# 15.26.2 Chronic pancreatitis 3218 # 15.26.2 Chronic pancreatitis 3218 section 15  Gastroenterological disorders 3218 Specific complications of acute pancreatitis Acute pancreatic pseudocyst It is rare that an acute inflammatory collection persists beyond 4 weeks and contains little or no debris (as required by the Atlanta definitions). Unfortunately, necrosis is poorly demonstrated by CT (MRI is more sensitive), and an acute fluid collection on CT may appear homogeneous. Pancreatic pseudocyst most commonly oc- curs in the lesser sac and often represents a closed pancreatic fis- tula, as a breach in the main or major pancreatic duct can frequently be demonstrated by ERCP. Transpapillary duct stenting and ERCP should be avoided if possible as these lead to the introduction of in- fection in more than 10% of patients. In the absence of sepsis, fluid-​ predominant acute fluid collections may be adequately drained as a one-​step procedure by EUS-​guided endoscopic transmural pro- cedures, although repeated tract dilatation is often required. By contrast, solid-​predominant acute fluid collections, especially in younger, fit patients, may be best dealt with by internal surgical drainage to the stomach or to a defunctioned Roux loop of jejunum. This procedure can be done either laparoscopically or during open surgery, depending on local expertise, and can also be combined with a cholecystectomy. Haemorrhage Poorly controlled sepsis within a collection can present with acute internal haemorrhage into a collection, or bleeding from a drain site (Fig. 15.26.1.4a). Venous bleeding can be controlled by tam- ponade, but arterial haemorrhage requires urgent CT angiography, proceeding to angiographic embolization where appropriate. Where this is unsuccessful and surgical intervention is required, the prog- nosis is grave as the bleed is usually associated with a combined hypovolaemic and septic deterioration and associated multiple organ dysfunction. Visceral fistulation Spontaneous discharge of a postacute collection into the gastro- intestinal tract is not uncommon and can decompress the collec- tion and result in clinical improvement. Fistulation into the lower gastrointestinal tract often results in a poorly drained collection and defunctioning ileostomy or resection of the affected segment is then required (Fig. 15.26.1.4b). Pancreatic ascites This condition rarely occurs in association with acute pancreatitis, but when it does it is due to spontaneous decompression of a pancre- atic pseudocyst, with escape of pancreatic juice into the peritoneal cavity. Amylase-​rich fistula fluid is common after percutaneous drainage, when internal control can often be successfully achieved by endoscopic transpapillary drainage. Splenic and portal vein thrombosis The use of CT to monitor progress has resulted in the increased recognition of splenic and segmental portal vein thrombosis. Splenic vein thrombosis does not usually require treatment, but thrombus in the portal or superior mesenteric vein requires anticoagulation either with low molecular weight heparin or war- farin (Fig. 15.26.1.4c). FURTHER READING Appelros S, Borgstrom A (1999). Incidence, aetiology and mortality rate of acute pancreatitis over 10 years in a defined urban popula- tion in Sweden. Br J Surg, 86, 465–​70. Banks PA, et al. (2013). Classification of acute pancreatitis –​ 2012: re- vision of the Atlanta classification and definitions by international consensus. Gut, 62, 102–​11. Cotton PB, et al. (2016). Rome IV. Gallbladder and sphincter of Oddi disorders. Gastroenterology, 150, 142–​9. Hollemans RA, et al. (2015). Predicting success of catheter drainage in infected necrotizing pancreatitis. Ann Surg, 263, 787–​92. Moretti A, et al. (2008). Is early endoscopic retrograde cholangiopan­ creatography useful in the management of acute biliary pancreatitis? A meta-​analysis of randomized controlled trials. Dig Liver Dis, 40, 379–​85. Petrov MS, et al. (2008). Early endoscopic retrograde cholangiopan­ creatography versus conservative management in acute biliary pancreatitis without cholangitis:  a meta-​analysis of randomized trials. Ann Surg, 247, 250–​7. van Brunschot S, et al. (2018). Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial. Lancet, 391(10115), 51–8. van Santvoort HC, et al. (2010). A step-​up approach or open necro­ sectomy for necrotizing pancreatitis. N Engl J Med, 362, 1491–​502. Villatoro E, Mulla M, Larvin M (2010). Antibiotic therapy for prophy- laxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev, 5, CD002941. Wilson C, Heath DI, Imrie CW (1990). Prediction of outcome in acute pancreatitis: a comparative study of APACHE II, clinical assessment and multiple factor scoring systems. Br J Surg, 77, 1260–​4. Working Group IAP/​APA Acute Pancreatitis Guidelines (2013). IAP/​APA evidence-​based guidelines for the management of acute pancreatitis. Pancreatology, 13 Suppl 2, e1–​15. 15.26.2  Chronic pancreatitis Marco J. Bruno and Djuna L. Cahen ESSENTIALS Chronic pancreatitis is a major source of morbidity, loss in quality of life, and healthcare expenditure. It is most commonly caused by chronic alcoholism in adults and cystic fibrosis in children, but there are many other causes. Patients typically present with severe abdom- inal pain, but this may vary and even be absent. Exo-​ and endocrine insufficiency usually occur late in the disease course and reflect per- manent loss of pancreatic parenchyma due to ongoing inflamma- tion and fibrosis, exocrine insufficiency, manifesting as steatorrhea and weight loss due to fat maldigestion and endocrine insufficiency as diabetes mellitus. Diagnosis is confirmed by imaging investigations such as CT, MRI, and endoscopic ultrasonography. Endoscopic retrograde cholan­ giopancreatography to diagnose chronic pancreatitis is obsolete. 15.26.2  Chronic pancreatitis 3219 Hormone stimulation tests (e.g. secretin–​cholecystokinin stimulation test) to diagnose exocrine insufficiency are largely abandoned because of their complexity and burden to patients. They are replaced by faecal elastase testing, even though this test is less sensitive. Management focuses on the treatment of pain using a stepwise approach. Initially, nonopioid analgesics are prescribed. Next, when feasible, endoscopic therapy is initiated, including pancreatic stone fragmentation by extracorporeal shock-​wave lithotripsy, endotherapy to remove stone fragments, and placement of plastic stents to dilate any concomitant pancreatic duct strictures. If that fails or when, for example, the pancreatic head is enlarged, surgical intervention is in- dicated. Medical management includes enteric-​coated pancreatic enzyme preparations and treatment of diabetes mellitus, usually by means of insulin. Abstinence from alcohol and smoking are important predictors of disease and treatment outcome. Introduction Chronic pancreatitis is an ongoing inflammatory disorder, char- acterized by irreversible structural and functional impairment of the pancreas. This is in contrast to acute pancreatitis, which is a re- versible condition. Chronic pancreatitis evolves slowly, over 10 to 20 years, and is often associated with disabling pain and loss of pancreatic function. The disease is relatively rare, but its prevalence is increasing, probably due to increased alcohol and tobacco use. Moreover, im- proved imaging techniques provide opportunities to detect the disease at an earlier stage. Treatment is challenging because of the variability in aetiology and presentation, the unpredictability of the disease course, and the lack of prospective evidence regarding treatment options. Aetiology The M-​ANNHEIM classification recognizes that chronic pancrea- titis is a complex disease in which multiple causative risk factors are likely to interact (Table 15.26.2.1). Alcohol has long been recog- nized as a risk factor and more recently, cigarette smoking has been added as an independent, dose-​related risk. Together, alcohol and smoking are responsible for over 60% of chronic pancreatitis cases and are a major determinant of disease progression. Hereditary pan- creatitis refers to the expression of a disease-​causing gene mutation. Familial pancreatitis refers to pancreatitis that occurs in a family with an incidence higher than would be expected by chance alone: it may or may not be caused by a genetic defect. Idiopathic pancreatitis is defined as pancreatitis in isolated cases in which other causes of the disease have been excluded. Epidemiology Chronic pancreatitis is a major source of morbidity, loss in quality of life, and healthcare expenditure. Its incidence is esti- mated at 4 to 14 per 100 000 per year and its prevalence as 42 to 50 per 100 000, albeit with marked geographical variation. It is ranked in the top 10 of digestive disease diagnoses in hospital registra- tions. In the United Kingdom (63 million inhabitants), it has been shown that patients with chronic pancreatitis consume a dispro- portionately high volume of resources, with costs estimated at £285.3 million per year. Over the years, the incidence of chronic pancreatitis has mark- edly increased, mainly due to an increase in the diagnosis of alcohol-​related chronic pancreatitis, although heightened clinical awareness and increased use of cross-​sectional imaging modalities (CT, MRI) and endoscopic ultrasonography (EUS) may also con- tribute. Traditionally, the disease was more common in men, but nowadays men and women are almost affected equally. Racial differences in the incidence have been reported, with African Americans affected two to three times more than Caucasians, but it remains unclear whether this is explained by differences in genetic susceptibility or by environmental and societal factors. Pathogenesis/​pathology The pathophysiological mechanisms and natural course of chronic pancreatitis are not well understood. The 1984 Cambridge system Table 15.26.2.1  The M-​ANNHEIM multiple risk factor classification of chronic pancreatitis M Pancreatitis with Multiple risk factors A Alcohol consumption:   Excessive (>80 g/​day)   Increased (20–​80 g/​day)   Moderate (<20 g/​day) N Nicotine consumption (in cigarette smokers: description by pack-​years) N Nutritional factors:   Nutrition (e.g. high caloric proportion of fat and protein)   Hyperlipidaemia H Hereditary factors:   Hereditary pancreatitis   Familial pancreatitis   Early-​onset idiopathic pancreatitis   Late-​onset idiopathic pancreatitis   Tropical pancreatitis (possible mutations in the PRSS1, CFTR,   or SPINK1 genes) E Efferent duct factors:   Pancreas divisum   Annular pancreas and other congenital abnormalities of the   pancreas   Pancreatic duct obstruction (e.g. tumours)   Post-​traumatic pancreatic duct scars   Sphincter of Oddi dysfunction I Immunological factors:   Autoimmune pancreatitis   Sjögren’s syndrome-​associated chronic pancreatitis   Inflammatory bowel disease-​associated chronic pancreatitis   Chronic pancreatitis with autoimmune diseases (e.g. primary   sclerosing cholangitis, primary biliary cirrhosis) M Miscellaneous and rare metabolic factors:   Hypercalcaemia and hyperparathyroidism   Chronic renal failure   Drugs   Toxins section 15  Gastroenterological disorders 3220 stated that acute and chronic pancreatitis were two completely separate disease entities. Later, in the proceedings of the Second International Symposium on the Classification of Pancreatitis in Marseille, it was acknowledged that acute pancreatitis can progress to chronic disease, albeit seldom. The so-​called necrosis–​fibrosis theory connects both entities by explaining that development of fi- brosis with obstruction of pancreatic ducts is triggered by ongoing acute inflammation. This finally evolved into the ‘sentinel acute pancreatitis event’ (SAPE) hypothesis, which suggests that acute and chronic pancreatitis constitute different ends of a disease con- tinuum, the latter being triggered by the former, provided that there is ongoing damage to the pancreas, for example, by repeated bouts of acute inflammation. Observational studies indicate that about 10% of patients with a first episode of pancreatitis and a third of patients with recurrent episodes develop chronic disease, the risk being higher among smokers, alcoholics, and men. When the initial pancreatitis attack is not too severe, anti-​ inflammatory mechanisms prevent further influx of macrophages and activation of stellate cells, leading to a full clinical, morpho- logical, and functional recovery. However, when the initial hit is of sufficient severity, or when recurrent acute pancreatitis attacks occur (second hit), this may act as a driving force to attract mono- cytes which become resident macrophages. Through the produc- tion of transforming growth factor-​β, such macrophages activate pancreatic stellate cells, leading to glandular fibrosis. Several life- style factors known to induce oxidative stress (e.g. smoking and al- cohol use) promote ongoing or recurrent inflammation and acinar cell injury. A genetic predisposition also plays an important role in the pathogenesis of chronic pancreatitis. The classical example is her- editary pancreatitis, in which autosomal dominant mutations in the cationic trypsinogen genes (PRSS1, -​2, and -​3) cause a severe form of chronic pancreatitis that develops in 80% of affected indi- viduals, starting in early childhood. Other known polymorphisms related to the development of chronic pancreatitis include muta- tions in genes such as CTRC (chymotrypsin C), CASR (calcium sensing receptor), CTSB (cathepsin B), SPINK1 (serine protease inhibitor kazal type 1), CFTR (cystic fibrosis transmembrane conductance regulator), and CLDN2 (claudin 2). The import- ance of genetic susceptibly is exemplified by the discovery of mu- tations in half of the patients with presumed idiopathic chronic pancreatitis. The combined effect of various risk factors, for ex- ample, moderate drinking, smoking, and having a mutation in one of the relevant genes, is poorly understood. This also is a likely explanation of why certain people develop chronic pancreatitis, while others do not, despite being exposed to the same environ- mental risk factors. Clinical features Pain Pain is the most prominent symptom in patients with chronic pancreatitis. Classically, pancreatic pain is located in the epigas- trium and radiates to the back. It may be chronic or intermittent and is frequently aggravated or provoked by food intake. It is often accompanied by nausea and vomiting. Over 90% of patients are hospitalized for debilitating pain at least once in their lifetime. Patients suffering from constant pain are admitted to a hospital more than five times as frequently as those with intermittent pain. A few patients do not have pain but may develop pancreatic insufficiency. Chronic pancreatitis may run an unpredictable course. Often there is a discrepancy between the severity of clinical symptoms and the extent of morphological changes; in other words, patients with minor morphological changes on imaging may have se- vere pain, while patients with prominent ductal dilation and large intrapancreatic stones may be completely asymptomatic. Pain in chronic pancreatitis is thought to be multifactorial, resulting from increased ductal and parenchymal pressure due to pancreatic duct obstruction caused by strictures and stones, neuropathic changes due to entrapment of pancreatic nerves by fibrotic tissue and injury due to oxidative stress, and centrally acting mechanisms related to chronic exposure to pain stimuli. Psychosocial factors and coping mechanisms (personal and social network) are deemed of great im- portance in the perception of pain and the requirement and depend- ence on (opioid) analgesics. Quality of life Chronic pancreatitis has an adverse effect on quality of life. The dis- ease burden is often such that it interferes with normal daily activ- ities and work productivity, and many patients become unemployed. Patients often suffer from severe opioid-​dependent chronic pain, chronic fatigue, and fear of future health problems. Exo-​ and endocrine function More than half of chronic pancreatitis patients develop exocrine pancreatic insufficiency at some point in their disease course. On average, it takes 5 to 8 years to develop exocrine insufficiency as more than 90% of maximal secretory capacity of pancreatic en- zymes needs to be lost before clinical symptoms develop. Symptoms include fat malabsorption with steatorrhea (fatty, pale coloured, voluminous, fool smelling stool), abdominal pain and discom- fort, weight loss, and deficiencies of fat-​soluble vitamins (A, D, E, K). Besides fat digestion due to lipase deficiency, protein (prote- ases deficiency) and carbohydrate (amylase deficiency) digestion also are affected. From a clinical perspective, however, treatment of fat maldigestion and adequate supplementation of lipase is the hallmark of treatment because there are endogenous compensa- tory mechanisms for protein and carbohydrate digestion. Lately, it has become apparent that metabolic bone disease secondary to osteopenia (45%) and osteoporosis (10%) occurs more frequently in patients with chronic pancreatitis compared to a reference popu- lation, even in exocrine-​sufficient patients. More than half of all patients with chronic pancreatitis develop diabetes mellitus, which most often occurs after exocrine pancre- atic insufficiency has developed, some 10 to 15 years after disease onset. This form of pancreatogenic diabetes is referred to as type 3c diabetes mellitus. It differs from diabetes type 1 and 2 with regard to the underlying pathophysiological mechanism as well as the clin- ical consequences. In pancreatogenic diabetes, there is a loss of com- plete islet cell mass. Therefore, not only insulin function is affected, such as in type 1 diabetes mellitus (reduced number of β cells) and type 2 diabetes mellitus (insulin resistance), but also the function of 15.26.2  Chronic pancreatitis 3221 counter-​regulatory hormones such as glucagon and pancreatic poly- peptide. This renders patients with pancreatogenic diabetes more susceptible to hypoglycaemia. Prognosis The life expectancy of patients with chronic pancreatitis is signifi- cantly lower than that of the general population. In some series, years of life lost are reported to be as high as 10 to 15. Principal causes of death are often indirectly related to chronic pancreatitis and associated with a lifestyle of self-​neglect and chronic substance abuse, for instance, lung and throat cancer (due to heavy cigarette smoking), malnutrition, complications of diabetes including cardio- vascular events, and suicide. Chronic pancreatitis also confers an in- creased risk for developing pancreatic cancer, with a relative risk of 2 to 5 and an absolute risk of 4% per 20 years. Recent studies from Denmark suggest that, according to the duration of pancreatitis, the risk of cancer may be greater. Other complications Pancreatic pseudocysts are among the most common complications and occur in about a quarter of patients. Cysts may develop in the course of an exacerbation (‘acute-​on-​chronic pancreatitis’) or as a result of ductal disruption or obstruction. Depending on the size, location, and whether the content is sterile or not, pseudocysts may be asymptomatic. Larger cysts may give rise to pain, gastric outlet obstruction, or biliary obstruction. Biliary obstruction may also be caused by a benign stricture of the intrapancreatic portion of the common bile duct. Vascular complications include portal and splenic vein thrombosis in case of recurrent or ongoing acute in- flammation and, rarely, an acute bleeding from a pseudoaneurysm, which is mostly located in the wall of a pseudocyst. Differential diagnosis The M-​ANNHEIM diagnostic criteria classification system ranks the probability of a patient having chronic pancreatitis into three categories; definite, probable, or borderline (Box 15.26.2.1). When obvious risk factors are involved and characteristic mor- phological features are present (i.e. pancreatic duct dilation and calcifications), the diagnosis of chronic pancreatitis does not pose much of a challenge. In advanced cases, however, the possibility of concurrent pancreatic cancer must always be considered, in particular when a patient with previous stable disease develops new symptoms such as weight loss, jaundice, or diabetes. The M-​ANNHEIM clinical staging system for chronic pancreatitis is shown in Table 15.26.2.2. A challenging disease entity that is increasingly being recognized is so-​called early chronic pancreatitis. These patients have symp- toms resembling pancreatic-​type pain, but without morphological or functional abnormalities of the pancreas. In such cases, EUS may be helpful to establish a diagnosis of ‘early chronic pancreatitis’ (see ‘Clinical investigations’). Autoimmune pancreatitis is a unique form of pancreatitis. Type 1 autoimmune pancreatitis is the classical form, histologically characterized as ‘lymphoplasmacytic sclerosing pancreatitis’ and part of a systemic relapsing–​remitting immune-​mediated fibroinflammatory IgG4-​related disease, which can involve mul- tiple organs (i.e. biliary tract, kidneys, and salivary glands) and re- lapses frequently. Type 2, or ‘idiopathic duct-​centric pancreatitis’, is histologically characterized by granulocyte epithelial lesions, with few or no IgG4-​positive cells. The diagnosis of autoimmune pancreatitis is challenging. In some cases, it may resemble the clin- ical presentation of pancreatic cancer. It has a dramatic response to immunosuppressive medication, with quick resolution of as- sociated symptoms. Nevertheless, many patients develop chronic pancreatitis-​like features, including pancreatic duct abnormalities and glandular atrophy. After a median follow-​up of 6 years, about half of the patient still use immunosuppressive medication to pre- vent relapses and exocrine and endocrine insufficiency are highly prevalent, 82% and 57% respectively. In patients presenting with isolated exocrine insufficiency but without abdominal pain, the Shwachman–​Diamond syn- drome must be considered, which is the second most common cause for exocrine pancreatic insufficiency in children, after cystic fibrosis. Box 15.26.2.1  M-​ANNHEIM diagnostic criteria of chronic pancreatitis The diagnosis of chronic pancreatitis requires a typical clinical history (such as recurrent pancreatitis or abdominal pain, except for primary painless pancreatitis) Based on these features, three forms are defined: Definite chronic pancreatitis Definite chronic pancreatitis is established by one or more of the fol- lowing additional criteria: 1 Pancreatic calcifications 2 Moderate or marked ductal abnormalities (according to the Cambridge classification) 3 Marked and persistent exocrine insufficiency, defined as pancreatic steatorrhea markedly reduced by enzyme supplementation 4 Typical histology of an adequate histological specimen Probable chronic pancreatitis Probable chronic pancreatitis is established by one or more of the fol- lowing additional criteria: 1 Mild ductal alterations (according to the Cambridge classification) 2 Recurrent or persistent pseudocysts 3 Pathological test of pancreatic exocrine function (such as faecal elastase-​1 test, secretin test, or secretin–​pancreozymin test) 4 Endocrine insufficiency (i.e. abnormal glucose tolerance test) Borderline chronic pancreatitis Borderline chronic pancreatitis is already established and is defined by a typical clinical history of the disease, but without any of the add- itional criteria required for a definite or probable diagnosis. This form is also established as a first episode of acute pancreatitis with or without (1) a family history of pancreatic disease (i.e. other family members with acute pancreatitis or pancreatic cancer) or (2)  the presence of M-​ANNHEIM risk factors. Pancreatitis associated with alcohol consumption Pancreatitis associated with alcohol consumption requires in addition to the above-​listed criteria, one of the following features: 1 History of excessive alcohol intake (>80 g/​day for some years in men, smaller amounts in women), or 2 History of increased alcohol intake (20–​80 g/​day for some years), or 3 History of moderate alcohol intake (<20 g/​day for some years) section 15  Gastroenterological disorders 3222 Clinical investigation Imaging Transabdominal ultrasonography is a rapid, noninvasive, and in- expensive diagnostic tool, but not well suited to diagnose chronic pancreatitis. It lacks sensitivity and specificity, in particular in less advanced cases. CT allows for a comprehensive diagnostic evaluation of the pan- creas and surrounding organs. The diagnosis and staging of chronic pancreatitis relies on the presence and severity of dilatation of the pancreatic duct and its side branches, pancreatic calcifications, and parenchymal atrophy (Fig. 15.26.2.1). It is also helpful to screen for complications, such as pseudocysts, portosplenic venous throm- bosis, arterial pseudoaneurysms, and pancreaticopleural fistulas. It is also useful to exclude other nonpancreatic abnormalities. MRI is a sensitive and specific diagnostic tool for the diagnosis of chronic pancreatitis and its complications. There are many different MRI techniques, conventional and more experimental methods, including perfusion MRI and diffusion-​weighted MRI. The latter technique has the potential to diagnose chronic pancreatitis at an early stage as it can measure the diffusion of water molecules, which is likely to be diminished in the case of fibrosis. Parenchymal fea- tures of chronic pancreatitis on conventional MRI include abnormal (a) (c) (d) (b) Fig. 15.26.2.1  CT series in a patient with chronic pancreatitis. A large obstructing intraductal stone is visible in the main pancreatic duct within the pancreatic head ((a), arrow) with upstream dilation and an associated pancreatic pseudocyst ((b), arrow). In the pancreatic tail, multiple stones are visible both in the main pancreatic duct as well as within the pancreatic parenchyma ((c, d) arrows). Table 15.26.2.2  M-​ANNHEIM clinical staging of chronic pancreatitis Asymptomatic chronic pancreatitis 0: subclinical stage a: period without symptoms (determination by chance, e.g. autopsy) b: acute pancreatitis—​single episode (possible onset of chronic pancreatitis) c: acute pancreatitis with severe complications Symptomatic chronic pancreatitis I: stage without pancreatic insufficiency a: (recurrent) rcute pancreatitis (no pain in between episodes)* b: recurrent or chronic abdominal pain (including pain in between episodes of acute pancreatitis) c: I a/​b with severe complications II: stage of partial pancreatic insufficiency a: isolated exocrine (or endocrine) pancreatic insufficiency (without pain) b: isolated exocrine (or endocrine) pancreatic insufficiency (with pain) c: II a/​b with severe complications III: stage of painful complete pancreatic insufficiency a: exocrine and endocrine insufficiency (with pain, e.g. requiring pain medication) b: III a with severe complications IV: stage of secondary painless disease (burnout) a: exocrine and endocrine insufficiency without pain or severe complications b: exocrine and endocrine insufficiency without pain, but with severe complications 15.26.2  Chronic pancreatitis 3223 decreased signal intensity on fat-​suppressed T1-​weighted images and delayed and limited enhancement after contrast administration. Its diagnostic accuracy can be augmented by using hormonal stimu- lation of the pancreas by means of intravenous secretin to stimu- late exocrine secretion in order to search for subtle changes in the pancreatic ductal system caused by early periductal fibrosis, and by quantitatively measuring pancreatic fluid excretion into the duo- denal lumen using multislice fast T2-​weighted sequences to evaluate the exocrine pancreatic function. EUS may be particularly sensitive to detect early morphological changes in chronic pancreatitis. Ductal and glandular features that are suggestive of early fibrosis include hyperechoic foci, strands, in- creased lobularity, hyperechoic duct margins, and atrophy. In the Rosemont EUS classification for early pancreatitis, the likelihood of (early) chronic pancreatitis is based on the presence of minor criteria, including cysts, dilated ducts 3.5  mm in size or greater, irregular pancreatic duct contour, dilated side branches of at least 1 mm, hyperechoic duct wall, strands, nonshadowing hyperechoic foci, and lobularity with noncontiguous lobules, and major fea- tures, including hyperechoic foci with shadowing, main pancreatic duct calculi, and lobularity with honeycombing (Table 15.26.2.3, Fig. 15.26.2.2). Long-​term follow-​up will reveal whether this con- cept of early chronic pancreatitis, based on the presence of EUS criteria, holds. Pancreatic function tests Pancreatic function tests can be divided into direct and indirect tests, the former being dependent on direct hormonal (secretin) stimulation of the pancreas, and into noninvasive and invasive tests, the latter involving oral intubation. The oral intubation test, with collection of pancreatic secretions by means of duodenal fluid aspiration, is the most sensitive test and able to detect subtle im- pairment of pancreatic function before clinical symptoms have developed. However, the test is cumbersome and available only in selected tertiary referral centres where it is mainly used for research purposes. Generally, indirect noninvasive pancreatic function tests are used, including faecal trypsinogen, faecal elastase, 13C/​14C-​octanoate breath test, or faecal fat measurements. The latter is a test of fat (mal)digestion and not a pancreas-​specific function test. Overall, indirect pancreatic function tests are not very sensitive and usu- ally become positive when a patient has already developed clinical symptoms of maldigestion. False-​positive test results occur when, for example, faecal elastase measurements are performed in watery stools. Measuring faecal fat excretion is useful to quantity the de- gree of maldigestion. For a reliable assessment of the fecal fat ab- sorption coefficient, it is important to collect stool for 2 to 3 days after a run-​in period of 2 to 3 days while using a diet with a fixed fat intake between 80 and 100 g/​day. Management Abstinence from alcohol and smoking Alcohol and smoking are important factors in the initiation and disease progression of chronic pancreatitis. Often, physicians fail to discuss the negative impact of smoking. Both alcohol and smoking cessation should play a prominent role in chronic pan- creatitis treatment. Apart from giving information and support, patients should be encouraged to enrol in a substance abuse treat- ment programme. Pain relief Analgesics Most patients with chronic pancreatitis require analgesics. Acetaminophen and nonsteroidal anti-​inflammatory drugs are first line, but pain is often debilitating and half of the patients will require opioids. To prevent substance abuse in this susceptible patient group, tramadol, a less strong synthetic opioid derivate, may serve as an alternative. Other drug treatments Several drugs other than analgesics have been advocated for pain relief in chronic pancreatitis patients, but without solid evidence. Table 15.26.2.3  Diagnosis of (early) chronic pancreatitis based on the Rosemont criteria (EUS diagnosis of chronic pancreatitis should be made in the appropriate clinical setting) I. Consistent with chronic pancreatitis A. 1 major A feature and ≥3 minor features B. 1 major A feature and 1 major B feature C. 2 major A features II. Suggestive of chronic pancreatitisa A. 1 major A feature and <3 minor features B. 1 major B feature and ≥3minor features C. ≥5 minor features (any) III. Indeterminate for chronic pancreatitisa A. 3 to 4 minor features, no major features B. major B feature alone or with <3 minor features IV. Normal ≤2 minorb features, no major features a Diagnosis requires confirmation by additional imaging study (ERCP, CT, MRI, or pancreatic function test). b Excludes cysts, dilated main pancreatic duct, hyperechoic nonshadowing foci, dilated side branch. Adapted from Catalano MF, et al. (2009). EUS-​based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc, 69, 1251–​61. Fig. 15.26.2.2  EUS features of ‘early’ chronic pancreatitis; hypoechoic foci without shadowing (1), hyperechoic strands (2), and lobularity with honeycombing (three or more contiguous lobules) (3). section 15  Gastroenterological disorders 3224 Pancreatic enzyme replacement therapy to treat pancreatic-​type pain is still widely used. The presumed rationale is its capacity to decrease duodenal cholecystokinin release, resulting in a lower hor- monal drive to stimulate pancreatic enzyme secretion and hence, a lower intrapancreatic pressure. A meta-​analysis of six randomized controlled trials showed no benefit. Two trials, however, studying non-​enteric-​coated preparations, as opposed to enteric-​coated pre­ parations, demonstrated some positive effect. Therefore, if one considers a pancreatic enzyme preparation to ameliorate pancreatic-​ type pain, one should prescribe a non-​enteric-​coated preparation in combination with a proton pump inhibitor to prevent early gastric denaturation of lipase. Antioxidants, such as methionine, vitamin C, and selenium have also been advocated. The underlying theory is based on studies showing increased oxidant stress, dietary insufficiency of antioxidants, and reduced antioxidant capacity in chronic pancreatitis patients. A  recent review assessed 12 randomized trials and concluded that antioxidants reduce pancreatic pain to some extent, but that the clinical relevance of this small re- duction is uncertain and more evidence is needed. Finally, octreotide, a synthetic somatostatin analogue, has been tried in the management of chronic pancreatitis pain, with insufficient supporting data. Other medical interventions Medical treatment is often unable to offer satisfactory pain relief. Sometimes, temporary placement of a feeding tube can result in an effective pancreatic ‘rest’. EUS-​guided coeliac plexus block or neurolysis are less ef- fective in chronic pancreatitis than in pancreatic cancer. They provide a transient effect (2–​4 months) in about half of the pa- tients. Nevertheless, this may form a welcome break in a patient having debilitating pain. It appears that surgical thoracoscopic splanchnicectomy provides similar pain relief to endoscopic coeliac plexus interventions, but randomized trials are lacking. As pancreatic duct obstruction is considered to play a key role in the development of pain, ductal drainage has become standard treatment for patients with painful obstructive chronic pancreatitis. An obstruction may be caused by strictures, ductal stones, or both, and can be decompressed either surgically or endoscopically. In contrast to biliary obstruction, decompression is not considered to be indicated in the absence of symptoms. Endoscopic pancreatic duct drainage The aim of endoscopic drainage is to decompress the pancreatic duct and restore outflow of pancreatic juices into the duodenum. It involves sphincterotomy, extracorporeal shock-​wave lithotripsy of pancreatic duct stones, removal of stone fragments, and dilatation of strictures by means of temporary stent insertion (Fig. 15.26.2.3). There is sufficient data to conclude that endoscopic pancreatic duct drainage is technically feasible and safe. Morbidity is observed in 6 to 58%, but most complications are stent related and easy to treat. Prospective studies comparing different techniques are practically nonexistent. Fibrotic pancreatic duct strictures are typically resilient and re- quire rigorous dilation therapy by means of long-​term stenting. For this, the European Society of Gastrointestinal Endoscopy (ESGE) recommends use of a 10 FG plastic stent, tailored to the shape of the pancreatic duct and the length of the stricture. To prevent compli- cations, planned stent exchanges are recommended every 6 months. If possible, it is recommended to insert a cumulative number of stents to increase the dilatation force. Even more aggressive dilation may be achieved by larger-​diameter self-​expandable metal stents. Although still in an experimental phase, studies with pancreatic duct self-​expandable metal stents have shown promising results, with success rates up to 86%. Intraductal stones are found in 32 to 90% of patients presenting with chronic pancreatitis and hence, endoscopic shockwave litho- tripsy has become a cornerstone of endotherapy. Not only does it improve outcomes, it also expands the scope of endoscopic drainage as most ductal stones are impacted and too large (>7 mm) to be removed without fragmentation. Complications are rare and the reported morbidity varies between 5 and 10% (most fre- quently acute pancreatitis). Mortality seems extremely low; only two studies have reported procedure-​related deaths. However, it is notable that extracorporeal shock-​wave lithotripsy is not a simple procedure:  it requires general anaesthesia, multiple procedures, specialized equipment, and experience. Whether stone fragments need to be removed during a consecutive endoscopic retrograde cholangiopancreatography (ERCP) remains to be resolved. The only prospective study on this subject showed no advantage of stone clearance. The ESGE guidelines, however, recommend that (a) (c) (d) (b) Fig. 15.26.2.3  Patient with calcifying obstructive chronic pancreatitis and opioid-​dependent pain. (a) Pancreaticogram after extracorporeal shock wave lithotripsy showing a highly abnormal pancreatic duct with a severe stricture in the pancreatic head after removal of stone fragments. (b) Dilation of the pancreatic duct stricture with an 8-​mm dilation balloon. (c) The patient underwent progressive stenting of the pancreatic duct stricture for a period of 12 months with a maximum of three 10 FG stents. (d) Pancreaticogram after stent removal after 1 year showing adequate dilation of the stricture. The clinical response was good. The patient could stop using opioids and had mild intermittent pain responsive to the use of paracetamol. 15.26.2  Chronic pancreatitis 3225 this restrictive policy of not removing stone fragments should be reserved for expert centres only. Surgical treatments Surgery for chronic pancreatitis is well documented, with favourable perioperative morbidity and mortality when compared to equivalent procedures for neoplasms. Surgical treatment encompasses decom- pression (drainage) and various resection procedures, or a combin- ation of both. An obvious advantage of a drainage-​only procedure is the preservation of functional pancreatic tissue. In contrast, when the pancreatic head is enlarged, a combination of decompression and head resection is often advocated. As such, the ‘motor of the disease’ is removed, which may attenuate the disease course. A tail resection may be performed in the case of a segmental (obstructing) chronic pancreatitis of the pancreatic tail (Fig. 15.26.2.4). The most definitive surgical treatment is a total pancreatectomy with islet autotransplantation to prevent diabetes. In the largest series to date of 409 consecutive recipients, pain relief was accom- plished in 85%, while the endocrine pancreatic function was pre- served in 94% of those who received more than 300 000 islets. As this technique requires islet-​cell isolation facilities, it will remain limited to expert centres and is still considered a procedure of last resort. Timing and choice of pancreatic duct drainage procedures The only two prospective randomized trials comparing endoscopic and surgical drainage concluded that surgery was superior, at least in patients with complex disease and a combination of strictures and stones. Cahen et al. reported pain relief in 32% of the patients assigned to endoscopic drainage, as compared with 75% of the group assigned to surgical treatment. However, this does not necessarily write off endoscopic pancreatic duct drainage. It may well be that chronic pan- creatitis patients with less complex pathology benefit from endoscopic treatment at an earlier disease stage, but this remains to be proven. The latest ESGE guidelines state that endoscopic drainage should be considered the first-​line intervention. Although it is acknow- ledged that surgery provides better pain control according to ran- domized trials, it is stated that based on certain prognostic factors, such as stones located in the head, absence of strictures, a short disease duration and discontinuation of alcohol and tobacco, those patients can be identified with a potentially favourable response to endoscopic therapy. This should be followed by multidisciplinary response evaluation. Pain relief must be assessed 6 to 8 weeks after endoscopic drainage and unresponsive patients should be referred for surgery. When stricture resolution is not accomplished after (a) (c) (b) Fig. 15.26.2.4  Patient with segmental chronic pancreatitis of the tail. (a) CT showing the pancreatic body (1), an intraductal stone (2), and an atrophic pancreatic tail with a dilated pancreatic duct (3). (b) Magnetic resonance cholangiopancreatography showing an irregular and dilated pancreatic duct in the tail (1) and a normal pancreatic duct in pancreatic head and body (2). In between these, a stricture is visible. (c) Surgical resection specimen showing the intraductal stone with periductal fibrosis. Courtesy of Dr. B. Groot Koerkamp, Dept. of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands. section 15  Gastroenterological disorders 3226 a treatment period of 1 to 2 years, patients should be advised to undergo definite surgical treatment. The typical surgical patient has had a 5-​ to 10-​year history of chronic pancreatitis, including chronic pain, prior to their oper- ation. Rather than subjecting patients to years of pain, chronic an- algesic use, and multiple endoscopic procedures, several studies suggest that early surgery may mitigate disease progression, prevent the development of intractable and difficult-​to-​treat pain, and pre- serve pancreatic function, all leading to a substantial improvement in quality of life. Further prospective studies are required. Treatment of pancreatic insufficiency Exocrine insufficiency In exocrine insufficiency, pancreatic enzyme supplementation can prevent steatorrhea-​related symptoms and malnutrition. The individual enzyme dose varies according to the remainder pan- creatic function and the dietary fat content. Generally, dosages range from 25 000 to 75 000 units of lipase for a main meal and 10 000 to 25 000 units for snacks. Patients should be instructed to vary their dose according to their fat intake and to increase the dose in case of ongoing steatorrhea-​related symptoms and weight loss (up to a maximum of 400 000 units of lipase per day). It is important to stress that, in principle, patients should main- tain a normal diet without fat restriction. Because malnutrition is common and optimal usage of pancreatic enzyme preparations confusing, patients should be referred for dietary counselling. Every patient with chronic pancreatitis should be screened regu- larly for vitamin deficiencies and a decreased bone mass (by per- forming bone densitometry). Endocrine insufficiency Patients with chronic pancreatitis should also be monitored for pancreatogenic or type 3c diabetes. In pancreatogenic diabetes, hyperglycaemia typically manifests in the postprandial state and may be overlooked. In the latest European Pancreatic Club and International Association of Pancreatology recommendations, use of the oral glucose tolerance test is advocated apart from annual de- termination of fasting glucose and haemoglobin A1c levels. There is no consensus on the treatment of pancreatogenic dia- betes and prospective studies examining the effects of different glucose-​lowering agents are lacking. Generally, insulin regimens are considered to be most effective, despite an increased risk of hypogly- caemia, due to reduced counter-​regulation by glucagon. Management of other complications Biliary obstruction An estimated 3 to 23% of patients with chronic pancreatitis de- velop common bile duct obstruction, either because of acute in- flammatory oedema or due to a fibrotic stricture. Biliary drainage is always indicated, regardless of obstructive symptoms, to prevent secondary biliary cirrhosis. Fibrotic strictures related to chronic pancreatitis are difficult to treat. Success rates using plastic stents vary between 10 and 40%. If endoscopic therapy is chosen, an ag- gressive approach should be taken with cumulative insertion of an increasing number of stents at each 3-​monthly scheduled ERCP. When a stricture has not resolved after 1 year, the chance of endo- scopic resolution has become practically nil and the patient should be referred for surgery. Currently, fully covered self-​expandable metal stents seem a promising treatment alternative to use of (a) (e) (c) (d) (b) Fig. 15.26.2.5  EUS-​guided drainage of a pancreatic pseudocyst. (a) A large pseudocyst in the head of the pancreas punctured under EUS guidance with a 19 G EUS needle. (b) Under fluoroscopic control, a long guidewire is introduced into the pseudocyst. (c) The cystogastrostomy tract is dilated with an 8-​mm dilation balloon. (d) Endoscopic view of the first pigtail plastic stent being positioned with its distal end into the cyst and its proximal end into the stomach. (e) Fluoroscopic image of two pigtail stents internally draining the pancreatic pseudocyst.