Alcoholic Chronic Pancreatitis David Whitcomb, MD, PhD* Roland H . Pfützer, MD Adam Slivka MD , PhD * Address Division of Gastroenterology and Hepatology, 571 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Current Treatment Options in Gastroenterology 1999, 2:273–282 Current Science Inc., ISSN 1092–8472 Copyright © 1999 by Current Science Inc. Opinion statement The most important intervention in the treatment of alcoholic chronic pancreatitis is alcohol cessation, and therefore, it should be a primary treatment goal. This measure alters the natural course of the disease and may improve long-term survival. Smoking cessation should also be encouraged, since the risk of pancreatic cancer increases with prolonged chronic pancreatitis, and is again doubled by smoking. Maldigestion is treated in a way similar to other types of chronic pancreatitis. Treatment of pain should begin with an effort to identify reversible causes, including pseudocysts and duct obstruction. Chronic pain management should follow a multi-step treatment regimen that reserves narcotics for only the most severe cases. Since pain tends to diminish during the natural history of pancreatitis, treatment of pain needs to be continually reevaluated. Endoscopic or surgical interventions are indicated only for the management of complications, but have no significant effect on the natural history of alcoholic chronic pancreatitis. In the future, diagnosis of patients within the earliest stages of alcoholic chronic pancreatitis, and intervention with effective strategies to prevent progression of fibrosis and other complications, may offer the best solution for eliminating this disease. Thus, the focus of management should be early identification of patients at risk, and institution of effective new therapies. Introduction Alcohol-associated pancreatitis is usually recognized in the late chronic phase, which is characterized structurally by pancreatic sclerosis with ectatic pancreatic ducts and calcifications, and functionally by steatorrhea, diabetes mellitus, and intractable pain. Current opinion on the pathogenesis of acute and/or chronic pancreatitis in the alcoholic differs widely, and this reflects relative ignorance about the disease. Three principles are generally accepted. First, individuals who stop drinking alcohol do better than those who continue drinking. Second, endoscopic and surgical interventions offer temporary pain relief for wellselected patients with specific complications. Third, endoscopic or surgical interventions fail to change the natural history of the disease. Alcoholic chronic pancreatitis is often heralded by acute pancreatitis [1••]. Some experts theorize that underlying chronic pancreatitis leads to episodes of acute pancreatitis [2•], while others believe that acute pancreatitis initiates the process leading to chronic pancreatitis either by a necrosis-fibrosis sequence [1••,3•], or by causing infiltration and differentiation of the inflammatory cells necessary to cause fibrosis [4]. The natural history of chronic pancreatitis is illustrated in Figure 1. Once alcoholic chronic pancreatitis is established, it usually progresses along an unrelenting course, regardless of current surgical or medical interventions. The figure also illustrates the clinical observation that loss of pancreatic exocrine function and development of malabsorption (eg, fecal chymotrypsin value of >120 µg/g) usually occurs 10 to 15 years before pancreatic endocrine dysfunction and diabetes mellitus. The primary treatments for end-stage alcoholic chronic pancreatitis center on replacement of the previous functions of the pancreas with pancreatic enzymes supplementation and insulin for diabetes, management of pseudocysts and other structural complications, and management of pain. 274 Pancreas Figure 1. Probability of remaining free of exocrine insufficiency (---) or diabetes mellitus (—) after the onset of alcoholic chronic pancreatitis. Note that the onset of diabetes occurs about 10 to 15 years after exocrine insufficiency. (Adapted from Ammann et al. [6••], Figures 4 and 5.) ACKNOWLEDGEMENT The authors wish to thank Kenneth K. W. Lee, MD, for a critical review and suggestions for the manuscript. This work was supported by a VA Merit Review (DCW) and a grant from the NIH DK50236 (DCW) Treatment Diet and lifestyle • Excessive alcohol intake by any patients suggests underlying social and/or emotional dysfunction, and leads to numerous health related problems. • Cessation of alcohol intake is the single most important intervention known. Some studies have shown that cessation of alcohol use delays the progression of pancreatic dysfunction in alcoholic pancreatitis [5•], and that the rate of marked physical impairment, unemployment and death rate is three times higher in those who continue to drink [6••]. • Specific supporting psychotherapy (eg, Alcoholics Anonymous) should be considered in patients with alcoholism. Failure of a previous therapy should not preclude attempts at future therapy, since the long-term costs of alcohol addiction and its role on the outcome of chronic pancreatitis justify further therapy attempts. • Smoking increases the risk of alcoholic chronic pancreatitis [7] and pancreatic cancer [8]. Therefore, smoking should also be discontinued. Dietary modifications • Although some recommend specific dietary modifications (eg, a low-fat diet), no clear consensus has been reached. Fats remain an important source for calories and vitamins in malnourished patients, and additional restrictions must be considered in the diabetic. With progressive pancreatic dysfunction, fat absorption is most severely affected because functional loss of lipase occurs early. This differs from carbohydrate digestion because Alcoholic Chronic Pancreatitis Whitcomb et. al. • • • • 275 there are no brush border lipases, lipase is pH sensitive and pancreatic bicarbonate secretion is limited, and lipase is rapidly destroyed by proteases in the small intestine [9]. Fat malabsorption is recognized clinically as steatorrhea. Pancreatic enzyme supplementation is the primary therapy for this condition ([9] and below). A partial substitution of dietary long-chain triglycerides with medium-chain triglycerides (MCT) has the theoretic advantage of being absorbed without requiring pancreatic lipase digestion. However, a recent study failed to show improved fat absorption with MCT [10]. Because of malnutrition and maldigestion, alcoholic patients may require supplementation of the fat-soluble vitamins A, D, E and K, and vitamin B12. Several smaller meals during the day are usually tolerated better than large meals because of limited meal-stimulated enzyme secretion. Diabetes mellitus is a major complication of alcoholic chronic pancreatitis. The most important therapeutic intervention in patients with alcoholic chronic pancreatitis and diabetes mellitus is the adequate dietary education and training of the patient and the person who prepares his or her meals. If possible, patients should be trained to monitor their own diet and blood glucose levels. Pharmacologic treatment • The treatment of alcoholic pancreatitis is geared toward relief of symptoms. • Maldigestion occurs with loss of more than 90% of pancreatic exocrine function [11] and is treated most effectively with enteric or nonenteric-coated pancreatic enzymes when >20,000 IU of lipase are delivered to the duodenum with every meal. Although this amount of lipase only represents about 10% of the secretory capacity of the normal pancreas [11], it is sufficient to treat steatorrhea in most cases. • Dietary fibers may alter pancreatic enzyme activity, so patients should avoid fiber-enriched diets [12]. • Gastric acid suppression may improve the effectiveness of enzyme supplementation. • Overt diabetes with the need for oral hypoglycemic agents or insulin develops within 20% of patients within 6 years of the onset of alcoholic chronic pancreatitis, and 50% at 10 years [6••]. • Narcotics should be avoided in the alcoholic when possible, but prescribed when necessary. Since the natural history of pain in alcoholic pancreatitis leads to its eventual disappearance, the use of narcotics should be considered a temporary measure. • When using NSAIDs in the required doses, the risk of gastrointestinal side effects always has to be considered. (For a recent review on gastrointestinal toxicity of NSAIDs see [13].) • Pain from duct obstruction or pseudocysts should be recognized, and endoscopic or surgical treatment considered (see below). 276 Pancreas Treatment of maldigestion Pharmacologic therapy Non-enteric coated pancreatic enzymes Standard dosage Contraindications Main drug interactions Main side effects Special points Viokase 6-8 capsules per meal; Cotazym 6-8 capsules per meal. Hypersensitivity to pork digestive enzymes, acute pancreatitis (controversial). May bind to dietary fiber. Nausea, cramping, diarrhea; hyperuricosuria, hyperuricemia (in high doses). Must be given in high doses or with adequate meal-stimulated acid suppression to overcome destruction in the stomach. Cost effectiveness May be more expensive than enteric coated preparations if gastric acid suppression is included. Enteric coated pancreatic enzymes Standard dosage Creon 20, 2 capsules per meal; Pancrease MT20, 2 capsules per meal; Ultrase MT20, 2 capsules per meal; Zymase 3 capsules with each meal. Contraindications Hypersensitivity to pork digestive enzymes; acute pancreatitis. Main drug interactions May bind to dietary fibers. Main side effects Nausea, cramping, diarrhea; hyperuricosuria, hyperuricemia (in high doses); colonic strictures in children with cystic fibrosis. Special points Usually does not require additional acid suppression. Cost effectiveness Overall cost may be less than the cost of non-enteric coated preparations when the number of capsules per meal, the need for acid suppression, and compliance issues are considered. G astric acid suppression by H2 receptor antagonists Standard dosage Cimetidine, 400 mg b.i.d. (before meals); Ranitidine, 150 mg b.i.d. (before meals); Famotidine, 20 mg b.i.d.; Nizatidine, 150 mg b.i.d. Contraindications None. Main drug interactions May potentiate effect of drugs metabolized by liver microsomal enzymes, particularly Cimetidine. Main side effects Headache, dizziness, constipation, diarrhea, somnolence, seizures, palpitations, depression. May cause arrhythmia, gynecomastia, increased serum transaminases, particularly Cimetidine. Special points Must suppress meal-stimulated acid secretion. If used with a non-enteric coated pancreatic enzyme supplement and symptoms of maldigestion persist, the dosage should be increased or a proton pump inhibitor (PPI) employed. Cost effectiveness Less expensive than PPIs. G astric acid suppression by a proton pump inhibitor (PPI) Standard dosage Omeprazole, 20 mg daily; Lansoprazole,15–30 mg daily Contraindications Drug hypersensitivity. Main drug interactions May potentiate diazepam, phenytoin, warfarin (omeprazole); may alter absorption of pH-dependent drugs; clearance of lansoprazole may be altered in liver disease. Main side effects Diarrhea, abdominal pain, nausea, headache, dizziness, constipation. Special points May improve enzyme treatment of steatorrhea better than H2 receptor blockers. Cost effectiveness More expensive but more effective than H 2 receptor blockers. Alcoholic Chronic Pancreatitis Whitcomb et. al. 277 Treatment of pain • See recent reviews by Conwell (this issue), Warshaw [14••], and Mõssner [15••]. Non-narcotics Acetaminophen Standard dosage Contraindications Main drug interactions Main side effects Special points Acetaminophen 500 mg up to q.i.d. Active consumption of alcohol; poor nutrition [16]. Hepatotoxicity risk increased by chronic, heavy, alcohol use. Hepatotoxicity, nephrotoxicity. Dose should be limited to a maximum of 2 g per day if the patient is suspected of drinking more than two alcoholic beverages per day. Cost effectiveness Least expensive pain medication. Nonsteroidal antiinflammatory drugs ( NSAI Ds) Standard dosage Aspirin, 250–500 mg po q 4–6 hr up to 4 g per day; diclofenac, 50 mg po q 8–12 hr; ibuprofen 200–400 mg po q 4h up to 1.2 g per day; indomethacin 25–50 mg po q 6–8 hr; ketoprofen 12.5–25 mg po q 4h up to 75 mg per day; nabumetone 500–1000 mg po q 12 h; naproxen 200–400 mg po q 8–12 h. Contraindications History of GI bleed, drug hypersensitivity. Main drug interactions Lithium serum levels increase; many drug-specific considerations. Main side effects GI bleeding [13], hepatotoxicity. Special points Misoprostol may reduce the risk of GI bleed but complicate the assessment of diarrhea. Duration of therapy should be limited if possible. NSAIDs should not be used in combination. Cost effectiveness Variable. Tramadol ( Ultram ) Standard dosage Contraindications Main drug interactions Main side effects Special points Cost effectiveness Tramadol 50 mg po q 4–6 h. Alcohol or hypnotic intoxication. MAO inhibitors. Seizures, dizziness, nausea, vomiting, constipation. Narcotic-like effects. Relatively expensive. Narcotics Standard dosage Codeine, 30–60 mg po q 6 h; fentanyl patches, 25–100 µg/h; hydrocodone, 5–10 mg po q 4–6 h; hydromorphone, 2–4 mg po q 4–6 h; methadone, 2.5–10 mg po q 4–6 h; morphine sulfate (extended release), 30–60 mg po q 8–12 h; oxycodone, 5–10 mg po q 6 h; pentazocine, 25–50 mg po q 4–6 h; propoxyphene, 65 mg po q 4–6 hours up to 390 mg per day. Contraindications Impaired respiration, drug hypersensitivity. Main drug interaction Potentiation with alcohol. May increase serum levels of antidepressants, anticonvulsants, and coumarin anticoagulants. Main side effects Euphoria, dysphoria, constipation, nausea, vomiting, respiratory depression, and hypotension. Special points The timing of narcotic dosing in practice remains empiric, and the authors use different approaches. Some use narcotics before meals based on the rationale that pain is often worse during meals and therefore limits nutritional intake; that the 278 Pancreas narcotics inhibit pancreatic exocrine secretion and thereby reduce secretory pressure within the pancreas; and that narcotics slow intestinal transit, thereby prolonging the time for digestion and absorption. Others use narcotics after the meal based on the rationale that narcotics cause sphincter of Oddi spasm through inhibition of inhibitory neurotransmitter release, thereby causing functional pancreatic duct outlet obstruction. Morphine, for example, is a potent inhibitor of sphincter of Oddi relaxation. Dosing based on providing continuous pain relief is also used. Dependence is common. Narcotic abuse is always a concern in alcoholics. In their case, the physician should consider involving a multidisciplinary pain management team. Tolerance to narcotics may develop in patients receiving them. Narcotics are available in combination with acetanophen and NSAIDs. Cost effectiveness For a week’s dosage equivalent of oxycodone 5 mg q6 hours, methadone is the least expensive (~$7 per week), followed by codeine. Progressively more expensive are hydrocodone, oxycodone, and hydrocodone ($10–$20 per week), and fentanyl patches are the most expensive (~$45 per week). Endoscopic therapy • Endoscopic retrograde cholangiopancreatography (ERCP) is indicated for the diagnosis of chronic pancreatitis by evaluating the pancreatic duct for strictures or stones (Cambridge classification [17]). May be effective in the treatment of pancreatic duct obstruction, stones, disruption, or symptomatic pseudocysts. ERCP is the gold standard for evaluating the pancreatic duct. Endoscopic ultrasound Standard procedure An endoscope with an ultrasound transducer at its tip (usually 5–12 MHz) is passed into the stomach and duodenum for evaluation of the pancreas. Contraindications General contraindications for upper endoscopy. Complications Perforation, with fine needle aspiration (FNA); bleeding, infection, pancreatitis. Special points May be the most sensitive imaging modality to diagnose chronic pancreatitis based on heterogeneous echogenicity of the parenchyma and ectasia of the ducts. Cannot differentiate focal inflammation from malignancy. May be used to guide FNA. Cost effectiveness More expense compared to test of maldigestion or CT, which must be balanced against a greater sensitivity in identifying pancreatitis at an earlier stage. Endoscopic retrograde cholangiopancreatography (ERCP) Standard procedure A side view duodenoscope is moved into the duodenum and the papilla of Vater identified. A catheter is placed in the bile or pancreatic duct, followed by injection of a radio-opaque contrast to obtain a ductogram under fluoroscopic visualization. Contraindications General contraindications for upper endoscopy. Complications Acute pancreatitis, perforation, bleeding, and infection. Chronic pancreatitis may have a protective role in preventing post-ERCP pancreatitis. Special points Important therapeutic options are available: Pancreatic stricture dilation and short-term stent therapy for symptomatic obstruction or duct disruption; transpapillary pseudocyst drainage; endoscopic stone removal; transluminal pseudocyst drainage. Symptomatic biliary strictures from chronic pancreatitis respond poorly to chronic endoscopic therapy. Cost effectiveness More expensive and invasive than CT or MRCP in diagnosing chronic pancreatitis, but less expensive than surgery for therapeutic interventions. Alcoholic Chronic Pancreatitis Whitcomb et. al. 279 Surgery • Surgery may not be effective in decelerating the natural history of chronic pancreatitis with respect to exocrine or endocrine insufficiency or calcifications [6••]. Lasting pain relief occurs in 70% of patients with cyst drainage, 66% with lateral pancreaticojejunal drainage, and 60% of patients with a partial resection [6••]. • Surgical procedures can be divided into drainage procedures and resection procedures, or combinations of both. Drainage procedures may be more effective than partial or complete resections for pain relief in patients with a dilated duct system, whereas surgery for pain relief in patients without ductal dilatation generally has a less satisfactory outcome. • Drainage and limited resection procedures provide comparable benefit in pain relief in appropriately selected patients. Some have claimed that resection procedures have shown superiority to pure drainage procedures in regard to long-lasting pain relief, and reoperation rates. Morbidity and mortality are higher than in pure drainage procedures, but may reflect more complicated pancreatic pathology. (For an overview about current surgical procedures see Buchler et al. [18•].) • In the United States, most surgeons require that the patient remain abstinent from alcohol for three to six months or more before any surgery is considered. Drainage Procedure Partington-Rochelle (or Rochelle-Partington)—Lateral pancreaticojejunostomy (sometimes incorrectly called a Puestow—see below). Contraindications Inflammatory masses in the pancreas, acute pancreatitis, Non-dilated pancreatic duct (<6–7 mm). Complications Recurrence of symptoms in up to 50% after five years, as the cause for the obstruction (often an inflammatory process in the head of the pancreas) remains untouched. Pain relief may be 80% after five years or higher in highly selected patients. Special points Since no functional tissue is resected, exocrine and endocrine functions remain unchanged or even improve slightly over a limited time. Combined surgical procedures Procedures Puestow: end and lateral pancreaticojejunostomy combined with a pancreatic resection; Frey: lateral pancreaticojejunostomy in combination with limited resection of inflamed tissue of the head of the pancreas Contraindications Acute pancreatitis, non-dilated pancreatic duct (<6–7 mm) Complications Higher percentage of iatrogenic diabetes with a drastically worsened long-time prognosis compared to pure drainage procedures. Special points The Puestow is mostly of historical importance since a resection of the tail of the pancreas is now used only in patients with an inflammatory process in that area. The Frey procedure is used for treatment of a dilated pancreatic duct and enlarged pancreatic head. Resection procedures Procedures Traverso-Longmire (pylorus-preserving Whipple): pancreatoduodenectomy; Beger: duodenum-preserving pancreatic head resection [19]; total pancreatectomy. Contraindications Acute pancreatitis. Complications Possible occurrence of ulcers at the anastomosis, diabetes, exocrine insufficiency. 280 Pancreas Special points The resection procedures are usually reserved for patients with a large inflammatory mass in the head of the pancreas. The reported success in relieving pain varies greatly among various centers. Total pancreatectomies are associated with brittle diabetes and exocrine insufficiency. Recurrence of pain in many patients. Management of pseudocysts • Pseudocysts develop in 15%–30% of patients with alcoholic chronic pancreatitis, but usually early in the disease process. Only symptomatic pseudocysts require therapy. • Common complications include pain, infection, compression of surrounding organs, rupture, and bleeding. • Different treatment options are available and should be considered. The main options are CT or ultrasound-guided transcutaneous needle or pigtail catheter drainage, endoscopic cystenterostomy, cystgastrostomy or transpapillary drainage, and surgical drainage procedures. Transcutaneous drainage Procedure The pseudocyst is drained with a needle or percutaneous catheter placed under CT or ultrasound guidance. Indication Pseudocysts must be easily accessible. Complications Pancreatocutaneous fistula, infections, pseudocyst recurrence. Special points Simple and safe procedure. Should not be used if a pancreatic duct disruption has been demonstrated or suspected. May be temporizing or definitive therapy for infected pseudocysts. Endoscopic drainage Procedure The pseudocyst is localized by visualization of the pseudocyst bulging into the gastric or duodenal lumen. Endoscopic ultrasound may be used to assist localization. A small window into the pseudocyst is made with needle puncture with or without cautery, and the entry point is enlarged by balloon dilation. A stent or multiple stents are temporarily left in the window to facilitate drainage. In other cases, a transpapillary stent is may be placed. Indication Pseudocysts located <1 cm from lumen wall by CT. Complications Infection, bleeding, stent occlusion, dislocation, or free perforation. Special points EUS may be useful in identifying puncture site and avoiding blood vessels. Surgical management Procedure Cystogastro-, cystoduodeno- or cystojejunostomy. Occasionally, external drainage may be used depending on the location of the pseudocyst, and other factors. Indications Operative candidate without active pancreatic inflammation, failure of nonsurgical drainage, complicated pseudocysts (bleeding, rupture, infection). Complications Pancreatic abscess and gastric ulceration with cystogastrostomy. Special points Internal drainage requires a durable wall of the pseudocyst that is usually reached within six weeks. In case of recurrence, a resection should be considered. Additional treatments (pain) • Celiac plexus blockade—Usually provides pain relief for three to six months. • Somatostatin analogues—May reduce the severity of pain in a subset of patients. The treatment is very expensive. Alcoholic Chronic Pancreatitis Whitcomb et. al. 281 • Pancreatic enzymes—Non-enteric coated enzymes may be useful for pain control in mild to moderated idiopathic chronic pancreatitis, but do not appear to play a role in pain management of alcoholic chronic pancreatitis. • Antioxidants—Various vitamins and antioxidants may have a theoretical role in limiting the progression of alcoholic pancreatitis, but convincing controlled trials are lacking. • Extracoporal shock wave lithotripsy (ESWL)—May be used as an adjunct to endoscopic pancreatic stone extraction. Fluoroscopic targeting is superior to ultrasound-guided targeting. Emerging technologies Magnetic Resonance Cholangiopancreatography (MRCP) with or without the use of secretin MRCP is a less invasive alternative to diagnostic ERCP, and is particularly attractive in children. Stimulation with secretin provides non-invasive imaging of the pancreatic duct. The absence of duct dilation following the intravenous administration of secretin may suggest pancreatic insufficiency, but further validating studies are needed. Supplies of secretin are currently quite limited. Persistent duct dilation after secretin may suggest pancreatic duct obstruction. MRCP may be useful for distinguishing primary pancreatic insufficiency and duct obstruction. Modified bacterial lipases for enzyme supplemental therapy Since porcine lipase is very susceptible to acid degradation and proteases, various attempts have been made to find another source of supplemental enzymes. A recently published study in dogs showed that steatorrhea could be abolished with bacterial lipase, and that the total mass of lipase (in mg) required was 75 times lower than with porcine lipase [20]. Gene therapy for exocrine insufficiency In 1994, the in-vitro infection of a human gallbladder epithelial cell line with a vector containing pancreatic lipase cDNA was reported. The infected cells showed lipase activity for about two weeks [21]. Clinical applications are possible in the future. References and Recommended Reading Papers of particular interest have been highlighted as: • Of special interest •• Of outstanding interest 1.•• Ammann RW, Heitz PU, Kloppel G: Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study. Gastroenterology 1996, 111(1):224–231. This paper correlates the clinical and histopathologic findings of 73 patients with alcoholic chronic pancreatitis. Progressive pancreatic dysfunction was found to correlate with histologic deterioration. 2.• Freedman SD: New concepts in understanding the pathophysiology of chronic pancreatitis. Int J Pancreatol 1998, 24(1):1–8. An important review of the traditional views on the pathophysiology of chronic pancreatitis. 3.• Kloppel G, Maillet B: Pathology of acute and chronic pancreatitis. Pancreas 1993, 8(6):659–670. A clear presentation on the necrosis-fibrosis sequence hypothesis. 4. Whitcomb DC: Hereditary panceatitis: new insights into acute and chronic pancreatitis. Gut 1999, in press. 5.• Gullo L, Barbara L, Labo G: Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology 1988, 95(4):1063–1068. This article demonstrates that pancreatic damage continues even after cessation of alcohol intake, but the rate of damage slows compared to what occurs with continued drinking. 282 Pancreas 6.•• Ammann RW, Muellhaupt B, Group SPS: The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999, 116:1132–1140. The clinical course of 290 patients with alcoholic chronic pancreatitis is documented with respect to pain. Two pain patterns are recognized. Comparison of surgical and medical interventions for pain could not be assessed, but the probability of pain relief, probability of loss of exocrine function and probability of the development of diabetes was identical between interventions. 7. Talamini G, Bassi C, Falconi M, et al.: Cigarette smoking: an independent risk factor in alcoholic pancreatitis. Pancreas 1996, 12(2):131–137. 8. Lowenfels AB, Maisonneuve P, Cavallini G, et al.: Pancreatitis and the risk of pancreatic cancer. N Engl J MedInternational Pancreatitis Study Group. 1993,328(20):1433–1437. 9. Layer P, Keller J: Pancreatic enzymes: secretion and luminal nutrient digestion in health and disease. J Clin Gastroenterol 1999, 28(1):3–10. 10. Caliari S, Benini L, Sembenini C, et al.: Medium-chain triglyceride absorption in patients with pancreatic insufficiency. Scand J Gastroenterol 1996, 31(1):90–94. 11. DiMagno EP, Go VL, Summerskill WH: Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufficiency. N Engl J Med 1973, 288(16):813–815. 12. Dutta SK, Hlasko J: Dietary fiber in pancreatic disease: effect of high fiber diet on fat malabsorption in pancreatic insufficiency and in vitro study of the interaction of dietary fiber with pancreatic enzymes. Am J Clin Nutr 1985, 41(3):517–255. 13. Wolfe M, Lichtenstein D, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999, 340(24):1888–1899. 14.••Warshaw A, Banks PA, Femandez-del Castillo C: AGA technical review: treatment of pain in chronic pancreatitis. Gastroenterology 1998, 115:765–776. A critical review of the current literature on pain management in chronic pancreatitis. 15.••Mossner J, Keim V, Niederau C, et al.: Guidelines for therapy of chronic pancreatitis. Consensus Conference of the German Society of Digestive and Metabolic Diseases [German]. Z Gastroenterol 1998, 36(5):359–367. An organized and rational step-wise guide to management of chronic pancreatitis. 16. Whitcomb DC, Block GD: Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994, 272(23):1845. 17. Sarner M, Cotton PB: Classification of pancreatitis. Gut 1984, 25:756–759. 18.• Büchler MW, Friess H, Baer H-U, et al.: Surgical treatment of chronic pancreatitis: new standards. Digest Surg 1996, 13(2): 1–96. An excellent journal issue dedicated to a review of the major surgeries used in treating chronic pancreatic diseases. 19. Beger HG, Schlosser W, Siech M, et al.: The surgical management of chronic pancreatitis: duodenumpreserving pancreatectomy. Adv Surg 1999, 32:87–104. 20. Suzuki A, Mizumoto A, Rerknimitr R, et al.: Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption in pancreatic-insufficient dogs. Gastroenterology 1999, 116(2):431–437. 21. Maeda H, Danel C, Crystal RG: Adenovirus-mediated transfer of human lipase complementary DNA to the gallbladder [see comments]. Gastroenterology 1994, 106(6):1638–1644.