective, computed tomography based determinati- on of resectability and histologic confirmation of PC, Recently published study ESPAC-4 by Neoptolemos and the patients underwent resection with a uniform et al. compared adjuvant chemotherapy with gemcita- surgical technique. Median overall survival durations bine and capecitabine versus gemcitabine alone. This as long as 34 months were observed among the 54–74 was a phase III multicenter, open-label, randomized % of enrolled patients who completed all therapy, study. 730 patients who had undergone a complete including surgery; in contrast, patients who did not macroscopic resection of ductal adenocarcinoma of complete treatment had median overall survival times the pancreas (R0 or R1 resection) were randomly assi- of only 7–11 months (13). gned to receive gemcitabine plus capecitabine of gem- citabine alone. The median overall survival for pati- TREATMENT OF LOCALLY ADVANCED ents in the gemcitabine plus capecitabine group was PANCREATIC CANCER 28.0 months (95% CI 23.5–31.5) compared with 25.5 The median survival of patients with locally advanced months (22.7–27.9) in the gemcitabine group (hazard pancreatic cancer is better when compared to metastatic ratio 0.82 [95% CI 0.68–0.98], p=0.032). They con- disease. The question of optimal treatment for locally cluded that combination of gemcitabine and capecita- advanced disease remains unresolved. Chemotherapy bine should be the new standard of care (12). alone and chemoradiation therapy trials report medium survival of ten months. In the European Union, These trials clearly show the benefit of adjuvant chemotherapy alone remains standard of care. One chemotherapy; data regarding radiotherapy is less clear as recent meta-analysis suggested gemcitabine based che- direct comparisons are rare and it may not be required for moradiation therapy may be both, more effective and majority of patients. Most importantly - it should be noted more toxic than 5-FU based chemoradiation (14). that we still lack good criteria for selection of patients for surgical treatment. Despite resectability, we still loose In a recent prospective clinical trial, presented at 30% of patients with stage 1 and 2 disease after radical ASCO GI 2013, 74 patients with locally advanced surgery in first six months. pancreatic cancer were randomized after 4 cycles of combination chemotherapy to either gemcitabine or NEOADJUVANT TREATMENT OF capecitabine radiotherapy arm. The split radiation PANCREATIC CANCER dose in both arms was 15,4 Gy. Medium overall survi- Neoadjuvant therapy has several potential advantages. val was significantly higher in patients with capecita- Better tumor response is aided by delivery of bine radioterapy arm -15,2 months versus 13,4 months chemotherapy and /or radiation to an intact and well- in the Gemcitabine radioterapy arm (p=0. 012). Medi- vascularized primary tumor, furthermore it provides an progression free survival was also longer in this early treatment of micrometastatic diseases and offers a arm (20 versus 10.4 months). Furthermore, following time interval within which unfavorable tumor biology induction chemotherapy the combination of unmasks and identifies patients in whom surgery radiotherapy with capecitabine was significantly less would not be of benefit. It can reduce the risk of panc- toxic than combination with gemcitabine. The benefit reatic leakage after surgical reconstruction and lower was archived with no compromise in local control and the rate of local recurrences to less than 10%. Despite improvement in overall survival. these advantages, there is no evidence and no clinical trials that would support the administration of Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 61 TREATMENT OF METASTATIC bine monotherapy and 9.0 months for GemOx combi- PANCREATIC CANCER nation ( p=0.13; HR 1.20; 95 % CI 0.95 to 1.54) (17). In the last 15 years the gemcitabine in dose 1000 mg per m2 on weekly schedule has been standard treatment for As showed by another trial with 360 enrolled patients, metastatic pancreatic cancer. In prospective clinical trial irinotecan plus gemcitabine combination does not conducted by Buris at al in 1997, 126 patients were ran- affect overall survival or time to progression when domized in two treatment arms with either 5-FU or gem- compared with gemcitabine monotherapy in patients citabine. The difference in progression free survival and with locally advanced or metastatic pancreatic cancer medium overall survival was significant across the two (median overall survival 6.3 months and 6.6 months, arms (medium overall survival – 5.65 months in gemci- respectively) (18). tabine versus 4.41 months in 5-FU arm, 1 year survival 18 % in gemcitabine and 2% in 5-FU arm, p=0.002). The first gemcitabine combination regimen, which Furthermore, the survival benefit was accompanied by showed modest improvement in overall survival over significant clinical benefit in gemcitabine arm patients gemcitabine monotherapy, was gemcitabine with erlo- (15). tinib. One-year overall survival of 24% versus 17% was reported for the combination and monotherapy Several trials with combination chemotherapy approa- (HR 0.76), respectively. The study also supported the ches aimed to improve treatment efficacy in following concept of effective EGFR pathway targeting in panc- years. In an attempt to assess the combination of gem- reatic cancer patients (19). citabine with a fluoropyrimidine, phase III trial was performed, comparing combination chemotherapy Recently, gemcitabine monotherapy was compared to with gemcitabine plus capecitabine (GemCap) versus another promising combination in 342 patients with single-agent gemcitabine in 319 patients with advan- metastatic pancreatic cancer. They were randomized ced or metastatic pancreatic cancer. Patients were to either 5-FU, irinotecan, oxaliplatine randomly assigned to receive either GemCap (oral (FOLFORINOX) combination or gemcitabine capecitabine 650 mg/m2 twice daily on days 1 to 14 monotherapy arm and median overall survival was plus Gem 1,000 mg/m2 by 30-minute infusion on days 1 significantly longer in the FOLFIRINOX arm with and 8, every 3 weeks) or gemcitabine alone. Median 11.1 months as compared with 6.8 months in the gem- overall survival time was 8.4 and 7.2 months in the citabine arm (p<0.001). Median progression-free sur- GemCap and gemcitabine arms, respectively (p= vival was 6.4 months in the FOLFIRINOX group and 0.234). Post-hoc analysis in patients with good 3.3 months in the gemcitabine group (p<0.001). Not Karnofsky performance status (score of 90 to 100) surprisingly, the FOLFIRINOX regimen was associa- showed a significant prolongation of median overall ted with higher rates of grade 3 and 4 toxicities than survival in the GemCap arm compared to the gemcita- gemcitabine and 42.5% of patients in the experimental bine monotherapy arm (10.1 v 7.4 months, arm received G-CSF and almost 1/4 of the patients respectively; p=0.014) (16). had grade 3 or 4 fatigue. 10–15% experienced grade 3 or 4 vomiting, diarrhea, or neuropathy (20). Combination chemotherapy trial with gemcitabine and oxaliplatin in metastatic pancreatic cancer randomized MPACT recently compared the combination of nab- 156 patients into gemcitabine and 157 patients into paclitaxel with gemcitabine, in a international phase III gemcitabine with oxaliplatin (GemOx) arm. The com- study; 842 patients were randomized and significant bination was found to be significantly superior to gem- survival benefit was reported for the combination in citabine in terms of response rate (26.8% and 7.1%, comparison to gemcitabine monotherapy (median ove- respectively; p = 0.044) , clinical benefit (42.3% and rall survival 8.5 versus 6.7 months, respectively). One-8.3%; p = .01), median progression free survival (5.8 year survival was 35% in the experimental and 22% in and 3.7 months, p = 0.04). One-year survival probability the control arm, a 5% relative difference. Hematological was 27.8% in the gemcitabine arm and 34.7% in the toxicity and neuropathy levels were acceptable and GemOx arm ( p =0.22). Median overall survival time did manageable and the combination of gemcitabine with not differ significantly and was 7.1 months for gemcita- nab-paclitaxel may be considered a new standard for the Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 62 treatment of patients with metastatic pancreatic cancer tive resection. Arch. Surg. Chic. Ill 1960. 1985 Aug;120 (21). (8):899–903. 4. Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, et al. Adjuvant radiotherapy Until recently, no chemotherapy was approved for pati- and 5-fluorouracil after curative resection of cancer of the ents with disease progression on first line treatment. pancreas and periampullary region: phase III trial of the Wang-Gillam et al. however, proved that nanoliposomal EORTC gastrointestinal tract cancer cooperative group. Ann. Surg. 1999 Dec;230(6):776–782; discussion 782–784. irinotecan combined with fluorouracil and folinic acid 5. Neoptolemos JP, Stocken DD, Friess H, Bassi C, extends survival with manageable safety profile. NAPO- Dunn JA, Hickey H, et al. A randomized trial of LI-1 study was a global, randomized, open-label, phase chemoradiotherapy and chemotherapy after resection of III trial with 417 patient who were randomly assigned pancreatic cancer. N. Engl. J. Med. 2004 Mar 18;350 (12):1200–10. either nanoliposomal irinotecan plus fluorouracil and 6. Corsini MM, Miller RC, Haddock MG, Donohue folinic acid, nanoliposomal irinotecan monotherapy or JH, Farnell MB, Nagorney DM, et al. Adjuvant fluorouracil and folinic acid. radiotherapy and chemotherapy for pancreatic carcinoma: the Mayo Clinic experience (1975–2005). J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008 Jul 20;26(21):3511–6. Median overall survival in study group was significantly 7. Herman JM, Swartz MJ, Hsu CC, Winter J, Pawlik higher in group receiving nanoliposomal irinotecan with TM, Sugar E, et al. Analysis of fluorouracil-based adjuvant fluorourail and flonic acid (6.1 vs 4.2 months, p=0,012). chemotherapy and radiation after They concluced that nanoliposomal irinotecan represents pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected a valid treatment option for these patients (22). database at the Johns Hopkins Hospital. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2008 Jul 20;26(21):3503–10. CONCLUSION 8. Van Laethem J-L, Hammel P, Mornex F, Azria D, Pancreatic cancer remains a malignancy with grave Van Tienhoven G, Vergauwe P, et al. Adjuvant gemcitabi- ne alone versus gemcitabine-based chemoradiotherapy prognosis. Adjuvant therapy after radical surgery after curative resection for pancreatic cancer: a randomized improves patient survival. In metastatic disease, gem- EORTC-40013-22012/FFCD-9203/GERCOR phase II citabine monotherapy remained the main treatment study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010 option in the last 15 years. No clear survival benefit Oct 10;28(29):4450–6. 9. Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, was achieved with gemcitabine combination Ridwelski K, et al. Adjuvant chemotherapy with gemcitabi- chemotherapy until modest two-week median survival ne vs observation in patients undergoing curative-intent improvement was shown by addition of EGFR- resection of pancreatic cancer: a randomized controlled targeting erlotinib. FOLFIRINOX regimen has proven trial. Jama J. Am. Med. Assoc. 2007 Jan 17;297(3):267–77. 10. Neoptolemos JP, Moore MJ, Cox TF, Valle JW, more effective than gemcitabine, however study popu- Palmer DH, McDonald AC, et al. Effect of adjuvant lation selection and unfavorable toxicity profile prohi- chemotherapy with fluorouracil plus folinic acid or gemci- bit its wide use. Nab-paclitaxel combination with tabine vs observation on survival in patients with resected gemcitabine has recently emerged as a new standard periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. Jama J. Am. Med. treatment for metastatic pancreatic cancer with a more Assoc. 2012 Jul 11;308(2):147–56. favorable safety profile. Nanoliposomal irinotecan 11. Maeda A, Boku N, Fukutomi A, Kondo S, Kinos- combined with fluorouracil and folinic acid was hita T, Nagino M, et al. Randomized phase III trial of adju- shown to be effective as a valid second line treatment vant chemotherapy with gemcitabine versus S-1 in patients with resected pancreatic cancer: Japan Adjuvant Study option. Group of Pancreatic Cancer (JASPAC-01). Jpn. J. Clin. Oncol. 2008 Mar;38(3):227–9. REFERENCES 12. Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli 1. Primic Žakelj M. Rak v Sloveniji 2008. Ljubljana: EE, Valle JW, Halloran CM et al. Comparisonof adjuvant Onkološki inštitut, Epidemiologija in register raka, Regis- gemcitabine and capecitabine with gemcitabine ter raka Republike Slovenije; 2011. monotherapy in patients with resected pancreatic cancer 2. American gastroenterological association medical (ESPA-4): a multicentre, open-label, randomised, phase 3 position statement: epidemiology, diagnosis, and treatment trial. Lancet. 2017; 389:1011-24 of pancreatic ductal adenocarcinoma. Gastroenterology. 13. Katz MHG, Fleming JB, Lee JE, Pisters PWT. 1999 Dec;117(6):1463–84. Current status of adjuvant therapy for pancreatic cancer. 3. Kalser MH, Ellenberg SS. Pancreatic cancer. Adju- Oncologist. 2010;15(11):1205–13. vant combined radiation and chemotherapy following cura- 14. Zhu C-P, Shi J, Chen Y-X, Xie W-F, Lin Y. Gemcitabine in the chemoradiotherapy for locally advan- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 63 ced pancreatic cancer: a meta-analysis. Radiother. Oncol. J. 19. Moore MJ, Goldstein D, Hamm J, Figer A, Hecht Eur. Soc. Ther. Radiol. Oncol. 2011 May;99(2):108–13. JR, Gallinger S, et al. Erlotinib plus gemcitabine compared 15. Burris HA 3rd, Moore MJ, Andersen J, Green with gemcitabine alone in patients with advanced pancrea- MR, Rothenberg ML, Modiano MR, et al. Improvements in tic cancer: a phase III trial of the National Cancer Institute survival and clinical benefit with gemcitabine as first-line of Canada Clinical Trials Group. J. Clin. Oncol. Off. J. therapy for patients with advanced pancreas cancer: a ran- Am. Soc. Clin. Oncol. 2007 May 20;25(15):1960–6. domized trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 20. Conroy T, Desseigne F, Ychou M, Bouché O, 1997 Jun;15(6):2403–13. Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus 16. Herrmann R, Bodoky G, Ruhstaller T, Glimelius gemcitabine for metastatic pancreatic cancer. N. Engl. J. B, Bajetta E, Schüller J, et al. Gemcitabine plus capecitabi- Med. 2011 May 12;364(19):1817–25. ne compared with gemcitabine alone in advanced pancrea- 21. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, tic cancer: a randomized, multicenter, phase III trial of the Infante J, Moore M et al. Increased survival in pancreatic Swiss Group for Clinical Cancer Research and the Central cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. European Cooperative Oncology Group. J. Clin. Oncol. Med. 2013; 369:1691-703 Off. J. Am. Soc. Clin. Oncol. 2007 Jun 1;25(16):2212–7. 22. Wang-Gillam A, Li CP, Bodoky G, Dean A, Shan 16. André T, Tournigand C, Rosmorduc O, Provent YS, Jameson G et al. Nanoliposomal irinotecan with fluo- S, Maindrault-Goebel F, Avenin D, et al. Gemcitabine rouracil and folinic acid I metastatic pancreatic cancer after combined with oxaliplatin (GEMOX) in advanced biliary previous gemcitabine-based therapy (NAPOLI-1): a global, tract adenocarcinoma: a GERCOR study. Ann. Oncol. Off. randomised, open-label, phase 3 trial. Lancet. 2016 Feb 6; J. Eur. Soc. Med. Oncol. Esmo. 2004 Sep;15(9):1339–43. 387:545-57 18. Rocha Lima CM, Green MR, Rotche R, Miller WH Jr, Jeffrey GM, Cisar LA, et al. Irinotecan plus gemci- tabine results in no survival advantage compared with gem- citabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor res- ponse rate. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2004 Sep 15;22(18):3776–83. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 64 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology PANCREATIC PAIN MANAGEMENT Neli Vintar*, Katja Režonja** University Medical Center Ljubljana, Slovenia, Clinical Department for Anesthesiology and Periopera- tive Intensive Care *** ABSTRACT The pain relief of pancreatic cancer, of acute and chronic pancreatitis represents a major challenge for pain specialists, gastroenterologists and surgeons and has a devastating effect on patient’s quality of life. The mod- els for the pathogenesis of visceral and neuropathic pain are presented. The ranges of treatment strategies including pharmacological and non-pharmacological methods are reviewed. The pain of chronic pancreatitis remains refractory to effective treatment in many cases and further study and understanding of the underlying pathophysiology are required. Keywords pancreatitis, pancreatic cancer, pain, chronic, acute, visceral, neuropathic INTRODUCTION cess. Recurrent episodes of pancreatic inflammation Pain is the cardinal sign of acute pancreatitis. Gradual will involve adjacent structures such as the biliary sys- or sudden pain is severe and persisting. The manage- tem, duodenum, stomach and spleen. Current concepts ment of abdominal pain remained one of the most in the pathogenesis of pain in chronic pancreatitis re- challenging issues also in patients with chronic pan- gard neuronal damage leading to peripheral sensitiza- creatitis. It is described as constant pain in the epigas- tion and resultant central sensitization as fundamental tric area with radiation to the back. Pain is intensified to the development of persistent, often refractory pain after food or alcochol intake. Painful episodes are in chronic pancreatitis (1). therefore often accompanied by fatigue, nausea, vom- iting, food avoidance, and weight loss. In the periphery, multiple local mediators such as prostanoids, bradykinin, serotonin, tachykinins and Pain can be a major problem for people with pancreat- other unknown compounds sustain and contribute to ic cancer. These cancers can invade and press on the peripheral sensitization seen in chronic pancreati- nerves near the pancreas. Severe visceral and inten- tis. Nerve growth factor, important in nociceptive sen- sive neuropathic abdominal pain management is very sitization, has increased pancreatic expression in chellenging for gastroenterologists, surgeons and chronic pancreatitis. Trypsin may have direct effects anestesiologists. on sensory neurons via the protease-activated receptor 2 (PAR-2). PAR-2 activation has been shown to result PATHOPHYSIOLOGY OF PANCREATIC PAIN in TRPV1 receptor sensitization through capsaicin- Neuronal tissues within the pancreas and within adja- evoked release of calcitonin gene related peptide cent structures are affected by the inflammatory pro- (CGRP) (1).In addition to changes in the periphery, * Assistant Professor Neli Vintar, MD, PhD University Medical Center Ljubljana, Slovenia, Clinical Department for Anesthesiology and Perioperative Intensive Care, Zaloška 2 ,SI–1000 Ljubljana. ** Katja Režonja, MD, PhD University Medical Center Ljubljana, Slovenia, Clinical Department for Anesthesiology and Perioperative Intensive Care, Zaloška 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 66 the central nervous system is altered by prolonged and ticity, of which several molecular components have repeated attacks of pain in chronic pancreatitis. already been identified, mediates the central amplifi- cation of the visceral afferent signals that leads to the NEUROIMMUNOLOGY hypersensitivity of central neurons. In addition to the Fregni and coworkers found out that total pancreatec- hyperalgesia triggered as a consequence of the injury tomy fails to relieve pain in up to 30% of chronic pan- or inflammation of an internal organ (pancreas), there creatitis patients (2). They hypothesize that there must are also functional pain states, characterized by pain be a role for a pancreas-independent mechanism in the reported from the abdominal or pelvic cavities but in unremitting pain seen in chronic pancreatitis. They the absence of a demonstrable peripheral cause. Alt- further hypothesize that, in addition to anatomical and hough not much is known about the causes of such neuronal factors modulating pain, the immune system states it is thought that hypersensitivity of peripheral is involved in a ‘salutogenic’ mechanism perpetuating sensory receptors or an enhanced responsiveness of cycles of inflammation and ongoing pain – a saluto- central visceral pathways may be responsible for such genic response being modulation of the immune re- functional pain states. sponse by centres in the brain. Therefore, one could enhance the function of the immune system to pro- ABDOMINAL NEUROPATHIC PAIN mote healing of the inflamed pancreas. What might In addition to the constant background pain, patients occur instead is that abnormal immune processes, universally describe an ‘extra’ pain. It may be de- linked to brain-mediated mechanisms, sustain the vis- scribed as the ‘bad’ pain that comes unexpectedly, ceral inflammation and prolong the duration of pain. without warning, ‘out of the blue’. If patients are una- This process is ultimately a maladaptive brain re- ble to control this pain with their usual analgesic re- sponse and they consider that fresh approaches to gime, the end result is usually a hospital admission. treating the pain of chronic pancreatitis are necessary. Areas of hyperalgesia and allodynia can be demon- They propose that transcranial magnetic stimulation strated in those patients who have had surgery, but needs further evaluation as a treatment option in the also in those awaiting surgery. Pancreatic pain has management of chronic pancreatitis. some of the features of somatic pain, as well as some of visceral pain, but the neuropathic component of VISCERAL PAIN IN PANCREATIC DESEASES pain is often under-diagnosed and under-treated. The The functional properties of visceral nociceptors are characteristics of the severe, sudden, unexpected pain different from those of their somatic counterparts and experienced by patients with pancreatic pain are indis- the microenvironments where visceral nociceptors are tinguishable from those seen in many other neuro- located, and especially the motor and secretory func- pathic pain syndromes. Detailed history-taking and tions of organs like the gut, play a key role in the acti- specific questions looking for, in particular, neuro- vation and sensitization of visceral sensory receptors. pathic symptoms are essential in guiding therapy. All forms of visceral pain include the development of a hyperalgesic state that originates from the internal NEUROPLASTICITY AND SUPRASPINAL organ that has been damaged or inflamed and is re- MODULATION ferred to a remote and superficial region of the body. There is a growing body of evidence that neuroplastic In some cases visceral hyperalgesia appears in the ab- changes such as those seen in neuropathic pain and sence of an identifiable peripheral cause, perhaps as a other chronic pain disorders may be of importance. consequence of the sensitization and hyper- The current findings of cortical reorganization in the excitability of visceral afferents evoked by subclinical insula together with reduced evoked potential latency changes in their microenvironment. Hyperalgesia is support the theory that cortical reorganization is a the most prominent feature of the visceral pain pro- mechanism involved in patients with chronic pancrea- cess and is the expression of hypersensitivity of the titis. This insight may lead to changes in the current pain pathway induced by the sensitization of the pe- concept for treatment of pain originating from the ripheral receptors that signal visceral sensory events pancreas, and medications affecting central hyperex- or of the neurons that transmit and process this senso- citability and neuroplastic changes may be of major ry information to the CNS. A process of synaptic plas- value. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 67 Dimcevski and colleagues measured electroenceph- MEDICAL PAIN MANAGEMENT alography traces in patients with chronic pancreatitis, Many drugs are given alongside analgesics to combat who received electrical stimulation of the oesophagus, exocrine and endocrine disorders, nutritional deficien- stomach and duodenum via an endoscope (3). They cies and concomitant gastrointestinal symptoms (e.g. recorded changes in the limbic system and in cortical nausea, bloating). Non-pharmacological interventions, centres such as the anterior cingulate cortex. They such as endoscopic sphincterotomy, insertion of pan- concluded that chronic pancreatitis leads to changes in creatic duct stents and removal of pancreatic stones, cortical projections of the nociceptive system. Further also come within the category of medical therapy (1). understanding of these processes may lead to a more targeted approach in terms of the choice of analgesic The World Health Organization (WHO) analgesic lad- therapies. der provides a logical and consistent framework for the initiation of analgesic medication in the manage- PAIN MANAGEMENT STRATEGIES ment of pancreatic pain (4). Multimodal and interdisciplinary treatment strategies are used for pancreatic pain relief. Nonpharmacologi- The approach in establishing an oral analgesia mainte- cal and medical therapies are combined and tailored to nance regime in the patient with pancreatic pain patients needs. Patient's collaboration and collabora- should emphasize simplicity and safety. One drug tion of family members are crucial for successful re- should be chosen from each drug category, a multi- sults. modal approach should be used, adjuncts should be used appropriately and medical therapy should be Lifestyle changes are suggested, it is strongly advised maximized (e.g. enzyme supplementation, proton to avoid alcohol consumption even to patients who pump inhibitors, diabetic control, octreotide, antioxi- have other causes for chronic pancreatitis. Patients are dants). encouraged to stop smoking. Low-fat diets, vitamin supplements and antioxidant therapies are all recom- Nonopioid of choice for visceral pain is metamizol. mended in chronic pancreatitis. Maximal daily oral dose is 3000 mg to 4000 mg, giv- en in doses of 1000 mg / 6–8 h. Support groups give the opportunity to patients to share their experience with chronic pancreatitis . Pa- For acute pain relief metamizol is given i.v. 1000 mg tients often share knowledge as to the best analgesics to 1500 mg, possibly in 100 ml of saline slowly 10–20 available or new treatments they have tried. Chronic min. If needed, opioids are added, for moderate pain pancreatitis is a condition with no clear-cut reliable tramadol in maximal daily dose up to 400 mg. For se- treatment strategies and most patients have tried many vere pain strong opioids are given i.v., in Slovenia pi- different therapies. Because of the impact of ongoing ritramid is traditionally administered for pain relief. It chronic disease, many patients with chronic pancreati- can be titrated in boluses 3-5mg i.v. or administered in tis have complex social and marital/relationship situa- continuous i.v. infusion 3–5 mg / hr plus boli on de- tions. They can often become isolated socially, and mand. peer support groups can be invaluable in helping pa- tients with the difficulties that arise from their symp- For chronic pain the decision to embark on long-term toms. use of strong opioids should be taken only when other measures have failed or are inadequate (5, 6, 7). The Chronic pain is a desease per se. Inspite of different use of immediate-release opioid preparations should pain treatments, the pain persists. With psychological be restricted to ‘breakthrough’ pain only and should approaches we help the patient to accept treatment be kept to a minimum. The use of these preparations strategies , improve pain tolerance and starts a new leads to peaks and troughs in the plasma concentration quality of life. of the opioid. If episodes of breakthrough pain are be- coming more severe or more frequent, the dose of the long-acting medication should be reviewed first. The Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 68 majority of the opioid dose should be administered in For persistent severe neuropathic pain, patient can be a slow- or modified-release formulation. given i.v. infusion of lidocaine (100–150 mg in 50 ml saline, infused 3 hrs 15 ml/h, during infusion ECG The use of strong opioids in chronic pancreatitis is monitoring obligatory!). controversial and undoubtedly carries risk in a group For cancer patients’ ketamine, midazolam and lido- of patients, many of whom have had a history of alco- caine are combined with opioids and other drugs in hol or drug misuse. There is a risk of addiction or opi- the analgesic mixture for continuous s.c. infusion via oid-seeking behaviour developing. There is the addi- elastomeric pumps. tional danger of accidental overdose of prescribed medication if it is taken in combination with alcohol WAYS OF ANALGESIC DRUGS or other recreational drugs. Close monitoring of drug ADMINISTRATION dose and avoidance of dose escalation help to mini- First option is always oral administration. Subcuta- mize this risk. neous or intravenous administration is chosen in cas- es of swallowing disorders or bowel disfuntion In the case of strong opioids, it is strongly recom- (diarrhoea, ileus), in patients with cognitive disorders mended that there is a single prescriber (usually the or patients taking many different therapies. Subcuta- general practitioner), that the dispensing of the drug neous infusion can be safely adminstrated at home. by the pharmacist is monitored to avoid stockpiling For adequate titration of opioid dosage and optimisa- and there are strong lines of communication between tion of drug combination (metoclopramide, dexame- hospital specialists and general practitioners to main- thason, ketamine, lidocaine) patients are often admit- tain consistency of prescriptions. Constipation is an ted to hospital for some days. important side-effect in any patient on long-term opi- oids. It can confuse the clinical picture of pancreatic Epidural or intrathecal analgesia are advanced inva- desease by worsening abdominal pain and bloating. sive methods of analgesic administration. Epidural or Conversely, many patients, despite opioid use, still intrathecal catheters are inserted by anaesthesiologist, experience diarrhoea as a result of the malabsorption patients are often hospitalized for titration and optimi- commonplace in chronic pancreatitis. All opioid- zation of analgesic doses and combinations. related side-effects should be monitored regularly and specific questions should be asked at regular out- Coeliac plexus block is a regional technique that can patient or primary care consultations. be performed directly at the time of pancreatic sur- gery, transcutaneous approach is using anatomical There is a growing body of evidence to suggest that landmarks, modern approaches are CT-guided and peripheral and central sensitization of the pain are im- endoscopic ultrasound (EUS)-guided coeliac plexus portant in magnifying the pancreatic pain and that spi- block. Separate reviews by Kaufman et al in 2010 and nal cord and cortical reorganization occurs. Allodynia Puli et al in 2009 demonstrated that EUS-guided coe- and hyperalgesia have been demonstrated. For neuro- liac plexus block can be effective in treating pain in pathic pain management pregabalin and duloxetin or chronic non-malignant and malignant pancreatic pain gabapentin and amytriptillin are recommended (8). (9, 10). In Slovenia we have limited experiences with Not only will this help to alleviate neuropathic symp- coeliac plexus blocks. toms, the use of pregabalin or gabapentin stabilizes opioid usage and delays or prevents dangerous dose Thoracoscopic splanhnicectomy is an invasive surgi- escalation and opioid-induced hyperalgesia. cal denervation method in palliating the pain of pa- The use of ketamine is also an option in the manage- tients with chronic pancreatitis; several ribs are re- ment of neuropathic pancreatic pain. Hyperalgesia can moved during the procedure. Possible and often side be modulated by the use of an infusion of S-ketamine. effects include postural hypotension, interscostal neu- In an outpatinet setting, 25mg - 50 mg ketamin and ralgia and diarrhoea. It is an effective but not longlast- midazolam 2–3 mg , are diluted in 100 ml saline and ing method, so it is performed only in a few centers administered approximately 3hrs (30 ml/hrs). Patients (11). are continuously monitored (ECG, BP and SaO2). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 69 ANTIOXIDANTS FOR PAIN RELIEF IN REFERENCES CHRONIC PANCREATITIS 1. Goulden MR. The pain in chronic pancreatitis: a Due to malabsorbtion and also to insufficient food in- persistent clinical chalenge. Br J Pain 2013;7:8-22. 2. Fregni F, Pascual – LeoneA, Freedman SD. Pain in take because of pain, patients with chronic pancreatitis chronic pancreatitis: a salutogenic mechanism or a mala- often develop antioxidant insuficiency. Current evi- daptive brain response. Pancreatology 2007;7:411-22. dence shows that antioxidants (vitamin C, vitamin E, 3. Dimcevski G, Sami SA, Funch-Jensen P et al. Pain flavonoids) can reduce pain slightly. The clinical rele- in chronic pancreatitis: the role of reorganization in the central nervous system. Gastroenterology 2007;132:1546- vance of this small reduction is uncertain. Adverse 56. events in one of six patients may prevent the use of 4. World Health Organization. WHO’s pain ladder antioxidants. Effects of antioxidants on other outcome [online] 2006. measures, such as use of analgesics, exacerbation of 5. Vintar N, Lopuh M. Bolečina In Košnik M, Mrevlje F, Štajer D, Koželj M, Černelč P Interna medicina pancreatitis and quality of life remain uncertain so fur- 4th ed, Ljubljana 2011. 49 – 53. ther studies with more evidence are needed (12). 6. Čavlovič Lahajnar S, Škvarč Krčevski N, Stepa- novič A, Čufer T. Usmeritve za zdravljenje bolečine pri odraslem bolniku z rakom. Zdrav Vestn, 2008; 77: 7–12. Endoscopic and open surgery for pancreatic pain 7. Krčevski Škvarč N, Godec M, Komar Cesar M, in relief is discussed elsewhere. Surgery brings specific sod. Usmeritve za uporabo opioidov pri bolnikih s kronično risks. There may be ongoing post-surgical pain from a boleznijo, ki ni posledica rakave bolezni. Zdrav Vestn large wound and the associated drain sites. Chronic 2007; 76: 381–7. 8. Finnerup NB, Attal N, Haroutounian S, McNicol wound pain may occur months or years after surgery. E, Baron R et al. Pharmacotherapy for neuropathic pain in Although many patients with chronic pancreatitis im- adults: systematic review, meta-analysis and updated prove after surgery, a significant number do not. Ex- NeuPSIG reccomendations. Lancet Neurol 2015;14(2):162- tensive pre-operative counselling, before the decision 173. 9. Kaufman M, Singh G, Das S, et al. Efficacy of en- to undergo surgery is made, is essential to clarify the doscopic guided celiac plexus block and celiac plexus neu- risks and benefits of surgery (1). rolysis for managing abdominal pain associated with chronic pancreatitis and pancreatic cancer. J Clin Gastroen- CONCLUSION terol 2010;44:127-34. 10.Puli SR, Reddy JB, Bechtold ML, et al. EUS guid- Pancreatic desease and the accompaning pain have a ed celiac plexus neurolysis for pain due to chronic pancrea- devastating effect on patient's quality of life. Pain that titis or pancreatic cancer pain: a meta-analysis and system- some describe as unbearable, relentless and all con- atic review. Dig Dis Sci 2009;54:2330-7. suming can dominate every aspect of their life. Non- 11. Baghdadi S, Abbas MH, Albouz F, et al. System- atic review of the role of thoracoscopic splanhnicectomy in opioids remain first choice analgesics, but opioids as palliating the pain of patients with chronic pancreatitis. part analgesic regimen for severe pain relief still have Surg Endosc 2008;22:580-8. an important role and cause several opioid related side 12. Ahmed Ali U1, Jens S, Busch OR, et al. Antioxi-effects and risks. Close monitoring of opioid usage as dants for pain in chronic pancreatitis. Cochrane Database Syst Rev. 2014 Aug 21;(8):CD008945. doi: well as consistent prescribing is fundamental to pre- 10.1002/14651858.CD008945. serving patient's safety. Effective treatment of underlying pancreatic desease and pain management can only be achieved by inter- disciplinary approach. Collaboration of different ex- perts is crucial. Inspite of different pain management strategies availa- ble, pancreatic pain often remains unsuccessfully treated. Further studies are needed to improve our understanding of the pathophisyology of the underly- ing desease and concommitant pain, which will help us to treat also the intractable pancreatic pain. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 70 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology EXOCRINE PANCREATIC INSUFFICIENCY Rado Janša* University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT Exocrine pancreatic insufficiency (EPI) is a medical condition which is characterized by reduced secretion of pancreatic enzymes in the alimentary tract. In certain disease states of the gastrointestinal tract, especially af- ter surgery, however, the secretion of enzymes may be normal, but they don’t come in contact with the nutri- ents at the right time. All this leads to maldigestion and consequent malabsorption and malnutrition. The se- cretion of pancreatic enzymes is dependent on hormonal and neural signals; a malfunction of the secretory functions can occur in several different ways. The reasons for EPI can be divided into: pancreatic or primary, and non-pancreatic or secondary. EPI is often overlooked, particularly in conditions outside the pancreas, be- cause the symptoms are often non-significant. Only in the most severe forms of EPI is steatorrhea present. EPI is diagnosed based on the clinical picture and pancreatic function tests, which are divided into direct and indirect. The basis of the treatment represents a pancreatic enzyme replacement therapy; however, it is also important to introduce a change in lifestyle and an additional intake of vitamin preparations. Long-term tar- gets for the treatment of EPI are: introduction of a change in the diet, treatment of symptoms and treatment of the underlying disease, whenever possible. Keywords: pancreas, exocrine pancreatic insufficiency, diagnosis, symptoms, treatment of EPI INTRODUCTION etc. A common but perhaps underestimated reason for Adverse food reactions are common complaints with adverse food reaction is also a failure of pancreatic increasing prevalence that affect both children and exocrine tissue. adults. They occur in affected individuals after inges- Exocrine pancreatic insufficiency (EPI) is character- tion of food, which otherwise does not induce any dis- ized by a deficiency of exocrine pancreatic enzymes turbances in healthy individuals. Adverse food reac- to level that is inadequate to maintain normal diges- tions could be induced by different kinds of food and tive process. Maldigestion because of impaired lu- by different pathogenic mechanisms, however their minal phase of digestion causes malabsorption of nu- clinical presentations are similar and often nonspecif- trient and lead to poor nutrition (1). EPI is etiological- ic, making diagnosis challenging. Mechanism of these ly heterogenous condition. The leading cause of EPI is reactions can have an immunological basis (food al- primary pancreatic disease, although many conditions lergy, celiac disease) or a non-immunological basis can indirectly impair pancreatic exocrine function (food intolerance). (secondary EPI) (1–4). An estimated prevalence of EPI in general population is 8/100.000 for men and Food allergy is an adverse immune response driven by 2/10.000 for women (5). Ig E antibodies towards food proteins, whereas celiac disease is immune-mediated enteropathy triggered by Clinical manifestation of EPI varies depending on the the ingestion of gluten. Beside non-immunological, stage of disease. The severe form is associated with most common causes are food poisoning, infection of malnutrition and fat malabsorption shown as steator- gastrointestinal tract, deficiency of a digestive enzyme rhea, pale, bulky, and malodorous stools, while milder * Assistant Professor Rado Janša, MD, PhD University Medical Centre Ljubljana, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 72 forms of disease (faecal elastase 100-200 mcg/g) ulates release of pancreatic enzyme acting on CCK cause fewer symptoms and are therefore easily over- receptors on acinar cell (see Figure 1). looked. They show only few unspecific symptoms such as cramps, bloating, abdominal distension and chronic diarrhoea. Diarrhoea results from the presence of osmotically active, poorly absorbed solutes in the bowel lumen that inhibit normal water and electrolyte absorption (6, 7). Laboratory studies are important in the diagnosis of EPI and reveal a malabsorption syndrome: deficiency of microelements, fat-soluble vitamins and lipopro- teins. To confirm the diagnosis of EPI multitude of tests have been developed, which directly or indirectly measure pancreatic exocrine function. Furthermore, studies revealed that EPI has been asso- ciated with high morbidity and mortality secondary to malnutrition-related complications and high risk of cardiovascular events. Timely and accurate diagnos- ing of EPI is hence crucial, because delays in treat- Figure 1: Physiology of exocrine pancreas. ment may prolong malnutrition related complications and have important impact on patient’s quality of life. ETIOLOGY OF EXOCRINE PANCREATIC Treatment of EPI consists of lifestyle modifications, INSUFFICIENCY substitution of deficiencies and compensation for en- Exocrine pancreatic insufficiency can be classified dogenous deficiency with pancreatic enzyme replace- as primary or secondary. Primary EPI is due to a lack ment therapy. of exocrine pancreatic tissue or disturbances in the innervation. In secondary EPI there is impaired exo- PHYSIOLOGY OF EXOCRINE PANCREAS crine pancreatic function and insufficient enzyme ac- Pancreas daily secrets about 15.000 ml of colourless, tivity (8, 9). isotonic and alkaline juice with high concentration of pancreatic enzymes, especially lipase. The secretion is Etiologies of primary EPI: under tight neuro-humoral regulation. Secretin and a. Acute and chronic pancreatitis – most common cholecystokinin are the main hormones which regulate causes of diverse etiologie; pancreas secretion in a negative feedback manner. b. Cystic fibrosis – mutation of the gene that en- codes for a chloride channel leads to protein precipita- Secretin is released from duodenal mucosa as a re- tion within the ductal lumen and loss of normal acinar sponse to acid gastric juice coming to duodenum from cell function; the stomach. Secretin then stimulates the pancreatic c. Diabetes mellitus type 1 and type 2; interlobular ductal cells to secrete more water and bi- d. Obstruction of pancreatic duct (e.g. ampullary or carbonate, making the pancreatic juice more alkaline pancreatic cancer); and therefore reducing acid level in duodenum. e. Shwachman-Diamond syndrome (SDS) – rare autosomal recessive disorder characterized by exo- Another important hormone in regulation of exocrine crine pancreatic insufficiency, bone marrow dysfunc- pancreas is cholecystokinin (CCK). CCK is released tion, leukemia predisposition, and skeletal abnormali- from enterocyte’s endocrine cell under the presence of ties. (10). fat and proteins in himus. In addition, CCK is also se- creted from vagal afferent nerves. CCK directly stim- Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 73 Etiologies of secondary EPI: Peripheral oedema may result from hypoalbuminemia a. Celiac disease – EIP occurs in about one third of caused by protein malabsorption. With severe protein celiac disease patients. We should be aware of EPI depletion, ascites may develop. when celiac disease resistant to gluten-free diet; Anaemia resulting from malabsorption can be either b. Crohn's disease; microcytic (related to iron deficiency) or macrocytic c. Zollinger-Ellison syndrome – hypergastrinemia (related to vitamin B-12 deficiency). Anaemia may and consequent hyperacidity inactivates pancreatic also be associated with the underlying disease causing enzymes; EPI. For instance, iron deficiency anaemia is often a d. Pancreatic and gastrointestinal surgery – any sur- manifestation of celiac disease. Ileal involvement in gical procedure in upper gastrointestinal tract is asso- Crohn disease or ileal resection can cause megalo- ciated with disturbance of neuro-humoral balance, re- blastic anaemia due to vitamin B-12 deficiency. duced pancreatic stimulation or loss of pancreatic pa- renchyma that leads to EPI (5, 11–13). Vitamin K is a fat-soluble vitamin which is absorbed with fats and is an essential cofactor in synthesis of CLINICAL PICTURE coagulation factors. Vitamin K deficiency predisposes The hallmark of severe EPI, when more than 90% of patients to haemorrhagic diathesis, which is clinically acinar cell are destroyed, are steatorrhea and uninten- visible as ecchymosis, though melena and haematuria tional weight loss (6, 7). However, clinical manifesta- may occur on occasion. Metabolic bone disease tions of EPI can vary widely, depending on the stage caused by vitamin D deficiency, a core vitamin in cal- of disease. Clinical features directly reflect the im- cium regulation, can result in osteopenia or osteoporo- paired absorption of maldigested nutrients. Patients sis. Rarely, osteomalacia with bone pain and patholog- often complain about nonspecific gastrointestinal ic fracture occur. Persistent low calcium levels lead to symptoms such as watery diarrhoea, flatulence, ab- compensatory secondary hyperparathyroidism dominal discomfort and cramps. Peripheral oedema or even ascites indicates severe protein malabsorption. Other manifestations of fat-soluble vitamin deficien- cies are rarely seen today. However, generalized mo- A complete laboratory evaluation is crucial in the as- tor weakness is seen with hypovitaminosis D, periph- sessment of a patient with suspected EPI. It deter- eral neuropathy reflects thiamine deficiency, B12 defi- mines the extent of malabsorption and assesses mani- ciency causes loss of the sense of vibration and posi- festations such as hypoalbuminemia, coagulation dis- tion, hypovitaminosis A provokes night blindness and order, osteopenia and anaemia. biotin deficiency is a reason for seizures. Steatorrhea is the result of fat malabsorption and is DIAGNOSIS OF EPI characterized by pale, bulky, and malodorous stools. Assessing patient with suspected EPI begins with a These stools often float on top of the toilet water with comprehensive overview of symptoms, obtaining rele- oily droplets and are difficult to flush. vant patient history and a clinical examination. Fol- lowing that, various tests for EPI are used. These are Another common, yet nonspecific symptom is unin- classified as direct versus indirect measures of exo- tentional weight loss. However, differential diagnosis crine pancreatic function. Many of tests used have of weight loss is broad and could be associated with poor sensitivity or specificity, especially in investiga- EPI comorbidities or other enteropathy like celiac dis- tion of milder forms (see Tabel 1). In everyday clini- ease or inflammatory bowel disease. cal practice, the most widely used test is the determi- nation of faecal elastase level. However, secretin Flatulence, bloating and abdominal colic occurs when MRCP, an indirect test, has been showing promising indigested food enters colon and is then fermented by results and is more extensively used (14). Another non colonic bacteria. Bacterial fermentation of unabsorbed -invasive 13C mixed triglyceride breath test is of lim- food substances releases gaseous products (hydrogen ited value, because it is available just at selected few and methane), which distend intestine, causing flatu- centres, specifically for studying purpose (see Tabel lence and cramps. 2). Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 74 Secretion of pancreatic enzymes and bicarbo- nate Fecal Elastase (Secretin-CCK test) Mild > 75% 100–200 mcg/g Moderate 30–75% 50–100 mcg/g Severe < 30% <50 mcg/g Tabel 1: Classification of EPI based on secretin CKK test and fecal elastase (1, 5). TEST SENSITIVITY SPECIFITY DIRECT STIMULATION Secretin-CCK test 89–97 % >90 % Lundh's test 88–92 % >90 % Endoscopic secretin test 70–80 % Not available Secretin MRCP 80–85 % 90% INDIRECT TESTS Pancreolauryl test 39–100 % 55-100 % FECAL TEST Fecal elastase-1 37–100 % 93 % Chymotrypsin 25–96 % 84 % BREATH TEST 13C-MTG breath test 70–81 % Not available Tabel 2: Diagnostic specifity and sensitivity of tests for exocrine pancreatic function (1, 14). Tests for exocrine function of pancreas: PERT are orally available pancreatic enzymes extract- Direct tests ed from porcine pancreas, which could be diagnostic 1. Lundh's test; as well as therapeutic. Empiric trail in patients with 2. Stimulation with exogenous hormones; suspected EPI is in some case indicated without for- 3. Secretin test; mal testing, because clear response to therapy con- 4. Cholecystokinin (CCK) test; firms the diagnosis. Therapeutic goal of PERT therapy 5. Secretin-CCK test. is amelioration of symptoms, elimination of malab- sorption and prevention of malnutrition - related mor- Indirect tests bidity and mortality. 1.Serum trypsinogen 2.Fecal fat test The overall daily dose of PERT should be divided be- 3. Fecal chymotrypsin and elastase determina- tween meals (for example 3 meals and 2 snacks, at tion which the dose for a snack is a half of that for a meal). 4.Pancreo- lauryl test Appropriate initial dose starts at 40.000–80.000 units 5.13C mixed triglyceride (13C-MTG) breath test of lipase per meal, and 10.000–20.000 units per snack. 6.Secretin MRCP According to EPI severity and persistence of symp- toms, the dose is up-titrated to the maximum daily TREATMENT dose of 10000 units of lipase/per mass/day (15). In Treatment of EPI is multimodal and consists of die- patients with EPI and an incomplete response to tary and lifestyle modifications (well-balanced, low PERT, an addition of proton pump inhibitor (PPI) can fat diet, cessation of alcohol consumption and smok- lead to enhanced PERT efficiency and an improve- ing); substitution of deficient microelements and fat- ment of response to treatment (1). soluble vitamins; however, the backbone of treat- ment is the pancreatic enzyme replacement thera- PERT is considered to have an overall safety and tol- py (PERT). erability profile with only few side effects. Among Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 75 them, the most common is constipation, which is often 9. Report of the expert committee on the diagnosis self-limiting (1). and classification of diabetes mellitus. Diabetes Care 2 003;26:Suppl 1:S5-20. 10. Sanklecha M, Balani K. Chronic pancreatic insuf- CONCLUSION ficiency-think of Shwachmann Diamond Syndrome. Indian Early diagnosis of EIP is of great importance as delay Pediatr 2012;49:417-8. prolongs malnutrition related complications, increase 11. Sah RP, Chari ST. Autoimmune pancreatitis: an update on classification, diagnosis, natural history and morbidity and mortality and lowers quality of life. Di- management. Curr Gastroenterol Rep 2012;14:95-105. agnosis of EPI remains a challenge in mild-to- 12. Ali S, N T, M Gagloo, S Dhar. Revisiting The moderate forms of the condition, due to the lack of a Problem Of Pancreatic Exocrine Insufficiency In Surgical reliable test available. Mild-to- moderate forms are Patients. Internet J Surg 2012;28. 13. Huddy JR, Macharg FM, Lawn AM, Preston SR. therefore often diagnosed late. Another reason for Exocrine pancreatic insufficiency following esophagecto- missed diagnosis seems to be secondary EPI, due to my. Dis Esophagus 2013;26:594-7. many non-pancreatic conditions that indirectly affect 14. Secretin-stimulated MR cholangiopancreatog- exocrine pancreases like diabetes, cystic fibrosis pan- raphy: spectrum of ...dosegljivo na https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC5110475/. creatic cancer etc. In these conditions EPI should be 15. Toouli J, Biankin AV, Oliver MR, Pearce CB, considered as possible cause of gastrointestinal symp- Wilson JS, Wray NH, Management of pancreatic exocrine toms. When diagnosis of EPI is made, it is necessary insufficiency: Australasian Pancreatic Club recommenda- to initiate PERT. Treatment with PERT leads to im- tions. Med J Aust 2010;193:461-7. proved nutrition, resolving malabsorption and in- creased quality of life and last, but not the least, it has significant influence on individual’s immunity. REFERENCES 1. Löhr M, Oliver M, Frulloni L. Synopsis of recent guidelines on pancreatic exocrine insufficiency. United European Gastroenterology Journal 2013;1:279-83. 2. Pancreas Study Group, Chinese Society of Gastro- enterology. Guidelines for the diagnosis and treatment of chronic pancreatitis. Chin J Dig Dis 2005; 6: 198-201. 3. King S, Collins C, Crowder T, Matson A, Volders E Nutritional management of cystic fibrosis in Australia and New Zealand. Nutr Dietet 2008;65: 253-8. 4. Banks PA, Freeman ML; Practice parameters com- mittee of the American College of Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006;101:2379-400. 5. Pancreatic Section, British Society of Gastroenter- ology; Pancreatic Society of Great Britain and Ireland; As- sociation of Upper Gastrointestinal Surgeons of Great Brit- ain and Ireland; Royal College of Pathologists; Special In- terest Group for Gastro-Intestinal Radiology. Guidelines for the management of patients with pancreatic cancer peri- ampullary and ampullary carcinomas. Gut 2005;54:Suppl 5:v1-v16. 6. Lowenfels AB, Sullivan T, Fiorianti J, Mai- sonneuve P. The epidemiology and impact of pancreatic diseases in the United States. Curr Gastroenterol Rep 2005;7:90-5. 7. Fine KD, Meyer RL, Lee EL. The prevalence and causes of chronic diarrhea in patients with celiac sprue treated with a gluten-free diet. Gastroenterology 1997;112:1830-8. 8. Dominguez-Munoz JE. Pancreatic enzyme therapy for pancreatic exocrine insufficiency. Curr Gastroenterol Rep 2007;9:116-22. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 76 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology NUTRITION IN ACUTE AND CHRONIC PANCREATITIS Sanela Banović* University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology *** ABSTRACT Nutritional support is different in acute and chronic pancreatitis. Enteral nutrition is unnecessary if the patient can consume normal food after 5-7 days. On the other side, EN should be established in patients with severe (necrotizing) pancreatitis. In chronic pancreatitis, about 80% of patients can be managed by analgesics, dietary recommendations and pancreatic enzyme supplements. 10–15% need oral nutritional supplements, 5% need enteral tube feeding and almost 1% require parenteral nutrition. Keywords: nutrition, acute and chronic pancreatitis, guidelines ACUTE PANCREATITIS Nutrition support - indication The two major forms of inflammatory pancreatic dis- 1. Mild pancreatitis: eases – acute and chronic pancreatitis – are different a) step I (2–5 days) – fasting: treat the cause of entities which require different nutritional approaches. pancreatitis, i.v. replacement of fluid and electrolytes It is generally accepted that nutritional management and analgesics; depends on the underlying pancreatic disease. Ap- b) step II (3–7 days) – refeeding: diet rich in carbo- proximately 75% of the patients with acute pancreati- hydrates, moderate in protein and fat; tis have a mild disease with a mortality rate well be- c) step III –no pain and normal enzymes: normal low 1% (31) as classified by the Atlanta criteria (32). diet. The majority of these patients can be managed with 2. Severe necrotizing pancreatitis – enteral nutrition standard supportive measures that do not need special is indicated first if possible. Enteral feeding has been nutritional treatment; most will resume a normal diet shown to reduce catabolism and the loss of lean body within 3–7 days. The mortality for mild-to-moderate mass, modulate the acute phase response, preserve pancreatitis is low, but increases to 19-30% for severe visceral protein metabolism and have the potential to pancreatitis. Mortality approaches 50% if necrosis of downregulate the splanchnic cytokine response. If the pancreatic gland is more than 50% and can in- complete enteral nutrition is not possible, nutritional crease up to 80% if sepsis occurs. Approximately half support should be combined with parenteral nutrition. of the deaths in acute pancreatitis occur within the first two weeks of illness and are mainly attributed to STEPS: organ failure. The remaining 50% of deaths occur 1. Start with aggressive fluid resuscitation; weeks-to-months after this period and are related to 2. Try to start with continuous enteral jejunal feed- organ failure associated with infective necrosis. ing over 24h with a polymeric–, elemental-or immune -enhancing diet; * Sanela Banović, MD, University Medical Centre Ljubljana, Slovenia, Clinical Department of Gastroenterology, Japljeva 2, SI–1000 Ljubljana. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 78 3. If side effects occur or the caloric goal cannot be outcome of patients with mild-to-moderate pancreati- achieved, TPN should be combined with enteral nutri- tis as defined by complication rate, days of oral food tion; intake, or by the total hospital stay. However, an in- 4. If enteral nutrition is not possible (e.g. prolonged crease in catheter-related infections was observed in paralytic ileus), TPN should be given with a small the patients receiving total parenteral nutrition. These amount of an elemental diet infused continuously into data indicate that total parenteral nutrition is associat- the jejunum according to tolerance (less 10-30 ml/h) ed with certain disadvantages. Besides the increased 5. The use of intravenous lipids as part of parenter- risk of catheter-related sepsis, severe hyperglycemia al nutrition is safe when hypertriglyceridemia (412 and other metabolic disturbances have been reported. mmol/l) is avoided. It is clear, therefore, that overfeeding is a major risk factor for complications in patients receiving parenter- Enteral nutrition: The use of early enteral feeding in al nutrition. In recent years, more concern has been patients with severe disease decreases, however, the expressed about the possibility of parenteral nutrition incidence of nosocomial infection, reduces the dura- adversely affecting gut barrier function. Whilst there tion of SIRS and decreases the overall disease severi- is more evidence to support this hypothesis in animals ty. Decisions involved in nutritional management are there is tenuous little evidence in clinical practice therefore driven by the disease severity. Greater sever- ity of the disease dictates the need for nutritional sup- Nutrient requirements (mild AP): K energy B25–35 port and predicts those patients with acute pancreatitis kcal/kg BW/day; K protein 1.2–1.5 g/kg BW/day; car- which most likely will benefit from nutritional thera- bohydrates 3–6 g/kg BW/day corresponding to blood py. Several factors remain to be clarified: optimal tim- glucose concentration (aim: o10 mmol/l); K lipids up ing of nutritional therapy, route of administration to 2 g/kg BW/day corresponding to blood triglyceride (jejunum or duodenum? stomach?) or parenteral and concentration (aim: o12 mmol/l): nutrient formulations remain uncertain at present due to the lack of controlled clinical trials in order to de- If the course of the disease is complicated by an MOF fine optimal nutritional therapy. It is clear, however, syndrome, then the calorie and protein requirements that enteral feeding is safe; jejunal tubes are well tol- have to be adapted. Lower protein loads B1.2 g/kg/ erated without an exacerbation of pancreatitis-related day should be given to patients with renal or hepatic symptoms. When the caloric goal with enteral nutri- failure. Monitoring urinary urea excretion may help to tion is not possible, parenteral nutrition should be meet actual nitrogen requirements. used. Nutrient requirements (necrotising AP): energy 15- Parenteral nutrition: Total parenteral nutrition has 20 kcal/kg BW/day- in early phase of catabolism, pro- been the standard treatment for providing nutrients to tein 1,2-1,5 g/kg BW/day – in case of acute liver fail- patients with severe acute pancreatitis. The concept ure 1 g/kg TT/per day, carbohydrates 36 g/kg ideal behind this strategy was two-fold: firstly, to avoid BMI (need to control blood glucose), lipids to 2 g/kg stimulation of exocrine pancreatic secretory responses ideal BMI (blood triglyceride concentration). (‘to put the pancreas at rest’) and secondly, to improve the nutritional status of the patient. The evidence in CHRONIC PANCREATITIS favor of intravenous feeding is, however, not support- Chronic pancreatitis (CP) is an inflammatory disorder ed by clinical trials. Two clinical prospective studies that causes irreversible anatomical changes and dam- have been performed on the use of parenteral nutrition age, including infiltration of inflammatory cells, fibro- in acute pancreatitis. The study of McClave et al. sis and calcification of the pancreas with destruction compared nasojejunal feeding with total parenteral of the glandular structure and thereby affects normal nutrition showing no difference on the outcome but digestion and absorption of nutrients. the costs for enteral nutrition was four times lower. In the study of Sax et al., intravenous feeding was com- Maldigestion is often a late complication of CP and pared with no nutritional support. The results demon- depends on the severity of the underlying disease. The strated that intravenous nutrition did not affect the medium latency between onset of first symptoms and Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 79 signs of maldigestion is about 8–9 years in alcoholic dominal surgery have provided evidence that preoper- CP and more than 15 years in idiopathic non-alcoholic ative enteral or oral nutrition support with an immune- pancreatitis. Nutrient deficiencies are common in CP, enhancing diet improves outcome by reducing the driven by many risk factors including malabsorption, prevalence of postoperative infective complications diabetes and, in alcoholic CP, alcoholism. However, and duration of hospital stay. deficiencies are frequently overlooked, leading to mal- nutrition. Parenteral nutrition is very seldom used in patients with chronic pancreatitis. PN must be instituted if: During the course of chronic pancreatitis, enzyme se- gastric emptying is blocked, the patient needs gastric cretion is decreased, resulting in maldigestion with decompression, a tube cannot be introduced into the steatorrhoea and azotorrhoea. Deficiencies of fat- jejunum or complicated fistula s present. soluble vitamins are the consequence of steatorrhoea. CONCLUSION About 80% of patients can be managed by analgesics, Nutrition support is very important in acute and dietary recommendations and pancreatic enzyme sup- chronic pancreatitis. Nutritional deficiencies can occur plements, 10–15% need oral nutrition supplements, in AP and CP. We have oral, enteral and parenteral 5% need enteral tube feeding and less of 1% need par- way of feeding. It is very important to know the me- enteral nutrition. tabolism in normal and pathological conditions. Nutrient requirements – active patients: 30-35 kcal/ REFERENCES kg TT/per day. 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Despite bio-medical advances, cancer remains a disease that is frequently associated with pain, suffering and death. Clearly, cancer is not just a one-time event that leads to certain death, but is a long-term chronic dis- ease. A number of studies have shown that psychiatric disorders are more common amongst cancer patients. The most common psychiatric disorders include depression and anxiety. In pancreatic cancer of particular in- terest are symptoms of depression. There has been a long held belief among clinicians that pancreatic cancer patients at times have a history of unexplained depression and distress that preceded the appearance of physi- cal symptoms. There are marked differences in the occurrence of severe depression in both acute and chronic illnesses, which reflect the meaning to the individual patient in terms of threat, disability, pain and other s ymptoms. It is not uncommon for depressive symptoms to be accompanied by other comorbid psychiatric symptoms and disorder whose occurrence and pattern again relates to the type of illness. Symptoms of depres- sion not only lead to a deterioration in a cancer patients’ quality of life, but also represent an independent fac- tor that affects their survival. Depressed cancer patients also suffer a higher rate of recurrence and more pain than patients that do not suffer from depression. It is therefore important that depression is diagnosed in a timely manner and properly treated. Although depression and anxiety disorders are the psychiatric symptoms most common to all cancer and chronically ill patients, they remain largely undetected or are overlooked. These symptoms warrant evaluation and the use of pharmacologic, psychological and social interventions to relieve suffering. Suffering should not be regarded as an “unavoidable” consequence of cancer. Recognition of the treatment of depression in relation to acute and chronic physical illness remains a major challenge for medicine and for those psychiatrists who work with medical patients. The trend followed in recent years clearly stresses the importance for integrating psychosocial aspects into routine medical care. The need for a multidisciplinary approach is highlighted by the fact that physical and emotional component of psychological burden are inextricably mingled in these patients. Without multidisciplinary efforts it is not possible to imple- ment goals of psycho-oncology, palliative care, and “quality of life” into routine care. Keywords: depression, anxiety, psychiatric disorders, chronically ill patients, cancer patients, psycho- oncology, treatment, multidisciplinary approach * Zvezdana Snoj, MD, PhD Clinic of Integrative Psychiatry and Psycho-oncology EIRINI, Ljubljana, Slovenia. Pancreatic Diseases. Textbook of Selected Topics in Clinical Gastroenterology 83 PANCREATIC DISEASES Textbook of Selected Topics in Clinical Gastroenterology The textbook entitled “Pancreatic Diseases. A Text- The textbook “Pancreatic diseases. Textbook of book of Selected Topics in Clinical Gastroenterolo- selected topics in Clinical Gastroenterology” pre- gy” comprises of an editorial and 12 chapters, in sents a thorough illustrated review on the subject. which the authors discus modern diagnostics as The book consists of an editorial and 12 chapters. Its wheel as the management and treatment of patients contents include description of various pathologies, with pancreatic diseases. The contributions describe underlying mechanisms, diagnostic procedures and the most common and rare clinical conditions that treatments of the diseases and their symptoms. Also, arise because of a malfunction of the pancreas. The each chapter presents a survey of relevant basic and textbook describes the etiology of pancreatic diseas- recent literature on the corresponding subject. The es, their clinical course, and lists algorithms in mod- descriptions in the textbook are clear and written in ern diagnostic treatments. Special attention is devot- good English language. The textbook collects vari- ed to the treatment of pancreatic diseases; including ous aspects on pancreatic diseases valuable for spe- modern methods of surgical treatment of the most cialists, general medical audience and students. complex pancreatic diseases and the role of systemic Veronika KRALJ-IGLIČ treatment of pancreatic cancer. The reader gets com- prehensive information on novelties in the diagnostic and therapeutic treatments of patients from different perspectives of medical professions. The textbook also addresses the quality of life of patients with pancreatic diseases from a medical and social point of view. Highlighted is the psychological importance of treating patients with chronic diseases and the role of relatives in maintaining the quality of life of these patients. The textbook is an important and high quality contri- bution to the domestic and international multidisci- plinary professional public, which focuses on a par- ticularly demanding field of gastroenterology. Vladka SALAPURA