Secondary Logo

Share this article on:

Conservative treatment of chronic pancreatitis

Khalid, Asif; Whitcomb, David C.

European Journal of Gastroenterology & Hepatology: September 2002 - Volume 14 - Issue 9 - p 943-949
Review in Depth

Chronic pancreatitis has been difficult to treat because the origin, pathophysiologic mechanisms and causes of unrelenting pain are so poorly understood. Furthermore, the pharmacologic agents often employed in other diseases with pain appear to be ineffective in many cases. The conservative management of chronic pancreatitis aims at (1) limiting progression and complications of the disease; (2) replacing lost exocrine and endocrine function; and (3) pain control. Thus, life style changes such as cessation of alcohol consumption and tobacco smoking, trials of pancreatic enzymes, treatment of duct obstruction and pseudocysts, and surgical therapies are currently employed. The good news is that the understanding of the underlying pathophysiological mechanisms is now advancing rapidly, and hopefully patient-specific and highly effective therapies will become available in the near future.

Department of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence to Dr David C. Whitcomb, University of Pittsburgh, 571 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA Tel: +1 412 648 9604; fax: +1 412 383 7236; e-mail:

Back to Top | Article Outline


Chronic pancreatitis is characterized by progressive and irreversible loss of pancreatic structure and function. The majority of cases in the Western world are attributed to alcohol abuse, but other factors such as genetic mutations, duct obstruction from strictures or tumours, hypertriglyceridaemia and hypercalcaemic states have also been implicated. Current evidence suggests that a combination of predisposing factors, including environmental, toxic and genetic, are likely involved in most cases rather than one single factor. Repeated episodes of necroinflammation initiated by autodigestion, one or more episodes of severe pancreatitis, oxidative stress, and/or toxic–metabolic factors lead to activation and continued stimulation of pancreatic stellate cells. These cells cause the fibrosis characteristic of chronic pancreatitis. Histologically, chronic pancreatitis is characterized by acinar cell atrophy, obstruction of pancreatic ductules by protein plugs and calcifications, and finally fibrosis, [1–7].

A major component of the conservative (and surgical) treatment of chronic pancreatitis centers on management of complications. The reason is that we are just now discovering the aetiological mechanisms causing pancreatitis itself. The major complications of chronic pancreatitis include abdominal pain, maldigestion, diabetes, pseudocyst, splenic vein thrombosis with gastric varicies and bleeding risk, bile duct obstruction, duodenal obstruction, and pancreatic cancer [8–12]. The management of these complications requires a synchronized interplay of conservative medical, endoscopic and surgical approaches. This multifaceted approach requires individualization in nearly every case. A complication of chronic pancreatitis managed medically in one patient may be best handled surgically in another because of confounding factors. Hence the importance of the team approach.

The conservative management of chronic pancreatitis aims at (1) limiting progression and complications of the disease; (2) replacing lost exocrine and endocrine function; and (3) pain control. In the following section we will discuss the medical management of pain, maldigestion and diabetes secondary to chronic pancreatitis, with a major emphasis on pain.

Back to Top | Article Outline


Elucidation of the cause of pain and its management remains one the most challenging aspects in the management of patients with chronic pancreatitis. The aetiology of pain in chronic pancreatitis varies from patient to patient, while some have multiple sources of pain. It should be recognized, however, that chronic inflammation and the resulting release of various growth factors may lead to irreversible and pathologic changes in the neuroanatomy of the pancreas and it's central connection resulting in exaggerated and irreversible pain patterns. In other patients improvement in pain can be achieved. The first step therefore is to identify and treat causes of pain that are amenable to therapy. Examples include pseudocysts, biliary and duodenal obstruction, and coincident peptic ulceration. The origin of pain in a majority of patients is multifactorial initiated by a combination of mechanisms including recurrent tissue inflammation and necrosis, pancreatic ductal hypertension [13], increased interstitial fluid pressure [14,15], and pancreatic ischaemia [16–18]. Furthermore, histopathological examination of pancreatic tissue from patients with chronic pancreatitis reveals proliferation of unmyelinated nerve fibres, infiltrates of mononuclear cells around nerve sheaths, and upregulation of pain mediators such as substance P and calcitonin gene related peptide [19]. These later features reflect the complex neuroadaptation to pancreatic inflammation as noted above.

The literature contains a paucity of well-designed, prospective, randomized, and placebo controlled, double-blind trials utilizing adequate measures for the evaluation of pain and quality of life criteria in chronic pancreatitis. The primary reason lies in the difficulty in collecting a homogeneous population for study. This has led to data from other disease processes being used as a surrogate in guiding pain management in chronic pancreatitis, which is often not ideal. Most centres have developed a practice style based on their experience and the literature that is available. Our own group has come to the conclusion that an organized team approach in the management of these patients is critical for success.

In the initial evaluation of a patient with chronic pancreatitis it is important to document the duration and character of pain. It is not sufficient to estimate the severity of pain subjectively; rather objective measures like the visual analogue scale should be a part of the history and physical examination, and are useful upon follow-up as well. Narcotic use and the presence/potential for addiction should be evaluated. A measure with accepted validity and reliability like the SF-36 should be used to document quality of life, and social and family support structure should be documented.

Concomitant complications of chronic pancreatitis should be evaluated and treated while other possible sources of abdominal pain are excluded. Evidence for coexistent depression, alcohol use and drug abuse should be sought. A clear plan as to the aims of therapy and realistic expectations thereof, and parameters for narcotics analgesia should be mutually agreed upon early in the doctor–patient relationship. The success of this approach depends on the team involvement of the primary care physician, a gastroenterologist, a pancreatic surgeon, a psychiatrist or psychologist and social services. Frequently, pain specialists need to be involved.

Avoidance of alcohol and tobacco are the first step in limiting the progression in pancreatic structural and functional loss. Frequent small meals with a low fat content may help to limit pancreatic stimulation while maintaining caloric intake. However, the role of a high fat diet in exacerbating pain has not been fully defined. Analgesics remain the cornerstone of therapy. Many experts recommend that non-narcotic analgesic agents be used. However, most patients will require narcotic analgesics at some time. Frequently, it is impossible to determine the difference between pain, drug seeking behaviour and impending addiction. This is especially an issue if the aetiology for chronic pancreatitis is alcohol. One safeguard is to identify one physician who coordinates and provides all prescriptions, thereby limiting overprescription and limiting the potential for abuse or addiction. Input from a pain specialist is frequently valuable in managing difficult cases. Like many pancreatic centres, we frequently use tri-cyclic antidepressants and serotonin reuptake inhibitors for their visceral pain perception altering properties. Again, much of the critical literature on their benefit, specifically in chronic pancreatitis, is lacking.

Antisecretory therapy, most commonly in the form of acid suppressive therapy with either H2-receptor antagonists or proton pump inhibitors, has become a mainstay in the management of chronic pancreatitis. The aim of this therapy is to reduce acid-induced secretin release from the duodenum and consequent pancreatic stimulation. Acid suppression may have added benefit for reducing pain arising from other acid related disorders, and by improving the survival of non-enteric coated pancreatic enzyme supplements. Theoretically, the pancreatic pain is diminished by reducing pancreatic ductal and/or parenchymal pressure from pancreatic stimulation. An alternative approach to decrease pancreatic secretion is to administer somatostatin or octreotide. However, the role of octreotide in managing pain of pancreatic origin remains controversial [20].

Another topic of controversy amongst pancreatologists remains the use of pancreatic enzyme supplementation for pain control. The rationale for enzyme use lies in the observed negative feedback mechanism regulating pancreatic stimulation. The enzymes are given to digest cholecystokinin (CCK) releasing peptide and therefore inhibit CCK release [21,22]. This negative feedback mechanism is hypothesized to be disrupted in chronic pancreatitis, secondary to diminished pancreatic enzyme secretion, thereby leading to intraduodenal accumulation of CCK releasing factors, marked CCK release, and pancreatic stimulation by CCK. There have been six randomized, controlled trials on the use of pancreatic enzyme replacement therapy in painful chronic pancreatitis [23–28]. Two trials utilized pancreatic enzymes in tablet form and reported benefit [23,24]. The patients more likely to benefit were females with idiopathic pancreatitis and less advanced disease. Four trials used enteric-coated enzymes in advanced disease, and showed no benefit [25,28]. It has been suggested that enteric-coated preparations may be less effective because of sub-optimal quantities of protease delivery to the duodenum. However, the study design of the trials using enteric-coated enzyme preparations may have been flawed by including patients with steatorrhoea, having too short an evaluation period, and inadequate numbers. In patients with steatorrhoea, the functional pancreatic mass is minimal, enzymes would have minimal pancreatic secretion to suppress, and the pain would likely be from a different mechanism. Due to the often frustrating nature of pain management in chronic pancreatitis, most centres consider a trial of enzyme therapy worthwhile, usually in tablet form, especially in idiopathic and early disease.

An area of recent interest is the use of antioxidants in chronic pancreatitis related pain. There have been two trials addressing such. The first was a randomized, double-blind, cross over trial looking at the role of allopurinol in reducing pain and improving daily life activities. No benefit was seen over placebo [29]. Another randomized, double-blind, cross over trial involving 20 patients found decreased attacks of pain in patients receiving a cocktail of vitamin E, vitamin C, methionine, selenium, and β-carotene, compared to those receiving placebo [30]. This study, however, has been criticized for inadequate blinding and an inhomogeneous patient population.

Back to Top | Article Outline

Exocrine insufficiency

The normal pancreas secretes digestive enzymes in excess of the amount that is required for normal nutrient absorption. A reduction in digestive enzyme output to less than 10% of normal is required before malabsorption occurs [31]. The ‘tubed’ secretin–pancreozymin test is considered the ‘gold standard’ in evaluating exocrine pancreatic function, allowing a direct evaluation of enzymatic and electrolyte secretory capacity of the pancreas. It is, however, invasive and unpleasant for the patient and no uniform standards have been accepted. Human faecal elastase-1 (EL-1) is a non-invasive, moderately sensitive, and specific pancreatic function test. Recent literature suggests that EL-1 is the most accurate non-invasive test in the evaluation of pancreatic function both in adults [32–36] and children [37–39]. Although it has been available in Europe for some time, it has just recently become available in the United States of America. A number of studies have documented properties of this test that make its use in the clinical arena very attractive, including (1) EL-1 is not completely destroyed in the intestine; thus its concentration in stools reflects pancreatic secretion [40,41]; (2) enzyme therapy does not interfere with its measurement by ELISA since it is specific for human elastase; and (3) the correlation with the direct measure of pancreatic function is good. Advocates of its use have faced some criticism for its reported inability to distinguish between pancreatic insufficiency and intestinal malabsorption [42,43]. In a recent study faecal EL-1 determination was less sensitive, but more specific than faecal chymotrypsin in identifying pancreatic maldigestion from intestinal malabsorption in patients with cystic fibrosis [44].

In alcohol induced chronic pancreatitis, fat malabsorption occurs earlier than protein and carbohydrate malabsorption, as the loss of proteolytic enzymes and amylase lags behind lipase secretion [45]. The cardinal sign of fat malabsorption is steatorrhoea, defined as 7–15 g/day of fat in the stool (mild steatorrhoea) to > 15 g/day (severe steatorrhoea) on a diet containing 100 g of fat. Patients with maldigestion of fat often report loose, greasy, foul-smelling stools that are difficult to flush away, bloating, abdominal cramps, and excessive flatus. The passage of ‘oil’ in the faeces (representing a faecal fat excretion of 30–40 g per day) is considered pathognomonic of chronic pancreatitis [46]. Clinically apparent steatorrhoea is seen in approximately 30% of patients with chronic pancreatitis [47]. Mild to moderate steatorrhoea, however, is often not obvious clinically and should be documented biochemically [46]. The van de Kamer [48] technique is considered the gold standard for the diagnosis of steatorrhoea. This test involves a 72 h stool collection in the setting of a standardized dietary fat intake and preparation of faecal homogenates, followed by extraction, hydrolysis and titration of faecal fat. A fat content of 7 g/24 h in a patient consuming 100 g fat per day is considered abnormal. This test, of course, is not specific for steatorrhoea secondary to pancreatic insufficiency alone, and therefore a two-stage test with and without pancreatic enzymes has been advocated by some. A newer technique involving near-infrared reflectance analysis [49] is reported to have comparable accuracy. Most experts, however, agree that a simple qualitative microscopic examination for fat globules in the stool (e.g. the Sudan III method [50]) will suffice in most cases. Whichever test is used, the important point to remember is that steatorrhoea should be documented biochemically and is invaluable when following response to pancreatic enzyme replacement therapy.

The absorption of the fat soluble vitamins (A, D, E and K) is better in pancreatic insufficiency than in mucosal malabsorptive disorders such as coeliac disease [51]. About 40% of patients with pancreatic exocrine insufficiency malabsorb vitamin B12 but clinical deficiency of fat soluble vitamins or vitamin B12 in chronic pancreatitis is uncommon [52].

Before embarking on pancreatic enzyme replacement therapy (ERT) for pancreatic failure it is necessary that the physician is cognizant of a number of factors that affect the efficacy of ERT. These can be broadly divided into issues related to delivering sufficient quantity of digestive enzyme to the duodenum and use of antacid therapy.

Sufficient enzyme must be delivered to the duodenum to digest a meal. For adequate digestion of protein, fat and carbohydrate at least 5–10% of the normal maximal digestive enzyme output needs to be delivered to the duodenum. The minimum amount of enzymes required to achieve this goal are 30 000 IU of lipase and 10 000 IU of trypsin during a 4 h postprandial period [31,45]. Most commercially available enzyme preparations contain from 4000 to 17 000 IU of lipase per tablet or capsule. Preparations with high lipase activity have raised concerns, given their reported association with colonic strictures (fibrosing colonopathy), especially in children with cystic fibrosis [53–55]. However, the ‘epidemic’ of fibrosing colonopathy has nearly vanished, and fear of this disorder should not interfere with efforts to achieve adequate treatment.

Antacid therapy is also important in treating pancreatic insufficiency. Pancreatic enzymes are susceptible to degradation by gastric acid. It is estimated that 35% of trypsin and 17% of lipase in non-enteric coated supplements ingested with a meal arrives in the duodenum if gastric acid is not suppressed [31]. In chronic pancreatitis there is insufficient bicarbonate secretion in pancreatic juice [56–58], leading to abnormally low duodenal pH in the late postprandial period. This problem is compounded in cystic fibrosis where the duodenal epithelial cell bicarbonate secretion is also impaired. This bicarbonate deficiency can lead to a scenario where the patient continues to have steatorrhoea and azotorrhoea despite seemingly adequate concentrations of ERT. To counteract this adverse effect of hyperacidity on the activity of ingested pancreatic enzymes, antacids [59], H2-blockers [59,60], and proton pump inhibitors [61–63] are frequently used. Enteric coated preparations [64,65] (the polymer coating is resistant to dissolution at pH < 5) or using lipases that are resistant to acid denaturation [56,66–69] are additional measures that can be used. At this time the search for the ideal acid resistant and bile acid resistant lipase has not met with clinical success, although a bacterial lipase has been extracted which shows promise [69–71]. Some antacids may interfere with digestive enzyme supplementation. Therefore, the use of proton pump inhibitors, which also suppress meal stimulated acid secretion, are growing in utilization.

Enteric coating of pancreatin tablets or capsules effectively prevents acidic denaturation of lipase activity. Clinical studies, however, have not shown these preparations to be superior to unprotected preparations. The reason being that particles that exceed 1–2 mm in diameter are retained in the stomach during the digestive period and are delivered into the duodenum only during phase III of recurring interdigestive motility several hours after meal ingestion [72,73]. To overcome this problem, preparations that contain enzyme encapsulated in acid resistant enteric-coated microspheres (micropellets or microtablets) have been developed. These microspheres mix with gastric chyme without releasing their enzyme content and are then emptied into the duodenum together with the meal where enzymatic activity is released due to an increase in pH to about 6. The superior efficacy of enteric-coated mini-microsphere preparations compared with conventional pancreatin extracts has been demonstrated [73–75]. Studies suggest that > 60% of the lipase contained in microspheres survives passage through the stomach [76], and dose–response studies indicate that with these preparations, administration of 20 000 to 30 000 units of lipase per meal markedly reduces steatorrhoea [74]. Finally, there are increasing anecdotal reports of failure of ERT even when mini-microspheres are used. This can be sometimes traced to substitution of a name brand product with a generic product of questionable biological equivalency without the physicians knowledge. Returning to a name band product should solve this problem.

Several other observations about the digestive process in patients with chronic pancreatitis should be noted. For example, it has been demonstrated that the survival of lipolytic activity is increased in the presence of fat and protein during duodenal–ileal transit in humans [77,78]. Thus, a high-fat diet with ERT may improve fat absorption in pancreatic insufficiency. However, low-fat diets are used to reduce pancreatic stimulation and pain. Adequate studies are needed to determine the appropriate recommendations for fat intake.

Motility may also be altered in chronic pancreatitis. There is evidence that the site of maximal digestion and absorption in chronic pancreatitis is shifted from the duodenum to the more distal small bowel [79]. This leads to increased amounts of nutrients being delivered to the distal ileum, which results in disturbed regulation of motor and secretory function of upper gastrointestinal tract [80–84]. Finally, small intestinal transit is decreased by up to 50% in patients with pancreatic insufficiency compared with healthy subjects [78]. Hence, the available time for digestion and absorption is altered. The observation that both digestion and gastrointestinal transit is improved by enzyme replacement suggests that malabsorption is both a consequence and a cause of abnormal motor function [78]. Taken together, much remains to be learned about the pathophysiology of digestion in chronic pancreatitis.

Back to Top | Article Outline

Endocrine insufficiency

Managing endocrine failure associated with chronic pancreatitis is particularly challenging. Diabetes is reported to occur in 30–50% of patients with chronic pancreatitis [7,9,85]. Although glucose intolerance is not uncommon in patients with chronic pancreatitis, overt diabetes mellitus usually occurs late (i.e. more than 20 years after onset of the disease). Most of these patients develop insulin dependence. A number of factors are involved in the development of this complication. Firstly, there is loss of islet cell function, possibly related to ischaemia. The ischaemia may develop from disruption in the normal vasculature due to inflammation and fibrosis in the surrounding exocrine tissue [86]. Secondly, there is decreased secretion of hormones such as glucose dependent insulinotropic peptide (due to malabsorption, particularly of glucose [87,88]), and impaired release of glucagon [89–91]. Lastly, due to the attendant malabsorption and frequently associated alcohol abuse in chronic pancreatitis, there is irregular caloric intake and therefore a high risk of hypoglycaemia [46]. For these reasons patients are frequently under-treated to avoid hypoglycaemia, occasionally avoiding insulin altogether. This is despite the risks of retinopathy, [92] neuropathy, [93] and nephropathy secondary to ‘pancreatic’ diabetes being as high as those seen in primary diabetes, [94] hence the term ‘brittle diabetes'. Again, a multidisciplinary team that, in this case includes an endocrinologist, is important for optimal care.

The future of medical management of chronic pancreatitis may be much different than the present. Efforts to classify, organize, stage and intervene early in the course of chronic pancreatitis are being considered [9]. Indeed, the true advances will come with the ability to delay or prevent the natural course of this disease rather than to only manage the many complications.

Back to Top | Article Outline


1. Comfort HW, Gambill EE, Baggenstoss AH. Chronic relapsing pancreatitis: a study of 29 cases without associated disease of the biliary or gastrointestinal tract. Gastroenterology 1946; 6: 239–285.
2. Kloppel G, Maillet B. The morphological basis for the evolution of acute pancreatitis into chronic pancreatitis. Virchows Arch 1992; 420: 1–4.
3. Ammann RW, Muellhaupt B. Progression of alcoholic acute to chronic pancreatitis. Gut 1994; 35: 552–556.
4. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A. et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115: 421–432.
5. Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA. et al. Periacinar stellate-shaped cells in rat pancreas: identification, isolation and culture. Gut 1998; 42: 128–133.
6. Apte MV, Haber PS, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA. et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 1999; 44: 534–541.
7. Ammann RW, Akovbiantz A, Largiader F, Schueler G. Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical–surgical series of 245 patients. Gastroenterology 1984; 86: 820–828.
8. Etemad B, Whitcomb DC. Chronic pancreatitis: diagnosis, classification, and new genetic developments. Gastroenterology 2001; 120: 682–707.
9. Lankisch PG, Lohr-Happe A, Otto J, Creutzfeldt W. Natural course in chronic pancreatitis. Pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion 1993; 54: 148–155.
10. Lankisch PG, Seidensticker F, Lohr HA, Otto J, Creutzfeldt W. The course of pain is the same in alcohol- and non-alcohol-induced chronic pancreatitis. Pancreas 1995; 10: 338–341.
11. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107: 1481–1487.
12. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR. et al. Prognosis of chronic pancreatitis: an international multicenter study. International Pancreatitis Study Group. Am J Gastroenterol 1994; 89: 1467–1471.
13. Bradley ED. Pancreatic duct pressure in chronic pancreatitis. Am J Surg 1982; 144: 313–316.
14. Ebbehoj N, Borly L, Bulow J, Rasmussen SG, Madsen P, Matzen P. et al. Pancreatic tissue fluid pressure in chronic pancreatitis. Relation to pain, morphology, and function. Scand J Gastroenterol 1990; 25: 1046–1051.
15. Jalleh RP, Aslam M, Williamson RC. Pancreatic tissue and ductal pressures in chronic pancreatitis. Br J Surg 1991; 78: 1235–1237.
16. Ashley SW, Sherman S, Reber HA. Endoscopic measurement of pancreatic blood flow. Gastrointest Endosc Clin North Am 1994; 4: 369–382.
17. Karanjia ND, Widdison AL, Leung F, Alvarez C, Lutrin FJ, Reber HA. Compartment syndrome in experimental chronic obstructive pancreatitis: effect of decompressing the main pancreatic duct. Br J Surg 1994; 81: 259–264.
18. Patel AG, Toyama MT, Alvarez C, Nguyen TN, Reber PU, Ashley SW. et al. Pancreatic interstitial pH in human and feline chronic pancreatitis. Gastroenterology 1995; 109: 1639–1645.
19. Bockman DE, Buchler M, Malfertheiner P, Beger HG. Analysis of nerves in chronic pancreatitis. Gastroenterology 1988; 94: 1459–1469.
20. Malfertheiner P, Mayer D, Buchler M, Dominguez MJ, Schiefer B, Ditschuneit H. Treatment of pain in chronic pancreatitis by inhibition of pancreatic secretion with octreotide. Gut 1995; 36: 450–454.
21. Owyang C, Louie DS, Tatum D. Feedback regulation of pancreatic enzyme secretion. Suppression of cholecystokinin release by trypsin. J Clin Invest 1986; 77: 2042–2047.
22. Layer P, Jansen JB, Cherian L, Lamers CB, Goebell H. Feedback regulation of human pancreatic secretion. Effects of protease inhibition on duodenal delivery and small intestinal transit of pancreatic enzymes. Gastroenterology 1990; 98: 1311–1319.
23. Isaksson G, Ihse I. Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Dig Dis Sci 1983; 28: 97–102.
24. Slaff J, Jacobson D, Tillman CR, Curington C, Toskes P. Protease-specific suppression of pancreatic exocrine secretion. Gastroenterology 1984; 87: 44–52.
25. Halgreen H, Pedersen NT, Worning H. Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol 1986; 21: 104–108.
26. Larvin M, McMahon MJ, Thomas WEG, Puntis MCA. Creon (enteric coated pancreatin microspheres) for the treatment of pain in chronic pancreatitis: a double-blind randomised placebo-controlled crossover study. Gastroenterology 1991; 100: A283.A283.
27. Mossner J, Secknus R, Meyer J, Niederau C, Adler G. Treatment of pain with pancreatic extracts in chronic pancreatitis: results of a prospective placebo-controlled multicenter trial. Digestion 1992; 53: 54–66.
28. Malesci A, Gaia E, Fioretta A, Bocchia P, Ciravegna G, Cantor P. et al. No effect of long-term treatment with pancreatic extract on recurrent abdominal pain in patients with chronic pancreatitis. Scand J Gastroenterol 1995; 30: 392–398.
29. Banks PA, Hughes M, Ferrante M, Noordhoek EC, Ramagopal V, Slivka A. Does allopurinol reduce pain of chronic pancreatitis? Int J Pancreatol 1997; 22: 171–176.
30. Uden S, Bilton D, Nathan L, Hunt LP, Main C, Braganza JM. Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial. Aliment Pharmacol Ther 1990; 4: 357–371.
31. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973; 288: 813–815.
32. Dominguez-Munoz JE, Hieronymus C, Sauerbruch T, Malfertheiner P. Fecal elastase test: Evaluation of a new non-invasive pancreatic function test. Am J Gastroenterol 1995; 90: 1834–1837.
33. Loser C, Mollgaard A, Folsch VR. Faecal elastase 1: A novel highly sensitive and specific tubeless pancreatic function test. Gut 1996; 39: 580–586.
34. Stein J, Jung M, Sziegoleit A, Zeuzem S, Caspary WF, Lembeke B. Immunoreactive elastase 1: Clinical evaluation of a new non-invasive test of pancreatic function. Clin Chem 1996; 42: 222–226.
35. Glassbrenner B, Beckh KH, Adler G. Comparison of fecal elastase-1 with other indirect pancreatic function tests. Digestion 1994; 55: 301–302.
36. Gullo L, Ventrucci M, Tomasetti P, Migliori M, Pezzilli R. Fecal elastase 1 determination in chronic pancreatitis. Dig Dis Sci 1999; 44: 210–213.
37. Soldan W, Henker J, Sprossig C. Sensitivity and specificity of quantitative determination of pancreatic elastase 1 in feces of children. J Pediatr Gastroenterol Nutr 1997; 24: 53–55.
38. Gullo L, Graziano L, Babbini S, Battistini A, Lazzari R, Pezzilli R. Faecal elastase 1 in children with cystic fibrosis. Eur J Pediatr 1997; 156: 770–772.
39. Wallis C, Leung T, Cubitt D, Reynolds A. Stool elastase as a diagnostic test for pancreatic function in children with cystic fibrosis. Lancet 1997; 350: 1001.1001.
40. Sziegoleit A, Krause E, Klor HU, Linder D. Elastase and chymotrypsin B in pancreatic juice and feces. Clin Biochem 1989; 22: 85–89.
41. Sziegoleit A, Linder D. Studies on the sterol-binding capacity of human pancreatic elastase. Gastroenterology 1991; 100: 768–774.
42. Amann ST, Bishop M, Curington C, Toskes PP. Fecal pancreatic elastase 1 is inaccurate in the diagnosis of chronic pancreatitis. Pancreas 1996; 3: 226–230.
43. Lankisch PG, Schmidt I, Konig H, Lehnick D, Knollmann R, Lohr M. et al. Fecal elastase-1: Not helpful in diagnosing chronic pancreatitis associated with mild to moderate exocrine pancreatic insufficiency. Gut 1998; 42: 551–554.
44. Carroccio A, Verghi F, Santini B, Lucidi V, Iacono G, Cavataio F. et al. Diagnostic accuracy of fecal elastase 1 assay in patients with pancreatic maldigestion or intestinal malabsorption: a collaborative study of the Italian Society of Pediatric Gastroenterology and Hepatology. Dig Dis Sci 2001; 46: 1335–1342.
45. DiMagno EP, Malagelada JR, Go VL. Relationship between alcoholism and pancreatic insufficiency. Ann NY Acad Sci 1975; 252: 200–207.
46. DiMagno EP, Layer P, Clain JE. Chronic pancreatitis. In:The Pancreas: Biology, Pathobiology and Disease. Go VLW, DiMagno EP, Gardner JD, Lebenthal L, Reber HA, Scheele GA (editors). New York: Plenum Press; 1993. pp. 676–677.
47. Lankisch PG, Droge M, Hofses S, Konig H, Lembcke B. Steatorrhoea: you cannot trust your eyes when it comes to diagnosis. Lancet 1996; 347: 1620–1621.
48. van de Kamer JM, Ten Bokkel T, Huinink H, Weyers HA. Rapid method for the determination of fat in feces. J Biol Chem 1949; 177: 347–355.
49. Nakamura T, Takeuchi T, Terada A, Tando Y, Suda T. Near-infrared spectrometry analysis of fat, neutral sterols, bile acids, and short-chain fatty acids in the feces of patients with pancreatic maldigestion and malabsorption. Int J Pancreatol 1998; 23: 137–143.
50. Drummey GD, Benson JAJ, Jones CM. Microscopic examination of the stool for steatorrhoea. N Engl J Med 1961; 264: 85–87.
51. Evans WB, Wollaeger EE. Incidence and severity of nutritional deficiency states in chronic exocrine pancreatic insufficiency: comparison with nontropical sprue. Am J Dig Dis 1966; 11: 594–606.
52. Toskes PP, Hansell J, Cerda J, Deren JJ. Vitamin B12 malabsorption in chronic pancreatic insufficiency. N Engl J Med 1971; 284: 627–632.
53. Delhaye M, Meuris S, Gohimont AC, Buedts K, Cremer M. Comparative evaluation of a high lipase pancreatic enzyme preparation and a standard pancreatic supplement for treating exocrine pancreatic insufficiency in chronic pancreatitis. Eur J Gastroenterol Hepatol 1996; 8: 699–703.
54. Smyth RL, van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures of ascending colon in cystic fibrosis and high-strength pancreatic enzymes. Lancet 1994; 343: 85–86.
55. Taylor CJ. Colonic strictures in cystic fibrosis. Lancet 1994; 343: 1108.1108.
56. DiMagno EP, Malagelada JR, Go VL, Moertel CG. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. N Engl J Med 1977; 296: 1318–1322.
57. Dutta SK, Russell RM, Iber FL. Impaired acid neutralization in the duodenum in pancreatic insufficiency. Dig Dis Sci 1979; 24: 775–780.
58. Dutta SK, Russell RM, Iber FL. Influence of exocrine pancreatic insufficiency on the intraluminal pH of the proximal small intestine. Dig Dis Sci 1979; 24: 529–534.
59. Graham DY. Pancreatic enzyme replacement: the effect of antacids or cimetidine. Dig Dis Sci 1982; 27: 485–490.
60. Regan PT, Malagelada JR, DiMagno EP, Go VL. Cimetidine as an adjunct to oral enzymes in the treatment of malabsorption due to pancreatic insufficiency. Gastroenterology 1978; 74: 468–469.
61. Heijerman HG, Lamers CB, Bakker W. Omeprazole enhances the efficacy of pancreatin (pancrease) in cystic fibrosis. Ann Intern Med 1991; 114: 200–201.
62. Heijerman HG, Lamers CB, Bakker W, Dijkman JH. Improvement of fecal fat excretion after addition of omeprazole to pancrease in cystic fibrosis is related to residual exocrine function of the pancreas. Dig Dis Sci 1993; 38: 1–6.
63. Tran TM, Van den Neucker A, Hendriks JJ, Forget P, Forget PP. Effects of a proton-pump inhibitor in cystic fibrosis. Acta Paediatr 1998; 87: 553–558.
64. Dutta SK, Rubin J, Harvey J. Comparative evaluation of the therapeutic efficacy of a pH-sensitive enteric coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the treatment of exocrine pancreatic insufficiency. Gastroenterology 1983; 84: 476–482.
65. Bruno MJ, Haverkort EB, Tijssen GP, Tytgat GN, van Leeuwen DJ. Placebo controlled trial of enteric coated pancreatin microsphere treatment in patients with unresectable cancer of the pancreatic head region. Gut 1998; 42: 92–96.
66. Zentler-Munro PL, Assoufi BA, Balasubramanian K, Cornell S, Benoliel D, Northfield TC. et al. Therapeutic potential and clinical efficacy of acid-resistant fungal lipase in the treatment of pancreatic steatorrhea due to cystic fibrosis. Pancreas 1992; 7: 311–319.
67. Regan PT, Malagelada JR, DiMagno EP, Glanzman SL, Go VL. Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufficiency. N Engl J Med 1977; 297: 854–858.
68. Thiruvengadam R, DiMagno EP. Inactivation of human lipase by proteases. Am J Physiol 1988; 255: G476–G481.
69. Cleasby A, Garman E, Egmond MR, Batenburg M. Crystallization and preliminary X-ray study of a lipase from Pseudomonas glumae. J Mol Biol 1992; 224: 281–282.
70. Raimondo M, DiMagno EP. Lipolytic activity of bacterial lipase survives better than that of porcine lipase in human gastric and duodenal content. Gastroenterology 1994; 107: 231–235.
71. Suzuki A, Mizumoto A, Sarr MG, DiMagno EP. Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: a new therapy of steatorrhea? Gastroenterology 1997; 112: 2048–2055.
72. Goebell H, Klotz U, Nehlsen B, Layer P. Oroileal transit of slow release 5–ASA. Gut 1993; 34: 669–675.
73. Code CF, Schlegel JF. The gastrointestinal interdigestive housekeeper: motor correlates of the interdigestive myoelectric complex of the dog. In:Proceedings of the 4th International Symposium on GI Motility. Daniel EE (editor). Vancouver: Mitchell Press; 1973. pp. 631–634.
74. Schlegel JF, Code CF. The gastric peristalsis of the interdigestive housekeeper. In:Proceedings of the 5th International Symposium on GI Motility. Vantrappen G (editor). Leuven: Typoff-Press; 1975. pp. 321321.
75. Kölbel C, Layer P, Hotz J, Goebell H. Der Einfluß eines säuregeschützten, mikroverkapselten Pankreatinpräparats auf die pankreatogene Steatorrhö. Med Klin 1986; 81: 85–86.
76. Lankisch PG, Lembcke B, Göke B, Creutzfeldt W. Therapie der pankreatogenen Steatorrhoea: bietet der Säureschutz für Pankreasenzyme Vorteile? Verh Dtsch Ges Inn Med 1983; 89: 864–867.
77. Holtmann G, Kelly DG, Sternby B, DiMagno EP. Survival of human pancreatic enzymes during small bowel transit: effect of nutrients, bile acids, and enzymes. Am J Physiol 1997; 273: G553–G558.
78. Layer P, von der Ohe MR, Holst JJ, Jansen JBMJ, Grandt D, Holtmann G. et al. Altered post prandial motility in chronic pancreatitis: role of malabsorption. Gastroenterology 1997; 112: 1624–1634.
79. Layer P, von der Ohe M, Gröger G, Dicke D, Goebell H. Luminal availability and digestive efficacy of substituted enzymes in pancreatic insufficiency. Pancreas 1992; 7: 745.745.
80. Keller J, Rünzi M, Goebell H, Layer P. Duodenal and ileal nutrient deliveries regulate human intestinal motor and pancreatic responses to a meal. Am J Physiol 1997; 272: G632–G637.
81. Read NW, McFarlane A, Kinsman RJ, Bates TE, Blackhall NW, Farrar GB. et al. Effect of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels of neurotensin and enteroglucagon. Gastroenterology 1984; 86: 274–280.
82. Spiller RC, Trotman IF, Higgins BE, Ghatei MA, Grimble GK, Lee YC. et al. The ileal brake-inhibition of jejunal motility after ileal fat perfusion in man. Gut 1984; 25: 365–374.
83. Layer P, Peschel S, Schlesinger T, Goebell H. Human pancreatic secretion and intestinal motility: effects of ileal nutrient perfusion. Am J Physiol 1990; 258: G196–G201.
84. Layer P, Schlesinger T, Goebell H. Modulation of periodic interdigestive gastrointestinal motor and pancreatic function by the ileum. Pancreas 1993; 8: 426–432.
85. Wakasugi H, Funakoshi A, Iguchi H. Clinical assessment of pancreatic diabetes caused by chronic pancreatitis. J Gastroenterol 1998; 33: 254–259.
86. Foulis AK, Clark A. Pathology of the pancreas in diabetes mellitus. In:Joslin's Diabetes Mellitus. Kahn CR, Weir GC (editors). Philadelphia: Lea & Febiger; 1994. pp. 276–277.
87. Marks V. The enteroinsular axis. J Clin Pathol 1980; 33: 38–42.
88. Ebert R, Creutzfeldt W. Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution. Diabetologia 1980; 19: 198–204.
89. Donowitz M, Hendler R, Spiro HM, Binder HJ, Felig P. Glucagon secretion in acute and chronic pancreatitis. Ann Intern Med 1975; 83: 778–781.
90. Larsen S, Hilsted J, Philipsen EK, Tronier B, Christensen NJ, Damkjaer Nielsen M. et al. Glucose counterregulation in diabetes secondary to chronic pancreatitis. Metabolism 1990; 39: 138–143.
91. Larsen S. Diabetes mellitus secondary to chronic pancreatitis. Dan Med Bull 1993; 40: 153–162.
92. Gullo L, Parenti M, Monti L, Pezzilli R, Barbara L. Diabetic retinopathy in chronic pancreatitis. Gastroenterology 1990; 98: 1577–1581.
93. Bank S, Marks IN. Alcohol-induced pancreatitis (AIP). Med South Afr 1973; 8: 577–586.
94. Levitt NS, Adams G, Salmon J, Marks IN, Musson G, Swanepoel C. et al. The prevalence and severity of microvascular complications in pancreatic diabetes and IDDM. Diabetes Care 1995; 18: 971–974.

pancreas; cholecystokinin; digestive enzymes; pseudocysts; pancreatitis; stelate cells

© 2002 Lippincott Williams & Wilkins, Inc.